tbuckley/cabot-search huggingface dataset:
Abstract 2851: Trop-2 inactivates E-cadherin for metastatic diffusion in the absence of EMT
Authors: Saverio Alberti, Emanuela Guerra, Valeria Relli, Rossano Lattanzio, Martina Ceci, Khouloud Boujnah, Valeria Garbo, Antonino Moschella, donato F. Altomare, Raffaella Depalo, Marco Trerotola
Journal: Cancer Research (2021)

Abstract Trop-2 is a type I transmembrane glycoprotein, which is overexpressed in the majority of carcinomas, where it drives tumor cell proliferation. In its mature, glycosylated/functionally-competent form, Trop-2 associates with worse prognosis. A global quest was conducted for identifying decisive drivers of cancer metastasis. Cancer cell spheroids, wound healing and cell aggregation assays were utilized to assess cell-cell adhesion capacity. Immunofluorescence confocal microscopy and flow cytometry analysis were utilized to quantify expression of target signaling proteins, IHC analysis quantified the expression of target molecules in primary tumors and metastases. Pre-clinical models of orthotopic growth of colon cancer and metastatic diffusion to the liver were utilized. Xenotransplant transcriptome profiling analyzed transcription of EMT-related determinants. This led us to identify Trop-2 as a unique upregulated gene in colon cancer metastasis. Trop-2 was here shown to bind highly-expressed E-cadherin at the cell membrane. Trop-2 binding released E-cadherin from the cytoskeleton, inhibited cell-cell adhesion functions and activated signaling through β-catenin. This occurred in the absence of transcriptional downregulation of the CDH1 gene by EMT-associated transcription factors. The Trop-2/E-cadherin/β-catenin program was shown to lead to anti-apoptotic signaling, increased cell migration and enhanced cancer cell survival. In an orthotopic model of colon cancer, Trop-2 caused metastatic diffusion to the liver. The Trop-2-led E-cadherin-inactivation metastasis program was then found to induce metastatic relapse and shorter overall survival of colon cancer patients. Corresponding impact was indicated on breast, colon, ovary, uterus, stomach cancer metastatic diffusion, for broad impact on metastatic diffusion in human cancer. Acknowledgments:Support was provided by grants of Italian Ministry of Development (MI01_00424) and of University and Research (SCN_00558). M.T. was supported by the Programma Per Giovani Ricercatori “Rita Levi Montalcini” (Grant PGR12I7N1Z). Citation Format: Saverio Alberti, Emanuela Guerra, Valeria Relli, Rossano Lattanzio, Martina Ceci, Khouloud Boujnah, Valeria Garbo, Antonino Moschella, donato F. Altomare, Raffaella Depalo, Marco Trerotola. Trop-2 inactivates E-cadherin for metastatic diffusion in the absence of EMT [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 2851.
Global cost assessment of robot-assisted versus open radical cystectomy: Results of a prospective randomized controlled trial
Authors: R. Mastroianni, G. Tuderti, U. Anceschi, A.M. Bove, A. Brassetti, M. Ferriero, L. Misuraca, A. Zampa, M. Covotta, E. Ghiani, S. Guaglianone, G. Navanteri, A. Spano, M. Gallucci, G. Simone
Journal: European Urology (2021)
Prevalence and Landscape of Actionable Genomic Alterations in Renal Cell Carcinoma
Authors: Kyrollis Attalla, Renzo G. DiNatale, Phillip M. Rappold, Christopher J. Fong, Francisco Sanchez-Vega, Andrew W. Silagy, Stanley Weng, Jonathan Coleman, Chung-Han Lee, Maria I. Carlo, Jeremy C. Durack, Stephen B. Solomon, Victor E. Reuter, Paul Russo, Timothy A. Chan, Robert J. Motzer, Nikolaus D. Schultz, Ed Reznik, Martin H. Voss, A. Ari Hakimi
Journal: Clinical Cancer Research (2021)

