Integrated genomic characterization of oesophageal carcinoma

Oesophageal cancers are prominent worldwide; however, there are few targeted therapies and survival rates for these cancers remain dismal. Here we performed a comprehensive molecular analysis of 164 carcinomas of the oesophagus derived from Western and Eastern populations. Beyond known histopathological and epidemiologic distinctions, molecular features differentiated oesophageal squamous cell carcinomas from oesophageal adenocarcinomas. Oesophageal squamous cell carcinomas resembled squamous carcinomas of other organs more than they did oesophageal adenocarcinomas. Our analyses identified three molecular subclasses of oesophageal squamous cell carcinomas, but none showed evidence for an aetiological role of human papillomavirus. Squamous cell carcinomas showed frequent genomic amplifications of CCND1 and SOX2 and/or TP63, whereas ERBB2, VEGFA and GATA4 and GATA6 were more commonly amplified in adenocarcinomas. Oesophageal adenocarcinomas strongly resembled the chromosomally unstable variant of gastric adenocarcinoma, suggesting that these cancers could be considered a single disease entity. However, some molecular features, including DNA hypermethylation, occurred disproportionally in oesophageal adenocarcinomas. These data provide a framework to facilitate more rational categorization of these tumours and a foundation for new therapies.ope

Biosynthetic Gene Cluster for the Cladoniamides, Bis-Indoles with a Rearranged Scaffold

The cladoniamides are bis-indole alkaloids isolated from Streptomyces uncialis, a lichen-associated actinomycete strain. The cladoniamides have an unusual, indenotryptoline structure rarely observed among bis-indole alkaloids. I report here the isolation, sequencing, and annotation of the cladoniamide biosynthetic gene cluster and compare it to the recently published gene cluster for BE-54017, a closely related indenotryptoline natural product. The cladoniamide gene cluster differs from the BE-54017 gene cluster in gene organization and in the absence of one N-methyltransferase gene but otherwise contains close homologs to all genes in the BE-54017 cluster. Both gene clusters encode enzymes needed for the construction of an indolocarbazole core, as well as flavin-dependent enzymes putatively involved in generating the indenotryptoline scaffold from an indolocarbazole. These two bis-indolic gene clusters exemplify the diversity of biosynthetic routes that begin from the oxidative dimerization of two molecules of l-tryptophan, highlight enzymes for further study, and provide new opportunities for combinatorial engineering

Synaptic Depression Via Mglur1 Positive Allosteric Modulation Suppresses Cue-Induced Cocaine Craving

Cue-induced cocaine craving is a major cause of relapse in abstinent addicts. In rats, cue-induced craving progressively intensifies (incubates) during withdrawal from extended-access cocaine self-administration. After ~1 month of withdrawal, incubated craving is mediated by Ca(2+)-permeable AMPA receptors (CP-AMPARs) that accumulate in the nucleus accumbens (NAc). We found that decreased mGluR1 surface expression in the NAc preceded and enabled CP-AMPAR accumulation. Thus, restoring mGluR1 transmission by administering repeated injections of an mGluR1 positive allosteric modulator (PAM) prevented CP-AMPAR accumulation and incubation, whereas blocking mGluR1 transmission at even earlier withdrawal times accelerated CP-AMPAR accumulation. In studies conducted after prolonged withdrawal, when CP-AMPAR levels and cue-induced craving are high, we found that systemic administration of an mGluR1 PAM attenuated the expression of incubated craving by reducing CP-AMPAR transmission in the NAc to control levels. These results suggest a strategy in which recovering addicts could use a systemically active compound to protect against cue-induced relapse

Cocaine Is Low on the Value Ladder of Rats: Possible Evidence for Resilience to Addiction

