Unfolded protein response in cancer: the Physician's perspective

The unfolded protein response (UPR) is a cascade of intracellular stress signaling events in response to an accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum (ER). Cancer cells are often exposed to hypoxia, nutrient starvation, oxidative stress and other metabolic dysregulation that cause ER stress and activation of the UPR. Depending on the duration and degree of ER stress, the UPR can provide either survival signals by activating adaptive and antiapoptotic pathways, or death signals by inducing cell death programs. Sustained induction or repression of UPR pharmacologically may thus have beneficial and therapeutic effects against cancer. In this review, we discuss the basic mechanisms of UPR and highlight the importance of UPR in cancer biology. We also update the UPR-targeted cancer therapeutics currently in clinical trials

Platelet inhibition to target reperfusion injury trial: Rationale and study design

BACKGROUND: In ST-segment elevation myocardial infarction (STEMI) patients treated with primary percutaneous coronary intervention (PPCI), current oral P2Y12 platelet inhibitors do not provide maximal platelet inhibition at the time of reperfusion. Furthermore, administration of cangrelor prior to reperfusion has been shown in pre-clinical studies to reduce myocardial infarct (MI) size. Therefore, we hypothesize that cangrelor administered prior to reperfusion in STEMI patients will reduce the incidence of microvascular obstruction (MVO) and limit MI size in STEMI patients treated with PPCI. METHODS: The Platelet Inhibition to Target Reperfusion Injury (PITRI) trial, is a phase 2A, multi-center, double-blinded, randomized controlled trial, in which 210 STEMI patients will be randomized to receive either an intravenous (IV) bolus of cangrelor (30μg/kg) followed by a 120 minutes infusion (4 μg/kg/min) or matching saline placebo, initiated prior to reperfusion (NCT03102723). RESULTS: The study started in October 2017 and the anticipated end date would be July 2020. The primary end-point will be MI size quantified by cardiovascular magnetic resonance (CMR) on day 3 post-PPCI. Secondary endpoints will include markers of reperfusion, incidence of MVO, MI size and adverse left ventricular remodelling at 6 months, and major adverse cardiac and cerebrovascular events. SUMMARY: The aim of the PITRI trial is to assess whether cangrelor administered prior to reperfusion would reduce acute MI size and MVO, as assessed by CMR. This article is protected by copyright. All rights reserved

Determining informative priors for cognitive models

The development of cognitive models involves the creative scientific formalization of assumptions, based on theory, observation, and other relevant information. In the Bayesian approach to implementing, testing, and using cognitive models, assumptions can influence both the likelihood function of the model, usually corresponding to assumptions about psychological processes, and the prior distribution over model parameters, usually corresponding to assumptions about the psychological variables that influence those processes. The specification of the prior is unique to the Bayesian context, but often raises concerns that lead to the use of vague or non-informative priors in cognitive modeling. Sometimes the concerns stem from philosophical objections, but more often practical difficulties with how priors should be determined are the stumbling block. We survey several sources of information that can help to specify priors for cognitive models, discuss some of the methods by which this information can be formalized in a prior distribution, and identify a number of benefits of including informative priors in cognitive modeling. Our discussion is based on three illustrative cognitive models, involving memory retention, categorization, and decision making