Abstract Purpose: We report our experience with next-generation sequencing to characterize the landscape of actionable genomic alterations in renal cell carcinoma (RCC). Experimental Design: A query of our institutional clinical sequencing database (MSK-IMPACT) was performed that included tumor samples from 38,468 individuals across all cancer types. Somatic variations were annotated using a precision knowledge database (OncoKB) and the available clinical data stratified by level of evidence. Alterations associated with response to immune-checkpoint blockade (ICB) were analyzed separately; these included DNA mismatch repair (MMR) gene alterations, tumor mutational burden (TMB), and microsatellite instability (MSI). Data from The Cancer Genome Atlas (TCGA) consortium as well as public data from several clinical trials in metastatic RCC were used for validation purposes. Multiregional sequencing data from the TRAcking Cancer Evolution through Therapy (TRACERx) RENAL cohort were used to assess the clonality of somatic mutations. Results: Of the 753 individuals with RCC identified in the MSK-IMPACT cohort, 115 showed evidence of targetable alterations, which represented a prevalence of 15.3% [95% confidence interval (CI), 12.7%–17.8%). When stratified by levels of evidence, the alterations identified corresponded to levels 2 (11.3%), 3A (5.2%), and 3B (83.5%). A low prevalence was recapitulated in the TCGA cohort at 9.1% (95% CI, 6.9%–11.2%). Copy-number variations predominated in papillary RCC tumors, largely due to amplifications in the MET gene. Notably, higher rates of actionability were found in individuals with metastatic disease (stage IV) compared with those with localized disease (OR, 2.50; 95% CI, 1.16–6.16; Fisher's P = 0.01). On the other hand, the prevalence of alterations associated with response to ICB therapy was found to be approximately 5% in both the MSK-IMPACT and TCGA cohorts and no associations with disease stage were identified (OR, 1.35; 95% CI, 0.46–5.40; P = 0.8). Finally, multiregional sequencing revealed that the vast majority of actionable mutations occurred later during tumor evolution and were only present subclonally in RCC tumors. Conclusions: RCC harbors a low prevalence of clinically actionable alterations compared with other tumors and the evidence supporting their clinical use is limited. These aberrations were found to be more common in advanced disease and seem to occur later during tumor evolution. Our study provides new insights on the role of targeted therapies for RCC and highlights the need for additional research to improve treatment selection using genomic profiling.
Abstract 16943: Dissecting the Molecular Interaction of Caveolin3 and the Regulatory Subunit (SUR2) of Cardiac KATP Channels
Authors: Nan Shi, Bin Ye, Jessie Ou, Timothy Kamp, Jonathan Makielski
Journal: Circulation (2011)

Macromolecular signaling complexes including ion channels present in caveolar microdomains can provide highly specific and localized regulation of cell function. Prior studies have shown that Caveolin3 (Cav3) may interact with a Kir6.2 pore of the cardiac ATP-sensitive potassium channels (KATP). In this report, we studied the molecular interaction of Cav3 and SUR2, the regulatory subunit of KATP. Cav3 and SUR2 were detected in the same caveolar fractions isolated from mouse left ventricles. A P104L-Cav3 mutation was used to probe Cav3-SUR2 trafficking and molecular interaction in COS1 cells. Immunostaining data showed that SUR2 co-localized with Cav3, however, P104L caused retention of SUR2-specific fluorescent signals intracellularly. A quantitative Bioluminescence Resonance Energy Transfer (BRET) assay using coelenterazine-h as substrate was established to study Cav3-SUR2 interaction. WT or P104L-Cav3 was fused to a Renilla Luciferase (Rluc) while SUR2 was fused to YFP. Both WTCav3/SUR2 (0.19±0.04, n=10) and P104LCav3/SUR2 (0.17±0.02, n=10, P=0.05) pairs displayed positive BRET ratios, suggesting that the two proteins were within a 10-100 Å distance to permit energy transfer from RLuc (470-nm) to YFP (530-nm). We did not record positive BRET ratios from negative control samples containing no substrate. Our data showed that Cav3 could directly bind to SUR2, and this interaction was not significantly affected by the P104L mutation, indicating that aa104 is probably not a binding site for the two proteins. To determine which portion of SUR2 binds to Cav3, 3 expression clones harboring SUR2 transmembrane domain TMD0, TMD1 or TMD2 were made. BRET results showed that Cav3 preferably binds to TMD0 (0.19±0.01, n=5) or TMD1 (0.15±0.03, n=5) over TMD2 (0.02±0.01, n=5). Co-immunoprecipitation results confirmed our BRET data. Mouse neonatal myocytes infected with adenoviral particles expressing P104LCav3 displayed a significantly prolonged action potential (APD90, 20.5±4, n=6) than WTCav3-expressing cells (9.3±4, n=4, p&lt;0.05), which suggested that Cav3 levels affected membrane electrical properties. Together with other data, a Cav3-SUR2-Kir6.2 complex that resides in the caveolar microdomains may play an important role in cardiac signaling.
Abstract 356: Association of <i>LRP1B</i> mutation with tumor mutation burden and survival in bladder cancer patients treated with immune checkpoint inhibitors
Authors: Mengmei Yang, Wenzhuan Xie, Mengli Huang, Peng Wu
Journal: Cancer Research (2021)

