tbuckley/cabot-search huggingface dataset:
Case Studies of Gastric, Lung, and Oral Cancer Connect Etiologic Agent Prevalence to Cancer Incidence
Authors: Andrew F. Brouwer, Marisa C. Eisenberg, Rafael Meza
Journal: Cancer Research (2018)

Abstract Obtaining detailed individual-level data on both exposure and cancer outcomes is challenging, and it is difficult to understand and characterize how temporal aspects of exposures translate into cancer risk. We show that, in lieu of individual-level information, population-level data on cancer incidence and etiologic agent prevalence can be leveraged to investigate cancer mechanisms and to better characterize and predict cancer trends. We use mechanistic carcinogenesis models [multistage clonal expansion (MSCE) models] and data on smoking, Helicobacter pylori (H. pylori), and HPV infection prevalence to investigate trends of lung, gastric, and HPV-related oropharyngeal cancers. MSCE models are based on the initiation–promotion–malignant conversion paradigm and allow for interpretation of trends in terms of general biological mechanisms. We assumed the rates of initiation depend on the prevalence of the corresponding risk factors. We performed two types of analysis, using the agent prevalence and cancer incidence data to estimate the model parameters and using cancer incidence data to infer the etiologic agent prevalence as well as the model parameters. By including risk factor prevalence, MSCE models with as few as three parameters closely reproduced 40 years of age-specific cancer incidence data. We recovered trends of H. pylori prevalence in the United States and demonstrated that cohort effects can explain the observed bimodal, age-specific pattern of oral HPV prevalence in men. Our results demonstrate the potential for joint analyses of population-level cancer and risk factor data through mechanistic modeling. This approach can be a first step in systematically testing relationships between exposures and cancer risk when individual-level data is lacking. Significance: Analysis of trends in risk-factor prevalence and cancer incidence can shed light on cancer mechanisms and the way that carcinogen exposure through time shapes the risk of cancer at different ages. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/12/3386/F1.large.jpg. Cancer Res; 78(12); 3386–96. ©2018 AACR.
Abstract 9905: Nitrative Modification of Caveolin-3 and Subsequent Dissociation From AdipoR1 Occurs in Failing Heart and Contributes to Adiponectin Resistance
Authors: Wayne Bond Lau, Yajing Wang, Wei Yi, Yang Sun, Xiaoliang Wang, Yuexing Yuan, Bernard Lopez, Theodore Christopher, Erhe Gao, Walter Koch, Xin Ma
Journal: Circulation (2013)

Cardiac response to adiponectin (APN), a cardioprotective molecule, is significantly reduced during heart failure (HF), due to unknown underlying mechanisms. We recently reported Caveolin-3 (Cav3) plays an essential role in APN signaling by holding AdipoR1 in close proximity with its downstream signaling molecules. The current study investigated whether Cav3/AdipoR1 expression and/or their interaction are altered in the failing heart, thereby contributing to APN resistance and HF progression. Adult male mice were subjected to MI. Molecular, biochemical, and functional assays were performed 2 weeks post-MI, a time point during which significant APN resistance develops. Expression (mRNA and protein) of Cav3, AdipoR1, and known intracellular APN signaling molecules remained unchanged. However, Cav3/AdipoR1 complex formation significantly decreased. Among multiple post-translational modifications observed in the failing heart, Cav3 nitrative modification was the most significant (3.57±0.4-fold, P&lt;0.01). In vivo treatment with a peroxynitrite (ONOO - ) decomposition catalyst reduced Cav3 nitration and restored Cav3/AdipoR1 association. In vitro exposure of adult cardiomyocytes (CM) to SIN-1 (an ONOO - donor) or authentic chemical ONOO - caused significant Cav3 nitration, reduced Cav3/AdipoR1 association, and blocked APN-induced AMPK phosphorylation (P&lt;0.01). APN treatment significantly attenuated Ang-II induced neonatal CM hypertrophy (P&lt;0.01). However, the anti-hypertrophic effect of APN was virtually abolished by knockout of either Cav3 or AdipoR1, or SIN-1 pre-treatment in CM. Finally, in neonatal CM isolated from Cav3KO mice transfected with WT Cav3 vector, SIN-1 caused significant Cav3 nitration, Cav3/AdipoR1 dissociation, and blocked APN-induced AMPK activation. In contrast, in neonatal CM isolated from Cav3KO mice transfected with mutated Cav3 (in which all 5 tyrosine residues were substituted by phenylalanine) vector, no Cav3 nitration was observed after SIN-1 exposure; Cav3/AdipoR1 association was maintained, and APN-induced AMPK activation was preserved. These results demonstrate Cav3 tyrosine residue modification during HF progression causes Cav3/AdipoR1 dissociation, blocking APN cardioprotection.
