tbuckley/cabot-search huggingface dataset:
Antibody blockade of IL-15 signaling has the potential to durably reverse vitiligo
Authors: Jillian M. Richmond, James P. Strassner, Lucio Zapata, Madhuri Garg, Rebecca L. Riding, Maggi A. Refat, Xueli Fan, Vincent Azzolino, Andrea Tovar-Garza, Naoya Tsurushita, Amit G. Pandya, J. Yun Tso, John E. Harris
Journal: Science Translational Medicine (2018)

Vitiligo is an autoimmune disease of the skin mediated by CD8+ T cells that kill melanocytes and create white spots. Skin lesions in vitiligo frequently return after discontinuing conventional treatments, supporting the hypothesis that autoimmune memory is formed at these locations. We found that lesional T cells in mice and humans with vitiligo display a resident memory (TRM) phenotype, similar to those that provide rapid, localized protection against reinfection from skin and mucosal-tropic viruses. Interleukin-15 (IL-15)-deficient mice reportedly have impaired TRM formation, and IL-15 promotes TRM function ex vivo. We found that both human and mouse TRM express the CD122 subunit of the IL-15 receptor and that keratinocytes up-regulate CD215, the subunit required to display the cytokine on their surface to promote activation of T cells. Targeting IL-15 signaling with an anti-CD122 antibody reverses disease in mice with established vitiligo. Short-term treatment with anti-CD122 inhibits TRM production of interferon-γ (IFNγ), and long-term treatment depletes TRM from skin lesions. Short-term treatment with anti-CD122 can provide durable repigmentation when administered either systemically or locally in the skin. On the basis of these data, we propose that targeting CD122 may be a highly effective and even durable treatment strategy for vitiligo and other tissue-specific autoimmune diseases involving TRM.
Type IV Hyperlipoproteinemia in a Consanguinous Family
Authors: Mortezaamidi
Journal: Circulation (1972)

The involvement of all five offspring of consanguinous and hypertriglyceridemic parents (first cousins) is reported. Three sons and two daughters of this family have increased triglycerides, normal cholesterol, and normal or slightly increased phospholipids. Mother and elder daughter have abnormal glucose tolerance. Father and mother are hypertensive; father had recent development of myocardial infarction and gout. The two elder sons had myocardial infarction and repeated bouts of angina. All three male offspring of this family have gout and are being treated with xanthinoxidase inhibitor (allopurinol). Planar xanthoma was present in one son with myocardial infarction. No chylomicronemia was noted. The response to diet and Atromid-S was satisfactory.
Phosphorylation of LKB1 at Serine 428 by Protein Kinase C-ζ Is Required for Metformin-Enhanced Activation of the AMP-Activated Protein Kinase in Endothelial Cells
Authors: ZhonglinXie, YunzhouDong, RolandScholz, DietbertNeumann, Ming-HuiZou
Journal: Circulation (2008)

Background— Metformin, one of most commonly used antidiabetes drugs, is reported to exert its therapeutic effects by activating AMP-activated protein kinase (AMPK); however, the mechanism by which metformin activates AMPK is poorly defined. The objective of the present study was to determine how metformin activates AMPK in endothelial cells. Methods and Results— Exposure of human umbilical vein endothelial cells or bovine aortic endothelial cells to metformin significantly increased AMPK activity and the phosphorylation of both AMPK at Thr172 and LKB1 at Ser428, an AMPK kinase, which was paralleled by increased activation of protein kinase C (PKC)-ζ, as evidenced by increased activity, phosphorylation (Thr410/403), and nuclear translocation of PKC-ζ. Consistently, either pharmacological or genetic inhibition of PKC-ζ ablated metformin-enhanced phosphorylation of both AMPK-Thr172 and LKB1-Ser428, suggesting that PKC-ζ might act as an upstream kinase for LKB1. Furthermore, adenoviral overexpression of LKB1 ...
Repeated Mesenchymal Stromal Cell Treatment Sustainably Alleviates Machado-Joseph Disease
Authors: Catarina Oliveira Miranda, Adriana Marcelo, Teresa Pereira Silva, João Barata, Ana Vasconcelos-Ferreira, Dina Pereira, Clévio Nóbrega, Sónia Duarte, Inês Barros, Joana Alves, José Sereno, Lorena Itatí Petrella, João Castelhano, Vitor Hugo Paiva, Paulo Rodrigues-Santos, Vera Alves, Isabel Nunes-Correia, Rui Jorge Nobre, Célia Gomes, Miguel Castelo-Branco, Luís Pereira de Almeida
Journal: Molecular Therapy (2018)

Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3, the most common dominant spinocerebellar ataxia (SCA) worldwide, is caused by over-repetition of a CAG repeat in the ATXN3/MJD1 gene, which translates into a polyglutamine tract within the ataxin-3 protein. There is no treatment for this fatal disorder. Despite evidence of the safety and efficacy of mesenchymal stromal cells (MSCs) in delaying SCA disease progression in exploratory clinical trials, unanticipated regression of patients to the status prior to treatment makes the investigation of causes and solutions urgent and imperative. In the present study, we compared the efficacy of a single intracranial injection with repeated systemic MSC administration in alleviating the MJD phenotype of two strongly severe genetic rodent models. We found that a single MSC transplantation only produces transient effects, whereas periodic administration promotes sustained motor behavior and neuropathology alleviation, suggesting that MSC therapies should be re-designed to get sustained beneficial results in clinical practice. Furthermore, MSC promoted neuroprotection, increased the levels of GABA and glutamate, and decreased the levels of Myo-inositol, which correlated with motor improvements, indicating that these metabolites may serve as valid neurospectroscopic biomarkers of disease and treatment. This study makes important contributions to the design of new clinical approaches for MJD and other SCAs/polyglutamine disorders.
Molecular Actions of PPARα in Lipid Metabolism and Inflammation
Authors: Nadia Bougarne, Basiel Weyers, Sofie J Desmet, Julie Deckers, David W Ray, Bart Staels, Karolien De Bosscher
Journal: Endocrine Reviews (2018)

Peroxisome proliferator–activated receptor α (PPARα) is a nuclear receptor of clinical interest as a drug target in various metabolic disorders. PPARα also exhibits marked anti-inflammatory capacities. The first-generation PPARα agonists, the fibrates, have however been hampered by drug–drug interaction issues, statin drop-in, and ill-designed cardiovascular intervention trials. Notwithstanding, understanding the molecular mechanisms by which PPARα works will enable control of its activities as a drug target for metabolic diseases with an underlying inflammatory component. Given its role in reshaping the immune system, the full potential of this nuclear receptor subtype as a versatile drug target with high plasticity becomes increasingly clear, and a novel generation of agonists may pave the way for novel fields of applications.
Endogenous Testosterone and Mortality Due to All Causes, Cardiovascular Disease, and Cancer in Men
Authors: Kay-TeeKhaw, MitchDowsett, ElizabethFolkerd, SheilaBingham, NicholasWareham, RobertLuben, AilsaWelch, NicholasDay
Journal: Circulation (2007)

Background— The relation between endogenous testosterone concentrations and health in men is controversial. Methods and Results— We examined the prospective relationship between endogenous testosterone concentrations and mortality due to all causes, cardiovascular disease, and cancer in a nested case-control study based on 11 606 men aged 40 to 79 years surveyed in 1993 to 1997 and followed up to 2003. Among those without prevalent cancer or cardiovascular disease, 825 men who subsequently died were compared with a control group of 1489 men still alive, matched for age and date of baseline visit. Endogenous testosterone concentrations at baseline were inversely related to mortality due to all causes (825 deaths), cardiovascular disease (369 deaths), and cancer (304 deaths). Odds ratios (95% confidence intervals) for mortality for increasing quartiles of endogenous testosterone compared with the lowest quartile were 0.75 (0.55 to 1.00), 0.62 (0.45 to 0.84), and 0.59 (0.42 to 0.85), respectively (P<0.001 fo...
Selecting target papers for replication
Authors: Anton Kuehberger, Michael Schulte-Mecklenbeck
Journal: Behavioral and Brain Sciences (2018)

Abstract Randomness in the selection process of to-be-replicated target papers is critical for replication success or failure. If target papers are chosen because of the ease of doing a replication, or because replicators doubt the reported findings, replications are likely to fail. To date, the selection of replication targets is biased.
Comparison of Antibiotic Prescribing in Retail Clinics, Urgent Care Centers, Emergency Departments, and Traditional Ambulatory Care Settings in the United States
Authors: Danielle L. Palms, Lauri A. Hicks, Monina Bartoces, Adam L. Hersh, Rachel Zetts, David Y. Hyun, Katherine E. Fleming-Dutra
Journal: JAMA Internal Medicine (2018)

