ORCID Profile
0000-0003-3084-2287
Current Organisations
University of Alberta
,
Monash University Malaysia
,
Stanford University
,
Monash University
,
Universiti Putra Malaysia
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Publisher: Oxford University Press (OUP)
Date: 15-03-2018
DOI: 10.1093/BIOINFORMATICS/BTY164
Abstract: The three-dimensional organization of chromatin plays a critical role in gene regulation and disease. High-throughput chromosome conformation capture experiments such as Hi-C are used to obtain genome-wide maps of three-dimensional chromatin contacts. However, robust estimation of data quality and systematic comparison of these contact maps is challenging due to the multi-scale, hierarchical structure of chromatin contacts and the resulting properties of experimental noise in the data. Measuring concordance of contact maps is important for assessing reproducibility of replicate experiments and for modeling variation between different cellular contexts. We introduce a concordance measure called DIfferences between Smoothed COntact maps (GenomeDISCO) for assessing the similarity of a pair of contact maps obtained from chromosome conformation capture experiments. The key idea is to smooth contact maps using random walks on the contact map graph, before estimating concordance. We use simulated datasets to benchmark GenomeDISCO's sensitivity to different types of noise that affect chromatin contact maps. When applied to a large collection of Hi-C datasets, GenomeDISCO accurately distinguishes biological replicates from s les obtained from different cell types. GenomeDISCO also generalizes to other chromosome conformation capture assays, such as HiChIP. Software implementing GenomeDISCO is available at undajelab/genomedisco. Supplementary data are available at Bioinformatics online.
Publisher: Springer Science and Business Media LLC
Date: 13-02-2023
Publisher: The Royal Society
Date: 04-2018
Abstract: Deep learning describes a class of machine learning algorithms that are capable of combining raw inputs into layers of intermediate features. These algorithms have recently shown impressive results across a variety of domains. Biology and medicine are data-rich disciplines, but the data are complex and often ill-understood. Hence, deep learning techniques may be particularly well suited to solve problems of these fields. We examine applications of deep learning to a variety of biomedical problems—patient classification, fundamental biological processes and treatment of patients—and discuss whether deep learning will be able to transform these tasks or if the biomedical sphere poses unique challenges. Following from an extensive literature review, we find that deep learning has yet to revolutionize biomedicine or definitively resolve any of the most pressing challenges in the field, but promising advances have been made on the prior state of the art. Even though improvements over previous baselines have been modest in general, the recent progress indicates that deep learning methods will provide valuable means for speeding up or aiding human investigation. Though progress has been made linking a specific neural network's prediction to input features, understanding how users should interpret these models to make testable hypotheses about the system under study remains an open challenge. Furthermore, the limited amount of labelled data for training presents problems in some domains, as do legal and privacy constraints on work with sensitive health records. Nonetheless, we foresee deep learning enabling changes at both bench and bedside with the potential to transform several areas of biology and medicine.
Publisher: American Association for Cancer Research (AACR)
Date: 08-2023
DOI: 10.1158/0008-5472.23814641.V1
Abstract: supplementary materials
Publisher: Springer Science and Business Media LLC
Date: 02-06-2021
DOI: 10.1038/S41467-021-23143-7
Abstract: Using the Cap Analysis of Gene Expression (CAGE) technology, the FANTOM5 consortium provided one of the most comprehensive maps of transcription start sites (TSSs) in several species. Strikingly, ~72% of them could not be assigned to a specific gene and initiate at unconventional regions, outside promoters or enhancers. Here, we probe these unassigned TSSs and show that, in all species studied, a significant fraction of CAGE peaks initiate at microsatellites, also called short tandem repeats (STRs). To confirm this transcription, we develop Cap Trap RNA-seq, a technology which combines cap trapping and long read MinION sequencing. We train sequence-based deep learning models able to predict CAGE signal at STRs with high accuracy. These models unveil the importance of STR surrounding sequences not only to distinguish STR classes, but also to predict the level of transcription initiation. Importantly, genetic variants linked to human diseases are preferentially found at STRs with high transcription initiation level, supporting the biological and clinical relevance of transcription initiation at STRs. Together, our results extend the repertoire of non-coding transcription associated with DNA tandem repeats and complexify STR polymorphism.
