tbuckley/cabot-search huggingface dataset:
Abstract 72: PARK2 enhances chemosensitivity of antimicrotubule drugs in breast cancer via promoting degradation of BCL-2
Authors: Hengxing Chen, Yun Li, Yu Li, Zhen Chen, Limin Xie, Wenjia Li, Yuanxin Zhu, Daning Lu, Xue Hong, H. Phillip Koeffler, Wenjing Wu, Kaishun Hu, Dong Yin
Journal: Cancer Research (2020)

Abstract Chemotherapy is applied in over 70% of breast cancer patients. Antimicrotubule drugs and DNA-damaging drugs are the most popular medicine used for chemotherapy. However, it still lack of predictor for indicating which chemotherapy drug will benefit to patients. An urgent need is to develop biomarker used to determine which chemotherapy will work for individual patient. Antimicrotubule drugs such as docetaxel and vinorelbine are prescribed widely for breast cancer, nevertheless, about one-third of breast cancer patients suffer from the side effects of anti-microtubule drugs chemotherapy without benefit from it. Here, we report that PARK2 is a potential biomarker for chemosensitivity to antimicrotubule drugs in breast cancer. PARK2 gene encodes an E3 ubiquitin ligase. 34% of breast cancer patients exhibited PARK2 deletion. Interestingly, high PARK2 expression was positively correlated with favorable survival in breast cancer patients receiving chemotherapy, but not in those not receiving chemotherapy. Moreover, PARK2 overexpression specifically rendered cells more sensitive to antimicrotubule drugs, but not to DNA-damaging drugs. Depletion of PARK2 augmented resistance to antimicrotubule drugs. Mechanistically, PARK2 markedly activated the mitochondrial pathway of apoptosis after exposure to antimicrotubule drugs. This occurred through downregulating the antiapoptotic protein BCL-2. Notably, PARK2 physically interacted with BCL-2 and promoted ubiquitination of BCL-2 in an E3 ligase-dependent manner. Hence, PARK2 significantly enhanced the chemosensitivity of antimicrotubule drugs both in vitro and in vivo, while loss-of-function PARK2 mutants failed to enhance the sensitivity of antimicrotubule drugs. Taken together, we identified PARK2 as a novel mediator of antimicrotubule drug which provides a predictor for the chemosensitivity of antimicrotubule drugs in breast cancer. Citation Format: Hengxing Chen, Yun Li, Yu Li, Zhen Chen, Limin Xie, Wenjia Li, Yuanxin Zhu, Daning Lu, Xue Hong, H. Phillip Koeffler, Wenjing Wu, Kaishun Hu, Dong Yin. PARK2 enhances chemosensitivity of antimicrotubule drugs in breast cancer via promoting degradation of BCL-2 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 72.
The transcription factor E2A activates multiple enhancers that drive <i>Rag</i> expression in developing T and B cells
Authors: Kazuko Miyazaki, Hitomi Watanabe, Genki Yoshikawa, Kenian Chen, Reiko Hidaka, Yuki Aitani, Kai Osawa, Rie Takeda, Yotaro Ochi, Shizue Tani-ichi, Takuya Uehata, Osamu Takeuchi, Koichi Ikuta, Seishi Ogawa, Gen Kondoh, Yin C. Lin, Hiroyuki Ogata, Masaki Miyazaki
Journal: Science Immunology (2020)

Cell type-specific gene expression is driven by the interplay between lineage-specific transcription factors and cis-regulatory elements to which they bind. Adaptive immunity relies on RAG-mediated assembly of T cell receptor (TCR) and immunoglobulin (Ig) genes. Although Rag1 and Rag2 expression is largely restricted to adaptive lymphoid lineage cells, it remains unclear how Rag gene expression is regulated in a cell lineage-specific manner. Here, we identified three distinct cis-regulatory elements, a T cell lineage-specific enhancer (R-TEn) and the two B cell-specific elements, R1B and R2B By generating mice lacking either R-TEn or R1B and R2B, we demonstrate that these distinct sets of regulatory elements drive the expression of Rag genes in developing T and B cells. What these elements have in common is their ability to bind the transcription factor E2A. By generating a mouse strain that carries a mutation within the E2A binding site of R-TEn, we demonstrate that recruitment of E2A to this site is essential for orchestrating changes in chromatin conformation that drive expression of Rag genes in T cells. By mapping cis-regulatory elements and generating multiple mouse strains lacking distinct enhancer elements, we demonstrate expression of Rag genes in developing T and B cells to be driven by distinct sets of E2A-dependent cis-regulatory modules.
Abstract 3628: Multiregional sequencing reveals the heterogeneity and underlying complex evolutionary history in liver cancer metastasis
Authors: Yun-Fan Sun, Pin Wu, Ze-Jian Wang, Min-Fang Song, Kai-Qian Zhou, Li-Ye Zhang, David P. Peng, Jia Fan
Journal: Cancer Research (2020)

