TRAIL-induced variation of cell signaling states provides nonheritable resistance to apoptosis.

TNFα-related apoptosis-inducing ligand (TRAIL), specifically initiates programmed cell death, but often fails to eradicate all cells, making it an ineffective therapy for cancer. This fractional killing is linked to cellular variation that bulk assays cannot capture. Here, we quantify the diversity in cellular signaling responses to TRAIL, linking it to apoptotic frequency across numerous cell systems with single-cell mass cytometry (CyTOF). Although all cells respond to TRAIL, a variable fraction persists without apoptotic progression. This cell-specific behavior is nonheritable where both the TRAIL-induced signaling responses and frequency of apoptotic resistance remain unaffected by prior exposure. The diversity of signaling states upon exposure is correlated to TRAIL resistance. Concomitantly, constricting the variation in signaling response with kinase inhibitors proportionally decreases TRAIL resistance. Simultaneously, TRAIL-induced de novo translation in resistant cells, when blocked by cycloheximide, abrogated all TRAIL resistance. This work highlights how cell signaling diversity, and subsequent translation response, relates to nonheritable fractional escape from TRAIL-induced apoptosis. This refined view of TRAIL resistance provides new avenues to study death ligands in general

Site-Specific Effects of PECAM-1 on Atherosclerosis in LDL Receptor-Deficient Mice

Objective—Atherosclerosis is a vascular disease that involves lesion formation at sites of disturbed flow under the influence of genetic and environmental factors. Endothelial expression of adhesion molecules that enable infiltration of immune cells is important for lesion development. Platelet/endothelial cell adhesion molecule-1 (PECAM-1; CD31) is an adhesion and signaling receptor expressed by many cells involved in atherosclerotic lesion development. PECAM-1 transduces signals required for proinflammatory adhesion molecule expression at atherosusceptible sites; thus, it is predicted to be proatherosclerotic. PECAM-1 also inhibits inflammatory responses, on which basis it is predicted to be atheroprotective. Methods and Results—We evaluated herein the effect of PECAM-1 deficiency on development of atherosclerosis in LDL receptor– deficient mice. We found that PECAM-1 has both proatherosclerotic and atheroprotective effects, but that the former dominate in the inner curvature of the aortic arch whereas the latter dominate in the aortic sinus, branching arteries, and descending aorta. Endothelial cell expression of PECAM-1 was sufficient for its atheroprotective effects in the aortic sinus but not in the descending aorta, where the atheroprotective effects of PECAM-1 also required its expression on bone marrow–derived cells. Conclusion—We conclude that PECAM-1 influences initiation and progression of atherosclerosis both positively and negatively, and that it does so in a site-specific manner. (Arterioscler Thromb Vasc Biol. 2008;28:1996-2002

Digoxin use after diagnosis of prostate cancer and survival: a population-based cohort study

PURPOSE:Preclinical studies have shown that digoxin exerts anticancer effects on different cancer cell lines including prostate cancer. A recent observational study has shown that digoxin use was associated with a 25% reduction in prostate cancer risk. The aim of this study was to investigate whether digoxin use after diagnosis of prostate cancer was associated with decreased prostate cancer-specific mortality.METHODS:A cohort of 13 134 patients with prostate cancer newly diagnosed from 1998 to 2009 was identified from English cancer registries and linked to the UK Clinical Practice Research Datalink (to provide digoxin and other prescription records) and to the Office of National Statistics mortality data (to identify 2010 prostate cancer-specific deaths). Using time-dependent Cox regression models, unadjusted and adjusted hazard ratios (HR) and 95% confidence intervals (CIs) were calculated for the association between post-diagnostic exposure to digoxin and prostate cancer-specific mortality.RESULTS:Overall, 701 (5%) patients with prostate cancer used digoxin after diagnosis. Digoxin use was associated with an increase in prostate cancer-specific mortality before adjustment (HR = 1.59; 95% CI 1.32-1.91), but after adjustment for confounders, the association was attenuated (adjusted HR = 1.13; 95% CI 0.93-1.37) and there was no evidence of a dose response.CONCLUSIONS:In this large population-based prostate cancer cohort, there was no evidence of a reduction in prostate cancer-specific mortality with digoxin use after diagnosis

Diffusion MR Characteristics Following Concurrent Radiochemotherapy Predicts Progression-Free and Overall Survival in Newly Diagnosed Glioblastoma.

