alphaB-crystallin promotes tumor angiogenesis by increasing vascular survival during tube morphogenesis

Selective targeting of endothelial cells in tumor vessels requires delineation of key molecular events in formation and survival of blood vessels within the tumor microenvironment. To this end, proteins transiently up-regulated during vessel morphogenesis were screened for their potential as targets in antiangiogenic tumor therapy. The molecular chaperone alphaB-crystallin was identified as specifically induced with regard to expression level, modification by serine phosphorylation, and subcellular localization during tubular morphogenesis of endothelial cells. Small interfering RNA-mediated knockdown of alphaB-crystallin expression did not affect endothelial proliferation but led to attenuated tubular morphogenesis, early activation of proapoptotic caspase-3, and increased apoptosis. alphaB-crystallin was expressed in a subset of human tumor vessels but not in normal capillaries. Tumors grown in alphaB-crystallin(-/-) mice were significantly less vascularized than wild-type tumors and displayed increased areas of apoptosis/necrosis. Importantly, tumor vessels in alphaB-crystallin(-/-) mice were leaky and showed signs of caspase-3 activation and extensive apoptosis. Ultrastructural analyses showed defective vessels partially devoid of endothelial lining. These data strongly implicate alphaB-crystallin as an important regulator of tubular morphogenesis and survival of endothelial cell during tumor angiogenesis. Hereby we identify the small heat shock protein family as a novel class of angiogenic modulators.     

A novel stop mutation in the EDNRB gene in a family with Hirschsprung’s disease associated with Multiple Sclerosis

Purpose

We identified a girl with Hirschsprung’s disease (HSCR) whose mother and grandmother had HSCR associated with multiple sclerosis (MS). The aim of this study was to outline mutations in HSCR-related genes and MS susceptibility alleles in these three individuals.

Methods

The phenotypes were reviewed based on medical records. The three subjects had rectosigmoid HSCR verified with histopathology. The mother and grandmother fulfilled the McDonald criteria for MS. DNA was isolated from EDTA-preserved blood according to standard procedures. Exome sequencing aiming mainly at analyzing HSCR associated genes as well as Sanger sequencing for confirmation was performed.

Results

All affected individuals carry a novel heterozygous nonsense mutation in the EDNRB gene (c.C397T,p.R133X,refNM_000115), changing an arginine at position 133 into a premature stop codon. None of the subjects were homozygous for the HLA risk alleles for MS.

Conclusion

We report a novel non-sense EDNRB gene mutation in a girl with HSCR and her mother and grandmother with HSCR and MS. We propose that this EDNRB gene mutation plays a role in the etiology of HSCR and also makes the subjects susceptible to MS.     

Low-Risk Diet and Lifestyle Habits in the Primary Prevention of Myocardial Infarction in Men : A Population-Based Prospective Cohort Study

Background

Adherence to a combination of healthy dietary and lifestyle practices may have an impressive impact on the primary prevention of myocardial infarction (MI).

Objectives

The aim of this study was to examine the benefit of combined low-risk diet and healthy lifestyle practices on the incidence of MI in men.

Methods

The population-based, prospective cohort of Swedish men comprised 45- to 79-year-old men who completed a detailed questionnaire on diet and lifestyle at baseline in 1997. In total, 20,721 men with no history of cancer, cardiovascular disease, diabetes, hypertension, or high cholesterol levels were followed through 2009. Low-risk behavior included 5 factors: a healthy diet (top quintile of Recommended Food Score), moderate alcohol consumption (10 to 30 g/day), no smoking, being physically active (walking/bicycling ≥40 min/day and exercising ≥1 h/week), and having no abdominal adiposity (waist circumference <95 cm).

Results

During 11 years of follow-up, we ascertained 1,361 incident cases of MI. The low-risk dietary choice together with moderate alcohol consumption was associated with a relative risk of 0.65 (95% confidence interval [CI]: 0.48 to 0.87) compared with men having 0 of 5 low-risk factors. Men having all 5 low-risk factors compared with those with 0 low-risk factors had a relative risk of 0.14 (95% CI: 0.04 to 0.43). This combination of healthy behaviors, present in 1% of the men, could prevent 79% (95% CI: 34% to 93%) of the MI events on the basis of the study population.

Conclusions

Almost 4 of 5 MIs in men may be preventable with a combined low-risk behavior.     

Should plasma from female donors be avoided? A population‐based cohort study of plasma recipients in Sweden from 1990 through 2002

BACKGROUND: Plasma from female donors has been implicated in the sometimes fatal complication known as transfusion‐related acute lung injury. In studies of patients in intensive care units, worsened gas exchange of the lungs has also been attributed to female plasma. Despite a lack of population‐based evidence, policies have already been introduced to exclude female donor plasma. STUDY DESIGN AND METHODS: Short‐term mortality after plasma transfusion was investigated using data from the Scandinavian Donations and Transfusions (SCANDAT) database. A cohort of 92,565 patients in 30 Swedish hospitals were followed for 14 days after their first plasma transfusion. The relative risk (RR) of death in recipients of female plasma compared to recipients of only male plasma was estimated from Poisson regression. RESULTS: Recipients had median age 70 years, received a mean of 4.4 plasma units, and had an overall 14‐day mortality of 8.43%. Sixty‐eight percent were exposed to female plasma, with a 14‐day mortality of 8.85% compared to 7.53% in the nonexposed group. After adjustment for potential confounding factors, the RRs were 1.16 (confidence interval [CI], 1.06‐1.27) and 1.32 (CI, 1.17‐1.49) for those receiving 3 to 4 and 5 or more units of female plasma, respectively. Risk estimates were increased in an analysis of deaths with a concomitant discharge diagnosis involving the respiratory or circulatory system or an adverse reaction. CONCLUSIONS: This large population‐based cohort study of unselected patients suggests that transfusion of plasma from female donors confers a short‐term survival disadvantage on recipients.