Capsaicin, the pungent ingredient of chili peppers, displays potent anti-neoplastic activity in a wide array of human cancer cells. The present manuscript examines the signaling pathways underlying the apoptotic activity of capsaicin in human small cell lung cancer (SCLC) in vitro and in vivo. Studies in neuronal cells show that capsaicin exerts its biological activity via the transient receptor potential vanilloid (TRPV) superfamily of cation-channel receptors. The TRPV family is comprised of six members (TRPV1-6). Capsaicin is an agonist of the TRPV1 receptor. We observed that capsaicin-induced apoptosis in human SCLC cells was mediated via the TRPV receptor family; however it was independent of TRPV1. Surprisingly, the apoptotic activity of capsaicin required the TRPV6 receptor. Depletion of TRPV6 receptor by siRNA methodology abolished the apoptotic activity of capsaicin in SCLC cells. Immunostaining and ELISA showed that TRPV6 receptor was robustly expressed on human SCLC tissues (from patients) and SCLC cell lines but almost absent in normal lung tissues. This correlates with our results that capsaicin induced very little apoptosis in normal lung epithelial cells. The proapoptotic activity of was mediated by the intracellular calcium and calpain pathway. The treatment of human SCLC cells with capsaicin induced increased the activity of calpain 1 and 2 by three-fold relative to untreated SCLC cells. Such calpain activation, in response to capsaicin, was downstream of the TRPV6 receptor. Taken together, our data provide insights into the mechanism underlying the apoptotic activity of capsaicin in human SCLCs.

Recent case-controlled clinical studies show that bronchioalveolar carcinomas (BAC) are correlated with smoking. Nicotine, the addictive component of cigarettes, accelerates cell proliferation through nicotinic acetylcholine receptors (nAChR). In this study, we show that human BACs produce acetylcholine (ACh) and contain several cholinergic factors including acetylcholinesterase (AChE), choline acetyltransferase (ChAT), choline transporter 1 (CHT1, SLC5A7), vesicular acetylcholine transporter (VAChT, SLC18A3), and nACh receptors (AChRs, CHRNAs). Nicotine increased the production of ACh in human BACs, and ACh acts as a growth factor for these cells. Nicotine-induced ACh production was mediated by a7-, a3b2-, and b3-nAChRs, ChAT and VAChT pathways. We observed that nicotine upregulated ChAT and VAChT. Therefore, we conjectured that VAChT antagonists, such as vesamicol, may suppress the growth of human BACs. Vesamicol induced potent apoptosis of human BACs in cell culture and nude mice models. Vesamicol did not have any effect on EGF or insulin-like growth factor-II-induced growth of human BACs. siRNA-mediated attenuation of VAChT reversed the apoptotic activity of vesamicol. We also observed that vesamicol inhibited Akt phosphorylation during cell death and that overexpression of constitutively active Akt reversed the apoptotic activity of vesamicol. Taken together, our results suggested that disruption of nicotine-induced cholinergic signaling by agents such as vesamicol may have applications in BAC therapy. Cancer Res; 73(4); 1328-39. Ó2012 AACR.

Small cell lung cancer (SCLC) demonstrates a strong etiological association with smoking. Although cigarette smoke is a mixture of about 4,000 compounds, nicotine is the addictive component of cigarette smoke. Several convergent studies have shown that nicotine promotes angiogenesis in lung cancers via the α7-nicotinic acetylcholine receptor (α7-nAChR) on endothelial cells. Therefore, we conjectured that α7-nAChR antagonists may attenuate nicotine-induced angiogenesis and be useful for the treatment of human SCLC. For the first time, our study explores the anti-angiogenic activity of MG624, a small-molecule α7-nAChR antagonist, in several experimental models of angiogenesis. We observed that MG624 potently suppressed the proliferation of primary human microvascular endothelial cells of the lung (HMEC-Ls). Furthermore, MG624 displayed robust anti-angiogenic activity in the Matrigel, rat aortic ring and rat retinal explant assays. The anti-angiogenic activity of MG624 was assessed by two in vivo models, namely the chicken chorioallantoic membrane model and the nude mice model. In both of these experimental models, MG624 inhibited angiogenesis of human SCLC tumors. Most importantly, the administration of MG624 was not associated with any toxic side effects, lethargy or discomfort in the mice. The anti-angiogenic activity of MG624 was mediated via the suppression of nicotine-induced FGF2 levels in HMEC-Ls. MG624 decreased nicotine-induced early growth response gene 1 (Egr-1) levels in HMEC-Ls, and reduced the levels of Egr-1 on the FGF2 promoter. Consequently, this process decreased FGF2 levels and angiogenesis. Our findings suggest that the anti-angiogenic effects of MG624 could be useful in anti-angiogenic therapy of human SCLCs.

