spalde-v3-lexical
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the most lethal of all gynecological cancers, and there is an urgent unmet need to develop new therapies. Epithelial ovarian cancer (EOC) is characterized by an immune suppressive microenvironment, and response of ovarian cancers to immune therapies has thus far been disappointing. We now find, in a mouse model of EOC, that clinically relevant doses of DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi, respectively) reduce the immune suppressive microenvironment through type I IFN signaling and improve response to immune checkpoint therapy. These data indicate that the type I IFN response is required for effective in vivo antitumorigenic actions of the DNMTi 5-azacytidine (AZA). Through type I IFN signaling, AZA increases the numbers of CD45+ immune cells and the percentage of active CD8+ T and natural killer (NK) cells in the tumor microenvironment, while reducing tumor burden and extending survival. AZA also increases viral defense gene expression in both tumor and immune cells, and reduces the percentage of macrophages and myeloid-derived suppressor cells in the tumor microenvironment. The addition of an HDACi to AZA enhances the modulation of the immune microenvironment, specifically increasing T and NK cell activation and reducing macrophages over AZA treatment alone, while further increasing the survival of the mice. Finally, a triple combination of DNMTi/HDACi plus the immune checkpoint inhibitor α-PD-1 provides the best antitumor effect and longest overall survival, and may be an attractive candidate for future clinical trials in ovarian cancer. | Epigenetic therapy activates type I interferon signaling in murine ovarian cancer to reduce immunosuppression and tumor burden. |
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"28586": 0.32058215141296387, "28685": 0.08244366943836212, "29044": 0.026025565341114998, "29101": 0.045809537172317505, "29107": 0.13925230503082275, "29206": 0.30917787551879883} | 9769310 | The phenomenon of parental imprinting involves the preferential expression of one parental allele of a subset of chromosomal genes and has so far only been documented in the mouse. We show here, by exploiting sequence polymorphisms in exon nine of the human insulin–like growth factor 2 (IGF2) gene, that only the paternally–inherited allele is active in embryonic and extra–embryonic cells from first trimester pregnancies. In addition, only the paternal allele is expressed in tissues from a patient who suffered from Beckwith–Wiedemann syndrome. Thus the parental imprinting of IGF2 appears to be evolutionarily conserved from mouse to man and has implications for the generation of the Beckwith–Wiedemann syndrome. | IGF2 is parentally imprinted during human embryogenesis and in the Beckwith–Wiedemann syndrome |
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0.4938860833644867, "26986": 0.00875066313892603, "27011": 1.2516462802886963, "27080": 0.2026219218969345, "27280": 0.07431721687316895, "27312": 0.10906458646059036, "27354": 0.1229778528213501, "27404": 0.7182208299636841, "28173": 0.11256109178066254, "28624": 0.42416930198669434, "28648": 0.20818853378295898, "29361": 0.319873183965683} | 9769684 | BACKGROUND Radio Frequency Identification (RFID) devices are becoming more and more essential for patient safety in hospitals. The purpose of this study was to determine patient safety, data reliability and signal loss wearing on skin RFID devices during magnetic resonance imaging (MRI) and computed tomography (CT) scanning. METHODS Sixty RFID tags of the type I-Code SLI, 13.56 MHz, ISO 18000-3.1 were tested: Thirty type 1, an RFID tag with a 76 x 45 mm aluminum-etched antenna and 30 type 2, a tag with a 31 x 14 mm copper-etched antenna. The signal loss, material movement and heat tests were performed in a 1.5 T and a 3 T MR system. For data integrity, the tags were tested additionally during CT scanning. Standardized function tests were performed with all transponders before and after all imaging studies. RESULTS There was no memory loss or data alteration in the RFID tags after MRI and CT scanning. Concerning heating (a maximum of 3.6 degrees C) and device movement (below 1 N/kg) no relevant influence was found. Concerning signal loss (artifacts 2 - 4 mm), interpretability of MR images was impaired when superficial structures such as skin, subcutaneous tissues or tendons were assessed. CONCLUSIONS Patients wearing RFID wristbands are safe in 1.5 T and 3 T MR scanners using normal operation mode for RF-field. The findings are specific to the RFID tags that underwent testing. | Safety and reliability of Radio Frequency Identification Devices in Magnetic Resonance Imaging and Computed Tomography |
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We now show that LXR signaling not only regulates macrophage cholesterol metabolism but also impacts antimicrobial responses. Mice lacking LXRs are highly susceptible to infection with the intracellular bacteria Listeria monocytogenes (LM). Bone marrow transplant studies point to altered macrophage function as the major determinant of susceptibility. LXR-null macrophages undergo accelerated apoptosis when challenged with LM and exhibit defective bacterial clearance in vivo. These defects result, at least in part, from loss of regulation of the antiapoptotic factor SPalpha, a direct target for regulation by LXRalpha. Expression of LXRalpha or SPalpha in macrophages inhibits apoptosis in the setting of LM infection. Our results demonstrate that LXR-dependent gene expression plays an unexpected role in innate immunity and suggest that common nuclear receptor pathways mediate macrophage responses to modified lipoproteins and intracellular pathogens. | LXR-Dependent Gene Expression Is Important for Macrophage Survival and the Innate Immune Response |
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0.045809537172317505, "26451": 0.010684899985790253, "26569": 0.011650617234408855, "26572": 0.04394211992621422, "26646": 0.04207121208310127, "26835": 0.2763880789279938, "26874": 0.016465263441205025, "27009": 0.06977381557226181, "27058": 0.02792670577764511, "27321": 0.3381449282169342, "27759": 0.15442965924739838, "27814": 0.29400965571403503, "27965": 0.3005385100841522, "28032": 0.06429435312747955, "28089": 0.10731173306703568, "28518": 0.1946154683828354, "28696": 1.225611925125122, "28742": 0.18492233753204346, "28767": 0.27786844968795776, "28788": 0.7047978043556213, "28873": 0.34508460760116577, "28935": 0.20421554148197174, "29091": 0.06886265426874161, "29222": 0.1734936386346817, "29491": 0.3622259199619293} | 9787715 | BACKGROUND The effects of Plasmodium falciparum on B-cell homeostasis have not been well characterized. This study investigated whether an episode of acute malaria in young children results in changes in the peripheral B cell phenotype. METHODS Using flow-cytofluorimetric analysis, the B cell phenotypes found in the peripheral blood of children aged 2-5 years were characterized during an episode of acute uncomplicated clinical malaria and four weeks post-recovery and in healthy age-matched controls. RESULTS There was a significant decrease in CD19+ B lymphocytes during acute malaria. Characterization of the CD19+ B cell subsets in the peripheral blood based on expression of IgD and CD38 revealed a significant decrease in the numbers of naive 1 CD38-IgD+ B cells while there was an increase in CD38+IgD- memory 3 B cells during acute malaria. Further analysis of the peripheral B cell phenotype also identified an expansion of transitional CD10+CD19+ B cells in children following an episode of acute malaria with up to 25% of total CD19+ B cell pool residing in this subset. CONCLUSION Children experiencing an episode of acute uncomplicated clinical malaria experienced profound disturbances in B cell homeostasis. | Alterations on peripheral B cell subsets following an acute uncomplicated clinical malaria infection in children |
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0.28450319170951843} | 9791313 | In the past decade important progress has been made in our understanding of the epigenetic regulatory machinery. It has become clear that genetic aberrations in multiple epigenetic modifier proteins are associated with various types of cancer. Moreover, targeting the epigenome has emerged as a novel tool to treat cancer patients. Recently, the first drugs have been reported that specifically target SETD2-negative tumors. In this review we discuss the studies on the associated protein, Set domain containing 2 (SETD2), a histone modifier for which mutations have only recently been associated with cancer development. Our review starts with the structural characteristics of SETD2 and extends to its corresponding function by combining studies on SETD2 function in yeast, Drosophila, Caenorhabditis elegans, mice, and humans. SETD2 is now generally known as the single human gene responsible for trimethylation of lysine 36 of Histone H3 (H3K36). H3K36me3 readers that recruit protein complexes to carry out specific processes, including transcription elongation, RNA processing, and DNA repair, determine the impact of this histone modification. Finally, we describe the prevalence of SETD2-inactivating mutations in cancer, with the highest frequency in clear cell Renal Cell Cancer, and explore how SETD2-inactivation might contribute to tumor development. | SETD2: an epigenetic modifier with tumor suppressor functionality |
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The energy use on the different subcellular processes underlying neural information processing has been estimated previously for the grey matter of the cerebral and cerebellar cortex. However, these estimates need reevaluating following recent work demonstrating that action potentials in mammalian neurons are much more energy efficient than was previously thought. Using this new knowledge, this paper provides revised estimates for the energy expenditure on neural computation in a simple model for the cerebral cortex and a detailed model of the cerebellar cortex. In cerebral cortex, most signaling energy (50%) is used on postsynaptic glutamate receptors, 21% is used on action potentials, 20% on resting potentials, 5% on presynaptic transmitter release, and 4% on transmitter recycling. In the cerebellar cortex, excitatory neurons use 75% and inhibitory neurons 25% of the signaling energy, and most energy is used on information processing by non-principal neurons: Purkinje cells use only 15% of the signaling energy. The majority of cerebellar signaling energy use is on the maintenance of resting potentials (54%) and postsynaptic receptors (22%), while action potentials account for only 17% of the signaling energy use. | Updated energy budgets for neural computation in the neocortex and cerebellum. |
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"26319": 0.23556606471538544, "26445": 0.0019512200960889459, "26745": 0.7445381283760071, "27268": 0.9139442443847656, "27321": 0.0058422754518687725, "27339": 1.706876516342163, "27532": 0.1693800985813141, "27709": 0.02412080205976963, "28093": 0.8845420479774475, "28297": 0.1229778528213501, "28353": 0.009718249551951885, "28667": 0.6394867897033691, "28697": 0.176772341132164, "28767": 0.4624064862728119, "28774": 0.8780695199966431, "28915": 0.2696990668773651, "29048": 0.08692999184131622, "29264": 0.8212929964065552, "29458": 0.04207121208310127} | 9813098 | Young patients with an ischaemic stroke or transient ischaemic attack (TIA) often have no vascular risk factors. Hyperhomocysteinaemia is an established risk factor for stroke in elderly patients but it is uncertain whether it is also important for the prognosis of young ischaemic stroke and TIA patients. We examined the possible effect of the plasma homocysteine level on the risk of recurrent vascular events in patients between 18 and 45 years of age. The study population consisted of 161 consecutive patients with a recent cerebral infarction or TIA. Data on the primary event and the homocysteine level were collected retrospectively from hospital records. General practitioners and patients were contacted by telephone to record vascular events and the type of medication used during the follow–up period. Vascular events included cerebral infarction, TIA, pulmonary embolism, venous thrombosis, myocardial infarction and peripheral arterial disease. A Kaplan- Meier curve showed a dose effect relationship between event-free survival time and tertiles of the homocysteine level (Log rank statistic 5.91; p = 0.05). The Cox hazard ratio, after adjustment for homocysteine lowering treatment, was 1.7 (95 % CI, 1.1 to 2.8) for any vascular outcome event, 1.9 (95% CI, 1.1 to 3.0) for arterial outcome events and 1.8 (95 % CI, 1.1 to 2.9) for cerebral outcome events. In spite of our small number of outcome events we found a significant association at the 95% confidence level between homocysteine level and the risk of recurrent vascular events in young patients with an ischaemic stroke or TIA. The association is of the same magnitude as in elderly people. | Plasma homocysteine is a risk factor for recurrent vascular events in young patients with an ischaemic stroke or TIA |
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0.06886265426874161, "26402": 1.2324692010879517, "26632": 1.240975022315979, "27321": 0.26296505331993103, "27598": 0.7827593088150024, "27777": 0.04767346754670143, "27833": 1.468738079071045, "28041": 0.255429208278656, "28086": 0.14686977863311768, "28093": 0.2026219218969345, "28696": 0.0009760859538801014, "28788": 0.3027053773403168, "29109": 0.006812678650021553, "29166": 0.981317400932312, "29167": 0.011650617234408855, "29215": 0.09672962874174118, "29258": 0.6223390698432922, "29494": 0.7314660549163818} | 9814332 | Although the accumulation of cholesterol in macrophages appears to be an initial step in atherogenesis, low-density lipoprotein (LDL), a major risk factor for atherosclerosis, does not promote cholesterol accumulation in macrophages in its native form. On the other hand, apolipoprotein (apo) A-I-containing lipoprotein removes cholesterol from cholesterol-loaded macrophages (foam cells) and prevents cholesterol from accumulating in the cells. We examined the effect of LDL on cholesterol removal by two species of apoA-I-containing lipoproteins, one containing only apoA-I (LpA-I) and the other containing apoA-I and apoA-II (LpA-I/A-II). When foam cells were incubated with LpA-I or LpA-I/A-II, cellular cholesterol mass was reduced. In contrast, when LDL was added, the cholesterol-reducing capacities of these lipoproteins were dose-dependently inhibited by LDL. In the presence of LDL, LpA-I and LpA-I/A-II removed free cholesterol preferentially from LDL rather than from the plasma membrane of foam cells. In addition, a fair amount of cellular cholesterol was directly moved to LDL rather than to LpA-I or LpA-I/A-II. The cellular cholesterol that moved to LDL was completely compensated for by the cholesterol influx from LDL to foam cells. Thus, net cholesterol efflux (a combination of influx and efflux) from foam cells was inhibited by LDL. These results, taken together, indicate that LDL may accelerate foam cell formation by inhibiting cholesterol removal from the cells and that elevated levels of plasma LDL may become a risk factor for atherosclerosis by inhibiting the function of LpA-I and LpA-I/A-II at the cellular level. | LDL inhibits the mediation of cholesterol efflux from macrophage foam cells by apoA-I-containing lipoproteins. A putative mechanism for foam cell formation. |
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"25269": 1.0621482133865356, "25604": 0.13755162060260773, "26163": 0.5668440461158752, "26237": 0.043007105588912964, "26476": 0.029824240133166313, "26844": 0.6054253578186035, "27102": 0.23479416966438293, "27467": 0.10555581003427505, "27794": 0.5347557663917542, "28055": 0.04860413447022438, "28093": 0.18004031479358673, "28248": 0.055094651877880096, "28268": 0.3283478021621704, "28753": 0.259204238653183, "28910": 0.09761575609445572, "29593": 0.0842406153678894} | 9822397 | CONTEXT Sugar-sweetened beverages like soft drinks and fruit punches contain large amounts of readily absorbable sugars and may contribute to weight gain and an increased risk of type 2 diabetes, but these relationships have been minimally addressed in adults. OBJECTIVE To examine the association between consumption of sugar-sweetened beverages and weight change and risk of type 2 diabetes in women. DESIGN, SETTING, AND PARTICIPANTS Prospective cohort analyses conducted from 1991 to 1999 among women in the Nurses' Health Study II. The diabetes analysis included 91,249 women free of diabetes and other major chronic diseases at baseline in 1991. The weight change analysis included 51,603 women for whom complete dietary information and body weight were ascertained in 1991, 1995, and 1999. We identified 741 incident cases of confirmed type 2 diabetes during 716,300 person-years of follow-up. MAIN OUTCOME MEASURES Weight gain and incidence of type 2 diabetes. RESULTS Those with stable consumption patterns had no difference in weight gain, but weight gain over a 4-year period was highest among women who increased their sugar-sweetened soft drink consumption from 1 or fewer drinks per week to 1 or more drinks per day (multivariate-adjusted means, 4.69 kg for 1991 to 1995 and 4.20 kg for 1995 to 1999) and was smallest among women who decreased their intake (1.34 and 0.15 kg for the 2 periods, respectively) after adjusting for lifestyle and dietary confounders. Increased consumption of fruit punch was also associated with greater weight gain compared with decreased consumption. After adjustment for potential confounders, women consuming 1 or more sugar-sweetened soft drinks per day had a relative risk [RR] of type 2 diabetes of 1.83 (95% confidence interval [CI], 1.42-2.36; P<.001 for trend) compared with those who consumed less than 1 of these beverages per month. Similarly, consumption of fruit punch was associated with increased diabetes risk (RR for > or =1 drink per day compared with <1 drink per month, 2.00; 95% CI, 1.33-3.03; P =.001). CONCLUSION Higher consumption of sugar-sweetened beverages is associated with a greater magnitude of weight gain and an increased risk for development of type 2 diabetes in women, possibly by providing excessive calories and large amounts of rapidly absorbable sugars. | Sugar-sweetened beverages, weight gain, and incidence of type 2 diabetes in young and middle-aged women. |
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0.1510767638683319, "27673": 0.19622190296649933, "27777": 0.12986256182193756, "27781": 0.9864287376403809, "27881": 0.040196798741817474, "28156": 0.3339579105377197, "28413": 1.0914250612258911, "28636": 0.5427330136299133, "28788": 0.16524957120418549, "28873": 0.2184450328350067, "29290": 0.14939609169960022} | 9831859 | Pancreatic stellate cells (PSC) produce the stromal reaction in pancreatic cancer, but their role in cancer progression is not fully elucidated. We examined the influence of PSCs on pancreatic cancer growth using (a) an orthotopic model of pancreatic cancer and (b) cultured human PSCs (hPSC) and human pancreatic cancer cell lines MiaPaCa-2 and Panc-1. Athymic mice received an intrapancreatic injection of saline, hPSCs, MiaPaCa-2 cells, or hPSCs + MiaPaCa-2. After 7 weeks, tumor size, metastases, and tumor histology were assessed. In vitro studies assessed the effect of cancer cell secretions on PSC migration and the effect of hPSC secretions on cancer cell proliferation, apoptosis, and migration. Possible mediators of the effects of hPSC secretions on cancer cell proliferation were examined using neutralizing antibodies. Compared with mice receiving MiaPaCa-2 cells alone, mice injected with hPSCs + MiaPaCa-2 exhibited (a) increased tumor size and regional and distant metastasis, (b) fibrotic bands (desmoplasia) containing activated PSCs within tumors, and (c) increased tumor cell numbers. In vitro studies showed that, in the presence of pancreatic cancer cells, PSC migration was significantly increased. Furthermore, hPSC secretions induced the proliferation and migration, but inhibited the apoptosis, of MiaPaCa-2 and Panc-1 cells. The proliferative effect of hPSC secretions on pancreatic cancer cells was inhibited in the presence of neutralizing antibody to platelet-derived growth factor. Our studies indicate a significant interaction between pancreatic cancer cells and stromal cells (PSCs) and imply that pancreatic cancer cells recruit stromal cells to establish an environment that promotes cancer progression. | Pancreatic stellate cells: partners in crime with pancreatic cancer cells. |
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if preoperative statin treatment is associated with a reduction in systemic inflammatory response (SIR) and myocardial damage markers following cardiac surgery with cardiopulmonary bypass (CPB). METHODS We study a prospective cohort of 138 patients who underwent coronary and valvular surgery with CPB. We differentiate two study groups: patients with (group A, n=72) or without (group B, n=66) statins. Plasma levels of pro-inflammatory interleukins (tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, IL-8 and IL-2R), creatine phosphokinase (CPK), CPK-MB and troponin I were measured before and 1, 6, 24 and >72 h after surgery. RESULTS The baseline, operative and postoperative morbidity and mortality characteristics were similar for both the groups. Group A had significantly lower postoperative levels of IL-6 than group B at 6h (68.8+/-5 pg ml(-1) vs 108.9+/-108 pg ml(-1), p=0.01), 24h (71.7+/-7 pg ml(-1) vs 110.4+/-106 pg ml(-1), p=0.01) and before hospital discharge (21.6+/-12 pg ml(-1) vs 32.8+/-27 pg ml(-1), p=0.005), as well as significantly lower average IL-6 levels in the first 24h following surgery (71.8+/-5 pgml(-1) vs 112.8+/-82 pg ml(-1), p=0.002). The postoperative CPK-MB at 24h (19.7+/-23 ng ml(-1) vs 33.1+/-32 ng ml(-1), p=0.02) and troponin I levels at the end of the intervention (2.2+/-2.2 ng ml(-1) vs 3.3+/-3.1 ng ml(-1), p=0.03) and at 24h (4.1+/-3.5 ng ml(-1) vs 6.6+/-8 ng ml(-1), p=0.04) were also significantly lower in the group treated with statins prior to surgery. CONCLUSIONS Preoperative treatment with statins is associated with a lower biochemical parameters of SIR and myocardial damage following cardiac surgery with CPB, regardless of it being coronary bypass grafting (CABG) or valvular surgery. | Preoperative statin treatment reduces systemic inflammatory response and myocardial damage in cardiac surgery. |