Abstract Cancer metastasis is still the major cause of death, and poorly understood mechanistically. Therefore, increasing number of studies begins to study the genetic profiles of metastatic samples. However, studies from different tumor types show contradicting conclusions on evolution pattern. In this study, we focus on metastasis in hepatocellular carcinoma (HCC). We analyzed 92 primary and their matched 177 metastatic samples from a cohort of 64 HCC patients encompassing 10 distinct metastatic sites. To study the heterogeneity, we generated multi-regional exome and RNA sequencing for both primary and metastatic tumors. The inferred phylogenies showed both monoclonal (48 %) and polyclonal (52%) metastasis. The polyclonal metastasis is further divided into two subgroups: single branch-multiple waves and multiple-branch metastasis, while the majority of polyclonal evolution is derived from single branch-multiple waves metastasis (12 out of 13). In addition, we observed similar frequency of early, intermediate and late dissemination for tumor metastasis. Therefore, both the clonal and temporal heterogeneity lead to the genetic diversity in metastasis of HCC, which results in the inconsistency in driver (potentially targetable) mutations between primary and metastatic tumor samples for over 60% of patients in our cohort. To identify the potential driver genes for metastasis, we included another two cohorts including no-relapse/metastasis (n=32) and intrahepatic relapse (n=42) as a control. However, similar to published datasets, only TP53 showed a significant increase of frequency in metastatic cohort compared with other cohorts. To conclude, to our knowledge, we provided by far the largest metastatic HCC cohort of multi-regional sequencing and revealed the complex evolutionary history of HCC metastasis regarding to the clonal and temporal composition. We speculate that huge heterogeneity in HCC, especially in metastatic tumors, may be the main reason for frequent failure in targeted therapy in HCC. Citation Format: Yun-Fan Sun, Pin Wu, Ze-Jian Wang, Min-Fang Song, Kai-Qian Zhou, Li-Ye Zhang, David P. Peng, Jia Fan. Multiregional sequencing reveals the heterogeneity and underlying complex evolutionary history in liver cancer metastasis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3628.
Multiorgan Immune-Related Adverse Events During Treatment With Atezolizumab
Authors: Ganessan Kichenadasse, John O. Miners, Arduino A. Mangoni, Andrew Rowland, Ashley M. Hopkins, Michael J. Sorich
Journal: Journal of the National Comprehensive Cancer Network (2020)

Background: Immune-related adverse events (irAEs) are known to occur in patients with cancer who are treated with immune checkpoint inhibitors. However, limited literature exists on the incidence, time of onset, and risk factors for irAEs, particularly those affecting multiple organs, associated with anti–PD-L1 inhibitors. Methods: A post hoc pooled analysis was conducted using individual patient data from atezolizumab monotherapy arms of 4 non–small cell lung cancer clinical trials. Incidence, clinical patterns, outcomes, and risk factors were investigated of selected organ-specific and multiorgan irAEs during treatment using the anti–PD-L1 inhibitor atezolizumab. Results: From a total of 1,548 patients, 730 irAE episodes were reported in 424 patients (27%). Skin irAEs were the most common (42%), followed by laboratory abnormalities (27%) and endocrine (11.6%), neurologic (7.6%), and pulmonary (6.2%) irAEs. A total of 84 patients (5.4%) had multiorgan irAEs, 70 had 2, 13 had 3, and 1 had 4 different organs affected. “Skin plus” or “laboratory plus” were the most common irAE multiorgan clusters. Patients with multiorgan irAEs were more likely to be white and have a good performance status, a lower baseline neutrophil-lymphocyte ratio, and a good or intermediate lung immune prognostic index score. Multiorgan irAEs were also associated with improved overall survival (hazard ratio, 0.47; 95% CI, 0.28–0.78; P &lt;.0001) but not with progression-free survival (hazard ratio, 0.92; 95% CI, 0.62–1.35; P =.74) compared with the cohort with no irAEs. Conclusions: Multiorgan irAEs occurred in 5.4% of patients treated with atezolizumab in non–small cell lung cancer trials. Future trials should consider routine reporting of data on multiorgan toxicities in addition to organ-specific toxicities.
Medicaid Expansion and Utilization of Antihyperglycemic Therapies
Authors: Andrew Sumarsono, Leo F. Buckley, Sara R. Machado, Rishi K. Wadhera, Haider J. Warraich, Rishi J. Desai, Brendan M. Everett, Darren K. McGuire, Gregg C. Fonarow, Javed Butler, Ambarish Pandey, Muthiah Vaduganathan
Journal: Diabetes Care (2020)

