tbuckley/cabot-search huggingface dataset:
Abstract 2784: Simultaneous checkpoint-checkpoint or checkpoint-costimulatory receptor targeting with bispecific antibodies promotes enhanced human T cell activation
Authors: Michael Hedvat, Christine Bonzon, Matthew J. Bernett, Gregory L. Moore, Kendra Avery, Rumana Rashid, Alex Nisthal, Suzanne Schubert, Rajat Varma, Sung-Hyung Lee, Liz Bogaert, Irene W.L. Leung, Seung Chu, Umesh Muchhal, John Desjarlais
Journal: Cancer Research (2018)

Abstract Combination checkpoint blockade promotes productive anti-tumor clinical responses often associated with an increase in immune-related adverse events. We developed optimized bispecific antibody candidates that simultaneously engage PD1 and CTLA4 (XmAb20717), CTLA4 and LAG3 (XmAb22841), and PD1 and ICOS (XmAb23104), that preferentially bind to cells co-expressing the targeted receptors. Because tumor infiltrating lymphocytes (TILs) typically express multiple immune checkpoints and costimulatory receptors, we hypothesized that these bispecific antibodies will enable selective targeting of tumor-reactive TILs, leading to safer and more cost-effective combination checkpoint blockade. The PD1 x CTLA4 bispecific antibody XmAb20717 and the PD1 x ICOS bispecific antibody XmAb23104 promoted superior in vitro T cell activation when compared to an anti-PD1 bivalent antibody. The CTLA4 x LAG3 bispecific antibody XmAb22841 combines productively with an anti-PD1 bivalent antibody achieving additive T cell activation through triple checkpoint blockade. Treatment with bispecific antibodies caused superior engraftment and activation of human T cells in NSG mice compared to an anti-PD1 bivalent antibody. Bispecific antibodies also potentiate allogeneic anti-tumor activity against human cancer cells in vivo. Each bispecific antibody promoted a unique RNA gene signature suggesting distinct mechanisms of action. These bispecific antibodies demonstrate compelling immune modulatory activity suggesting clinical development is warranted for the treatment of human malignancies. Citation Format: Michael Hedvat, Christine Bonzon, Matthew J. Bernett, Gregory L. Moore, Kendra Avery, Rumana Rashid, Alex Nisthal, Suzanne Schubert, Rajat Varma, Sung-Hyung Lee, Liz Bogaert, Irene W.L. Leung, Seung Chu, Umesh Muchhal, John Desjarlais. Simultaneous checkpoint-checkpoint or checkpoint-costimulatory receptor targeting with bispecific antibodies promotes enhanced human T cell activation [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 2784.
Abstract 21004: Relation Between Optimal Medical Therapy Trends on Outcomes in Patients With Peripheral Arterial Disease and Coronary Artery Disease Undergoing Cardiac Catheterization
Authors: Kevin P Cohoon, Joerg Herrmann, Ryan J Lennon, Rajiv Gulati, Paul W Wennberg
Journal: Circulation (2017)

Introduction: Peripheral arterial disease (PAD) is a strong predictor of systemic atherosclerosis with substantial morbidity and mortality. Medical management in PAD and coronary artery disease (CAD) has changed in recent eras with the use of high intensity statin and dual antiplatelet therapies. Hypothesis: Test whether mortality and major adverse cardiovascular events (MACE) (death and MI) has decreased over eras among PAD patients undergoning revascularization with percutaneous coronary intervention (PCI). Methods: Longitudinal cohort study of 549 patients who underwent PCI and non-invasive lower arterial study between 1997 and 2008 as identified in the Mayo Clinic PCI registry were stratified into 2 time eras: 1997-2003 (era1), and 2004-2008 (era2). PAD was assessed using the highest resting ABI and stratified according to established categories; &lt; 0.90 (definite PAD); 1.00-1.39 (normal); and ≥ 1.40 defined a non-compressible artery. Kaplan-Meier methods were used to analyze follow-up survival. Results: Stratified by ABI over both time eras, 225 patients had PAD, 94 were non-compressible, and 142 were normal. Overall mortality rates were higher in era2 non-compressible and PAD patients than in non-PAD patients when compared to era1 (58%, 33%, 26%, vs 49% 32%, 19%, p&lt;0.001 for all within-era comparisons) (Figure 1). MACE-free survival were higher in era2 non-compressible and PAD patients than in non-PAD patients when compared to the era1 (64%, 41%, 29% vs 59% 39%, 25%, p≤0.005 for all within-era comparisons). There were significant differences in medical therapy between era2 vs. era1 with higher discharge use of aspirin (98%; 94%), beta-blockers (88%; 66%), any lipid lowering drugs (86%; 76%), ACE inhibitors (67%; 56%), and diuretics (52%; 40%). Conclusions: Over the past two eras, the overall mortality has increased among patients with PAD and non-compressible vessels in era2 vs. era1 despite higher utilization of statin and antiplatelet therapies.
A New Threat to Immigrants’ Health — The Public-Charge Rule
Authors: Krista M. Perreira, Hirokazu Yoshikawa, Jonathan Oberlander
Journal: New England Journal of Medicine (2018)

