Hsp90 and PKM2 Drive the Expression of Aromatase in Li-Fraumeni Syndrome Breast Adipose Stromal Cells

Li-Fraumeni syndrome (LFS) patients harbor germ line mutations in the TP53 gene and are at increased risk of hormone receptor-positive breast cancers. Recently, elevated levels of aromatase, the rate-limiting enzyme for estrogen biosynthesis, were found in the breast tissue of LFS patients. Although p53 down-regulates aromatase expression, the underlying mechanisms are incompletely understood. In the present study, we found that LFS stromal cells expressed higher levels of Hsp90 ATPase activity and aromatase compared with wild-type stromal cells. Inhibition of Hsp90 ATPase suppressed aromatase expression. Silencing Aha1 (activator of Hsp90 ATPase 1), a co-chaperone of Hsp90 required for its ATPase activity, led to both inhibition of Hsp90 ATPase activity and reduced aromatase expression. In comparison with wild-type stromal cells, increased levels of the Hsp90 client proteins, HIF-1α, and PKM2 were found in LFS stromal cells. A complex comprised of HIF-1α and PKM2 was recruited to the aromatase promoter II in LFS stromal cells. Silencing either HIF-1α or PKM2 suppressed aromatase expression in LFS stromal cells. CP-31398, a p53 rescue compound, suppressed levels of Aha1, Hsp90 ATPase activity, levels of PKM2 and HIF-1α, and aromatase expression in LFS stromal cells. Consistent with these in vitro findings, levels of Hsp90 ATPase activity, Aha1, HIF-1α, PKM2, and aromatase were increased in the mammary glands of p53 null versus wild-type mice. PKM2 and HIF-1α were shown to co-localize in the nucleus of stromal cells of LFS breast tissue. Taken together, our results show that the Aha1-Hsp90-PKM2/HIF-1α axis mediates the induction of aromatase in LFS

Psychological impact of COVID-19 and lock down measures: An online cross-sectional multicounty study on Asian university students

The COVID-19 pandemic and the lockdown measures have taken a toll on every level of the society, worldwide. This study examines their psychological impact on university students in Asia. A cross-sectional online survey was conducted between April and May 2020 in Malaysia, Saudi Arabia, Pakistan, Bangladesh, China, India and Indonesia. The Zung\u27s self-rating anxiety scale (SAS) and questions on adaptive and maladaptive coping strategies were used in this study. A total of 3,679 students from the seven countries participated in this study. Overall, 21.9% and 13.7% of the students in this study experienced mild to moderate and severe to extreme levels of anxiety. More than 20% of the students from China and Bangladesh reported severe to extreme level of anxiety compared to below 10% of the students from Indonesia, Malaysia and India. Among the female students, 15.9% experienced severe to extreme level of anxiety compared to 10.6% among the males. Females from Bangladesh, China, Malaysia, Pakistan and Saudi Arabia experienced significantly higher levels of anxiety compared to their male counterparts. Acceptance was the most used and Seeking Social Support was the least used coping strategies among the students. There were significant differences in the usage of the four strategies by countries. Stressors are predominantly financial constraints, remote online learning, and uncertainty related to their academic performance, and future career prospects

Investigation the nonlinear optical properties of silver nanoparticles using femtosecond laser

© 2020 Published under licence by IOP Publishing Ltd. In this research, the fabrication of silver nanoparticles and experimental nonlinear response (NLO). The fabrication of the silver nanoparticles has been done using E-Beam evaporation on a glass substrate (Ag-NPs) and investigation of their nonlinear optical response (NLO). The silver nanoparticles was evaluated by optical spectrum (UV-Vis) that shows localized surface Plasmon band at 375 nm. The experiment shows the nonlinear absorption and nonlinear refraction effect of silver nanoparticles, the silver nanoparticles is analysed by Z-Scan technique using a femtoseconds laser with 800 nm wavelength. The result shows the nonlinear absorption (NLA) is at 4.8710-4cmW-1, while (NLR) is at 7.9410-9cmW-1

Sestrin2 suppression aggravates oxidative stress and apoptosis in endothelial cells subjected to pharmacologically induced endoplasmic reticulum stress

