المؤلفون: Salehi, Sohrab, Dorri, Fatemeh, Chern, Kevin, Kabeer, Farhia, Rusk, Nicole, Funnell, Tyler, Williams, Marc J., Lai, Daniel, Andronescu, Mirela, Campbell, Kieran R., McPherson, Andrew, Aparicio, Samuel, Roth, Andrew, Shah, Sohrab P., Bouchard-Côté, Alexandre

المصدر: Peer Community Journal, Vol 3, Iss , Pp - (2023)

مصطلحات موضوعية: Phylogenetics, Cancer evolution, Bayesian statistics, MCMC, Copy number evolution, PDX, Triple negative breast cancer, Archaeology, CC1-960, Science

الوصف: A new generation of scalable single cell whole genome sequencing (scWGS) methods allows unprecedented high resolution measurement of the evolutionary dynamics of cancer cell populations. Phylogenetic reconstruction is central to identifying sub-populations and distinguishing the mutational processes that gave rise to them. Existing phylogenetic tree building models do not scale to the tens of thousands of high resolution genomes achievable with current scWGS methods. We constructed a phylogenetic model and associated Bayesian inference procedure, sitka, specifically for scWGS data. The method is based on a novel phylogenetic encoding of copy number (CN) data, the sitka transformation, that simplifies the site dependencies induced by rearrangements while still forming a sound foundation to phylogenetic inference. The sitka transformation allows us to design novel scalable Markov chain Monte Carlo (MCMC) algorithms. Moreover, we introduce a novel point mutation calling method that incorporates the CN data and the underlying phylogenetic tree to overcome the low per-cell coverage of scWGS. We demonstrate our method on three single cell datasets, including a novel PDX series, and analyse the topological properties of the inferred trees. Sitka is freely available at https://github.com/UBC-Stat-ML/sitkatree.gitTest

وصف الملف: electronic resource

العلاقة: https://peercommunityjournal.org/articles/10.24072/pcjournal.292Test/; https://doaj.org/toc/2804-3871Test

الوصول الحر: https://doaj.org/article/7d336692a2954e17ba3b00dfa26ea966Test

المؤلفون: Salehi, Sohrab, Schallmayer, Espen, Bandomir, Nils, Kärcher, Annette, Güth, Jan‐Frederik, Heitel, Pascal

المصدر: Archiv der Pharmazie ; ISSN 0365-6233 1521-4184

الوصف: The nuclear receptors hepatocyte nuclear factor 4α (HNF4α) and retinoic acid receptor‐related orphan receptor‐β (RORβ) are ligand‐regulated transcription factors and potential drug targets for metabolic disorders. However, there is a lack of small molecular, selective ligands to explore the therapeutic potential in further detail. Here, we report the discovery of greater celandine ( Chelidonium majus ) isoquinoline alkaloids as nuclear receptor modulators: Berberine is a selective RORβ inverse agonist and modulated target genes involved in the circadian clock, photoreceptor cell development, and neuronal function. The structurally related chelidonine was identified as a ligand for the constitutively active HNF4α receptor, with nanomolar potency in a cellular reporter gene assay. In human liver cancer cells naturally expressing high levels of HNF4α, chelidonine acted as an inverse agonist and downregulated genes associated with gluconeogenesis and drug metabolism. Both berberine and chelidonine are promising tool compounds to further investigate their target nuclear receptors and for drug discovery.

الإتاحة: https://doi.org/10.1002/ardp.202300756Test

المؤلفون: Salehi, Sohrab, Dorri, Fatemeh, Chern, Kevin, Kabeer, Farhia, Rusk, Nicole, Funnell, Tyler, Williams, Marc J, Lai, Daniel, Andronescu, Mirela, Campbell, Kieran R., McPherson, Andrew, Aparicio, Samuel, Roth, Andrew, Shah, Sohrab, Bouchard-Côté, Alexandre

الوصف: Supplementary material for "Cancer phylogenetic tree inference at scale from 1000s of single cell genomes"

العلاقة: https://zenodo.org/record/8078323Test; https://doi.org/10.5281/zenodo.8078323Test; oai:zenodo.org:8078323

الإتاحة: https://doi.org/10.5281/zenodo.8078323Test
https://doi.org/10.5281/zenodo.8078322Test
https://zenodo.org/record/8078323Test

المؤلفون: Ceglia, Nicholas, Sethna, Zachary, Freeman, Samuel S., Uhlitz, Florian, Bojilova, Viktoria, Rusk, Nicole, Burman, Bharat, Chow, Andrew, Salehi, Sohrab, Kabeer, Farhia, Aparicio, Samuel, Greenbaum, Benjamin D., Shah, Sohrab P., McPherson, Andrew

