tbuckley/cabot-search huggingface dataset:
Abstract 4963: Targeting glutamine metabolism as a means of enhancing antitumor T-cell responses
Authors: Robert Leone, Judson Englert, Im-Meng Sun, Min-Hee Oh, Jesse Alt, Im-Hong Sun, Ada J. Tam, Pavel Majer, Rana Rais, Barbara Slusher, Jonathan Powell
Journal: Cancer Research (2018)

Abstract Tumors possess specialized metabolic programming that facilitates their rapid growth. We have developed a novel glutamine antagonist (JHU-083) that not only demonstrates single-agent efficacy in a variety of mouse tumor models but also synergizes with anti-PD-1, adoptive cellular therapy (ACT) and A2aR antagonism to overcome resistance to immunotherapy and promote durable cures. Interestingly, we have observed that JHU-083 markedly enhances endogenous antitumor T-cell responses even in the absence of additional immunotherapy. Flow cytometry analyses of tumor-infiltrating lymphocyte (TIL) reveal markedly increased infiltration of CD8+ T cells with increased proliferative index (Ki67) and the generation of robust memory phenotypes in JHU-083 treated mice. Interestingly, Gene Set Enrichment Analyses (GSEA) using RNA-sequencing data revealed that CD8+ TIL from vehicle treated mice showed significantly enhanced expression of apoptotic transcriptional programs compared with TIL from mice treated with JHU-083. Consistent with flow cytometry data, GSEA showed CD8+ TILs from mice treated with glutamine antagonism expressed transcriptional programs characteristic of long-lived memory cells. To this end, vaccination experiments in mice treated with JHU-083 demonstrate that many of the phenotypic changes observed in TIL can be generated outside the TME and are due to direct effects of glutamine blockade on effector T cells. Our studies show that these transcriptional changes are associated with profound remodeling of the histone epigenetic code and correlate with decreased intracellular levels of α-ketoglutarate in response to glutamine antagonism. Supplementation with dimethyl α-ketoglutarate, a cell-permeable form of α-ketoglutarate, partially reverses phenotypic and epigenetic changes in CD8 T cells undergoing activation in the setting of glutamine antagonism. These findings are consistent with inhibition of a family of enzymes known as α-ketoglutarate dependent dioxygenases, which are responsible for a broad range of demethylation reactions, including histone and DNA demethylation. Overall, our work demonstrates that glutamine antagonism can directly inhibit tumor growth and survival while also reprogramming maladaptive antitumor T-cell responses to enhance endogenous antitumor immunity. Such observations support the development of our novel glutamine antagonists as both monotherapy and in combination with immunotherapy. Citation Format: Robert Leone, Judson Englert, Im-Meng Sun, Min-Hee Oh, Jesse Alt, Im-Hong Sun, Ada J. Tam, Pavel Majer, Rana Rais, Barbara Slusher, Jonathan Powell. Targeting glutamine metabolism as a means of enhancing antitumor T-cell responses [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 4963.
Mailed Outreach Invitations Significantly Improve HCC Surveillance Rates in Patients With Cirrhosis
Authors: Amit G. Singal, Jasmin A. Tiro, Caitlin C. Murphy, Jorge A. Marrero, Katharine McCallister, Hannah Fullington, Caroline Mejias, Akbar K. Waljee, Wendy Pechero Bishop, Noel O. Santini, Ethan A. Halm
Journal: Hepatology (2018)