Association of Retinoic Acid Receptor β Gene With Onset and Progression of Lichen Sclerosus–Associated Vulvar Squamous Cell Carcinoma
Authors: John Charles Rotondo, Alessandro Borghi, Rita Selvatici, Elisa Mazzoni, Ilaria Bononi, Monica Corazza, Jacqueline Kussini, Elena Montinari, Roberta Gafà, Mauro Tognon, Fernanda Martini
Journal: JAMA Dermatology (2018)

Molecular alterations in lichen sclerosus-associated vulvar squamous cell carcinoma (LS-VSCC) are largely unknown.To determine whether the retinoic acid receptor β (RARβ) tumor-suppressor gene is involved in the onset and/or progression of LS-VSCC.The case-control study, conducted at University-Hospital of Ferrara, Italy, included 20 LS-VSCC (mean [SD] age, 75 [3] years) and 20 cancer-associated vulvar LS (caVLS; mean [SD] age, 62 [11] years) formalin-fixed embedded tissue specimens, 20 cancer-free vulvar LS (cfVLS), and 20 normal skin fresh specimens from diagnostic biopsies and women surgically treated for nonmalignant skin lesions, respectively. RARβ gene expression and promoter methylation were investigated in LS-VSCC and caVLS adjacent to VSCC specimens, and in cfVLS and normal skin specimens, as controls, by RT-Q real-time polymerase chain reaction (PCR) analysis, and sequencing of PCR-amplified bisulfite-treated DNA. c-Jun expression, an RARβ pathway-related gene, was also investigated.RARβ expression, correlation with its promoter methylation and c-Jun expression, and association with onset or progression of LS-VSCC.In LS-VSCC, RARβ messenger RNA was 3.4-, 3.6-, and 4.8-fold lower than in caVLS (P = .001), cfVLS (P = .005), and normal skin (P < .001), respectively. The RARβ mRNA levels were similar in caVLS, cfVLS, and normal skin. The RARβ promoter was hypermethylated in 18 (90%) of 20 LS-VSCC, 11 (55%) of 20 cfVLS, 10 (50%) of 20 caVLS, and 5 (25%) of 20 in the normal skin group. The degree of methylation of RARβ promoter was higher in LS-VSCC, ranging from 5 to 9 (full promoter methylation) CpGs methylated, than in caVLS (P = .02), cfVLS (P = .03), or normal skin (P < .001), which was up to 5 CpGs methylated. Importantly, 0 of 8 LS-VSCC with 5 to 6 CpGs methylated and 5 (63%) of 8 LS-VSCC with 7 to 8 CpGs methylated were from patients with lymph node metastasis at diagnosis, respectively, whereas there were 2 of 2 (100%) LS-VSCC samples with 9 CpG methylated from patients with lymph node metastasis at diagnosis and subsequent recurrence. In LS-VSCC c-Jun mRNA was 4.3-, 1.4-, and 2.6-fold higher than in caVLS (P < .001), cfVLS (P = .001), and normal skin (P < .001), respectively. The expression of c-Jun was similar in caVLS, cfVLS, and normal skin.Hypermethylation-induced RARβ down-expression was associated with LS-VSCC and correlates with the upregulation of c-Jun. The degree of methylation of RARβ promoter increased with the malignancy of LS-VSCC. Therefore, RARβ gene dysregulation may play a role in progression of LS-VSCC, and RARβ promoter methylation status may be used as a prognostic marker in clinical treatment of patients with LS-VSCC.
