tbuckley/cabot-search huggingface dataset:
Abstract 3195: Hijacked senescence secretomes as 'immune primers' of antiangiogenic TKI efficacy
Authors: Melissa Dolan, Yuhao Shi, James W. Hill, Michalis Mastri, Cristina Vaghi, Joseph Barbi, Sebastien Benzekry, John M. Ebos
Journal: Cancer Research (2021)

Abstract VEGF receptor tyrosine kinase inhibitors (VEGFR TKIs) and immune checkpoint inhibitors (ICIs) are approved together as a treatment regimen for multiple metastatic cancers, yet the mechanistic basis for this combinatory benefit remains unclear. Previously we have shown that resistance to VEGFR TKI treatment can transiently hijack the secretory machinery typically associated with senescence - the process of cellular aging. Here we report that these senescence-associated secretory programs can also drive immune cell activation, potentially ‘priming' the tumor for PD-1 pathway inhibition. Using a novel live-cell sorting method based on C12FDG - a substrate for senescence-associated beta-galactosidase activity - we isolated senescence-marker (SM) expressing VEGFR TKI-treated cells for transcriptomic analysis. SM+ cell populations were enriched for senescence, immune, and interferon secretory processes, with a unique gene signature validated using published preclinical and clinical datasets. Notably, SM+ cells were found to be more sensitive to CD8 T-cell mediated tumor inhibition in vivo and ex vivo and be sensitive to PD-L1 blockade and inhibitors of mTOR, a key secretory regulator. Together, these results suggest VEGFR TKI controlled secretory programs contributing to resistance can simultaneously prime the tumor microenvironment for immune cell activation, providing an explanation for improved effects of antiangiogenic and immunotherapy combinations in patients. Citation Format: Melissa Dolan, Yuhao Shi, James W. Hill, Michalis Mastri, Cristina Vaghi, Joseph Barbi, Sebastien Benzekry, John M. Ebos. Hijacked senescence secretomes as 'immune primers' of antiangiogenic TKI efficacy [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 3195.
Abstract 12886: Effect of Pre-Procedure Transesophageal Echocardiography on the Risk of Stroke After Atrial Fibrillation Ablation
Authors: Zaid Gheith, Bilal Alqam, Fuad Habash, Khaldia Khaled, Amjad Abualsuod, Mohammed Madmani, Srikanth Vallurupalli, Waddah Maskoun
Journal: Circulation (2018)

Background: Ischemic stroke/transient ischemic attack (CVA) is a known complication of atrial fibrillation (AF) ablation. Mechanisms include procedural complications (introduction of air, char and ...
Abstract 851: Associations of dietary calcium and magnesium intakes with lung cancer risk among low-income Americans: Results from the Southern Community Cohort Study
Authors: Hyung-Suk Yoon, Xiao Ou Shu, Hui Cai, Wei Zheng, William J. Blot, Qiuyin Cai
Journal: Cancer Research (2021)