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0.10731173306703568, "23737": 0.0354953333735466, "23848": 0.5324648022651672, "23924": 0.8374842405319214, "23943": 0.3034266233444214, "24134": 0.06337817758321762, "24203": 0.25088030099868774, "24278": 0.09317722171545029, "24558": 0.48850810527801514, "24635": 0.083342544734478, "24710": 0.31560876965522766, "25095": 0.6112717390060425, "25206": 0.13414156436920166, "25524": 0.9886114001274109, "25837": 0.12384103983640671, "25925": 0.21372433006763458, "26282": 0.06886265426874161, "26458": 0.5995445251464844, "26835": 0.04674193635582924, "27605": 0.7674643993377686, "27691": 0.3339579105377197, "27793": 0.2800849378108978, "27965": 0.022212404757738113, "28086": 0.2741633653640747, "28516": 0.23864774405956268, "28637": 0.040196798741817474, "29003": 0.08064348995685577, "29098": 0.21135559678077698, "29206": 0.06154331564903259, "29336": 0.17922431230545044, "29458": 0.6070231795310974} | 9872468 | We present the latest version of the Molecular Evolutionary Genetics Analysis (Mega) software, which contains many sophisticated methods and tools for phylogenomics and phylomedicine. In this major upgrade, Mega has been optimized for use on 64-bit computing systems for analyzing larger datasets. Researchers can now explore and analyze tens of thousands of sequences in Mega The new version also provides an advanced wizard for building timetrees and includes a new functionality to automatically predict gene duplication events in gene family trees. The 64-bit Mega is made available in two interfaces: graphical and command line. The graphical user interface (GUI) is a native Microsoft Windows application that can also be used on Mac OS X. The command line Mega is available as native applications for Windows, Linux, and Mac OS X. They are intended for use in high-throughput and scripted analysis. Both versions are available from www.megasoftware.net free of charge. | MEGA7: Molecular Evolutionary Genetics Analysis Version 7.0 for Bigger Datasets. |
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"29292": 0.12384103983640671} | 9875570 | DNA replication fidelity is a key determinant of genome stability and is central to the evolution of species and to the origins of human diseases. Here we review our current understanding of replication fidelity, with emphasis on structural and biochemical studies of DNA polymerases that provide new insights into the importance of hydrogen bonding, base pair geometry, and substrate-induced conformational changes to fidelity. These studies also reveal polymerase interactions with the DNA minor groove at and upstream of the active site that influence nucleotide selectivity, the efficiency of exonucleolytic proofreading, and the rate of forming errors via strand misalignments. We highlight common features that are relevant to the fidelity of any DNA synthesis reaction, and consider why fidelity varies depending on the enzymes, the error, and the local sequence environment. | DNA replication fidelity |
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able to bind and kill microorganisms. It is believed that they are generated by neutrophils undergoing cell death, allowing these dying or dead cells to kill microbes. We show that, following priming with granulocyte/macrophage colony-stimulating factor (GM-CSF) and subsequent short-term toll-like receptor 4 (TLR4) or complement factor 5a (C5a) receptor stimulation, viable neutrophils are able to generate NETs. Strikingly, NETs formed by living cells contain mitochondrial, but no nuclear, DNA. Pharmacological or genetic approaches to block reactive oxygen species (ROS) production suggested that NET formation is ROS dependent. Moreover, neutrophil populations stimulated with GM-CSF and C5a showed increased survival compared with resting neutrophils, which did not generate NETs. In conclusion, mitochondrial DNA release by neutrophils and NET formation do not require neutrophil death and do also not limit the lifespan of these cells. | Viable neutrophils release mitochondrial DNA to form neutrophil extracellular traps |
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How histone variants such as H2AZ are incorporated into nucleosomes has been obscure. We have found that Swr1, a Swi2/Snf2-related adenosine triphosphatase, is the catalytic core of a multisubunit, histone-variant exchanger that efficiently replaces conventional histone H2A with histone H2AZ in nucleosome arrays. Swr1 is required for the deposition of histone H2AZ at specific chromosome locations in vivo, and Swr1 and H2AZ commonly regulate a subset of yeast genes. These findings define a previously unknown role for the adenosine triphosphate-dependent chromatin remodeling machinery. | ATP-driven exchange of histone H2AZ variant catalyzed by SWR1 chromatin remodeling complex. |
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We show that the H2A-H2B binding activity that is central to FACT function resides in short acidic regions near the C termini of each subunit. Mutations throughout these regions affect binding and cause correlated phenotypes that range from mild to lethal, with the largest individual contributions unexpectedly coming from an aromatic residue and a nearby carboxylate residue within each domain. Spt16 and Pob3 bind overlapping sites on H2A-H2B, and Spt16-Pob3 heterodimers simultaneously bind two H2A-H2B dimers, the same stoichiometry as the components of a nucleosome. An Spt16:H2A-H2B crystal structure explains the biochemical and genetic data, provides a model for Pob3 binding, and implies a mechanism for FACT reorganization that we confirm biochemically. Moreover, unexpected similarity to binding of ANP32E and Swr1 with H2A.Z-H2B reveals that diverse H2A-H2B chaperones use common mechanisms of histone binding and regulating nucleosome functions. | FACT Disrupts Nucleosome Structure by Binding H2A-H2B with Conserved Peptide Motifs. |
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"27295": 0.16607704758644104, "27321": 0.5191890001296997, "27891": 0.6139179468154907, "28155": 0.6358738541603088, "28156": 0.18573370575904846, "29021": 0.7201237678527832} | 9899292 | Metformin is a widely used drug for treatment of type 2 diabetes with no defined cellular mechanism of action. Its glucose-lowering effect results from decreased hepatic glucose production and increased glucose utilization. Metformin's beneficial effects on circulating lipids have been linked to reduced fatty liver. AMP-activated protein kinase (AMPK) is a major cellular regulator of lipid and glucose metabolism. Here we report that metformin activates AMPK in hepatocytes; as a result, acetyl-CoA carboxylase (ACC) activity is reduced, fatty acid oxidation is induced, and expression of lipogenic enzymes is suppressed. Activation of AMPK by metformin or an adenosine analogue suppresses expression of SREBP-1, a key lipogenic transcription factor. In metformin-treated rats, hepatic expression of SREBP-1 (and other lipogenic) mRNAs and protein is reduced; activity of the AMPK target, ACC, is also reduced. Using a novel AMPK inhibitor, we find that AMPK activation is required for metformin's inhibitory effect on glucose production by hepatocytes. In isolated rat skeletal muscles, metformin stimulates glucose uptake coincident with AMPK activation. Activation of AMPK provides a unified explanation for the pleiotropic beneficial effects of this drug; these results also suggest that alternative means of modulating AMPK should be useful for the treatment of metabolic disorders. | Role of AMP-activated protein kinase in mechanism of metformin action. |
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The aim of this study was to evaluate the safety and efficacy of interferon alfa (IFN-alpha) in children with chronic hepatitis B and increased transaminase levels. METHODS Children were given either IFN-alpha2b (6 megaunits/m2 thrice weekly for 24 weeks) or no treatment. Clearance of markers of viral replication was evaluated 24 weeks after therapy and after 48 weeks of observation in controls. RESULTS Of 149 children enrolled, 144 were evaluable (70 treated and 74 controls). Serum hepatitis B e antigen and viral DNA became negative in 26% of treated children and 11% of controls (P < 0.05). Serum aminotransferase levels normalized and liver histology improved among responders. Hepatitis B surface antigen became undetectable in 10% of treated patients and 1% of controls. Female gender and interferon treatment were the only significant predictors of response. Ethnic origin, baseline aminotransferase level, initial DNA levels, and histology did not correlate with response. Most adverse reactions were mild or moderate, and dose was reduced in 24% of children. CONCLUSIONS In children with chronic hepatitis B, INF-alpha promotes loss of viral replication markers and surface antigen and improves aminotransferases and histology. | Interferon alfa therapy for chronic hepatitis B in children: a multinational randomized controlled trial. |
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Designing therapeutic interventions that achieve this goal has proven challenging, but now a greater understanding of the complexities of immune responses is beginning to produce some notable breakthroughs. ImmTACs (immune-mobilising monoclonal TCRs against cancer) are a new class of bispecific reagents, based on soluble monoclonal T cell receptors, which have been engineered to possess extremely high affinity for cognate tumour antigen. In this way, ImmTACs overcome the problem of low affinity tumour-specific T cells imposed by thymic selection and provide access to the large number of antigens presented as peptide-HLA complexes. Once bound to tumour cells the anti-CD3 effector end of the ImmTAC drives recruitment of polyclonal T cells to the tumour site, leading to a potent redirected T cell response and tumour cell destruction. Extensive in vitro testing coupled with promising early clinical data has provided an enhanced appreciation of ImmTAC function in vivo and indicates their potential therapeutic benefit in terms of a durable response and ultimately the breaking of T cell tolerance. This review introduces ImmTACs in the context of immunotherapy, and outlines their design, construction and mechanism of action, as well as examining target selection and aspects of preclinical safety testing. | ImmTACs for targeted cancer therapy: Why, what, how, and which. |
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Here we show that hematopoietic stem cells (HSCs) in Angptl3-null mice are decreased in number and quiescence. HSCs transplanted into Angptl3-null recipient mice exhibited impaired repopulation. Bone marrow sinusoidal endothelial cells express high levels of Angptl3 and are adjacent to HSCs. Importantly, bone marrow stromal cells or endothelium deficient in Angptl3 have a significantly decreased ability to support the expansion of repopulating HSCs. Angptl3 represses the expression of the transcription factor Ikaros, whose unregulated overexpression diminishes the repopulation activity of HSCs. Angptl3, as an extrinsic factor, thus supports the stemness of HSCs in the bone marrow niche. | Angiopoietin-like protein 3 supports the activity of hematopoietic stem cells in the bone marrow niche. |
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0.11778303235769272, "25409": 0.7881022095680237, "25456": 0.9621002674102783, "25468": 0.2830325961112976, "25605": 0.02887592278420925, "25708": 0.21372433006763458, "25778": 0.16359257698059082, "26163": 0.11168810725212097, "26402": 0.2317005842924118, "26419": 0.05046287178993225, "26651": 0.1905880719423294, "27144": 1.2797396183013916, "28027": 0.037378571927547455, "28517": 0.06795065850019455, "28518": 0.05046287178993225, "28775": 0.13499516248703003, "29191": 0.03831886500120163, "29235": 0.3269403576850891, "29521": 0.11951763927936554} | 9929089 | BACKGROUND Patients with advanced or metastatic non-small cell lung cancer (NSCLC) can develop acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib. Here, we report the successful treatment with alternating chemotherapy and TKIs of two cases of advanced NSCLC who developed resistance to TKI. CASE PRESENTATION Two patients with advanced or metastatic NSCLC were treated with palliative chemotherapy followed by erlotinib/gefitinib. When TKI therapy failed, two cycles of chemotherapy were provided, which were followed by re-challenge with erlotinib or gefitinib. CONCLUSION NSCLC patients with acquired TKI resistance should be managed aggressively whenever possible. Subsequent chemotherapy and target treatment is one of the reasonable choices for those with an initial dramatic clinical response with erlotinib/gefitinib treatment. Further studies are warranted to substantiate the association of erlotinib /gefitinib treatment with the efficacy of NSCLC patients with acquired TKI failure. | Subsequent chemotherapy reverses acquired tyrosine kinase inhibitor resistance and restores response to tyrosine kinase inhibitor in advanced non-small-cell lung cancer |
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0.17840765416622162} | 9955779 | Combining DNA-demethylating agents (DNA methyltransferase inhibitors [DNMTis]) with histone deacetylase inhibitors (HDACis) holds promise for enhancing cancer immune therapy. Herein, pharmacologic and isoform specificity of HDACis are investigated to guide their addition to a DNMTi, thus devising a new, low-dose, sequential regimen that imparts a robust anti-tumor effect for non-small-cell lung cancer (NSCLC). Using in-vitro-treated NSCLC cell lines, we elucidate an interferon α/β-based transcriptional program with accompanying upregulation of antigen presentation machinery, mediated in part through double-stranded RNA (dsRNA) induction. This is accompanied by suppression of MYC signaling and an increase in the T cell chemoattractant CCL5. Use of this combination treatment schema in mouse models of NSCLC reverses tumor immune evasion and modulates T cell exhaustion state towards memory and effector T cell phenotypes. Key correlative science metrics emerge for an upcoming clinical trial, testing enhancement of immune checkpoint therapy for NSCLC. | Epigenetic Therapy Ties MYC Depletion to Reversing Immune Evasion and Treating Lung Cancer |
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highlight the notion that peroxisome proliferator-activated receptors gamma (PPARγ) has protective properties in the pathophysiology of osteoarthritis (OA). The aim of this study was to define the roles of PPARγ in AGEs-induced inflammatory response in human chondrocytes. METHODS Primary human chondrocytes were stimulated with AGEs in the presence or absence of neutralizing antibody against RAGE (anti-RAGE), MAPK specific inhibitors and PPARγ agonist pioglitazone. The expression of IL-1, MMP-13, TNF-α, PPARγ, nuclear NF-κB p65 and cytosol IκBα was determined by western blotting and real-time PCR. RESULTS AGEs could enhance the expression of IL-1, TNF-α, and MMP-13, but the level of PPARγ was decreased in a time- and dose-dependent manner, which was inhibited by anti-RAGE, SB203580 (P38 MAPK specific inhibitor) and SP600125 (a selective inhibitor of JNK). PPARγ agonist pioglitazone could inhibit the effects of AGEs-induced inflammatory response and PPARγ down-regulation. In human chondrocytes, AGEs could induce cytosol IκBα degradation and increase the level of nuclear NF-κB p65, which was inhibited by PPARγ agonist pioglitazone. CONCLUSIONS In primary human chondrocytes, AGEs could down-regulate PPARγ expression and increase the inflammatory mediators, which could be reversed by PPARγ agonist pioglitazone. Activation of RAGE by AGEs triggers a cascade of downstream signaling, including MAPK JNK/ p38, PPARγ and NF-κB. Taken together, PPARγ could be a potential target for pharmacologic intervention in the treatment of OA. | The Role of PPARγ in Advanced Glycation End Products-Induced Inflammatory Response in Human Chondrocytes |
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0.38308101892471313, "26708": 0.46363574266433716, "27144": 0.23402166366577148, "27162": 0.15693697333335876, "27292": 0.5489565134048462, "27312": 0.06154331564903259, "27480": 0.5092619061470032, "27718": 0.23864774405956268, "27815": 0.8517522215843201, "27969": 0.2223619967699051, "28086": 0.06246116757392883, "28282": 0.06246116757392883, "28350": 0.09850110858678818, "28353": 0.1011524572968483, "28389": 0.0354953333735466, "28835": 1.1689931154251099, "28926": 0.1693800985813141, "29242": 0.25088030099868774, "29474": 0.659380316734314} | 9967265 | BACKGROUND Patent ductus arteriosus (PDA) with significant left to right shunt in preterm infants increases morbidity and mortality. Early closure of the ductus arteriosus may be achieved pharmacologically using cyclooxygenase inhibitors or by surgery. The efficacy of both treatment modalities is well established. However, the preferred initial treatment of a symptomatic PDA in a preterm infant, surgical ligation or treatment with indomethacin, has not been well established. OBJECTIVES To compare the effect of surgical ligation of PDA vs. medical treatment with cyclooxygenase inhibitors (using indomethacin, ibuprofen, or mefenamic acid), each used as the initial treatment, on neonatal mortality in preterm infants with a symptomatic PDA. SEARCH STRATEGY The standard search strategy of the Cochrane Neonatal Review Group was used. This included search of electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2007), MEDLINE (1966 - July 2007), CINAHL (1982 - July 2007), EMBASE (1980 - July 2007); and hand search of abstracts of Pediatric Academic Societies annual meetings published in Pediatric Research (1990 - April 2002) or on line from May 2002 -July 2007. No language restrictions were applied. SELECTION CRITERIA All trials 1) using randomized or quasi-randomized patient allocation, 2) in preterm infants < 37 weeks gestational age or low-birth-weight infants (< 2500 grams) with symptomatic PDA in the neonatal period (< 28 days) and 3) comparing surgical ligation with medical treatment with cyclooxygenase inhibitors, each used as the initial treatment for closure of PDA. DATA COLLECTION AND ANALYSIS Assessment of methodological quality and extraction of data for included trials was undertaken independently by the authors. RevMan 4.1 was used for analysis of the data. MAIN RESULTS Only one study, trial B in the report of Gersony 1983, was found eligible. No additional studies were identified in the literature searches performed in July 2007. The trial compared the effect of surgical ligation of PDA vs. medical treatment with indomethacin, each used as the primary treatment. No trials comparing surgery to other cyclooxygenase inhibitors (ibuprofen, mefenamic acid) were found. Trial B of Gersony 1983 enrolled 154 infants. The study found no statistically significant difference between surgical closure and indomethacin treatment in mortality during hospital stay, chronic lung disease, other bleeding, necrotizing enterocolitis, sepsis, creatinine level, or intraventricular hemorrhage. There was a statistically significant increase in the surgical group in incidence of pneumothorax [RR 2.68 (95% CI 1.45, 4.93); RD 0.25 (95% CI 0.11, 0.38); NNH 4 (95% CI 3, 9)] and retinopathy of prematurity stage III and IV [RR 3.80 (95% CI 1.12, 12.93); RD 0.11 (95% CI 0.02, 0.20), NNH 9 (95% CI 5, 50] compared to the indomethacin group. There was as expected a statistically significant decrease in failure of ductal closure rate in the surgical group as compared to the indomethacin group: [RR 0.04 (95% CI 0.01, 0.27); RD -0.32 (95% CI -0.43, -0.21), NNT 3 (95% CI 2, 4)]. AUTHORS' CONCLUSIONS The data regarding net benefit/harm are insufficient to make a conclusion as to whether surgical ligation or medical treatment with indomethacin is preferred as initial treatment for symptomatic PDA in preterm infants. It should be noted that three recent observational studies indicated an increased risk for one or more of the following outcomes associated with PDA ligation; chronic lung disease, retinopathy of prematurity and neurosensory impairment . It is possible that the duration of the "waiting-time" and transport to another facility with surgical capacity to have the PDA ligated could adversely affect outcomes, as could the perioperative care. | Surgical versus medical treatment with cyclooxygenase inhibitors for symptomatic patent ductus arteriosus in preterm infants. |
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"28252": 0.015504186972975731, "28436": 0.17267228662967682, "28475": 0.07250232994556427, "28648": 0.11343330889940262, "28739": 0.2881702482700348, "28987": 0.022212404757738113, "29060": 0.272677481174469, "29458": 0.8666408061981201, "29490": 0.02887592278420925, "29494": 0.27934664487838745, "29561": 0.8764448165893555, "29566": 0.056018441915512085} | 9973014 | Purpose. To demonstrate how correlations among predictor variables in a population pharmacokinetic model affect the ability to discern which covariates should enter into the structural pharmacokinetic model. Methods. Monte Carlo simulation was used to generate multiple-dose concentration-time data similar to that seen in a Phase III clinical trial. The drugs' pharmacokinetics were dependent on two covariates. Five data sets were simulated with increasing correlation between the two covariates. All data sets were analyzed using NONMEM both with and without inclusion of the covariates in the structural pharmacokinetic model. Summary measures for ill-conditioning and sensitivity analysis were used to examine how increasing correlation among covariates affects the accuracy and precision of the parameter estimates. Results. When covariates were included in the structural pharmacokinetic model and the correlation between covariates increased, the standard error of the parameter estimates increased and the value of parameter estimates themselves became increasingly biased. When the correlation between predictor variables was 0.75, the standard errors of the parameter estimates were too large to declare statistical significance. Conclusions. Correlations among predictor variables greater than 0.5 when entered into the model simultaneously should be a warning to researchers because the (1) the accuracy of the parameter estimates themselves may be biased and (2) the precision of the estimates may be inflated due to ill-conditioning. | The Effect of Collinearity on Parameter Estimates in Nonlinear Mixed Effect Models |
