22 results on '"Omer H. Yilmaz"'
Search Results
2. PKM2 is not required for colon cancer initiated by APC loss
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Allison N. Lau, William J. Israelsen, Jatin Roper, Mark J. Sinnamon, Larissa Georgeon, Talya L. Dayton, Alissandra L. Hillis, Omer H. Yilmaz, Dolores Di Vizio, Kenneth E. Hung, and Matthew G. Vander Heiden more...
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PKM2 ,APC ,β-catenin ,Colon cancer ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Cancer cells express the M2 isoform of the glycolytic enzyme pyruvate kinase (PKM2). PKM2 expression is not required for some cancers, and PKM2 loss can promote cancer progression; however, PKM2 has been reported to be essential in other tumor contexts, including a proposed non-metabolic role in β-catenin nuclear translocation. PKM2 is expressed in colon cancers where loss of the Apc tumor suppressor results in β-catenin nuclear translocation and aberrant activation of the canonical Wnt signaling pathway. Whether PKM2 is required in this colon cancer context has not been investigated. Results Colon tumorigenesis was induced in mice harboring conditional Apc and Pkm2 alleles, and tumor progression was monitored by serial colonoscopy. PKM2 deletion had no effect on overall survival, the number of mice that developed tumors, or the number of tumors that developed per animal. Immunohistochemical analysis demonstrated PKM2 expression in wild-type tumors and the expected loss of PKM2 expression in tumors from Pkm2 conditional mice. Loss of PKM2 resulted in pyruvate kinase M1 expression but had no effect on nuclear β-catenin staining. These findings are consistent with tumor growth and activated Wnt signaling despite PKM2 loss in this model. We also found a large fraction of human colon cancers had very low or undetectable levels of PKM2 expression. Conclusions PKM2 is not required for Apc-deficient colon cancer or for nuclear translocation of β-catenin in Apc-null tumor cells. These findings suggest that PKM2 expression is not required for colon tumor formation or progression. more...
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- 2017
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Catalog
3. ZFHX4 Interacts with the NuRD Core Member CHD4 and Regulates the Glioblastoma Tumor-Initiating Cell State
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Yakov Chudnovsky, Dohoon Kim, Siyuan Zheng, Warren A. Whyte, Mukesh Bansal, Mark-Anthony Bray, Shuba Gopal, Matthew A. Theisen, Steve Bilodeau, Prathapan Thiru, Julien Muffat, Omer H. Yilmaz, Maya Mitalipova, Kevin Woolard, Jeongwu Lee, Riko Nishimura, Nobuo Sakata, Howard A. Fine, Anne E. Carpenter, Serena J. Silver, Roel G.W. Verhaak, Andrea Califano, Richard A. Young, Keith L. Ligon, Ingo K. Mellinghoff, David E. Root, David M. Sabatini, William C. Hahn, and Milan G. Chheda more...
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Biology (General) ,QH301-705.5 - Abstract
Glioblastoma (GBM) harbors subpopulations of therapy-resistant tumor-initiating cells (TICs) that are self-renewing and multipotent. To understand the regulation of the TIC state, we performed an image-based screen for genes regulating GBM TIC maintenance and identified ZFHX4, a 397 kDa transcription factor. ZFHX4 is required to maintain TIC-associated and normal human neural precursor cell phenotypes in vitro, suggesting that ZFHX4 regulates differentiation, and its suppression increases glioma-free survival in intracranial xenografts. ZFHX4 interacts with CHD4, a core member of the nucleosome remodeling and deacetylase (NuRD) complex. ZFHX4 and CHD4 bind to overlapping sets of genomic loci and control similar gene expression programs. Using expression data derived from GBM patients, we found that ZFHX4 significantly affects CHD4-mediated gene expression perturbations, which defines ZFHX4 as a master regulator of CHD4. These observations define ZFHX4 as a regulatory factor that links the chromatin-remodeling NuRD complex and the GBM TIC state. more...
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- 2014
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4. Supplementary Figure S9 from Agrin in the Muscularis Mucosa Serves as a Biomarker Distinguishing Hyperplastic Polyps from Sessile Serrated Lesions
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Richard O. Hynes, Vikram Deshpande, Omer H. Yilmaz, Katherine Boylan, Lieve G.J. Leijssen, Azfar Neyaz, Gregory Y. Lauwers, Runjan Chetty, Qing Zhao, Lawrence Zukerberg, Anthony R. Mattia, Ian Brown, Deepa T. Patil, Jatin Roper, Christina Pfirschke, Charlie Whittaker, Miyeko Mana, Charlene Condon, and Steffen Rickelt more...