The standard of care for newly diagnosed glioblastoma (GBM) is surgery, then radiotherapy (RT) with concurrent temozolomide (TMZ), followed by adjuvant TMZ. We hypothesized patients with low diffusivity measured using apparent diffusion coefficient (ADC) histogram analysis evaluated after RT+TMZ, prior to adjuvant TMZ, would have a significantly shorter progression-free (PFS) and overall survival (OS). To test this hypothesis we evaluated 120 patients with newly diagnosed GBM receiving RT+TMZ followed by adjuvant TMZ. MRI was performed after completion of RT+TMZ, prior to initiation of adjuvant TMZ. A double Gaussian mixed model was used to describe the ADC histograms within the enhancing tumor, where ADCL and ADCH were defined as the mean ADC value of the lower and higher Gaussian distribution, respectively. An ADCL value of 1.0 um2/ms and ADCH value of 1.6 um2/ms were used to stratify patients into high and low risk categories. Results suggest patients with low ADCL had significantly shorter PFS (Cox Hazard Ratio = 0.12, P = 0.0006). OS was significantly shorter with low ADCL tumors, showing a median OS of 407 vs. 644 days (Cox Hazard Ratio = 0.31, P = 0.047). ADCH was not predictive of PFS or OS when accounting for age and ADCL. In summary, newly diagnosed glioblastoma patients with low ADCL after completion of RT+TMZ are likely to progress and die earlier than patients with higher ADCL. Results suggest ADC histogram analysis may be useful for patient risk stratification following completion of RT+TMZ

Economic evaluation of prophylactic antiemetic regimens for prevention of chemotherapy -induced nausea and vomiting (CINV)

New antiemetic agents, aprepitant and palonosetron have been approved for prevention of chemotherapy-induced nausea and vomiting (CINV). The objectives of the two phases of the study were: (1) to conduct cost-effectiveness analysis of antiemetic regimens for prevention of CINV in patients receiving highly emetogenic chemotherapy (HEC) and in patients receiving moderately emetogenic chemotherapy (MEC) using decision models, and (2) to determine the monetary value of improved emesis control and conduct cost-benefit analysis of the new antiemetic regimens. Regimen A, one of the four antiemetic strategies included in the HEC decision model was a combination of aprepitant and the standard regimen of ondansetron+dexamethasone. The other three regimens had standard regimen in the acute phase but differed in the delayed phase regimens: regimen B - dexamethasone only, regimen C - dexamethasone+metoclopramide and regimen D - dexamethasone+ondansetron. The four antiemetic strategies for prevention of CINV due to MEC were: regimen (1) IV palonosetron, (2) IV ondansetron, (3) ondansetron+dexamethasone in acute phase, only dexamethasone in delayed phase, (4) ondansetron+dexamethasone in acute and delayed phase. The outcome measure was the incremental cost-effectiveness ratios (ICER) measured as cost/patient with complete control of emesis. For the HEC model, the ICER of regimen A compared to C was {dollar}3,363.18 and {dollar}2,881.61 per patient with complete control of emesis, from payer and societal perspectives respectively. One-way and probabilistic sensitivity analyses indicated that the conclusions were relatively stable to variations in multiple parameters. For MEC model, regimen 1 was found to be most cost-effective with ICER of {dollar}3,582.48 and {dollar}3,549.02, from payer and societal perspectives respectively. Overall, the ICER results showed that the regimen A and regimen 1 could be considered cost-effective therapies for prevention of CINV. In phase II, a contingent valuation survey was developed and administered to 120 cancer patients who were either receiving or had received chemotherapy. The results showed that respondents were willing-to-pay on average {dollar}83.50 for a single dose of palonosetron and {dollar}89.90 for a three-day regimen of aprepitant. Phase II qualitative results also emphasized that cancer patients receiving chemotherapy placed a high importance on receiving even a modest improvement in the control of CINV

Taking Healthy Steps: rationale, design and baseline characteristics of a randomized trial of a pedometer-based internet-mediated walking program in veterans with chronic obstructive pulmonary disease

Abstract Background Low levels of physical activity are common in patients with chronic obstructive pulmonary disease (COPD), and a sedentary lifestyle is associated with poor outcomes including increased mortality, frequent hospitalizations, and poor health-related quality of life. Internet-mediated physical activity interventions may increase physical activity and improve health outcomes in persons with COPD. Methods/Design This manuscript describes the design and rationale of a randomized controlled trial that tests the effectiveness of Taking Healthy Steps, an Internet-mediated walking program for Veterans with COPD. Taking Healthy Steps includes an uploading pedometer, a website, and an online community. Eligible and consented patients wear a pedometer to obtain one week of baseline data and then are randomized on a 2:1 ratio to Taking Healthy Steps or to a wait list control. The intervention arm receives iterative step-count feedback; individualized step-count goals, motivational and informational messages, and access to an online community. Wait list controls are notified that they are enrolled, but that their intervention will start in one year; however, they keep the pedometer and have access to a static webpage. Discussion Participants include 239 Veterans (mean age 66.7 years, 93.7% male) with 155 randomized to Taking Healthy Steps and 84 to the wait list control arm; rural-living (45.2%); ever-smokers (93.3%); and current smokers (25.1%). Baseline mean St. George’s Respiratory Questionnaire Total Score was 46.0; 30.5% reported severe dyspnea; and the average number of comorbid conditions was 4.9. Mean baseline daily step counts was 3497 (+/- 2220). Veterans with COPD can be recruited to participate in an online walking program. We successfully recruited a cohort of older Veterans with a significant level of disability including Veterans who live in rural areas using a remote national recruitment strategy. Trial registration Clinical Trials.gov NCT01102777http://deepblue.lib.umich.edu/bitstream/2027.42/109506/1/12890_2014_Article_479.pd

