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OBJECTIVE: Diabetes is associated with reduced health-related quality of life (HRQoL). Information on the relationship between HRQoL and glucose-lowering medications in recently diagnosed type 2 diabetes (T2D) is limited. We assessed changes in HRQoL in participants with T2D receiving metformin plus one of four glucose-lowering medications in Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE). RESEARCH DESIGN AND METHODS: A total of 5,047 participants, baseline mean age 57 years, with <10 years T2D duration and glycated hemoglobin level 6.8–8.5% and taking metformin monotherapy, were randomly assigned to glargine, glimepiride, liraglutide, or sitagliptin. HRQoL was evaluated at baseline for 4,885 participants, and at years 1, 2, and 3, with use of the self-administered version of the Quality of Well-being Scale (QWB-SA) and SF-36 physical (PCS) and mental (MCS) component summary scales. Linear models were used to analyze changes in HRQoL over time in intention-to-treat analyses. RESULTS: None of the medications worsened HRQoL. There were no differences in QWB-SA or MCS by treatment group at any time point. PCS scores improved with liraglutide versus other groups at year 1 only. Greater weight loss during year 1 explained half the improvement in PCS scores with liraglutide versus glargine and glimepiride. Liraglutide participants in the upper tertile of baseline BMI showed the greatest improvement in PCS scores at year 1. CONCLUSIONS: Adding liraglutide to metformin in participants within 10 years of T2D diagnosis showed improvement in the SF-36 PCS in comparisons with the other medications at 1 year, which was no longer significant at years 2 and 3. Improvement was related to weight loss and baseline BMI. [ABSTRACT FROM AUTHOR]

OBJECTIVE: In Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) (5,047 participants, mean follow-up 5.0 years), differences in glycemic control were demonstrated over time among four randomized therapies added to metformin. Weight gain and hypoglycemia are also important outcomes for people with type 2 diabetes. We compared the effects of the four randomized GRADE medications on a composite outcome incorporating glycemic deterioration, weight gain, and hypoglycemia. RESEARCH DESIGN AND METHODS: The composite outcome was time to first occurrence of any of the following: HbA1c >7.5%, confirmed; ≥5% weight gain; or severe or recurrent nonsevere hypoglycemia. Secondary analyses included examination of individual components of the composite outcome, subgroup effects and potential mediators, and treatment satisfaction. Cumulative incidence was estimated with the Kaplan-Meier estimator. Cox proportional hazards models were used to assess pairwise group differences in risk of an outcome. RESULTS: Risk of reaching the composite outcome (events per 100 participants per treatment year [PTYs]) was lowest with liraglutide (19 per 100 PTYs) followed by sitagliptin (26 per 100 PTYs), glargine (29 per 100 PTYs), and glimepiride (40 per 100 PTYs); all pairwise comparisons were statistically significant. The order was the same for risk of weight gain and hypoglycemia, but risk of glycemic deterioration was lowest with glargine, followed by liraglutide, glimepiride, and sitagliptin. No significant heterogeneity in risk of composite outcome was detected across prespecified covariates. Participants who reached the composite outcome had modestly but significantly lower treatment satisfaction. CONCLUSIONS: Among participants treated with common second-line drug classes for type 2 diabetes, the liraglutide group had the lowest and glimepiride the highest risk of reaching a composite outcome encompassing glycemic deterioration, weight gain, and hypoglycemia. These findings may inform decision-making regarding type 2 diabetes therapy. [ABSTRACT FROM AUTHOR]

