Clinical and translational advances in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is among the most deadly forms of human malignancy characterized by late stage diagnosis, metastasis, therapy resistance and frequent recurrence. Clinical management of ESCC remains challenging and the disease presently lacks approved targeted therapeutics. However, emerging data from recent clinical and translational investigations hold great promise for future progress toward improving patient outcomes in this deadly disease. Here, we review current clinical perspectives in ESCC epidemiology, pathophysiology, and clinical care, highlighting recent advances with potential to impact ESCC prevention, diagnosis and management. We further provide an overview of recent translational investigations contributing to our understanding of the molecular mechanisms underlying ESCC development, progression and therapy response, including insights gained from genetic studies and various murine model systems. Finally, we discuss future perspectives in the clinical and translational realms, along with remaining hurdles that must be overcome to eradicate ESCC.

Autophagy as a cytoprotective mechanism in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is amongst the most aggressive human malignancies, representing a significant health burden worldwide. Autophagy is an evolutionarily conserved catabolic process that degrades and recycles damaged organelles and misfolded proteins to maintain cellular homeostasis. Alterations in autophagy are associated with cancer pathogenesis, including ESCC; however, the functional role of autophagy in ESCC remains elusive. Here, we discuss the clinical relevance of autophagy effectors in ESCC and review current knowledge regarding the molecular mechanisms through which autophagy contributes to ESCC. We highlight the cytoprotective role of autophagy in ESCC and discuss autophagy inhibitors as novel experimental therapeutics to potentiate the effects of anti-cancer therapies and/or to overcome therapeutic resistance in ESCC.

Human influence on tropical cyclone intensity.

Recent assessments agree that tropical cyclone intensity should increase as the climate warms. Less agreement exists on the detection of recent historical trends in tropical cyclone intensity. We interpret future and recent historical trends by using the theory of potential intensity, which predicts the maximum intensity achievable by a tropical cyclone in a given local environment. Although greenhouse gas-driven warming increases potential intensity, climate model simulations suggest that aerosol cooling has largely canceled that effect over the historical record. Large natural variability complicates analysis of trends, as do poleward shifts in the latitude of maximum intensity. In the absence of strong reductions in greenhouse gas emissions, future greenhouse gas forcing of potential intensity will increasingly dominate over aerosol forcing, leading to substantially larger increases in tropical cyclone intensities.

Delayed coronary reperfusion is ineffective at impeding the dynamic increase in cardiac efferent sympathetic nerve activity following myocardial ischemia.

Acute myocardial infarction (MI) is associated with an adverse and sustained increase in cardiac sympathetic nerve activity (SNA), triggering potentially fatal ventricular arrhythmias. While myocardial reperfusion undoubtedly improves patient prognosis, it remains unknown whether reperfusion therapy also attenuates the dangerous increase in SNA. This study aimed to investigate the effect of time-dependent coronary reperfusion therapy on cardiac SNA following acute MI. Electrophysiological recordings of cardiac efferent SNA were performed in urethane-anaesthetized rats following ligation of the left anterior descending coronary artery (i.e., MI) for either 15 or 45 min, followed by 'early' or 'delayed' reperfusion, respectively. Another group of rats had permanent ischemia with no reperfusion. Forty-five minutes of ischemia induced a 55 % increase in efferent SNA. Subsequent 'delayed' reperfusion was ineffective at ameliorating further increases in SNA (maximal 153 % increase), so that MI-induced increases in SNA mirrored that observed in rats with permanent MI. Although SNA did not increase during 15 min of ischemia, it did significantly increase, albeit delayed, during the subsequent reperfusion period (max. 75 % increase). Importantly, however, this increase in SNA, which tended to be lower in the 'early'-reperfusion group, was matched with a lower incidence of arrhythmias and mortality rate, compared to the 'delayed'-reperfusion and permanent-MI groups. These results highlight that 'prompt' coronary reperfusion, before SNA becomes activated, may provide a crucial window of opportunity for improving outcome. Further research is essential to identify the mechanisms that underpin, not only sympathetic activation, but also importantly sympathetic deactivation as a potential therapeutic target for MI.

Time-Site Survey of Substance Use, Sexual Behaviours, and HIV-Testing Practices among Women Attending Social Venues in Prague.

AIM: The rates of HIV acquired through heterosexual contact are increasing in the Czech Republic. This study explored potential HIV risk associa-tions with alcohol, illicit drugs and sexual behaviours among adults from a community-based sample attending gay- and non-gay venues in Prague. METHODS: Women attending bars, cafes and beer gardens in central Prague responded to the self-administered, time-site survey. Alcohol use was measured by the AUDIT-C and CAGE questionnaires. Sexual network structuring identified number, gender and coital frequency with current and recent sexual partners. Statistical analysis included central tendency, chi-square and logistic regression. Female participants (n=124) ranged from 18 to 67 years of age (mean 29 years); 25% self-identified as non-heterosexual. RESULTS: We found alcohol to be the preferred drug of choice. Younger heterosexual women with new and casual sexual partners were more likely to use alcohol excessively. Women with children reported the least alcohol use. Sixty percent of the sample had never used condoms; condom-use was associated with longer relationship duration and discussions about HIV status with a sexual partner; non-use tended to occur among unmarried women with multiple male partners in short, serial sexual relationships. Women who sought HIV testing tended to be younger and more self-identified as non-heterosexual. Protective practices were rarely reported even when HIV transmission increases via heterosexual sexual partnering. CONCLUSION: Further research is recommended regarding cultural and contextual influences on HIV risk behaviours among Czech women.

Randomized, placebo-controlled trial of bupropion in methamphetamine-dependent participants with less than daily methamphetamine use.

AIMS: Two previous randomized trials found an effect for bupropion in reducing methamphetamine use in the subgroup with lower frequency of methamphetamine use at baseline. This study aimed to replicate these results by comparing bupropion versus placebo in methamphetamine-dependent participants with less than daily methamphetamine use at baseline. METHODS: Methamphetamine-dependent volunteers reporting methamphetamine use on ≤29 of past 30 days were randomized to bupropion 150 mg twice daily (n = 41) or placebo (n = 43) and out-patient counseling for 12 weeks. The primary outcome was the proportion achieving end-of-treatment (EOT) methamphetamine abstinence (weeks 11 and 12) for bupropion versus placebo. A post-hoc analysis compared EOT abstinence by medication adherence assessed via plasma bupropion/hydroxybupropion level. RESULTS: There was no significant difference in EOT abstinence between bupropion (29%, 12 of 41) and placebo (14%, six of 43; P = 0.087). Among participants receiving bupropion, EOT abstinence was significantly higher in participants assessed as medication adherent by plasma bupropion/hydroxybupropion levels (54%, seven of 13) compared to non-adherent participants (18%, five of 28; P = 0.018). Medication adherence by plasma levels was low (32%). CONCLUSIONS: Bupropion may be efficacious for reducing methamphetamine in people with less than daily baseline methamphetamine use, but the evidence remains inconclusive.