A multicentre, randomised, double-blind, double-dummy, parallel-controlled, phase 3 clinical trial assessing the efficacy and safety of intravenous nemonoxacin malate vs. levofloxacin for community-acquired pneumonia in adult patients.

BACKGROUND: Nemonoxacin malate is a novel non-fluorinated quinolone for oral and intravenous (IV) administration. This phase 3, multicentre, randomised, double-blind, double-dummy, parallel-controlled clinical trial (NCT02205112) evaluated the efficacy and safety of IV nemonoxacin vs. levofloxacin for the treatment of community-acquired pneumonia (CAP) in adult patients. METHODS: Eligible patients were randomised to receive 500 mg nemonoxacin or levofloxacin via IV infusion, once daily for 7-14 days. The primary endpoint was the clinical cure rate at the test-of-cure (TOC) visit in the modified intent-to-treat (mITT) population. Secondary efficacy and safety were also compared between nemonoxacin and levofloxacin. RESULTS: Overall, 525 patients were randomised and treated with nemonoxacin (n = 349) or levofloxacin (n = 176). The clinical cure rate was 91.8% (279/304) for nemonoxacin and 85.7% (138/161) for levofloxacin in the mITT population (P > 0.05). The clinical efficacy of nemonoxacin was non-inferior to levofloxacin for treatment of CAP. Microbiological success rate with nemonoxacin was 88.8% (95/107) and with levofloxacin was 87.8% (43/49) (P > 0.05) at the TOC visit in the bacteriological mITT population. The incidence of drug-related adverse events (AEs) was 37.1% in the nemonoxacin group and 22.2% in the levofloxacin group. These AEs were mostly local reactions at the infusion site, nausea, elevated alanine aminotransferase/aspartate aminotransferase (ALT/AST), and QT interval prolongation. The nemonoxacin-related AEs were mostly mild and resolved after discontinuation of nemonoxacin. CONCLUSIONS: Nemonoxacin 500 mg IV once daily for 7-14 days is effective and safe and non-inferior to levofloxacin for treating CAP in adult patients.

2'-Hydroxychalcone Induces Autophagy and Apoptosis in Breast Cancer Cells via the Inhibition of the NF-κB Signaling Pathway: In Vitro and In Vivo Studies.

2'-Hydroxychalcone is a hydroxyl derivative of chalcones, which are biosynthetic precursors of flavonoids and rich in the human diet. The anticancer activity of 2'-hydroxychalcone has been reported in several cancers but remains to be investigated in breast cancer. In the current study, 2'-hydroxychalcone showed significant cytotoxicity against breast cancer cell lines MCF-7 and CMT-1211. It could inhibit breast cancer cell proliferation, migration, and invasion in vitro and suppress tumor growth and metastasis in vivo. Mechanistic investigation revealed that the NF-κB pathway was significantly inhibited by 2'-hydroxychalcone treatment accompanied by an excessive intracellular accumulation of reactive oxygen species, induction of endoplasmic reticulum stress, and activation of JNK/MAPK. In addition, 2'-hydroxychalcone elevated the autophagic levels in breast cancer cells equipped with increasing numbers of autophagy vesicles and complete autophagic flux. Finally, autophagy-dependent apoptosis was observed in 2'-hydroxychalcone-induced cell death. In conclusion, 2'-hydroxychalcone enhances the autophagic levels and induces apoptosis in breast cancer cells, which could be contributed to the inhibition of the pro-survival NF-κB signaling, indicating a promising potential for 2'-hydroxychalcone in future anticancer drug development.

The Association of Preoperative Diabetes With Postoperative Delirium in Older Patients Undergoing Major Orthopedic Surgery: A Prospective Matched Cohort Study.