OBJECTIVE Certain antihyperglycemic therapies modify cardiovascular and kidney outcomes among patients with type 2 diabetes, but early uptake in practice appears restricted to particular demographics. We examine the association of Medicaid expansion with use of and expenditures related to antihyperglycemic therapies among Medicaid beneficiaries. RESEARCH DESIGN AND METHODS We employed a difference-in-difference design to analyze the association of Medicaid expansion on prescription of noninsulin antihyperglycemic therapies. We used 2012–2017 national and state Medicaid data to compare prescription claims and costs between states that did (n = 25) and did not expand (n = 26) Medicaid by January 2014. RESULTS Following Medicaid expansion in 2014, average noninsulin antihyperglycemic therapies per state/1,000 enrollees increased by 4.2%/quarter in expansion states and 1.6%/quarter in nonexpansion states. For sodium–glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1RA), quarterly growth rates per 1,000 enrollees were 125.3% and 20.7% for expansion states and 87.6% and 16.0% for nonexpansion states, respectively. Expansion states had faster utilization of SGLT2i and GLP-1RA than nonexpansion states. Difference-in-difference estimates for change in volume of prescriptions after Medicaid expansion between expansion versus nonexpansion states was 1.68 (95% CI 1.09–2.26; P &amp;lt; 0.001) for all noninsulin therapies, 0.125 (−0.003 to 0.25; P = 0.056) for SGLT2i, and 0.12 (0.055–0.18; P &amp;lt; 0.001) for GLP-1RA. CONCLUSIONS Use of noninsulin antihyperglycemic therapies, including SGLT2i and GLP-1RA, increased among low-income adults in both Medicaid expansion and nonexpansion states, with a significantly greater increase in overall use and in GLP-1RA use in expansion states. Future evaluation of the population-level health impact of expanded access to these therapies is needed.
Abstract 396: The bile acid receptor FXR suppress colitis-induced colon cancer
Authors: Ting Fu, Ronald Evans
Journal: Cancer Research (2020)

Abstract Colorectal cancer (CRC) is the third most common cancer and a major cause of cancer related death. Colitis-associated colorectal carcinoma (CAC) is a type of CRC that develops in patients with inflammatory bowel disease (IBD), and is associated with chronic, idiopathic intestinal inflammation. While the underlying cause(s) are poorly understood, environmental factors including high fat diets and aberrant intestinal immune responses contribute to disease progression. Bile acid (BA) overproduction is implicated in diarrhea associated with IBD and CAC. As early sensors of dietary status, BAs are critical mediators of gut inflammation and immunity, in part through their ability to affect the activity of the Farnesoid X Receptor (FXR). FXR is considered the master regulator of BA homeostasis, also a key modulator of the pro- and anti-inflammatory responses in the intestinal epithelium, whose function severely compromised in both CAC patients and in AOM/DSS mouse model. Here, we show that inflammation-induced epithelial abnormalities altered the BAs profile, given the role of the crypt-villus architecture in establishing a BA gradient necessary for homeostasis. In addition, AOM/DSS treatment enhanced immune cell infiltration, as well as induced the formation of massive tumors in the colon. Given that intestinally-restricted FXR agonist FexD can reduced tumorigenesis in APCmin/+ mice, we also treated AOM/DSS mice with FexD. Notably, FexD activated FXR signaling pathway and restored BA homeostasis. Further, it reduced fecal bleeding, intestinal permeability, and decreased serum levels of the late carcinogenesis markers CEA and CA19. Treatment of FexD also resulted in a smaller spleen and reduced pro-inflammatory cytokine levels such as IL17 and IL6. The present study highlights the role of FXR in inflammation induced colon cancer, opening new therapeutic avenues for the treatment of CAC. Citation Format: Ting Fu, Ronald Evans. The bile acid receptor FXR suppress colitis-induced colon cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 396.
Abstract 4421: Development of a clinical-genomic database to study tumor evolution and molecular biomarkers of drug resistance in a real-world setting
Authors: Naveen Kumar, Rajesh Kucharlapati, Aaron Hardin, Victoria M. Raymond, Stephen Fairclough, Kathryn Lang
Journal: Cancer Research (2020)