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Study summary.
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- 2023
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5. Supplementary Table S2 from Agrin in the Muscularis Mucosa Serves as a Biomarker Distinguishing Hyperplastic Polyps from Sessile Serrated Lesions
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Richard O. Hynes, Vikram Deshpande, Omer H. Yilmaz, Katherine Boylan, Lieve G.J. Leijssen, Azfar Neyaz, Gregory Y. Lauwers, Runjan Chetty, Qing Zhao, Lawrence Zukerberg, Anthony R. Mattia, Ian Brown, Deepa T. Patil, Jatin Roper, Christina Pfirschke, Charlie Whittaker, Miyeko Mana, Charlene Condon, and Steffen Rickelt more...
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Sample information and results.
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- 2023
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6. Supplementary Documents from Agrin in the Muscularis Mucosa Serves as a Biomarker Distinguishing Hyperplastic Polyps from Sessile Serrated Lesions
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Richard O. Hynes, Vikram Deshpande, Omer H. Yilmaz, Katherine Boylan, Lieve G.J. Leijssen, Azfar Neyaz, Gregory Y. Lauwers, Runjan Chetty, Qing Zhao, Lawrence Zukerberg, Anthony R. Mattia, Ian Brown, Deepa T. Patil, Jatin Roper, Christina Pfirschke, Charlie Whittaker, Miyeko Mana, Charlene Condon, and Steffen Rickelt more...
- Abstract
File contains: Supplementary Materials and Methods, Supplementary Figure Legends and Supplementary References
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- 2023
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7. Supplementary Data from Agrin Loss in Barrett's Esophagus-Related Neoplasia and Its Utility as a Diagnostic and Predictive Biomarker
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Richard O. Hynes, Vikram Deshpande, Deepa T. Patil, Robert D. Odze, Blair A. Jobe, Won-Tak Choi, Elizabeth Y. Wu, Osman Yilmaz, Omer H. Yilmaz, Stuti G. Shroff, Lawrence Zukerberg, Anthony R. Mattia, Genevieve Abbruzzese, Martin S. Taylor, Ali H. Zaidi, Charles A. Whittaker, Charlene Condon, Azfar Neyaz, and Steffen Rickelt more...
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Supplementary Data from Agrin Loss in Barrett's Esophagus-Related Neoplasia and Its Utility as a Diagnostic and Predictive Biomarker
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- 2023
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8. Data from Agrin in the Muscularis Mucosa Serves as a Biomarker Distinguishing Hyperplastic Polyps from Sessile Serrated Lesions
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Richard O. Hynes, Vikram Deshpande, Omer H. Yilmaz, Katherine Boylan, Lieve G.J. Leijssen, Azfar Neyaz, Gregory Y. Lauwers, Runjan Chetty, Qing Zhao, Lawrence Zukerberg, Anthony R. Mattia, Ian Brown, Deepa T. Patil, Jatin Roper, Christina Pfirschke, Charlie Whittaker, Miyeko Mana, Charlene Condon, and Steffen Rickelt more...
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Purpose:Sessile serrated lesions (SSL) are precursors to colon carcinoma, and their distinction from other polyps, in particular hyperplastic polyps (HP), presents significant diagnostic challenges. We evaluated expression patterns in colonic polyps of previously identified colon carcinoma–associated extracellular matrix (ECM) proteins to identify markers distinguishing SSLs from other polyps.Experimental Design:Gene-expression analyses of ECM proteins were performed using publicly available data on preneoplastic colonic polyps. In parallel, we evaluated by IHC the expression of agrin (AGRN) in over 400 colonic polyps, including HP, SSL with and without dysplasia, traditional serrated adenomas (TSA), and tubular adenomas (TA), and compared the consistency of standard histologic diagnosis of SSLs by experienced gastrointestinal pathologists with that of AGRN IHC.Results:Differential gene expression analysis and IHC identified AGRN, serine peptidase inhibitor (SERPINE2), and TIMP metallopeptidase inhibitor 1 (TIMP1) elevated in SSLs and HPs but decreased in TAs and absent in normal colon. AGRN-positive basal laminae were noted in all TA, TSA, HP, and SSL in distinguishable patterns, whereas other polyps and normal mucosa were negative. SSL with or without dysplasia consistently showed IHC staining for AGRN in the muscularis mucosae, which was absent in HP, TSA, TA, and other polyps. In contrast, histologic evaluation showed only weak interobserver agreement (kappa value = 0.493) in distinguishing SSLs.Conclusions:Muscularis mucosae–based AGRN immunostaining is a novel biomarker to distinguish SSL from HP, TSA, and TA, with a specificity of 97.1% and sensitivity of 98.9% and can assist in diagnosis of morphologically challenging colonic polyps. more...