BACKGROUND: Postoperative delirium (POD) is a common form of postoperative brain dysfunction, especially in the elderly. However, its risk factors remain largely to be determined. This study aimed to investigate whether (1) preoperative diabetes is associated with POD after elective orthopedic surgery and (2) intraoperative frontal alpha power is a mediator of the association between preoperative diabetes and POD. METHODS: This was a prospective matched cohort study of patients aged 60 years or more, with a preoperative diabetes who underwent elective orthopedic surgery. Nondiabetic patients were matched 1:1 to diabetic patients in terms of age, sex, and type of surgery. Primary outcome was occurrence of POD, assessed using the 3-minute Diagnostic Confusion Assessment Method (3D-CAM) once daily from 6 pm to 8 pm during the postoperative days 1-7 or until discharge. Secondary outcome was the severity of POD which was assessed for all participants using the short form of the CAM-Severity. Frontal electroencephalogram (EEG) was recorded starting before induction of anesthesia and lasting until discharge from the operating room. Intraoperative alpha power was calculated using multitaper spectral analyses. Mediation analysis was used to estimate the proportion of the association between preoperative diabetes and POD that could be explained by intraoperative alpha power. RESULTS: A total of 138 pairs of eligible patients successfully matched 1:1. After enrollment, 6 patients in the diabetes group and 4 patients in the nondiabetes group were excluded due to unavailability of raw EEG data. The final analysis included 132 participants with preoperative diabetes and 134 participants without preoperative diabetes, with a median age of 68 years and 72.6% of patients were female. The incidence of POD was 16.7% (22/132) in patients with preoperative diabetes vs 6.0% (8/134) in patients without preoperative diabetes. Preoperative diabetes was associated with increased odds of POD after adjustment of age, sex, body mass index, education level, hypertension, arrhythmia, coronary heart disease, and history of stroke (odds ratio, 3.2; 95% confidence interval [CI], 1.4-8.0; P = .009). The intraoperative alpha power accounted for an estimated 20% (95% CI, 2.6-60%; P = .021) of the association between diabetes and POD. CONCLUSIONS: This study suggests that preoperative diabetes is associated with an increased risk of POD in older patients undergoing major orthopedic surgery, and that low intraoperative alpha power partially mediates such association.

Development of organic three-phase laminar flow microfluidic chip for extraction of ginsenosides from Panax ginseng.

BACKGROUND: Herbal extracts contain multiple active constituents, so the sample preparation based on the liquid-liquid extraction (LLE) is demanding, especially when a study subsequent to extraction is needed. Since the laminar flow occurring in microchannels can be formed between two miscible organic phases, a new method of extracting polar compounds from the crude extract of Panax ginseng Meyer in aqueous ethanol by pure n-butanol in the three-phase laminar flow microfluidic chip was established. METHODS: A new chip consisting of long microchannels with a guide structure was employed to improve the extraction efficiency caused by the low diffusion ability of saponins. The method was evaluated by using the extraction yields and purities of ginsenosides Rg1, Re and Rb1 as the indicators, and extraction conditions such as flow rate, temperature and other governing factors were optimized. RESULTS: Using the new chip method, the extraction efficiencies of ginsenoside Rg1, Re and Rb1 were 63.1%, 69.5% and 71.6%, respectively, which are higher than the 26% achieved in a previous report. The extraction yields of 1.53, 0.51, 0.90 mg/g were also higher than those obtained previously by the successive laminar flow microchip method. CONCLUSION: The proposed new microfluidic chip method has simplified the sample pretreatment steps to improve the yield of ginsenoside extraction from ginseng samples.

Cathepsin B is a potential therapeutic target for coronavirus disease 2019 patients with lung adenocarcinoma.

Coronavirus disease 2019 (COVID-19) was declared a serious global public health emergency. Hospitalization and mortality rates of lung cancer patients diagnosed with COVID-19 are higher than those of patients presenting with other cancers. However, the reasons for the outcomes being disproportionately severe in lung adenocarcinoma (LUAD) patients with COVID-19 remain elusive. The present study aimed to identify the possible causes for disproportionately severe COVID-19 outcomes in LUAD patients and determine a therapeutic target for COVID-19 patients with LUAD. We used publicly available data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and various bioinformatics tools to identify and analyze the genes implicated in SARS-CoV-2 infection in LUAD patients. Upregulation of the SARS-CoV-2 infection-related molecules dipeptidyl peptidase 4, basigin, cathepsin B (CTSB), methylenetetrahydrofolate dehydrogenase, and peptidylprolyl isomerase B rather than angiotensin-converting enzyme 2 may explain the relatively high susceptibility of LUAD patients to SARS-CoV-2 infection. CTSB was highly expressed in the LUAD tissues after SARS-CoV-2 infection, and its expression was positively correlated with immune cell infiltration and proinflammatory cytokine expression. These findings suggest that CTSB plays a vital role in the hyperinflammatory response in COVID-19 patients with LUAD and is a promising target for the development of a novel drug therapy for COVID-19 patients.