Abstract Background: Previous studies have suggested the potential roles of dietary intakes of calcium and magnesium in human cancer development, but little is known about their associations with lung cancer risk, especially among African Americans (AAs) and low-income populations. Objectives: We conducted a nested case-control study to investigate the associations of dietary calcium and magnesium intakes with lung cancer risk among a low-income population of AAs and European Americans (EAs) in the Southeastern United States. Methods: A total of 1,560 incident lung cancer cases who were diagnosed at least two years after enrollment and 5,926 matched controls from the Southern Community Cohort Study were included. Dietary calcium and magnesium intakes were assessed using a validated food frequency questionnaire at study enrollment. Multivariate logistic regression models were used to estimate odds ratios (ORs) and corresponding confidence intervals (95% CIs) for lung cancer risk associated with intakes of calcium and magnesium, and calcium/magnesium ratios after adjusting for enrollment age, education, smoking status, and pack-years, physical activity, alcohol drinking, household income, history of chronic obstructive pulmonary disease, body mass index, energy intake, and calcium or magnesium intake. Results: Calcium intake was significantly associated with an increased risk of lung cancer among AAs but not among EAs; ORs (95% CI) for the highest compared with lowest quartiles were 1.56 (1.03-2.36) and 1.14 (0.68-1.92) for AAs and EAs, respectively (p for interaction: 0.03). Meanwhile, magnesium intake was significantly associated with a reduced risk of lung cancer risk among AAs but not among EAs; ORs (95% CI) for the highest compared with lowest quartiles were 0.55 (0.35-0.89) and 0.68 (0.39-1.18), respectively (p for interaction: 0.68). ORs (95% CI) for the highest compared with the lowest quartiles for calcium/magnesium ratios were 1.21 (0.96-1.53) for AAs and 1.17 (0.85-1.61) for EAs. These associations were more evident among men and never-smokers. Conclusion: Our results suggest that higher dietary calcium and lower dietary magnesium intakes are associated with an increased risk of lung cancer, especially among AAs, raising the possibility that dietary factors may contribute to a higher risk of lung cancer among AA than EA men. Citation Format: Hyung-Suk Yoon, Xiao Ou Shu, Hui Cai, Wei Zheng, William J. Blot, Qiuyin Cai. Associations of dietary calcium and magnesium intakes with lung cancer risk among low-income Americans: Results from the Southern Community Cohort Study [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 851.
Probiotic and commensal gut microbial therapies in multiple sclerosis and its animal models: a comprehensive review
Authors: Lorrie L. Blais, Theresa L. Montgomery, Eyal Amiel, Paula B. Deming, Dimitry N. Krementsov
Journal: Gut Microbes (2021)

The need for alternative treatments for multiple sclerosis (MS) has triggered copious amounts of research into microbial therapies focused on manipulating the microbiota-gut-brain axis. This comprehensive review was intended to present and systematically evaluate the current clinical and preclinical evidence for various probiotic and commensal gut microbial therapies as treatments for MS, using the Bradford Hill criteria (BHC) as a multi-parameter assessment rubric. Literature searches were performed to identify a total of 37 relevant studies (6 human, 31 animal), including 28 probiotic therapy and 9 commensal therapy studies. In addition to presenting qualitative summaries of these findings, therapeutic evidence for each bacterial formulation was assessed using the BHC to generate summative scores. These scores, which encompassed study quality, replication, and other considerations, were used to rank the most promising therapies and highlight deficiencies. Several therapeutic formulations, including VSL#3,
ALKBH1 reduces DNA N6-methyladenine to allow for vascular calcification in chronic kidney disease
Authors: Ke Zhu, Jochen Reiser
Journal: Journal of Clinical Investigation (2021)

Vascular calcification is a common complication of chronic kidney disease (CKD), and one of the main risk factors for increased cardiovascular morbidity and mortality in patients with CKD. In this issue of the JCI, Ouyang and Su et al. report that Alkb homolog 1 (ALKBH1), a DNA demethylase, reduced DNA N6-methyladenine (6mA) in vascular smooth muscle cells (VSMCs) and leukocytes, thus leading to aortic arch calcification in the patients with CKD. During the progression of vascular calcification, increased ALKBH1 expression was linked to decreased 6mA levels, findings that the authors noted in both patients with CKD and CKD mouse models. The kidney and vascular disease risk factor soluble urokinase receptor (suPAR) was also elevated in the plasma. Notably, lower 6mA levels induced BMP2-mediated osteogenic reprogramming in the VSMCs. These findings present a function of ALKBH1 in vascular calcification and provide a framework for therapeutic strategies.
Abstract 1197: A multi tumor survey of Nectin-4 expression to guide BT8009 indication selection
Authors: Carly T. Campbell, Robert Smale, Michael Rigby, Shawn Watson, Amy Dickson, Tara Gelb, Heather Cohen, Pierre Lee, Josette William Ragheb, Stephen J. Blakemore
Journal: Cancer Research (2021)

