tbuckley/cabot-search huggingface dataset:
Abstract 5737: Genomic drivers of cancer are enriched and mutually exclusive within non-T cell-inflamed tumors
Authors: Brian Olson, Riyue Bao, Jessica Fessler, Jason Luke, Thomas F. Gajewski, Akash Patnaik
Journal: Cancer Research (2018)

Abstract While immunotherapy has seen dramatic successes in a variety of malignancies, the majority of patients fail to respond. In particular, less than 10% of patients with metastatic, castrate-resistant prostate cancer (mCRPC) respond to immunotherapy. Based on previous work demonstrating robust clinical activity of immunotherapies in patients with a T cell-inflamed tumor microenvironment, we investigated whether non-T cell-inflamed cancers show evidence for distinct genomic alterations that might mediate immune escape. RNA-seq gene expression data were analyzed from two prostate cancer cohorts, The Cancer Genome Atlas (TCGA) of primary tumors (n=437) and a Stand Up to Cancer (SU2C) mCRPC cohort (n=43). These datasets were interrogated for common molecular alterations and their association with non-T cell-inflamed and T cell-inflamed cancers, focusing on copy number deletions of PTEN, RB1/CDKN2A, and activating mutations in CTNNB1 (β-catenin). Similar approaches were used to analyze 30 solid tumor types from TCGA (n=9555). Our analysis identified that 94% of primary prostate cancers harbor a non-T cell-inflamed tumor microenvironment, with only 6% of patients having a T cell-inflamed gene signature. Similar results were found in mCRPC patients from the SU2C cohort. Higher frequencies of PTEN loss and CTNNB1 activation, as well as a significant enrichment of RB1/CDKN2A deletion, were found in non-T cell-inflamed primary and metastatic prostate tumors. Moreover, we observed a direct correlation between the expression of PTEN/RB1 and CD8A expression within the tumor microenvironment. Strikingly, analysis of 30 human cancers revealed that loss of PTEN and/or RB1/CDKN2A correlates with T-cell exclusion across multiple malignancies. When combined with β-catenin pathway activation, we found that these alterations are mutually exclusive, with only 1% of non-T cell-inflamed cancers sharing all three mechanisms, 24% sharing two out of the three, and 75% of the samples harboring only one mechanism. Taken together, these data reveal that deregulated PTEN/PI3K, Rb and Wnt-β-catenin signaling networks are enriched in a mutually exclusive manner within non-T cell-inflamed cancers, suggesting that such cancers evolutionarily co-opt nonredundant signaling pathways to achieve a common goal of immune evasion. Targeting these pathways pharmacologically may provide an opportunity to enhance responsiveness to immunotherapy across multiple malignancies. Citation Format: Brian Olson, Riyue Bao, Jessica Fessler, Jason Luke, Thomas F. Gajewski, Akash Patnaik. Genomic drivers of cancer are enriched and mutually exclusive within non-T cell-inflamed tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5737.
Abstract 3994: Anti-metastatic drug MBQ-167 regulates cell polarity via Cdc42
Authors: Michael John Rivera-Robles, Julia Medina-Velázquez, Gabriela M. Asencio-Torres, Sahily González-Crespo, Brian C. Rymond, José Rodríguez-Medina, Suranganie Dharmawardhane
Journal: Cancer Research (2018)

