tbuckley/cabot-search huggingface dataset:
Effects of canagliflozin versus glimepiride on adipokines and inflammatory biomarkers in type 2 diabetes
Authors: W. Timothy Garvey, Luc Van Gaal, Lawrence A. Leiter, Ujjwala Vijapurkar, James List, Robert Cuddihy, Jimmy Ren, Michael J. Davies
Journal: Metabolism (2018)

Highlights•Canagliflozin reduced HbA1c and provided greater weight loss vs glimepiride.•Canagliflozin decreased serum leptin and increased serum adiponectin vs glimepiride.•Canagliflozin also decreased serum IL-6 and increased TNFα vs glimepiride.•No meaningful changes in biomarkers were seen with glimepiride.•Canagliflozin may improve adipose tissue function and cardiometabolic health.AbstractObjectiveType 2 diabetes and obesity are pro-inflammatory states associated with increased risk of cardiovascular disease. Canagliflozin, an SGLT2 inhibitor, demonstrated superiority in lowering HbA1c versus glimepiride with less hypoglycemia and greater weight reduction via loss of fat mass in a 52-week trial of type 2 diabetes patients. This post hoc, exploratory analysis assessed the effects of canagliflozin versus glimepiride on select adipokines, inflammatory biomarkers, and chemokines.MethodsChanges from baseline to Week 52 in serum leptin, adiponectin, IL-6, TNFα, CRP, PAI-1, VCAM-1, and MCP-1 were measured in a randomly selected subset of type 2 diabetes patients on metformin receiving canagliflozin 300 mg (n = 100) or glimepiride (n = 100) in the overall study. Correlations between change in biomarkers and change in select metabolic and anthropometric variables were assessed.ResultsAt Week 52, canagliflozin decreased median serum leptin by 25% (95% CI: −34%, −15%) and increased median serum adiponectin by 17% (95% CI: 11%, 23%) compared with glimepiride. There was a 22% reduction in median serum IL-6 (95% CI: −34%, −10%) and a 7% increase in median serum TNFα (95% CI: 1%, 12%) with canagliflozin versus glimepiride. No between-group differences were observed with the other biomarkers. The decrease in serum leptin with canagliflozin was correlated with change in weight (r ≥ 0.3) only; the increase in adiponectin and decrease in IL-6 with canagliflozin occurred independently of changes in HbA1c, weight, or lipids.ConclusionsThese results indicate that canagliflozin may improve adipose tissue function and induce changes in serum leptin, adiponectin, and IL-6 that favorably impact insulin sensitivity and cardiovascular disease risk.
Integrated Pharmacokinetic/Pharmacodynamic Model of a Bispecific CD3xCD123 DART Molecule in Nonhuman Primates: Evaluation of Activity and Impact of Immunogenicity
Authors: Olivia Campagne, Audrey Delmas, Sylvain Fouliard, Marylore Chenel, Gurunadh R. Chichili, Hua Li, Ralph Alderson, Jean-Michel Scherrmann, Donald E. Mager
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Flotetuzumab (MGD006 or S80880) is a bispecific molecule that recognizes CD3 and CD123 membrane proteins, redirecting T cells to kill CD123-expressing cells for the treatment of acute myeloid leukemia. In this study, we developed a mathematical model to characterize MGD006 exposure–response relationships and to assess the impact of its immunogenicity in cynomolgus monkeys. Experimental Design: Thirty-two animals received multiple escalating doses (100-300-600-1,000 ng/kg/day) via intravenous infusion continuously 4 days a week. The model reflects sequential binding of MGD006 to CD3 and CD123 receptors. Formation of the MGD006/CD3 complex was connected to total T cells undergoing trafficking, whereas the formation of the trimolecular complex results in T-cell activation and clonal expansion. Activated T cells were used to drive the peripheral depletion of CD123-positive cells. Anti-drug antibody development was linked to MGD006 disposition as an elimination pathway. Model validation was tested by predicting the activity of MGD006 in eight monkeys receiving continuous 7-day infusions. Results: MGD006 disposition and total T-cell and CD123-positive cell profiles were well characterized. Anti-drug antibody development led to the suppression of T-cell trafficking but did not systematically abolish CD123-positive cell depletion. Target cell depletion could persist after drug elimination owing to the self-proliferation of activated T cells generated during the first cycles. The model was externally validated with the 7-day infusion dosing schedule. Conclusions: A translational model was developed for MGD006 that features T-cell activation and expansion as a key driver of pharmacologic activity and provides a mechanistic quantitative platform to inform dosing strategies in ongoing clinical studies. Clin Cancer Res; 24(11); 2631–41. ©2018 AACR.
