The Renin Angiotensin System (RAS) mediates bifunctional growth regulation in melanoma and is a novel target for therapeutic intervention

Despite emergence of new systemic therapies, metastatic melanoma remains a challenging and often fatal form of skin cancer. The renin–angiotensin system (RAS) is a major physiological regulatory pathway controlling salt–water equilibrium, intravascular volume and blood pressure. Biological effects of the RAS are mediated by the vasoactive hormone angiotensin II (AngII) via two receptor subtypes, AT1R (encoded by AGTR1) and AT2R (encoded by AGTR2). We report decreasing expression and increasing CpG island methylation of AGTR1 in metastatic versus primary melanoma and detection in serum of methylated genomic DNA from the AGTR1 CpG island in metastatic melanoma implying that AGTR1 encodes a tumour suppressor function in melanoma. Consistent with this hypothesis, antagonism of AT1R using losartan or shRNA-mediated knockdown in melanoma cell lines expressing AGTR1 resulted in acquisition of the ability to proliferate in serum-free conditions. Conversely, ectopic expression of AGTR1 in cell lines lacking endogenous expression inhibits proliferation irrespective of the presence of AngII implying a ligand-independent suppressor function for AT1R. Treatment of melanoma cell lines expressing endogenous AT2R with either AngII or the AT2R-selective agonist Y6AII induces proliferation in serum-free conditions whereas the AT2R-specific antagonists PD123319 and EMA401 inhibit melanoma growth and angiogenesis and potentiate inhibitors of BRAF and MEK in cells with BRAF V600 mutations. Our results demonstrate that the RAS has both oncogenic and tumour suppressor functions in melanoma. Pharmacological inhibition of AT2R may provide therapeutic opportunities in melanomas expressing this receptor and AGTR1 CpG island methylation in serum may serve as a novel biomarker of metastatic melanoma

Characterization of active and infiltrative tumorous subregions from normal tissue in brain gliomas using multiparametric MRI

Background: Targeted localized biopsies and treatments for diffuse gliomas rely on accurate identification of tissue subregions, for which current MRI techniques lack specificity. Purpose: To explore the complementary and competitive roles of a variety of conventional and quantitative MRI methods for distinguishing subregions of brain gliomas. Study Type: Prospective. Population: Fifty‐one tissue specimens were collected using image‐guided localized biopsy surgery from 10 patients with newly diagnosed gliomas. Field Strength/Sequence: Conventional and quantitative MR images consisting of pre‐ and postcontrast T1w, T2w, T2‐FLAIR, T2‐relaxometry, DWI, DTI, IVIM, and DSC‐MRI were acquired preoperatively at 3T. Assessment: Biopsy specimens were histopathologically attributed to glioma tissue subregion categories of active tumor (AT), infiltrative edema (IE), and normal tissue (NT) subregions. For each tissue sample, a feature vector comprising 15 MRI‐based parameters was derived from preoperative images and assessed by a machine learning algorithm to determine the best multiparametric feature combination for characterizing the tissue subregions. Statistical Tests: For discrimination of AT, IE, and NT subregions, a one‐way analysis of variance (ANOVA) test and for pairwise tissue subregion differentiation, Tukey honest significant difference, and Games‐Howell tests were applied (P < 0.05). Cross‐validated feature selection and classification methods were implemented for identification of accurate multiparametric MRI parameter combination. Results: After exclusion of 17 tissue specimens, 34 samples (AT = 6, IE = 20, and NT = 8) were considered for analysis. Highest accuracies and statistically significant differences for discrimination of IE from NT and AT from NT were observed for diffusion‐based parameters (AUCs >90%), and the perfusion‐derived parameter as the most accurate feature in distinguishing IE from AT. A combination of “CBV, MD, T2_ISO, FLAIR” parameters showed high diagnostic performance for identification of the three subregions (AUC ∼90%). Data Conclusion: Integration of a few quantitative along with conventional MRI parameters may provide a potential multiparametric imaging biomarker for predicting the histopathologically proven glioma tissue subregions

Patterns of oral anticoagulant use and outcomes in Asian patients with atrial fibrillation: a post-hoc analysis from the GLORIA-AF Registry

BackgroundPrevious studies suggested potential ethnic differences in the management and outcomes of atrial fibrillation (AF). We aim to analyse oral anticoagulant (OAC) prescription, discontinuation, and risk of adverse outcomes in Asian patients with AF, using data from a global prospective cohort study.MethodsFrom the GLORIA-AF Registry Phase II-III (November 2011-December 2014 for Phase II, and January 2014-December 2016 for Phase III), we analysed patients according to their self-reported ethnicity (Asian vs. non-Asian), as well as according to Asian subgroups (Chinese, Japanese, Korean and other Asian). Logistic regression was used to analyse OAC prescription, while the risk of OAC discontinuation and adverse outcomes were analysed through Cox-regression model. Our primary outcome was the composite of all-cause death and major adverse cardiovascular events (MACE). The original studies were registered with ClinicalTrials.gov, NCT01468701, NCT01671007, and NCT01937377.Findings34,421 patients were included (70.0&nbsp;±&nbsp;10.5 years, 45.1% females, 6900 (20.0%) Asian: 3829 (55.5%) Chinese, 814 (11.8%) Japanese, 1964 (28.5%) Korean and 293 (4.2%) other Asian). Most of the Asian patients were recruited in Asia (n&nbsp;=&nbsp;6701, 97.1%), while non-Asian patients were mainly recruited in Europe (n&nbsp;=&nbsp;15,449, 56.1%) and North America (n&nbsp;=&nbsp;8378, 30.4%). Compared to non-Asian individuals, prescription of OAC and non-vitamin K antagonist oral anticoagulant (NOAC) was lower in Asian patients (Odds Ratio [OR] and 95% Confidence Intervals (CI): 0.23 [0.22-0.25] and 0.66 [0.61-0.71], respectively), but higher in the Japanese subgroup. Asian ethnicity was also associated with higher risk of OAC discontinuation (Hazard Ratio [HR] and [95% CI]: 1.79 [1.67-1.92]), and lower risk of the primary composite outcome (HR [95% CI]: 0.86 [0.76-0.96]). Among the exploratory secondary outcomes, Asian ethnicity was associated with higher risks of thromboembolism and intracranial haemorrhage, and lower risk of major bleeding.InterpretationOur results showed that Asian patients with AF showed suboptimal thromboembolic risk management and a specific risk profile of adverse outcomes; these differences may also reflect differences in country-specific factors. Ensuring integrated and appropriate treatment of these patients is crucial to improve their prognosis.FundingThe GLORIA-AF Registry was funded by Boehringer Ingelheim GmbH

