spalde-v3-lexical
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Wnt/β-catenin signaling is essential for blastemal cell proliferation and patterning of the overlying epidermis. Yet, we find that β-catenin signaling is neither active in the epidermis nor the majority of the proliferative blastemal cells. Rather, tissue-specific pathway interference indicates that Wnt signaling in the nonproliferative distal blastema is required for cell proliferation in the proximal blastema, and signaling in cells lining the osteoblasts directs osteoblast differentiation. Thus, Wnt signaling regulates epidermal patterning, blastemal cell proliferation, and osteoblast maturation indirectly via secondary signals. Gene expression profiling, chromatin immunoprecipitation, and functional rescue experiments suggest that Wnt/β-catenin signaling acts through Fgf and Bmp signaling to control epidermal patterning, whereas retinoic acid and Hedgehog signals mediate its effects on blastemal cell proliferation. We propose that Wnt signaling orchestrates fin regeneration by defining organizing centers that instruct cellular behaviors of adjacent tissues. | Wnt/β-catenin signaling defines organizing centers that orchestrate growth and differentiation of the regenerating zebrafish caudal fin. |
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0.42096930742263794, "28055": 0.22626367211341858, "28711": 0.33115679025650024, "29215": 0.43434104323387146, "29361": 0.5080875158309937} | 23816832 | Diagnosis of multiple sclerosis (MS) requires the exclusion of other possible diagnoses. For this reason, the cerebrospinal fluid (CSF) should be routinely analysed in patients with a first clinical event suggestive of MS. CSF analysis is no longer mandatory for diagnosis of relapsing–remitting MS, as long as MRI diagnostic criteria are fulfilled. However, caution is required in diagnosing MS in patients with negative MRI findings or in the absence of CSF analysis, as CSF investigation is useful to eliminate other causes of disease. The detection of oligoclonal IgG bands in CSF has potential prognostic value and is helpful for clinical decision-making. In addition, CSF analysis is important for research into the pathogenesis of MS. Pathophysiological and neurodegenerative findings of inflammation in MS have been derived from CSF investigations. Novel CSF biomarkers, though not yet validated, have been identified for diagnosis of MS and for ascertaining disease activity, prognosis and response to treatment, and are likely to increase in number with modern detection techniques. In this Review, we summarize CSF findings that shed light on the differential diagnosis of MS, and highlight the potential of novel biomarkers for this disease that could advance understanding of its pathophysiology. | The utility of cerebrospinal fluid analysis in patients with multiple sclerosis |
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Recent studies have suggested that circadian genes participate in the growth and development of various cancers. This study examined the relations of circadian gene expression to clinicopathological factors and outcomes in patients with colorectal cancer. We studied surgical specimens of cancer tissue and adjacent normal mucosa obtained from 202 patients with untreated colorectal cancer. The relative expression levels of the circadian genes in the specimens were measured by quantitative real-time, reverse-transcription polymerase chain reaction. Expression of the Clock gene and the CKIε gene in cancer tissue were significantly higher compared to that in adjacent normal mucosa. Expression of the Per1 and Per3 genes in cancer tissue was significantly lower compared to that in adjacent normal mucosa. Analysis of the relations between clinicopathological features and expression of the eight circadian genes in cancer tissue showed that high expression of the Bmal1 gene and low expression of the Per1 gene correlated with liver metastasis. On analysis of the relations between outcomes and gene expression, high expression of the Per2 gene was associated with significantly better outcomes than low expression of the Per2 gene. Overexpression of the Bmal1 gene and reduced expression of the Per1 gene may thus be useful predictors of liver metastasis. Moreover, reduced expression of the Per2 gene may be a predictor of outcomes in patients with colorectal cancer. | Expression of circadian genes correlates with liver metastasis and outcomes in colorectal cancer. |
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"27614": 0.0913962796330452, "27615": 0.3070250153541565, "27698": 0.26820653676986694, "27796": 0.05786345899105072, "28295": 0.4518963396549225, "28321": 0.3777405619621277, "28393": 0.8255793452262878, "28637": 0.1889725625514984, "28775": 0.016465263441205025, "29134": 0.1510767638683319, "29234": 0.3897167444229126} | 23841828 | The extensive computerisation of Danish pharmacies has permitted the establishment of two large prescription registries: The Odense University Pharmacoepidemiological Database (OPED) and the Pharmacoepidemiological Prescription Database of North Jutland (PDNJ). The Danish prescription registries content, coverage, completeness and the quality of the data are discussed in this article. Furthermore, conditions for access to the data are presented. The two prescription registries cover a background population of approximately one million or 18% of the Danish population. The populations covered by the registries are stable and representative of the Danish population in general. The registries cover all reimbursed medicine at the level of the individual user. Registration of a unique and permanent personal identifier enables the compilation of longitudinal drug histories and allows the linking of prescription data to other population-based Danish registries. The degree of completeness of the Danish prescription registries is excellent for reimbursed prescription drugs. A small number of comparison studies also indicate high validity of the register information. The Danish prescription registries represent a useful new data source for pharmacoepidemiological studies. | The Danish prescription registries. |
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"28406": 0.5191890001296997, "28723": 0.9271688461303711, "28756": 0.8707374930381775, "28765": 0.05139094591140747, "28788": 0.14264501631259918, "28847": 0.2145126610994339, "29166": 0.7295845746994019, "29167": 0.0797421783208847, "29490": 0.9576126337051392, "29610": 0.1994270235300064} | 23848916 | This study found that oridonin, a natural diterpenoid purified from Rabdosia rubescens, inhibited growth of multiple myeloma (MM; U266, RPMI8226), acute lymphoblastic T-cell leukemia (Jurkat), and adult T-cell leukemia (MT-1) cells with an effective dose that inhibited 50% of target cells (ED50) ranging from 0.75 to 2.7 microg/mL. Terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling staining showed that oridonin caused apoptosis of MT-1 cells in a time-dependent manner. We explored effects of oridonin on antiapoptotic Bcl-2 family members and found that it down-regulated levels of Mcl-1 and BCL-x(L), but not Bcl-2 protein, in both MT-1 and RPMI8226 cells. Further studies found that oridonin inhibited nuclear factor-kappa B (NF-kappa B) DNA-binding activity in these cells as measured by luciferase reporter gene, ELISA-based, and electrophoretic mobility shift assays. Oridonin also blocked tumor necrosis factor-alpha- and lipopolysaccharide-stimulated NF-kappa B activity in Jurkat cells as well as RAW264.7 murine macrophages. Of note, oridonin decreased survival of freshly isolated adult T-cell leukemia (three samples), acute lymphoblastic leukemia (one sample), chronic lymphocytic leukemia (one sample), non-Hodgkin's lymphoma (three samples), and MM (four samples) cells from patients in association with inhibition of NF-kappa B DNA-binding activity. On the other hand, oridonin did not affect survival of normal lymphoid cells from healthy volunteers. Taken together, oridonin might be useful as adjunctive therapy for individuals with lymphoid malignancies, including the lethal disease adult T-cell leukemia. | Oridonin, a diterpenoid purified from Rabdosia rubescens, inhibits the proliferation of cells from lymphoid malignancies in association with blockade of the NF-kappa B signal pathways. |
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"29458": 0.15777134895324707} | 23851261 | Integrative structural modeling uses multiple types of input information and proceeds in four stages: (i) gathering information, (ii) designing model representation and converting information into a scoring function, (iii) sampling good-scoring models, and (iv) analyzing models and information. In the first stage, uncertainty originates from data that are sparse, noisy, ambiguous, or derived from heterogeneous samples. In the second stage, uncertainty can originate from a representation that is too coarse for the available information or a scoring function that does not accurately capture the information. In the third stage, the major source of uncertainty is insufficient sampling. In the fourth stage, clustering, cross-validation, and other methods are used to estimate the precision and accuracy of the models and information. | Uncertainty in integrative structural modeling. |
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"24840": 0.42353010177612305, "25381": 0.08961215615272522, "25536": 0.41065993905067444, "25604": 0.013579257763922215, "25665": 0.27564704418182373, "25775": 0.14686977863311768, "25815": 0.5528968572616577, "25850": 0.75193190574646, "25947": 0.1734936386346817, "25949": 0.07612881064414978, "25969": 0.1913948506116867, "26210": 0.08154398202896118, "26217": 0.1221139207482338, "26528": 0.15860503911972046, "27420": 0.12814582884311676, "27993": 0.05694137513637543, "28082": 0.10906458646059036, "28241": 0.015504186972975731, "28319": 1.2910817861557007, "28321": 0.5685047507286072, "28436": 0.09495500475168228, "28472": 0.21922965347766876, "28516": 0.24631060659885406, "28667": 0.08064348995685577, "28817": 0.02412080205976963, "28838": 0.10291612148284912, "29109": 1.2835346460342407, "29130": 0.0009760859538801014, "29584": 0.8091925978660583} | 23862975 | INTRODUCTION The face is the central point of the physical features; it transmits expressions and emotions, communicates feelings and allows for individual identity. Facial burns are very common and are devastating to the affected patient and results into numerous physical, emotional and psychosocial sequels. Partial thickness facial burns are very common especially among children. This study compares the effect of standard moist open technique management and a moist closed technique for partial thickness burns of the face. PATIENTS AND METHODS Patients with partial-thickness facial burns admitted in the burn unit, Ain Shams University, Cairo, Egypt in the period from April 2009 to December 2009 were included in this study. They were divided into two groups to receive either open treatment with MEBO(®) (n=20) or coverage with Aquacel(®) Ag (n=20). Demographics (age, gender, ethnicity, TBSA, burn areas), length of hospital stay (LOS), rate of infections, time to total healing, frequency of dressing changes, pain, cost benefit and patient discomfort were compared between the two groups. The long-term outcome (incidence of hypertrophic scarring) was assessed for up to 6 months follow-up period. RESULTS There were no significant differences in demographics between the two groups. In the group treated with the Aquacel(®) Ag, the mean time for re-epithelialization was 10.5 days, while it was 12.4 days in the MEBO(®) group (p<0.05). Frequency of changes, pain and patient discomfort were less with Aquacel(®) Ag. Cost was of no significant difference between the two groups. Scar quality improved in the Aquacel(®) Ag treatment group. Three and 6 months follow-up was done and long-term outcomes were recorded in both groups. CONCLUSION Moist occlusive dressing (Aquacel(®) Ag) significantly improves the management and healing rate of partial thickness facial burns with better long-term outcome compared to moist open dressing (MEBO(®)). | Moist occlusive dressing (Aquacel(®) Ag) versus moist open dressing (MEBO(®)) in the management of partial-thickness facial burns: a comparative study in Ain Shams University. |
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"25194": 0.13925230503082275, "25409": 0.6664261221885681, "25456": 1.2677175998687744, "25468": 0.0174254160374403, "25499": 0.004870930220931768, "25644": 0.0029254043474793434, "25708": 0.9987343549728394, "25761": 0.1401015669107437, "25808": 0.0058422754518687725, "26046": 0.950843095779419, "26224": 0.22937409579753876, "26244": 0.030771657824516296, "26402": 1.2158164978027344, "26520": 0.16276304423809052, "26721": 0.19220098853111267, "26773": 0.3656192123889923, "26927": 0.053244512528181076, "26942": 0.12384103983640671, "27144": 0.46853771805763245, "27263": 0.0038986403960734606, "27854": 0.4041621685028076, "27922": 0.09850110858678818, "28311": 0.026976587250828743, "28712": 0.9929623603820801, "28848": 0.3283478021621704, "29290": 0.2145126610994339} | 23863551 | We examined the effects of an inhibitor of PI3K, XL147, against human breast cancer cell lines with constitutive PI3K activation. Treatment with XL147 resulted in dose-dependent inhibition of cell growth and levels of pAKT and pS6, signal transducers in the PI3K/AKT/TOR pathway. In HER2-overexpressing cells, inhibition of PI3K was followed by up-regulation of expression and phosphorylation of multiple receptor tyrosine kinases, including HER3. Knockdown of FoxO1 and FoxO3a transcription factors suppressed the induction of HER3, InsR, IGF1R, and FGFR2 mRNAs upon inhibition of PI3K. In HER2(+) cells, knockdown of HER3 with siRNA or cotreatment with the HER2 inhibitors trastuzumab or lapatinib enhanced XL147-induced cell death and inhibition of pAKT and pS6. Trastuzumab and lapatinib each synergized with XL147 for inhibition of pAKT and growth of established BT474 xenografts. These data suggest that PI3K antagonists will inhibit AKT and relieve suppression of receptor tyrosine kinase expression and their activity. Relief of this feedback limits the sustained inhibition of the PI3K/AKT pathway and attenuates the response to these agents. As a result, PI3K pathway inhibitors may have limited clinical activity overall if used as single agents. In patients with HER2-overexpressing breast cancer, PI3K inhibitors should be used in combination with HER2/HER3 antagonists. | Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors. |
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"29076": 0.08603433519601822, "29101": 0.41840189695358276, "29290": 0.38574060797691345, "29401": 0.45623743534088135} | 23863576 | UNLABELLED Morphological characteristics of dendritic spines form the basis of cognitive ability. However, molecular mechanisms involved in fine-tuning of spine morphology during development are not fully understood. Moreover, it is unclear whether, and to what extent, these developmental mechanisms determine the normal adult spine morphological features. Here, we provide evidence that α2-isoform of Rac-specific GTPase-activating protein α-chimaerin (α2-chimaerin) is involved in spine morphological refinement during late postnatal period, and furthermore show that this developmental α2-chimaerin function affects adult spine morphologies. We used a series of mice with global and conditional knock-out of α-chimaerin isoforms (α1-chimaerin and α2-chimaerin). α2-Chimaerin disruption, but not α1-chimaerin disruption, in the mouse results in an increased size (and density) of spines in the hippocampus. In contrast, overexpression of α2-chimaerin in developing hippocampal neurons induces a decrease of spine size. Disruption of α2-chimaerin suppressed EphA-mediated spine morphogenesis in cultured developing hippocampal neurons. α2-Chimaerin disruption that begins during the juvenile stage results in an increased size of spines in the hippocampus. Meanwhile, spine morphologies are unaltered when α2-chimaerin is deleted only in adulthood. Consistent with these spine morphological results, disruption of α2-chimaerin beginning in the juvenile stage led to an increase in contextual fear learning in adulthood; whereas contextual learning was recently shown to be unaffected when α2-chimaerin was deleted only in adulthood. Together, these results suggest that α2-chimaerin signaling in developmental stages contributes to determination of the morphological features of adult spines and establishment of normal cognitive ability. SIGNIFICANCE STATEMENT Recent studies of neurodevelopmental disorders in humans and their animal models have led to an attractive hypothesis that spine morphogenesis during development forms the basis of adult cognition. In particular, the roles of Rac and its regulators, such as Rac-specific GTPase-activating proteins (RacGAPs) and Rac guanine nucleotide exchange factors, are a topic of focus in spine morphogenesis and cognitive ability. Using a series of mice with global and conditional knock-out (KO) of RacGAP α-chimaerin isoforms (α1-chimaerin and α2-chimaerin), we provide compelling evidence demonstrating that α2-chimaerin is involved in spine morphological refinement during late postnatal development and that this developmental α2-chimaerin function affects adult spine morphologies. Furthermore, our results clearly showed that α2-chimaerin signaling during late postnatal development contributes to normal cognitive ability in adult mice. | Developmental RacGAP α2-Chimaerin Signaling Is a Determinant of the Morphological Features of Dendritic Spines in Adulthood. |
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0.06886265426874161} | 23865182 | Amitriptyline is the medication of first choice in the treatment of chronic tension-type headache. In 197 patients with chronic tension-type headache (87M and 110F with a mean age of 38 +/- 13 (18-68)) efficacy and tolerability of 60-90 mg amitriptylinoxide (AO) were compared with 50-75 mg amitriptyline (AM) and placebo (PL) in a double-blind, parallel-group trial consisting of a four weeks' baseline phase and 12 weeks of treatment. The primary study endpoint was a reduction of at least 50% of the product of headache duration and frequency and a reduction of at least 50% in headache intensity. Statistics used were Fisher's exact test and analysis of variance. No significant difference emerged between AO, AM and PL with respect to the primary study endpoint. Treatment response occurred in 30.3% of the AO, 22.4% of the AM and 21.9% of the PL group. A reduction in headache duration and frequency of at least 50% was found in 39.4% on AO, in 25.4% on AM and in 26.6% on PL (PAO-PL = .1384, PAM-PL = 1.000, PAO-AM = .0973). A reduction in headache intensity of at least 50% was found in 31.8% on AO, in 26.9% on AM and in 26.6% on PL (PAO-PL = .5657, PAM-PL = 1.000, PAO-AM = .5715). Trend analysis with respect to a significant reduction of headache intensity (p < 0.05) and the product of headache duration and frequency revealed a superior effect of AO.(ABSTRACT TRUNCATED AT 250 WORDS) | Efficacy and tolerability of amitriptylinoxide in the treatment of chronic tension-type headache: a multi-centre controlled study. |
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Epidemiological studies supported the beneficial effect of supplementation of antioxidants. Superoxide dismutase (SOD) is an endogenous enzyme which can scavenge reactive oxygen species. This study investigated the effect of supplementation with ascorbic acid (vitamin C) on the changes of SOD in cultured neurological cells. Rat brain astrocytes (RBA-1 cells) were incubated with vitamin C and divided into four groups: a control group (without vitamin C) and three treatment groups with vitamin C at 40, 80, and 160 µmol/l. After short-term (2 days) and long-term (7 days) incubation, SOD activity, SOD mRNA level by Northern blotting, and SOD protein amounts by Western blotting were measured. After 2 days of incubation, vitamin C resulted in a decrease in the activity of SOD in a concentration-dependent manner (Mn-SOD from 14.8 ± 1.2 to 13.2 ± 0.5 U/mg protein and Cu/Zn-SOD from 64.8 ± 1.2 to 51.7 ± 0.9 U/mg protein; p < 0.05), and vitamin C also attenuated the Cu/Zn-SOD mRNA level from 100 to 86.3 ± 6.7%; p < 0.01), whereas the protein amounts of these two SODs remained unchanged. After 7 days of incubation with vitamin C, the SOD activity of RBA-1 cells decreased significantly (Mn-SOD from 14.9 ± 0.3 to 11.8 ± 0.3 U/mg protein and Cu/Zn SOD from 61.8 ± 1.8 to 54.6 ± 0.9 U/mg protein; p < 0.01), and the mRNA level was also attenuated (Mn-SOD from 100 to 86.8 ± 8.7% and Cu/Zn-SOD from 100 to 84.7 ± 4.8%; p < 0.01). These results suggest that 2 and 7 days of incubation with relatively high concentrations of vitamin C may downregulate activity and gene expression of SOD in cultured RBA-1 cells. | Downregulation of Superoxide Dismutase Activity and Gene Expression in Cultured Rat Brain Astrocytes after Incubation with Vitamin C |
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1.2210142612457275, "24685": 0.9591107368469238, "25194": 0.7239188551902771, "25456": 0.14686977863311768, "25714": 0.3339579105377197, "25761": 0.030771657824516296, "26243": 0.6862877607345581, "26369": 0.29400965571403503, "26402": 0.623910129070282, "26475": 0.6415454745292664, "26773": 0.7314660549163818, "26786": 0.18978065252304077, "26909": 0.1212492436170578, "27169": 0.022212404757738113, "27295": 0.49982786178588867, "27651": 0.06612417846918106, "27891": 0.04113444685935974, "27892": 1.1109062433242798, "28046": 1.0979610681533813, "28156": 0.19220098853111267, "28268": 0.11430477350950241, "28282": 1.210009217262268, "29050": 0.13499516248703003, "29172": 0.18978065252304077, "29180": 0.9842413663864136, "29290": 0.1602703034877777, "29458": 0.5629584193229675} | 23869951 | UNLABELLED The overconsumption of calorically dense, highly palatable foods is thought to be a major contributor to the worldwide obesity epidemic; however, the precise neural circuits that directly regulate hedonic feeding remain elusive. Here, we show that lateral hypothalamic area (LHA) glutamatergic neurons, and their projections to the lateral habenula (LHb), negatively regulate the consumption of palatable food. Genetic ablation of LHA glutamatergic neurons increased daily caloric intake and produced weight gain in mice that had access to a high-fat diet, while not altering general locomotor activity. Anterior LHA glutamatergic neurons send a functional glutamatergic projection to the LHb, a brain region involved in processing aversive stimuli and negative reward prediction outcomes. Pathway-specific, optogenetic stimulation of glutamatergic LHA-LHb circuit resulted in detectable glutamate-mediated EPSCs as well as GABA-mediated IPSCs, although the net effect of neurotransmitter release was to increase the firing of most LHb neurons. In vivo optogenetic inhibition of LHA-LHb glutamatergic fibers produced a real-time place preference, whereas optogenetic stimulation of LHA-LHb glutamatergic fibers had the opposite effect. Furthermore, optogenetic inhibition of LHA-LHb glutamatergic fibers acutely increased the consumption of a palatable liquid caloric reward. Collectively, these results demonstrate that LHA glutamatergic neurons are well situated to bidirectionally regulate feeding and potentially other behavioral states via their functional circuit connectivity with the LHb and potentially other brain regions. SIGNIFICANCE STATEMENT In this study, we show that the genetic ablation of LHA glutamatergic neurons enhances caloric intake. Some of these LHA glutamatergic neurons project to the lateral habenula, a brain area important for generating behavioral avoidance. Optogenetic stimulation of this circuit has net excitatory effects on postsynaptic LHb neurons. This is the first study to characterize the functional connectivity and behavioral relevance of this circuit within the context of feeding and reward-related behavior. | Lateral Hypothalamic Area Glutamatergic Neurons and Their Projections to the Lateral Habenula Regulate Feeding and Reward. |
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extensively, yet the precise advantage of this adaptation remains unclear. These two seemingly disparate cell types also show an increased regulation of the apoptotic pathway, which allows for their long-term survival. Here we show that both neurons and cancer cells strictly inhibit cytochrome c-mediated apoptosis by a mechanism dependent on glucose metabolism. We report that the pro-apoptotic activity of cytochrome c is influenced by its redox state and that increases in reactive oxygen species (ROS) following an apoptotic insult lead to the oxidation and activation of cytochrome c. In healthy neurons and cancer cells, however, cytochrome c is reduced and held inactive by intracellular glutathione (GSH), generated as a result of glucose metabolism by the pentose phosphate pathway. These results uncover a striking similarity in apoptosis regulation between neurons and cancer cells and provide insight into an adaptive advantage offered by the Warburg effect for cancer cell evasion of apoptosis and for long-term neuronal survival. | Glucose Metabolism Inhibits Apoptosis in Neurons and Cancer Cells by Redox Inactivation of Cytochrome c |
