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|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
PMC11276485_p9
|
PMC11276485
|
sec[1]/sec[3]/p[0]
|
2.4. Variant Filtering
| 4.070313 |
biomedical
|
Study
|
[
0.99951171875,
0.0003345012664794922,
0.00027108192443847656
] |
[
0.99951171875,
0.00020945072174072266,
0.00021946430206298828,
0.00006759166717529297
] |
We filtered for private variants in the affected cat by comparing its genome sequence data to a control cohort comprising 96 publicly available WGS datasets from genetically diverse cats ( Table S1 ). Variants in the affected cat that also occurred in at least one of the control cats were excluded from further analysis. In a second step, protein-changing variants were prioritized. We considered variants with an SnpEff predicted impact of “high” or “moderate” as protein-changing.
|
[
"Stefan J. Rietmann",
"Noëlle Cochet-Faivre",
"Helene Dropsy",
"Vidhya Jagannathan",
"Lucie Chevallier",
"Tosso Leeb"
] |
https://doi.org/10.3390/genes15070854
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276485_p10
|
PMC11276485
|
sec[1]/sec[4]/p[0]
|
2.5. In Silico Pathogenicity Prediction
| 4.199219 |
biomedical
|
Study
|
[
0.99951171875,
0.00038361549377441406,
0.00013208389282226562
] |
[
0.998046875,
0.0013980865478515625,
0.0004794597625732422,
0.0002796649932861328
] |
The online classification tools Polyphen-2 , PredictSNP and MutPred2 were utilized to predict the potential functional impact of the XP_011290083.1:p.Ala348Thr missense variant. The Mol*3D viewer from the RCSB Protein Data Bank was used to visualize the protein structure 1RJ7 of the TNF signaling domain of the human ectodysplasin A protein .
|
[
"Stefan J. Rietmann",
"Noëlle Cochet-Faivre",
"Helene Dropsy",
"Vidhya Jagannathan",
"Lucie Chevallier",
"Tosso Leeb"
] |
https://doi.org/10.3390/genes15070854
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276485_p11
|
PMC11276485
|
sec[2]/sec[0]/p[0]
|
3.1. Clinical Phenotype
| 1.584961 |
clinical
|
Clinical case
|
[
0.25537109375,
0.7001953125,
0.044464111328125
] |
[
0.0038509368896484375,
0.0377197265625,
0.0029354095458984375,
0.95556640625
] |
A 9-year-old neutered male European domestic shorthair cat was presented for pruritus of the limbs and abdomen. The cat had been adopted at the age of 7 years old from a rescue organization. The cat had been given regular external antiparasitic treatment.
|
[
"Stefan J. Rietmann",
"Noëlle Cochet-Faivre",
"Helene Dropsy",
"Vidhya Jagannathan",
"Lucie Chevallier",
"Tosso Leeb"
] |
https://doi.org/10.3390/genes15070854
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11276485_p12
|
PMC11276485
|
sec[2]/sec[0]/p[1]
|
3.1. Clinical Phenotype
| 2.898438 |
clinical
|
Clinical case
|
[
0.2958984375,
0.6953125,
0.00872802734375
] |
[
0.003719329833984375,
0.009429931640625,
0.002819061279296875,
0.98388671875
] |
At presentation, diffuse truncal alopecia with complete alopecia of the abdomen, alopecia and hyperpigmentation of the inner thighs and alopecia of ungual ridges was evident . Coat inspection revealed reduction to absence of the undercoat with presence of guard hair only. Diffuse squamosis, follicular casts, diffuse erythema and overall loss of skin elasticity were also present. The hair loss had not changed since adoption, and the erythema and pruritus appeared a few weeks prior to presentation. The cat had a history of chronic rhinitis.
|
[
"Stefan J. Rietmann",
"Noëlle Cochet-Faivre",
"Helene Dropsy",
"Vidhya Jagannathan",
"Lucie Chevallier",
"Tosso Leeb"
] |
https://doi.org/10.3390/genes15070854
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276485_p13
|
PMC11276485
|
sec[2]/sec[0]/p[2]
|
3.1. Clinical Phenotype
| 1.532227 |
biomedical
|
Clinical case
|
[
0.52587890625,
0.41845703125,
0.055633544921875
] |
[
0.01593017578125,
0.295654296875,
0.00327301025390625,
0.68505859375
] |
At the time of presentation, the cat had only six teeth, the four canines and two lower premolars. The incisors, upper premolars and molars were missing. The canines and the present premolars had an abnormal conical shape .
|
[
"Stefan J. Rietmann",
"Noëlle Cochet-Faivre",
"Helene Dropsy",
"Vidhya Jagannathan",
"Lucie Chevallier",
"Tosso Leeb"
] |
https://doi.org/10.3390/genes15070854
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276485_p14
|
PMC11276485
|
sec[2]/sec[0]/p[3]
|
3.1. Clinical Phenotype
| 3.841797 |
biomedical
|
Study
|
[
0.92919921875,
0.0701904296875,
0.0005068778991699219
] |
[
0.50390625,
0.0426025390625,
0.004947662353515625,
0.448486328125
] |
Blood hematology and biochemistry revealed only moderate eosinophilia and marked neutrophilic leukocytosis, probably secondary to chronic dermatopathy ( Tables S2 and S3 ). Cushing syndrome was ruled out by abdominal ultrasonography, which revealed normal, normoechoic adrenal glands of normal size and shape, as well as normal blood and urine tests and a normal urine specific gravity of 1.050 ( Table S4 ). FIV and FelV tests were negative. The owner declined skin biopsies for further histopathological examinations.
|
[
"Stefan J. Rietmann",
"Noëlle Cochet-Faivre",
"Helene Dropsy",
"Vidhya Jagannathan",
"Lucie Chevallier",
"Tosso Leeb"
] |
https://doi.org/10.3390/genes15070854
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276485_p15
|
PMC11276485
|
sec[2]/sec[0]/p[4]
|
3.1. Clinical Phenotype
| 2.816406 |
biomedical
|
Clinical case
|
[
0.74755859375,
0.2486572265625,
0.003604888916015625
] |
[
0.0113525390625,
0.10968017578125,
0.003276824951171875,
0.87548828125
] |
Altogether, the clinical signs of hypotrichosis, squamosis, follicular casts and dental agenesis, along with the exclusion of a metabolic disease such as Cushing syndrome, led to a suspicion of hypohidrotic ectodermal dysplasia .
|
[
"Stefan J. Rietmann",
"Noëlle Cochet-Faivre",
"Helene Dropsy",
"Vidhya Jagannathan",
"Lucie Chevallier",
"Tosso Leeb"
] |
https://doi.org/10.3390/genes15070854
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276485_p16
|
PMC11276485
|
sec[2]/sec[1]/p[0]
|
3.2. Genetic Analysis
| 4.066406 |
biomedical
|
Study
|
[
0.99951171875,
0.0003769397735595703,
0.00022912025451660156
] |
[
0.99951171875,
0.0001970529556274414,
0.00020694732666015625,
0.00010651350021362305
] |
We sequenced the genome of the affected cat and compared the sequence data to 96 genetically diverse control genomes in a search for plausible causative variants. Several filtering steps were performed based on hypothetical dominant or recessive modes of inheritance, allele frequency in the control cohort and predicted variant impact. Variants in the known candidate genes EDA , EDAR and EDARADD were prioritized ( Table 1 and Table S5 ).
|
[
"Stefan J. Rietmann",
"Noëlle Cochet-Faivre",
"Helene Dropsy",
"Vidhya Jagannathan",
"Lucie Chevallier",
"Tosso Leeb"
] |
https://doi.org/10.3390/genes15070854
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276485_p17
|
PMC11276485
|
sec[2]/sec[1]/p[1]
|
3.2. Genetic Analysis
| 4.265625 |
biomedical
|
Study
|
[
0.9990234375,
0.0004982948303222656,
0.00025010108947753906
] |
[
0.99755859375,
0.0016765594482421875,
0.0002415180206298828,
0.0003407001495361328
] |
The analyses identified a single candidate variant on the X chromosome, NC_058386.1:g.57,148,944G>A. It is a missense variant in the EDA gene, XM_011291781.3:c.1042G>A, predicted to change an alanine into a threonine residue on the protein level, XP_011290083.1:p.(Ala348Thr). This predicted amino acid substitution is located in the TNF signaling domain of ectodysplasin A . The mutant allele was absent from 404 cat genomes of the 99 Lives Consortium .
|
[
"Stefan J. Rietmann",
"Noëlle Cochet-Faivre",
"Helene Dropsy",
"Vidhya Jagannathan",
"Lucie Chevallier",
"Tosso Leeb"
] |
https://doi.org/10.3390/genes15070854
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276485_p18
|
PMC11276485
|
sec[2]/sec[1]/p[2]
|
3.2. Genetic Analysis
| 4.308594 |
biomedical
|
Study
|
[
0.99853515625,
0.001483917236328125,
0.000156402587890625
] |
[
0.98876953125,
0.007297515869140625,
0.0014638900756835938,
0.00231170654296875
] |
In silico pathogenicity prediction tools classified the p.Ala348Thr variant as potentially deleterious. MutPred2 gave a score of 0.541, marginally above the pathogenicity threshold of 0.5. PredictSNP classified the p.Ala348Thr variant as deleterious with 72% probability. Polyphen-2 classified the variant as probably damaging with a score of 0.995.
|
[
"Stefan J. Rietmann",
"Noëlle Cochet-Faivre",
"Helene Dropsy",
"Vidhya Jagannathan",
"Lucie Chevallier",
"Tosso Leeb"
] |
https://doi.org/10.3390/genes15070854
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276485_p19
|
PMC11276485
|
sec[2]/sec[1]/p[3]
|
3.2. Genetic Analysis
| 4.351563 |
biomedical
|
Study
|
[
0.99951171875,
0.00034928321838378906,
0.0002923011779785156
] |
[
0.99560546875,
0.0037822723388671875,
0.0005030632019042969,
0.00024771690368652344
] |
The amino acid sequence of the TNF signaling domain is highly conserved between vertebrates. The alanine corresponding to the feline Ala-348 residue is invariable in all vertebrate sequences analyzed . This alanine is located in a β-sheet at the contact interface between the three EDA-A1 monomers . The small methyl side chain is in close proximity to three phenyl rings from neighboring amino acids .
|
[
"Stefan J. Rietmann",
"Noëlle Cochet-Faivre",
"Helene Dropsy",
"Vidhya Jagannathan",
"Lucie Chevallier",
"Tosso Leeb"
] |
https://doi.org/10.3390/genes15070854
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11276485_p20
|
PMC11276485
|
sec[3]/p[0]
|
4. Discussion
| 4.167969 |
biomedical
|
Study
|
[
0.9990234375,
0.0010442733764648438,
0.0001678466796875
] |
[
0.99755859375,
0.0008563995361328125,
0.00043654441833496094,
0.000942230224609375
] |
In this study, we investigated a male cat with a syndromic phenotype involving partially missing hair and missing or abnormally shaped teeth. This combination of clinical signs was classified as hypohidrotic ectodermal dysplasia. This phenotype is highly characteristic, and especially in male individuals, the X-chromosomal EDA is the primary functional candidate gene. Many pathogenic variants in EDA have been reported in human patients , dogs and cattle . The history of chronic rhinitis in the affected cat might have been caused by defects in respiratory mucous glands, which are a common feature of hypohidrotic ectodermal dysplasia in humans, cattle and dogs . Keratoconjunctivitis sicca, another frequent phenotype in human X-linked hypohidrotic ectodermal dysplasia due to defects in lacrimal glands, was not observed in the investigated cat.
|
[
"Stefan J. Rietmann",
"Noëlle Cochet-Faivre",
"Helene Dropsy",
"Vidhya Jagannathan",
"Lucie Chevallier",
"Tosso Leeb"
] |
https://doi.org/10.3390/genes15070854
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276485_p21
|
PMC11276485
|
sec[3]/p[1]
|
4. Discussion
| 2.185547 |
biomedical
|
Other
|
[
0.9755859375,
0.0159454345703125,
0.00827789306640625
] |
[
0.0018177032470703125,
0.99658203125,
0.0005068778991699219,
0.0013294219970703125
] |
For practicing veterinarians, it is important to consider all organ systems that may be affected in XHED to provide an optimal management of potential future cases. Special attention should be paid to good management of respiratory infections and surveillance of eye irritations due to possible gland defects in XHED-affected animals.
|
[
"Stefan J. Rietmann",
"Noëlle Cochet-Faivre",
"Helene Dropsy",
"Vidhya Jagannathan",
"Lucie Chevallier",
"Tosso Leeb"
] |
https://doi.org/10.3390/genes15070854
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11276485_p22
|
PMC11276485
|
sec[3]/p[2]
|
4. Discussion
| 4.484375 |
biomedical
|
Study
|
[
0.9990234375,
0.0007700920104980469,
0.00022363662719726562
] |
[
0.9970703125,
0.0015230178833007812,
0.0005502700805664062,
0.0006613731384277344
] |
The identified EDA missense variant in the affected cat, p.Ala348Thr, is predicted to affect a single amino acid within the TNF signaling domain, located at the contact interface between the three monomers. Interestingly, the homologous human variant, p.Ala349Thr, has been identified in at least two independent human XHED families . The available knowledge on the homologous human variant provides very strong support for the pathogenicity of the feline p.Ala348Thr variant. It seems conceivable that replacement of the alanine with the slightly larger and more polar threonine might interfere with correct assembly of the trimeric TNF signaling domain. The hydroxy group of the mutant threonine might potentially disrupt a hydrogen bond that normally bridges two adjacent tyrosine side chains from two different subunits .