Abstract 13451: Oxldl-derived Lysophosphatidic Acid Generates a Nf-κB Signature Through Lpar1 That Promotes the Progression of Aortic Valve Stenosis
Authors: Mohamed J Nsaibia, Marie C Boulanger, Ghada Mkannez, Rihab Bouchareb, Yohan Bossé, Philippe Pibarot, Benoît Arsenault, André Marette, Patrick Mathieu
Journal: Circulation (2016)

Background: Mendelian randomization studies have revealed an association between low-density lipoprotein (LDL) and calcific aortic valve stenosis (CAVS). Circulating level of oxidized phospholipids, a component of oxidized LDL (OxLDL), is associated with the progression rate of CAVS. Autotaxin (ATX) is a lysophospholipase D enzyme that transforms lysophosphatidylcholine (LPC), into lysophosphatidic acid (LPA). Recently, we demonstrated that LPA, which is generated by ATX, was present in the aortic valve and was an important driver of aortic valve mineralization. However, the process whereby oxidatively transformed LDL promotes the development/progression of CAVS is largely unknown. Objective: We aimed to examine the molecular processes whereby OxLDL promotes the mineralization of the aortic valve and the progression of CAVS. Methods: We documented the expression of LPA receptor 1 (LPAR1) in explanted CAVS and in control non-mineralized aortic valves. Effects of OxLDL-LPA on osteoblastic differentiation of cultured valve interstitial cells (VICs) were investigated by using promoter luciferase assay and RT-qPCR analysis for the osteoblastic markers. Results: We found that autotaxin (ATX), a lysophospholipase D, is transported by the LDL fraction. Upon oxidation of LDL, LPA is generated through the activity of ATX, promoting a strong osteogenic activity in VICs. In-depth functional assays showed that OxLDL/LPA-mediated osteogenic activity in VICs relied on LPAR1 and phosphorylation of p65 on serine 536, which is recruited to the promoter of bone morphogenetic protein 2 ( BMP2 ). In human and mouse mineralized aortic valves, the expression of LPAR1 is increased. In obese diabetic LDLR -/- /ApoB 100/100 /IGFII transgenic mice (IGFII), the development of CAVS was associated with a rise of circulating LPA, which correlated with the plasma ATX activity and cholesterol level. In this murine model of an established CAVS, inhibition of LPAR1 with Ki16425 decreased the progression rate of CAVS by 3.0-fold. Conclusion: These findings indicate that OxLDL-mediated progression of CAVS is promoted by LPA driving an inflammatory pathway that promotes the osteogenic activity of VICs. LPAR1 may thus constitute a novel target to prevent the progression of CAVS.
Comparison of a low-cost immunohistochemistry marker panel with a cell-cycle progression assay for the prediction of outcome after radical prostatectomy.
