Proteasomal degradation of sphingosine kinase 1 and inhibition of dihydroceramide desaturase by the sphingosine kinase inhibitors, SKi or ABC294640, induces growth arrest in androgen-independent LNCaP-AI prostate cancer cells

Sphingosine kinases (two isoforms termed SK1 and SK2) catalyse the formation of the bioactive lipid sphingosine 1-phosphate. We demonstrate here that the SK2 inhibitor, ABC294640 (3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide) or the SK1/SK2 inhibitor, SKi (2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole)) induce the proteasomal degradation of SK1a (Mr = 42 kDa) and inhibit DNA synthesis in androgen-independent LNCaP-AI prostate cancer cells. These effects are recapitulated by the dihydroceramide desaturase (Des1) inhibitor, fenretinide. Moreover, SKi or ABC294640 reduce Des1 activity in Jurkat cells and ABC294640 induces the proteasomal degradation of Des1 (Mr = 38 kDa) in LNCaP-AI prostate cancer cells. Furthermore, SKi or ABC294640 or fenretinide increase the expression of the senescence markers, p53 and p21 in LNCaP-AI prostate cancer cells. The siRNA knockdown of SK1 or SK2 failed to increase p53 and p21 expression, but the former did reduce DNA synthesis in LNCaP-AI prostate cancer cells. Moreover, N-acetylcysteine (reactive oxygen species scavenger) blocked the SK inhibitor-induced increase in p21 and p53 expression but had no effect on the proteasomal degradation of SK1a. In addition, siRNA knockdown of Des1 increased p53 expression while a combination of Des1/SK1 siRNA increased the expression of p21. Therefore, Des1 and SK1 participate in regulating LNCaP-AI prostate cancer cell growth and this involves p53/p21-dependent and -independent pathways. Therefore, we propose targeting androgen-independent prostate cancer cells with compounds that affect Des1/SK1 to modulate both de novo and sphingolipid rheostat pathways in order to induce growth arrest

A Mixture of Regressions Model of COVID-19 Death Rates and Population Comorbidities

As the COVID-19 pandemic spread worldwide, it has become clearer that prevalence of certain comorbidities in a given population could make it more vulnerable to serious outcomes of that disease, including fatality. Indeed, it might be insightful from a health policy perspective to identify clusters of populations in terms of the associations between their prevalent comorbidities and the observed COVID-19 specific death rates. In this study, we described a mixture of polynomial time series (MoPTS) model to simultaneously identify (a) three clusters of 86 U.S. cities in terms of their dynamic death rates, and (b) the different associations of those rates with 5 key comorbidities among the populations in the clusters. We also described an EM algorithm for efficient maximum likelihood estimation of the model parameters

Pre-Exercise Whole- or Partial-Body Cryotherapy Exposure to Improve Physical Performance:A Systematic Review

Whole- (WBC) and partial-body cryotherapy (PBC) are commonly used sports medicine modalities for the treatment of injury and exercise recovery. Physiological and perceptual effects have the potential to be utilised in a novel application that involves pre-exercise WBC and PBC exposure to improve physical performance. A systematic literature search of multiple databases was conducted in July 2021 to identify and evaluate the effects of pre-exercise exposure of WBC or PBC on physical performance measures, and any potential translational effects. The following inclusion criteria were applied: (1) use of WBC or PBC exposure pre-exercise, (2) use of WBC or PBC in healthy and/or athletic populations, (3) control group was used in the data collection, and (4) investigated physiological, psychosocial or direct physical performance impacts of pre-exercise cryotherapy exposure. A total of 759 titles were identified, with twelve relevant studies satisfying the inclusion criteria after full-text screening. The twelve studies were categorised into three key areas: performance testing (n = 6), oxidative stress response (n = 4) and lysosomal enzyme activity (n = 2). The potential for eliciting favourable physical and physiological responses from pre-exercise WBC or PBC is currently unclear with a paucity of good quality research available. Furthermore, a lack of standardisation of cryotherapy protocols is a current challenge

Therapeutic potential of targeting sphingosine kinases and sphingosine 1-phosphate in hematological malignancies

Sphingolipids, such as ceramide, sphingosine and sphingosine 1-phosphate (S1P) are bioactive molecules that have important functions in a variety of cellular processes, which include proliferation, survival, differentiation and cellular responses to stress. Sphingolipids have a major impact on the determination of cell fate by contributing to either cell survival or death. Although ceramide and sphingosine are usually considered to induce cell death, S1P promotes survival of cells. Sphingosine kinases (SPHKs) are the enzymes that catalyze the conversion of sphingosine to S1P. There are two isoforms, SPHK1 and SPHK2, which are encoded by different genes. SPHK1 has recently been implicated in contributing to cell transformation, tumor angiogenesis and metastatic spread, as well as cancer cell multidrug-resistance. More recent findings suggest that SPHK2 also has a role in cancer progression. This review is an overview of our understanding of the role of SPHKs and S1P in hematopoietic malignancies and provides information on the current status of SPHK inhibitors with respect to their therapeutic potential in the treatment of haematological cancers

Role of sphingosine 1-phosphate receptors, sphingosine kinases and sphingosine in cancer and inflammation

