tbuckley/cabot-search huggingface dataset:
Fluoroquinolone Use and Concern About the Cerebral Vasculature
Authors: Mark R. Goldstein, Luca Mascitelli
Journal: JAMA Surgery (2018)

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Abstract 17819: Clinical Outcomes of Patients With ST-Elevation Myocardial Infarction and Cardiogenic Shock According to the Right Coronary Versus Non-Right Coronary Involvement as Culprit Lesion
Authors: Jeong Cheon Choe, Kwang Soo Cha, Sun Hack Lee, Doo Yeop Kim, Jinhee Ahn, Jin Sup Park, Hye Won Lee, Jun-Hyok Oh, Jung Hyun Choi, Han Cheol Lee, Taek Jong Hong, Myeong Ho Jeong
Journal: Circulation (2017)

Introduction: Patients with ST-elevation myocardial infarction (MI) (STEMI) who present with cardiogenic shock (CS) still have unfavorable prognosis. We evaluated the clinical outcomes of patients ...
Endoscopic ultrasound-guided needle-based confocal laser endomicroscopy for diagnosis of gastric subepithelial tumors: a pilot study
Authors: Ming-Ming Zhang, Ning Zhong, Xiao Wang, Chang-Qing Li, Rui Ji, Zhen Li, Xiang Gu, Yan-Bo Yu, Li-Xiang Li, Xiu-Li Zuo, Yan-Qing Li
Journal: Endoscopy (2018)

The diagnostic yield of current techniques for gastric subepithelial tumors (SETs) is suboptimal. This prospective study aimed to develop diagnostic criteria for needle-based confocal laser endomicroscopy (nCLE) of gastric SETs, and to evaluate the diagnostic efficacy, feasibility, and safety of endoscopic ultrasound-guided nCLE (EUS-nCLE).Eligible patients were prospectively recruited to undergo EUS-nCLE. Four unblinded investigators evaluated nCLE videos and corresponding histopathology to develop the nCLE criteria. The recorded nCLE videos were reviewed off-line by one endoscopist 3 months later. Image quality (five-point scale, 1 = poor and 5 = very good) and the interobserver agreements were assessed.All 33 patients underwent successful EUS-nCLE procedures. The nCLE criteria for gastric SETs were established. Overall accuracy of off-line nCLE was significantly higher than that of EUS alone (87.9 % vs. 63.6 %; P = 0.02). The mean image quality score was 3.9. The kappa values of the interobserver agreements were 0.66 for gastrointestinal stromal tumor, 0.89 for ectopic pancreas, 0.58 for leiomyoma, and 0.72 for carcinoma.EUS-nCLE was feasible and safe to accurately diagnose gastric SETs.
Abstract 13638: Risk Stratification for Sudden Death in Children With Hypertrophic Cardiomyopathy. An International Multi-Center Study
Authors: Seshadri Balaji, Michael P DeLorenzo, Frank A Fish, Susan P Etheridge, Peter F Aziz, Mark W Russell, Svjetlana Tisma, Andreas Pflaumer, Narayanswami Sreeram, Peter Kubus, Ian H Law, Michal J Kantoch, Naomi J Kertesz, Margaret J Strieper, Christopher C Erickson, Jeremy P Moore, Stephanie J Nakano, Harinder R Singh, Philip Chang, Mitchell I Cohen, Anne Fournier, Maria V Ilina, Richard T Smith, Frank Zimmerman, Michaela Horndasch, Walter Li, Anjan Batra, Leo Liberman, Robert M Hamilton, Christopher M Janson, Shubayan Sanatani, Ilana Zeltser, George McDaniel, Andrew D Blaufox, Jason M Garnreiter, Hannah Katcoff, Maully Shah
Journal: Circulation (2017)

Introduction: Children with Hypertrophic Cardiomyopathy (HCM) are at high risk for sudden cardiac death (SCD). Yet, risk stratification for SCD is poorly defined in children with HCM. Methods: We c...
2-Deoxy-d-glucose induces unfolded protein response mediated apoptosis via CHOP/GADD153 in select tumor cells growing under normoxia
Authors: Metin Kurtoglu, Johnathan Maher, Medhi Wangpaichitr, Niramol Savaraj, Theodore Lampidis
Journal: Cancer Research (2007)

