bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diminished Innate Antiviral Response to Adenovirus Vectors in cGAS/STING-Deficient Mice Minimally Impacts Adaptive Immunity
Authors: Anghelina Daniela , Lam Eric , Falck-Pedersen Erik 
Published: April 2016

ABSTRACTInfection by adenovirus, a nonenveloped DNA virus, induces antiviral innate and adaptive immune responses. Studies of transformed human and murine cell lines using short hairpin RNA (shRNA) knockdown strategies identified cyclic guanine adenine synthase (cGAS) as a pattern recognition receptor (PRR) that contributes to the antiadenovirus response. Here we demonstrate how the cGAS/STING cascade influences the antiviral innate and adaptive immune responses in a murine knockout model. Using knockout bone marrow-derived dendritic cells (BMDCs) and bone marrow-derived macrophages (BMMOs), we determined that cGAS and STING are essential to the induction of the antiadenovirus response in these antigen-presenting cells (APCs)in vitro. We next determined how the cGAS/STING cascade impacts the antiviral response following systemic administration of a recombinant adenovirus type 5 vector (rAd5V). Infection of cGAS−/−and STING−/−mice results in a compromised early antiviral innate response compared to that in wild-type (WT) controls: significantly lower levels of beta interferon (IFN-β) secretion, low levels of proinflammatory chemokine induction, and reduced levels of antiviral transcript induction in hepatic tissue. At 24 h postinfection, levels of viral DNA and reporter gene expression in the liver were similar in all strains. At 28 days postinfection, clearance of infected hepatocytes in cGAS or STING knockout mice was comparable to that in WT C57BL/6 mice. Levels of neutralizing anti-Ad5V antibody were modestly reduced in infected cGAS mice. These data support a dominant role for the cGAS/STING cascade in the early innate antiviral inflammatory response to adenovirus vectors. However, loss of the cGAS/STING pathway did not affect viral clearance, and cGAS deficiency had a modest influence on the magnitude of the antiviral humoral immune response to adenovirus infections.IMPORTANCEThe detection of viral infection by host sentinel immune cells contributes to the activation of a complex and varied antiviral innate and adaptive immune response, which limits virus replication, spread, and susceptibility to infection. In this study, we have characterized how the cGAS/STING DNA-sensing cascade contributes to early detection of adenovirus infections. cGAS influences APC activation and early innate antiviral inflammatory immune responses, but adaptive immune pathways associated with virus clearance and anti-Ad antibody production were minimally influenced by the loss of the cGAS PRR signaling cascade.
Training load--injury paradox: is greater preseason participation associated with lower in-season injury risk in elite rugby league players?
Authors: Windt Johann , Gabbett Tim J , Ferris Daniel , Khan Karim M 
Published: April 2016

AimTo determine whether players who completed a greater number of planned preseason training sessions were more or less likely to be injured during the competitive season.MethodsA cohort of 30 elite rugby league players was prospectively studied during their 17-week preseason and 26-round competitive season. Injuries were recorded using a match time loss definition. Preseason participation was quantified as the number of ‘full’ training sessions that players completed, excluding modified, rehabilitation or missed sessions. In-season training load variables, collected using global positioning system (GPS) data, included distance covered (m), high-speed distance covered (m) and the percentage of distance covered at high speeds (%). Multilevel logistic regression models were used to determine injury likelihood in the current and subsequent week, with random intercepts for each player. Odds ratios (OR) were used as effect size measures to determine the changes in injury likelihood with (1) a 10-session increase in preseason training participation or (2) standardised changes in training load variables.ResultsControlling for training load in a given week, completing 10 additional preseason sessions was associated with a 17% reduction in the odds of injury in the subsequent week (OR=0.83, 95% CI=0.70 to 0.99). Increased preseason participation was associated with a lower percentage of games missed due to injury (r=−0.40, p<0.05), with 10 preseason sessions predicting a 5% reduction in the percentage of games missed.ConclusionsMaximising participation in preseason training may protect elite rugby league players against in-season injury.
Stanford's Outcomes Research in Kids (STORK): a prospective study of healthy pregnant women and their babies in Northern California
Authors: Ley Catherine , Sanchez Maria de la Luz , Mathur Ankur , Yang Shufang , Sundaram Vandana , Parsonnet Julie 
Published: April 2016