Licofelone Enhances the Efficacy of Paclitaxel in Ovarian Cancer by Reversing Drug Resistance and Tumor Stem-like Properties
Authors: Jeff Hirst, Harsh B. Pathak, Stephen Hyter, Ziyan Y. Pessetto, Thuc Ly, Stefan Graw, Devin C. Koestler, Adam J. Krieg, Katherine F. Roby, Andrew K. Godwin
Journal: Cancer Research (2018)

Abstract Drug development for first-line treatment of epithelial ovarian cancer (EOC) has been stagnant for almost three decades. Traditional cell culture methods for primary drug screening do not always accurately reflect clinical disease. To overcome this barrier, we grew a panel of EOC cell lines in three-dimensional (3D) cell cultures to form multicellular tumor spheroids (MCTS). We characterized these MCTS for molecular and cellular features of EOC and performed a comparative screen with cells grown using two-dimensional (2D) cell culture to identify previously unappreciated anticancer drugs. MCTS exhibited greater resistance to chemotherapeutic agents, showed signs of senescence and hypoxia, and expressed a number of stem cell–associated transcripts including ALDH1A and CD133, also known as PROM1. Using a library of clinically repurposed drugs, we identified candidates with preferential activity in MCTS over 2D cultured cells. One of the lead compounds, the dual COX/LOX inhibitor licofelone, reversed the stem-like properties of ovarian MCTS. Licofelone also synergized with paclitaxel in ovarian MCTS models and in a patient-derived tumor xenograft model. Importantly, the combination of licofelone with paclitaxel prolonged the median survival of mice (&amp;gt;141 days) relative to paclitaxel (115 days), licofelone (37 days), or vehicle (30 days). Increased efficacy was confirmed by Mantel–Haenszel HR compared with vehicle (HR = 0.037) and paclitaxel (HR = 0.017). These results identify for the first time an unappreciated, anti-inflammatory drug that can reverse chemotherapeutic resistance in ovarian cancer, highlighting the need to clinically evaluate licofelone in combination with first-line chemotherapy in primary and chemotherapy-refractory EOC. Significance: This study highlights the use of an in vitro spheroid 3D drug screening model to identify new therapeutic approaches to reverse chemotherapy resistance in ovarian cancer. Cancer Res; 78(15); 4370–85. ©2018 AACR.
Fasting-induced JMJD3 histone demethylase epigenetically activates mitochondrial fatty acid β-oxidation
Authors: Sunmi Seok, Young-Chae Kim, Sangwon Byun, Sunge Choi, Zhen Xiao, Naoki Iwamori, Yang Zhang, Chaochen Wang, Jian Ma, Kai Ge, Byron Kemper, Jongsook Kim Kemper
Journal: Journal of Clinical Investigation (2018)

Jumonji D3 (JMJD3) histone demethylase epigenetically regulates development and differentiation, immunity, and tumorigenesis by demethylating a gene repression histone mark, H3K27-me3, but a role for JMJD3 in metabolic regulation has not been described. SIRT1 deacetylase maintains energy balance during fasting by directly activating both hepatic gluconeogenic and mitochondrial fatty acid β-oxidation genes, but the underlying epigenetic and gene-specific mechanisms remain unclear. In this study, JMJD3 was identified unexpectedly as a gene-specific transcriptional partner of SIRT1 and epigenetically activated mitochondrial β-oxidation, but not gluconeogenic, genes during fasting. Mechanistically, JMJD3, together with SIRT1 and the nuclear receptor PPARα, formed a positive autoregulatory loop upon fasting-activated PKA signaling and epigenetically activated β-oxidation-promoting genes, including Fgf21, Cpt1a, and Mcad. Liver-specific downregulation of JMJD3 resulted in intrinsic defects in β-oxidation, which contributed to hepatosteatosis as well as glucose and insulin intolerance. Remarkably, the lipid-lowering effects by JMJD3 or SIRT1 in diet-induced obese mice were mutually interdependent. JMJD3 histone demethylase may serve as an epigenetic drug target for obesity, hepatosteatosis, and type 2 diabetes that allows selective lowering of lipid levels without increasing glucose levels.