Abstract Introduction: Bicycles® are a novel class of fully synthetic, short, constrained peptides. BT8009 consists of a bicyclic peptide targeting the tumor antigen Nectin-4, linked to the cytotoxin monomethyl auristatin E (MMAE) via a molecular spacer and cleavable linker. Nectin-4 is a validated tumor target and is highly expressed in a wide range of tumors. A Phase I/II dose escalation/expansion study, BT8009-100 (NCT04561362), enrolling patients with advanced solid tumors associated with Nectin-4 expression is ongoing in the US. Here we report the analysis of tumor tissue microarrays (TMAs) stained with a Nectin-4 immunohistochemistry (IHC) assay to support patient selection for the BT8009-100 study. Methods: We developed a clinical grade Nectin-4 IHC assay on the Leica platform using a proprietary rabbit monoclonal α-Nectin-4 primary antibody (Abcam, Burlingame, CA) and the BOND Polymer Refine detection kit. TMAs of cancer types reported to have high Nectin-4 expression, including esophageal, pancreatic, bladder, head &amp; neck, stomach, non-small cell lung, breast, and ovarian cancer, were stained and manually scored for Nectin-4 levels, with the tumor microenvironment evaluated in a subset of samples. Nectin-4 H-scores (stain intensity on a scale of 0-3 x percent positive tumor cells) were generated by a pathologist independently for tumor cell membrane and tumor cytoplasm. H-scores ≥ 100 in the tumor membrane or cytoplasm were considered positive. Results: In all indications tested, a greater degree of Nectin-4 positivity was observed in the tumor cytoplasm as compared to tumor membrane. Breast and bladder cancer had the greatest frequency of Nectin-4 positivity. Subtype analysis in breast cancer identified enrichment of Nectin-4 expression in hormone receptor negative and human epidermal growth factor receptor 2 positive tumors. Conclusion: The frequency of Nectin-4 expression as measured by IHC across multiple tumor types may guide clinical strategy for the BT8009 program. TableIndicationTotal cores (n)Percent Tumor Membrane PositivePercent Tumor Cytoplasm PositivePercent Tumor Membrane or Cytoplasm PositiveBreast225164957Bladder142274256Esophagus14073032Head &amp; Neck69102532Lung15731717Ovarian8921315Pancreas96123Stomach131022 Citation Format: Carly T. Campbell, Robert Smale, Michael Rigby, Shawn Watson, Amy Dickson, Tara Gelb, Heather Cohen, Pierre Lee, Josette William Ragheb, Stephen J. Blakemore. A multi tumor survey of Nectin-4 expression to guide BT8009 indication selection [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 1197.
Abstract 1029: Dissecting the mechanism of action targeting TNFR2 with a lignd blocking anti-TNFR2 antibody that elicits potent anti-tumor activity
Authors: Xiaofeng Zhao, Xiaoqing Liu, Zhenna Gao, Mengyu Wang, Wenjing Li, Ran Pang, Wenqing Yang, Zhuoxiao Cao, Renhong Tang
Journal: Cancer Research (2021)

Abstract Tumor necrosis factor receptor-2 (TNFR2) is a TNF receptor superfamily member and has been reported to have restricted expression in the immune system, including potent suppressive Tregs, myeloid suppressor cells and endothelial cells. The therapeutic potential of targeting TNFR2 for cancers has been previously demonstrated but with conflicting data reported by different groups. In order to gain further insight into the mechanism of action (MoA) of targeting TNFR2, we used an anti-murine TNFR2 surrogate antibody (suAb) and tested its functional activities both in vitro and in vivo. suAb was able to bind murine TNFR2 with high sub-nanomolar affinity, in the meantime, it can also block the interaction between murine TNFα and TNFR2 at both protein and cellular levels. CD4+ T cells were isolated from spleens of wildtype Balb/c mice, the co-incubation of which with murine TNFα and IL-2 rendering the significant proliferation of Treg within the CD4+ T cell population. Addition of suAb can potently reduce Treg proliferation while downregulating the expression of TNFR2 on these Tregs. Further detailed analysis by using isolated mouse FoxP3+ Treg confirmed that suAb could effectively suppress murine Treg proliferation induced by TNFα and IL-2. In vivo, suAb treatment resulted in significant tumor growth inhibition across various syngeneic tumor models (CT26, EMT6 and LL/2) as single agent or when combined with anti-mPD-1 (CT26). Tumor infiltrating lymphocytes (TILs) analysis revealed dramatic increase of the effective-memory pool of both CD4+ and CD8+ T cells together with an significantly improved CD8/Treg ratio. In addition, treatment with suAb led to decreased expression of PD-1 on tumor infiltrating CD8+ T cells suggesting a potential relieved exhaustion phenotype after the treatment. Based on this careful MoA characterization, corresponding human anti-TNFR2 lead antibodies have been identified and are currently under development as potential novel treatment for cancer patients. Citation Format: Xiaofeng Zhao, Xiaoqing Liu, Zhenna Gao, Mengyu Wang, Wenjing Li, Ran Pang, Wenqing Yang, Zhuoxiao Cao, Renhong Tang. Dissecting the mechanism of action targeting TNFR2 with a lignd blocking anti-TNFR2 antibody that elicits potent anti-tumor activity [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 1029.
Abstract 3042: Generation, characterization and functional validation of novel preclinical models for human pediatric glioma
Authors: Or Zohar, Itai Moshe, Ismer Britta, David T. Jones, Dinorah Friedmann-Morvinski
Journal: Cancer Research (2021)