PurposeStanford's Outcomes Research in Kids (STORK) is an ongoing prospective cohort of healthy pregnant women and their babies established to determine the effect of infectious diseases on weight, linear growth and immune system development during childhood. Additionally, a nested randomised intervention of household and personal cleaning products tests the effects of the microbicides triclosan and triclocarban on these outcomes and incidence of infection.ParticipantsHealthy pregnant women were identified and enrolled primarily at public clinics; their babies, enrolled shortly after birth, are followed to age 36 months. Automated weekly surveys assess daily health status, infectious disease symptoms, healthcare provider visits and antibiotic use, in the mother during pregnancy and the baby once born. At 4-monthly household visits, information and samples are collected from the mother (urine, stool, saliva, skin swab), the baby (blood by heel/toe stick, urine, stool, saliva, skin swab) and the household (environmental swabs). Annual blood samples are obtained by venipuncture (mother and baby). Medical charts are abstracted for allergy and infectious illness in the mother during pregnancy and the baby.Findings to dateFrom 7/2011 to 2/2015, 158 mothers were enrolled at approximately 20 weeks gestation; 127 babies were enrolled. Two-thirds of mothers are Hispanic, one-third are non-US born and one-third speak primarily Spanish; mean years of education is 13 (SD 6.2) years. Households have on average 4.5 residents. Most households (97%) were randomised to participate in the intervention. Completion of weekly surveys (86%) and follow-up (75% after 14 months) is excellent in this young, mobile population; collection of samples is ongoing with thousands of specimens stored.Future plansEnrolled babies will be followed until age 36 months (last anticipated visit: 07/2018) with medical chart review completed soon thereafter. All epidemiological information and samples will be available for collaborative hypothesis testing.Trial registration numberNCT01442701; Pre-results.
Flow diversion with Pipeline Embolic Device as treatment of subarachnoid hemorrhage secondary to blister aneurysms: dual-center experience and review of the literature
Authors: Linfante Italo , Mayich Michael , Sonig Ashish , Fujimoto Jena , Siddiqui Adnan , Dabus Guilherme 
Published: April 2016

BackgroundAneurysmal subarachnoid hemorrhage (aSAH) secondary to blister-type aneurysms (BAs) is associated with high morbidity and mortality. Microsurgical clipping or wrapping and/or use of traditional endovascular techniques to repair the lesion result in frequent regrowth and rebleeds and ultimately high fatality rates. Because of the purely endoluminal nature of arterial reconstruction, flow diversion may represent an ideal option to repair ruptured BAs.MethodsWe performed a retrospective analysis of our database including all consecutive patients with aSAH secondary to BAs treated with the Pipeline Embolic Device (PED) between November 2013 and November 2015 in two institutions. We collected basic patient demographics, aneurysm size, location, number and sizes of PEDs used, use of coiling, 30-day modified Rankin Scale (mRS) score, and follow-up imaging data.ResultsTen cases of aSAH were found as a result of a ruptured BA. Patients had a mean age of 47.2 years (range 27–68). Mean Hunt and Hess score was 1.6 (range 1–4). Lesions were predominantly left-sided, mostly along the dorsal aspect of the internal carotid artery, either paraclinoid or paraophthalmic (8/10). In two patients the BA was located in the left middle cerebral artery. All lesions were very small (mean 1.4×1.5 mm; range 0.75–2.1 mm). Placement of a single PED resulted in immediate occlusion or near-occlusion of the BA in 9 out of 10 patients. Nine patients did very well; eight had a 90-day mRS score of 0 and one had a 90-day mRS score of 1. Follow-up digital subtraction angiography was performed in all patients (mean 15 months; range 7–24). In the surviving nine patients there was complete occlusion of the BA on long-term follow-up angiography.ConclusionsRepair of ruptured BA with PED may be a safe and durable option.
Microwave NIMs: Using a Uniform AC Electric Field for Manipulating Ag Nanorods Embedded in Co0.05Ti0.95O2 Matrix
Authors: Khorshidi Zahra , Bahari Ali 
Published: April 2016

In the present work, we synthesized a composite medium consisting of Ag nanorods embedded in Co[Formula: see text]Ti[Formula: see text]O2 matrix (Ag/CTO) using the sol-gel method. We applied a uniform AC electric field at the beginning of gelation and during drying for manipulating Ag nanorods in the matrix. The structure and morphology characterizations of Ag/CTO nanocomposites were studied by X-ray diffraction (XRD), scanning electron microscopy (SEM), and transmission electron microscopy (TEM) techniques. The permittivity and permeability behaviors of samples were investigated. Results showed that for the sample dried in the existence of the electric field, simultaneous negative permittivity and permeability were realized. These results imply the realization of double negative properties in this sample. Therefore, this work suggests that Ag/Co[Formula: see text]Ti[Formula: see text]O2 nanocomposites can be introduced as a negative index metamaterials (NIMs).
Insulin Induces Cation Fluxes and Increases Intracellular Calcium in the HTC Rat Hepatoma Cell Line
Authors: Mathé Laurence , Vallerand Diane , Haddad Pierre S 
Published: April 2016

