A putative biomarker signature for clinically effective AKT inhibition: correlation of in vitro,in vivo and clinical data identifies the importance of modulation of the mTORC1 pathway

Our identification of dysregulation of the AKT pathway in ovarian cancer as a platinum resistance specific event led to a comprehensive analysis of in vitro, in vivo and clinical behaviour of the AKT inhibitor GSK2141795. Proteomic biomarker signatures correlating with effects of GSK2141795 were developed using in vitro and in vivo models, well characterised for related molecular, phenotypic and imaging endpoints. Signatures were validated in temporally paired biopsies from patients treated with GSK2141795 in a clinical study. GSK2141795 caused growth-arrest as single agent in vitro, enhanced cisplatin-induced apoptosis in vitro and reduced tumour volume in combination with platinum in vivo. GSK2141795 treatment in vitro and in vivo resulted in ~50-90% decrease in phospho-PRAS40 and 20-80% decrease in fluoro-deoxyglucose (FDG) uptake. Proteomic analysis of GSK2141795 in vitro and in vivo identified a signature of pathway inhibition including changes in AKT and p38 phosphorylation and total Bim, IGF1R, AR and YB1 levels. In patient biopsies, prior to treatment with GSK2141795 in a phase 1 clinical trial, this signature was predictive of post-treatment changes in the response marker CA125. Development of this signature represents an opportunity to demonstrate the clinical importance of AKT inhibition for re-sensitisation of platinum resistant ovarian cancer to platinum.     

Silyl diol ester as a new selectivity control agent in MgCl2-supported Ziegler–Natta systems for propylene polymerization: catalyst structure and polymer properties

In this study, bis(benzoyloxy)dimethylsilane (SDE) was developed as a non-phthalate selectivity control agent (internal donor (ID) and external donor (ED)) in MgCl₂-supported Ziegler–Natta (ZN) systems. The impact of SDE as an ID was investigated in regards to chemical composition, morphology, adsorption behavior (using FTIR spectroscopy, WAXD and SEM studies) and the propylene polymerization performance of the catalyst. The results of the adsorption behavior of SDE revealed that SDE, while able to stabilize the electronically unsaturated surfaces of MgCl₂ [(104) and (110)], has a rather high tendency to be absorbed on strongly acidic Mg ions at the corners of these crystals. The catalyst with optimum SDE content as an ID afforded a system with reasonable activity and isotacticity (even in the absence of ED) along with broader molecular weight distribution (PDI: 6.2–10) and greater flexural modulus than phthalate-based ZN systems. SDE was also used as a new ED in most widely used fourth- and fifth-generation catalyst systems. The results revealed that in fifth-generation catalyst systems, there was an increase in hydrogen response (>40%) along with an increase of activity without any change in the thermal properties of the final polymer in comparison to a conventional ED (alkoxy silane).

In this study, bis(benzoyloxy)dimethylsilane (SDE) was developed as a non-phthalate selectivity control agent (internal donor (ID) and external donor (ED)) in MgCl₂-supported Ziegler–Natta (ZN) systems for polypropylene polymerization.     

Disaster events and the risk of sudden cardiac death: a Washington State investigation

BACKGROUND: Psychological distress following disaster events may increase the risk of sudden cardiac death. In 2001, the Nisqually earthquake and the 11 September terrorist attacks profoundly affected Washington state residents. HYPOTHESIS: This research investigated the theory that the incidence of sudden cardiac death would increase following these disaster events. METHODS: Death certificates were abstracted using a uniform case definition to determine the number of sudden cardiac deaths for the 48-hour and one-week periods following the two disaster events. Sudden cardiac deaths from the corresponding 48-hour and one-week periods in the three weeks before the events, and the analogous periods in 1999 and 2000 were designated as control times. Using t-tests, the number of sudden cardiac deaths for the periods following the disaster events was compared to those of the control periods. RESULTS: In total, 32 sudden cardiac deaths occurred in the four counties affected by the Nisqually earthquake during the 48 hours after the event, compared to an average of 22 +/- 3.5 (standard deviation) in the same counties during the control periods (p = 0.02). No difference was observed for the one-week period (94 compared to 79.2 +/- 12.4, p = 0.28). No difference was observed in the number of sudden cardiac deaths in the 48-hours or one-week following the terrorist attacks compared to control periods. CONCLUSIONS: A local disaster caused by a naturally occurring hazard, but not a geographically remote human disaster, was associated with an increased risk of sudden cardiac death. A better understanding of the underlying mechanisms may have implications for prevention of sudden cardiac death.     