|
[
"Stefan J. Rietmann",
"Noëlle Cochet-Faivre",
"Helene Dropsy",
"Vidhya Jagannathan",
"Lucie Chevallier",
"Tosso Leeb"
] |
https://doi.org/10.3390/genes15070854
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276485_p23
|
PMC11276485
|
sec[3]/p[3]
|
4. Discussion
| 4.136719 |
biomedical
|
Study
|
[
0.99951171875,
0.00038433074951171875,
0.00034046173095703125
] |
[
0.943359375,
0.055084228515625,
0.0006885528564453125,
0.0009226799011230469
] |
At the nucleotide level, the substitution affects a CpG dinucleotide. CpG dinucleotides represent known mutational hotspots due to the spontaneous deamination of 5-methylated or unmethylated cytosines, which results in CG → TG or CG → CA substitutions as in the cat described herein .
|
[
"Stefan J. Rietmann",
"Noëlle Cochet-Faivre",
"Helene Dropsy",
"Vidhya Jagannathan",
"Lucie Chevallier",
"Tosso Leeb"
] |
https://doi.org/10.3390/genes15070854
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276485_p24
|
PMC11276485
|
sec[3]/p[4]
|
4. Discussion
| 4.601563 |
biomedical
|
Study
|
[
0.99951171875,
0.0004050731658935547,
0.0002486705780029297
] |
[
0.9970703125,
0.0007581710815429688,
0.0019245147705078125,
0.0003027915954589844
] |
The ~400 kb EDA gene is one of the largest genes in the mammalian genome. Many different types of deleterious sequence variants have been identified that lead to a loss of function of ectodysplasin A and result in XHED. These include single-nucleotide variants representing missense variants such as in the cat described herein and several examples in humans and cattle . Other single-base substitutions represent nonsense variants or were reported to disrupt splicing . Additionally, small coding insertions and deletions, either in-frame or frame-shifting , and large structural variants were reported in XHED-affected individuals . Exon 2 of the EDA gene is flanked by very large introns on either side, which complicates the correct splicing of the primary transcript. Splicing aberrations in XHED-affected cattle have been reported in an animal with a partial LINE-1 insertion into intron 1 that resulted in “exonization” of the inserted sequence and a non-functional transcript . Finally, in three XHED-affected dogs, skipping of exon 2 was observed, although the genomic sequence of exon 2 and its flanking splice sites were unaltered. The genomic variant causing this splice defect has not yet been identified .
|
[
"Stefan J. Rietmann",
"Noëlle Cochet-Faivre",
"Helene Dropsy",
"Vidhya Jagannathan",
"Lucie Chevallier",
"Tosso Leeb"
] |
https://doi.org/10.3390/genes15070854
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11276485_p25
|
PMC11276485
|
sec[4]/p[0]
|
5. Conclusions
| 4.210938 |
biomedical
|
Study
|
[
0.99560546875,
0.004421234130859375,
0.00019860267639160156
] |
[
0.982421875,
0.005397796630859375,
0.0012483596801757812,
0.01104736328125
] |
We characterized the clinical phenotype of a male cat with X-linked hypohidrotic ectodermal dysplasia (XHED). Similar to XHED in other mammalian species, the primary phenotypic alterations include partially missing hair and a complete absence of the undercoat. Furthermore, the affected cat lacked most teeth, and the remaining teeth had an abnormal conical shape. The genetic investigation identified EDA :c.1042G>A, a single-nucleotide variant affecting a CpG dinucleotide and resulting in the p.Ala348Thr missense change as the most likely causative defect. A homologous missense variant, p.Ala349Thr, caused by recurring mutations of the homologous CpG dinucleotide has been reported in several human patients with XHED. To the best of our knowledge, we report the first instance of an EDA -related hypohidrotic ectodermal dysplasia in a cat.
|
[
"Stefan J. Rietmann",
"Noëlle Cochet-Faivre",
"Helene Dropsy",
"Vidhya Jagannathan",
"Lucie Chevallier",
"Tosso Leeb"
] |
https://doi.org/10.3390/genes15070854
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276497_p0
|
PMC11276497
|
sec[0]/p[0]
|
Cultural differences in perception and memory
| 1.854492 |
other
|
Other
|
[
0.04718017578125,
0.0006880760192871094,
0.9521484375
] |
[
0.0496826171875,
0.93212890625,
0.01702880859375,
0.00091552734375
] |
There is ample evidence that culture affects perception and associated memory processes . According to the analytic and holistic framework , Westerners (e.g., people from North America and Western Europe) are more analytic in thinking style, such that an object is perceived and identified through its key features (i.e., intrinsic features) and separated from its context (i.e., extrinsic features). In contrast, Easterners (e.g., people from East Asia) are more holistic in thinking style, such that objects are perceived as an integral part of their context. This means that binding extrinsic features is more automatic and akin to intrinsic binding for Easterners compared to Westerners. Consequently, the framework predicts that Westerners focus on and remember foreground objects, whereas Easterners focus on and remember foreground objects and their backgrounds similarly.
|
[
"Hiu Wah Cheung",
"Nicolas Geeraert",
"Vanessa M. Loaiza"
] |
https://doi.org/10.5334/joc.390
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276497_p1
|
PMC11276497
|
sec[0]/p[1]
|
Cultural differences in perception and memory
| 3.914063 |
biomedical
|
Study
|
[
0.919921875,
0.000629425048828125,
0.07958984375
] |
[
0.9951171875,
0.0027790069580078125,
0.00208282470703125,
0.00010585784912109375
] |
Consistent with this prediction, prior work has demonstrated that object recognition memory was relatively unaffected by any background change for Westerners, whereas Easterners were less likely to recognise the target objects when tested with different backgrounds to what had been initially presented during encoding . These cultural differences have not been considered in the WM literature, but they may inform the previous discussion regarding unitisation and feature binding, such that extrinsic binding is less automatic for Westerners versus Easterners. Moreover, the potential dissociation between extrinsic and intrinsic binding may likewise clarify what drives the previously described cultural differences in perception and memory performance. In other words, these cultural differences may reflect more basic differences in the relative automaticity of extrinsic binding in WM, thus helping to inform the underlying mechanisms of the observed differences between Westerners and Easterners.
|
[
"Hiu Wah Cheung",
"Nicolas Geeraert",
"Vanessa M. Loaiza"
] |
https://doi.org/10.5334/joc.390
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276497_p2
|
PMC11276497
|
sec[1]/p[0]
|
Prior knowledge benefit
| 3.451172 |
biomedical
|
Study
|
[
0.69775390625,
0.0011205673217773438,
0.30126953125
] |
[
0.65869140625,
0.283203125,
0.0572509765625,
0.0006928443908691406
] |
There is some evidence showing that prior knowledge from long-term memory boosts WM performance , particularly for bindings between presented information . Thus, prior knowledge may enhance WM by facilitating the construction of extrinsic bindings specifically, whereas intrinsic bindings may be unaffected, given that they are more automatically established in WM. Furthermore, if extrinsic binding is more automatic in Easterners than in Westerners, then prior knowledge may facilitate extrinsic binding for Westerners. However, if extrinsic and intrinsic bindings are similarly automatic, then prior knowledge should similarly benefit intrinsic and extrinsic binding in both cultural groups.
|
[
"Hiu Wah Cheung",
"Nicolas Geeraert",
"Vanessa M. Loaiza"
] |
https://doi.org/10.5334/joc.390
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276497_p3
|
PMC11276497
|
sec[2]/p[0]
|
Present study
| 3.853516 |
biomedical
|
Study
|
[
0.85595703125,
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[
0.99853515625,
0.0008258819580078125,
0.0003409385681152344,
0.00008422136306762695
] |
Based on this background, we recruited participants from the UK (Western) and China (Eastern) to take part in two visual WM experiments . 1 Experiment 1 concerned whether Easterners show greater extrinsic binding memory than Western participants given previous work suggesting that Easterners process extrinsic information more automatically . For intrinsic binding memory, one of two possible patterns is likely to emerge. If intrinsic binding is automatic for Easterners, then intrinsic binding memory should be similar between Easterners and Westerners. Alternatively, Easterners’ focus on context may be at the expense of intrinsic binding, in which case Westerners should have greater intrinsic binding memory than their Eastern counterparts. Moreover, much of the prior work has limited analyses to observed task performance, which does not directly reflect item (i.e. individual features) or binding (i.e. the combination of features) memory. Therefore, this study expanded upon prior work by applying hierarchical Bayesian multinomial processing tree (MPT) modelling to derive and analyse latent cognitive parameters of item and binding memory.
|
[
"Hiu Wah Cheung",
"Nicolas Geeraert",
"Vanessa M. Loaiza"
] |
https://doi.org/10.5334/joc.390
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999994 |
PMC11276497_p4
|
PMC11276497
|
sec[2]/p[1]
|
Present study
| 4.003906 |
biomedical
|
Study
|
[
0.92333984375,
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[
0.99853515625,
0.0010395050048828125,
0.0005249977111816406,
0.00007587671279907227
] |
Experiment 2 further investigated whether prior knowledge in long-term memory (LTM) influences feature binding in WM differently between the two cultural groups. The prior knowledge of the presented information was manipulated by varying the consistency between the presented shapes and colours (e.g., red apple vs. blue apple). If prior knowledge promotes WM performance by specifically facilitating extrinsic binding , then prior knowledge should improve extrinsic binding more strongly than intrinsic binding. Furthermore, if there is a cultural difference in the automaticity of extrinsic binding, then this facilitation effect should be greater in Western than Eastern participants. However, if extrinsic and intrinsic binding are similarly automatic, then both cultural groups should show a prior knowledge benefit to both extrinsic and intrinsic binding memory.
|
[
"Hiu Wah Cheung",
"Nicolas Geeraert",
"Vanessa M. Loaiza"
] |
https://doi.org/10.5334/joc.390
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276497_p5
|
PMC11276497
|
sec[3]/sec[0]/p[0]
|
Participants
| 2.576172 |
biomedical
|
Study
|
[
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] |
[
0.9970703125,
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0.00016427040100097656
] |
For each experiment, 60 unique Chinese and British participants (30 of each group) aged 18–35 with normal colour vision were recruited from the University of Essex or Prolific to participate. Eastern and Western participants were respectively qualified as such if they self-identified as either Chinese or British, born in China or the UK, and have not lived outside of their home countries for more than 3 years. The sample size was determined in a simulation-based power analysis (see the OSF for more details). Table 1 shows the sample characteristics and pre-registered exclusions.
|
[
"Hiu Wah Cheung",
"Nicolas Geeraert",
"Vanessa M. Loaiza"
] |
https://doi.org/10.5334/joc.390
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276497_p6
|
PMC11276497
|
sec[3]/sec[0]/p[1]
|
Participants
| 1.157227 |
other
|
Other
|
[
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] |
[
0.08465576171875,
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0.0010023117065429688
] |
Participants were compensated with partial course credit or £8/hour of participation. All participants in this experiment provided informed consent and were fully debriefed at the conclusion of the experiment. The University of Essex Ethics Subcommittee 3 approved this project .
|
[
"Hiu Wah Cheung",
"Nicolas Geeraert",
"Vanessa M. Loaiza"
] |
https://doi.org/10.5334/joc.390
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276497_p7
|
PMC11276497
|
sec[3]/sec[1]/p[0]
|
Materials and Procedure
| 3.029297 |
biomedical
|
Study
|
[
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] |
[
0.99755859375,
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0.00010007619857788086
] |
Both experiments were programmed in PsychoPy and took place online with two phases. In the first phase, participants were invited to complete a brief demographics questionnaire and colour blindness test. Those who met the aforementioned inclusion criteria were invited to the second phase, wherein participants completed eight practice trials preceding the first block and 12 blocks of a visual WM task, with 24 critical trials per block. Participants received ongoing feedback on their performance and were offered a break after each block.
|
[
"Hiu Wah Cheung",
"Nicolas Geeraert",
"Vanessa M. Loaiza"
] |
https://doi.org/10.5334/joc.390
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276497_p8
|
PMC11276497
|
sec[3]/sec[1]/p[1]
|
Materials and Procedure
| 4.039063 |
biomedical
|
Study
|
[
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[
0.9990234375,
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] |
The trial sequence of Experiment 1 is presented in Figure 1A . Each trial began with a fixation cross appearing on the screen for 1s. Four different to-be-remembered shapes, either presented in four different colours on a white background (intrinsic) or white shapes on differently coloured backgrounds (extrinsic), then appeared in an invisible 2 × 2 quadrant array for 1s. After a retention interval of 1s, three test probes appeared in a single row at the centre of the screen: the target (i.e., exactly the same coloured shape as one of the originally presented items), a lure (i.e., a recombination of a presented colour and shape from the trial), and a new item (i.e., a colour or shape that were new to the trial). These probes either comprised different probe shapes (i.e., target, lure, new shape) integrated with the same target colour or the same target shape integrated with different probe colours (i.e., target, lure, new colour) to balance the nature of the decision across the features of the stimuli. Participants selected an option with their mouse at their own pace, after which a new trial began following an inter-trial interval of 1s.
|
[
"Hiu Wah Cheung",
"Nicolas Geeraert",
"Vanessa M. Loaiza"
] |
https://doi.org/10.5334/joc.390
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276497_p9
|
PMC11276497
|
sec[3]/sec[1]/p[2]
|
Materials and Procedure
| 3.083984 |
biomedical
|
Study
|
[
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[
0.9892578125,
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0.00023758411407470703
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The shapes of the memoranda were abstract shapes randomly drawn from a shape wheel , with an angular separation of 72° between the four shape memoranda and a fifth shape serving as the new probe. This experiment used the same set of 12 colours, comprising two of options of the following six principal colours: red, yellow, blue, green, grey, and brown. The colours of the four memoranda presented during encoding were randomly drawn from two of these colour families (e.g., two shapes presented in yellow, and two shapes presented in blue), and the colour of the new probe was randomly selected from the remaining colour families. In this experiment, the recombined lure was a shape or colour from the other colour family in order to avoid an easy rejection of the new colour that is not in the same colour family . The on-screen arrangement of the memoranda during encoding and the probes during retrieval were random.
