tbuckley/cabot-search huggingface dataset:
Abstract C53: Liver X receptor ligand targets glutamine metabolism in pancreatic cancer
Authors: Shivangi Srivastava, Scott Widmann, Chin-Yo Lin
Journal: Cancer Research (2019)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent form of pancreatic cancer. It is predicted to become the third leading cause of cancer-related deaths by 2030. PDAC has a poor survival rate of 5 years with a 7% success rate. Current treatments include nontargeted highly toxic chemotherapeutic agents. More than 95% of PDAC patients have activating mutations of Kristen RAt Sarcoma virus (KRAS) gene, and it is known to drive metabolic reprogramming that increases cancer cell survival and resistance against the chemotherapeutic drugs. KRAS promotes noncanonical consumption of glutamine by upregulating the expression of glutaminase 1 (GLS1) enzyme. This, in turn, supports PDAC growth and survival by maintaining redox homeostasis and also by replenishing citric acid cycle intermediates. Liver X receptor beta (LXRβ), a nuclear receptor, is a ligand-dependent transcription factor that is ubiquitously expressed in all tissues. It plays an important role in maintaining cholesterol, lipid, and glucose homeostasis under normal physiologic conditions. Agonist-bound LXRβ activates the transcription of genes involved in lipogenesis, reverse cholesterol transport, and glucose metabolism. Our group has previously shown that LXRβ is expressed in PDAC tissues, and treatment with GW3965, an LXRβ agonist, reduced PDAC proliferation. However, LXRβ agonists have adverse side effects of increasing liver and circulating triglycerides. This study identified a novel ligand of LXRβ 1E5, which significantly reduced PDAC cell proliferation. 1E5 decreased the basal expression of LXRβ target genes such as sterol regulatory element-binding protein 1 (SREBP1c) and ATP binding cassette subfamily A member 1 (ABCA1). It also increased the binding of co-repressor peptides such as nuclear receptor co-repressor (NCoR) and silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) to the LXRβ ligand binding domain, whereas it decreased the binding of the co-activator peptide as demonstrated by the time-resolved fluorescence energy transfer (TR-FRET) assay, thereby inhibiting the transcriptional activity of LXRβ. Therefore, 1E5 acts as an LXRβ inverse agonist. Furthermore, the metabolomics study revealed that 1E5 disrupts glutamine metabolism in PDAC cells by downregulating the glutamine, aspartate, and alpha-ketoglutarate levels in cells. Gene expression analysis showed that it significantly downregulated GLS1 expression. These results demonstrate that the novel inverse agonist is a candidate agent in the treatment of PDAC by targeting glutamine metabolism. Citation Format: Shivangi Srivastava, Scott Widmann, Chin-Yo Lin. Liver X receptor ligand targets glutamine metabolism in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C53.
Gastric 99mTc-Methylene Diphosphonate Accumulation in a Patient With Primary Upper Gastrointestinal Tract Melanoma
Authors: Yi Zhou, Qiu-ping Fan, Rong Tian, Ming-gang Su
Journal: Clinical Nuclear Medicine (2019)

Abstract Unexpected extraosseous uptake is common on 99m Tc–methylene diphosphonate bone scintigraphy, but accumulation by primary upper gastrointestinal tract malignant melanoma is rarely reported. The present case is a 58-year-old woman with a 10-day history of diffuse bone pain and weakness. Her bone scintigraphy showed unexpected diffuse gastric tracer uptake. Subsequent gastroscopy revealed a number of hyperpigmented lesions in the stomach and duodenal bulb. Malignant melanoma was confirmed by histopathology and immunohistochemistry. Because extensive physical examination failed to identify any other site of ocular and cutaneous melanoma, a diagnosis of primary upper gastrointestinal tract malignant melanoma was established.