Anticoagulant selection in relation to the SAMe-TT2R2 score in patients with atrial fibrillation: The GLORIA-AF registry

AimThe SAMe-TT2R2 score helps identify patients with atrial fibrillation (AF) likely to have poor anticoagulation control during anticoagulation with vitamin K antagonists (VKA) and those with scores &gt;2 might be better managed with a target-specific oral anticoagulant (NOAC). We hypothesized that in clinical practice, VKAs may be prescribed less frequently to patients with AF and SAMe-TT2R2 scores &gt;2 than to patients with lower scores.Methods and resultsWe analyzed the Phase III dataset of the Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF), a large, global, prospective global registry of patients with newly diagnosed AF and ≥1 stroke risk factor. We compared baseline clinical characteristics and antithrombotic prescriptions to determine the probability of the VKA prescription among anticoagulated patients with the baseline SAMe-TT2R2 score &gt;2 and&nbsp;≤&nbsp;2. Among 17,465 anticoagulated patients with AF, 4,828 (27.6%) patients were prescribed VKA and 12,637 (72.4%) patients an NOAC: 11,884 (68.0%) patients had SAMe-TT2R2 scores 0-2 and 5,581 (32.0%) patients had scores &gt;2. The proportion of patients prescribed VKA was 28.0% among patients with SAMe-TT2R2 scores &gt;2 and 27.5% in those with scores ≤2.ConclusionsThe lack of a clear association between the SAMe-TT2R2 score and anticoagulant selection may be attributed to the relative efficacy and safety profiles between NOACs and VKAs as well as to the absence of trial evidence that an SAMe-TT2R2-guided strategy for the selection of the type of anticoagulation in NVAF patients has an impact on clinical outcomes of efficacy and safety. The latter hypothesis is currently being tested in a randomized controlled trial.Clinical trial registrationURL: https://www.clinicaltrials.gov//Unique identifier: NCT01937377, NCT01468701, and NCT01671007

PREVALENCE AND RISK FACTORS OF SCHISTOSOMIASIS AMONG HAUSA COMMUNITIES IN KANO STATE, NIGERIA

SUMMARY Schistosomiasis remains one of the most prevalent neglected tropical diseases especially in Nigeria which has the greatest number of infected people worldwide. A cross-sectional study was conducted among 551 participants from Kano State, North Central Nigeria. Fecal samples were examined for the presence of Schistosoma mansoni eggs using the formalin-ether sedimentation method while the urine samples were examined using the filtration technique for the presence of S. haematobium eggs. Demographic, socioeconomic and environmental information was collected using a pre-validated questionnaire. The overall prevalence of schistosomiasis was 17.8%, with 8.9% and 8.3% infected with S. mansoni and S. haematobium, respectively and 0.5% presenting co-infection with both species. The multiple logistic regression analysis revealed that age < 18 years (OR = 2.13; 95% CI; 1.34- 3.41), presence of infected family members (OR = 3.98; 95% CI; 2.13-7.46), and history of infection (OR = 2.87; 95% CI; 1.87- 4.56) were the significant risk factors associated with schistosomiasis in these communities. In conclusion, this study revealed that schistosomiasis is still prevalent among Hausa communities in Nigeria. Mass drug administration, health education and community mobilization are imperative strategies to significantly reduce the prevalence and morbidity of schistosomiasis in these communities

Media dan integrasi sosial : jembatan antar umat beragama

Diskursus media dan integrasi sosial dewasa ini tidak lagi hanya terbatas pada kritik pemberitaan tentang konflik yang sensasional dan bombastis, tapi juga mencakup tentang bagaimana media mendorong dialog dan komunikasi.xxiii, 122 hlm.; 22 c

The occidentalism in the novel river of smoke

viii, 41 hlm.; ilus.; 30 cm

Media dan integrasi sosial : jembatan antar umat beragama

Buku ini membahas tentang pemikiran mengenai media dan integrasi sosial dewasa tidak lagi hanya terbatas pada kritik pemberitaan tentang konflik yang sensasional dan bombastis, tetapi juga mencakup tentang bagaimana media mendorong dialog dan komunikasi.xxiv, 135 hlm.: 22 cm

Media dan integrasi sosial : jembatan antar umat beragama

Buku ini membahas tentang pemikiran mengenai media dan integrasi sosial dewasa tidak lagi hanya terbatas pada kritik pemberitaan tentang konflik yang sensasional dan bombastis, tetapi juga mencakup tentang bagaimana media mendorong dialog dan komunikasi.xxiv, 135 hlm.: 22 cm