Diabetes mellitus and obesity among South Asians with ischemic stroke across three countries.

BACKGROUND: Diabetes mellitus and central obesity are more common among South Asian populations than among White British people. This study explores the differences in diabetes and obesity in South Asians with stroke living in the United Kingdom, India, and Qatar compared with White British stroke patients. METHODS: The study included the UK, Indian, and Qatari arms of the ongoing large Bio-Repository of DNA in Stroke (BRAINS) international prospective hospital-based study for South Asian stroke. BRAINS includes 4580 South Asian and White British recruits from UK, Indian, and Qatar sites with first-ever ischemic stroke. RESULTS: The study population comprises 1751 White British (WB) UK residents, 1165 British South Asians (BSA), 1096 South Asians in India (ISA), and 568 South Asians in Qatar (QSA). ISA, BSA, and QSA South Asians suffered from higher prevalence of diabetes compared with WB by 14.5% (ISA: 95% confidence interval (CI) = 18.6-33.0, p < 0.001), 31.7% (BSA: 95% CI = 35.1-50.2, p < 0.001), and 32.7% (QSA: 95% CI = 28.1-37.3, p < 0.001), respectively. Although WB had the highest prevalence of body mass index (BMI) above 27 kg/m2 compared with South Asian patients (37% vs 21%, p < 0.001), South Asian patients had a higher waist circumference than WB (94.8 cm vs 90.8 cm, p < 0.001). Adjusting for traditional stroke risk factors, ISA, BSA, and QSA continued to display an increased risk of diabetes compared with WB by 3.28 (95% CI: 2.53-4.25, p < 0.001), 3.61 (95% CI: 2.90-4.51, p < 0.001), and 5.24 (95% CI: 3.93-7.00, p < 0.001), respectively. CONCLUSION: South Asian ischemic stroke patients living in Britain and Qatar have a near 3.5-fold risk of diabetes compared with White British stroke patients. Their body composition may partly help explain that increased risk. These findings have important implications for public health policymakers in nations with large South Asian populations.

Atrial fibrillation in UK South Asian hospitalized ischemic stroke patients: The BRAINS study.

INTRODUCTION: South Asian diaspora comprise one of the largest ethnic minority groups in the world yet data about atrial fibrillation (AF) in this demographic is understudied. Our aim is to identify differences in AF prevalence and treatment between South Asians and white British stroke patients. METHOD: The UK arm of a prospective ongoing large international repository on stroke was analysed. Ethnic differences in AF prevalence and management in those with ischemic stroke were analysed. RESULTS: Of the 3515 individuals recruited with ischemic stroke, 1482 (men: 972, women: 510) were South Asian and 2033 (men:1141, women:892) of white British ethnicity. AF was present in 462 white British and 193 South Asians stroke patients, with South Asians displaying a lower prevalence of AF (South Asians: 13.0% vs white British 22.7%, P<0.001). Despite adjustment for traditional AF risk factors, South Asians had a significantly lower OR of AF compared to white British stroke patients (OR: 0.40, 95%CI: 0.33:0.49, P<0.001). Among confirmed AF cases, 31.8% of South Asians and 41.4% of white British were untreated at admission (P = 0.02). Antiplatelet treatment was significantly higher among South Asians at both admission (South Asian: 47.4% vs. white British: 29.9%, P<0.001) and discharge (South Asian: 49.5% vs. white British: 34.7%, P = 0.001), although anticoagulation treatment was similar across both ethnic groups at admission (South Asian: 28.5% vs white British: 28.1%, P = 0.93), and discharge (South Asian: 45.1% vs white British: 43.1%, P = 0.64). CONCLUSION: Stroke patients of South Asian descent are at significantly lower risk of AF but more likely to be on antiplatelet treatment compared to their white British counterparts.

Ischaemic stroke in South Asians: The BRAINS study.

BACKGROUND AND PURPOSE: Studies on stroke in South Asian populations are sparse. The aim of this study was to compare differences in age of onset of ischaemic stroke in South Asian patients living in the United Kingdom and South Asian patients living in India versus White British stroke patients. METHODS: We studied the UK and Indian arms of the ongoing BRAINS study, an international prospective hospital-based study of South Asian stroke patients. The BRAINS study includes 4038 South Asian and White British patients with first-ever ischaemic stroke, recruited from sites in the United Kingdom and India. RESULTS: Of the included patients, 1126 were South Asians living in India (ISA), while 1176 were British South Asian (BSA) and 1736 were White British (WB) UK residents. Patients in the ISA and BSA groups experienced stroke 19.5 years and 7.2 years earlier than their WB counterparts, respectively (mean [interquartile range] age: BSA 64.3 [22] years vs. ISA 52.0 [18] years vs. WB 71.5 [19] years; p < 0.001). Patients in the BSA group had higher rates of hypertension, diabetes mellitus and hypercholesterolaemia than those in the ISA and WB groups. After adjustment for traditional stroke risk factors, an earlier age of stroke onset of 18.9 years (p < 0.001) and 8.9 years (p < 0.001) was still observed in the ISA and BSA groups, respectively. In multivariable stepwise linear regression analysis, ethnicity accounted for 24.7% of the variance in early age onset. CONCLUSION: Patients in the BSA and ISA groups experienced ischaemic stroke approximately 9 and 19 years earlier, respectively, than their WB counterparts. Ethnicity is an independent predictor of early age of stroke onset. Our study has considerable implications for public health policymakers in countries with sizable South Asian populations.