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- 2023
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9. Data from Agrin Loss in Barrett's Esophagus-Related Neoplasia and Its Utility as a Diagnostic and Predictive Biomarker
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Richard O. Hynes, Vikram Deshpande, Deepa T. Patil, Robert D. Odze, Blair A. Jobe, Won-Tak Choi, Elizabeth Y. Wu, Osman Yilmaz, Omer H. Yilmaz, Stuti G. Shroff, Lawrence Zukerberg, Anthony R. Mattia, Genevieve Abbruzzese, Martin S. Taylor, Ali H. Zaidi, Charles A. Whittaker, Charlene Condon, Azfar Neyaz, and Steffen Rickelt more...
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Purpose:There is an unmet need for identifying novel biomarkers in Barrett's esophagus that could stratify patients with regards to neoplastic progression. We investigate the expression patterns of extracellular matrix (ECM) molecules in Barrett's esophagus and Barrett's esophagus–related neoplasia, and assess their value as biomarkers for the diagnosis of Barrett's esophagus–related neoplasia and to predict neoplastic progression.Experimental Design:Gene-expression analyses of ECM matrisome gene sets were performed using publicly available data on human Barrett's esophagus, Barrett's esophagus–related dysplasia, esophageal adenocarcinoma (ADCA) and normal esophagus. Immunohistochemical expression of basement membrane (BM) marker agrin (AGRN) and p53 was analyzed in biopsies of Barrett's esophagus–related neoplasia from 321 patients in three independent cohorts.Results:Differential gene-expression analysis revealed significant enrichment of ECM matrisome gene sets in dysplastic Barrett's esophagus and ADCA compared with controls. Loss of BM AGRN expression was observed in both Barrett's esophagus–related dysplasia and ADCA. The mean AGRN loss in Barrett's esophagus glands was significantly higher in Barrett's esophagus–related dysplasia and ADCA compared with non-dysplastic Barrett's esophagus (NDBE; P < 0.001; specificity = 82.2% and sensitivity = 96.4%). Loss of AGRN was significantly higher in NDBE samples from progressors compared with non-progressors (P < 0.001) and identified patients who progressed to advanced neoplasia with a specificity of 80.2% and sensitivity of 54.8%. Moreover, the combination of AGRN loss and abnormal p53 staining identified progression to Barrett's esophagus–related advanced neoplasia with a specificity and sensitivity of 86.5% and 58.7%.Conclusions:We highlight ECM changes during Barrett's esophagus progression to neoplasia. BM AGRN loss is a novel diagnostic biomarker that can identify patients with NDBE at increased risk of developing advanced neoplasia. more...
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- 2023
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10. Clinical, pathological genetics and intratumoral immune milieu of serrated adenocarcinoma of the colon
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Osman Yılmaz, Andrew Crabbe, Azfar Neyaz, Amaya Pankaj, Soo Hyun Lee, Sahar Hosseini, Steffen Rickelt, Sandra Cerda, Qing Zhao, Lieve Leijsen, Anne Dineaux, Stuti G Shroff, Rory Crotty, M Lisa Zhang, Omer H Yilmaz, Deepa T Patil, David Berger, and Vikram Deshpande more...
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Adenoma ,Proto-Oncogene Proteins B-raf ,Histology ,Carcinoma ,Colonic Polyps ,Forkhead Transcription Factors ,General Medicine ,Adenocarcinoma ,B7-H1 Antigen ,Pathology and Forensic Medicine ,Colonic Neoplasms ,Biomarkers, Tumor ,Tumor Microenvironment ,Humans ,Colorectal Neoplasms - Abstract
Serrated adenocarcinoma (SAC), a recognised WHO variant of colonic adenocarcinoma, is the purported end-product of serrated neoplasia. However, the diagnosis of SAC is infrequently rendered, and little is known about its prognosis, immune microenvironment and molecular alterations.We assessed 903 consecutive colon carcinomas and recognised tumours with ≥ 5% (n = 77) serrated and ≥ 50% serrated patterns (n = 13). We assessed precursor polyps and synchronous polyps. We recorded demographic/clinical parameters, histological features and mismatch repair (MMR) status. We performed immunohistochemistry and quantification on tissue microarray for HLA class I/II proteins, B2MG, CD8, CD163, LAG3, FoxP3, PD-L1 and BRAF V600E.We identified ≥ 5% epithelial serration prevalence in 8.5% of cases and ≥ 50% epithelial serration prevalence in 1.4% of cases. Precursor lesions were present in 21.4% of cases; these were mostly tubular adenomas with two traditional serrated adenomas identified. SAC with ≥ 5% serrations exhibited lower numbers of CD8-positive lymphocytes (P = 0.002) and lower B2MG expression (P = 0.048), although neither value was significant at ≥ 50% serration threshold. There was no difference in HLA class I/II, or PD-L1 expression on tumour cells and no difference in PD-L1, LAG3, FoxP3 and CD163 expression on immune cells. There was no association with MMR status, or BRAFV600E relative to conventional adenocarcinoma. There was improved disease-specific survival on univariate (but not multivariate) analysis between carcinomas with serrated pattern and non-mucinous conventional colonic carcinomas at ≥ 5% epithelial serrations (P = 0.04).SAC category shows a limited impact on survival, and this phenotype may harbour a unique immunological milieu. more...