Hepatocellular carcinoma (HCC) surveillance is associated with early tumor detection and improved survival in patients with cirrhosis; however, effectiveness is limited by underuse. We compared the effectiveness of mailed outreach and patient navigation strategies to increase HCC surveillance in a racially diverse cohort of patients with cirrhosis. We conducted a pragmatic randomized clinical trial comparing mailed outreach for screening ultrasound (n = 600), mailed outreach plus patient navigation (n = 600), or usual care with visit-based screening (n = 600) among 1800 patients with cirrhosis at a large safety-net health system from December 2014 to March 2017. Patients who did not respond to outreach invitations within 2 weeks received reminder telephone calls. Patient navigation included an assessment of barriers to surveillance and encouragement of surveillance participation. The primary outcome was HCC surveillance (abdominal imaging every 6 months) over an 18-month period. All 1800 patients were included in intention-to-screen analyses. HCC surveillance was performed in 23.3% of outreach/navigation patients, 17.8% of outreach-alone patients, and 7.3% of usual care patients. HCC surveillance was 16.0% (95% confidence interval [CI]: 12.0%-20.0%) and 10.5% (95% CI: 6.8%-14.2%) higher in outreach groups than usual care (P < 0.001 for both) and 5.5% (95% CI: 0.9%-10.1%) higher for outreach/navigation than outreach alone (P = 0.02). Both interventions increased HCC surveillance across predefined patient subgroups. The proportion of HCC patients detected at an early stage did not differ between groups; however, a higher proportion of patients with screen-detected HCC across groups had early-stage tumors than those with HCC detected incidentally or symptomatically (83.3% versus 30.8%, P = 0.003). Conclusion: Mailed outreach invitations and navigation significantly increased HCC surveillance versus usual care in patients with cirrhosis.
Abstract 5403: Discovery of high metastatic potential microRNAs in human colorectal cancer
Authors: Jee Hyun Lee, Gyeonghwa Kim, Hye Jin Kim, Gyu-Seog Choi, Keun Hur
Journal: Cancer Research (2018)

Abstract Background and Aim: Colorectal cancer (CRC) is the third most common cancer worldwide. More than half of the CRC patients have liver metastasis at the time of diagnosis, which is the major cause of cancer-related death in CRC. MicroRNAs (miRNAs) have been identified as modulators of the epithelial-mesenchymal transition (EMT)-mesenchymal to epithelial transition (MET) process by regulating transcription factors. However, it is not clear which specific miRNAs are critical drivers of CRC metastasis development. The aim of this study was to discovery novel high metastatic potential miRNAs in matched CRC and metastasis tissues, serum-exosome, and CRC cells with high metastasis property. Materials and Methods: We isolated total RNAs from pairs of normal colon (NC), primary CRC (pCRC), liver metastasis (LM), normal liver (NL) tissue specimens, and pre-OP/post-OP serum-exosome sample from 15 each CRC patients. We also prepared total RNAs from 4 CRC cell lines (SW480, LS174T, COLO 205, and EMT-induced SW480) as well as exosome from their culture medium. To induce EMT process, epithelial phenotype CRC cell (SW480) was treated with epidermal growth factor (EGF). Next, miRNAs discovery step was conducted via NanoString analysis. Further miRNAs expression was determined by quantitative real-time PCR (qRT-PCR), and miRNAs expression was normalized relative to U6 and cel-miR-39 expression for tissue and serum-exosome samples, respectively. Results: We successfully generated miRNAs expression profiles to distinguish NC vs. pCRC, pCRC vs. LM, LM vs. NL, and epithelial phenotype cells vs. high metastatic phenotype cells. Interestingly, a subset of miRNAs, including miRNA-100-5p, -339-3p, -549a, -1304-5p, and -1972, was commonly enhanced in LM, EMT-induced SW480, and high metastatic phenotype CRC cells compared to pCRC, SW480, and low metastatic phenotype CRC cells. In our further miRNAs validation analysis using pairs of pCRC and LM tissues from 15 CRC patients, miRNA-100-5p (P&amp;lt;0.0001), miR-339-3p (P=0.0022), and miR-1972 (P&amp;lt;0.0001) were significantly upregulated in pCRC than matched LM tissues. We also observed discordance expression patterns of miRNAs between CRC tissues and serum-exosome specimens. Conclusions: Our findings suggest that a unique subset of miRNAs is involved in CRC metastasis development, which may associate with EMT process and acquiring of high metastatic potential in CRC cells. Moreover, our metastasis specific miRNAs profile might be useful for development of markers predicting and/or treatment of CRC patients with metastasis. Citation Format: Jee Hyun Lee, Gyeonghwa Kim, Hye Jin Kim, Gyu-Seog Choi, Keun Hur. Discovery of high metastatic potential microRNAs in human colorectal cancer [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 5403.
Abstract 2156: Lung niche factors for progenitor cell self-renewal sustain lung cancer stem cells and contribute to drug resistance to kinase inhibitors in non-small cell lung cancer
Authors: Akinori Mitsui, Sachiko Yokokawa, Osamu Nagano, Hideyuki Saya
Journal: Cancer Research (2018)

