tbuckley/cabot-search huggingface dataset:
Abstract 20349: Left Ventricular Diastolic Dysfunction and Obstructive Sleep Apnea in a Large Middle-Aged Asymptomatic Population
Authors: Rupa L Iyengar, Cynara Maceda, Jacqueline O’Boyle, Mary Ann McLaughlin
Journal: Circulation (2016)

Introduction: The diagnosis of obstructive sleep apnea (OSA) has been increasing through the years due to better patient and physician awareness and education. We know that OSA is associated with left ventricular diastolic dysfunction (LVDD) as well as cardiovascular events. We aim to describe the relationship between LVDD, and OSA risk as compared to OSA diagnosis. Methods: Analysis was performed on 940 participants enrolled in the World Trade Center (WTC)-CHEST program. Participants underwent an echo Doppler study to evaluate peak mitral inflow velocities at early (E) and late (A) diastole, transmitral E/A ratio and Tissue Doppler Imaging (TDI) of the left ventricular (LV) septum in the apical four-chamber view. LVDD is computed by the JASE 2009 guidelines and Left Ventricular index (LVindex) as defined by JASE 2015 guidelines. High risk for OSA (OSA+) was identified as 2 or more positive categories from the Berlin Questionnaire (BQ) and diagnosis of OSA was patient reported physician diagnosis (OSAdx)....
Extracellular HMGA1 Promotes Tumor Invasion and Metastasis in Triple-Negative Breast Cancer
Authors: Olga Méndez, Vicente Peg, Cándida Salvans, Mireia Pujals, Yolanda Fernández, Ibane Abasolo, José Pérez, Ana Matres, Marta Valeri, Josep Gregori, Laura Villarreal, Simó Schwartz, Santiago Ramon y Cajal, Josep Tabernero, Javier Cortés, Joaquín Arribas, Josep Villanueva
Journal: Clinical Cancer Research (2018)

Abstract Purpose: The study of the cancer secretome suggests that a fraction of the intracellular proteome could play unanticipated roles in the extracellular space during tumorigenesis. A project aimed at investigating the invasive secretome led us to study the alternative extracellular function of the nuclear protein high mobility group A1 (HMGA1) in breast cancer invasion and metastasis. Experimental Design: Antibodies against HMGA1 were tested in signaling, adhesion, migration, invasion, and metastasis assays using breast cancer cell lines and xenograft models. Fluorescence microscopy was used to determine the subcellular localization of HMGA1 in cell lines, xenograft, and patient-derived xenograft models. A cohort of triple-negative breast cancer (TNBC) patients was used to study the correlation between subcellular localization of HMGA1 and the incidence of metastasis. Results: Our data show that treatment of invasive cells with HMGA1-blocking antibodies in the extracellular space impairs their migration and invasion abilities. We also prove that extracellular HMGA1 (eHMGA1) becomes a ligand for the Advanced glycosylation end product-specific receptor (RAGE), inducing pERK signaling and increasing migration and invasion. Using the cytoplasmic localization of HMGA1 as a surrogate marker of secretion, we showed that eHMGA1 correlates with the incidence of metastasis in a cohort of TNBC patients. Furthermore, we show that HMGA1 is enriched in the cytoplasm of tumor cells at the invasive front of primary tumors and in metastatic lesions in xenograft models. Conclusions: Our results strongly suggest that eHMGA1 could become a novel drug target in metastatic TNBC and a biomarker predicting the onset of distant metastasis.
Amplification of Glyceronephosphate O-Acyltransferase and Recruitment of USP30 Stabilize DRP1 to Promote Hepatocarcinogenesis
Authors: Li Gu, Yahui Zhu, Xi Lin, Yajun Li, Kaisa Cui, Edward V. Prochownik, Youjun Li
Journal: Cancer Research (2018)

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, and the underlying pathophysiology of HCC is highly complex. In this study, we report that, in a bioinformatic screen of 2,783 genes encoding metabolic enzymes, GNPAT, which encodes the enzyme glyceronephosphate O-acyltransferase, is amplified, upregulated, and highly correlated with poor clinical outcome in human patients with HCC. High GNPAT expression in HCC was due to its amplification and transcriptional activation by the c-Myc/KDM1A complex. GNPAT compensated the oncogenic phenotypes in c-Myc-depleted HCC cells. Mechanistically, GNPAT recruited the enzyme USP30, which deubiquitylated and stabilized dynamin-related protein 1 (DRP1), thereby facilitating regulation of mitochondrial morphology, lipid metabolism, and hepatocarcinogenesis. Inhibition of GNPAT and DRP1 dramatically attenuated lipid metabolism and hepatocarcinogenesis. Furthermore, DRP1 mediated the oncogenic phenotypes driven by GNPAT. Taken together, these results indicate that GNPAT and USP30-mediated stabilization of DRP1 play a critical role in the development of HCC.Significance: This study identifies and establishes the role of the enzyme GNPAT in liver cancer progression, which may serve as a potential therapeutic target for liver cancer. Cancer Res; 78(20); 5808-19. ©2018 AACR.
Dietary Nitrate and Physical Performance
Authors: Andrew M. Jones, Christopher Thompson, Lee J. Wylie, Anni Vanhatalo
Journal: Annual Review of Nutrition (2018)

