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Drug-induced cardiovascular complications are the most common adverse drug events and account for the withdrawal or severe restrictions on the use of multitudinous postmarketed drugs. In this study, we developed new in silico models for systematic identification of drug-induced cardiovascular complications in drug discovery and postmarketing surveillance. Specifically, we collected drug-induced cardiovascular complications covering the five most common types of cardiovascular outcomes (hypertension, heart block, arrhythmia, cardiac failure, and myocardial infarction) from four publicly available data resources: Comparative Toxicogenomics Database, SIDER, Offsides, and MetaADEDB. Using these databases, we developed a combined classifier framework through integration of five machine-learning algorithms: logistic regression, random forest, k-nearest neighbors, support vector machine, and neural network. The totality of models included 180 single classifiers with area under receiver operating characteristic curves (AUC) ranging from 0.647 to 0.809 on 5-fold cross-validations. To develop the combined classifiers, we then utilized a neural network algorithm to integrate the best four single classifiers for each cardiovascular outcome. The combined classifiers had higher performance with an AUC range from 0.784 to 0.842 compared to single classifiers. Furthermore, we validated our predicted cardiovascular complications for 63 anticancer agents using experimental data from clinical studies, human pluripotent stem cell-derived cardiomyocyte assays, and literature. The success rate of our combined classifiers reached 87%. In conclusion, this study presents powerful in silico tools for systematic risk assessment of drug-induced cardiovascular complications. This tool is relevant not only in early stages of drug discovery but also throughout the life of a drug including clinical trials and postmarketing surveillance.
Macrophages are cells of the innate immune system that are resident in all tissues, including metabolic organs such as the liver and adipose tissue (AT). Because of their phenotypic flexibility, they play beneficial roles in tissue homeostasis, but they also contribute to the progression of metabolic disease. Thus, they are ideal therapeutic targets for diseases such as insulin resistance (IR), nonalcoholic fatty liver disease (NAFLD), and atherosclerosis. Recently, discoveries in the area of drug delivery have facilitated phenotype-specific targeting of macrophages. In this review we discuss advances in potential therapeutics for metabolic diseases via macrophage-specific delivery. We highlight micro- and nanoparticles, liposomes, and oligopeptide complexes, and how they can be used to alter macrophage phenotype for a more metabolically favorable tissue environment.
Published by Elsevier Ltd.
Inactivation of the retinoblastoma gene () product, pRB, is common in many human cancers. Targeting downstream effectors of pRB that are central to tumorigenesis is a promising strategy to block the growth of tumors harboring loss-of-function mutations. One such effector is retinoblastoma-binding protein 2 (RBP2, also called JARID1A or KDM5A), which encodes an H3K4 demethylase. Binding of pRB to RBP2 has been linked to the ability of pRB to promote senescence and differentiation. Importantly, genetic ablation of RBP2 is sufficient to phenocopy pRB's ability to induce these cellular changes in cell culture experiments. Moreover, germline deletion significantly impedes tumorigenesis in mice. The value of RBP2 as a therapeutic target in cancer, however, hinges on whether loss of RBP2 could block the growth of established tumors as opposed to simply delaying their onset. Here we show that conditional, systemic ablation of RBP2 in tumor-bearing mice is sufficient to slow tumor growth and significantly extend survival without causing obvious toxicity to the host. These findings show that established -null tumors require RBP2 for growth and further credential RBP2 as a therapeutic target in human cancers driven by inactivation.