Abstract Tumors of the central nervous system are the most common form of childhood malignancy, and remain the leading cause of cancer-related morbidity and mortality in children. Despite extensive efforts, the efficacy of the traditional treatments is limited and the overall prognosis is poor. In recent years it has become apparent that pediatric gliomas differ from their adult counterparts, explaining in part why the therapies extrapolated from adult gliomas have failed, and further supporting the need to understand the biology of the childhood disease. Deep sequencing studies on brain tumor specimens within various cancer genome consortia (e.g. ICGC PedBrain, TCGA) has yielded a wealth of information about molecular aberrations that had accumulated in tumors. This has unravelled a considerable degree of heterogeneity and thus resulted in the delineation of different molecular subgroups. Furthermore, it has provided comprehensive insights into tumor genomes deduction. Nevertheless, validation of oncogenically relevant genes and therapeutically actionable targets in an in vivo context still remains a major challenge in the process of developing novel treatment approaches. We have generated state-of-the-art in vivo methodologies based on somatic gene transfer for generating animal models faithfully recapitulating the molecular and clinical characteristics of the respective human counterpart. In this study, we focused on NTRK2 fusions and FGFR1 mutations and characterized the tumors obtained by either in utero electroporation or lentiviral injection into postnatal (P0-P1) mice. Tumor derived cell lines grown in stem cell media were tested for conventional therapies (e.g. TMZ) and screening of available small inhibitor compounds. In addition, we have characterized the tumor microenvironment of these lesions, mainly the infiltrating immune cell populations. This study thus represents an important contribution to the understanding of pediatric glioma biology as well as to translational efforts in developing new treatment approaches for these malignant tumors. Citation Format: Or Zohar, Itai Moshe, Ismer Britta, David T. Jones, Dinorah Friedmann-Morvinski. Generation, characterization and functional validation of novel preclinical models for human pediatric glioma [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 3042.
Abstract 1069: Determining the effect of bazedoxifene in combination with chemotherapy on colon cancer cells
Authors: Rhynelle S. Dmello, Pathum Thilakasiri, Belinda Duscio, Ivan Poon, Matthias Ernst, Ashwini Chand
Journal: Cancer Research (2021)