المصدر: Nature Communications ; volume 14, issue 1 ; ISSN 2041-1723

مصطلحات موضوعية: General Physics and Astronomy, General Biochemistry, Genetics and Molecular Biology, General Chemistry, Multidisciplinary

الوصف: Deciphering individual cell phenotypes from cell-specific transcriptional processes requires high dimensional single cell RNA sequencing. However, current dimensionality reduction methods aggregate sparse gene information across cells, without directly measuring the relationships that exist between genes. By performing dimensionality reduction with respect to gene co-expression, low-dimensional features can model these gene-specific relationships and leverage shared signal to overcome sparsity. We describe GeneVector, a scalable framework for dimensionality reduction implemented as a vector space model using mutual information between gene expression. Unlike other methods, including principal component analysis and variational autoencoders, GeneVector uses latent space arithmetic in a lower dimensional gene embedding to identify transcriptional programs and classify cell types. In this work, we show in four single cell RNA-seq datasets that GeneVector was able to capture phenotype-specific pathways, perform batch effect correction, interactively annotate cell types, and identify pathway variation with treatment over time.

الإتاحة: https://doi.org/10.1038/s41467-023-39985-2Test
https://www.nature.com/articles/s41467-023-39985-2.pdfTest
https://www.nature.com/articles/s41467-023-39985-2Test

المؤلفون: Salehi, Sohrab

الوصف: Improving our understanding of intra-tumour heterogeneity in cancer has important clinical implications, including an opportunity to understand mechanisms behind relapses and drug resistance. Next generation bulk sequencing is a mature tech- nology that has been used to study subclonal tumour populations at an aggregate level. Inference of populations from bulk sequencing requires sophisticated com- putational deconvolution methods. An alternative is to identify populations directly with single cell sequencing. However, single cell sequencing is a very error-prone process, and this impedes its ability to completely replace bulk sequencing for now. In this work we present dd-PyClone, a statistical model to combine single cell and bulk sequencing data to study clonal subpopulation architecture and improve clustering assignment and cellular prevalence estimates of a set of genomic loci. We introduce a single nucleotide variant and copy number aberration aware genotype simulation scheme based on a phylogenetic tree, termed the Generalized Dollo model. This model is an improvement over previous genotype generator models in that it also accounts for the evolutionary process before a rare event (here the single nucleotide variant) occurs. We show that incorporating genomic loci co-occurrence patterns from single cell sequencing studies in inferring clonal subpopulation structure from bulk se- quencing data is beneficial. Our method outperforms existing methods in simula- tion studies and performs comparably in real dataset benchmarking. We also show that our method is fairly robust as to the choice of hyperparameters and performs reasonably in presence of noise. We hope that our method will further the under- standing of the evolutionary basis of cancer.
Science, Faculty of
Graduate

الإتاحة: http://hdl.handle.net/2429/56179Test

المؤلفون: Funnell, Tyler, O’Flanagan, Ciara H., Williams, Marc J., McPherson, Andrew, McKinney, Steven, Kabeer, Farhia, Lee, Hakwoo, Salehi, Sohrab, Vázquez-García, Ignacio, Shi, Hongyu, Leventhal, Emily, Masud, Tehmina, Eirew, Peter, Yap, Damian, Zhang, Allen W., Lim, Jamie L.P., Wang, Beixi, Brimhall, Jazmine, Biele, Justina, Ting, Jerome, CRUK IMAXT grand Challenge TEam, Bodenmiller, Bernd

المصدر: Nature, 612 (7938)

الوصف: How cell-to-cell copy number alterations that underpin genomic instability1 in human cancers drive genomic and phenotypic variation, and consequently the evolution of cancer2, remains understudied. Here, by applying scaled single-cell whole-genome sequencing3 to wild-type, TP53-deficient and TP53-deficient;BRCA1-deficient or TP53-deficient;BRCA2-deficient mammary epithelial cells (13,818 genomes), and to primary triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSC) cells (22,057 genomes), we identify three distinct ‘foreground’ mutational patterns that are defined by cell-to-cell structural variation. Cell- and clone-specific high-level amplifications, parallel haplotype-specific copy number alterations and copy number segment length variation (serrate structural variations) had measurable phenotypic and evolutionary consequences. In TNBC and HGSC, clone-specific high-level amplifications in known oncogenes were highly prevalent in tumours bearing fold-back inversions, relative to tumours with homologous recombination deficiency, and were associated with increased clone-to-clone phenotypic variation. Parallel haplotype-specific alterations were also commonly observed, leading to phylogenetic evolutionary diversity and clone-specific mono-allelic expression. Serrate variants were increased in tumours with fold-back inversions and were highly correlated with increased genomic diversity of cellular populations. Together, our findings show that cell-to-cell structural variation contributes to the origins of phenotypic and evolutionary diversity in TNBC and HGSC, and provide insight into the genomic and mutational states of individual cancer cells. ; ISSN:0028-0836 ; ISSN:1476-4687