THU0033 The chemokine mip-1alpha in rheumatoid arthritis – possible significance on inflammation and anaemia
Authors: WC Kullich, G Pöllmann, H Neff, G Klein
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Chemokines play a key role in modulating leukocyte functions at sites of inflammation. In rheumatoid arthritis (RA) an enhancement of the chemokine macrophage inflammatory protein-1alpha (MIP-1a) was observed and may be indicative for inflammatory processes.<sup>1</sup> In addition to its proinflammatory activities several lines of evidence indicate that MIP-1a modulates the proliferation of hematopoietic progenitor cells.<sup>2</sup> Anaemia is a common feature of active rheumatoid arthritis. Very little information on the significance of MIP-1a on the pathogenesis of anaemia in RA is available. <h3>Objectives</h3> Basing on theoretical, haematological and immunological data, the chemokine MIP-1a was to be determined about its importance in RA concerning the activity of inflammation and the development of anaemia. <h3>Methods</h3> 84 patients (18 male, 66 female) with rheumatoid arthritis (ACR criteria) were included to detect inflammatory processes and anaemia. White and red blood cell count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum iron and the rheumatoid factor were assessed by routine laboratory methods. MIP-1a, serum amyloid A (SAA) and transferrin receptor (TfR) were measured by solid phase enzyme immunoassay; erythropoietin (EPO) and neopterin by radioimmunoassay techniques. <h3>Results</h3> High MIP-1a levels were accompanied by increased parameters of inflammation (SAA, CRP, ESR). Patients with RA and anaemia showed significantly higher MIP-1a levels than those without anaemia (p &lt; 0.03). However, high MIP-1a levels together with decreased serum iron were not associated with increased EPO levels. It might be of importance that patients with high MIP-1a levels in parallel with anaemia and activation of inflammation had a twofold frequency of disability pension compared to RA patients without anaemia. <h3>Conclusion</h3> The enhanced expression of MIP-1a in RA is indicative of the inflammatory activation. Moreover besides the regulation of inflammatory processes this chemokine may influence the pathogenesis of anaemia in RA. <h3>References</h3> Koch AE, Kunkel SL, Harlow LA, <i>et al</i>. Macrophage inflammatory protein-1 alpha. A novel chemotactic cytokine for macrophages in rheumatoid arthritis. J Clin Invest. 1994;93: 921–8 Su SB, Mukaida N, Wang JB, Zhang Y, Takami A, Nakao S, Matsushima K. Inhibition of immature erythroid progenitor cell proliferation by macrophage inflammatory protein-1a by interacting mainly with a C-C chemokine receptor, CCR1. Blood 1997;90(2):605–11
Lung Screen Uptake Trial (LSUT): Randomized Controlled Clinical Trial Testing Targeted Invitation Materials
Authors: Samantha L. Quaife, Mamta Ruparel, Jennifer L. Dickson, Rebecca J. Beeken, Andy McEwen, David R. Baldwin, Angshu Bhowmik, Neal Navani, Karen Sennett, Stephen W. Duffy, Jane Wardle, Jo Waller, Samuel M. Janes
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Rationale: Low uptake of low-dose computed tomography (LDCT) lung cancer screening, particularly by current smokers of a low socioeconomic position, compromises effectiveness and equity.Objectives: To compare the effect of a targeted, low-burden, and stepped invitation strategy versus control on uptake of hospital-based Lung Health Check appointments offering LDCT screening.Methods: In a two-arm, blinded, between-subjects, randomized controlled trial, 2,012 participants were selected from 16 primary care practices using these criteria: 1) aged 60 to 75 years, 2) recorded as a current smoker within the last 7 years, and 3) no prespecified exclusion criteria contraindicating LDCT screening. Both groups received a stepped sequence of preinvitation, invitation, and reminder letters from their primary care practitioner offering prescheduled appointments. The key manipulation was the accompanying leaflet. The intervention group's leaflet targeted psychological barriers and provided low-burden information, mimicking the concept of the U.K. Ministry of Transport's annual vehicle test ("M.O.T. For Your Lungs").Measurements and Main Results: Uptake was 52.6%, with no difference between intervention (52.3%) and control (52.9%) groups in unadjusted (odds ratio [OR], 0.98; 95% confidence interval [CI], 0.82–1.16) or adjusted (OR, 0.98; 95% CI, 0.82–1.17) analyses. Current smokers were less likely to attend (adjusted OR, 0.70; 95% CI, 0.56–0.86) than former smokers. Socioeconomic deprivation was significantly associated with lower uptake for the control group only (P < 0.01).Conclusions: The intervention did not improve uptake. Regardless of trial arm, uptake was considerably higher than previous clinical and real-world studies, particularly given that the samples were predominantly lower socioeconomic position smokers. Strategies common to both groups, including a Lung Health Check approach, could represent a minimum standard.Clinical trial registered with www.clinicaltrials.gov (NCT02558101) and registered prospectively with the International Standard Registered Clinical/Social Study (N21774741).