Abstract A mechanism underlying anti-cancer drug resistance relies on the existence of cancer stem cells (CSCs). However, CSCs are either absent or are few in number in xenograft tumors and syngeneic mouse models. We developed new lung cancer mouse models with CSCs to elucidate the role of CSCs in resistance to targeted therapeutics in non-small cell lung cancer (NSCLC). Mouse lung organoids containing progenitor cells were cultured in complete medium containing lung niche factors, FGF-10 and HGF, and were infected with a retrovirus encoding a Kras mutation (G12D), an Egfr deletion, and the EML4-ALK fusion protein. These induced CSCs were transplanted into mice, and the established tumors were cultured in vitro to test for drug sensitivity to trametinib, erlotinib, and crizotinib in the presence or absence of niche factors. The tumors that were poorly differentiated contained EpCAM-, Cd49f-, and Sca-1-positive CSCs. These mouse models allowed the prediction of clinical responses to targeted therapeutics, i.e., the tumor cells with the Egfr deletion and those with EML4-ALK fusion proteins showed strong responses to erlotinib and crizotinib, respectively. In addition, we found that Kras mutant cancer cells were resistant to trametinib due to activation of the HGF/Met pathway since HGF is an essential niche factor for lung progenitor cell proliferation. Combination treatment with trametinib and a Met inhibitor showed a synergistic effect in Kras mutant tumors. Based on these results, we propose a treatment approach that focuses on the use of niche factors for lung progenitor cells in NSCLC. Citation Format: Akinori Mitsui, Sachiko Yokokawa, Osamu Nagano, Hideyuki Saya. Lung niche factors for progenitor cell self-renewal sustain lung cancer stem cells and contribute to drug resistance to kinase inhibitors in non-small cell lung cancer [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 2156.
Unstable Coronary Plaque and Its Relation to Coronary Calcium
Authors: AxelSchmermund, RaimundErbel
Journal: Circulation (2001)

Coronary calcium is intimately associated with coronary atherosclerotic plaque development. The use of electron-beam computed tomography (EBCT) for accurate quantitative measurements has led to an increased interest in understanding the clinical importance of coronary calcium, particularly in terms of the ability to identify unstable coronary plaques that underlie the clinical acute coronary syndromes. Histopathologic studies have demonstrated that calcium is a frequent feature of ruptured plaques, but the presence or absence of calcium does not allow for reliable distinction between unstable versus stable plaques. This issue is complicated by the lack of a prospective definition for “unstable.” Plaque rupture is sometimes found in apparently healthy subjects and in patients with clinically stable disease. Coronary atherosclerosis is a coronary systemic disease process. Imaging of coronary calcium, although unable to identify a localized unstable plaque, potentially can identify the more clinically pertin...
Abstract 19346: Cardiac Myosin Binding Protein-C Phosphorylation Preserves Diastolic Function in Aging Hearts
Authors: Paola C Rosas, Giusseppina Dusio, Piayli Chatterjee, Yang Liu, Carl W Tong
Journal: Circulation (2016)

