Structure-function studies of the bHLH phosphorylation domain of TWIST1 in prostate cancer cells

The TWIST1 gene has diverse roles in development and pathologic diseases such as cancer. TWIST1 is a dimeric basic helix-loop-helix (bHLH) transcription factor existing as TWIST1-TWIST1 or TWIST1-E12/47. TWIST1 partner choice and DNA binding can be influenced during development by phosphorylation of Thr125 and Ser127 of the Thr-Gln-Ser (TQS) motif within the bHLH of TWIST1. The significance of these TWIST1 phosphorylation sites for metastasis is unknown. We created stable isogenic prostate cancer cell lines overexpressing TWIST1 wild-type, phospho-mutants, and tethered versions. We assessed these isogenic lines using assays that mimic stages of cancer metastasis. In vitro assays suggested the phospho-mimetic Twist1-DQD mutation could confer cellular properties associated with pro-metastatic behavior. The hypo-phosphorylation mimic Twist1-AQA mutation displayed reduced pro-metastatic activity compared to wild-type TWIST1 in vitro, suggesting that phosphorylation of the TWIST1 TQS motif was necessary for pro-metastatic functions. In vivo analysis demonstrates that the Twist1-AQA mutation exhibits reduced capacity to contribute to metastasis, whereas the expression of the Twist1-DQD mutation exhibits proficient metastatic potential. Tethered TWIST1-E12 heterodimers phenocopied the Twist1-DQD mutation for many in vitro assays, suggesting that TWIST1 phosphorylation may result in heterodimerization in prostate cancer cells. Lastly, the dual phosphatidylinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) inhibitor BEZ235 strongly attenuated TWIST1-induced migration that was dependent on the TQS motif. TWIST1 TQS phosphorylation state determines the intensity of TWIST1-induced pro-metastatic ability in prostate cancer cells, which may be partly explained mechanistically by TWIST1 dimeric partner choice

Mitochondrial polymorphisms in rat genetic models of hypertension

Hypertension is a complex trait that has been studied extensively for genetic contributions of the nuclear genome. We examined mitochondrial genomes of the hypertensive strains: the Dahl Salt-Sensitive (S) rat, the Spontaneously Hypertensive Rat (SHR), and the Albino Surgery (AS) rat, and the relatively normotensive strains: the Dahl Salt-Resistant (R) rat, the Milan Normotensive Strain (MNS), and the Lewis rat (LEW). These strains were used previously for linkage analysis for blood pressure (BP) in our laboratory. The results provide evidence to suggest that variations in the mitochondrial genome do not account for observed differences in blood pressure between the S and R rats. However, variants were detected among the mitochondrial genomes of the various hypertensive strains, S, SHR, and AS, and also among the normotensive strains R, MNS, and LEW. A total of 115, 114, 106, 106, and 16 variations in mtDNA were observed between the comparisons S versus LEW, S versus MNS, S versus SHR, S versus AS, and SHR versus AS, respectively. Among the 13 genes coding for proteins of the electron transport chain, 8 genes had nonsynonymous variations between S, LEW, MNS, SHR, and AS. The lack of any sequence variants between the mitochondrial genomes of S and R rats provides conclusive evidence that divergence in blood pressure between these two inbred strains is exclusively programmed through their nuclear genomes. The variations detected among the various hypertensive strains provides the basis to construct conplastic strains and further evaluate the effects of these variants on hypertension and associated phenotypes

General anaesthetic and airway management practice for obstetric surgery in England: a prospective, multi-centre observational study