Gene Expression Signature Predicts Deep Molecular Response (DMR) in Chronic Myeloid Leukemia (CML): An Exploratory Biomarker Analysis from ENESTnd
Authors: Jerald P. Radich, Richard A. Larson, Hagop M. Kantarjian, Michael W. Deininger, Javier Pinilla Ibarz, Daniel J. DeAngelo, Susan Branford, Islam Sadek, Shalini Chaturvedi, Manu Sondhi, Matthew Wall, Kaushal Mishra, Das Purkayastha, Alok Shrestha, Vanessa Obourn, Brian S. White, Brian J. Druker
Journal: Blood (2019)
HPV16 E5 Mediates Resistance to PD-L1 Blockade and Can Be Targeted with Rimantadine in Head and Neck Cancer
Authors: Sayuri Miyauchi, P. Dominick Sanders, Kripa Guram, Sangwoo S. Kim, Francesca Paolini, Aldo Venuti, Ezra E.W. Cohen, J. Silvio Gutkind, Joseph A. Califano, Andrew B. Sharabi
Journal: Cancer Research (2019)

Abstract There is a critical need to understand mechanisms of resistance and to develop combinatorial strategies to improve responses to checkpoint blockade immunotherapy (CBI). Here, we uncover a novel mechanism by which the human papillomavirus (HPV) inhibits the activity of CBI in head and neck squamous cell carcinoma (HNSCC). Using orthotopic HNSCC models, we show that radiation combined with anti–PD-L1 immunotherapy significantly enhanced local control, CD8+ memory T cells, and induced preferential T-cell homing via modulation of vascular endothelial cells. However, the HPV E5 oncoprotein suppressed immune responses by downregulating expression of major histocompatibility complex and interfering with antigen presentation in murine models and patient tumors. Furthermore, tumors expressing HPV E5 were rendered entirely resistant to anti–PD-L1 immunotherapy, and patients with high expression of HPV16 E5 had worse survival. The antiviral E5 inhibitor rimantadine demonstrated remarkable single-agent antitumor activity. This is the first report that describes HPV E5 as a mediator of resistance to anti–PD-1/PD-L1 immunotherapy and demonstrates the antitumor activity of rimantadine. These results have broad clinical relevance beyond HNSCC to other HPV-associated malignancies and reveal a powerful mechanism of HPV-mediated immunosuppression, which can be exploited to improve response rates to checkpoint blockade. Significance: This study identifies a novel mechanism of resistance to anti–PD-1/PD-L1 immunotherapy mediated by HPV E5, which can be exploited using the HPV E5 inhibitor rimantadine to improve outcomes for head and neck cancer patients.
Letter to the Editor: Consider More Factors When Studying Risk of Cirrhosis and Hepatocellular Cancer in Patients With Nonalcoholic Fatty Liver Disease
Authors: Nai‐Bin Yang, Guo‐Xiang Li, Jin‐Guo Chu, Yun‐Jing Wang
Journal: Hepatology (2019)

Potential conflict of interest: Nothing to report. To the Editor: In a recent issue of Hepatology, Kanwal et al.1 conducted retrospective research on 271,906 patients to evaluate the effects of metabolic traits (diabetes, hypertension, dyslipidemia, obesity) as independent and joint indicators on time to develop cirrhosis or hepatocellular carcinoma (HCC) among patients with nonalcoholic fatty liver disease (NAFLD). They report that the risk of progression was the lowest in patients with only one or no metabolic trait. Each additional metabolic trait, especially diabetes, increased the risk of cirrhosis and HCC in patients with NAFLD. It is a meaningful study; however, there are some concerns based on the following issues. First, there was no histological information from liver biopsy and noninvasive measurement to estimate hepatic fibrosis and inflammation in patients with NAFLD at baseline. If hepatic fibrosis was more significant in metabolic traits groups, patients were more likely to develop cirrhosis or HCC in this cohort. Aspartate aminotransferase‐to‐platelet ratio index and Fibrosis‐4 index may identify fibrosis with a certain sensitivity and accuracy in evaluating hepatic fibrosis severity.2 Second, some important factors should be considered when using competing‐risk, adjusted cause‐specific Cox models to evaluate the effects of metabolic traits. For example, no data on the history of statin therapy were shown in this article. Researchers have reported the impact of statins in cirrhosis development and progression among patients with NAFLD/nonalcoholic steatohepatitis.3 Meanwhile, the role of thyroid diseases in the progression of NAFLD is emerging. Bano et al.4 reported that patients with hypothyroidism have an increased risk for NAFLD development and progression to cirrhosis/HCC. However, whether patients have thyroid diseases is not discussed elaborately. Finally, and more importantly, the level of uric acid is an important indicator in metabolic traits. However, we did not find any data about uric acid in this paper. Data from the National Health and Nutrition Examination Survey5 showed that elevated serum uric acid level was associated with severity of NAFLD. We suggest that the effect of the level of uric acid as an independent and joint indicator on time to develop cirrhosis or HCC among these patients with NAFLD should be assessed.