Targeted therapy is an effective standard of care in BRAF-mutated malignant melanoma. However, the duration of tumor remission varies unpredictably among patients, and relapse is almost inevitable. Here, we examine the responses of several BRAF-mutated melanoma cell lines (including isogenic subclones) to BRAF inhibitors. We observe complex response dynamics across cell lines, with short-term responses (<100 h) varying from cell line to cell line. In the long term, however, we observe equilibration of all drug-treated populations into a nonquiescent state characterized by a balanced rate of death and division, which we term the "idling" state, and to our knowledge, this state has not been previously reported. Using mathematical modeling, we propose that the observed population-level dynamics are the result of cells transitioning between basins of attraction within a drug-modified phenotypic landscape. Each basin is associated with a drug-induced proliferation rate, a recently introduced metric of an antiproliferative drug effect. The idling population state represents a new dynamic equilibrium in which cells are distributed across the landscape such that the population achieves zero net growth. By fitting our model to experimental drug-response data, we infer the phenotypic landscapes of all considered melanoma cell lines and provide a unifying view of how BRAF-mutated melanomas respond to BRAF inhibition. We hypothesize that the residual disease observed in patients after targeted therapy is composed of a significant number of idling cells. Thus, defining molecular determinants of the phenotypic landscape that idling populations occupy may lead to "targeted landscaping" therapies based on rational modification of the landscape to favor basins with greater drug susceptibility.
Copyright © 2018 Biophysical Society. Published by Elsevier Inc. All rights reserved.
BACKGROUND - Cardiac metastases from renal cell carcinoma (RCC) are uncommon and there are limited data regarding the presentation and outcomes of this population. The objective of this study was to evaluate the characteristics and outcomes of patients with RCC with cardiac metastasis without inferior vena cava (IVC) involvement.
MATERIALS AND METHODS - We conducted a pooled retrospective analysis of metastatic RCC patients treated in 4 clinical trials. Additionally, we conducted a systematic review of cases reported in the literature from 1973 to 2015. Patients with cardiac metastases from RCC without IVC involvement were included. Patient and disease characteristics were described. Additionally, treatments, response to therapy, and survival outcomes were summarized.
RESULTS - Of 1765 metastatic RCC patients in the clinical trials database, 10 had cardiac metastases without IVC involvement. All patients received treatment with targeted therapy. There was 1 observed partial response (10%) and 6 patients showed stable disease (60%). The median progression-free survival was 6.9 months. The systematic review of reported clinical cases included 39 patients. In these patients, the most common cardiac site of involvement was the right ventricle (51%; n = 20). Patients were treated with medical (28%; n = 11) and/or surgical treatment (49%; n = 19) depending on whether disease was isolated (n = 13) or multifocal (n = 26).
CONCLUSION - To our knowledge, this is the first series to report on the presentation and outcomes of patients with cardiac metastasis without IVC involvement in RCC. We highlight that although the frequency of patients with cardiac metastases without IVC involvement is low, these patients have a unique clinical presentation and warrant special multidisciplinary management.
Copyright © 2017 Elsevier Inc. All rights reserved.
Multiplex genomic profiling is standard of care for patients with advanced lung adenocarcinomas. The Lung Cancer Mutation Consortium (LCMC) is a multi-institutional effort to identify and treat oncogenic driver events in patients with lung adenocarcinomas. Sixteen U.S. institutions enrolled 1,367 patients with lung cancer in LCMC2; 904 were deemed eligible and had at least one of 14 cancer-related genes profiled using validated methods including genotyping, massively parallel sequencing, and IHC. The use of targeted therapies in patients with or p.V600E mutations, , or rearrangements, or amplification was associated with a survival increment of 1.5 years compared with those with such mutations not receiving targeted therapy, and 1.0 year compared with those lacking a targetable driver. Importantly, 60 patients with a history of smoking derived similar survival benefit from targeted therapy for alterations in //, when compared with 75 never smokers with the same alterations. In addition, coexisting mutations were associated with shorter survival among patients with , or alterations. Patients with adenocarcinoma of the lung and an oncogenic driver mutation treated with effective targeted therapy have a longer survival, regardless of prior smoking history. Molecular testing should be performed on all individuals with lung adenocarcinomas irrespective of clinical characteristics. Routine use of massively parallel sequencing enables detection of both targetable driver alterations and tumor suppressor gene and other alterations that have potential significance for therapy selection and as predictive markers for the efficacy of treatment. .
©2017 American Association for Cancer Research.