OBJECTIVE: We report mortality outcomes in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) among people with type 2 diabetes diagnosed within 10 years and no recent history of cardiovascular events or cancer. RESEARCH DESIGN AND METHODS: Overall mortality rates and major causes of death were assessed over an average of 5 years of follow-up. Cause of death was adjudicated centrally by a committee masked to treatment assignment. We examined baseline covariates and the 10-year Framingham Risk Score for associations. RESULTS: Mortality rate was low (0.59 per 100 participant-years). Participants who died during follow-up were likely to be older, be male, have a history of hypertension, have a history of smoking, and have moderate albuminuria. The two most common underlying causes of death were "cardiovascular-cause" (a composite of underlying causes) (38.6%) and cancer (26.8%). There were no differences by treatment group. CONCLUSIONS: Among people with diabetes of relatively short duration, cause of death was varied. Attention to health risks beyond cardiovascular diseases is warranted. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To evaluate whether baseline levels of depressive symptoms and diabetes-specific distress are associated with glycemic control in Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE), a large randomized controlled trial comparing the metabolic effects of four common glucose-lowering medications when combined with metformin in individuals with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: The primary and secondary outcomes were defined as an HbA1c value ≥7%, subsequently confirmed, and an HbA1c value >7.5%, subsequently confirmed, respectively. Separate Cox proportional hazards models assessed the association between baseline levels of each exposure of interest (depressive symptoms measured with the eight-item Patient Health Questionnaire and diabetes distress measured with the Diabetes Distress Scale) and the subsequent risk of metabolic outcomes. RESULTS: This substudy included 1,739 participants (56% of whom were non-Hispanic White, 18% non-Hispanic Black, 17% Hispanic, and 68% male; mean [SD] age 58.0 [10.2] years, diabetes duration 4.2 [2.8] years, and HbA1c 7.5% [0.48%]). A total of 1,157 participants reached the primary outcome, with time to event of 2.1 years on average, while 738 participants reached the secondary outcome at 3 years on average. With adjustment for sex, race/ethnicity, treatment group, baseline age, duration of T2DM, BMI, and HbA1c, there were no significant associations between the depressive symptoms or diabetes distress and the subsequent risk of the primary or secondary outcomes. CONCLUSIONS: The current findings suggest that, at least for individuals with diabetes of relatively short duration, baseline levels of emotional distress are not associated with glycemic control over time. [ABSTRACT FROM AUTHOR]

The transplant community is focused on prolonging the ex vivo preservation time of kidney grafts to allow for long-distance kidney graft transportation, assess the viability of marginal grafts, and optimize a platform for the translation of innovative therapeutics to clinical practice, especially those focused on cell and vector delivery to organ conditioning and reprogramming. We describe the first case of feasible preservation of a kidney from a donor after uncontrolled circulatory death over a 73-h period using normothermic perfusion and analyze hemodynamic, biochemical, histological, and transcriptomic parameters for inflammation and kidney injury. The mean pressure and flow values were 71.24 ± 9.62 mmHg and 99.65 ± 18.54 mL/min, respectively. The temperature range was 36.7°C-37.2°C. The renal resistance index was 0.75 ± 0.15 mmHg/mL/min. The mean pH was 7.29 ± 0.15. The lactate concentration peak increased until 213 mg/dL at 6 h, reaching normal values after 34 h of perfusion (8.92 mg/dL). The total urine output at the end of perfusion was 1.185 mL. Histological analysis revealed no significant increase in acute tubular necrosis (ATN) severity as perfusion progressed. The expression of KIM-1, VEGF, and TGFβ decreased after 6-18 h of perfusion until 60 h in which the expression of these genes increased again together with the expression of β -catenin, Ki67, and TIMP1. We show that normothermic perfusion can maintain a kidney graft viable ex vivo for 3 days, thus allowing a rapid translation of pre-clinical therapeutics to clinical practice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Montagud-Marrahi, Luque, Ros, Ajami, Cuadrado-Payan, Estrella, Arancibia, Sánchez-Etayo, Bohils, Marrero, Fundora, Ramírez-Bajo, Banon-Maneus, Rovira, Larque, Campistol, Diekmann and Musquera.)