Abstract Background: Bladder cancer is a common genitourinary malignancy worldwide. Immune checkpoint inhibitors(ICIs) including atezolizumab, pembrolizumab, nivolumab have shown durable responses and have been approved by FDA. However ICIs demonstrate antitumor effects only in a fraction of patients, and research exploring the association between gene mutation and clinical benefit is limited. Mutations of LRP1B(The low-density lipoprotein receptor-related protein 1B) are frequently seen in solid tumors and have been reported to be associated with higher tumor mutation burden(TMB) and prolonged survival in NSCLC, melanoma and liver cancer. The association between LRP1B mutation and survival in bladder cancer is unknown. Methods: The association between LRP1B mutation with TMB was analyzed in bladder cancer patients from the public immunotherapy-treated cohort published by Miao et. al as well as a clinical cohort from 3D Medicines database involving 118 Chinese patients. Wilcoxon test was used for the comparison of TMB. Overall survival(OS) and progression-free survival (PFS) analyses were conducted in the public cohort using Kaplan-Meier curves and log-rank tests. Statistical significance was set at p = 0.05. Results: 15%(5/33) bladder cancer patients in the public immunotherapy-treated cohort and 18.6% (22/118) patients in the clinical cohort harbored LRP1B mutation. LRP1B mutation is associated with higher TMB in both public cohort(p=0.028) and clinical cohort(p=0.003). Survival analysis in the public cohort demonstrated that LRP1B mutation resulted in significantly longer OS ( 16.8 vs 8.08 months; HR, 0.16; p=0.043) and a increasing trend on PFS without significant difference (15.9 vs 4.1 months; HR, 0.62; P = 0.39) in bladder cancer patients treated with ICIs. Conclusions: This study shows that LRP1B mutation is relatively common and correlated with higher TMB in bladder cancer. LRP1B mutation may serve as a predictive biomarker of ICI benefit in bladder cancer. Citation Format: Mengmei Yang, Wenzhuan Xie, Mengli Huang, Peng Wu. Association of LRP1B mutation with tumor mutation burden and survival in bladder cancer patients treated with immune checkpoint inhibitors [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 356.
Abstract 1558: Radiation therapy and immune checkpoint inhibitor combinations in the E0771 medullary breast adenocarcinoma
Authors: Patrick Fadden, Thi Bui, Kelli Davis, David Hurtado, Emily Sugg, Abigail Svancarek, Ian Belle, Chassidy Hall
Journal: Cancer Research (2021)

Abstract Greater than 50% of all cancer patients receive radiation therapy at some point during their cancer treatment to control solid tumor growth (Harrington 2011). In addition to the direct action of radiation on tumor cell proliferation, radiation also has the potential to stimulate an anti-tumor immune response (Weichselbaum 2017). The success of immune checkpoint therapies such as anti-PD-1, anti-PD-L1, and anti-CTLA-4 inhibitory antibodies has driven large investment into the discovery of novel immune-oncology therapies. While the clinical response to immune checkpoint inhibitors can be profound for those patients that respond, there still exists a large percentage of patients that do not see benefit. In order to expand the number of patients that may respond to immune checkpoint inhibition, combination with radiation therapy needs to be tested and in fact a large number of preclinical and clinical studies are being conducted (for review see Asna 2019). Preclinical syngeneic tumor models are a critical means to assess new immunotherapies and drive preclinical programs. E0771 is a medullary breast adenocarcinoma cell line originally isolated from a spontaneous tumor and can be implanted subcutaneously in C57BL/6 mice (Ewens 2005). In order to characterize the E0771 syngeneic breast tumor model for future studies with radiation and immunotherapy, we assessed the efficacy changes in response to various schedules of radiation doses with and without either anti-PD-1 or anti-CTLA-4 antibody therapies. In addition, we analyzed the tumor infiltrating immune cell populations following radiation therapy. E0771 is sensitive to radiation therapy with a clear dose response. Radiation administered either as a single dose, hypofractionated, or hyperfractionated gave similar tumor responses. Flow cytometry analysis shows a higher infiltration of T regulatory cells compared with CD8+ T cells at baseline, which is exacerbated by irradiation. The CD8/Treg ratio is reversed with the addition of anti-CTLA-4 treatment to radiation and resulted in curative responses for 9 of 10 mice in the combination group. Citation Format: Patrick Fadden, Thi Bui, Kelli Davis, David Hurtado, Emily Sugg, Abigail Svancarek, Ian Belle, Chassidy Hall. Radiation therapy and immune checkpoint inhibitor combinations in the E0771 medullary breast adenocarcinoma [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 1558.
Abstract 725: LIFR promotes SUCLG2-dependent castration resistance and neuroendocrine differentiation of prostate cancer
Authors: Hsiu-Lien Yeh, Shian-Ren Lin, Kuo-Ching Jiang, Wei-Hao Chen, Yen-Nien Liu
Journal: Cancer Research (2021)