There are no current descriptions of general anaesthesia characteristics for obstetric surgery, despite recent changes to patient baseline characteristics and airway management guidelines. This analysis of data from the direct reporting of awareness in maternity patients' (DREAMY) study of accidental awareness during obstetric anaesthesia aimed to describe practice for obstetric general anaesthesia in England and compare with earlier surveys and best-practice recommendations. Consenting patients who received general anaesthesia for obstetric surgery in 72 hospitals from May 2017 to August 2018 were included. Baseline characteristics, airway management, anaesthetic techniques and major complications were collected. Descriptive analysis, binary logistic regression modelling and comparisons with earlier data were conducted. Data were collected from 3117 procedures, including 2554 (81.9%) caesarean deliveries. Thiopental was the induction drug in 1649 (52.9%) patients, compared with propofol in 1419 (45.5%). Suxamethonium was the neuromuscular blocking drug for tracheal intubation in 2631 (86.1%), compared with rocuronium in 367 (11.8%). Difficult tracheal intubation was reported in 1 in 19 (95%CI 1 in 16-22) and failed intubation in 1 in 312 (95%CI 1 in 169-667). Obese patients were over-represented compared with national baselines and associated with difficult, but not failed intubation. There was more evidence of change in practice for induction drugs (increased use of propofol) than neuromuscular blocking drugs (suxamethonium remains the most popular). There was evidence of improvement in practice, with increased monitoring and reversal of neuromuscular blockade (although this remains suboptimal). Despite a high risk of difficult intubation in this population, videolaryngoscopy was rarely used (1.9%)

Cognitive deficits and self-care behaviors in elderly adults with heart failure

Izabella Uchmanowicz,1 Beata Jankowska-Polańska,1 Grzegorz Mazur,2 Erika Sivarajan Froelicher3,4 1Department of Clinical Nursing, Faculty of Health Sciences, Wroclaw Medical University, Wroclaw, Poland; 2Department and Clinic of Internal and Occupational Diseases and Hypertension, Wroclaw Medical University, Wroclaw, Poland; 3Department of Physiological Nursing, School of Nursing; 4Department of Epidemiology & Biostatistics, School of Medicine, University of California San Francisco, San Francisco, CA, USA Introduction: Elderly adults with heart failure (HF) may have problems with self-care behaviors because of cognitive deficits. Self-care deficits have been found to be significantly associated with negative health care outcomes among HF patients. The aim of this paper was to assess cognitive deficits and the level of self-care ability in elderly patients with HF, and to determine if a relationship exists between cognitive deficits and self-care. Materials and methods: The study included 270 elderly patients (mean age: 72.5 years) with HF. We used the Mini Mental State Examination Scale (MMSE) to evaluate cognitive functioning, and the European Heart Failure Self-care Behavior Scale, revised into a nine-item scale (EHFScBS-9), to evaluate self-care behaviors. Associations between the variables were examined using multiple regression analysis. Results: Lower scores in both MMSE and EHFScBS-9 questionnaires were correlated with older age, living alone, lower education, longer duration of illness, higher number of rehospitalizations, as well as lower left ventricular ejection fraction and higher New York Heart Association (NYHA) class. The multiple regression analysis was used for evaluation of the impact of the following predictors: MMSE score, age, duration of illness, ejection fraction, number of hospitalizations, sex, residence, education, relationship status, and NYHA class on EHFScBS-9 score. Conclusions: Elderly patients with HF may have worse self-care behaviors because of their cognitive deficits. Age was the strongest predictor of worse MMSE scores. Multidisciplinary health teams should pay attention to the special needs of elderly patients who live with their illness for many years and have no social support because of living alone. Keywords: self-care behaviors, aging car

Being part of something: transformative outcomes of a community-based participatory study.

ObjectivesCalls for public health practices, including research, to better integrate social theories of power, agency, and social change suggest that increased reflexivity about both the process and outcomes of community engagement is warranted. Yet few community-based participatory research (CBPR) projects specifically report nonresearch outcomes of such projects. The authors analyzed "secondary outcomes" of Protecting the 'Hood Against Tobacco (PHAT), a CBPR project conducted in San Francisco, California.MethodsInterpretive analysis of quasi-ethnographic project documentation, including meeting minutes, field notes, retrospective observations, and interviews.ResultsPHAT participation created "ripple effects," encouraging healthier behaviors and public health promotion among community research partners, prompting academics to confront power asymmetries and recognize community knowledge, and widening social networks.ConclusionsCBPR benefits both communities and researchers beyond the findings of the research itself. More systematically capturing these effects, perhaps through wider use of ethnographic approaches, could help enhance understanding of CBPR's true contributions