BACKGROUND/AIMS: Rat hepatoma HTC cells were used to study conductive pathways implicated in insulin-induced cation and calcium influx into liver cells.METHODS: Membrane potentials and currents were measured by whole-cell patch clamp. Cytosolic calcium was measured using FURA-2 fluorescence.RESULTS: Insulin induced a gradual and reversible depolarization of 5.7±0.8 mV. Insulin-induced currents showed a linear slope conductance of 663 pS and a reversal potential of -17.9 mV. Ion substitution experiments showed that these currents were composed mainly of a nonselective cation component. In FURA-2 experiments, insulin caused a slow monophasic rise in HTC cell calcium, which depended on the presence of extracellular calcium. Insulin also induced significant increases of 1.58- and 1.54-fold in basal calcium influx when studied by external calcium withdrawal and readmission, or by the manganese quench method, respectively. Using the latter approach, we found that 100 µM gadolinium and 10 µM SKF96365 blocked the rise of the basal manganese quench rate induced by insulin whereas 100 µM verapamil was without effect.CONCLUSIONS: Insulin induces inward cation currents that depolarize HTC cell membrane potentials and participate in increased calcium influx.
Protective Effect of Vitamin E on Gastric Mucosal Injury in Rats with Biliary Obstruction
Authors: Cantürk Nuh Zafer , Cantürk Zeynep , Özbilim G , Yenisey C 
Published: April 2016

Patients with liver disease display increased susceptibility to gastric mucosal damage. A role of free radicals has been suggested in the development of gastric mucosal damage in normal subjects. The effects of antioxidant vitamin E treatment on the liver and stomach in cirrhotic rats were examined. Fifty rats were divided into three groups. Cirrhosis was induced by bile duct ligation in 40 of 50 rats. Controls underwent a sham operation. Gastric mucosal lesions were produced by intragastric administration of 1 mL of 95% ethanol in all three groups. Twenty bile duct-ligated rats were injected intramuscularly with vitamin E (100 mg/kg/day). Liver and stomach histology, and stomach malondialdehyde and glutathione levels were determined. Portal hypertension was measured. Macroscopic and microscopic gastric mucosal injury were significantly greater in the control and common bile duct-ligated groups than in the vitamin E-pretreated group (P<0.05). The tissue malondialdehyde and glutathione levels were significantly decreased in the vitamin E-administrated group compared with the common bile duct-ligated group (P<0.001). Vitamin E administration may be cytoprotective for both the liver and gastric mucosa in bile duct-ligated rats.
Outcomes Following Liver Transplantation for Patients with Alcohol- Versus Nonalcohol-Induced Liver Disease
Authors: Abosh Dory , Rosser Barry , Kaita Kelly , Bazylewski Rose , Minuk Gerald 
Published: April 2016

OBJECTIVE: To document and compare the outcomes of adult patients who received liver transplants for alcohol- and nonalcohol-induced liver diseases who attended a liver transplantation follow-up clinic in an urban, nontransplantation centre at a time when no formal alcohol abuse program for transplant candidates and/or recipients was offered.PATIENTS AND METHODS: The study population comprised 10 alcoholic patients and 48 nonalcoholic patients followed for an average of 41 months (range five to 79 months) and 46 months (range two to 116 months), respectively. Primary outcome variables included rates of recidivism, duration of abstinence after transplantation and compliance with post-transplant medical follow-up visits. Time to discharge after transplantation, episodes of graft rejection, liver and renal biochemical abnormalities, diabetes, hypertension, sepsis, strictures, complications unrelated to transplantation and changes in psychosocial status were secondary outcome variables.RESULTS: Significant differences were found with respect to a higher incidence of recidivism (50% for alcoholic patients compared with 2% for nonalcoholic patients, P<0.0001), a shorter period of abstinence after transplantation (14.7±17.2 months for alcoholic patients compared with 26.3±23.0 months for nonalcoholic patients, P<0.05) and more missed office visits (2.7±3.5 for alcoholic patients compared with 1.0±1.9 for nonalcoholic patients, P=0.05) in the alcoholic group. The alcoholic group also had a lower incidence of rejection episodes (10% for alcoholic patients compared with 44% for nonalcoholic patients, P<0.05) but higher rates of post-transplantation diabetes (40% for alcoholic patients compared with 2% for nonalcoholic patients, P<0.05), more nontransplantation-related complications (20% for alcoholic patients compared with 0% for nonalcoholic patients, P<0.05), and higher serum creatinine but lower bilirubin and cyclosporine A levels (P<0.05, respectively). Marital separations were also more common in the alcoholic group (20% for alcoholic patients compared with 0% for nonalcoholic patients, P<0.05).CONCLUSIONS: In the absence of formal alcohol abuse programs, the post-transplantation outcome in alcoholic patients generally does not compare well with that of patients who undergo transplantation for nonalcohol-related liver diseases.
Omeprazole Once or Twice Daily with Clarithromycin and Metronidazole forHelicobacter pyloriEradicaiton in a Canadian Community Practice
Authors: Chiba Naoki , Marshall Cheryl P 
Published: April 2016