Preparation and Evaluation of Valnemulin Hydrochloride Taste-Masking Granules.

BACKGROUND: The bitter taste and strong irritation of valnemulin hydrochloride limit its wide clinical application in pigs by oral. METHOD: In order to improve its palatability and residence time in the body, the valnemulin hydrochloride taste-masking granules with sustained-release were prepared by combining solid dispersion based on fatty acid with wet granulation. The formulation was screened by orthogonal test with content, yield, grain size and angle of repose as evaluation indexes. RESULT: The results showed that the optimal granules were composed of corn starch, sucrose, citric acid, valnemulin hydrochloride and myristic acid at a ratio of 40: 20: 20: 11: 19. The daily feed intake of pigs in the optimum taste-masking granule groups was similar to that of its self-control, and significantly higher than that in the valnemulin hydrochloride active ingredient group, suggesting that the optimum granules have satisfactory palatability. The prepared granules improved the oral bioavailability of valnemulin hydrochloride by 3.04 folds and extended its mean residence time (MRT) by 2.33 folds. CONCLUSION: The granules developed in this study could obviously improve the palatability and sustained release of valnemulin hydrochloride. The producing method of granules by combining solid dispersion powder with wet granulation can provide ideas for other drugs with poor palatability and a short half-life.

Gastrodin Improves Nonalcoholic Fatty Liver Disease Through Activation of the Adenosine Monophosphate-Activated Protein Kinase Signaling Pathway.

BACKGROUND AND AIMS: NASH is currently one of the most common causes of liver transplantation and hepatocellular carcinoma. Thus far, there is still no effective pharmacological therapy for this disease. Recently, Gastrodin has demonstrated hepatoprotective effects in a variety of liver diseases. The aim of this study is to investigate the function of Gastrodin in NASH. APPROACH AND RESULTS: In our study, Gastrodin showed potent therapeutic effects on NASH both in vivo and in vitro. In high-fat diet or high-fat and high-cholesterol diet-fed mice, the liver weight, hepatic and serum triglyceride and cholesterol contents, and serum alanine aminotransferase and aspartate aminotransferase activity levels were markedly reduced by Gastrodin treatment as compared with the corresponding vehicle groups. Notably, Gastrodin showed minimal effects on the function and histological characteristics of other major organs in mice. We further examined the effects of Gastrodin on lipid accumulation in primary mouse hepatocytes and human hepatocyte cell line and observed that Gastrodin showed a significant decrease in lipid accumulation and inflammatory response in hepatocytes under metabolic stress. Furthermore, RNA-sequencing analysis systemically indicated that Gastrodin suppressed the pathway and key regulators related to lipid accumulation, inflammation, and fibrosis in the pathogenesis of NASH. Mechanistically, we found that Gastrodin protected against NASH by activating the adenosine monophosphate-activated protein kinase (AMPK) pathway, which was supported by the result that the AMPK inhibitor Compound C or AMPK knockdown blocked the Gastrodin-mediated hepatoprotective effect. CONCLUSIONS: Gastrodin attenuates steatohepatitis by activating the AMPK pathway and represents a therapeutic for the treatment of NASH.

A randomized, controlled, multicenter clinical trial to evaluate the efficacy and safety of oral sitafloxacin versus moxifloxacin in adult patients with community-acquired pneumonia.