Endoplasmic reticulum (ER) stress is an inflammatory response that contributes to endothelial dysfunction, a hallmark of cardiovascular diseases, in close interplay with oxidative stress. Recently, Sestrin2 (SESN2) emerged as a novel stress-inducible protein protecting cells from oxidative stress. We investigated here, for the first time, the impact of SESN2 suppression on oxidative stress and cell survival in human endothelial cells subjected to pharmacologically (thapsigargin)-induced ER stress and studied the underlying cellular pathways. We found that SESN2 silencing, though did not specifically induce ER stress, it aggravated the effects of thapsigargin-induced ER stress on oxidative stress and cell survival. This was associated with a dysregulation of Nrf-2, AMPK and mTORC1 signaling pathways. Furthermore, SESN2 silencing aggravated, in an additive manner, apoptosis caused by thapsigargin. Importantly, SESN2 silencing, unlike thapsigargin, caused a dramatic decrease in protein expression and phosphorylation of Akt, a critical pro-survival hub and component of the AMPK/Akt/mTORC1 axis. Our findings suggest that patients with conditions characterized by ER stress activation, such as diabetes, may be at higher risk for cardiovascular complications if their endogenous ability to stimulate and/or maintain expression levels of SESN2 is disturbed or impaired. Therefore, identifying novel or repurposing existing pharmacotherapies to enhance and/or maintain SESN2 expression levels would be beneficial in these conditions

The Epidemiology and Outcome of Biliary Atresia: Saudi Arabian National Study (2000–2018)

BackgroundThe epidemiology and outcomes of biliary atresia (BA) have been well-documented in national cohorts from two main ethnicities, namely, the Asian Orientals and Caucasians, with incidence ranging from 1 in 5,000 to 1 in 9,000 live births in East Asia and 1 in 15,000 to 19,000 live births in Europe and North America.ObjectiveWe report the first nationwide BA study outside North America, Europe, and East Asia to describe the epidemiology and outcomes of BA in Saudi Arabia.MethodsA national database of BA cases diagnosed between 2000 and 2018 was analyzed. We assessed clearance of jaundice (bilirubin <20 μmol/L) in all cases that underwent Kasai portoenterostomy (KPE). We then estimated survival using the Kaplan–Meier method with endpoints of liver transplantation (LT), death, or survival with native liver (SNL).ResultsBA was diagnosed in 204 infants (106 females; 10% pre-term). The incidence of BA was 1 in 44,365, or 2.254 in 100,000 live births (range, 0.5–4 in 100,000). Polysplenia was diagnosed in 22 cases (11%). The median age at referral was 65 days. A total of 146 children (71.5%) underwent KPE at a median age of 70 days. Clearance of jaundice was achieved in 66 of the 146 (45%) infants. The 10-year SNL after KPE was 25.5%, and the overall 10-year estimated survival was 72.5%. The Kaplan–Meier survival curves for patients undergoing KPE at the age of <60, 61–90, and >90 days showed a SNL rate at 51.6, 33, and 12.5%, respectively, at 5 years (P < 0.001). The 2-, 5-, and 10-year post-LT survival rates were 92.5, 90.6, and 90%, respectively. Undergoing an initial KPE did not impact negatively on the overall LT survival rate when compared to BA cases that underwent primary LT (P = 0.88).ConclusionThe incidence rate of BA in Saudi Arabia is lower than the incidence reported elsewhere. Late referral of BA cases remains a problem in Saudi Arabia; as a result, the SNL rate was lower than reported by other national registries. Hence, national policies devoted to timely referral and earlier age at KPE are needed

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Assessing the Knowledge and Attitude toward COVID-19 Vaccination in Saudi Arabia

