tbuckley/cabot-search huggingface dataset:
Abstract 835: T-cell abundance, clonality and disease specific survival in colorectal cancer
Authors: Joseph Bonner, Sephanie L. Schmit, Sidney S. Lindsey, Ya-Yu Tsai, Rebeca Sanz-Pamplona, M. Henar Alonso, Marilena Melas, Hedy S. Rennert, Kevin J. McDonnell, Gregory Idos, Christopher P. Walker, W. Martin Kast, Diane Da Silva, Harlan S. Robins, Joel K. Greenson, Victor Moreno, Gad Rennert, Stephen B. Gruber
Journal: Cancer Research (2021)

Abstract Immune responses to colorectal cancer (CRC) are important prognostic factors as measured by either tumor infiltrating lymphocytes per high powered field or the presence of Crohn's like lymphoid reaction. New technologies to quantify specific features of immune responses include immunoSeq (Adaptive Biotechnologies), which accurately quantifies T-cell receptor (TCR) abundance and T-cell receptor clonality. Here we measured the independent contributions of TCR abundance and TCR clonality to 5-year CRC-specific survival in the Molecular Epidemiology of Colorectal Cancer (MECC) study. The MECC study consented, interviewed, and followed 6,006 incident cases of CRC diagnosed between March 31, 1998 and July 1, 2017 (median follow-up time = 6.9 years). Archived paraffin blocks were retrieved, and 2,750 cases had sufficient tissue and adequate DNA extraction to perform the immunoSeq assay. Analyses were restricted to 1,625 samples with more than 100 T-cells to permit accurate quantification of TCR abundance and TCR clonality as measured by Simpson Clonality Index. TCR abundance was log2 transformed for analyses, and Simpson Clonality Index was log2-transformed and z-scale normalized separately by assay version. In unadjusted models, dichotomized log2 transformed TCR abundance (Hazard Ratio (HR) = 0.57, 95% confidence interval (CI) 0.47-0.71, p=9.77E-08) and dichotomized TCR clonality (HR = 0.77, 95% CI 0.63-0.94, p=0.01) were each statistically significantly associated with 5-year CRC-specific survival. In a model with adjustment for age, sex, microsatellite instability, stage and assay version, both dichotomized log2 transformed TCR abundance (HR = 0.61, 95% CI, 0.49-0.75, p=3.03E-06), and dichotomized TCR clonality (HR = 0.81, 95% CI, 0.66-0.99, p=0.048) were associated with improved 5-year disease-specific survival. Conclusion: TCR abundance and TCR clonality are independent prognostic indicators in CRC. Citation Format: Joseph Bonner, Sephanie L. Schmit, Sidney S. Lindsey, Ya-Yu Tsai, Rebeca Sanz-Pamplona, M. Henar Alonso, Marilena Melas, Hedy S. Rennert, Kevin J. McDonnell, Gregory Idos, Christopher P. Walker, W. Martin Kast, Diane Da Silva, Harlan S. Robins, Joel K. Greenson, Victor Moreno, Gad Rennert, Stephen B. Gruber. T-cell abundance, clonality and disease specific survival in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 835.
Mast cells in the urinary bladders of interstitial cystitis/bladder pain syndrome patients express the Mast cell Related G-Protein coupled Receptor X2 (MRGPRX2): Potential role in the pathogenesis of neurogenic inflammation
Authors: O.K. Abdelwahab, H. Markham, M Yusuh, K. Garba, K. Bodey, M.A.M. Lopez, L. Lau, D. Johnston, A. Walls, B. Birch, B. Lwaleed
Journal: European Urology (2021)
Risk of genitourinary malignancies in Lynch syndrome patients with DNA mismatch repair gene mutations in a large Canadian Familial Registry
Authors: K. Rebullar, O. Hemminki, S. Skeldon, K. Semotiuk, M. Aronson, C. Kuk, K. Lajkosz, S. Gallinger, Z. Cohen, A.R. Zlotta
Journal: European Urology (2021)
Predicting complications after robotic partial nephrectomy: Back to simplicity
Authors: Z-E. Khene, C. Mazouin, A. Larcher, B. Peyronnet, A. Gasmi, M. Roumiguié, G. Verhoest, U. Capitanio, R. Mathieu, N. Doumerc, F. Montorsi, K. Bensalah
Journal: European Urology (2021)
Immunomodulatory therapy, risk factors and outcomes of hospital-acquired bloodstream infection in patients with severe COVID-19 pneumonia: a Spanish case–control matched multicentre study (BACTCOVID)
Authors: Gabriela Abelenda-Alonso, Alexander Rombauts, Carlota Gudiol, Isabel Oriol, Antonella Simonetti, Ana Coloma, Alejandro Rodríguez-Molinero, Elisenda Izquierdo, Vicens Díaz-Brito, Montserrat Sanmartí, Ariadna Padullés, Inmaculada Grau, Mar Ras, Alba Bergas, Lluïsa Guillem, Alejandro Blanco-Arévalo, Claudia Alvarez-Pouso, Natalia Pallarés, Sebastián Videla, Cristian Tebé, Jordi Carratalà
Journal: Clinical Microbiology and Infection (2021)

