Oncogenic transformation of mesenchymal stem cells decreases Nrf2 expression favoring in vivo tumor growth and poorer survival

BACKGROUND: The transcription factor Nrf2 is a key regulator of the cellular antioxidant response, and its activation by chemoprotective agents has been proposed as a potential strategy to prevent cancer. However, activating mutations in the Nrf2 pathway have been found to promote tumorigenesis in certain models. Therefore, the role of Nrf2 in cancer remains contentious. METHODS: We employed a well-characterized model of stepwise human mesenchymal stem cell (MSC) transformation and breast cancer cell lines to investigate oxidative stress and the role of Nrf2 during tumorigenesis. The Nrf2 pathway was studied by microarray analyses, qRT-PCR, and western-blotting. To assess the contribution of Nrf2 to transformation, we established tumor xenografts with transformed MSC expressing Nrf2 (n = 6 mice per group). Expression and survival data for Nrf2 in different cancers were obtained from GEO and TCGA databases. All statistical tests were two-sided. RESULTS: We found an accumulation of reactive oxygen species during MSC transformation that correlated with the transcriptional down-regulation of antioxidants and Nrf2-downstream genes. Nrf2 was repressed in transformed MSC and in breast cancer cells via oncogene-induced activation of the RAS/RAF/ERK pathway. Furthermore, restoration of Nrf2 function in transformed cells decreased reactive oxygen species and impaired in vivo tumor growth (P = 0.001) by mechanisms that included sensitization to apoptosis, and a decreased hypoxic/angiogenic response through HIF-1α destabilization and VEGFA repression. Microarray analyses showed down-regulation of Nrf2 in a panel of human tumors and, strikingly, low Nrf2 expression correlated with poorer survival in patients with melanoma (P = 0.0341), kidney (P = 0.0203) and prostate (P = 0.00279) cancers. CONCLUSIONS: Our data indicate that oncogene-induced Nrf2 repression is an adaptive response for certain cancers to acquire a pro-oxidant state that favors cell survival and in vivo tumor growth

Burden of diseases and injuries attributable to alcohol consumption in the Middle East and North Africa region, 1990–2019

Alcohol consumption is associated with a number of diseases and injuries, including cardiovascular diseases, cancers, mental and neurological disorders, as well as transport-related injuries. This article reports the alcohol-attributable burden of diseases and injuries at the regional and national levels in the Middle East and North Africa (MENA) region between 1990 and 2019, by sex, age, underlying cause, and Socio-demographic Index (SDI). The regional deaths and disability-adjusted life-years (DALYs) attributable to alcohol consumption were reported for the MENA region, between 1990 and 2019, using the methodological framework and analytical strategies adopted by the Global Burden of Disease (GBD) study 2019. The estimates were all reported as counts, population-attributable fractions, and age-standardised rates per 100,000 population, along with their corresponding 95% uncertainty intervals (UIs). Also, the average annual percentage changes were used to represent the trends of age-standardised rates. In 2019, there were an estimated 22.0 thousand deaths (95% UI: 16.1–29.4) and 1.1 million DALYs (0.8–1.3) attributable to alcohol consumption in the MENA region. The number of DALYs attributable to alcohol consumption were much higher in men (878.0 thousand, 691.4–1104.8) than among women (181.8, 138.6–232.0). The overall age-standardised death and DALY rates attributable to alcohol consumption decreased by 34.5% (13.2–48.3) and 31.9% (16.9–42.5), respectively, over the study period. Egypt (10.1 [5.7–16.6]) and Kuwait (1.1 [0.8–1.5]) had the highest and lowest age-standardised death rates attributable to alcohol consumption, respectively. In 2019, the number of deaths and DALYs in the MENA region were highest in those aged 60–64 and 50–54 years, respectively. A negative association was observed between a country’s SDI and their corresponding age-standardised DALY rates over the period 1990 to 2019. Digestive diseases were the main contributor to the alcohol-attributable burden. Over 1990–2019, the regional deaths and DALYs of diseases and injuries attributable to alcohol consumption decreased with AAPC of − 1.45 (− 1.78 to − 1.12) and − 1.31 (− 1.46 to − 1.15), respectively. The death and DALY rates attributable to alcohol consumption in the MENA region have decreased over the past three decades. Further decreases can be facilitated by implementing country-level policies and increasing public awareness

Unmet needs and current and future approaches for osteoporotic patients at high risk of hip fracture.