In the future, farmers will have increasing opportunities to use collaborative smartphone applications for agricultural management. Geospatial information in combination with agricultural-relevant information is a great source of knowledge for farmers. Including maps in collaborative mobile agriculture applications benefits communication processes related to agricultural-relevant questions. Ensuring a positive user experience with map interfaces depends on their design. To develop design guidelines for map-oriented mobile agricultural applications, this study evaluates 24 different map design variations (varying in their elements and degrees of complexity) and characterizes their user experience with 72 coffee farmers as study participants. Our findings show that the most crucial factors for a positive user experience were restricted interactivity, simple tasks to conduct (selecting single point features), and a simplified base map style, highlighting relevant landmarks. Since our farmers consisted primarily of less-experienced smartphone and map users, our findings may also be helpful for users in general, sharing similar user characteristics. While empirical, in-situ studies pose many challenges, they provide relevant insights into the real use situation and user behavior of mobile map applications. Our findings help establish some basic principles for designing map adaptations, serving as a guideline for creating effective mapping applications, which adapt to the farmers' contextual factors. Based on our study results, we suggest future research for continuing conceptualizing principles of map design adaptation and support this effort through empirical, in-situ studies for relating contextual user factors to the adaptation behavior of map applications., Competing Interests: The authors have declared that no competing interests exist.

Drug-induced neurotoxicity is a leading cause of safety-related attrition for therapeutics in clinical trials, often driven by poor predictivity of preclinical in vitro and in vivo models of neurotoxicity. Over a dozen different iPSC-derived 3D spheroids have been described in recent years, but their ability to predict neurotoxicity in patients has not been evaluated nor compared with the predictive power of nonclinical species. To assess the predictive capabilities of human iPSC-derived neural spheroids (microBrains), we used 84 structurally diverse pharmaceuticals with robust clinical and pre-clinical datasets with varying degrees of seizurogenic and neurodegenerative liability. Drug-induced changes in neural viability and phenotypic calcium bursts were assessed using 7 endpoints based on calcium oscillation profiles and cel-lular ATP levels. These endpoints, normalized by therapeutic exposure, were used to build logistic regression models to establish endpoint cutoffs and evaluate probability for clinical neurotoxicity. The neurotoxicity score calculated from the logistic regression model could distinguish neurotoxic from non-neurotoxic clinical molecules with a specificity as high as 93.33% and a sensitivity of 53.49%, demonstrating a very low false positive rate for the prediction of seizures, convulsions, and neurodegeneration. In contrast, nonclinical species showed a higher sensitivity (75%) but much lower specificity (30.4%). The neural spheroids demonstrated higher likelihood ratio positive and inverse likelihood ratio neg-ative values compared with nonclinical safety studies. This assay has the potential to be used as a predictive assay to detect neurotoxicity in early drug discovery, aiding in the early identification of compounds that eventually may fail due to neurotoxicity.

Background: A phase 1 trial was used to evaluate a combination of cisplatin, gemcitabine, and escalating doses of veliparib in patients with untreated advanced pancreatic ductal adenocarcinoma (PDAC) in 2 cohorts: a germline BRCA1/2-mutated (BRCA+) cohort and a wild-type BRCA (BRCA-) cohort. The aims were to determine the safety, dose-limiting toxicities (DLTs), maximum tolerated dose, and recommended phase 2 dose (RP2D) of veliparib combined with cisplatin and gemcitabine and to assess the antitumor efficacy (Response Evaluation Criteria in Solid Tumors, version 1.1) and overall survival., Methods: Gemcitabine and cisplatin were dosed at 600 and 25 mg/m 2 , respectively, over 30 minutes on days 3 and 10 of a 21-day cycle. Four dose levels of veliparib were evaluated: 20 (dose level 0), 40 (dose level 1), and 80 mg (dose level 2) given orally twice daily on days 1 to 12 and 80 mg given twice daily on days 1 to 21 (dose level 2A [DL2A])., Results: Seventeen patients were enrolled: 9 BRCA+ patients, 7 BRCA- patients, and 1 patient with an unknown status. DLTs were reached at DL2A (80 mg twice daily on days 1 to 21). Two of the 5 patients in this cohort (40%) experienced grade 4 neutropenia and thrombocytopenia. Two grade 5 events occurred on protocol. The objective response rate in the BRCA+ cohort was 7 of 9 (77.8%). The median overall survival for BRCA+ patients was 23.3 months (95% confidence interval [CI], 3.8-30.2 months). The median overall survival for BRCA- patients was 11 months (95% CI, 1.5-12.1 months)., Conclusions: The RP2D of veliparib was 80 mg by mouth twice daily on days 1 to 12 in combination with cisplatin and gemcitabine; the DLT was myelosuppression. Substantial antitumor activity was seen in BRCA+ PDAC. A randomized phase 2 trial is currently evaluating cisplatin and gemcitabine with and without veliparib for BRCA+ PDAC (NCT01585805). Cancer 2018;124:1374-82. © 2018 American Cancer Society., (© 2018 American Cancer Society.)