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"26402": 0.8949713706970215, "26524": 0.6568518877029419, "26773": 0.7182208299636841, "26786": 0.6369074583053589, "27099": 0.05694137513637543, "27144": 0.6096806526184082, "27179": 0.175953671336174, "27292": 0.4879087805747986, "27777": 0.043007105588912964, "27854": 0.306306391954422, "27881": 0.2034190446138382, "27891": 0.7463917136192322, "28207": 0.021256839856505394, "28282": 1.2070930004119873, "28517": 0.14264501631259918, "28712": 0.16359257698059082, "28935": 0.02887592278420925, "29336": 0.7701805830001831} | 23895668 | Mutations in cancer reprogram amino acid metabolism to drive tumor growth, but the molecular mechanisms are not well understood. Using an unbiased proteomic screen, we identified mTORC2 as a critical regulator of amino acid metabolism in cancer via phosphorylation of the cystine-glutamate antiporter xCT. mTORC2 phosphorylates serine 26 at the cytosolic N terminus of xCT, inhibiting its activity. Genetic inhibition of mTORC2, or pharmacologic inhibition of the mammalian target of rapamycin (mTOR) kinase, promotes glutamate secretion, cystine uptake, and incorporation into glutathione, linking growth factor receptor signaling with amino acid uptake and utilization. These results identify an unanticipated mechanism regulating amino acid metabolism in cancer, enabling tumor cells to adapt to changing environmental conditions. | mTORC2 Regulates Amino Acid Metabolism in Cancer by Phosphorylation of the Cystine-Glutamate Antiporter xCT. |
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"25437": 0.6497380137443542, "25714": 1.0735615491867065, "26236": 0.6212902665138245, "26237": 0.24018502235412598, "26419": 0.8509185314178467, "26524": 0.823009729385376, "26591": 0.036437395960092545, "26702": 0.04860413447022438, "26835": 0.1677299439907074, "27097": 0.04394211992621422, "27144": 0.259204238653183, "27292": 0.13925230503082275, "27354": 0.75193190574646, "27630": 0.8691008687019348, "27800": 0.1946154683828354, "27830": 0.04674193635582924, "28024": 0.0770333781838417, "28251": 0.7105726003646851, "29003": 0.24018502235412598, "29090": 0.15860503911972046, "29490": 0.3757305145263672, "29521": 0.08961215615272522} | 23897346 | Identification of unique leads represents a significant challenge in drug discovery. This hurdle is magnified in neglected diseases such as tuberculosis. We have leveraged public high-throughput screening (HTS) data to experimentally validate a virtual screening approach employing Bayesian models built with bioactivity information (single-event model) as well as bioactivity and cytotoxicity information (dual-event model). We virtually screened a commercial library and experimentally confirmed actives with hit rates exceeding typical HTS results by one to two orders of magnitude. This initial dual-event Bayesian model identified compounds with antitubercular whole-cell activity and low mammalian cell cytotoxicity from a published set of antimalarials. The most potent hit exhibits the in vitro activity and in vitro/in vivo safety profile of a drug lead. These Bayesian models offer significant economies in time and cost to drug discovery. | Bayesian models leveraging bioactivity and cytotoxicity information for drug discovery. |
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cells at different stages of differentiation. It has been proposed that they may be of potential benefit for use in cell transplantation approaches for neurodegenerative disorders and trauma. Prolonged release of interleukin-1β (IL-1β) from activated microglia has a deleterious effect on hippocampal neurons and is implicated in the impaired neurogenesis and cognitive dysfunction associated with aging, Alzheimer's disease and depression. This study assessed the effect of IL-1β on the proliferation and differentiation of embryonic rat hippocampal NPCs in vitro. We show that IL-1R1 is expressed on proliferating NPCs and that IL-1β treatment decreases cell proliferation and neurosphere growth. When NPCs were differentiated in the presence of IL-1β, a significant reduction in the percentages of newly-born neurons and post-mitotic neurons and a significant increase in the percentage of astrocytes was observed in these cultures. These effects were attenuated by IL-1 receptor antagonist. These data reveal that IL-1β exerts an anti-proliferative, anti-neurogenic and pro-gliogenic effect on embryonic hippocampal NPCs, which is mediated by IL-1R1. The present results emphasise the consequences of an inflammatory environment during NPC development, and indicate that strategies to inhibit IL-1β signalling may be necessary to facilitate effective cell transplantation approaches or in conditions where endogenous hippocampal neurogenesis is impaired. | A role for interleukin-1β in determining the lineage fate of embryonic rat hippocampal neural precursor cells. |
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"27268": 0.8383291959762573, "27480": 0.0317181795835495, "27598": 0.11778303235769272, "27651": 0.0174254160374403, "28041": 0.09672962874174118, "28297": 0.669430673122406, "28498": 0.02792670577764511, "28507": 0.9394577741622925, "28689": 0.9363996982574463, "28691": 0.1011524572968483, "28723": 0.6451379656791687, "28828": 0.010684899985790253, "28873": 0.025073638185858727, "28929": 0.38174858689308167, "28939": 1.256105661392212, "29129": 0.28743788599967957, "29166": 0.11604541540145874, "29292": 0.29036402702331543, "29295": 0.6218147873878479, "29458": 0.5990082025527954, "29477": 0.08692999184131622, "29486": 0.22626367211341858, "29491": 0.0058422754518687725, "29514": 0.10906458646059036, "29596": 0.11256109178066254, "29610": 0.7445381283760071} | 23908217 | The histologic features of renal osteodystrophy and the prevalence of bone aluminum deposition in children receiving regular dialysis have not been described. Forty-four pediatric patients undergoing continuous ambulatory (CAPD) or cycling (CCPD) peritoneal dialysis had bone biopsies and deferoxamine (DFO) infusion tests; all were receiving oral calcitriol. Osteitis fibrosa (OF) was found in 39%, mild lesions (M) in 25%, normal histology (NH) in 16%, aplastic lesions (AP) in 11%, and osteomalacia (OM) in 9%. Bone surface aluminum (SA) was present by histochemical staining in 10 out of 20 given aluminum-containing phosphate-binding agents and in 0 of 24 treated with calcium carbonate; chi 2 = 15.5, P less than 0.0001. Serum biochemistries and DFO infusion tests failed to predict bone histology, but plasma aluminum levels were markedly elevated and bone aluminum content was highest in patients with OM. Bone formation rate (BFR) correlated with serum parathyroid hormone (PTH), r = 0.55, P less than 0.001; BFR was inversely related to bone aluminum content (r = -0.42, P less than 0.01), even in patients with OF (r = -0.66, P less than 0.05). All patients with SA greater than 30% had normal or reduced BFR when compared to those with SA less than 30%; chi 2 = 12.2, P less than 0.005. Based on SA greater than 30%, six patients were classified as aluminum-related bone disease: three OM, one AP, and two NH. Two-thirds of pediatric patients undergoing CAPD/CCPD have persistent hyperparathyroidism despite treatment with calcitriol, but aluminum can adversely affect BFR when SA exceeds 30% regardless of histologic lesion or serum PTH level. | Bone disease in pediatric patients undergoing dialysis with CAPD or CCPD. |
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Previous studies using a VISTA-neutralizing monoclonal antibody show that VISTA blockade enhances T-cell activation. The current study describes a comprehensive characterization of mice in which the gene for VISTA has been deleted. Despite the apparent normal hematopoietic development in young mice, VISTA genetic deficiency leads to a gradual accumulation of spontaneously activated T cells, accompanied by the production of a spectrum of inflammatory cytokines and chemokines. Enhanced T-cell responsiveness was also observed upon immunization with neoantigen. Despite the presence of multiorgan chronic inflammation, aged VISTA-deficient mice did not develop systemic or organ-specific autoimmune disease. Interbreeding of the VISTA-deficient mice with 2D2 T-cell receptor transgenic mice, which are predisposed to the development of experimental autoimmune encephalomyelitis, drastically enhanced disease incidence and intensity. Disease development is correlated with the increase in the activation of encephalitogenic T cells in the periphery and enhanced infiltration into the CNS. Taken together, our data suggest that VISTA is a negative checkpoint regulator whose loss of function lowers the threshold for T-cell activation, allowing for an enhanced proinflammatory phenotype and an increase in the frequency and intensity of autoimmunity under susceptible conditions. | Disruption of the immune-checkpoint VISTA gene imparts a proinflammatory phenotype with predisposition to the development of autoimmunity. |
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silencing. Although piRNAs are produced independently of Dicer, miRNA and esiRNA biogenesis pathways require Dicer1 and Dicer2, respectively. Recent studies have shown that among the four isoforms of Loquacious (Loqs), Loqs-PB and Loqs-PD are involved in miRNA and esiRNA processing pathways, respectively. However, how these Loqs isoforms function in their respective small RNA biogenesis pathways remains elusive. Here, we show that Loqs-PD associates specifically with Dicer2 through its C-terminal domain. The Dicer2-Loqs-PD complex contains R2D2, another known Dicer2 partner, and excises both exogenous siRNAs and esiRNAs from their corresponding precursors in vitro. However, Loqs-PD, but not R2D2, enhanced Dicer2 activity. The Dicer2-Loqs-PD complex processes esiRNA precursor hairpins with long stems, which results in the production of AGO2-associated small RNAs. Interestingly, however, small RNAs derived from terminal hairpins of esiRNA precursors are loaded onto AGO1; thus, they are classified as a new subset of miRNAs. These results suggest that the precursor RNA structure determines the biogenesis mechanism of esiRNAs and miRNAs, thereby implicating hairpin structures with long stems as intermediates in the evolution of Drosophila miRNA. | Molecular mechanisms that funnel RNA precursors into endogenous small-interfering RNA and microRNA biogenesis pathways in Drosophila. |
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"26651": 0.34577593207359314, "26835": 0.33325836062431335, "27152": 0.1718502640724182, "27281": 0.23092569410800934, "27325": 0.13071982562541962, "27391": 0.26446542143821716, "27781": 1.3300546407699585, "27790": 0.07068414986133575, "28389": 0.19220098853111267, "28873": 0.8135309815406799, "28896": 0.9515975713729858, "29125": 0.9240728616714478, "29290": 0.20022670924663544, "29490": 0.1930064558982849} | 23915841 | The study of the evolution and specificities of neutralizing antibodies during the course of human immunodeficiency virus type 1 (HIV-1) infection may be important in the discovery of possible targets for vaccine design. In this study, we assessed the autologous and heterologous neutralization responses of 14 HIV-1 subtype C-infected individuals, using envelope clones obtained within the first 2 months postinfection. Our data show that potent but relatively strain-specific neutralizing antibodies develop within 3 to 12 months of HIV-1 infection. The magnitude of this response was associated with shorter V1-to-V5 envelope lengths and fewer glycosylation sites, particularly in the V1-V2 region. Anti-MPER antibodies were detected in 4 of 14 individuals within a year of infection, while antibodies to CD4-induced (CD4i) epitopes developed to high titers in 12 participants, in most cases before the development of autologous neutralizing antibodies. However, neither anti-MPER nor anti-CD4i antibody specificity conferred neutralization breadth. These data provide insights into the kinetics, potency, breadth, and epitope specificity of neutralizing antibody responses in acute HIV-1 subtype C infection. | Neutralizing antibody responses in acute human immunodeficiency virus type 1 subtype C infection. |
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The factors controlling endomitosis are accessible to analysis in our megakaryocytic cell line, MegT, generated by targeted expression of temperature-sensitive simian virus 40 large T antigen to megakaryocytes of transgenic mice. We aimed to define whether endomitosis consists of a continuous phase of DNA synthesis (S) or of S phases interrupted by gaps. Analysis of the cell cycle in MegT cells revealed that, upon inactivation of large T antigen, the cells shifted from a mitotic cell cycle to an endomitotic cell cycle consisting of S/Gap phases. The level of the G1/S cyclin, cyclin A, as well as of the G1 phase cyclin, cyclin D3, were elevated at the onset of DNA synthesis, either in MegT cells undergoing a mitotic cell cycle or during endomitosis. In contrast, the level of the mitotic cyclin, cyclin B1, cycled in cells displaying a mitotic cell cycle while not detectable during endomitosis. Comparable levels of the mitotic kinase protein, Cdc2, were detected during the mitotic cell cycle or during endomitosis; however, cyclin B1-dependent Cdc2 kinase activity was largely abolished in the polyploid cells. Fibroblasts immortalized with the same heat-labile oncogene do not display reduced levels of cyclin B1 upon shifting to high temperature nor do they become polyploid, indicating that reduced levels of cyclin B1 is a property of megakaryocytes and not of the T-antigen mutant. We conclude that cellular programming during endoreduplication in megakaryocytes is associated with reduced levels of cyclin B1. | The cell cycle in polyploid megakaryocytes is associated with reduced activity of cyclin B1-dependent cdc2 kinase. |
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severe calorie deprivation, an event that is essential to maintain life. The mechanism for this increase is not understood. Here, we study the control of ghrelin secretion in tissue culture cells derived from mice bearing ghrelinomas induced by a tissue-specific SV40 T-antigen transgene. We found that the ghrelin-secreting cells express high levels of mRNA encoding beta(1)-adrenergic receptors. Addition of norepinephrine or epinephrine to the culture medium stimulated ghrelin secretion, and this effect was blocked by atenolol, a selective beta(1)-adrenergic antagonist. When WT mice were treated with reserpine to deplete adrenergic neurotransmitters from sympathetic neurons, the fasting-induced increase in plasma ghrelin was blocked. Inhibition was also seen following atenolol administration. We conclude that ghrelin secretion during fasting is induced by adrenergic agents released by sympathetic neurons and acting directly on beta(1) receptors on the ghrelin-secreting cells of the stomach. | Ghrelin secretion stimulated by {beta}1-adrenergic receptors in cultured ghrelinoma cells and in fasted mice. |
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"26034": 0.28082266449928284, "26083": 0.2447827309370041, "26268": 0.306306391954422, "26285": 0.272677481174469, "26305": 0.7951818704605103, "26453": 1.4404643774032593, "26468": 0.058784693479537964, "26739": 0.15023678541183472, "26741": 1.2610986232757568, "26874": 0.11604541540145874, "27152": 0.5568217039108276, "27559": 0.030771657824516296, "27811": 0.17020416259765625, "27876": 0.3423145115375519, "28290": 1.197703242301941, "28309": 1.0546929836273193, "28739": 0.08871890604496002, "28758": 0.09495500475168228, "28771": 0.06429435312747955, "28873": 0.022212404757738113, "28901": 0.004870930220931768, "29273": 0.16524957120418549, "29532": 0.0842406153678894} | 23932173 | Dominance relationships were studied for 249 out of 276 possible pair-wise combinations between 24 S-alleles of Brassica campestris that had been isolated from two natural populations from Turkey and Japan. Each F1 hybrid was test-crossed reciprocally against its respective parental S-homozygotes to determine the dominance relationships between the pair of S-alleles it contained. The 24 S-alleles were classified into two groups on the stigma side and three groups on the pollen side. In the stigma, codominance occurred frequently, and dominance or recessiveness seemed to appear according to the combination of S-alleles. In the pollen, codominance was less frequent, and there seemed to be a certain hierarchy of the dominance relationships as a whole, although dominance appeared with certain specific combinations of S-alleles. Interactions among 24 S-alleles were different in the stigma and in the pollen. Independent weakening of S-alleles was found between 20 pairs in the pollen, but only two in the stigma. This interaction seems to be correlated with recessiveness of S-alleles. | Dominance relationships between S-alleles in self-incompatible Brassica campestris L. |
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"24978": 1.0688776969909668, "25030": 0.025073638185858727, "25175": 0.36494144797325134, "25409": 0.7436100244522095, "25456": 0.5662899017333984, "25468": 1.19829261302948, "25507": 0.05970508232712746, "25524": 0.22626367211341858, "25644": 0.06246116757392883, "25714": 0.8187123537063599, "25778": 0.10026945173740387, "26013": 0.2719337046146393, "26402": 1.057410478591919, "26520": 0.3318578004837036, "26601": 0.04394211992621422, "26773": 0.554580807685852, "26835": 0.16110190749168396, "26986": 0.05139094591140747, "27144": 0.23402166366577148, "27165": 1.0887986421585083, "27781": 0.09850110858678818, "27854": 0.052318159490823746, "27881": 0.13499516248703003, "28848": 0.28597161173820496, "29490": 0.37371641397476196} | 23934390 | MicroRNAs are proposed to serve vital functions in the regulation of tumor progression and invasion. However, the expression levels of miR-203 in non-small cell lung cancer (NSCLC) and its clinical significance remain unknown. In the present study, the association between B-cell-specific moloney murine leukemia virus insertion site 1 (Bmi1) and miR-203 was investigated. miR-203 was demonstrated to act as a tumor suppressor by regulating the expression of Bmi1. miR-203 expression levels were downregulated in NSCLC tissues while Bmi1 expression was upregulated in NSCLC tissues and cell lines. Furthermore, downregulated Bmi1 or enhanced miR-203 expression inhibited NSCLC cell proliferation and invasion in vitro. In addition, a dual-luciferase reporter assay was performed, which identified Bmi1 as a novel target of miR-203. In conclusion, the present study demonstrated that miR-203 functions as a tumor suppressor and is important in inhibiting the proliferation of NSCLC cells through targeting Bmi1. These findings indicate that miR-203 may be useful as a novel potential therapeutic target for NSCLC. | MicroRNA-203 inhibits cellular proliferation and invasion by targeting Bmi1 in non-small cell lung cancer. |
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23938319 | Retinoid receptors (RARs and RXRs) are ligand-activated transcription factors that regulate the transcription of target genes by recruiting coregulator complexes at cognate promoters. To understand the effects of heterodimerization and ligand binding on coactivator recruitment, we solved the crystal structure of the complex between the RARbeta/RXRalpha ligand-binding domain heterodimer, its 9-cis retinoic acid ligand, and an LXXLL-containing peptide (termed NR box 2) derived from the nuclear receptor interaction domain (NID) of the TRAP220 coactivator. In parallel, we measured the binding affinities of the isolated NR box 2 peptide or the full-length NID of the coactivator SRC-1 for retinoid receptors in the presence of various types of ligands. Our correlative analysis of three-dimensional structures and fluorescence data reveals that heterodimerization does not significantly alter the structure of individual subunits or their intrinsic capacity to interact with NR box 2. Similarly, we show that the ability of a protomer to recruit NR box 2 does not vary as a function of the ligand binding status of the partner receptor. In contrast, the strength of the overall association between the heterodimer and the full-length SRC-1 NID is dictated by the combinatorial action of RAR and RXR ligands, the simultaneous presence of the two receptor agonists being required for highest binding affinity. We identified an LXXLL peptide-driven mechanism by which the concerted reorientation of three phenylalanine side chains generates an "aromatic clamp" that locks the RXR activation helix H12 in the transcriptionally active conformation. Finally, we show how variations of helix H11-ligand interactions can alter the communication pathway linking helices H11, H12, and the connecting loop L11-12 to the coactivator-binding site. Together, our results reveal molecular and structural features that impact on the ligand-dependent interaction of the RAR/RXR heterodimer with nuclear receptor coactivators. | Characterization of the interaction between retinoic acid receptor/retinoid X receptor (RAR/RXR) heterodimers and transcriptional coactivators through structural and fluorescence anisotropy studies. |
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0.11343330889940262, "28901": 0.6902132034301758, "29290": 0.27044451236724854} | 23959496 | Polycomb repressive complex two (PRC2) has been implicated in embryonic stem (ES) cell pluripotency; however, the mechanistic roles of this complex are unclear. It was assumed that ES cells contain PRC2 with the same subunit composition as that identified in HeLa cells and Drosophila embryos. Here, we report that PRC2 in mouse ES cells contains at least three additional subunits: JARID2, MTF2, and a novel protein denoted esPRC2p48. JARID2, MTF2, and esPRC2p48 are highly expressed in mouse ES cells compared to differentiated cells. Importantly, knockdowns of JARID2, MTF2, or esPRC2p48 alter the level of PRC2-mediated H3K27 methylation and result in the expression of differentiation-associated genes in ES cells. Interestingly, expression of JARID2, MTF2, and esPRC2p48 together, but not individually, enhances Oct4/Sox2/Klf4-mediated reprogramming of mouse embryonic fibroblasts (MEFs) into induced pluripotent stem cells, whereas knockdown or knockout of JARID2, MTF2, or esPRC2p48 significantly inhibits reprogramming. JARID2, MTF2, and esPRC2p48 modulate H3K27 methylation and facilitate repression of lineage-associated gene expression when transduced into MEFs, and synergistically stimulate the histone methyltransferase activity of PRC2 in vitro. Therefore, these studies identify JARID2, MTF2, and esPRC2p48 as important regulatory subunits of PRC2 in ES cells and reveal critical functions of these subunits in modulating PRC2's activity and gene expression both in ES cells and during somatic cell reprogramming. | PRC2 complexes with JARID2, MTF2, and esPRC2p48 in ES cells to modulate ES cell pluripotency and somatic cell reprogramming. |
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0.3723714053630829, "25519": 0.5865923762321472, "25523": 0.8450632095336914, "25604": 0.7067264318466187, "25927": 0.040196798741817474, "25949": 0.12556517124176025, "26163": 0.052318159490823746, "26237": 1.1051015853881836, "26319": 0.08513788133859634, "26404": 0.27044451236724854, "26462": 0.28670501708984375, "26745": 0.08513788133859634, "26786": 0.1332872211933136, "26906": 0.32553088665008545, "27133": 1.130645751953125, "27204": 0.12986256182193756, "27833": 0.04394211992621422, "28093": 0.2637155055999756, "28268": 0.24325250089168549, "28436": 0.12384103983640671, "28530": 0.18816383183002472, "29015": 0.14179791510105133, "29166": 0.2696990668773651, "29299": 0.5483922958374023, "29361": 0.009718249551951885, "29458": 0.956112265586853} | 23967973 | BACKGROUND Previous studies have relied predominantly on the body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) to assess the association of adiposity with the risk of death, but few have examined whether the distribution of body fat contributes to the prediction of death. METHODS We examined the association of BMI, waist circumference, and waist-to-hip ratio with the risk of death among 359,387 participants from nine countries in the European Prospective Investigation into Cancer and Nutrition (EPIC). We used a Cox regression analysis, with age as the time variable, and stratified the models according to study center and age at recruitment, with further adjustment for educational level, smoking status, alcohol consumption, physical activity, and height. RESULTS During a mean follow-up of 9.7 years, 14,723 participants died. The lowest risks of death related to BMI were observed at a BMI of 25.3 for men and 24.3 for women. After adjustment for BMI, waist circumference and waist-to-hip ratio were strongly associated with the risk of death. Relative risks among men and women in the highest quintile of waist circumference were 2.05 (95% confidence interval [CI], 1.80 to 2.33) and 1.78 (95% CI, 1.56 to 2.04), respectively, and in the highest quintile of waist-to-hip ratio, the relative risks were 1.68 (95% CI, 1.53 to 1.84) and 1.51 (95% CI, 1.37 to 1.66), respectively. BMI remained significantly associated with the risk of death in models that included waist circumference or waist-to-hip ratio (P<0.001). CONCLUSIONS These data suggest that both general adiposity and abdominal adiposity are associated with the risk of death and support the use of waist circumference or waist-to-hip ratio in addition to BMI in assessing the risk of death. | General and abdominal adiposity and risk of death in Europe. |
