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BackgroundThe supraclavicular fossa is the dominant location for human brown adipose tissue (BAT). Activation of BAT promotes non-shivering thermogenesis by utilization of glucose and free fatty acids and has been the focus of pharmacological and non-pharmacological approaches for modulation in order to improve body weight and glucose homeostasis. Sympathetic neural control of supraclavicular BAT has received much attention, but its innervation has not been extensively investigated in humans.MethodsDissection of the cervical region in human cadavers was performed to find the distribution of sympathetic nerve branches to supraclavicular fat pad. Furthermore, proximal segments of the 4th cervical nerve were evaluated histologically to assess its sympathetic components.ResultsNerve branches terminating in supraclavicular fat pad were identified in all dissections, including those from the 3rd and 4th cervical nerves and from the cervical sympathetic plexus. Histology of the proximal segments of the 4th cervical nerves confirmed tyrosine hydroxylase positive thin nerve fibers in all fascicles with either a scattered or clustered distribution pattern. The scattered pattern was more predominant than the clustered pattern (80% vs. 20%) across cadavers. These sympathetic nerve fibers occupied only 2.48% of the nerve cross sectional area on average.ConclusionsHuman sympathetic nerves use multiple pathways to innervate the supraclavicular fat pad. The present finding serves as a framework for future clinical approaches to activate human BAT in the supraclavicular region.

Abstract Winter wheat (Triticum aestivum L.) is essential to maintain food security for a large proportion of the world’s population. With increased risk from abiotic stresses due to climate variability, it is imperative to understand and minimize the negative impact of these stressors, including high night temperature (HNT). Both globally and at regional scales, a differential rate of increase in day and night temperature is observed, wherein night temperatures are increasing at a higher pace and the trend is projected to continue into the future. Previous studies using controlled environment facilities and small field-based removable chambers have shown that post-anthesis HNT stress can induce a significant reduction in wheat grain yield. A prototype was previously developed by utilizing field-based tents allowing for simultaneous phenotyping of popular winter wheat varieties from US Midwest and advanced breeding lines. Hence, the objectives of the study were to (i) design and build a new field-based infrastructure and test and validate the uniformity of HNT stress application on a scaled-up version of the prototype (ii) improve and develop a more sophisticated cyber-physical system to sense and impose post-anthesis HNT stress uniformly through physiological maturity within the scaled-up tents; and (iii) determine the impact of HNT stress during grain filling on the agronomic and grain quality parameters including starch and protein concentration. The system imposed a consistent post-anthesis HNT stress of + 3.8 °C until maturity and maintained uniform distribution of stress which was confirmed by (i) 0.23 °C temperature differential between an array of sensors within the tents and (ii) statistically similar performance of a common check replicated multiple times in each tent. On average, a reduction in grain-filling duration by 3.33 days, kernel weight by 1.25% per °C, grain number by 2.36% per °C and yield by 3.58% per °C increase in night temperature was documented. HNT stress induced a significant reduction in starch concentration indicating disturbed carbon balance. The pilot field-based facility integrated with a robust cyber-physical system provides a timely breakthrough for evaluating HNT stress impact on large diversity panels to enhance HNT stress tolerance across field crops. The flexibility of the cyber-physical system and movement capabilities of the field-based infrastructure allows this methodology to be adaptable to different crops.

Histone H3 at lysine 27 (H3K27M) is often mutated in cancer but its role in tumour initiation is unclear. Here, the authors generated a transgenic model expressing H3.3K27M from the Fabp7 gene promoter, demonstrating that H3.3K27M can initiate diverse tumorigesis on its own, acting through a RAS/MYC transcriptomic programme.