Hepatocellular carcinoma (HCC) is one of the most common human malignancies with poor prognosis and urgent unmet medical need. Aberrant expression of multiple members of the miR-17 family are frequently observed in HCC, and their overexpression promotes tumorigenic properties of HCC cells. However, whether pharmacologic inhibition of the miR-17 family inhibits HCC growth remains unknown. In this study, we validated that the miR-17 family was upregulated in a subset of HCC tumors and cell lines and its inhibition by a tough decoy inhibitor suppressed the growth of Hep3B and HepG2 cells, which overexpress the miR-17 family. Furthermore, inhibition of the miR-17 family led to a global derepression of direct targets of the family in all three HCC cell lines tested. Pathway analysis of the deregulated genes indicated that the genes associated with TGFβ signaling pathway were highly enriched in Hep3B and HepG2 cells. A miR-17 family target gene signature was established and used to identify RL01-17(5), a lipid nanoparticle encapsulating a potent anti-miR-17 family oligonucleotide. To address whether pharmacologic modulation of the miR-17 family can inhibit HCC growth, RL01-17(5) was systemically administrated to orthotopic Hep3B xenografts. Suppression of Hep3B tumor growth in vivo was observed and tumor growth inhibition correlated with induction of miR-17 family target genes. Together, this study provides proof-of-concept for targeting the miR-17 family in HCC therapy. Mol Cancer Ther; 16(5); 905-13. ©2017 AACR ., (©2017 American Association for Cancer Research.)