Didactic lessons are only one part of the multimodal teaching strategies used in gross anatomy courses today. Increased emphasis is placed on providing more opportunities for students to develop lifelong learning and critical thinking skills during medical training. In a pilot program designed to promote more engaged and independent learning in anatomy, self-study modules were introduced to supplement human gross anatomy instruction at Joan C. Edwards School of Medicine at Marshall University. Modules use three-dimensional constructs to help students understand complex anatomical regions. Resources are self-contained in portable bins and are accessible at any time. Students use modules individually or in groups in a structured self-study format that augments material presented in lecture and laboratory. Pilot outcome data, measured by feedback surveys and examination performance statistics, suggest that the activity may be improving learning in gross anatomy. Positive feedback on both pre- and post-examination surveys showed that students felt the activity helped to increase their understanding of the topic. In concordance with student perception, average examination scores on module-related laboratory and lecture questions were higher in the two years of the pilot program compared with the year before its initiation. Modules can be fabricated on a modest budget using minimal resources, making implementation practical for smaller institutions. Upper level medical students assist in module design and upkeep, enabling continuous opportunities for vertical integration across the curriculum. This resource offers a feasible mechanism for enhancing independent and lifelong learning competencies, which could be a valuable complement to any gross anatomy curriculum.

The α7-nAChR is vital for the proangiogenic activity of nicotine. The α7-nAChRs expressed on HRMECs upregulate levels of MMP-2 and -9, which stimulate retinal angiogenesis. The data also suggest that α7-nAChR antagonists could be useful agents for the therapy of angiogenesis-related retinal diseases.

Purpose of review The use of low dose aspirin (LDA) has become routine in prenatal care for a variety of diagnoses, most importantly in women with a history of preeclampsia and associated poor pregnancy outcomes. Although LDA is currently indicated in patients considered to be at risk for development of preeclampsia, optimal dosing, timing of treatment initiation, and persons of benefit are under investigation. Several studies have also looked at LDA treatment and its effect on other maternal and fetal outcomes. This review summarizes the current guidelines for the use of LDA, incorporating the most recent research findings, and offers possible future implications of LDA treatment. Recent findings Over 10 years ago, the American College of Obstetricians and Gynecologists, the World Health Organization, and the United States Preventive Service Task Force began publishing guidelines focused on the use of LDA in pregnancy. Since the release of these guidelines, several large studies have re-evaluated the use of LDA with a focus on initiation of treatment and dosing. The combined results of these studies suggest a decreased rate of preeclampsia at aspirin doses >100 mg when treatment is initiated prior to 16 weeks of gestation. Summary Overall, early initiation of LDA has been shown to decrease the development of preeclampsia in patients considered at increased risk. Current literature suggests increasing the recommended dose to >100 mg to optimize these risk reductions. Although LDA use seems promising for other outcomes like preterm delivery and intrauterine growth restriction, further studies to strengthen recommendations are warranted.

Purpose of review Multifetal pregnancy carries increased risk of preterm delivery, and consensus on management options to prevent early birth in this population has not been reached. This review serves to summarize the most contemporary findings on this controversial topic. Recent findings Examination-indicated cerclage is effective in reducing preterm birth in twin pregnancies, whereas cerclages for other indications are less convincing. Cervical pessary may be beneficial for patients with a short cervix and in those who have had threatened preterm labor. Progesterone supplementation for multifetal gestation alone is not beneficial, but it can be considered in those with a history of prior singleton preterm birth. Summary Interventions for preterm birth prevention in multiple gestations remain under investigation, and further data is required in order to reach consensus for this high-risk population.

There was an error in the section entitled ''Antitumor studies in nude mice'' on page 104.The control group of H69 tumor-bearing mice was fed AIN-76A diet containing 10% corn oil. The treatment group of H69 tumor-bearing mice was fed MG624 (dose = 50 mg/kg food) in AIN-76A diet containing 10% corn oil and 0.2% DMSO. The conclusions of the article are unaltered. The authors regret these misstatements in the original article.The online version of the original article can be found under