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0.08064348995685577} | 9976969 | Psychiatric illness is a significant risk factor for both attempted and completed suicide and psychotropic medications account for 80% of all drug overdoses involving prescription medications. One challenge facing clinicians is to balance the benefit of treatment against the risk of drug overdose. The aim of the present study was to compare the age and gender distribution of patients prescribed psychotropic drugs with patients attempting and completing suicide with these drugs. Data were obtained from the Australian census and studies of general practitioner prescribing, patients who committed suicide or presented with self-poisoning within a defined geographic area. The characteristics of these populations were compared to calculate odds ratios for attempting or completing suicide with psychotropic drugs, before and after correction for rates of prescription, in different age and gender groups. The odds ratios (ORs) for self-poisoning were higher for those aged less than 45 years and yet this group was least likely to be prescribed psychotropic drugs. Men had a much higher rate of completed suicide using more lethal methods. The ORs for self-poisoning and suicide with psychotropic drugs, after correction for prescription rates, for those aged 15 to 24 years were 11.1 and 1.7, respectively. Those aged 25 to 44 years had ORs of 4.9 and 4.3, and, by contrast, those over 75 years had ORs of 0.03 and 0. Women were slightly more likely to poison themselves with psychotropic drugs (OR 1.2). However, the situation reversed after correction for prescription rates (OR 0.69). It is concluded that greater caution should be exercised in prescribing for those under 45 years of age, given their relatively higher risk of drug overdose, and that the least toxic compounds should be used. The risk (of self-poisoning) among the elderly may have been overstated, so that some patients may have been denied the benefit of adequate treatment. | An analysis of age and gender influences on the relative risk for suicide and psychotropic drug self-poisoning. |
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"25243": 0.058784693479537964, "25605": 0.08064348995685577, "25722": 0.07612881064414978, "25775": 0.6461620330810547, "25969": 0.2786078155040741, "26045": 0.26146242022514343, "26290": 0.014542185701429844, "26402": 0.18167030811309814, "26604": 0.12384103983640671, "26651": 0.4938860833644867, "26770": 0.006812678650021553, "26835": 1.2471669912338257, "27285": 0.022212404757738113, "27325": 0.45870962738990784, "28064": 0.2160874605178833, "28170": 0.26820653676986694, "28283": 0.2763880789279938, "28696": 0.3864043951034546, "28837": 0.3560888469219208, "28873": 0.1718502640724182, "29090": 0.151916041970253, "29172": 0.026025565341114998, "29486": 0.014542185701429844} | 9977329 | The host response to pathogens involves complex inflammatory responses and immune reactions. While these are central to host defense and vital to clearing infections, they are often accompanied by injury to surrounding tissue. Most organ systems can tolerate these responses without permanent consequences. However, there are sites that limit the spread of inflammation because it can threaten organ function. The most prominent examples of these are the eye, brain, and reproductive organs (testis, ovary), where even minor bouts of inflammation can have long-term consequences for the survival of the organism. In these organs immune responses either do not proceed, or proceed in a manner different from other areas; thus, they are called "immunologically privileged. " Here a functioning immune response can be the culprit that leads to disease. | Cell death and immune privilege. |
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"28228": 0.029824240133166313, "28405": 0.347847044467926, "28522": 0.6624060273170471, "28573": 0.38905516266822815, "28625": 0.8682814836502075, "28691": 0.11865071207284927, "28788": 0.13499516248703003, "29129": 0.6553317308425903, "29235": 0.36967599391937256, "29280": 0.4926934838294983, "29290": 0.2105647772550583, "29415": 0.259204238653183} | 9988425 | Pluripotent mouse embryonic stem (ES) cells multiply in simple monoculture by symmetrical divisions. In vivo, however, stem cells are generally thought to depend on specialised cellular microenvironments and to undergo predominantly asymmetric divisions. Ex vivo expansion of pure populations of tissue stem cells has proven elusive. Neural progenitor cells are propagated in combination with differentiating progeny in floating clusters called neurospheres. The proportion of stem cells in neurospheres is low, however, and they cannot be directly observed or interrogated. Here we demonstrate that the complex neurosphere environment is dispensable for stem cell maintenance, and that the combination of fibroblast growth factor 2 (FGF-2) and epidermal growth factor (EGF) is sufficient for derivation and continuous expansion by symmetrical division of pure cultures of neural stem (NS) cells. NS cells were derived first from mouse ES cells. Neural lineage induction was followed by growth factor addition in basal culture media. In the presence of only EGF and FGF-2, resulting NS cells proliferate continuously, are diploid, and clonogenic. After prolonged expansion, they remain able to differentiate efficiently into neurons and astrocytes in vitro and upon transplantation into the adult brain. Colonies generated from single NS cells all produce neurons upon growth factor withdrawal. NS cells uniformly express morphological, cell biological, and molecular features of radial glia, developmental precursors of neurons and glia. Consistent with this profile, adherent NS cell lines can readily be established from foetal mouse brain. Similar NS cells can be generated from human ES cells and human foetal brain. The extrinsic factors EGF plus FGF-2 are sufficient to sustain pure symmetrical self-renewing divisions of NS cells. The resultant cultures constitute the first known example of tissue-specific stem cells that can be propagated without accompanying differentiation. These homogenous cultures will enable delineation of molecular mechanisms that define a tissue-specific stem cell and allow direct comparison with pluripotent ES cells. | Niche-Independent Symmetrical Self-Renewal of a Mammalian Tissue Stem Cell |
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This suggests that HCNE-rich regions may contain key regulatory controls involved in development. We explored this by examining histone methylation in mouse embryonic stem (ES) cells across 56 large HCNE-rich loci. We identified a specific modification pattern, termed "bivalent domains," consisting of large regions of H3 lysine 27 methylation harboring smaller regions of H3 lysine 4 methylation. Bivalent domains tend to coincide with TF genes expressed at low levels. We propose that bivalent domains silence developmental genes in ES cells while keeping them poised for activation. We also found striking correspondences between genome sequence and histone methylation in ES cells, which become notably weaker in differentiated cells. These results highlight the importance of DNA sequence in defining the initial epigenetic landscape and suggest a novel chromatin-based mechanism for maintaining pluripotency. | A Bivalent Chromatin Structure Marks Key Developmental Genes in Embryonic Stem Cells |
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0.2667117714881897, "26988": 1.0409941673278809, "27094": 0.1384023278951645, "27116": 0.31845372915267944, "27545": 0.19381128251552582, "28086": 0.18573370575904846, "28179": 0.2447827309370041, "28241": 0.10993985831737518, "28405": 0.29328158497810364, "28613": 0.6369074583053589, "28723": 0.0058422754518687725, "28788": 0.7629209756851196, "28815": 0.08064348995685577, "28873": 0.38574060797691345, "28991": 1.013020396232605} | 9997636 | The aim of this study was to confirm the presence of stem cells in the ovarian surface epithelium of patients with premature ovarian failure and no mature follicles and oocytes. In these patients, small round cells of unknown origin expressing SOX-2 marker of pluripotency were observed among the epithelial cells just after the ovarian surface epithelium scraping. These cells were an integral part of the ovarian surface epithelium. When the scraped cells were cultured in a medium with added follicular fluid to provide some ovarian niche, primitive oocyte-like cells and typical round-shaped cell clusters positively stained on alkaline phosphatase, and markers of pluripotency, such as SOX-2 and SSEA-4, were developed. These markers were expressed early and also later in the culture. Single oocyte-like cells expressed genes OCT4A, SOX-2, NANOG, NANOS, STELLA, CD9, LIN28, KLF4, GDF3, and MYC, characteristic for pluripotent stem cells. The results of this study confirmed the presence of putative stem cells in the ovarian surface epithelium of these patients and provided some basis to create a stem cell line in the future. | Ovarian Surface Epithelium in Patients with Severe Ovarian Infertility: A Potential Source of Cells Expressing Markers of Pluripotent/Multipotent Stem Cells |
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Despite this variability, neural circuits form that are functional and remarkably robust. One way in which neurons deal with variability in their inputs is through compensatory, homeostatic changes in their electrical properties. Here, we show that neurons also make compensatory adjustments to their structure. We analysed the development of dendrites on an identified central neuron (aCC) in the late Drosophila embryo at the stage when it receives its first connections and first becomes electrically active. At the same time, we charted the distribution of presynaptic sites on the developing postsynaptic arbor. Genetic manipulations of the presynaptic partners demonstrate that the postsynaptic dendritic arbor adjusts its growth to compensate for changes in the activity and density of synaptic sites. Blocking the synthesis or evoked release of presynaptic neurotransmitter results in greater dendritic extension. Conversely, an increase in the density of presynaptic release sites induces a reduction in the extent of the dendritic arbor. These growth adjustments occur locally in the arbor and are the result of the promotion or inhibition of growth of neurites in the proximity of presynaptic sites. We provide evidence that suggest a role for the postsynaptic activity state of protein kinase A in mediating this structural adjustment, which modifies dendritic growth in response to synaptic activity. These findings suggest that the dendritic arbor, at least during early stages of connectivity, behaves as a homeostatic device that adjusts its size and geometry to the level and the distribution of input received. The growing arbor thus counterbalances naturally occurring variations in synaptic density and activity so as to ensure that an appropriate level of input is achieved. | Structural Homeostasis: Compensatory Adjustments of Dendritic Arbor Geometry in Response to Variations of Synaptic Input |
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0.16442140936851501, "29361": 0.08064348995685577} | 10010651 | Cancer survivors are often highly motivated to seek information about food choices, physical activity, and dietary supplements to improve their treatment outcomes, quality of life, and overall survival. To address these concerns, the American Cancer Society (ACS) convened a group of experts in nutrition, physical activity, and cancer survivorship to evaluate the scientific evidence and best clinical practices related to optimal nutrition and physical activity after the diagnosis of cancer. This report summarizes their findings and is intended to present health care providers with the best possible information with which to help cancer survivors and their families make informed choices related to nutrition and physical activity. The report discusses nutrition and physical activity guidelines during the continuum of cancer care, briefly highlighting important issues during cancer treatment and for patients with advanced cancer, but focusing largely on the needs of the population of individuals who are disease free or who have stable disease following their recovery from treatment. It also discusses select nutrition and physical activity issues such as body weight, food choices, food safety, and dietary supplements; issues related to selected cancer sites; and common questions about diet, physical activity, and cancer survivorship. | Nutrition and physical activity guidelines for cancer survivors. |
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10012166 | The ability to maintain a functional proteome, or proteostasis, declines during the ageing process. Damaged and misfolded proteins accumulate with age, impairing cell function and tissue homeostasis. The accumulation of damaged proteins contributes to multiple age-related diseases such as Alzheimer's, Parkinson's or Huntington's disease. Damaged proteins are degraded by the ubiquitin-proteasome system or through autophagy-lysosome, key components of the proteostasis network. Modulation of either proteasome activity or autophagic-lysosomal potential extends lifespan and protects organisms from symptoms associated with proteostasis disorders, suggesting that protein clearance mechanisms are directly linked to ageing and age-associated diseases. | The role of protein clearance mechanisms in organismal ageing and age-related diseases. |
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"27287": 0.7845434546470642, "27321": 0.1946154683828354, "27491": 0.3388410806655884, "27528": 0.06886265426874161, "27531": 0.11865071207284927, "27598": 0.6348392367362976, "28041": 0.15023678541183472, "28086": 0.0317181795835495, "28281": 0.02412080205976963, "28297": 0.669430673122406, "28424": 0.22937409579753876, "28548": 0.2231435477733612, "28577": 0.10203468054533005, "28591": 0.05139094591140747, "28667": 0.014542185701429844, "28691": 0.30486753582954407, "28696": 0.14264501631259918, "28788": 0.2089812457561493, "28805": 0.07793712615966797, "28964": 0.0029254043474793434, "29109": 0.02316705882549286, "29290": 0.4679262638092041, "29486": 0.20102575421333313, "29516": 0.03360854089260101} | 10015292 | Highly regenerative tissues such as blood must possess effective DNA damage responses (DDR) that balance long-term regeneration with protection from leukemogenesis. Hematopoietic stem cells (HSCs) sustain life-long blood production, yet their response to DNA damage remains largely unexplored. We report that human HSCs exhibit delayed DNA double-strand break rejoining, persistent gammaH2AX foci, and enhanced p53- and ASPP1-dependent apoptosis after gamma-radiation compared to progenitors. p53 inactivation or Bcl-2 overexpression reduced radiation-induced apoptosis and preserved in vivo repopulating HSC function. Despite similar protection from irradiation-induced apoptosis, only Bcl-2-overexpressing HSCs showed higher self-renewal capacity, establishing that intact p53 positively regulates self-renewal independently from apoptosis. The reduced self-renewal of HSCs with inactivated p53 was associated with increased spontaneous gammaH2AX foci in secondary transplants of HSCs. Our data reveal distinct physiological roles of p53 that together ensure optimal HSC function: apoptosis regulation and prevention of gammaH2AX foci accumulation upon HSC self-renewal. | A distinctive DNA damage response in human hematopoietic stem cells reveals an apoptosis-independent role for p53 in self-renewal. |
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In addition, wildtype (WT) and NPY knockout (KO) mice were tested in locomotor monitors, elevated plus maze, inhibitory avoidance, acoustic startle, prepulse inhibition, and hot plate assays. One of the major findings was that the NPY KO mice have a reduced food intake relative to WT controls in response to fasting. Also, based on data from the behavioral models, the NPY KO mice may have an anxiogenic-like phenotype, and appear to be hypoalgesic in the hot plate paradigm. The data from these studies provide further evidence of involvement of NPY in energy balance, anxiety, and possibly nociception. | Behavioral characterization of neuropeptide Y knockout mice. |
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0.07431721687316895, "29206": 0.8949713706970215, "29598": 0.6583697199821472} | 10024681 | Deregulation of microRNA (miRNA) expression can have a critical role in carcinogenesis. Here we show in prostate cancer that miRNA-205 (miR-205) transcription is commonly repressed and the MIR-205 locus is hypermethylated. LOC642587, the MIR-205 host gene of unknown function, is also concordantly inactivated. We show that miR-205 targets mediator 1 (MED1, also called TRAP220 and PPARBP) for transcriptional silencing in normal prostate cells, leading to reduction in MED1 mRNA levels, and in total and active phospho-MED1 protein. Overexpression of miR-205 in prostate cancer cells negatively affects cell viability, consistent with a tumor suppressor function. We found that hypermethylation of the MIR-205 locus was strongly related with a decrease in miR-205 expression and an increase in MED1 expression in primary tumor samples (n=14), when compared with matched normal prostate (n=7). An expanded patient cohort (tumor n=149, matched normal n=30) also showed significant MIR-205 DNA methylation in tumors compared with normal, and MIR-205 hypermethylation is significantly associated with biochemical recurrence (hazard ratio=2.005, 95% confidence interval (1.109, 3.625), P=0.02), in patients with low preoperative prostate specific antigen. In summary, these results suggest that miR-205 is an epigenetically regulated tumor suppressor that targets MED1 and may provide a potential biomarker in prostate cancer management. | Epigenetic-induced repression of microRNA-205 is associated with MED1 activation and a poorer prognosis in localized prostate cancer |
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"25610": 0.0009760859538801014, "25714": 0.06154331564903259, "25930": 0.8821197748184204, "26402": 0.06977381557226181, "26646": 0.025073638185858727, "26657": 0.6064908504486084, "26773": 0.13755162060260773, "27321": 0.16442140936851501, "27484": 1.2318994998931885, "27641": 0.14433705806732178, "27781": 0.15526613593101501, "27854": 0.004870930220931768, "28228": 1.070887804031372, "28286": 0.9240728616714478, "28466": 0.27786844968795776, "28774": 0.04394211992621422, "28788": 0.6353566646575928, "28873": 0.22392450273036957, "29310": 0.20421554148197174, "29398": 0.5860490798950195, "29610": 0.26446542143821716} | 10029891 | In Major Depressive Disorder (MDD), the neuroendocrine and immune systems interactions are impaired. We investigated the pro/anti-inflammatory Th1/Th2 cytokine balance in MDD patients and in non-depressed control group. The MDD subjects showed higher levels of cortisol and TNF-alpha, increased CD3+CD8+ and NK percentages, diminished B cell counts and no significant variations in CD3+CD4+ lymphocyte. Moreover, higher levels of IL-4 and IL-13 (Th2) and significantly lower measurements of IL-2 and IFN-gamma (Th1) cytokines were also observed in the MDD group. Overall, we propose that all these changes could be related to the elevated cortisol levels seen in the MDD patients. Further studies are necessary to explore these findings and its implication in future therapeutic approach of MDD patients. | Th2 cytokine response in Major Depressive Disorder patients before treatment |
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http://www.ncbi.nlm.nih.gov/Structure/cdd/cdd.shtml. CDD provides annotation of protein sequences with the location of conserved domain footprints and functional sites inferred from these footprints. Pre-computed annotation is available via Entrez, and interactive search services accept single protein or nucleotide queries, as well as batch submissions of protein query sequences, utilizing RPS-BLAST to rapidly identify putative matches. CDD incorporates several protein domain and full-length protein model collections, and maintains an active curation effort that aims at providing fine grained classifications for major and well-characterized protein domain families, as supported by available protein three-dimensional (3D) structure and the published literature. To this date, the majority of protein 3D structures are represented by models tracked by CDD, and CDD curators are characterizing novel families that emerge from protein structure determination efforts. | CDD: conserved domains and protein three-dimensional structure |
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However, whether molecular diversity contributes to immune protection in invertebrates is unknown. We present evidence that Drosophila immune-competent cells have the potential to express more than 18,000 isoforms of the immunoglobulin (Ig)-superfamily receptor Down syndrome cell adhesion molecule (Dscam). Secreted protein isoforms of Dscam were detected in the hemolymph, and hemocyte-specific loss of Dscam impaired the efficiency of phagocytic uptake of bacteria, possibly due to reduced bacterial binding. Importantly, the molecular diversity of Dscam transcripts generated through a mechanism of alternative splicing is highly conserved across major insect orders, suggesting an unsuspected molecular complexity of the innate immune system of insects. | Extensive diversity of Ig-superfamily proteins in the immune system of insects. |