Abstract Inflammatory cytokines, such as interleukin-6 (IL-6) and IL-11, activate the signal transducer and activator of transcription 3 (STAT3), which drives the gene transcription of cellular processes attributed as hallmarks of cancer. High levels of these cytokines, in combination with driver mutations, facilitate tumour growth and progression in preclinical models of colon cancer. Previous studies in our laboratory identified bazedoxifene (BZA), currently approved for the treatment of osteoporosis, as a small molecule inhibitor of GP130 (the receptor common to the IL-6 family of cytokines), selectively suppressing IL-6 and IL-11 signalling to reduce colon and gastric cancer growth in vivo (Thilakasiri et al. EMBO Mol Med 2019). The aim of this study is to determine the key cellular mechanisms influenced by GP130 inhibition to mediate anti-tumour effects in colon cancer cells. Additionally, we assessed the combined effects of BZA with standard of care chemotherapy drugs on cell proliferation and apoptosis. Using LIM2405 and HT29 colon cancer cells, the combined effect of BZA, fluorouracil and oxaliplatin on inducing apoptosis in LIM2405 and HT29 colon cancer cells was analysed using flow cytometry and confirmed using Western blotting and DIC microscopy. The effects of BZA was further analysed on HT29 xenograft growth and metastasis in vivo. Levels of STAT3 activation in response to IL-11/STAT3 signalling was characterised by Western blotting. Our results demonstrated that combination treatment with BZA, fluorouracil and oxaliplatin significantly increased apoptosis in LIM2405 cells and BZA significantly induced apoptosis in HT29 cells. Our data showed that BZA inhibited GP130-dependent STAT3 activity in the human colon cancer cell line LIM2405 and HT29. BZA treatment sensitized cells to chemotherapy leading to increased apoptosis. BZA treatment also reduced both primary tumour and metastatic burden in vivo demonstrating that gp130 mediated STAT3 inhibition is an attractive target for the treatment of early stage and advanced stage colon cancer. Citation Format: Rhynelle S. Dmello, Pathum Thilakasiri, Belinda Duscio, Ivan Poon, Matthias Ernst, Ashwini Chand. Determining the effect of bazedoxifene in combination with chemotherapy on colon 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 1069.
Propensity score based comparison of nephroureterectomy versus segmental ureterectomy for ureteral tumors
Authors: M. Paciotti, K. Yim, D. Nguyen, M. Marchese, L. Häuser, D. Modonutti, M. Kölker, G. Lughezzani, N.M. Buffi, M. Mossanen, Q-D. Trinh, A.P. Cole
Journal: European Urology (2021)
Abstract 202: Identification of survival associated hub genes in prostate cancer patients from the TCGA database
Authors: Niradiz Reyes, Raj Tiwari, Jan Geliebter
Journal: Cancer Research (2021)

Abstract Background: Prostate cancer is the most frequently diagnosed malignancy and the fourth leading cause of cancer-related death in the global male population. Although the disease has a relatively low mortality rate with some patients surviving for 10-20 years after treatment, others respond poorly to treatment and die of metastatic disease within 2-3 years. Therefore, there is an urgent need to develop strategies to identify patients with clinically significant prostate cancer requiring aggressive treatment to improve survival, while sparing others unnecessary side effects. The purpose of this study was to identify survival associated genes in prostate cancer patients from the TCGA database using bioinformatics tools. Methods: Data from prostate cancer patients in the TCGA database were divided into two study groups: a high and a low expression group, relative to the median expression. The Gene Expression Profiling Interactive Analysis (GEPIA2) tool was used for the identification of the most differential survival genes. Metascape bioinformatics tool was subsequently used for clustering of genes based on processes, pathway enrichment analysis, and construction of Protein-Protein Interaction (PPI) network. Metascape was also used for molecular Complex Detection (MCODE) to identify the genes with the highest degree of connection, known as hub genes, and to screen modules of the PPI network. Results: Bioinformatics analysis allowed the identification of 361 genes whose expression levels were significantly associated with overall survival in prostate cancer patients from the TCGA. Survival associated genes were primarily enriched in mRNA processing, DNA repair, ncRNA processing, DNA replication, macromolecule methylation, among others. The 12 most connected genes were selected as hub genes and Kaplan-Meier analysis was used to verify survival associated with this set of genes. Hub genes included several splicing factors and components of the processing machinery of cellular pre-mRNAs. Conclusions: These hub genes may reveal basic mechanisms underlying the development of clinically relevant prostate cancer and contribute to the identification of novel markers for prognosis of this cancer. Citation Format: Niradiz Reyes, Raj Tiwari, Jan Geliebter. Identification of survival associated hub genes in prostate cancer patients from the TCGA database [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 202.