Abstract Background: Real-world evidence (RWE), specifically the integration of clinical and molecular data, plays an increasingly important role in elucidating the molecular landscape of advanced solid tumors, at diagnosis and at progression, and furthering precision oncology research. However, reliance on tissue genomic testing results within these RWE databases significantly limits our understanding of tumor evolution as tissue profiles are typically limited to a single time point, generally at diagnosis, and biopsies are not routinely completed at progression. Circulating tumor DNA (ctDNA) analysis at diagnosis and progression is an alternative to serial tissue testing. Studying the real-world data derived from ctDNA testing results can provide additional information, specifically around tumor evolution and mechanisms of innate and acquired resistance in response to intervening therapies (targeted and non-targeted). Methods: Anonymized results from patients consecutively tested with Guardant360®, a CLIA-certified, CAP-accredited, NYSDOH-approved ctDNA test indicated for patients with advanced and metastatic solid tumor cancers (Guardant Health, Redwood City, California) were analyzed. Using a secure and HIPAA-compliant methodology, these results were then linked to a de-identified encounters database containing medical and pharmacy claims to provide a longitudinal view of patients' journeys, including diagnosis, treatments, and real-world outcomes. Results: Of 85,874 patients, the disease groups most highly represented were lung, breast, colorectal, prostate, and pancreas cancers. 48,317 patients (56.3%) had a record of treatment with an antineoplastic treatment (i.e. chemo, hormonal, small molecule, or immuno-therapy). Of patients with a record of therapy, 14,608 (30.2%) had a record of therapy following, but none prior to, the Guardant360 test date, 14,493 (30.0%) had a record of therapy prior to, but not following theGuardant360 test date, and 19,216 (39.8%) had a record of therapy both before and after Guardant360 test date. Conclusions: In a cohort of patients who underwent ctDNA testing and for whom treatment information was available, post-therapy molecular results were available in 69.8%. The availability of genomic information following systemic therapy suggest that this dataset is a viable resource to study drug resistance and tumor evolution in the real-world setting. Citation Format: Naveen Kumar, Rajesh Kucharlapati, Aaron Hardin, Victoria M. Raymond, Stephen Fairclough, Kathryn Lang. Development of a clinical-genomic database to study tumor evolution and molecular biomarkers of drug resistance in a real-world setting [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4421.
Abstract 3563: Fatty acid binding protein 7 regulates beige fat-like differentiation of breast cancer cells and thermogenesis
Authors: Masahiro Kawashima, Karim Bensaad, Christos Zois, Alessandro Barberis, Esther Bridges, Christoffer Lagerholm, Ruslan I. Dmitriev, Masakazu Toi, Dmitri B. Papkovsky, Francesca Buffa, Adrian L. Harris
Journal: Cancer Research (2020)