OBJECTIVES: To evaluate the efficacy and safety of oral sitafloxacin versus oral moxifloxacin in the treatment of Chinese adults with community-acquired pneumonia (CAP). PATIENTS AND METHODS: This is a multicenter, randomized, open-label, positive-controlled clinical trial (chinadrugtrials.org.cn identifier: CTR20130046). CAP patients received sitafloxacin tablets 100 mg once daily (qd) or 100 mg twice daily (bid) to compare with moxifloxacin tablets 400 mg qd, for 7-10 days. The primary outcome was non-inferiority of sitafloxacin to moxifloxacin in clinical cure rate at test of cure (TOC) visit in per-protocol set (PPS). RESULTS: A total of 343 patients were randomized (sitafloxacin 100 mg qd, n = 117; sitafloxacin 100 mg bid, n = 116; moxifloxacin, n = 110), 291 patients were included in the PPS (sitafloxacin 100 mg qd, n = 96; sitafloxacin 100 mg bid, n = 94; moxifloxacin, n = 101). The clinical cure rate was 94.8% in the sitafloxacin 100 mg qd group, 96.8% in the sitafloxacin 100 mg bid group and 95.0% in the moxifloxacin group. At the TOC visit, the microbiological success rate was 97.0% (32/33) in the sitafloxacin 100 mg qd group, 97.1% (34/35) in the sitafloxacin 100 mg bid group and 94.9% (37/39) in the moxifloxacin group in the microbiological evaluable set (MES). The incidence of study-drug-related adverse events (AEs) was 23.3% (27/116) in the sitafloxacin 100 mg qd group, 29.8% (34/114) in the sitafloxacin 100 mg bid group and 28.2% (31/110) in the moxifloxacin group (p > .05). The common AEs related to study drug were dizziness, nausea, diarrhea, increased platelet count and alanine transaminase (ALT) elevation. All the AEs resolved completely after discontinuation of study drug. CONCLUSION: Sitafloxacin 100 mg qd or 100 mg bid for 7-10 days is not inferior to moxifloxacin 400 mg qd for 7-10 days in clinical efficacy for adult CAP patients. Sitafloxacin provides a safety profile comparable to moxifloxacin.

Evaluation of the clinical value of retroperitoneal laparoscopic pyeloplasty in the treatment of ureteropelvic junction obstruction in infants: A single-center experience involving 22 consecutive patients.

Retroperitoneal laparoscopic pyeloplasty (RLP) is 1 method for treating ureteropelvic junction obstruction (UPJO) in children, but reports are more common in children than in infants younger than 2 years old. The purpose of this study was to evaluate the clinical value of RLP for infants with UPJO.From January 2015 to December 2017, a retrospective analysis of 22 infants aged 2 to 24 (11.95 ±â€Š6.00) months with UPJO who were treated with RLP in our hospital was performed. During the same period, 14 infants who underwent conventional transperitoneal laparoscopic pyeloplasty (TLP) were compared with those who underwent RLP. Postoperative recovery and complications, including bleeding, infection, urinary leakage and anastomotic stenosis, postoperative resumption of oral feeding, postoperative hospitalization time and surgical success rate were evaluated. Drainage and function were assessed with isotope scan at 6 months and later during the yearly follow-up and by intravenous urography (IVU) and mercaptoacetyltriglycine (MAG3) renography.Both groups underwent successful surgery. The operative time in the RLP group was 88 to 205 (120.59 ±â€Š24.59) min, and there was no significant difference compared with the TLP group (P = .767). The estimated intraoperative blood loss was 2 to 10 (3.75 ±â€Š1.59) ml, which was not significantly different between the 2 groups (P = .386). In the RLP group, the mean postoperative resumption of oral feeding was faster than that in the TLP group (3.55 ±â€Š0.74 vs 5.50 ±â€Š0.85 hour, P < .001), and the postoperative hospitalization time was shorter in the TLP group than in the RLP group (6.59 ±â€Š0.50 vs 7.07 ±â€Š0.47 day, P = .007 < .05). Follow-up lasted from 6 months to 3 years, and there was a significant reduction in postoperative hydronephrosis in both groups (P < .05, respectively).RLP is a safe procedure for infants. This procedure is associated with relatively little trauma, a quick recovery and good cosmetic effects. RLP also has the advantages of relatively little interference with the abdominal cavity and sufficient operating space; thus, this technique is worth promoting.