Sphingosine kinase (there are two isoforms, SK1 and SK2) catalyses the formation of sphingosine 1-phosphate (S1P), a bioactive lipid that can be released from cells to activate a family of G protein-coupled receptors, termed S1P1-5. In addition, S1P can bind to intracellular target proteins, such as HDAC1/2, to induce cell responses. There is increasing evidence of a role for S1P receptors (e.g. S1P4) and SK1 in cancer, where high expression of these proteins in ER negative breast cancer patient tumours is linked with poor prognosis. Indeed, evidence will be presented here to demonstrate that S1P4 is functionally linked with SK1 and the oncogene HER2 (ErbB2) to regulate mitogen-activated protein kinase pathways and growth of breast cancer cells. Although much emphasis is placed on SK1 in terms of involvement in oncogenesis, evidence will also be presented for a role of SK2 in both T-cell and B-cell acute lymphoblastic leukemia. In patient T-ALL lymphoblasts and T-ALL cell lines, we have demonstrated that SK2 inhibitors promote T-ALL cell death via autophagy and induce suppression of c-myc and PI3K/AKT pathways. We will also present evidence demonstrating that certain SK inhibitors promote oxidative stress and protein turnover via proteasomal degradative pathways linked with induction of p53-and p21-induced growth arrest. In addition, the SK1 inhibitor, PF-543 exacerbates disease progression in an experimental autoimmune encephalomyelitis mouse model indicating that SK1 functions in an anti-inflammatory manner. Indeed, sphingosine, which accumulates upon inhibition of SK1 activity, and sphingosine-like compounds promote activation of the inflammasome, which is linked with multiple sclerosis, to stimulate formation of the pro-inflammatory mediator, IL-1β. Such compounds could be exploited to produce antagonists that diminish exaggerated inflammation in disease. The therapeutic potential of modifying the SK-S1P receptor pathway in cancer and inflammation will therefore, be reviewed

Practical and clinical approaches using pacing to improve selfregulation in special populations such as children and people with mental health or learning disabilities

For special populations such as people with a mental health issue or learning disability, a disconnect between the ability to accurately monitor and regulate exercise behaviour can lead to reduced levels of physical activity, which, in turn, is associated with additional physical or mental health problems. Activity pacing is a strategy used in clinical settings to address issues of pain amelioration, while self-pacing research is now well addressed in sport and exercise science literature. It has been proposed recently that these overlapping areas of investigation collectively support the development of self-regulatory, lifestyle exercise skills across broad population groups. Activity pacing appears to have substantial application in numerous development and rehabilitation settings and, therefore, the purpose of this short communication is to articulate how an activity pacing approach could be utilized among population groups in whom self-regulatory skills may require development. This paper provides specific examples of exercise practice across 2 discrete populations: children, and people with mental health and learning difficulties. In these cases, homeostatic regulatory processes may either be altered, or the individual may require extrinsic support to appropriately self-regulate exercise performance. A support-based exercise environment or approach such as programmatic activity (lifestyle) pacing would be beneficial to facilitate supervised and education-based self-regulation until such time as fully self-regulated exercise is feasible. [Abstract copyright: Journal Compilation © 2021 Foundation of Rehabilitation Information.

The effect of exercise on innate mucosal immunity

METHODS The authors conducted a prospective observational study comparing salivary lactoferrin and lysozyme concentration over 5 months (chronic changes) in elite rowers (n=17, mean age 24.3+/-4.0 years) with sedentary individuals (controls) (n=18, mean age=27.2+/-7.1 years) and a graded exercise test to exhaustion (acute changes) with a cohort of elite rowers (n=11, mean age 24.7+/-4.1). RESULTS Magnitudes of differences and changes were interpreted as a standardised (Cohen's) effect size (ES). Lactoferrin concentration in the observational study was approximately 60% lower in rowers than control subjects at baseline (7.9+/-1.2 microg/ml mean+/-SEM, 19.4+/-5.6 microg/ml, p=0.05, ES=0.68, 'moderate') and at the midpoint of the season (6.4+/-1.4 microg/ml mean +/- SEM, 21.5+/-4.2 microg/ml, p=0.001, ES=0.89, 'moderate'). The concentration of lactoferrin at the end of the study was not statistically significant (p=0.1) between the groups. There was no significant difference between rowers and control subjects in lysozyme concentration during the study. There was a 50% increase in the concentration of lactoferrin (p=0.05, ES=1.04, 'moderate') and a 55% increase in lysozyme (p=0.01, ES=3.0, 'very large') from pre-exercise to exhaustion in the graded exercise session. CONCLUSION Lower concentrations of these proteins may be indicative of an impairment of innate protection of the upper respiratory tract. Increased salivary lactoferrin and lysozyme concentration following exhaustive exercise may be due to a transient activation response that increases protection in the immediate postexercise period

Cosmic Microwave Background anisotropies from second order gravitational perturbations

This paper presents a complete analysis of the effects of second order gravitational perturbations on Cosmic Microwave Background anisotropies, taking explicitly into account scalar, vector and tensor modes. We also consider the second order perturbations of the metric itself obtaining them, for a universe dominated by a collision-less fluid, in the Poisson gauge, by transforming the known results in the synchronous gauge. We discuss the resulting second order anisotropies in the Poisson gauge, and analyse the possible relevance of the different terms. We expect that, in the simplest scenarios for structure formation, the main effect comes from the gravitational lensing by scalar perturbations, that is known to give a few percent contribution to the anisotropies at small angular scales.Comment: 15 pages, revtex, no figures. Version to be published in Phys. Rev.