Androgen Receptor Activation Induces Senescence in Thyroid Cancer Cells.

Thyroid cancer (TC) is the most common endocrine malignancy, with an approximately three-fold higher incidence in women. TCGA data indicate that androgen receptor (AR) RNA is significantly downregulated in PTC. In this study, AR-expressing 8505C (anaplastic TC) (84E7) and K1 (papillary TC) cells experienced an 80% decrease in proliferation over 6 days of exposure to physiological levels of 5α-dihydrotestosterone (DHT). In 84E7, continuous AR activation resulted in G1 growth arrest, accompanied by a flattened, vacuolized cell morphology, with enlargement of the cell and the nuclear area, which is indicative of senescence; this was substantiated by an increase in senescence-associated ß-galactosidase activity, total RNA and protein content, and reactive oxygen species. Additionally, the expression of tumor suppressor proteins p16, p21, and p27 was significantly increased. A non-inflammatory senescence-associated secretory profile was induced, significantly decreasing inflammatory cytokines and chemokines such as IL-6, IL-8, TNF, RANTES, and MCP-1; this is consistent with the lower incidence of thyroid inflammation and cancer in men. Migration increased six-fold, which is consistent with the clinical observation of increased lymph node metastasis in men. Proteolytic invasion potential was not significantly altered, which is consistent with unchanged MMP/TIMP expression. Our studies provide evidence that the induction of senescence is a novel function of AR activation in thyroid cancer cells, and may underlie the protective role of AR activation in the decreased incidence of TC in men.

Primary Aldosteronism: Cardiovascular Risk, Diagnosis, and Management.

Primary aldosteronism remains a leading cause of secondary hypertension, and its diagnosis and management continue to pose a challenge for clinicians. In this article, we review the diagnosis of primary aldosteronism along with its cardiovascular manifestations. Treatment is described depending on the diagnostic outcome, focusing on medical management with mineralocorticoid receptor antagonists and unilateral adrenalectomy. Although screening and diagnosing hyperaldosteronism follows well-known algorithms, in practice, physicians may find difficulty establishing the best course of action due to complexity in testing and confirming laterality of aldosterone production by the adrenals. Recognizing and treating primary aldosteronism requires a multidisciplinary approach with primary care physicians, cardiologists, endocrinologists, and radiologists working collaboratively.

Nilotinib-Associated Destructive Thyroiditis.

Protein tyrosine kinase inhibitors are currently an important drug class in the treatment of leukemia. They represent targeted cancer therapy and have become the treatment of choice in chronic myeloid leukemia. Tyrosine kinases are enzymes expressed in multiple tissues and are involved in several signaling pathways influencing cellular growth. Below we describe a patient who developed an unusual complication of tyrosine kinase inhibitor therapy: thyrotoxicosis due to destructive thyroiditis. We review the pathophysiology of tyrosine kinase inhibitor-induced thyroid dysfunction particularly with regard to new second-generation tyrosine kinase inhibitors.

Growth hormone and the cardiovascular system.

Growth hormone (GH) exerts its effects through insulin-like growth factor-1, and although ubiquitous in human tissues, it has a significant role in cardiovascular function. In recent years, there has been a great deal of interest in GH as an etiologic factor in many cardiovascular disease states. Acromegaly, a state of endogenous GH excess, results in myocardial hypertrophy and decreased cardiac performance with increased cardiovascular mortality. Additional insight into the role of excess GH on the cardiovascular system has been gained from data collected in athletes doping with GH. Likewise, GH deficiency is associated with increased mortality, possibly from the associated increase in atherosclerosis, lipid abnormalities, and endothelial dysfunction. However, further research is required to clarify the benefit of GH treatment in both deficient states and in heart failure patients.

Tracking outpatient continuity and chronic disease indicators-a novel use of the new innovations clinic module.

The Accreditation Council for Graduate Medical Education common program requirements for Practice-based Learning and Improvement in Internal Medicine specify that trainees must "systematically analyze [his/her] practice using quality improvement methods, and implement changes with the goal of practice improvement" and that the training program "must include use of performance data" in the assessment of the resident's practice. Before implementation of an electronic health record at our academic medical center, we found meeting these requirements to be challenging. This prompted us to set up the New Innovations (New Innovations, Inc, Uniontown, OH) Software Suite's Patient Continuity module to permit analysis and tracking of both quality of care indicators and patient continuity. By using the system, our residents were better able to monitor their patient panel sizes and composition and to correlate their practices with quality of care data. Residency programs, which currently utilize New Innovations software but lack an electronic health record, may find the continuity clinic module useful for engaging their house staff in structured practice improvement initiatives and in satisfying the Accreditation Council for Graduate Medical Education's common program requirements for practice-based learning.

Testosterone and coronary artery disease.

Cardiovascular disease remains the leading cause of death in most of the developed world despite advances in both prevention and treatment. At the same time, the incidence rates of cardiovascular disease differ greatly between the genders, with men more likely than women to manifest ischemic heart disease. This observation has prompted new research initiatives to explain the discrepancy in heart disease prevalence and incidence between the sexes. Whether androgens affect cardiovascular disease adversely remains a contentious issue, with some data pointing to a deleterious effect of androgens on lipid profiles, and other studies revealing androgens' possible benefits on cardiovascular function. This review will examine the relationship between the endogenous production of androgen as well as the exogenous replacement of testosterone in men and the possible links to cardiovascular disease. The role of testosterone in male cardiovascular health is not completely understood, and additional studies are needed to explain its effect on atherosclerosis and its complications.

Impact of glycemic treatment choices on cardiovascular complications in type 2 diabetes.

As the diabetic population has significant morbidity and mortality from cardiovascular disease (CVD), much of its medical care focuses on CVD prevention and treatment. Some medications used to treat hyperglycemia may have beneficial effects on CV outcomes, others may have negative effects, while still others seem to have no direct effect. Although past epidemiological studies have shown a relationship between glycated hemoglobin levels and CV events in patients with type 2 diabetes, recent large randomized clinical trials (ACCORD, ADVANCE, and VADT) lasting 3.5 to 5.6 years have found that intensive glycemic control either has no impact on CV outcomes or even worsens them. Results of the 10-year follow-up of the UKPDS suggest that tight glycemic control of younger, newly diagnosed patients with type 2 diabetes may have CV benefits many years later. Because the pathogenesis of atherosclerosis spans decades, it may be that beneficial effects of tight glycemic control on CV outcomes are mainly in younger patients without established macrovascular disease. There is an emerging notion that tight glycemic control may be beneficial in primary prevention of CVD in younger patients with diabetes, but may become deleterious in older patients with established or subclinical CVD. Thus, while tight control may lessen microvascular disease, it may increase the risk of hypoglycemia and possibly of adverse CV events. In each patient, the goals of glycemic control need to be individualized based on age, overall prognosis, presence of macrovascular disease, and risk of hypoglycemia.