Corticotropin releasing factor (CRF) is a neuropeptide that plays a key role in behavioral and physiological responses to stress. A large body of animal literature implicates CRF acting at type 1 CRF receptors (CRFR1) in consumption by alcohol-dependent subjects, stress-induced reinstatement of alcohol seeking, and possibly binge alcohol consumption. These studies have encouraged recent pilot studies of CRFR1 antagonists in humans with alcohol use disorder (AUD). It was a great disappointment to many in the field that these studies failed to show an effect of these compounds on stress-induced alcohol craving. Here, we examine these studies to explore potential limitations and discuss preclinical and human literature to ask whether CRFR1 is still a valid drug target to pursue for the treatment of AUD.
Copyright © 2017 by the Research Society on Alcoholism.
Hypoxia in the embryo is a frequent cause of intra-uterine growth retardation, low birth weight, and multiple organ defects. In the kidney, this can lead to low nephron endowment, predisposing to chronic kidney disease and arterial hypertension. A key component in cellular adaptation to hypoxia is the hypoxia-inducible factor pathway, which is regulated by prolyl-4-hydroxylase domain (PHD) dioxygenases PHD1, PHD2, and PHD3. In the adult kidney, PHD oxygen sensors are differentially expressed in a cell type-dependent manner and control the production of erythropoietin in interstitial cells. However, the role of interstitial cell PHDs in renal development has not been examined. Here we used a genetic approach in mice to interrogate PHD function in FOXD1-expressing stroma during nephrogenesis. We demonstrate that PHD2 and PHD3 are essential for normal kidney development as the combined inactivation of stromal PHD2 and PHD3 resulted in renal failure that was associated with reduced kidney size, decreased numbers of glomeruli, and abnormal postnatal nephron formation. In contrast, nephrogenesis was normal in animals with individual PHD inactivation. We furthermore demonstrate that the defect in nephron formation in PHD2/PHD3 double mutants required intact hypoxia-inducible factor-2 signaling and was dependent on the extent of stromal hypoxia-inducible factor activation. Thus, hypoxia-inducible factor prolyl-4-hydroxylation in renal interstitial cells is critical for normal nephron formation.
Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
amplification occurs in approximately 15% of estrogen receptor-positive (ER) human breast cancers. We investigated mechanisms by which amplification confers antiestrogen resistance to ER breast cancer. ER tumors from patients treated with letrozole before surgery were subjected to Ki67 IHC, FGFR1 FISH, and RNA sequencing (RNA-seq). ER/-amplified breast cancer cells, and patient-derived xenografts (PDX) were treated with FGFR1 siRNA or the FGFR tyrosine kinase inhibitor lucitanib. Endpoints were cell/xenograft growth, FGFR1/ERα association by coimmunoprecipitation and proximity ligation, ER genomic activity by ChIP sequencing, and gene expression by RT-PCR. ER/-amplified tumors in patients treated with letrozole maintained cell proliferation (Ki67). Estrogen deprivation increased total and nuclear FGFR1 and FGF ligands expression in ER/amplified primary tumors and breast cancer cells. In estrogen-free conditions, FGFR1 associated with ERα in tumor cell nuclei and regulated the transcription of ER-dependent genes. This association was inhibited by a kinase-dead FGFR1 mutant and by treatment with lucitanib. ChIP-seq analysis of estrogen-deprived ER/-amplified cells showed binding of FGFR1 and ERα to DNA. Treatment with fulvestrant and/or lucitanib reduced FGFR1 and ERα binding to DNA. RNA-seq data from -amplified patients' tumors treated with letrozole showed enrichment of estrogen response and E2F target genes. Finally, growth of ER/amplified cells and PDXs was more potently inhibited by fulvestrant and lucitanib combined than each drug alone.s These data suggest the ERα pathway remains active in estrogen-deprived ER/-amplified breast cancers. Therefore, these tumors are endocrine resistant and should be candidates for treatment with combinations of ER and FGFR antagonists. .
©2017 American Association for Cancer Research.