|
[
"Hiu Wah Cheung",
"Nicolas Geeraert",
"Vanessa M. Loaiza"
] |
https://doi.org/10.5334/joc.390
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11276497_p10
|
PMC11276497
|
sec[3]/sec[1]/p[3]
|
Materials and Procedure
| 2.042969 |
other
|
Study
|
[
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[
0.98388671875,
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Experiment 2 was very similar to Experiment 1, with the following exceptions: First, this experiment included nameable shapes (e.g., an apple) drawn from Sutterer and Awh . These images were presented in different colours (intrinsic) or on different-coloured backgrounds (extrinsic) that are consistent or inconsistent with reality . Because of the difficulty in selecting three colour shades in each colour family, we only used the “shape” probe type. In addition, the recombined lure was a shape from the same colour family to ensure that the probes were similarly consistent or inconsistent with reality depending on the condition. The new probe was also selected such that its colour was consistent or inconsistent with reality to ensure that it was a plausible option.
|
[
"Hiu Wah Cheung",
"Nicolas Geeraert",
"Vanessa M. Loaiza"
] |
https://doi.org/10.5334/joc.390
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276497_p11
|
PMC11276497
|
sec[3]/sec[2]/p[0]
|
Design and Analysis
| 4.085938 |
biomedical
|
Study
|
[
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[
0.99951171875,
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0.000041484832763671875
] |
Experiment 1 followed a 2 (Culture: British, Chinese) × 2 (Binding Type: Intrinsic, Extrinsic) × 2 (Probe Type: Shape, Colour) mixed design, whereas Experiment 2 followed a 2 (Culture: British, Chinese) × 2 (Binding Type: Intrinsic, Extrinsic) × 2 (Prior Knowledge: Consistent, Inconsistent) mixed design (the latter two factors of each design manipulated within-subjects). The key measure of frequency of responses of each possible category (i.e., target, lure, and new) were fitted with separate hierarchical Bayesian MPT models for each cultural group using the TreeBUGS package in R. MPT models are a class of measurement models that estimate the cognitive parameters assumed to underlie the observed response frequencies. Hierarchical MPT models explicitly allow for heterogeneity across participants and trials and assume that the resulting individual parameter estimates are drawn from a population distribution. Furthermore, the Bayesian approach focuses on the posterior distribution of the parameters that are sampled using Markov-Chain Monte Carlo (MCMC) methods. The measures of interest are the mean and quantiles computed for the posterior distribution of the samples, which reflect the updated knowledge about the parameters in light of the data and given some prior beliefs. We used the default weakly informative priors of TreeBUGS that follow the recommendations of prior work .
|
[
"Hiu Wah Cheung",
"Nicolas Geeraert",
"Vanessa M. Loaiza"
] |
https://doi.org/10.5334/joc.390
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11276497_p12
|
PMC11276497
|
sec[3]/sec[2]/p[1]
|
Design and Analysis
| 4.089844 |
biomedical
|
Study
|
[
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[
0.99951171875,
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] |
The two tested models are visually depicted in Figure 2 . The difference between these models is the assumption of whether binding memory is independent of (i.e. independence model) or dependent on (i.e. dependence model) accurate memory of the individual features (i.e. item memory). The dependence model assumes that participants may correctly select the target probe when they first accurately remember the independent shape or colour features of the item ( P I ) as well as their correct binding ( P B ). In the absence of binding memory (1 – P B ), then they may guess with equal probability between the target ( g B = 0.5) and the lure (1 – g B ). Fixing the guessing parameters ( g B = 0.5 and g I = 0.5) in both models allows them to be identifiable and follows prior work . Thereafter the dependence model follows the same structure as the independence model in the absence of item memory (1 – P I ). Both models successfully converged (all Ȓs < 1.02) and provided good fit to the data (all ppp s > .05).
|
[
"Hiu Wah Cheung",
"Nicolas Geeraert",
"Vanessa M. Loaiza"
] |
https://doi.org/10.5334/joc.390
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276497_p13
|
PMC11276497
|
sec[3]/sec[2]/p[2]
|
Design and Analysis
| 4.074219 |
biomedical
|
Study
|
[
0.98046875,
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0.01904296875
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[
0.9990234375,
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The comparative fit of the independence model or dependence model to the data was tested to understand the structure of these processes by comparing the deviance information criterion (DIC) of the resulting models. For the winning model, the binding memory and item memory parameter estimates were compared between cultural groups as a function of binding type (extrinsic and intrinsic) and probe type (shape and colour) in order to address the hypotheses. Specifically, given the Bayesian approach and following prior work , we drew inferences by inspecting the 95% credibility interval (CI) of the mean cultural and binding difference for each of the posterior estimates of binding and item memory. The cultural difference reflects the mean difference between the two cultural groups for each type of binding and probe (i.e., extrinsic-shape, extrinsic-colour, intrinsic-shape, intrinsic-colour) or consistency (i.e., extrinsic-consistent, extrinsic-inconsistent, intrinsic-consistent, intrinsic-inconsistent). The binding difference reflects the mean difference between the extrinsic and intrinsic binding conditions for each cultural group and probe/consistency type. A 95% CI that does not contain 0 would suggest a difference between conditions for the corresponding parameter estimates.
|
[
"Hiu Wah Cheung",
"Nicolas Geeraert",
"Vanessa M. Loaiza"
] |
https://doi.org/10.5334/joc.390
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276497_p14
|
PMC11276497
|
sec[4]/p[0]
|
Results
| 1.808594 |
other
|
Study
|
[
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0.6923828125
] |
[
0.9765625,
0.0218048095703125,
0.00141143798828125,
0.0004239082336425781
] |
Comparison between the independence and dependence models is shown in Table 2 . In Experiment 1, the dependence model fit the data of Chinese participants better than the independence model, whereas the independence model fit the data of British participants better than the dependence model. In Experiment 2, the dependence model fit the data of both British and Chinese participants better than the independence model. The results of both models were similar and are shown for comprehensiveness .
|
[
"Hiu Wah Cheung",
"Nicolas Geeraert",
"Vanessa M. Loaiza"
] |
https://doi.org/10.5334/joc.390
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276497_p15
|
PMC11276497
|
sec[4]/p[1]
|
Results
| 3.185547 |
biomedical
|
Study
|
[
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[
0.998046875,
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For all binding-probe combinations in both Experiments, the 95% CI of the estimated mean cultural difference in all the parameters contained 0 (see the column labelled cultural difference in Tables 3 and 4 ). This suggests that the parameter estimates of binding and item memory were similar between the Western and Eastern participants. There was also no credible difference between extrinsic and intrinsic binding, for either colour or shape conditions in Experiment 1, and in either cultural group . This suggests that extrinsic and intrinsic binding were similar regardless of the type of probe or cultural group. Furthermore, in Experiment 2, there were no credible prior knowledge benefits for either intrinsic or extrinsic binding in either cultural group .
|
[
"Hiu Wah Cheung",
"Nicolas Geeraert",
"Vanessa M. Loaiza"
] |
https://doi.org/10.5334/joc.390
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11276497_p16
|
PMC11276497
|
sec[5]/p[0]
|
Discussion
| 4.050781 |
biomedical
|
Study
|
[
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[
0.9990234375,
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The results of Experiments 1 and 2 yielded four main findings. First, the binding memory parameter estimates were similar between intrinsic and extrinsic trials, suggesting little distinction between intrinsic and extrinsic binding. Second, there were no credible differences between the two cultural groups in extrinsic binding memory. This result goes against the prediction that extrinsic binding memory should be greater in Eastern participants based on the Analytic and Holistic framework that Easterners equally focus on foreground objects and their backgrounds given their more holistic style of thinking . Third, Experiment 2 showed that there were no differences between consistent and inconsistent conditions for either cultural group, thus suggesting that prior knowledge in long-term memory does not facilitate binding memory. Finally, the results cannot distinguish whether the dependence or independence model best captures the underlying process of feature binding in WM as the penalised deviance in both models was similar in both experiments. Overall, the findings of this report show evidence against the notion that the automaticity of feature binding depends on unitisation, and that cultural differences and prior knowledge can influence feature binding.
|
[
"Hiu Wah Cheung",
"Nicolas Geeraert",
"Vanessa M. Loaiza"
] |
https://doi.org/10.5334/joc.390
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276497_p17
|
PMC11276497
|
sec[6]/p[0]
|
Data Accessibility Statement
| 0.922852 |
biomedical
|
Other
|
[
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[
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All the experiments were pre-registered. The pre-registration, raw data, analysis scripts, and study materials are available on the Open Science Framework (OSF): https://osf.io/md2rz/ .
|
[
"Hiu Wah Cheung",
"Nicolas Geeraert",
"Vanessa M. Loaiza"
] |
https://doi.org/10.5334/joc.390
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057120_p0
|
39057120
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|
1. Introduction
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biomedical
|
Study
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[
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Personalized cancer vaccines are a rising innovation in the field of vaccine design . These vaccines induce an antigen-specific CD8 + and CD4 + T-cell response to enhance anti-tumor activity based on a patient’s individual tumor. Technological innovation has led to the ability to rapidly sequence and analyze patient genome data, which led to the selection of gene targets and on-demand production of personalized therapy . A phase I clinical trial synthesized personalized mRNA vaccines against PDAC from solid tumors, which led to improved disease-free survival . The trial analyzed a patient population who underwent surgical resection of PDAC tumors. Future development of personalized cancer vaccines directly to demonstrate significant efficacy in patients without major surgical intervention.
|
[
"Kush Savsani",
"Sivanesan Dakshanamurthy"
] |
https://doi.org/10.3390/diseases12070149
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
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|
1. Introduction
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|
Review
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[
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Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer and is projected to be the second-leading cause of cancer mortality by 2030 . Current clinical therapies involve neoadjuvant therapy followed by possible surgical resection . However, patients with PDAC suffer from poor prognosis, with a median survival rate of 22.1 months and an actual survival rate of 17.0% . PDAC is often diagnosed late, and as a result, surgical resection may not be a viable option for many patients . As the cancer progresses and possible treatment options decrease, survival outcomes also significantly worsen. The five-year survival rate for patients diagnosed with late-stage PDAC is less than 10% .
|
[
"Kush Savsani",
"Sivanesan Dakshanamurthy"
] |
https://doi.org/10.3390/diseases12070149
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
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39057120
|
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|
1. Introduction
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|
Study
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[
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PDAC progresses as a complex activation of driver genes and inactivation of tumor suppressor genes . Commonly mutated genes observed in PDAC include KRAS, TP53, CDNK2A, DPC4/SMAD4, and BRCA2. Studies of key mutations in these genes are conducted with the goal of developing targeted gene therapies. One particular mutation, the KRAS G12D mutation, is present in over 40% of PDAC patients . However, this specific mutation has been found not to be significantly associated with overall survival outcomes. The TP53 gene is mutated in about 50% of PDAC patients . These mutations include gain-of-function point mutations and null mutations as a result of deletions. Mutations of the CDNK2A gene have been found to be significantly associated with poorer survival outcomes for patients with PDAC compared to mutations of KRAS and TP53 .
|
[
"Kush Savsani",
"Sivanesan Dakshanamurthy"
] |
https://doi.org/10.3390/diseases12070149
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
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39057120
|
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|
1. Introduction
| 4.1875 |
biomedical
|
Study
|
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[
0.998046875,
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Several PDAC vaccines are under development, and clinical trials are being conducted using a variety of immunologic targeting methods . These methods include cell-based, protein-based, microorganism-based, DNA-based, exosome-based, and peptide-based vaccines. Peptide-based vaccines have been growing in popularity due to their ability to be quickly and cheaply developed and their flexibility in patient populations . For PDAC, the first peptide vaccine to undergo clinical trials was a KRAS-targeting peptide co-administered with GM-CSF to promote a greater immune response . The vaccine successfully induced specific immune responses in 58% of patients, contributing to a longer survival time for treated patients. Other peptide vaccines targeting survivin, gastrin, VEGFR-1, VEGFR-2, and WT1 have been ineffective in inducing immune response or contributing to significantly improved survival . However, the design of personalized-based peptide cancer vaccines is completely absent. This study focuses on the development of a design protocol to create personalized peptide vaccines with application to PDAC. The protocol identifies genetic variants using RNAseq analysis and designs a personalized peptide vaccine using a vaccine development protocol and omics pipeline previously developed by our group .
|
[
"Kush Savsani",
"Sivanesan Dakshanamurthy"
] |
https://doi.org/10.3390/diseases12070149
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
39057120_p4
|
39057120
|
sec[1]/sec[0]/p[0]
|
2.1. Patient Genomic Data
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|
Study
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[
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We obtained patient genomic data from the Gene Expression Omnibus (GEO) database , a publicly accessible repository of comprehensive microarray, next-generation sequencing, and other forms of high-throughput functional genomic data. For this study, we specifically collected raw Illumina sequencing data pertaining to human patient solid tumor samples. These samples were part of a detailed study focused on analyzing long-term heterogeneity in patients with pancreatic ductal adenocarcinoma (PDAC) . This study included genomic data from a cohort of 19 patients, consisting of 10 long-term and 9 short-term survivors, providing a diverse basis for examining genetic variations linked to survival outcomes. For the objectives of this study, we selected one patient classified as a short-term survivor and one patient classified as a long-term survivor to design personalized vaccines, serving as a proof-of-concept for our approach. This selection was strategic, allowing us to explore the potential of personalized medicine in cases with poorer prognoses and to evaluate the efficacy of targeted therapies based on genomic insights. The design and development of the vaccine were personalized to the unique genetic profile of the chosen patient, focusing on the anomalies most likely to influence tumor behavior and treatment response. To confirm that our personalized vaccine design was rigorous and potentially effective, we compared the targeted genetic components of the vaccine to key genes previously identified as significant in the survival of PDAC patients by Bhardwaj et al. . This comparison enabled us to validate our personalized vaccine design approach and increase the therapeutic relevance of the vaccine design. This properly controlled process of data selection and comparison with established genetic markers supports our vaccine design methodology, which is detailed further in the section below.