Abstract Cdc42 (cell division control protein 42 homolog) is a Rho GTPase highly conserved among eukaryotes in structure and function. Mechanical or chemical cues in the microenvironment stimulate the localized activation of Cdc42, aiding cells to polarize and arrange their components accordingly. Its role in cell polarity was first described in budding yeast and subsequently in other eukaryotes, including animal cells determining the direction of motility. Accordingly, in cancer Cdc42 mediates migration, invasion, and spread of tumor cells. Therefore, we target Cdc42 as therapeutic strategy to treat metastatic breast cancer. Our group designed and characterized the small molecule MBQ-167 as a potent inhibitor against Cdc42 activation (IC50=0.1 µM), demonstrating its effectiveness in preventing tumor growth and cell migration in vitro and in vivo. Because in yeast S. cereviciae Cdc42 is well known for regulating the location of budding events, we used this well-characterized model of cell polarization to test our previous findings of MBQ-167 and its specificity for Cdc42. By using a tetracycline-controlled transcriptional inactivation (Tet-Off) system at the promoter region of the CDC42 gene of yeast, we knocked down Cdc42 supplementing the media with doxycycline (DOX; IC=10ug/uL). Next, we analyzed the growth, budding pattern, and Cdc42 activity of budding yeast exposed to DOX, MBQ-167 or in combination. The maximum growth, doubling time and budding polarity of recombinant yeast with the Tet-Off system were reduced when treated with DOX (EC50=10ug/mL), as expected. The same effect was seen in the group treated with MBQ-167 (ED50=100uM), both alone and in combination with DOX. Ultimately, pull-down assays of the active Cdc42-GTP complex confirmed our hypothesis that MBQ-167 disrupts cell polarity through impeding Cdc42 activation. Here we validated MBQ-167 as a Cdc42 inhibitor in another biologic context. and present a method for screening Cdc42 inhibitors and potential therapeutics against metastatic cancer. Citation Format: Michael John Rivera-Robles, Julia Medina-Velázquez, Gabriela M. Asencio-Torres, Sahily González-Crespo, Brian C. Rymond, José Rodríguez-Medina, Suranganie Dharmawardhane. Anti-metastatic drug MBQ-167 regulates cell polarity via Cdc42 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3994.
Differential Effects of Anti–β2-Glycoprotein I Antibodies on Endothelial Cells and on the Manifestations of Experimental Antiphospholipid Syndrome
Authors: JacobGeorge, MiriBlank, YairLevy, PierluigiMeroni, MayaDamianovich, AngelaTincani, YehudaShoenfeld
Journal: Circulation (1998)

Background—The antiphospholipid syndrome (APS) entails a prothrombotic state associated with the presence of anticardiolipin antibodies (aCL). aCL were shown to promote endothelial cell and platelet activation and to induce an APS-like syndrome in mice when administered intravenously. Recent data suggest that aCL target the plasma cofactor β2-glycoprotein I (β2GPI) rather than negatively charged phospholipids. However, it has not been determined whether different epitope-specific anti-β2GPI antibodies obtained from one patient possess pathogenic properties. Methods and Results—Three β2GPI-binding IgM monoclonal antibodies (mAbs) (ILA-1, ILA-3, and ILA-4) were cloned from a patient with APS. The three antibodies were shown to bind β2GPI immobilized on irradiated plates, yet only ILA-1 bound β2GPI coated onto nonirradiated plates. Furthermore, when using the anti-β2GPI enzyme-linked immunosorbent assay, ILA-1 was the only mAb inhibited by fluid phase β2GPI. ILA-1 and ILA-3, but not ILA-4, induced adherence ...
Abstract B25: Hormone receptor expression and response in ovarian tumors of low malignant potential
Authors: Sarah E. Taylor, Courtney L. Andersen, Rohit Bhargava, George Tseng, Steffi Oesterreich, Robert P. Edwards, Adrian V. Lee
Journal: Clinical Cancer Research (2018)

Abstract Objective: Primary treatment for ovarian low malignant potential (LMP) tumors is surgical resection with little proven effect of cytotoxic chemotherapy. New therapeutic strategies are needed to prevent and treat recurrence. The objective of this study is to investigate the role of hormone receptors in ovarian low malignant potential tumors. Methods: We obtained formalin-fixed, paraffin embedded (FFPE) tissue samples from patients with ovarian LMP tumors. Clinicopathologic data were collected for all available specimens. Immunohistochemistry (IHC) was performed to determine protein expression. Gene expression was measured using the NanoString nCounter platform. Differences in expression between histologic subtypes were by t-test, followed by a Bonferroni adjustment for multiple comparisons (p&amp;lt;0.01). Results: Thirty-eight patients were included in this study. The histologic subtypes were divided between 20 serous and 18 mucinous tumors. All serous tumors were ERα and PR positive by IHC and 6 of 20 (30%) were ERβ positive. Only one of the 18 mucinous tumors (5.6%) was positive for both ERα and PR, and all the samples were negative for ERβ. ERβ mRNA levels were elevated in the mucinous LMP tumors and ERα mRNA was higher in the serous samples. ERα and PR protein expression correlated with mRNA expression of ESR1 (r2=0.5606) and PR (r2=0.42), respectively. ERβ expression did not correlate with mRNA expression of ESR2 (r2=0.038). Measurement of estrogen-regulated genes and genes involved in ER signaling (n=236) revealed a clear separation of serous from mucinous subtypes, with 44 genes showing a statistically significant difference (p&amp;lt;0.01) between the serous and mucinous subtypes. Conclusion: High levels of ERα, PR, and downstream ERα targets in serous LMP tumors suggest hormone responsiveness and that these tumors are potentially treatable with endocrine therapy. Mucinous tumors largely did not express hormone receptors. In light of this, differences in gene expression observed are more likely attributable to underlying lineage differences than differences in estrogen signaling. Additional large-scale analyses are warranted to better understand the differences between subtypes and to identify avenues for targeted therapy in mucinous LMPs. Citation Format: Sarah E. Taylor, Courtney L. Andersen, Rohit Bhargava, George Tseng, Steffi Oesterreich, Robert P. Edwards, Adrian V. Lee. Hormone receptor expression and response in ovarian tumors of low malignant potential. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B25.
Abstract 1515: NCOA3 promotes tumor growth by activating telomerase reverse transcriptase and predicts poor prognosis in hepatocellular carcinoma
Authors: Miao Chen, Wenbin Li, Yixin Li, Changlin Zhang, Ge Qin, Qian Long, Dingbo Shi, Wei Guo, Shuihan Shi, Kefang Zhang, Wuguo Deng
Journal: Cancer Research (2018)

