tbuckley/cabot-search huggingface dataset:
Abstract 591: Developing an immunofluorescence assay for detecting Rb and phospho-Rb on circulating tumor cells in breast cancer
Authors: Tanya Kumar, Hariprasad Thangavel, Noor Mazin Abdulkareem, Raksha Bhat, Meghana V. Trivedi
Journal: Cancer Research (2021)

Abstract Endocrine therapies (ET) such as tamoxifen, fulvestrant, and aromatase inhibitors (AIs) are the standard-of-care first-line treatment in majority of estrogen receptor (ER)-positive breast cancers (BC). Recent clinical studies using cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) plus AIs or fulvestrant have shown significant improvement in survival outcomes in patients with ER+ metastatic BC compared to standalone ETs. CDK4/6i exert their action by inhibiting the phosphorylation of retinoblastoma (Rb) protein and consequently inducing cell cycle arrest. However, not all patients respond to this combination therapy and those, who initially respond, eventually develop resistance. Emerging studies suggest that the intrinsic resistance to CDK4/6i could be due to the loss of Rb or its mutations. Therefore, CDK4/6i resistance can be evaluated by measuring expression of total and phospho-Rb and Rb mutations. However, repeated biopsies to evaluate biomarkers in tumors is not feasible in patients. In this research, we aimed to develop an immunofluorescence assay to evaluate the expression of Rb and phospho-Rb using circulating tumor cells (CTCs) which can help predict response and resistance to CDK4/6i. CTCs serve as representative of the tumor bulk in patients and animal models and allow for less-invasive, frequent blood collection and real-time monitoring of treatment response. MCF7 cells treated with vehicle or abemaciclib (500 nM) for 48 hours were spiked into blood from non-tumor bearing mice. The MCF7 cells-spiked blood was processed using ScreenCell® device and the cells were transferred to slides and stained with DAPI, pan-cytokeratin, CD45, estrogen receptor, Rb and phospho-Rb. Tumor cells were defined as pan-cytokeratin-positive, CD45-negative, and nuclear stain-positive cells. Various antibody combinations were examined to increase the sensitivity of the IF assay for individual markers as well as the multiplexed assay. We also developed quantitative assessment approach to detect per-cell intensity of various markers. Treatment with abemaciclib reduced the intensity of phospho/Total Rb from 2.6 +/- 0.6 to 0.8 +/- 0.2 units (p &amp;lt; 0.05, t-test, n=8-9) in the vehicle-treated samples. There was no significant difference in the Rb intensity between the treatment groups. Ongoing studies focus on validation of the assay using preclinical models and clinical samples. Citation Format: Tanya Kumar, Hariprasad Thangavel, Noor Mazin Abdulkareem, Raksha Bhat, Meghana V. Trivedi. Developing an immunofluorescence assay for detecting Rb and phospho-Rb on circulating tumor cells in breast 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 591.
Is robotic surgery safe and feasible for horseshoe kidneys? A multicentre case series
Authors: A. Ng, A. Nathan, N. Campain, M. Fortune-Ely, S. Patki, Y. Yuminaga, F. Mumtaz, A. Gulamhusein, M. Tran, R. Barod, P. Patki, A. Bex
Journal: European Urology (2021)
Development and external validation of a novel tool predicting lymph node invasion in patients with prostate cancer detected at targeted-biopsies
Authors: A. Stabile, E. Mazzone, F. Barletta, G. Sorce, U. Pinar, T. Seisen, M. Roupret, G. Ploussard, P. De Visschere, E. Borgmann, I. Heidegger, A. Kretschmer, C. Surcel, D. Tilki, I. Tsaur, M. Valerio, R. Van Der Bergh, P. Ost, N. Fossati, G. Gandaglia, F. De Cobelli, P.I. Karakiewicz, F. Montorsi, A. Briganti
Journal: European Urology (2021)
Abstract 2853: Transposon-activated <i>POU5F1B</i> promotes colorectal cancer growth and metastasis
Authors: Laia Simó-Riudalbas, Evarist Planet, Sandra Offner, Julien Duc, Laurence Abrami, Sagane Dind, Alexandre Coudray, Mairene Coto-Llerena, Salvatore Piscuoglio, Claus L. Andersen, Jesper Bertram Bramsen, Didier Trono
Journal: Cancer Research (2021)