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- 2022
11. Quantitative p53 immunostaining aids in the detection of prevalent dysplasia
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Azfar Neyaz, Steffen Rickelt, Omer H Yilmaz, Paige H Parrack, Chenyue Lu, Osman Yilmaz, Elizabeth Y Wu, Won-Tak Choi, Manish Gala, David T Ting, Robert D Odze, Deepa T Patil, and Vikram Deshpande
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General Medicine ,Pathology and Forensic Medicine - Abstract
AimsThe lack of accepted scoring criteria has precluded the use of p53 in routine practice. We evaluate the utility of automated quantitative p53 analysis in risk stratifying Barrett’s oesophagus (BE) patients using non-dysplastic BE (NDBE) biopsies in a multicentric cohort of BE progressor (P) and non-progressor (NP) patients.MethodsNDBE biopsies prior to the diagnosis of advanced neoplasia from 75 BE-P, and index and last surveillance biopsies from 148 BE-NP were stained for p53, and scored digitally as 1+, 2+ and 3+. A secondary cohort of 30 BE-P was evaluated.ResultsCompared with BE-NP, BE-P was predominantly men (p=0.001), ≥55 years of age (p=0.008), with longer BE segments (71% vs 33%; pConclusionsAutomated p53 analysis in NDBE biopsies serves as a promising tool for assessing BE neoplastic progression and risk stratification. Our study highlights the practical applicability of p53 assay to routine surveillance practice and its ability to detect prevalent dysplasia. more...
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- 2023
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12. Correlation of clinical, pathologic, and genetic parameters with intratumoral immune milieu in mucinous adenocarcinoma of the colon
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Azfar Neyaz, Amaya Pankaj, Andrew Crabbe, Steffen Rickelt, Lieve Leijssen, Anne Dinaux, Martin Taylor, Stuti G. Shroff, Rory Crotty, M. Lisa Zhang, Omer H. Yilmaz, Osman Yılmaz, Deepa T. Patil, Aparna R. Parikh, David T. Ting, David Berger, and Vikram Deshpande more...
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Proto-Oncogene Proteins B-raf ,Mucins ,Forkhead Transcription Factors ,DNA Mismatch Repair ,Adenocarcinoma, Mucinous ,B7-H1 Antigen ,Pathology and Forensic Medicine ,MutS Homolog 2 Protein ,Colonic Neoplasms ,Biomarkers, Tumor ,Humans ,Colorectal Neoplasms ,Biomarkers ,Mismatch Repair Endonuclease PMS2 - Abstract
Mucinous adenocarcinoma (MAD), the most common subtype of colonic adenocarcinoma (CA), requires50% intratumoral mucin. There is limited data regarding the impact of MAD on key lymphocyte subsets and therapeutically critical immune elements. In this study we address: (1) the definition of MAD, (2) grading of MAD, and (3) the impact of MAD and extracellular mucin on intratumoral immune milieu. Estimation of the percentage of intratumoral mucin was performed by two pathologists. Tissue microarrays were stained for immune markers including CD8, CD163, PD-L1, FoxP3, β2 microglobulin, HLA class I, and HLA class II. Immunohistochemistry for BRAF V600E was performed. MMR status was determined on immunohistochemistry for MSH2, MSH6, MLH1, PMS2. Manual and automated HALO platforms were used for quantification. The 903 CAs included 62 (6.9%) MAD and 841 CA with ≤ 50% mucin. We identified 225 CAs with mucinous differentiation, defined by ≥10% mucin. On univariate analysis neither cut point, 50% (p = 0.08) and 10% (p = 0.08) mucin, correlated with disease-specific survival (DSS). There were no differences in key clinical, histological and molecular features between MAD and CA with mucinous differentiation. On univariate analysis of patients with MAD, tumor grade correlated with DSS (p = 0.0001) while MMR status did not (p = 0.86). There was no statistically significant difference in CD8 (P = 0.17) and CD163 (P = 0.05) positive immune cells between MAD and conventional CA. However, deficient (d) MMR MADs showed fewer CD8 (P = 0.0001), CD163 (P = 0.0001) and PD-L1 (P = 0.003) positive immune cells compared to proficient (p)MMR MADs, a finding also seen with at 10% mucin cut point. Although MAD does not impact DSS, this study raises the possibility that the immune milieu of dMMR MADs and tumors with =10% mucin may differ from pMMR MADs and tumors with10% mucin, a finding that may impact immune-oncology based therapeutics. more...
