Proteasome Inhibitor-Related Cardiotoxicity: Mechanisms, Diagnosis, and Management.

Multiple myeloma is the second most common hematologic malignancy in the USA, with over 32,000 new cases and nearly 13,000 deaths expected in 2019. The past few decades in myeloma research have yielded significant advances, leading to the expansion of novel anti-myeloma agents. This review describes the incidence and mechanisms of cardiotoxicity for the FDA-approved proteasome inhibitors in myeloma and proposes strategies to assess and manage resultant cardiovascular adverse events.Proteasome inhibition precipitates protein aggregation and alters transcriptional activation of NF-κB targets which contributes to a pro-apoptotic signaling cascade in myeloma cells. Similar effects in cardiomyocytes and vascular smooth muscle endothelium, along with off-target downregulation of autophagy and signaling alterations of nitric oxide homeostasis, may be linked to observed cardiotoxic effects. There is preliminary evidence for cardioprotective potential for rutin, dexrazoxane, and apremilast that could have clinical applicability in the future. Of the proteasome inhibitors used in clinical practice, carfilzomib is the most strongly associated with cardiotoxicity. Patients with anticipated carfilzomib treatment should undergo assessment and optimization of baseline cardiovascular risk, with close monitoring during treatment. Previous clinical trials were not specifically designed to assess proteasome inhibitor-related cardiotoxicity, creating a need for future studies to identify and risk stratify vulnerable individuals and to develop potential cardioprotective strategies in attenuating cardiac injury

Create a translational medicine knowledge repository - Research downsizing, mergers and increased outsourcing have reduced the depth of in-house translational medicine expertise and institutional memory at many pharmaceutical and biotech companies: how will they avoid relearning old lessons?

Pharmaceutical industry consolidation and overall research downsizing threatens the ability of companies to benefit from their previous investments in translational research as key leaders with the most knowledge of the successful use of biomarkers and translational pharmacology models are laid off or accept their severance packages. Two recently published books may help to preserve this type of knowledge but much of this type of information is not in the public domain. Here we propose the creation of a translational medicine knowledge repository where companies can submit their translational research data and access similar data from other companies in a precompetitive environment. This searchable repository would become an invaluable resource for translational scientists and drug developers that could speed and reduce the cost of new drug development

HIPAD - A Hybrid Interior-Point Alternating Direction algorithm for knowledge-based SVM and feature selection

We consider classification tasks in the regime of scarce labeled training data in high dimensional feature space, where specific expert knowledge is also available. We propose a new hybrid optimization algorithm that solves the elastic-net support vector machine (SVM) through an alternating direction method of multipliers in the first phase, followed by an interior-point method for the classical SVM in the second phase. Both SVM formulations are adapted to knowledge incorporation. Our proposed algorithm addresses the challenges of automatic feature selection, high optimization accuracy, and algorithmic flexibility for taking advantage of prior knowledge. We demonstrate the effectiveness and efficiency of our algorithm and compare it with existing methods on a collection of synthetic and real-world data.Comment: Proceedings of 8th Learning and Intelligent OptimizatioN (LION8) Conference, 201

Why growth equals power - and why it shouldn't : constructing visions of China

When discussing the success of China's transition from socialism, there is a tendency to focus on growth figures as an indication of performance. Whilst these figures are indeed impressive, we should not confuse growth with development and assume that the former necessarily automatically generates the latter. Much has been done to reduce poverty in China, but the task is not as complete as some observers would suggest; particularly in terms of access to health, education and welfare, and also in dealing with relative (rather than absolute) depravation and poverty. Visions of China have been constructed that exaggerate Chinese development and power in the global system partly to serve political interests, but partly due to the failure to consider the relationship between growth and development, partly due to the failure to disaggregate who gets what in China, and partly due to the persistence of inter-national conceptions of globalised production, trade, and financial flows

Developing a clinical trial unit to advance research in an academic institution

AbstractResearch, clinical care, and education are the three cornerstones of academic health centers in the United States. The research climate has always been riddled with ebbs and flows, depending on funding availability. During a time of reduced funding, the number and scope of research studies have been reduced, and in some instances, a field of study has been eliminated. Recent reductions in the research funding landscape have led institutions to explore new ways to continue supporting research. Mayo Clinic in Rochester, MN has developed a clinical trial unit within the Department of Medicine, which provides shared resources for many researchers and serves as a solution for training and mentoring new investigators and study teams. By building on existing infrastructure and providing supplemental resources to existing research, the Department of Medicine clinical trial unit has evolved into an effective mechanism for conducting research. This article discusses the creation of a central unit to provide research support in clinical trials and presents the advantages, disadvantages, and required building blocks for such a unit

A Novel Unsupervised Method to Identify Genes Important in the Anti-viral Response: Application to Interferon/Ribavirin in Hepatitis C Patients

