Heparin-II domain of fibronectin is a vascular endothelial growth factor-binding domain: enhancement of VEGF biological activity by a singular growth factor/matrix protein synergism

We describe extracellular interactions between fibronectin (Fn) and vascular endothelial growth factor (VEGF) that influence integrin-growth factor receptor crosstalk and cellular responses. In previous work, we found that VEGF bound specifically to fibronectin (Fn) but not vitronectin or collagens. Herein we report that VEGF binds to the heparin-II domain of Fn and that the cell-binding and VEGF-binding domains of Fn, when physically linked, are necessary and sufficient to promote VEGF-induced endothelial cell proliferation, migration, and Erk activation. Using recombinant Fn domains, the C-terminal heparin-II domain of Fn (type III repeats 13 to 14) was identified as a key VEGF-binding site. Mutation of the heparin-binding residues on FnIII(13-14) abolished VEGF binding, and peptides corresponding to the heparin-binding sequences in FnIII(13-14) inhibited VEGF binding to Fn. Fn fragments containing both the alpha5beta1 integrin-binding domain (III 9 to 10) and the VEGF-binding domain (III 13 to 14) significantly enhanced VEGF-induced EC migration and proliferation and induced strong phosphorylation of the VEGF receptor and Erk. Neither the cell-binding or VEGF-binding fragment of Fn alone had comparable VEGF-promoting effects. These results suggest that the mechanism of VEGF/Fn synergism is mediated extracellularly by the formation of a novel VEGF/Fn complex requiring both the cell-binding and VEGF-binding domains linked in a single molecular unit. These data also highlight a new function for the Fn C-terminal heparin-binding domain that may have important implications for angiogenesis and tumor growth.     

Distinct gene expression profiles in ovarian cancer linked to Lynch syndrome

Ovarian cancer linked to Lynch syndrome represents a rare subset that typically presents at young age as early-stage tumors with an overrepresentation of endometrioid and clear cell histologies. We investigated the molecular profiles of Lynch syndrome-associated and sporadic ovarian cancer with the aim to identify key discriminators and central tumorigenic mechanisms in hereditary ovarian cancer. Global gene expression profiling using whole-genome c-DNA-mediated Annealing, Selection, extension, and Ligation was applied to 48 histopathologically matched Lynch syndrome-associated and sporadic ovarian cancers. Lynch syndrome-associated and sporadic ovarian cancers differed by 349 significantly deregulated genes, including PTPRH, BIRC3, SHH and TNFRSF6B. The genes involved were predominantly linked to cell growth, proliferation, and cell-to-cell signaling and interaction. When stratified for histologic subtype, hierarchical clustering confirmed distinct differences related to heredity in the endometrioid and serous subtypes. Furthermore, separate clustering was achieved in an independent, publically available data set. The distinct genetic signatures in Lynch syndrome-associated and sporadic ovarian cancers point to alternative preferred tumorigenic routes and suggest that genetic discriminators may be relevant for molecular diagnostics and targeted therapeutics.     

Arsenic trioxide in patients with refractory multiple myeloma: a prospective, phase II, single-arm study

Multiple myeloma (MM) characterized by proliferation of plasma cells in bone marrow and production of monoclonal immunoglobulin's. Recently, arsenic trioxide (ATO), has been considered for treatment refractory MM. We assessed the safety and efficacy of ATO for patients with refractory MM. A phase 2, study of arsenic trioxide was conducted in 12 MM patients, whose refractory to two standard therapy. Patients received arsenic trioxide, 0.25 mg/kg/d for 5 d/week during the first 2 consecutive weeks of each 4-week cycle with 2 week rest. Patients who completed one 4-week cycle were evaluated for response to treatment. Twelve patients with refractory multiple myeloma received ATO. Disease assessment was based the amount of serum proteins electrophoresis. Of the10 patients; stable disease was observed in four patients(33%), progression disease in five patients (41.6%), complete response in one patient (3.8%) and the remaining two patients could not be assessed for a response (because of increased liver enzymes after the first week). Some adverse events: increase liver enzymes and serum creatinine, neutropenia, pruritus, nausea, vomiting, lower extremities edema, noninfectious diarrhea was observed. These results indicate that ATO is active and well tolerated as a single-agent salvage therapy, even in patients with late-stage, refractory MM.     

Improving neuropathy scores in type 2 diabetic patients using micronutrients supplementation

Aim

The aim of the present study was to determine if micronutrients supplementation can improve neuropathy indices in type 2 diabetes.

Materials and methods

In this randomized, double-blind, placebo-controlled clinical trial, 75 type 2 diabetes patients were assigned to three treatment groups, receiving one of the following daily supplement for 4 months: Group MV: zinc (20 mg), magnesium (250 mg), vitamin C (200 mg) and E (100 mg); Group MVB: both of the above mineral and vitamin supplements plus vitamin B1 (10 mg), B2 (10 mg), B6 (10 mg), biotin (200 μg), B12 (10 μg) and folic acid (1 mg); Group P: placebo.

Results

67 patients completed the study. Neuropathic symptoms based on the MNSI questionnaire improved from 3.45 to 0.64 (p = 0.001) in group MVB, from 3.96 to 1.0 (p = 0.001) in group MV and from 2.54 to 1.95 in placebo group after 4 months. There was no significant difference between three treatment groups in MNSI examinations after 4 months supplementations. Over 4 months of treatment, patients showed no significant changes in glycemic control, capillary blood flow or electrophysiological measures in MV and MVB groups compared with placebo group.

