miR-620 promotes tumor radioresistance by targeting 15-hydroxyprostaglandin dehydrogenase (HPGD)

MicroRNA contribute to tumor radiation resistance, which is an important clinical problem, and thus we are interested in identifying and characterizing their function. We demonstrate that miR-620 contributes to radiation resistance in cancer cells by increasing proliferation, and decreasing the G2/M block. We identify the hydroxyprostaglandin dehydrogenase 15-(nicotinamide adenine dinucleotide) (HPGD/15-PGDH) tumor suppressor gene as a direct miR-620 target, which results in increased prostaglandin E2 (PGE2) levels. Furthermore, we show that siRNA targeting of HPGD or administration of exogenous PGE2 recapitulates radioresistance. Targeting of the EP2 receptor that responds to PGE2 using pharmacological or genetic approaches, abrogates radioresistance. Tumor xenograft experiments confirm that miR-620 increases proliferation and tumor radioresistance in vivo. Regulation of PGE2 levels via targeting of HPGD by miR-620 is an innovative manner by which a microRNA can induce radiation resistance.     

Expression of Phosphofructokinase in Skeletal Muscle Is Influenced by Genetic Variation and Associated With Insulin Sensitivity

Using an integrative approach in which genetic variation, gene expression, and clinical phenotypes are assessed in relevant tissues may help functionally characterize the contribution of genetics to disease susceptibility. We sought to identify genetic variation influencing skeletal muscle gene expression (expression quantitative trait loci [eQTLs]) as well as expression associated with measures of insulin sensitivity. We investigated associations of 3,799,401 genetic variants in expression of >7,000 genes from three cohorts (n = 104). We identified 287 genes with cis-acting eQTLs (false discovery rate [FDR] <5%; P < 1.96 × 10⁻⁵) and 49 expression–insulin sensitivity phenotype associations (i.e., fasting insulin, homeostasis model assessment–insulin resistance, and BMI) (FDR <5%; P = 1.34 × 10⁻⁴). One of these associations, fasting insulin/phosphofructokinase (PFKM), overlaps with an eQTL. Furthermore, the expression of PFKM, a rate-limiting enzyme in glycolysis, was nominally associated with glucose uptake in skeletal muscle (P = 0.026; n = 42) and overexpressed (Bonferroni-corrected P = 0.03) in skeletal muscle of patients with T2D (n = 102) compared with normoglycemic controls (n = 87). The PFKM eQTL (rs4547172; P = 7.69 × 10⁻⁶) was nominally associated with glucose uptake, glucose oxidation rate, intramuscular triglyceride content, and metabolic flexibility (P = 0.016–0.048; n = 178). We explored eQTL results using published data from genome-wide association studies (DIAGRAM and MAGIC), and a proxy for the PFKM eQTL (rs11168327; r² = 0.75) was nominally associated with T2D (DIAGRAM P = 2.7 × 10⁻³). Taken together, our analysis highlights PFKM as a potential regulator of skeletal muscle insulin sensitivity.     

Association of MMP‐1 ‐1607 1G/2G (rs1799750) polymorphism with primary knee osteoarthritis in the Greek population

Osteoarthritis is the most common form of arthritis with still unknown pathogenic etiology and considerable contribution of genetic factors. One of the mechanisms of cartilage degradation in osteoarthritis is enzymatic proteolysis of the extracellular matrix by metalloproteinases. MMP‐1, produced by chondrocytes and synovial cells, is a major proteinase of the MMPs family. The present study aims at evaluating the association of MMP1 gene ‐1607 1G/2G (rs1799750) polymorphism with primary knee osteoarthritis in the Greek population. One hundred fifty five patients with primary symptomatic knee osteoarthritis participated in the study along with 139 controls. Genotypes were determined using PCR—RLFP technique. Allelic and genotypic frequencies were compared between both study groups. There was no significant association between MMP1 ‐1607 1G/2G polymorphism and knee osteoarthritis, in crude analysis; however, after multiple logistic regression analysis, 1G/2G was associated with reduced odds of knee osteoarthritis by 75% in males, compared to genotypes 1G/1G + 2G/2G, adjusting for age and BMI (adjusted OR: 0.25, 95% CI: 0.069, 0.910, p = 0.035). The present study shows that MMP1 ‐1607 1G/2G (rs1799750) polymorphism might be a risk factor for knee osteoarthritis susceptibility in the Greek population. Further investigations are needed to confirm this association in the pathogenesis of osteoarthritis. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:1155–1160, 2014.