Abstract 11692: First Evaluation of Corvue Algorithm Efficacy to Predict Heart Failure in Real Life: An Unnecessary Waste of Energy?
Authors: JA Palfy, J Benezet-Mazuecos, J Martinez Milla, M Lopez Castillo, JA Iglesias, JJ de la Vieja, I Hernandez Gonzalez, JM Rubio, J Farre
Journal: Circulation (2015)

Introduction and hypothesis: Repeated hospitalizations for heart failure (HF) have a negative effect on quality of life and imply an important cost for the health care system. A drop of intrathoracic impedance due to pulmonary congestion detected by cardiac devices has been hypothesized to decrease hospitalization rate. Although Optivol algorithm (Medtronic) has been widely studied, we present the first study that evaluates the efficacy of CorVue algorithm (St. Jude Medical) to predict HF in a “real-life” cohort. Methods: CorVue algorithm (St Jude Medical) was activated in ICD or CRT-D patients to store information about intrathoracic impedance changes using nominal settings (with patient’s alarm emission off). Patients were followed every 3 months. Clinical events (new episodes of HF requiring ambulatory or emergency room (ER) treatment modification or hospitalization) and CorVue data were recorded. Appropriate CorVue detection for HF was considered if it occurred in the 4 prior weeks to the clinical event. Results: Sixty-five ICD/CRT-D patients (70 ± 1 year-old, 78% male) were included (36 ICD (55%) and 29 CRT-D patients). Device position was subcutaneous in 43 patients (69%) and submuscular in 19 cases. Time from implantation to algorithm activation was 21 ± 2 months. At inclusion, mean LVEF was 33.8 ± 1.7 % and 38 patients (59%) were in NYHA class I, 20 (31%) class II and 7 (11%) class III. After a mean follow-up of 14 ± 1 months, 51 patients (78%) remained in a clinically stable condition and 14 patients (21%) presented 20 episodes of HF: 9 hospitalizations and 11 ER/ambulatory treatment modification. On the other hand, a total of 83 CorVue algorithm alarm episodes were registered in 32 patients (49%), with a mean number of alarms per patient of 2.6 ± 0.2 (range 1 - 6). Only 5 alarm episodes (6%) resulted to be appropriate: 2 ambulatory diuretic therapy intensification and 3 hospitalizations. The sensitivity of CorVue algorithm was 25%. None of the variables analyzed to determine a better scenario for this algorithm improved significantly the diagnostic efficacy. Conclusion: CorVue algorithm (St Jude Medical) resulted to have a low sensitivity for the prediction of HF and its routinary activation could generate misleading information.
SP0095 Inflammatory cytokines as key messengers of the immune system
Authors: M.I. Koenders
Journal: Annals of the Rheumatic Diseases (2018)

<h3></h3> Intercellular communication is mediated by direct cell contact as well as via soluble factors like cytokines. Cytokines are signalling proteins that bind to a receptor on a recipient cell, thereby activating an intracellular signalling pathway. This in turn may affect various biological functions like activation, differentiation or proliferation of the cell. In this lecture, the role of inflammatory cytokines as key messengers of the immune system will be discussed. Targeting of hallmark cytokines in rheumatic diseases, like TNF, IL-6, GM-CSF, and IL-17, has changed the therapeutic landscape, and novel pro-inflammatory cytokines are currently under investigation as therapeutic targets. Furthermore, anti-inflammatory cytokines may be applied as therapeutic agents. Cytokines act on the innate and adaptive immune system, as well as on non-immune cells. How exactly do these key messengers control our immune system in health and disease? To unravel the cytokine network that drives the dysregulated immune system in rheumatic diseases, findings from <i>in vitro</i> studies, animal experiments and clinical trials will be combined. <h3>Disclosure of Interest</h3> None declared