Publisher: American Association for Cancer Research (AACR)
Date: 28-12-2022
DOI: 10.1158/1055-9965.EPI-22-0763
Abstract: Tobacco smoking is an established risk factor for colorectal cancer. However, genetically defined population subgroups may have increased susceptibility to smoking-related effects on colorectal cancer. A genome-wide interaction scan was performed including 33,756 colorectal cancer cases and 44,346 controls from three genetic consortia. Evidence of an interaction was observed between smoking status (ever vs. never smokers) and a locus on 3p12.1 (rs9880919, P = 4.58 × 10−8), with higher associated risk in subjects carrying the GG genotype [OR, 1.25 95% confidence interval (CI), 1.20–1.30] compared with the other genotypes (OR & .17 for GA and AA). Among ever smokers, we observed interactions between smoking intensity (increase in 10 cigarettes smoked per day) and two loci on 6p21.33 (rs4151657, P = 1.72 × 10−8) and 8q24.23 (rs7005722, P = 2.88 × 10−8). Subjects carrying the rs4151657 TT genotype showed higher risk (OR, 1.12 95% CI, 1.09–1.16) compared with the other genotypes (OR & .06 for TC and CC). Similarly, higher risk was observed among subjects carrying the rs7005722 AA genotype (OR, 1.17 95% CI, 1.07–1.28) compared with the other genotypes (OR & .13 for AC and CC). Functional annotation revealed that SNPs in 3p12.1 and 6p21.33 loci were located in regulatory regions, and were associated with expression levels of nearby genes. Genetic models predicting gene expression revealed that smoking parameters were associated with lower colorectal cancer risk with higher expression levels of CADM2 (3p12.1) and ATF6B (6p21.33). Our study identified novel genetic loci that may modulate the risk for colorectal cancer of smoking status and intensity, linked to tumor suppression and immune response. These findings can guide potential prevention treatments.
Publisher: American Association for Cancer Research (AACR)
Date: 08-2023
DOI: 10.1158/0008-5472.23814635.V1
Abstract: Selected characteristics of the participants.
Publisher: BMJ
Date: 25-02-2021
DOI: 10.1136/GUTJNL-2020-321534
Abstract: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including in idualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined. To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling. We identified 13 loci that reached genome-wide significance (p ×10 −8 ) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer. Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.
Publisher: Springer Science and Business Media LLC
Date: 18-02-2015
DOI: 10.1038/NATURE14248
Publisher: Cold Spring Harbor Laboratory
Date: 09-03-2023
DOI: 10.1101/2023.03.09.531820
Abstract: Positively charged repeat peptides are emerging as key players in neurodegenerative diseases. These peptides can perturb erse cellular pathways but a unifying framework for how such promiscuous toxicity arises has remained elusive. We used mass-spectrometry-based proteomics to define the protein targets of these neurotoxic peptides and found that they all share similar sequence features that drive their aberrant condensation with these positively charged peptides. We trained a machine learning algorithm to detect such sequence features and unexpectedly discovered that this mode of toxicity is not limited to human repeat expansion disorders but has evolved countless times across the tree of life in the form of cationic antimicrobial and venom peptides. We demonstrate that an excess in positive charge is necessary and sufficient for this killer activity, which we name ‘polycation poisoning’. These findings reveal an ancient and conserved mechanism and inform ways to leverage its design rules for new generations of bioactive peptides.
Publisher: Cold Spring Harbor Laboratory
Date: 28-05-2017
DOI: 10.1101/142760
Abstract: Deep learning, which describes a class of machine learning algorithms, has recently showed impressive results across a variety of domains. Biology and medicine are data rich, but the data are complex and often ill-understood. Problems of this nature may be particularly well-suited to deep learning techniques. We examine applications of deep learning to a variety of biomedical problems—patient classification, fundamental biological processes, and treatment of patients—and discuss whether deep learning will transform these tasks or if the biomedical sphere poses unique challenges. We find that deep learning has yet to revolutionize or definitively resolve any of these problems, but promising advances have been made on the prior state of the art. Even when improvement over a previous baseline has been modest, we have seen signs that deep learning methods may speed or aid human investigation. More work is needed to address concerns related to interpretability and how to best model each problem. Furthermore, the limited amount of labeled data for training presents problems in some domains, as do legal and privacy constraints on work with sensitive health records. Nonetheless, we foresee deep learning powering changes at both bench and bedside with the potential to transform several areas of biology and medicine.