4464  Cells growing under hypoxia are solely dependent on glucose metabolism via glycolysis for energy production. Consequently, when this pathway is blocked, with 2-deoxy-D-glucose (2DG), hypoxic cells die. In contrast, when glycolysis is blocked under normoxia most cells survive since fats and proteins can substitute as energy sources to fuel mitochondrial oxidative phosphorylation. However, here we find that under normal oxygen tension, a select number of tumor cell lines undergo an unfolded protein response (UPR) mediated apoptosis via CHOP/GADD153 at a relatively low dose of 2-DG (4 mM). These results coincide with previous studies on viral coat glycoprotein synthesis in which it was shown that 2-DG interferes with the process of N-linked glycosylation, that can be reversed by addition of exogenous mannose. Thus, our results which show that 2-DG toxicity under normoxia can be completely reversed by low dose mannose (1 mM), implicate glycosylation and not glycolysis as the mechanism responsible for this phenomenon. Additionally, 2-fluoro-deoxy-D-glucose (2-FDG) which is more potent than 2-DG in blocking glycolysis and killing these cells when grown under anaerobic conditions, shows little or no toxicity to these same cells under normoxia. Furthermore, the molecular chaperones, GRP 94 and 78, which are known to be induced by an unfolded protein response (UPR) when N-linked glycosylation is altered, were found to be upregulated by 2-DG and this induction could be reversed by mannose. In addition, 2-DG was more potent in inducing UPR in sensitive vs. resistant cells growing under normoxia. Since 2-DG has been shown to be well-tolerated in phase I clinical trials when used in combination with chemotherapeutic agents, our results raise the possibility that in certain tumor cell types, this sugar analog could be used as a single agent to selectively kill both the aerobic (via interference with glycosylation) as well as the hypoxic (via inhibition of glycolysis) cells of a solid tumor.
Trends and Gaps in National Blood Transfusion Services — 14 Sub-Saharan African Countries, 2014–2016
Authors: Udhayashankar Kanagasabai, Michelle S. Chevalier, Bakary Drammeh, Fatima D. Mili, Michael L. Qualls, Naomi Bock, Irene Benech, Lisa J. Nelson, George Alemnji, D. Heather Watts, Daniel Kimani, Dejana Selenic
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

Ensuring availability of safe blood products through recruitment of voluntary, nonremunerated, blood donors (VNRDs) and prevention of transfusion-transmissible infections (TTIs), including human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), and syphilis, is important for public health (1,2). During 2004-2016, the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) provided approximately $468 million in financial support and technical assistance* to 14 sub-Saharan African countries† with high HIV prevalence to strengthen national blood transfusion services (NBTSs)§ and improve blood safety and availability. CDC analyzed these countries' 2014-2016 blood safety surveillance data to update previous reports (1,2) and summarize achievements and programmatic gaps as some NBTSs begin to transition funding and technical support from PEPFAR to local ministries of health (MOHs) (2,3). Despite a 60% increase in blood supply since 2004 and steady declines in HIV prevalence (to <1% among blood donors in seven of the 14 countries), HIV prevalence among blood donors still remains higher than that recommended by the World Health Organization (WHO) (4). PEPFAR support has contributed to significant reductions in HIV prevalence among blood donors in the majority of PEPFAR-supported countries, and linking donors who screen HIV-positive to confirmatory testing and indicated treatment, as well as further reducing TTIs, remains a public health priority (5).
Phase I Dose-Escalation Study of Once Weekly or Once Every Two Weeks Administration of High-Dose Sunitinib in Patients With Refractory Solid Tumors
Authors: Maria Rovithi, Sophie L. Gerritse, Richard J. Honeywell, Albert J. ten Tije, Rita Ruijter, Godefridus J. Peters, Jens Voortman, Mariette Labots, Henk M.W. Verheul
Journal: Journal of Clinical Oncology (2018)