Conclusions

These studies suggest that micronutrients supplementation might ameliorate diabetic neuropathy symptoms.     

Comparison of carpal tunnel release with three different techniques

Background

Carpal tunnel syndrome is one of the most common compression neuropathies in the upper limbs and requires surgery if conservative treatment fails. This article compares the result of regular open incision, mid-palmar mini incision and endoscopic technique in carpal tunnel release.

Methods

This is a clinical trial study on 105 patients (10 males, 95 females) within one year, who were surgical candidates. The surgery was done with regular open incision or with mid-palmar small incision. The clinical outcomes were evaluated one week, 4 weeks and 4 months post-surgery.

Results

Relief and satisfaction were better in the first month in the endoscopic and mid-palmar mini incision group. All 3 techniques had similar outcomes after 4 months. In the 4-month follow-up, night pain relief, followed by parasthesia relief had the best improvement. Weakness was the symptom with the least improvement. Longer incision cases were associated with more delay to return to work.

Conclusion

Carpal tunnel release with endoscopic and mini incision techniques have better early satisfaction rates compared to regular open incision, but no difference is seen between the two groups after four months.     

Sleep architecture and obstructive sleep apnea in obese children with and without metabolic syndrome: a case control study

Purpose

Obesity and biochemical parameters of metabolic disorders are both closely related to obstructive sleep apnea (OSA). The aim of this study was to compare sleep architecture and OSA in obese children with and without metabolic syndrome.

Methods

Forty-two children with metabolic syndrome were selected as case group and 38 children without metabolic syndrome were matched for age, sex, and BMI as control group. The standardized Persian version of bedtime problems, excessive daytime sleepiness, awakenings during the night, regularity and duration of sleep, snoring (BEARS) and Children’s Sleep Habits Questionnaires were completed, and polysomnography (PSG) was performed for all study subjects. Scoring was performed using the manual of American Academy of Sleep Medicine for children. Data were analyzed using chi-square test, T test, Mann–Whitney U test, and logistic regression analysis.

Results

Non-rapid eye movement (NREM) sleep and N1 stage in the case group were significantly longer than the control group, while REM sleep was significantly shorter. Waking after sleep onset (WASO) was significantly different between two groups. Severe OSA was more frequent in the control group. Multivariate logistic regression analysis showed that severe OSA (OR 21.478, 95 % CI 2.160–213.600; P = 0.009) and REM sleep (OR 0.856, 95 % CI 0.737–0.994; P = 0.041) had independent association with metabolic syndrome.

Conclusions

Obese children with metabolic syndrome had increased WASO, N1 sleep stage, and severe OSA. But the results regarding sleep architecture are most likely a direct result of OSA severity. More longitudinal studies are needed to confirm the association of metabolic syndrome and OSA.

     

Identification of disease-causing variants in the EXOSC gene family underlying autosomal recessive intellectual disability in Iranian families

Neurodevelopmental delay and intellectual disability (ID) can arise from numerous genetic defects. To date, variants in the EXOSC gene family have been associated with such disorders. Using next-generation sequencing (NGS), known and novel variants in this gene family causing autosomal recessive ID (ARID) have been identified in five Iranian families. By collecting clinical information on these families and comparing their phenotypes with previously reported patients, we further describe the clinical variability of ARID resulting from alterations in the EXOSC gene family, and emphasize the role of RNA processing dysregulation in ARID.     

The possible pathophysiology mechanism of cytokine storm in elderly adults with COVID-19 infection: the contribution of “inflame-aging”

Inflammation Research - Novel Coronavirus disease 2019 (COVID-19), is an acute respiratory distress syndrome (ARDS), which is emerged in Wuhan, and recently become worldwide pandemic. Strangely,...     

Prevalence of hepatitis B and hepatitis D coinfection in asymptomatic blood donors in Iran

Hepatitis delta virus (HDV) is a satellite virus that needs hepatitis B virus (HBV) surface antigen for amplification and transition. HDV appears in HBsAg carriers as acute coinfection and superinfection in patients with chronic hepatitis B. This coinfection leads to chronic hepatitis, cirrhosis, and liver carcinoma. The aim of this study was to detect the prevalence of coinfection and superinfection of HBVs and HDVs in blood donor individuals in Iran. Sera from 854 asymptomatic blood donors from the Bank of positive samples storage at the National Blood Transfusion Organization of Iran that were positive for hepatitis B surface antigen were analysed. The presence of antibody against HDV in blood donors was detected using ELISA followed by conventional PCR, seminested PCR and real‐time PCR to determine coinfection and/or superinfection. Restriction fragment length polymorphism was used for HDV genotyping. All 854 samples were HBsAg and anti‐HBc positive whereas only 18 (2%) of them were positive for anti‐HDV. Of the 854 samples, 154 (18%) were HBV‐DNA positive. HDV‐RNA was detected in 0.6% of the total samples by seminested PCR and real‐time PCR and the two PCR methods produced similar results. Moreover, 16.6% and 83.4% of anti‐HDV‐positive samples exhibited coinfection and superinfection with HBV, respectively. Genotype I of HDV was determined in positive samples.