Publisher: Public Library of Science (PLoS)
Date: 19-04-2011
Publisher: Springer Science and Business Media LLC
Date: 26-06-2023
DOI: 10.1038/S41416-023-02312-Z
Abstract: Diabetes is an established risk factor for colorectal cancer. However, the mechanisms underlying this relationship still require investigation and it is not known if the association is modified by genetic variants. To address these questions, we undertook a genome-wide gene-environment interaction analysis. We used data from 3 genetic consortia (CCFR, CORECT, GECCO 31,318 colorectal cancer cases/41,499 controls) and undertook genome-wide gene-environment interaction analyses with colorectal cancer risk, including interaction tests of genetics(G)xdiabetes (1-degree of freedom d.f.) and joint testing of Gxdiabetes, G-colorectal cancer association (2-d.f. joint test) and G-diabetes correlation (3-d.f. joint test). Based on the joint tests, we found that the association of diabetes with colorectal cancer risk is modified by loci on chromosomes 8q24.11 (rs3802177, SLC30A8 – OR AA : 1.62, 95% CI: 1.34–1.96 OR AG : 1.41, 95% CI: 1.30–1.54 OR GG : 1.22, 95% CI: 1.13–1.31 p -value 3-d.f. : 5.46 × 10 −11 ) and 13q14.13 (rs9526201, LRCH1 – OR GG : 2.11, 95% CI: 1.56–2.83 OR GA : 1.52, 95% CI: 1.38–1.68 OR AA : 1.13, 95% CI: 1.06–1.21 p -value 2-d.f. : 7.84 × 10 −09 ). These results suggest that variation in genes related to insulin signaling ( SLC30A8 ) and immune function ( LRCH1 ) may modify the association of diabetes with colorectal cancer risk and provide novel insights into the biology underlying the diabetes and colorectal cancer relationship.
Publisher: Elsevier BV
Date: 10-2020
Publisher: Wiley
Date: 30-09-2009
DOI: 10.1002/GLIA.20936
Abstract: Poly(ADP-ribose) polymerase-1 (PARP-1) is a ubiquitous nuclear enzyme involved in genomic stability. Excessive oxidative DNA strand breaks lead to PARP-1-induced depletion of cellular NAD(+), glycolytic rate, ATP levels, and eventual cell death. Glutamate neurotransmission is tightly controlled by ATP-dependent astrocytic glutamate transporters, and thus we hypothesized that astrocytic PARP-1 activation by DNA damage leads to bioenergetic depletion and compromised glutamate uptake. PARP-1 activation by the DNA alkylating agent, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), caused a significant reduction of cultured cortical astrocyte survival (EC(50) = 78.2 +/- 2.7 microM). HPLC revealed MNNG-induced time-dependent reductions in NAD(+) (98%, 4 h), ATP (71%, 4 h), ADP (63%, 4 h), and AMP (66%, 4 h). The maximal [(3)H]glutamate uptake rate (V(max)) also declined in a manner that corresponded temporally with ATP depletion, falling from 19.3 +/- 2.8 in control cells to 2.1 +/- 0.8 nmol/min/mg protein 4 h post-MNNG. Both bioenergetic depletion and loss of glutamate uptake capacity were attenuated by genetic deletion of PARP-1, directly indicating PARP-1 involvement, and by adding exogenous NAD(+) (10 mM). In mixed neurons/astrocyte cultures, MNNG neurotoxicity was partially mediated by extracellular glutamate and was reduced by co-culture with PARP-1(-/-) astrocytes, suggesting that impairment of astrocytic glutamate uptake by PARP-1 can raise glutamate levels sufficiently to have receptor-mediated effects at neighboring neurons. Taken together, these experiments showed that PARP-1 activation leads to depletion of the total adenine nucleotide pool in astrocytes and severe reduction in neuroprotective glutamate uptake capacity.