BACKGROUND: Triple therapy for one week with omeprazole, clarithromycin and metronidazole (OCM) is accepted worldwide as a first line therapy forHelicobacter pylorieradication. It is unclear whether omeprazole needs to be given once or twice daily.OBJECTIVES: To assess the efficacy and safety of these regimens in a single-centre, Canadian practice.METHODS: Histologically provenH pylori-positive patients were treated for seven days with clarithromycin 250 mg bid and metronidazole 500 mg bid, and randomly allocated to omeprazole 20 mg either once or twice daily in this open, cohort study. Endoscopy with histology (two antrum and two body biopsies, Giemsa stain) was done four weeks or longer after the pills were completed to assessH pylorieradication.RESULTS: Whether omeprazole was given once or twice daily, eradication was high and the same in both arms. All-patients-treated eradication was 85% (39 of 46 in the omeprazole once daily group and 41 of 48 in the omeprazole twice daily group) and intent-to-treat eradication was 80% (39 of 49 in the omeprazole once daily group and 41 of 51 in the omeprazole twice daily group). Side effects were frequently seen, suffered by 65% to 69% of patients treated. However, these were mild and compliance was high, with 94% of patients taking all of their pills. Mild side effects included loose stools, taste disturbance, nausea, headache and upper or lower gastrointestinal gas. Only one patient (1%) from the omeprazole once daily arm stopped taking metronidazole due to excessive perspiring.CONCLUSIONS: In this community practice, OCM triple therapy was effective whether omeprazole was given once or twice daily. For those with financial constraint, omeprazole 20 mg once daily can be considered. The regimens were well tolerated without serious adverse events.
Effect of Acid-Suppressive Therapy onHelicobactor pyloriProduction of Interleukin-8 in Gastric Mucosa
Authors: Yoshinaga Masahiro , Ohtani Akira , Tsuruta Satoru , Kato Tetsuya , Higashi Eishi , Yamada Yukio , Harada Naohiko , Nawata Hajime 
Published: April 2016

BACKGROUND: Recent studies have shown that acid-suppressive therapy increases the severity ofHelicobacter pylori- associated gastritis in the corpus.PURPOSE: To evaluate interleukin (IL)-8 production in the gastric corpus mucosa before and during acid-suppressive therapy inH pylori-infected patients.PATIENTS AND METHODS: Ten patients with reflux esophagitis (fiveH pylori-positive and fiveH pylori-negative) were treated with omeprazole 20 mg. Serum gastrin concentrations,H pyloricolonization density and mucosal IL-8 levels in the corpus were investigated at entry and two weeks after starting therapy. IL-8 levels were measured by ELISA. The organism density was determined, and scored according to area occupied by the bacterial colonies. The presence ofH pyloriwas assessed by rapid urease testing and histological finding of gastric biopsy specimens.RESULTS: InH pylori-positive patients, concentrations of IL-8 during therapy significantly exceeded those before therapy (36.2±6.8 versus 18.3±3.8 pg/mg protein; P<0.05) without alteringH pyloridensity. InH pylori-negative patients, IL-8 levels were similar before and during therapy (6.1±2.7 versus 6.3±3.0 pg/mg protein). Concentrations of gastrin during therapy were significantly higher than those before therapy in all patients.CONCLUSIONS: The results suggest that acid suppression increases mucosal IL-8 levels inH pylori-infected patients with reflux esophagitis.
The Small Molecule IMR-1 Inhibits the Notch Transcriptional Activation Complex to Suppress Tumorigenesis
Authors: Astudillo Luisana , Da Silva Thiago G. , Wang Zhiqiang , Han Xiaoqing , Jin Ke , VanWye Jeffrey , Zhu Xiaoxia , Weaver Kelly , Oashi Taiji , Lopes Pedro E.M. , Orton Darren , Neitzel Leif R. , Lee Ethan , Landgraf Ralf , Robbins David J. , MacKerell Alexander D. , Capobianco Anthony J. 
Published: April 2016

