Dostarlimab is an immune-checkpoint inhibitor that targets the programmed cell death 1 receptor. The combination of chemotherapy and immunotherapy may have synergistic effects in the treatment of ...endometrial cancer.
We conducted a phase 3, global, double-blind, randomized, placebo-controlled trial. Eligible patients with primary advanced stage III or IV or first recurrent endometrial cancer were randomly assigned in a 1:1 ratio to receive either dostarlimab (500 mg) or placebo, plus carboplatin (area under the concentration-time curve, 5 mg per milliliter per minute) and paclitaxel (175 mg per square meter of body-surface area), every 3 weeks (six cycles), followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. The primary end points were progression-free survival as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, and overall survival. Safety was also assessed.
Of the 494 patients who underwent randomization, 118 (23.9%) had mismatch repair-deficient (dMMR), microsatellite instability-high (MSI-H) tumors. In the dMMR-MSI-H population, estimated progression-free survival at 24 months was 61.4% (95% confidence interval CI, 46.3 to 73.4) in the dostarlimab group and 15.7% (95% CI, 7.2 to 27.0) in the placebo group (hazard ratio for progression or death, 0.28; 95% CI, 0.16 to 0.50; P<0.001). In the overall population, progression-free survival at 24 months was 36.1% (95% CI, 29.3 to 42.9) in the dostarlimab group and 18.1% (95% CI, 13.0 to 23.9) in the placebo group (hazard ratio, 0.64; 95% CI, 0.51 to 0.80; P<0.001). Overall survival at 24 months was 71.3% (95% CI, 64.5 to 77.1) with dostarlimab and 56.0% (95% CI, 48.9 to 62.5) with placebo (hazard ratio for death, 0.64; 95% CI, 0.46 to 0.87). The most common adverse events that occurred or worsened during treatment were nausea (53.9% of the patients in the dostarlimab group and 45.9% of those in the placebo group), alopecia (53.5% and 50.0%), and fatigue (51.9% and 54.5%). Severe and serious adverse events were more frequent in the dostarlimab group than in the placebo group.
Dostarlimab plus carboplatin-paclitaxel significantly increased progression-free survival among patients with primary advanced or recurrent endometrial cancer, with a substantial benefit in the dMMR-MSI-H population. (Funded by GSK; RUBY ClinicalTrials.gov number, NCT03981796.).
Abstract
Background
Sedentary behaviour (SB) has been identified as an important mortality risk factor. Health organizations have recognised SB as a public health challenge with major health, social, ...and economic consequences. Researchers have alerted the need to develop specific strategies, to monitor, prevent, and reduce SB. However, there is no systematic analysis of the SB changes in European Union adults. We aimed to examine SB changes between 2002 and 2017 in the European Union (EU) adult population.
Methods
SB prevalence (>4h30mins of sitting time/day) of 96,004 adults as a whole sample and country-by-country was analysed in 2002, 2005, 2013, and 2017 of the Sport and Physical Activity EU Special Eurobarometers’ data. The SB question of a modified version of the International Physical Activity Questionnaire was considered. SB prevalence between countries and within years was analysed with a χ2 test, and SB between genders was analysed with the Z-Score test for two population proportions.
Results
An association between the SB prevalence and the years was found (
p
< 0.001), with increases for the whole sample (2002: 49.3%, 48.5–50.0 95% confidence interval (CI); 2017: 54.5%, 53.9–55.0 95% CI) and men (2002: 51.2%, 50.0–52.4 95% CI; 2017: 55.8%, 55.0–56.7 95% CI) and women (2002: 47.6%, 46.6–48.7 95% CI; 2017: 53.4%, 52.6–54.1 95% CI) separately. The adjusted standardised residuals showed an increase in the observed prevalence versus the expected during 2013 and 2017 for the whole sample and women and during 2017 for men. For all years, differences were observed in the SB prevalence between countries for the whole sample, and men and women separately (
p
< 0.001). Besides, the SB prevalence was always higher in men versus women in the overall EU sample (
p
< 0.001).
Conclusions
SB prevalence increased between 2002 and 2017 for the EU as a whole and for both sexes separately. Additionally, differences in SB prevalence were observed for all years between EU countries in the whole sample and both sexes separately. Lastly, SB was consistently higher in men than women. These findings reveal a limited impact of current policies and interventions to tackle SB at the EU population level.