|
[
"Kush Savsani",
"Sivanesan Dakshanamurthy"
] |
https://doi.org/10.3390/diseases12070149
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057120_p5
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39057120
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sec[1]/sec[1]/p[0]
|
2.2. RNAseq Analysis of Patient Data
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We performed an RNAseq analysis using the Partek Flow genomic analysis suite, as shown in Figure 1 , which outlines our comprehensive RNAseq workflow to obtain and confirm variant data. Initially, we imported the raw sequence data in a fastq format into Partek Flow. This format is widely used for storing the output from high-throughput sequencing instruments and contains both nucleotide sequence data and corresponding quality scores. Following data importation, the first computational step involved trimming the Illumina sequencing adapters. These adapters, which are artificial sequences added during library preparation, can interfere with the analysis if not removed, as they may be misinterpreted as part of the genomic sequence. After trimming, we aligned the reads to a reference genome using the Burrows–Wheeler Aligner (BWA) algorithm version 0.7.18. BWA is a software tool that efficiently aligns relatively short sequences (such as those from Illumina sequencers) against a long reference sequence, such as a complete genome. This alignment is important for locating the genomic origins of each read and is fundamental to identifying variations from the reference sequence. In the post-alignment, we executed somatic variant calling using the Strelka algorithm, which was specifically designed to detect somatic variants with high sensitivity and accuracy in tumor-normal paired samples. This step was important for identifying potentially significant genetic mutations that could be relevant in the context of disease, herein cancer. To ensure the reliability of our findings, we manually inspected each significant gene variant using the Integrative Genomics Viewer (IGV) (Partek Inc., Chesterfield, Missouri). IGV is an interactive visualization tool that allows us to visually explore genomic data, thus facilitating the validation of computational predictions through a critical human-oversight step. We excluded gene variants of inadequate quality from further analysis. This quality control step is key to avoiding false positives that could skew the results of downstream applications, such as vaccine development. Finally, we focused our efforts on analyzing single nucleotide polymorphisms (SNPs) that held potential for inclusion in our vaccine development process. SNPs, being the most common type of genetic variation among cancer patients, provide valuable insights into genetic variability, which can be exploited to design targeted vaccines.
|
[
"Kush Savsani",
"Sivanesan Dakshanamurthy"
] |
https://doi.org/10.3390/diseases12070149
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057120_p6
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39057120
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sec[2]/sec[0]/p[0]
|
Development and Application of SCGeneID
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After obtaining and processing genomic data through Partek Flow, we advanced to the next step by developing a Python program named ‘SCGeneID’. The code for this innovative tool is comprehensively detailed in Supplementary File S1 and is freely available for download. SCGeneID was specifically designed to enhance our analytical capabilities in gene annotation by using both chromosome number and locus information. Using the hg38 reference set accessible via the UCSC Genome Browser , SCGeneID systematically identifies corresponding gene names based on their chromosomal location. The tool operates by exploiting web-scraping techniques to extract relevant genomic data directly from the browser. Once the data are retrieved, SCGeneID processes this information to generate a detailed output that includes a table formatted with chromosome numbers, locus details, and the names of associated genes. This functionality not only streamlines the gene identification process but also warrants accuracy by referencing updated genomic data. The application of SCGeneID in our study was twofold. Primarily, it served to externally validate the alignment accuracy and overall reliability of our RNAseq analysis process. By cross-verifying the gene annotations provided by Partek Flow with those extracted by SCGeneID, we could confirm the consistency and validity of our results. Additionally, as shown in Figure 2 , we employed a modified version of SCGeneID to specifically extract a list of genes from a given variant file. This adaptation was particularly important for our personalized vaccine as it allowed us to focus on particular genomic variants of interest, facilitating a more targeted approach in our subsequent analyses.
|
[
"Kush Savsani",
"Sivanesan Dakshanamurthy"
] |
https://doi.org/10.3390/diseases12070149
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057120_p7
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39057120
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sec[3]/p[0]
|
4. Personalized Vaccine Design Protocol
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We employed a vaccine design protocol that has been previously outlined in our published studies . This protocol integrates cutting-edge bioinformatics tools to predict and select epitopes from mutations identified in genomic data.
|
[
"Kush Savsani",
"Sivanesan Dakshanamurthy"
] |
https://doi.org/10.3390/diseases12070149
|
N/A
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https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
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39057120
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4.1. Epitope Prediction and Selection
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Initially, we used the IEDB NetMHC 4.1 tool to predict epitopes. NetMHC 4.1 is specifically designed to return potential epitopes along with their predicted binding affinity for the top 27 expressed HLA alleles in the human population. The binding affinity indicated by the IC 50 value measured in nanomolar (nM) determines the strength of the interaction between the epitope and the HLA molecules, which is a critical factor in the immune response efficacy.
|
[
"Kush Savsani",
"Sivanesan Dakshanamurthy"
] |
https://doi.org/10.3390/diseases12070149
|
N/A
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https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
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39057120
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4.2. Clinical Checkpoint Parameters
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Subsequently, we computed several epitope-specific clinical checkpoint parameters. The immunogenicity of each epitope was determined using the IEDB Class I Immunogenicity Tool, which assesses the potential of an epitope to trigger an immune response. The antigenicity, which evaluates the capability of the epitope to be recognized by antibodies, was determined using VaxiJen v2.0.
|
[
"Kush Savsani",
"Sivanesan Dakshanamurthy"
] |
https://doi.org/10.3390/diseases12070149
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
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4.3. Data Filtering and Selection Criteria
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With the binding affinity, immunogenicity, and antigenicity data computed for each epitope and its associated HLA allele, we employed stringent filters to select the most promising epitopes. These filters were applied based on the criteria outlined in Table 1 , focusing on identifying epitopes that are strong binders, highly immunogenic, and antigenic.
|
[
"Kush Savsani",
"Sivanesan Dakshanamurthy"
] |
https://doi.org/10.3390/diseases12070149
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
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39057120
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4.4. Physicochemical Property Assessment
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In addition to these functional assessments, we analyzed various physicochemical properties of the epitopes using ProtParam https://web.expasy.org/protparam/ . This analysis included determining parameters such as half-life, instability index, isoelectric point, aliphatic index, and GRAVY score. Although these parameters were informative for understanding the physical and chemical characteristics of the epitopes, they were not used in the epitope selection process. Further, we assessed toxicity using ToxinPred and screened for allergenic potential using AllerTOP v2.0, ensuring that only non-toxic and non-allergenic epitopes were considered for further analysis.
|
[
"Kush Savsani",
"Sivanesan Dakshanamurthy"
] |
https://doi.org/10.3390/diseases12070149
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057120_p12
|
39057120
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sec[3]/sec[4]/p[0]
|
4.5. Epitope Selection and Workflow Integration
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After applying the filtration restrictions ( Table 1 ), we selected the top 50 and 100 epitopes that met all the specified criteria, warranting a robust selection of candidates for potential vaccine design. We employed binary filters on toxicity and allergenicity to ensure the selection of epitopes that were both non-toxic and non-allergenic.
|
[
"Kush Savsani",
"Sivanesan Dakshanamurthy"
] |
https://doi.org/10.3390/diseases12070149
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057120_p13
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39057120
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sec[3]/sec[5]/p[0]
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4.6. Methodological Workflow
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[
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Figure 3 shows the comprehensive workflow of our methodology, starting from the collection of Illumina sequencing data, performing RNAseq analysis, and the selection of top epitopes for the development of peptide vaccines. This streamlined workflow integrates multiple stages of data processing and epitope evaluation, indicating the robustness of our approach in vaccine design.
|
[
"Kush Savsani",
"Sivanesan Dakshanamurthy"
] |
https://doi.org/10.3390/diseases12070149
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057120_p14
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39057120
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sec[4]/p[0]
|
5. Results
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We obtained Illumina sequencing data from two patients out of the 19 available in the GEO accession project . The sequencing data represent the genetic landscape of the patient’s solid tumor sample. We performed RNAseq analysis to determine prevalent mutations. Using these mutations, we determined strong and normal binding MHC class I epitopes that are immunogenic, antigenic, non-toxic, and non-allergenic. We selected the top 50 and top 100 epitopes from these data for a peptide vaccine.
|
[
"Kush Savsani",
"Sivanesan Dakshanamurthy"
] |
https://doi.org/10.3390/diseases12070149
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057120_p15
|
39057120
|
sec[4]/sec[0]/p[0]
|
5.1. Determination of Genetic Variants with RNAseq Analysis
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We performed RNAseq analysis on Illumina sequencing data to obtain a list of genetic variants identified in a solid PDAC tumor. For Patient 1, the RNAseq analysis performed using Partek Flow resulted in 100,819 mutations. These mutations included single-nucleotide polymorphisms, multi-nucleotide polymorphisms, deletions, and insertions. Isolating the single-nucleotide polymorphisms, we identified 189 unique variants, which we could use to develop the peptide vaccine. For Patient 2, the RNAseq analysis resulted in 87,128 mutations., of which we identified 125 unique variants we could use to develop the peptide vaccine.
|
[
"Kush Savsani",
"Sivanesan Dakshanamurthy"
] |
https://doi.org/10.3390/diseases12070149
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
39057120_p16
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39057120
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sec[4]/sec[1]/p[0]
|
5.2. Confirmation of Genetic Variants and Sequencing Alignment Using SCGeneID
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We confirmed the alignment of the sequencing data to the hg38 human reference genome using our SCGeneID program version 1. Using SCGeneID, we qualitatively identified the corresponding genes to all mutations obtained through RNAseq analysis loci against the hg38 human reference genome. We found 100% similarity between the genes identified through Partek Flow and genes identified using SCGeneID for both Patients 1 and 2. Therefore, we were confident that the variant genes identified using Partek Flow were correctly aligned to the reference genome.
|
[
"Kush Savsani",
"Sivanesan Dakshanamurthy"
] |
https://doi.org/10.3390/diseases12070149
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057120_p17
|
39057120
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sec[4]/sec[2]/p[0]
|
5.3. Collection of 9-Mer and 10-Mer Top Epitopes from Genetic Variants
| 4.105469 |
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From the pool of identified genetic variants, we curated lists of the top 50 and top 100 epitopes, prioritized based on their binding affinity and immunogenic properties. The top epitopes for Patients 1 and 2 can be found in Supplementary Files S2–S5 . All selected epitopes consisted of 9 or 10 amino acids, representing an epitope capable of binding to an MHC class I molecule. All the top 50 epitopes were classified as having strong binding affinity to their associated HLA allele. The top 100 epitopes included both strong and normal binders. We found no epitopes in the top 100, which were classified as weak binders. Table 2 shows the top 50 epitopes for Patient 1, along with their associated genes, mutations, and binding HLA alleles.
|
[
"Kush Savsani",
"Sivanesan Dakshanamurthy"
] |
https://doi.org/10.3390/diseases12070149
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
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5.4. Population Coverage Analysis of Top 100 Epitopes
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[
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We also performed a population coverage analysis to assess the extent of the global population that could potentially benefit from the personalized vaccine. The analysis for Patient 1 showed that the vaccine could cover 69.64% of the global population. Table 3 provides this coverage along with average hit rates and PC 90 data for various world subregions. While the population coverage may appear relatively low at first glance, it is essential to consider the context of this study. The vaccine was uniquely designed based on the gene expression profile of a specific individual, making it personalized and tailored to the specific mutations and characteristics of their tumor. Consequently, the expectation for widespread coverage across diverse populations is not high. As the patient cohort from whom the vaccine was developed predominantly comprised individuals with European ancestry, the vaccine’s performance in these regional subgroups aligned with the genetic background of the patients involved.
|
[
"Kush Savsani",
"Sivanesan Dakshanamurthy"
] |
https://doi.org/10.3390/diseases12070149
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057120_p19
|
39057120
|
sec[4]/sec[4]/p[0]
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5.5. 3D-Structure Modeling of Epitope-MHC and TCR Interaction Complex
| 4.261719 |
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[
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TCR (T-cell receptor) and pMHC (peptide-major histocompatibility complex) interactions play a fundamental role in immunogenicity, which involves the ability of a peptide to initiate an immune response against tumor cells. TCRs on the surface of T cells recognize antigens that are presented by MHC molecules on the surface of antigen-presenting cells. This recognition is specific to the peptide being presented by the MHC. The correct configuration and interaction of a TCR with a pMHC complex is essential for the T cell to become activated and initiate an immune response. Thus, to explore the binding of our designed peptide vaccines, we initiated TCR-pMHC peptide interaction modeling. We found the PDB files for the HLA alleles HLA-B*58:01 on the RCSB protein data bank https://www.rcsb.org/ . Using MDockPeP https://zougrouptoolkit.missouri.edu/mdockpep/ and CABS-dock , we attached a top epitope to the binding grooves of the HLA allele. We created two models of the peptide-MHC binding complex . TCR binding models were created using the same method as Kim et al. . We used TCRModel https://tcrmodel.ibbr.umd.edu/ to create 3D models of a TCR complex binding to our peptide-MHC complexes. Subsequently, we used PyMOL version 2.5.5 to edit all of the 3D models. In Figure 4 , yellow color represents HLA alleles, and red represents epitopes. The 3D models we obtained were KSFEDIHHY, a mutation of the KRAS gene, binding to the MHC Class I molecule HLA-B*58:01 as well as KTYQGSYGF, a mutation of the TP53 gene, binding to the MHC Class I molecule HLA-B*58:01. All pMHC-TCR 3D molecular model structures generated in this study can be found in Figure 5 and Supplementary Files S6–S9 .
