Therapeutic resistance is a major clinical challenge in oncology. Evidence identifies cancer stem cells (CSCs) as a driver of tumor evolution. Accordingly, the key stemness property unique to CSCs ...may represent a reservoir of therapeutic target to improve cancer treatment. Here, we carried out a genome‐wide RNA interference screen to identify genes that regulate breast CSCs‐fate (bCSC). Using an interactome/regulome analysis, we integrated screen results in a functional mapping of the CSC‐related processes. This network analysis uncovered potential therapeutic targets controlling bCSC‐fate. We tested a panel of 15 compounds targeting these regulators. We showed that mifepristone, salinomycin, and JQ1 represent the best anti‐bCSC activity. A combination assay revealed a synergistic interaction of salinomycin/JQ1 association to deplete the bCSC population. Treatment of primary breast cancer xenografts with this combination reduced the tumor‐initiating cell population and limited metastatic development. The clinical relevance of our findings was reinforced by an association between the expression of the bCSC‐related networks and patient prognosis. Targeting bCSCs with salinomycin/JQ1 combination provides the basis for a new therapeutic approach in the treatment of breast cancer.
A multicenter, comparative study was performed to determine the epidemiological, clinical, and prognostic differences between the diseases caused by Mycobacterium tuberculosis and Mycobacterium ...kansasii in human immunodeficiency virus (HIV)-infected patients. From 1 January 1995 through 31 December 1999, 25 HIV-infected patients received diagnoses of M. kansasii infection, and another 75 were selected as control subjects from among patients who had M. tuberculosis infection. Variables associated with M. tuberculosis disease in the multivariate analysis were previous intravenous drug use (odds ratio OR, 8; 95% confidence interval CI, 1.5-41.4) and interstitial radiologic pattern (OR, 12.7; 95% CI, 1.7-94.3). Variables associated with M. kansasii were previous diagnosis of acquired immunodeficiency syndrome (OR, 15.8; 95% CI, 4.2-59.6) and concomitant opportunistic infections (OR, 14.2; 95% CI, 2-105.7). Clinical and radiologic features were similar for both groups, but epidemiological characteristics and prognosis were different. M. kansasii disease was associated more closely with level of immunosuppression and progression of HIV infection than was disease caused by M. tuberculosis.
This study was designed to compare the combined effect of two different drilling techniques (conventional expansion and one-step) and four different implant geometries in a beagle dog model. The ...nondecalcified bone-implant samples underwent histologic/metric analysis at 2 and 6 weeks. Morphologic analysis showed similarities between different drilling technique groups and implant geometries. Histomorphometric parameters, bone-to-implant contact (BIC), and bone area fraction occupancy (BAFO) were analyzed, and no statistical difference between drilling groups and/or implant geometry was found. Time was the only variable that affected BIC and BAFO, suggesting that the two protocols are equally biocompatible and osseoconductive.
Diabetes is a consequence of a decrease on functional β-cell mass. We have recently demonstrated that epoxypukalide (Epoxy) is a natural compound with beneficial effects on primary cultures of rat ...islets. In this study, we extend our previous investigations to test the hypothesis that Epoxy protects β-cells and improves glucose metabolism in STZ-induced diabetic mice.
We used 3-months old male mice that were treated with Epoxy at 200 μg/kg body weight. Glucose intolerance was induced by multiple intraperitoneal low-doses of streptozotocin (STZ) on 5 consecutive days. Glucose homeostasis was evaluated measuring plasma insulin levels and glucose tolerance. Histomorphometry was used to quantify the number of pancreatic β-cells per islet. β-cell proliferation was assessed by BrdU incorporation, and apoptosis by TUNEL staining. Epoxy treatment significantly improved glucose tolerance and plasma insulin levels. These metabolic changes were associated with increased β-cell numbers, as a result of a two-fold increase in β-cell proliferation and a 50% decrease in β-cell death.
Our results demonstrate that Epoxy improves whole-body glucose homeostasis by preventing pancreatic β-cell death due to STZ-induced toxicity in STZ-treated mice.
ABSTRACT
Background
Early reports on the pandemic nature of coronavirus disease 2019 (COVID-19) directed the nephrology community to develop infection prevention and control (IPC) guidance. We aimed ...to make an inventory of strategies that dialysis centres followed to prevent infection with COVID-19 in the first pandemic wave.
Methods
We analyzed IPC measures taken by hemodialysis centres treating patients presenting with COVID-19 between 1 March 2020 and 31 July 2020 and that completed the European Renal Association COVID-19 Database centre questionnaire. Additionally, we made an inventory of guidelines published in European countries to prevent spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in dialysis centres.
Results
Data from 73 dialysis units located in and bordering Europe were analyzed. All participating centres implemented IPC measures to mitigate the impact of SARS-CoV-2 during the first pandemic wave. Measures mentioned most often included triage with questions before entering the dialysis ward, measuring body temperature, hand disinfection, masking for all patients and staff, and personal protective equipment for staff members. These measures were also recommended in most of the 14 guidelines that were identified in the inventory of national guidelines and were also scored as being among the most important measures by the authors of this paper. Heterogeneity existed between centres and national guidelines regarding the minimal distance between dialysis chairs and recommendations regarding isolation and cohorting.
Conclusions
Although variation existed, measures to prevent transmission of SARS-CoV-2 were relatively similar across centres and national guidelines. Further research is needed to assess causal relationships between measures taken and spread of SARS-CoV-2.