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- 2021
13. Abstract 3447: T cell antigen expression levels govern progression and therapy response in a novel model of colon cancer
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Mary Clare Beytagh, William L. Hwang, Olivia Smith, Peter M. K. Westcott, Omer H Yilmaz, Tyler Jacks, Nathan J. Sacks, Jatin Roper, Jason M. Schenkel, Zackery A. Ely, George Eng, and Daniel Zhang
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Cancer Research ,Therapy response ,Oncology ,Colorectal cancer ,business.industry ,medicine ,Cancer research ,T-cell Antigen ,medicine.disease ,business - Abstract
Genetically-engineered mouse models have greatly advanced our understanding of cancer, yet do not recapitulate the mutational complexity of human cancer, and likely lack neo-antigens capable of eliciting potent anti-tumor T cell responses. We developed a novel orthotopic organoid transplant model of colorectal cancer (CRC) harboring the strong T cell antigen SIINFEKL, and demonstrate the importance of antigen expression level in the anti-tumor T cell response. Although SIINFEKL low-expressing organoids (SIINLow) elicit an endogenous antigen-specific T cell response, the magnitude is substantially lower and kinetics delayed relative to SIINFEKL high-expressing organoids (SIINHi). Consistently, transplant of SIINHi results in rejection and T cell memory, while SIINLow results in tumor progression, terminally-exhausted T cells, and metastasis to the liver. We have shown that suboptimal T cell priming is the major factor underlying SIINLow tumor escape. Importantly, co-transplant of SIINHi and SIINLow organoids at distinct sites in the colon of the same animal results in complete rejection of both lines. In addition, co-transplant rescues the SIINLow tumor-infiltrating antigen-specific T cell response to a magnitude and quality comparable to that of SIINHi tumors. Single-cell RNA-sequencing of antigen-specific T cells from SIINHi and SIINLow tumors 8 days post-transplant revealed distinct clusters dominated by SIINLow-primed T cells, including a cluster enriched for immediate early response genes, Tox, and a number of immune checkpoints, indicative of early dysfunction. Collectively, our results establish the existence of a neo-antigen expression threshold at which T cell priming is limiting, resulting in attenuated magnitude and functionality of the T cell response, and tumor escape. To assess the therapeutic relevance of a poorly-expressed neo-antigen in CRC, we performed preclinical trials with immune checkpoint blockade and agonistic-CD40 (aCD40), which has been shown to potentiate T cell priming and response in poorly-immunogenic mouse and human pancreatic adenocarcinoma. While monotherapies showed only modest effects, the combination of checkpoint blockade and aCD40 resulted in an 80% response rate with a number of complete responses. In conclusion, antigen expression level is a critical determinant of T cell dysfunction, resulting from poor priming. Our results argue that targeting T cell priming may be a promising therapeutic strategy to invigorate anti-tumor immunity in human CRC, the majority of which remains refractory to immunotherapy. Citation Format: Peter Maxwell Kienitz Westcott, Nathan J. Sacks, Olivia Smith, Jason Schenkel, Zackery Ely, Daniel Zhang, Mary Clare Beytagh, William Hwang, George Eng, Jatin Roper, Omer Yilmaz, Tyler Jacks. T cell antigen expression levels govern progression and therapy response in a novel model of colon cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3447. more...
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- 2020
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14. Ablative radiotherapy improves survival but does not cure autochthonous mouse models of prostate and colorectal cancer
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Daniel R. Schmidt, Iva Monique T. Gramatikov, Allison Sheen, Christopher L. Williams, Martina Hurwitz, Laura E. Dodge, Edward Holupka, W. S. Kiger, Milton R. Cornwall-Brady, Wei Huang, Howard H. Mak, Kathleen S Cormier, Charlene Condon, K. Dane Wittrup, Ömer H. Yilmaz, Mary Ann Stevenson, Julian D. Down, Scott R. Floyd, Jatin Roper, and Matthew G. Vander Heiden more...