Abstract The human genome contains some 4 million transposable element (TE)-derived sequences, which collectively influence gene expression from early embryogenesis to adulthood. The illegitimate production of oncogene-encoding TE-driven transpochimeric gene transcripts (TcGTs) has been noted in tumors, but their participation in the oncogenic process has seldom been demonstrated. Here we describe how the aberrant de-repression of a primate-specific LTR66 endogenous retroviral promoter generates a TcGT overexpressing the great-ape-restricted POU5F1B retrogene in ~65% of 286 colorectal cancers (CRC) patients, correlating with more advanced tumor stages and shorter relapse-free and overall survival. We further demonstrate that the POU5F1B protein stimulates the clonogenic and proliferation capacity of human CRC cell lines in vitro, and their tumorigenic and metastatic potential in mouse xenotransplantation models. Although POU5F1B is a retrotransposition-mediated derivative of the POU5F1/OCT4 transcription factor, its product is a predominantly cytoplasmic protein enriched in membranes that associates with mediators of signal transduction, notably the ERBB2 receptor tyrosine kinase and several of its known interactors. POU5F1B overexpression results in activating genes involved in signaling, and conditioned medium of POU5F1B-overexpressing cells enhances the clonogenic potential of CRC cells in trans. As POU5F1B is encoded by an apparently non-essential gene only lowly expressed in normal tissues, and as POU5F1B-containing TcGTs are detected in other tumors besides CRC, it represents an attractive target for the development of cancer therapies. Citation Format: Laia Simó-Riudalbas, Evarist Planet, Sandra Offner, Julien Duc, Laurence Abrami, Sagane Dind, Alexandre Coudray, Mairene Coto-Llerena, Salvatore Piscuoglio, Claus L. Andersen, Jesper Bertram Bramsen, Didier Trono. Transposon-activated POU5F1B promotes colorectal cancer growth and metastasis [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 2853.
Metformin generates profound alterations in systemic and tumor immunity with associated antitumor effects
Authors: Ratna Veeramachaneni, Wangjie Yu, Jared M Newton, Jan O Kemnade, Heath D Skinner, Andrew G Sikora, Vlad C Sandulache
Journal: Journal for ImmunoTherapy of Cancer (2021)

Metformin is a commonly used antidiabetic medication which has demonstrated promise as an anticancer agent alone and in combination with conventional treatment regimens. There is increasing evidence that metformin can also generate immunomodulatory effects in solid tumors and is currently being investigated as an adjunct to immune checkpoint inhibitors (ICIs). We hypothesized that metformin would generate a shift in immunity unfavorable to tumor growth and tested this hypothesis in a preclinical model of head and neck cancer.Using a syngeneic mouse model of human papillomavirus-associated head and neck cancer (mEER/MTEC), we tested the impact of metformin on systemic and local immunity and tumor growth velocity. We compared the effects of acute and chronic treatment regimens on immunocyte presence and activation using a combination of flow cytometry and targeted transcriptomic analysis.Acute metformin exposure generated measurable shifts in systemic myeloid and T-cell populations in non-tumor-bearing mice and decreased myeloid derived suppressor cell (MDSC) levels in tumor draining lymph nodes of tumor-bearing mice. Although metformin decreased regulatory T-cell (T-reg) and MDSC levels and increased CD8+ levels in murine tumors when combined with ICIs, acute metformin exposure was insufficient to generate substantial antitumor activity. Conversely, long-term metformin treatment significantly reduced tumor growth velocity, increased the CD8+/T-reg ratio, increased tumor infiltrating lymphocyte levels and upregulated component genes of the previously validated T-cell inflamed expression profile.Metformin generates complex systemic and local immune effects which vary as a function of treatment duration. Combinatorial strategies with ICIs must take into account both the complexity and variability of these effects in order to generate maximal antitumor activity in future clinical trials.
Abstract 2144: STAT3 regulates the expression of XRCC1 in triple negative breast cancer
Authors: Griffin M. Wright, Natalie R. Gassman
Journal: Cancer Research (2021)