Publisher: Institute of Mathematical Statistics
Date: 09-2019
DOI: 10.1214/19-AOAS1244
Publisher: Elsevier BV
Date: 09-2019
DOI: 10.1016/J.LFS.2019.116695
Abstract: Alzheimer's disease (AD) is neurodegenerative disorder that is associated with memory and cognitive decline in the older adults. Scopolamine is commonly used as a behavioral model in studying cognitive disorders including AD. Many studies have also concurrently examined the neurochemical mechanisms underlying the behavioral modifications by scopolamine treatment. Nonetheless, the scopolamine model has not become a standard tool in the early assessment of drugs. Furthermore, the use of scopolamine as a pharmacological model to study AD remains debatable. This report reviews the scopolamine-induced cellular and molecular changes and discusses how these changes relate to AD pathogenesis.
Publisher: Cold Spring Harbor Laboratory
Date: 05-12-2017
Abstract: Induced pluripotent stem cells (iPSCs) are an essential tool for studying cellular differentiation and cell types that are otherwise difficult to access. We investigated the use of iPSCs and iPSC-derived cells to study the impact of genetic variation on gene regulation across different cell types and as models for studies of complex disease. To do so, we established a panel of iPSCs from 58 well-studied Yoruba lymphoblastoid cell lines (LCLs) 14 of these lines were further differentiated into cardiomyocytes. We characterized regulatory variation across in iduals and cell types by measuring gene expression levels, chromatin accessibility, and DNA methylation. Our analysis focused on a comparison of inter-in idual regulatory variation across cell types. While most cell-type–specific regulatory quantitative trait loci (QTLs) lie in chromatin that is open only in the affected cell types, we found that 20% of cell-type–specific regulatory QTLs are in shared open chromatin. This observation motivated us to develop a deep neural network to predict open chromatin regions from DNA sequence alone. Using this approach, we were able to use the sequences of segregating haplotypes to predict the effects of common SNPs on cell-type–specific chromatin accessibility.
Publisher: Oxford University Press (OUP)
Date: 05-05-2022
DOI: 10.1093/JNCI/DJAC094
Abstract: The use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk. We conducted a genome-wide, gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen only, and combined estrogen-progestogen therapy with CRC risk, among 28 486 postmenopausal women (11 519 CRC patients and 16 967 participants without CRC) from 38 studies, using logistic regression, 2-step method, and 2– or 3–degree-of-freedom joint test. A set-based score test was applied for rare genetic variants. The use of any MHT, estrogen only and estrogen-progestogen were associated with a reduced CRC risk (odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.64 to 0.78 OR = 0.65, 95% CI = 0.53 to 0.79 and OR = 0.73, 95% CI = 0.59 to 0.90, respectively). The 2-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-associated CRC risk was statistically significantly reduced in women with the GG genotype (OR = 0.68, 95% CI = 0.64 to 0.72) but not within strata of GC or CC genotypes. A statistically significant interaction between a DCBLD1 intronic variant at 6q22.1 (rs10782186) and MHT use was identified by the 2–degree-of-freedom joint test. The MHT-associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing odds ratios of 0.78 (95% CI = 0.70 to 0.87) for TT, 0.68 (95% CI = 0.63 to 0.73) for TC, and 0.66 (95% CI = 0.60 to 0.74) for CC genotypes. In addition, 5 genes in rare variant analysis showed suggestive interactions with MHT (2-sided P & 1.2 × 10−4). Genetic variants that modify the association between MHT and CRC risk were identified, offering new insights into pathways of CRC carcinogenesis and potential mechanisms involved.