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Although several autophagy receptors have been identified, little is known about mechanisms controlling their functions in vivo. In this work, we found that phosphorylation of an autophagy receptor, optineurin, promoted selective autophagy of ubiquitin-coated cytosolic Salmonella enterica. The protein kinase TANK binding kinase 1 (TBK1) phosphorylated optineurin on serine-177, enhancing LC3 binding affinity and autophagic clearance of cytosolic Salmonella. Conversely, ubiquitin- or LC3-binding optineurin mutants and silencing of optineurin or TBK1 impaired Salmonella autophagy, resulting in increased intracellular bacterial proliferation. We propose that phosphorylation of autophagy receptors might be a general mechanism for regulation of cargo-selective autophagy. | Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. |
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Exposure to a high glucose concentration has recently been shown to increase phosphorylation of AMPK at Ser(485/491) of its α1/α2 subunit; however, the mechanism by which it does so is not known. Diacylglycerol (DAG), which is also increased in muscle exposed to high glucose, activates a number of signaling molecules including protein kinase (PK)C and PKD1. We sought to determine whether PKC or PKD1 is involved in inhibition of AMPK by causing Ser(485/491) phosphorylation in skeletal muscle cells. C2C12 myotubes were treated with the PKC/D1 activator phorbol 12-myristate 13-acetate (PMA), which acts as a DAG mimetic. This caused dose- and time-dependent increases in AMPK Ser(485/491) phosphorylation, which was associated with a ∼60% decrease in AMPKα2 activity. Expression of a phosphodefective AMPKα2 mutant (S491A) prevented the PMA-induced reduction in AMPK activity. Serine phosphorylation and inhibition of AMPK activity were partially prevented by the broad PKC inhibitor Gö6983 and fully prevented by the specific PKD1 inhibitor CRT0066101. Genetic knockdown of PKD1 also prevented Ser(485/491) phosphorylation of AMPK. Inhibition of previously identified kinases that phosphorylate AMPK at this site (Akt, S6K, and ERK) did not prevent these events. PMA treatment also caused impairments in insulin-signaling through Akt, which were prevented by PKD1 inhibition. Finally, recombinant PKD1 phosphorylated AMPKα2 at Ser(491) in cell-free conditions. These results identify PKD1 as a novel upstream kinase of AMPKα2 Ser(491) that plays a negative role in insulin signaling in muscle cells. | PKD1 Inhibits AMPKα2 through Phosphorylation of Serine 491 and Impairs Insulin Signaling in Skeletal Muscle Cells. |
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"29458": 0.8925741910934448} | 23983289 | OBJECTIVES We sought to determine which ICD-9-CM codes in Medicare Part A data identify cardiovascular and stroke risk factors. DESIGN AND PARTICIPANTS This was a cross-sectional study comparing ICD-9-CM data to structured medical record review from 23,657 Medicare beneficiaries aged 20 to 105 years who had atrial fibrillation. MEASUREMENTS Quality improvement organizations used standardized abstraction instruments to determine the presence of 9 cardiovascular and stroke risk factors. Using the chart abstractions as the gold standard, we assessed the accuracy of ICD-9-CM codes to identify these risk factors. MAIN RESULTS ICD-9-CM codes for all risk factors had high specificity (>0.95) and low sensitivity (< or =0.76). The positive predictive values were greater than 0.95 for 5 common, chronic risk factors-coronary artery disease, stroke/transient ischemic attack, heart failure, diabetes, and hypertension. The sixth common risk factor, valvular heart disease, had a positive predictive value of 0.93. For all 6 common risk factors, negative predictive values ranged from 0.52 to 0.91. The rare risk factors-arterial peripheral embolus, intracranial hemorrhage, and deep venous thrombosis-had high negative predictive value (> or =0.98) but moderate positive predictive values (range, 0.54-0.77) in this population. CONCLUSIONS Using ICD-9-CM codes alone, heart failure, coronary artery disease, diabetes, hypertension, and stroke can be ruled in but not necessarily ruled out. Where feasible, review of additional data (eg, physician notes or imaging studies) should be used to confirm the diagnosis of valvular disease, arterial peripheral embolus, intracranial hemorrhage, and deep venous thrombosis. | Accuracy of ICD-9-CM codes for identifying cardiovascular and stroke risk factors. |
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Since p53 mutations are the most frequently reported genetic defects in human cancers, it becomes important to study the effects of mutations of p53 on promoter functions. We, therefore, have studied the effects of wild-type and mutant human p53 on the human proliferating-cell nuclear antigen (PCNA) promoter and on several viral promoters, including the herpes simplex virus type 1 UL9 promoter, the human cytomegalovirus major immediate-early promoter-enhancer, and the long terminal repeat promoters of Rous sarcoma virus and human T-cell lymphotropic virus type I. HeLa cells were cotransfected with a wild-type or mutant p53 expression vector and a plasmid containing a chloramphenicol acetyltransferase reporter gene under viral (or cellular) promoter control. As expected, expression of the wild-type p53 inhibited promoter function. Expression of a p53 with a mutation at any one of the four amino acid positions 175, 248, 273, or 281, however, correlated with a significant increase of the PCNA promoter activity (2- to 11-fold). The viral promoters were also activated, although to a somewhat lesser extent. We also showed that activation by a mutant p53 requires a minimal promoter containing a lone TATA box. A more significant increase (25-fold) in activation occurs when the promoter contains a binding site for the activating transcription factor or cyclic AMP response element-binding protein. Using Saos-2 cells that do not express p53, we showed that activation by a mutant p53 was a direct enhancement. The mutant forms of p53 used in this study are found in various cancer cells. The activation of PCNA by mutant p53s may indicate a way to increase cell proliferation by the mutant p53s. Thus, our data indicate a possible functional role for the mutants of p53 found in cancer cells in activating several important loci, including PCNA. | Modulation of cellular and viral promoters by mutant human p53 proteins found in tumor cells. |
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"26261": 0.10026945173740387, "26402": 1.0519683361053467, "26520": 0.12986256182193756, "26563": 0.0038986403960734606, "26986": 0.11081436276435852, "27159": 0.07612881064414978, "27306": 0.8925741910934448, "27480": 0.0752234235405922, "27531": 0.04394211992621422, "28086": 0.2983669638633728, "28228": 0.9893379211425781, "28788": 0.11168810725212097, "28848": 0.7352184057235718, "28873": 0.22937409579753876, "29129": 0.6853039860725403, "29166": 0.045809537172317505} | 24003461 | BACKGROUND Calcific aortic valve disease (CAVD) is the most common heart valve disease in the Western world. We previously proposed that valvular endothelial cells (VECs) replenish injured adult valve leaflets via endothelial-to-mesenchymal transformation (EndMT); however, whether EndMT contributes to valvular calcification is unknown. We hypothesized that aortic VECs undergo osteogenic differentiation via an EndMT process that can be inhibited by valvular interstitial cells (VICs). APPROACH AND RESULTS VEC clones underwent TGF-β1-mediated EndMT, shown by significantly increased mRNA expression of the EndMT markers α-SMA (5.3 ± 1.2), MMP-2 (13.5 ± 0.6) and Slug (12 ± 2.1) (p < 0.05), (compared to unstimulated controls). To study the effects of VIC on VEC EndMT, clonal populations of VICs were derived from the same valve leaflets, placed in co-culture with VECs, and grown in control/TGF-β1 supplemented media. In the presence of VICs, EndMT was inhibited, shown by decreased mRNA expression of α-SMA (0.1 ± 0.5), MMP-2 (0.1 ± 0.1), and Slug (0.2 ± 0.2) (p < 0.05). When cultured in osteogenic media, VECs demonstrated osteogenic changes confirmed by increase in mRNA expression of osteocalcin (8.6 ± 1.3), osteopontin (3.7 ± 0.3), and Runx2 (5.5 ± 1.5). The VIC presence inhibited VEC osteogenesis, demonstrated by decreased expression of osteocalcin (0.4 ± 0.1) and osteopontin (0.2 ± 0.1) (p < 0.05). Time course analysis suggested that EndMT precedes osteogenesis, shown by an initial increase of α-SMA and MMP-2 (day 7), followed by an increase of osteopontin and osteocalcin (day 14). CONCLUSIONS The data indicate that EndMT may precede VEC osteogenesis. This study shows that VICs inhibit VEC EndMT and osteogenesis, indicating the importance of VEC-VIC interactions in valve homeostasis. | Valvular interstitial cells suppress calcification of valvular endothelial cells. |
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We show here that statins rapidly activate the protein kinase Akt/PKB in endothelial cells. Accordingly, simvastatin enhanced phosphorylation of the endogenous Akt substrate endothelial nitric oxide synthase (eNOS), inhibited apoptosis and accelerated vascular structure formation in vitro in an Akt-dependent manner. Similar to vascular endothelial growth factor (VEGF) treatment, both simvastatin administration and enhanced Akt signaling in the endothelium promoted angiogenesis in ischemic limbs of normocholesterolemic rabbits. Therefore, activation of Akt represents a mechanism that can account for some of the beneficial side effects of statins, including the promotion of new blood vessel growth. | The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. |
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0.0797421783208847, "23267": 0.083342544734478, "24054": 0.18573370575904846, "24269": 0.21922965347766876, "24336": 0.1229778528213501, "24394": 0.9271688461303711, "25006": 0.20660123229026794, "25158": 0.0038986403960734606, "25502": 0.7898768186569214, "25519": 0.9515975713729858, "25778": 0.1677299439907074, "26369": 0.21687394380569458, "26402": 0.016465263441205025, "26557": 0.16359257698059082, "26775": 0.5914691090583801, "26855": 0.7728893756866455, "26942": 0.7809720039367676, "27292": 0.6075552701950073, "27755": 0.9878844022750854, "27969": 0.0752234235405922, "28879": 0.3134697377681732, "29336": 0.08871890604496002, "29358": 0.4831010699272156, "29566": 0.11951763927936554} | 24019260 | Alcohol dependence is a disease that impacts millions of individuals worldwide. There has been some progress with pharmacotherapy for alcohol-dependent individuals; however, there remains a critical need for the development of novel and additional therapeutic approaches. Alcohol and nicotine are commonly abused together, and there is evidence that neuronal nicotinic acetylcholine receptors (nAChRs) play a role in both alcohol and nicotine dependence. Varenicline, a partial agonist at the alpha4beta2 nAChRs, reduces nicotine intake and was recently approved as a smoking cessation aid. We have investigated the role of varenicline in the modulation of ethanol consumption and seeking using three different animal models of drinking. We show that acute administration of varenicline, in doses reported to reduce nicotine reward, selectively reduced ethanol but not sucrose seeking using an operant self-administration drinking paradigm and also decreased voluntary ethanol but not water consumption in animals chronically exposed to ethanol for 2 months before varenicline treatment. Furthermore, chronic varenicline administration decreased ethanol consumption, which did not result in a rebound increase in ethanol intake when the varenicline was no longer administered. The data suggest that the alpha4beta2 nAChRs may play a role in ethanol-seeking behaviors in animals chronically exposed to ethanol. The selectivity of varenicline in decreasing ethanol consumption combined with its reported safety profile and mild side effects in humans suggest that varenicline may prove to be a treatment for alcohol dependence. | Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, selectively decreases ethanol consumption and seeking. |
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"24797": 0.04860413447022438, "24906": 0.2539152204990387, "25117": 1.034073829650879, "25194": 0.7276995778083801, "25281": 0.23787821829319, "25354": 1.2301886081695557, "25456": 0.6754127144813538, "25458": 1.104454517364502, "25761": 0.040196798741817474, "26244": 0.2160874605178833, "26315": 0.4537591338157654, "26402": 1.181056022644043, "26616": 0.3963087201118469, "26632": 0.4752389192581177, "26721": 0.997294545173645, "26910": 0.9333322048187256, "26942": 0.8772575259208679, "27211": 1.436757206916809, "27295": 0.20102575421333313, "27777": 0.0009760859538801014, "27843": 0.5528968572616577, "27854": 0.4400174915790558, "28424": 0.1212492436170578, "28691": 0.026976587250828743, "28847": 0.3409265875816345, "28848": 0.48430517315864563, "29237": 0.44753631949424744, "29290": 0.4093637466430664, "29304": 0.2954642176628113} | 24042363 | Agonist-induced dimerization of TLR4 Toll/IL-1R (TIR) domains initiates intracellular signaling. Therefore, identification of the TLR4-TIR dimerization interface is one key to the rational design of therapeutics that block TLR4 signaling. A library of cell-permeating decoy peptides, each of which represents a nonfragmented patch of the TLR4 TIR surface, was designed such that the peptides entirely encompass the TLR4 TIR surface. Each peptide was synthesized in tandem with a cell-permeating Antennapedia homeodomain sequence and tested for the ability to inhibit early cytokine mRNA expression and MAPK activation in LPS-stimulated primary murine macrophages. Five peptides--4R1, 4R3, 4BB, 4R9, and 4αE--potently inhibited all manifestations of TLR4, but not TLR2 signaling. When tested for their ability to bind directly to TLR4 TIR by Förster resonance energy transfer using time-resolved fluorescence spectroscopy, Bodipy-TMR-X-labeled 4R1, 4BB, and 4αE quenched fluorescence of TLR4-Cerulean expressed in HeLa or HEK293T cells, whereas 4R3 was partially active, and 4R9 was least active. These findings suggest that the area between the BB loop of TLR4 and its fifth helical region mediates TLR4 TIR dimerization. Moreover, our data provide direct evidence for the utility of the decoy peptide approach, in which peptides representing various surface-exposed segments of a protein are initially probed for the ability to inhibit protein function, and then their specific targets are identified by Förster resonance energy transfer to define recognition sites in signaling proteins that may be targeted therapeutically to disrupt functional transient protein interactions. | Targeting TLR4 signaling by TLR4 Toll/IL-1 receptor domain-derived decoy peptides: identification of the TLR4 Toll/IL-1 receptor domain dimerization interface. |
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"27059": 0.11604541540145874, "27152": 0.05139094591140747, "27287": 0.8169882297515869, "27321": 0.1718502640724182, "27343": 0.018384648486971855, "27528": 0.09584271162748337, "27896": 0.04394211992621422, "28086": 0.3019835948944092, "28436": 0.11778303235769272, "28507": 1.0094679594039917, "28522": 0.8633513450622559, "28685": 0.07250232994556427, "28691": 0.3019835948944092, "28699": 0.09584271162748337, "28723": 0.1751343309879303, "28788": 0.48430517315864563, "28828": 0.7601850032806396, "28873": 0.21214580535888672, "28939": 1.1598494052886963, "29060": 0.06154331564903259, "29090": 0.34023189544677734, "29109": 0.8433839678764343, "29111": 0.7934166193008423, "29217": 0.052318159490823746, "29280": 0.1064341589808464, "29292": 0.14433705806732178, "29415": 0.02792670577764511, "29490": 0.11865071207284927, "29491": 0.0058422754518687725} | 24042919 | We examined the morphological and functional characteristics of erythroblasts derived from marrow erythroid progenitor cells grown in a methylcellulose microculture, which were taken from a female child with rare atypical sideroblastic anaemia (SA) partially responsive to pyridoxine. Colony formation was within the normal range in three successive cultures (median values: 82.25 CFU-E and 16.4 BFU-E derived colonies/6.6 X 10(4) cells) compared to growth by normal cells (65-315 CFU-E and 9-40 BFU-E). We evaluated in vitro differentiation by biochemical microassay of a cytosol enzyme involved in the haem pathway: uroporphyrinogen I synthase (UROS). The UROS values in the erythroid colonies from SA marrow were at the lowere end of the normal range (median values: 6.7 +/- 0.3 and 14.4 +/- 3.8 pmol uroporphyrinogen/h in CFU-E and BFU-E-derived colonies respectively versus 17.4 +/- 7.3 and 25 +/- 7.2 pmol/h in CFU-E and BFU-E colonies from normal subjects. Ultrastructural examination of the SA erythroblasts from non-cultured bone marrow or derived from cultured BFU-E revealed the characteristic deposition of iron in mitochondria around the nucleus of most cells (ringed sideroblasts). However, the majority of cultured cells had marked dyserythropoietic features, with a large number of bilobulated or trilobulated erythroblasts, multiple cytoplasmic vacuoles, numerous abnormalities of the nucleus, and excessive membrane material beneath the plasma membrane, all features difficult to observe in non-cultured marrows. | A paediatric case of sideroblastic anaemia. Ultrastructural studies of erythroblasts cultured from marrow BFU-E in a methylcellulose micromethod. |
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0.10906458646059036, "26651": 0.011650617234408855, "26835": 0.4891071021556854, "27287": 0.06612417846918106, "27295": 0.09938567131757736, "27321": 0.4349733293056488, "27395": 0.4267219603061676, "27448": 0.38441169261932373, "27781": 0.4228905141353607, "27929": 0.20102575421333313, "28788": 0.6553317308425903, "28873": 1.057410478591919, "28896": 0.11865071207284927, "29109": 0.29109421372413635, "29197": 0.04953393340110779, "29490": 0.06429435312747955, "29610": 0.5370414853096008} | 24044977 | Innate lymphoid cells (ILCs) are immune cells that lack a specific antigen receptor yet can produce an array of effector cytokines that in variety match that of T helper cell subsets. ILCs function in lymphoid organogenesis, tissue remodeling, antimicrobial immunity, and inflammation, particularly at barrier surfaces. Their ability to promptly respond to insults inflicted by stress-causing microbes strongly suggests that ILCs are critical in first-line immunological defenses. Here, we review current data on developmental requirements, lineage relationships, and effector functions of two families of ILCs: (a) Rorγt-expressing cells involved in lymphoid tissue formation, mucosal immunity, and inflammation and (b) type 2 ILCs that are important for helminth immunity. We also discuss the potential roles of ILCs in the pathology of immune-mediated inflammatory and infectious diseases including allergy. | Innate lymphoid cells: emerging insights in development, lineage relationships, and function. |
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0.020300358533859253, "28466": 0.14179791510105133, "28674": 0.24325250089168549, "28696": 0.07431721687316895, "29336": 0.06337817758321762, "29454": 0.13925230503082275, "29516": 0.07793712615966797} | 24049225 | BACKGROUND The pathophysiological mechanism of hyperhomocysteinemia in chronic renal failure in humans is unknown. The loss of a putative renal homocysteine extraction in chronic renal failure has been hypothesized as significant homocysteine uptake has been demonstrated in the normal rat kidney. We studied homocysteine extraction in the normal human kidney. METHODS We measured plasma total (free and protein-bound) and free homocysteine (tHcy and fHcy, respectively) in arterial and renal venous blood sampled from the aorta and right-side renal vein during cardiac catheterization in 20 fasting patients with normal renal function. Renal homocysteine extraction was calculated as the arteriovenous difference divided by the arterial levels times 100%. RESULTS No significant renal extraction was demonstrated either for tHcy: 0.9% (SD 5.8; 95% CI -1.8 to +3.6) or for fHcy: -0.2% (11.0; -5.4 to +4.9). CONCLUSIONS We conclude that no significant net renal uptake of homocysteine occurs in fasting humans with normal renal function. The loss of such uptake, therefore, cannot cause hyperhomocysteinemia in patients with renal failure. | No net renal extraction of homocysteine in fasting humans. |
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0.09228714555501938, "25817": 0.13157635927200317, "25850": 1.1726272106170654, "25940": 0.11343330889940262, "26163": 0.9013357162475586, "26319": 0.053244512528181076, "26456": 0.7105726003646851, "26643": 0.06886265426874161, "26651": 0.5139457583427429, "27166": 0.1905880719423294, "27347": 0.4770587682723999, "27348": 0.08961215615272522, "27354": 0.03925827145576477, "27641": 0.034552380442619324, "27718": 0.46914875507354736, "28093": 0.13414156436920166, "28616": 0.1064341589808464, "28739": 0.2976420819759369, "29129": 0.010684899985790253, "29299": 0.5393219590187073, "29458": 0.4818955361843109, "29477": 0.04394211992621422} | 24055603 | Thirty patients with tension-type headache were randomly chosen to undergo a trial of traditional Chinese acupuncture and sham acupuncture. Five measures were used to assess symptom severity and treatment response: intensity, duration and frequency of headache pain episodes, headache index and analgesic intake. The five measures were assessed during a 4 week baseline period, after 4 and 8 weeks of treatment, and 1, 6 and 12 months thereafter. Before the start of the study, each patient was administered the MMPI. Split-plot ANOVAs showed that, compared to baseline, at 1 month after the end of treatment and for the 12 month follow-up, the frequency of headache episodes, analgesic consumption and the headache index (but not the duration or intensity of headache episodes) significantly decreased over time; however, no difference between acupuncture and placebo treatment was found. No single MMPI scale predicted the response to treatment, but the mean MMPI profile of acupuncture non-responders showed the presence of 'Conversion V'. | Traditional Chinese acupuncture in tension-type headache: a controlled study. |
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0.3743882179260254, "29533": 0.15693697333335876} | 24069089 | Modified anti-CD3 mAbs are emerging as a possible means of inducing immunologic tolerance in settings including transplantation and autoimmunity such as in type 1 diabetes. In a trial of a modified anti-CD3 mAb [hOKT3gamma1(Ala-Ala)] in patients with type 1 diabetes, we identified clinical responders by an increase in the number of peripheral blood CD8+ cells following treatment with the mAb. Here we show that the anti-CD3 mAb caused activation of CD8+ T cells that was similar in vitro and in vivo and induced regulatory CD8+CD25+ T cells. These cells inhibited the responses of CD4+ cells to the mAb itself and to antigen. The regulatory CD8+CD25+ cells were CTLA4 and Foxp3 and required contact for inhibition. Foxp3 was also induced on CD8+ T cells in patients during mAb treatment, which suggests a potential mechanism of the anti-CD3 mAb immune modulatory effects involving induction of a subset of regulatory CD8+ T cells. | TCR stimulation with modified anti-CD3 mAb expands CD8+ T cell population and induces CD8+CD25+ Tregs. |
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0.14095009863376617, "27292": 0.7863243818283081, "27325": 0.0174254160374403, "27453": 0.3012613356113434, "27615": 0.2317005842924118, "27937": 0.2763880789279938, "28675": 0.02316705882549286, "28731": 0.619189441204071, "28804": 0.0058422754518687725, "28823": 0.25467249751091003, "29234": 0.8247235417366028, "29300": 0.5865923762321472} | 24077493 | BACKGROUND With increasing restrictions placed on physician-industry interactions, industry marketing may target other health professionals. Recent health policy developments confer even greater importance on the decision making of non-physician clinicians. The purpose of this systematic review is to examine the types and implications of non-physician clinician-industry interactions in clinical practice. METHODS AND FINDINGS We searched MEDLINE and Web of Science from January 1, 1946, through June 24, 2013, according to PRISMA guidelines. Non-physician clinicians eligible for inclusion were: Registered Nurses, nurse prescribers, Physician Assistants, pharmacists, dieticians, and physical or occupational therapists; trainee samples were excluded. Fifteen studies met inclusion criteria. Data were synthesized qualitatively into eight outcome domains: nature and frequency of industry interactions; attitudes toward industry; perceived ethical acceptability of interactions; perceived marketing influence; perceived reliability of industry information; preparation for industry interactions; reactions to industry relations policy; and management of industry interactions. Non-physician clinicians reported interacting with the pharmaceutical and infant formula industries. Clinicians across disciplines met with pharmaceutical representatives regularly and relied on them for practice information. Clinicians frequently received industry "information," attended sponsored "education," and acted as distributors for similar materials targeted at patients. Clinicians generally regarded this as an ethical use of industry resources, and felt they could detect "promotion" while benefiting from industry "information. " Free samples were among the most approved and common ways that clinicians interacted with industry. Included studies were observational and of varying methodological rigor; thus, these findings may not be generalizable. This review is, however, the first to our knowledge to provide a descriptive analysis of this literature. CONCLUSIONS Non-physician clinicians' generally positive attitudes toward industry interactions, despite their recognition of issues related to bias, suggest that industry interactions are normalized in clinical practice across non-physician disciplines. Industry relations policy should address all disciplines and be implemented consistently in order to mitigate conflicts of interest and address such interactions' potential to affect patient care. Please see later in the article for the Editors' Summary. | Interactions between Non-Physician Clinicians and Industry: A Systematic Review |
