Insulin resistance as a determinant of platelet activation in obese women

OBJECTIVES We tested the hypothesis that insulin resistance, per se, contributes to increased platelet activation in obesity, independently of underlying inflammation. BACKGROUND Obesity, insulin resistance, and atherosclerosis are closely linked phenomena associated with low-grade inflammation. Obesity is associated with persistent platelet activation in otherwise healthy women. METHODS We performed a cross-sectional study in 40 obese and 20 non-obese healthy women using urinary thromboxane metabolite excretion as a non-invasive index of platelet activation. An index of insulin sensitivity, S, and plasma adiponectin, C-reactive protein (CRP), and CD40 ligand (CD40L) levels were measured. RESULTS Obese women had significantly (p < 0.0001) higher 11-dehydro-thromboxane B-2 (11-dehydro-TXB2) excretion (median 718 vs. 211 pg/mg creatinine), CRP (1.13 vs. 0.48 mg/1), and CD40L levels (4.45 vs. 0.90 ng/ml) than controls. Obese women had lower S, (median 2.51 vs. 5.0 10(4) min(-1)/[mu U/ml], p < 0.002) and adiponectin (6.3 vs. 10 mu g/ml, p < 0.01) than control subjects. On multiple regression analysis, waist-to-hip ratio (beta = 0.27, p < 0.05) and S, (beta = -0.72, p < 0.04) predicted 11-dehydro-TXB2 excretion rate, independently of adiponectin, CRP, CD40L, and lipid patterns. In order to investigate the cause-effect relationship of these associations, we examined the effects of a 12-week weight loss program or a 3-week pioglitazone treatment on urinary 11-dehydro-TXB2 in 10 women with impaired S-1 and visceral obesity. Successful weight loss (0.6 kg loss/week) achieved in 5 subjects was associated with increased S-1 (+92%) and decreased CD40L (-27%), CRP (-37%), and 11-dehydro-TXB2 (-53%) (p < 0.05). Consistently, improvement of insulin sensitivity achieved with pioglitazone significantly decreased urinary 11-dehydro-TXB2 excretion (-43%, p < 0.05) without changes in body weight. CONCLUSIONS Insulin resistance is a major determinant of platelet activation in female obesity

Mature PMN-MDSCs from G-CSF-treated healthy donors and cancer patients share a suppressive gene signature and CD84 expression

Recently, we demonstrated that neutrophil populations displaying polymorphonuclear myeloid derived suppressor cell (PMN-MDSC)-like features appear in abundance in both CD66b+ low-density neutrophils (LDNs) and normal-density neutrophils (NDNs) of healthy subjects receiving G-CSF for stem cell mobilization (GDs). We also uncovered that the mature, but not immature, fraction of PMN-MDSC populations present in GDs, similarly to what also shown by others in cancer patients, are those exerting the most potent immunosuppressive functions. Herein, by RNA-seq computational analysis, we report the identification and characterization of a distinct gene signature common to mature CD66b+CD11b+CD16+CD10+ LDNs/mNDNs from GDs (GD-mNDNs/mLDNs) and mature CD66b+CD11b+CD16+CD10+ PMN-MDSCs (mPMN-MDSCs) from head and neck (HNC) and non-small cell lung (NSCLC) cancer patients. We also show that this GD/NSCLC/HNC mPMN-MDSC gene signature derives, mostly from the maintenance of genes already expressed by normal immature neutrophil precursors, and in a minor, but more specific, quote, from genes selectively upregulated along the maturation of PMN-MDSC-committed cells. Furthermore, by searching for mRNAs included within the latter group of genes encoding surface proteins, we found CD84 expression markedly elevated on mPMN-MDSC populations, not only from GDs and HNC/NSCLC, but also from diffuse large B cell lymphoma (DLBCL), renal cell cancer (RCC), transitional cell carcinoma (TCC) and breast cancer (BC) patients. Overall, data prove that mLDNs and mNDNs from GDs represent excellent cellular models suitable either to define the molecular features, or to identify specific markers, that can be shared by mPMN-MDSC populations from different origin

Pre-Therapeutic VEGF Level in Plasma Is a Prognostic Bio-Marker in Head and Neck Squamous Cell Carcinoma (HNSCC)

Vascular endothelial growth factor (VEGF) is centrally involved in cancer angiogenesis. We hypothesized that pre-therapeutic VEGF levels in serum and plasma differ in their potential as biomarkers for outcomes in head and neck squamous cell carcinoma (HNSCC) patients. As prospectively defined in the study protocols of TRANSCAN-DietINT and NICEI-CIH, we measured VEGF in pretreatment serum and plasma of 75 HNSCC test cohort (TC) patients. We analyzed the prognostic value of VEGF concentrations in serum (VEGFSerum) and plasma (VEGFPlasma) for event-free survival (EFS) utilizing receiver-operating characteristics (ROC). Mean VEGF concentrations in plasma (34.6, 95% CI 26.0–43.3 ng/L) were significantly lower (p = 3.35 × 10−18) than in serum (214.8, 95% CI 179.6–250.0 ng/L) but, based on ROC (area under the curve, AUCPlasma = 0.707, 95% CI 0.573–0.840; p = 0.006 versus AUCSerum = 0.665, 95% CI 0.528–0.801; p = 0.030), superiorly correlated with event-free survival (EFS) of TC patients. Youden indices revealed optimum binary classification with VEGFPlasma 26 ng/L and VEGFSerum 264 ng/L. Kaplan–Meier plots demonstrated superiority of VEGFPlasma in discriminating patients regarding outcome. Patients with VEGFPlasma &lt; 26 ng/L had superior nodal (NC), local (LC) and loco-regional control (LRC) leading to significant prolonged progression-free survival (PFS) and EFS. We successfully validated VEGFPlasma according the cut-off &lt;26 ng/L as predictive for superior outcome in an independent validation cohort (iVC) of 104 HNSCC patients from the studies DeLOS-II and LIFE and found better outcomes including prolonged tumor-specific (TSS) and overall survival (OS). Outcomes in TC and iVC combined again was related to VEGFPlasma, and multivariate Cox regression revealed that VEGFPlasma was an independent outcome predictor. In HNSCC, pre-therapeutic VEGFPlasma is prognostic for outcomes