|
[
"Kush Savsani",
"Sivanesan Dakshanamurthy"
] |
https://doi.org/10.3390/diseases12070149
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
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6. Discussion
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We developed a personalized peptide-based vaccine for two patients with pancreatic ductal adenocarcinoma (PDAC). This process began with RNA sequencing (RNAseq) analysis, which enabled the identification of specific genetic mutations driving the development of PDAC in the patients. Based on this analysis, we developed a personalized cancer vaccine using our previously published peptide vaccine development strategy. Our approach involved targeting 100 epitopes that were prevalent in the PDAC patient and identified as viable candidates for peptide vaccine design. By focusing on the specific gene targets present in each patient, we intended to improve the specificity of the vaccine, ensuring that it effectively targeted the unique genetic alterations present in the patient’s tumor. This method not only enhances the potential efficacy of the vaccine by adapting it to the individual’s genetic landscape but also minimizes potential off-target effects, thus optimizing the therapeutic outcome.
|
[
"Kush Savsani",
"Sivanesan Dakshanamurthy"
] |
https://doi.org/10.3390/diseases12070149
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
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6. Discussion
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The final filtered epitopes are predicted to be immunogenic and antigenic, have a high or normal binding affinity, and are non-toxic and non-allergenic. The binding affinity restriction used in this study differs from other previous in silico vaccine design methodologies using the same NetMHC tool. Our previous methods of peptide vaccine design used quantitative filters on the percentile rank of the binding affinity value. However, the percentile rank compares the epitopes to a test set of data in IEDB and, therefore, is not an accurate nor absolute assessment of binding affinity necessary for this study. Using the IC 50 value instead is an absolute measure of the binding affinity of the epitopes. We are also able to specify the strength of the binding affinity based on the IC 50 value, which provides more qualitative measures for comparison when transitioning to murine studies. By tailoring the vaccine to each patient’s specific genetic makeup, we expect to enhance its effectiveness and improve clinical outcomes. This approach represents a significant step forward in the field of immunotherapy for PDAC, offering a more targeted and personalized treatment option that has the potential to transform the management of this challenging disease.
|
[
"Kush Savsani",
"Sivanesan Dakshanamurthy"
] |
https://doi.org/10.3390/diseases12070149
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
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|
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6. Discussion
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0.0000908970832824707
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The top epitopes selected using our novel methodology are widely recognized in the literature as common drivers and tumor-suppressor genes in PDAC . Additionally, these specific epitopes have been identified in trials involving the sequencing of human tumor samples . The consistent presence of our top epitopes in both our reference study and other clinical trials of PDAC patients serves as strong validation of our personalized cancer vaccine design methodology. Using RNA sequencing analysis by Partek Flow, along with our peptide cancer vaccine design processes, we created a peptide vaccine derived from the individual’s tumor tissue genetic data. This integrative approach not only emphasizes the relevance of our vaccine targets but also enhances the precision medicine framework by adapting the therapeutic strategy to the genetic individualities of each patient’s tumor. This could potentially lead to improved clinical outcomes by specifically targeting the molecular abnormalities driving the cancer.
|
[
"Kush Savsani",
"Sivanesan Dakshanamurthy"
] |
https://doi.org/10.3390/diseases12070149
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057120_p23
|
39057120
|
sec[5]/p[3]
|
6. Discussion
| 4.195313 |
biomedical
|
Study
|
[
0.99951171875,
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] |
[
0.9970703125,
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0.00010198354721069336
] |
Previous studies on the development of peptide vaccines have primarily concentrated on creating generalized vaccines that could be used for a large and broad population . These generalized vaccines target a limited set of gene mutations to increase sensitivity but often at the expense of specificity. The development of effective global peptide vaccines poses additional challenges. The vast global diversity of HLA alleles complicates the creation of a peptide vaccine that can effectively target a comprehensive population . Each individual’s HLA type influences how well their immune system can recognize and respond to the peptides presented by the vaccine, making it difficult to design a universally effective vaccine. The development of personalized peptide vaccines has historically been limited by the cost and time to produce the peptides . However, implementing a novel design method described in this study offers a unique and innovative solution to quickly design neoantigen personalized peptide-based vaccines. Recently, with the advent of advanced sequencing technology, neoantigen peptide vaccines are becoming a more viable solution for patients . However, the design process has been complicated by a multitude of software required to design a personalized vaccine. Our methodology using Partek Flow provides a simple and streamlined RNAseq analysis procedure to obtain the list of neoantigens. Our program, SCGeneID, is useful for identifying and confirming proper alignment and identification of genes from the RNAseq analysis process. Overall, our methodology employs only two tools throughout the entire design process, significantly simplifying the development of personalized cancer vaccines. This streamlined approach not only reduces the complexity and duration of vaccine design but also enhances the precision with which these vaccines can be personalized to individual genetic profiles.
|
[
"Kush Savsani",
"Sivanesan Dakshanamurthy"
] |
https://doi.org/10.3390/diseases12070149
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057120_p24
|
39057120
|
sec[6]/p[0]
|
7. Limitations
| 4.15625 |
biomedical
|
Study
|
[
0.99951171875,
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[
0.99853515625,
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0.00008910894393920898
] |
While this study presents a promising personalized cancer vaccine strategy targeting neoantigens in pancreatic ductal adenocarcinoma (PDAC) patients, there are several limitations that should be acknowledged. Firstly, the pilot trial size of two patients is relatively small, which could limit the generalizability of the methodology. A larger sample size would provide more robust data and a better account for variations and accommodate the heterogeneity inherent in the genetic landscape of PDAC more effectively. The purpose of this paper was to demonstrate a successful method for designing personalized peptide cancer vaccines. However, in future outcome-oriented studies, the use of a larger sample size would be favorable. While the absence of experimental confirmation may appear as a limitation, the significance of this innovative methodological framework for personalized cancer vaccines, being the first of its kind, corroborates the importance of this work. This framework enables the efficient prioritization of the most promising personalized vaccine candidates, thus accelerating the vaccine design process, enhancing the probability of success in subsequent preclinical and clinical evaluations, and also helping to optimize resources by focusing on the candidates for further preclinical studies. Peptide vaccines have their weaknesses in functionality as well. If a patient’s cancer significantly downregulates MHC, the probability of a peptide binding to an MHC receptor significantly decreases.
|
[
"Kush Savsani",
"Sivanesan Dakshanamurthy"
] |
https://doi.org/10.3390/diseases12070149
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057120_p25
|
39057120
|
sec[7]/p[0]
|
8. Future Directions
| 4.03125 |
biomedical
|
Study
|
[
0.99951171875,
0.00022912025451660156,
0.0003612041473388672
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[
0.94189453125,
0.05596923828125,
0.0016756057739257812,
0.00029397010803222656
] |
We have developed an automation of the peptide vaccine design process using web scraping and API tools . Implementation of such software would further simplify the personalized cancer vaccine process. Additionally, the use of these programs would allow for the prediction of MHC class II epitopes as well. Furthermore, moving the RNAseq analysis process from a cloud-based solution using Partek Flow to a hardware process using Python or R would allow for complete automation of the personalized vaccine design process. Given such a scaled program and processes, the only limitation to the vaccine design process would be the time to sequence a patient’s tumor tissue.
|
[
"Kush Savsani",
"Sivanesan Dakshanamurthy"
] |
https://doi.org/10.3390/diseases12070149
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057120_p26
|
39057120
|
sec[8]/p[0]
|
9. Conclusions
| 4.144531 |
biomedical
|
Study
|
[
0.99951171875,
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] |
[
0.9990234375,
0.00031113624572753906,
0.0006122589111328125,
0.00008916854858398438
] |
We developed a personalized cancer vaccine targeting specific gene mutations prevalent among PDAC patients by implementing our novel personalized vaccine design workflow. This study addresses the limitations of generalized vaccines specifically for pancreatic ductal adenocarcinoma (PDAC). By analyzing the genetic alterations driving PDAC in a patient’s tumor tissue, we identified 100 gene mutations as targets for our personalized vaccine strategy. The gene targets were identified and validated using our SCGeneID program, which used the chromosome number and nucleotide position data. By integrating SCGeneID into our workflow, we not only enhanced the precision of our gene annotations but also significantly improved the efficiency of our data analysis process. This development represents a significant step forward in the application of computational tools in personalized vaccine design, providing a robust method for accurate gene identification and the validity of complex genomic analyses.
|
[
"Kush Savsani",
"Sivanesan Dakshanamurthy"
] |
https://doi.org/10.3390/diseases12070149
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057120_p27
|
39057120
|
sec[8]/p[1]
|
9. Conclusions
| 4.074219 |
biomedical
|
Study
|
[
0.99951171875,
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[
0.9990234375,
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The top 50 epitopes consisted of only high-affinity binding epitopes, indicating the potential efficacy of the vaccine. The use of IC 50 values as an absolute measure of binding affinity provided more accurate and quantitative comparisons. To visualize the interactions between epitopes and HLA alleles, 3D models of TCR-peptide-MHC complexes were created. The personalized cancer vaccine developed in this study may hold great promise for PDAC patients. By targeting the unique genetic alterations in each patient’s tumor, this approach offers a more specific and personalized treatment option. Further research is warranted to simplify the variant identification and epitope ranking process.
|
[
"Kush Savsani",
"Sivanesan Dakshanamurthy"
] |
https://doi.org/10.3390/diseases12070149
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
39057080_p0
|
39057080
|
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|
1. Introduction
| 4.570313 |
biomedical
|
Review
|
[
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[
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Cholangiocellular carcinoma (CCA) is a tumor arising from cholangiocytes in the bile ducts. It accounts for 3–5% of gastrointestinal cancers and is the second most common liver tumor after hepatocellular carcinoma (HCC) . In CCA, a distinction must be made between intrahepatic (ICC) and extrahepatic (ECC) tumors depending on their anatomical localization . ICC arises from bile ducts deeply within the liver, whereas ECC involves the larger perihilar and extrahepatic (distal) bile ducts . Thereby, perihilar CCA is the most common form, accounting for 50–60% of CCAs, while 20–30% are distal CCAs. ICC accounts for 10% of all primary liver tumors . Even though ICC remains a rare tumor, its incidence has been increasing worldwide in the last 30 years, e.g., in the USA, by approximately 165% to currently 0.95 per 100,000 inhabitants . The majority of CCAs, approximately 70%, develop for no apparent reason. However, there are a number of risk factors such as liver flukes Opisthorchis viverrini and Clonorchis sinensis , whose cercariae are transmitted through eating raw freshwater fish. Liver flukes occur primarily in East Asia and increase the risk of contracting CCA . Primary sclerosing cholangitis (PSC) and hepatitis B and C with associated cirrhosis, diabetes, or obesity are other risk factors . Strikingly, in industrial countries, ICC often occurs in the absence of cirrhosis . The diagnosis of ICC is difficult because symptoms appear late and tend to be nonspecific, such as weight loss, abdominal discomfort, jaundice, malaise, or hepatomegaly. A curative treatment option for ICC is surgical resection. However, this is only possible in early stages and can therefore be performed in no more than 20–40% of cases. In the majority of patients, the tumor is too advanced for resection . The first-line chemotherapy for unresectable CCA consists of gemcitabine and cisplatin, and second-line chemotherapeutics can be effective in selected patients .
|
[
"Jessica Schüler",
"Martina Vockerodt",
"Niloofar Salehzadeh",
"Jürgen Becker",
"Jörg Wilting"
] |
https://doi.org/10.3390/cimb46070439
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
39057080_p1
|
39057080
|
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|
1. Introduction
| 4.289063 |
biomedical
|
Review
|
[
0.9990234375,
0.0006079673767089844,
0.0004699230194091797
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[
0.46337890625,
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A promising strategy in cancer therapy is targeted therapy, which targets proteins that regulate cell survival and proliferation . Although this concept has been proposed for CCA quite some time ago , it has not yet been firmly established in clinics. In particular, the molecular heterogeneity of ECC and ICC must be taken into account , which is very likely due to the fact that extra- and intrahepatic bile ducts develop differently in the embryo. The embryonic development, differentiation and migration potency of the respective cell has a major influence on the pathophysiology. While the extrahepatic bile duct emerges directly by sprouting from the foregut endoderm, the intrahepatic bile ducts develop from bipotent progenitor cells, which transiently form a sheath of epithelial cells called the ductal plate. Only later do the cells acquire a tubular morphology . Therefore, ICC and ECC must be regarded as heterogenous tumor entities. For targeted therapy, this must be taken into account. For ICC patients, targeted therapy (with pemigatinib) has only been approved for a small cohort of patients with gene fusions affecting fibroblast growth factor receptor 2 ( FGFR2 ) .
|
[
"Jessica Schüler",
"Martina Vockerodt",
"Niloofar Salehzadeh",
"Jürgen Becker",
"Jörg Wilting"
] |
https://doi.org/10.3390/cimb46070439
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057080_p2
|
39057080
|
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|
1. Introduction
| 4.226563 |
biomedical
|
Study
|
[
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[
0.9990234375,
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A frequently used strategy is the targeted inhibition of the MAPK/ERK signaling pathway, which is hyperactive in at least 40% of cancers . Furthermore, the PI3K/AKT/mTOR signaling pathway is highly active in numerous types of cancer . Although the effects of the inhibition of the two pathways were tested in CCA in vitro , the three human cell lines used in this study were either ECC (one cell line) or cannot be clearly assigned to ECC or ICC. Here, we focused on ICC and the cell lines HuH28, RBE and SSP25. The three cell lines represent the spectrum of spindle-shaped to epithelial-like cell morphology typically found in ICC (for references, see below in Materials and Methods). We studied the AKT inhibitor MK2206 and the MEK inhibitor selumetinib and determined their single and dual effects on the cell cycle, proliferation, the phosphorylation of signaling molecules and apoptosis. We observed additive effects of dual pathway inhibition on proliferation in conjunction with a G1 phase arrest but no apoptosis. Therefore, cell counts never dropped below baseline. In sum, dual pathway inhibition is highly effective in blocking the proliferation of ICC in vitro, but it must obviously be performed in conjunction with a standard therapy that kills the remaining tumor cells.