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We evaluated drug concentrations among men who have sex with men in a substudy of the iPrEx trial (1). In this randomized placebo-controlled trial, daily oral doses of emtricitabine/tenofovir disoproxil fumarate were used as pre-exposure prophylaxis (PrEP) in men who have sex with men. Drug was detected less frequently in blood plasma and in viable cryopreserved peripheral blood mononuclear cells (PBMCs) in HIV-infected cases at the visit when HIV was first discovered compared with controls at the matched time point of the study (8% versus 44%; P < 0.001) and in the 90 days before that visit (11% versus 51%; P < 0.001). An intracellular concentration of the active form of tenofovir, tenofovir-diphosphate (TFV-DP), of 16 fmol per million PBMCs was associated with a 90% reduction in HIV acquisition relative to the placebo arm. Directly observed dosing in a separate study, the STRAND trial, yielded TFV-DP concentrations that, when analyzed according to the iPrEx model, corresponded to an HIV-1 risk reduction of 76% for two doses per week, 96% for four doses per week, and 99% for seven doses per week. Prophylactic benefits were observed over a range of doses and drug concentrations, suggesting ways to optimize PrEP regimens for this population. | Emtricitabine-tenofovir concentrations and pre-exposure prophylaxis efficacy in men who have sex with men. |
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"26591": 0.9886114001274109, "26708": 0.055094651877880096, "26835": 0.41840189695358276, "27144": 0.15442965924739838, "27159": 0.06520967930555344, "27177": 0.0058422754518687725, "27441": 0.1808556467294693, "27528": 0.02412080205976963, "27627": 0.06246116757392883, "27794": 0.8600510358810425, "27994": 0.1384023278951645, "28093": 0.15777134895324707, "28215": 0.48430517315864563, "28405": 0.07884006202220917, "28472": 0.058784693479537964, "28507": 0.14686977863311768, "28601": 0.052318159490823746, "28741": 0.009718249551951885, "28929": 0.36086538434028625, "29299": 0.45499902963638306, "29427": 0.7755908370018005} | 24088502 | CONTEXT A number of countries have implemented a policy of universal leukoreduction of their blood supply, but the potential role of leukoreduction in decreasing postoperative mortality and infection is unclear. OBJECTIVE To evaluate clinical outcomes following adoption of a national universal prestorage leukoreduction program for blood transfusions. DESIGN, SETTING, AND POPULATION Retrospective before-and-after cohort study conducted from August 1998 to August 2000 in 23 academic and community hospitals throughout Canada, enrolling 14 786 patients who received red blood cell transfusions following cardiac surgery or repair of hip fracture, or who required intensive care following a surgical intervention or multiple trauma. INTERVENTION Universal prestorage leukoreduction program introduced by 2 Canadian blood agencies. A total of 6982 patients were enrolled during the control period and 7804 patients were enrolled following prestorage leukoreduction. MAIN OUTCOME MEASURES All-cause in-hospital mortality and serious nosocomial infections (pneumonia, bacteremia, septic shock, all surgical site infections) occurring after first transfusion and at least 2 days after index procedure or intensive care unit admission. Secondary outcomes included rates of posttransfusion fever and antibiotic use. RESULTS Unadjusted in-hospital mortality rates were significantly lower following the introduction of leukoreduction compared with the control period (6.19% vs 7.03%, respectively; P =.04). Compared with the control period, the adjusted odds of death following leukoreduction were reduced (odds ratio [OR], 0.87; 95% confidence interval [CI], 0.75-0.99), but serious nosocomial infections did not decrease (adjusted OR, 0.97; 95% CI, 0.87-1.09). The frequency of posttransfusion fevers decreased significantly following leukoreduction (adjusted OR, 0.86; 95% CI, 0.79-0.94), as did antibiotic use (adjusted OR, 0.90; 95% CI, 0.82-0.99). CONCLUSION A national universal leukoreduction program is potentially associated with decreased mortality as well as decreased fever episodes and antibiotic use after red blood cell transfusion in high-risk patients. | Clinical outcomes following institution of the Canadian universal leukoreduction program for red blood cell transfusions. |
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0.06612417846918106, "28674": 1.072893738746643, "28689": 0.1693800985813141, "28696": 0.004870930220931768, "28715": 0.13670019805431366, "28804": 0.8004589080810547, "28879": 0.14686977863311768, "28940": 0.28890204429626465, "29090": 0.5495203733444214, "29125": 0.18573370575904846, "29166": 0.030771657824516296, "29543": 0.12038381397724152, "29596": 0.23710809648036957, "29598": 0.8169882297515869} | 24097933 | Paraquat poisoning is characterized by multiorgan failure and pulmonary fibrosis with respiratory failure. Multiorgan failure with circulatory collapse is a major cause of early death within 3 days of paraquat ingestion. Recent studies suggested that continuous venovenous hemofiltration (CVVH) had a role in the treatment of multiorgan failure by promoting hemodynamic stability. We therefore evaluated the effect of prophylactic CVVH in 80 patients with paraquat poisoning (August 1996 to February 1999). The amount ingested was 2.1 +/- 1.0 mouthfuls (as 20% concentrate). All patients were treated with hemoperfusion (HP; duration, 6.4 +/- 3.0 hours) within 24 hours of ingestion and then randomly assigned to the HP-alone or HP-CVVH group. Forty-four patients underwent HP only, and 36 patients underwent CVVH (duration, 57.4 +/- 31.3 hours; ultrafiltration volume, 40.2 +/- 4.8 L/d) after HP. Although time to death after ingestion was significantly longer in the HP-CVVH than HP group (5.0 +/- 5.0 versus 2.5 +/- 2.1 days; P < 0.05), there was no difference in mortality rates between the two groups (66.7% versus 63.6%; P = 0.82). In the HP group, early circulatory collapse was a major cause of death compared with the HP-CVVH group, in which late respiratory failure was a major cause of death. In conclusion, prophylactic CVVH after HP prevented early death caused by circulatory collapse and prolonged survival time. However, it could not prevent late death caused by respiratory failure and did not provide a survival benefit in acute paraquat poisoning. | Failure of continuous venovenous hemofiltration to prevent death in paraquat poisoning. |
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"28873": 0.083342544734478, "28965": 0.08603433519601822, "29226": 0.16359257698059082} | 24101431 | Type 1 diabetes mellitus (T1DM) is a chronic metabolic disease that results from cell-mediated autoimmune destruction of insulin-producing cells. In T1DM animal models, it has been shown that the systemic administration of multipotent mesenchymal stromal cells, also referred as to mesenchymal stem cells (MSCs), results in the regeneration of pancreatic islets. Mechanisms underlying this effect are still poorly understood. Our aims were to assess whether donor MSCs (a) differentiate into pancreatic β-cells and (b) modify systemic and pancreatic pathophysiologic markers of T1DM. After the intravenous administration of 5 × 10(5) syngeneic MSCs, we observed that mice with T1DM reverted their hyperglycemia and presented no donor-derived insulin-producing cells. In contrast, 7 and 65 days post-transplantation, MSCs were engrafted into secondary lymphoid organs. This correlated with a systemic and local reduction in the abundance of autoaggressive T cells together with an increase in regulatory T cells. Additionally, in the pancreas of mice with T1DM treated with MSCs, we observed a cytokine profile shift from proinflammatory to antinflammatory. MSC transplantation did not reduce pancreatic cell apoptosis but recovered local expression and increased the circulating levels of epidermal growth factor, a pancreatic trophic factor. Therefore, the antidiabetic effect of MSCs intravenously administered is unrelated to their transdifferentiation potential but to their capability to restore the balance between Th1 and Th2 immunological responses along with the modification of the pancreatic microenvironment. Our data should be taken into account when designing clinical trials aimed to evaluate MSC transplantation in patients with T1DM since the presence of endogenous precursors seems to be critical in order to restore glycemic control. | The antidiabetic effect of mesenchymal stem cells is unrelated to their transdifferentiation potential but to their capability to restore Th1/Th2 balance and to modify the pancreatic microenvironment. |
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"28024": 0.6451379656791687, "28156": 0.4356052577495575, "28691": 0.9379299283027649, "28848": 0.053244512528181076} | 24142891 | The signals and molecular mechanisms that regulate the replication of terminally differentiated beta cells are unknown. Here, we report the identification and characterization of transmembrane protein 27 (Tmem27, collectrin) in pancreatic beta cells. Expression of Tmem27 is reduced in Tcf1(-/-) mice and is increased in islets of mouse models with hypertrophy of the endocrine pancreas. Tmem27 forms dimers and its extracellular domain is glycosylated, cleaved and shed from the plasma membrane of beta cells. This cleavage process is beta cell specific and does not occur in other cell types. Overexpression of full-length Tmem27, but not the truncated or soluble protein, leads to increased thymidine incorporation, whereas silencing of Tmem27 using RNAi results in a reduction of cell replication. Furthermore, transgenic mice with increased expression of Tmem27 in pancreatic beta cells exhibit increased beta cell mass. Our results identify a pancreatic beta cell transmembrane protein that regulates cell growth of pancreatic islets. | Tmem27: a cleaved and shed plasma membrane protein that stimulates pancreatic beta cell proliferation. |
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"29533": 1.3133876323699951} | 24144677 | Homozygous mutation in the ATM gene causes ataxia telangiectasia and heterozygous mutation carriers may be at increased risk of breast cancer. We studied a total of 22 ATM variants; 18 variants were analyzed in one of two large population-based studies from the U.S. and Poland, and four variants were analyzed in all 2,856 breast cancer cases and 3,344 controls from the two studies. The missense mutation Ser49Cys (c.146C>G, p. S49C), carried by approximately 2% of subjects, was more common in cases than controls in both study populations, combined odds ratio (OR) 1.69 (95% CI, 1.19-2.40; P=0.004). Another missense mutation at approximately 2% frequency, Phe858Leu (c.2572T>C, p. F858L), was associated with a significant increased risk in the U.S. study but not in Poland, and had a combined OR of 1.44 (95% CI, 0.98-2.11; P=0.06). These analyses provide the most convincing evidence thus far that missense mutations in ATM, particularly p. S49C, may be breast cancer susceptibility alleles. Because of their low frequency, even larger sample sizes are required to more firmly establish these associations. | The ATM missense mutation p.Ser49Cys (c.146C>G) and the risk of breast cancer. |
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1.2829933166503906, "26535": 0.1873544454574585, "26743": 0.015504186972975731, "26786": 0.09761575609445572, "27011": 0.630689799785614, "27404": 0.30989447236061096, "27484": 0.8957691192626953, "27532": 0.33325836062431335, "28102": 0.06337817758321762, "28105": 0.6160298585891724, "28125": 0.022212404757738113, "28177": 0.040196798741817474, "28246": 0.1485546976327896, "28309": 0.09495500475168228, "28436": 0.22548456490039825, "28466": 0.12728634476661682, "28472": 0.0058422754518687725, "28685": 0.4196864068508148, "28742": 0.00875066313892603, "28756": 0.15943801403045654, "28767": 0.013579257763922215, "28828": 0.9425065517425537, "28868": 0.347847044467926, "29053": 0.0029254043474793434, "29212": 0.28155985474586487, "29295": 0.07884006202220917, "29398": 0.08961215615272522, "29458": 0.13157635927200317, "29477": 0.1221139207482338} | 24148722 | OBJECTIVE The aim of this study was to investigate the possible microstructural abnormalities of the corpus callosum (CC) in adult patients with migraine without aura complicated with depressive/anxious disorder. BACKGROUND Emotional disorders, especially depression and anxiety, are with relatively higher incidence in migraine population. However, the mechanism of migraine complicated with depressive/anxious disorder remains unclear. METHODS Diffusion tensor magnetic resonance imaging was carried out in 12 adult patients with simple migraine (without aura and without depressive/anxious disorder) (S-M group), 12 adult patients with complicated migraine (without aura but complicated with depressive/anxious disorder) (Co-M group), and 12 age- and sex-matched healthy subjects (Control group). Fractional anisotropy (FA) and apparent diffusion coefficient were measured at genu, body, and splenium of the CC, respectively. RESULTS There were significant differences in FA values at all locations of the CC among the 3 groups. The FA values from both the SM and Co-M groups were significantly lower than the control (P < .05 and P < .01, respectively). The FA values from Co-M group were significantly lower than the SM group (P < .01). The apparent diffusion coefficient values of the above regions had no significant differences among these groups (P > .05). There were negative correlations between FA value of genu of the CC and disease course as well as FA value of genu and body of the CC and headache frequency (P < .05). Negative correlations were also found between FA values at all locations of the CC and Hamilton anxiety and Hamilton depression scores (both P < .05). CONCLUSIONS There might be an integrity change of neurofibrotic microstructures existing as a possible neuroanatomical basis in the CC of migraine patients complicated with depressive/anxious disorder. | A diffusion tensor magnetic resonance imaging study of corpus callosum from adult patients with migraine complicated with depressive/anxious disorder. |
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0.2659635543823242, "25761": 0.08244366943836212, "26061": 0.1718502640724182, "26089": 0.19220098853111267, "26163": 0.7086513638496399, "26226": 0.33115679025650024, "26445": 0.09938567131757736, "26601": 0.16524957120418549, "26651": 0.25239890813827515, "26802": 0.14179791510105133, "26942": 0.5849615335464478, "27019": 0.0797421783208847, "27085": 0.03831886500120163, "27115": 0.10291612148284912, "27292": 0.05139094591140747, "27339": 0.3070250153541565, "27651": 0.17840765416622162, "27718": 0.2689530849456787, "27833": 0.3656192123889923, "27854": 0.05139094591140747, "28093": 0.06886265426874161, "28297": 0.06429435312747955, "28667": 0.5370414853096008, "28807": 0.11691460013389587, "29129": 0.25088030099868774, "29166": 0.19541899859905243, "29172": 0.13670019805431366, "29264": 0.6679295301437378, "29339": 0.06977381557226181, "29480": 0.2881702482700348, "29533": 0.15526613593101501} | 24150328 | BACKGROUND Patients with metabolic syndrome are at increased risk for cardiovascular complications. We sought to determine whether peroxisome proliferator-activated receptor gamma agonists had any beneficial effect on patients with metabolic syndrome undergoing percutaneous coronary intervention (PCI). METHODS A total of 200 patients with metabolic syndrome undergoing PCI were randomized to rosiglitazone or placebo and followed for 1 year. Carotid intima-medial thickness (CIMT), inflammatory markers, lipid levels, brain natriuretic peptide, and clinical events were measured at baseline, 6 months, and 12 months. RESULTS There was no significant difference in CIMT between the 2 groups. There was no difference in the 12-month composite end point of death, myocardial infarction (MI), stroke, or any recurrent ischemia (31.4% vs 30.2%, P = .99). The rate of death, MI, or stroke at 12 months was numerically lower in the rosiglitazone group (11.9% vs 6.4%, P = .19). There was a trend toward a greater decrease over time in high-sensitivity C-reactive protein values compared with baseline in the group randomized to rosiglitazone versus placebo both at 6 months (-35.4% vs -15.8%, P = .059) and 12 months (-40.0% vs -20.9%, P = .089) and higher change in high-density lipoprotein (+15.5% vs +4.1%, P = .05) and lower triglycerides (-13.9% vs +14.9%, P = .004) in the rosiglitazone arm. There was a trend toward less new onset diabetes in the rosiglitazone group (0% vs 3.3%, P = .081) and no episodes of symptomatic hypoglycemia. There was no excess of new onset of clinical heart failure in the rosiglitazone group, nor was there a significant change in brain natriuretic peptide levels. CONCLUSIONS Patients with metabolic syndrome presenting for PCI are at increased risk for subsequent cardiovascular events. Rosiglitazone for 12 months did not appear to affect CIMT in this population, although it did have beneficial effects on high-sensitivity C-reactive protein, high-density lipoprotein, and triglycerides. Further study of peroxisome proliferator-activated receptor agonism in patients with metabolic syndrome undergoing PCI may be warranted. | Peroxisome proliferator-activated receptor gamma agonists for the Prevention of Adverse events following percutaneous coronary Revascularization--results of the PPAR study. |
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0.7665573358535767, "28041": 0.1619328260421753, "28297": 0.5347557663917542, "28389": 0.30917787551879883, "28405": 0.20818853378295898, "28466": 0.4574742913246155, "28522": 0.3963087201118469, "29111": 0.7352184057235718, "29166": 0.9944084882736206, "29172": 0.14095009863376617, "29454": 0.1332872211933136, "29474": 0.7710843086242676, "29486": 0.6603899002075195, "29592": 0.12986256182193756, "29598": 0.13755162060260773} | 24155601 | To systematically review clinical and preclinical data on hydroxyethyl starch (HES) tissue storage. MEDLINE (PubMed) was searched and abstracts were screened using defined criteria to identify articles containing original data on HES tissue accumulation. Forty-eight studies were included: 37 human studies with a total of 635 patients and 11 animal studies. The most frequent indication for fluid infusion was surgery accounting for 282 patients (45.9 %). HES localization in skin was shown by 17 studies, in kidney by 12, in liver by 8, and in bone marrow by 5. Additional sites of HES deposition were lymph nodes, spleen, lung, pancreas, intestine, muscle, trophoblast, and placental stroma. Among major organs the highest measured tissue concentration of HES was in the kidney. HES uptake into intracellular vacuoles was observed by 30 min after infusion. Storage was cumulative, increasing in proportion to dose, although in 15 % of patients storage and associated symptoms were demonstrated at the lowest cumulative doses (0.4 g kg−1). Some HES deposits were extremely long-lasting, persisting for 8 years or more in skin and 10 years in kidney. Pruritus associated with HES storage was described in 17 studies and renal dysfunction in ten studies. In one included randomized trial, HES infusion produced osmotic nephrosis-like lesions indicative of HES storage (p = 0.01) and also increased the need for renal replacement therapy (odds ratio, 9.50; 95 % confidence interval, 1.09–82.7; p = 0.02). The tissue distribution of HES was generally similar in animals and humans. Tissue storage of HES is widespread, rapid, cumulative, frequently long-lasting, and potentially harmful. | Accumulation of hydroxyethyl starch in human and animal tissues: a systematic review |
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"25476": 0.29619070887565613, "25502": 0.23402166366577148, "25605": 1.1994705200195312, "25700": 0.3141832649707794, "26045": 0.4926934838294983, "26282": 0.27564704418182373, "26402": 0.2394166737794876, "26419": 0.06520967930555344, "26489": 0.21214580535888672, "26524": 0.48670899868011475, "26591": 0.6684301495552063, "26661": 0.11256109178066254, "26835": 0.7086513638496399, "27781": 0.3615458607673645, "27937": 0.014542185701429844, "28079": 0.5092619061470032, "28283": 0.35403475165367126, "28498": 0.24325250089168549, "28775": 0.022212404757738113, "28873": 0.34370049834251404, "28896": 0.07431721687316895, "29490": 0.08692999184131622} | 24157077 | Members of the cationic host defense (antimicrobial) peptide family are widely distributed in nature, existing in organisms from insects to plants to mammals and non-mammalian vertebrates. Although many demonstrate direct antimicrobial activity against bacteria, fungi, eukaryotic parasites and/or viruses, it has been established that cationic peptides have a key modulatory role in the innate immune response. More recent evidence suggests that host defense peptides are effective adjuvants, are synergistic with other immune effectors, polarize the adaptive response, and support wound healing. In addition, the mechanisms of action are being unraveled, which support more effective implementation of derivatives of these endogenous peptides as therapeutic agents. | Cationic host defense (antimicrobial) peptides. |
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0.35060185194015503, "26237": 0.11604541540145874, "26243": 0.037378571927547455, "26445": 0.013579257763922215, "26497": 0.4849066734313965, "26886": 0.1710275560617447, "27327": 0.5313173532485962, "27354": 0.09495500475168228, "27484": 0.27934664487838745, "27718": 0.5074998140335083, "27756": 0.07793712615966797, "28093": 0.3127557039260864, "28436": 0.06612417846918106, "28466": 0.8796916007995605, "28586": 0.28597161173820496, "28648": 0.24171993136405945, "28767": 0.006812678650021553, "28823": 0.02887592278420925, "29101": 0.11256109178066254, "29391": 0.28450319170951843, "29513": 0.15860503911972046} | 24159217 | CONTEXT No randomized controlled studies have been conducted to date on the effectiveness of psychological interventions for children with symptoms of posttraumatic stress disorder (PTSD) that has resulted from personally witnessing or being personally exposed to violence. OBJECTIVE To evaluate the effectiveness of a collaboratively designed school-based intervention for reducing children's symptoms of PTSD and depression that has resulted from exposure to violence. DESIGN A randomized controlled trial conducted during the 2001-2002 academic year. SETTING AND PARTICIPANTS Sixth-grade students at 2 large middle schools in Los Angeles who reported exposure to violence and had clinical levels of symptoms of PTSD. INTERVENTION Students were randomly assigned to a 10-session standardized cognitive-behavioral therapy (the Cognitive-Behavioral Intervention for Trauma in Schools) early intervention group (n = 61) or to a wait-list delayed intervention comparison group (n = 65) conducted by trained school mental health clinicians. MAIN OUTCOME MEASURES Students were assessed before the intervention and 3 months after the intervention on measures assessing child-reported symptoms of PTSD (Child PTSD Symptom Scale; range, 0-51 points) and depression (Child Depression Inventory; range, 0-52 points), parent-reported psychosocial dysfunction (Pediatric Symptom Checklist; range, 0-70 points), and teacher-reported classroom problems using the Teacher-Child Rating Scale (acting out, shyness/anxiousness, and learning problems; range of subscales, 6-30 points). RESULTS Compared with the wait-list delayed intervention group (no intervention), after 3 months of intervention students who were randomly assigned to the early intervention group had significantly lower scores on symptoms of PTSD (8.9 vs 15.5, adjusted mean difference, - 7.0; 95% confidence interval [CI], - 10.8 to - 3.2), depression (9.4 vs 12.7, adjusted mean difference, - 3.4; 95% CI, - 6.5 to - 0.4), and psychosocial dysfunction (12.5 vs 16.5, adjusted mean difference, - 6.4; 95% CI, -10.4 to -2.3). Adjusted mean differences between the 2 groups at 3 months did not show significant differences for teacher-reported classroom problems in acting out (-1.0; 95% CI, -2.5 to 0.5), shyness/anxiousness (0.1; 95% CI, -1.5 to 1.7), and learning (-1.1, 95% CI, -2.9 to 0.8). At 6 months, after both groups had received the intervention, the differences between the 2 groups were not significantly different for symptoms of PTSD and depression; showed similar ratings for psychosocial function; and teachers did not report significant differences in classroom behaviors. CONCLUSION A standardized 10-session cognitive-behavioral group intervention can significantly decrease symptoms of PTSD and depression in students who are exposed to violence and can be effectively delivered on school campuses by trained school-based mental health clinicians. | A mental health intervention for schoolchildren exposed to violence: a randomized controlled trial. |