Publisher: American Association for Cancer Research (AACR)
Date: 24-02-2022
DOI: 10.1158/1055-9965.EPI-21-1003
Abstract: Currently known associations between common genetic variants and colorectal cancer explain less than half of its heritability of 25%. As alcohol consumption has a J-shape association with colorectal cancer risk, nondrinking and heavy drinking are both risk factors for colorectal cancer. In idual-level data was pooled from the Colon Cancer Family Registry, Colorectal Transdisciplinary Study, and Genetics and Epidemiology of Colorectal Cancer Consortium to compare nondrinkers (≤1 g/day) and heavy drinkers (& g/day) with light-to-moderate drinkers (1–28 g/day) in GxE analyses. To improve power, we implemented joint 2df and 3df tests and a novel two-step method that modifies the weighted hypothesis testing framework. We prioritized putative causal variants by predicting allelic effects using support vector machine models. For nondrinking as compared with light-to-moderate drinking, the hybrid two-step approach identified 13 significant SNPs with pairwise r2 & 0.9 in the 10q24.2/COX15 region. When stratified by alcohol intake, the A allele of lead SNP rs2300985 has a dose–response increase in risk of colorectal cancer as compared with the G allele in light-to-moderate drinkers [OR for GA genotype = 1.11 95% confidence interval (CI), 1.06–1.17 OR for AA genotype = 1.22 95% CI, 1.14–1.31], but not in nondrinkers or heavy drinkers. Among the correlated candidate SNPs in the 10q24.2/COX15 region, rs1318920 was predicted to disrupt an HNF4 transcription factor binding motif. Our study suggests that the association with colorectal cancer in 10q24.2/COX15 observed in genome-wide association study is strongest in nondrinkers. We also identified rs1318920 as the putative causal regulatory variant for the region. The study identifies multifaceted evidence of a possible functional effect for rs1318920.
Publisher: Bentham Science Publishers Ltd.
Date: 05-2020
DOI: 10.2174/1573399816999201012201111
Abstract: Diabetes mellitus is a metabolic disease that requires immediate attention. Oxidative stress that leads to the generation of reactive oxygen species is a contributing factor to the disease progression. Yttrium oxide nanoparticles (Y 2 O 3 NPs) have a profound effect on alleviating oxidative damage. The literature related to Y 2 O 3 NPs and oxidative stress has been thoroughly searched using PubMed and Scopus databases and relevant studies from inception until August 2020 were included in this scoping review. Y 2 O 3 NPs altered oxidative stress-related biochemical parameters in different disease models including diabetes. Although Y 2 O 3 NPs are a promising antidiabetic agent due to their antioxidant and anti- inflammatory properties, more studies are required to further elucidate the pharmacological and toxicological properties of these nanoparticles.
Publisher: American Association for Cancer Research (AACR)
Date: 08-2023
DOI: 10.1158/0008-5472.23814635
Abstract: Selected characteristics of the participants.
Publisher: Springer Science and Business Media LLC
Date: 29-06-2023
Publisher: Springer Science and Business Media LLC
Date: 20-12-2022
Publisher: Springer Science and Business Media LLC
Date: 03-2022
Publisher: American Association for Cancer Research (AACR)
Date: 08-2023
DOI: 10.1158/0008-5472.23814632.V1
Abstract: Summary of G × BMI analyses using 1DF, two-step, and 3DF analyses.
Publisher: American Association for Cancer Research (AACR)
Date: 08-2023
DOI: 10.1158/0008-5472.C.6769316
Abstract: Abstract Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 ( i FMN1/GREM1 /i ) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the i FMN1/GREM1 /i gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer. Significance: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies. /
Publisher: Bentham Science Publishers Ltd.
Date: 31-12-2020
DOI: 10.2174/1570159X18666200611144825
Abstract: Dementia is a collection of symptoms affecting a person’s cognition. Dementia is debilitating, and therefore, finding an effective treatment is of utmost importance. Resveratrol, which exhibits neuroprotective effects, has low bioavailability. However, its glucoside polydatin is more bioavailable. Here, the evidence that supports the protective role of polydatin against dementia- related diseases such as Alzheimer’s disease, vascular dementia, alcohol-related dementia, and Lewy body dementias is presented. The beneficial effects of polydatin from a mechanistic perspective are specifically emphasized in this review. Future directions in this area of research are also discussed.