Abstract Hepatocellular carcinoma (HCC) is one of the most common cancers and a leading cause of cancer death worldwide. The rising incidence and mortality rate of HCC in most countries are due to an increased rate of chronic Hepatitis C virus infection, alcohol abuse and obesity. The molecular mechanisms leading to the development of HCC are complicated, consist of various genetic and epigenetic changes, and are associated with altered signaling pathways. Among these molecular events, elevated expression of human telomerase reverse transcriptase (TERT) is an important alteration in HCC and a hallmark of human cancers. TERT is highly expressed in HCC and positively correlated with the development of HCC. However, the detailed mechanism of TERT activation in HCC remains largely unclear. Here, we identified nuclear receptor coactivator-3 (NCOA3) as a TERT promoter-binding protein, which specifically bound to the -234~-144 region of the TERT promoter. Overexpression of NCOA3 enhanced TERT promoter activity and expression, and promoted HCC cell growth. Moreover, we demonstrated that NCOA3 interacted with the transcription factor SP1 to promote TERT expression. The clinical data showed that the expression of NCOA3 and TERT were positively correlated and elevated in HCC tissues, and HCC patients with high level of NCOA3/TERT had poor prognosis. Collectively, our study revealed that NCOA3 bound to the TERT promoter and activated TERT expression to promote HCC growth, indicating that the NCOA3/TERT signaling pathway could be a potential therapeutic target for HCC. [Funding support: This work was supported by the funds from the National Natural Science Foundation of China (81772925, 81472178, 81702761), the State “973 Program” of China (2014CB542005), and the Natural Science Foundation of Guangdong Province (2016A03031100, 2015A030313018, 2017A030313615)]. Citation Format: Miao Chen, Wenbin Li, Yixin Li, Changlin Zhang, Ge Qin, Qian Long, Dingbo Shi, Wei Guo, Shuihan Shi, Kefang Zhang, Wuguo Deng. NCOA3 promotes tumor growth by activating telomerase reverse transcriptase and predicts poor prognosis in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1515.
Abstract 14772: Routine Coronary Angiography Prior to Pulmonary Thromboendarterectomy in Patients With Chronic Thromboembolic Pulmonary Hypertension
Authors: Noel SLee, Kirk UKnowlton, Anna MMcDivit, Daniel GBlanchard, VictorPretorius, Michael MMadani, Peter FFedullo, Kim MKerr, Nick HKim, David SPoch, William RAuger, Lori BDaniels
Journal: Circulation (2015)

