Adipocyte-specific protein tyrosine phosphatase 1B deletion increases lipogenesis, adipocyte cell size and is a minor regulator of glucose homeostasis

Peer reviewedPublisher PD

Weight changes and lifestyle behaviors in women after breast cancer diagnosis: a cross-sectional study

Background: Weight gain rather than weight loss often occurs after breast cancer diagnosis despite breast cancer survivors frequently reported making healthful lifestyle changes. This study describes the prevalence and magnitude of changes in weight before and after breast cancer diagnosis and examines lifestyle behaviors of breast cancer survivors with stable weight, weight gain or weight loss. Methods. Respondents were 368 women with breast cancer characterized by stages I, II and III. All were recruited from hospitals or breast cancer support groups and had completed conventional treatment. Current weight and height were measured while weight at cancer diagnosis and 1 year before diagnosis were self-reported. Weight change was calculated as the difference between current weight and weight a year preceding breast cancer diagnosis. A 24-hour diet recall and Global Physical Activity Questionnaire assessed dietary intake and physical activity, respectively. Differences in lifestyle behaviors among weight change groups were examined using Analysis of Covariance (ANCOVA). Results: Mean weight change from a year preceding diagnosis to study entry was 2.73 kg (95% CI: 1.90-3.55). Most women (63.3%) experienced weight gain rather than weight loss (36.7%) with a higher percentage (47.8%) having at least 5% weight gain (47.8%) rather than weight loss (22%), respectively. Compared to other weight change groups, women in >10% weight gain group had the lowest fruit and vegetable servings (1.58 servings/day; 95% CI: 1.36-1.82) and highest servings of dairy products (0.41 servings/day; 95% CI: 0.30-0.52). Conclusions: Weight gain was evident in this sample of women after breast cancer diagnosis. Information on magnitude of weight change after breast cancer diagnosis and lifestyle behaviors of breast cancer survivors with varying degrees of weight change could facilitate the development and targeting of effective intervention strategies to achieve healthy weight and optimal health for better survival

Abundant Fas expression by gastrointestinal stromal tumours may serve as a therapeutic target for MegaFasL

Although the tyrosine kinase inhibitor imatinib has been shown to be an active agent in patients with gastrointestinal stromal tumours (GIST), complete remissions are almost never seen and most patients finally experience disease progression during their course of treatment. An alternative therapeutic option is to target death receptors such as Fas. We showed that a panel of imatinib-sensitive (GIST882) and imatinib-resistant (GIST48, GIST430 and GIST430K-) cell lines expressed Fas. MegaFasL, a recently developed hexameric form of soluble Fas ligand (FasL), appeared to be an active apoptosis-inducing agent in these cell lines. Moreover, MegaFasL potentiated the apoptotic effects of imatinib. Immunohistochemical evaluations, in 45 primary GISTs, underscored the relevance of the Fas pathway: Fas was expressed in all GISTs and was expressed strongly in 93%, whereas FasL was expressed at moderate and strong levels in 35 and 53% of GISTs, respectively. Fas and FasL expression were positively correlated in these primary GISTs, but there was no association between Fas or FasL expression and primary site, histological subtype, tumour size, mitotic index, risk classification, and KIT mutation status. The abundant immunohistochemical Fas and FasL expression were corroborated by western blot analysis. In conclusion, our data implicate Fas as a potential therapeutic target in GIST

Basal and ?-Adrenergic cardiomyocytes contractility dysfunction induced by dietary protein restriction is associated with downregulation of SERCA2a expression and disturbance of endoplasmic reticulum Ca2+ regulation in rats.