ObjectivesThe effect of the use of immunomodulatory drugs on the risk of developing hospital-acquired bloodstream infection (BSI) in patients with COVID-19 has not been specifically assessed. We aim to identify risk factors for, and outcomes of, BSI among hospitalized patients with severe COVID-19 pneumonia.MethodsWe performed a severity matched case–control study (1:1 ratio) nested in a large multicentre prospective cohort of hospitalized adults with COVID-19. Cases with BSI were identified from the cohort database. Controls were matched for age, sex and acute respiratory distress syndrome. A Cox proportional hazard ratio model was performed.ResultsOf 2005 patients, 100 (4.98%) presented 142 episodes of BSI, mainly caused by coagulase-negative staphylococci, Enterococcus faecalis and Pseudomonas aeruginosa. Polymicrobial infection accounted for 23 episodes. The median time from admission to the first episode of BSI was 15 days (IQR 9–20), and the most frequent source was catheter-related infection. The characteristics of patients with and without BSI were similar, including the use of tocilizumab, corticosteroids, and combinations. In the multivariate analysis, the use of these immunomodulatory drugs was not associated with an increased risk of BSI. A Cox proportional hazard ratio (HR) model showed that after adjusting for the time factor, BSI was associated with a higher in-hospital mortality risk (HR 2.59; 1.65–4.07; p < 0.001).DiscussionHospital-acquired BSI in patients with severe COVID-19 pneumonia was uncommon and the use of immunomodulatory drugs was not associated with its development. When adjusting for the time factor, BSI was associated with a higher mortality risk.
Abstract 2380: MiR29b may suppress peritoneal metastasis via the effects on peritoneal mesothelial cells
Authors: Yuki Kimura, Hideyuki Ohzawa, Yuki Kaneko, Yurie Futoh, Kohei Tamura, Kazuya Takahashi, Akira Saito, Mineyuki Tojo, Yuko Kumagai, Hideyo Miyato, Naohiro Sata, Joji Kitayama
Journal: Cancer Research (2021)

Abstract Background: Mesothelial cells play tumor-promoting roles in the development of peritoneal metastasis (PM) through mesothelial-mesenchymal transition (MMT). MiR-29 family is well known as tumor suppressor. Methods: MiR-29b mimics and negative control miRNA were transfected by lipofection method. Proliferation and migration of human gastric cancer cell lines, MKN45 and NUGC-4, were examined with MTT assay and transwell assay, respectively. MMT of human peritoneal mesothelial cells (HPMCs) was induced 10 ng/ml of TGF-β. Proliferation and migration of HPMCs were examined with the same methods, and MMT was evaluated with immunofluorescence staining for epithelial, mesothelial and mesenchymal markers. To evaluate the effect of miR-29b in vivo, we developed a highly metastatic subclone YTN16P2 from a murine gastric cancer cell line, YTN16, with in vivo selection, and inoculated the YTN16P2 in peritoneal cavity of syngenic C57BL/6 mice. MiR-29b mimics or negative control miRNA with atelocollagen were intraperitoneally (ip) injected every 3 days from tumor implantation. The mice were sacrificed at 14 days after tumor implantation, and formation of peritoneal metastasis were evaluated. Results: Transfection of miR-29b mimics significantly decreased the proliferation of MKN45 and NUGC-4 by 20-60% (p&amp;lt;0.01) as compared with negative control miRNA. Migration was inhibited more strongly by 90% (p&amp;lt;0.001). After 48 hr-culture with TGF-β, HPMCs apparently changed the morphology from round to spindle shape. The expression level of E-cadherin and Calretinin in HPMCs was decreased while vimentin tended to be upregulated by TGF-β. However, transfection of miR-29b mimics significantly suppressed the morphological changes and reduced the expression levels of vimentin with restored expression of E-cadherin and Calretinin, suggesting the inhibition of MMT in HPMCs. MiR-29b also decreased the proliferation and migration of HPMCs by 20% (p&amp;lt;0.05) and 90% (p&amp;lt;0.001) as compared with negative control miRNA. Finally, mice treated with miR-29b developed less PM nodules than those treaded with negative control miRNA and only atelocollagen. Conclusion: MiR-29b efficiently suppresses MMT. Replacement of the miR-29b in peritoneal cavity might be used for the treatment of PM partially via the effects on mesothelial cell. Citation Format: Yuki Kimura, Hideyuki Ohzawa, Yuki Kaneko, Yurie Futoh, Kohei Tamura, Kazuya Takahashi, Akira Saito, Mineyuki Tojo, Yuko Kumagai, Hideyo Miyato, Naohiro Sata, Joji Kitayama. MiR29b may suppress peritoneal metastasis via the effects on peritoneal mesothelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2380.