Abstract Neuroendocrine (NE) differentiation is a well-recognized phenotypic change of prostate cancer after androgen-deprivation therapy (ADT) that ultimately develops an aggressive subtype. An increasing number of patients with NE histologic type prostate cancer present with metabolic genes disorder. However, the metabolic pathways that influence the malignant transformation and the NE differentiation of prostate cancer remain unclear. In this study, we found that ADT induced the upregulation of leukemia inhibitory factor receptor (LIFR), which contributes to the expression of succinate-CoA ligase GDP-forming beta subunit (SUCLG2), thus activating metabolic reprogramming to enable NE differentiation and increase aggressiveness. Activated LIF-LIFR-STAT3 axis stimulates SUCLG2 expression, subsequently upregulating glucose metabolism and the NE differentiation of prostate cancer. SUCLG2 knockdown markedly reduced mitochondrial DNA content and inhibited the enzymatic activity of succinyl-CoA synthetase and nucleoside diphosphate kinase (NDPK) in prostate cancer cells. SUCLG2 overexpression promoted androgen-independent proliferation; however, SUCLG2 knockdown suppressed NE differentiation and the ADT resistance of prostate cancer cells. Analysis of prostate tissue samples showed an increased intensity of LIFR associated with SUCLG2 in castration-resistant prostate cancer tumors. Our study identifies SUCLG2 as a potential prognostic marker of ADT-resistant prostate cancer and suggests it could be a target for prostate cancer treatment. Citation Format: Hsiu-Lien Yeh, Shian-Ren Lin, Kuo-Ching Jiang, Wei-Hao Chen, Yen-Nien Liu. LIFR promotes SUCLG2-dependent castration resistance and neuroendocrine differentiation of prostate 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 725.
癌再発に対する周術期局所麻酔の効果:ランダム化比較試験のメタ分析【JST・京大機械翻訳】
Authors: Lee Zong Xuan, Ng Ka Ting, Ang Eshen, Wang Chew Yin, Binti Shariffuddin Ina Ismiarti
Journal: International Journal of Surgery (2020)
Listening to the parents as key to early infant male circumcision efforts in fight against HIV: Perspectives of a contemporary cohort of legal adult representatives of infants enrolled in the ShangRing vs. mogen clamp trial
Authors: Q. Nang, S. Basourakos, N. Punjani, O. Al Hussein, M. Barone, M. Goldstein, P. Li, R. Lee
Journal: European Urology (2021)
Integrated Functional Genomic and Pharmacological Characterization of the Kinome of Myeloma Cells
Authors: Ricardo De Matos Simoes, Eugen Dhimolea, Ryosuke Shirasaki, Sara Gandolfi, Geoffrey Matthews, Michal Sheffer, Olga Dashevsky, Brian Glassner, Constantine S. Mitsiades
Journal: Blood (2017)
For appreciable ethnic differences in false positive rates, use different cut off points
Authors: P J Holloway, S Bulusu
Journal: BMJ (1996)

EDITOR,—Lucy Gilbert and colleagues report ethnic differences in biochemical screening for Down's syndrome and the relative ineffectiveness of the programme in Indian Asians.1 At national meetings of the Association of Clinical Biochemists we presented our findings on the ethnic differences in maternal serum (alpha) fetoprotein and free β human chorionic gonadotrophin concentrations2 and the differences in false positive rates in the various groups, which remain unchanged even after the use of “ethnospecific” medians.3

The false positive rate …
Abstract 2262: Comprehensive characterization of cancer drivers and therapeutic targets
Authors: Yize Li
Journal: Cancer Research (2021)