Nitric oxide (NO) plays a plethora of important roles in the human body. Insufficient production of NO (for example, during older age and in various disease conditions) can adversely impact health and physical performance. In addition to its endogenous production through the oxidation of l-arginine, NO can be formed nonenzymatically via the reduction of nitrate and nitrite, and the storage of these anions can be augmented by the consumption of nitrate-rich foodstuffs such as green leafy vegetables. Recent studies indicate that dietary nitrate supplementation, administered most commonly in the form of beetroot juice, can ( a) improve muscle efficiency by reducing the O 2 cost of submaximal exercise and thereby improve endurance exercise performance and ( b) enhance skeletal muscle contractile function and thereby improve muscle power and sprint exercise performance. This review describes the physiological mechanisms potentially responsible for these effects, outlines the circumstances in which ergogenic effects are most likely to be evident, and discusses the effects of dietary nitrate supplementation on physical performance in a range of human populations.
The Value of Open Deliberation in Clinical Ethics, and the Role of Parents’ Reasons in the Zone of Parental Discretion
Authors: Rosalind McDougall, Clare Delany, Lynn Gillam
Journal: The American Journal of Bioethics (2018)

Winters (2018) provides an overview of two frameworks (the harm principle and the zone of parental discretion), developed for use when there are entrenched disagreements between clinicians and pare...
Abstract 16475: Enhanced Expression of Hemoglobin Scavenger Receptor is Associated With Aortic Valve Stenosis in Patients With Bicuspid Aortic Valve
Authors: Tsukasa Matsushita, Yoshiki Mastumura, Kenji Simeno, Ryo Mastumoto, Yukio Abe, Kimio Kamimori, Takahiko Naruko, Kenichi Sugioka, Masashi Nakagawa, Minoru Yoshiyama Yoshiyama, Makiko Ueda
Journal: Circulation (2016)

Background: Recent studies have shown that intraleaflet hemorrhage occurs in aortic valve leaflets and is associated with accelerated progression of aortic stenosis (AS) in patients with bicuspid aortic valve (BAV) compared to patients with tricuspid aortic valve (TAV). Hemoglobin (Hb)-induced oxidative damage is caused by the protein haptoglobin (Hp), which rapidly and irreversibly binds to extracorpuscular Hb, forming an Hp-Hb complex. In aortic valve leaflets, the only route for clearance of the Hp-Hb complex is via macrophages, mediated by the membrane receptor CD163. In this study, we immunohistochemically examined the relationship between intraleaflet hemorrhage, 4-HNE (4-hydroxy-2-nonenal), an index of lipid peroxidation, and CD163 in aortic valve specimens from AS patients with either TAV or BAV. Methods: Frozen aortic valve samples were obtained surgically from AS patients with either TAV (n=35) or BAV (n=34). Samples were stained with antibodies against smooth muscle cells, macrophages, glycopho...
Voice of cancer patients (VoCP): Use and experience of acupuncture in cancer patients.
Authors: Sangeeta Aggarwal, Rahul Sharma, Rishi Sharma, Alok Aggarwal
Journal: Journal of Clinical Oncology (2018)