Publisher: Cold Spring Harbor Laboratory
Date: 05-12-2016
DOI: 10.1101/091660
Abstract: Induced pluripotent stem cells (iPSCs) are an essential tool for studying cellular differentiation and cell types that are otherwise difficult to access. We investigated the use of iPSCs and iPSC-derived cells to study the impact of genetic variation across different cell types and as models for studies of complex disease. We established a panel of iPSCs from 58 well-studied Yoruba lymphoblastoid cell lines (LCLs) 14 of these lines were further differentiated into cardiomyocytes. We characterized regulatory variation across in iduals and cell types by measuring gene expression, chromatin accessibility and DNA methylation. Regulatory variation between in iduals is lower in iPSCs than in the differentiated cell types, consistent with the intuition that developmental processes are generally canalized. While most cell type-specific regulatory quantitative trait loci (QTLs) lie in chromatin that is open only in the affected cell types, we found that 20% of cell type-specific QTLs are in shared open chromatin. Finally, we developed a deep neural network to predict open chromatin regions from DNA sequence alone and were able to use the sequences of segregating haplotypes to predict the effects of common SNPs on cell type-specific chromatin accessibility.
Publisher: Public Library of Science (PLoS)
Date: 21-11-2017
Publisher: Oxford University Press (OUP)
Date: 17-03-2023
DOI: 10.1093/JNCI/DJAD043
Abstract: The shared inherited genetic contribution to risk of different cancers is not fully known. In this study, we leverage results from 12 cancer genome-wide association studies (GWAS) to quantify pairwise genome-wide genetic correlations across cancers and identify novel cancer susceptibility loci. We collected GWAS summary statistics for 12 solid cancers based on 376 759 participants with cancer and 532 864 participants without cancer of European ancestry. The included cancer types were breast, colorectal, endometrial, esophageal, glioma, head and neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancers. We conducted cross-cancer GWAS and transcriptome-wide association studies to discover novel cancer susceptibility loci. Finally, we assessed the extent of variant-specific pleiotropy among cancers at known and newly identified cancer susceptibility loci. We observed widespread but modest genome-wide genetic correlations across cancers. In cross-cancer GWAS and transcriptome-wide association studies, we identified 15 novel cancer susceptibility loci. Additionally, we identified multiple variants at 77 distinct loci with strong evidence of being associated with at least 2 cancer types by testing for pleiotropy at known cancer susceptibility loci. Overall, these results suggest that some genetic risk variants are shared among cancers, though much of cancer heritability is cancer-specific and thus tissue-specific. The increase in statistical power associated with larger s le sizes in cross-disease analysis allows for the identification of novel susceptibility regions. Future studies incorporating data on multiple cancer types are likely to identify additional regions associated with the risk of multiple cancer types.
Publisher: American Association for Cancer Research (AACR)
Date: 08-2023
DOI: 10.1158/0008-5472.23814632
Abstract: Summary of G × BMI analyses using 1DF, two-step, and 3DF analyses.
Publisher: Wiley
Date: 02-02-2005
DOI: 10.1111/J.1471-4159.2004.02944.X
Abstract: We employed carbon fiber erometry to measure the amount of catecholamine released from in idual granules (i.e. the quantal size, Q) of rat chromaffin cells. The distribution of Q1/3 of erometric events could be reasonably described by the summation of at least three Gaussians, suggesting that rat chromaffin cells contained at least three distinct populations of granules, with a small, medium or large modal Q. After 3 days of culture, the mean cellular Q reduced by approximately 14%, which did not arise from a uniform percentage decrease in the Q of every granule. Instead, the rundown involved a > 11% decrease in the proportional release from large Q granules and a > 19% decrease in the modal Q-value of small Q granules. In contrast, when cells were cultured with dibutyryl-cAMP (dBcAMP) for 3 days, their mean cellular Q increased by approximately 38% (relative to time-matched controls). This increase in Q was not associated with any shift in the proportional release from the three populations of granules. Instead, cAMP increased the average amount of catecholamines released from all three populations of granules. Our data raise the possibility that distinct populations of granules in rat chromaffin cells can be regulated either differentially or uniformly.
