STAT3 regulated ARF expression suppresses prostate cancer metastasis.

Prostate cancer (PCa) is the most prevalent cancer in men. Hyperactive STAT3 is thought to be oncogenic in PCa. However, targeting of the IL-6/STAT3 axis in PCa patients has failed to provide therapeutic benefit. Here we show that genetic inactivation of Stat3 or IL-6 signalling in a Pten-deficient PCa mouse model accelerates cancer progression leading to metastasis. Mechanistically, we identify p19(ARF) as a direct Stat3 target. Loss of Stat3 signalling disrupts the ARF-Mdm2-p53 tumour suppressor axis bypassing senescence. Strikingly, we also identify STAT3 and CDKN2A mutations in primary human PCa. STAT3 and CDKN2A deletions co-occurred with high frequency in PCa metastases. In accordance, loss of STAT3 and p14(ARF) expression in patient tumours correlates with increased risk of disease recurrence and metastatic PCa. Thus, STAT3 and ARF may be prognostic markers to stratify high from low risk PCa patients. Our findings challenge the current discussion on therapeutic benefit or risk of IL-6/STAT3 inhibition.Lukas Kenner and Jan Pencik are supported by FWF, P26011 and the Genome Research-Austria project “Inflammobiota” grants. Helmut Dolznig is supported by the Herzfelder Family Foundation and the Niederösterr. Forschungs-und Bildungsges.m.b.H (nfb). Richard Moriggl is supported by grant SFB-F2807 and SFB-F4707 from the Austrian Science Fund (FWF), Ali Moazzami is supported by Infrastructure for biosciences-Strategic fund, SciLifeLab and Formas, Zoran Culig is supported by FWF, P24428, Athena Chalaris and Stefan Rose-John are supported by the Deutsche Forschungsgemeinschaft (Grant SFB 877, Project A1and the Cluster of Excellence --“Inflammation at Interfaces”). Work of the Aberger lab was supported by the Austrian Science Fund FWF (Projects P25629 and W1213), the European FP7 Marie-Curie Initial Training Network HEALING and the priority program Biosciences and Health of the Paris-Lodron University of Salzburg. Valeria Poli is supported by the Italian Association for Cancer Research (AIRC, No IG13009). Richard Kennedy and Steven Walker are supported by the McClay Foundation and the Movember Centre of Excellence (PC-UK and Movember). Gerda Egger is supported by FWF, P27616. Tim Malcolm and Suzanne Turner are supported by Leukaemia and Lymphoma Research.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms873

Proteomics of Buccal Cavity Mucus in Female Tilapia Fish (Oreochromis spp.): A Comparison between Parental and Non-Parental Fish

Mouthbrooding is an elaborate form of parental care displayed by many teleost species. While the direct benefits of mouthbrooding such as protection and transportation of offsprings are known, it is unclear if mouthbrooding offers additional benefits to embryos during incubation. In addition, mouthbrooding could incur negative costs on parental fish, due to limited feeding opportunities. Parental tilapia fish (Oreochromis spp.) display an elaborated form of parental care by incubating newly hatched embryos in oral buccal cavity until the complete adsorption of yolk sac. In order to understand the functional aspects of mouthbrooding, we undertake a proteomics approach to compare oral mucus sampled from mouthbrooders and non-mouthbrooders, respectively. Majority of the identified proteins have also been previously identified in other biological fluids or mucus-rich organs in different organisms. We also showed the upregulation of 22 proteins and down regulation of 3 proteins in mucus collected from mouthbrooders. Anterior gradient protein, hemoglobin beta-A chain and alpha-2 globin levels were lower in mouthbrooder samples. Mouthbrooder oral mucus collectively showed increase levels of proteins related to cytoskeletal properties, glycolytic pathway and mediation of oxidative stress. Overall the findings suggest cellular stress response, probably to support production of mucus during mouthbrooding phase

Effect of age, sex and gender on pain sensitivity: A narrative review

© 2017 Eltumi And Tashani. Introduction: An increasing body of literature on sex and gender differences in pain sensitivity has been accumulated in recent years. There is also evidence from epidemiological research that painful conditions are more prevalent in older people. The aim of this narrative review is to critically appraise the relevant literature investigating the presence of age and sex differences in clinical and experimental pain conditions. Methods: A scoping search of the literature identifying relevant peer reviewed articles was conducted on May 2016. Information and evidence from the key articles were narratively described and data was quantitatively synthesised to identify gaps of knowledge in the research literature concerning age and sex differences in pain responses. Results: This critical appraisal of the literature suggests that the results of the experimental and clinical studies regarding age and sex differences in pain contain some contradictions as far as age differences in pain are concerned. While data from the clinical studies are more consistent and seem to point towards the fact that chronic pain prevalence increases in the elderly findings from the experimental studies on the other hand were inconsistent, with pain threshold increasing with age in some studies and decreasing with age in others. Conclusion: There is a need for further research using the latest advanced quantitative sensory testing protocols to measure the function of small nerve fibres that are involved in nociception and pain sensitivity across the human life span. Implications: Findings from these studies should feed into and inform evidence emerging from other types of studies (e.g. brain imaging technique and psychometrics) suggesting that pain in the older humans may have unique characteristics that affect how old patients respond to intervention