|
[
"Jessica Schüler",
"Martina Vockerodt",
"Niloofar Salehzadeh",
"Jürgen Becker",
"Jörg Wilting"
] |
https://doi.org/10.3390/cimb46070439
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
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|
39057080
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|
2.1. Cell Culture
| 4.140625 |
biomedical
|
Study
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[
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The human ICC cell lines (HuH28, RBE, SSP25) were purchased freshly from RIKEN BioResources Research Center (Tsukuba, Japan). The three cell lines represent the spectrum of spindle-shaped to epithelial-like cell morphology typically found in ICC. HuH28 is an intrahepatic CCA line with mainly spindle-cell morphology and a small percentage of polygonal-shaped cells, maintained at RIKEN since 1995 . SSP-25 is an intrahepatic CCA line, with fibroblast-like morphology, maintained at RIKEN since 1996 and used in multiple studies . RBE is an intrahepatic CCA line with epithelial-like morphology, maintained at RIKEN since 1996 and used in multiple studies . The cells were incubated at 37 °C with 5% CO 2 under humidified atmosphere in RPMI medium (10% FCS, 1% penicillin/streptomycin). Cells were amplified and used usually during passages 9–10 but not beyond passage 16.
|
[
"Jessica Schüler",
"Martina Vockerodt",
"Niloofar Salehzadeh",
"Jürgen Becker",
"Jörg Wilting"
] |
https://doi.org/10.3390/cimb46070439
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
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|
39057080
|
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|
2.2. Proliferation Assay and Drug Preparation
| 4.082031 |
biomedical
|
Study
|
[
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Proliferation assays were performed in 96-well plates as described previously . Cells were seeded at a concentration of 5 × 10 3 cells/mL in 100 µL RPMI and incubated at 37 °C overnight. Cells were treated with the inhibitors MK2206 and selumetinib (both from Selleckchem, Munich, Germany) and DMSO (control). For single treatment, 0.1 µM, 0.5 µM, 1 µM and 5 µM were used. Dual treatment: 0.5 µM (each) MK2206+selumetinib and 1 µM (each) MK2206+selumetinib were used. The stock solution was 10 mM of the respective drug dissolved in DMSO. Stock solutions were then diluted with cell medium to the respective final concentration. DMSO controls contained the same amount of DMSO as in the highest inhibitor concentration.
|
[
"Jessica Schüler",
"Martina Vockerodt",
"Niloofar Salehzadeh",
"Jürgen Becker",
"Jörg Wilting"
] |
https://doi.org/10.3390/cimb46070439
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057080_p5
|
39057080
|
sec[1]/sec[1]/p[1]
|
2.2. Proliferation Assay and Drug Preparation
| 4.089844 |
biomedical
|
Study
|
[
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[
0.9990234375,
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] |
After 0 h, 24 h, 48 h and 72 h, cells were fixed with 5% glutaraldehyde and stained with crystal violet. After drying, 10% acetic acid was added and incubated for 15 min. Extinction was measured at 595 nm with an iMark™ Microplate Absorbance Reader (Bio-Rad, Tokyo, Japan). Extinction was measured at various time points, normalized to the extinction at 0 h, and converted to percent. Experiments were repeated at least 3 times with 8 replicates each.
|
[
"Jessica Schüler",
"Martina Vockerodt",
"Niloofar Salehzadeh",
"Jürgen Becker",
"Jörg Wilting"
] |
https://doi.org/10.3390/cimb46070439
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999994 |
39057080_p6
|
39057080
|
sec[1]/sec[2]/p[0]
|
2.3. Protein Extraction and Western Blot
| 4.160156 |
biomedical
|
Study
|
[
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] |
Cells were seeded at concentrations of 3 × 10 6 cells/mL in RPMI in cell culture dishes and incubated for 12 h at 37 °C. Then, cells were treated with inhibitors (1 µM) for 12 h and washed with PBS containing 1 mM sodium orthovanadate on ice. Lysis was performed with a lysis buffer mixture containing RIPA lysis buffer (aqua dest., 140 mM NaCl, 10 mM TrisHcl pH 8, 1 mM EDTA, 1% Triton, 0,1% SDS, 0,1% Sodiumdeox) with 1 mM SOV and 1× Sample Complete Protease Inhibitor (Roche Diagnostics) for 30 min on ice. Lysates were centrifuged at 14,000 rpm for 15 min at 4 °C, and the supernatant was transferred. Protein concentration was measured by the Pierce BCA protein assay according to the manufacturer’s instructions (Thermo Fisher Scientific, Waltham, MA, USA). Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-Page) was performed. A total of 20 µg of protein was denatured at 70 °C for 10 min. Proteins were transferred onto a PVDF membrane and incubated with a primary antibody ( Table 1 ) overnight at 4 °C followed by washing processes. Then, secondary horseradish peroxidase (HRP)-conjugated antibodies were incubated for 1 h at RT. Visualization was performed with an enhanced chemiluminescence (ECL) solution (SignalFire™ ECL Reagent or Clarity Western ECL Substrate) in BioRad ChemiDoc (Bio-Rad). WB analyses were repeated at least three times, and luminescence signals were quantified using Image Lab Software 6.0.1 (Bio-Rad).
|
[
"Jessica Schüler",
"Martina Vockerodt",
"Niloofar Salehzadeh",
"Jürgen Becker",
"Jörg Wilting"
] |
https://doi.org/10.3390/cimb46070439
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057080_p7
|
39057080
|
sec[1]/sec[3]/p[0]
|
2.4. Semiquantitative Real-Time PCR (qPCR)
| 3.181641 |
biomedical
|
Study
|
[
0.99755859375,
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[
0.9736328125,
0.0244598388671875,
0.0013990402221679688,
0.0006041526794433594
] |
Cells were treated for 24 h with 1 µM MK2206 or selumetinib or with 1 µM of each drug.
|
[
"Jessica Schüler",
"Martina Vockerodt",
"Niloofar Salehzadeh",
"Jürgen Becker",
"Jörg Wilting"
] |
https://doi.org/10.3390/cimb46070439
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
39057080_p8
|
39057080
|
sec[1]/sec[3]/p[1]
|
2.4. Semiquantitative Real-Time PCR (qPCR)
| 4.125 |
biomedical
|
Study
|
[
0.99951171875,
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[
0.998046875,
0.0016155242919921875,
0.0003256797790527344,
0.00009441375732421875
] |
For RNA isolation, the medium was removed, and cells were washed with PBS. NucleoZOL (Machery-Nagel) was used according to the manufacturer’s instructions. A total of 2 µg of RNA was transcribed with Qiagen Omniscript reverse transcriptase (QIAGEN). The relative RNA expression was determined with the 2 −ΔΔCT method . Experiments were performed three times in duplicate. The following primers were used to detect Apoptosis-inducing factor mitochondria-associated 1 (AIFM1); Fwd: 5′-TGGGCTTATCAACAGTAGGAGC-3′; Rev: 5′-TTCTGGTGTCAGCCCTAACC-3′, Actin Fwd: 5′-GCATCCCCCAAAGTTCACAA-3′; Rev: 5′-AGGACTGGGCCATTCTCCTT-3′.
|
[
"Jessica Schüler",
"Martina Vockerodt",
"Niloofar Salehzadeh",
"Jürgen Becker",
"Jörg Wilting"
] |
https://doi.org/10.3390/cimb46070439
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057080_p9
|
39057080
|
sec[1]/sec[4]/p[0]
|
2.5. Flow Cytometry
| 4.105469 |
biomedical
|
Study
|
[
0.99951171875,
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[
0.99853515625,
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0.00007861852645874023
] |
Cells were seeded in 6-well plates in concentrations of 8 × 10 4 cells/mL and were treated with inhibitors or DMSO (control) after 24 h and were further incubated for 24 h. Both adherent cells and centrifuged supernatant containing floating (dying) cells were washed with PBS and suspended in Nicoletti buffer with 50 µg/mL propidium iodide (PI). Flow cytometry was measured with the BD LSRFortessa™ X-20. The maximum number of detectable events was 5000. Experiments were repeated 5 times. Cell cycle analysis was performed using FlowJo TM Software V10.
|
[
"Jessica Schüler",
"Martina Vockerodt",
"Niloofar Salehzadeh",
"Jürgen Becker",
"Jörg Wilting"
] |
https://doi.org/10.3390/cimb46070439
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057080_p10
|
39057080
|
sec[1]/sec[5]/p[0]
|
2.6. Statistical Analysis
| 3.638672 |
biomedical
|
Study
|
[
0.99951171875,
0.00015866756439208984,
0.0003528594970703125
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[
0.99609375,
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0.0007071495056152344,
0.00010472536087036133
] |
The data were analyzed with Graph Prism 5 software and Microsoft Excel 2019 MSO 16.78.3. The standard deviation (SD) was calculated for all experiments. Statistical significance was calculated with two-way ANOVA (proliferation assays) or one-way ANOVA (qPCR, flow cytometry) between the treatment and DMSO control groups. The statistical level of significance is shown as follows: * p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.001, with a 95% level of confidence.
|
[
"Jessica Schüler",
"Martina Vockerodt",
"Niloofar Salehzadeh",
"Jürgen Becker",
"Jörg Wilting"
] |
https://doi.org/10.3390/cimb46070439
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057080_p11
|
39057080
|
sec[2]/sec[0]/p[0]
|
3.1. AKT Inhibitor MK2206 Effectively Reduces Proliferation in ICC Cell Lines
| 4.128906 |
biomedical
|
Study
|
[
0.99951171875,
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[
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0.00007659196853637695
] |
To determine the effects of MK2206, proliferation assays were performed with concentrations ranging from 0.1 µM to 5 µM, in addition to previous studies on 10 µM and 25 µM . The results show that the numbers of all three ICC cell lines (HuH28, RBE, SSP25) increased steadily over time in both the medium control group and the DMSO control group. The IC50 (95% CI) values after 72 h treatment were similar for all three cell lines: HuH28 5.92 µM (3.37–10.41); RBE 6.09 µM (2.9–12.69) and SSP25 5.08 µM (2.8–9.2). MK2206 application induced a dose-dependent inhibition of cell proliferation in all cell lines . Highly significant inhibition in comparison with the DMSO control was observed at 0.5 µM after 24 h in HUH28 cells, resulting in 15% growth inhibition . Cell counts after inhibition with 0.5 µM–5 µM MK2206 reached the baseline (100%) but did not drop below this value . MK2206 induced highly significant inhibition at 1 µM after 24 h in RBE cells as well, again with 15% growth inhibition . In SSP25, significant effects were noticed at 0.5 µM after 48 h . In sum, all three cell lines responded very well to treatment with MK2206, with slight differences in the dose and treatment time.
|
[
"Jessica Schüler",
"Martina Vockerodt",
"Niloofar Salehzadeh",
"Jürgen Becker",
"Jörg Wilting"
] |
https://doi.org/10.3390/cimb46070439
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057080_p12
|
39057080
|
sec[2]/sec[1]/p[0]
|
3.2. MEK Inhibitor Selumetinib Significantly Reduces Proliferation of HuH28 and RBE but Less in SSP25
| 4.140625 |
biomedical
|
Study
|
[
0.99951171875,
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] |
[
0.99951171875,
0.00020051002502441406,
0.0004398822784423828,
0.0000776052474975586
] |
In the controls, again, ICC cell lines (HuH28, RBE, SSP25) showed a steady increase in cell numbers over time. A dose-dependent inhibition of proliferation by selumetinib was observed in all three ICC cell lines, with HuH28 and RBE being more sensitive than SSP25. Again, cell numbers never dropped below baseline . Highly effective inhibition was observed in RBE cells with the highest significance ( p ≤ 0.001) at 0.5 µM selumetinib after 48 h , with 32% growth inhibition . In HuH28 cells, selumetinib inhibited cell proliferation highly significantly at 1 µM after 48 h, with 15% growth inhibition . The effects of selumetinib were the weakest in SSP25. However, significant effects were observed at 1 µM after 72 h, with 15% growth inhibition . In sum, HuH28 and RBE responded very well to treatment with selumetinib. SSP25 showed the highest resistance but responded after prolonged treatment.
|
[
"Jessica Schüler",
"Martina Vockerodt",
"Niloofar Salehzadeh",
"Jürgen Becker",
"Jörg Wilting"
] |
https://doi.org/10.3390/cimb46070439
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
39057080_p13
|
39057080
|
sec[2]/sec[2]/p[0]
|
3.3. Dual Inhibition Shows Additive Effects as Compared with Single Treatments
| 4.097656 |
biomedical
|
Study
|
[
0.99951171875,
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] |
[
0.99951171875,
0.0001742839813232422,
0.0002715587615966797,
0.000056684017181396484
] |
To investigate whether additive or synergistic effects could be achieved, concentrations of either 0.5 µM or 1 µM of MK2206 and selumetinib were tested in combination. In single treatment, these dosages induce between 10% and 35% inhibition . Highly significant inhibition in comparison with DMSO controls was achieved with both concentrations already after 24 h in HuH28 and RBE, which is earlier than with each single application . Cell numbers nearly reached baseline values but barely dropped below. In SSP25, the combined application of 0.5 µM of inhibitors achieved a significant cell number reduction only after 72 h. With each 1 µM of MK2206 and selumetinib, robust effects were seen after 48 h .
|
[
"Jessica Schüler",
"Martina Vockerodt",
"Niloofar Salehzadeh",
"Jürgen Becker",
"Jörg Wilting"
] |
https://doi.org/10.3390/cimb46070439
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
39057080_p14
|
39057080
|
sec[2]/sec[2]/p[1]
|
3.3. Dual Inhibition Shows Additive Effects as Compared with Single Treatments
| 4.105469 |
biomedical
|
Study
|
[
0.99951171875,
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] |
[
0.99951171875,
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0.00005823373794555664
] |
Compared with single MK2206 (0.5 µM) treatment, dual inhibition with both 0.5 µM MK2206 and selumetinib significantly decreased the proliferation of HuH28 and RBE cells after 72 h , with 37% growth inhibition in HuH28 and 52% in RBE . No additive effect was observed in SSP25 with each 0.5 µM . However, the dual treatment of SSP25 with 1 µM induced a significant decrease in cell proliferation after 72 h , with 32% growth inhibition .
