Topical application of gemcitabine generates microvesicle particles in human and murine skin.

Chemotherapy has remained the mainstay for the treatment of multiple types of cancers. In particular, topical use of chemotherapy has been used for skin cancers. Though effective, topical chemotherapy has been limited due to adverse effects such as local and even systemic toxicities. Our recent studies demonstrated that exposure to pro-oxidative stressors, including therapeutic agents induces the generation of extracellular vesicles known as microvesicle particles (MVP) which are dependent on activation of the Platelet-activating factor-receptor (PAFR), a G-protein coupled receptor present on various cell types, and acid sphingomyelinase (aSMase), an enzyme required for MVP biogenesis. Based upon this premise, we tested the hypothesis that topical application of gemcitabine will induce MVP generation in human and murine skin. Our ex vivo studies using human skin explants demonstrate that gemcitabine treatment results in MVP generation in a dose-dependent manner in a process blocked by PAFR antagonist and aSMase inhibitor. Importantly, gemcitabine-induced MVPs carry PAFR agonists. To confirm the mechanisms, we employed PAFR-expressing and deficient (Ptafr-/- ) mouse models as well as mice deficient in aSMase enzyme (Spmd1-/- ). Similar to the findings using pharmacologic tools, genetic-based approaches demonstrate that gemcitabine-induced MVP release in WT mice was blunted in Ptafr-/- and Spmd1-/- mice. These findings demonstrate a novel mechanism by which local chemotherapy can generate bioactive components as a bystander effect in a process that is dependent upon the PAFR-aSMase pathway.

Myeloid-Derived Suppressor Cells and Pancreatic Cancer: Implications in Novel Therapeutic Approaches.

Pancreatic ductal adenocarcinoma (PDAC) remains a devastating human malignancy with poor prognosis and low survival rates. Several cellular mechanisms have been linked with pancreatic carcinogenesis and also implicated in inducing tumor resistance to known therapeutic regimens. Of various factors, immune evasion mechanisms play critical roles in tumor progression and impeding the efficacy of cancer therapies including PDAC. Among immunosuppressive cell types, myeloid-derived suppressor cells (MDSCs) have been extensively studied and demonstrated to not only support PDAC development but also hamper the anti-tumor immune responses elicited by therapeutic agents. Notably, recent efforts have been directed in devising novel approaches to target MDSCs to limit their effects. Multiple strategies including immune-based approaches have been explored either alone or in combination with therapeutic agents to target MDSCs in preclinical and clinical settings of PDAC. The current review highlights the roles and mechanisms of MDSCs as well as the implications of this immunomodulatory cell type as a potential target to improve the efficacy of therapeutic regimens for PDAC.

Heart failure and "inoperable" aortic stenosis: staged balloon aortic valvuloplasty and aortic valve bypass.

The prognosis for patients with symptomatic aortic stenosis is poor but is improved significantly by surgical aortic valve replacement. Unfortunately, many patients are refused surgery because of age, comorbidities, and hemodynamic instability. This report describes the successful use of balloon aortic valvuloplasty as a bridge to aortic valve bypass surgery (apicoaortic conduit) in an elderly patient with class IV congestive heart failure and severe left ventricular systolic dysfunction as a consequence of aortic stenosis who was not a candidate for traditional surgical valve replacement.

Moving from evidence to practice in the care of patients who have acute coronary syndrome.

Both acute management and secondary prevention for patients presenting with the spectrum of ACS have evolved greatly during the last decade, as evidenced by the multitude of clinical trials and the development of CPGs. The goal of the next decade is to ensure the accurate, equal,and timely application of these therapies and management strategies in clinical practice. In the emergency department, initiation of guideline-based management is especially challenging given the dynamic process of risk stratification that must take place to ensure properly directed care. It is clear, however, that application of such therapies leads to improved outcomes. Lessons learned from previous and ongoing quality improvement initiatives will provide the tools needed to ensure that widespread adoption of guideline-based therapy is complete.

Complementary and alternative medicine in cardiovascular disease: a review of biologically based approaches.

BACKGROUND: The use of complementary and alternative medical (CAM) practices in the United States is growing rapidly. In this manuscript, we review some of the most commonly used biologically based approaches, including herbs, supplements, and other pharmacological therapies, that are encountered in caring for patients with cardiovascular disease, focusing on potential effects, adverse effects, and treatment interactions. METHODS: Between November 2002 and April 2003, we searched Medline and the National Center for Complementary and Alternative Medicine (NCCAM) web site and its various references and several complementary medicine text books. The key words used were: "cardiovascular diseases," "coronary disease," "heart failure, congestive," "complementary and alternative medicine," "complementary therapies," "drug interactions," and "plants, medicinal." A keyword search of each individual supplement identified was also performed. Additionally, we relied on expert opinion in the field. RESULTS: Potentially serious adverse effects and interactions with conventional cardiovascular therapies exist for many herbs and supplements. There are currently scarce mechanistic data and very limited data on the effect of CAM therapies on clinical outcomes. CONCLUSIONS: Randomized clinical trials with adequate power to detect effects of CAM therapies on clinical outcomes and safety are needed. Until these data are available, clinicians must be aware of the increasing use of CAM approaches by their patients and the potential for interactions with conventional therapies and should focus on treatment with proven, evidence-based strategies.