Sustained proliferation in cancer: mechanisms and novel therapeutic targets

Proliferation is an important part of cancer development and progression. This is manifest by altered expression and/or activity of cell cycle related proteins. Constitutive activation of many signal transduction pathways also stimulates cell growth. Early steps in tumor development are associated with a fibrogenic response and the development of a hypoxic environment which favors the survival and proliferation of cancer stem cells. Part of the survival strategy of cancer stem cells may manifested by alterations in cell metabolism. Once tumors appear, growth and metastasis may be supported by overproduction of appropriate hormones (in hormonally dependent cancers), by promoting angiogenesis, by undergoing epithelial to mesenchymal transition, by triggering autophagy, and by taking cues from surrounding stromal cells. A number of natural compounds (e.g., curcumin, resveratrol, indole-3-carbinol, brassinin, sulforaphane, epigallocatechin-3-gallate, genistein, ellagitannins, lycopene and quercetin) have been found to inhibit one or more pathways that contribute to proliferation (e.g., hypoxia inducible factor 1, nuclear factor kappa B, phosphoinositide 3 kinase/Akt, insulin-like growth factor receptor 1, Wnt, cell cycle associated proteins, as well as androgen and estrogen receptor signaling). These data, in combination with bioinformatics analyses, will be very important for identifying signaling pathways and molecular targets that may provide early diagnostic markers and/or critical targets for the development of new drugs or drug combinations that block tumor formation and progression

A multi-targeted approach to suppress tumor-promoting inflammation

Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-κB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes

Challenges in Evaluating Safety and Efficacy in Drug Development for Rare Diseases: A Review for Pharmacists

A rare disease, or orphan disease, in the United States is a condition with a national prevalence of fewer than 200,000 diagnoses. As therapies for rare diseases are developed and brought to market, pharmacists should understand the challenges of drug development for rare diseases and aid in educating patients about the approval process for rare disease therapies. Developing drugs for treating rare diseases presents unique challenges in proving the drug’s safety and efficacy with adequate study design, power, and validity. Results of the clinical trials for rare diseases may be weakened by small patient populations, limited disease information, and difficulty defining end points and biomarkers. In addition to investigational barriers, pharmaceutical companies face financial barriers in justifying the investment of bringing a rare disease therapy to market. Federal programs, such as the Orphan Drug Act of 1983, expedited review, the Rare Pediatric Disease Priority Review Vouchers (RPD PRV) program, and the 21st Century Cures Act, give pharmaceutical companies motivation to develop therapies for rare diseases. The objective of this article is to provide pharmacists with an understanding of the challenges in designing clinical trials for drugs for rare diseases and discuss federal programs that address efforts to develop safe and efficacious drugs for rare diseases

Behavior-based diabetes management: Impact on care, hospitalizations, and costs

OBJECTIVES: To (1) examine the impact of the Diabetes Care Rewards (DCR) program on adherence to care standards and (2) evaluate the economic impact of adherence to care standards. STUDY DESIGN: A retrospective observational cohort study design with propensity matching. Additional covariates adjustment was used to minimize residual imbalance. METHODS: Utilization and cost data were compared between individuals enrolled vs individuals eligible for but not enrolled in the DCR program using a standard mean difference. Individuals were employees or their dependents from self-insured companies throughout the United States. Outcomes included adherence to the care standards, service utilization, and costs. RESULTS: A total of 3318 propensity-matched participants were included. Primary analysis revealed that enrolled members increased adherence to semiannual glycated hemoglobin, annual lipid, and annual urine albumincreatinine ratio testing. Additionally, enrolled members experienced less utilization of high-acuity services and increased rates of physician visits. In a secondary analysis, the enrolled group was associated with greater pharmaceutical costs but lower medical costs. CONCLUSIONS: A behavioral science- and incentive-based diabetes management program was associated with greater rates of adherence to recommended diabetes monitoring care standards, increased routine clinic visits, decreased hospital admissions, and decreased inpatient days. Anticipated increases in pharmaceutical expenditures were offset by overall lower medical expenditures. Results indicate the economic benefits of adherence to evidencebased standards for diabetes care

Firefly: The Case for a Holistic Understanding of the Global Structure and Dynamics of the Sun and the Heliosphere

This white paper is on the HMCS Firefly mission concept study. Firefly focuses on the global structure and dynamics of the Sun's interior, the generation of solar magnetic fields, the deciphering of the solar cycle, the conditions leading to the explosive activity, and the structure and dynamics of the corona as it drives the heliosphere