GLI1-dependent transcriptional repression of CYLD in basal cell carcinoma

CYLD is a deubiquitination enzyme that regulates different cellular processes, such as cell proliferation and cell survival. Mutation and loss of heterozygosity of the CYLD gene causes development of cylindromatosis, a benign tumour originating from the skin. Our study shows that CYLD expression is dramatically downregulated in basal cell carcinoma (BCC), the most common cancer in humans. Reduced CYLD expression in basal cell carcinoma was mediated by GLI1-dependent activation of the transcriptional repressor Snail. Inhibition of GLI1 restored the CYLD expression-mediated Snail signaling pathway, and caused a significant delay in the G1 to S phase transition, as well as proliferation. Our data suggest that GLI1-mediated suppression of CYLD has a significant role in basal cell carcinoma progression. Oncogene (2011) 30, 4523-4530; doi: 10.1038/onc.2011.163; published online 16 May 201

Behavior-based diabetes management: Impact on care, hospitalizations, and costs

OBJECTIVES: To (1) examine the impact of the Diabetes Care Rewards (DCR) program on adherence to care standards and (2) evaluate the economic impact of adherence to care standards. STUDY DESIGN: A retrospective observational cohort study design with propensity matching. Additional covariates adjustment was used to minimize residual imbalance. METHODS: Utilization and cost data were compared between individuals enrolled vs individuals eligible for but not enrolled in the DCR program using a standard mean difference. Individuals were employees or their dependents from self-insured companies throughout the United States. Outcomes included adherence to the care standards, service utilization, and costs. RESULTS: A total of 3318 propensity-matched participants were included. Primary analysis revealed that enrolled members increased adherence to semiannual glycated hemoglobin, annual lipid, and annual urine albumincreatinine ratio testing. Additionally, enrolled members experienced less utilization of high-acuity services and increased rates of physician visits. In a secondary analysis, the enrolled group was associated with greater pharmaceutical costs but lower medical costs. CONCLUSIONS: A behavioral science- and incentive-based diabetes management program was associated with greater rates of adherence to recommended diabetes monitoring care standards, increased routine clinic visits, decreased hospital admissions, and decreased inpatient days. Anticipated increases in pharmaceutical expenditures were offset by overall lower medical expenditures. Results indicate the economic benefits of adherence to evidencebased standards for diabetes care

Development of Hospice and Palliative Medicine Knowledge and Skills for Emergency Medicine Residents: Using the Accreditation Council for Graduate Medical Education Milestone Framework.

Objectives: Emergency medicine (EM) physicians commonly care for patients with serious life-limiting illness. Hospice and palliative medicine (HPM) is a subspecialty pathway of EM. Although a subspecialty level of practice requires additional training, primary-level skills of HPM such as effective communication and symptom management are part of routine clinical care and expected of EM residents. However, unlike EM residency curricula in disciplines like trauma and ultrasound, there is no nationally defined HPM curriculum for EM resident training. An expert consensus group was convened with the aim of defining content areas and competencies for HPM primary-level practice in the ED setting. Our overall objective was to develop HPM milestones within a competency framework that is relevant to the practice of EM. Methods: The American College of Emergency Physicians Palliative Medicine Section assembled a committee that included academic EM faculty, community EM physicians, EM residents, and nurses, all with interest and expertise in curricular design and palliative medicine. Results: The committee peer reviewed and assessed HPM content for validity and importance to EM residency training. A topic list was developed with three domains: provider skill set, clinical recognition of HPM needs, and logistic understanding related to HPM in the ED. The group also developed milestones in HPM-EM to identify relevant knowledge, skills, and behaviors using the framework modeled after the Accreditation Council for Graduate Medical Education (ACGME) EM milestones. This framework was chosen to make the product as user-friendly and familiar as possible to facilitate use by EM educators. Conclusions: Educators in EM residency programs now have access to HPM content areas and milestones relevant to EM practice that can be used for curriculum development in EM residency programs. The HPM-EM skills/competencies presented herein are structured in a familiar milestone framework that is modeled after the widely accepted ACGME EM milestones