Background: Treating hepatitis C with interferon/ribavirin results in a varied response in terms of decrease in viral titer and ultimate outcome. Marked responders have a sharp decline in viral titer within a few days of treatment initiation, whereas in other patients there is no effect on the virus (poor responders). Previous studies have shown that combination therapy modifies expression of hundreds of genes in vitro and in vivo. However, identifying which, if any, of these genes have a role in viral clearance remains challenging. Aims: The goal of this paper is to link viral levels with gene expression and thereby identify genes that may be responsible for early decrease in viral titer. Methods: Microarrays were performed on RNA isolated from PBMC of patients undergoing interferon/ribavirin therapy. Samples were collected at pre-treatment (day 0), and 1, 2, 7, 14 and 28 days after initiating treatment. A novel method was applied to identify genes that are linked to a decrease in viral titer during interferon/ribavirin treatment. The method uses the relationship between inter-patient gene expression based proximities and inter-patient viral titer based proximities to define the association between microarray gene expression measurements of each gene and viral-titer measurements. Results: We detected 36 unique genes whose expressions provide a clustering of patients that resembles viral titer based clustering of patients. These genes include IRF7, MX1, OASL and OAS2, viperin and many ISG's of unknown function. Conclusion: The genes identified by this method appear to play a major role in the reduction of hepatitis C virus during the early phase of treatment. The method has broad utility and can be used to analyze response to any group of factors influencing biological outcome such as antiviral drugs or anti-cancer agents where microarray data are available. © 2007 Brodsky et al

Dairy Foods in a Moderate Energy Restricted Diet Do Not Enhance Central Fat, Weight, and Intra-Abdominal Adipose Tissue Losses nor Reduce Adipocyte Size or Inflammatory Markers in Overweight and Obese Adults: A Controlled Feeding Study

Background. Research on dairy foods to enhance weight and fat loss when incorporated into a modest weight loss diet has had mixed results. Objective. A 15-week controlled feeding study to determine if dairy foods enhance central fat and weight loss when incorporated in a modest energy restricted diet of overweight and obese adults. Design. A 3-week run-in to establish energy needs; a 12-week 500 kcal/d energy reduction with 71 low-dairy-consuming overweight and obese adults randomly assigned to diets: ≤1 serving dairy/d (low dairy, LD) or ≤4 servings dairy/d (adequate dairy, AD). All foods were weighed and provided by the metabolic kitchen. Weight, fat, intra-abdominal adipose tissue (IAAT), subcutaneous adipose tissue (SAT) macrophage number, SAT inflammatory gene expression, and circulating cytokines were measured. Results. No diet differences were observed in weight, fat, or IAAT loss; nor SAT mRNA expression of inflammation, circulating cytokines, fasting lipids, glucose, or insulin. There was a significant increase (P = 0.02) in serum 25-hydroxyvitamin D in the AD group. Conclusion. Whether increased dairy intake during weight loss results in greater weight and fat loss for individuals with metabolic syndrome deserves investigation. Assessment of appetite, hunger, and satiety with followup on weight regain should be considered

Impact of actin filament stabilization on adult hippocampal and olfactory bulb neurogenesis

Rearrangement of the actin cytoskeleton is essential for dynamic cellular processes. Decreased actin turnover and rigidity of cytoskeletal structures have been associated with aging and cell death. Gelsolin is a Ca(2+)-activated actin-severing protein that is widely expressed throughout the adult mammalian brain. Here, we used gelsolin-deficient (Gsn(-/-)) mice as a model system for actin filament stabilization. In Gsn(-/-) mice, emigration of newly generated cells from the subventricular zone into the olfactory bulb was slowed. In vitro, gelsolin deficiency did not affect proliferation or neuronal differentiation of adult neural progenitors cells (NPCs) but resulted in retarded migration. Surprisingly, hippocampal neurogenesis was robustly induced by gelsolin deficiency. The ability of NPCs to intrinsically sense excitatory activity and thereby implement coupling between network activity and neurogenesis has recently been established. Depolarization-induced [Ca(2+)](i) increases and exocytotic neurotransmitter release were enhanced in Gsn(-/-) synaptosomes. Importantly, treatment of Gsn(-/-) synaptosomes with mycotoxin cytochalasin D, which, like gelsolin, produces actin disassembly, decreased enhanced Ca(2+) influx and subsequent exocytotic norepinephrine release to wild-type levels. Similarly, depolarization-induced glutamate release from Gsn(-/-) brain slices was increased. Furthermore, increased hippocampal neurogenesis in Gsn(-/-) mice was associated with a special microenvironment characterized by enhanced density of perfused vessels, increased regional cerebral blood flow, and increased endothelial nitric oxide synthase (NOS-III) expression in hippocampus. Together, reduced filamentous actin turnover in presynaptic terminals causes increased Ca(2+) influx and, subsequently, elevated exocytotic neurotransmitter release acting on neural progenitors. Increased neurogenesis in Gsn(-/-) hippocampus is associated with a special vascular niche for neurogenesis