Soccer dynamics have evolved in response to environmental factors such as match status, type of competition, and competition stage. Observational analysis has shed light into the behavior of players, ...but few re-searchers have looked at the complexity of the interactions between players and their teams over time. Here we investigated the variables influencing the patterns of play and the evolution of tactical and technical behaviors through the last three decades. A retrospective inferential study was applied. SoccerEye observational instrument and recording software were used to observe and record 45 matches and 6791 attacks from European and World Cup semi-<nals and <nals between 1982 and 2010. Publicly available broadcast footage was used for the analysis. Generalizability theory was used as the basis of the statistical analysis. =e patterns of play changed by 31.4% from 1982 to 2010. Team dynamics were in;uenced by match status (28.0%), competition stage (26.5%), and game period (18.1%). During the last decade (2002-2010), teams tended to use less the dribble and running with the ball but to increase long passing rate. During 2002-2010 decade, the frequency of attacks down the wings was higher than in 1982-2000, probably a result of the numerical disadvantage of the attacking team in the area of play. Soccer dynamics have changed towards more teamwork and less individual work over the last 30 years. However, not only time, but also match status, competition stage, and game period have influenced the patterns of play.
Background: Bacille Calmette-Guérin (BCG) vaccination has off-target (non-specific) effects that are associated with protection against unrelated infections and decreased all-cause mortality in ...infants. We aimed to determine whether BCG vaccination prevents febrile and respiratory infections in adults. Methods: This randomised controlled phase 3 trial was done in 36 healthcare centres in Australia, Brazil, the Netherlands, Spain, and the United Kingdom. Healthcare workers were randomised to receive BCG-Denmark (single 0.1 ml intradermal injection) or no BCG in a 1:1 ratio using a web-based procedure, stratified by stage, site, age, and presence of co-morbidity. The difference in occurrence of febrile or respiratory illness were measured over 12 months (prespecified secondary outcome) using the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, NCT04327206. Findings: Between March 30, 2020, and April 1, 2021, 6828 healthcare workers were randomised to BCG-Denmark (n = 3417) or control (n = 3411; no intervention or placebo) groups. The 12-month adjusted estimated risk of ≥1 episode of febrile or respiratory illness was 66.8% in the BCG group (95% CI 65.3%–68.2%), compared with 63.4% in the control group (95% CI 61.8%–65.0%), a difference of +3.4 percentage points (95% CI +1.3% to +5.5%; p 0.002). The adjusted estimated risk of a severe episode (defined as being incapacitated for ≥3 consecutive days or hospitalised) was 19.4% in the BCG group (95% CI 18.0%–20.7%), compared with 18.8% in the control group (95% CI 17.4%–20.2%) a difference of +0.6 percentage points (95% CI −1.3% to +2.5%; p 0.6). Both groups had a similar number of episodes of illness, pneumonia, and hospitalisation. There were three deaths, all in the control group. There were no safety concerns following BCG vaccination. Interpretation: In contrast to the beneficial off-target effects reported following neonatal BCG in infants, a small increased risk of symptomatic febrile or respiratory illness was observed in the 12 months following BCG vaccination in adults. There was no evidence of a difference in the risk of severe disease. Funding: Bill & Melinda Gates Foundation, Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, the National Health and Medical Research Council, the Swiss National Science Foundation and individual donors.
ABSTRACT
Background
In the general population with coronavirus disease 2019 (COVID-19), obesity is associated with an increased risk of mortality. Given the typically observed obesity paradox among ...patients on kidney function replacement therapy (KFRT), especially dialysis patients, we examined the association of obesity with mortality among dialysis patients or living with a kidney transplant with COVID-19.
Methods
Data from the European Renal Association COVID-19 Database (ERACODA) were used. KFRT patients diagnosed with COVID-19 between 1 February 2020 and 31 January 2021 were included. The association of Quetelet's body mass index (BMI) (kg/m2), divided into: <18.5 (lean), 18.5–24.9 (normal weight), 25–29.9 (overweight), 30–34.9 (obese I) and ≥35 (obese II/III), with 3-month mortality was investigated using Cox proportional-hazards regression analyses.
Results
In 3160 patients on KFRT (mean age: 65 years, male: 61%), 99 patients were lean, 1151 normal weight (reference), 1160 overweight, 525 obese I and 225 obese II/III. During follow-up of 3 months, 28, 20, 21, 23 and 27% of patients died in these categories, respectively. In the fully adjusted model, the hazard ratios (HRs) for 3-month mortality were 1.65 95% confidence interval (CI): 1.10, 2.47, 1 (ref.), 1.07 (95% CI: 0.89, 1.28), 1.17 (95% CI: 0.93, 1.46) and 1.71 (95% CI: 1.27, 2.30), respectively. Results were similar among dialysis patients (N = 2343) and among those living with a kidney transplant (N = 817) (Pinteraction = 0.99), but differed by sex (Pinteraction = 0.019). In males, the HRs for the association of aforementioned BMI categories with 3-month mortality were 2.07 (95% CI: 1.22, 3.52), 1 (ref.), 0.97 (95% CI: 0.78. 1.21), 0.99 (95% CI: 0.74, 1.33) and 1.22 (95% CI: 0.78, 1.91), respectively, and in females corresponding HRs were 1.34 (95% CI: 0.70, 2.57), 1 (ref.), 1.31 (95% CI: 0.94, 1.85), 1.54 (95% CI: 1.05, 2.26) and 2.49 (95% CI: 1.62, 3.84), respectively.
Conclusion
In KFRT patients with COVID-19, on dialysis or a kidney transplant, obesity is associated with an increased risk of mortality at 3 months. This is in contrast to the obesity paradox generally observed in dialysis patients. Additional studies are required to corroborate the sex difference in the association of obesity with mortality.
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