COVID-19 was declared a pandemic by the WHO in March 2020. The most promising strategy to control the pandemic was to develop a vaccine. However, vaccination hesitancy is a major threat to world public health. Understanding the reasons behind this hesitancy might help in developing encouragement strategies. This cross-sectional study aimed to assess the knowledge and attitude toward the COVID-19 vaccine in Saudi Arabia. A total of 1599 responses were received; the overall vaccine acceptancy was 79.2%. Age, sex, and nationality of participants significantly predicted the vaccination status. A significantly higher proportion of participants, who reported being vaccinated, or intended to receive the vaccine, stated that the COVID-19 infection is dangerous, or varies from person to person; the vaccine is safe, and think there is a definite need for the vaccine (p &lt; 0.001). The major encouragement factors to receive the vaccine were either confidence in the government decisions (54.8%), or the feeling of responsibility to stop the pandemic (48.7%), whereas the main discouraging factors were concerns about the insufficient clinical trials (11.4%), or the undiscovered side effects (11%). The results of this study indicate good acceptance toward the COVID-19 vaccine among residents of Saudi Arabia

Obesity-Associated Breast Cancer: Clinical Evidence for a Molecular Link

Obesity is associated with an increased risk of postmenopausal, estrogen-dependent breast cancer. Adipose tissue undergoes important changes in obesity due to excess storage of lipids, leading to adipocyte cell death and the recruitment of macrophages resulting in chronic low-grade inflammation and elevated levels of aromatase, the rate-limiting enzyme in estrogen biosynthesis. My research aimed to determine whether the p53-HIF1α/PKM2-aromatase axis is altered with obesity. In addition, whether obesity leads to DNA damage, a key determinant of tumour formation. Further, whether caloric restriction reverses the obesity effect on this axis and DNA damage, thus serve as a strategy to prevent cancer

Analysis of Cardiovascular Complications During Delivery Admissions Among Patients With Systemic Lupus Erythematosus, 2004-2019

Importance: Individuals with systemic lupus erythematosus (SLE) have an increased risk of pregnancy-related complications. However, data on acute cardiovascular complications during delivery admissions remain limited. Objective: To investigate whether SLE is associated with an increased risk of acute peripartum cardiovascular complications during delivery hospitalization among individuals giving birth. Design, setting, and participants: This population-based cross-sectional study was conducted with data from the National Inpatient Sample (2004-2019) by using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, Clinical Modification (ICD-10-CM) codes to identify delivery hospitalizations among birthing individuals with a diagnosis of SLE. A multivariable logistic regression model was developed to report an adjusted odds ratio (OR) for the association between SLE and acute peripartum cardiovascular complications. Data were analyzed from May 1 through September 1, 2022. Exposure: Diagnosed SLE. Main outcomes and measures: Primary study end points were preeclampsia, peripartum cardiomyopathy, and heart failure. Secondary end points included ischemic and hemorrhagic stroke, pulmonary edema, cardiac arrhythmias, acute kidney injury (AKI), venous thromboembolism (VTE), length of stay, and cost of hospitalization. Results: A total of 63 115 002 weighted delivery hospitalizations (median [IQR] age, 28 [24-32] years; all were female patients) were identified, of which 77 560 hospitalizations (0.1%) were among individuals with SLE and 63 037 442 hospitalizations (99.9%) were among those without SLE. After adjustment for age, race and ethnicity, comorbidities, insurance, and income level, SLE remained an independent risk factor associated with peripartum cardiovascular complications, including preeclampsia (adjusted OR [aOR], 2.12; 95% CI, 2.07-2.17), peripartum cardiomyopathy (aOR, 4.42; 95% CI, 3.79-5.13), heart failure (aOR, 4.06; 95% CI, 3.61-4.57), cardiac arrhythmias (aOR, 2.06; 95% CI, 1.94-2.21), AKI (aOR, 7.66; 95% CI, 7.06-8.32), stroke (aOR, 4.83; 95% CI, 4.18-5.57), and VTE (aOR, 6.90; 95% CI, 6.11-7.80). For resource use, median (IQR) length of stay (3 [2-4] days vs 2 [2-3] days; P \u3c .001) and cost of hospitalization ($4953 [$3305-$7517] vs$3722 [$2606-$5400]; P \u3c .001) were higher for deliveries among individuals with SLE. Conclusions and relevance: This study found that SLE was associated with increased risk of complications, including preeclampsia, peripartum cardiomyopathy, heart failure, arrhythmias, AKI, stroke, and VTE during delivery hospitalization and an increased length and cost of hospitalization