Novel anti-4-1BB×PD-L1 bispecific antibody augments anti-tumor immunity through tumor-directed T-cell activation and checkpoint blockade
Authors: Seongju Jeong, Eunyoung Park, Hyung-Don Kim, Eunsil Sung, Hyunjoo Kim, Jaehyoung Jeon, Youngkwang Kim, Ui-jung Jung, Yong-Gyu Son, Youngeun Hong, Hanbyul Lee, Shinai Lee, Yangmi Lim, Jonghwa Won, Minwoo Jeon, Shin Hwang, Lei Fang, Wenqing Jiang, Zhengyi Wang, Eui-Cheol Shin, Su-Hyung Park, Jaeho Jung
Journal: Journal for ImmunoTherapy of Cancer (2021)

Stimulation of 4-1BB with agonistic antibodies is a promising strategy for improving the therapeutic efficacy of immune checkpoint inhibitors (ICIs) or for overcoming resistance to ICIs. However, dose-dependent hepatotoxicity was observed in clinical trials with monoclonal anti-4-1BB agonistic antibodies due to the activation of 4-1BB signaling in liver resident Kupffer cells.To avoid this on-target liver toxicity, we developed a novel bispecific antibody (4-1BB×PD-L1 bispecific antibody, termed "ABL503") uniquely designed to activate 4-1BB signaling only in the context of PD-L1, while also blocking PD-1/PD-L1 signaling.Functional evaluation using effector cells expressing both 4-1BB and PD-1 revealed superior biological activity of ABL503 compared with the combination of each monoclonal antibody. ABL503 also augmented T-cell activation in in vitro assays and further enhanced the anti-PD-L1-mediated reinvigoration of tumor-infiltrating CD8+ T cells from patients with cancer. Furthermore, in humanized PD-L1/4-1BB transgenic mice challenged with huPD-L1-expressing tumor cells, ABL503 induced superior anti-tumor activity and maintained an anti-tumor response against tumor rechallenge. ABL503 was well tolerated, with normal liver function in monkeys.The novel anti-4-1BB×PD-L1 bispecific antibody may exert a strong anti-tumor therapeutic efficacy with a low risk of liver toxicity through the restriction of 4-1BB stimulation in tumors.
Abstract 1804: Modulation of Nr2f2 reprograms tumor blood vessels to enhance anti-tumor immunity and immunotherapy
Authors: Yu Zhu, Nicole Lazarus, Kevin Brulois, Nicole Salazar, Theresa Dinh, Junliang Pan, Eugene Butcher
Journal: Cancer Research (2021)

Abstract A critical limitation to cancer immunotherapy is posed by the paucity of anti-tumor T cells in tumor tissues, even after therapeutic intervention. Development of effective strategies to enhance T cell recruitment remains challenging. As a critical regulator of immune cell trafficking, the tumor vasculature is a promising target that can be utilized to enhance anti-tumor immunity. Functional vasculature requires specialization of endothelial cells (ECs): capillary ECs transport oxygen and nutrients to promote tumor growth, while venular ECs regulate the recruitment and extravasation of immune cells. The majority of the current vessel-targeting therapies are designed to deplete endothelial cells indiscriminately with the goal of starving tumor cells. Loss of venules as a consequence could further block sustained recruitment of anti-tumor T cells. An alternative strategy that instead promotes capillary-to-venule “reprogramming” could simultaneously inhibit the tumor-promoting activities of capillaries and preserve the T cell-recruiting functions of tumor vessels, and thus better augment anti-tumor immunity and benefit immunotherapies. Through single cell transcriptomic profiling of tumor ECs, we found the nuclear receptor Nr2f2 to be specifically expressed in tumor-associated venules but not in capillaries. Upon ectopic expression of Nr2f2 in tumor ECs, capillary vessels undergo fate switch and adopt the venular phenotype and functions, as confirmed by immune profiling and single cell transcriptomic analyses. Nr2f2-driven capillary-to-venule reprogramming enhanced the recruitment of cytotoxic T cells into the tumor tissue, and led to a significant reduction of tumor burden in mouse breast and pancreatic tumor models. Interestingly, Nr2f2-driven EC fate switch enhanced the anti-tumor efficacy of immunotherapies, including immune checkpoint blockade and adoptive cell therapy by transferring T cells specific for a surrogate tumor cell antigen. Collectively, these data suggest that strategies that reprogram tumor vessels from capillaries into venules can be exploited to enhance anti-tumor immune responses and sensitize tumors to immunotherapy, especially in immunologically cold tumors. Citation Format: Yu Zhu, Nicole Lazarus, Kevin Brulois, Nicole Salazar, Theresa Dinh, Junliang Pan, Eugene Butcher. Modulation of Nr2f2 reprograms tumor blood vessels to enhance anti-tumor immunity and immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1804.