Summary: This review provides a critical analysis of currently available approaches to increase bone mass, structure and strength through drug therapy and of possible direct intraosseous interventions for the management of patients at imminent risk of hip fracture. Purpose : Osteoporotic hip fractures represent a particularly high burden in morbidity-, mortality- and health care-related costs. There are challenges and unmet needs in the early prevention of hip fractures, opening the perspective of new developments for the management of osteoporotic patients at imminent and/or at very high risk of hip fracture. Amongst them, preventive surgical intervention needs to be considered. Methods: A European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO)/International Osteoporosis Foundation (IOF) working group reviewed the presently available intervention modalities including preventive surgical options for hip fragility. This paper represents a summary of the discussions. Results: Prevention of hip fracture is currently based on regular physical activity; prevention of falls; correction of nutritional deficiencies, including vitamin D repletion; and pharmacological intervention. However, efficacy of these various measures to reduce hip fractures is at most 50% and may need months or years before becoming effective. To face the challenges of early prevention of hip fractures for osteoporotic patients at imminent and/or at very high risk of hip fracture, preventive surgical intervention needs further investigation. Conclusion: Preventive surgical intervention needs to be appraised for osteoporotic patients at imminent and/or at very high risk of hip fracture

Photodissociation and the Morphology of HI in Galaxies

Young massive stars produce Far-UV photons which dissociate the molecular gas on the surfaces of their parent molecular clouds. Of the many dissociation products which result from this ``back-reaction'', atomic hydrogen \HI is one of the easiest to observe through its radio 21-cm hyperfine line emission. In this paper I first review the physics of this process and describe a simplified model which has been developed to permit an approximate computation of the column density of photodissociated \HI which appears on the surfaces of molecular clouds. I then review several features of the \HI morphology of galaxies on a variety of length scales and describe how photodissociation might account for some of these observations. Finally, I discuss several consequences which follow if this view of the origin of HI in galaxies continues to be successful.Comment: 18 pages, 7 figures in 8 files, invited review paper for the conference "Penetrating Bars Through Masks of Cosmic Dust: The Hubble Tuning Fork Strikes a New Note", South Africa, June 2004. Proceedings to be published by Kluwer, eds. D.L. Block, K.C. Freeman, I. Puerari, R. Groess, & E.K. Bloc

Evidence for D1 Dopamine Receptor Activation by a Paracrine Signal of Dopamine in Tick Salivary Glands

Ticks that feed on vertebrate hosts use their salivary secretion, which contains various bioactive components, to manipulate the host's responses. The mechanisms controlling the tick salivary gland in this dynamic process are not well understood. We identified the tick D1 receptor activated by dopamine, a potent inducer of the salivary secretion of ticks. Temporal and spatial expression patterns examined by immunohistochemistry and reverse transcription polymerase chain reaction suggest that the dopamine produced in the basal cells of salivary gland acini is secreted into the lumen and activates the D1 receptors on the luminal surface of the cells lining the acini. Therefore, we propose a paracrine function of dopamine that is mediated by the D1 receptor in the salivary gland at an early phase of feeding. The molecular and pharmacological characterization of the D1 receptor in this study provides the foundation for understanding the functions of dopamine in the blood-feeding of ticks

The burden of rheumatoid arthritis in the Middle East and North Africa region, 1990–2019

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease. The present study reported the burden of RA in the Middle East and North Africa (MENA) region from 1990 to 2019 by age, sex, and socio-demographic index (SDI). Publicly available data from the Global Burden of Disease (GBD) 2019 study was used to report the modelled point prevalence, annual incidence, and disability-adjusted life-years (DALYs) of RA, as counts and age-standardised rates with their corresponding 95% uncertainty intervals (UIs). In 2019, RA had an age-standardised point prevalence of 120.6 per 100,000 population (107.0–135.7) and an annual incidence rate of 5.9 (5.2–6.6) in MENA, which have increased 28.3% and 25.2%, respectively, since 1990. In 2019, the number of DALYs due to RA in the region was 103.6 thousand (74.2–136.7), with an age-standardised rate of 19.0 (13.9–24.9) DALYs per 100,000 population, which has increased by 18.6% since 1990 (6.7–28.2). The highest point prevalence was found in females aged 50–54, and in males aged 45–49. The highest number of DALYs was observed in the 50–54 age group. The MENA DALY rate was lower than the global rate (19.0 vs. 39.6 per 100,000), but the rate was higher in all age groups in 2019, when compared with 1990. In addition, from 1990 to 2019 an increased burden from RA was associated with an increase in SDI. In line with global trends, the burden of RA in the MENA region showed a steady increase from 1990 to 2019. This highlights the increasing need for updating the available health data to design more accurate guidelines to enable the early detection and treatment of RA in the MENA countries

The burden of low back pain and its association with socio-demographic variables in the Middle East and North Africa region, 1990–2019