Interview with Dr. Breanne Grace on immigrant and refugee health and the effects of systematic personal, social, and institutional instability. (09:02)Download The Trump administration is aiming to expand the criteria for deeming an immigrant likely to become a "public charge." Such a change would have important consequences for access to medical care and for the health of millions of immigrants and their families.
Abstract 5159: FLOT1 is associated with HGF mediated cell invasion and proliferation by increased MMP9
Authors: Sung Ae Koh, Kyung Hee Lee, Jae Ryong Kim, Sang woon Kim, Byung Ik Jang
Journal: Cancer Research (2018)

Abstract The flotillin protein family, including flotillin-1 (FLOT1 ) and flotillin-2 (FLOT2), have been known as markers of lipid rafts. Recentely, FLOT1 was reported that FLOT1 overexpression was found in several advanced cancer including breast, colorectal, prostate tumors, and renal cell carcinomas and correlate with poor prognosis in advanced tumors. The purpose of this study is to identify the role of HGF upregulated FLOT1 associated with cancer cell proliferation and invasion in gastric cancer. We used cell culture, western blotting, RT-PCR, MTT assays, CHIP assay, zymography and FLOT 1 knock-down with short hairpin RNA (shRNA). First, we confirmed that the expression level of FLOT1 was up-regulated by HGF(hepatocyte growth factor). To determine the role for FLOT1, we used the knock down cell of FLOT1. FLOT1 -sh RNA cells showed a decreased level of MMP9 and NFkB. We also examined to confirm the role of HGF-mediated FLOT1. HGF-mediated cell proliferation and in vitro invasion was decreased in FLOT1 knock down cell. We perforomed the zymography to evaluate the activity of MMP9 . The activity of MMP9 was decreased in FLOT1 knock down cell. The level of AKT phosphorylation was decreased in the knock down cell of FLOT1. Also, We identified the putative binding site of NFkB in MMP9 promotor region and confirmed the function by CHIP assay. Our study showed that upregulation FLOT1 by HGF increased the level of MMP9 through AKT/NFkB pathway and associated with cell proliferation and invasion in gastric cancer. Citation Format: Sung Ae Koh, Kyung Hee Lee, Jae Ryong Kim, Sang woon Kim, Byung Ik Jang. FLOT1 is associated with HGF mediated cell invasion and proliferation by increased MMP9 [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 5159.
Abstract 18894: The Myocardial Contraction Fraction Predicts Survival in Patients With AL Cardiac Amyloidosis. A Report From iCCAT, The International Consortium for Cardiac Amyloid Transplantation
Authors: Van N Selby, Karla Verkouw, Jerry D Estep, Ronald M Witteles, Giuseppe Feltrin, Mark Zucker, David Baran, David C Seldin, Jignesh Patel, Mazen Hanna, Teresa De Marco, Marc J Semigran, Mathew S Maurer
Journal: Circulation (2015)