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0.272677481174469, "26237": 0.45994341373443604, "26428": 0.09584271162748337, "26629": 0.1510767638683319, "26770": 0.045809537172317505, "27135": 0.3269403576850891, "27197": 0.861702561378479, "27204": 0.0038986403960734606, "27694": 0.9958525896072388, "27805": 0.27342069149017334, "27833": 1.1616848707199097, "27974": 0.22548456490039825, "28093": 0.23247487843036652, "28321": 0.2184450328350067, "28353": 0.20022670924663544, "28389": 0.04487626627087593, "29048": 0.7352184057235718, "29160": 0.33953672647476196, "29166": 0.27564704418182373, "29361": 0.23092569410800934, "29415": 0.21372433006763458} | 24163770 | BACKGROUND Although South Asians are at higher risk for coronary heart disease (CHD) than most other U.S. racial/ethnic groups, very little research has addressed this disparity. PURPOSE As a first step in developing culturally targeted CHD prevention messages for this rapidly growing community, this study examined South Asians' knowledge and beliefs about CHD. METHODS Analyses, conducted in 2009, were based on data collected from January to July 2008 in a cross-sectional study population of 270 South Asian adults in Illinois. Interviews were conducted in English, Hindi, or Urdu using a standardized questionnaire. Multivariate regression models were used to examine the associations between sociodemographics and CHD knowledge and attitudes about preventability. RESULTS Eighty-one percent of respondents had one or more CHD risk factors. Most participants (89%) said they knew little or nothing about CHD. Stress was the most frequently mentioned risk factor (44%). Few mentioned controlling blood pressure (11%); cholesterol (10%); and diabetes (5%) for prevention. Fifty-three percent said that heart attacks are not preventable. Low education level, being interviewed in Urdu or Hindi, and low level of acculturation were associated with less knowledge and believing that CHD is not preventable. CONCLUSIONS A majority of South Asians in this study believed that CHD is not preventable and had low awareness of modifiable risk factors. As a first step, CHD education should target the knowledge gaps that may affect risk factor control and behavior change. Educational messages may need to be somewhat different for subgroups (e.g., by education and language) to be maximally effective. | Knowledge gaps and misconceptions about coronary heart disease among U.S. South Asians. |
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Understanding such tight control of host defense requires the elucidation of the transcription factors involved. By using an unbiased approach in the model Caenorhabditis elegans, we discovered that HLH-30 (known as TFEB in mammals) is a key transcription factor for host defense. HLH-30 was activated shortly after Staphylococcus aureus infection, and drove the expression of close to 80% of the host response, including antimicrobial and autophagy genes that were essential for host tolerance of infection. TFEB was also rapidly activated in murine macrophages upon S. aureus infection and was required for proper transcriptional induction of several proinflammatory cytokines and chemokines. Thus, our data suggest that TFEB is a previously unappreciated, evolutionarily ancient transcription factor in the host response to infection. | Innate host defense requires TFEB-mediated transcription of cytoprotective and antimicrobial genes. |
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"24054": 0.7258110046386719, "24133": 0.012615402229130268, "24312": 0.09850110858678818, "25006": 0.13670019805431366, "25194": 0.25694093108177185, "25222": 0.8813109993934631, "25456": 0.5232481360435486, "25499": 0.0317181795835495, "25644": 0.1808556467294693, "25761": 0.21372433006763458, "26244": 0.8885661959648132, "26402": 0.9447870850563049, "26435": 0.04394211992621422, "26651": 0.10026945173740387, "26709": 0.28597161173820496, "26773": 0.5701626539230347, "26785": 0.9769153594970703, "27427": 0.07793712615966797, "27854": 0.15693697333335876, "29017": 0.0317181795835495, "29166": 0.28155985474586487, "29290": 0.4145384132862091} | 24185667 | The stress-activated kinase JNK mediates key cellular responses to oxidative stress. Here we show that DAP kinase (DAPk), a cell death promoting Ser/Thr protein kinase, plays a main role in oxidative stress-induced JNK signaling. We identify protein kinase D (PKD) as a novel substrate of DAPk and demonstrate that DAPk physically interacts with PKD in response to oxidative stress. We further show that DAPk activates PKD in cells and that induction of JNK phosphorylation by ectopically expressed DAPk can be attenuated by knocking down PKD expression or by inhibiting its catalytic activity. Moreover, knockdown of DAPk expression caused a marked reduction in JNK activation under oxidative stress, indicating that DAPk is indispensable for the activation of JNK signaling under these conditions. Finally, DAPk is shown to be required for cell death under oxidative stress in a process that displays the characteristics of caspase-independent necrotic cell death. Taken together, these findings establish a major role for DAPk and its specific interaction with PKD in regulating the JNK signaling network under oxidative stress. | DAP kinase regulates JNK signaling by binding and activating protein kinase D under oxidative stress |
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"25714": 0.6096806526184082, "25950": 1.0030416250228882, "26061": 0.010684899985790253, "26089": 0.02792670577764511, "26394": 0.040196798741817474, "26402": 0.3374483287334442, "26692": 0.02316705882549286, "26702": 0.13499516248703003, "26721": 0.7417513132095337, "27138": 0.026025565341114998, "27144": 0.19622190296649933, "27543": 0.02316705882549286, "27651": 0.18816383183002472, "28086": 0.11256109178066254, "28156": 0.3325583338737488, "28173": 0.11256109178066254, "28479": 0.12642613053321838, "28613": 0.7445381283760071, "28848": 0.7881022095680237, "29290": 0.18816383183002472, "29490": 0.151916041970253} | 24186125 | Quercetin may have the opposite effect, namely anti- as well as pro-oxidant. The aim of this study was to assess the results of quercetin anti- and/or pro-oxidant activity in the bone marrow and spleen cells of rats. The experimental rats were treated daily, with quercetin in a dose of 8 or 80mg/kg b.w. by gavage for 40 days. The intracellular redox state in cells were assessed by measuring the ferric ion reducing antioxidant power (FRAP) level and malonodialdehyde concentration. HO-1 mRNA expression was examined with real-time PCR. The extent of DNA damage was determined by the alkaline-labile comet assay. A potential pro-apoptotic quercetin action was determined using the FITC-Annexin V kit. The quercetin and isorhamnetin concentrations in serum were analyzed by HPLC-ECD. MDA concentration and FRAP values, were significantly decreased in the spleen and bone marrow cells of rats treated with quercetin, in a dose of 80mg/kg b.w. in comparison with the control rats; no significant changes were observed after quercetin was administered in a dose ten times as low. Treatment with quercetin dose-dependently upregulated the expression of HO-1 mRNA in the bone marrow cells. Quercetin administration to the rats did not induce either DNA damage or apoptosis in the examined cells. The results of our study prove that changes in the antioxidant state, caused by quercetin, do not lead to DNA damage or exert any pro-apoptotic activity in vivo. | The changes of antioxidant defense system caused by quercetin administration do not lead to DNA damage and apoptosis in the spleen and bone marrow cells of rats. |
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0.2231435477733612, "26976": 0.004870930220931768, "27144": 0.4512746334075928, "27363": 0.7408206462860107, "27391": 0.05694137513637543, "27496": 0.058784693479537964, "27502": 0.09584271162748337, "27709": 0.861702561378479, "27781": 0.7951818704605103, "27814": 0.010684899985790253, "28154": 0.823009729385376, "28518": 0.03266380727291107, "28667": 0.9724938273429871, "28731": 0.015504186972975731, "28835": 0.015504186972975731, "28873": 0.14349138736724854, "29206": 0.05786345899105072, "29458": 0.7426811456680298, "29490": 0.1913948506116867} | 24190159 | Mutations of the KRAS oncogene are predictive for resistance to treatment with antibodies against the epithelial growth factor receptor in patients with colorectal cancer. Overcoming this therapeutic dilemma could potentially be achieved by the introduction of drugs that inhibit signaling pathways that are activated by KRAS mutations. To identify comprehensively such signaling pathways, we profiled pretreatment biopsies and normal mucosa from 65 patients with locally advanced rectal cancer-30 of which carried mutated KRAS-using global gene expression microarrays. By comparing all tumor tissues exclusively to matched normal mucosa, we could improve assay sensitivity, and identified a total of 22,297 features that were differentially expressed (adjusted P-value <0.05) between normal mucosa and cancer, including several novel potential rectal cancer genes. We then used this comprehensive description of the rectal cancer transcriptome as the baseline for identifying KRAS-dependent alterations. The presence of activating KRAS mutations is significantly correlated to an upregulation of 13 genes (adjusted P-value <0.05), among them DUSP4, a MAP-kinase phosphatase, and SMYD3, a histone methyltransferase. Inhibition of the expression of both genes has previously been shown using the MEK1-inhibitor PD98059 and the antibacterial compound Novobiocin, respectively. These findings suggest a potential approach to overcome resistance to treatment with antibodies against the epithelial growth factor receptor in patients with KRAS-mutant rectal carcinomas. | Mutated KRAS results in overexpression of DUSP4, a MAP-kinase phosphatase, and SMYD3, a histone methyltransferase, in rectal carcinomas. |
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0.009718249551951885, "26402": 0.9131608605384827, "26520": 0.36900100111961365, "26642": 0.1011524572968483, "26745": 0.7473171949386597, "26805": 0.4196864068508148, "26986": 0.1485546976327896, "27354": 0.0058422754518687725, "27374": 0.29400965571403503, "27781": 0.0174254160374403, "27794": 0.7172679901123047, "27837": 0.1905880719423294, "27881": 0.0354953333735466, "27885": 0.6853039860725403, "28091": 0.9710156321525574, "28207": 0.026976587250828743, "28711": 1.4094613790512085, "28739": 0.817850649356842, "28775": 0.5701626539230347, "28848": 0.8666408061981201, "28873": 0.4196864068508148, "28976": 0.03360854089260101, "29206": 0.7333439588546753, "29290": 0.1994270235300064, "29295": 0.018384648486971855, "29392": 0.9178520441055298, "29477": 0.016465263441205025, "29490": 0.57457035779953, "29551": 0.29328158497810364} | 24205118 | OBJECTIVE To investigate the clinical significance of Bmi-1 expression as a prognostic marker for cervical cancer. Design. Retrospectively collected data from a population-based cohort. SETTING Jiangsu Province Hospital. Population. Eighty-eight women diagnosed with cervical carcinoma between 2000 and 2003. METHODS RT-PCR assay was performed to determine Bmi-1 mRNA expression in 18 cervical cancer and noncancerous tissue samples and immunohistochemistry to detect Bmi-1 protein expression in 88 cervical cancer samples. The correlation between Bmi-1 expression and clinicopathological factors was analyzed. Additionally, statistical analyses were applied to test for prognostic associations. RNA interference was used to downregulate Bmi-1 expression in a cervical cancer cell line (HeLa). In vitro cytotoxicity was measured by the methylthiazoletetrazolium and colony formation assays. Effects of Bmi-1 inhibition on in vivo growth of cancer cells was detected by the tumorigenicity assay. Cell cycle distribution and cell apoptosis were measured by flow cytometry. MAIN OUTCOME MEASURES The levels of Bmi-1 mRNA and protein expression in tissues were evaluated by RT-PCR and Western Blot assays. RESULTS The level of Bmi-1 mRNA expression in cervical cancer tissues was significantly higher than that in corresponding noncancerous tissues. High Bmi-1 expression was significantly correlated with poor tumor differentiation, advanced International Federation of Gynecology and Obstetrics stage and positive lymph node metastasis. Patients with high Bmi-1 expression showed shorter overall survival than those with low expression. Univariate and multivariate analyses showed that high Bmi-1 expression was an independent prognostic factor. CONCLUSIONS RNA interference-mediated Bmi-1 inhibition could inhibit in vitro and in vivo growth, enhance apoptosis and induce cell cycle arrest of cervical cancer cells. Bmi-1 might be an independent prognostic marker for cervical cancer patients. | Clinicopathological and prognostic significance of Bmi-1 expression in human cervical cancer. |
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"27165": 0.09317722171545029, "27211": 0.25088030099868774, "27572": 0.010684899985790253, "27896": 0.021256839856505394, "28139": 0.015504186972975731, "28413": 0.07793712615966797, "28507": 0.8065804839134216, "28648": 0.1485546976327896, "28804": 0.7333439588546753, "28965": 0.10993985831737518, "29110": 0.07431721687316895, "29160": 0.18411032855510712, "29290": 0.347847044467926, "29295": 0.3916989266872406, "29454": 0.2034190446138382, "29598": 0.7333439588546753} | 24211561 | We evaluated the effect of dexamethasone on vomiting after elective tonsillectomy in 133 healthy children aged 2-12 yr in a randomized, stratified, blocked, double-blind, placebo-controlled study. General anesthesia was induced by inhalation of N2O and halothane or intravenously (IV) with propofol. Anesthesia was maintained with N2O and halothane. Dexamethasone 150 micrograms/kg up to a maximum dose of 8 mg, or placebo, was administered IV before surgery. All patients received 1.5 mg/kg codeine intramuscularly (IM) intraoperatively. Perioperative IV fluids, management of emesis, postoperative pain and hospital discharge criteria were all standardized. The groups were similar with respect to number, age, weight, length of surgery, and estimated intraoperative blood loss. Dexamethasone reduced the overall incidence of vomiting from 72% (placebo) to 40% (P < 0.001). Vomiting, both in-hospital and postdischarge, was decreased by the prophylactic administration of dexamethasone. Each episode of in-hospital vomiting prolonged discharge by 13 +/- 2 min, mean +/- SD (P < 0.001). In conclusion, dexamethasone markedly decreased vomiting by healthy children after elective tonsillectomy in an ambulatory hospital setting. | Dexamethasone decreases vomiting by children after tonsillectomy. |
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"27709": 0.9842413663864136, "27781": 0.23864774405956268, "27895": 0.08064348995685577, "28691": 0.09495500475168228, "28848": 1.179255723953247, "28873": 0.20501139760017395, "28896": 0.17431432008743286, "29076": 1.0533316135406494, "29461": 0.31204116344451904} | 24221369 | The cytosolic helicase retinoic acid-inducible gene-I (RIG-I) initiates immune responses to most RNA viruses by detecting viral 5'-triphosphorylated RNA (pppRNA). Although endogenous mRNA is also 5'-triphosphorylated, backbone modifications and the 5'-ppp-linked methylguanosine ((m7)G) cap prevent immunorecognition. Here we show that the methylation status of endogenous capped mRNA at the 5'-terminal nucleotide (N1) was crucial to prevent RIG-I activation. Moreover, we identified a single conserved amino acid (H830) in the RIG-I RNA binding pocket as the mediator of steric exclusion of N1-2'O-methylated RNA. H830A alteration (RIG-I(H830A)) restored binding of N1-2'O-methylated pppRNA. Consequently, endogenous mRNA activated the RIG-I(H830A) mutant but not wild-type RIG-I. Similarly, knockdown of the endogenous N1-2'O-methyltransferase led to considerable RIG-I stimulation in the absence of exogenous stimuli. Studies involving yellow-fever-virus-encoded 2'O-methyltransferase and RIG-I(H830A) revealed that viruses exploit this mechanism to escape RIG-I. Our data reveal a new role for cap N1-2'O-methylation in RIG-I tolerance of self-RNA. | A Conserved Histidine in the RNA Sensor RIG-I Controls Immune Tolerance to N1-2'O-Methylated Self RNA. |
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0.03925827145576477, "26251": 0.07068414986133575, "26319": 0.17840765416622162, "26601": 0.619189441204071, "26892": 1.259437084197998, "27011": 0.11517547070980072, "27448": 0.09495500475168228, "27697": 0.08603433519601822, "27776": 0.043007105588912964, "27790": 0.2478361576795578, "28024": 0.6223390698432922, "28295": 0.5381823778152466, "28436": 0.19541899859905243, "28664": 0.020300358533859253, "28715": 0.5027855634689331, "28991": 0.07431721687316895, "29105": 0.00875066313892603, "29490": 0.058784693479537964} | 24234341 | UNLABELLED Illumina microarray is becoming a popular microarray platform. The BeadArray technology from Illumina makes its preprocessing and quality control different from other microarray technologies. Unfortunately, most other analyses have not taken advantage of the unique properties of the BeadArray system, and have just incorporated preprocessing methods originally designed for Affymetrix microarrays. lumi is a Bioconductor package especially designed to process the Illumina microarray data. It includes data input, quality control, variance stabilization, normalization and gene annotation portions. In specific, the lumi package includes a variance-stabilizing transformation (VST) algorithm that takes advantage of the technical replicates available on every Illumina microarray. Different normalization method options and multiple quality control plots are provided in the package. To better annotate the Illumina data, a vendor independent nucleotide universal identifier (nuID) was devised to identify the probes of Illumina microarray. The nuID annotation packages and output of lumi processed results can be easily integrated with other Bioconductor packages to construct a statistical data analysis pipeline for Illumina data. AVAILABILITY The lumi Bioconductor package, www.bioconductor.org | lumi: a pipeline for processing Illumina microarray. |
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"29206": 0.08782484382390976, "29458": 0.10906458646059036, "29467": 0.08513788133859634, "29533": 0.08692999184131622, "29537": 0.0317181795835495} | 24237492 | AIMS A recent genome-wide association study identified a haplotype block on chromosome 4q25 associated with atrial fibrillation (AF). We sought to replicate this association in four independent cohorts. METHODS AND RESULTS The Framingham Heart Study and Rotterdam Study are community-based longitudinal studies. The Vanderbilt AF Registry and German AF Network (AFNet) are case-control studies. Participants with AF (n = 3508) were more likely to be male and were older than referent participants (n = 12 173; Framingham 82 +/- 10 vs. 71 +/- 13 years; Rotterdam 73 +/- 8 vs. 69 +/- 9 years; Vanderbilt 54 +/- 14 vs. 57 +/- 14 years; AFNet 62 +/- 12 vs. 49 +/- 14 years). Single nucleotide polymorphism (SNP) rs2200733 was associated with AF in all four cohorts, with odds ratios (ORs) ranging from 1.37 in Rotterdam [95% confidence interval (CI) 1.18-1.59; P = 3.1 x 10(-5)] to 2.52 in AFNet (95% CI 2.22-2.8; P = 1.8 x 10(-49)). There also was a significant association between AF and rs10033464 in Framingham (OR 1.34; 95% CI 1.03-1.75; P = 0.031) and AFNet (OR 1.30; 95% CI 1.13-1.51; P = 0.0002), but not Vanderbilt (OR 1.16; 95% CI 0.86-1.56; P = 0.33). A meta-analysis of the current and prior AF studies revealed an OR of 1.90 (95% CI 1.60-2.26; P = 3.3 x 10(-13)) for rs2200733 and of 1.36 (95% CI 1.26-1.47; P = 6.7 x 10(-15)) for rs10033464. CONCLUSION The non-coding SNPs rs2200733 and rs10033464 are strongly associated with AF in four cohorts of European descent. These results confirm the significant relations between AF and intergenic variants on chromosome 4. | Large scale replication and meta-analysis of variants on chromosome 4q25 associated with atrial fibrillation. |
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1.1437997817993164, "26728": 0.1751343309879303, "26786": 0.015504186972975731, "26828": 0.41840189695358276, "27135": 0.18329764902591705, "27247": 0.0770333781838417, "27322": 0.056018441915512085, "27974": 0.3750596046447754, "28102": 0.7881022095680237, "28139": 0.0174254160374403, "28321": 0.23247487843036652, "28558": 0.02412080205976963, "28689": 0.0913962796330452, "28739": 0.9394577741622925, "28936": 0.004870930220931768, "29299": 0.9598589539527893, "29516": 1.4246132373809814} | 24241932 | OBJECTIVE To examine the effect of ethnicity on the relation between tuberculosis and deprivation. DESIGN Retrospective ecological study comparing incidence of tuberculosis in white and south Asian residents of the 39 electoral wards in Birmingham with ethnic specific indices of deprivation. SETTING Birmingham, 1989-93. SUBJECTS 1516 notified cases of tuberculosis. MAIN OUTCOME MEASURES Rates of tuberculosis and measures of deprivation. RESULTS Univariate analysis showed significant associations of tuberculosis rates for the whole population with several indices of deprivation (P<0.01) and with the proportion of the population of south Asian origin (P<0.01). All deprivation covariates were positively associated with each other but on multiple regression, higher level of overcrowding was independently associated with tuberculosis rates. For the white population, overcrowding was associated with tuberculosis rates independently of other variables (P=0.0036). No relation with deprivation was found for the south Asian population in either single or multivariable analyses. CONCLUSIONS Poverty is significantly associated with tuberculosis in the white population, but no such relation exists for those of Asian ethnicity. These findings suggest that causal factors, and therefore potential interventions, will also differ by ethnic group. | Ecological analysis of ethnic differences in relation between tuberculosis and poverty. |
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"26305": 0.015504186972975731, "26402": 0.2223619967699051, "26499": 0.27564704418182373, "26512": 0.8989537954330444, "26534": 0.06337817758321762, "26914": 0.25088030099868774, "26986": 0.03266380727291107, "27011": 0.1751343309879303, "27216": 0.2954642176628113, "27854": 0.1477125883102417, "27881": 0.08603433519601822, "28207": 0.15359249711036682, "28297": 0.37102460861206055, "28507": 0.20977331697940826, "28517": 0.06703783571720123, "28667": 0.659380316734314, "28808": 1.0001721382141113, "28873": 0.255429208278656, "29206": 0.17267228662967682, "29264": 0.1358480453491211, "29486": 0.49626702070236206, "29598": 0.7491656541824341, "29720": 0.05139094591140747} | 24249915 | To gain insights into the possible role of oestrogen receptor (ER) beta in breast carcinogenesis, immunohistochemical analysis of ER beta was performed on 512 breast specimens encompassing normal (n = 138), pure ductal carcinoma in situ (n = 16), invasive cancers (n = 319), lymph node metastases (n = 31), and recurrences (n = 8). Real-time polymerase chain reaction (PCR) was used to investigate the methylation status of the ER beta gene in the ER beta negative breast cancer cell lines SkBr3 and MDA-MB-435. A gradual reduction in, but not a complete loss of, ER beta expression was observed during the transition from normal and pre-invasive lesions to invasive cancers, where ER beta was lost in 21% of cases. This was more pronounced in invasive ductal than in lobular carcinomas, a significantly higher proportion of which were ER beta-positive (74% compared with 91%, respectively, p = 0.0004). Examination of paired primary cancers with their axillary lymph node metastases showed that if ER beta was present in the primary tumour, it persisted in the metastasis. Treatment of ER beta-negative cell lines with DNA methyl transferase inhibitors restored ER beta expression, providing experimental evidence that silencing of ER beta in breast carcinomas could be due to promoter hypermethylation. These results suggest that loss of ER beta expression is one of the hallmarks of breast carcinogenesis and that it may be a reversible process involving methylation. | Reduced expression of oestrogen receptor beta in invasive breast cancer and its re-expression using DNA methyl transferase inhibitors in a cell line model. |
