The role of concurrent chemoradiotherapy in the treatment of locoregionally advanced nasopharyngeal carcinoma among endemic population: a meta-analysis of the phase iii randomized trials

<p>Abstract</p> <p>Background</p> <p>The main objective of this meta-analysis was to determine the clinical benefit of concurrent chemoradiotherapy (CCRT) compared with radiation alone (RT) in the treatment of nasopharyngeal carcinoma (NPC) patients in endemic geographic areas.</p> <p>Methods</p> <p>Using a prospective meta-analysis protocol, two independent investigators reviewed the publications and extracted the data. Published randomized controlled trials (RCTs) in which patients with NPC in endemic areas were randomly assigned to receive CCRT or RT alone were included.</p> <p>Results</p> <p>Seven trials (totally 1608 patients) were eligible. Risk ratios (RRs) of 0.63 (95% CI, 0.50 to 0.80), 0.76 (95% CI, 0.61 to 0.93) and 0.74 (95% CI, 0.62 to 0.89) were observed for 2, 3 and 5 years OS respectively in favor of the CCRT group. The RRs were larger than that detected in the previously reported meta-analyses (including both endemic and non-endemic), indicating that the relative benefit of survival was smaller than what considered before.</p> <p>Conclusions</p> <p>This is the first meta-analysis of CCRT vs. RT alone in NPC treatment which included studies only done in endemic area. The results confirmed that CCRT was more beneficial compared with RT alone. However, the relative benefit of CCRT in endemic population might be less than that from previous meta-analyses.</p

High dietary diversity is associated with obesity in Sri Lankan adults: An evaluation of three dietary scores.

Background: Dietary diversity is recognized as a key element of a high quality diet. However, diets that offer a greater variety of energy-dense foods could increase food intake and body weight. The aim of this study was to explore association of diet diversity with obesity in Sri Lankan adults. Methods: Six hundred adults aged > 18 years were randomly selected by using multi-stage stratified sample. Dietary intake assessment was undertaken by a 24 hour dietary recall. Three dietary scores, Dietary Diversity Score (DDS), Dietary Diversity Score with Portions (DDSP) and Food Variety Score (FVS) were calculated. Body mass index (BMI) ≥ 25 kg.m−2 is defined as obese and Asian waist circumference cut-offs were used diagnosed abdominal obesity. Results: Mean of DDS for men and women were 6.23 and 6.50 (p=0.06), while DDSP was 3.26 and 3.17 respectively (p=0.24). FVS values were significantly different between men and women 9.55 and 10.24 (p=0.002). Dietary diversity among Sri Lankan adults was significantly associated with gender, residency, ethnicity, education level but not with diabetes status. As dietary scores increased, the percentage consumption was increased in most of food groups except starches. Obese and abdominal obese adults had the highest DDS compared to non-obese groups (p<0.05). With increased dietary diversity the level of BMI, waist circumference and energy consumption was significantly increased in this population. Conclusion: Our data suggests that dietary diversity is positively associated with several socio-demographic characteristics and obesity among Sri Lankan adults. Although high dietary diversity is widely recommended, public health messages should emphasize to improve dietary diversity in selective food items

Linking soil microbial community structure to potential carbon mineralization: A continental scale assessment of reduced tillage

Potential carbon mineralization (Cmin) is a commonly used indicator of soil health, with greater Cmin values interpreted as healthier soil. While Cmin values are typically greater in agricultural soils managed with minimal physical disturbance, the mechanisms driving the increases remain poorly understood. This study assessed bacterial and archaeal community structure and potential microbial drivers of Cmin in soils maintained under various degrees of physical disturbance. Potential carbon mineralization, 16S rRNA sequences, and soil characterization data were collected as part of the North American Project to Evaluate Soil Health Measurements (NAPESHM). Results showed that type of cropping system, intensity of physical disturbance, and soil pH influenced microbial sensitivity to physical disturbance. Furthermore, 28% of amplicon sequence variants (ASVs), which were important in modeling Cmin, were enriched under soils managed with minimal physical disturbance. Sequences identified as enriched under minimal disturbance and important for modeling Cmin, were linked to organisms which could produce extracellular polymeric substances and contained metabolic strategies suited for tolerating environmental stressors. Understanding how physical disturbance shapes microbial communities across climates and inherent soil properties and drives changes in Cmin provides the context necessary to evaluate management impacts on standardized measures of soil microbial activity

Underlying image data for the corrected Fig 2D (correct DMSO panel from the original experiment).