Dose and schedule optimization of treatment with tyrosine kinase inhibitors is of utmost importance. On the basis of preclinical data, a phase I clinical trial of once weekly or once every 2 weeks administration of high-dose sunitinib in patients with refractory solid malignancies was conducted.Patients with advanced cancer refractory to standard treatment were eligible. With use of a standard 3 + 3 phase I design, patients received escalating doses of sunitinib, in 100 mg increments, starting at 200 mg once weekly. In both the once weekly and once every 2 weeks cohorts, 10 more patients were included at the maximum tolerated dose level. Primary end points were safety and tolerability.Sixty-nine patients with advanced cancer, predominantly colorectal cancer (42%), were treated with this alternative dosing regimen. Maximum tolerated dose was established at 300 mg once weekly and 700 mg once every 2 weeks, resulting in nine- and 18-fold higher maximum plasma concentrations compared with standard dose, respectively. Treatment was well tolerated, with fatigue (81%), nausea (48%), and anorexia (33%) being the most frequent adverse events. The only grade 3 or 4 treatment-related adverse event in 5% or more of patients was fatigue (6%). Sixty-three percent of patients had significant clinical benefit, with a 30% progression-free survival of 5 months or more.Sunitinib administered once weekly at 300 mg or once every 2 weeks at 700 mg is feasible, with comparable tolerability as daily administration. Administration of 700 mg once every 2 weeks can be considered as the most optimal schedule because of the highest maximum plasma concentration being reached. The promising preliminary antitumor activity of this alternative schedule in heavily pretreated patients warrants further clinical evaluation and might ultimately indicate a class characteristic of tyrosine kinase inhibitors.
Sequestering and inhibiting a vascular endothelial growth factor in vivo by systemic administration of a synthetic polymer nanoparticle
Authors: Hiroyuki Koide, Keiichi Yoshimatsu, Yu Hoshino, Saki Ariizumi, Anna Okishima, Takafumi Ide, Hiromichi Egami, Yoshitaka Hamashima, Yuri Nishimura, Hiroaki Kanazawa, Yoshiko Miura, Tomohiro Asai, Naoto Oku, Kenneth J. Shea
Journal: Journal of Controlled Release (2018)
Anti-tumour activity of low molecular weight heparin doxorubicin nanoparticles for histone H1 high-expressive prostate cancer PC-3M cells
Authors: Shuang Zhang, Zhan-Tao Li, Man Liu, Jing-Ru Wang, Mei-Qi Xu, Zhuo-Yue Li, Xiao-Chuan Duan, Yan-Li Hao, Xiu-Chai Zheng, Hui Li, Zhen-Han Feng, Xuan Zhang
Journal: Journal of Controlled Release (2018)
Abstract 15401: A Novel Mechanism That Modulates Hypertensive Cardiac Hypertrophy via Angiotensin-ii and Sodium-Proton Exchanger-1 Axis
Authors: Yasuko K Bando, Haruya Kawase, Kazuyuki Nishimura, Toyoaki Murohara
Journal: Circulation (2016)

Introduction: Sodium-proton pump exchanger type 1 (NHE-1) is a regulator of intracellular acidity (pHi). Interestingly, NHE-1 is up-regulated in various malignancies and NHE-1 becomes activated dur...
Human Immunodeficiency Virus/Hepatitis C Virus (HCV) Co‐infected Patients With Cirrhosis Are No Longer at Higher Risk for Hepatocellular Carcinoma or End‐Stage Liver Disease as Compared to HCV Mono‐infected Patients
Authors: Dominique Salmon‐Ceron, Pierre Nahon, Richard Layese, Valérie Bourcier, Philippe Sogni, Firouze Bani‐Sadr, Etienne Audureau, Laurence Merchadou, François Dabis, Linda Wittkop, Françoise Roudot‐Thoraval
Journal: Hepatology (2018)

It is widely accepted that human immunodeficiency virus (HIV) infection is a risk factor for increased severity of hepatitis C virus (HCV) liver disease. However, owing to better efficacy and safety of combination antiretroviral therapy (cART), and increased access to HCV therapy, whether this condition remains true is still unknown. Overall, 1,253 HCV mono‐infected patients and 175 HIV/HCV co‐infected patients with cirrhosis, included in two prospective French national cohorts (ANRS CO12 CirVir and CO13 HEPAVIH), were studied. Cirrhosis was compensated (Child‐Pugh A), without past history of complication, and assessed on liver biopsy. Incidences of liver decompensation (LD), hepatocellular carcinoma (HCC), and death according to HIV status were calculated by a Fine‐Gray model adjusted for age. Propensity score matching was also performed to minimize confounding by baseline characteristics. At baseline, HIV/HCV patients were younger (47.5 vs. 56.0 years; P &lt; 0.001), more frequently males (77.1% vs. 62.3%; P &lt; 0.001), and had at baseline and at end of follow‐up similar rates of HCV eradication than HCV mono‐infected patients. A total of 80.4% of HIV/HCV patients had an undetectable HIV viral load. After adjustment for age, 5‐year cumulative incidences of HCC and decompensation were similar in HIV/HCV and HCV patients (8.5% vs. 13.2%, P = 0.12 and 12.8% vs. 15.6%, P = 0.40, respectively). Overall mortality adjusted for age was higher in HIV/HCV co‐infected patients (subhazard ratio [SHR] = 1.88; 95% confidence interval [CI], 1.15‐3.06; P = 0.011). Factors associated with LD and HCC were age, absence of sustained virological response, and severity of cirrhosis, but not HIV status. Using a propensity score matching 95 patients of each group according to baseline features, similar results were observed. Conclusion : In HCV‐infected patients with cirrhosis, HIV co‐infection was no longer associated with higher risks of HCC and hepatic decompensation. Increased mortality, however, persisted, attributed to extrahepatic conditions.
Germline <i>BMP9</i> mutation causes idiopathic pulmonary arterial hypertension
Authors: Xiao-Jian Wang, Tian-Yu Lian, Xin Jiang, Shao-Fei Liu, Su-Qi Li, Rong Jiang, Wen-Hui Wu, Jue Ye, Chun-Yan Cheng, Yao Du, Xi-Qi Xu, Yan Wu, Fu-Hua Peng, Kai Sun, Yi-Min Mao, Huan Yu, Chen Liang, John Y-J. Shyy, Shu-Yang Zhang, Xue Zhang, Zhi-Cheng Jing
Journal: European Respiratory Journal (2018)