The BioMart Community Portal (www.biomart.org) is a community-driven effort to provide a unified interface to biomedical databases that are distributed worldwide. The portal provides access to numerous database projects supported by 30 scientific organizations. It includes over 800 different biological datasets spanning genomics, proteomics, model organisms, cancer data, ontology information and more. All resources available through the portal are independently administered and funded by their host organizations. The BioMart data federation technology provides a unified interface to all the available data. The latest version of the portal comes with many new databases that have been created by our ever-growing community. It also comes with better support and extensibility for data analysis and visualization tools. A new addition to our toolbox, the enrichment analysis tool is now accessible through graphical and web service interface. The BioMart community portal averages over one million requests per day. Building on this level of service and the wealth of information that has become available, the BioMart Community Portal has introduced a new, more scalable and cheaper alternative to the large data stores maintained by specialized organizations., (© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: Prognosis prediction for resected primary colon cancer is based on the T-stage Node Metastasis (TNM) staging system. We investigated if four well-documented gene expression risk scores can improve patient stratification., Methods: Microarray-based versions of risk-scores were applied to a large independent cohort of 688 stage II/III tumors from the PETACC-3 trial. Prognostic value for relapse-free survival (RFS), survival after relapse (SAR), and overall survival (OS) was assessed by regression analysis. To assess improvement over a reference, prognostic model was assessed with the area under curve (AUC) of receiver operating characteristic (ROC) curves. All statistical tests were two-sided, except the AUC increase., Results: All four risk scores (RSs) showed a statistically significant association (single-test, P < .0167) with OS or RFS in univariate models, but with HRs below 1.38 per interquartile range. Three scores were predictors of shorter RFS, one of shorter SAR. Each RS could only marginally improve an RFS or OS model with the known factors T-stage, N-stage, and microsatellite instability (MSI) status (AUC gains < 0.025 units). The pairwise interscore discordance was never high (maximal Spearman correlation = 0.563) A combined score showed a trend to higher prognostic value and higher AUC increase for OS (HR = 1.74, 95% confidence interval [CI] = 1.44 to 2.10, P < .001, AUC from 0.6918 to 0.7321) and RFS (HR = 1.56, 95% CI = 1.33 to 1.84, P < .001, AUC from 0.6723 to 0.6945) than any single score., Conclusions: The four tested gene expression-based risk scores provide prognostic information but contribute only marginally to improving models based on established risk factors. A combination of the risk scores might provide more robust information. Predictors of RFS and SAR might need to be different., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Constitutive activation of phosphoinositide 3-kinase (PI3K) occurs frequently in many human tumors via either gene mutation in the p110α catalytic subunit of PI3K or functional loss of tumor suppressor PTEN. Patients with small-cell lung cancer (SCLC) have very poor prognosis and survival rates such that an effective targeted therapy is in strong demand for these patients. In this study, we characterized the highly selective oral PI3K inhibitor, PF-4989216, in preclinical SCLC models to investigate whether targeting the PI3K pathway is an effective targeted therapy option for SCLCs that harbor a PIK3CA mutation., Experimental Design: A panel of SCLC cell lines with PIK3CA mutation or PTEN loss were treated with PF-4989216 in several in vitro assays, including PI3K pathway signaling, cell viability, apoptosis, cell-cycle progression, and cell transformation. SCLC cell lines that were sensitive in vitro to PF-4989216 were further evaluated by in vivo animal studies to determine the pharmacokinetic/pharmacodynamic relationship and tumor growth inhibition (TGI) by PF-4989216 treatment., Results: PF-4989216 inhibited PI3K downstream signaling and subsequently led to apoptosis induction, and inhibition in cell viability, transformation, and xenograft tumor growth in SCLCs harboring PIK3CA mutation. In SCLCs with PTEN loss, PF-4989216 also inhibited PI3K signaling but did not induce BCL2-interacting mediator (BIM)-mediated apoptosis nor was there any effect on cell viability or transformation. These results implicate differential tumorigenesis and apoptosis mechanisms in SCLCs harboring PIK3CA mutation versus PTEN loss., Conclusions: Our results suggest that PF-4989216 is a potential cancer drug candidate for patients with SCLC with PIK3CA mutation but not PTEN loss., (©2013 AACR.)

Hepatocellular carcinoma (HCC) is one of the most deadly cancers worldwide and has no effective treatment, yet the molecular basis of hepatocarcinogenesis remains largely unknown. Here we report findings from a whole-genome sequencing (WGS) study of 88 matched HCC tumor/normal pairs, 81 of which are Hepatitis B virus (HBV) positive, seeking to identify genetically altered genes and pathways implicated in HBV-associated HCC. We find beta-catenin to be the most frequently mutated oncogene (15.9%) and TP53 the most frequently mutated tumor suppressor (35.2%). The Wnt/beta-catenin and JAK/STAT pathways, altered in 62.5% and 45.5% of cases, respectively, are likely to act as two major oncogenic drivers in HCC. This study also identifies several prevalent and potentially actionable mutations, including activating mutations of Janus kinase 1 (JAK1), in 9.1% of patients and provides a path toward therapeutic intervention of the disease.