Background: Cardiac amyloidosis is characterized by progressive ventricular thickening and diastolic heart failure. The left ventricular ejection fraction (EF) often remains normal even in advanced disease. The myocardial contraction fraction (MCF, the ratio of left ventricular stroke volume to myocardial volume) is a novel measure of myocardial shortening and may be superior to EF for predicting survival in cardiac amyloidosis. Methods: We measured MCF and EF from two-dimensional echocardiograms obtained in 86 subjects undergoing heart transplant evaluation for AL cardiac amyloidosis. Cox proportional hazards models and Kaplan-Meier survival analysis were used to compare MCF and EF as predictors of all-cause mortality. Subjects were censored at the time of heart transplant. Results: The mean age was 54.6 ± 7.9 years. The mean EF was 49.3 ± 12.7% and the mean MCF was 13.0 ± 5.5%. Over a median follow-up of 59 days (IQR 29-110 days), 38 subjects (44.2%) died and 48 (55.8%) underwent heart transplant. In unadjusted analyses, both MCF (HR 0.89, 95% CI 0.82-0.96, p = 0.002) and EF (HR 0.96, 95% CI 0.94-0.99, p = 0.015) predicted overall survival. In multivariate analyses adjusted for serum free light chain difference, the hazard ratio associated with each 5% absolute decrease in MCF was 2.11 (95% CI 1.32-3.38, p= 0.002). The hazard ratio associated with each 5% absolute decrease in EF was not statistically significant (HR 1.16, 95% CI 0.97-1.39, p=0.09). Conclusions: Myocardial contraction fraction is superior to EF for predicting survival in patients undergoing heart transplant evaluation for AL cardiac amyloidosis.
Abstract 5206: The biological significance of CCL 16 regulated by thyroid hormone in liver cancer cells
Authors: Cheng-Heng Wu, Kwang-Huei Lin
Journal: Cancer Research (2018)

Abstract Thyroid hormones(THs) are multi-function mediators that modulate various physiological processes. Thyroid hormone receptors(TRs) are type II nuclear receptors, TRs binds to thyroid hormone response elements (TREs) of target promoter regions modulates target gene expression at the transcriptional level upon THs binding. Previous literatures illustrate an association between aberrant TR regulation and human hepatocellular carcinoma (HCC). We employed cDNA microarrays and SILAC secretome analysis to identify the T3-regulated secreted proteins after T3 treatment in TR-expressing hepatoma cell lines, Chemokine (C-C motif) ligand 16 (CCL16) expression is positively regulated by T3 treatment. The patients with higher expression of CCL16 have poor recurrence survival rate. Ectopic expression of CCL16 in HCC cell lines increased tumor growth rate in vivo but not in vitro. CCL16 induced chemotaxis of monocytes and macrophages via interacting with its receptors CCR1 and CCR5. Expression of proangiogenic genes in macrophages were increased while co-cultured with HCC cell lines. The motility of HUVECs were increased after treated with conditional medium of macrophages co-cultured with HCC cell lines. Our study revealed that CCL16 recruited macrophage and promoted tumor progression. Citation Format: Cheng-Heng Wu, Kwang-Huei Lin. The biological significance of CCL 16 regulated by thyroid hormone in liver cancer cells [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 5206.
Abstract 3936: Bromodomain testis-specific protein BRDT is expressed in a subset of esophageal squamous cell carcinomas and controls expression of differentiation-associated genes
Authors: Xin Wang, Feda H. Hamdan, Madhobi Sen, Ana P. Kutschat, Steven A. Johnsen
Journal: Cancer Research (2018)

Abstract Esophageal cancer is one of the most malignant cancers, ranking as the sixth leading cause of cancer-related deaths worldwide. The poor survival rate and prognosis highlight the limitations in the biological understanding of esophageal cancer and the urgent need for identification of novel targeted molecular therapies. Recently, large scale genomic analyses have revealed the extensive alternations of epigenetic regulators which may be used as a basis for developing new “epigenetic drugs “. BRDT, bromodomain testis-specific protein, is a member of the bromodomain and extra-terminal (BET) family of epigenetic reader proteins. BET proteins can regulate gene expression by recognizing acetylated lysines, thus playing important roles in both normal development and disease progression. Inhibition of BET proteins has emerged as a potential therapy for many types of cancer. In normal human tissues, unlike the other members of BET family, BRDT is exclusively highly expressed in testes where it drives the meiotic and post-meiotic gene expression to promote spermatogenesis. We have identified BRDT to be expressed in over 20% of esophageal squamous cell carcinoma (ESCC), a predominant subtype of esophageal cancer. Knockdown of BRDT does not affect cell proliferation, but leads to alterations in the expression of differentiation markers. In addition, RNA-seq following BRDT knockdown also supports a role of BRDT in cell differentiation. Depletion of BRDT does not alter the cellular response to BET inhibition. Surprisingly, we also identified BRDT transcripts encoding two truncated isoforms lacking the first bromodomain, which could potentially alter its epigenetic reader function. The genome occupancy profile of BRDT showed a significant enrichment at transcription start site (TSS), which is distinct from BRD4. It also showed potential interactions between BRDT and E2F family and SMAD family. Together, we showed that BRDT is overexpressed in ESCC cell lines and may influence ESCC development or progression in a subset of tumors by regulating cell differentiation-associated genes. Citation Format: Xin Wang, Feda H. Hamdan, Madhobi Sen, Ana P. Kutschat, Steven A. Johnsen. Bromodomain testis-specific protein BRDT is expressed in a subset of esophageal squamous cell carcinomas and controls expression of differentiation-associated genes [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 3936.
Isolated Ambulatory Hypertension Predicts Cardiovascular Morbidity in Elderly Men
Authors: KristinaBjörklund, LarsLind, BjörnZethelius, BertilAndrén, HansLithell
Journal: Circulation (2003)