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0.052318159490823746, "26629": 1.1437997817993164, "26651": 0.0058422754518687725, "26745": 0.5729197263717651, "26835": 0.6639154553413391, "26986": 0.0606246218085289, "27152": 0.21135559678077698, "27325": 0.5209306478500366, "27781": 0.28450319170951843, "27937": 1.0403043031692505, "28024": 0.010684899985790253, "28293": 0.07341018319129944, "28389": 0.026025565341114998, "28637": 0.3464667797088623, "28664": 0.04394211992621422, "28873": 0.3297532796859741, "28896": 0.29255300760269165, "29490": 0.5607312321662903} | 10068634 | BACKGROUND Late April 2009, human infection with variant influenza virus A(H1N1)v emerged in the Northern Americas posing a threat that this virus may become the next pandemic influenza virus. OBJECTIVES To prepare laboratories for surge capacity for molecular diagnosis of patients suspected for A(H1N1)v infection in the Netherlands. STUDY DESIGN A panel of 10 blinded specimens containing seasonal A(H1N1) or A(H3N2), or A/Netherlands/602/2009(H1N1)v influenza virus, or negative control was distributed to the outbreak assistance laboratories (OAL) together with influenza virus A (M-gene), swine influenza virus A (NP-gene) and influenza virus A(H1N1)v (H1v-gene) specific primers and probes and protocol (CDC Atlanta, USA). Laboratories were asked to implement and test this protocol. RESULTS All OAL were able to detect A(H1N1)v using the CDC M-gene reagents, the majority with similar sensitivity as the in-house M-gene based assays. RT-PCRs used in routine diagnostic setting in the OAL specifically designed to detect H1, H3, or NS1 from seasonal influenza A viruses, did not or at very low level cross-react with A(H1N1)v. The CDC swine NP-gene and H1v-gene RT-PCRs showed somewhat reduced sensitivity compared to the CDC and in-house M-gene RT-PCRs. In contrast, in-house developed A(H1N1)v specific H1v-gene and N1v-gene RT-PCRs showed equal sensitivity to CDC and in-house M-gene RT-PCRs. CONCLUSIONS The Dutch OAL are prepared for detection and specific identification of A(H1N1)v, although some level of cross-reactivity was observed with seasonal influenza viruses. Additionally, M-gene based generic influenza A virus detection is recommended to be able to detect emerging influenza A viruses in routine settings. | Preparing the outbreak assistance laboratory network in the Netherlands for the detection of the influenza virus A(H1N1) variant. |
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0.27342069149017334, "29180": 0.7028654217720032, "29299": 0.19782574474811554, "29494": 0.4132472574710846} | 10071552 | BACKGROUND Taxing sugar-sweetened beverages (SSBs) has been proposed in high-income countries to reduce obesity and type 2 diabetes. We sought to estimate the potential health effects of such a fiscal strategy in the middle-income country of India, where there is heterogeneity in SSB consumption, patterns of substitution between SSBs and other beverages after tax increases, and vast differences in chronic disease risk within the population. METHODS AND FINDINGS Using consumption and price variations data from a nationally representative survey of 100,855 Indian households, we first calculated how changes in SSB price alter per capita consumption of SSBs and substitution with other beverages. We then incorporated SSB sales trends, body mass index (BMI), and diabetes incidence data stratified by age, sex, income, and urban/rural residence into a validated microsimulation of caloric consumption, glycemic load, overweight/obesity prevalence, and type 2 diabetes incidence among Indian subpopulations facing a 20% SSB excise tax. The 20% SSB tax was anticipated to reduce overweight and obesity prevalence by 3.0% (95% CI 1.6%-5.9%) and type 2 diabetes incidence by 1.6% (95% CI 1.2%-1.9%) among various Indian subpopulations over the period 2014-2023, if SSB consumption continued to increase linearly in accordance with secular trends. However, acceleration in SSB consumption trends consistent with industry marketing models would be expected to increase the impact efficacy of taxation, averting 4.2% of prevalent overweight/obesity (95% CI 2.5-10.0%) and 2.5% (95% CI 1.0-2.8%) of incident type 2 diabetes from 2014-2023. Given current consumption and BMI distributions, our results suggest the largest relative effect would be expected among young rural men, refuting our a priori hypothesis that urban populations would be isolated beneficiaries of SSB taxation. Key limitations of this estimation approach include the assumption that consumer expenditure behavior from prior years, captured in price elasticities, will reflect future behavior among consumers, and potential underreporting of consumption in dietary recall data used to inform our calculations. CONCLUSION Sustained SSB taxation at a high tax rate could mitigate rising obesity and type 2 diabetes in India among both urban and rural subpopulations. | Averting Obesity and Type 2 Diabetes in India through Sugar-Sweetened Beverage Taxation: An Economic-Epidemiologic Modeling Study |
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"28105": 0.9302552938461304, "28353": 0.11865071207284927, "28389": 0.2493593990802765, "28667": 0.09317722171545029, "28748": 1.024303913116455, "28775": 0.175953671336174, "28896": 0.7809720039367676, "29101": 0.7028654217720032, "29207": 0.45994341373443604, "29361": 0.02792670577764511} | 10071590 | We report a case of postvaccination acute myopericarditis in an adolescent. The patient presented with acute chest pain, diffuse ST-segment elevation, and elevated cardiac enzyme levels. Cardiac MRI was consistent with acute myocarditis. He recovered within a few days with nonsteroidal antiinflammatory treatment and remains clinically stable, with improvement of MRI findings at the 10-week follow-up. Postvaccination cases of myopericarditis reported in the pediatric literature are also reviewed. | Acute myopericarditis after multiple vaccinations in an adolescent: case report and review of the literature. |
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0.13243216276168823, "26451": 0.176772341132164, "26651": 0.1229778528213501, "27144": 0.09050461649894714, "27184": 0.15359249711036682, "27204": 0.08154398202896118, "27347": 0.022212404757738113, "27833": 0.043007105588912964, "28093": 0.469759464263916, "28155": 0.22157983481884003, "28353": 0.1930064558982849, "28548": 0.011650617234408855, "28613": 0.045809537172317505, "28696": 0.3027053773403168, "29048": 1.0960047245025635, "29166": 0.03925827145576477, "29361": 0.24631060659885406, "29458": 0.05417001247406006} | 10072941 | Epidemiological studies demonstrate that a lower blood pressure and decline in blood pressure over months or years are associated with higher mortality in dialysis patients. In contrast, randomized, controlled trials lack power to establish benefits of antihypertensive therapy. Patients on long-term dialysis participating in randomized, controlled trials and receiving antihypertensive drug therapy were the subject of this meta-analysis. Outcomes assessed were the hazard ratio of cardiovascular events and all-cause mortality in treated group compared with controls. Among 1202 patients who we identified in 5 studies, the overall benefit of antihypertensive therapy compared with the control or placebo group had a combined hazard ratio for cardiovascular events of 0.69 (95% CI: 0.56 to 0.84) using a fixed-effects model and 0.62 (95% CI: 0.45 to 0.86) using a random-effects model. In a sensitivity analysis, we found that the hypertensive group had a pooled hazard ratio of 0.49 (95% CI: 0.35 to 0.67), but when normotensives were included in the trial, lesser cardiovascular protection was seen (pooled hazard ratio of 0.86 [95% CI: 0.67 to 1.12]). Test for heterogeneity between hypertensive and "normotensive-included" groups was significant (P<0.006). Similar results were seen for risk ratio for death and cardiovascular events. There was evidence of publication bias based on Egger's test and funnel plot. Randomized trials suggested a benefit of antihypertensive therapy among hemodialysis patients. Adequately powered randomized trials are required to confirm these observations, especially among those with hypertension. | Cardiovascular protection with antihypertensive drugs in dialysis patients: systematic review and meta-analysis. |
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Recent reports have also begun to suggest that physiologically, and perhaps functionally, diverse forms of these cells may be present in the CNS. Our current understanding of astrocyte form and distribution is based predominantly on studies that used the astrocytic marker glial fibrillary acidic protein (GFAP) and on studies using metal-impregnation techniques. The prevalent opinion, based on studies using these methods, is that astrocytic processes overlap extensively and primarily share the underlying neuropil. However, both of these techniques have serious shortcomings for visualizing the interactions among these structurally complex cells. In the present study, intracellular injection combined with immunohistochemistry for GFAP show that GFAP delineates only approximately 15% of the total volume of the astrocyte. As a result, GFAP-based images have led to incorrect conclusions regarding the interaction of processes of neighboring astrocytes. To investigate these interactions in detail, groups of adjacent protoplasmic astrocytes in the CA1 stratum radiatum were injected with fluorescent intracellular tracers of distinctive emissive wavelengths and analyzed using three-dimensional (3D) confocal analysis and electron microscopy. Our findings show that protoplasmic astrocytes establish primarily exclusive territories. The knowledge of how the complex morphology of protoplasmic astrocytes affects their 3D relationships with other astrocytes, oligodendroglia, neurons, and vasculature of the brain should have important implications for our understanding of nervous system function. | Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains. |
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We found that Leptin Receptor (LepR) is a marker that highly enriches bone marrow MSCs. Approximately 0.3% of bone marrow cells were LepR(+) , 10% of which were CFU-Fs, accounting for 94% of bone marrow CFU-Fs. LepR(+) cells formed bone, cartilage, and adipocytes in culture and upon transplantation in vivo. LepR(+) cells were Scf-GFP(+), Cxcl12-DsRed(high), and Nestin-GFP(low), markers which also highly enriched CFU-Fs, but negative for Nestin-CreER and NG2-CreER, markers which were unlikely to be found in CFU-Fs. Fate-mapping showed that LepR(+) cells arose postnatally and gave rise to most bone and adipocytes formed in adult bone marrow, including bone regenerated after irradiation or fracture. LepR(+) cells were quiescent, but they proliferated after injury. Therefore, LepR(+) cells are the major source of bone and adipocytes in adult bone marrow. | Leptin-receptor-expressing mesenchymal stromal cells represent the main source of bone formed by adult bone marrow. |
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0.05417001247406006, "25952": 0.10906458646059036, "25971": 0.2089812457561493, "26083": 0.23710809648036957, "26296": 0.417115718126297, "26305": 1.0312920808792114, "26478": 0.5127768516540527, "26524": 0.15943801403045654, "26601": 0.13243216276168823, "26616": 0.6338034868240356, "26741": 0.34508460760116577, "26874": 0.42096930742263794, "28086": 0.029824240133166313, "28156": 0.45251765847206116, "28290": 0.2026219218969345, "28309": 1.1109062433242798, "28314": 0.4425300657749176, "28424": 0.1212492436170578, "28436": 0.21530038118362427, "28637": 1.0748957395553589, "28667": 0.8893690705299377, "28691": 0.09317722171545029, "28820": 0.034552380442619324, "29050": 0.8161250352859497} | 10086360 | Meiotic crossovers detected by pedigree analysis in the mouse MHC cluster into hotspots. To explore the properties of hotspots, we subjected the class II E(beta) gene to high-resolution sperm crossover analysis. We confirm the presence of a highly localized hotspot 1.0-1.6 kb wide in the second intron of E(beta) and show that it is flanked by DNA which is almost completely recombinationally inert. Mice heterozygous for haplotype s and another MHC haplotype show major haplotype-dependant variation in crossover rate but always the same hotspot, even in crosses including the highly diverged p haplotype. Crossovers in reciprocal orientations occur at similar rates but show different distributions across the hotspot, with the position of centre points in the two orientations shifted on average by 400 bp. This asymmetry results in crossover products showing biased gene conversion in favour of hotspot markers from the non-initiating haplotype, and supports the double-strand break repair model of recombination, with haplotype s as the most efficient crossover initiator. The detailed behaviour of the E(beta) hotspot, including evidence for highly localized recombination initiation, is strikingly similar to human hotspots. | High-resolution sperm typing of meiotic recombination in the mouse MHC Ebeta gene. |
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"26236": 1.1858406066894531, "26445": 0.10379679501056671, "26462": 0.5069117546081543, "26745": 0.07341018319129944, "26835": 0.0174254160374403, "26886": 0.3464667797088623, "26906": 0.1718502640724182, "27102": 1.202995777130127, "27144": 0.7086513638496399, "27159": 0.4556184411048889, "27528": 0.35745587944984436, "27794": 0.9958525896072388, "28086": 0.2822965085506439, "28155": 0.013579257763922215, "28254": 0.053244512528181076, "28353": 0.08064348995685577, "28723": 0.319873183965683, "28788": 0.15693697333335876, "29109": 0.13414156436920166, "29217": 0.21293537318706512, "29251": 0.07341018319129944, "29458": 0.10467668622732162, "29461": 0.987156867980957, "29513": 0.010684899985790253} | 10128893 | Allogeneic hematopoietic stem cell transplantation (HSCT) in thalassemia remains a challenge. We reported a single-centre case-control study of a large cohort of 516 children and adult patients treated with HSCT or blood transfusion support and iron chelation therapy; 258 patients (median age 12, range 1-45) underwent sibling (67%) or unrelated (33%) HSCT; 97 patients were adults (age ≥ 16 years). The median follow-up after HSCT was 11 years (range 1-30). The conditioning regimen was busulfan (80.6%) or treosulfan-based (19.4%). A cohort of 258 age-sex matched conventionally treated (CT) patients was randomly selected. In transplanted patients the 30-year overall survival (OS) and thalassemia-free survival (TFS) were 82.6 ± 2.7% and 77.8 ± 2.9%, compared to the OS of 85.3 ± 2.7% in CT patients (P = NS); The incidence of grade II-IV acute and chronic graft versus host disease (GvHD) was 23.6% and 12.9% respectively. The probability of rejection was 6.9%. Transplant-related mortality (TRM) (13.8%) was similar to the probability of dying of cardiovascular events in CT patients (12.2%). High-risk Pesaro score (class 3) was associated with lower OS (OR = 1.99, 95% C.I.=1.31-3.03) and TFS (OR = 1.54, 95% C.I.=1.12-2.12). In adult patients, the 23-years OS and TFS after HSCT were 70 ± 5% and 67.3 ± 5%, compared to 71.2 ± 5% of OS in CT (P = NS). Finally, treosulfan was associated with lower risk of acute GvHD (P = .004; OR = 0.28, 95% C.I.=0.12-0.67). In conclusion, the 30-year survival rate of ex-thalassemia patients after HSCT was similar to that expected in CT thalassemia patients, with the vast majority of HSCT survivors cured from thalassemia. | Long-term survival of beta thalassemia major patients treated with hematopoietic stem cell transplantation compared with survival with conventional treatment. |
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0.2696990668773651, "27754": 0.684319257736206, "28093": 0.4067663550376892, "28156": 0.19541899859905243, "28290": 0.2719337046146393, "28350": 0.04487626627087593, "28436": 0.5963221788406372, "28667": 0.46914875507354736, "28685": 0.26446542143821716, "28828": 0.4196864068508148, "29206": 0.18654440343379974, "29533": 1.1356772184371948} | 10145528 | ATM, the gene that is mutated in ataxia-telangiectasia, is associated with cerebellar degeneration, abnormal proliferation of small blood vessels, and cancer. These clinically important manifestations have stimulated interest in defining the sequence variation in the ATM gene. Therefore, we undertook a comprehensive survey of sequence variation in ATM in diverse human populations. The protein-encoding exons of the gene (9,168 bp) and the adjacent intron and untranslated sequences (14,661 bp) were analyzed in 93 individuals from seven major human populations. In addition, the coding sequence was analyzed in one chimpanzee, one gorilla, one orangutan, and one Old World monkey. In human ATM, 88 variant sites were discovered by denaturing high-performance liquid chromatography, which is 96%-100% sensitive for detection of DNA sequence variation. ATM was compared to 14 other autosomal genes for nucleotide diversity. The noncoding regions of ATM had diversity values comparable to other genes, but the coding regions had very low diversity, especially in the last 29% of the protein sequence. A test of the neutral evolution hypothesis, through use of the Hudson/Kreitman/Aguadé statistic, revealed that this region of the human ATM gene was significantly constrained relative to that of the orangutan, the Old World monkey, and the mouse, but not relative to that of the chimpanzee or the gorilla. ATM displayed extensive linkage disequilibrium, consistent with suppression of meiotic recombination at this locus. Seven haplotypes were defined. Two haplotypes accounted for 82% of all chromosomes analyzed in all major populations; two others carrying the same D126E missense polymorphism accounted for 33% of chromosomes in Africa but were never observed outside of Africa. The high frequency of this polymorphism may be due either to a population expansion within Africa or to selective pressure. | Global analysis of ATM polymorphism reveals significant functional constraint. |
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"28207": 0.4158279001712799, "28227": 0.1510767638683319, "28788": 0.4067663550376892, "28873": 0.37640097737312317, "28896": 0.20421554148197174, "29090": 0.13071982562541962, "29125": 0.7592713832855225, "29290": 0.8788808584213257, "29610": 0.14179791510105133} | 10162553 | Immunosuppressive drugs and cytotoxic chemotherapy agents are designed to kill or suppress autoreactive, alloaggressive, or hyperinflammatory T cells, or disseminated malignancies. However, they also cause severe immunological side effects ranging from interrupted thymopoiesis and general immunodeficiency to, paradoxically, autoimmunity. Consistent with the cross-talk between thymocytes and stromal cells, we now show that these common therapeutic agents have major effects on murine thymic epithelial cells (TEC), crucially required to rebuild immunity posttreatment. We show that the immunosuppressant cyclosporine A, which has been linked to a thymus-dependent autoimmune syndrome in some patients, causes extensive loss of autoimmune regulator (Aire(+)) tolerance-inducing MHC class II(high) medullary TEC (mTEC(high)). Post-cyclosporine A, Aire expression was restored within 7 days. Full recovery of the mTEC(high) subset occurred within 10 days and was linked to a decrease in a relatively resistant MHC class II(low) mTEC subset (mTEC(low)), consistent with a previously described precursor-product relationship. Cyclophosphamide and dexamethasone caused more extensive ablation of thymocytes and stromal cells but again severely depleted tolerance-inducing mTEC(high). Together, these data show that Aire(+) mTECs are highly sensitive to damage and that mTEC regeneration follows a conserved pattern regardless of the treatment regimen used. | Ablation and regeneration of tolerance-inducing medullary thymic epithelial cells after cyclosporine, cyclophosphamide, and dexamethasone treatment. |
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Approximately 75% of cells in a highly enriched long-term repopulating HSC (LT-HSC) pool (Lin(-)Sca1(+)c-Kit(hi)CD150(+)CD48(-)) are quiescent, with only a small percentage of the LT-HSCs in cycle. Transcription factor GATA-3 is known to be vital for the development of T cells at multiple stages in the thymus and for Th2 differentiation in the peripheral organs. Although it is well documented that GATA-3 is expressed in HSCs, a role for GATA-3 in any prethymic progenitor cell has not been established. In the present study, we show that Gata3-null mutant mice generate fewer LT-HSCs and that fewer Gata3-null LT-HSCs are in cycle. Furthermore, Gata3 mutant hematopoietic progenitor cells fail to be recruited into an increased cycling state after 5-fluorouracil-induced myelosuppression. Therefore, GATA-3 is required for the maintenance of a normal number of LT-HSCs and for their entry into the cell cycle. | GATA-3 regulates hematopoietic stem cell maintenance and cell-cycle entry. |