Abstract
In many cancers, aberrant Notch activity has been demonstrated to play a role in the initiation and maintenance of the neoplastic phenotype and in cancer stem cells, which may allude to its additional involvement in metastasis and resistance to therapy. Therefore, Notch is an exceedingly attractive therapeutic target in cancer, but the full range of potential targets within the pathway has been underexplored. To date, there are no small-molecule inhibitors that directly target the intracellular Notch pathway or the assembly of the transcriptional activation complex. Here, we describe an in vitro assay that quantitatively measures the assembly of the Notch transcriptional complex on DNA. Integrating this approach with computer-aided drug design, we explored potential ligand-binding sites and screened for compounds that could disrupt the assembly of the Notch transcriptional activation complex. We identified a small-molecule inhibitor, termed Inhibitor of Mastermind Recruitment-1 (IMR-1), that disrupted the recruitment of Mastermind-like 1 to the Notch transcriptional activation complex on chromatin, thereby attenuating Notch target gene transcription. Furthermore, IMR-1 inhibited the growth of Notch-dependent cell lines and significantly abrogated the growth of patient-derived tumor xenografts. Taken together, our findings suggest that a novel class of Notch inhibitors targeting the transcriptional activation complex may represent a new paradigm for Notch-based anticancer therapeutics, warranting further preclinical characterization. Cancer Res; 76(12); 3593–603. ©2016 AACR.
Myc-Driven Glycolysis Is a Therapeutic Target in Glioblastoma
Authors: Tateishi Kensuke , Iafrate A. John , Ho Quan , Curry William T. , Batchelor Tracy T. , Flaherty Keith T. , Onozato Maristela L. , Lelic Nina , Sundaram Sudhandra , Cahill Daniel P. , Chi Andrew S. , Wakimoto Hiroaki 
Published: April 2016

Abstract
Purpose: Deregulated Myc drives an oncogenic metabolic state, including pseudohypoxic glycolysis, adapted for the constitutive production of biomolecular precursors to feed rapid tumor cell growth. In glioblastoma, Myc facilitates renewal of the tumor-initiating cell reservoir contributing to tumor maintenance. We investigated whether targeting the Myc-driven metabolic state could be a selectively toxic therapeutic strategy for glioblastoma.
Experimental Design: The glycolytic dependency of Myc-driven glioblastoma was tested using 13C metabolic flux analysis, glucose-limiting culture assays, and glycolysis inhibitors, including inhibitors of the NAD+ salvage enzyme nicotinamide phosphoribosyl-transferase (NAMPT), in MYC and MYCN shRNA knockdown and lentivirus overexpression systems and in patient-derived glioblastoma tumorspheres with and without MYC/MYCN amplification. The in vivo efficacy of glycolyic inhibition was tested using NAMPT inhibitors in MYCN-amplified patient-derived glioblastoma orthotopic xenograft mouse models.
Results: Enforced Myc overexpression increased glucose flux and expression of glycolytic enzymes in glioblastoma cells. Myc and N-Myc knockdown and Myc overexpression systems demonstrated that Myc activity determined sensitivity and resistance to inhibition of glycolysis. Small-molecule inhibitors of glycolysis, particularly NAMPT inhibitors, were selectively toxic to MYC/MYCN–amplified patient-derived glioblastoma tumorspheres. NAMPT inhibitors were potently cytotoxic, inducing apoptosis and significantly extended the survival of mice bearing MYCN-amplified patient-derived glioblastoma orthotopic xenografts.
Conclusions: Myc activation in glioblastoma generates a dependency on glycolysis and an addiction to metabolites required for glycolysis. Glycolytic inhibition via NAMPT inhibition represents a novel metabolically targeted therapeutic strategy for MYC or MYCN-amplified glioblastoma and potentially other cancers genetically driven by Myc. Clin Cancer Res; 22(17); 4452–65. ©2016 AACR.