Underlying image data for the corrected Fig 2D (correct DMSO panel from the original experiment).</p

Bispidine-Amino Acid Conjugates Act as a Novel Scaffold for the Design of Antivirals That Block Japanese Encephalitis Virus Replication

<div><h3>Background</h3><p>Japanese encephalitis virus (JEV) is a major cause of viral encephalitis in South and South-East Asia. Lack of antivirals and non-availability of affordable vaccines in these endemic areas are a major setback in combating JEV and other closely related viruses such as West Nile virus and dengue virus. Protein secondary structure mimetics are excellent candidates for inhibiting the protein-protein interactions and therefore serve as an attractive tool in drug development. We synthesized derivatives containing the backbone of naturally occurring lupin alkaloid, sparteine, which act as protein secondary structure mimetics and show that these compounds exhibit antiviral properties.</p> <h3>Methodology/Principal Findings</h3><p>In this study we have identified 3,7-diazabicyclo[3.3.1]nonane, commonly called bispidine, as a privileged scaffold to synthesize effective antiviral agents. We have synthesized derivatives of bispidine conjugated with amino acids and found that hydrophobic amino acid residues showed antiviral properties against JEV. We identified a tryptophan derivative, Bisp-W, which at 5 µM concentration inhibited JEV infection in neuroblastoma cells by more than 100-fold. Viral inhibition was at a stage post-entry and prior to viral protein translation possibly at viral RNA replication. We show that similar concentration of Bisp-W was capable of inhibiting viral infection of two other encephalitic viruses namely, West Nile virus and Chandipura virus.</p> <h3>Conclusions/Significance</h3><p>We have demonstrated that the amino-acid conjugates of 3,7-diazabicyclo[3.3.1]nonane can serve as a molecular scaffold for development of potent antivirals against encephalitic viruses. Our findings will provide a novel platform to develop effective inhibitors of JEV and perhaps other RNA viruses causing encephalitis.</p> </div

Bispidine and its derivatives.

<p>(A) Structural relationship of bispidine to natural product sparteine. (B) General structure of bispidine compounds (i) and (ii) represent the conformer equilibrium in diimides of bispidine (iii) Conjugates of bispidine wherein the nitrogen is part of the amino acids. (C) The genesis of design of bispidine. (D) Synthesis of bispidine conjugates i) N-hydroxysuccinimide/DCC/NEt₃/Boc-Leu-OH/dry dichloromethane; ii) N-hydroxysuccinimide/DCC/NEt₃/Z-Leu-OH/dry dichloromethane; iii) Br-CH₂-CO-Leu-Val-OMe; NEt₃, acetonitrile; iv) 25% TFA in dichloromethane.</p

Bispidine conjugates as secondary structure mimetics.

<p>(A) Secondary structure showing a β-sheet-like arrangement of BLB in the solid state involving a 10 membered H-bonded ring. (B) CD spectra of 500 µM of Bisp-LF, BLB in MeOH.</p

Synthesis of amino acid conjugates of bispidine.

<p>(A) Structure of bispidine conjugated with tryptophan (Bisp-W), lecine+phenylalanine (Bisp-LF) and lysine (Bisp-K). (B) Viral titers were determined by plaque assay of N2A cell culture supernatants (22 h pi) infected with JEV and treated with 5 µM of derivatives of bispidine. *** P = 0.0004 and 0.0004, ** P = 0.0034 and as determined by two-tailed, t-test. Error bars represent Mean ± SEM of three replicates. (C) Cytotoxicity was measured by lactate dehydrogenase (LDH) assay from culture supernatants treated with 5 µM of the indicated bispidine conjugates or DMSO. LDH released from cells incubated with detergent buffer was used as 100% LDH release. (D) IC₅₀ value for Bisp-W in the indicated cell lines was estimated by measuring viral titers in cell culture supernatants (22 h pi) infected with JEV and treated with the indicated concentration of Bisp-W. Error bars represent Mean ± SEM of three replicates. All the data are representative of experiments performed at least twice with three replicates.</p

Synthesis of Bisp-W derivatives and its effect on JEV.

<p>(A) Structure of Bisp-W derivatives with tryptophan on one arm of bispidine and benzyl on the other (Bisp-W-Benzyl) and with Boc group deprotected (Bisp-W-NH). (B) Viral titers were determined by plaque assay of N2A cell culture supernatants (22 h pi) infected with JEV and treated with 5 µM derivatives of Bisp-W as indicated. *** P = 0.0003 and 0.0004 and ns: not significant (P = 0.425) as determined by two-tailed, t-test. Error bars represent Mean ± SEM of three replicates. Data are representative of experiments performed twice with three replicates.</p

Effect of Bispidine derivatives on JEV infection.

<p>(A) Viral titers were determined by plaque assay of N2A cell culture supernatants (22 h pi) infected with JEV and treated with 100 µM of derivatives of bispidine. * P<0.01 determined by two-tailed, t-test. (B) Cytotoxicity was measured by lactate dehydrogenase (LDH) assay from culture supernatants treated with 100 µM of BLB or DMSO. LDH released from cells incubated with detergent buffer was used as 100% LDH release. (C) Viral titers were determined by plaque assay from Huh7 and C6/36 cell culture supernatants (22 h pi) infected with JEV and treated with 100 µM of BLB. *** P = 0.0002 and **P = 0.0041 determined by two-tailed, t-test. (D) N2A cells were infected as above and at 22 h pi cells were fixed and stained with anti-E antibodies followed by alexa 568-conjugated secondary antibodies. Nuclei were stained by DAPI. (E) Viral titers were determined by plaque assay of N2A cell culture supernatants (22 h pi) infected with JEV and treated with 100 µM of BLB at the indicated time points. UT- Untreated. All the data presented are representative of two or more experiments performed with two or more replicates. *** P = 0.0007, 0.0005 and **P = 0.007 as determined by two-tailed, t-test. Error bars in all figures represent Mean ± SEM.</p