Abstract Background: Base excision repair (BER) addresses base lesions and abasic sites induced by endogenous and exogenous environmental stresses. XRCC1 is a scaffold protein that facilitates and coordinates the BER repair machinery. Alterations in the protein and gene expression of XRCC1 have been observed in a multitude of cancers, including triple negative breast cancers (TNBC). Increased expression of XRCC1 is associated with aggressiveness and resistance to DNA damaging chemotherapeutics. However, only two transcription factors, E2F1 and Sp1 have been implicated in the transcriptional regulation of XRCC1 to date. Methods: Utilizing promoter luciferase, transcription factor promoter binding ELISA, and chromatin immunoprecipitation (CHiP), STAT3 binding was identified and mapped in the XRCC1 promoter. Results: In the current study, we identify a STAT3 binding site within the XRCC1 promoter. Importantly, STAT3 regulation of XRCC1 appears to be constitutive in TNBC cell line models where STAT3 is highly activated. In HEK293T cells, the STAT3 binding site shows low occupancy under basal growth condition, but STAT3 regulation of XRCC1 can be stimulated by cytokine or mitogenic signaling by IL-6 and epidermal growth factor (EGF). Summary: STAT3 conditionally regulates XRCC1 under specific stress conditions to promote BER. In TNBC, the overexpression of XRCC1 by activated STAT3 likely contributes to increased resistance to DNA damaging chemotherapeutics. Citation Format: Griffin M. Wright, Natalie R. Gassman. STAT3 regulates the expression of XRCC1 in triple negative breast 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 2144.
Abstract 2179: Identification of ROS1 alterations in ctDNA from colorectal cancer patients in China
Authors: Mojin Wang, Lili Zhu, Depei Huang, Xudong Shen, Hushan Zhang, Xueke She
Journal: Cancer Research (2021)

Abstract Background: ROS proto-oncogene 1 (ROS1) is an oncogenic driver involved in various cancer types for which has FDA approved therapies. ROS1 has shown to undergo genetic rearrangements in a variety of human cancers including glioblastoma, non-small cell lung cancer (NSCLC), ovarian cancer, gastric adenocarcinoma and colorectal cancer. The rearrangements create fusion proteins in which the kinase domain of ROS1 becomes constitutively active and drives cellular proliferation. Although previous data have reported ROS1 fusions occur in 0.2% to 2.4% of colorectal cancers, the frequency and type of ROS1 alterations in Chinese CRC patients have not been fully reported. Methods: This study queried data from 1,083 colorectal cancer samples which underwent a targeted next-generation sequencing assay performed by 3DMed Clinical Laboratory Inc., a College of American Pathologists (CAP) certified and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory of 3D Medicines Inc. between January, 2017 and June, 2020 in China, to identify the incidence of ROS1 alterations detected in ctDNA in colorectal cancer patients. The detected genetic alteration types included single-nucleotide variants (SNVs), copy number variations (CNVs) and gene rearrangements/fusions. Results: ROS1 alterations were found in 114 patients among the 1,083 (10.5%) CRC patients' cohort, including 72 males and 42 females, median age was 58 years old. The ROS1 alterations included 110 (96.5%) SNVs, 3 (2.6%) CNVs and 1 (0.9%) GOPC-ROS1 fusion. Among the 110 single nucleotide variants, we identified 91 (82.7%) of ROS1 SNVs were nonsynonymous mutations. The top 5 co-occurring mutations in samples with ROS1 alterations were TP53 (71, 62.2%), CYP2C19 (48, 42.1%), APC (48, 42.1%), KRAS (46, 40.3%) and DPYD (42, 36.8%). Conclusion: Our study indicated that ctDNA can be used as a nonvasive methodology to detect cancer-specific genetic aberrations in plasma for CRC. ROS1 alterations occurred modestly in Chinese colorectal cancer patients. Co-occurring mutations may provide different biological subsets of patients with ROS1-mutant colorectal cancer to reveal patient outcomes and response to therapy. Further investigation could be focused on the effect of ROS1 nonsynonymous mutations on the ROS1 proteins in vitro to identify whether these are more actionable than currently recognized. Citation Format: Mojin Wang, Lili Zhu, Depei Huang, Xudong Shen, Hushan Zhang, Xueke She. Identification of ROS1 alterations in ctDNA from colorectal cancer patients in China [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 2179.
Cabozantinib for radioiodine-refractory differentiated thyroid cancer (COSMIC-311): a randomised, double-blind, placebo-controlled, phase 3 trial
Authors: Marcia S Brose, Bruce Robinson, Steven I Sherman, Jolanta Krajewska, Chia-Chi Lin, Fernanda Vaisman, Ana O Hoff, Erika Hitre, Daniel W Bowles, Jorge Hernando, Leonardo Faoro, Kamalika Banerjee, Jennifer W Oliver, Bhumsuk Keam, Jaume Capdevila
Journal: The Lancet Oncology (2021)
Abstract 12691: Variables Associated With Lipoprotein (a) Levels and Clinical Significances
Authors: Moonki Jung, Iksung Cho, Hoyoun Won, Seung Yong Shin, Wang Soo Lee, Kwang Je Lee, Sang Wook Kim, Tae Ho Kim, Chee Jeong Kim
Journal: Circulation (2018)