|
[
"Jessica Schüler",
"Martina Vockerodt",
"Niloofar Salehzadeh",
"Jürgen Becker",
"Jörg Wilting"
] |
https://doi.org/10.3390/cimb46070439
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057080_p15
|
39057080
|
sec[2]/sec[2]/p[2]
|
3.3. Dual Inhibition Shows Additive Effects as Compared with Single Treatments
| 4.089844 |
biomedical
|
Study
|
[
0.99951171875,
0.0002677440643310547,
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] |
[
0.9990234375,
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0.00021350383758544922,
0.00006186962127685547
] |
The cell line HuH28 showed a strong significant decrease in cell number after 48 h of dual treatment with 1 µM compared with each single treatment with MK2206 or selumetinib , with 39% growth inhibition .
|
[
"Jessica Schüler",
"Martina Vockerodt",
"Niloofar Salehzadeh",
"Jürgen Becker",
"Jörg Wilting"
] |
https://doi.org/10.3390/cimb46070439
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057080_p16
|
39057080
|
sec[2]/sec[2]/p[3]
|
3.3. Dual Inhibition Shows Additive Effects as Compared with Single Treatments
| 4.128906 |
biomedical
|
Study
|
[
0.99951171875,
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] |
[
0.99951171875,
0.00018084049224853516,
0.0002663135528564453,
0.00005334615707397461
] |
In RBE, dual treatment with 1 µM induced a significant decrease in cell proliferation compared to the respective single treatments already after 24 h , which was highly significant ( p ≤ 0.001) thereafter , with 60% growth inhibition after 72 h; see Supplementary Figure S1B . In sum, all three cell lines responded more strongly and earlier to the double treatment than to the respective single treatments. SSP25 showed the highest resistance and responded the latest.
|
[
"Jessica Schüler",
"Martina Vockerodt",
"Niloofar Salehzadeh",
"Jürgen Becker",
"Jörg Wilting"
] |
https://doi.org/10.3390/cimb46070439
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057080_p17
|
39057080
|
sec[2]/sec[3]/p[0]
|
3.4. MK2206 Alone or in Combination Effectively Inhibits Phosphorylation of AKT (Ser473)
| 4.089844 |
biomedical
|
Study
|
[
0.99951171875,
0.00026106834411621094,
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] |
[
0.99951171875,
0.00030040740966796875,
0.0002510547637939453,
0.00006449222564697266
] |
In all three ICC cell lines, single inhibition with MK2206 as well as dual inhibition with MK2206 and selumetinib caused a significant downregulation of phospho (p)-AKT at Ser473 after 12 h. Total AKT protein and loading control α-tubulin remained unchanged throughout the treatment .
|
[
"Jessica Schüler",
"Martina Vockerodt",
"Niloofar Salehzadeh",
"Jürgen Becker",
"Jörg Wilting"
] |
https://doi.org/10.3390/cimb46070439
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057080_p18
|
39057080
|
sec[2]/sec[4]/p[0]
|
3.5. Selumetinib Alone or in Combination Effectively Inhibits ERK1/2 Phosphorylation (Thr202/Tyr204)
| 4.171875 |
biomedical
|
Study
|
[
0.99951171875,
0.0002846717834472656,
0.00019598007202148438
] |
[
0.99951171875,
0.00020253658294677734,
0.00036525726318359375,
0.0000693202018737793
] |
In all three ICC cell lines, the signal of phospho (p)-ERK1/2 (Thr202/Tyr204) was downregulated after 12 h through selumetinib, both in single and in dual inhibition with MK2206. Interestingly, selumetinib inhibits ERK1/2 phosphorylation in SSP25, but in combination with MK2206, the inhibitory effect is neutralized when compared to the DMSO controls . However, our proliferation studies show an additive effect after 72 h . The upregulation of pERK1/2 by single MK2206 was observed in all three cell lines, indicating interactions between the two pathways . The total ERK1/2 protein and α-tubulin remained unchanged. In sum, selumetinib effectively inhibits ERK1/2 phosphorylation, but AKT inhibition with MK2206 increases pERK1/2. In SSP25, this effect was even seen after dual treatment.
|
[
"Jessica Schüler",
"Martina Vockerodt",
"Niloofar Salehzadeh",
"Jürgen Becker",
"Jörg Wilting"
] |
https://doi.org/10.3390/cimb46070439
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057080_p19
|
39057080
|
sec[2]/sec[5]/p[0]
|
3.6. Dual Inhibition with MK2206 and Selumetinib Causes Cell Cycle Arrest in ICC Cell Lines
| 3.976563 |
biomedical
|
Study
|
[
0.99951171875,
0.0001773834228515625,
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] |
[
0.9990234375,
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] |
In order to determine if apoptosis may be responsible for the decrease in cell numbers, we used WB analysis against cleaved caspase-3 and qPCR against Apoptosis-inducing factor mitochondria-associated 1 (AIFM1).
|
[
"Jessica Schüler",
"Martina Vockerodt",
"Niloofar Salehzadeh",
"Jürgen Becker",
"Jörg Wilting"
] |
https://doi.org/10.3390/cimb46070439
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057080_p20
|
39057080
|
sec[2]/sec[5]/p[1]
|
3.6. Dual Inhibition with MK2206 and Selumetinib Causes Cell Cycle Arrest in ICC Cell Lines
| 4.109375 |
biomedical
|
Study
|
[
0.99951171875,
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] |
[
0.99951171875,
0.00019371509552001953,
0.00018334388732910156,
0.000058591365814208984
] |
We did not observe cleaved caspase-3 after inhibitor treatment in all three ICC cell lines . As a positive control, we incubated cells with 1 µM staurosporine, which induces caspase-dependent and -independent apoptosis . Especially in SSP25, staurosporine was highly effective and dramatically reduced cell numbers. As a result, only very weak signals could be found after 12 h staurosporine incubation . The transcriptional regulation of AIFM1 during apoptosis has been described . Our qPCR studies did not show any AIFM1 regulation by the two inhibitors , which again excludes the involvement of apoptosis as a contributor to cell number reduction in the experiments.
|
[
"Jessica Schüler",
"Martina Vockerodt",
"Niloofar Salehzadeh",
"Jürgen Becker",
"Jörg Wilting"
] |
https://doi.org/10.3390/cimb46070439
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057080_p21
|
39057080
|
sec[2]/sec[5]/p[2]
|
3.6. Dual Inhibition with MK2206 and Selumetinib Causes Cell Cycle Arrest in ICC Cell Lines
| 4.15625 |
biomedical
|
Study
|
[
0.99951171875,
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] |
[
0.99951171875,
0.00018727779388427734,
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0.00007110834121704102
] |
Flow cytometry showed a slight increase in cells in the G1 phase after a single treatment of HuH28 with 1 µM MK2206 or selumetinib. The percentage of cells in the G2 phase slightly decreased. Dual inhibition induced a significant increase in cells in the G1 phase as compared to the DMSO control . Similar results were obtained in RBE cells. Here, selumetinib induced a significant decrease in cells in G2, while dual inhibition caused both a significant decrease in the G2 phase and a significant increase in G1-phase cells . In SSP25, we observed a tendency for an increase in G1 and a significant decrease in cells in the G2 phase after dual inhibition . For all three cell lines, we made sure to include dying cells in the supernatant. In all experiments and controls, this population is consistently extremely low, and there are no inhibitor effects (1.5–1.8% in DMSO controls vs. 0.6–2.1% in experimental groups). In sum, we did not notice any changes in the sub-G0/G1 phase , which is characteristic for apoptotic and fragmented cells . Typical FACS histograms are shown in Supplementary Figure S3 .
|
[
"Jessica Schüler",
"Martina Vockerodt",
"Niloofar Salehzadeh",
"Jürgen Becker",
"Jörg Wilting"
] |
https://doi.org/10.3390/cimb46070439
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057080_p22
|
39057080
|
sec[3]/sec[0]/p[0]
|
4.1. Dual Inhibition of MAPK/ERK and PI3K/AKT/mTOR Is Highly Effective in ICC
| 4.488281 |
biomedical
|
Study
|
[
0.99951171875,
0.0004019737243652344,
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] |
[
0.98193359375,
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] |
Because of the increasing incidence of CCA and the limited therapeutic options, new drugs are urgently needed. A more specific combination of targeted drugs could be a solution to the problem. It has become increasingly clear that from both the molecular and surgical point of view, CCA is not a uniform tumor entity. Topographically, CCA is subdivided into intrahepatic (ICC) and extrahepatic (ECC) tumors, and ECC can be further divided into perihilar and distal types . Based, most likely, on the differential embryonic origin of intra- and extrahepatic cholangiocytes , distinct molecular differences between ICC and ECC have been observed. ICC patients are more likely to have FGFR2 fusions, FGFR mutations and IDH1 mutations than ECC patients. ECC patients, however, more commonly show KRAS , TP53 , SMAD4 and APC mutations . A transcriptomic analysis of ICC and ECC cells identified subgroups which revealed different tumor biology. Thereby, gene expression profiles from 340 ICC and 203 ECC patients were compared. ICC cells were enriched in molecular pathways such as EMT, IL6, RTK-RAS-PIK3K and DNA repair. ECC cells were enriched in EGFR, VEGF signaling and integrin pathways . This suggests that differential treatment for the subtypes of CCA will be necessary to achieve promising therapeutic results.
|
[
"Jessica Schüler",
"Martina Vockerodt",
"Niloofar Salehzadeh",
"Jürgen Becker",
"Jörg Wilting"
] |
https://doi.org/10.3390/cimb46070439
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057080_p23
|
39057080
|
sec[3]/sec[0]/p[1]
|
4.1. Dual Inhibition of MAPK/ERK and PI3K/AKT/mTOR Is Highly Effective in ICC
| 4.351563 |
biomedical
|
Study
|
[
0.99951171875,
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[
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] |
Here, we focused on ICC and studied three human ICC cell lines in vitro (HuH28, RBE and SSP25) in order to determine the effects of inhibitors of two common tumor signaling pathways. We tested the AKT inhibitor MK2206 and the MEK inhibitor selumetinib and studied proliferation, the phosphorylation of signaling molecules of the PI3K/AKT/mTOR and the MAPK/ERK pathways and the cell cycle. We used concentrations of MK2206 well below the IC50 values, assuming that additive or synergistic effects should be seen at a significantly reduced dose. Basically, this type of research is not new. However, it has so far been performed on uncharacterized CCA cell lines and on ECC lines . We show that ICC cell lines behave differently in their response to the inhibitors. Thereby, single treatment with MK2206 or selumetinib induced the inhibition of proliferation, and the effect was clearly enhanced by the dual application of the inhibitors . Thereby, HuH28 and RBE were more sensitive, but at a 1 µM dosage of inhibitors, SSP25 responded significantly, too. Western blot analyses with antibodies against p-AKT (Ser473) and p-ERK confirmed the effectiveness of the two inhibitors. Thereby, single as well as dual inhibition showed the downregulation of the phosphorylation of the respective proteins in all three ICC cell lines . A potential direct interaction between the two pathways was well visible. The WB pERK quantification showed that selumetinib significantly downregulates pERK, while MK2206 upregulates pERK both alone and, in SSP25, also in combination with selumetinib . We have previously observed the upregulation of pERK by MK2206 in various liver cancer cell lines . Such interactions have been observed in other tumor types, including melanoma, colorectal, pancreatic and breast carcinoma , and were also reported for CCA . For a review on the crosstalk of the pathways, see .
|
[
"Jessica Schüler",
"Martina Vockerodt",
"Niloofar Salehzadeh",
"Jürgen Becker",
"Jörg Wilting"
] |
https://doi.org/10.3390/cimb46070439
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057080_p24
|
39057080
|
sec[3]/sec[1]/p[0]
|
4.2. Dual Inhibition of MAPK/ERK and PI3K/AKT/mTOR Does Not Induce Apoptosis in ICC
| 4.328125 |
biomedical
|
Study
|
[
0.99951171875,
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[
0.9990234375,
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In contrast to previous studies on CCA cell lines , we did not observe any signs for apoptosis or other forms of cell death by the dual inhibition of the MAPK/ERK and PI3K/AKT/mTOR signaling pathways in ICC. There was no expression of cleaved caspase-3, which is the dominant effector caspase , or expression of AIFM1 . In previous studies, antibodies against pro-caspase-3 and -9 were used to identify apoptosis . The number of dying cells in the sub-G0/G1 phase was neglectable and only about 1%, as in the controls . Neither single treatment with MK2206 or selumetinib nor dual treatment with both inhibitors reduced cell numbers below baseline. The inhibitors effectively induced a proliferation block but not apoptosis or other types of cell death. In line with this, we observed cell cycle arrest, which was evident from a significant increase in cells in the G1 phase . Since autophagy is inhibited by mitosis , prolonged cell cycle arrest might increase the susceptibility of ICC to selective autophagy induction, as an additional therapeutic target .
|
[
"Jessica Schüler",
"Martina Vockerodt",
"Niloofar Salehzadeh",
"Jürgen Becker",
"Jörg Wilting"
] |
https://doi.org/10.3390/cimb46070439
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057080_p25
|
39057080
|
sec[3]/sec[1]/p[1]
|
4.2. Dual Inhibition of MAPK/ERK and PI3K/AKT/mTOR Does Not Induce Apoptosis in ICC
| 4.203125 |
biomedical
|
Study
|
[
0.99951171875,
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[
0.99462890625,
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] |
The in vitro results seem to suggest that the dual application of MK2206 and selumetinib in ICC may stop tumor growth but may probably not eliminate residual tumors. A phase I dose escalation study of MK2206 and selumetinib in therapy-refractory solid tumors has shown clinical effects in patients with different tumors with K-RAS mutations. However, the study also shows that not all patients responded well, and it was assumed that this was due to the heterogeneity of tumor biology. However, the study did not include patients with biliary or hepatic carcinoma . A biomarker-driven phase II trial in patients with colorectal cancer has also been conducted for MK2206 and selumetinib, in which no clinical efficacy was observed . Whether the dual inhibition with MK2206 and selumetinib could be a treatment option for patients with ICC must be critically scrutinized and tested. Proliferation block may even induce resistance against standard therapies, which target highly proliferative cells. However, the inhibition of important signaling pathways, including PI3K-AKT-mTOR, not only affects tumor cells but also the tumor microenvironment and immune cells. Anti-tumorigenic macrophage polarization and increased antigen presentation on dendritic cells have been observed in various tumor types .