Background Low back pain (LBP) is the most common musculoskeletal disorder globally. Providing region- and national-specific information on the burden of low back pain is critical for local healthcare policy makers. The present study aimed to report, compare, and contextualize the prevalence, incidence and years lived with disability (YLDs) of low back pain in the Middle East and North Africa (MENA) region by age, sex and sociodemographic index (SDI), from 1990 to 2019. Methods Publicly available data were obtained from the Global Burden of Disease (GBD) study 2019. The burden of LBP was reported for the 21 countries located in the MENA region, from 1990 to 2019. All estimates were reported as counts and age-standardised rates per 100,000 population, together with their corresponding 95% uncertainty intervals (UIs). Results In 2019, the age-standardised point prevalence and incidence rate per 100,000 in MENA were 7668.2 (95% UI 6798.0 to 8363.3) and 3215.9 (95%CI 2838.8 to 3638.3), which were 5.8% (4.3 to 7.4) and 4.4% (3.4 to 5.5) lower than in 1990, respectively. Furthermore, the regional age-standardised YLD rate in 2019 was 862.0 (605.5 to 1153.3) per 100,000, which was 6.0% (4.2 to 7.7) lower than in 1990. In 2019, Turkey [953.6 (671.3 to 1283.5)] and Lebanon [727.2 (511.5 to 966.0)] had the highest and lowest age-standardised YLD rates, respectively. There was no country in the MENA region that showed increases in the age-standardised prevalence, incidence or YLD rates of LBP over the measurement period. Furthermore, in 2019 the number of prevalent cases were highest in the 35–39 age group, with males having a higher number of cases in all age groups. In addition, the age-standardised YLD rates for males in the MENA region were higher than the global estimates in almost all age groups, in both 1990 and 2019. Furthermore, the burden of LBP was not associated with the level of socio-economic development during the measurement period. Conclusion The burden attributable to LBP in the MENA region decreased slightly from 1990 to 2019. Furthermore, the burden among males was higher than the global average. Consequently, more integrated healthcare interventions are needed to more effectively alleviate the burden of low back pain in this region

The method of bladder drainage in spinal cord injury patients may influence the histological changes in the mucosa of neuropathic bladder – a hypothesis

BACKGROUND: In spinal cord injury (SCI) patients, no correlation was found between the number of bladder infections per year, the period since injury, the neurologic level of the spinal cord lesion and the histopathology of the urinary bladder mucosa. The use of chronic indwelling urethral and/or suprapubic catheters in SCI patients is often associated with inflammatory and proliferative pathological conditions in neuropathic bladder. PRESENTATION OF THE HYPOTHESIS: We propose a hypothesis that the type of bladder drainage in SCI patients influences the histological changes in the mucosa of neuropathic bladder. This hypothesis implies that SCI patients with long-term indwelling urinary catheters develop certain histological changes in bladder mucosa, which are seen less frequently in SCI patients, who do not use long-term indwelling catheters. The latter group includes patients, who perform regular intermittent catheterisation and those, who wear a penile sheath and empty their bladders satisfactorily by reflex voiding. We hypothesise that the following histological lesions are seen more frequently in the neuropathic bladder of SCI patients with long-term indwelling catheters. (1) Papillary or polypoid cystitis; (2) widespread cystitis glandularis; (3) moderate to severe, acute and chronic inflammatory changes in bladder mucosa; (4) follicular cystitis; (5) squamous metaplasia; and (6) urothelial dysplasia As per this hypothesis, it is postulated that the above pathological conditions are seen less often in SCI patients, who achieve complete, low-pressure emptying of the neuropathic bladder by regular intermittent catheterisation, and SCI patients with penile sheath drainage, who empty their bladders satisfactorily by reflex voiding. TESTING THE HYPOTHESIS: A large prospective study of bladder biopsies in SCI patients practising different methods of bladder drainage is required to validate this hypothesis that the histological changes in bladder mucosa are related to the method of bladder drainage in SCI patients. IMPLICATIONS OF THE HYPOTHESIS: We propose a hypothesis that the method of bladder drainage in SCI patients influences histological changes in the bladder mucosa. If this hypothesis is validated, methods of bladder drainage such as intermittent catheterisation, which do not require the use of chronic indwelling catheters, should be recommended, in order to minimise adverse histological changes in the mucosa of neuropathic bladder of spinal cord injury patients

On the nonequilibrium entropy of large and small systems

Thermodynamics makes definite predictions about the thermal behavior of macroscopic systems in and out of equilibrium. Statistical mechanics aims to derive this behavior from the dynamics and statistics of the atoms and molecules making up these systems. A key element in this derivation is the large number of microscopic degrees of freedom of macroscopic systems. Therefore, the extension of thermodynamic concepts, such as entropy, to small (nano) systems raises many questions. Here we shall reexamine various definitions of entropy for nonequilibrium systems, large and small. These include thermodynamic (hydrodynamic), Boltzmann, and Gibbs-Shannon entropies. We shall argue that, despite its common use, the last is not an appropriate physical entropy for such systems, either isolated or in contact with thermal reservoirs: physical entropies should depend on the microstate of the system, not on a subjective probability distribution. To square this point of view with experimental results of Bechhoefer we shall argue that the Gibbs-Shannon entropy of a nano particle in a thermal fluid should be interpreted as the Boltzmann entropy of a dilute gas of Brownian particles in the fluid