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"28805": 0.02792670577764511, "28815": 0.04207121208310127, "28873": 0.17922431230545044, "28896": 0.14264501631259918, "29101": 0.7086513638496399, "29158": 0.24171993136405945, "29167": 0.23092569410800934, "29361": 0.12642613053321838, "29486": 0.5795059204101562} | 24269361 | There are two main families of polyunsaturated fatty acids (PUFAs), the n-6 and the n-3 families. It has been suggested that there is a causal relationship between n-6 PUFA intake and allergic disease, and there are biologically plausible mechanisms, involving eicosanoid mediators of the n-6 PUFA arachidonic acid, that could explain this. Fish and fish oils are sources of long-chain n-3 PUFAs and these fatty acids act to oppose the actions of n-6 PUFAs. Thus, it is considered that n-3 PUFAs will protect against atopic sensitization and against the clinical manifestations of atopy. Evidence to examine this has been acquired from epidemiologic studies investigating associations between fish intake in pregnancy, lactation, infancy, and childhood, and atopic outcomes in infants and children and from intervention studies with fish oil supplements in pregnancy, lactation, infancy, and childhood, and atopic outcomes in infants and children. All five epidemiological studies investigating the effect of maternal fish intake during pregnancy on atopic or allergic outcomes in infants/children of those pregnancies concluded protective associations. One study investigating the effects of maternal fish intake during lactation did not observe any significant associations. The evidence from epidemiological studies investigating the effects of fish intake during infancy and childhood on atopic outcomes in those infants or children is inconsistent, although the majority of the studies (nine of 14) showed a protective effect of fish intake during infancy or childhood on atopic outcomes in those infants/children. Fish oil supplementation during pregnancy and lactation or during infancy or childhood results in a higher n-3 PUFA status in the infants or children. Fish oil provision to pregnant women is associated with immunologic changes in cord blood and such changes may persist. Studies performed to date indicate that provision of fish oil during pregnancy may reduce sensitization to common food allergens and reduce prevalence and severity of atopic dermatitis in the first year of life, with a possible persistence until adolescence with a reduction in eczema, hay fever, and asthma. Fish oil provision to infants or children may be associated with immunologic changes in the blood but it is not clear if these are of clinical significance and whether they persist. Fish oil supplementation in infancy may decrease the risk of developing some manifestations of allergic disease, but this benefit may not persist as other factors come into play. It is not clear whether fish oil can be used to treat children with asthma as the two studies conducted to date give divergent results. Further studies of increased long-chain n-3 PUFA provision in during pregnancy, lactation, and infancy are needed to more clearly identify the immunologic and clinical effects in infants and children and to identify protective and therapeutic effects and their persistence. | Atopy risk in infants and children in relation to early exposure to fish, oily fish, or long-chain omega-3 fatty acids: a systematic review. |
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0.7134475708007812, "25860": 0.2478361576795578, "26163": 0.30989447236061096, "26237": 0.9857001900672913, "26319": 0.08244366943836212, "26640": 0.16359257698059082, "26780": 0.4537591338157654, "27108": 0.6123310327529907, "27196": 0.27342069149017334, "27400": 0.04953393340110779, "27622": 0.5307431221008301, "27776": 0.052318159490823746, "27841": 0.011650617234408855, "27974": 0.16607704758644104, "28268": 0.43623676896095276, "28483": 0.08603433519601822, "29050": 0.16524957120418549} | 24273592 | BACKGROUND Healthy dietary patterns are a global priority to reduce non-communicable diseases. Yet neither worldwide patterns of diets nor their trends with time are well established. We aimed to characterise global changes (or trends) in dietary patterns nationally and regionally and to assess heterogeneity by age, sex, national income, and type of dietary pattern. METHODS In this systematic assessment, we evaluated global consumption of key dietary items (foods and nutrients) by region, nation, age, and sex in 1990 and 2010. Consumption data were evaluated from 325 surveys (71·7% nationally representative) covering 88·7% of the global adult population. Two types of dietary pattern were assessed: one reflecting greater consumption of ten healthy dietary items and the other based on lesser consumption of seven unhealthy dietary items. The mean intakes of each dietary factor were divided into quintiles, and each quintile was assigned an ordinal score, with higher scores being equivalent to healthier diets (range 0-100). The dietary patterns were assessed by hierarchical linear regression including country, age, sex, national income, and time as exploratory variables. FINDINGS From 1990 to 2010, diets based on healthy items improved globally (by 2·2 points, 95% uncertainty interval (UI) 0·9 to 3·5), whereas diets based on unhealthy items worsened (-2·5, -3·3 to -1·7). In 2010, the global mean scores were 44·0 (SD 10·5) for the healthy pattern and 52·1 (18·6) for the unhealthy pattern, with weak intercorrelation (r=-0·08) between countries. On average, better diets were seen in older adults compared with younger adults, and in women compared with men (p<0·0001 each). Compared with low-income nations, high-income nations had better diets based on healthy items (+2·5 points, 95% UI 0·3 to 4·1), but substantially poorer diets based on unhealthy items (-33·0, -37·8 to -28·3). Diets and their trends were very heterogeneous across the world regions. For example, both types of dietary patterns improved in high-income countries, but worsened in some low-income countries in Africa and Asia. Middle-income countries showed the largest improvement in dietary patterns based on healthy items, but the largest deterioration in dietary patterns based on unhealthy items. INTERPRETATION Consumption of healthy items improved, while consumption of unhealthy items worsened across the world, with heterogeneity across regions and countries. These global data provide the best estimates to date of nutrition transitions across the world and inform policies and priorities for reducing the health and economic burdens of poor diet quality. FUNDING The Bill & Melinda Gates Foundation and Medical Research Council. | Dietary quality among men and women in 187 countries in 1990 and 2010: a systematic assessment |
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"26319": 0.27934664487838745, "26462": 0.6931471824645996, "26629": 0.034552380442619324, "26718": 0.23710809648036957, "26745": 0.4818955361843109, "26786": 0.820433497428894, "26876": 0.009718249551951885, "26906": 0.15023678541183472, "27354": 0.036437395960092545, "27484": 1.1695996522903442, "27718": 0.3141832649707794, "27756": 0.20660123229026794, "27788": 0.4770587682723999, "27805": 0.22157983481884003, "28024": 0.1685553640127182, "28093": 0.22782009840011597, "28173": 0.5947071313858032, "28297": 0.22392450273036957, "28321": 0.14095009863376617, "28466": 0.32058215141296387, "28744": 1.0144377946853638, "28767": 0.2607102394104004, "29100": 0.04113444685935974, "29310": 0.09228714555501938, "29398": 0.6212902665138245} | 24276304 | CONTEXT Uncertainties exist about prevalence and correlates of major depressive disorder (MDD). OBJECTIVE To present nationally representative data on prevalence and correlates of MDD by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, and on study patterns and correlates of treatment and treatment adequacy from the recently completed National Comorbidity Survey Replication (NCS-R). DESIGN Face-to-face household survey conducted from February 2001 to December 2002. SETTING The 48 contiguous United States. PARTICIPANTS Household residents ages 18 years or older (N = 9090) who responded to the NCS-R survey. MAIN OUTCOME MEASURES Prevalence and correlates of MDD using the World Health Organization's (WHO) Composite International Diagnostic Interview (CIDI), 12-month severity with the Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR), the Sheehan Disability Scale (SDS), and the WHO disability assessment scale (WHO-DAS). Clinical reinterviews used the Structured Clinical Interview for DSM-IV. RESULTS The prevalence of CIDI MDD for lifetime was 16.2% (95% confidence interval [CI], 15.1-17.3) (32.6-35.1 million US adults) and for 12-month was 6.6% (95% CI, 5.9-7.3) (13.1-14.2 million US adults). Virtually all CIDI 12-month cases were independently classified as clinically significant using the QIDS-SR, with 10.4% mild, 38.6% moderate, 38.0% severe, and 12.9% very severe. Mean episode duration was 16 weeks (95% CI, 15.1-17.3). Role impairment as measured by SDS was substantial as indicated by 59.3% of 12-month cases with severe or very severe role impairment. Most lifetime (72.1%) and 12-month (78.5%) cases had comorbid CIDI/DSM-IV disorders, with MDD only rarely primary. Although 51.6% (95% CI, 46.1-57.2) of 12-month cases received health care treatment for MDD, treatment was adequate in only 41.9% (95% CI, 35.9-47.9) of these cases, resulting in 21.7% (95% CI, 18.1-25.2) of 12-month MDD being adequately treated. Sociodemographic correlates of treatment were far less numerous than those of prevalence. CONCLUSIONS Major depressive disorder is a common disorder, widely distributed in the population, and usually associated with substantial symptom severity and role impairment. While the recent increase in treatment is encouraging, inadequate treatment is a serious concern. Emphasis on screening and expansion of treatment needs to be accompanied by a parallel emphasis on treatment quality improvement. | The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). |
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0.034552380442619324, "27641": 0.025073638185858727, "28093": 0.26446542143821716, "28436": 0.18167030811309814, "28648": 0.04394211992621422, "28664": 0.12470348179340363, "28667": 0.0009760859538801014, "28723": 0.08244366943836212, "29234": 0.043007105588912964, "29235": 0.06429435312747955, "29477": 0.03360854089260101, "29576": 0.18167030811309814} | 24276902 | Previous studies with undergraduates have provided support for the reliability and oblique three-factor structure of a new scale, the Pain Catastrophizing Scale (PCS). We examined the reliability and validity of the PCS in adult community and pain outpatient samples. The PCS showed a high internal consistency in both groups. Using data from the community sample, confirmatory factor analyses showed that the PCS taps a single construct characterized by three related dimensions. Gender differences were obtained on the PCS total score in the community and the outpatient samples. The analyses also showed significant differences between the community and the outpatient samples on the PCS total and subscales. Overall, the results showed strong evidence of criterion-related, concurrent, and discriminant validity for the PCS in the community sample. Limitations of the present study are discussed. | The Pain Catastrophizing Scale: Further Psychometric Evaluation with Adult Samples |
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"25456": 0.6941232681274414, "25468": 0.0842406153678894, "25604": 0.5278670787811279, "25643": 0.8764448165893555, "25708": 0.052318159490823746, "25714": 0.09228714555501938, "26163": 0.37304413318634033, "26187": 0.4926934838294983, "26402": 0.3897167444229126, "26462": 0.13670019805431366, "26524": 0.5767669677734375, "26721": 0.637939989566803, "26745": 0.6664261221885681, "26906": 0.020300358533859253, "27144": 0.3519764244556427, "27204": 0.10467668622732162, "27528": 0.13670019805431366, "28139": 0.05970508232712746, "28225": 0.14939609169960022, "28774": 0.06795065850019455, "28817": 0.06612417846918106} | 24278870 | BACKGROUND Interferon alfa is widely used for metastatic renal-cell carcinoma but has limited efficacy and tolerability. Temsirolimus, a specific inhibitor of the mammalian target of rapamycin kinase, may benefit patients with this disease. METHODS In this multicenter, phase 3 trial, we randomly assigned 626 patients with previously untreated, poor-prognosis metastatic renal-cell carcinoma to receive 25 mg of intravenous temsirolimus weekly, 3 million U of interferon alfa (with an increase to 18 million U) subcutaneously three times weekly, or combination therapy with 15 mg of temsirolimus weekly plus 6 million U of interferon alfa three times weekly. The primary end point was overall survival in comparisons of the temsirolimus group and the combination-therapy group with the interferon group. RESULTS Patients who received temsirolimus alone had longer overall survival (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.58 to 0.92; P=0.008) and progression-free survival (P<0.001) than did patients who received interferon alone. Overall survival in the combination-therapy group did not differ significantly from that in the interferon group (hazard ratio, 0.96; 95% CI, 0.76 to 1.20; P=0.70). Median overall survival times in the interferon group, the temsirolimus group, and the combination-therapy group were 7.3, 10.9, and 8.4 months, respectively. Rash, peripheral edema, hyperglycemia, and hyperlipidemia were more common in the temsirolimus group, whereas asthenia was more common in the interferon group. There were fewer patients with serious adverse events in the temsirolimus group than in the interferon group (P=0.02). CONCLUSIONS As compared with interferon alfa, temsirolimus improved overall survival among patients with metastatic renal-cell carcinoma and a poor prognosis. The addition of temsirolimus to interferon did not improve survival. (ClinicalTrials.gov number, NCT00065468 [ClinicalTrials.gov].). | Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. |
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"26402": 0.24554696679115295, "26512": 0.304147332906723, "26520": 0.053244512528181076, "26616": 0.6980181336402893, "26632": 1.5348490476608276, "26702": 1.005902886390686, "26982": 0.11081436276435852, "27099": 0.26820653676986694, "27144": 0.5903874635696411, "27295": 0.45870962738990784, "27321": 0.4938860833644867, "27673": 0.47584590315818787, "27777": 0.4132472574710846, "27881": 0.9340999722480774, "28031": 0.26296505331993103, "28207": 0.7201237678527832, "28465": 0.1751343309879303, "28636": 0.1685553640127182, "28788": 0.39762192964553833, "29290": 0.23402166366577148} | 24282306 | There is persuasive clinical and experimental evidence that macrophages promote cancer initiation and malignant progression. During tumor initiation, they create an inflammatory environment that is mutagenic and promotes growth. As tumors progress to malignancy, macrophages stimulate angiogenesis, enhance tumor cell migration and invasion, and suppress antitumor immunity. At metastatic sites, macrophages prepare the target tissue for arrival of tumor cells, and then a different subpopulation of macrophages promotes tumor cell extravasation, survival, and subsequent growth. Specialized subpopulations of macrophages may represent important new therapeutic targets. | Macrophage Diversity Enhances Tumor Progression and Metastasis |
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0.38041436672210693, "26497": 0.9531047344207764, "26535": 0.07341018319129944, "26563": 0.823009729385376, "26745": 0.02316705882549286, "26837": 0.19622190296649933, "26906": 0.08244366943836212, "27011": 0.15442965924739838, "27029": 0.02316705882549286, "27196": 0.3824150264263153, "27354": 0.05786345899105072, "27641": 0.0038986403960734606, "27794": 1.059443712234497, "28093": 0.0752234235405922, "28329": 0.21372433006763458, "28436": 0.014542185701429844, "28466": 0.24018502235412598, "28767": 1.200646996498108, "28774": 0.5860490798950195, "28915": 0.603290855884552, "29166": 0.9739698171615601, "29299": 0.8264343738555908, "29458": 0.8281423449516296, "29516": 0.1485546976327896} | 24285403 | OBJECTIVES To determine whether the ankle brachial index (ABI, a marker of generalized atherosclerosis) is associated with cognitive impairment after 10 years in older people. DESIGN Cohort study (Edinburgh Artery Study). SETTING Eleven general practices in Edinburgh, Scotland. PARTICIPANTS Seven hundred seventeen men and women aged 55 to 74 from the general population, followed for 10 years. MEASUREMENTS ABI measured at baseline and major cognitive functions (including premorbid function using the National Adult Reading Test, NART) tested after 10 years. RESULTS After adjustment for age and sex, a low ABI was associated with lower scoring (bottom tertile vs top tertile) on Raven's Matrices (odds ratio (OR)=1.6, 95% confidence interval (CI) =1.0-2.6), Verbal Fluency (OR =1.8, 95% CI =1.1-3.0), and Digit Symbol Test (OR =2.3, 95% CI =1.3-4.2), suggesting that the ABI is predictive of poorer performance in nonverbal reasoning, verbal fluency, and information processing speed. The association between ABI and the Digit Symbol Test remained significant after further adjustment for premorbid cognitive function (tested using the NART), suggesting that the ABI is also predictive of decline in information processing speed (from premorbid ability to that measured here in older age). CONCLUSION The ABI may be useful in identifying older individuals at higher risk of cognitive impairment. In the future, preventive measures developed to target individuals with a low ABI should consider measures to reduce vascular-related cognitive decline as well as cardiovascular events, in an effort to reduce the incidence and consequences of subsequent cognitive impairment and dementia. | Ankle brachial index as a predictor of cognitive impairment in the general population: ten-year follow-up of the Edinburgh Artery Study. |
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heavily mutated in cancer. Class I PI3Ks synthesize the lipid messenger PI(3,4,5)P3. PI(3,4,5)P3 can be dephosphorylated by 3- or 5-phosphatases, the latter producing PI(3,4)P2. The PTEN tumor suppressor is thought to function primarily as a PI(3,4,5)P3 3-phosphatase, limiting activation of this pathway. Here we show that PTEN also functions as a PI(3,4)P2 3-phosphatase, both in vitro and in vivo. PTEN is a major PI(3,4)P2 phosphatase in Mcf10a cytosol, and loss of PTEN and INPP4B, a known PI(3,4)P2 4-phosphatase, leads to synergistic accumulation of PI(3,4)P2, which correlated with increased invadopodia in epidermal growth factor (EGF)-stimulated cells. PTEN deletion increased PI(3,4)P2 levels in a mouse model of prostate cancer, and it inversely correlated with PI(3,4)P2 levels across several EGF-stimulated prostate and breast cancer lines. These results point to a role for PI(3,4)P2 in the phenotype caused by loss-of-function mutations or deletions in PTEN. | PTEN Regulates PI(3,4)P2 Signaling Downstream of Class I PI3K |
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function as origins of DNA replication in yeast. We report the first fine-structure analysis of ars1, an ARS element of the fission yeast Schizosaccharomyces pombe. Characterization of a series of nested deletion mutations indicated that the minimal fragment of DNA encompassing ars1 is surprisingly large. No fragment < 650 bp retained significant ARS activity. Analysis of deletion and substitution mutations scanning the entire minimal ars1 identified a single essential 50 bp fragment (segment 1). Only one other 50 bp mutation reduced activity as much as 5-fold and most deletions were without effect. Thus, the minimal ars1 is composed of two general types of genetic elements, a small segment that is absolutely required for efficient ARS activity and a much larger region that is tolerant of internal structural alterations. Higher resolution analysis of segment 1 defined a critical 30 bp A/T-rich segment which appears to contain redundant genetic elements. Schizosaccharomyces pombe ars1 promoted high frequency transformation in the budding yeast S.cerevisiae but this heterologous activity was not dependent on segment 1. Our analysis indicates that the functional elements required for ARS function in S.pombe and S.cerevisiae are clearly different. | Genetic analysis of an ARS element from the fission yeast Schizosaccharomyces pombe. |
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0.28082266449928284, "22953": 0.9591107368469238, "23767": 0.4041621685028076, "23797": 0.11343330889940262, "23892": 0.3897167444229126, "23936": 0.20739519596099854, "24054": 0.13925230503082275, "24184": 0.036437395960092545, "24269": 0.19220098853111267, "24312": 1.2375813722610474, "25172": 0.4974553883075714, "25339": 0.04394211992621422, "25430": 1.2238903045654297, "25644": 0.0842406153678894, "25714": 0.9209672808647156, "25835": 0.025073638185858727, "26236": 0.04207121208310127, "26244": 0.5197699069976807, "26261": 0.25694093108177185, "26402": 0.28082266449928284, "26520": 0.034552380442619324, "26601": 0.07431721687316895, "26773": 0.44691193103790283, "26874": 0.11081436276435852, "27211": 1.158010721206665, "27321": 0.22859740257263184, "27642": 0.5629584193229675, "27854": 0.14686977863311768, "28247": 0.7333439588546753, "28691": 0.1212492436170578, "29297": 1.0506030321121216} | 24311787 | Variant histone H2AZ-containing nucleosomes are involved in the regulation of gene expression. In Saccharomyces cerevisiae, chromatin deposition of histone H2AZ is mediated by the fourteen-subunit SWR1 complex, which catalyzes ATP-dependent exchange of nucleosomal histone H2A for H2AZ. Previous work defined the role of seven SWR1 subunits (Swr1 ATPase, Swc2, Swc3, Arp6, Swc5, Yaf9, and Swc6) in maintaining complex integrity and H2AZ histone replacement activity. Here we examined the function of three additional SWR1 subunits, bromodomain containing Bdf1, actin-related protein Arp4 and Swc7, by analyzing affinity-purified mutant SWR1 complexes. We observed that depletion of Arp4 (arp4-td) substantially impaired the association of Bdf1, Yaf9, and Swc4. In contrast, loss of either Bdf1 or Swc7 had minimal effects on overall complex integrity. Furthermore, the basic H2AZ histone replacement activity of SWR1 in vitro required Arp4, but not Bdf1 or Swc7. Thus, three out of fourteen SWR1 subunits, Bdf1, Swc7, and previously noted Swc3, appear to have roles auxiliary to the basic histone replacement activity. The N-terminal region of the Swr1 ATPase subunit is necessary and sufficient to direct association of Bdf1 and Swc7, as well as Arp4, Act1, Yaf9 and Swc4. This same region contains an additional H2AZ-H2B specific binding site, distinct from the previously identified Swc2 subunit. These findings suggest that one SWR1 enzyme might be capable of binding two H2AZ-H2B dimers, and provide further insight on the hierarchy and interdependency of molecular interactions within the SWR1 complex. | N terminus of Swr1 binds to histone H2AZ and provides a platform for subunit assembly in the chromatin remodeling complex. |
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phagocytosis by different subsets of leukocytes. Recently, a large number of regulatory elements and structural constituents of the leukocyte cytoskeleton have been identified. In this review, we discuss the composition and regulation of the different cytoskeletal elements and their role in immune responses. | Role of the cytoskeleton during leukocyte responses |
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While this has led to renewed interest in this potential method of mental health service delivery, it has also prompted criticism. Some concerns raised are that it would contribute to the medicalization of social and psychological problems, and narrowly focus on primary care without sufficient attention given to strengthening other levels of the healthcare system, notably community-based care and care on district levels. This paper discusses seven elements that may be critical to preventing inadvertently contributing to increasing a narrow biomedical approach to mental healthcare when integrating mental health into non-specialized healthcare: (1) using task shifting approaches within a system of stepped care, (2) ensuring primary mental healthcare also includes brief psychotherapeutic interventions, (3) promote community-based recovery-oriented interventions for people with disabling chronic mental disorders, (4) conceptualizing training as a continuous process of strengthening clinical competencies through supervision, (5) engaging communities as partners in psychosocial interventions, (6) embedding shifts to primary mental healthcare within wider health policy reforms, and (7) promoting inter-sectoral approaches to address social determinants of mental health. | Integration of mental health into primary healthcare in low-income countries: avoiding medicalization. |
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0.018384648486971855, "23760": 0.42353010177612305, "23900": 0.15860503911972046, "24226": 0.083342544734478, "24718": 0.17431432008743286, "25003": 0.05139094591140747, "25022": 0.472198486328125, "25025": 0.28082266449928284, "25032": 0.9333322048187256, "25714": 0.26446542143821716, "25855": 0.8143964409828186, "25937": 0.09406650811433792, "26189": 0.3262358605861664, "26402": 0.04860413447022438, "26572": 0.969535231590271, "26651": 0.41065993905067444, "27019": 0.0842406153678894, "27144": 0.08871890604496002, "27841": 0.10555581003427505, "29021": 0.4926934838294983, "29290": 0.678390383720398, "29458": 0.5174443125724792} | 24323369 | OBJECTIVE To determine which first-line medication is more effective in polycystic ovary syndrome (PCOS) patients for ovulation induction and pregnancy achievement and to verify whether any patient characteristic is associated with a better response to therapy. DESIGN Observational comparative study. SETTING Fertility clinic. PATIENT(S) One hundred fifty-four infertile women with oligomenorrhea and hyperandrogenism. INTERVENTION(S) Group 1 (56 patients) received clomiphene citrate (CC) 50 mg from days 5-9 of the cycle. Group 2 (57 patients) received 500 mg of metformin 3 times a day. Group 3 (41 patients) received both medications. MAIN OUTCOME MEASURE(S) Ovulation and pregnancy. RESULT(S) Patients receiving metformin alone had an increased ovulation rate compared with those receiving CC alone (75.4% vs. 50%). Patients on metformin had similar ovulation rates compared with those in the combination group (75.4% vs. 63.4%). Pregnancy rates were equivalent in the 3 groups. Response to metformin was independent of body weight and dose. Finally, nonsmoking predicted better ovulatory response overall as well as lower fasting glucose for CC and lower androgens for metformin. CONCLUSION(S) Metformin is better for ovulation induction than CC alone and equivalent for pregnancy achievement. We suggest that metformin can be used first for ovulation induction in patients with PCOS regardless of their weight and insulin levels because of its efficacy and known safety profile. | Comparison of clomiphene citrate, metformin, or the combination of both for first-line ovulation induction and achievement of pregnancy in 154 women with polycystic ovary syndrome. |