Authors: Michael Leapman, Hao Gia Nguyen, Janet E. Cowan, Lingru Xue, Bradley Stohr, Jeffry Simko, Matthew R. Cooperberg, Peter Carroll
Journal: Journal of Clinical Oncology (2018)

118 Background: Gene expression assays appear to stratify prostate cancer risk, however tests involving amplification techniques are expensive and may strain payment systems. We aimed to compare the prognostic utility of a low-cost immunohistochemistry (IHC) panel consisting of three validated markers with an RNA expression based cell-cycle progression (CCP) score. Methods: Among 5,748 patients with PCa within an institutional database, we identified 424 with localized PCa treated with radical prostatectomy (RP). IHC analysis was performed using tissue microarrays to examine the expression status of PTEN, Ki67, and ERG compared with previously calculated CCP scores derived from 31 genes normalized to 15 housekeeper genes. Associations of IHC status, CCP scores, adjusted for clinical and pathologic characteristics (Cancer of the Prostate Risk Assessment Score, CAPRA-S) were performed using Cox proportional hazards regression to examine risk of biochemical recurrence (BCR), and metastasis or PCa- specific mortality (PCSM). We compared models using concordance index (c-index) testing. Results: Median age at treatment was 59 years and patients were followed for a median of 114 months post RP. By 10 years after RP, 27% experienced BCR and 4% developed metastasis or PCSM. Adjusted for CAPRA-S, the triad of PTEN loss, high Ki67, and positive ERG expression was independently associated with risk of BCR (HR 2.3, 95% CI 1.1-4.7) and metastasis/PCSM (HR 8.3, 95% CI 3.3-21.2). In a model including CAPRA-S, IHC panel, and CCP, the CCP score was independently associated with both recurrence and metastasis/PCSM (HR 1.9, 95% CI 1.5-2.5 and HR 2.5, 95% CI 1.5-4.1, respectively), but IHC expression status of PTEN/Ki67/ERG remained an independent predictor of both endpoints. The addition of the CCP assay marginally improved the c-index of a combined IHC and CAPRA-S model from 0.78 to 0.81 for the prediction of metastasis/PCSM. Conclusions: A low-cost three-marker IHC panel examining PTEN, Ki67, and ERG expression was independently associated with downstream PCa endpoints following RP. Efforts are warranted to reduce the cost of PCa prognostic tools in order to expand access.
Ramucirumab treatment in patients with gastric cancer/gastroesophageal junction adenocarcinoma: Secondary analysis of efficacy and safety results of 4 dosing regimens in the phase II trial I4T-MC-JVDB.
Authors: Jaffer A. Ajani, Anghel Adrian Udrea, Tomasz Sarosiek, Michael Schenker, Carys Morgan, Joanna Pikiel, Mano Joseph, Tomas Salek, Christophe Tournigand, David Raymond Ferry, Yawei Zhang, Amanda Long, Wen-Ling Kuo, Ling Gao, Francesca Russo, Wasat Mansoor
Journal: Journal of Clinical Oncology (2018)

117 Background: Ramucirumab (RAM) is approved for treatment of advanced gastric cancer or gastroesophageal junction adenocarcinoma with disease progression after prior platinum and/or fluoropyrimidine chemotherapy at 8 mg/kg every 2 weeks (Q2W). Previous phase 3 trials indicated that efficacy of RAM correlated with exposure. While the primary objectives of the open-label RAM monotherapy JVDB study were pharmacokinetics and safety, a secondary analysis was conducted on efficacy and safety of the 3 higher exposure regimens vs. the standard regimen. Methods: Patients ( n = 164) were randomized 1:1:1:1 to 4 treatment arms: 8 mg/kg Q2W (Arm 1), 12 mg/kg Q2W (Arm 2), 6 mg/kg every week (Arm 3), and 8 mg/kg Days 1 and 8 (D1D8) every 3 weeks (Q3W) (Arm 4). Treatment-emergent adverse events (TEAEs) were graded by NCI CTCAE v4.0. Tumor response was assessed by RECIST 1.1. Results: Median (months) progression-free survival (PFS) of the 3 arms and overall survival (OS) of 2 arms was increased compared to the standard regimen (Table). Best overall response was partial response (Arm 2, n = 4; Arm 3, n = 2). The majority of patients experienced ≥1 TEAE (81.4%); 39.1% had ≥1 