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0.5995445251464844} | 10165723 | PURPOSE The CpG island methylator phenotype (CIMP) may be associated with development of malignancy through coordinated inactivation of tumor suppressor and tumor-related genes (TRG) and methylation of multiple noncoding, methylated-in-tumor (MINT) loci. These epigenetic changes create a distinct CIMP pattern that has been linked to recurrence and survival in gastrointestinal cancers. Because epigenetic inactivation of TRGs also has been shown in malignant melanoma, we hypothesized the existence of a clinically significant CIMP in cutaneous melanoma progression. EXPERIMENTAL DESIGN The methylation status of the CpG island promoter region of TRGs related to melanoma pathophysiology (WIF1, TFPI2, RASSF1A, RARbeta2, SOCS1, and GATA4) and a panel of MINT loci (MINT1, MINT2, MINT3, MINT12, MINT17, MINT25, and MINT31) in primary and metastatic tumors of different clinical stages (n=122) was assessed. RESULTS Here, we show an increase in hypermethylation of the TRGs WIF1, TFPI2, RASSF1A, and SOCS1 with advancing clinical tumor stage. Furthermore, we find a significant positive association between the methylation status of MINT17, MINT31, and TRGs. The methylation status of MINT31 is associated with disease outcome in stage III melanoma. CONCLUSIONS These findings show the significance of a CIMP pattern that is associated with advancing clinical stage of malignant melanoma. Future prospective large-scale studies may determine if CIMP-positive primary melanomas are at high risk of metastasis or recurrence. | CpG island methylator phenotype predicts progression of malignant melanoma. |
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0.9302552938461304, "25117": 0.08961215615272522, "25409": 0.7791815400123596, "25456": 0.8641747236251831, "25468": 0.18978065252304077, "25524": 0.5729197263717651, "25714": 0.22626367211341858, "25778": 0.13243216276168823, "25937": 0.1212492436170578, "26402": 0.6813592314720154, "26982": 0.053244512528181076, "27144": 0.3353555500507355, "27179": 0.6369074583053589, "27292": 0.8400169610977173, "27642": 0.1229778528213501, "27711": 0.8169882297515869, "27717": 0.0009760859538801014, "27781": 0.08782484382390976, "27854": 0.4093637466430664, "27881": 0.07250232994556427, "28207": 0.025073638185858727, "28282": 0.0058422754518687725, "28696": 0.0174254160374403, "29516": 1.1635169982910156} | 10169908 | PURPOSE We have previously identified solute-linked carrier family A1 member 5 (SLC1A5) as an overexpressed protein in a shotgun proteomic analysis of stage I non-small cell lung cancer (NSCLC) when compared with matched controls. We hypothesized that overexpression of SLC1A5 occurs to meet the metabolic demand for lung cancer cell growth and survival. EXPERIMENTAL DESIGN To test our hypothesis, we first analyzed the protein expression of SLC1A5 in archival lung cancer tissues by immunohistochemistry and immunoblotting (N = 98) and in cell lines (N = 36). To examine SLC1A5 involvement in amino acid transportation, we conducted kinetic analysis of l-glutamine (Gln) uptake in lung cancer cell lines in the presence and absence of a pharmacologic inhibitor of SLC1A5, gamma-l-Glutamyl-p-Nitroanilide (GPNA). Finally, we examined the effect of Gln deprivation and uptake inhibition on cell growth, cell-cycle progression, and growth signaling pathways of five lung cancer cell lines. RESULTS Our results show that (i) SLC1A5 protein is expressed in 95% of squamous cell carcinomas (SCC), 74% of adenocarcinomas (ADC), and 50% of neuroendocrine tumors; (ii) SLC1A5 is located at the cytoplasmic membrane and is significantly associated with SCC histology and male gender; (iii) 68% of Gln is transported in a Na(+)-dependent manner, 50% of which is attributed to SLC1A5 activity; and (iv) pharmacologic and genetic targeting of SLC1A5 decreased cell growth and viability in lung cancer cells, an effect mediated in part by mTOR signaling. CONCLUSIONS These results suggest that SLC1A5 plays a key role in Gln transport controlling lung cancer cells' metabolism, growth, and survival. | SLC1A5 mediates glutamine transport required for lung cancer cell growth and survival. |
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0.08513788133859634, "26408": 0.3084607720375061, "26524": 0.0174254160374403, "26534": 0.09495500475168228, "26601": 0.07159364968538284, "26773": 0.5272908806800842, "26874": 0.3864043951034546, "27166": 1.1369311809539795, "27521": 1.158010721206665, "27642": 0.11691460013389587, "27854": 0.19862671196460724, "28024": 0.5472630262374878, "28079": 0.08871890604496002, "28616": 1.1487655639648438, "28691": 0.4093637466430664, "29228": 0.11951763927936554} | 10189634 | CENP-A chromatin forms the foundation for kinetochore assembly. Replication-independent incorporation of CENP-A at centromeres depends on its chaperone HJURP(Scm3), and Mis18 in vertebrates and fission yeast. The recruitment of Mis18 and HJURP(Scm3) to centromeres is cell cycle regulated. Vertebrate Mis18 associates with Mis18BP1(KNL2), which is critical for the recruitment of Mis18 and HJURP(Scm3). We identify two novel fission yeast Mis18-interacting proteins (Eic1 and Eic2), components of the Mis18 complex. Eic1 is essential to maintain Cnp1(CENP-A) at centromeres and is crucial for kinetochore integrity; Eic2 is dispensable. Eic1 also associates with Fta7(CENP-Q/Okp1), Cnl2(Nkp2) and Mal2(CENP-O/Mcm21), components of the constitutive CCAN/Mis6/Ctf19 complex. No Mis18BP1(KNL2) orthologue has been identified in fission yeast, consequently it remains unknown how the key Cnp1(CENP-A) loading factor Mis18 is recruited. Our findings suggest that Eic1 serves a function analogous to that of Mis18BP1(KNL2), thus representing the functional counterpart of Mis18BP1(KNL2) in fission yeast that connects with a module within the CCAN/Mis6/Ctf19 complex to allow the temporally regulated recruitment of the Mis18/Scm3(HJURP) Cnp1(CENP-A) loading factors. The novel interactions identified between CENP-A loading factors and the CCAN/Mis6/Ctf19 complex are likely to also contribute to CENP-A maintenance in other organisms. | Eic1 links Mis18 with the CCAN/Mis6/Ctf19 complex to promote CENP-A assembly |
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"29021": 0.10291612148284912, "29171": 1.0815403461456299, "29222": 0.23864774405956268, "29391": 0.2018241584300995, "29720": 0.5827828645706177} | 10190462 | Background: Reduced brain insulin signaling and low CSF-to-plasma insulin ratios have been observed in patients with Alzheimer disease (AD). Furthermore, intracerebroventricular or IV insulin administration improve memory, alter evoked potentials, and modulate neurotransmitters, possibly by augmenting low brain levels. After intranasal administration, insulin-like peptides follow extracellular pathways to the brain within 15 minutes. Objective: We tested the hypothesis that daily intranasal insulin treatment would facilitate cognition in patients with early AD or its prodrome, amnestic mild cognitive impairment (MCI). The proportion of verbal information retained after a delay period was the planned primary outcome measure. Secondary outcome measures included attention, caregiver rating of functional status, and plasma levels of insulin, glucose, β-amyloid, and cortisol. Methods: Twenty-five participants were randomly assigned to receive either placebo (n = 12) or 20 IU BID intranasal insulin treatment (n = 13) using an electronic atomizer, and 24 participants completed the study. Participants, caregivers, and all clinical evaluators were blinded to treatment assignment. Cognitive measures and blood were obtained at baseline and after 21 days of treatment. Results: Fasting plasma glucose and insulin were unchanged with treatment. The insulin-treated group retained more verbal information after a delay compared with the placebo-assigned group ( p = 0.0374). Insulin-treated subjects also showed improved attention ( p = 0.0108) and functional status ( p = 0.0410). Insulin treatment raised fasting plasma concentrations of the short form of the β-amyloid peptide (Aβ40; p = 0.0471) without affecting the longer isoform (Aβ42), resulting in an increased Aβ40/42 ratio ( p = 0.0207). Conclusions: The results of this pilot study support further investigation of the benefits of intranasal insulin for patients with Alzheimer disease, and suggest that intranasal peptide administration may be a novel approach to the treatment of neurodegenerative disorders. | INTRANASAL INSULIN IMPROVES COGNITION AND MODULATES β-AMYLOID IN EARLY AD |
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In mice, the induction of such tolerance is thought to be attributable to the deletion of self-reactive cells. Here, we show that the human fetal immune system takes advantage of an additional mechanism: the generation of regulatory T cells (Tregs) that suppress fetal immune responses. We find that substantial numbers of maternal cells cross the placenta to reside in fetal lymph nodes, inducing the development of CD4+CD25highFoxP3+ Tregs that suppress fetal antimaternal immunity and persist at least until early adulthood. These findings reveal a form of antigen-specific tolerance in humans, induced in utero and probably active in regulating immune responses after birth. | Maternal alloantigens promote the development of tolerogenic fetal regulatory T cells in utero. |
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0.10555581003427505, "25002": 0.3304552733898163, "25117": 1.1816552877426147, "25449": 1.1816552877426147, "25456": 0.9409833550453186, "25458": 0.20739519596099854, "25714": 0.2622140049934387, "26402": 0.6197150945663452, "26520": 0.058784693479537964, "26698": 0.15693697333335876, "27011": 0.15943801403045654, "27144": 0.13243216276168823, "27292": 0.3019835948944092, "27373": 0.34300774335861206, "27642": 0.09495500475168228, "27697": 0.14602625370025635, "27710": 1.1653456687927246, "27781": 0.38174858689308167, "27790": 0.2089812457561493, "27854": 0.16359257698059082, "27953": 0.9900637865066528, "28487": 0.07068414986133575, "28699": 0.8195732831954956, "28767": 0.77198725938797, "28835": 0.053244512528181076, "28873": 0.18411032855510712, "28896": 0.02887592278420925, "28987": 0.8400169610977173, "29226": 0.5381823778152466, "29490": 0.6353566646575928, "29720": 0.9302552938461304} | 10207180 | INTRODUCTION The β-secretase enzyme, β-site amyloid precursor protein-cleaving enzyme 1 (BACE1), cleaves amyloid precursor protein (APP) in the first step in β-amyloid (Aβ) peptide production. Thus, BACE1 is a key target for candidate disease-modifying treatment of Alzheimer's disease. In a previous exploratory Aβ biomarker study, we found that BACE1 inhibitor treatment resulted in decreased levels of Aβ1-34 together with increased Aβ5-40, suggesting that these Aβ species may be novel pharmacodynamic biomarkers in clinical trials. We have now examined whether the same holds true in humans. METHODS In an investigator-blind, placebo-controlled and randomized study, healthy subjects (n =18) were randomly assigned to receive a single dose of 30 mg of LY2811376 (n =6), 90 mg of LY2811376 (n =6), or placebo (n =6). We used hybrid immunoaffinity-mass spectrometry (HI-MS) and enzyme-linked immunosorbent assays to monitor a variety of Aβ peptides. RESULTS Here, we demonstrate dose-dependent changes in cerebrospinal fluid (CSF) Aβ1-34, Aβ5-40 and Aβ5-X after treatment with the BACE1-inhibitor LY2811376. Aβ5-40 and Aβ5-X increased dose-dependently, as reflected by two independent methods, while Aβ1-34 dose-dependently decreased. CONCLUSION Using HI-MS for the first time in a study where subjects have been treated with a BACE inhibitor, we confirm that CSF Aβ1-34 may be useful in clinical trials on BACE1 inhibitors to monitor target engagement. Since it is less hydrophobic than longer Aβ species, it is less susceptible to preanalytical confounding factors and may thus be a more stable marker. By independent measurement techniques, we also show that BACE1 inhibition in humans is associated with APP-processing into N-terminally truncated Aβ peptides via a BACE1-independent pathway. TRIAL REGISTRATION ClinicalTrials.gov NCT00838084. Registered: First received: January 23, 2009, Last updated: July 14, 2009, Last verified: July 2009. | β-site amyloid precursor protein-cleaving enzyme 1(BACE1) inhibitor treatment induces Aβ5-X peptides through alternative amyloid precursor protein cleavage |
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0.07068414986133575, "29048": 0.6043586730957031, "29166": 0.40285754203796387} | 10209731 | STUDY OBJECTIVE The aim of the study was to analyse differences in mortality from the main cardiovascular diseases (ischaemic heart disease, hypertensive disease, and cerebrovascular disease) among Chinese, Malays, and Indians in Singapore. DESIGN The study was a survey using national death registration data in Singapore for the five years 1980 to 1984. The underlying cause of death, coded according to the ninth revision of the International Classification of Diseases, was taken for the analyses. SETTING The study was confined to the independent island state of Singapore, population 2.53 million (Chinese 76.5%, Malays 14.8%, Indians 6.4%, Others 2.3%). Death registration is thought to be complete. SUBJECTS All registered deaths in the age range 30-69 years during the study period were analysed by ethnic group. MEASUREMENT AND MAIN RESULTS Indians had higher mortality from ischaemic heart disease than the other ethnic groups in both sexes, with age-standardised relative risks of Indian v Chinese (males 3.8, females 3.4), Indian v Malay (males 1.9, females 1.6), and Malay v Chinese (males 2.0, females 2.2). The excess mortality in Indians declined with age. For hypertensive disease Malays had the highest mortality, with age-standardised relative risks of Malay v Chinese (males 3.4, females 4.4), Malay v Indian (males 2.0, females 2.5), and Indian v Chinese (males 1.6, females 1.6). For cerebrovascular disease there was little ethnic difference except for lower rates in Chinese females, with age-standardised relative risks of Malay v Chinese (males 1.1, females 1.9), Malay v Indian (males 1.0, females 1.1), and Indian v Chinese (males 1.1, females 1.7). CONCLUSIONS There are significant differences in mortality from the three main cardiovascular diseases in the different ethnic groups in Singapore. | Cardiovascular diseases in Chinese, Malays, and Indians in Singapore. I. Differences in mortality. |
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Immunocytochemical electron microscopy can reveal locations of proteins with nanometer resolution but is limited by the quality of fixation, the paucity of antibodies and the inaccessibility of antigens. Here we describe correlative fluorescence electron microscopy for the nanoscopic localization of proteins in electron micrographs. We tagged proteins with the fluorescent proteins Citrine or tdEos and expressed them in Caenorhabditis elegans, fixed the worms and embedded them in plastic. We imaged the tagged proteins from ultrathin sections using stimulated emission depletion (STED) microscopy or photoactivated localization microscopy (PALM). Fluorescence correlated with organelles imaged in electron micrographs from the same sections. We used these methods to localize histones, a mitochondrial protein and a presynaptic dense projection protein in electron micrographs. | Protein localization in electron micrographs using fluorescence nanoscopy |
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1.133164644241333, "25950": 1.0008903741836548, "26402": 0.7755908370018005, "26591": 0.09050461649894714, "26872": 0.21687394380569458, "26886": 0.20421554148197174, "27144": 0.36494144797325134, "27152": 0.010684899985790253, "27711": 0.6265231370925903, "27781": 0.01934296265244484, "28196": 0.44753631949424744, "28424": 0.8821197748184204, "28691": 0.23247487843036652, "29105": 0.10818854719400406, "29336": 0.9798521995544434, "29490": 0.43812891840934753} | 10218447 | Isorhamnetin is one member of flavonoid components which has been used in the treatment of heart disease. Recently the in vitro anti-cancer effect of isorhamnetin on human esophageal squamous carcinoma cell line Eca-109 was investigated in our lab. When Eca-109 cells were in vitro exposed to the graded doses of isorhamnetin (0-80 microg/ml) for 48 h, respectively, isorhamnetin exhibited cytostatic effect on the treated cells, with an IC(50) of 40+/-0.08 microg/ml as estimated by MTT assay. Inhibition on proliferation by isorhamnetin was detected by trypan blue exclusion assay, clone formation test, immunocytochemical assay of PCNA and (3)H-thymidine uptake analysis. Cell cycle distribution was measured by FCM. It was found that the viability of Eca-109 cells was significantly hampered by isorhamnetin. Compared with the negative control group, the treated group which was exposed to isorhamnetin had increased population in G(0)/G(1) phase from 74.6 to 84 while had a significant reduction in G(2)/M phase from 11.9 to 5.8. In addition to its cytostatic effect, isorhamnetin also showed stimulatory effect on apoptosis. Typical apoptotic morphology such as condensation and fragmentation of nuclei and blebbing membrane of the apoptotic cells could be observed through transmission electron microscope. Moreover, the sharp increase in apoptosis rate between the control and treated group were detected by FCM from 6.3 to 16.3. To explore the possible molecular mechanisms that underlie the growth inhibition and apoptosis stimulatory effects of isorhamnetin, the expressions of six proliferation- and death-related genes were detected by FCM. Expressions of bcl-2, c-myc and H-ras were downregulated whereas Bax, c-fos and p53 were upregulated. However, the in vivo experiments were required to further confirm the anti-cancer effects of isorhamnetin. In conclusion, isorhamnetin appears to be a potent drug against esophageal cancer due to its in vitro potential to not only inhibit proliferation but also induce apoptosis of Eca-109 cells. | The flavonoid component isorhamnetin in vitro inhibits proliferation and induces apoptosis in Eca-109 cells. |
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"27032": 0.0752234235405922, "27152": 0.4412745535373688, "27325": 0.013579257763922215, "27651": 0.13755162060260773, "27854": 0.012615402229130268, "28156": 0.503966212272644, "28228": 0.7057625651359558, "28518": 0.18004031479358673, "28696": 0.1946154683828354, "28835": 1.156782865524292, "29299": 0.18816383183002472, "29592": 0.11517547070980072} | 10247282 | In the rat isolated perfused kidney, arachidonic acid elicits cyclooxygenase-dependent vasoconstriction through activation of PGH2/TxA2 receptors; responses are enhanced in kidneys from diabetic rats. This study examined the roles of cyclooxygenase-1/cyclooxygenase-2 in the enhanced renal vasoconstrictor effect of arachidonic acid in streptozotocin-diabetic rats. Release of 20-HETE was also determined, as this eicosanoid has been reported to elicit cyclooxygenase-dependent vasoconstriction. We confirmed that vasoconstrictor responses to arachidonic acid were enhanced in the diabetic rat kidney associated with a 2-fold-greater increase in the release of 6-ketoPGF1alpha, which was used as an index of cyclooxygenase activity. One and three micrograms of arachidonic acid increased perfusion pressure by 85+/-37 and 186+/-6 mm Hg, respectively, in diabetic rat kidneys compared with 3+/-1 and 17+/-8 mm Hg, respectively, in control rat kidneys. Inhibition of both cyclooxygenase isoforms with indomethacin (10 micromol/L) abolished the vasoconstrictor response to arachidonic acid in both diabetic and control rat kidneys, whereas inhibition of cyclooxygenase-2 with nimesulide (5 micromol/L) reduced perfusion pressure responses to 1 and 3 microg arachidonic acid only in the diabetic rat kidney to 15+/-8 and 108+/-26 mm Hg, respectively, consistent with a 3-fold increase in the renal cortical expression of cyclooxygenase-2. 20-HETE release from the diabetic rat kidney was reduced almost 6-fold and was not increased in response to arachidonic acid. These results demonstrate that the renal vasoconstrictor effect of arachidonic acid is solely dependent on cyclooxygenase activity, with no evidence for a contribution from 20-HETE; in the diabetic rat, cyclooxygenase-2 activity contributes to the renal vasoconstrictor effect of arachidonic acid. | Arachidonic Acid in the Diabetic Rat Kidney |
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To characterize the putative interaction, we mapped the binding of the core domain of p53 (p53c) to an array of immobilized HIF-1alpha-derived peptides and found two peptide-sequence motifs that bound to p53c with micromolar affinity in solution. One sequence was adjacent to and the other coincided with the two proline residues of the oxygen-dependent degradation domain (P402 and P564) that act as switches for the oxygen-dependent regulation of HIF-1alpha. The binding affinity was independent of the hydroxylation state of P564. We found from NMR spectroscopy that these sequence motifs bind to the DNA-binding site of p53c. Because the two sequences are homologous and separated by 120 residues, and one is in a largely unstructured transactivation domain, we speculate that each sequence motif in HIF-1alpha binds to a different subunit of the p53 tetramer, leading to very tight binding. The binding data support the proposal that p53 provides a route for the degradation in hypoxic tumor cells of HIF-1alpha that is not hydroxylated at the two proline residues. | Two sequence motifs from HIF-1alpha bind to the DNA-binding site of p53. |
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However, reported variability in the behavior of iPSCs has called their utility into question. We established a test set of 16 iPSC lines from seven individuals of varying age, sex and health status, and extensively characterized the lines with respect to pluripotency and the ability to terminally differentiate. Under standardized procedures in two independent laboratories, 13 of the iPSC lines gave rise to functional motor neurons with a range of efficiencies similar to that of human embryonic stem cells (ESCs). Although three iPSC lines were resistant to neural differentiation, early neuralization rescued their performance. Therefore, all 16 iPSC lines passed a stringent test of differentiation capacity despite variations in karyotype and in the expression of early pluripotency markers and transgenes. This iPSC and ESC test set is a robust resource for those interested in the basic biology of stem cells and their applications. | A functionally characterized test set of human induced pluripotent stem cells |