|
[
"Jessica Schüler",
"Martina Vockerodt",
"Niloofar Salehzadeh",
"Jürgen Becker",
"Jörg Wilting"
] |
https://doi.org/10.3390/cimb46070439
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11276533_p0
|
PMC11276533
|
sec[0]/p[0]
|
1. Introduction
| 2.294922 |
biomedical
|
Other
|
[
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[
0.0171661376953125,
0.9619140625,
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The terms race, ethnicity, and ancestry have been widely used interchangeably in population studies , highlighting a discrepancy in how society defines, labels, and categorizes individuals. This inconsistency extends to how populations are classified for research purposes and how findings are applied to promote health for all human beings independent of their pre-defined classification .
|
[
"Jaqueline L. Pereira",
"Camila A. de Souza",
"Jennyfer E. M. Neyra",
"Jean M. R. S. Leite",
"Andressa Cerqueira",
"Regina C. Mingroni-Netto",
"Julia M. P. Soler",
"Marcelo M. Rogero",
"Flavia M. Sarti",
"Regina M. Fisberg"
] |
https://doi.org/10.3390/genes15070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276533_p1
|
PMC11276533
|
sec[0]/p[1]
|
1. Introduction
| 2.384766 |
biomedical
|
Other
|
[
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] |
[
0.03173828125,
0.86767578125,
0.0994873046875,
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In the last three decades, discussions surrounding these three terms have significantly intensified in population health and medical studies as a response to the rising debates concerning the importance of the ethnic–racial aspects in health–disease processes , and after a series of circumstances of racial injustice stemming from the utilization of race and ethnicity as biologic constructs to foster hierarchical discrimination .
|
[
"Jaqueline L. Pereira",
"Camila A. de Souza",
"Jennyfer E. M. Neyra",
"Jean M. R. S. Leite",
"Andressa Cerqueira",
"Regina C. Mingroni-Netto",
"Julia M. P. Soler",
"Marcelo M. Rogero",
"Flavia M. Sarti",
"Regina M. Fisberg"
] |
https://doi.org/10.3390/genes15070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276533_p2
|
PMC11276533
|
sec[0]/p[2]
|
1. Introduction
| 4.035156 |
biomedical
|
Review
|
[
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0.0003161430358886719
] |
Efforts have been made to set recommendations regarding the use of these terms to enhance their application in research; however, no established consensus exists . In general, most definitions consider that race and ethnicity are dynamic social constructs influenced by geographic, cultural, and sociopolitical factors . However, in recent years, the term race has been considered pejorative because it classifies humans based on phenotype—observable physical traits—perpetuating the incorrect belief in biological differences among sociopolitically constructed racial categories , whereas studies of human genetics have consistently shown that the concept of race has no genetic or scientific basis . Many authors recommend using the terms ethnic group or ethnicity instead of race, as these terms encompass shared cultural background, including nationality, language, religion, and dietary practices, and may also, but not necessarily, reflect common biological characteristics . Conversely, the term ancestry can be defined geographically (ancestors from similar regions), genealogically (an individual’s ancestral pedigree), or genetically .
|
[
"Jaqueline L. Pereira",
"Camila A. de Souza",
"Jennyfer E. M. Neyra",
"Jean M. R. S. Leite",
"Andressa Cerqueira",
"Regina C. Mingroni-Netto",
"Julia M. P. Soler",
"Marcelo M. Rogero",
"Flavia M. Sarti",
"Regina M. Fisberg"
] |
https://doi.org/10.3390/genes15070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276533_p3
|
PMC11276533
|
sec[0]/p[3]
|
1. Introduction
| 3.757813 |
biomedical
|
Other
|
[
0.9990234375,
0.0004475116729736328,
0.0006756782531738281
] |
[
0.1380615234375,
0.4833984375,
0.376953125,
0.0015392303466796875
] |
Understanding genetic ancestry provides an opportunity for a deeper comprehension of human history, movement, evolution, and admixture. Likewise, distinct ancestry backgrounds result in different allelic frequencies, potentially influencing aspects such as health, longevity, disease susceptibility, and severity , response to drugs , and accuracy of genetic risk scores .
|
[
"Jaqueline L. Pereira",
"Camila A. de Souza",
"Jennyfer E. M. Neyra",
"Jean M. R. S. Leite",
"Andressa Cerqueira",
"Regina C. Mingroni-Netto",
"Julia M. P. Soler",
"Marcelo M. Rogero",
"Flavia M. Sarti",
"Regina M. Fisberg"
] |
https://doi.org/10.3390/genes15070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276533_p4
|
PMC11276533
|
sec[0]/p[4]
|
1. Introduction
| 3.833984 |
biomedical
|
Study
|
[
0.9990234375,
0.00015103816986083984,
0.0006203651428222656
] |
[
0.94775390625,
0.034820556640625,
0.01715087890625,
0.0002143383026123047
] |
Nevertheless, epidemiological studies frequently categorize groups based on phenotypes that inadequately represent genetic ancestry , relying on self-reported race, skin color, or ethnicity to determine an individual’s ancestral origin, a subjective and arbitrary classification. This approach may lead to the inclusion of individuals with vastly different levels of population ancestry in the same group, particularly among those of multiracial backgrounds, making the categorization challenging .
|
[
"Jaqueline L. Pereira",
"Camila A. de Souza",
"Jennyfer E. M. Neyra",
"Jean M. R. S. Leite",
"Andressa Cerqueira",
"Regina C. Mingroni-Netto",
"Julia M. P. Soler",
"Marcelo M. Rogero",
"Flavia M. Sarti",
"Regina M. Fisberg"
] |
https://doi.org/10.3390/genes15070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11276533_p5
|
PMC11276533
|
sec[0]/p[5]
|
1. Introduction
| 3.501953 |
biomedical
|
Study
|
[
0.9912109375,
0.0001665353775024414,
0.0084991455078125
] |
[
0.95263671875,
0.04510498046875,
0.0020008087158203125,
0.00016260147094726562
] |
The Brazilian population has one of the most heterogeneous genetic constitutions in the world with an extensive recent admixture, the result of nearly 500 years of interaction between three primary ancestral roots, Sub-Saharan African, European, and Native American populations, reflecting its history of colonization, slavery, and migration . These three populations present different proportions of ancestries when comparing Brazilians with other admixed populations with similar histories of colonization from Latin America and the Caribbean , as well as among Brazilians from different geographical regions of the country .
|
[
"Jaqueline L. Pereira",
"Camila A. de Souza",
"Jennyfer E. M. Neyra",
"Jean M. R. S. Leite",
"Andressa Cerqueira",
"Regina C. Mingroni-Netto",
"Julia M. P. Soler",
"Marcelo M. Rogero",
"Flavia M. Sarti",
"Regina M. Fisberg"
] |
https://doi.org/10.3390/genes15070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 1 |
PMC11276533_p6
|
PMC11276533
|
sec[0]/p[6]
|
1. Introduction
| 2.445313 |
biomedical
|
Study
|
[
0.984375,
0.0002989768981933594,
0.01531982421875
] |
[
0.79541015625,
0.200439453125,
0.00392913818359375,
0.00042700767517089844
] |
Many epidemiological studies with the Brazilian population use the census classification , based on five ethnoracial self-classification groups , Black (”Preta”), Indigenous (“Indígena”), Mixed (“Parda”), White (“Branca”), or Yellow (“Amarela”), where the skin tone is the primary defining characteristic for clustering individuals. Nonetheless, previous studies have indicated that in Brazil, skin color is a poor predictor of genetic ancestry .
|
[
"Jaqueline L. Pereira",
"Camila A. de Souza",
"Jennyfer E. M. Neyra",
"Jean M. R. S. Leite",
"Andressa Cerqueira",
"Regina C. Mingroni-Netto",
"Julia M. P. Soler",
"Marcelo M. Rogero",
"Flavia M. Sarti",
"Regina M. Fisberg"
] |
https://doi.org/10.3390/genes15070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276533_p7
|
PMC11276533
|
sec[0]/p[7]
|
1. Introduction
| 4.058594 |
biomedical
|
Study
|
[
0.99951171875,
0.00016438961029052734,
0.00022077560424804688
] |
[
0.9990234375,
0.0004229545593261719,
0.00040984153747558594,
0.000050187110900878906
] |
In this context, exploring the genetic ancestry of the study population from the Health Survey of São Paulo with a Focus on Nutrition Study is the first step to evaluate how genetics is associated with lifestyle, environmental, and biochemical factors in the development of cardiometabolic diseases in the population of Sao Paulo, the largest Brazilian city. The proposed genetic analysis and data analysis workflow can contribute to the basis of genetics-based medical therapies. In addition, investigating the interrelation between genetic ancestry and ethnoracial self-classification may contribute to a more comprehensive understanding of human genetic diversity and self-perceptions of identity in a multiethnic society.
|
[
"Jaqueline L. Pereira",
"Camila A. de Souza",
"Jennyfer E. M. Neyra",
"Jean M. R. S. Leite",
"Andressa Cerqueira",
"Regina C. Mingroni-Netto",
"Julia M. P. Soler",
"Marcelo M. Rogero",
"Flavia M. Sarti",
"Regina M. Fisberg"
] |
https://doi.org/10.3390/genes15070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11276533_p8
|
PMC11276533
|
sec[0]/p[8]
|
1. Introduction
| 3.779297 |
biomedical
|
Study
|
[
0.99853515625,
0.00043773651123046875,
0.0009636878967285156
] |
[
0.99951171875,
0.00029754638671875,
0.00014257431030273438,
0.00006335973739624023
] |
Therefore, this study aimed to characterize both the global and the local genome-wide genetic ancestries and to assess their relationship with self-reported skin color/race in an admixed representative urban population of Sao Paulo city.
|
[
"Jaqueline L. Pereira",
"Camila A. de Souza",
"Jennyfer E. M. Neyra",
"Jean M. R. S. Leite",
"Andressa Cerqueira",
"Regina C. Mingroni-Netto",
"Julia M. P. Soler",
"Marcelo M. Rogero",
"Flavia M. Sarti",
"Regina M. Fisberg"
] |
https://doi.org/10.3390/genes15070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11276533_p9
|
PMC11276533
|
sec[1]/sec[0]/p[0]
|
2.1. Study Design, Population, and Skin Color/Race Information
| 3.289063 |
biomedical
|
Study
|
[
0.9990234375,
0.00032806396484375,
0.00052642822265625
] |
[
0.9990234375,
0.0008115768432617188,
0.0003063678741455078,
0.00008213520050048828
] |
We analyzed 841 individuals living in permanent private households from the cross-sectional, population-based Health Survey of São Paulo with a Focus on Nutrition Study , which aims to evaluate the relationship between lifestyle, environmental, biochemical, and genetic factors in the development of cardiometabolic disease in the population of São Paulo city. Details of the study were described elsewhere .
|
[
"Jaqueline L. Pereira",
"Camila A. de Souza",
"Jennyfer E. M. Neyra",
"Jean M. R. S. Leite",
"Andressa Cerqueira",
"Regina C. Mingroni-Netto",
"Julia M. P. Soler",
"Marcelo M. Rogero",
"Flavia M. Sarti",
"Regina M. Fisberg"
] |
https://doi.org/10.3390/genes15070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11276533_p10
|
PMC11276533
|
sec[1]/sec[0]/p[1]
|
2.1. Study Design, Population, and Skin Color/Race Information
| 4.023438 |
biomedical
|
Study
|
[
0.99853515625,
0.00032210350036621094,
0.0009527206420898438
] |
[
0.99951171875,
0.00017464160919189453,
0.00013756752014160156,
0.000032842159271240234
] |
Briefly, 2015 ISA-Nutrition is a sub-sample of the Health Survey of São Paulo (ISA-Capital), which evaluated the health status and the use of health services of the population. The study assessed a probabilistic sample of individuals aged 12 years and older, not pregnant or lactating, and living in permanent households from the urban area of São Paulo city, Southern Brazil, with sampling stratified by clusters in two stages (urban census tracts and households) to ensure representativeness at the population level. In ISA-Capital, demographic and other information were collected in the households throughout the year 2015 using a structured questionnaire applied by trained interviewers to 4024 individuals . In this interview, among other questions, participants were asked the following: “Which is your skin color or race?”. Therefore, skin color/race was self-reported by study participants, categorized by themselves according to the five ethnoracial categories used by the Brazilian census , which relies on self-perception of skin pigmentation: Black, Indigenous, Mixed, White, or Yellow. Alternatively, they could answer “other”, and specify any description they prefer for their skin color/race. Other terms used to describe the admixed character of the Brazilian population (e.g., “moreno/a”, “moreno/a claro/a”, and “moreninho/a”, which correspond to terms referring to tanned/light dark skin color) were collapsed into the category Mixed (n = 36) .
|
[
"Jaqueline L. Pereira",
"Camila A. de Souza",
"Jennyfer E. M. Neyra",
"Jean M. R. S. Leite",
"Andressa Cerqueira",
"Regina C. Mingroni-Netto",
"Julia M. P. Soler",
"Marcelo M. Rogero",
"Flavia M. Sarti",
"Regina M. Fisberg"
] |
https://doi.org/10.3390/genes15070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
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