Emergency Departments, and Traditional Ambulatory Care Settings in the United StatesAntibiotic use contributes to antibiotic resistance and is associated with adverse events, including Clostridium difficile infections. 1 Antibiotic overuse, especially for viral respiratory infections, is common. 2Only 60% of outpatient antibiotic prescriptions dispensed in the United States are written in traditional ambulatory care settings (hereinafter "medical offices") and emergency departments (EDs). 2 Growing markets, including urgent care centers and retail clinics, may contribute to the remaining 40%. 3,4Our objective was to compare antibiotic prescribing among urgent care centers, retail clinics, EDs, and medical offices.Methods | We conducted a retrospective cohort study using the 2014 Truven Health MarketScan Commercial Claims and Encounters Database, which captures claims data on individuals younger than 65 years with employer-sponsored insurance. 5he National Center for Emerging and Zoonotic Infectious Diseases human subjects advisor deemed these to be deidentified data and thus exempt from ethical approval and patient written informed consent.Outpatient claims with facility codes for urgent care center, retail clinic, hospital-based ED, or medical office were included.We included all visits for which medical and prescription coverage data were captured for the months of, prior to, and following the visit (except December 2014 visits).We excluded visits for which diagnoses were missing or for patients with recent hospitalizations or recent outpatient systemic antibiotic prescription fills.Each visit was assigned a single diagnosis using a previously described, tiered system of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. 2 Data on systemic (oral and parenteral) antibiotic prescriptions, identified using national drug codes from the 2016 Truven Health Red Book supplement, were extracted from outpatient pharmaceutical claims.Oral antibiotic prescriptions were linked to each enrollee's most recent outpatient visit within 3 days. 6Parenteral antibiotics were linked to same-day outpatient visits.The unit of analysis was unique visits, and the outcome was percentage of visits linked to prescription of antibiotics, stratified by setting and diagnosis.We focused on antibiotic-inappropriate respiratory diagnoses (ie, diagnoses for which antibiotics are
POLO: A randomized phase III trial of olaparib maintenance monotherapy in patients (pts) with metastatic pancreatic cancer (mPC) who have a germline <i>BRCA1/2</i> mutation (g<i>BRCA</i>m).
Authors: Talia Golan, Do-Youn Oh, Michele Reni, Teresa Mercade Macarulla, Giampaolo Tortora, Michael J. Hall, Anke C. Reinacher-Schick, Christophe Borg, Daniel Hochhauser, Thomas Walter, Howard S. Hochster, Nigel Baker, Gershon Y. Locker, Hedy L. Kindler
Journal: Journal of Clinical Oncology (2016)

TPS4152 Background: Defective double-strand DNA break repair caused by a gBRCAm is a risk factor for mPC. In the general population of mPC pts, the prevalence of a gBRCAm may be around 4.5%; but, in some populations of mPC pts, such as Ashkenazi Jews, the prevalence could be up to 15%. Monotherapy with the PARP inhibitor olaparib (Lynparza) has led to tumor responses in a Phase II trial that enrolled gBRCAm pts with a variety of solid tumor types, including in pts with mPC (Kaufman et al JCO 2014: Study 42; NCT01078662). This trial supported preclinical data showing that gBRCAm-defective tumors are intrinsically sensitive to PARP inhibitors, and led to a double-blind, placebo-controlled Phase III trial (NCT02184195; POLO) of olaparib ‘switch maintenance’ monotherapy in pts with mPC and a gBRCAm who have not progressed on first-line platinum-based chemotherapy. Methods: Eligible pts with mPC must have documented disease control after completing ≥16 weeks of a first-line, platinum-based regimen, with a deleterious gBRCAm, which will be assayed and confirmed by Integrated BRACAnalysis (Myriad Genetic Laboratories) during the trial. Pts are randomized (3:2) to olaparib tablets (300 mg orally bd) or placebo. The primary endpoint is PFS, determined by blinded independent central review using RECIST 1.1. The primary PFS analysis will be performed after ≈87 PFS events (≈60% maturity) using a log-rank test. Enrollment began in Q4 2014. As of 16 January 2016, 635 pts have been screened. Of 590 pts for whom BRCA1/2 mutation testing results are currently available, 46 pts (7.8%) with a gBRCAm have been identified: 10 pts were known to have a gBRCAm at screening, while 36/580 (6.2%) had a newly identified gBRCAm. Outside the USA or Israel (where screened populations may be enriched for Ashkenazi Jews), a gBRCAm was newly identified in 23/568 pts (4%). The target number for randomization is ≈145 pts across ≈90 centers worldwide. Clinical trial information: NCT02184195.Country Screened (n) Spain 95 France 85 Korea 81 USA 75 Israel 73 UK 61 Italy 61 Germany 44 Australia 29 Belgium 7 Canada 6 Netherlands 4 Total 621* *The breakdown by country is based on an initial 621 pts screened.
Lifestyle Intervention in Danish Obese Pregnant Women With Early Gestational Diabetes Mellitus According to WHO 2013 Criteria Does Not Change Pregnancy Outcomes: Results From the LiP (Lifestyle in Pregnancy) Study
Authors: Christina A. Vinter, Mette H. Tanvig, Maria H. Christensen, Per G. Ovesen, Jan S. Jørgensen, Marianne S. Andersen, Harold D. McIntyre, Dorte M. Jensen
Journal: Diabetes Care (2018)