Long-term oncological outcomes of bladder Carcinoma In Situ (CIS) treated with BCG immunotherapy: Prognostic implications of 6-month pathological response assessed by a propensity score matching analysis
Authors: J.D. Subiela Henríquez, O. Rodríguez-Faba, J. Aumatell, J. Calderón, A. Mercadé, J. Balañà, C. Esquinas, R. Parada, J. Huguet, F. Algaba, A. Breda, J. Palou
Journal: European Urology (2021)
Abstract 164: Development of DeepCytoFlow: A novel deep learning pipeline enabling automated gating of flow cytometry data
Authors: Arjun Chandran, Jennifer Tsau, Dalia Gaddis, Shyam Sarikonda, Naveen Dakappagari, Christian Laing, Swetha Ann Thomas
Journal: Cancer Research (2021)

Abstract Introduction Following the advent of cellular therapies, flow cytometry has become a central tool for simultaneous assessment of drug levels and disease burden due to its ability for high dimensional cellular analysis. However, identification and monitoring of myriad immune- and leukemic cell phenotypes requires a manual gating process by subject matter experts. Although this process is the current gold standard for flow data analysis, it is slow, tedious, and prone to subjectivity. Herein, we describe our approach to automate flow data analysis using novel strategies that reduces the reliance on clustering methods that are unable to filter challenging noisy data sets inherent in flow data. Methods We developed DeepCytoFlow, a novel deep learning framework adapted for flow cytometry data analysis. DeepCytoFlow utilizes a convoluted neural network structure to analyze flow cytometry data files to generate appropriately gated cell populations in a matter of minutes significantly reducing the time required for manual analysis. The neural networks were first trained using a unique data set generated manually by multiple operators and tested using an independent data set to establish concordance in assessments. In addition, we evaluated the performance of our method using both accuracy and F1-score. Results Our integrated DeepCytoFlow pipeline employing neural network design shows promise on clustering-based analysis methods in terms of accuracy, precision and recall. More specifically, DeepCytoFlow is capable of correctly classifying various immune cell lineages (e.g., CD4 and CD8 T-cells). However, a limitation was observed on its ability to classify rare cell populations with a very limited prevalence. In an effort to improve performance, we are currently designing a new network architecture, and increasing our training and test dataset's size and quality. Conclusions DeepCytoFlow provides proof of concept of the applicability of deep learning for automation of gating in flow cytometry. The high adaptability of deep learning to a large set of problems suggests that this technique can be broadly applied to a larger set of biomarkers for the purpose for automated gating. With additional improvements, we believe DeepCytoFlow can enable a fast, accurate, and robust platform for analysts to perform consistent and, repeatable flow analysis for biomarker monitoring in clinical trials investigating novel immunotherapies. Citation Format: Arjun Chandran, Jennifer Tsau, Dalia Gaddis, Shyam Sarikonda, Naveen Dakappagari, Christian Laing, Swetha Ann Thomas. Development of DeepCytoFlow: A novel deep learning pipeline enabling automated gating of flow cytometry data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 164.