Background— Little is known about isolated ambulatory hypertension, a state with elevated ambulatory but normal office blood pressure (BP). This study aimed to investigate the prognostic significance of isolated ambulatory hypertension for cardiovascular morbidity in a population of elderly men. Methods and Results— At baseline, 24-hour ambulatory BP and metabolic and cardiac risk profiles were evaluated in 578 untreated 70-year-old men, participants of a population-based cohort. Subjects with isolated ambulatory hypertension (office BP <140/90 and daytime BP ≥135/85) and sustained hypertension (office BP ≥140/90 and daytime BP ≥135/85) had increased plasma glucose, body mass index, and echocardiographically determined left ventricular relative wall thickness compared with normotensive subjects (office BP <140/90 and daytime BP <135/85). Seventy-two cardiovascular morbid events (2.37 per 100 person-years at risk) occurred over 8.4 years of follow-up. The prognostic value of isolated ambulatory and sustain...
Abstract 1955: Suppression of hormone receptor-positive and triple-negative breast cancers by new inhibitors of the transcription factor FOXM1
Authors: Mary J. Laws, Sung Hoon Kim, Yvonne Ziegler, Noah Bindman, Ping Gong, Valeria Sanabria Guillen, Mayuri Yasuda, Divya Singh, Dorraya El-Ashry, John A. Katzenellenbogen, Benita S. Katzenellenbogen
Journal: Cancer Research (2018)

Abstract The transcription factor FOXM1 is up-regulated and overexpressed in aggressive, therapy-resistant forms of hormone receptor-positive and triple negative breast cancers, and is associated with less good patient survival. FOXM1 pathway signaling is also a key driver in other aggressive cancers including those in prostate, lung, ovary, and gastrointestinal tract, and in glioblastoma. Therefore, our goal has been to identify FOXM1 inhibitors effective in suppressing breast cancer proliferation both in vitro and in vivo and displaying potency, selectivity and good pharmacokinetic properties for in vivo efficacy. We screened large chemical libraries of over 130,000 compounds from which several were identified and characterized as potential FOXM1 inhibitors. These were then chemically modified and optimized for potency and good pharmacokinetic properties. The best were shown to effectively suppress the proliferation of FOXM1 expressing breast cancer cells, decrease the expression of FOXM1 and FOXM1- regulated genes, and inhibit the chromatin binding of FOXM1 to FOXM1 binding sites in these genes. Inhibitors that had long half-lives (t1/2 greater than 24H) were selected for studies in experimental preclinical mouse models. One inhibitor had good oral efficacy in suppressing the growth of FOXM1-containing breast tumors in NOD-SCID-gamma (NSG) mice, and several others had good efficacy in tumor suppression by subcutaneous but not oral administration. Our findings identify and characterize several compounds that effectively antagonize FOXM1 actions and tumor growth that may be suitable for further clinical evaluation in targeting aggressive breast cancers driven by FOXM1. Citation Format: Mary J. Laws, Sung Hoon Kim, Yvonne Ziegler, Noah Bindman, Ping Gong, Valeria Sanabria Guillen, Mayuri Yasuda, Divya Singh, Dorraya El-Ashry, John A. Katzenellenbogen, Benita S. Katzenellenbogen. Suppression of hormone receptor-positive and triple-negative breast cancers by new inhibitors of the transcription factor FOXM1 [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 1955.
Abstract SY19-02: Novel mechanisms of acquired resistance to selective CDK4/6 inhibition
Authors: Geoffrey I. Shapiro
Journal: Cancer Research (2018)