OBJECTIVE To study effects of lifestyle intervention on metabolic and clinical outcomes in obese women fulfilling the World Health Organization (WHO) 2013 diagnostic criteria for gestational diabetes mellitus (GDM) in early gestation. RESEARCH DESIGN AND METHODS Secondary analysis of data from the Lifestyle in Pregnancy (LiP) study, a lifestyle randomized controlled trial in 304 pregnant women with BMI ≥30 kg/m2. Early GDM (week 12–15) was diagnosed according to modified WHO 2013 GDM criteria: fasting venous plasma glucose ≥5.1 mmol/L and/or 2-h capillary blood glucose (CBG) ≥8.5 mmol/L (75-g oral glucose tolerance test [OGTT]). Women with treated GDM fulfilling local Danish GDM criteria (2-h CBG ≥9.0 mmol/L) (n = 16) and women with normal OGTT (n = 198) were excluded. RESULTS Of 90 women with early GDM, 36 received lifestyle intervention and 54 standard care. All were Caucasian, and median age was 29 years (interquartile range 27–33) and BMI 34.5 kg/m2 (32.3–38.1). All baseline characteristics were similar in the lifestyle intervention and standard care groups. At gestational week 28–30, the women in the lifestyle intervention group had significantly higher fasting total cholesterol and fasting LDL. All other metabolic parameters including measurements of glucose, insulin, and HOMA of insulin resistance were similar. There were more planned cesarean sections in the lifestyle intervention group (22.2 vs. 5.6%), but all other obstetric outcomes were similar. CONCLUSIONS Lifestyle intervention in obese women fulfilling WHO 2013 GDM criteria in early pregnancy was not effective in improving obstetric or metabolic outcomes. Future studies should focus on interventions starting prepregnancy.
The relationship between HER2 expression and Lauren classification in Chinese gastric cancer patients.
Authors: Rui-hua Xu, Miao-Zhen Oiu, Yi-xin Zhou, Xin-ke Zhang, Fang Wang, Jian-Yong Shao, Ying Jin, Zhiqiang Wang, Sheng Dong Zhang, Fenghua Wang, Yu-hong Li
Journal: Journal of Clinical Oncology (2014)

4065 Background: Intestinal type of gastric cancer has a better prognosis than diffuse type and intestinal type tends to have a higher incidence rate of HER2 positive. However the prognosis value of HER2 is still controversial. There might be some factors affecting the HER2’s survival value. What is the relationship between HER2 expression and Lauren classification? We would also analyze the survival differences among the gastric cancer patients with different HER2 and Lauren classification status. Methods: All the patients received the detection of human epidermal growth factor receptor 2 (HER2) by immunohistochemistry (IHC). HER2 amplification levels were detected when the result of IHC was 2+. Fluorescence in situ hybridization (FISH) analysis was carried out according to the manufacturer’s protocol using the PathVysion HER2 DNA Probe kit (LSI HER2/neu Spectrum OrangeTM/ chromosome 7 centromere probe (CEP) 17 Spectrum GreenTM). FISH positive was defined as HER2:CEP17 ratio ≥2. Any case with IHC 3+ or IHC2+/FISH+ was considered to be HER2-positive, while the cases with IHC 0 and IHC 1+ as well as IHC 2+/FISH− were considered to be HER2-negative according to the European Medicines Agency. Two pathologists were responsible for the Lauren classification. There were totally 840 patients for analysis. Survival was defined as the time from metastasis to the time of death. Results: The positive rate of HER2 is 11.2% (94/840). As for the Lauren classifications, there are 51.8% (435/840) diffuse type, 33.0% (277/840) intestinal type and 15.2% (128/840) mixed type. The HER2 positive rate was 25.6%, 2.8% and 8.6% in intestinal type, diffuse type and mixed type, respectively (P<0.001). We ignored the mixed type and divided the rest patients into four groups: A, HER2 positive and diffuse type; B, HER2 positive and intestinal type; C, HER2 negative and diffuse type; D, HER2 negative and intestinal type. The median overall survival was 7.9months, 10.2 months, 10.8 months and 13.7 months, P=0.001. Conclusions: Intestinal cancer has a higher incidence rate of HER2 positive. Patients with HER2 negative and intestinal type have a best survival, while patients with HER2 positive and diffuse type have a worst survival.
Abstract 180: Myocardial Triacylglycerole Accumulation Is Related To BNP And Myocardial Redox State In Advanced Systolic Heart Failure
Authors: JanBenes, LudmilaKazdova, HanaMalinska, JanPirk, JaroslavSpatenka, JosefKautzner, VojtechMelenovsky
Journal: Circulation Research (2013)