Background: The androgen receptor plays a critical role throughout the progression of prostate cancer and is an important drug target for this disease. While chromatin immunoprecipitation coupled with massively parallel sequencing (ChIP-Seq) is becoming an essential tool for studying transcription and chromatin modification factors, it has rarely been employed in the context of drug discovery., Results: Here we report changes in the genome-wide AR binding landscape due to dose-dependent inhibition by drug-like small molecules using ChIP-Seq. Integration of sequence analysis, transcriptome profiling, cell viability assays and xenograft tumor growth inhibition studies enabled us to establish a direct cistrome-activity relationship for two novel potent AR antagonists. By selectively occupying the strongest binding sites, AR signaling remains active even when androgen levels are low, as is characteristic of first-line androgen ablation therapy. Coupled cistrome and transcriptome profiling upon small molecule antagonism led to the identification of a core set of AR direct effector genes that are most likely to mediate the activities of targeted agents: unbiased pathway mapping revealed that AR is a key modulator of steroid metabolism by forming a tightly controlled feedback loop with other nuclear receptor family members and this oncogenic effect can be relieved by antagonist treatment. Furthermore, we found that AR also has an extensive role in negative gene regulation, with estrogen (related) receptor likely mediating its function as a transcriptional repressor., Conclusions: Our study provides a global and dynamic view of AR's regulatory program upon antagonism, which may serve as a molecular basis for deciphering and developing AR therapeutics.

Purpose: Our purpose was development and assessment of a BRAF-mutant gene expression signature for colon cancer (CC) and the study of its prognostic implications., Materials and Methods: A set of 668 stage II and III CC samples from the PETACC-3 (Pan-European Trails in Alimentary Tract Cancers) clinical trial were used to assess differential gene expression between c.1799T>A (p.V600E) BRAF mutant and non-BRAF, non-KRAS mutant cancers (double wild type) and to construct a gene expression-based classifier for detecting BRAF mutant samples with high sensitivity. The classifier was validated in independent data sets, and survival rates were compared between classifier positive and negative tumors., Results: A 64 gene-based classifier was developed with 96% sensitivity and 86% specificity for detecting BRAF mutant tumors in PETACC-3 and independent samples. A subpopulation of BRAF wild-type patients (30% of KRAS mutants, 13% of double wild type) showed a gene expression pattern and had poor overall survival and survival after relapse, similar to those observed in BRAF-mutant patients. Thus they form a distinct prognostic subgroup within their mutation class., Conclusion: A characteristic pattern of gene expression is associated with and accurately predicts BRAF mutation status and, in addition, identifies a population of BRAF mutated-like KRAS mutants and double wild-type patients with similarly poor prognosis. This suggests a common biology between these tumors and provides a novel classification tool for cancers, adding prognostic and biologic information that is not captured by the mutation status alone. These results may guide therapeutic strategies for this patient segment and may help in population stratification for clinical trials.

Previous work showed that immunotherapy with a DNA vaccine encoding Trypanosoma cruzi antigen TSA-1 reduced cardiac tissue damage and improved survival in mice when administered during the acute or chronic phases of T. cruzi infection. In the present study, we investigated changes in T-cell populations induced by DNA vaccine immunotherapy. ICR mice were infected with 500 T. cruzi blood trypomastigotes and treated during the acute or chronic phases with two 100 microg doses of DNA vaccine. Analysis of stained splenocytes by flow cytometry indicated that the therapeutic vaccine induced a rapid increase in the number of CD4+ and CD8+ T cells in both the acute and chronic phases. Also, there was a rapid increase in T. cruzi-specific IFNgamma-producing CD8+ T cells following treatment during the chronic phase. The effects of these changes on the control of infection required longer time periods to be detectable but resulted in a reduction in myocarditis and T. cruzi parasite burden in both phases of the infection, as assessed by histopathologic analysis and semi-quantitative PCR detection of T. cruzi in cardiac tissue. These results suggest that DNA vaccines that induce CD8+ T-cells activity and IFNgamma production, would be good candidates for effective therapeutic vaccination against T. cruzi infection.