PHAST, PHASTER and PHASTEST: Tools for finding prophage in bacterial genomes.

PHAST (PHAge Search Tool) and its successor PHASTER (PHAge Search Tool - Enhanced Release) have become two of the most widely used web servers for identifying putative prophages in bacterial genomes. Here we review the main capabilities of these web resources, provide some practical guidance regarding their use and discuss possible future improvements. PHAST, which was first described in 2011, made its debut just as whole bacterial genome sequencing and was becoming inexpensive and relatively routine. PHAST quickly gained popularity among bacterial genome researchers because of its web accessibility, its ease of use along with its enhanced accuracy and rapid processing times. PHASTER, which appeared in 2016, provided a number of much-needed enhancements to the PHAST server, including greater processing speed (to cope with very large submission volumes), increased database sizes, a more modern user interface, improved graphical displays and support for metagenomic submissions. Continuing developments in the field, along with increased interest in automated phage and prophage finding, have already led to several improvements to the PHASTER server and will soon lead to the development of a successor to PHASTER (to be called PHASTEST).

Phase III study of dulanermin (recombinant human tumor necrosis factor-related apoptosis-inducing ligand/Apo2 ligand) combined with vinorelbine and cisplatin in patients with advanced non-small-cell lung cancer.

Background Dulanermin is a recombinant soluble human Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) that activates apoptotic pathways by binding to proapoptotic death receptor (DR) 4 and DR5. The purpose of this study was to evaluate the efficacy and safety of dulanermin combined with vinorelbine and cisplatin (NP) as the first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC). Experimental design Patients were randomly assigned to receive NP chemotherapy (vinorelbine 25 mg/m2 on days 1 and 8 and cisplatin 30 mg/m2 on days 2 to 4) for up to six cycles plus dulanermin (75 µg/kg on days 1 to 14) or placebo every three weeks until disease progression, intolerable toxicity, or withdrawal of consent. The primary end point was progression-free survival (PFS), and the secondary end points included objective response rate (ORR), overall survival (OS), and safety evaluation. Results Between October 2009 and June 2012, 452 untreated patients with stage IIIB to IV NSCLC were randomly assigned to receive dulanermin plus NP (n = 342) and placebo plus NP (n = 110). Median PFS was 6.4 months in the dulanermin arm versus 3.5 months in the placebo arm (hazard ratio (HR), 0.4034; 95% CI, 0.3181 to 0.5117, p < 0.0001). ORR was 46.78% in the dulanermin arm versus 30.00% in the placebo arm (p = 0.0019). Median OS was 14.6 months in the dulanermin arm versus 13.9 months in the placebo arm (HR, 0.94; 95% CI, 0.74 to 1.21, p = 0.64). The most common grade ≥ 3 adverse events (AEs) were oligochromemia, leukopenia, neutropenia, and oligocythemia. Overall incidence of AEs, grade ≥ 3 AEs, and serious AEs were similar across the two arms. Conclusion Addition of dulanermin to the NP regimen significantly improved PFS and ORR. However, our results showed that the combination of dulanermin with chemotherapy had a synergic activity and favorable toxic profile in the treatment of patients with advanced NSCLC.

A randomized, double-blind, multicenter Phase II study comparing the efficacy and safety of oral nemonoxacin with oral levofloxacin in the treatment of community-acquired pneumonia.