Grade ≥3 event and 26.7% had ≥1 serious event. The most frequent Grade ≥3 events were fatigue (5.6%), abdominal pain (5.05%), hypertension (5.0%), anemia (4.3%), and vomiting (3.7%). Conclusions: Although the study was not powered for statistical comparisons, some trends toward improved efficacy vs. the standard regimen were observed; the greatest median PFS months and OS improvement was 1 month (Arm 2 vs. Arm 1; PFS = 2.50 vs. 1.45; OS = 6.74 vs. 5.68). Despite higher RAM exposures with the experimental regimens, the safety profile is similar to the standard dose regimen, and no unexpected safety findings were observed. Clinical trial information: NCT02443883. [Table: see text]
THE OPSUMIT® USERS REGISTRY: A GENDER SUBGROUP ANALYSIS OF PATIENT CHARACTERISTICS, TREATMENT PATTERNS AND SURVIVAL IN PULMONARY ARTERIAL HYPERTENSION
Authors: Vallerie V. McLaughlin, Richard Channick, Kelly M. Chin, Monika Brand, Erwan Muros-Le Rouzic, Mona Selej, Nick H. Kim
Journal: Journal of the American College of Cardiology (2018)
Abstract P184: Meat Cooking Methods and Risk of Hypertension: Results From Three Prospective Cohort Studies
Authors: Gang Liu
Journal: Circulation (2018)

Background: The role of open-flame and/or high-temperature cooking (grilling/barbequing, broiling, or roasting) and doneness preferences (rare, medium, or well-done) in the association between meat consumption and risk of hypertension remains unknown. This study aimed to examine cooking methods for meats (red meats, chicken, or fish) in relation to hypertension risk among men and women who consumed meat regularly (≥2 servings/week). Methods: Study population consisted of 32,925 women from the Nurses’ Health Study (NHS 1996-2012), 53,852 women from the NHSII (2001-2013), and 17,104 men from the Health Professionals Follow-Up Study (HPFS 1996-2012), who were free of hypertension, diabetes, cardiovascular disease, and cancer at baseline. Results: We documented 37,123 incident hypertension cases during 1.06 million person-years of follow-up. After multivariate adjustments of covariates including total consumption of red meats, chicken, and fish, a higher frequency of open-flame and/or high-temperature cooking and a preference for higher meat doneness level were both independently associated with an increased hypertension risk. When comparing open-flame and/or high-temperature cooking &gt;15 times/month with &lt;4 times/month, the pooled hazard ratio (HR) and 95% confidence interval (CI) of hypertension was 1.17 (1.12, 1.21; P trend &lt;0.001). When comparing the extreme quartiles of meat doneness level score, the pooled HR (95% CI) of hypertension was 1.15 (1.12, 1.19; P trend &lt;0.001). The associations persisted when data were analyzed by individual meat groups: comparing extreme groups, for red meats, the pooled HR (95% CI) of hypertension was 1.18 (1.13, 1.23; P trend &lt;0.001) for open-flame and/or high-temperature cooking and 1.15 (1.12, 1.19; P trend &lt;0.001) for high meat doneness level; for white meats (chicken and fish), the pooled HR (95% CI) of hypertension was 1.12 (1.08, 1.16; P trend &lt;0.001) for open-flame and/or high-temperature cooking and 1.10 (1.07, 1.14; P trend &lt;0.001) for high meat doneness level. Moreover, levels of estimated intake of heterocyclic aromatic amines (HAAs) were also independently associated with an increased risk of hypertension. Comparing extreme quintiles of HAAs, the pooled HR (95% CI) of hypertension was 1.16 (1.13, 1.21; P trend &lt;0.001). These associations were attenuated but remained significant when further adjusting for baseline body mass index. Conclusions: Our results suggest that, independent of the amount of meat consumption, open-flame and/or high-temperature cooking and high doneness level for both red meats and white meats are associated with an increased risk of hypertension.
What does the recent reduction in GP registrar funding mean for doctors applying directly at GP registrar level having completed their own rotation or decided to change career to general practice?
