Interaction of anticancer reduced Schiff base coumarin derivatives with human serum albumin investigated by fluorescence quenching and molecular modeling

The specific binding of five reduced Schiff base derived 7-amino-coumarin compounds with antitumor activity to human serum albumin, the principal binding protein of blood, was studied by fluorescence spectroscopy. Their conditional binding constants were computed and the reversible binding at the Sudlow’s site I was found to be strong (KD ~ 0.03-2.09 M). Based on the data albumin can provide a depot for the compounds and is responsible for their biodistribution and transport processes. The experimental data is complemented by protein– ligand docking calculations for two representatives which support the observations. The proton dissociation constants of the compounds were also determined by UV-Vis spectrophotometric and fluorometric titrations to obtain the actual charges and distribution of the species in the various protonation states at physiological pH

Resting-state functional connectivity and reading subskills in children

Individual differences in reading ability have been linked to characteristics of functional connectivity in the brain in both children and adults. However, many previous studies have used single or composite measures of reading, leading to difficulty characterizing the role of functional connectivity in discrete subskills of reading. The present study addresses this issue using resting-state fMRI to examine how resting-state functional connectivity (RSFC) related to individual differences in children\u27s reading subskills, including decoding, sight word reading, reading comprehension, and rapid automatized naming (RAN). Findings showed both positive and negative RSFC-behaviour relationships that diverged across different reading subskills. Positive relationships included increasing RSFC among left dorsal and anterior regions with increasing decoding proficiency, and increasing RSFC between the left thalamus and right fusiform gyrus with increasing sight word reading, RAN, and reading comprehension abilities. In contrast, negative relationships suggested greater functional segregation of attentional and reading networks with improved performance on RAN, decoding, and reading comprehension tasks. Importantly, the results suggest that although reading subskills rely to some extent on shared functional networks, there are also distinct functional connections supporting different components of reading ability in children

Manual / Issue 5 / Unfinished

Manual, a journal about art and its making. Unfinished.The fifth issue. Loose threads unknotted. Ideas unrealized. Outlines left bare. Function unperformed. Patterns uncut. Luster removed with time and wear. We rarely examine unfinished things. The unfinished is easily overlooked in favor of the fully rendered and complete, but consider those sketchy lines, those fraying ends: the unfinished has potency. The unfinished offers evidence of process, reveals traces of technique, trembles with latent possibility. The essays, images, and projects presented in the fifth issue of Manual attend to the fluid potential of objects that are in some way incomplete. Softcover, 68 pages. Published 2015 by the RISD Museum. Manual 5 (Unfinished) contributors include Jen Bervin, Jean Blackburn, Gina Borromeo, Laurie Brewer, A. Will Brown, Bolaji Campbell, Dennis Congdon, Jeremy Deller, Jan Howard, Kate Irvin, Maureen C. O’Brien, Emily J. Peters, Siebren Versteeg, Elizabeth A. Williams, and C. D. Wright.https://digitalcommons.risd.edu/risdmuseum_journals/1004/thumbnail.jp

Estimating EQ-5D utilities based on the Short-Form Long Term Conditions Questionnaire (LTCQ-8)

Purpose: The aim of this work was to develop a mapping algorithm for estimating EuroQoL 5 Dimension (EQ-5D) utilities from responses to the Long-Term Conditions Questionnaire (LTCQ), thus increasing LTCQ’s potential as a comprehensive outcome measure for evaluating integrated care initiatives. Methods: We combined data from three studies to give a total sample of 1334 responses. In each of the three datasets, we randomly selected 75% of the sample and combined the selected random samples to generate the estimation dataset, which consisted of 1001 patients. The unselected 25% observations from each dataset were combined to generate an internal validation dataset of 333 patients. We used direct mapping models by regressing responses to the LTCQ-8 directly onto EQ-5D-5L and EQ-5D-3L utilities as well as response (or indirect) mapping to predict the response level that patients selected for each of the five EQ-5D-5L domains. Several models were proposed and compared on mean squared error and mean absolute error. Results: A two-part model with OLS was the best performing based on the mean squared error (0.038) and mean absolute error (0.147) when estimating the EQ-5D-5L utilities. A multinomial response mapping model using LTCQ-8 responses was used to predict EQ-5D-5L responses levels. Conclusions: This study provides a mapping algorithm for estimating EQ-5D utilities from LTCQ responses. The results from this study can help broaden the applicability of the LTCQ by producing utility values for use in economic analyses

