GPCRs and cancer

G-protein-coupled receptors (GPCRs), which represent the largest gene family in the human genome, play a crucial role in multiple physiological functions as well as in tumor growth and metastasis. For instance, various molecules like hormones, lipids, peptides and neurotransmitters exert their biological effects by binding to these seven-transmembrane receptors coupled to heterotrimeric G-proteins, which are highly specialized transducers able to modulate diverse signaling pathways. Furthermore, numerous responses mediated by GPCRs are not dependent on a single biochemical route, but result from the integration of an intricate network of transduction cascades involved in many physiological activities and tumor development. This review highlights the emerging information on the various responses mediated by a selected choice of GPCRs and the molecular mechanisms by which these receptors exert a primary action in cancer progression. These findings provide a broad overview on the biological activity elicited by GPCRs in tumor cells and contribute to the identification of novel pharmacological approaches for cancer patients.     

The Potential Role of Intragastric Balloon in the Treatment of Obese-Related Infertility: Personal Experience

The prevalence of people who are overweight or obese has increased dramatically in high-income countries over the past 20 years. There is a strong association between obesity and infertility, and weight loss can result in increased fecundity in obese women. The aim of this study is to demonstrate the potential role of intragastric balloon in the treatment of obese-related infertility. This is a retrospective study. A chart review of 27 obese women seen between September 2003 and July 2008 was performed. They all presented with the diagnosis of infertility and had undergone endoscopic intragastric balloon positioning. Among these women who tried unsuccessfully to become pregnant before weight loss, 15 became pregnant afterward. The pregnancies proceeded without complications and ended with live births. An improvement in the fertility status after weight loss has been described, although data on fertility after weight loss following bariatric surgery are still limited. The results obtained in our experience are not different from data reported in literature for bariatric surgery. Therefore, balloon treatment might be effective in young infertile obese women who wish to become pregnant.     

Different effect of statins on platelet oxidized-LDL receptor (CD36 and LOX-1) expression in hypercholesterolemic subjects.

Hydroxymethyl-glutaryl-CoA-reductase inhibitors (statins) reduce cardiovascular mortality by decreasing cholesterol as well as by non-lipid-related actions. Oxidized low-density lipoproteins (ox-LDL) are pro-atherogenic molecules and potent platelet agonists. CD36 and lectin-like ox-LDL receptor-1 (LOX-1) are specific ox-LDL receptors also expressed in platelets. This study was planned to address whether treatment with atorvastatin 10 mg/day, pravastatin 40 mg/day or simvastatin 20 mg/day could affect platelet CD36 and LOX-1 expression. Twenty-four patients for each treatment were evaluated after 3, 6, and 9 days and at 6 weeks for complete lipid profile (chromogenic), ox-LDL (ELISA), platelet P-selectin (P-sel), CD36, LOX-1 (FACS), and intracellular citrullin recovery (iCit) (HPLC). Data show hyperactivated platelets (P-sel absolute values, percent variation in activated cells, all p < 0.001), and CD36 and LOX-1 overexpression (all p < 0.001) in patients at baseline. P-sel, CD36, and LOX-1 were significantly decreased by atorvastatin and simvastatin (all p < 0.01) and related with iCit increase (r = 0.58, p < 0.001) and platelet-associated ox-LDL (r = 0.51, p < 0.01) at 9 days. Pravastatin reduced LOX-1 and P-sel (p < 0.05) at 6 weeks in relation with decreased LDL and ox-LDL (r = 0.39, p < 0.01 and r = 0.37, p < 0.01, respectively). These data suggest that atorvastatin and simvastatin reduce platelet activity by exposure of CD36 and LOX-1 before significant LDL reduction, whereas pravastatin action is detected later and in relation with LDL and ox-LDL lowering. Rapid and consistent reduction of CD36 and LOX-1 could be considered a direct anti-atherothrombotic mechanism related to the role of ox-LDL in platelet activation, platelet-endothelium interactions, and NO synthase activity.     