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0.05786345899105072, "27531": 0.00875066313892603, "27615": 0.8691008687019348, "27776": 0.7791815400123596, "27794": 0.8715548515319824, "27881": 0.03266380727291107, "27885": 0.5887627601623535, "28027": 0.22704219818115234, "28207": 0.07068414986133575, "28258": 0.07159364968538284, "28436": 0.1751343309879303, "28472": 0.03360854089260101, "28739": 0.16110190749168396, "28879": 0.12642613053321838, "29025": 0.040196798741817474, "29139": 0.03266380727291107, "29172": 0.026976587250828743, "29191": 0.34508460760116577, "29458": 0.13499516248703003} | 24323695 | RATIONALE Up to 80% of patients with lung cancer have comorbid chronic obstructive pulmonary disease (COPD). Many of them are poor candidates for stage-specific lung cancer treatment due to diminished lung function and poor functional status, and many forego treatment. The negative effect of COPD may be moderated by pulmonologist-guided management. OBJECTIVES This study examined the association between pulmonologist management and the probability of receiving the recommended stage-specific treatment modality and overall survival among patients with non-small cell lung cancer (NSCLC) with preexisting COPD. METHODS Early- and advanced-stage NSCLC cases diagnosed between 2002 and 2005 with a prior COPD diagnosis (3-24 months before NSCLC diagnosis) were identified in Surveillance, Epidemiology, and End Results tumor registry data linked to Medicare claims. Study outcomes included receipt of recommended stage-specific treatment (surgical resection for early-stage NSCLC and chemotherapy for advanced-stage NSCLC [advNSCLC]) and overall survival. Pulmonologist management was considered present if one or more Evaluation and Management visit claims with pulmonologist specialty were observed within 6 months after NSCLC diagnosis. Stage-specific multivariate logistic regression tested association between pulmonologist management and treatment received. Cox proportional hazard models examined the independent association between pulmonologist care and mortality. Two-stage residual inclusion instrumental variable (2SRI-IV) analyses tested and adjusted for potential confounding based on unobserved factors or measurement error. MEASUREMENTS AND MAIN RESULTS The cohorts included 5,488 patients with early-stage NSCLC and 6,426 patients with advNSCLC disease with preexisting COPD. Pulmonologist management was recorded for 54.9% of patients with early stage NSCLC and 35.7% of patients with advNSCLC. Of those patients with pulmonologist involvement, 58.5% of patients with early NSCLC received surgical resection, and 43.6% of patients with advNSCLC received chemotherapy. Pulmonologist management post NSCLC diagnosis was associated with increased surgical resection rates (odds ratio, 1.26; 95% confidence interval, 1.11-1.45) for early NSCLC and increased chemotherapy rates (odds ratio, 1.88; 95% confidence interval, 1.67-2.10) for advNSCLC. Pulmonologist management was also associated with reduced mortality risk for patients with early-stage NSCLC but not AdvNSCLC. CONCLUSIONS Pulmonologist management had a positive association with rates of stage-specific treatment in both groups and overall survival in early-stage NSCLC. These results provide preliminary support for the recently published guidelines emphasizing the role of pulmonologists in lung cancer management. | Pulmonologist involvement, stage-specific treatment, and survival in adults with non-small cell lung cancer and chronic obstructive pulmonary disease. |
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"24879": 0.034552380442619324, "24888": 0.9798521995544434, "25022": 1.1894142627716064, "25117": 1.1031591892242432, "25172": 0.4286321699619293, "25181": 0.1913948506116867, "25194": 0.42225050926208496, "25456": 0.15526613593101501, "25458": 0.14095009863376617, "25708": 0.7863243818283081, "25714": 1.2175520658493042, "25761": 0.23633737862110138, "25992": 0.9363996982574463, "26243": 0.16524957120418549, "26244": 0.24171993136405945, "26402": 0.39762192964553833, "26601": 0.11343330889940262, "26721": 0.083342544734478, "26773": 0.5651806592941284, "26820": 0.1994270235300064, "27295": 0.2983669638633728, "27325": 0.21214580535888672, "27491": 0.8731874823570251, "27697": 0.9754437208175659, "27781": 0.09584271162748337, "27790": 0.8332487344741821, "27854": 1.117316484451294, "28667": 0.9225212931632996, "28715": 0.5816917419433594, "29107": 0.007782140281051397, "29290": 0.47766464948654175, "29490": 0.15610189735889435} | 24335068 | We have used recombinant or synthetic alphaIIb and beta3 integrin cytoplasmic peptides to study their in vitro complexation and ligand binding capacity by surface plasmon resonance. alpha.beta heterodimerization occurred in a 1:1 stoichiometry with a weak KD in the micromolar range. Divalent cations were not required for this association but stabilized the alpha.beta complex by decreasing the dissociation rate. alpha.beta complexation was impaired by the R995A substitution or the KVGFFKR deletion in alphaIIb but not by the beta3 S752P mutation. Recombinant calcium- and integrin-binding protein (CIB), an alphaIIb-specific ligand, bound to the alphaIIb cytoplasmic peptide in a Ca2+- or Mn2+-independent, one-to-one reaction with a KD value of 12 microM. In contrast, in vitro liquid phase binding of CIB to intact alphaIIbbeta3 occurred preferentially with Mn2+-activated alphaIIbbeta3 conformers, as demonstrated by enhanced coimmunoprecipitation of CIB with PAC-1-captured Mn2+-activated alphaIIbbeta3, suggesting that Mn2+ activation of intact alphaIIbbeta3 induces the exposure of a CIB-binding site, spontaneously exposed by the free alphaIIb peptide. Since CIB did not stimulate PAC-1 binding to inactive alphaIIbbeta3 nor prevented activated alphaIIbbeta3 occupancy by PAC-1, we conclude that CIB does not regulate alphaIIbbeta3 inside-out signaling, but rather is involved in an alphaIIbbeta3 post-receptor occupancy event. | Divalent cations differentially regulate integrin alphaIIb cytoplasmic tail binding to beta3 and to calcium- and integrin-binding protein. |
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0.010684899985790253, "27427": 0.6118015646934509, "27698": 0.15526613593101501, "27781": 0.3409265875816345, "27854": 0.12642613053321838, "28156": 0.4709797203540802, "28227": 0.42608439922332764, "28297": 0.4500300884246826, "28352": 1.104454517364502, "28517": 0.9724938273429871, "28873": 0.12642613053321838, "28896": 0.4450363218784332, "29290": 0.6634125709533691, "29486": 0.08961215615272522, "29721": 0.53589928150177} | 24338780 | BACKGROUND Interferon-gamma (IFN-gamma) is an essential cytokine in the regulation of inflammatory responses in autoimmune diseases. Little is known about its role in inflammatory heart disease. METHODS AND RESULTS We showed that IFN-gamma receptor-deficient mice (IFN-gammaR(-/-)) on a BALB/c background immunized with a peptide derived from cardiac alpha-myosin heavy chain develop severe myocarditis with high mortality. Although myocarditis subsided in wild-type mice after 3 weeks, IFN-gammaR(-/-) mice showed persistent disease. The persistent inflammation was accompanied by vigorous in vitro CD4 T-cell responses and impaired inducible nitric oxide synthase expression, together with evidence of impaired nitric oxide production in IFN-gammaR(-/-) hearts. Treatment of wild-type mice with the nitric oxide synthetase inhibitor N:-nitro-l-arginine-methyl-ester enhanced in vitro CD4 T-cell proliferation and prevented healing of myocarditis. CONCLUSIONS Our data provide evidence that IFN-gamma protects mice from lethal autoimmune myocarditis by inducing the expression of inducible nitric oxide synthase followed by the downregulation of T-cell responses. | Lethal autoimmune myocarditis in interferon-gamma receptor-deficient mice: enhanced disease severity by impaired inducible nitric oxide synthase induction. |
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"28687": 0.13499516248703003, "29264": 0.07793712615966797, "29323": 1.1255888938903809, "29477": 0.6714286804199219} | 24341590 | CONTEXT The growth inhibitory effect of tamoxifen, which is used for the treatment of hormone receptor-positive breast cancer, is mediated by its metabolites, 4-hydroxytamoxifen and endoxifen. The formation of active metabolites is catalyzed by the polymorphic cytochrome P450 2D6 (CYP2D6) enzyme. OBJECTIVE To determine whether CYP2D6 variation is associated with clinical outcomes in women receiving adjuvant tamoxifen. DESIGN, SETTING, AND PATIENTS Retrospective analysis of German and US cohorts of patients treated with adjuvant tamoxifen for early stage breast cancer. The 1325 patients had diagnoses between 1986 and 2005 of stage I through III breast cancer and were mainly postmenopausal (95.4%). Last follow-up was in December 2008; inclusion criteria were hormone receptor positivity, no metastatic disease at diagnosis, adjuvant tamoxifen therapy, and no chemotherapy. DNA from tumor tissue or blood was genotyped for CYP2D6 variants associated with reduced (*10, *41) or absent (*3, *4, *5) enzyme activity. Women were classified as having an extensive (n=609), heterozygous extensive/intermediate (n=637), or poor (n=79) CYP2D6 metabolism. MAIN OUTCOME MEASURES Time to recurrence, event-free survival, disease-free survival, and overall survival. RESULTS Median follow-up was 6.3 years. At 9 years of follow-up, the recurrence rates were 14.9% for extensive metabolizers, 20.9% for heterozygous extensive/intermediate metabolizers, and 29.0% for poor metabolizers, and all-cause mortality rates were 16.7%, 18.0%, and 22.8%, respectively. Compared with extensive metabolizers, there was a significantly increased risk of recurrence for heterozygous extensive/intermediate metabolizers (time to recurrence adjusted hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.04-1.90) and for poor metabolizers (time to recurrence HR, 1.90; 95% CI, 1.10-3.28). Compared with extensive metabolizers, those with decreased CYP2D6 activity (heterozygous extensive/intermediate and poor metabolism) had worse event-free survival (HR, 1.33; 95% CI, 1.06-1.68) and disease-free survival (HR, 1.29; 95% CI, 1.03-1.61), but there was no significant difference in overall survival (HR, 1.15; 95% CI, 0.88-1.51). CONCLUSION Among women with breast cancer treated with tamoxifen, there was an association between CYP2D6 variation and clinical outcomes, such that the presence of 2 functional CYP2D6 alleles was associated with better clinical outcomes and the presence of nonfunctional or reduced-function alleles with worse outcomes. | Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen. |
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0.007782140281051397, "26965": 0.3560888469219208, "28322": 0.3353555500507355, "28424": 0.025073638185858727, "28616": 0.3141832649707794, "29251": 0.6613984704017639, "29477": 0.2145126610994339, "29566": 0.1229778528213501} | 24346598 | PURPOSE To assess the efficacy, dose stability, safety, and abuse potential of long-term, nightly benzodiazepine treatment of chronic disorders of disrupted nocturnal sleep. PATIENTS AND METHODS During a 12-year period, one author evaluated and treated 170 adult referrals for > or = 6 months with nightly benzodiazepine therapy for longstanding, sleep-disruptive disorders: injurious sleepwalking and sleep terrors (69); rapid eye movement sleep behavior disorder (52); chronic, severe insomnia (25); and restless legs syndrome/periodic limb movement disorder (24). RESULTS Complete/substantial control of the sleep disorders was achieved by 146 patients (86%); 8% had adverse effects requiring medication changes; 2% had relapses of alcohol or chemical abuse requiring hospitalization; another 2% at times misused their medications. A total of 136 patients received clonazepam nightly for a mean 3.5 (+/- 2.4) years, with no significant difference in inital versus final mean dose: 0.77 mg (+/- 0.46) versus 1.10 mg (+/- 0.96). Similar results were obtained with chronic alprazolam treatment and with other benzodiazepine treatments. CONCLUSION Long-term, nightly benzodiazepine treatment of injurious parasomnias and other disorders of disrupted nocturnal sleep resulted in sustained efficacy in most cases, with low risk of dosage tolerance, adverse effects, or abuse. Data from this study on the treatment of chronic, severe insomnia (a small subset of all insomnia) are not generalizable to the typical insomnia patient. | Long-term, nightly benzodiazepine treatment of injurious parasomnias and other disorders of disrupted nocturnal sleep in 170 adults. |
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"28964": 0.22157983481884003, "29290": 0.12986256182193756} | 24347647 | The proteasome is a multicatalytic enzyme complex responsible for the degradation of both normal and damaged proteins. An age-related decline in proteasomal activity has been implicated in various age-related pathologies. The relevance of decreased proteasomal activity to aging and age-related diseases remains unclear, however, because suitable animal models are not available. In the present study, we established a transgenic (Tg) mouse model with decreased proteasomal chymotrypsin-like activity. Tg mice exhibited a shortened life span and developed age-related phenotypes. In Tg mice, polyubiquitinated and oxidized proteins accumulated, and the expression levels of cellular proteins such as Bcl-xL and RNase L were altered. When Tg mice were fed a high-fat diet, they developed more pronounced obesity and hepatic steatosis than did wild-type mice. Consistent with its role in lipid droplet formation, the expression of adipose differentiation-related protein (ADRP) was elevated in the livers of Tg mice. Of note, obesity and hepatic steatosis induced by a high-fat diet were more pronounced in aged than in young wild-type mice, and aged wild-type mice had elevated levels of ADRP, suggesting that the metabolic abnormalities present in Tg mice mimic those in aged mice. Our results provide the first in vivo evidence that decreased proteasomal chymotrypsin-like activity affects longevity and aggravates age-related metabolic disorders, such as obesity and hepatic steatosis. | Decreased proteasomal activity causes age-related phenotypes and promotes the development of metabolic abnormalities. |
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0.05417001247406006, "29290": 0.1930064558982849, "29490": 0.3777405619621277} | 24349430 | BACKGROUND Orai1/CRACM1 is a principal component of the store-operated calcium channels. Store-operated calcium influx is highly correlated with inflammatory reactions, immunological regulation, and cell proliferation. Epidermal growth factor (EGF), which plays an important role in the regulation of cell proliferation, can activate store-operated calcium channels. However, the consequences of Orai1/CRACM1 overexpression in EGF-mediated lung cancer cells growth are not known. METHODS To investigate the role of Orai1/CRACM1 in EGF-mediated lung cancer cell proliferation, Orai1/CRACM1 plasmids were transfected into cells by lipofection. A cell proliferation assay, immunofluorescence staining, flow cytometry, and real-time polymerase chain reaction were employed to monitor cell proliferation. The calcium influx signals were investigated using a fluorescent-based calcium assay. RESULTS Transfection of Orai1/CRACM1 plasmids resulted in the inhibition of EGF-mediated cell proliferation. ERK1/2 and Akt phosphorylation were inhibited by Orai1/CRACM1 overexpression. Expression of the cell cycle modulator p21 was induced in the Orai1/CRACM1-overexpressing cells, whereas the expression of cyclin D3 was reduced. Flow cytometry revealed that overexpression of Orai1/CRACM1 resulted in G0/G1 cell cycle arrest. Importantly, Orai1/CRACM1 overexpression significantly attenuated EGF-mediated store-operated calcium influx. In addition, application of 2-APB, a store-operated calcium channel inhibitor, resulted in the inhibition of EGF-mediated cancer cell proliferation. CONCLUSIONS We conclude that Orai1/CRACM1 overexpression attenuates store-operated Ca(2+) influx that in turn blocks EGF-mediated proliferative signaling and drives cell cycle arrest. | Orai1/CRACM1 overexpression suppresses cell proliferation via attenuation of the store-operated calcium influx-mediated signalling pathway in A549 lung cancer cells. |
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"25714": 0.20421554148197174, "25778": 0.8433839678764343, "26305": 0.18492233753204346, "26394": 0.11604541540145874, "26402": 0.2622140049934387, "26520": 0.0038986403960734606, "26702": 1.018678069114685, "26745": 0.6931471824645996, "26780": 0.5027855634689331, "27144": 0.2501201331615448, "27295": 0.3388410806655884, "27881": 0.052318159490823746, "27989": 0.0606246218085289, "28268": 0.20022670924663544, "28466": 0.7333439588546753, "28522": 1.243794322013855, "28667": 0.5882205963134766, "28697": 0.00875066313892603, "28765": 0.010684899985790253, "28829": 0.5984715819358826, "28927": 0.1889725625514984, "29021": 0.43053874373435974, "29290": 0.5174443125724792, "29323": 0.8264343738555908, "29458": 0.7314660549163818, "29516": 0.33115679025650024} | 24349992 | Loss of stromal fibroblast caveolin-1 (Cav-1) is a powerful single independent predictor of poor prognosis in human breast cancer patients, and is associated with early tumor recurrence, lymph node metastasis and tamoxifen-resistance. We developed a novel co-culture system to understand the mechanism(s) by which a loss of stromal fibroblast Cav-1 induces a "lethal tumor micro-environment. " Here, we propose a new paradigm to explain the powerful prognostic value of stromal Cav-1. In this model, cancer cells induce oxidative stress in cancer-associated fibroblasts, which then acts as a "metabolic" and "mutagenic" motor to drive tumor-stroma co-evolution, DNA damage and aneuploidy in cancer cells. More specifically, we show that an acute loss of Cav-1 expression leads to mitochondrial dysfunction, oxidative stress and aerobic glycolysis in cancer associated fibroblasts. Also, we propose that defective mitochondria are removed from cancer-associated fibroblasts by autophagy/mitophagy that is induced by oxidative stress. As a consequence, cancer associated fibroblasts provide nutrients (such as lactate) to stimulate mitochondrial biogenesis and oxidative metabolism in adjacent cancer cells (the "Reverse Warburg Effect"). We provide evidence that oxidative stress in cancer-associated fibroblasts is sufficient to induce genomic instability in adjacent cancer cells, via a bystander effect, potentially increasing their aggressive behavior. Finally, we directly demonstrate that nitric oxide (NO) over-production, secondary to Cav-1 loss, is the root cause for mitochondrial dysfunction in cancer associated fibroblasts. In support of this notion, treatment with anti-oxidants (such as N-acetyl-cysteine, metformin and quercetin) or NO inhibitors (L-NAME) was sufficient to reverse many of the cancer-associated fibroblast phenotypes that we describe. Thus, cancer cells use "oxidative stress" in adjacent fibroblasts (i) as an "engine" to fuel their own survival via the stromal production of nutrients and (ii) to drive their own mutagenic evolution towards a more aggressive phenotype, by promoting genomic instability. We also present evidence that the "field effect" in cancer biology could also be related to the stromal production of ROS and NO species. eNOS-expressing fibroblasts have the ability to downregulate Cav-1 and induce mitochondrial dysfunction in adjacent fibroblasts that do not express eNOS. As such, the effects of stromal oxidative stress can be laterally propagated, amplified and are effectively "contagious"--spread from cell-to-cell like a virus--creating an "oncogenic/mutagenic" field promoting widespread DNA damage. | Oxidative stress in cancer associated fibroblasts drives tumor-stroma co-evolution: A new paradigm for understanding tumor metabolism, the field effect and genomic instability in cancer cells. |
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As we learn more, it has become clear that the mechanism is elegant but not as simple as first thought. It is also evident that, although many species use similar, sometimes identical, DNA sequences for telomeres, these species express their own individuality in the way they regulate these sequences and, perhaps, in the additional tasks that they have imposed on their telomeric DNA. The striking similarities between telomeres in different species have revealed much about chromosome ends; the differences are proving to be equally informative. In addition to the differences between species that use telomerase, there are also a few exceptional organisms with atypical telomeres for which no telomerase activity has been detected. This review addresses recent studies, the insights they offer, and, perhaps more importantly, the questions they raise. | Telomeres and telomerase: more than the end of the line |
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0.043007105588912964, "26819": 0.255429208278656, "27094": 0.5301685929298401, "27169": 0.7124901413917542, "27170": 0.23402166366577148, "27178": 0.28597161173820496, "27295": 1.0158531665802002, "27321": 0.151916041970253, "27528": 0.06520967930555344, "27776": 0.3464667797088623, "27989": 0.17020416259765625, "28032": 0.9209672808647156, "28086": 0.6848117709159851, "28156": 0.7115318179130554, "28227": 0.06154331564903259, "28450": 0.25694093108177185, "28466": 0.09672962874174118, "28613": 0.7163142561912537, "28685": 0.13499516248703003, "28691": 0.1693800985813141, "28723": 1.076228141784668, "28788": 0.823009729385376, "28828": 0.2881702482700348, "28829": 0.9717550277709961, "28835": 0.23402166366577148, "28927": 0.5849615335464478, "28929": 0.06520967930555344, "29105": 0.7220231294631958, "29477": 0.01934296265244484, "29489": 0.2622140049934387} | 24356383 | Osteopetrotic (op/op) mice fail to exhibit bone remodeling because of a defective osteoclast formation due to a lack of macrophage colony-stimulating factor. In this study, we investigated the femora of op/op mice to clarify whether the osteoblastic population and bone mineralization are involved in osteoclasts or their bone resorption. The op/op mice extended the meshwork of trabecular bones from the chondro-osseous junction to the diaphyseal region. In the femoral metaphyses of op/op mice, intense alkaline phosphatase (ALPase)-positive osteoblasts were observed on the metaphyseal bone in close proximity to the erosion zone of the growth plates. Von Kossa's staining revealed scattered mineralized nodules and a fine meshwork of mineralized bone matrices while the wild-type littermates developed well-mineralized trabeculae parallel to the longitudinal axis. In contrast to the metaphysis, some op/op diaphyses showed flattened osteoblasts with weak ALPase-positivity, and the other diaphyses displayed bone surfaces without a covering by osteoblasts. It is likely, therefore, that the osteoblastic population and activity were lessened in the op/op diaphyses. Despite the osteopetrotic model, von Kossa's staining demonstrated patchy unmineralized areas in the op/op diaphyses, indicating that a lower population and/or the activity of osteoblasts resulted in defective mineralization in the bone. Transmission electron microscopy disclosed few osteoblasts on the diaphyseal bones, and instead, bone marrow cells and vascular endothelial cells were often attached to the unmineralized bone. Osteocytes were embedded in the unmineralized bone matrix. Thus, osteoclasts appear to be involved in the osteoblastic population and activity as well as subsequent bone mineralization. | Reduced osteoblastic population and defective mineralization in osteopetrotic (op/op) mice. |
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0.21214580535888672} | 24384587 | Interleukin-18 (IL18) participates in atherogenesis through several putative mechanisms. Interruption of IL18 action reduces atherosclerosis in mice. Here, we show that absence of the IL18 receptor (IL18r) does not affect atherosclerosis in apolipoprotein E–deficient (Apoe−/−) mice, nor does it affect IL18 cell surface binding to or signaling in endothelial cells. As identified initially by co-immunoprecipitation with IL18, we found that IL18 interacts with the Na-Cl co-transporter (NCC; also known as SLC12A3), a 12-transmembrane-domain ion transporter protein preferentially expressed in the kidney. NCC is expressed in atherosclerotic lesions, where it colocalizes with IL18r. In Apoe−/− mice, combined deficiency of IL18r and NCC, but not single deficiency of either protein, protects mice from atherosclerosis. Peritoneal macrophages from Apoe−/− mice or from Apoe−/− mice lacking IL18r or NCC show IL18 binding and induction of cell signaling and cytokine and chemokine expression, but macrophages from Apoe−/− mice with combined deficiency of IL18r and NCC have a blunted response. An interaction between NCC and IL18r on macrophages was detected by co-immunoprecipitation. IL18 binds to the cell surface of NCC-transfected COS-7 cells, which do not express IL18r, and induces cell signaling and cytokine expression. This study identifies NCC as an IL18-binding protein that collaborates with IL18r in cell signaling, inflammatory molecule expression, and experimental atherogenesis. | Interleukin 18 function in atherosclerosis is mediated by the interleukin 18 receptor and the Na-Cl co-transporter |
