“
“The overexpression of Hdm2 and HdmX is a common mechanism used by many tumor cells to inactive the p53 tumor suppressor pathway promoting cell survival. Targeting Hdm2 and HdmX has emerged BKM120 molecular weight as a validated therapeutic strategy for treating cancers with wild-type p53. Small linear peptides mimicking the N-terminal fragment of p53 have been shown to be potent Hdm2/HdmX antagonists. The potential therapeutic use of these peptides, however, is limited by their poor stability and bioavailability. Here, we report the engineering of the cyclotide MCoTI-I to efficiently antagonize intracellular

p53 degradation. The resulting cyclotide MCo-PMI was able to bind with low nanomolar affinity to both Hdm2 and HdmX, showed high stability in human serum, and was cytotoxic to wild-type p53 cancer cell lines by activating the p53 tumor suppressor G418 in vitro pathway both in vitro and in vivo. These features make the cyclotide MCoTI-I an optimal scaffold for targeting intracellular protein-protein interactions.”
“Background:

Alcoholic hepatitis is the most florid presentation of alcohol-related liver disease. In its severe form, defined by a Maddrey’s discriminant function (DF) >= 32, the 28-day mortality rate is approximately 35%. A number of potential treatments have been subjected to clinical trials, of which two, corticosteroids and pentoxifylline, may have therapeutic benefit. The role of corticosteroids is controversial as trial results have been inconsistent, whereas the role of pentoxifylline requires confirmation as only one previous placebo-controlled trial has been published. Methods/design: STOPAH is a multicentre, double-blind, factorial (2 x 2) trial in which patients are randomised to one of four groups:\n\n1. Group A: placebo / placebo\n\n2. Group B: placebo / prednisolone\n\n3. Group C: pentoxifylline / placebo\n\n4. Group D: pentoxifylline / prednisolone\n\nThe trial aims to randomise 1,200 patients with severe alcoholic hepatitis, in order to provide sufficient power to determine whether

either of the two interventions is effective. The primary endpoint of the study is mortality at 28 days, with secondary SB525334 mouse endpoints being mortality at 90 days and 1 year. Discussion: STOPAH aims to be a definitive study to resolve controversy around the existing treatments for alcoholic hepatitis. Eligibility criteria are based on clinical parameters rather than liver biopsy, which are aligned with standard clinical practice in most hospitals. The use of a factorial design will allow two treatments to be evaluated in parallel, with efficient use of patient numbers to achieve high statistical power.”
“Background: The contrast between the low proportion of tuberculosis (TB) suspects referred from private practitioners in Bali province and the high volume of TB suspects seeking care at private practices suggests problems with TB suspect referral from private practitioners to the public health sector.