وصف الملف: application/application/pdf

العلاقة: http://hdl.handle.net/20.500.11850/595502Test

الإتاحة: https://doi.org/20.500.11850/595502Test
https://doi.org/10.3929/ethz-b-000595502Test
https://doi.org/10.1038/s41586-022-05249-0Test
https://hdl.handle.net/20.500.11850/595502Test

المؤلفون: Eirew, Peter, O’Flanagan, Ciara, Ting, Jerome, Salehi, Sohrab, Brimhall, Jazmine, Wang, Beixi, Biele, Justina, Algara, Teresa, Lee, So Ra, Hoang, Corey, Yap, Damian, McKinney, Steven, Bates, Cherie, Kong, Esther, Lai, Daniel, Beatty, Sean, Andronescu, Mirela, Zaikova, Elena, Funnell, Tyler, Ceglia, Nicholas, Chia, Stephen, Gelmon, Karen, Mar, Colin, Shah, Sohrab, Roth, Andrew, Bouchard-Côté, Alexandre, Aparicio, Samuel

المساهمون: Gouvernement du Canada | Instituts de Recherche en Santé du Canada | CIHR Skin Research Training Centre, Provincial Health Services Authority, British Columbia | BC Cancer Agency, Canada Research Chairs, Terry Fox Research Institute, Canadian Cancer Society Research Institute, Breast Cancer Research Foundation

المصدر: Nature Communications ; volume 13, issue 1 ; ISSN 2041-1723

مصطلحات موضوعية: General Physics and Astronomy, General Biochemistry, Genetics and Molecular Biology, General Chemistry, Multidisciplinary

الوصف: Assessing tumour gene fitness in physiologically-relevant model systems is challenging due to biological features of in vivo tumour regeneration, including extreme variations in single cell lineage progeny. Here we develop a reproducible, quantitative approach to pooled genetic perturbation in patient-derived xenografts (PDXs), by encoding single cell output from transplanted CRISPR-transduced cells in combination with a Bayesian hierarchical model. We apply this to 181 PDX transplants from 21 breast cancer patients. We show that uncertainty in fitness estimates depends critically on the number of transplant cell clones and the variability in clone sizes. We use a pathway-directed allelic series to characterize Notch signaling, and quantify TP53 / MDM2 drug-gene conditional fitness in outlier patients. We show that fitness outlier identification can be mirrored by pharmacological perturbation. Overall, we demonstrate that the gene fitness landscape in breast PDXs is dominated by inter-patient differences.

الإتاحة: https://doi.org/10.1038/s41467-022-31830-2Test
https://www.nature.com/articles/s41467-022-31830-2.pdfTest
https://www.nature.com/articles/s41467-022-31830-2Test

المؤلفون: Salehi, Sohrab, Neyshabouri, Seyed Ali Akbar Salehi

الوصف: Estimation of extreme climate trends is a crucial, influential, and also controversial step in long-term water resources planning studies. One of the main approaches to capturing the variability of climate trends is to use a diverse set of General Circulation Models (GCMs). As climate change models refine following deepening climate knowledge, utilizing updated models is unavoidable. The California Central Valley (CCV), a key agricultural zone in the western U.S., derives the bulk of its surface water from the Sacramento and San Joaquin rivers. Moreover, this area serves as a water source for several megacities, including Los Angeles, San Francisco, San Diego, and Sacramento. On average, over 80% of the total Sacramento-San Joaquin Delta outflow comes from the north and eastern upgradient regions (called rim watersheds) surrounding the valley. In this study, the effect of climate change on extreme trends in precipitation and temperature is evaluated for 12 CCV rim watersheds using downscaled CMIP6 data. Downscaled data are derived from NASA Earth Exchange Global Daily Downscaled Projections (NEX-GDDP-CMIP6), which were downscaled using the Bias-Correction Spatial Disaggregation (BCSD) statistical method. Based on the availability of precipitation and temperature data from historical and future time spans, 21 models were selected out of 35 available models. For comparison and consistency with previous studies, 1980–2010 is selected to represent the base period, and 2040–2070 is selected to represent the future period. Average daily temperature and precipitation are calculated for each period under historical and SSP126, SSP245, SSP370, and SSP585 scenarios at each grid point lying inside the rim watershed boundaries. Figure 1 shows the average changes in temperature and precipitation for each GCM and SSP scenario during the historical period. As shown in Figure 1, which is an average across all specified rim watersheds, extreme trends show a maximum of 10.75% decrease to a maximum of 28.25% increase in ...