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Medicine - Abstract
Abstract Background Genetically engineered mouse models (GEMMs) of cancer are powerful tools to study mechanisms of disease progression and therapy response, yet little is known about how these models respond to multimodality therapy used in patients. Radiation therapy (RT) is frequently used to treat localized cancers with curative intent, delay progression of oligometastases, and palliate symptoms of metastatic disease. Methods Here we report the development, testing, and validation of a platform to immobilize and target tumors in mice with stereotactic ablative RT (SART). Xenograft and autochthonous tumor models were treated with hypofractionated ablative doses of radiotherapy. Results We demonstrate that hypofractionated regimens used in clinical practice can be effectively delivered in mouse models. SART alters tumor stroma and the immune environment, improves survival in GEMMs of primary prostate and colorectal cancer, and synergizes with androgen deprivation in prostate cancer. Complete pathologic responses were achieved in xenograft models, but not in GEMMs. Conclusions While SART is capable of fully ablating xenografts, it is unable to completely eradicate disease in GEMMs, arguing that resistance to potentially curative therapy can be modeled in GEMMs. more...
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- 2023
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15. Defining the Intestinal Stem Cell Niche for Tissue Engineering and Disease Modeling
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Ken S. Lau, Sun Wook Kim, Omer H. Yilmaz, Alina Starchenko, and Amrita Banerjee
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Ecological niche ,Extracellular matrix ,Cell signaling ,Tissue engineering ,Niche ,Biology ,Stem cell ,Regenerative medicine ,Adult stem cell ,Cell biology - Abstract
The small and large intestines are two of the fastest renewing epithelia in the body. The rapid turnover of intestinal epithelial cells requires continuous generation of new, functional cells fueled by stem cells that must balance between self-renewal and differentiation. The environment where stem cells reside, called the niche, provides key signals to dictate stem cell behavior. Because of its constant activity and well-defined cryptal structure, the intestinal stem cell niche is one of the most studied adult stem cell niches in the body. We will review current knowledge regarding the components that comprise the intestinal stem cell niche, including signaling molecules, nurse cells, extracellular matrix, and metabolites. We will discuss how to leverage current knowledge of the stem cell niche to develop a physiologically relevant intestinal model for tissue engineering and regenerative medicine. more...
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- 2018
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16. Comprehensive Electrocardiographic Analysis of Lead Exposed Workers: An Arrhythmic Risk Assessment Study
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Ugur N. Karakulak, Emine Ercan Onay, Engin Tutkun, Meşide Gündüzöz, and Omer H. Yilmaz
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Adult ,Male ,medicine.medical_specialty ,Urine ,030204 cardiovascular system & hematology ,010501 environmental sciences ,01 natural sciences ,QT interval ,Risk Assessment ,03 medical and health sciences ,Surface ecg ,Electrocardiography ,0302 clinical medicine ,Cardiac Conduction System Disease ,Heart Conduction System ,Physiology (medical) ,Internal medicine ,Occupational Exposure ,medicine ,Humans ,Lead (electronics) ,Letters to the Editor ,0105 earth and related environmental sciences ,Brugada Syndrome ,P wave dispersion ,Arrhythmic risk ,business.industry ,Corrected qt ,Arrhythmias, Cardiac ,Original Articles ,General Medicine ,Lead Poisoning ,Cross-Sectional Studies ,Cardiology ,Female ,Cardiology and Cardiovascular Medicine ,business ,Cardiovascular outcomes - Abstract
Background To evaluate electrocardiographic parameters which are related with atrial and ventricular arrhythmias measured from 12-lead surface electrocardiogram (ECG) in workers occupationally exposed to lead. Methods Sixty lead-exposed workers and 60 healthy controls were enrolled. Twelve-lead surface ECG was recorded and measurements of P wave durations (Pmax, Pmin) and P wave dispersion (PWD), QT durations and dispersion (QTd), corrected QT (QTc), Tp-e interval, and Tp-e/QT ratio were analyzed. Results The lead-exposed and control groups were similar with respect to baseline demographic, laboratory, and transthoracic echocardiographic indices. PWD (26.3 ± 9.7 vs 22.0 ± 9.0 ms, P = 0.014), Pmin (89.9 ± 13.8 vs 79.2 ± 10.1 ms, P < 0.001), and Pmax (116.2 ± 15.0 vs 101.2 ± 14.2 ms, P < 0.001), QT maximum (377.0 ± 27.6 vs 364.9 ± 28.5 ms, P = 0.02), QTd (38.4 ± 16.5 vs 30.5 ± 12.4 ms, P = 0.004), Tp-e interval (78.9 ± 16.5 vs 70.3 ± 14.5 ms, P = 0.003), and Tp-e/QT ratio (0.22 ± 0.04 vs 0.20 ± 0.04, P = 0.013) were significantly higher in lead-exposed workers. QT minimum and QTc values did not differ significantly. QT maximum, QTd, and Tp-e/QT ratio were correlated with urine lead level and Tp-e interval was correlated with both blood and urine lead levels. Conclusions Lead-exposed workers have a higher risk for atrial and ventricular arrhythmias even without overt cardiac diseases compared with healthy subjects. These workers should be followed closely for adverse cardiovascular outcomes especially arrhythmias. more...