Publisher: Elsevier BV
Date: 04-2007
Publisher: American Physiological Society
Date: 11-2005
DOI: 10.1152/AJPCELL.00514.2004
Abstract: Glucocorticoid is reported to regulate catecholamine synthesis and storage. However, it is not clear whether the actual amount of catecholamine released from in idual granules (quantal size, Q) in mature chromaffin cells is affected by glucocorticoid. Using carbon fiber erometry, we found that dexamethasone did not affect mean cellular Q or the proportional release from different populations of granules in rat chromaffin cells cultured for 1 day in a serum-free defined medium. After two extra days of culture in the defined medium, there was a rundown in mean cellular Q, and it was associated with a shift in the proportional release from the different granule populations. This phenomenon could not be rescued by serum supplementation but could be prevented by dexamethasone via an action that was independent of changes in voltage-gated Ca 2+ channel (VGCC) density. Using simultaneous measurements of membrane capacitance and cytosolic Ca 2+ concentration, we found that for cells cultured in defined medium dexamethasone enhanced the exocytotic response triggered by a brief depolarization (50 ms) without affecting the VGCC density or the fast exocytotic response triggered via flash photolysis of caged Ca 2+ . Thus glucocorticoid may regulate the number of immediately releasable granules that are in close proximity to a subset of VGCC. Because chromaffin cells in vivo are exposed to high concentrations of glucocorticoid, our findings suggest that the paracrine actions of glucocorticoid maintain the mean catecholamine content in chromaffin cell granules as well as the colocalization of releasable granules with VGCCs.
Publisher: Springer Science and Business Media LLC
Date: 09-2012
DOI: 10.1038/NATURE11247
Publisher: Springer Science and Business Media LLC
Date: 19-03-2022
DOI: 10.1007/S12035-022-02799-2
Abstract: Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the cardinal features of tremor, bradykinesia, rigidity, and postural instability, in addition to other non-motor symptoms. Pathologically, PD is attributed to the loss of dopaminergic neurons in the substantia nigra pars compacta, with the hallmark of the presence of intracellular protein aggregates of α-synuclein in the form of Lewy bodies. The pathogenesis of PD is still yet to be fully elucidated due to the multifactorial nature of the disease. However, a myriad of studies has indicated several intracellular events in triggering apoptotic neuronal cell death in PD. These include oxidative stress, mitochondria dysfunction, endoplasmic reticulum stress, alteration in dopamine catabolism, inactivation of tyrosine hydroxylase, and decreased levels of neurotrophic factors. Laboratory studies using the herbicide paraquat in different in vitro and in vivo models have demonstrated the induction of many PD pathological features. The selective neurotoxicity induced by paraquat has brought a new dawn in our perspectives about the pathophysiology of PD. Epidemiological data have suggested an increased risk of developing PD in the human population exposed to paraquat for a long term. This model has opened new frontiers in the quest for new therapeutic targets for PD. The purpose of this review is to synthesize the relationship between the exposure of paraquat and the pathogenesis of PD in in vitro and in vivo models.
Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1016/J.LFS.2019.117011
Abstract: Diabetes mellitus (DM) is a multifaceted and costly disease, which requires serious attention. Finding a cheaper anti-diabetic alternative that can act on multiple disease-related targets and pathways is the ultimate treatment goal for DM. Nanotechnology has offered some exciting possibilities in biomedical and drug delivery applications. Zinc oxide nanoparticles (ZnO-NPs), a novel agent to deliver zinc, have great implications in many disease therapies including DM. This review summarizes the pharmacological mechanisms by which ZnO-NPs alleviate DM and diabetic complications. Research implications and future perspectives were also discussed.