Background: The mechanisms responsible for the cardiac dysfunction associated with dietary protein restriction (PR) are poorly understood. Thus, this study was designed to evaluate the effects of PR on calcium kinetics, basal and ?-adrenergic contractility in murine ventricular cardiomyocytes. Methods: After breastfeeding male Fisher rats were distributed into a control group (CG, n = 20) and a protein-restricted group (PRG, n = 20), receiving isocaloric diets for 35 days containing 15% and 6% protein, respectively. Biometric and hemodynamic variables were measured. After euthanasia left ventricles (LV) were collected for histopathological evaluation, SERCA2a expression, cardiomyocytes contractility and Ca2+ sparks analysis. Results: PRG animals showed reduced general growth, increased heart rate and arterial pressure. These animals presented extracellular matrix expansion and disorganization, cardiomyocytes hypotrophy, reduced amplitudes of shortening and maximum velocity of contraction and relaxation at baseline and after ?-adrenergic stimulation. Reduced SERCA2a expression as well as higher frequency and lower amplitude of Ca2+ sparks were observed in PRG cardiomyocytes. Conclusion: The observations reveal that protein restriction induces marked myocardial morphofunctional damage. The pathological changes of cardiomyocyte mechanics suggest the potential involvement of the ?-adrenergic system, which is possibly associated with changes in SERCA2a expression and disturbances in Ca2+ intracellular kinetics

Involvement of bcl-2 and p21waf1 proteins in response of human breast cancer cell clones to Tomudex

Mechanisms of resistance to Tomudex include increased thymidylate synthase activity, as well as reduced intracellular drug uptake and polyglutamation. However, little is known about other mechanisms of resistance, such as a possible protection against Tomudex-induced apoptosis mediated by bcl-2. We transfected the MDA-MB-435 human breast cancer cell line, which is characterized by a mutated p53 gene, with cDNA of the bcl-2 gene and generated two clones (MDA-bcl4 and MDA-bcl7) characterized by bcl-2 expression twofold and fourfold that observed in the control cell clone (MDAneo). A concomitant overexpression of p21wafl was also detected in the MDA-bcl7 clone. The MDA-bcl4 clone was three times more resistant to a 24-h Tomudex exposure than the MDAneo clone, whereas the MDA-bcl7 clone was as sensitive to Tomudex as the control cell clone. A lower sensitivity of the MDA-bcl4 clone than MDAneo and MDA-bcl7 clones to 5-fluorouracil and gemcitabine was also observed. No significant difference was noted in the susceptibility of clones to fludarabine and methothrexate. Basal levels of thymidylate synthase activity were superimposable in the three clones. Tomudex induced a marked accumulation of cells in the S phase in all the clones. However, an apoptotic hypodiploid DNA peak and the characteristic nuclear morphology of apoptosis were observed only in the MDA-bcl7 clone after exposure to Tomudex. No difference in the treatment-induced modulation of proteins involved in cell cycle progression (cyclin A, cdk2, pRB, E2F-1) and apoptosis (bcl-2, bax) was observed in the three clones. The only exception was that the expression of p21wafl in the MDA-bcl4 clone was inducible at a Tomudex concentration much higher than that required to induce the protein in the other clones. Overall, the results indicate that bcl-2 and p21wafl proteins concur in determining the cellular profile of sensitivity/resistance to Tomudex. © 1999 Cancer Research Campaig

Comparative Analysis of the Subventricular Zone in Rat, Ferret and Macaque: Evidence for an Outer Subventricular Zone in Rodents

