Searching the protein structure database for ligand-binding site similarities using CPASS v.2

<p>Abstract</p> <p>Background</p> <p>A recent analysis of protein sequences deposited in the NCBI RefSeq database indicates that ~8.5 million protein sequences are encoded in prokaryotic and eukaryotic genomes, where ~30% are explicitly annotated as "hypothetical" or "uncharacterized" protein. Our Comparison of Protein Active-Site Structures (CPASS v.2) database and software compares the sequence and structural characteristics of experimentally determined ligand binding sites to infer a functional relationship in the absence of global sequence or structure similarity. CPASS is an important component of our Functional Annotation Screening Technology by NMR (FAST-NMR) protocol and has been successfully applied to aid the annotation of a number of proteins of unknown function.</p> <p>Findings</p> <p>We report a major upgrade to our CPASS software and database that significantly improves its broad utility. CPASS v.2 is designed with a layered architecture to increase flexibility and portability that also enables job distribution over the Open Science Grid (OSG) to increase speed. Similarly, the CPASS interface was enhanced to provide more user flexibility in submitting a CPASS query. CPASS v.2 now allows for both automatic and manual definition of ligand-binding sites and permits pair-wise, one versus all, one versus list, or list versus list comparisons. Solvent accessible surface area, ligand root-mean square difference, and Cβ distances have been incorporated into the CPASS similarity function to improve the quality of the results. The CPASS database has also been updated.</p> <p>Conclusions</p> <p>CPASS v.2 is more than an order of magnitude faster than the original implementation, and allows for multiple simultaneous job submissions. Similarly, the CPASS database of ligand-defined binding sites has increased in size by ~ 38%, dramatically increasing the likelihood of a positive search result. The modification to the CPASS similarity function is effective in reducing CPASS similarity scores for false positives by ~30%, while leaving true positives unaffected. Importantly, receiver operating characteristics (ROC) curves demonstrate the high correlation between CPASS similarity scores and an accurate functional assignment. As indicated by distribution curves, scores ≥ 30% infer a functional similarity. Software URL: <url>http://cpass.unl.edu</url>.</p

Trade-Off between Toxicity and Signal Detection Orchestrated by Frequency- and Density-Dependent Genes

Behaviors in insects are partly highly efficient Bayesian processes that fulfill exploratory tasks ending with the colonization of new ecological niches. The foraging (for) gene in Drosophila encodes a cGMP-dependent protein kinase (PKG). It has been extensively described as a frequency-dependent gene and its transcripts are differentially expressed between individuals, reflecting the population density context. Some for transcripts, when expressed in a population at high density for many generations, concomitantly trigger strong dispersive behavior associated with foraging activity. Moreover, genotype-by-environment interaction (GEI) analysis has highlighted a dormant role of for in energetic metabolism in a food deprivation context. In our current report, we show that alleles of for encoding different cGMP-dependent kinase isoforms influence the oxidation of aldehyde groups of aromatic molecules emitted by plants via Aldh-III and a phosphorylatable adaptor. The enhanced efficiency of oxidation of aldehyde odorants into carboxyl groups by the action of for lessens their action and toxicity, which should facilitate exploration and guidance in a complex odor environment. Our present data provide evidence that optimal foraging performance requires the fast metabolism of volatile compounds emitted by plants to avoid neurosensory saturation and that the frequency-dependent genes that trigger dispersion influence these processes

Early Oncologic Failure after Robot-Assisted Radical Cystectomy: Results from the International Robotic Cystectomy Consortium