AB0232 Disease activity state in patients with rheumatoid arthritis included in the biobadabrasil registry
Authors: I.M.M. Laurindo, M. Pinheiro, J. Macieira, A. Duarte, B. Kahlow, R. Ranza, J. Miranda, M. Bertolo, V. Valim, G. Castro, M.D.F. Lobato, D. Titton, R. Teodoro, J. Moraes, C. Brenol, I. Costa, V. Fernandes, H. Carvalho, I. Pereira, W. Bianchi, A. Hayata, P. Louzada, A. Kakehasi, R. Toledo, G. Castelar, I. Silva, A. Ranzoline, G. Christopoulos
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Objectives</h3> to analyse disease activity of RA patients at the start of treatment with a biologic agent (adalimumab, infliximab, certolizumab, etanercept, golimumab, abatacept, rituximab and tocilizumab -bDMARDs), target (tofacitinib-tsDMARDs) therapy or conventional DMARDs (comparison cohort of RA patients – csDMARDs). <h3>Methods</h3> BiobadaBrasil is a prospective observational cohort study, part of an international initiative (biobadaAmerica) in collaboration with BiobadaSeR; established in 2009, is an ongoing study supported by the Brazilian Society of Rheumatology (29 public centres located at academic instituitions and 2 in private practice) focused on the study of adverse events in patients on biologic therapy. Additionally, by decision of its investigators, disease activity scores were also recorded at the beginning of each treatment. Sex, age, disease duration, RA -DAS-28, concomitant treatments at baseline were collected. Results expressed in mean ±SD,%(n) <h3>Results</h3> -Data from 1984 RA patients (67% on ts/bDMARDs) were analysed: 86% of the patients were women; mean age=56.6±14.95 years; disease duration=14.4±9.42; 87% RF positive. There were 3802 treatment courses, 67% with aTNF (Adalimumab-ADA, Certolizumab-CTZ, Etanercept-ETA, Golimumab-GOL, Infliximab-INFL), 33% non-aTNF (Abatacept-ABA, Rituximab-RIT, Tocilizumab-TCL) including Tofacitinib-TOF. The table 1 below depicted the medications prescribed at the initiation of a new treatment course: Considering the more recent medications patients beginning TCL have more active disease than the ones beginning GOL and CTZ (p&lt;0,006); anti-TNF are prescribed in association with MTX in less than 60% of the treatments. Extensive use of corticosteroids was identified besides consistent use of leflunomide and of hydroxychloroquine. Starting of new treatments was related to moderate/high levels of disease activity. <h3>Conclusions</h3> patterns of bDMARDS, csDMARDS and corticosteroid use clearly surfaced. Possibilities of improvement can be addressed. <h3>Acknowledgements</h3> for data monitoring P Cabral; contributing to BiobadaBrasil registry, R. Giorgi, H. Pereira, M. Scheinberg, F. Sztajnbok, W. Vieira <h3>Disclosure of Interest</h3> None declared
Food based dietary patterns and chronic disease prevention
Authors: Matthias B Schulze, Miguel A Martínez-González, Teresa T Fung, Alice H Lichtenstein, Nita G Forouhi
Journal: BMJ (2018)

<b>Matthias B Schulze and colleagues</b> discuss current knowledge on the associations between dietary patterns and cancer, coronary heart disease, stroke, and type 2 diabetes, focusing on areas of uncertainty and future research directions
AB0141 Certolizumab pegol like reduces inflammation and bone damage in tmtnf transgenic mice
Authors: E. Vieira-Sousa, S. Caetano Silva, B. Vidal, I. Lopes, H. Canhão, J.E. Fonseca