Abstract CDK4/6 inhibition is now part of the standard armamentarium for patients with estrogen receptor (ER)-positive breast cancer, so that understanding mechanisms of resistance is a pressing issue. We have identified identified increased CDK6 expression as a key determinant of acquired resistance after exposure to palbociclib in ER-positive breast cancer cells. Increased CDK6 in resistant cells is dependent on TGF-β pathway suppression via miR-432-5p expression. Exosomal miR-432-5p expression mediated transfer of the resistance phenotype between neighboring cell populations, causing previously sensitive cells to acquire CDK4/6 inhibitor resistance. We confirmed these data in pretreatment and postprogression biopsies from a parotid cancer patient who had responded to ribociclib, demonstrating that this resistance mechanism is clinically relevant. Additionally, this CDK4/6 inhibitor resistance phenotype can be reversed in vitro and in vivo by a prolonged drug holiday, which restored drug sensitivity. CDK4 is also emerging as a target in KRAS-mutant non-small cell lung cancer (NSCLC). We have demonstrated that KRAS-mutant NSCLC cell lines are initially sensitive to palbociclib, but readily acquire resistance associated with increased expression of CDK6, D-cyclins, and cyclin E. Resistant cells also demonstrated increased ERK1/2 activity and sensitivity to MEK and ERK inhibitors. Moreover, MEK inhibition reduced the expression and activity of cell cycle proteins mediating palbociclib resistance. In resistant cells, ERK activated mTOR, driven in part by upstream FGFR1 signaling resulting from the extracellular secretion of FGF ligands. A genetically engineered mouse model of KRAS-mutant NSCLC initially sensitive to palbociclib similarly developed acquired resistance with increased expression of cell cycle mediators, ERK1/2 and FGFR1. In this model, resistance was delayed with combined palbociclib and MEK inhibitor treatment. These findings implicate an FGFR1-MAP kinase-mTOR pathway resulting in increased expression of D-cyclins and CDK6 that confers palbociclib resistance, and indicate that CDK4/6 inhibition acts to promote MAP kinase dependence. Citation Format: Geoffrey I. Shapiro. Novel mechanisms of acquired resistance to selective CDK4/6 inhibition [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 SY19-02.
Biochemical and Epigenetic Insights into L-2-Hydroxyglutarate, a Potential Therapeutic Target in Renal Cancer
Authors: Sandeep Shelar, Eun-Hee Shim, Garrett J. Brinkley, Anirban Kundu, Francesca Carobbio, Tyler Poston, Jubilee Tan, Vishwas Parekh, Daniel Benson, David K. Crossman, Phillip J. Buckhaults, Dinesh Rakheja, Richard Kirkman, Yusuke Sato, Seishi Ogawa, Shilpa Dutta, Sadanandan E. Velu, Ethan Emberley, Alison Pan, Jason Chen, Tony Huang, Devin Absher, Anja Becker, Conrad Kunick, Sunil Sudarshan
Journal: Clinical Cancer Research (2018)

Elevation of L-2-hydroxylgutarate (L-2-HG) in renal cell carcinoma (RCC) is due in part to reduced expression of L-2-HG dehydrogenase (L2HGDH). However, the contribution of L-2-HG to renal carcinogenesis and insight into the biochemistry and targets of this small molecule remains to be elucidated.Genetic and pharmacologic approaches to modulate L-2-HG levels were assessed for effects on in vitro and in vivo phenotypes. Metabolomics was used to dissect the biochemical mechanisms that promote L-2-HG accumulation in RCC cells. Transcriptomic analysis was utilized to identify relevant targets of L-2-HG. Finally, bioinformatic and metabolomic analyses were used to assess the L-2-HG/L2HGDH axis as a function of patient outcome and cancer progression.L2HGDH suppresses both in vitro cell migration and in vivo tumor growth and these effects are mediated by L2HGDH's catalytic activity. Biochemical studies indicate that glutamine is the predominant carbon source for L-2-HG via the activity of malate dehydrogenase 2 (MDH2). Inhibition of the glutamine-MDH2 axis suppresses in vitro phenotypes in an L-2-HG-dependent manner. Moreover, in vivo growth of RCC cells with basal elevation of L-2-HG is suppressed by glutaminase inhibition. Transcriptomic and functional analyses demonstrate that the histone demethylase KDM6A is a target of L-2-HG in RCC. Finally, increased L-2-HG levels, L2HGDH copy loss, and lower L2HGDH expression are associated with tumor progression and/or worsened prognosis in patients with RCC.Collectively, our studies provide biochemical and mechanistic insight into the biology of this small molecule and provide new opportunities for treating L-2-HG-driven kidney cancers.