Introduction: Prevalence of heart failure with preserved ejection fraction (HFpEF) increases with age. Cardiac myosin binding protein-C (cMyBP-C), a heart muscle thick filament protein, regulates c...
Fas-Mediated Apoptosis in Adriamycin-Induced Cardiomyopathy in Rats
Authors: TsuneyukiNakamura, YoshimichiUeda, YangJuan, ShogoKatsuda, HiroakiTakahashi, EikanKoh
Journal: Circulation (2000)

Background—The precise molecular mechanism of Adriamycin-induced cardiomyopathy (ADR-CM) is still unknown. We address the demonstration of apoptotic myocardial cell death and the apoptosis-inducing molecules in ADR-CM induced in rats. Methods and Results—Until 8 weeks after the first administration of ADR, there was no increase in the number of labeled cells by terminal deoxynucleotidyl transferase assay (TUNEL method). Apoptotic indices increased significantly at weeks 9 and 10 in hearts of the ADR-treated group but not in those of the control group (0.42±0.12% versus 0.10±0.02% and 0.86±0.11% versus 0.09±0.04% at weeks 9 and 10, respectively). DNA ladder formation was also observed in the myocardial tissues during the late stages of the ADR-CM of rats. There was no significant difference in expression of p53 gene between the ADR group and the control group at either the message or the protein level. An overexpression of Fas antigen was shown in myocardial cells of ADR-treated hearts at weeks 9 and 10 by...
Abstract 01: Supplemental Nutrition Assistance Program (SNAP) Participants Exhibit Higher Rates of Cardiometabolic Mortality Compared to SNAP Eligible Non-participants and SNAP Ineligible Americans
Authors: ZachConrad, ColinRehm, DariushMozaffarian
Journal: Circulation (2016)

Introduction: The Supplemental Nutrition Assistance Program (SNAP) is the largest food assistance program for low-income Americans. Investigating mortality in this population is crucial to determining what further efforts are needed to reduce health disparities. The National Center for Health Statistics (NCHS) does not provide mortality data by SNAP participation status, so diet-related mortality according to SNAP eligibility and participation is not well established. Objective: To examine cardiometabolic mortality among SNAP participants, SNAP eligible non-participants, and the SNAP ineligible population. Methods: We used data from the National Health Interview Survey for 499,741 US adults age≥25y from 2000-2009 to assess SNAP eligibility and participation. These data were merged with the NCHS Linked Mortality file (2000-2009) to create a nationally representative cohort. Participants were followed until death or through Dec 31, 2011. Survey-weighted Cox-proportional hazards models were used to estimate ...
Induction of Bone-Type Alkaline Phosphatase in Human Vascular Smooth Muscle Cells
Authors: AtsushiShioi, MiwakoKatagi, YasuhisaOkuno, KatsuhitoMori, ShuichiJono, HidenoriKoyama, YoshikiNishizawa
Journal: Circulation Research (2002)

Inflammatory cells such as macrophages and T lymphocytes play an important role in vascular calcification associated with atherosclerosis and cardiac valvular disease. In particular, macrophages activated with cytokines derived from T lymphocytes such as interferon-γ (IFN-γ) may contribute to the development of vascular calcification. Moreover, we have shown the stimulatory effect of 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) on in vitro calcification through increasing the expression of alkaline phosphatase (ALP), an ectoenzyme indispensable for bone mineralization, in vascular smooth muscle cells. Therefore, we hypothesized that macrophages may induce calcifying phenotype, especially the expression of ALP in human vascular smooth muscle cells (HVSMCs) in the presence of IFN-γ and 1,25(OH)2D3. To test this hypothesis, we used cocultures of HVSMCs with human monocytic cell line (THP-1) or peripheral blood monocytes (PBMCs) in the presence of IFN-γ and 1,25(OH)2D3. THP-1 cells or PBMCs induced ALP activity an...
Evaluation of the airway microbiome in nontuberculous mycobacteria disease
Authors: Imran Sulaiman, Benjamin G. Wu, Yonghua Li, Adrienne S. Scott, Patrick Malecha, Benjamin Scaglione, Jing Wang, Ashwin Basavaraj, Samuel Chung, Katrina Bantis, Joseph Carpenito, Jose C. Clemente, Nan Shen, Jamie Bessich, Samaan Rafeq, Gaetene Michaud, Jessica Donington, Charissa Naidoo, Grant Theron, Gail Schattner, Suzette Garofano, Rany Condos, David Kamelhar, Doreen Addrizzo-Harris, Leopoldo N. Segal
Journal: European Respiratory Journal (2018)