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"24848": 0.8383291959762573, "25002": 0.18167030811309814, "25086": 1.0822023153305054, "25194": 0.603290855884552, "25409": 0.5472630262374878, "25456": 0.7047978043556213, "25761": 0.3723714053630829, "25969": 0.5668440461158752, "26131": 0.2026219218969345, "26244": 0.8550800085067749, "26402": 0.757441520690918, "26520": 0.15943801403045654, "26709": 0.630689799785614, "27118": 0.5404602885246277, "27295": 0.22782009840011597, "27559": 0.2696990668773651, "27642": 0.49982786178588867, "27854": 0.21293537318706512, "28691": 0.05046287178993225, "28835": 0.42225050926208496, "28873": 0.0842406153678894, "29290": 0.22782009840011597, "29494": 0.3910386264324188, "29535": 0.2983669638633728} | 10279084 | MAP kinase phosphatase-2 (MKP-2) is a member of the family of dual specificity phosphatases that functions to inactivate the ERK and JNK MAP kinase signalling pathways. Here, we identify a novel human MKP-2 variant (MKP-2-S) lacking the MAP kinase binding site but retaining the phosphatase catalytic domain. Endogenous MKP-2-S transcripts and proteins were found in PC3 prostate and MDA-MB-231 breast cancer cells and also human prostate biopsies. Cellular transfection of MKP-2-S gave rise to a nuclear protein of 33kDa which displayed phosphatase activity comparable to the formerly described long form of MKP-2 (MKP-2-L). Due to its lack of a kinase interacting motif (KIM), MKP-2-S did not bind to JNK or ERK; MKP-2-L bound ERK and to a lesser extent JNK. Protein turnover of adenoviral expressed MKP-2-S was accelerated relative to MKP-2-L, with a greater susceptibility to proteosomal-mediated degradation. MKP-2-S retained its ability to deactivate JNK in a similar manner as MKP-2-L and was an effective inhibitor of LPS-stimulated COX-2 induction. However, unlike MKP-2-L, MKP-2-S was unable to reverse serum-induced ERK activation or significantly inhibit endothelial cell proliferation. These findings reveal the occurrence of a novel splice variant of MKP-2 which is unable to bind ERK and may be significant in the dysregulation of MAP kinase activity in certain disease states, particularly in breast and prostate cancers. | Differential regulation of MAP kinase activation by a novel splice variant of human MAP kinase phosphatase-2. |
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clinical and ex vivo studies have established a strong association between atrial fibrillation and inflammation. However, whether inflammation is the cause or the consequence of atrial fibrillation and which specific inflammatory mediators may increase the atria's susceptibility to fibrillation remain elusive. Here we provide experimental and clinical evidence for the mechanistic involvement of myeloperoxidase (MPO), a heme enzyme abundantly expressed by neutrophils, in the pathophysiology of atrial fibrillation. MPO-deficient mice pretreated with angiotensin II (AngII) to provoke leukocyte activation showed lower atrial tissue abundance of the MPO product 3-chlorotyrosine, reduced activity of matrix metalloproteinases and blunted atrial fibrosis as compared to wild-type mice. Upon right atrial electrophysiological stimulation, MPO-deficient mice were protected from atrial fibrillation, which was reversed when MPO was restored. Humans with atrial fibrillation had higher plasma concentrations of MPO and a larger MPO burden in right atrial tissue as compared to individuals devoid of atrial fibrillation. In the atria, MPO colocalized with markedly increased formation of 3-chlorotyrosine. Our data demonstrate that MPO is a crucial prerequisite for structural remodeling of the myocardium, leading to an increased vulnerability to atrial fibrillation. | Myeloperoxidase acts as a profibrotic mediator of atrial fibrillation |
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0.13157635927200317, "28196": 0.04860413447022438, "28227": 0.026976587250828743, "28321": 0.5021947622299194, "28335": 0.07250232994556427, "28436": 0.13071982562541962, "28520": 0.0606246218085289, "28616": 0.05786345899105072, "28687": 1.1249549388885498, "28711": 0.4400174915790558, "28727": 0.08603433519601822, "28804": 0.1384023278951645, "28829": 0.09495500475168228, "28927": 0.04953393340110779, "28943": 0.015504186972975731, "28947": 0.1889725625514984, "29094": 1.1249549388885498, "29125": 0.20102575421333313, "29242": 0.12642613053321838, "29324": 0.4938860833644867} | 10300000 | The results of a survey of 769 patients attending the St. James's University Fertility Control Clinic, England, for abortion services showed that patients seeing general practitioners were less knowledgeable than those attending specialist clinics. There was a demonstrated need for counseling on pill and condom use and protection against sexually transmitted diseases. Knowledge of postcoital methods was also found to be lacking. The survey was conducted between April 1, 1991, and January 31, 1992. Respondents included minorities such as Afro-Caribbean (8%) and Asian (9%). 307 of the cases were using a less effective form of contraception at the time of conception, usually a change from the pill to condoms. Of the 171 people reporting failure of contraception, 93 noted a split or leaking condom; 13, a condom falling off during intercourse; 32, inconsistent use of condoms;l 32, forgetting to take contraceptive pills or using antibiotics with the pill; and 1, a late injection of medroxyprogesterone acetate. 45 of the 309 people who had conceived while using condoms recognized a potential condom failure, and only 20 attempted any emergency contraceptive method such as the postcoital pill. Only 30% of the 171 patients with recognized condom failure and 12% of the 210 who had not used any contraception had adequate knowledge of the existence, timing, and source of postcoital pills; i.e., 20% of 381. Only 2% of the 171 nd 2% of the 381 patients, had knowledge of postcoital insertion of an intrauterine contraceptive device. Given the choice between and unplanned pregnancy and postcoital contraceptive, most (718 out of 769) preferred using postcoital contraception. Contraceptive information was given to 501 by a general practitioner, to 102 by a community family planning clinic, and 163 had no medical advice. There was a range of knowledge of postcoital contraceptive methods. Knowledge of how to deal with forgotten pills, severe vomiting, severe diarrhea, and concurrent antibiotic treatment among the 422 patients who had ever used the combined pill also was variable. 19% of the 372 patients treated by general practitioners knew 4 correct answers, but 50% of the 50 patients in community family planning clinics answered correctly 4 times. Differences could not be explained by other demographic characteristics. | Knowledge and use of secondary contraception among patients requesting termination of pregnancy. |
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0.009718249551951885, "29129": 0.44753631949424744, "29297": 1.2070930004119873} | 10300888 | Whereas domestication of livestock, pets, and crops is well documented, it is still unclear to what extent microbes associated with the production of food have also undergone human selection and where the plethora of industrial strains originates from. Here, we present the genomes and phenomes of 157 industrial Saccharomyces cerevisiae yeasts. Our analyses reveal that today's industrial yeasts can be divided into five sublineages that are genetically and phenotypically separated from wild strains and originate from only a few ancestors through complex patterns of domestication and local divergence. Large-scale phenotyping and genome analysis further show strong industry-specific selection for stress tolerance, sugar utilization, and flavor production, while the sexual cycle and other phenotypes related to survival in nature show decay, particularly in beer yeasts. Together, these results shed light on the origins, evolutionary history, and phenotypic diversity of industrial yeasts and provide a resource for further selection of superior strains. PAPERCLIP. | Domestication and Divergence of Saccharomyces cerevisiae Beer Yeasts |
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"27806": 0.16110190749168396, "27965": 0.05970508232712746, "28138": 0.997294545173645, "28282": 0.0009760859538801014, "28321": 0.06246116757392883, "28498": 0.10026945173740387, "28561": 0.21922965347766876, "28742": 0.1384023278951645} | 10314816 | Until the 1990s, Amblyomma americanum was regarded primarily as a nuisance species, but a tick of minor importance as a vector of zoonotic pathogens affecting humans. With the recent discoveries of Ehrlichia chaffeensis, Ehrlichia ewingii, and "Borrelia lonestari," the public health relevance of lone star ticks is no longer in question. During the next 25 years, the number of cases of human disease caused by A. americanum-associated pathogens will probably increase. Based on current trajectories and historic precedents, the increase will be primarily driven by biological and environmental factors that alter the geographic distribution and intensity of transmission of zoonotic pathogens. Sociologic and demographic changes that influence the likelihood of highly susceptible humans coming into contact with infected lone star ticks, in addition to advances in diagnostic capabilities and national surveillance efforts, will also contribute to the anticipated increase in the number of recognized cases of disease. | The ascendancy of Amblyomma americanum as a vector of pathogens affecting humans in the United States. |
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0.34508460760116577} | 10326242 | PALB2 was recently identified as a nuclear binding partner of BRCA2. Biallelic BRCA2 mutations cause Fanconi anemia subtype FA-D1 and predispose to childhood malignancies. We identified pathogenic mutations in PALB2 (also known as FANCN) in seven families affected with Fanconi anemia and cancer in early childhood, demonstrating that biallelic PALB2 mutations cause a new subtype of Fanconi anemia, FA-N, and, similar to biallelic BRCA2 mutations, confer a high risk of childhood cancer. | Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer |
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No hybridization was observed in other regions of the chromosomes. Another cloned EcoRI fragment, 525 bp long has also been studied. This represents a partial duplication of the 340-bp sequence. Genomic blot hybridization experiments show that the 340-bp sequence is a representative monomeric unit of tandemly repeated arrays which account for 1.2% of the Chironomus genome, on average 300 kb per telomere. The repeat unit contains two types of subrepeats each present twice per repeat unit. Northern blot hybridization experiments show that the telomere-associated sequences are transcribed into a discrete RNA species approximately 20 kb in size. The evolution of this telomere-associated DNA is discussed. | Long tandem arrays of complex repeat units in Chironomus telomeres. |
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To address this, we have studied the expression of Na(V)1.5 and other Na+ channel isoforms in the AVN. METHODS AND RESULTS The rat AVN was identified by Masson's trichrome staining together with immunolabeling of marker proteins: connexin40, connexin43, desmoplakin, atrial natriuretic peptide, and hyperpolarization-activated and cyclic nucleotide-gated channel 4. Na+ channel expression was investigated with immunohistochemistry with isoform-specific Na+ channel antibodies. Na(V)1.1 was distributed in a similar manner to Na(V)1.5. Na(V)1.2 was not detected. Na(V)1.3 labeling was present in nerve fibers and cell bodies (but not myocytes) and was abundant in the penetrating atrioventricular (AV) bundle and the common bundle but was much less abundant in other regions. Na(V)1.5 labeling was abundant in the atrial and ventricular myocardium and the left bundle branch. Na(V)1.5 labeling was absent in the open node, penetrating AV bundle, AV ring bundle, and common bundle but present at a reduced level in the inferior nodal extension and transitional zone. Na(V)1.6 was not detected. CONCLUSIONS Our findings provide molecular evidence of multiple electrophysiological cell types at the AV junction. Impaired AV conduction as a result of mutations in or loss of Na(V)1.5 must be the result of impaired conduction in the AVN inputs (inferior nodal extension and transitional zone) or output (bundle branches) rather than the AVN itself (open node and penetrating AV bundle). | Localization of Na+ channel isoforms at the atrioventricular junction and atrioventricular node in the rat. |
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locations within the spleen, but the genetic basis for this separation is still enigmatic. We now report that B cell sequestration requires lineage-specific regulation of migratory receptors by the transcription factor Klf2. Moreover, using gene-targeted mice we show that altered splenic B cell migration confers a significant in vivo gain-of-function phenotype to FO B cells, including the ability to quickly respond to MZ-associated antigens and pathogens in a T cell-dependent manner. This work demonstrates that in wild-type animals, naive FO B cells are actively removed from the MZ, thus restricting their capacity to respond to blood-borne pathogens. | Follicular B cell trafficking within the spleen actively restricts humoral immune responses. |
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"26512": 0.7172679901123047, "26520": 0.2976420819759369, "26534": 0.1384023278951645, "26616": 0.16690383851528168, "26657": 0.07068414986133575, "26721": 0.16607704758644104, "26773": 0.7863243818283081, "26775": 0.1873544454574585, "26835": 0.3353555500507355, "27099": 0.08871890604496002, "27295": 0.4818955361843109, "27321": 0.08961215615272522, "27777": 0.09938567131757736, "27854": 0.2689530849456787, "27929": 0.15777134895324707, "28093": 0.7854343056678772, "28156": 0.1751343309879303, "28227": 0.25694093108177185, "28297": 0.5495203733444214, "28309": 0.1229778528213501, "28691": 0.030771657824516296, "28696": 0.0058422754518687725, "28767": 0.18248429894447327, "28788": 0.6075552701950073, "28848": 0.18248429894447327, "28873": 0.29255300760269165, "29222": 0.24631060659885406, "29278": 1.2398450374603271, "29290": 0.4444103240966797, "29490": 0.25088030099868774} | 10359591 | Interleukin(IL)-2 and inflammation regulate effector and memory cytolytic T-lymphocyte (CTL) generation during infection. We demonstrate a complex interplay between IL-2 and inflammatory signals during CTL differentiation. IL-2 stimulation induced the transcription factor eomesodermin (Eomes), upregulated perforin (Prf1) transcription, and repressed re-expression of memory CTL markers Bcl6 and IL-7Ralpha. Binding of Eomes and STAT5 to Prf1 cis-regulatory regions correlated with transcriptional initiation (increased recruitment of RNA polymerase II to the Prf1 promoter). Inflammation (CpG, IL-12) enhanced expression of IL-2Ralpha and the transcription factor T-bet, but countered late Eomes and perforin induction while preventing IL-7Ralpha repression by IL-2. After infection of mice with lymphocytic choriomeningitis virus, IL-2Ralpha-deficient effector CD8(+) T cells expressed more Bcl6 but less perforin and granzyme B, formed fewer KLRG-1(+) and T-bet-expressing CTL, and killed poorly. Thus, inflammation influences both effector and memory CTL differentiation, whereas persistent IL-2 stimulation promotes effector at the expense of memory CTL development. | Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells. |
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"26164": 0.13925230503082275, "26237": 0.3318578004837036, "26419": 1.4624232053756714, "26478": 0.1477125883102417, "26786": 0.11256109178066254, "26828": 0.4431571960449219, "26835": 0.2247048318386078, "27196": 0.24859806895256042, "27322": 0.34577593207359314, "27480": 0.010684899985790253, "27535": 0.3723714053630829, "27894": 0.06612417846918106, "28321": 0.18492233753204346, "28648": 0.03831886500120163, "28739": 0.6902132034301758, "29382": 0.3241194784641266, "29516": 0.35950297117233276} | 10365749 | BACKGROUND Tuberculosis (TB) has been reported to be associated with poverty, especially in developing countries. Hong Kong is one of the few industrialised areas with a high incidence of TB where previous reports on the effect of poverty at neighbourhood level have been conflicting. OBJECTIVE To examine the spatial distribution of TB and its association with neighbourhood risk factors. METHOD A total of 17 294 TB cases notified from 2005 to 2007 were mapped down to the District Council Constituency Area (DCCA) level, and were indirectly standardised by age and sex using 2006 census population data. The standardised TB ratio was correlated with neighbourhood risk factors classified by family, ethnicity, economic and environmental domains. RESULTS The indirect age- and sex-standardised ratio demonstrated a spatially varied pattern, and was significantly associated with all neighbourhood factors on univariate analysis. Only marital status, place of birth and low household income were independently associated with the standardised TB ratio on multivariate analysis. CONCLUSION Despite the virtual elimination of absolute poverty by a well-developed social assistance scheme, low household income in the neighbourhood was significantly associated with TB, independently of place of birth, marital status and other risk factors. | Neighbourhood risk factors for tuberculosis in Hong Kong. |
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"26520": 0.5069117546081543, "26524": 0.7009293437004089, "26629": 1.0305955410003662, "26702": 0.0354953333735466, "26874": 0.28743788599967957, "26989": 0.7445381283760071, "27166": 0.08064348995685577, "27287": 0.8315495252609253, "27295": 0.25694093108177185, "27491": 0.1685553640127182, "27598": 0.40806588530540466, "27642": 0.7872136831283569, "27777": 0.07068414986133575, "27781": 0.0019512200960889459, "27790": 0.20660123229026794, "27989": 0.777387797832489, "28086": 1.0960047245025635, "28156": 0.41840189695358276, "28227": 0.4067663550376892, "28466": 0.08961215615272522, "28522": 0.9108069539070129, "28691": 0.28597161173820496, "28765": 0.8374842405319214, "28828": 0.26446542143821716, "28829": 0.29255300760269165, "28873": 0.029824240133166313, "29060": 0.08782484382390976, "29125": 0.2531573474407196, "29290": 0.3325583338737488} | 10365787 | The anaphase promoting complex or cyclosome (APC/C) is a ubiquitin protein ligase that, together with Cdc20 or Cdh1, targets cell-cycle proteins for degradation. APC/C–Cdh1 specifically promotes protein degradation in late mitosis and G1. Mutant embryos lacking Cdh1 die at E9.5–E10.5 due to defects in the endoreduplication of trophoblast cells and placental malfunction. This lethality is prevented when Cdh1 is expressed in the placenta. Cdh1-deficient cells proliferate inefficiently and accumulate numeric and structural chromosomal aberrations, indicating that Cdh1 contributes to the maintenance of genomic stability. Cdh1 heterozygous animals show increased susceptibility to spontaneous tumours, suggesting that Cdh1 functions as a haploinsufficient tumour suppressor. These heterozygous mice also show several defects in behaviour associated with increased proliferation of stem cells in the nervous system. These results indicate that Cdh1 is required for preventing unscheduled proliferation of specific progenitor cells and protecting mammalian cells from genomic instability. | Genomic stability and tumour suppression by the APC/C cofactor Cdh1 |