Real-world Data of Nivolumab for Patients With Advanced Renal Cell Carcinoma in the Netherlands:An Analysis of Toxicity, Efficacy, and Predictive Markers

Background: Nivolumab, a programmed death 1 inhibitor, has been approved as second-line treatment for advanced renal cell carcinoma (RCC) in Europe since 2016. We investigated the toxicity and efficacy of nivolumab as well as potential predictive biomarkers in the Dutch population. Patients and Methods: This was a retrospective, multicenter study of the Dutch national registry of nivolumab for the treatment of advanced RCC. The main outcome parameters included toxicity, objective response rate (ORR), overall survival (OS), progression-free survival (PFS), time to progression (TTP), and time to treatment failure (TTF). In addition, potential predictive and prognostic biomarkers for outcomes were evaluated. Results: Data on 264 patients were available, of whom 42% were International Metastatic RCC Database Consortium (IMDC) poor risk at start of nivolumab, 16% had ≥ 3 lines of previous therapy, 7% had non–clear-cell RCC, 11% had brain metastases, and 20% were previously treated with everolimus. Grade 3/4 immune-related adverse events occurred in 15% of patients. The median OS was 18.7 months (95% confidence interval, 13.7-23.7 months). Progression occurred in 170 (64.4%) of 264 patients, with a 6-and 12-months TTP of 49.8% and 31.1%, respectively. The ORR was 18.6% (49 of 264; 95% confidence interval, 14%-23%). Elevated baseline lymphocytes were associated with improved PFS (P =.038) and elevated baseline lactate dehydrogenase with poor OS, PFS, and TTF (P =.000). On-treatment increase in eosinophils by week 8 predicted improved OS (P =.003), PFS (P =.000), and TTF (P =.014), whereas a decrease of neutrophils was associated with significantly better TTF (P =.023). Conclusions: The toxicity and efficacy of nivolumab for metastatic RCC after previous lines of therapy are comparable with the results in the pivotal phase III trial and other real-world data. On-treatment increase in eosinophil count is a potential biomarker for efficacy and warrants further investigation

Validation of the Body Concealment Scale for Scleroderma (BCSS): Replication in the Scleroderma Patient-centered Intervention Network (SPIN) Cohort

© 2016 Elsevier Ltd Body concealment is an important component of appearance distress for individuals with disfiguring conditions, including scleroderma. The objective was to replicate the validation study of the Body Concealment Scale for Scleroderma (BCSS) among 897 scleroderma patients. The factor structure of the BCSS was evaluated using confirmatory factor analysis and the Multiple-Indicator Multiple-Cause model examined differential item functioning of SWAP items for sex and age. Internal consistency reliability was assessed via Cronbach's alpha. Construct validity was assessed by comparing the BCSS with a measure of body image distress and measures of mental health and pain intensity. Results replicated the original validation study, where a bifactor model provided the best fit. The BCSS demonstrated strong internal consistency reliability and construct validity. Findings further support the BCSS as a valid measure of body concealment in scleroderma and provide new evidence that scores can be compared and combined across sexes and ages

Safety of procuring research tissue during a clinically indicated kidney biopsy from patients with lupus: data from the Accelerating Medicines Partnership RA/SLE Network