BackgroundYoung adults aged 18-39 years commonly experience persistent side effects following cancer treatment that can impair their quality of life. Physical activity (PA) holds promise as a behavioral intervention to mitigate persistent side effects and improve quality of life. Yet, few young adults are active enough to incur these benefits and efforts to promote PA after cancer treatment ends are lacking. Therefore, we developed a novel theory-driven behavior change intervention to promote PA via videoconferencing technology in young adults who have completed cancer treatment, and are undertaking a pilot randomized controlled trial (RCT) to gather evidence to inform the design of a large, full-scale RCT. The specific aims of this parallel, two-arm pilot RCT are to: (1) assess intervention and trial protocol feasibility and acceptability; and (2) generate data on PA behavior. To promote transparency, improve reproducibility, and serve as a reference for forthcoming publication of results, we present the study protocol for this pilot RCT (version 7) within this paper.MethodsYoung adults who have completed cancer treatment are being recruited from across Canada. After informed consent is obtained and baseline assessments are completed, participants are randomized to the intervention group (i.e., a 12-week behavior change intervention delivered via videoconferencing technology by trained PA counsellors) or usual care group (i.e., no intervention). Several feasibility outcomes covering enrollment, allocation, follow-up, and analysis are tracked by study staff. Acceptability is assessed through interviews exploring participants' experiences, thoughts, and perspectives of the trial protocol (i.e., intervention and usual care groups), as well as participants' views of the intervention and its mode of delivery (i.e., intervention group only) and PA counsellors' experiences delivering the intervention. PA behavior is measured using accelerometers at baseline (pre-randomization), post-intervention, and at follow-up (24 weeks post-baseline).DiscussionThere are growing calls to develop interventions to support young adults' motivation to engage in PA and adopt an active lifestyle to improve their quality of life after cancer treatment ends. Real-time videoconferencing shows promise for disseminating behavior change interventions to young adults and addressing participation barriers. Considering the importance of establishing intervention and trial protocol feasibility and acceptability prior to evaluating intervention efficacy (or effectiveness), this pilot RCT is critical to understand how participants embrace, engage with, and complete the intervention and trial protocol. Indeed, these data will help to determine which refinements, if any, are required to the intervention and trial protocol (e.g., implementation approach, evaluation methods) prior to a large, full-scale RCT aiming to test the effects of the intervention on PA behavior. Additionally, the PA behavior data collected will be useful to inform the sample size calculation for a large, full-scale RCT.Trial registrationThe trial was registered with the ClinicalTrials.gov database (ID: NCT04163042) on November 14, 2019, prior to the start of the trial in February, 2021.

Abstract We have previously reported that the α1 subunit of sodium potassium adenosine triphosphatase (Na/K-ATPase), acts as a receptor and an amplifier for reactive oxygen species, in addition to its distinct pumping function. On this background, we speculated that blockade of Na/K-ATPase-induced ROS amplification with a specific peptide, pNaKtide, might attenuate the development of steatohepatitis. To test this hypothesis, pNaKtide was administered to a murine model of NASH: the C57Bl6 mouse fed a “western” diet containing high amounts of fat and fructose. The administration of pNaKtide reduced obesity as well as hepatic steatosis, inflammation and fibrosis. Of interest, we also noted marked improvement in mitochondrial fatty acid oxidation, insulin sensitivity, dyslipidemia and aortic streaking in this mouse model. To further elucidate the effects of pNaKtide on atherosclerosis, similar studies were performed in ApoE knockout mice also exposed to the western diet. In these mice, pNaKtide not only improved steatohepatitis, dyslipidemia, and insulin sensitivity, but also ameliorated significant aortic atherosclerosis. Collectively, this study demonstrates that the Na/K-ATPase/ROS amplification loop contributes significantly to the development and progression of steatohepatitis and atherosclerosis. And furthermore, this study presents a potential treatment, the pNaKtide, for the metabolic syndrome phenotype.

The Western Ghats are well known as a biodiversity hotspot, but the full extent of its snake diversity is yet to be uncovered. Here, we describe a new genus and species of vine snake Proahaetulla antiqua gen. et sp. nov., from the Agasthyamalai hills in the southern Western Ghats. It was found to be a member of the Ahaetuliinae clade, which currently comprises the arboreal snake genera Ahaetulla, Dryophiops, Dendrelaphis and Chrysopelea, distributed in South and Southeast Asia. Proahaetulla shows a sister relationship with all currently known taxa belonging to the genus Ahaetulla, and shares ancestry with Dryophiops. In addition to its phylogenetic position and significant genetic divergence, this new taxon is also different in morphology from members of Ahaetuliinae in a combination of characters, having 12-13 partially serrated keels on the dorsal scale rows, 20 maxillary teeth and 3 postocular scales. Divergence dating reveals that the new genus is ancient, dating back to the Mid-Oligocene, and is one of the oldest persisting monotypic lineages of snakes in the Western Ghats. This discovery adds to the growing list of ancient lineages endemic to the Agasthyamalai hills and underscores the biogeographic significance of this isolated massif in the southern Western Ghats.