PURPOSE: We sought to investigate the prevalence and variables associated with early oncologic failure. MATERIALS AND METHODS: We retrospectively reviewed the IRCC (International Radical Cystectomy Consortium) database of patients who underwent robot-assisted radical cystectomy since 2003. The final cohort comprised a total of 1,894 patients from 23 institutions in 11 countries. Early oncologic failure was defined as any disease relapse within 3 months of robot-assisted radical cystectomy. All institutions were surveyed for the pneumoperitoneum pressure used, breach of oncologic surgical principles, and techniques of specimen and lymph node removal. A multivariate model was fit to evaluate predictors of early oncologic failure. The Kaplan-Meier method was applied to depict disease specific and overall survival, and Cox proportional regression analysis was used to evaluate predictors of disease specific and overall survival. RESULTS: A total of 305 patients (22%) experienced disease relapse, which was distant in 220 (16%), local recurrence in 154 (11%), peritoneal carcinomatosis in 17 (1%) and port site recurrence in 5 (0.4%). Early oncologic failure developed in 71 patients (5%) at a total of 10 institutions. The incidence of early oncologic failure decreased from 10% in 2006 to 6% in 2015. On multivariate analysis the presence of any complication (OR 2.87, 95% CI 1.38–5.96, p = 0.004), pT3 or greater disease (OR 3.73, 95% CI 2.00–6.97, p <0.001) and nodal involvement (OR 2.14, 95% CI 1.21–3.80, p = 0.008) was a significant predictor of early oncologic failure. Patients with early oncologic failure demonstrated worse disease specific and overall survival (23% and 13%, respectively) at 1 and 3 years compared to patients who experienced later or no recurrences (log rank p <0.001). CONCLUSIONS: The incidence of early oncologic failure following robot-assisted radical cystectomy has decreased with time. Disease related rather than technical related factors have a major role in early oncologic failure after robot-assisted radical cystectomy

Development of a patient and institutional-based model for estimation of operative times for robot-assisted radical cystectomy: results from the International Robotic Cystectomy Consortium

OBJECTIVES: To design a methodology to predict operative times for robot-assisted radical cystectomy (RARC) based on variation in institutional, patient, and disease characteristics to help in operating room scheduling and quality control. PATIENTS AND METHODS: The model included preoperative variables and therefore can be used for prediction of surgical times: institutional volume, age, gender, body mass index, American Society of Anesthesiologists score, history of prior surgery and radiation, clinical stage, neoadjuvant chemotherapy, type, technique of diversion, and the extent of lymph node dissection. A conditional inference tree method was used to fit a binary decision tree predicting operative time. Permutation tests were performed to determine the variables having the strongest association with surgical time. The data were split at the value of this variable resulting in the largest difference in means for the surgical time across the split. This process was repeated recursively on the resultant data sets until the permutation tests showed no significant association with operative time. RESULTS: In all, 2 134 procedures were included. The variable most strongly associated with surgical time was type of diversion, with ileal conduits being 70 min shorter (P 66 RARCs) was important, with those with a higher volume being 55 min shorter (P < 0.001). The regression tree output was in the form of box plots that show the median and ranges of surgical times according to the patient, disease, and institutional characteristics. CONCLUSION: We developed a method to estimate operative times for RARC based on patient, disease, and institutional metrics that can help operating room scheduling for RARC

A meta-analysis of N-acetylcysteine in contrast-induced nephrotoxicity: unsupervised clustering to resolve heterogeneity

<p>Abstract</p> <p>Background</p> <p>Meta-analyses of N-acetylcysteine (NAC) for preventing contrast-induced nephrotoxicity (CIN) have led to disparate conclusions. Here we examine and attempt to resolve the heterogeneity evident among these trials.</p> <p>Methods</p> <p>Two reviewers independently extracted and graded the data. Limiting studies to randomized, controlled trials with adequate outcome data yielded 22 reports with 2746 patients.</p> <p>Results</p> <p>Significant heterogeneity was detected among these trials (<it>I</it>²= 37%; <it>p </it>= 0.04). Meta-regression analysis failed to identify significant sources of heterogeneity. A modified L'Abbé plot that substituted groupwise changes in serum creatinine for nephrotoxicity rates, followed by model-based, unsupervised clustering resolved trials into two distinct, significantly different (<it>p </it>< 0.0001) and homogeneous populations (<it>I</it>²= 0 and <it>p </it>> 0.5, for both). Cluster 1 studies (<it>n </it>= 18; 2445 patients) showed no benefit (relative risk (RR) = 0.87; 95% confidence interval (CI) 0.68–1.12, <it>p </it>= 0.28), while cluster 2 studies (<it>n </it>= 4; 301 patients) indicated that NAC was highly beneficial (RR = 0.15; 95% CI 0.07–0.33, <it>p </it>< 0.0001). Benefit in cluster 2 was unexpectedly associated with NAC-induced decreases in creatinine from baseline (<it>p </it>= 0.07). Cluster 2 studies were relatively early, small and of lower quality compared with cluster 1 studies (<it>p </it>= 0.01 for the three factors combined). Dialysis use across all studies (five control, eight treatment; <it>p </it>= 0.42) did not suggest that NAC is beneficial.</p> <p>Conclusion</p> <p>This meta-analysis does not support the efficacy of NAC to prevent CIN.</p