The molecular underpinning of geminin-overexpressing triple-negative breast cancer cells homing specifically to lungs.

Triple-negative breast cancer (TNBCs) display lung metastasis tropism. However, the mechanisms underlying this organ-specific pattern remains to be elucidated. We sought to evaluate the utility of blocking extravasation to prevent lung metastasis. To identify potential geminin overexpression-controlled genetic drivers that promote TNBC tumor homing to lungs, we used the differential/suppression subtractive chain (D/SSC) technique. A geminin overexpression-induced lung metastasis gene signature consists of 24 genes was discovered. We validated overexpression of five of these genes (LGR5, HAS2, CDH11, NCAM2, and DSC2) in worsening lung metastasis-free survival in TNBC patients. Our data demonstrate that LGR5-induced ß-catenin signaling and stemness in TNBC cells are geminin-overexpression dependent. They also demonstrate for the first-time expression of RSPO2 in mouse lung tissue only and exacerbation of its secretion in the circulation of mice that develop geminin overexpressing/LGR5+-TNBC lung metastasis. We identified a novel extravasation receptor complex, consists of CDH11, CD44v6, c-Met, and AXL on geminin overexpressing/LGR5+-TNBC lung metastatic precursors, inhibition of any of its receptors prevented geminin overexpressing/LGR5+-TNBC lung metastasis. Overall, we propose that geminin overexpression in normal mammary epithelial (HME) cells promotes the generation of TNBC metastatic precursors that home specifically to lungs by upregulating LGR5 expression and promoting stemness, intravasation, and extravasation in these precursors. Circulating levels of RSPO2 and OPN can be diagnostic biomarkers to improve risk stratification of metastatic TNBC to lungs, as well as identifying patients who may benefit from therapy targeting geminin alone or in combination with any member of the newly discovered extravasation receptor complex to minimize TNBC lung metastasis.

The Immunosuppressive Microenvironment in BRCA1-IRIS-Overexpressing TNBC Tumors Is Induced by Bidirectional Interaction with Tumor-Associated Macrophages.

Tumor-associated macrophages (TAM) promote triple-negative breast cancer (TNBC) progression. Here, we report BRCA1-IRIS-overexpressing (IRISOE) TNBC cells secrete high levels of GM-CSF in a hypoxia-inducible factor-1α (HIF1α)- and a NF-κB-dependent manner to recruit macrophages to IRISOE cells and polarize them to protumor M2 TAMs. GM-CSF triggered TGFß1 expression by M2 TAMs by activating STAT5, NF-κB, and/or ERK signaling. Despite expressing high levels of TGFß1 receptors on their surface, IRISOE TNBC cells channeled TGFß1/TßRI/II signaling toward AKT, not SMAD, which activated stemness/EMT phenotypes. In orthotopic and syngeneic mouse models, silencing or inactivating IRIS in TNBC cells lowered the levels of circulating GM-CSF, suppressed TAM recruitment, and decreased the levels of circulating TGFß1. Coinjecting macrophages with IRISOE TNBC cells induced earlier metastasis in athymic mice accompanied by high levels of circulating GM-CSF and TGFß1. IRISOE TNBC cells expressed low levels of calreticulin (the "eat me" signal for macrophages) and high levels of CD47 (the "do not eat me" signal for macrophages) and PD-L1 (a T-cell inactivator) on their surface. Accordingly, IRISOE TNBC tumors had significantly few CD8+/PD-1+ cytotoxic T cells and more CD25+/FOXP3+ regulatory T cells. These data show that the bidirectional interaction between IRISOE cells and macrophages triggers an immunosuppressive microenvironment within TNBC tumors that is favorable for the generation of immune-evading/stem-like/IRISOE TNBC metastatic precursors. Inhibiting this interaction may inhibit disease progression and enhance patients' overall survival. SIGNIFICANCE: The BRCA1-IRIS oncogene promotes breast cancer aggressiveness by recruiting macrophages and promoting their M2 polarization.