BACKGROUND:Germline mutations in the BRCA1 and BRCA2 genes are the most frequent known hereditary causes of familial breast cancer. Little is known about the interaction of age at diagnosis, estrogen receptor (ER) and progesterone receptor (PgR) expression and outcomes in patients with BRCA1 or BRCA2 mutations. METHODS:A PubMed search identified publications exploring the association between BRCA mutations and clinical outcome. Hazard ratios (HR) for overall survival were extracted from multivariable analyses. Hazard ratios were weighted and pooled using generic inverse-variance and random-effect modeling. Meta-regression weighted by total study sample size was conducted to explore the influence of age, ER and PgR expression on the association between BRCA mutations and overall survival. RESULTS:A total of 16 studies comprising 10,180 patients were included in the analyses. BRCA mutations were not associated with worse overall survival (HR 1.06, 95% CI 0.84-1.34, p = 0.61). A similar finding was observed when evaluating the influence of BRCA1 and BRCA2 mutations on overall survival independently (BRCA1: HR 1.20, 95% CI 0.89-1.61, p = 0.24; BRCA2: HR 1.01, 95% CI 0.80-1.27, p = 0.95). Meta-regression identified an inverse association between ER expression and overall survival (β = -0.75, p = 0.02) in BRCA1 mutation carriers but no association with age or PgR expression (β = -0.45, p = 0.23 and β = 0.02, p = 0.97, respectively). No association was found for BRCA2 mutation status and age, ER, or PgR expression. CONCLUSION:ER-expression appears to be an effect modifier in patients with BRCA1 mutations, but not among those with BRCA2 mutations.

Treatment with small molecule tyrosine kinase inhibitors (TKIs) has improved survival in many cancers, yet has been associated with an increased risk of adverse events. Warnings of cardiovascular events are common in drug labels of many TKIs. Despite these warnings, cardiovascular toxicity of patients treated with TKIs remains unclear. Here, we evaluate the cardiovascular outcomes of advanced cancer patients treated with small molecule tyrosine kinase inhibitors.A population based cohort study was undertaken involving adults aged >18 years in Ontario, Canada, diagnosed with any advanced malignancy between 2006 and 2012. Data were extracted from linked administrative governmental databases. Adults with advanced cancer receiving TKIs were identified and followed throughout the time period. The main outcomes of interest were rates of hospitalization for ischemic heart disease (acute myocardial infarction and angina) or cerebrovascular accidents and death.1642 patients with a mean age of 62.5 years were studied; 1046 were treated with erlotinib, 166 with sorafenib and 430 with sunitinib. Over the 380 day median follow-up period (range 6-1970 days), 1.1% of all patients had ischemic heart events, 0.7% had cerebrovascular accidents and 72.1% died. Rates of cardiovascular events were similar to age and gender-matched individuals without cancer. In a subgroup analysis of treatment patients with a prior history of ischemic heart disease, 3.3% had ischemic heart events while 1.2% had cerebrovascular accidents.TKIs do not appear to increase the cause-specific hazard of ischemic heart disease and cerebrovascular accidents compared to age and gender-matched individuals without advanced cancer.

Sarcopenia often co-exists with obesity, and may have additive effects on insulin resistance. Sarcopenic obese individuals could be at increased risk for type 2 diabetes. We performed a study to determine whether sarcopenia is associated with impairment in insulin sensitivity and glucose homeostasis in obese and non-obese individuals.We performed a cross-sectional analysis of National Health and Nutrition Examination Survey III data utilizing subjects of 20 years or older, non-pregnant (N = 14,528). Sarcopenia was identified from bioelectrical impedance measurement of muscle mass. Obesity was identified from body mass index. Outcomes were homeostasis model assessment of insulin resistance (HOMA IR), glycosylated hemoglobin level (HbA1C), and prevalence of pre-diabetes (6.0≤ HbA1C