e22216 Background: Acupuncture, an ancient medical treatment originating in China, is gaining momentum and acceptance as a valid form of complimentary therapy in treating symptoms related to cancer treatment. Specific use of acupuncture by cancer patients is estimated to range between 1.7% and 31%. In this study we analyzed patients’ experiences and acupuncture use in cancer patients. Methods: Many patients share their experiences as freely shared messages in online forums. We collected 15.7 million messages million unique messages from 37 unrestricted cancer forums that provide clinically relevant information. We built custom ontologies for various cancers, acupuncture, and cancer related side effects such as pain, insomnia, neuropathy, fatigue, shortness of breath and depression. We then used out automated system VoCP) that uses techniques from Big Data Science and Artificial Intelligence (e.g., deep learning, topic modeling, information retrieval, and natural language processing) to extract relevant information and insights from these messages. Results: We found 20,922 messages (from 9,440 distinct members) discussed the use of acupuncture. Many of them were inquiring or providing information 395 members reported its use for managing symptoms and side-effects associated with various cancer therapies and for general well-being. Of 395 members, 290 were in Breast cancer, 27 in Head and neck Cancer, 22 in Lymphoma, 20 in Colorectal cancer, 6 in lung cancer, 60 in Ovarian cancer, and 30 had more than one cancers. Some specific uses included the management of Hot flashes (63), Neuropathy (42), Nausea (31), Relief of side effects of chemo (28), Body aches (27) and dry mouth (20). Efficacy was reported by 395: Very Effective (230), somewhat effective (125) and not effective (40). Sentiment analysis: Positive (343), Mixed/neutral: (12) and negative (34). Conclusions: Many patients find Acupuncture useful as adjunct to cancer therapy to improve quality of life and alleviate chemo related side effects. This VoCP interactive system reliably provides significant insights into patient’s concerns, unmet needs and where research and resources should be focused.
Dupilumab for the Treatment of Recalcitrant Bullous Pemphigoid
Authors: Alex Kaye, Samantha C. Gordon, Sandhya C. Deverapalli, Min Ji Her, David Rosmarin
Journal: JAMA Dermatology (2018)

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Genomic epidemiology of meticillin-resistant Staphylococcus aureus ST22 widespread in communities of the Gaza Strip, 2009
Authors: Qiuzhi Chang, Izzeldin Abuelaish, Asaf Biber, Hanaa Jaber, Alanna Callendrello, Cheryl P Andam, Gili Regev-Yochay, William P Hanage
Journal: Eurosurveillance (2018)

Background Remarkably high carriage prevalence of a community-associated meticillin-resistant Staphylococcus aureus (MRSA) strain of sequence type (ST) 22 in the Gaza strip was reported in 2012. This strain is linked to the pandemic hospital-associated EMRSA-15. The origin and evolutionary history of ST22 in Gaza communities and the genomic elements contributing to its widespread predominance are unknown. Methods: We generated high-quality draft genomes of 61 ST22 isolates from Gaza communities and, along with 175 ST22 genomes from global sources, reconstructed the ST22 phylogeny and examined genotypes unique to the Gaza isolates. Results: The Gaza isolates do not exhibit a close relationship with hospital-associated ST22 isolates, but rather with a basal population from which EMRSA-15 emerged. There were two separate resistance acquisitions by the same MSSA lineage, followed by diversification of other genetic determinants. Nearly all isolates in the two distinct clades, one characterised by staphylococcal cassette chromosome mec (SCC mec) IVa and the other by SCC mec V and MSSA isolates, contain the toxic shock syndrome toxin-1 gene. Discussion: The genomic diversity of Gaza ST22 isolates is not consistent with recent emergence in the region. The results indicate that two divergent Gaza clones evolved separately from susceptible isolates. Researchers should not assume that isolates identified as ST22 in the community are examples of EMRSA-15 that have escaped their healthcare roots. Future surveillance of MRSA is essential to the understanding of ST22 evolutionary dynamics and to aid efforts to slow the further spread of this lineage.
Abstract 18188: Chronic Obstructive Pulmonary Disease (COPD) and Alpha-1 Antitrypsin Deficiency (A1ATD) are Associated With Increased Aortic Inflammation and Stiffness
Authors: Marie Fisk, Joseph Cheriyan, Carmel M McEniery, John R Cockcroft, James H Rudd, Timothy D Fryer, Ruth Tal-Singer, Nicholas S Hopkinson, Michael I Polkey, Ian B Wilkinson
Journal: Circulation (2015)