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0.20022670924663544, "26563": 0.08603433519601822, "26773": 0.4145384132862091, "27000": 0.28670501708984375, "27854": 1.1671710014343262, "27896": 0.043007105588912964, "28032": 0.7454653382301331, "28616": 0.015504186972975731, "28765": 0.9628462791442871, "29610": 0.21687394380569458} | 24387017 | Notch signals are necessary for the functional outcomes of T cell receptor β-selection, including differentiation, proliferation and rescue from apoptosis. The mechanism underlying this requirement for T cell development is unknown. Here we show that Notch receptor and Delta-like 1 ligand interactions promoted the survival of CD4−CD8− pre–T cells through the maintenance of cell size, glucose uptake and metabolism. Furthermore, the trophic effects of Notch signaling were mediated by the pathway of phosphatidylinositol-3-OH kinase and the kinase Akt, such that expression of active Atk overcame the requirement for Notch in β-selection. Collectively, our results demonstrate involvement of Notch receptor–ligand interactions in the regulation of cellular metabolism, thus enabling the autonomous signaling capacity of the pre–T cell receptor complex.*Note: In the version of this article initially published online, in the fourth sentence of the abstract, the term "Atk" was a misspelling; this should be "Akt. " In the fourth sentence of the second paragraph of the introduction, the name of the second kinase mentioned, "PI(3)K-dependent kinase 1," was incorrect; this should read "phosphoinositide-dependent kinase 1. " These errors have been corrected for the HTML and print versions of the article. | Notch promotes survival of pre–T cells at the β-selection checkpoint by regulating cellular metabolism |
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"29048": 0.5718178153038025, "29080": 0.1229778528213501, "29166": 0.8796916007995605, "29490": 0.08782484382390976} | 24396137 | Older cancer survivors are a vulnerable population due to an increased risk for chronic diseases (e.g., cardiovascular disease) compounded with treatment late-effects and declines in physical functioning. Therefore, interventions that reduce chronic disease risk factors (i.e., blood pressure, chronic inflammation, and cortisol) are important in this population. Tai chi chih (TCC) is a mind-body exercise associated with reductions in chronic disease risk factors, but has not been examined with older cancer survivors. In a feasibility randomized controlled trial of TCC, we examined secondary outcomes of blood pressure, salivary cortisol, and inflammatory cytokines (interleukin (IL)-6, IL-12, tumor necrosis factor-α, IL-10, IL-4) due to their implications in chronic diseases. Sixty-three senior female cancer survivors (M age = 67 years, SD = 7.15) with physical functioning limitations (SF-12 physical functioning ≤80 or role-physical ≤72) were randomized to 12-weeks (60-min, three times a week) of TCC or Health Education control (HEC) classes. Resting blood pressure, 1-day salivary cortisol samples, and fasting plasma samples for cytokine multiplex assays were collected at baseline and 1-week post-intervention. Controlling for baseline values, the TCC group had significantly lower systolic blood pressure (SBP, p = 0.002) and cortisol area-under-curve (AUC, p = 0.02) at post-intervention than the HEC group. There was no intervention effect on inflammatory cytokines (p’s > 0.05). This TCC feasibility trial was associated with significant reductions in SBP and cortisol AUC in senior female cancer survivors. Larger, definitive trials are needed to confirm these findings. Senior survivors’ have an increased risk for chronic diseases; however, TCC interventions may help reduce associated risk factors. | Blood pressure, salivary cortisol, and inflammatory cytokine outcomes in senior female cancer survivors enrolled in a tai chi chih randomized controlled trial |
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0.036437395960092545, "26163": 0.5057345628738403, "26208": 0.08244366943836212, "26226": 0.12986256182193756, "26236": 0.3923587501049042, "26237": 1.1141164302825928, "26261": 0.0058422754518687725, "26462": 0.07884006202220917, "26478": 0.17922431230545044, "26897": 0.6451379656791687, "27108": 1.0587663650512695, "27159": 0.8666408061981201, "27480": 1.246605634689331, "27615": 0.13755162060260773, "27694": 0.0174254160374403, "27994": 0.08782484382390976, "28353": 0.16607704758644104, "28389": 0.09228714555501938, "28829": 0.3423145115375519, "29048": 0.11430477350950241, "29125": 0.3339579105377197, "29458": 0.23402166366577148} | 24408040 | BACKGROUND Heart failure (HF) is a serious complication and often the cause of death in adults with congenital heart disease (CHD). Therefore, our aims were to determine the frequency of HF-admissions, and to assess risk factors of first HF-admission and of mortality after first HF-admission in adults with CHD. METHODS The Dutch CONCOR registry was linked to the Hospital Discharge Registry and National Mortality Registry to obtain data on HF-admissions and mortality. Risk factors for both HF-admission and mortality were assessed using Cox regression models. RESULTS Of 10,808 adult patients (49% male), 274 (2.5%) were admitted for HF during a median follow-up period of 21 years. The incidence of first HF-admission was 1.2 per 1000 patient-years, but the incidence of HF itself will be higher. Main defect, multiple defects, and surgical interventions in childhood were identified as independent risk factors of HF-admission. Patients admitted for HF had a five-fold higher risk of mortality than patients not admitted (hazard ratio (HR)=5.3; 95% confidence interval 4.2-6.9). One- and three-year mortality after first HF-admission were 24% and 35% respectively. Independent risk factors for three-year mortality after first HF-admission were male gender, pacemaker implantation, admission duration, non-cardiac medication use and high serum creatinine. CONCLUSIONS The incidence of HF-admission in adults with CHD is 1.2 per 1000 patient-years. Mortality risk is substantially increased after HF-admission, which emphasises the importance to identify patients at high risk of HF-admission. These patients might benefit from closer follow-up and earlier medical interventions. The presented risk factors may facilitate surveillance. | Heart failure admissions in adults with congenital heart disease; risk factors and prognosis. |
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0.015504186972975731, "29129": 0.29619070887565613} | 24414345 | We summarize significant changes in pathologic classification of lung cancer resulting from the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) lung adenocarcinoma classification. The classification was developed by an international core panel of experts representing IASLC, ATS, and ERS with oncologists/pulmonologists, pathologists, radiologists, molecular biologists, and thoracic surgeons. Because 70% of patients with lung cancer present with advanced stages, a new approach to small biopsies and cytology with specific terminology and criteria focused on the need for distinguishing squamous cell carcinoma from adenocarcinoma and on molecular testing for EGFR mutations and ALK rearrangement. Tumors previously classified as non-small-cell carcinoma, not otherwise specified, because of the lack of clear squamous or adenocarcinoma morphology should be classified further by using a limited immunohistochemical workup to preserve tissue for molecular testing. The terms "bronchioloalveolar carcinoma" and "mixed subtype adenocarcinoma" have been discontinued. For resected adenocarcinomas, new concepts of adenocarcinoma in situ and minimally invasive adenocarcinoma define patients who, if they undergo complete resection, will have 100% disease-free survival. Invasive adenocarcinomas are now classified by predominant pattern after using comprehensive histologic subtyping with lepidic, acinar, papillary, and solid patterns; micropapillary is added as a new histologic subtype with poor prognosis. Former mucinous bronchioloalveolar carcinomas are now called "invasive mucinous adenocarcinoma. " Because the lung cancer field is now rapidly evolving with new advances occurring on a frequent basis, particularly in the molecular arena, this classification provides a much needed standard for pathologic diagnosis not only for patient care but also for clinical trials and TNM classification. | New pathologic classification of lung cancer: relevance for clinical practice and clinical trials. |
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0.2749055027961731, "28290": 0.9348671436309814, "28297": 0.4537591338157654, "28389": 1.531476378440857, "28436": 0.058784693479537964, "28472": 0.16110190749168396, "28739": 0.17020416259765625, "28837": 0.7791815400123596, "28873": 0.27712854743003845, "29107": 0.5074998140335083, "29206": 0.1510767638683319, "29458": 0.6926587820053101, "29486": 0.41840189695358276} | 24423427 | Although most hepatitis C virus (HCV)-infected individuals develop chronic infection, about 25% of them are able to clear the virus spontaneously without any therapeutic intervention. The aim of the present study was to identify genes associated with spontaneous HCV clearance in a population of Iranian patients. We genotyped 110 single-nucleotide polymorphisms (SNPs) in 59 selected—candidate—genes in a cohort of 107 HCV-infected participants who spontaneously cleared the infection and 176 participants whose infection persisted. Three out of the 110 SNPs were found to be associated with HCV outcome (P-values<0.03). rs11506105 in EGFR (epidermal growth factor receptor gene), and rs11881222 and rs12979860 in IL28B (interferon-λ3 gene). Multivariate logistic regression of the three markers showed that the A/A genotypes in both rs11506105 (EFGR) and rs11881222 (IL28B), and the C/C genotype in rs12979860 (IL28B) are associated with HCV clearance (recessive model: odds ratio (OR)=2.06, 95% confidence interval (95% CI)=1.09–3.88, P=0.025; OR=2.09, 95% CI=1.23–3.60, P=0.007; and OR=1.95, 95% CI=1.15–3.35, P=0.014 for rs11506105, rs12979860 and rs11881222, respectively). In conclusion, EGFR and IL28B SNPs are strong independent predictive markers of spontaneous viral clearance. | Polymorphisms in EGFR and IL28B are associated with spontaneous clearance in an HCV-infected iranian population |
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0.4349733293056488, "28466": 0.7389566898345947, "28674": 0.151916041970253, "28697": 0.22937409579753876, "28715": 0.0354953333735466, "29048": 0.18329764902591705, "29129": 0.08603433519601822, "29160": 0.06246116757392883, "29295": 0.043007105588912964, "29311": 0.21135559678077698, "29347": 0.09850110858678818, "29458": 0.21922965347766876, "29490": 0.02412080205976963, "29536": 0.9178520441055298} | 24443043 | PURPOSE Previous investigations have reported a relationship between variables obtained from echocardiography with tissue Doppler imaging (TDI) and cardiopulmonary exercise testing (CPX) in systolic heart failure (HF) cohorts. The purpose of the present investigation was to perform a comparative analysis between echocardiography with TDI and CPX in patients with HF and normal ejection fraction (NEF). METHODS Patients with HF-NEF (N = 32) underwent echocardiography with TDI and CPX to determine the following variables: (1) the ratio between mitral early velocity (E) and mitral annular velocity (E'), (2) ejection fraction, (3) left ventricular (LV) mass, (4) left ventricular end systolic volume, (5) peak oxygen uptake (.VO2), (6) ventilatory efficiency, (7) the partial pressure of end-tidal carbon dioxide (P(ET)CO2) at rest and peak exercise, and (8) heart rate recovery at 1 minute (HRR1). RESULTS Pearson correlation revealed that E/E' was significantly correlated with peak oxygen uptake (r = -0.55, P = .001), the ventilatory efficiency slope (r = 0.60, P < .001), resting P(ET)CO2 (r = -0.39, P = .03), peak P(ET)CO2 (r = -0.50, P = .004), and HRR1 (r = -0.63, P < .001). Left ventricular mass and left ventricular end systolic volume were not correlated with any CPX variable. Ejection fraction was correlated with HRR1 (r = -0.55, P = .001). An HRR1 threshold of less than 16 and/or 16 or more beats per minute (higher value positive) effectively identified subjects with an E/E' > 10 (positive likelihood ratio: 13:2). DISCUSSION E/E' provides an accurate reflection of LV filling pressure and thus, insight into diastolic function. The results of the present investigation indicate CPX provides insight into cardiac dysfunction in patients with HF-NEF and thus, may eventually prove to be a valuable and accepted clinical assessment. | Cardiopulmonary exercise testing variables reflect the degree of diastolic dysfunction in patients with heart failure-normal ejection fraction. |
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0.15526613593101501, "24759": 0.319873183965683, "25086": 1.4450790882110596, "25409": 0.6999598741531372, "25796": 0.2247048318386078, "25918": 0.8550800085067749, "25937": 0.045809537172317505, "26179": 0.04113444685935974, "26237": 0.14602625370025635, "26268": 0.22782009840011597, "26462": 0.29036402702331543, "26563": 0.1221139207482338, "26745": 0.8074519634246826, "26802": 0.05786345899105072, "26886": 0.6291293501853943, "27144": 0.5472630262374878, "27159": 0.022212404757738113, "27354": 0.021256839856505394, "27673": 0.33605360984802246, "27811": 0.0038986403960734606, "28177": 0.14095009863376617, "28207": 0.06977381557226181, "28739": 1.0464962720870972, "28794": 0.026025565341114998, "28873": 0.8340972661972046, "28941": 0.37371641397476196, "29458": 0.841701865196228} | 24450344 | PURPOSE We evaluated the long-term outcome of radical prostatectomy for pathological Gleason score 8 or greater prostate cancer and characterized the prognostic significance of other pathological variables. MATERIALS AND METHODS A total of 6,419 patients underwent radical prostatectomy between 1987 and 1996. There were 407 patients classified as having pathological Gleason 8 or greater, including 8 in 48%, 9 in 49% and 10 in 3%. Adjuvant treatment was used in 45% of patients and adjuvant hormonal therapy was administered to 155 (38%). Progression-free, including local or systemic, and/or prostate specific antigen (PSA) 0.4 ng./ml. or greater, and cancer specific survival were determined by the Kaplan-Meier method. The effect of pathological grade and stage, preoperative PSA, DNA ploidy, margin status, tumor dimension, seminal vesicle invasion, and adjuvant treatment was assessed with the univariate and multivariate analyses. RESULTS Pathological stage distribution was pT2 in 26% of patients, pT3 48% and pTxN+ 27%. Overall and progression-free survival at 10 years was 67% and 36%, respectively, compared to cancer specific survival 85%. Adjuvant treatment, pathological stage, preoperative PSA and pathological grade were significant (less than 0.05) univariate predictors of progression-free survival. Pathological stage, margin status and ploidy were univariately associated with cancer specific survival. Progression-free survival at 10 years of those patients who did and did not receive adjuvant treatment was 52% and 23%, respectively. In the multivariate analysis pathological grade (p=0.02), preoperative PSA (p <0.0001), adjuvant therapy (p <0.0001) and pathological stage (p=0.036) were significant independent predictors of progression-free survival. CONCLUSIONS High grade prostate cancer can be controlled with radical prostatectomy in some patients with disease confined pathologically, and 10-year cause specific survival is 96%. Predictors of outcome in patients with Gleason 8 disease or greater are similar to established predictors derived by using all grades. Although adjuvant hormonal therapy appears to improve disease progression rates after radical prostatectomy on the basis of this nonrandomized study, it may not affect prostate cancer death rates within 10 years in patients with high grade cancer. | Radical prostatectomy for pathological Gleason 8 or greater prostate cancer: influence of concomitant pathological variables. |
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0.7827593088150024, "27354": 0.06612417846918106, "27528": 0.016465263441205025, "28024": 0.1358480453491211, "28139": 0.08692999184131622, "28297": 0.23479416966438293, "28522": 0.7791815400123596, "28667": 0.04487626627087593, "28723": 1.2905446290969849, "28788": 0.5784112811088562, "28873": 0.15023678541183472, "29109": 0.022212404757738113, "29139": 0.18654440343379974, "29401": 0.21765978634357452, "29486": 0.18004031479358673} | 24466904 | We used bone marrow biopsies instead of mononuclear cells to maintain long-term cultures from 103 patients belonging to all five sub-categories of myelodysplastic syndromes (MDS), as well as 12 normal controls. By week 4, 30-50% confluency was reached and could be maintained for up to 12 weeks with 100% confluency. The four prominent cells were fibroblasts, macrophages, endothelial cells and adipocytes. Immunohistochemical and electron microscopic studies provided lineage confirmation. Normal hematopoiesis was well supported by MDS stroma. Neither the FAB nor cytogenetics was co-related with the potency of growth. MDS stroma appears to be both morphologically and functionally normal. | Successful establishment of long-term bone marrow cultures in 103 patients with myelodysplastic syndromes. |
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0.12038381397724152, "25276": 0.09228714555501938, "25344": 0.04767346754670143, "25360": 0.018384648486971855, "25750": 0.007782140281051397, "25775": 0.1221139207482338, "25785": 0.0317181795835495, "25811": 0.680370569229126, "25871": 0.08782484382390976, "25945": 0.02792670577764511, "25957": 1.060796856880188, "26067": 0.8973627090454102, "26089": 0.07159364968538284, "26094": 0.38374659419059753, "26119": 0.18573370575904846, "26348": 0.32199856638908386, "26445": 0.013579257763922215, "26456": 0.26446542143821716, "26521": 0.013579257763922215, "26541": 0.9613537192344666, "26886": 0.004870930220931768, "27339": 0.5534584522247314, "27484": 0.5540198087692261, "27790": 0.0354953333735466, "28767": 0.01934296265244484, "29048": 0.03831886500120163, "29234": 0.26146242022514343, "29235": 0.05970508232712746, "29398": 0.06977381557226181, "29477": 0.0038986403960734606, "29513": 0.07068414986133575} | 24494539 | OBJECTIVE To observe the clinical effects of acupuncture combined with auricular point sticking based on the western medication for post stroke depression (PSD). METHODS Sixty patients with PSD were randomly assigned into an acupuncture plus auricular application group (a combination group) and a medication group, 30 cases in each one. 20 mg paroxetine hydrochloride was prescribed orally in the medication group, once a day for continuous 8 weeks. Based on the above treatment, 30-minute acupuncture was used in the combination group for 8 weeks at Baihui (GV 20), Sishencong (EX-HN 1), Shenting (GV 24), Yintang (GV 29), Shenmen (HT 7), Neiguan (PC 6), Taichong (LR 3), Hegu (LI 4), Zusanli (ST 36), Sanyinjiao (SP 6) and Fenglong (ST 40), once the other day and three times a week. Auricular point sticking therapy for 8 weeks was applied at shenmen (TF4), pizhixia (AT4), xin (CO15), and gan (CO12), with pressing 3 times a day and once 3-5 days. The total score and each factor scores of Hamilton's depression scale (HAMD) were observed in the two groups before and after treatment, and Asberg's antidepressant side-effect rating scale (SERS) and clinical effect were evaluated. RESULTS After treatment, the total HAMD scores of the two groups decreased compared with those before treatment (both P<0.05), with better effect in the combination group (P<0.05). The scores of the combination group after treatment were lower than those in the medication group, including the anxiety/somatization factor, sleep disturbance factor, hopelessness factor (all P<0.05). The total effective rate of the combination group was 86.7% (26/30), which was better than 66.7% (20/30) of the medication group (P<0.05). The SERS score of the combination group was lower than that of the medication group (P<0.05). CONCLUSIONS Acupuncture combined with auricular point sticking can improve the clinical symptoms and are effective and safe for PSD. | [Acupuncture combined with auricular point sticking therapy for post stroke depression:a randomized controlled trial]. |
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However, selective targeting of this signaling pathway using BMP ligands has not yet been explored as a therapeutic strategy. Here, we identify BMP9 as the preferred ligand for preventing apoptosis and enhancing monolayer integrity in both pulmonary arterial endothelial cells and blood outgrowth endothelial cells from subjects with PAH who bear mutations in the gene encoding BMPR-II, BMPR2. Mice bearing a heterozygous knock-in allele of a human BMPR2 mutation, R899X, which we generated as an animal model of PAH caused by BMPR-II deficiency, spontaneously developed PAH. Administration of BMP9 reversed established PAH in these mice, as well as in two other experimental PAH models, in which PAH develops in response to either monocrotaline or VEGF receptor inhibition combined with chronic hypoxia. These results demonstrate the promise of direct enhancement of endothelial BMP signaling as a new therapeutic strategy for PAH. | Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension |
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0.6254787445068359, "27777": 0.09672962874174118, "28424": 0.025073638185858727, "28667": 0.8592242002487183, "28691": 1.2238903045654297, "28829": 0.010684899985790253, "29003": 0.004870930220931768, "29129": 0.13414156436920166, "29139": 1.04512357711792, "29171": 0.03925827145576477, "29304": 0.4349733293056488} | 24498673 | Holliday junctions (HJs) are four-way DNA intermediates that form during homologous recombination, and their efficient resolution is essential for chromosome segregation. Here, we show that three structure-selective endonucleases, namely SLX1-SLX4, MUS81-EME1, and GEN1, define two pathways of HJ resolution in human cells. One pathway is mediated by GEN1, whereas SLX1-SLX4 and MUS81-EME1 provide a second and genetically distinct pathway (SLX-MUS). Cells depleted for SLX-MUS or GEN1 pathway proteins exhibit severe defects in chromosome segregation and reduced survival. In response to CDK-mediated phosphorylation, SLX1-SLX4 and MUS81-EME1 associate at the G2/M transition to form a stable SLX-MUS holoenzyme, which can be reconstituted in vitro. Biochemical studies show that SLX-MUS is a HJ resolvase that coordinates the active sites of two distinct endonucleases during HJ resolution. This cleavage reaction is more efficient and orchestrated than that mediated by SLX1-SLX4 alone, which exhibits a potent nickase activity that acts promiscuously upon DNA secondary structures. | Coordinated actions of SLX1-SLX4 and MUS81-EME1 for Holliday junction resolution in human cells. |
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0.17759032547473907, "27086": 0.036437395960092545, "27811": 0.35950297117233276, "28093": 0.01934296265244484, "28321": 0.33953672647476196, "28498": 0.05046287178993225, "29264": 0.1994270235300064} | 24510595 | PURPOSE Patients with daily or near-daily headaches are commonly seen in neurology practices and in headache subspecialty centers, but there is little information on the prevalence of this condition in the general population. We present the first US-based study describing the prevalence and characteristics of frequent headache in the general population. METHODS In Baltimore County, Maryland, 13 343 individuals 18 to 65 years of age were selected by random-digit dialing and interviewed by telephone about their headaches. Subjects reporting 180 or more headaches per year were classified as having frequent headache. Three mutually exclusive subtypes of frequent headache were identified: frequent headache with migrainous features, chronic tension-type headache, and unclassified frequent headache. RESULTS The overall prevalence of frequent headache was 4.1% (5.0% female, 2.8% male; 1.8:1 female to male ratio). Frequent headache was 33% more common in Caucasians (4.4%) than in African Americans (3.3%). In both males and females, prevalence was highest in the lowest educational category. Among frequent headache sufferers, more than half (52% female, 56% male) met criteria for chronic tension-type headache, almost one third (33% female, 25% male) met criteria for frequent headache with migrainous features, and the remainder (15% female, 19% male) were unclassified. Overall, 30% of female and 25% of male frequent headache sufferers met International Headache Society (IHS) criteria for migraine (with or without aura). CONCLUSIONS Frequent headache is common in the general population and is more prevalent in Caucasians and in those with less than a high school education. Chronic tension-type headache is more common than frequent headache with migrainous features, though the latter is more disabling. Although more common in females than males, the female preponderance of frequent headache is less marked than in migraine. The sex ratio varies by frequent headache subtype. | Prevalence of frequent headache in a population sample. |
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