Endoplasmic reticulum stress regulates tumor growth and anti-tumor immunity: a promising opportunity for cancer immunotherapy

Abstract

The endoplasmic reticulum (ER) stress is a cellular process that occurs as a consequence of several stress circumstances, such as the accumulation of unfolded proteins in the lumen of the ER or distinct insults that disturb the ER normal function. Different conditions in the tumor microenvironment (TME), including hypoxia, nutrient deprivation, and the elevated production of reactive oxygen and nitrogen species destabilize the loading and dispatching of the newly synthesized proteins, triggering ER stress in cancer cells and tumor-infiltrating leukocytes. In order to cope with TME-induced ER stress, tumor and stromal cells initiate an adaptive response process that aims to resolve ER stress and to restore cellular homeostasis, which is referred as the unfolded protein responses (UPR). Paradoxically, the UPR can also induce cell death under severe and/or permanent ER stress. The UPR is started through three mediators, the activation of the inositol-requiring enzyme-1α, the pancreatic ER kinase-like ER kinase, and the activating transcription factor 6. In this minireview, we will discuss the pro- and anti-tumorigenic role of the UPR in cancer cells. In addition, we will describe the effects of the TME-induced ER stress in the immunosuppressive activity of tumor-infiltrating myeloid cells. Also, we will review the results of emerging therapeutic interventions that target ER stress and the UPR mediators in cancer. We postulate that the inhibition of ER stress or the UPR-related elements could represent a significant approach to increase the efficacy of various forms of cancer immunotherapy.

http://ift.tt/2smss2p

Mdm2 is required for survival and growth of p53-deficient cancer cells

p53 deletion prevents the embryonic lethality of normal tissues lacking Mdm2, suggesting that cells can survive without Mdm2 if p53 is also absent. Here we report evidence challenging this view, with implications for therapeutically targeting Mdm2. Deletion of Mdm2 in T cell lymphomas or sarcomas lacking p53 induced apoptosis and G2 cell cycle arrest, prolonging survival of mice with these tumors. p53-/- fibroblasts showed similar results, indicating that the effects of Mdm2 loss extend to pre-malignant cells. Mdm2 deletion in p53-/- cells upregulated p53 transcriptional target genes that induce apoptosis and cell cycle arrest. Mdm2 deletion also increased levels of p73, a p53 family member. RNAi-mediated attenuation of p73 rescued the transcriptional and biological effects of Mdm2 loss, indicating that p73 mediates the consequences of Mdm2 deletion. Additionally, Mdm2 deletion differed from blocking Mdm2 interaction with p53 family members, as Nutlin-3 induced G1 arrest but did not activate apoptosis in p53-/- sarcoma cells. Our results indicate that, in contrast to current dogma, Mdm2 expression is required for cell survival even in the absence of p53. Moreover, our results suggest that p73 compensates for loss of p53 and that targeting Mdm2 in p53-deficient cancers has therapeutic potential.

http://ift.tt/2rjVjpK

Improved diagnosis and prognostication of patients with pleural malignant mesothelioma using biomarkers in pleural effusions and peripheral blood samples – a short report

Abstract

Purpose

There is a lack of robust and clinically utilizable markers for the diagnosis and prognostication of malignant pleural mesothelioma (MPM). This research was aimed at optimizing and exploring novel approaches to improve the diagnosis and prognostication of MPM in pleural effusions and peripheral blood samples.

Methods

CellSearch-based and flow cytometry-based assays using melanoma cell adhesion molecule (MCAM) to identify circulating tumor cells (CTCs) in pleural effusions and peripheral blood samples of MPM patients were optimized, validated, explored clinically and, in case of pleural effusions, compared with cytological analyses. Additionally, tumor-associated circulating endothelial cells (CECs) were measured in peripheral blood samples. The assays were performed on a MPM cohort encompassing patients with histology-confirmed MPM (n=27) and in a control cohort of patients with alternative diagnoses (n=22). Exploratory analyses on the prognostic value of all assays were also performed.

Results

The malignancy of MCAM-positive cells in pleural effusions from MPM patients was confirmed. The detection of MPM CTCs in pleural effusions by CellSearch showed a poor specificity. The detection of MPM CTCs in pleural effusions by flow cytometry showed a superior sensitivity (48%) to standard cytological analysis (15%) (p = 0.03). In peripheral blood, CTCs were detected in 26% of the MPN patients, whereas in 42% of the MPM patients tumor-associated CECs were detected above the upper limit of normal (ULN). In exploratory analyses the absence of CTCs in pleural effusions, and tumor-associated CECs in peripheral blood samples above the ULN, appeared to be associated with a worse overall survival.