Introduction: COPD is associated with increased cardiovascular events, even after adjusting for traditional risk factors. We hypothesised that this relates to aortic inflammation and stiffness, both surrogates of higher cardiac risk. For comparison, we also measured these parameters in A1ATD patients with emphysema and controls. Methods: Sixty subjects (24 COPD, 12 A1ATD, 12 smokers, 12 never smokers (controls)) were recruited. Aortic stiffness was estimated by aortic pulse wave velocity (aPWV). Aortic and carotid wall inflammation was measured by FDG PET/CT, with FDG uptake quantified as the target to blood ratio (TBR). Results: COPD and A1ATD subjects had both 1) increased aPWV compared to healthy smokers and controls (Table 1, p=0.01) and 2) more aortic inflammation, particularly in the abdominal aorta (p=0.0001, 24% and 29% difference to controls, respectively, Figure 1). FDG uptake was also higher in the carotid arteries of COPD but not A1ATD subjects (p=0.0001). There was no difference in stiffness between healthy smokers and controls (p=1.0), but arterial inflammation in the abdominal aorta was greater in smokers than controls (p=0.0001). Conclusions: COPD is associated with both increased aortic inflammation and stiffness. These mechanisms might explain the unexplained heightened cardiovascular risk in COPD patients and are potential therapeutic targets. A1ATD subjects also have increased aortic inflammation and stiffness suggestive of increased cardiovascular risk. Susceptibility to smoke injury in the lungs and vasculature, or systemic inflammation associated with lung disease, are possible explanations.
Dose and Schedule Determine Distinct Molecular Mechanisms Underlying the Efficacy of the p53–MDM2 Inhibitor HDM201
Authors: Sébastien Jeay, Stéphane Ferretti, Philipp Holzer, Jeanette Fuchs, Emilie A. Chapeau, Markus Wartmann, Dario Sterker, Vincent Romanet, Masato Murakami, Grainne Kerr, Eric Y. Durand, Swann Gaulis, Marta Cortes-Cros, Stephan Ruetz, Therese-Marie Stachyra, Joerg Kallen, Pascal Furet, Jens Würthner, Nelson Guerreiro, Ensar Halilovic, Astrid Jullion, Audrey Kauffmann, Emil Kuriakose, Marion Wiesmann, Michael R. Jensen, Francesco Hofmann, William R. Sellers
Journal: Cancer Research (2018)

Abstract Activation of p53 by inhibitors of the p53–MDM2 interaction is being pursued as a therapeutic strategy in p53 wild-type cancers. Here, we report distinct mechanisms by which the novel, potent, and selective inhibitor of the p53–MDM2 interaction HDM201 elicits therapeutic efficacy when applied at various doses and schedules. Continuous exposure of HDM201 led to induction of p21 and delayed accumulation of apoptotic cells. By comparison, high-dose pulses of HDM201 were associated with marked induction of PUMA and a rapid onset of apoptosis. shRNA screens identified PUMA as a mediator of the p53 response specifically in the pulsed regimen. Consistent with this, the single high-dose HDM201 regimen resulted in rapid and marked induction of PUMA expression and apoptosis together with downregulation of Bcl-xL in vivo. Knockdown of Bcl-xL was identified as the top sensitizer to HDM201 in vitro, and Bcl-xL was enriched in relapsing tumors from mice treated with intermittent high doses of HDM201. These findings define a regimen-dependent mechanism by which disruption of MDM2–p53 elicits therapeutic efficacy when given with infrequent dosing. In an ongoing HDM201 trial, the observed exposure–response relationship indicates that the molecular mechanism elicited by pulse dosing is likely reproducible in patients. These data support the clinical comparison of daily and intermittent regimens of p53–MDM2 inhibitors. Significance: Pulsed high doses versus sustained low doses of the p53-MDM2 inhibitor HDM201 elicit a proapoptotic response from wild-type p53 cancer cells, offering guidance to current clinical trials with this and other drugs that exploit the activity of p53. Cancer Res; 78(21); 6257–67. ©2018 AACR.
Assessment of the US Federal Retailer Violation Rate as an Estimate of the Proportion of Retailers That Illegally Sell Tobacco to Adolescents
Authors: Arnold H. Levinson, Ming Ma, Leonard A. Jason, Joseph G. L. Lee, Hope Landrine, Deborah H. Glueck, Joseph R. DiFranza
Journal: JAMA Pediatrics (2018)

Despite progress against tobacco sales to minors, retailers continue to violate state and federal laws and supply adolescent smokers with tobacco products. Government-sanctioned surveys underestimate the extent of the problem, and retailer associations use these data to block stricter enforcement policies.
Abstract 15912: MicroRNA-92a Mediates Endothelial Dysfunction in Chronic Kidney Disease
Authors: Fenqing Shang, Shen-Chih Wang, Chien-Yi Hsu, Yan-Ting E Shiu, Po-Hsun Huang, John Y Shyy, Zhen Chen
Journal: Circulation (2016)

Introduction: The emerging field in cardiorenal syndrome (CRS) emphasizes the crucial link between chronic kidney disease (CKD) and cardiovascular disease (CVD). Despite the epidemiological evidenc...
Abstract 18244: Macrophages Infiltrate the Heart With Activation of Adaptive Immunity During Compensated Pressure Overload Hypertrophy
Authors: Bindiya Patel, Mohamed A Ismahil, Shyam S Bansal, Amy Michaud, Sumanth D Prabhu
Journal: Circulation (2015)