Authors: Bill Irish
Journal: BMJ (2004)

<i>Got a career or related problem that needs answering? Can9t find the right person to point you in the right direction? Log on to the Advice Zone (www.bmjcareers.com/advicezone) for reliable medical careers advice. You can post a question or see if one of our 300 advisers has already answered a similar question. Here is a selection of questions and answers posted on the site.</i>
O025 Unopposed interleukin 18 signalling leads to severe toll like receptor 9-induced macrophage activation syndrome in mice
Authors: C Girard-Guyonvarc’h, J Palomo, P Martin, E Rodriguez, S Troccaz, G Palmer, C Gabay
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Introduction</h3> Macrophage activation syndrome (MAS) is a severe condition, which can appear as a complication of inflammatory rheumatic diseases such as systemic juvenile idiopathic arthritis (sJIA) and adult onset Still's disease (AOSD), a viral infection, or a malignancy. Interleukin (IL)−18 is a pro-inflammatory cytokine of the IL-1 family, known as a strong interferon (IFN)-γ inducer, that is naturally inhibited by IL-18 binding protein (IL-18BP). High levels of unbound biologically active IL-18 have been described in patients with sJIA, AOSD, and MAS, suggesting that IL-18 is involved in the pathogenesis of these diseases. <h3>Objectives</h3> To examine the effect of excessive IL-18 signalling in a mouse model of MAS induced by repetitive toll like receptor (TLR)9 stimulation, and explore the consequences of IL-18 or IFN-γ blockade on MAS manifestations. <h3>Methods</h3> MAS was induced by repeated intraperitoneal CpG injections in IL-18BP deficient (<i>IL-18BP<sup>-/-</sup></i>) mice and in wild type (WT) littermates. Anti-IL-18 receptor (IL-18R) or anti-IFN-γ monoclonal antibodies were administered prior to CpG injections. Clinical and biological manifestations of MAS were studied. Plasma levels of free IL-18 were measured by ELISA. Expression levels of IFN-γ and downstream IFN-γ-induced effectors (CXCL9, CIITA) were explored by ELISA or Luminex in plasma, and by RT-qPCR in spleen and liver. <h3>Results</h3> Naïve<i> IL-18BP<sup>-/-</sup></i> mice had no spontaneous phenotype. After repeated CpG injections, <i>IL-18BP<sup>-/-</sup></i> mice displayed significantly more severe MAS phenotype than their WT littermates, including more pronounced weight loss, splenomegaly, anaemia, thrombocytopenia, hyperferritinemia and hepatitis. This phenotype was associated with elevated plasma levels of unbound IL-18 and the presence of bone marrow hemophagocytes in <i>IL-18BP<sup>-/-</sup></i> mice only. In addition, <i>IL-18BP<sup>-/-</sup></i> mice displayed higher plasma levels of IFN-γ and CXCL9, as well as increased <i>Ifnγ</i>, <i>Cxcl9</i> and <i>CIIta</i> mRNA expression in the spleen and liver. IL-18 blockade using an anti-IL-18R antibody attenuated MAS manifestations in <i>IL-18BP<sup>-/-</sup></i> mice and abrogated IFN-γ production and downstream signalling. IFN-γ blockade using an anti-IFN-γ antibody also attenuated the MAS phenotype. <h3>Conclusions</h3> By using <i>IL-18BP<sup>-/-</sup></i> mice, we showed that unopposed IL-18 signalling was detrimental in the TLR9-induced MAS model. Importantly, blocking IL-18, as well as IFN-γ, improved disease in <i>IL-18BP<sup>-/-</sup></i> mice. Altogether, our results suggest that IL-18 exerts a pathogenic role in this model of MAS, acting upstream of IFN-γ. <h3>Disclosure of interest</h3> None declared
Physical, emotional, and informational challenges of patients living with neuroendocrine tumors in the United States: Understanding their unmet needs.