Abstract LB097: MET inhibitor enhances efficacies of gemcitabine and olaparib in pancreatic cancer cells
Authors: Meikuang Chen, Yuan Gao, Dihua Yu, Mien-Chie Hung
Journal: Cancer Research (2021)

Abstract Gemcitabine is one of the current first-line chemotherapy agents in pancreatic cancer treatment. However, the response rate of pancreatic cancer patients to gemcitabine treatment is lower than 20%. Among the potential targeted therapies for pancreatic cancer patients, PARP inhibitor (Olaparib) has been approved by the U.S. Food and Drug Administration for maintenance treatment of metastatic pancreatic adenocarcinoma patients with germline BRCA-mutation. Taking advantages of the high oxidative stress in most pancreatic cancer cells, therapeutic agents that enhance the burden of oxidative DNA damages in these cancer cells can be introduced in novel treatment strategies. Because c-MET overexpression positively correlates with poor prognosis in pancreatic cancer, and our previous studies show that oxidative stress induced-nuclear c-MET phosphorylates PARP1 to reduce oxidative DNA damages, we focused on developing novel treatment strategies by combining c-MET inhibitors (crizotinib and tivantinib) with either gemcitabine or olaparib. In this study, we found that gemcitabine induced nuclear accumulation of c-MET, and that tivantinib reduced c-MET mediated PARP1 phosphorylation in both BxPC-3 and L3.6pl pancreatic cancer cell lines. We also found that combination of tivantinib with either gemcitabine or Olaparib induced more DNA damages than the single agent treatments. Further, we demonstrated the synergistic effects of c-MET inhibitors combined with gemcitabine or Olaparib in pancreatic cancer cell lines, suggesting that combining c-MET inhibitor with PARP inhibitor or gemcitabine is a novel and rational therapeutic strategy for pancreatic cancer treatment. Citation Format: Meikuang Chen, Yuan Gao, Dihua Yu, Mien-Chie Hung. MET inhibitor enhances efficacies of gemcitabine and olaparib in pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB097.
Abstract 477: Elevated EVL methylation level in the normal colon mucosa is a potential risk biomarker for developing metachronous polyps
Authors: Ming Yu, Ting Wang, Kelly T. Carter, Kelsey Baker, Mary W. Redman, Kathy Vickers, Lynda Ann Dzubinski, Robert E. Schoen, William M. Grady
Journal: Cancer Research (2021)

Abstract The purpose of this study is to evaluate the use of molecular markers for more accurately predicting the individual risk of metachronous polyps or cancer during colonoscopic surveillance. Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death in the United States. The risk of CRC varies among people; individuals who develop adenomas are at heightened risk of forming metachronous adenomas and interval cancer, compared to those without a personal history of adenoma or CRC. Yet, even in these high risk individuals, only 25-30% will develop subsequent adenomas. To date, few studies have evaluated the use of molecular markers for predicting the risk of metachronous lesions. We have demonstrated that aberrantly methylated mir342/EVL is present at a higher frequency in the normal colon of people with CRC compared to people with no colon cancer or polyps, suggesting it may indicate a field cancerization process. Further, we developed an ultra-sensitive quantitative Methylation-specific ddPCR (MS-ddPCR) assay to accurately determine the level of rare EVL methylation in the normal colon mucosa. To investigate the correlation of EVL methylation in normal mucosa and the risk of developing polyps during the follow-up colonoscopy, we conducted a retrospective cohort study (N=136 subjects) and EVL methylation status was determined in normal colon mucosa samples from these subjects. Among them, 71 subjects had polyps detected within 12 years of the index colonoscopy, and 11 subjects were polyp-free at all subsequent colonoscopic exams done within 8-16 years of the index colonoscopy (54 subjects did not meet the criteria for follow up, so were excluded from the following analysis). Applying the standard Inverse Probability Weighted Logistic Regression (IPWLR) model, we found that higher level of EVL methylation in the normal colon mucosa at the time of the index colonoscopy (which was when the tissue sample was collected) indicated an increased risk of having polyps detected within 12 years, compared to subjects with no polyps detected by colonoscopy done within 8-16 years (Odds Ratio (95% CI) = 4.35 (1.14, 16.60); p-value = 0.0317). Our results suggest that EVL methylation level in the normal colon mucosa can be used as a risk biomarker for metachronous adenomas. Citation Format: Ming Yu, Ting Wang, Kelly T. Carter, Kelsey Baker, Mary W. Redman, Kathy Vickers, Lynda Ann Dzubinski, Robert E. Schoen, William M. Grady. Elevated EVL methylation level in the normal colon mucosa is a potential risk biomarker for developing metachronous polyps [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 477.