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- 2016
17. Live cell tagging tracking and isolation for spatial transcriptomics using photoactivatable cell dyes
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Alex S Genshaft, Carly G. K. Ziegler, Constantine N. Tzouanas, Benjamin E. Mead, Alex M. Jaeger, Andrew W. Navia, Ryan P. King, Miyeko D. Mana, Siyi Huang, Vanessa Mitsialis, Scott B. Snapper, Ömer H. Yilmaz, Tyler Jacks, Jeffrey F. Van Humbeck, and Alex K. Shalek more...
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Science - Abstract
Spatial transcriptomics aims to pair omic data with tissue structure. Here the authors report Spatially PhotoActivatable Colour Encoded Cell Address Tags (SPACECAT) to track and isolate live cells by location; this enables spatially informed downstream assays like scRNA-seq and flow cytometry. more...
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- 2021
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18. Enhancing chemotherapy response through augmented synthetic lethality by co-targeting nucleotide excision repair and cell-cycle checkpoints
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Yi Wen Kong, Erik C. Dreaden, Sandra Morandell, Wen Zhou, Sanjeev S. Dhara, Ganapathy Sriram, Fred C. Lam, Jesse C. Patterson, Mohiuddin Quadir, Anh Dinh, Kevin E. Shopsowitz, Shohreh Varmeh, Ömer H. Yilmaz, Stephen J. Lippard, H. Christian Reinhardt, Michael T. Hemann, Paula T. Hammond, and Michael B. Yaffe more...
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Science - Abstract
Cell cycle checkpoint kinase, MK2, is in synthetic relationship with p53 in the DNA damage response to chemotherapeutic agents. Here, the authors report XPA as a third gene in which simultaneous targeting of MK2 and XPA further enhances sensitivity to cisplatin in p53-deficient tumours. more...
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- 2020
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19. Region-Specific Proteome Changes of the Intestinal Epithelium during Aging and Dietary Restriction
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Nadja Gebert, Chia-Wei Cheng, Joanna M. Kirkpatrick, Domenico Di Fraia, Jina Yun, Patrick Schädel, Simona Pace, George B. Garside, Oliver Werz, K. Lenhard Rudolph, Henri Jasper, Ömer H. Yilmaz, and Alessandro Ori more...
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Biology (General) ,QH301-705.5 - Abstract
Summary: The small intestine is responsible for nutrient absorption and one of the most important interfaces between the environment and the body. During aging, changes of the epithelium lead to food malabsorption and reduced barrier function, thus increasing disease risk. The drivers of these alterations remain poorly understood. Here, we compare the proteomes of intestinal crypts from mice across different anatomical regions and ages. We find that aging alters epithelial immunity, metabolism, and cell proliferation and is accompanied by region-dependent skewing in the cellular composition of the epithelium. Of note, short-term dietary restriction followed by refeeding partially restores the epithelium by promoting stem cell differentiation toward the secretory lineage. We identify Hmgcs2 (3-hydroxy-3-methylglutaryl-coenzyme A [CoA] synthetase 2), the rate-limiting enzyme for ketogenesis, as a modulator of stem cell differentiation that responds to dietary changes, and we provide an atlas of region- and age-dependent proteome changes of the small intestine. : Using proteomics, Gebert et al. find that aging has region-specific effects on the small intestine epithelium of mice. These effects can be partially reversed by modulating ketone body signaling in intestinal stem cells via dietary interventions. Keywords: proteomics, aging, intestine, stem cells, ketone bodies, dietary restriction, hmgcs2 more...
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- 2020
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20. Publisher Correction: Live cell tagging tracking and isolation for spatial transcriptomics using photoactivatable cell dyes
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Alex S. Genshaft, Carly G. K. Ziegler, Constantine N. Tzouanas, Benjamin E. Mead, Alex M. Jaeger, Andrew W. Navia, Ryan P. King, Miyeko D. Mana, Siyi Huang, Vanessa Mitsialis, Scott B. Snapper, Ömer H. Yilmaz, Tyler Jacks, Jeffrey F. Van Humbeck, and Alex K. Shalek more...