The mammalian cerebral cortex arises from precursor cells that reside in a proliferative region surrounding the lateral ventricles of the developing brain. Recent work has shown that precursor cells in the subventricular zone (SVZ) provide a major contribution to prenatal cortical neurogenesis, and that the SVZ is significantly thicker in gyrencephalic mammals such as primates than it is in lissencephalic mammals including rodents. Identifying characteristics that are shared by or that distinguish cortical precursor cells across mammalian species will shed light on factors that regulate cortical neurogenesis and may point toward mechanisms that underlie the evolutionary expansion of the neocortex in gyrencephalic mammals. We immunostained sections of the developing cerebral cortex from lissencephalic rats, and from gyrencephalic ferrets and macaques to compare the distribution of precursor cell types in each species. We also performed time-lapse imaging of precursor cells in the developing rat neocortex. We show that the distribution of Pax6+ and Tbr2+ precursor cells is similar in lissencephalic rat and gyrencephalic ferret, and different in the gyrencephalic cortex of macaque. We show that mitotic Pax6+ translocating radial glial cells (tRG) are present in the cerebral cortex of each species during and after neurogenesis, demonstrating that the function of Pax6+ tRG cells is not restricted to neurogenesis. Furthermore, we show that Olig2 expression distinguishes two distinct subtypes of Pax6+ tRG cells. Finally we present a novel method for discriminating the inner and outer SVZ across mammalian species and show that the key cytoarchitectural features and cell types that define the outer SVZ in developing primates are present in the developing rat neocortex. Our data demonstrate that the developing rat cerebral cortex possesses an outer subventricular zone during late stages of cortical neurogenesis and that the developing rodent cortex shares important features with that of primates

Weight change during chemotherapy changes the prognosis in non metastatic breast cancer for the worse

<p>Abstract</p> <p>Background</p> <p>Weight change during chemotherapy is reported to be associated with a worse prognosis in breast cancer patients, both with weight gain and weight loss. However, most studies were conducted prior to the common use of anthracycline-base chemotherapy and on North American populations with a mean BMI classified as overweight. Our study was aimed to evaluate the prognostic value of weight change during anthracycline-based chemotherapy on non metastatic breast cancer (European population) with a long term follow-up.</p> <p>Methods</p> <p>Patients included 111 women diagnosed with early stage breast cancer and locally advanced breast cancer who have been treated by anthracycline-based chemotherapy regimen between 1976 and 1989. The relative percent weight variation (WV) between baseline and postchemotherapy treatment was calculated and categorized into either weight change (WV > 5%) or stable (WV < 5%). The median follow-up was 20.4 years [19.4 - 27.6]. Cox proportional hazard models were used to evaluate any potential association of weight change and known prognostic factors with the time to recurrence and overall survival.</p> <p>Results</p> <p>Baseline BMI was 24.4 kg/m2 [17.1 - 40.5]. During chemotherapy treatment, 31% of patients presented a notable weight variation which was greater than 5% of their initial weight.</p> <p>In multivariate analyses, weight change (> 5%) was positively associated with an increased risk of both recurrence (RR 2.28; 95% CI: 1.29-4.03) and death (RR 2.11; 95% CI: 1.21-3.66).</p> <p>Conclusions</p> <p>Our results suggest that weight change during breast-cancer chemotherapy treatment may be related to poorer prognosis with higher reccurence and higher mortality in comparison to women who maintained their weight.</p

Relationship of imatinib-free plasma levels and target genotype with efficacy and tolerability

Imatinib has revolutionised the treatment of chronic myeloid leukaemia (CML) and gastrointestinal stromal tumours (GIST). Using a nonlinear mixed effects population model, individual estimates of pharmacokinetic parameters were derived and used to estimate imatinib exposure (area under the curve, AUC) in 58 patients. Plasma-free concentration was deduced from a model incorporating plasma levels of alpha1-acid glycoprotein. Associations between AUC (or clearance) and response or incidence of side effects were explored by logistic regression analysis. Influence of KIT genotype was also assessed in GIST patients. Both total (in GIST) and free drug exposure (in CML and GIST) correlated with the occurrence and number of side effects (e.g. odds ratio 2.7±0.6 for a two-fold free AUC increase in GIST; P<0.001). Higher free AUC also predicted a higher probability of therapeutic response in GIST (odds ratio 2.6±1.1; P=0.026) when taking into account tumour KIT genotype (strongest association in patients harbouring exon 9 mutation or wild-type KIT, known to decrease tumour sensitivity towards imatinib). In CML, no straightforward concentration–response relationships were obtained. Our findings represent additional arguments to further evaluate the usefulness of individualising imatinib prescription based on a therapeutic drug monitoring programme, possibly associated with target genotype profiling of patients