As opposed to chronic ischemic heart failure (HF), spleen-derived macrophages (Mf) are not prominent disease mediators during the chronic stages of pressure-overload (PO) HF. Increases in Mf during the early stages of PO, however, may serve as important drivers of both remodeling and activation of T-cell responses during later stages. Additionally, recent evidence indicates distinct groups of resident and circulating monocyte-derived infiltrating Mf that have different reparative vis-à-vis pro-inflammatory capacities. We hypothesized that cardiac Mf are expanded during the early stages of PO, primarily due to an increase in infiltrating Mf, and contribute to long-term T-cell activation in the PO heart. Cardiac Mf were characterized by flow cytometry as MerTK + CD64 + F480 + MHCII + cells, with infiltrating Mf populations identified as expressing chemokine receptor 2 (CCR2). One week after transverse aortic constriction (TAC), C57Bl/6 mice exhibited significant (p &lt; 0.05) hypertrophy (heart weight/body weight 7.7 ± 0.5 vs 5.7 ± 0.2 mg/g; LV wall thickness 0.84 ± 0.03 vs 0.74 ± 0.02), without change in LVEF as compared with sham. There were robust increases in cardiac macrophages (3.15 ± 0.64 vs 1.09 ± 0.24%), specifically in the infiltrating CCR2 + MHCII hi population (1.6 ± 0.5 vs 0.5 ± 0.1%). TAC mice also exhibited higher circulating Gr1 – CD11b + Ly6C hi monocytes (2.6 ± 0.5 vs 1.3 ± 0.2%) that are recruited to tissue via CCR2. To determine activation of the adaptive immune response, we analyzed the mediastinal heart draining lymph nodes (MLN) for T-cells and antigen presenting cells. As compared with sham mice, the MLN of TAC mice were larger with greater cellularity (10.8 x 10 5 vs 4.2 x 10 5 ), especially related to MerTK + CD169 + Mf and CD3 + CD8 + T cells. We conclude that there is both an organ-specific and systemic immune response during compensatory PO hypertrophy, despite the absence of ischemic tissue injury. As infiltrating Mf are known to be less reparative, potently pro-inflammatory, and robust activators of adaptive immune cells, specifically targeting Ly6C hi monocyte recruitment and CCR2 + infiltrating Mf during the early compensated stages of pressure-overload may prevent subsequent inflammatory activation, adverse remodeling, and the transition to HF.
Development of Microvascular Complications and Effect of Concurrent Risk Factors in Type 1 Diabetes: A Multistate Model From an Observational Clinical Cohort Study
Authors: Lasse Bjerg, Adam Hulman, Bendix Carstensen, Morten Charles, Marit E. Jørgensen, Daniel R. Witte
Journal: Diabetes Care (2018)

OBJECTIVE Type 1 diabetes is a complex disease, and development of multiple complications over time can be analyzed only with advanced statistical methods. This study describes the development of microvascular complications and explores the effect of complication burden and important concurrent risk factors by applying a multistate model. RESEARCH DESIGN AND METHODS We used a clinical cohort at the Steno Diabetes Center Copenhagen to study the development of diabetic kidney disease, retinopathy, and neuropathy. We extracted information from electronic patient records and estimated incidence rates of complications by concurrent complication burden. We explored the extent to which concurrent complications modify the effect of selected risk factors on the development of microvascular complications. RESULTS We included 3,586 individuals. Incidence rate ratios in individuals with two previous complications were 3.2 (95% CI 2.3–4.5) for diabetic kidney disease, 2.1 (1.5–3.1) for retinopathy, and 1.7 (1.2–2.4) for neuropathy compared with individuals without complications. The models included diabetes duration; calendar time and age as timescales; and sex, HbA1c, lipid-lowering and antihypertensive treatment, systolic blood pressure, BMI, estimated glomerular filtration rate (eGFR), cardiovascular disease (CVD), LDL cholesterol, insulin dose (units/kg/day), and smoking status as covariates. Effects of HbA1c, diabetes duration, systolic blood pressure, BMI, eGFR, and LDL cholesterol where not modified by concurrent complication burden, whereas the effect of sex and CVD were. CONCLUSIONS The risk of microvascular complications highly depends on the concurrent complication burden and risk factor profile in individuals with type 1 diabetes. The results emphasize attention to risk factors, regardless of existing number of complications, to prevent development of further microvascular complications.