Abstract Cancer is a family of diseases caused primarily by genetic “driver” mutations. Building upon a large-scale Pan-cancer study of ours, we expand our investigation to the proteogenomic level (including global proteome and phosphoproteome data) drawing &amp;gt;1,000 cases over 10 cancer types (BR, ccRCC, CO, EC, GBM, HNSCC, LSCC, LUAD, OV, PDAC) from the Clinical Proteomic Tumor Analysis Consortium (CPTAC). We concentrate on 6 aspects of drivers: (1) We identify genomic &amp; epigenomic drivers (mutations, SVs, CNVs, fusions, etc.), estimate their frequencies, and investigate their exclusivities &amp; co-occurrences. (2) We investigate the proteogenomic impact of drivers, especially recurrent ones, e.g. cis/trans effects, on miRNA, RNA, and protein expression. (3) We investigate their impact on Post Transcriptional Modifications (PTMs), comparing levels of protein and PTM, e.g. for one- and two-hit events. For example, we found upregulation of PTPN11 phosphorylation sites in EGFR-altered LUAD, GBM, and HNSCC samples, suggesting a pan-cancer effect, and observed high NRF2 phosphorylation and activation of antioxidant pathways in KEAP1 or NRF2-altered samples in lung cancer (LSCC and LUAD); (4) We compare tumors and normal adjacent tissues (NATs) to identify key protein level changes and regulations for oncogenic pathways and further examine cell type composition, proteomic variation, and association with driver mutations. For instance, we found VHL mutations often signify enrichment of endothelial cells. (5) We capture potential Significant Protein Drivers (SPRDs), independent of DNA level changes, to uncover hidden drivers in cause-ambiguous tumors. (6) We examine actionable driver alterations and expression changes across proteogenomic levels and associations with immune infiltration and immunogenic peptides to understand targeting, therapeutic implications and, influence on tumor micro-environment. We comment upon the clinical utility of comprehensive proteogenomics, especially in cases where a strictly genomic assessment is inconclusive. Proteomics can further prioritize gene targets with additional layers of evidence for differential expression among features such as cell-type composition, anatomical location, disease stage, and immune infiltration. Our approach has the potential for identifying cancer-type-specific and non-specific novel druggable targets, which would provide new biological and clinical insights into cancer. Citation Format: Yize Li, Oncogenic Drivers and Pathways GroupClinical Proteomic Tumor Analysis Consortium. Comprehensive characterization of cancer drivers and therapeutic targets [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 2262.
Abstract 834: Association between ABO and Duffy blood types and circulating chemokines and cytokines
Authors: Sarah C. Van Alsten, John Aversa, Loredana Santo, M. Constanza Camargo, Wen-Yi Huang, Troy Kemp, Jia Liu, Joshua Samspon, Charles S. Rabkin
Journal: Cancer Research (2021)

Abstract Background: Blood group antigens may play a role in immune and inflammatory processes. The aim of this analysis was to identify specific inflammatory pathways associated with blood group antigens. Methods: We investigated associations between blood type and circulating inflammatory markers in data for 3,537 non-Hispanic white participants selected from previous case-control studies nested in the Prostate, Lung, Colorectal, and Ovarian cancer screening trial. Whole genome scans were used to infer blood types for twelve common antigen systems (ABO, Duffy, Lewis, RhE, Kidd, Kell, Secretor, Lutheran, Colton, Dombrock, Auberger, and Knops) based on well-characterized single nucleotide polymorphisms. Circulating levels of 96 immune- and inflammation-related biomarkers were measured on multiplex fluorescent bead-based panels. We estimated associations between blood type and markers using design-weighted linear or logistic regression adjusted for age, sex, smoking status, and principal components of population substructure, and using a Bonferroni correction to control for multiple comparisons. Results: Among the 1,152 blood type-biomarker associations tested, we identified 10 which were significant after correction for multiple comparisons. ABO subtype was associated with levels of sVEGFR2, sVEGFR3, and sGP130, and Duffy subtype was associated with levels of CXCL6/GCP2, CXCL5/ENA78, CCL11/EOTAXIN, CXCL1/GRO, CCL2/MCP1, CCL13/MCP4, and CCL17/TARC. Post-hoc pairwise t-tests showed that individuals with type A blood had lower levels of all ABO-associated markers than individuals with type O or B blood, while individuals with type Fy(a+b-) had lower levels of all Duffy-associated markers than individuals with type Fy(a+b+) or Fy(a-b+). Conclusion: ABO blood type is associated with levels of three circulating angiogenic markers, while Duffy blood type is associated with eight chemokines. Additional work to understand the clinical implications of these differences is needed. Citation Format: Sarah C. Van Alsten, John Aversa, Loredana Santo, M. Constanza Camargo, Wen-Yi Huang, Troy Kemp, Jia Liu, Joshua Samspon, Charles S. Rabkin. Association between ABO and Duffy blood types and circulating chemokines and cytokines [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 834.