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Transmembrane (tm)TNF (TgA86) mice is a transgenic line that spontaneously develops peripheral arthritis and spondylitis at 4 weeks of age, mimicking human spondyloarthritis (SpA). <h3>Objectives</h3> The aim of this work is to understand the effect of TNF blockade in this SpA-like phenotype mouse strain, focusing on histological inflammation and bone damage. <h3>Methods</h3> (tm)TNF (TgA86) mice were treated with a certolizumab pegol like product mice equivalent (Ab501), 100 mg/kg twice a week intraperitoneal, or with vehicle (phosphate buffer saline), for 12 weeks, in a therapeutic (10 weeks of age) and preventive (4 weeks of age) experimental settings. A semi-quantitative score for the severity of histologic inflammation and bone damage, in the paws (infiltration, lining cells, erosions and global), and in the spine (inflammation, intervertebral disc destruction, cartilage damage, bone erosion and ectopic chondrocytes/chondrophyte) was applied to haematoxylin and eosin stained slides. <h3>Results</h3> 14 (tm)TNF (TgA86) mice (6M/8F) at 10 weeks of age (therapeutic group), and 15(tm)TNF (TgA86) mice (10M/5F) at 4 weeks of age (preventive group), were treated with Ab501; and 30 (tm)TNF (TgA86) mice with the respective vehicles, for a period of 12 weeks. A statistically significant reduction of the inflammatory infiltrate (p≤0.001), lining cells layers (p≤0.05), erosions (p≤0.05) and global inflammatory score (p≤0.05) of the paws, was observed in the Ab501 treated group, when compared to the vehicle group, both in the 10 and 4 weeks of age treatment groups. In the spine, statistically significant reductions of the inflammation (p≤0.001), intervertebral disc destruction (p≤0.05), cartilage damage (p≤0.001), bone erosion (p≤0.05), and ectopic chondrocytes/chondrophyte scores (p≤0.001) was also depicted in Ab501 treated group in comparison with vehicle. <h3>Conclusions</h3> The certolizumab pegol like product mice equivalent reduced histologic inflammatory infiltrate in paws and spine of (tm)TNF (TgA86) mice. Bone damage, as defined by erosions in the paws and spine and ectopic chondrocytes/chondrophyte formation in the spine, also significantly improved in (tm)TNF (TgA86) mice. <h3>Acknowledgements</h3> To Leonie M van Duivenvoorde and Dominique Baeten (Amsterdam Academic Medical Centre) for providing (tm)TNF (TgA86) mice for breeding and colony establishment. George Kollias from Flemming Institute for authorisation for the use this mice line. This investigator-initiated study was supported (financial and product) by UCB. <h3>Disclosure of Interest</h3> None declared
Immunological mechanisms of human resistance to persistent Mycobacterium tuberculosis infection
Authors: Jason D. Simmons, Catherine M. Stein, Chetan Seshadri, Monica Campo, Galit Alter, Sarah Fortune, Erwin Schurr, Robert S. Wallis, Gavin Churchyard, Harriet Mayanja-Kizza, W. Henry Boom, Thomas R. Hawn
Journal: Nature reviews. Immunology (2018)
制定方案以识别银屑病研究问题,并对其进行优先级排序:James Lind联盟优先级设立合作伙伴关系
Authors: R. Majeed-Ariss, M. McPhee, C. Bundy, C.E.M. Griffiths, H. Young
Journal: British Journal of Dermatology (2018)

银屑病是一种影响着两百多万英国民众的常见疾病,该疾病会导致皮肤发红、形成片状斑块,有时患者可能会感到疼痛或瘙痒。银屑病会给患者带来生理、心理和社交方面的影响。关于银屑病目前还有许多尚未解答的问题。为弄清楚最重要的问题有哪些,现将落实银屑病优先级设立合作伙伴关系(PSP)。PSP旨在让患者、家属、护理人员和医疗专业人士致力于共同遵守James Lind联盟概述的流程。首先,对银屑病感兴趣的各群体需完成一项有关他们认为哪些研究问题较为重要的调查。然后依照现有证据审视调查结果。在调查中提出的、但在先前已经回答过的问题将与相关组织分享,由他们来考虑如何能够更好地与临床医生、患者及其家属分享这些信息。在调查中提出的、但尚未回答的问题将被汇编成一个列表。在开展第二项调查时(在此阶段将按重要性对研究问题进行排序),该列表将被发送给利益相关者。在召开最终研讨会时,患者及其护理人员和医疗专业人士将对“前十项”尚未解决的问题列表予以认可。我们将与银屑病研究人员和研究资助方广泛地分享这份“前十项”列表,以鼓励研究人员专注于解决对患者、家属、护理人员和医疗专业人士而言真正重要的关键问题。