الإتاحة: https://doi.org/10.22541/essoar.170560733.30005225/v1Test

المؤلفون: Pakmanesh, Hamid¹, Mohammad-Salehi, Sohrab¹, Mirzaei, Mahboubeh¹ mirzaeimahboubeh@yahoo.com, Hashemian, Morteza², Eslami, Nazanin¹, Sharifian, Rayka¹

المصدر: Urology Journal. Jan/Feb2024, Vol. 21 Issue 1, p35-39. 5p.

مصطلحات موضوعية: *KIDNEY pelvis, *KIDNEY stones, *PERCUTANEOUS nephrolithotomy, *COMPUTED tomography, *REGRESSION analysis, *LASER lithotripsy

مستخلص: Purpose: To compare medium-term stone recurrence between laparoscopic pyelolithotomy (LP) and percutaneous nephrolithotomy (PCNL). Material and methods: 98 patients who underwent PCNL or LP (2015-2019) for large single renal pelvis or staghorn stones (≥ 2 cm) were selected. The stone-free rate was evaluated using a computed tomography scan at one month and then, ultrasonography at six months intervals during the first year and annually thereafter for up to three years. Time-to-stone recurrence was compared using the Kaplan-Meier estimate. Hazard ratio was estimated by Cox regression. Results: The one month stone-free rate was 93.88% in the LP group vs. 79% in the PCNL group (P = .03). The mean overall time-to-stone recurrence was 31 (CI:24-34) months in the LP vs. 28 (CI: 23-32) in the PCNL groups (P = .02). Cox regression analysis showed that PCNL increased the risk of stone recurrence with a hazard ratio of 2.3 (CI: 1.1 - 5.3) compared to the laparoscopy. (p = .03) In subgroup analysis, time-to-stone recurrence in those without previous history of intervention was estimated at 31 (CI: 27 to 35) months in the LP vs. 25 (CI:16 to 34) in PCNL groups (= 0.04). Subanalysis with a BMI cutoff of 25 kg/m² showed an overall time-to-stone recurrence of 34 (CI:30 to 37) months in the LP group and 28 (CI:22 to 33) months in the PCNL group (= 0.04) in those with BMI higher than 25 kg/m². Conclusion: Medium-term time to stone recurrence was in favor of LP compared with PCNL for large single renal pelvis or staghorn stones. [ABSTRACT FROM AUTHOR]

المؤلفون: Bodenmiller, Bernd, Salehi, Sohrab, Kabeer, Farhia, Ceglia, Nicholas, Andronescu, Mirela, Williams, Marc J., Campbell, Kieran R., Masud, Tehmina, Wang, Beixi, Biele, Justina, Brimhall, Jazmine, Gee, David, Lee, Hakwoo, Ting, Jerome, Zhang, Allen W., Tran, Hoa, O’Flanagan, Ciara, Dorri, Fatemeh, Rusk, Nicole, de Algara, Teresa T., Lee, So Ra

المصدر: Nature, 595 (7868)

الوصف: Progress in defining genomic fitness landscapes in cancer, especially those defined by copy number alterations (CNAs), has been impeded by lack of time-series single-cell sampling of polyclonal populations and temporal statistical models1-7. Here we generated 42,000 genomes from multi-year time-series single-cell whole-genome sequencing of breast epithelium and primary triple-negative breast cancer (TNBC) patient-derived xenografts (PDXs), revealing the nature of CNA-defined clonal fitness dynamics induced by TP53 mutation and cisplatin chemotherapy. Using a new Wright-Fisher population genetics model8,9 to infer clonal fitness, we found that TP53 mutation alters the fitness landscape, reproducibly distributing fitness over a larger number of clones associated with distinct CNAs. Furthermore, in TNBC PDX models with mutated TP53, inferred fitness coefficients from CNA-based genotypes accurately forecast experimentally enforced clonal competition dynamics. Drug treatment in three long-term serially passaged TNBC PDXs resulted in cisplatin-resistant clones emerging from low-fitness phylogenetic lineages in the untreated setting. Conversely, high-fitness clones from treatment-naive controls were eradicated, signalling an inversion of the fitness landscape. Finally, upon release of drug, selection pressure dynamics were reversed, indicating a fitness cost of treatment resistance. Together, our findings define clonal fitness linked to both CNA and therapeutic resistance in polyclonal tumours. ; ISSN:0028-0836 ; ISSN:1476-4687

وصف الملف: application/application/pdf

العلاقة: info:eu-repo/semantics/altIdentifier/wos/:000664844200003; http://hdl.handle.net/20.500.11850/529176Test

الإتاحة: https://doi.org/20.500.11850/529176Test
https://doi.org/10.3929/ethz-b-000529176Test
https://doi.org/10.1038/s41586-021-03648-3Test
https://hdl.handle.net/20.500.11850/529176Test