Background Idiopathic pulmonary arterial hypertension (IPAH) is a rare disease with high heritability. Although several predisposing genes have been linked to IPAH, the genetic aetiology remains unknown for a large number of IPAH cases. Methods We conducted an exome-wide gene-based burden analysis on two independent case–control studies, including a total of 331 IPAH cases and 10 508 controls. Functional assessments were conducted to analyse the effects of genetic mutations on protein biosynthesis and function. Results The gene encoding human bone morphogenetic protein 9 ( BMP9 ) was identified as a novel genetic locus displaying exome-wide association with IPAH in the discovery cohort (OR 18.8; p=1.9×10 −11 ). This association was authenticated in the independent replication cohort (p=1.0×10 −5 ). Collectively, the rare coding mutations in BMP9 occurred in 6.7% of cases, ranking this gene second to BMPR2 , comprising a combined significance of 2.7×10 −19 (OR 21.2). Intriguingly, the patients with BMP9 mutations had lower plasma levels of BMP9 than those without. Functional studies showed that the BMP9 mutations led to reduced BMP9 secretion and impaired anti-apoptosis ability in pulmonary arterial endothelial cells. Conclusion We identify BMP9 as an IPAH culprit gene.
Abstract 12896: ApoC3-Gln38Lys Variant is a Gain-of-function Mutation Associated With Human Hypertriglyceridemia
Authors: Zemin Yao, Meenakshi Sundaram, Kaitlin R Curtis, Mohsen A Alipour, Robin J Parks, Adam D McIntyre, Robert A Hegele
Journal: Circulation (2016)

Introduction: Cell culture and animal studies have suggested that expression of human apoC3 in liver cells can exert an intracellular role in promoting production of triglyceride (TG)-rich VLDL (VLDL1) under lipid-rich conditions. Previously, hypotriglyceridemia in human subjects have been linked to several loss-of-function apoC3 mutations, namely Ala23Thr and Lys58Glu. Conversely, hypertriglyceridemia has also been linked to an apoC3 variant. For example, the Gln38Lys variant was originally identified in human subjects of Mexican origin; heterozugous carriers of Gln38Lys exhibited moderate hypertriglyceridemia. Hypothesis: We hypothesized that the Gln38Lys variant is a gain-of-function mutation that promotes hepatic VLDL assembly/secretion. Methods: The recombinant Gln38Lys variant was either expressed in McA-RH7777 cells devoid of endogenous apoC3, or else expressed in apoc3-null mice using adenovirus-mediated gene transfer. The effect of Gln38Lys expression on hepatic lipogenesis, VLDL1 production, and glucose homeostasis was contrasted with that of wildtype apoC3. Results: Gln38Lys expression in McA-RH7777 cells and apoc3-null mice resulted in increased VLDL1-TG secretion, which was accompanied with increased de novo lipogenesis, increased adipogenesis, and severe hepatic steatosis (i.e. accumulation of TG and cholesteryl esters). Gln38Lys expression also increased glucose uptake and hepatic glycogen content, suggesting that apoC3 may play a role in hepatic glucose homeostasis. Live cell imaging revealed prominent association of apoC3 with endosomes, and the Gln38Lys-associated endosomes exhibited robust trafficking between Golgi apparatus and the cell periphery. Next generation sequencing of 1557 DNA samples from patients (of European, Chinese, African, and South Asian origins) with dyslipidemia (including hypertriglyceridemia, hypercholesterolemia and combined hyperlipidemia) did not detect Gln38Lys variant, nor was the Gln38Lys variant found in the ExAC databases containing 60,706 individuals. Conclusions: Gln38Lys is a rare, gain-of-function variant that may stimulate TG-rich VLDL1 production under lipid-rich conditions, contributing to hypertriglyceridemia..
‘Twisting the lion's tail’: Manipulationist tests of causation for psychological mechanisms in the occurrence of delusions and hallucinations
Authors: P. Brown, F. Waite, D. Freeman
Journal: Clinical Psychology Review (2018)