Introduction: At UC San Diego Health System, routine coronary angiography has been performed in men >40 years and women >45 years (or earlier in those with significant cardiovascular risk factors) prior to pulmonary thromboendarterectomy (PTE) for chronic thromboembolic pulmonary hypertension (CTEPH). However, the prevalence of significant coronary artery disease (CAD) in this population has not been evaluated, and the optimal screening strategy has not been systematically established. Hypothesis: We hypothesized that the current approach of routine age-based coronary angiography in screening candidates for PTE may be better optimized based on cardiac risk factors. Methods: The study included 349 consecutive patients (51.3% male) with CTEPH undergoing preoperative coronary angiography for PTE between January 1, 2007 and November 7, 2014. Charts were reviewed for baseline demographic and medical information. Major cardiac risk factors included: diabetes, hypertension, hyperlipidemia, obesity (BMI ≥25 kg/m2...
Abstract 15026: Association of De-Escalation of Anti-Anginal Medications With Angina After Percutaneous Coronary Intervention
Authors: Arooge Towheed, Mohammed Qintar, Fengming Tang, Adam C Salisbury, John A Spertus, Suzanne V Arnold
Journal: Circulation (2016)

Background: At the time of percutaneous coronary intervention (PCI), anti-anginal medications (AAM) may be discontinued, even though angina persists in ~20% of patients. Frequency of AAM discontinu...
Abstract 3469: Dual inhibition of the EGFR and Aurora A pathways in Kras mutated non-small cell lung cancers
Authors: Tetyana Bagnyukova, Brian Egleston, Mackenzie Kramer, Igor Astsaturov, Erica Golemis, Hossein Borghaei
Journal: Cancer Research (2018)

Abstract Lung cancer is the leading cause of cancer related death in the US. Patients with advanced disease generally have a poor prognosis with a median survival of around 10 to 12 months with standard chemotherapy. In patients with non-squamous non-small cell lung cancers (NSCLC) incidence of KRAS mutations reach ~22%. Specific treatments for Kras mutated NSCLC have not been developed although recent reports suggest an advantage for treatment with immunotherapy over chemotherapy in the second line setting. Published reports using a synthetic lethal screening method show that the combined inhibition of the EGFR and Aurora A kinase pathways could have synergistic effect on viability in head and neck and colon cancer cell lines suggesting a potential benefit of such combination therapy in these patients (Astsaturov and colleagues, 2010). Our study aims to examine the effects of combination of erlotinib (E), an EGFR small-molecule inhibitor, and Alisertib (MLN8237, A), an inhibitor of Aurora A kinase, in lung cancer models with different KRAS status. Human NSCLC cell lines with both wild type and mutated KRAS showed weak or moderate sensitivity to both drugs in vitro. Treatment with both E and A had synergistic activity in all examined cell lines, wild type KRAS (H2228, H1299) or mutated KRAS (A549, H1299, H358, H460, and H62). Western blot analysis confirmed that combination treatment enhanced apoptosis compared to single drug use as evidenced by cleaved PARP. In xenograft models, CB17 SCID mice were treated with single drug or E+A for three weeks. H322M xenograft tumors bearing wild type KRAS were moderately sensitive to growth inhibition by E (10 mg/kg/day) and A (20 mg/kg/twice daily) alone and the combination had an additive effect. A549 and H358 xenografts were insensitive to E because of the mutated KRAS and moderately sensitive to A. However, the combination of E+A had a synergistic effect and significantly inhibited tumor growth. Western blot analysis of signaling pathways downstream of the EGFR and Aurora A in tumor xenografts shows synergistic inhibition after two-drug treatment. Our results suggest that combined inhibition of both pathways might be an effective treatment strategy for lung cancers harboring KRAS mutations. Citation Format: Tetyana Bagnyukova, Brian Egleston, Mackenzie Kramer, Igor Astsaturov, Erica Golemis, Hossein Borghaei. Dual inhibition of the EGFR and Aurora A pathways in Kras mutated non-small cell lung cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3469.
Granulocyte-Macrophage Colony–Stimulating Factor Prevents the Progression of Atherosclerosis via Changes in the Cellular and Extracellular Composition of Atherosclerotic Lesions in Watanabe Heritable Hyperlipidemic Rabbits
Authors: JojiShindo, ToshiyukiIshibashi, KeikoYokoyama, KazuhikoNakazato, TakayukiOhwada, MasashiShiomi, YukioMaruyama
Journal: Circulation (1999)