Introduction: Lipoprotein (a) [Lp(a)] has been found to be an additional risk marker for atherosclerotic cardiovascular diseases in selected cases. Lp(a) level is mainly determined by genetic varia...
WNT6/ACC2-induced storage of triacylglycerols in macrophages is exploited by Mycobacterium tuberculosis
Authors: Julius Brandenburg, Sebastian Marwitz, Simone C. Tazoll, Franziska Waldow, Barbara Kalsdorf, Tim Vierbuchen, Thomas Scholzen, Annette Gross, Svenja Goldenbaum, Alexandra Hölscher, Martina Hein, Lara Linnemann, Maja Reimann, Andreas Kispert, Michael Leitges, Jan Rupp, Christoph Lange, Stefan Niemann, Jochen Behrends, Torsten Goldmann, Holger Heine, Ulrich E. Schaible, Christoph Hölscher, Dominik Schwudke, Norbert Reiling
Journal: Journal of Clinical Investigation (2021)

In view of emerging drug-resistant tuberculosis (TB), host-directed adjunct therapies are urgently needed to improve treatment outcomes with currently available anti-TB therapies. One approach is to interfere with the formation of lipid-laden "foamy" macrophages in the host, as they provide a nutrient-rich host cell environment for Mycobacterium tuberculosis (Mtb). Here, we provide evidence that Wnt family member 6 (WNT6), a ligand of the evolutionarily conserved Wingless/Integrase 1 (WNT) signaling pathway, promotes foam cell formation by regulating key lipid metabolic genes including acetyl-CoA carboxylase 2 (ACC2) during pulmonary TB. Using genetic and pharmacological approaches, we demonstrated that lack of functional WNT6 or ACC2 significantly reduced intracellular triacylglycerol (TAG) levels and Mtb survival in macrophages. Moreover, treatment of Mtb-infected mice with a combination of a pharmacological ACC2 inhibitor and the anti-TB drug isoniazid (INH) reduced lung TAG and cytokine levels, as well as lung weights, compared with treatment with INH alone. This combination also reduced Mtb bacterial numbers and the size of mononuclear cell infiltrates in livers of infected mice. In summary, our findings demonstrate that Mtb exploits WNT6/ACC2-induced storage of TAGs in macrophages to facilitate its intracellular survival, a finding that opens new perspectives for host-directed adjunctive treatment of pulmonary TB.
Abstract 2529: Specific racial CYP2R1 correlation with circadian rhythm genes in prostate adenocarcinoma
Authors: Isaacson Bababode Adelani, Solomon Oladapo Rotimi, Clayton Yates, Moray Campbell
Journal: Cancer Research (2021)

Abstract Introduction: Vitamin D in its hormonal form, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) binds to the vitamin D receptor (VDR) to regulate genes, for example, in skeletal mineralization. However, it also has other potent biological functions in regulating apoptosis, proliferation, and inflammation. In carcinogenesis, 1,25(OH)2D3 may be exploited to regulate these crucial pathways. It is also clear that a frequent cancer disparity exists amongst African American (AA) men with prostate cancer compared to European Americans (EA). AA men show a higher incidence rate and two to three times increased risk of mortality than EA counterparts. Various groups have suggested that 1,25(OH)2D3 levels and/or VDR functions are risk factors linked with increased prostate cancer incidence in AA men. Incidentally, reports showed that VD plays a crucial role in regulating circadian rhythm (CR). There is, therefore, a need to understand and evaluate 1,25(OH)2D3-dependent CR regulation and the association with racial disparity in prostate cancer. This study aimed to determine if there are differentially expressed VD metabolic enzymes in AA and EA and evaluate if the differential expression correlates with CR genes. Methods: The Cancer Genome Atlas Research Network (TCGA), 2015 database was queried for expression of VD metabolizing enzymes and CR genes. The search was carried out on prostate adenocarcinoma expressions of AA and EA. VD metabolizing enzymes queried are CYP2R1, CYP24A1, CYP27B1, CYP27A1, while CR genes queried include ARNTL, CLOCK, CRY1, CRY2, CSNK1E, NPAS2, PER1, PER2, PER3, and TIMELESS. Prostate adenocarcinoma racial differential expressions of AA and EA were evaluated, and a correlation study was done using the Pearson correlation. Results: VD metabolic enzyme, CYP2R1, and CR gene, ARNTL were significantly upregulated in AA compared to EA counterparts. Although CYPR1 correlates negatively with CLOCK, CRY2, and PER3 in both races, CYPR1 specifically showed a positive correlation with CR gene CRY1 in EA and negative correlations with CR genes NPAS2 and CSNK1E in AA. However, a significant correlation between CYP2R1 and ARNTL in EA and AA was not observed. Conclusion: The data suggest a relationship between racial influence and prostate cancer associated with VD metabolism and CR regulation. Hence, it is crucial to elucidate CYP2R1 regulation in prostate cancer related to VD levels and CR regulation, especially with a focus on racial disparities. Citation Format: Isaacson Bababode Adelani, Solomon Oladapo Rotimi, Clayton Yates, Moray Campbell. Specific racial CYP2R1 correlation with circadian rhythm genes in prostate 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 2529.
Abstract 2367: Role of miR-34a-MET axis in head and neck cancer squamous cell carcinoma
Authors: Xun Wu, Yi-Shing Lisa Cheng, Methew Matthen, Angela Yoon, Gary Schwartz, Shashi Bala, Alison M. Taylor, Fatemeh Momen-Heravi
Journal: Cancer Research (2021)