Authors: Grace Goldstein, Abdelali Majdi, Isabelle Bocher-Pianka, Rupert Watts, Mohid Khan
Journal: Journal of Clinical Oncology (2018)

299 Background: Surveys of neuroendocrine tumor (NET) burden on daily living rarely explore the impact that patient information sources can have on optimizing care. This subset of a large US survey focused on identifying the unmet needs, and available information sources and support that address the physical, emotional and informational challenges that patients with NETs experience. Methods: The Carcinoid Cancer Foundation is a US, non-profit organization that encourages and supports research and education on carcinoid and related NETs. A Carcinoid Cancer Foundation-approved survey was shared with patients with NETs via the Carcinoid Cancer Foundation website, e-newsletters and social media; some patients were emailed direct links to the online survey. Results: US, online surveys (N=428; 13 questions) were completed over 6 weeks in 2015. Patients had mostly small intestinal (40%), lung (13%) or pancreatic (11%) primary tumors; 66% of patients were diagnosed in the previous 5 years. Patients experienced multiple symptoms, most commonly diarrhea (47%), flushing (45%), changes in bowel/bladder habits (37%) and persistent pain (30%). Common emotions upon diagnosis were fear (58%), anxiety (53%), feeling overwhelmed (50%), confusion (39%) and sadness (34%). Greatest physical challenges were fatigue (66%), diarrhea (48%), pain/discomfort (40%) &amp; sleep disturbance (35%). “Very useful” information sources were (1) NET/carcinoid disease awareness website, (2) carcinoid/NET support group, (3) Google, (4) discussion forums and (5) governmental/health-authority websites. Favored information formats included “patients-like-me” case studies (67%), email (59%), e-newsletters (56%), FAQs (50%), short interactive tutorials (32%) and “top tips” (31%). Information sought, but not found, included simple advice on diet, holistic treatment, complementary therapies, where to find the best treatment, pain management &amp; prognosis. Conclusions: In the US, patients with NETs face negative emotions and multiple physical challenges that require psychological support/coping strategies, and they seek reliable, personally relevant, easily understood information, including that from interaction with other patients.
IDH1 mutant glioma initiating cells are predisposed to apoptosis under endoplasmic reticulum (ER) stress
Authors: Ying Zhang, Li Ningning, Joanne Lau, Angela Richard-londt, Andreas von Deimling, Stefan Pusch, Sebastian Brandner
Journal: Neuro-Oncology (2018)

Multiple studies have shown that patients with IDH mutant gliomas survive longer than those with IDH wild type gliomas. However, how the IDH mutation confers a better prognosis, is still largely unclear. To study the role of IDH mutation during glioma initiation and growth, we used a mouse model, which can express mutant Idh1 R132H upon Cre mediated recombination. In vitro, murine Idh1 R132H neural stem cells showed significantly lower proliferation but increased apoptosis rate when compared with normal SVZ derived stem/progenitor cells. We found that Idh1 R132H alone did not generate gliomas in neonatal or adult mice, and only upon crossing Idh1 R132H mice with PtenloxP/loxP;p53loxP/loxP mice, we observed formation of gliomas. In this context, the additional presence of the Idh mutation slowed down tumour growth and increased the rate of apoptosis. We performed RNA and miRNA sequencing on double (Pten/p53) and triple (Idh1/Pten/p53) mutant glioma initiating cells. Gene expression analysis shows a significant enrichment of genes involved in apoptosis and endoplasmic reticulum (ER) stress response in IDH mutant cells. Treatment of the cells with tunicamycin and tharpsigargin, two ER stress inducers, caused significant apoptosis in Idh1 mutant cells but not in Idh1 wt cells. Furthermore, the upregulation of Chop, Atf4 and Gadd34, constituents of the PERK branch (apoptosis), was increased after tunicamycin and tharpsigargin treatment. MiRNA sequencing data showed upregulation of miR-183-5p in Idh1 mutant cells. Subsequent overexpression of miR-183-5p promoted Idh1 wt cells to apoptosis under ER stress. In conclusion, we show here a pathway involved in triggering apoptosis in IDH mutant tumours. Triggering apoptosis with ER-Stress-inducing drugs may in the future provide an option for therapeutic intervention in IDH mutant tumours.
THE IMPACT OF DECREASED HIGH-DENSITY LIPOPROTEIN-CHOLESTEROL LEVEL AFTER LIPID-LOWERING THERAPY ON THE CLINICAL OUTCOMES IN PATIENTS WITH ACUTE CORONARY SYNDROME AND DYSLIPIDEMIA: A SUBANALYSIS OF THE HIJ-PROPER STUDY
Authors: Haruki Sekiguchi, Yuko Matsui, Erisa Kawada-Watanabe, Junichi Yamaguchi, Hiroyuki Arashi, Hiroshi Ogawa, Nobuhisa Hagiwara
Journal: Journal of the American College of Cardiology (2018)