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Science - Published
- 2021
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21. A novel histological index for evaluation of environmental enteric dysfunction identifies geographic-specific features of enteropathy among children with suboptimal growth.
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Ta-Chiang Liu, Kelley VanBuskirk, Syed A Ali, M Paul Kelly, Lori R Holtz, Omer H Yilmaz, Kamran Sadiq, Najeeha Iqbal, Beatrice Amadi, Sana Syed, Tahmeed Ahmed, Sean Moore, I Malick Ndao, Michael H Isaacs, John D Pfeifer, Hannah Atlas, Phillip I Tarr, Donna M Denno, and Christopher A Moskaluk more...
- Subjects
Arctic medicine. Tropical medicine ,RC955-962 ,Public aspects of medicine ,RA1-1270 - Abstract
BackgroundA major limitation to understanding the etiopathogenesis of environmental enteric dysfunction (EED) is the lack of a comprehensive, reproducible histologic framework for characterizing the small bowel lesions. We hypothesized that the development of such a system will identify unique histology features for EED, and that some features might correlate with clinical severity.MethodsDuodenal endoscopic biopsies from two cohorts where EED is prevalent (Pakistan, Zambia) and North American children with and without gluten sensitive enteropathy (GSE) were processed for routine hematoxylin & eosin (H&E) staining, and scanned to produce whole slide images (WSIs) which we shared among study pathologists via a secure web browser-based platform. A semi-quantitative scoring index composed of 11 parameters encompassing tissue injury and response patterns commonly observed in routine clinical practice was constructed by three gastrointestinal pathologists, with input from EED experts. The pathologists then read the WSIs using the EED histology index, and inter-observer reliability was assessed. The histology index was further used to identify within- and between-child variations as well as features common across and unique to each cohort, and those that correlated with host phenotype.ResultsEight of the 11 histologic scoring parameters showed useful degrees of variation. The overall concordance across all parameters was 96% weighted agreement, kappa 0.70, and Gwet's AC 0.93. Zambian and Pakistani tissues shared some histologic features with GSE, but most features were distinct, particularly abundance of intraepithelial lymphocytes in the Pakistani cohort, and marked villous destruction and loss of secretory cell lineages in the Zambian cohort.ConclusionsWe propose the first EED histology index for interpreting duodenal biopsies. This index should be useful in future clinical and translational studies of this widespread, poorly understood, and highly consequential disorder, which might be caused by multiple contributing processes, in different regions of the world. more...
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- 2020
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22. Intestinal colonization by Candida albicans alters inflammatory responses in Bruton's tyrosine kinase-deficient mice.
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Karin Strijbis, Omer H Yilmaz, Stephanie K Dougan, Alexandre Esteban, Andrea Gröne, Carol A Kumamoto, and Hidde L Ploegh
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Medicine ,Science - Abstract
The commensal yeast Candida albicans is part of the human intestinal microflora and is considered a "pathobiont", a resident microbe with pathogenic potential yet harmless under normal conditions. The aim of this study was to investigate the effect of C. albicans on inflammation of the intestinal tract and the role of Bruton's tyrosine kinase (Btk). Btk is an enzyme that modulates downstream signaling of multiple receptors involved in innate and adaptive immunity, including the major anti-fungal receptor Dectin-1. Colitis was induced in wild type and Btk-/- mice by treatment with dextran sodium sulfate (DSS) and the gastrointestinal tract of selected treatment groups were then colonized with C. albicans. Colonization by C. albicans neither dampened nor exacerbated inflammation in wild type mice, but colon length and spleen weight were improved in Btk-deficient mice colonized with C. albicans. Neutrophil infiltration was comparable between wild type and Btk-/- mice, but the knockout mice displayed severely reduced numbers of macrophages in the colon during both DSS and DSS/Candida treatment. Smaller numbers and reduced responsiveness of Btk-/- macrophages might partially explain the improved colon length of Btk-/- mice as a result of Candida colonization. Surprisingly, DSS/Candida-treated Btk-/- animals had higher levels of certain pro-inflammatory cytokines and levels of the anti-inflammatory cytokine TGF-β were reduced compared to wild type. A clustering and correlation analysis showed that for wild type animals, spleen TGF-β and colon IL-10 and for Btk-/- spleen and colon levels of IL-17A best correlated with the inflammatory parameters. We conclude that in Btk-/- immunocompromised animals, colonization of the gastrointestinal tract by the commensal yeast C. albicans alters inflammatory symptoms associated with colitis. more...
- Published
- 2014
- Full Text
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