Publisher: Elsevier BV
Date: 2018
DOI: 10.1016/J.EJPHAR.2018.10.039
Abstract: The prevalence of stroke is high in both developing and developed nations. It causes a heavy social and financial burden to the sufferers and their caregivers. Thrombolytic therapy is the only pharmacological treatment available for stroke. However, thrombolytic agents do not provide substantial improvement on long term motor and cognitive disabilities. Thus, there is a need to explore for new compounds that can halt or reverse the deterioration of neurons in the stroke patients' brain. Polydatin, a precursor of resveratrol, is a natural stilbene commonly found in food. This review article describes how different parameters were altered with ischemic injury and polydatin treatment, why it is important and how it could be beneficial or useful in future studies. Our review of polydatin provides convincing evidence regarding the potential of polydatin to be developed into preventive or therapeutic products for ischemic stroke. Nevertheless, additional studies are necessary in order to properly elucidate the biological mechanisms of polydatin, especially its molecular mechanisms of protection and target proteins, in cerebral ischemia.
Publisher: Springer Science and Business Media LLC
Date: 12-2014
Publisher: Cold Spring Harbor Laboratory
Date: 06-04-2023
DOI: 10.1101/2023.04.04.535623
Abstract: The Encyclopedia of DNA elements (ENCODE) project is a collaborative effort to create a comprehensive catalog of functional elements in the human genome. The current database comprises more than 19000 functional genomics experiments across more than 1000 cell lines and tissues using a wide array of experimental techniques to study the chromatin structure, regulatory and transcriptional landscape of the Homo sapiens and Mus musculus genomes. All experimental data, metadata, and associated computational analyses created by the ENCODE consortium are submitted to the Data Coordination Center (DCC) for validation, tracking, storage, and distribution to community resources and the scientific community. The ENCODE project has engineered and distributed uniform processing pipelines in order to promote data provenance and reproducibility as well as allow interoperability between genomic resources and other consortia. All data files, reference genome versions, software versions, and parameters used by the pipelines are captured and available via the ENCODE Portal. The pipeline code, developed using Docker and Workflow Description Language (WDL openwdl.org/ ) is publicly available in GitHub, with images available on Dockerhub ( hub.docker.com ), enabling access to a erse range of biomedical researchers. ENCODE pipelines maintained and used by the DCC can be installed to run on personal computers, local HPC clusters, or in cloud computing environments via Cromwell. Access to the pipelines and data via the cloud allows small labs the ability to use the data or software without access to institutional compute clusters. Standardization of the computational methodologies for analysis and quality control leads to comparable results from different ENCODE collections - a prerequisite for successful integrative analyses. Database URL: www.encodeproject.org/
Publisher: World Scientific Pub Co Pte Lt
Date: 10-2020
DOI: 10.1142/S0219581X20500015
Abstract: Zinc oxide nanoparticles (ZnO-NPs) are widely utilized in many applications due to distinct physical and chemical characteristics. There are growing concerns that abundant use of ZnO-NPs can cause harm to humans and the environment. There is a substantial problem with reproducibility in nanotoxicology research due to the inherent properties of nanoparticles. Dispersion media are used for the preparation of nanoparticles. However, the physical and biological behaviors of ZnO-NPs in aqueous dispersion media are poorly understood. In this study, we investigated the effect of ZnO-NPs on the viability of SH-SY5Y cells. Our results showed that ZnO-NPs diluted from water-dispersed stock solution caused significant cell death at a much lower dose compared to their counterpart diluted from the phosphate-buffered saline (PBS)-dispersed stock solution. Electron microscopic data indicated that ZnO-NPs from the PBS-dispersed stock solution form much larger agglomerates compared to the one from the water-dispersed stock solution. From these data, we can conclude that the types of media used for particle dispersion impact the change in the physical property and cytotoxicity of ZnO-NPs.
Publisher: Springer Science and Business Media LLC
Date: 10-01-2023
Publisher: American Association for Cancer Research (AACR)
Date: 08-2023
DOI: 10.1158/0008-5472.23814641
Abstract: supplementary materials
Publisher: American Association for Cancer Research (AACR)
Date: 08-2023
DOI: 10.1158/0008-5472.C.6769316.V1
Abstract: Abstract Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 ( i FMN1/GREM1 /i ) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the i FMN1/GREM1 /i gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer. Significance: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies. /
Publisher: American Association for Cancer Research (AACR)
Date: 30-05-2023
DOI: 10.1158/0008-5472.CAN-22-3713
Abstract: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.
No related grants have been discovered for Anshul Kundaje.