BACKGROUND/PURPOSE: To compare the clinical efficacy and safety of nemonoxacin with levofloxacin in treating community-acquired pneumonia (CAP) in a Phase II clinical trial. METHODS: One hundred ninety-two patients with CAP were randomized to receive oral nemonoxacin (500 mg or 750 mg) or levofloxacin (500 mg) once daily for 7-10 days. Clinical and bacteriological responses were determined at the test of cure (TOC) visit in the full analysis set (FAS). RESULTS: The clinical cure rate of nemonoxacin (500 mg), nemonoxacin (750 mg), and levofloxacin (500 mg) was 93.3%, 87.3%, and 88.5%, respectively, in the FAS (n = 168), and 93.0%, 93.9%, and 88.9%, respectively in the per protocol set (n = 152). At the TOC visit, nemonoxacin at 500 mg and 750 mg was proven to be noninferior to levofloxacin at 500 mg in the FAS in terms of clinical efficacy. The overall bacteriological success rate was 83.3% in both nemonoxacin groups and 80.0% in the levofloxacin 500 mg group in the bacteriological FAS. The comprehensive efficacy rate was comparable among the three groups (87.5% for the nemonoxacin 500 mg group, 93.8% for the nemonoxacin 750 mg group, and 81.3% for the levofloxacin 500 mg group). Most drug-related adverse events were mild and transient, mainly gastrointestinal symptoms such as nausea and vomiting, transient neutropenia, and elevated liver enzymes. No drug-related serious adverse events occurred. CONCLUSION: Either 500 mg or 750 mg of oral nemonoxacin taken once daily for 7-10 days demonstrated high clinical and bacteriological success rates in Chinese adult patients with CAP. Nemonoxacin at 500 mg once daily for 7-10 days is recommended for future Phase III clinical trials. ClinicalTrials.gov identifier: NCT01537250.

PHASTER: a better, faster version of the PHAST phage search tool.

PHASTER (PHAge Search Tool - Enhanced Release) is a significant upgrade to the popular PHAST web server for the rapid identification and annotation of prophage sequences within bacterial genomes and plasmids. Although the steps in the phage identification pipeline in PHASTER remain largely the same as in the original PHAST, numerous software improvements and significant hardware enhancements have now made PHASTER faster, more efficient, more visually appealing and much more user friendly. In particular, PHASTER is now 4.3× faster than PHAST when analyzing a typical bacterial genome. More specifically, software optimizations have made the backend of PHASTER 2.7X faster than PHAST, while the addition of 80 CPUs to the PHASTER compute cluster are responsible for the remaining speed-up. PHASTER can now process a typical bacterial genome in 3 min from the raw sequence alone, or in 1.5 min when given a pre-annotated GenBank file. A number of other optimizations have also been implemented, including automated algorithms to reduce the size and redundancy of PHASTER's databases, improvements in handling multiple (metagenomic) queries and higher user traffic, along with the ability to perform automated look-ups against 14 000 previously PHAST/PHASTER annotated bacterial genomes (which can lead to complete phage annotations in seconds as opposed to minutes). PHASTER's web interface has also been entirely rewritten. A new graphical genome browser has been added, gene/genome visualization tools have been improved, and the graphical interface is now more modern, robust and user-friendly. PHASTER is available online at www.phaster.ca.

Heatmapper: web-enabled heat mapping for all.

Heatmapper is a freely available web server that allows users to interactively visualize their data in the form of heat maps through an easy-to-use graphical interface. Unlike existing non-commercial heat map packages, which either lack graphical interfaces or are specialized for only one or two kinds of heat maps, Heatmapper is a versatile tool that allows users to easily create a wide variety of heat maps for many different data types and applications. More specifically, Heatmapper allows users to generate, cluster and visualize: (i) expression-based heat maps from transcriptomic, proteomic and metabolomic experiments; (ii) pairwise distance maps; (iii) correlation maps; (iv) image overlay heat maps; (v) latitude and longitude heat maps and (vi) geopolitical (choropleth) heat maps. Heatmapper offers a number of simple and intuitive customization options for facile adjustments to each heat map's appearance and plotting parameters. Heatmapper also allows users to interactively explore their numeric data values by hovering their cursor over each heat map cell, or by using a searchable/sortable data table view. Heat map data can be easily uploaded to Heatmapper in text, Excel or tab delimited formatted tables and the resulting heat map images can be easily downloaded in common formats including PNG, JPG and PDF. Heatmapper is designed to appeal to a wide range of users, including molecular biologists, structural biologists, microbiologists, epidemiologists, environmental scientists, agriculture/forestry scientists, fish and wildlife biologists, climatologists, geologists, educators and students. Heatmapper is available at http://www.heatmapper.ca.

