Derivatives of a benzoquinone acyl hydrazone with activity against Toxoplasma gondii

Toxoplasma gondii is an obligate intracellular parasite with global incidence. The acute infection, toxoplasmosis, is treatable but current regimens have poor host tolerance and no cure has been found for latent infections. This work builds upon a previous high throughput screen which identified benzoquinone acyl hydrazone (KG8) as the most promising compound; KG8 displayed potent in vitro activity against T. gondii but only marginal in vivoefficacy in a T. gondii animal model. To define the potential of this new lead compound, we now describe a baseline structure-activity relationship for this chemotype. Several derivatives displayed IC50\u27s comparable to that of the control treatment pyrimethamine with little to no cytotoxicity. The best of these, KGW44 and KGW59, had higher metabolic stability than KG8. In an in vivo T. gondii murine model, KGW59 significantly increased survivorship. This work provides new insights for optimization of this novel chemotype

Pharmacological inhibition of RAS overcomes FLT3 inhibitor resistance in FLT3-ITD+ AML through AP-1 and RUNX1

\ua9 2024 The Author(s). AML is characterized by mutations in genes associated with growth regulation such as internal tandem duplications (ITD) in the receptor kinase FLT3. Inhibitors targeting FLT3 (FLT3i) are being used to treat patients with FLT3-ITD+ but most relapse and become resistant. To elucidate the resistance mechanism, we compared the gene regulatory networks (GRNs) of leukemic cells from patients before and after relapse, which revealed that the GRNs of drug-responsive patients were altered by rewiring their AP-1-RUNX1 axis. Moreover, FLT3i induces the upregulation of signaling genes, and we show that multiple cytokines, including interleukin-3 (IL-3), can overcome FLT3 inhibition and send cells back into cycle. FLT3i leads to loss of AP-1 and RUNX1 chromatin binding, which is counteracted by IL-3. However, cytokine-mediated drug resistance can be overcome by a pan-RAS inhibitor. We show that cytokines instruct AML growth via the transcriptional regulators AP-1 and RUNX1 and that pan-RAS drugs bypass this barrier

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

Loss-of-function mutations in SLC30A8 protect against type 2 diabetes.

Neðst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkinn View/OpenLoss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ~150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10(-6)), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (-0.17 s.d., P = 4.6 × 10(-4)). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.US National Institutes of Health (NIH) Training 5-T32-GM007748-33 Doris Duke Charitable Foundation 2006087 Fulbright Diabetes UK Fellowship BDA 11/0004348 Broad Institute from Pfizer, Inc. NIH U01 DK085501 U01 DK085524 U01 DK085545 U01 DK085584 Swedish Research Council Dnr 521-2010-3490 Dnr 349-2006-237 European Research Council (ERC) GENETARGET T2D GA269045 ENGAGE 2007-201413 CEED3 2008-223211 Sigrid Juselius Foundation Folkh lsan Research Foundation ERC AdG 293574 Research Council of Norway 197064/V50 KG Jebsen Foundation University of Bergen Western Norway Health Authority Lundbeck Foundation Novo Nordisk Foundation Wellcome Trust WT098017 WT064890 WT090532 WT090367 WT098381 Uppsala University Swedish Research Council and the Swedish Heart- Lung Foundation Academy of Finland 124243 102318 123885 139635 Finnish Heart Foundation Finnish Diabetes Foundation, Tekes 1510/31/06 Commission of the European Community HEALTH-F2-2007-201681 Ministry of Education and Culture of Finland European Commission Framework Programme 6 Integrated Project LSHM-CT-2004-005272 City of Kuopio and Social Insurance Institution of Finland Finnish Foundation for Cardiovascular Disease NIH/NIDDK U01-DK085545 National Heart, Lung, and Blood Institute (NHLBI) National Institute on Minority Health and Health Disparities N01 HC-95170 N01 HC-95171 N01 HC-95172 European Union Seventh Framework Programme, DIAPREPP Swedish Child Diabetes Foundation (Barndiabetesfonden) 5U01DK085526 DK088389 U54HG003067 R01DK072193 R01DK062370 Z01HG000024info:eu-repo/grantAgreement/EC/FP7/20201

Improved imputation quality of low-frequency and rare variants in European samples using the ‘Genome of The Netherlands'