Abstract 04: Diagnostic Accuracy of Coronary CT in Survivors of Out-Of-Hospital Circulatory Arrest: Can CT Serve as a Gatekeeper for Invasive Coronary Angiography?
Authors: Kelley R Branch, Ravi Hira, Robin M Brusen, Charles Maynard, Medley Gatewood, Deborah L Fly, Bradley J Petek, Peter Kudenchuk, Justin A Strote, Michelle Olsufka, Michael R Sayre, David Carlbom, Martin Gunn
Journal: Circulation (2019)

Introduction: Out-of-hospital circulatory arrest (OHCA) is commonly assumed to be from a cardiac cause although routine early invasive coronary angiography (ICA) remains controversial and has a relatively high proportion of studies without obstructive coronary artery disease (CAD). The ability of coronary CT angiography (CCTA) to detect significant CAD in OHCA survivors has not been evaluated. Methods: The prospective CT-FIRST trial enrolled 104 OHCA survivors who had an early (&lt;6 hours from hospital arrival) head-to-pelvis CT scan that included an ECG-gated CCTA (FORCE CT, Siemens). The CCTA scanned 0-90% of the cardiac cycle without routine use of beta blockers or nitroglycerin. Treating physicians were blinded to the CCTA analysis. ICA was ordered at the discretion of treating physicians. Readers blinded to corresponding studies analyzed CCTA and ICA for coronary stenoses using a 20 segment coronary model. Obstructive CAD was assumed for &gt;50% stenosis. Patient-level diagnostic accuracy calculations for CCTA to identify obstructive CAD used ICA as the standard. Results: Of the 104 enrolled patients, 28 (27%) had both CT and ICA. All CCTA studies were evaluable. Diagnostic accuracy data are shown in the Table. Overall, diagnostic accuracy measures were excellent between CCTA and ICA at the patient level. Conclusions: Early CCTA in OHCA survivors has high diagnostic accuracy for obstructive coronary artery disease and could be used as a gatekeeper to ICA.
Endocrinological Toxicity Secondary to Treatment of Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs)
Authors: Krystallenia I. Alexandraki, Kosmas Daskalakis, Marina Tsoli, Ashley B. Grossman, Gregory A. Kaltsas
Journal: Trends in Endocrinology and Metabolism (2019)
A critical role for c‐Myc in group 2 innate lymphoid cell activation
Authors: Longyun Ye, Jiexue Pan, Mingwei Liang, Muhammad Asghar Pasha, Xiaofei Shen, Shanti S. D'Souza, Ivan Ting Hin Fung, Yinna Wang, Gargi Patel, Dale D. Tang, Qi Yang
Journal: Allergy (2019)

Asthma is a complicated chronic inflammatory disorder characterized by airway inflammation and bronchial hyperresponsiveness. Group 2 innate lymphoid cells (ILC2) are tissue-resident innate effector cells that can mediate airway inflammation and hyperresponsiveness through production of IL-5, IL-13 and VEGFA. ILC2 in asthma patients exhibit an activated phenotype. However, molecular pathways that control ILC2 activation are not well understood.MYC expression was examined in ILC2 sorted from peripheral blood of healthy controls and asthma patients or cultured with or without activating cytokines. CRISPR knockout technique was used to delete c-Myc in primary murine lung ILC2 or an ILC2 cell line. Cell proliferation was examined, gene expression pattern was profiled by genome-wide microarray analysis, and direct gene targets were identified by Chromatin immunoprecipitation (ChIP). ILC2 responses, airway inflammation and airway hyperresponsiveness were examined in Balb/c mice challenged with Alternaria extracts, with or without treatment with JQ1.ILC2 from asthma patients expressed increased amounts of MYC. Deletion of c-Myc in ILC2 results in reduced proliferation, decreased cytokine production, and reduced expression of many lymphocyte activation genes. ChIP identified Stat6 as a direct gene target of c-Myc in ILC2. In vivo inhibition of c-Myc by JQ1 treatment repressed ILC2 activity and suppressed Alternaria-induced airway inflammation and AHR.c-Myc expression is upregulated during ILC2 activation. c-Myc is essential for ILC2 activation and their in vivo pathogenic effects. These findings suggest that targeting c-Myc may unlock novel strategies to combat asthma or asthma exacerbation.