     

Secular trends in fitness,moderate-to-vigorous physical activity,and TV-viewing among first grade school children of Crete,Greece between 1992/93 and 2006/07

ObjectivesTo assess secular changes in physical fitness (PF), moderate-to-vigorous-physical activity (MVPA) and TV-viewing in 1st-grade children from Crete, Greece.DesignCross-sectional cohorts examined in academic years 1992/93 and 2006/07.MethodsTwo representative samples of children, aged 5.9–7.8 years, were studied during 1992/93 (N = 606) and 2006/07 (N = 361). PF (sit-and-reach, standing-broad-jump, sit-ups and 20 m-shuttle-run-test) was assessed by the European-PF test battery and MVPA by a physical activity (PA) questionnaire. Data on the frequency of TV-viewing was also collected.ResultsBetween 1992/93 and 2006/07, there was a significant increase in all fitness tests in both genders (P < 0.001) and in MVPA in boys (76.5 min/week vs. 38.7 min/week, P < 0.001). Time spent watching TV on weekdays was significantly more in both genders in 2006/07, compared to 1992/93 (P < 0.001). In 2006/07, active boys and active girls spent more time in MVPA than active boys and girls in 1992/93 (P < 0.001). Significantly higher proportions of boys and girls engaged in vigorous activities in 2006/07, than 1992/93 (P < 0.001 and P = 0.027, respectively).ConclusionsA significant increase in physical and cardiorespiratory fitness in both genders and MVPA in boys was observed in children from Crete between 1992/93 and 2006/07. The increase in weekday TV-viewing, despite being parallel to an increase in leisure-time MVPA, could have an unfavorable effect on health and should be tackled in future interventions in this population. Dietary, anthropometric and biochemical indices should also be investigated to assess their impact on the secular changes in physical fitness and activity observed in this sample of children.     

Human papillomavirus DNA load and p16INK4a expression predict for local control in patients with anal squamous cell carcinoma treated with chemoradiotherapy

As the detection rate of HPV‐DNA in anal carcinoma commonly exceeds 90%, a comparison between sole HPV‐positive and HPV‐negative cancers with respect to treatment response following chemoradiotherapy (CRT) and long‐term oncological outcome is challenging. Against this background, we aimed to assess HPV types and HPV DNA load in formalin‐fixed paraffin‐embedded tissue (FFPE) of 95 patients treated with standard CRT for anal cancer to correlate viral load (≤/> median) with local failure, distant metastases, cancer‐specific (CSS) and overall survival (OS) rates. Various clinicopathologic parameters and the immunohistochemical marker p16^INK4a were evaluated for any correlation with HPV16 DNA load and were included in uni‐ and multivariate analyses. The overall prevalence of HPV DNA was 95.8% with HPV16 monoinfection being the most commonly encountered HPV type (78.9%), followed by HPV16 and 31, 35, 39, 44, 58, 66 and 81 dual infection in 9 patients (9.5%). HPV16 DNA load was significantly associated with p16^INK4a expression (p = 0.001). Patients with HPV16 DNA load ≤ median and low p16^INK4a expression showed significantly worse local control (HPV16 DNA load: univariate p = 0.023, multivariate p = 0.042; p16^INK4a: univariate p = 0.021), and OS (HPV16 DNA load: univariate p = 0.02, multivariate p = 0.03). Moreover, a combined HPV16 DNA load and p16^INK4a variable revealed a significant correlation to decreased local failure, and increased CSS and OS (p = 0.019, p = 0.04 and p = 0.031). In conclusion, these data indicate that HPV16 DNA load and p16^INK4a expression are significant prognostic factors for local tumor control and overall survival of patients with anal SCC following CRT.     

Effects of terlipressin versus splenectomy on liver regeneration after partial hepatectomy in rats: What we know so far?

正To the editor:We read with great interest the article entitled "Comparative study of the effects of terlipressin versus splenectomy on liver regeneration after partial hepatectomy in rats" by Ulmer et al.[1].The aim of this study was to analyse the impact of terlipressin ver-     

Nasogastric aspiration/lavage in patients with gastrointestinal bleeding: a review of the evidence

Introduction: The usefulness of nasogastric aspiration and nasogastric lavage in patients with gastrointestinal bleeding is controversial, as evidenced by conflicting recommendations, both among and within society guidelines.

Areas covered: Considering these controversies, we reviewed the evidence regarding the following questions: 1) Can nasogastric lavage stop or slow down the bleeding and improve subsequent endoscopic visualization? 2) Is nasogastric aspiration helpful for the localization of bleeding? 3) Can nasogastric aspiration identify high risk patients that might benefit from earlier endoscopy? 4) Is there evidence for benefit in terms of outcomes from using nasogastric aspiration? 5) Is nasogastric intubation safe in patients with possible esophageal varices? Our review was conducted according to PRISMA guidelines.

Expert commentary: Based on the available literature, nasogastric lavage or aspiration cannot be routinely recommended unless a large properly designed randomized trial (which is currently lacking) proves otherwise. It is a painful and time-consuming procedure with no demonstrated benefit for the patient in terms of outcomes. Other clinical and laboratory parameters, and risk scores, are less invasive and are effective for guiding the stratification and management of patients, while pre-endoscopic erythromycin infusion is a good if not better alternative for improving visualization of the stomach.