[ROC curve-based evaluation of platelet parameters for predicting delayed renal graft function].

OBJECTIVE: To investigate the value of evaluating 5 platelet parameters in predicting delayed graft function (DGF) in patients following kidney transplantation. METHODS: We retrospectively analyzed the pre- and postoperative (within 2 months) data of 330 renal transplant recipients. The cases with DGF and those without were analyzed to assess the association between relationship between DGF following transplantation and the variations of blood platelet parameters including platelet count (PLT), large platelet ratio (P-LCR), mean platelet volume (MPV), platelet volume distribution width (PDW) and platelet hematocrit (PCT). RESULTS: The DGF and non-DGF cases were comparable for the platelet parameters before the operation. On postoperative day 7 when the diagnosis of DGF was made, PLT (P<0.05) and PCT (P<0.02) were significantly lower while MPV (P<0.01), PDW (P=0.036) and P-LCR (P=0.01) significantly higher in DGF group than in non-DGF group. The AUCs of P-LCR (0.611±0.047), PDW (0.603±0.048) and MPV (0.762±0.037) were significantly higher than the reference area (P<0.05) with cut-off values of 34.80%, 12.95fl and 11.55fl, respectively. MPV showed a high sensitivity, specificity and Youden index for predicting DFG; PDW and P-LCR had a high sensitivity but a low specificity for predicting DFG with a modest diagnostic value. PLT and PCT, with AUCs of were 0.37 and 0.38, respectively, did not have a predictive value for DGF. CONCLUSIONS: Significant variations in platelet parameters occur in the event of DGF in renal transplant recipients, and monitoring the postoperative changes in MPV, PDW, and P-LCR can help in early diagnosis and treatment of DGF. MPV has a moderate value (0.7-0.9) in predicting DGF, and a MPV>11.55 fl suggests the risk of DGF.

A robust algorithm for optimizing protein structures with NMR chemical shifts.

Over the past decade, a number of methods have been developed to determine the approximate structure of proteins using minimal NMR experimental information such as chemical shifts alone, sparse NOEs alone or a combination of comparative modeling data and chemical shifts. However, there have been relatively few methods that allow these approximate models to be substantively refined or improved using the available NMR chemical shift data. Here, we present a novel method, called Chemical Shift driven Genetic Algorithm for biased Molecular Dynamics (CS-GAMDy), for the robust optimization of protein structures using experimental NMR chemical shifts. The method incorporates knowledge-based scoring functions and structural information derived from NMR chemical shifts via a unique combination of multi-objective MD biasing, a genetic algorithm, and the widely used XPLOR molecular modelling language. Using this approach, we demonstrate that CS-GAMDy is able to refine and/or fold models that are as much as 10 Å (RMSD) away from the correct structure using only NMR chemical shift data. CS-GAMDy is also able to refine of a wide range of approximate or mildly erroneous protein structures to more closely match the known/correct structure and the known/correct chemical shifts. We believe CS-GAMDy will allow protein models generated by sparse restraint or chemical-shift-only methods to achieve sufficiently high quality to be considered fully refined and "PDB worthy". The CS-GAMDy algorithm is explained in detail and its performance is compared over a range of refinement scenarios with several commonly used protein structure refinement protocols. The program has been designed to be easily installed and easily used and is available at http://www.gamdy.ca.

Panax notoginseng saponins mitigate ovariectomy-induced bone loss and inhibit marrow adiposity in rats.