Aspiration is associated with nontuberculous mycobacterial (NTM) pulmonary disease and airway dysbiosis is associated with increased inflammation. We examined whether NTM disease was associated with a distinct airway microbiota and immune profile. 297 oral wash and induced sputum samples were collected from 106 participants with respiratory symptoms and imaging abnormalities compatible with NTM. Lower airway samples were obtained in 20 participants undergoing bronchoscopy. 16S rRNA gene and nested mycobacteriome sequencing approaches characterised microbiota composition. In addition, inflammatory profiles of lower airway samples were examined. The prevalence of NTM + cultures was 58%. Few changes were noted in microbiota characteristics or composition in oral wash and sputum samples among groups. Among NTM + samples, 27% of the lower airway samples were enriched with Mycobacterium . A mycobacteriome approach identified Mycobacterium in a greater percentage of samples, including some nonpathogenic strains. In NTM + lower airway samples, taxa identified as oral commensals were associated with increased inflammatory biomarkers. The 16S rRNA gene sequencing approach is not sensitive in identifying NTM among airway samples that are culture-positive. However, associations between lower airway inflammation and microbiota signatures suggest a potential role for these microbes in the inflammatory process in NTM disease.
Abstract P024: A Multimarker Approach to Evaluate Cardiac Structure in African Americans: The Jackson Heart Study
Authors: James D Pollard, Faren White, Ramachandran S Vasan, Aurelian Bidulescu, Ervin R Fox, Solomon K Musani
Journal: Circulation (2016)

Background: Cardiac structure is an independent predictor of cardiovascular outcomes including stroke, heart attack and death. Using a multimarker approach we investigated the potential association of a group of biological pathways with cardiac mass and geometry that would suggest a role in the pathophysiology of cardiac remodeling in African Americans, a high risk group. Objective: We examined the association of a panel of nine circulation biomarkers with cardiac structure in a community of African Americans. Methods and Results: The study sample included participants in the Jackson Heart Study who underwent an echocardiogram and phlebotomy for a panel of biomarkers that included pathways of inflammation (C-reactive protein, CRP); neurohormonal activation (B-type natriuretic peptide, BNP); renin-angiotensin system (aldosterone and renin modeled as a ratio ARR); endothelial (homocysteine, endothelin); adiposity (adiponectin and leptin); and insulin resistance (HOMAIR) with cardiac structure. The main outcomes were left ventricular mass (LVM) and LV geometry (normal geometry [reference] vs. concentric remodeling [CR], concentric hypertrophy [CH] or eccentric hypertrophy [EH]). We used multiple linear and multinomial logistic regression models to relate the biomarker panel to LVM and LV geometry, respectively. We selected the best multiple linear regression model for LVM using Akaike Information Content and backwards elimination in a multinomial logistic regression to evaluate biomarkers associated with LV geometry. Circulating concentrations of ARR, BNP and adiponectin were associated with LVM, multiple adjusted regression coefficients [beta] and standard error [±SE] per standard deviation (SD) increase in log-biomarker were, respectively; 0.056±0.009, p=0.0067; 0.020±0.005, p&lt;0.0001; and -0.011±0.005, p=0.0432. In terms of LV geometry, BNP concentrations was significantly associated with EH (1.38 [1.11-1.72], p=0.0045) and CH (1.34 [1.03-1.75], p=0.0314). ARR was significantly associated with EH (1.34, 95% CI [1.04-1.73] odds ratio [OR], p=0.0434) per SD increment and HOMAIR was significantly associated with CR (1.26, 95% CI [1.05-1.52], p=0.0212) and EH (1.22, 95% CI [1.00-1.48], p=0.0290). Conclusions: In a community-based sample of African Americans there were significant and positive relation of ARR and natriuretic peptide pathway to LVM and LV geometry, a significant and positive relation of HOMAIR to LV geometry and a significant and inverse relation of adiponectin to LVM. These observations support the notion of differential influences of biological pathways on cardiac structure.
Oral Beraprost Sodium, a Prostaglandin I2 Analogue, for Intermittent Claudication
Authors: MichelLièvre, SophieMorand, BrunoBesse, Jean-NoelFiessinger, Jean-PierreBoissel
Journal: Circulation (2000)