Abstract MicroRNAs (miR) are evolutionarily highly conserved non-coding RNAs that play roles in fundamental cellular functions by post-translational gene regulation. In cancer pathogenesis, miRs exert both anti-tumorigenic and pro-tumorigenic effects by virtue of miR-specific and context-dependent mechanisms. The role of chromosomal changes and mutation status on miR expression in cancer remains unknown. Here we provide evidence that chromosome arm 1p loss and P53 mutations are associated with lower levels of miR-34a, particularly in squamous cancers such as head and neck squamous cell carcinoma (HNSCC). miR-34a acts as a tumor suppressor and physically interacts with and functionally targets the proto-oncogene MET, and modulates cell proliferation. miR-34a expression is inversely correlated with MET in tumor tissue. We found that miR-34a suppresses HNSCC carcinogenesis, at least in part, by downregulating MET, consequently inhibiting HNSCC proliferation. Moreover, ectopic expression of miR-34a reduces HNSCC cell proliferation and tumor burden in vitro and in vivo, represses expression of genes and proteins involved in epithelial-mesenchymal transition, and negates the oncogenic effect of MET in mouse tumors. Our work demonstrates a role of miR-34a in maintaining tumor immunity, as overexpression of miR-34a resulted in a decease in percentage of anti-inflammatory (M2-like) TAMs and PDL1+TAMs, which are reported to have pro-tumorigenic activity. In HNSCC patient samples, higher levels of miR-34a are significantly associated with a higher frequency of Th1 cells, myeloid cells, and regulatory T cells. Our results demonstrate that miR-34a directly targets MET and maintains anti-tumor immune activity, and could potentially represent a new therapeutic approach for HNSCC. Citation Format: Xun Wu, Yi-Shing Lisa Cheng, Methew Matthen, Angela Yoon, Gary Schwartz, Shashi Bala, Alison M. Taylor, Fatemeh Momen-Heravi. Role of miR-34a-MET axis in head and neck cancer squamous cell carcinoma [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 2367.
Abstract 802: Multi-cancer profiles in high-risk CLL families
Authors: Nathan Scott Harris
Journal: Cancer Research (2021)

Abstract Discovery of novel etiological factors for B-cell malignancies is hindered by the heterogeneity of these diseases. The identification of important multi-cancer profiles provides a new avenue for discovery, but requires novel approaches and specific resources. The Utah Population Database (UPDB) includes extensive genealogy for 5 million Utahns (from three to 18 generations). The UPDB also includes over 360,000 cancer diagnoses from the NCI SEER Utah Cancer Registry, making it a unique and ideal resource for analyzing cancer patterns in families. Here we performed a multi-cancer clustering approach to identify patterns of familial clustering of cancers in high-risk CLL families. Other cancers considered in the cancer profiles were: Hodgkins lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, multiple myeloma and 25 solid tumors. High risk CLL pedigrees were extracted from the UPDB. Based on cancer rates in UPDB, standardized incidence ratios were calculated for each pedigree for each of the 29 cancers. These vectors of cancer risks per pedigree were used as the basis for k-mediods clustering of the high-risk CLL families. Resulting clusters of families share similar co-aggregations of other B-cell malignancies and solid tumors. High-risk CLL families with similar multi-cancer profiles may be more etiologically homogeneous and provide improved power for the identification of underlying risk factors. Citation Format: Nathan Scott Harris. Multi-cancer profiles in high-risk CLL families [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 802.