Torn Between the Real Me and the Social Me: Educated Women’s Perspectives of Surviving Marital Abuse

The perspectives of educated women on surviving abusive marital relationships have not been adequately explored, thus implying a gap in the literature regarding the role of education in enhancing or mitigating the prevalence of intimate partner violence (IPV). In this context, the question is how do educated women perceive surviving abusive relationships? Interpretative Phenomenological Analysis (IPA), using flexible semi-structured face-to-face interviews, was conducted to understand the experiences of eight highly educated women (master’s, Ph.D.) in abusive marriage. Four superordinate interrelated themes were developed: (a) developing an awareness of self-respect generating role confusion, (b) being torn between traditions and ambitions, (c) normalizing abuse as part of marriage, and (d) challenging abuse by self-promotion. Like other survivors of abuse, educated women tried to justify, blame themselves, work harder to please the perpetrator, and promote themselves; finally, they continued to live their lives by embracing abuse to bring peace and save their marriage. The effect of sociocultural context on educated women’s perspectives seems to play a crucial role in women’s decisions to stay in abusive relationships, despite the assumptions of empowerment and independence

Awareness of lifestyle modification in females diagnosed with polycystic ovarian syndrome in India: explorative study

Background: Polycystic ovarian syndrome (PCOS) adversely affect women at varying stages of their life and imperative to emphasis on prevention strategies since incidence of PCOS is on the rise. Study aims to explore perception on PCOS, awareness on life style modification, emotional attributes, concern regarding PCOS and utilization of physiotherapy services.Methods: The study was conducted in Mumbai and Navi Mumbai, India. Self-made validated questionnaire was administered. Descriptive analysis was done. Perception on PCOS, lifestyle modification, emotional attribution and biggest concern were calculated as absolute frequencies and were reported as overall percentages. Chi square test was applied on the demographic factor’s influence on level of awareness.Results: 21% of the respondents are very well aware about PCOS. 51% reported as doctor was their main source of information about PCOS. 81% expressed that PCOS is manageable one. 62% aware that exercise helps in the management of PCOS. Out of this, 39% are doing exercise on a regular basis. However all the study participants reported, they have not had any consultation from physiotherapist for their structured exercise program.32% attributed to anxiety after the diagnosis of PCOS. 64% of the respondents aware that changing in diet or eating habits can influence in PCOS. However 95% of the subjects concurred to follow life style modification.Conclusions: Efforts need to intensify in creating awareness on the general public about PCOS. Absolute majority of the study participant uncoerced to follow lifestyle modification however emphasis needs to address on multidisciplinary approach in managing PCOS

Nutrient Intakes among Jordanian Adolescents Based on Gender and Body Mass Index

Background: This study was conducted to examine the dietary intakes of macro- and micronutrients for a Jordanian adolescents based on gender and compare their intake to the Dietary Recommended Intakes (DRIs). Methods: A sample of 398 male and female adolescents, aged 14-18 years, were recruited from private and public schools using convenience sampling. Socio-demographic questionnaire and 3-days food record were self-reported. Bodyweight and height were measured and body mass index (BMI) was calculated for all participants. Results: There were no significant differences between male and female adolescents regarding the intake of micro and macronutrients except for protein, insoluble fibre, saturated fat, cholesterol, omega-6, vitamin E and calcium. The intake of insoluble fibre (g/day), omega-6(g/day), and vitamin E (mg/day) was significantly higher in female adolescents (3.1±0.1, 5.6±0.5, and 3.1±0.3, respectively, P≤0.05) compared to male adolescents (2.9±0.1, 5.1±0.4, and 2.5±0.2, respectively, P≤0.05). On the other hand, the intakes of protein (g/day), saturated fat (g/day), cholesterol (mg/day), calcium (mg/day) were significantly higher in male adolescents (90.1±2.3, 31.7±1.0, 339.2±18.3, and 651.5±27.8) as compared with female adolescents (79.2±2.1, 29.2±1.2, 263.6±14.9, and 555.2±21.7) (P≤ 0.05). Comparing of the adolescents’ nutrients intake to the DRIs, many nutrients were found to be below or above the recommendations. Conclusion: The study findings highlighted that there is an urgent need to establish a plan of action to combat malnutrition among adolescents in Jordan