An international group of experts convened to provide guidance for employers to promote the avoidance of prolonged periods of sedentary work. The set of recommendations was developed from the ...totality of the current evidence, including long-term epidemiological studies and interventional studies of getting workers to stand and/or move more frequently. The evidence was ranked in quality using the four levels of the American College of Sports Medicine. The derived guidance is as follows: for those occupations which are predominantly desk based, workers should aim to initially progress towards accumulating 2 h/day of standing and light activity (light walking) during working hours, eventually progressing to a total accumulation of 4 h/day (prorated to part-time hours). To achieve this, seated-based work should be regularly broken up with standing-based work, the use of sit-stand desks, or the taking of short active standing breaks. Along with other health promotion goals (improved nutrition, reducing alcohol, smoking and stress), companies should also promote among their staff that prolonged sitting, aggregated from work and in leisure time, may significantly and independently increase the risk of cardiometabolic diseases and premature mortality. It is appreciated that these recommendations should be interpreted in relation to the evidence from which they were derived, largely observational and retrospective studies, or short-term interventional studies showing acute cardiometabolic changes. While longer term intervention studies are required, the level of consistent evidence accumulated to date, and the public health context of rising chronic diseases, suggest initial guidelines are justified. We hope these guidelines stimulate future research, and that greater precision will be possible within future iterations.
Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is an enzyme with important regulatory functions in the heart and brain, and its chronic activation can be pathological. CaMKII activation is ...seen in heart failure, and can directly induce pathological changes in ion channels, Ca(2+) handling and gene transcription. Here, in human, rat and mouse, we identify a novel mechanism linking CaMKII and hyperglycaemic signalling in diabetes mellitus, which is a key risk factor for heart and neurodegenerative diseases. Acute hyperglycaemia causes covalent modification of CaMKII by O-linked N-acetylglucosamine (O-GlcNAc). O-GlcNAc modification of CaMKII at Ser 279 activates CaMKII autonomously, creating molecular memory even after Ca(2+) concentration declines. O-GlcNAc-modified CaMKII is increased in the heart and brain of diabetic humans and rats. In cardiomyocytes, increased glucose concentration significantly enhances CaMKII-dependent activation of spontaneous sarcoplasmic reticulum Ca(2+) release events that can contribute to cardiac mechanical dysfunction and arrhythmias. These effects were prevented by pharmacological inhibition of O-GlcNAc signalling or genetic ablation of CaMKIIδ. In intact perfused hearts, arrhythmias were aggravated by increased glucose concentration through O-GlcNAc- and CaMKII-dependent pathways. In diabetic animals, acute blockade of O-GlcNAc inhibited arrhythmogenesis. Thus, O-GlcNAc modification of CaMKII is a novel signalling event in pathways that may contribute critically to cardiac and neuronal pathophysiology in diabetes and other diseases.
A primary cilium is found on most mammalian cells, where it acts as a cellular antenna for the reception of both mechanical and chemical signals. A variety of diseases are associated with defective ...ciliogenesis, reflecting the ubiquity of the function of cilia and the number of proteins required for their assembly. Proper cilia length is necessary for cilia signaling and is regulated through a poorly understood balance of assembly and disassembly rates. FHDC1 is a unique member of the formin family of cytoskeletal regulatory proteins. Overexpression of FHDC1 induces F-actin accumulation and microtubule stabilization and acetylation. We find that overexpression of FHDC1 also has profound effects on ciliogenesis; in most cells FHDC1 overexpression blocks cilia assembly, but the cilia that are present are immensely elongated. FHDC1-induced cilia growth requires the FHDC1 FH2 and microtubule-binding domain and results from F-actin-dependent inhibition of cilia disassembly. FHDC1 depletion, or treatment with a pan-formin inhibitor, inhibits cilia assembly and induces cilia resorption. Endogenous FHDC1 protein localizes to cytoplasmic microtubules converging on the base of the cilia, and we identify the subdistal appendage protein Cep170 as an FHDC1 interacting protein. Our results suggest that FHDC1 plays a role in coordinating cytoskeletal dynamics during normal cilia assembly.
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