Molecular dynamics simulation on the low sensitivity of mutants of NEDD-8 activating enzyme for MLN4924 inhibitor as a cancer drug

MLN4924 is an experimental cancer drug known as inhibitor of NEDD8-activating enzyme (NAE). This anti-tumor candidate is a selective small-molecule inhibitor of NAE which is conjugated to cullin protein on Cullin-RING ligases (CRLs). This covalent modification actives cullin complex to recruit an ubiquitin-charged E2 and leads to downstream target protein polyubiquitination and proteasomal degradation. MLN4924, which can form a covalent adduct with NEDD8, and block NAE at the first step in this pathway, has shown anti-tumor activity in many kinds of cancer cell lines and also xenograft models, including lung cancer, colon cancer, melanoma and lymphoma. The anti-tumor activity of MLN4924 results from inactivation of CLRs, which causes DNA re-replication and inhibition of nuclear factor (NF)-κB signaling, thus leading to cancer cell death. A mutation can reduce the enzyme’s sensitivity to MLN4924. Verma et al. in 2013 studied on molecular dynamics simulation of a mutant A171T and consequently found out that this mutation reduce MLN4924 interaction with DNA Binding site of enzyme as a result of reduction of enzyme affinity to ATP. One year later, in 2014, Wei Xu et al. carried out a research on inhibitor resistant cell lines and revealed that a couple of mutations so called Y352H and I310N leads to enzyme resistance to MLN4924 inhibitor, interestingly, the cause reported was the increase of enzyme affinity to ATP. As in Wei Xu et al. experiment the molecular dynamics simulation was not considered, present study is conducted to identify enzyme mutation mechanism by molecular dynamics approach using advantages of Gromacs software version 4.5.6.     

Human Linguatulosis Caused by Linguatula serrata in the City of Kerman,South-eastern Iran- Case Report

Human linguatulosis poses an important medical and veterinary concern in endemic countries. Animals, as reservoir host, play a major role in transmission of infestation and epidemiology of the disease. This study reports a case of human linguatulosis caused by Linguatula serrata in the city of Kerman, South-eastern Iran. A woman suffering from upper respiratory symptoms is presented. The patient consumed raw liver of sheep who was admitted to the Afzalipour University Hospital in Kerman for the symptoms of upper respiratory tract. In microscopic examination of the nasopharyngeal discharge, L. serrata was detected. This report has future medical implication in precise diagnosis of L. serrata in patients with complaints of nasopharyngeal symptoms.     

Soy,Soy Isoflavones,and Protein Intake in Relation to Mortality from All Causes,Cancers, and Cardiovascular Diseases: A Systematic Review and Dose–Response Meta-Analysis of Prospective Cohort Studies

ObjectiveWe conducted a systematic review and dose–response meta-analysis of prospective studies to summarize findings on the associations between intakes of soy, soy isoflavones, and soy protein and risk of mortality from all causes, cancers, and cardiovascular diseases.MethodsOnline databases were systematically searched to identify relevant articles published earlier than May 2018. We applied restricted cubic splines using random-effects analysis to assess dose–response associations. Between-study heterogeneity was assessed by I² value and Cochrane Q test. Potential publication bias was assessed by visual inspection of funnel plots and Begg regression test.ResultsIn total, 23 prospective studies with an overall sample size of 330,826 participants were included in the current systematic review and the meta-analysis. Soy/soy products consumption was inversely associated with deaths from cancers (pooled relative risk 0.88, 95% CI 0.79 to 0.99; P=0.03; I²=47.1%, 95% CI 0.0% to 75.4%) and cardiovascular diseases (pooled effect size: 0.85, 95% CI 0.72 to 0.99; P=0.04; I²=50.0%, 95% CI 0.0% to 77.6%). Such significant associations were also observed for all-cause mortality in some subgroups of the included studies, particularly those with higher quality. In addition, higher intake of soy was associated with decreased risk of mortality from gastric, colorectal, and lung cancers as well as ischemic cardiovascular diseases. Participants in the highest category of dietary soy isoflavones intake had a 10% lower risk of all-cause mortality compared with those in the lowest category. We also found that a 10-mg/day increase in intake of soy isoflavones was associated with 7% and 9% decreased risk of mortality from all cancers and also breast cancer respectively. Furthermore, a 12% reduction in breast cancer death was indicated for each 5-g/day increase in consumption of soy protein. However, intake of soy protein was not significantly associated with all-cause and cardiovascular diseases mortality.ConclusionsSoy and its isoflavones may favorably influence risk of mortality. In addition, soy protein intake was associated with a decreased risk in the mortality of breast cancer. Our findings may support the current recommendations to increase intake of soy for greater longevity.     

Severe Hypoglycemia Due to Cryptic Insulin Use in a Bodybuilder

Background

Bodybuilding is a demanding sport, which requires high-volume, high-resistance weight training and augmented nutritional intake, toward an increase of overall body muscle mass accompanied by an overall decrease of body fat percentage and mass. Among bodybuilders, the use of various legal and illegal supplements is common. These supplements may be naturally occurring or man-made.

Comprehensive genomic profiling of metastatic collecting duct carcinoma,renal medullary carcinoma,and clear cell renal cell carcinoma

Introduction and ObjectiveUnlike clear cell renal cell carcinoma (CCRCC), collecting duct carcinoma (CDC) and renal medullary carcinoma (RMC) are rare tumors that progress rapidly and appear resistant to current systemic therapies. We queried comprehensive genomic profiling to uncover opportunities for targeted therapy and immunotherapy.Material and MethodsDNA was extracted from 40 microns of formalin-fixed, paraffin-embedded specimen from relapsed, mCDC (n = 46), mRMC (n = 24), and refractory and metastatic (m) mCCRCC (n = 626). Comprehensive genomic profiling was performed, and Tumor mutational burden (TMB) and microsatellite instability (MSI) were calculated. We analyzed all classes of genomic alterations.ResultsmCDC had 1.7 versus 2.7 genomic alterations/tumor in mCCRCC ( = 0.04). Mutations in VHL (P < 0.0001) and TSC1 (P = 0.04) were more frequent in mCCRCC. SMARCB1 (P < 0.0001), NF2 (P = 0.0007), RB1 (P = 0.02) and RET (P = 0.0003) alterations were more frequent in mCDC versus mCCRCC. No VHL alterations in mRMC and mCDC were identified. SMARCB1 genomic alterations were significantly more frequent in mRMC than mCDC (P = 0.0002), but were the most common alterations in both subtypes. Mutations to EGFR, RET, NF2, and TSC2 were more frequently identified in mCDC versus mRMC. The median TMB and MSI-High status was low with <1% of mCCRC, mCDC, and mRMC having ≥ 20 mut/Mb.ConclusionGenomic alteration patterns in mCDC and mRMC differ significantly from mCCRCC. Targeted therapies for mCDC and mRMC appear limited with rare opportunities to target alterations in receptor tyrosine kinase and MTOR pathways. Similarly, TMB and absence of MSI-High status in mCDC and mRMC suggest resistance to immunotherapies.