Comorbidities Do not Influence Primary Fistula Success in Incident Hemodialysis Patients: A Prospective Study

Background and objectives: Concern about primary fistula failure may contribute to the underuse of arteriovenous fistula. The objective of this study was to investigate the baseline clinical parameters associated with primary fistula success.Design, setting, participants, & measurements: Consecutive incident patients who commenced dialysis during a 28-mo period in a regional renal program were studied. Data on patient-related variables and on surgical approach (e.g., whether the surgeons routinely assess vessel size during the operation) were collected. Primary fistula success was defined as an arteriovenous fistula that was able to afford successful dialysis for 3 h with blood pump speed of ≥300 ml/min for three consecutive sessions.Results: A total of 205 (69%) patients had an AVF attempted as their first vascular access. The overall primary success rate was 64% and was similar for radiocephalic and brachiocephalic fistula. Logistic regression was done separately for patients with the two types of fistula because of the presence of statistical interaction. For radiocephalic fistula, male gender was the only parameter associated with primary fistula success (odds ratio 3.57; P = 0.01). The presence of comorbidity was not significantly associated with primary fistula failure.Conclusions: Despite significant patient comorbidity, there was a high primary fistula success rate among this incident hemodialysis cohort. Given that vessel size may be the ultimate determinant of fistula success, if surgeons assess vessel size perioperatively, then the presence of significant comorbidity might not preclude arteriovenous fistula from being attempted as the initial access.Given the well-documented advantages of arteriovenous fistula (AVF) over arteriovenous graft and central venous catheter (CVC), the current Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines suggest that AVF should be attempted as the initial vascular access in at least 50% of incident patients and that at least 40% of prevalent hemodialysis (HD) patients should undergo dialysis with an AVF (1–5). Despite these recommendations, it is clear that AVF are underused in many centers in North America, especially when compared with European centers (6,7). Recent data suggest that only 32% of prevalent US HD patients undergo dialysis with an AVF (8). In Canada, AVF are used by 53% of prevalent and only 26% of incident HD patients (7).One of the fears that may reduce the use of AVF is the high primary fistula failure rate (i.e., failure of AVF to mature) (9). Identifying risk factors that contribute to primary fistula failure may help clinicians and patients make an informed decision as to for whom to attempt an AVF. Only a few studies have prospectively examined the risk factors associated with primary fistula failure, which has been reported in 20 to 50% of patients (9–12).Most studies that have evaluated factors that are associated with primary fistula failure have typically used a retrospective design. For instance, Miller et al. (10) reported higher primary fistula failure rate in older and female patients with diabetes, although small numbers and a highly selected patient population limit the generalizability of these results. Feldman et al. (13) published data from a larger cohort (348 patients), reporting a primary success rate of 54%. Preexisting cerebrovascular disease, older age, and commencement of dialysis before access creation were noted to be associated with higher primary fistula failure in their study. Ravani et al. (11) noted that cardiovascular disease and late referral to nephrologists were associated with lower primary AVF success in patients from northern Italy.More recently, Lok et al. (14) studied a cohort of 422 HD patients who were undergoing their first AVF placement to identify preoperative clinical characteristics that are predictive of fistula failure to mature and to use this information to develop a prediction rule to estimate the risk for fistula failure to mature. This prediction rule was validated in an external data set from five North American centers. Age, peripheral vascular disease, coronary artery disease, and white race all were associated with fistula failure to mature in their study; however, in this and the previously mentioned studies, it is not clear whether there was any consistent surgical assessment performed perioperatively to guide fistula placement; as such, the results may not be applicable to programs that use pre- or intraoperative surgical assessment to guide fistula placement.Given these uncertainties, we sought to determine the association of various baseline clinical parameters with primary fistula success in a cohort that consisted of all incident dialysis patients between July 1, 1999, and November 1, 2001, in Calgary, Alberta, Canada, the majority of whom had an indirect assessment of vessel diameter intraoperatively to guide the location of fistula placement.