Background—A cytokine network is involved in atherogenesis. This study was conducted to investigate the effects of granulocyte-macrophage colony–stimulating factor (GM-CSF) on the development and composition of atherosclerotic lesions in Watanabe heritable hyperlipidemic (WHHL) rabbits. Methods and Results—GM-CSF (10 μg · kg−1 · d−1) was administered to 4-month-old WHHL rabbits (n=9) 5 days a week for 7.5 months, whereas an equal dose of human serum albumin was administered to controls (n=9). The cholesterol levels were not changed significantly by the treatment. Age-matched 4-month-old rabbits (n=7) had atheromatous plaques over 30.7±5.7% of the inner surface area of the aortic arch. After treatment, the percentages of surface atheromatous plaques to total aortic arch area were 45.0±12.6% in the GM-CSF group and 74.3±11.0% in controls (P<0.0001). Histological examination demonstrated that GM-CSF reduced the ratio of intima to media (P<0.01) and cross-sectional areas of atherosclerotic lesions (P<0.0001)....
Abstract LB-042: Successful tumor formation following xenotransplantation of primary human ovarian cancer cells into severe combined immunodeficient (SCID) pigs
Authors: Adeline N. Boettcher, Matti Kiupel, Malavika Adur, Emiliano Cocco, Alessandro Santin, Sara Charley, John Risinger, Christopher Tuggle, Erik Shapiro
Journal: Cancer Research (2018)

Abstract Ovarian cancer (OvCa) is the most lethal gynecologic malignancy, with 2/3 of patients having late-stage disease (stages II-IV) at diagnosis. Preclinical animal models for cancer research have primarily been restricted to rodents, but many preclinical cancer drug trials that succeed in mice fail in humans, potentially due to vast differences in physiology and size. Therefore, we sought to determine if pigs, which are more similar to humans in terms of anatomy and physiology, would be a viable preclinical animal model for OvCa. Our group has pioneered the development of severe combined immunodeficiency (SCID) pigs for biomedical research, a key technological advancement for xenotransplantation of human ovarian cancer cells to form tumors. In this study, we injected human OSPC-ARK-1 cells, a chemotherapy-resistant primary ovarian serous papillary carcinoma cell line, into the neck muscle and ear tissue of four SCID and two non-SCID pigs. Tumors developed in the ears of three SCID pigs, while two SCID pigs developed tumors in neck tissue, all of which were confirmed at pathology as true neoplasms. Non-SCID animals did not develop tumors in any location. Confirmation that OSPC-ARK1 cells can form tumors in SCID pigs substantiates further development of orthotopic models of OvCa in pigs for researching improved OvCa therapeutic and diagnostic methods. Citation Format: Adeline N. Boettcher, Matti Kiupel, Malavika Adur, Emiliano Cocco, Alessandro Santin, Sara Charley, John Risinger, Christopher Tuggle, Erik Shapiro. Successful tumor formation following xenotransplantation of primary human ovarian cancer cells into severe combined immunodeficient (SCID) pigs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-042.
Abstract 19772: The Significance of Blood Pressure on Cardiovascular Risk Attributable to Diabetes
Authors: RyosukeKomi, FumitakaTanaka, ShinjiMakita, ToshiyukiOnoda, KozoTanno, MasakiOhsawa, KazuyoshiItai, KiyomiSakata, Shin-itiOmama, KuniakiOgasawara, YasuhiroIshibashi, AkiraOkayama, MotoyukiNakamura
Journal: Circulation (2014)

Background: Diabetes mellitus (DM) is an established risk factor of atherosclerotic cardiovascular events (CVE). Individuals with DM often have elevated levels of blood pressure (BP) which is closely associated with CVE. Hypothesis: The risk of DM-related CVE may depend on BP levels. Methods: A population-based prospective cohort study was performed in 24,350 subjects aged 40 to 89 years (mean age = 63.0±10.0 years) who did not have a history of CVE. DM was defined as a casual blood glucose level ≥ 200 mg/dl or fasting blood glucose level ≥ 126 mg/dl, a glycated hemoglobin value ≥ 6.5%, and/or current anti-diabetic therapy. BP levels at the baseline examination were classified into three categories including normotension, pre-hypertension, and hypertension according to JNC7. This classification was applied also to subjects with antihypertensive agents use. After adjustment for age, sex, body mass index, eGFR, total and HDL cholesterol, smoking habits, and anti-hypertensive medication use, a multivariate C...
Large Aortic Pseudoaneurysm, From Left Coronary Ostium, With Aortopulmonary Fistula 10 Years After Aortic Root Replacement for Type A Aortic Dissection
Authors: RobertIbe, NabiBahktiari, ChrisDavidson, DavidHildick-Smith, MichaelLewis
Journal: Circulation (2011)