Although genome-wide association studies (GWAS) have identified many common variants associated with complex traits, low-frequency and rare variants have not been interrogated in a comprehensive manner. Imputation from dense reference panels, such as the 1000 Genomes Project (1000G), enables testing of ungenotyped variants for association. Here we present the results of imputation using a large, new population-specific panel: the Genome of The Netherlands (GoNL). We benchmarked the performance of the 1000G and GoNL reference sets by comparing imputation genotypes with ‘true' genotypes typed on ImmunoChip in three European populations (Dutch, British, and Italian). GoNL showed significant improvement in the imputation quality for rare variants (MAF 0.05–0.5%) compared with 1000G. In Dutch samples, the mean observed Pearson correlation, r2, increased from 0.61 to 0.71. We also saw improved imputation accuracy for other European populations (in the British samples, r2 improved from 0.58 to 0.65, and in the Italians from 0.43 to 0.47). A combined reference set comprising 1000G and GoNL improved the imputation of rare variants even further. The Italian samples benefitted the most from this combined reference (the mean r2 increased from 0.47 to 0.50). We conclude that the creation of a large population-specific reference is advantageous for imputing rare variants and that a combined reference panel across multiple populations yields the best imputation results

WGS-based telomere length analysis in Dutch family trios implicates stronger maternal inheritance and a role for RRM1 gene

Telomere length (TL) regulation is an important factor in ageing, reproduction and cancer development. Genetic, hereditary and environmental factors regulating TL are currently widely investigated, however, their relative contribution to TL variability is still understudied. We have used whole genome sequencing data of 250 family trios from the Genome of the Netherlands project to perform computational measurement of TL and a series of regression and genome-wide association analyses to reveal TL inheritance patterns and associated genetic factors. Our results confirm that TL is a largely heritable trait, primarily with mother’s, and, to a lesser extent, with father’s TL having the strongest influence on the offspring. In this cohort, mother’s, but not father’s age at conception was positively linked to offspring TL. Age-related TL attrition of 40 bp/year had relatively small influence on TL variability. Finally, we have identified TL-associated variations in ribonuclease reductase catalytic subunit M1 (RRM1 gene), which is known to regulate telomere maintenance in yeast. We also highlight the importance of multivariate approach and the limitations of existing tools for the analysis of TL as a polygenic heritable quantitative trait

Body mass index and outcome in renal transplant recipients: a systematic review and meta-analysis

BACKGROUND: Whether overweight or obese end stage renal disease (ESRD) patients are suitable for renal transplantation (RT) is often debated. The objective of this review and meta-analysis was to systematically investigate the outcome of low versus high BMI recipients after RT. METHODS: Comprehensive searches were conducted in MEDLINE OvidSP, Web of Science, Google Scholar, Embase, and CENTRAL (the Cochrane Library 2014, issue 8). We reviewed four major guidelines that are available regarding (potential) RT recipients. The methodology was in accordance with the Cochrane Handbook for Systematic Reviews of Interventions and written based on the PRISMA statement. The quality assessment of studies was performed by using the GRADE tool. A meta-analysis was performed using Review Manager 5.3. Random-effects models were used. RESULTS: After identifying 5,526 studies addressing this topic, 56 studies were included. We extracted data for 37 outcome measures (including data of more than 209,000 RT recipients), of which 26 could be meta-analysed. The following outcome measures demonstrated significant differences in favour of low BMI (<30) recipients: mortality (RR = 1.52), delayed graft function (RR = 1.52), acute rejection (RR = 1.17), 1-, 2-, and 3-year graft survival (RR = 0.97, 0.95, and 0.97), 1-, 2-, and 3-year patient survival (RR = 0.99, 0.99, and 0.99), wound infection and dehiscence (RR = 3.13 and 4.85), NODAT (RR = 2.24), length of hospital stay (2.31 days), operation duration (0.77 hours), hypertension (RR = 1.35), and incisional hernia (RR = 2.72). However, patient survival expressed in hazard ratios was in significant favour of high BMI recipients. Differences in other outcome parameters were not significant. CONCLUSIONS: Several of the pooled outcome measurements show significant benefits for ‘low’ BMI (<30) recipients. Therefore, we postulate that ESRD patients with a BMI >30 preferably should lose weight prior to RT. If this cannot be achieved with common measures, in morbidly obese RT candidates, bariatric surgery could be considered. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12916-015-0340-5) contains supplementary material, which is available to authorized users