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0.18573370575904846, "27348": 0.6714286804199219, "27504": 0.8281423449516296, "27590": 0.10555581003427505, "27606": 0.8682814836502075, "27881": 0.7086513638496399, "27885": 0.5427330136299133, "28207": 0.020300358533859253, "28667": 0.5925496220588684, "28804": 0.03360854089260101, "29076": 1.018678069114685, "29277": 0.5778634548187256, "29353": 0.15275461971759796} | 10374686 | Although 65% of people with cancer want to die at home, only about 30% are successful in doing so.1,2 A government committed to choice for patients must improve this figure.3 Developing palliative care services in primary care is essential for realising the expectations of dying people. Such services could also offer important opportunities for extending supportive humane care at an earlier stage, and to people not only with cancer but with chronic obstructive pulmonary disease, motor neurone disease, and cardiac failure, for example, who also often have palliative care needs. Primary care professionals have the potential and ability to provide end of life care for most patients, given adequate training, resources, and, when needed, specialist advice.4,5 They share common values with palliative care specialists—holistic, patient centred care, delivered in the context of families and friends.6 However, until recently, apart from Macmillan general practitioners and nurse facilitators, few comprehensive workforce initiatives have been undertaken in primary care that focus on end of life care. Many cancer patients and their carers experience existential distress long before they die.7 Recognising and alleviating such suffering is important, but it often goes unrecognised or is overlooked by services focusing on the terminal phase of illnesses. Primary care teams may know patients over long periods of time. They can readily identify patients from cancer and chronic disease registers who might benefit from an early palliative care approach. Such patients could be identified by clinicians asking one simple question of themselves: “Would I be surprised if my patient were to die in the next 12 months?”8 By identifying such patients proactively we could deliver, simultaneously, active treatment and patient centred supportive care, through a team with whom many patients have a valued long term relationship. Palliative care services need to be extended to patients with non-malignant conditions who have comparable concerns to and in some cases even greater unmet needs than cancer patients.9 Progress by palliative medicine specialists is hampered by issues such as uncertainty about the most effective models of care, lack of non-cancer expertise, and concerns about pressure on specialist services. General practitioners and community nurses can lead the way in providing a palliative care approach for patients with terminal organ failure illness. The first step in such an approach is for the goals of care to be discussed and agreed. Management plans are adjusted accordingly. Effective control of symptoms and maintaining quality of life are prioritised. In the light of these important opportunities it is regrettable that the new general medical services contract has not prioritised palliative care. By day, other developments to achieve the quality indicators are taking precedence. By night and at weekends, the new unscheduled care services (which are responsible for providing care for 75% of the hours in the week) are even less well configured than previous out of hours provision to facilitate dying at home. Such services specialise in dealing with acute emergencies and, as such, often struggle to meet the medical, nursing, and social care needs of dying people and their families. These changes will greatly affect care for dying people and may increase the number of hospital admissions. However, one important initiative is gaining momentum within primary care. The Gold Standards Framework is a resource for organising proactive palliative care in the community and is supported by funding from the Cancer Services Collaborative, Macmillan Cancer Relief, and the National Lottery.10 The framework provides a detailed guide to providing holistic, patient centred care and thereby facilitates effective care in the community. Other recently initiated mechanisms for developing primary palliative care include the training of general practitioners with a special interest in palliative care and the new end of life initiative in England to improve palliative care provision by generalists and to share examples of good practice. To support such developments it is essential that primary palliative care is supported by an adequate academic base.11 This is admittedly a challenging arena in which to undertake research, but progress has been made in recent years in developing conceptual models and research architectures for studying end of life issues. Now we need to build on this work to ensure that the understanding and insights gleaned can be translated into effective interventions. Every person with a progressive illness has a right to palliative care.12 Patients desire a reassuring professional presence in the face of death. General practitioners and community nurses are trusted by patients and are in a position to provide effective, equitable, and accessible palliative care. This will happen only if they have adequate time and resources and work in a system that encourages such care. Patients who receive holistic support in the community may be less likely to require expensive admission to hospital and often futile treatments at the end of their lives. | Developing primary palliative care. |
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"26340": 0.0174254160374403, "26360": 0.6970458030700684, "26563": 0.29255300760269165, "26708": 0.083342544734478, "26721": 0.04487626627087593, "26770": 0.036437395960092545, "26777": 0.011650617234408855, "26877": 0.2184450328350067, "26979": 0.11081436276435852, "27859": 0.10993985831737518, "28207": 0.5220900774002075, "28687": 1.1616848707199097, "28711": 0.417115718126297, "29031": 0.41647201776504517, "29094": 0.5444341897964478, "29234": 0.6043586730957031} | 10408324 | BACKGROUND Emergency postcoital contraception prevents pregnancy, but it must be prescribed by a doctor and taken within 72 hours of intercourse. It has been proposed that emergency contraception be made available without a prescription. We undertook a study to learn how women might behave if given a supply of emergency contraceptive pills to keep at home. METHODS We assigned 553 women to be given a replaceable supply of hormonal emergency contraceptive pills to take home (the treatment group) and 530 women to use emergency contraception obtained by visiting a doctor (the control group). The frequency of use of emergency contraception, the use of other contraceptives, and the incidence of unwanted pregnancy were determined in both groups of women one year later. RESULTS The results for 549 women in the treatment group and 522 women in the control group were available for analysis. Three hundred seventy-nine of the women in the treatment group (69 percent) and 326 of the women in the control group (62 percent) contributed detailed information at follow-up. One hundred eighty of the women in the treatment group (47 percent) used emergency contraception at least once. Among those who returned the study questionnaire, 98 percent used emergency contraception correctly. There were no serious adverse effects. Eighty-seven women in the control group (27 percent) used emergency contraception at least once (P<0.001 for the comparison with the treatment group). The women in the treatment group were not more likely to use emergency contraception repeatedly. Their use of other methods of contraception was no different from that of the women in the control group. There were 18 unintended pregnancies in the treatment group and 25 in the control group (relative risk, 0.7; 95 percent confidence interval, 0.4 to 1.2). CONCLUSIONS Making emergency contraception more easily obtainable does no harm and may reduce the rate of unwanted pregnancies. | The effects of self-administering emergency contraception. |
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(R)-rich protein associated with splicing complexes and is named here SRm160 (SR-related matrix protein of 160 kD). SRm160 contains multiple SR repeats, but unlike proteins of the SR family of splicing factors, lacks an RNA recognition motif. SRm160 and a related protein SRm300 (the 300-kD nuclear matrix antigen recognized by mAb B4A11) form a complex that is required for the splicing of specific pre-mRNAs. The SRm160/300 complex associates with splicing complexes and promotes splicing through interactions with SR family proteins. Binding of SRm160/300 to pre-mRNA is normally also dependent on U1 snRNP and is stabilized by U2 snRNP. Thus, SRm160/300 forms multiple interactions with components bound directly to important sites within pre-mRNA. The results suggest that a complex of the nuclear matrix proteins SRm160 and SRm300 functions as a coactivator of pre-mRNA splicing. | A coactivator of pre-mRNA splicing. |
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0.2983669638633728, "26721": 0.7482418417930603, "26754": 0.37907835841178894, "26927": 0.29255300760269165, "27115": 0.05046287178993225, "27144": 0.10555581003427505, "27263": 0.23015019297599792, "27312": 0.004870930220931768, "27606": 1.0587663650512695, "27673": 0.4837033152580261, "27833": 0.1685553640127182, "28032": 0.5816917419433594, "28093": 0.10993985831737518, "28177": 0.02316705882549286, "28225": 0.3262358605861664, "28295": 0.16442140936851501, "28353": 0.272677481174469, "28696": 0.14349138736724854, "28741": 0.06886265426874161, "29160": 0.2145126610994339, "29166": 1.013020396232605, "29207": 0.07793712615966797, "29235": 0.129004567861557, "29533": 0.045809537172317505} | 10430148 | CONTEXT No antidiabetic regimen has demonstrated the ability to reduce progression of coronary atherosclerosis. Commonly used oral glucose-lowering agents include sulfonylureas, which are insulin secretagogues, and thiazolidinediones, which are insulin sensitizers. OBJECTIVE To compare the effects of an insulin sensitizer, pioglitazone, with an insulin secretagogue, glimepiride, on the progression of coronary atherosclerosis in patients with type 2 diabetes. DESIGN, SETTING, AND PARTICIPANTS Double-blind, randomized, multicenter trial at 97 academic and community hospitals in North and South America (enrollment August 2003-March 2006) in 543 patients with coronary disease and type 2 diabetes. INTERVENTIONS A total of 543 patients underwent coronary intravascular ultrasonography and were randomized to receive glimepiride, 1 to 4 mg, or pioglitazone, 15 to 45 mg, for 18 months with titration to maximum dosage, if tolerated. Atherosclerosis progression was measured by repeat intravascular ultrasonography examination in 360 patients at study completion. MAIN OUTCOME MEASURE Change in percent atheroma volume (PAV) from baseline to study completion. RESULTS Least squares mean PAV increased 0.73% (95% CI, 0.33% to 1.12%) with glimepiride and decreased 0.16% (95% CI, -0.57% to 0.25%) with pioglitazone(P = .002). An alternative analysis imputing values for noncompleters based on baseline characteristics showed an increase in PAV of 0.64% (95% CI, 0.23% to 1.05%) for glimepiride and a decrease of 0.06% (-0.47% to 0.35%) for pioglitazone (between-group P = .02). Mean (SD) baseline HbA(1c) levels were 7.4% (1.0%) in both groups and declined during treatment an average 0.55% (95% CI, -0.68% to -0.42%) with pioglitazone and 0.36% (95% CI, -0.48% to -0.24%) with glimepiride (between-group P = .03). In the pioglitazone group, compared with glimepiride, high-density lipoprotein levels increased 5.7 mg/dL (95% CI, 4.4 to 7.0 mg/dL; 16.0%) vs 0.9 mg/dL (95% CI, -0.3 to 2.1 mg/dL; 4.1%), and median triglyceride levels decreased 16.3 mg/dL (95% CI, -27.7 to -11.0 mg/dL; 15.3%) vs an increase of 3.3 mg/dL (95% CI, -10.7 to 11.7 mg/dL; 0.6%) (P < .001 for both comparisons). Median fasting insulin levels decreased with pioglitazone and increased with glimepiride (P < .001). Hypoglycemia was more common in the glimepiride group and edema, fractures, and decreased hemoglobin levels occurred more frequently in the pioglitazone group. CONCLUSION In patients with type 2 diabetes and coronary artery disease, treatment with pioglitazone resulted in a significantly lower rate of progression of coronary atherosclerosis compared with glimepiride. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00225277. | Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. |
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"26775": 0.1734936386346817, "26835": 0.43623676896095276, "27099": 0.1685553640127182, "27287": 0.029824240133166313, "27572": 0.0752234235405922, "27631": 0.8247235417366028, "28038": 0.026976587250828743, "28173": 0.18573370575904846, "28848": 1.134421706199646, "28873": 0.05139094591140747, "28954": 1.5457323789596558, "29300": 0.15610189735889435, "29598": 0.5871354341506958} | 10443642 | RNAIII is the intracellular effector of the quorum-sensing system in Staphylococcus aureus. It is one of the largest regulatory RNAs (514 nucleotides long) that are known to control the expression of a large number of virulence genes. Here, we show that the 3' domain of RNAIII coordinately represses at the post-transcriptional level, the expression of mRNAs that encode a class of virulence factors that act early in the infection process. We demonstrate that the 3' domain acts primarily as an antisense RNA and rapidly anneals to these mRNAs, forming long RNA duplexes. The interaction between RNAIII and the mRNAs results in repression of translation initiation and triggers endoribonuclease III hydrolysis. These processes are followed by rapid depletion of the mRNA pool. In addition, we show that RNAIII and its 3' domain mediate translational repression of rot mRNA through a limited number of base pairings involving two loop-loop interactions. Since Rot is a transcriptional regulatory protein, we proposed that RNAIII indirectly acts on many downstream genes, resulting in the activation of the synthesis of several exoproteins. These data emphasize the multitude of regulatory steps affected by RNAIII and its 3' domain in establishing a network of S. aureus virulence factors. | Staphylococcus aureus RNAIII coordinately represses the synthesis of virulence factors and the transcription regulator Rot by an antisense mechanism. |
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0.4673144817352295, "26013": 1.2671676874160767, "26236": 0.18978065252304077, "26243": 0.7583568692207336, "26305": 0.1358480453491211, "26402": 0.12642613053321838, "26462": 0.13499516248703003, "26629": 1.034073829650879, "26646": 0.04487626627087593, "26651": 0.46486347913742065, "26835": 0.5936289429664612, "27325": 0.06612417846918106, "27484": 0.7737906575202942, "27781": 0.39696553349494934, "28297": 1.0695481300354004, "28389": 0.18248429894447327, "28498": 0.16359257698059082, "28788": 0.2659635543823242, "28873": 1.1369311809539795, "29107": 1.2152372598648071, "29486": 0.6950984001159668, "29721": 0.5849615335464478} | 10450300 | Human cytomegalovirus (HCMV) is a widely prevalent human herpesvirus, which, after primary infection, persists in the host for life. In healthy individuals, the virus is well controlled by the HCMV-specific T cell response. A key feature of this persistence, in the face of a normally robust host immune response, is the establishment of viral latency. In contrast to lytic infection, which is characterised by extensive viral gene expression and virus production, long-term latency in cells of the myeloid lineage is characterised by highly restricted expression of viral genes, including UL138 and LUNA. Here we report that both UL138 and LUNA-specific T cells were detectable directly ex vivo in healthy HCMV seropositive subjects and that this response is principally CD4⁺ T cell mediated. These UL138-specific CD4⁺ T cells are able to mediate MHC class II restricted cytotoxicity and, importantly, show IFNγ effector function in the context of both lytic and latent infection. Furthermore, in contrast to CDCD4⁺ T cells specific to antigens expressed solely during lytic infection, both the UL138 and LUNA-specific CD4⁺ T cell responses included CD4⁺ T cells that secreted the immunosuppressive cytokine cIL-10. We also show that cIL-10 expressing CD4⁺ T-cells are directed against latently expressed US28 and UL111A. Taken together, our data show that latency-associated gene products of HCMV generate CD4⁺ T cell responses in vivo, which are able to elicit effector function in response to both lytic and latently infected cells. Importantly and in contrast to CD4⁺ T cell populations, which recognise antigens solely expressed during lytic infection, include a subset of cells that secrete the immunosuppressive cytokine cIL-10. This suggests that HCMV skews the T cell responses to latency-associated antigens to one that is overall suppressive in order to sustain latent carriage in vivo. | Human Cytomegalovirus Latency-Associated Proteins Elicit Immune-Suppressive IL-10 Producing CD4+ T Cells |
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metastasis. It has recently been reported that pamidronate inhibits the mevalonate pathway, which is required for the prenylation of the small GTPase. We demonstrated a possible beneficial use of pamidronate in the treatment of hepatocellular carcinoma (HCC). METHODS The effect of pamidronate on cell proliferation was analyzed with five hepatoma cell lines using MTT assay. Apoptosis was evaluated by staining with DAPI and a histon ELISA assay. A cell migration assay was performed using the Modified Boyden Chamber. To analyze anti-proliferation effect of pamidronate in vivo, tumor volumes were monitored with the intraperitoneal injection of pamidronate after subcutaneous inoculation of PLC/PRF/5 cells into nude mice. RESULTS Pamidronate inhibited cell growth for all hepatoma cell lines. The amount of membrane associated Ras and phosphorylated extracellular signal-regulated kinase 2 (ERK 2) were reduced after pamidronate treatment. Pamidronate increased apoptosis and cleavage of Caspase-3, and -9. Pamidronate suppressed membrane associated RhoA and cell motility. In vivo, tumor volumes were significantly suppressed by pamidronate at three weeks (P<0.03). CONCLUSIONS We conclude that pamidronate has therapeutic potential in inducing anti-proliferative, apoptotic, and anti-migratory effects in HCC. | Pamidronate induced anti-proliferative, apoptotic, and anti-migratory effects in hepatocellular carcinoma. |
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0.20739519596099854, "23900": 0.13670019805431366, "23924": 0.0038986403960734606, "24133": 0.021256839856505394, "24269": 0.2493593990802765, "24278": 0.026976587250828743, "24552": 1.2666174173355103, "24952": 0.026025565341114998, "25006": 0.3191637098789215, "25714": 0.083342544734478, "25778": 0.0354953333735466, "25950": 0.6389714479446411, "25986": 0.18978065252304077, "26163": 0.45251765847206116, "26773": 0.5517725944519043, "26780": 0.44753631949424744, "26785": 0.6970458030700684, "27133": 1.0172666311264038, "27651": 0.03831886500120163, "27788": 0.7201237678527832, "28156": 0.6059582233428955, "28268": 0.11081436276435852, "28696": 0.12038381397724152, "28829": 0.34508460760116577, "29129": 0.11430477350950241, "29166": 0.8433839678764343, "29180": 0.7889899015426636, "29290": 0.2622140049934387, "29516": 0.09672962874174118, "29720": 0.1693800985813141} | 10463997 | Objectives: Autophagy is a highly regulated process that has an important role in the control of a wide range of cellular functions, such as organelle recycling, nutrient availability and tissue differentiation. A recent study has shown an increased autophagic activity in the adipose tissue of obese subjects, and a role for autophagy in obesity-associated insulin resistance was proposed. Body mass reduction is the most efficient approach to tackle insulin resistance in over-weight subjects; however, the impact of weight loss in adipose tissue autophagy is unknown. Subjects:Adipose tissue autophagy was evaluated in mice and humans. Results:First, a mouse model of diet-induced obesity and diabetes was maintained on a 15-day, 40% caloric restriction. At baseline, markers of autophagy were increased in obese mice as compared with lean controls. Upon caloric restriction, autophagy increased in the lean mice, whereas it decreased in the obese mice. The reintroduction of ad libitum feeding was sufficient to rapidly reduce autophagy in the lean mice and increase autophagy in the obese mice. In the second part of the study, autophagy was evaluated in the subcutaneous adipose tissue of nine obese-non-diabetic and six obese-diabetic subjects undergoing bariatric surgery for body mass reduction. Specimens were collected during the surgery and approximately 1 year later. Markers of systemic inflammation, such as tumor necrosis factor-1α, interleukin (IL)-6 and IL-1β were evaluated. As in the mouse model, human obesity was associated with increased autophagy, and body mass reduction led to an attenuation of autophagy in the adipose tissue. Conclusion:Obesity and caloric overfeeding are associated with the defective regulation of autophagy in the adipose tissue. The studies in obese-diabetic subjects undergoing improved metabolic control following calorie restriction suggest that autophagy and inflammation are regulated independently. | Defective regulation of adipose tissue autophagy in obesity |
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"28024": 0.03360854089260101, "28156": 0.34300774335861206, "28466": 0.129004567861557, "28568": 0.03266380727291107, "28577": 0.08961215615272522, "28667": 0.45870962738990784, "28788": 0.175953671336174, "28835": 0.2409527748823166, "29090": 0.18329764902591705, "29105": 0.6054253578186035, "29317": 0.0770333781838417, "29333": 0.4920966327190399, "29441": 0.16276304423809052} | 10474873 | Failure of axons of the central nervous system in adult mammals to regenerate spontaneously after injury is attributed in part to inhibitory molecules associated with oligodendrocytes. Regeneration of central nervous system axons in fish is correlated with the presence of a transglutaminase. This enzyme dimerizes interleukin-2, and the product is cytotoxic to oligodendrocytes in vitro. Application of this nerve-derived transglutaminase to rat optic nerves, in which the injury had caused the loss of visual evoked potential response to light, promoted the recovery of that response within 6 weeks after injury. Transmission electron microscopy analysis revealed the concomitant appearance of axons in the distal stump of the optic nerve. | Recovery of visual response of injured adult rat optic nerves treated with transglutaminase. |
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generate lipid droplets (LD), but the physiological relevance of this response is uncertain. Using complete nutrient deprivation of cells in culture as a simple model of stress, we have addressed whether LD biogenesis has a protective role in cells committed to die. Complete nutrient deprivation induced the biogenesis of LD in human LN18 glioblastoma and HeLa cells and also in CHO and rat primary astrocytes. In all cell types, death was associated with LD depletion and was accelerated by blocking LD biogenesis after pharmacological inhibition of Group IVA phospholipase A2 (cPLA2α) or down-regulation of ceramide kinase. Nutrient deprivation also induced β-oxidation of fatty acids that was sensitive to cPLA2α inhibition, and cell survival in these conditions became strictly dependent on fatty acid catabolism. These results show that, during nutrient deprivation, cell viability is sustained by β-oxidation of fatty acids that requires biogenesis and mobilization of LD. | Cell survival during complete nutrient deprivation depends on lipid droplet-fueled β-oxidation of fatty acids. |