International audienceBACKGROUND:Assessing the relative value of cocaine and how it changes with chronic drug use represents a long-standing goal in addiction research. Surprisingly, recent experiments in rats--by far the most frequently used animal model in this field--suggest that the value of cocaine is lower than previously thought.METHODOLOGY/PRINCIPAL FINDINGS:Here we report a series of choice experiments that better define the relative position of cocaine on the value ladder of rats (i.e., preference rank-ordering of different rewards). Rats were allowed to choose either taking cocaine or drinking water sweetened with saccharin--a nondrug alternative that is not biologically essential. By systematically varying the cost and concentration of sweet water, we found that cocaine is low on the value ladder of the large majority of rats, near the lowest concentrations of sweet water. In addition, a retrospective analysis of all experiments over the past 5 years revealed that no matter how heavy was past cocaine use most rats readily give up cocaine use in favor of the nondrug alternative. Only a minority, fewer than 15% at the heaviest level of past cocaine use, continued to take cocaine, even when hungry and offered a natural sugar that could relieve their need of calories.CONCLUSIONS/SIGNIFICANCE:This pattern of results (cocaine abstinence in most rats; cocaine preference in few rats) maps well onto the epidemiology of human cocaine addiction and suggests that only a minority of rats would be vulnerable to cocaine addiction while the large majority would be resilient despite extensive drug use. Resilience to drug addiction has long been suspected in humans but could not be firmly established, mostly because it is difficult to control retrospectively for differences in drug self-exposure and/or availability in human drug users. This conclusion has important implications for preclinical research on the neurobiology of cocaine addiction and for future medication development

Offshore snapper and shark distributions are predicted by prey and area of nearby estuarine environments in the Gulf of Mexico, USA

Seascape ecology has demonstrated that marine fishes are associated with multiscale habitat characteristics; however, most species distribution models focus on only a few predictors (e.g. depth, temperature), and this limits knowledge of essential fish habitat characteristics. Our objectives were to (1) determine habitat associations of offshore predatory marine fishes using a comprehensive suite of predictors, including area of nearby estuarine environments, (2) assess variable influence, and (3) model the spatial distribution of selected fishes in the families Carcharhinidae and Lutjanidae. We hypothesized that the concept of coastal outwelling would be evidenced by species associations with areas of nearby estuarine environments, and prey abundance would correlate with predator distributions. Species distribution models were developed for 2 snapper and 3 shark species in the northern Gulf of Mexico, USA. We used 34 multiscale predictors to evaluate how fish probability of presence or catch per unit effort (CPUE) were associated with oceanography, geography, substrate, area of nearby wetlands and estuaries, and prey abundance. Boosted regression trees, a machine-learning technique, modeled the most influential variables and predicted distributions. Model validation showed an overall accuracy of 79-86%, and CPUE models explained &gt;40% of model deviance. Oceanographic variables, particularly mixed layer depth, were most influential and most frequently selected. As hypothesized, predatory fish distributions were predicted by prey abundances, and shark distributions were predicted by area of nearby coastal wetlands and estuaries. Our findings suggest that spatial models can provide novel insights into prey associations and linkages of marine species with nearby wetlands and estuaries.</jats:p

ACL Injury Risk Reduction: Demonstration of Key Exercises

Background: Anterior cruciate ligament (ACL) rupture is a common injury that causes significant detriment to the athlete, including surgical cost, long recovery time, uncertain return to sport, and sequelae such as meniscus tears. Therefore, it is important to minimize the risk of sustaining an ACL injury. When adequately developed, trainable athletic attributes such as balance, proprioception, motor control, and strength can contribute to a reduction in injury. Indications: Athletic trainers or sports performance specialists may implement these exercises as part of a structured program during in-season or off-season training to reduce the risk of ACL injury in healthy athletes. Technique Description: The following exercises are categorized as training balance and proprioception or as training motor control and strength. The former category includes star squats on a balance board and 1-legged medicine ball tosses on a balance board. The latter category includes 1 hop to a 45° cut, weighted calf raises, and weighted single-leg squats. Discussion/Conclusion: Studies have found that engaging in a preventative program can significantly reduce the risk of sustaining an ACL injury. Athletes who did not partake in an ACL injury prevention program were nearly twice as likely to sustain an ACL rupture compared to those who did. Evidence suggests that neuromuscular training achieved specifically through incorporation of a balance board can contribute to injury prevention. Prevention of ACL injury is of paramount importance to athletes, coaches, athletic trainers, and physicians. Avoiding ACL injury can spare the athlete psychological distress, lost playing time, medical costs, and orthopaedic sequelae. Evidence suggests that a structured ACL prevention program can mitigate the risk of ACL injury. Furthermore, the exercises demonstrated are both time efficient and cost effective. It is important to note, however, that many factors contribute to ACL injury, including the athlete’s intrinsic biology and anatomy, the nature of their sport, and other confounding factors. Patient Consent Disclosure Statement: The author(s) attests that consent has been obtained from any patient(s) appearing in this publication. If the individual may be identifiable, the author(s) has included a statement of release or other written form of approval from the patient(s) with this submission for publication