Over the past 20 years the importance of psychological processes in psychosis has gained increasing attention. However, it is key to determine the causal status of these processes in order to inform understanding and identify treatment targets. Studies that directly manipulate a psychological mechanism provide the most robust causal evidence. This review evaluates for the first time the extent of manipulationist causal evidence for the role of specific psychological mechanisms in delusions and hallucinations. A systematic search identified controlled experiments or targeted interventions that both manipulated a specific psychological mechanism and measured the effect on individual psychotic experiences. Forty-three manipulationist studies were found of which 40 measured paranoia, 11 measured hallucinations, and two measured grandiosity. Twenty-eight studies were experiments and 15 were targeted intervention trials. Only 18 used clinical samples. Manipulation of the specified psychological mechanism was demonstrated in 35 cases. Of these, 28 found a subsequent change in a psychotic experience. Negative affect and related psychological processing in relation to paranoia have been most tested. There is a small body of direct causal evidence for the role of psychological mechanisms in psychotic experiences – that highlight important novel treatment directions – but the manipulationist approach has been used too infrequently.
Distinct Co-Occurring Mutational Profiles in Acute Myeloid Leukemia Confers Prognostic Significance in Children and Young Adults with FLT3/ITD Mutations
Authors: Katherine Tarlock, Todd A Alonzo, Robert B Gerbing, Rhonda E. Ries, Brenda Gibson, Naghmeh Niktoreh, Sanne Noort, Marry M. Van den Heuvel-Eibrink, C. Michel Zwaan, Soheil Meshinchi
Journal: Blood (2018)
Abstract 14655: Associations of Change in Physical Activity Levels With Changes in Cardiac Structure and Function in the Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Roberta Florido, Di Zhao, Eliseo Guallar, David A Bluemke, Susan R Heckbert, Matthew A Allison, Alain G Bertoni, Bharath Ambale-Venkatesh, Chia-Ying Liu, Joao A Lima, Chiadi E Ndumele, Erin D Michos
Journal: Circulation (2017)

Introduction: Physical activity (PA) is inversely associated with heart failure (HF) risk via unclear mechanisms. Increased left ventricular (LV) mass to volume ratio [i.e. concentric remodeling] is a risk factor for HF with preserved ejection fraction. Few studies have assessed longitudinal changes in cardiac structure/function associated with changes in leisure-time PA in a community population. Hypothesis: Higher levels of PA and PA change over time will lessen LV concentric remodeling. Methods: We included 4,627 MESA participants with available data on PA and cardiac MRI at Exam 1 (2000-2002). Of these, 3,233 had repeat PA and cardiac MRI assessed at Exam 5 (2010-2012) and were free of incident cardiovascular disease (CVD). PA was measured by a Typical Week Physical Activity Survey and converted to MET*min/wk of moderate or vigorous exercise. We used mixed effect models to estimate the associations of PA and PA change with baseline and change in cardiac structure/function over 10 years. Models were ad...
Infliximab for treatment-refractory transverse myelitis following immune therapy and radiation
Authors: Victoria A. Chang, Daniel R. Simpson, Gregory A. Daniels, David E. Piccioni
Journal: Journal for ImmunoTherapy of Cancer (2018)

Neurologic toxicities with immune therapy are rare, but can cause devastating and often permanent injury when they occur. Although there is increasing interest in the potential synergism between immune therapy and radiation, it is possible that such combinations may lead to a greater number or increased severity of immune-related adverse events. We present here a case of extensive and progressive transverse myelitis following combined therapy, which did not improve until treatment with infliximab. This case highlights the unmet need for treatment of adverse events that are refractory to consensus recommendations, and may ultimately require further study and incorporation into future published guidelines.We report a case of a 68-year-old with metastatic melanoma, who developed transverse myelitis in the setting of immune checkpoint blockade and spinal irradiation for vertebral metastases. Despite management according to published consensus guidelines: cessation of immune therapy, high-dose steroids, and plasmapheresis, he continued to deteriorate neurologically, and imaging revealed a progressive and ascending transverse myelitis. The patient was then treated with infliximab, and demonstrated dramatic imaging and modest clinical improvement following the first treatment cycle.This is the first report describing the successful use of infliximab in immune therapy and radiation-related transverse myelitis that was not responding to recommended therapy. Evaluation of additional treatment options such as infliximab for high-grade immune-related neurologic toxicities is warranted, and may be needed earlier in the disease process to prevent significant morbidity. The adverse effects of immune therapy when used in combination with radiation also require further investigation.