Conclusion

MCAM-based flow cytometric analysis of pleural effusions is more sensitive than routine cytological analysis. Flow cytometric analysis of pleural effusions and tumor-associated CECs in peripheral blood may serve as a promising approach for the prognostication of MPM patients and, therefore, warrants further study.

http://ift.tt/2rjM0WT

Endoplasmic reticulum stress regulates tumor growth and anti-tumor immunity: a promising opportunity for cancer immunotherapy

Abstract

The endoplasmic reticulum (ER) stress is a cellular process that occurs as a consequence of several stress circumstances, such as the accumulation of unfolded proteins in the lumen of the ER or distinct insults that disturb the ER normal function. Different conditions in the tumor microenvironment (TME), including hypoxia, nutrient deprivation, and the elevated production of reactive oxygen and nitrogen species destabilize the loading and dispatching of the newly synthesized proteins, triggering ER stress in cancer cells and tumor-infiltrating leukocytes. In order to cope with TME-induced ER stress, tumor and stromal cells initiate an adaptive response process that aims to resolve ER stress and to restore cellular homeostasis, which is referred as the unfolded protein responses (UPR). Paradoxically, the UPR can also induce cell death under severe and/or permanent ER stress. The UPR is started through three mediators, the activation of the inositol-requiring enzyme-1α, the pancreatic ER kinase-like ER kinase, and the activating transcription factor 6. In this minireview, we will discuss the pro- and anti-tumorigenic role of the UPR in cancer cells. In addition, we will describe the effects of the TME-induced ER stress in the immunosuppressive activity of tumor-infiltrating myeloid cells. Also, we will review the results of emerging therapeutic interventions that target ER stress and the UPR mediators in cancer. We postulate that the inhibition of ER stress or the UPR-related elements could represent a significant approach to increase the efficacy of various forms of cancer immunotherapy.

http://ift.tt/2smss2p

Starry Aims to Overcome Knowledge Translation Inertia: The Standards for Reporting Implementation Studies (StaRI) Guidelines

Abstract

In 2007, Academic Emergency Medicine hosted a Consensus Conference on "Knowledge Translation in Emergency Medicine" with the objective of identifying high-yield research priorities for the concept of moving from evidence to action.¹ Patients often fail to receive care that aligns with quality indicators, and the Institute of Medicine has estimated that on average 17 years pass before just 14% of effective interventions reach the bedside.^2-4 Equally important is the concept that de-implementing wasteful, inefficient, or outdated clinical approaches frequently require more time and effort than is available, so the trajectory of bedside decision-making often yields to the status quo.⁵

This article is protected by copyright. All rights reserved.

http://ift.tt/2rN60T2

Motivation of Dutch high school students from various backgrounds for applying to study medicine: a qualitative study

Objective

To explore high school students' motivation for applying to study medicine and the factors that influence this. To find explanations for under-representation of minority students in medical education, descriptions of motivation of students with different background characteristics were compared.

Design

Qualitative phenomenological study using semistructured one-on-one interviews.

Setting

One predominantly white and one mixed high school in a large multicultural city in the Netherlands. The study was conducted in March–December 2015.

Participants

Twenty-four high school students, purposively sampled for demographic characteristics.

Methods

The analysis consisted of the coding of data using a template based on the motivation types (autonomous and controlled motivation) described by self-determination theory and open coding for factors that influence motivation.

Results

The main reasons for pursuing a medical career pertained to autonomous motivation (interest in science and helping people), but controlled motivation (eg, parental pressure, prestige) was also mentioned. Experiences with healthcare and patients positively influenced students' autonomous motivation and served as a reality check for students' expectations. Having to go through a selection process was an important demotivating factor, but did not prevent most students from applying. Having medical professionals in their network also sparked students' interest, while facilitating easier access to healthcare experiences.

Conclusions

The findings showed a complex interplay between healthcare experiences, growing up in a medical family, selection processes and motivation. Healthcare experiences, often one of the selection criteria, help students to form autonomous motivation for studying medicine. However, such experiences as well as support in the selection process seem unequally accessible to students. As a result, under-represented students' motivation decreases. Medical schools should be aware of this and could create opportunities to acquire healthcare experiences. High schools could incorporate internships as part of their study counselling programmes and offer tailor-made guidance to each individual student.

http://ift.tt/2rMVc7x

The effect of life course socioeconomic position on crystallised cognitive ability in two large UK cohort studies: a structured modelling approach

Objectives

This study systematically compared accumulation, sensitive period, critical period and social mobility models relating life course socioeconomic position (SEP) and adult crystallised cognitive ability, which has not been comprehensively investigated.

Design

Two prospective cohort studies.

Participants

Five thousand three hundred and sixty-two participants in the Medical Research Council National Survey of Health and Development (NSHD) Birth Cohort Study and 10 308 participants in the Whitehall II Occupational Cohort Study.

Measures

Childhood SEP was measured by father's occupational SEP, early adulthood SEP by educational qualifications and adult SEP by own occupational SEP. Each life course model was compared with a saturated model.

Results

Using multiple imputation to account for missing data, the sensitive period model, which contained childhood, early adulthood and adult SEP terms, with different coefficients, provided the best fit for both men and women in the NSHD and Whitehall II cohorts. Early adulthood SEP had the largest coefficient in NSHD women, whereas for NSHD men early adulthood and adult SEP had similar coefficients. In Whitehall II adult SEP had the largest effect size for both men and women.

Conclusions

Sensitive period with all three time periods was the most appropriate life course models for adult crystallised cognitive ability in both cohorts, including an effect of childhood SEP. It is important to directly compare the life course models to determine which is the most appropriate.

http://ift.tt/2smmT40