Routine Esophagram for Detecting Anastomotic Leak After Esophagectomy
Authors: Jonathan Cools-Lartigue, Lorenzo E. Ferri
Journal: JAMA Surgery (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
IL6/STAT3 Signaling Orchestrates Premetastatic Niche Formation and Immunosuppressive Traits in Lung
Authors: Bo Jing, Tong Wang, Beibei Sun, Jianhua Xu, Dongliang Xu, Yueling Liao, Hongyong Song, Wenzheng Guo, Kaimi Li, Min Hu, Siwei Zhang, Jing Ling, Yanbin Kuang, Tuo Zhang, Binhua P. Zhou, Feng Yao, Jiong Deng
Journal: Cancer Research (2019)

Cancer cells that succeed in forming metastasis need to be reprogrammed to evade immune surveillance and survive in a new microenvironment. This is facilitated by metastatic niches that are either postformed through reciprocal signaling between tumor cells and local stromal cells or preformed as premetastatic niches before tumor cell arrival. IL6/STAT3 signaling is aberrantly activated in lung tumorigenesis and metastasis, however, the roles and mechanisms of action of IL6 remain controversial. Here, we showed that blockade of intrinsic STAT3 signaling in lung tumor cells suppressed lung metastasis in immune-competent syngeneic mice, but not in immune-deficient nude mice. Consistently, repression of STAT3 signaling in tumor cells made them susceptible to T-cell-mediated cytotoxicity. Thus, STAT3-mediated immunosuppression is crucial for metastasis. Noticeably, lung metastasis was greatly increased in Gprc5a-knockout (ko; 5a-/-) mice compared with wild-type mice, which correlated with upregulated IL6 in the tumor microenvironment. Depletion of IL6 via combined deletion of Il6 and Gprc5a genes almost completely eliminated lung metastasis in Gprc5a-ko/Il6-ko (5a-/-;Il6-/-) mice. Mechanistically, dysregulated IL6 reprogrammed the STAT3 pathway in metastatic tumor cells, and induced recruitment of myeloid-derived suppressor cells and polarized macrophages to evade host immunity. Consistently, IHC staining showed that activated STAT3 correlated with repressed infiltration of CD8+ T cells in non-small cell lung cancer. Therefore, IL6/STAT3 signaling is crucial for orchestrating premetastatic niche formation and immunosuppression in lung.Significance: IL6 plays important roles not only in cell autonomous propensity for metastasis, but also in establishing the metastatic niche.
Impact of enriched environment on tumor growth and adipokines secretion in a mouse model of mammary cancer.
Authors: Samar Basu, Kristell Combe, Rachida Nachat-Kappes, Marie-Chantal Farges, Adrien Rossary, Nicolas Goncalves-Mendes, Marie-Paule Vasson
Journal: Journal of Clinical Oncology (2013)

e11552 Background: Enriched environment (EE) by promoting physical activity and social communication reduces development of tumors such as in colon cancer. It seems to act particularly through a decrease of leptin production which linked to breast cancer risk. Thus, the aim of this study was to investigate the effect of EE on the mammary tumor development and to identify the molecular pathways in relation to adipokines secretion. Methods: 3-week-old female C57BL/6 mice were housed in standard environment (SE) or in EE for 9 weeks. A half of EE and SE mice received either EO771 syngeneic cells injection into the inguinal mammary fat pad (EE and SE tumor) or vehicle (EE and SE control). After 3 weeks, the mice were sacrificed for blood and tumor analysis : expression of leptin, COX-2 (inflammation), Ki-67 (proliferation) and caspase 3 (apoptosis) were determined using immunostaining and western blotting. Plasma adipokines were quantified by immunoassay (ELISA, Luminex). Results: Tumor volume and weight were lower in EE mice vs SE tumor (-29% and -26% respectively). COX-2 and Ki67 expressions were decreased (20% and 40% of positive cells respectively) while caspase-3 levels were increased (450% of positive cells) relative to SE tumor (100%). EE control mice showed a significant increase in adiponectin levels but no change in those of leptin, IL-6, TNF-α, PAI-1, MCP-1 and resistin vs SE control. No significant difference between EE and SE tumor groups were observed for these inflammatory markers. Conclusions: These data showed for the first time that EE housing inhibits mammary tumor growth which results in a marked intratumoral COX-2 under-expression and an increase in the plasma adiponectin/leptin ratio without any change in inflammatory response. So, COX-2 and adipokines seem to be key regulating factors in breast carcinogenesis. [Table: see text]