Abstract Cancer cells alter the metabolism in their microenvironment to sustain their survival, growth and progression. Heat is an essential factor that can affect metabolism. However, it is unclear whether cancer cells can alter their temperature by regulating heat production. Non-shivering thermogenesis is known to takes place in inducible beige adipocytes expressing the mitochondrial thermogenic protein, uncoupling protein 1 (UCP1). UCP1 dissipates the proton gradient of the mitochondrial inner membrane and converts its energy into heat. We found that the inhibition of a hypoxia-inducible protein, fatty acid binding protein 7 (FABP7), triggered beige fat-like differentiation and induced thermogenesis in breast cancer cells. We established the breast cancer cell line with a stable knockdown of FAPB7, using lentivirus transduction particles. UCP1-expressing cells were found in 21 ± 5% of the knockdown cells while they were found in only 4 ± 1.7% of the control cells: p = 0.004). UCP1 expression was maximized in the knockdown cells when cultured in hypoxia. A novel thermo-sensitive fluorescent probe confirmed that the cellular temperature of the knockdown cells was 2°C higher than the controls. In addition, the knockdown cells exhibited the increased mitochondrial depolarization, increased proton leak and increased respiration rate compared to controls, suggesting they had the similar energy profile with beige adipocytes. The knockdown cells became more sensitive to hypoxia and radiation, and the clinical manifestation of breast cancer patients differed depending on the expression levels of both UCP1 and FABP7. These observations suggested a missing link between hypoxia-related fatty acid metabolism and cellular thermogenesis which might be a novel therapeutic target for breast cancer. Citation Format: Masahiro Kawashima, Karim Bensaad, Christos Zois, Alessandro Barberis, Esther Bridges, Christoffer Lagerholm, Ruslan I. Dmitriev, Masakazu Toi, Dmitri B. Papkovsky, Francesca Buffa, Adrian L. Harris. Fatty acid binding protein 7 regulates beige fat-like differentiation of breast cancer cells and thermogenesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3563.
Abstract 2939: Canonical and noncanonical survivin isoforms translocate to the plasma membrane and are secreted in exosomes
Authors: Sheila Figel, Meaghan Birkemeier, Sanam Dharma, Emma Steinmetz, Michael Ciesielski, Robert Fenstermaker
Journal: Cancer Research (2020)

Abstract Background: Previously we found that survivin is expressed on the surface of cancer cells in vitro, and is targetable using certain survivin-specific antibodies. The survivin gene is alternatively spliced into two alternative isoforms, ΔEX3 and 2B, which diverge structurally from the canonical isoform in their C-termini but retain a conserved BIR (Baculovirus IAP Repeat) domain. Methods: In order to characterize plasma membrane survivin (PM-SVN), tagged proteins representing canonical survivin (isoform 1), Δex3 and 2B were transiently expressed in multiple cancer cell line backgrounds. Relative surface expression was measured by flow cytometry staining of intact cells. Mutant constructs were used to determine the structural requirements for translocation. Imaging flow cytometry (Imagestream) was used to visualize survivin isoform localization, and to detect co-localization on the cell surface. Secreted exosomes were examined for expression of survivin isoforms. Results: Isoforms 1, Δex3 and 2B could be detected on the surface of HEK293T embryonic kidney, HeLa cervical adenocarcinoma, U87 glioblastoma, and A1207 glioblastoma cells. PM-SVN expression was variable, however Δex3 showed robust membrane expression across all cell lines. Deletion of a predicted transmembrane sequence in Δex3's unique C-terminus did not impair its translocation, and deletion of the first 10 amino acids, thought to be required for dimerization, disrupted surface expression only in HEK293T cells. Imaging flow cytometry analysis of cells revealed polar localization of PM-SVN, with specific punctate areas seen in 13-20% of cells. Staining with antibodies targeting both isoform 1 and Δex3 showed co-immunofluorescence in cell membrane puncta, indicating the formation of heterodimers. Stressing cells by heat shock increased the proportion of PM-SVN in 293T and A1207 cells; in 293T, this was accompanied by enrichment of survivin protein in secreted exosomes. Conclusions: In addition to canonical survivin, isoforms Δex3 and 2B are displayed on the surface of cancer cells, and can be secreted as exosomal cargo. Membrane translocation may be stress-induced and appears to require the conserved BIR domain. PM-SVN shows a polar distribution on the cell membrane, and isoforms 1 and Δex3 heterodimerize within these puncta. Citation Format: Sheila Figel, Meaghan Birkemeier, Sanam Dharma, Emma Steinmetz, Michael Ciesielski, Robert Fenstermaker. Canonical and noncanonical survivin isoforms translocate to the plasma membrane and are secreted in exosomes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2939.
Potentiation of oral anticoagulants by ketoconazole
Authors: Erik Hagg, Mikael Eklund
Journal: BMJ (1984)

Case reports CASE 1The patient was a 19 year old previously healthy man who was injured while ski jumping and sustained complete tetraplegia.X ray examinations disdosed fractures of C4 and C5.On admission to hospital he had normal serum concentrations of calcium, phosphate, creatinine, and parathyroid and thyroid hormones.Repeated chest x ray films were normal, as were x ray films of the skull, lumbar spine, and pelvis.