Outcomes of Intracorporeal Urinary Diversion after Robot-Assisted Radical Cystectomy: Results from the International Robotic Cystectomy Consortium

INTRODUCTION AND OBJECTIVE: This study aims to provide an update and compare perioperative outcomes and complications of Intracorporeal urinary diversion (ICUD) and extracorporeal urinary diversion (ECUD) following RARC from a multi-institutional, prospectively maintained database, the International Robotic Cystectomy Consortium (IRCC). METHODS: A retrospective review of 2125 patients from 26 institutions was performed. ICUD was compared with ECUD Multivariate (stepwise variable selection) logistic regression models were fit to evaluate preoperative, operative, and postoperative predictors of receiving ICUD, operative time, high grade complications and 90-days readmissions after RARC. RESULTS: 51% (n=1094) patients underwent ICUD in our cohort. ICUD patients demonstrated shorter operative times (357 vs 400 minutes, p<0.001), less blood loss (300 vs 350 ml, p<0.001), and fewer blood transfusions (4% vs 19%, p<0.001). ICUD patients experienced more high grade complications (13 vs 10%, p=0.02). Utilization of ICUD increased from 9% of all urinary diversions in 2005 to 97% in 2015. Complications after ICUD decreased significantly over time (p<0.001). On multivariable analysis, higher annual cystectomy volume (OR 1.02, 95% CI (1.01-1.03), p<0.002) and year of RARC 2013-2016 (OR 68, 95% CI 44-105, p<0.001) and ASA score <3 (OR 1.75, 95% CI 1.38-2.22, p<0.001) were associated with receiving ICUD. ICUD was associated with shorter operative time (27 minutes, p=0.001). CONCLUSION: Utilization of ICUD has increased over the past decade. Higher annual institutional volume of RARCs was associated with performing ICUD. ICUD was associated with shorter operative times. Although ICUD was associated with higher grade complications compared to ECUD, they decreased over time

Evaluation of appendicitis risk prediction models in adults with suspected appendicitis

Background Appendicitis is the most common general surgical emergency worldwide, but its diagnosis remains challenging. The aim of this study was to determine whether existing risk prediction models can reliably identify patients presenting to hospital in the UK with acute right iliac fossa (RIF) pain who are at low risk of appendicitis. Methods A systematic search was completed to identify all existing appendicitis risk prediction models. Models were validated using UK data from an international prospective cohort study that captured consecutive patients aged 16–45 years presenting to hospital with acute RIF in March to June 2017. The main outcome was best achievable model specificity (proportion of patients who did not have appendicitis correctly classified as low risk) whilst maintaining a failure rate below 5 per cent (proportion of patients identified as low risk who actually had appendicitis). Results Some 5345 patients across 154 UK hospitals were identified, of which two‐thirds (3613 of 5345, 67·6 per cent) were women. Women were more than twice as likely to undergo surgery with removal of a histologically normal appendix (272 of 964, 28·2 per cent) than men (120 of 993, 12·1 per cent) (relative risk 2·33, 95 per cent c.i. 1·92 to 2·84; P < 0·001). Of 15 validated risk prediction models, the Adult Appendicitis Score performed best (cut‐off score 8 or less, specificity 63·1 per cent, failure rate 3·7 per cent). The Appendicitis Inflammatory Response Score performed best for men (cut‐off score 2 or less, specificity 24·7 per cent, failure rate 2·4 per cent). Conclusion Women in the UK had a disproportionate risk of admission without surgical intervention and had high rates of normal appendicectomy. Risk prediction models to support shared decision‐making by identifying adults in the UK at low risk of appendicitis were identified