Myc inhibition impairs autophagosome formation

Autophagy, a major clearance route for most long-lived proteins and organelles, has long been implicated in cancer development. Myc is a proto-oncogene often found to be deregulated in many cancers, and thus presents as an attractive target for design of cancer therapy. Therefore, understanding the relationship between anti-Myc strategies and autophagy will be important for development of effective therapy. Here we show that Myc depletion inhibits autophagosome formation and impairs clearance of autophagy substrates. Myc suppression has an inhibitory effect on autophagy via reduction of JNK1 and Bcl2 phosphorylation. Additionally, the decrease in JNK1 phosphorylation observed with Myc knockdown is associated with a reduction in ROS production. Our data suggest that targeting Myc in cancer therapy might have the additional benefit of inhibiting autophagy in the case of therapy resistance associated with chemotherapy-induced autophagy

Development of the International Severe Asthma Registry (ISAR) : A Modified Delphi Study

This study is cofunded by Optimum Patient Care Global and AstraZeneca.Peer reviewedPostprin

The Cholecystectomy As A Day Case (CAAD) Score: A Validated Score of Preoperative Predictors of Successful Day-Case Cholecystectomy Using the CholeS Data Set

Background Day-case surgery is associated with significant patient and cost benefits. However, only 43% of cholecystectomy patients are discharged home the same day. One hypothesis is day-case cholecystectomy rates, defined as patients discharged the same day as their operation, may be improved by better assessment of patients using standard preoperative variables. Methods Data were extracted from a prospectively collected data set of cholecystectomy patients from 166 UK and Irish hospitals (CholeS). Cholecystectomies performed as elective procedures were divided into main (75%) and validation (25%) data sets. Preoperative predictors were identified, and a risk score of failed day case was devised using multivariate logistic regression. Receiver operating curve analysis was used to validate the score in the validation data set. Results Of the 7426 elective cholecystectomies performed, 49% of these were discharged home the same day. Same-day discharge following cholecystectomy was less likely with older patients (OR 0.18, 95% CI 0.15–0.23), higher ASA scores (OR 0.19, 95% CI 0.15–0.23), complicated cholelithiasis (OR 0.38, 95% CI 0.31 to 0.48), male gender (OR 0.66, 95% CI 0.58–0.74), previous acute gallstone-related admissions (OR 0.54, 95% CI 0.48–0.60) and preoperative endoscopic intervention (OR 0.40, 95% CI 0.34–0.47). The CAAD score was developed using these variables. When applied to the validation subgroup, a CAAD score of ≤5 was associated with 80.8% successful day-case cholecystectomy compared with 19.2% associated with a CAAD score >5 (p < 0.001). Conclusions The CAAD score which utilises data readily available from clinic letters and electronic sources can predict same-day discharges following cholecystectomy

Pregnancy and susceptibility to parasites

This chapter discusses pregnancy and susceptibility to parasites

The role of mast cells and their mediators in reproduction, pregnancy and labour

BACKGROUND: Mast cells (MCs) are the classical mediators of allergy, however, their importance in the development of innate and adaptive immune responses is increasingly being recognized. Herein, the present MC literature is summarized, with particular focus on studies of MCs in the endometrium and myometrium, and their involvement in fertility, implantation, pregnancy and labour. METHODS: Recent developments in MC biology were identified by systematic searches of PubMed, Medline and Google Scholar from 2000 to November 2009. To specifically examine the role of MCs in fertility and pregnancy, we then performed a systematic review of English literature cited in the PubMed, Medline and Google Scholar databases, but extended the search period, from 1980 to January 2010 RESULTS: MCs can respond to immunoglobulin E-independent innate immune stimuli and are present within the endometrium, with activation and release of mediators occurring prior to menstruation and in association with endometriosis. With respect to pregnancy, MCs are redundant during blastocyst implantation and although their mediators can induce myometrial contractility, there is no epidemiological link of preterm birth with allergy, suggesting a non-essential role or robust regulation. In males, MCs are present in the testes and are increased in oligo- and azoospermia, with MC mediators directly suppressing sperm motility in a potentially reversible manner. CONCLUSIONS: MCs are prevalent in the female and male reproductive tract. However, whether MCs are absolutely required for a successful pregnancy or are fundamental to reproductive pathology, and thereby a therapeutic target, remains to be determined

Mast cells reside in myometrium and cervix, but are dispensable in mice for successful pregnancy and labor

Parturition is associated with myometrial and cervical inflammation. The causes and consequences of this inflammatory response are not clear. Mast cells (MCs) are important inducers of allergic and non-allergic inflammation, and their secreted products can induce myometrial contractions. Thus, mast cell activation has been hypothesized to have a role in initiating labor and/or driving labor-associated inflammation. We report that small numbers of MCs expressing chymase and tryptase are present in the myometrium and cervix of pregnant women. Labor did not lead to any change in mast cell abundance in these tissues, but was associated with reduced expression of the mast-cell regulator FcɛR1A, indicative of a change in mast cell properties. This coincided with contraction-dependent myocyte production of interleukin-10 (IL-10), a known suppressor of FcɛR1A expression. MCs were also found in the uterine horn and cervical region of pregnant C57BL/6 mice, increasing in number in the cervix, but not the myometrium, with labor. As expected, these cells were absent from mast-cell-deficient Kit(W-sh) mice. Nonetheless, pregnant Kit(W-sh) mice showed no defects in the timing of labor induction or in the upregulation of leukocyte markers during labor. Thus, MCs are present in the uterus and cervix of humans and mice, and our mouse studies suggest that they do not have a vital role in the induction of labor, or in the promotion of labor-associated inflammation