Background—Beraprost sodium (BPS) is a new stable, orally active prostaglandin I2 analogue with antiplatelet and vasodilating properties. We report the results of a phase III clinical trial of BPS in patients with intermittent claudication. Methods and Results—Patients (n=549) with a pain-free walking distance of between 50 and 300 m were entered into a 4-week single-blind placebo run-in phase. Patients whose pain-free walking distance had changed by  50% in pain-free walking distance at month 6 and in ≥1 earlier treadmill exercise test in the absence of critical cardiovascular events. Success was observed more frequently in the BPS group (43.5%) than in the placebo group (3...
Abstract 143: A Novel TAK1 Signaling Network Regulating Programmed Necrosis and Myocardial Remodeling
Authors: Qinghang Liu, Lei Li, Yi Chen, Jessica Doan, Jeffery Molkentin
Journal: Circulation Research (2013)

We recently identified a novel signaling molecule, TAK1 (TGFβ-activated kinase 1, also known as MAP3K7), as a key regulator of the hypertrophic signaling network. Importantly, TAK1 is activated in mouse models of heart failure as well as in diseased human myocardium. Here, we defined a previously unidentified, novel role for TAK1 in promoting cardiac cell survival and homeostasis using cardiac-specific gene-targeted mice. Indeed, cardiac-specific ablation of TAK1 in mice using a Cre-LoxP system showed enhanced pathological cardiac remodeling and massive cell death, and these mice gradually developed heart failure and spontaneous death. Remarkably, ablation of TNF receptor 1 (TNFR1) largely rescued the pathological phenotype of TAK1-deficient mice, preventing early lethality and cardiac fibrosis, suggesting that TNFR1 signaling is critical in mediating adverse remodeling and heart failure associated with TAK1 deficiency. Genetic or pharmacological inactivation of TAK1 in cardiomyocytes markedly induced programmed necrosis and apoptosis in response to TNFα. Conversely, overexpression of the constitutively active TAK1 mutant, or TAK1 plus its activator TAB1, protected cardiomyocytes from TNFα-induced cell death. Mechanistically, inactivation of TAK1 promoted formation of the necroptotic cell death complex consisting of RIP1, RIP3, caspase 8, and FADD. Genetic ablation of RIP1, RIP3, caspase 8, or FADD largely blocked TNFα-induced cell death in TAK1-deficient cells, whereas deletion of Bax/Bak or cyclophilin D showed no effects. Further, IKK/NFκB-mediated cell survival signaling was greatly impaired in TAK1-deficient cardiomyocytes. Taken together, our data indicate that TAK1 functions as a critical “molecular switch” in TNFα-induced programmed necrosis in cardiomyocytes, by interacting with the RIP1/3-caspase 8-FADD cell death pathway as well as the IKK-NFκB cell survival pathway. These findings thus define an important TAK1-mediated cardio-protective signaling network in the heart, which may suggest new therapeutic strategies in the treatment of heart disease.