PURPOSE: Experimental studies suggest that accumulation of triacylglyceroles (TAG) in myocardium and ensuing lipotoxicity may contribute to the progression of heart failure (HF), but relevance to human HF remains uncertain. We strived to quantify myocardial TAG in HF patients and controls and to identify their determinants. Methods: 49 myocardial samples from patients with terminal HF (52 yrs, 86% male, 45% CAD, 49% DCM, 6% other dg.) that underwent heart transplantation or LVAD implantation and 20 control samples from cadaverous organ donors without HF (42 years, 45% males) were analyzed. Myocardial TAG (determined chemically), reduced (GSH) and oxidized glutathione (GSSG) were determined. Results: Patients with HF had higher amount of myocardial TAG (8.07± 3.95 vs. 5.60±3.36 μmol/g wet tissue, p= 0.017) and lower levels of both GSH and GSSG (p< 0.05) with similar GSH/GSSG ratio. The amount of myocardial TAG was independent of age, gender, HF etiology, diabetes mellitus, BMI, mitral regurgitation grade a...
Oligosaccharyltransferase Inhibition Overcomes Therapeutic Resistance to EGFR Tyrosine Kinase Inhibitors
Authors: Cecilia Lopez Sambrooks, Marta Baro, Amanda Quijano, Azeet Narayan, Wei Cui, Patricia Greninger, Regina Egan, Abhijit Patel, Cyril H. Benes, W. Mark Saltzman, Joseph N. Contessa
Journal: Cancer Research (2018)

Asparagine (N)-linked glycosylation is a posttranslational modification essential for the function of complex transmembrane proteins. However, targeting glycosylation for cancer therapy has not been feasible due to generalized effects on all glycoproteins. Here, we perform sensitivity screening of 94 lung cancer cell lines using NGI-1, a small-molecule inhibitor of the oligosaccharyltransferase (OST) that partially disrupts N-linked glycosylation, and demonstrate a selective loss of tumor cell viability. This screen revealed NGI-1 sensitivity in just 11 of 94 (12%) cell lines, with a significant correlation between OST and EGFR inhibitors. In
Inhibition of activin signaling in lung adenocarcinoma increases the therapeutic index of platinum chemotherapy
Authors: Kieren D. Marini, David R. Croucher, Rachael A. McCloy, Vijesh Vaghjiani, Alvaro Gonzalez-Rajal, Jordan F. Hastings, Venessa Chin, Anette Szczepny, Kaja Kostyrko, Cesar Marquez, W. Samantha N. Jayasekara, Muhammad Alamgeer, Vishal Boolell, Jeremy Z. R. Han, Todd Waugh, Hong Ching Lee, Samantha R. Oakes, Beena Kumar, Craig A. Harrison, Mark P. Hedger, Nirmal Lorensuhewa, Badia Kita, Ross Barrow, Bruce W. Robinson, David M. de Kretser, Jianmin Wu, Vinod Ganju, E. Alejandro Sweet-Cordero, Andrew Burgess, Luciano G. Martelotto, Fernando J. Rossello, Jason E. Cain, D. Neil Watkins
Journal: Science Translational Medicine (2018)

Inhibition of activin signaling enhances the efficacy and safety of platinum chemotherapy in lung adenocarcinoma models.
Stem Cell Therapy for Heart Failure
Authors: PhilippeMenasché
Journal: Circulation (2009)

So far, the major safety issue raised by the use of stem cells for cardiac repair has been the occurrence of ventricular arrhythmias, particularly after skeletal myoblast transplantation. Although one cannot refute a potential intrinsic arrhythmogenicity of stem cells, primarily related to their common lack of electromechanical integration into the recipient myocardium, it is also important to recognize that patients eligible for cell replacement therapy are prone to develop arrhythmias because of their underlying ischemic heart disease. Another confounding factor is the method used for the intramyocardial delivery of the cells, which can cause enough inflammatory tissue damage to further increase ventricular irritability on top of an already high baseline level. Thus any strategy designed to minimize the risk of stem cell–associated ventricular arrhythmias should take into account, besides the cell-specific ability to appropriately couple with host cardiomyocytes, the method of cell transfer and the natu...