OBJECTIVE: Previous data have suggested that Panax notoginseng saponins (PNS) can prevent estrogen deficiency-induced bone loss by dual action: stimulation of new bone formation and inhibition of bone resorption. Marrow adipogenesis has been identified as a negative indicator of skeletal strength and integrity. This study assessed the effects of early PNS supplementation on bone microarchitecture preservation and marrow fat content in an ovariectomized rat model. METHODS: Forty adult female Sprague-Dawley rats were randomly assigned to four equal groups for 12 weeks of treatment: (1) sham operation (SHAM) + vehicle; (2) ovariectomy (OVX) + vehicle; (3) OVX + 17ß-estradiol (25 µg/kg); (4) OVX + PNS (300 mg/kg/d, PO). Marrow fat content of the femur was determined, using fat/water magnetic resonance imaging (MRI), at baseline and 6 and 12 weeks after operation. At the end of the experiment, bone turnover, trabecular microarchitecture, and marrow adipocytes were assessed by serum biomarkers, micro-computed tomography (micro-CT), and histopathology, respectively. The effects of PNS on adipocytic differentiation were reflected by expression levels of the adipogenic genes PPARγ2 and C/EBPα, as determined by reverse transcription-polymerase chain reaction. RESULTS: Ovariectomized rats experienced remarkable increases in marrow fat content across time points, which were accompanied by elevated rate of bone turnover, global volumetric bone density, and trabecular microarchitecture deterioration. These OVX-induced pathological changes are reversible in that most of them could be mostly corrected upon 17ß-estradiol treatment. PNS treatment significantly reduced marrow adipogenesis (adipocyte density, -27.2%; size, -22.7%; adipocyte volume-to-tissue volume ratio, -53.3%; all P < 0.01) and adipocyte marker gene expression, and prevented bone mass loss and microarchitecture deterioration. Moreover, PNS enhanced osteoblast activity but suppressed osteoclast turnover, as evidenced by decreased levels of serum C-terminal telopeptides of type I collagen and elevated levels of alkaline phosphatase. CONCLUSIONS: PNS mitigates estrogen deficiency-induced deterioration of trabecular microarchitecture and suppresses marrow adipogenesis.

PolySearch2: a significantly improved text-mining system for discovering associations between human diseases, genes, drugs, metabolites, toxins and more.

PolySearch2 (http://polysearch.ca) is an online text-mining system for identifying relationships between biomedical entities such as human diseases, genes, SNPs, proteins, drugs, metabolites, toxins, metabolic pathways, organs, tissues, subcellular organelles, positive health effects, negative health effects, drug actions, Gene Ontology terms, MeSH terms, ICD-10 medical codes, biological taxonomies and chemical taxonomies. PolySearch2 supports a generalized 'Given X, find all associated Ys' query, where X and Y can be selected from the aforementioned biomedical entities. An example query might be: 'Find all diseases associated with Bisphenol A'. To find its answers, PolySearch2 searches for associations against comprehensive collections of free-text collections, including local versions of MEDLINE abstracts, PubMed Central full-text articles, Wikipedia full-text articles and US Patent application abstracts. PolySearch2 also searches 14 widely used, text-rich biological databases such as UniProt, DrugBank and Human Metabolome Database to improve its accuracy and coverage. PolySearch2 maintains an extensive thesaurus of biological terms and exploits the latest search engine technology to rapidly retrieve relevant articles and databases records. PolySearch2 also generates, ranks and annotates associative candidates and present results with relevancy statistics and highlighted key sentences to facilitate user interpretation.

Pathways with PathWhiz.

PathWhiz (http://smpdb.ca/pathwhiz) is a web server designed to create colourful, visually pleasing and biologically accurate pathway diagrams that are both machine-readable and interactive. As a web server, PathWhiz is accessible from almost any place and compatible with essentially any operating system. It also houses a public library of pathways and pathway components that can be easily viewed and expanded upon by its users. PathWhiz allows users to readily generate biologically complex pathways by using a specially designed drawing palette to quickly render metabolites (including automated structure generation), proteins (including quaternary structures, covalent modifications and cofactors), nucleic acids, membranes, subcellular structures, cells, tissues and organs. Both small-molecule and protein/gene pathways can be constructed by combining multiple pathway processes such as reactions, interactions, binding events and transport activities. PathWhiz's pathway replication and propagation functions allow for existing pathways to be used to create new pathways or for existing pathways to be automatically propagated across species. PathWhiz pathways can be saved in BioPAX, SBGN-ML and SBML data exchange formats, as well as PNG, PWML, HTML image map or SVG images that can be viewed offline or explored using PathWhiz's interactive viewer. PathWhiz has been used to generate over 700 pathway diagrams for a number of popular databases including HMDB, DrugBank and SMPDB.