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"28691": 0.04860413447022438, "28828": 0.2447827309370041, "28873": 0.2786078155040741, "29237": 0.11430477350950241} | 10485142 | Nasopharyngeal carcinoma (NPC) is a common disease in Hong Kong and southern provinces of China. EBV infection is believed to play a critical role in the development of NPC. Previous studies on the transformation mechanism of EBV genes were mostly performed in either NPC or nonnasopharyngeal epithelial cells which may not be representative of premalignant nasopharyngeal epithelial cells. Establishment of a representative cell system would greatly facilitate the elucidation of the role of EBV infection in the development of NPC. Using telomerase alone, we were able to establish an immortalized nasopharyngeal epithelial cell line from primary nonmalignant nasopharyngeal biopsies. The telomerase-immortalized nasopharyngeal epithelial cells are largely diploid in karyotype. Interestingly, this newly immortalized nasopharyngeal epithelial cell line, referred as NP460hTert, harbors genetic alterations previously identified in premalignant and malignant nasopharyngeal epithelial cells. These include inactivation of p16 by homozygous deletion of the p16(INK4A) locus and downregulation of RASSF1A expression. The deletion of the p16(INK4A) locus appears to be the most crucial event for the immortalization of nasopharyngeal epithelial cells by telomerase and precedes RASSF1A downregulation. In addition, detailed analysis of the cytogenetic changes by conventional cytogenetics, spectral karyotyping (SKY) and array-based CGH revealed a gain of a 17q21-q25 fragment on 11p15 chromosome in all NP460hTert cells which occurred before deletion of the p16(INK4A) locus. Gain of 17q has been previously reported in NPC. In addition, activation of NF-kappaB was observed in immortalized NP460hTert cells at the later population doublings, and may play a role in the survival of immortalized NP epithelial cells. Id1 which is commonly expressed in various human cancers, including NPC, was also upregulated in the immortalized NP460hTert cells. Thus, the establishment of an immortalized nasopharyngeal epithelial cell line harboring common genetic alterations present in premalignant and cancerous nasopharyngeal epithelial cells may provide a valuable cell system to examine for early events involved in NPC carcinogenesis, particularly in elucidating the role of EBV infection in NPC development. | Molecular and cytogenetic changes involved in the immortalization of nasopharyngeal epithelial cells by telomerase. |
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0.02412080205976963, "29490": 0.32270604372024536} | 10486817 | BACKGROUND Cellular nucleic acid binding protein (CNBP) has been implicated in vertebrate craniofacial development and in myotonic dystrophy type 2 (DM2) and sporadic inclusion body myositis (sIBM) human diseases by controlling cell proliferation and survival to mediate neural crest expansion. CNBP has been found to bind single-stranded nucleic acid and promote rearrangements of nucleic acid secondary structure in an ATP-independent manner, acting as a nucleic acid chaperone. METHODS A variety of methods were used, including cell viability assays, wound-scratch assays, chemotaxis assays, invasion assays, circular dichroic (CD) spectroscopy, NMR spectroscopy, chromatin immunoprecipitation, expression and purification of recombinant human CNBP, electrophoretic mobility shift assay (EMSA), surface plasmon resonance (SPR), fluorescence resonance energy transfer (FRET) analyses, luciferase reporter assay, Western blotting, and isothermal titration calorimetry (ITC). RESULTS Up-regulation of CNBP induced human fibrosarcoma cell death and suppressed fibrosarcoma cell motility and invasiveness. It was found that CNBP transcriptionally down-regulated the expression of heterogeneous ribonucleoprotein K (hnRNP K) through its conversion of a G-rich sequence into G-quadruplex in the promoter of hnRNP K. G-quadruplex stabilizing ligand tetra-(N-methyl-4-pyridyl) porphyrin (TMPyP4) could interact with and stabilize the G-quadruplex, resulting in downregulation of hnRNP K transcription. CONCLUSIONS CNBP overexpression caused increase of cell death and suppression of cell metastasis through its induction of G-quadruplex formation in the promoter of hnRNP K resulting in hnRNP K down-regulation. GENERAL SIGNIFICANCE The present result provided a new solution for controlling hnRNP K expression, which should shed light on new anticancer drug design and development. | Cellular nucleic acid binding protein suppresses tumor cell metastasis and induces tumor cell death by downregulating heterogeneous ribonucleoprotein K in fibrosarcoma cells. |
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Although xenobiotic responses have been studied in vertebrates, little effort has been made to exploit a simple genetic system for characterizing the molecular basis of this coordinated transcriptional response. We show here that approximately 1000 transcripts are significantly affected by phenobarbital treatment in Drosophila. We also demonstrate that the Drosophila ortholog of the human SXR and CAR xenobiotic receptors, DHR96, plays a role in this response. A DHR96 null mutant displays increased sensitivity to the sedative effects of phenobarbital and the pesticide DDT as well as defects in the expression of many phenobarbital-regulated genes. Metabolic and stress-response genes are also controlled by DHR96, implicating its role in coordinating multiple response pathways. This work establishes a new model system for defining the genetic control of xenobiotic stress responses. | The DHR96 nuclear receptor regulates xenobiotic responses in Drosophila. |
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nature of cancer argues that cancer cells are a chance result of events that cause genomic and epigenetic variability. The prevailing view is that these events are mutations that affect chromosome segregation or stability. However, genomic and epigenetic variability is also triggered by cell fusion, which is often caused by viruses. Yet, cells fused by viruses are considered harmless because they die. We provide evidence that a primate virus uses both viral and exosomal proteins involved in cell fusion to produce transformed proliferating human cells. Although normal cells indeed fail to proliferate after fusion, expression of an oncogene or a mutated tumor suppressor p53 in just one of the fusion partners is sufficient to produce heterogeneous progeny. We also show that this virus can produce viable oncogenically transformed cells by fusing cells that are otherwise destined to die. Therefore, we argue that viruses can contribute to carcinogenesis by fusing cells. | A primate virus generates transformed human cells by fusion |
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"28553": 0.24248650670051575, "28593": 0.1384023278951645, "28696": 0.25239890813827515, "29206": 0.09317722171545029, "29290": 0.11256109178066254, "29598": 1.105748176574707} | 10504681 | Plants have evolved a tremendous ability to respond to environmental changes by adapting their growth and development. The interaction between hormonal and developmental signals is a critical mechanism in the generation of this enormous plasticity. A good example is the response to the hormone ethylene that depends on tissue type, developmental stage, and environmental conditions. By characterizing the Arabidopsis wei8 mutant, we have found that a small family of genes mediates tissue-specific responses to ethylene. Biochemical studies revealed that WEI8 encodes a long-anticipated tryptophan aminotransferase, TAA1, in the essential, yet genetically uncharacterized, indole-3-pyruvic acid (IPA) branch of the auxin biosynthetic pathway. Analysis of TAA1 and its paralogues revealed a link between local auxin production, tissue-specific ethylene effects, and organ development. Thus, the IPA route of auxin production is key to generating robust auxin gradients in response to environmental and developmental cues. | TAA1-Mediated Auxin Biosynthesis Is Essential for Hormone Crosstalk and Plant Development |
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"26514": 0.06703783571720123, "27001": 0.24171993136405945, "27050": 0.4311734735965729, "27203": 0.9568626880645752, "27937": 0.6086184978485107, "28296": 1.0855059623718262, "28400": 0.3106105625629425, "28804": 0.12556517124176025, "29003": 0.11256109178066254} | 10509344 | In the past decades, public health research has focused on categorical rather than cross-cutting or systems issues. Little research has been carried out on the infrastructure required to support public health programs. This article describes the results of an interactive process to develop a research agenda for public health workforce development to inform all those with stakes in the public health system. This research is defined as a multidisciplinary field of inquiry, both basic and applied, that examines the workforce in terms of costs, quality, accessibility, delivery, organization, financing, and outcomes of public health services to increase knowledge and understanding of the relationships among workforce and structure, processes, and effects of public health services. A logic model and five priority research areas resulted from meetings of expert panels during 2000 to 2003. Innovative public and private partnerships will be required to advance cross-cutting and systems-focused research. | A research agenda for public health workforce development. |
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This is commonly referred to as parallel processing, and starts as early as the first synapse of the retina, the cone pedicle. Here, the molecular composition of the transmitter receptors of the postsynaptic neurons defines which images are transferred to the inner retina. Within the second synaptic layer — the inner plexiform layer — circuits that involve complex inhibitory and excitatory interactions represent filters that select 'what the eye tells the brain'. | Parallel processing in the mammalian retina |
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Aged Fancd2(-/-) mice were used to assess the therapeutic efficacy of oxymetholone (OXM) and its mechanism of action. Eighteen-month-old Fancd2(-/-) mice recapitulated key human FA phenotypes, including reduced bone marrow cellularity, red cell macrocytosis, and peripheral pancytopenia. As in humans, chronic OXM treatment significantly improved these hematological parameters and stimulated the proliferation of hematopoietic stem and progenitor cells. RNA-Seq analysis implicated downregulation of osteopontin as an important potential mechanism for the drug's action. Consistent with the increased stem cell proliferation, competitive repopulation assays demonstrated that chronic OXM therapy eventually resulted in stem cell exhaustion. These results expand our knowledge of the regulation of hematopoietic stem cell proliferation and have direct clinical implications for the treatment of bone marrow failure. | Oxymetholone Therapy of Fanconi Anemia Suppresses Osteopontin Transcription and Induces Hematopoietic Stem Cell Cycling |
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0.10467668622732162, "28466": 0.7674643993377686, "28788": 0.6451379656791687, "28828": 0.29109421372413635, "28829": 0.32553088665008545, "28927": 0.007782140281051397, "29107": 0.3325583338737488, "29125": 0.4950772523880005, "29126": 0.08692999184131622, "29206": 0.0029254043474793434} | 10530014 | Monogenic deficiency diseases provide unique opportunities to define the contributions of individual molecules to human physiology and to identify pathologies arising from their dysfunction. Here we describe a deficiency disease in two human siblings that presented with severe bleeding, frequent infections and osteopetrosis at an early age. These symptoms are consistent with but more severe than those reported for people with leukocyte adhesion deficiency III (LAD-III). Mechanistically, these symptoms arose from an inability to activate the integrins expressed on hematopoietic cells, including platelets and leukocytes. Immortalized lymphocyte cell lines isolated from the two individuals showed integrin activation defects. Several proteins previously implicated in integrin activation, including Ras-associated protein-1 (RAP1) and calcium and diacylglycerol-regulated guanine nucleotide exchange factor-1 (CALDAG-GEF1), were present and functional in these cell lines. The genetic basis for this disease was traced to a point mutation in the coding region of the KINDLIN3 (official gene symbol FERMT3) gene. When wild-type KINDLIN-3 was expressed in the immortalized lymphocytes, their integrins became responsive to activation signals. These results identify a genetic disease that severely compromises the health of the affected individuals and establish an essential role of KINDLIN-3 in integrin activation in humans. Furthermore, allogeneic bone marrow transplantation was shown to alleviate the symptoms of the disease. | A point mutation in KINDLIN3 ablates activation of three integrin subfamilies in humans |
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0.4974553883075714, "29458": 0.14939609169960022, "29577": 0.08244366943836212} | 10534299 | AgRP neuron activity drives feeding and weight gain whereas that of nearby POMC neurons does the opposite. However, the role of excitatory glutamatergic input in controlling these neurons is unknown. To address this question, we generated mice lacking NMDA receptors (NMDARs) on either AgRP or POMC neurons. Deletion of NMDARs from AgRP neurons markedly reduced weight, body fat and food intake whereas deletion from POMC neurons had no effect. Activation of AgRP neurons by fasting, as assessed by c-Fos, Agrp and Npy mRNA expression, AMPA receptor-mediated EPSCs, depolarization and firing rates, required NMDARs. Furthermore, AgRP but not POMC neurons have dendritic spines and increased glutamatergic input onto AgRP neurons caused by fasting was paralleled by an increase in spines, suggesting fasting induced synaptogenesis and spinogenesis. Thus glutamatergic synaptic transmission and its modulation by NMDARs play key roles in controlling AgRP neurons and determining the cellular and behavioral response to fasting. | Fasting Activation of AgRP Neurons Requires NMDA Receptors and Involves Spinogenesis and Increased Excitatory Tone |
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"26040": 0.24248650670051575, "26163": 0.09317722171545029, "26290": 1.498855471611023, "26717": 0.05139094591140747, "26728": 0.025073638185858727, "26884": 0.22859740257263184, "27247": 0.1358480453491211, "27427": 0.1677299439907074, "27617": 0.09317722171545029, "27942": 0.5767669677734375, "28227": 0.009718249551951885, "28279": 0.15777134895324707} | 10536636 | Background Blindness and low vision are thought to be common in southern Sudan. However, the magnitude and geographical distribution are largely unknown. We aimed to estimate the prevalence of blindness and low vision, identify the main causes of blindness and low vision, and estimate targets for blindness prevention programs in Mankien payam (district), southern Sudan. | Prevalence and Causes of Blindness and Low Vision in Southern Sudan |
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nitrite have been found in exhaled breath condensate (EBC) in airway disease, and it has been postulated that this reflects increased nitric oxide (NO) metabolism. However, the chemical and anatomical origin of nitrate and nitrite in the airways has not yet been sufficiently studied. METHODS The fraction of exhaled NO at an exhalation flow rate of 50 ml/s (FE(NO)) and nitrite and nitrate in EBC, nasal condensate, and saliva were measured in 17 tracheostomised and 15 non-tracheostomised subjects, all of whom were non-smokers without respiratory disease. Tracheal and oral samples were taken from the tracheostomised subjects and nasal (during velum closure) and oral samples from the non-tracheostomised subjects. Measurements were performed before and after sodium nitrate ingestion (10 mg/kg) and use of antibacterial mouthwash (chlorhexidine 0.2%). RESULTS In tracheostomised subjects oral FE(NO) increased by 90% (p<0.01) while tracheal FE(NO) was not affected 60 minutes after nitrate ingestion. Oral EBC nitrite levels were increased 23-fold at 60 minutes (p<0.001) whereas the nitrite levels in tracheal EBC showed only a minor increase (fourfold, p<0.05). Nitrate was increased the same amount in oral and tracheal EBC at 60 minutes (2.5-fold, p<0.05). In non-tracheostomised subjects oral FE(NO) and EBC nitrite increased after nitrate ingestion and after chlorhexidine mouthwash they approached baseline levels again (p<0.001). Nasal NO, nitrate, and nitrite were not affected by nitrate intake or mouthwash. At baseline, mouthwash with deionised water did not affect nitrite in oral EBC or saliva, whereas significant reductions were seen after antibacterial mouthwash (p<0.05 and p<0.001, respectively). CONCLUSIONS Besides the salivary glands, plasma nitrate is taken up by the lower airways but not the nasal airways. Nitrate levels in EBC are thus influenced by dietary intake. Nitrate is reduced to nitrite by bacterial activity which takes place primarily in the oropharyngeal tract of healthy subjects. Only oropharyngeal nitrite seems to contribute to exhaled NO in non-inflamed airways, and there is also a substantial contribution of nitrite from the oropharyngeal tract during standard collection of EBC. | Origin of nitrite and nitrate in nasal and exhaled breath condensate and relation to nitric oxide formation. |
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0.006812678650021553, "25409": 0.8238670229911804, "25416": 0.6451379656791687, "25456": 1.147526502609253, "25468": 0.14349138736724854, "25524": 0.46117570996284485, "25714": 0.09938567131757736, "25778": 0.083342544734478, "26261": 0.4196864068508148, "26319": 0.24401791393756866, "26402": 0.5186077356338501, "26601": 0.9553611874580383, "26702": 0.08154398202896118, "27142": 0.46117570996284485, "27144": 0.3870677351951599, "27570": 0.8425432443618774, "27572": 0.1510767638683319, "27605": 0.05139094591140747, "27781": 0.06154331564903259, "28093": 1.2324692010879517, "28965": 0.3325583338737488, "29021": 0.21530038118362427, "29226": 0.14602625370025635, "29336": 0.08154398202896118, "29598": 0.7482418417930603} | 10542877 | Next-generation sequencing technologies have greatly expanded our understanding of cancer genetics. Antisense technology is an attractive platform with the potential to translate these advances into improved cancer therapeutics, because antisense oligonucleotide (ASO) inhibitors can be designed on the basis of gene sequence information alone. Recent human clinical data have demonstrated the potent activity of systemically administered ASOs targeted to genes expressed in the liver. We describe the preclinical activity and initial clinical evaluation of a class of ASOs containing constrained ethyl modifications for targeting the gene encoding the transcription factor STAT3, a notoriously difficult protein to inhibit therapeutically. Systemic delivery of the unformulated ASO, AZD9150, decreased STAT3 expression in a broad range of preclinical cancer models and showed antitumor activity in lymphoma and lung cancer models. AZD9150 preclinical activity translated into single-agent antitumor activity in patients with highly treatment-refractory lymphoma and non–small cell lung cancer in a phase 1 dose-escalation study. | AZD9150, a next-generation antisense oligonucleotide inhibitor of STAT3 with early evidence of clinical activity in lymphoma and lung cancer |
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0.00875066313892603, "28405": 0.1873544454574585, "28774": 0.960606575012207, "28788": 0.09317722171545029, "28901": 0.08961215615272522, "29280": 0.5267143249511719} | 10546779 | Somatic cell nuclear transfer (SCNT) technology has recently been used to generate animals with a common genetic composition. In this study, we report the derivation of a pluripotent embryonic stem (ES) cell line (SCNT-hES-1) from a cloned human blastocyst. The SCNT-hES-1 cells displayed typical ES cell morphology and cell surface markers and were capable of differentiating into embryoid bodies in vitro and of forming teratomas in vivo containing cell derivatives from all three embryonic germ layers in severe combined immunodeficient mice. After continuous proliferation for more than 70 passages, SCNT-hES-1 cells maintained normal karyotypes and were genetically identical to the somatic nuclear donor cells. Although we cannot completely exclude the possibility that the cells had a parthenogenetic origin, imprinting analyses support a SCNT origin of the derived human ES cells. | Evidence of a pluripotent human embryonic stem cell line derived from a cloned blastocyst. |
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"27480": 0.0606246218085289, "27524": 0.014542185701429844, "27605": 0.02887592278420925, "27642": 0.08064348995685577, "27651": 0.21530038118362427, "27756": 0.14686977863311768, "28024": 0.5838727951049805, "28290": 0.13243216276168823, "28335": 0.6064908504486084, "28389": 0.02316705882549286, "28436": 0.35813871026039124, "28498": 0.176772341132164, "28616": 0.42096930742263794, "28691": 0.07793712615966797, "28778": 0.19862671196460724, "28835": 0.46363574266433716, "28873": 0.13243216276168823, "29206": 0.10203468054533005, "29490": 0.3318578004837036} | 10548391 | The enzyme debrisoquine 4-hydroxylase (CYP2D6), which metabolizes many widely used drugs, is highly polymorphic. The activity of the enzyme ranges between subjects from ultrafast to a complete absence. Therefore, metabolic capacity varies, producing intersubject differences in therapeutic efficacy and side effects at standard recommended doses. Up to 7% of Caucasians may demonstrate ultrarapid drug metabolism (UM) because of inherited alleles with multiplicate functional CYP2D6 genes, causing an increased amount of enzyme to be expressed. Identification of UM subjects is of potential clinical importance for adjustment of doses in drug therapy, as well as to avoid misidentification of noncompliance. In our study, we tested recently designed PCR assays for the detection of the UM genotype. We found a 3.5% prevalence of UMs carrying duplicate active CYP2D6 genes in a population consisting of 202 psychiatric patients. | Ultrarapid drug metabolism: PCR-based detection of CYP2D6 gene duplication. |
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