Objectives In lupus nephritis the pathological diagnosis from tissue retrieved during kidney biopsy drives treatment and management. Despite recent approval of new drugs, complete remission rates remain well under aspirational levels, necessitating identification of new therapeutic targets by greater dissection of the pathways to tissue inflammation and injury. This study assessed the safety of kidney biopsies in patients with SLE enrolled in the Accelerating Medicines Partnership, a consortium formed to molecularly deconstruct nephritis.Methods 475 patients with SLE across 15 clinical sites in the USA consented to obtain tissue for research purposes during a clinically indicated kidney biopsy. Adverse events (AEs) were documented for 30 days following the procedure and were determined to be related or unrelated by all site investigators. Serious AEs were defined according to the National Institutes of Health reporting guidelines.Results 34 patients (7.2%) experienced a procedure-related AE: 30 with haematoma, 2 with jets, 1 with pain and 1 with an arteriovenous fistula. Eighteen (3.8%) experienced a serious AE requiring hospitalisation; four patients (0.8%) required a blood transfusion related to the kidney biopsy. At one site where the number of cores retrieved during the biopsy was recorded, the mean was 3.4 for those who experienced a related AE (n=9) and 3.07 for those who did not experience any AE (n=140). All related AEs resolved.Conclusions Procurement of research tissue should be considered feasible, accompanied by a complication risk likely no greater than that incurred for standard clinical purposes. In the quest for targeted treatments personalised based on molecular findings, enhanced diagnostics beyond histology will likely be required

Ehs-1 is required for the expulsion step of the Caenorhabditis elegans defecation motor program

The Caenorhabditis elegans digestive motor program occurs at approximately 50 second intervals and consists of three contractions. The first contraction occurs in the posterior body wall muscle and is followed by a contraction of the anterior body wall muscle approximately 4 seconds later. Finally, waste is expelled via contraction of the enteric muscles. The later contractions are controlled by the release of neuropeptides from the intestine, which activate two GABAergic neurons. A genome-wide RNA interference (RNAi) screen identified EPS-15 homologous sequence 1 (ehs-1) as a candidate gene involved in defecation. Ehs-1 knockdown does not affect the first contraction or the timekeeping mechanisms. However, the expulsion step occurs in only 10.9% percent of cycles. Ehs-1 has previously been implicated in synaptic vesicle recycling in neurons, suggesting that the expulsion defect is due to defective GABA release from DVB. However, intestine-specific knockdown of ehs-1 results in a 92.3% reduction in expulsion, matching the expulsion frequency following systemic knockdown. Our findings suggest that intestinal expression of ehs-1 is also required for expulsion. We hypothesize that ehs-1 is needed for recycling of vesicles in both neurons and intestines

Calcium signaling and neuropeptide secretion in the expulsion step of the Caenorhabditis elegans defecation motor program

A periodic posterior to anterior intestinal calcium wave initiates the defecation motor program of Caenorhabditis elegans (C. elegans). innexin-16 (inx-16) encodes an intestinal pannexin gap junction subunit. inx-16 mutants have faulty calcium waves and mostly lack the expulsion step of the motor program. Our work investigates how these defective calcium waves result in loss of expulsion. The anterior-ventral neuron L (AVL) and dorsal-ventral neuron B (DVB) are responsible for expulsion through a two-step signaling process. An intestinal neuropeptide-like protein, NLP-40, activates AVL and DVB which in turn release neurotransmitters to stimulate expulsion. NLP-40 release likely depends on intestinal calcium flux, as vesicular localization of NLP-40 requires synaptotagmin-2. We propose that the expulsion defects in the inx-16 mutant are due to improper NLP-40 release. To establish if inx-16’s AVL and DVB neurons are functional, we used optogenetic methods. Activation of a light-gated ion channel channelrhodopsin-2 (ChR2) in AVL and DVB of inx-16 animals resulted in normal expulsion 90% of the time. This demonstrates that an inx-16 animal’s AVL and DVB neurons are able to signal expulsion and supports our hypothesis that defects in inx-16’s intestinal NLP-40 release inhibit expulsion. Current work addresses whether NLP-40 is properly synthesized and released