Vitamin D, parathyroid hormone, and sudden cardiac death: results from the Cardiovascular Health Study

Recent studies have demonstrated greater risks of cardiovascular events and mortality among persons who have lower 25-hydroxyvitamin D (25-OHD) and higher parathyroid hormone (PTH) levels. We sought to evaluate the association between markers of mineral metabolism and sudden cardiac death (SCD) among the 2312 participants from the Cardiovascular Health Study who were free of clinical cardiovascular disease at baseline. We estimated associations of baseline 25-OHD and PTH concentrations individually and in combination with SCD using Cox proportional hazards models after adjustment for demographics, cardiovascular risk factors, and kidney function. During a median follow-up of 14 years, there were 73 adjudicated SCD events. The annual incidence of SCD was greater among subjects who had lower 25-OHD concentrations, 2 events per 1000 for 25-OHD ≥20 ng/mL and 4 events per 1000 for 25-OHD <20 ng/mL. Similarly, SCD incidence was greater among subjects who had higher PTH concentrations, 2 events per 1000 for PTH <65 pg/mL and 4 events per 1000 for PTH ≥65 pg/mL. Multivariate adjustment attenuated associations of 25-OHD and PTH with SCD. Finally, 267 participants (11.7% of the cohort) had high PTH and low 25-OHD concentrations. This combination was associated with a >2-fold risk of SCD after adjustment (hazard ratio: 2.19 [95% CI: 1.17-4.10]; P=0.017) compared with participants with normal levels of PTH and 25-OHD. The combination of lower 25-OHD and higher PTH concentrations appears to be associated independently with SCD risk among older adults without cardiovascular disease.     

Diverse responses of phenology to global changes in a grassland ecosystem

Shifting plant phenology (i.e., timing of flowering and other developmental events) in recent decades establishes that species and ecosystems are already responding to global environmental change. Earlier flowering and an extended period of active plant growth across much of the northern hemisphere have been interpreted as responses to warming. However, several kinds of environmental change have the potential to influence the phenology of flowering and primary production. Here, we report shifts in phenology of flowering and canopy greenness (Normalized Difference Vegetation Index) in response to four experimentally simulated global changes: warming, elevated CO(2), nitrogen (N) deposition, and increased precipitation. Consistent with previous observations, warming accelerated both flowering and greening of the canopy, but phenological responses to the other global change treatments were diverse. Elevated CO(2) and N addition delayed flowering in grasses, but slightly accelerated flowering in forbs. The opposing responses of these two important functional groups decreased their phenological complementarity and potentially increased competition for limiting soil resources. At the ecosystem level, timing of canopy greenness mirrored the flowering phenology of the grasses, which dominate primary production in this system. Elevated CO(2) delayed greening, whereas N addition dampened the acceleration of greening caused by warming. Increased precipitation had no consistent impacts on phenology. This diversity of phenological changes, between plant functional groups and in response to multiple environmental changes, helps explain the diversity in large-scale observations and indicates that changing temperature is only one of several factors reshaping the seasonality of ecosystem processes.     

Additive effects of simulated climate changes,elevated CO2, and nitrogen deposition on grassland diversity

Biodiversity responses to ongoing climate and atmospheric changes will affect both ecosystem processes and the delivery of ecosystem goods and services. Combined effects of co-occurring global changes on diversity, however, are poorly understood. We examined plant diversity responses in a California annual grassland to manipulations of four global environmental changes, singly and in combination: elevated CO2, warming, precipitation, and nitrogen deposition. After 3 years, elevated CO2 and nitrogen deposition each reduced plant diversity, whereas elevated precipitation increased it and warming had no significant effect. Diversity responses to both single and combined global change treatments were driven overwhelmingly by gains and losses of forb species, which make up most of the native plant diversity in California grasslands. Diversity responses across treatments also showed no consistent relationship to net primary production responses, illustrating that the diversity effects of these environmental changes could not be explained simply by changes in productivity. In two- to four-way combinations, simulated global changes did not interact in any of their effects on diversity. Our results show that climate and atmospheric changes can rapidly alter biological diversity, with combined effects that, at least in some settings, are simple, additive combinations of single-factor effects.     

COVID-19 risk index (CRI): a simple and validated emergency department risk score that predicts mortality and the need for mechanical ventilation

Journal of Thrombosis and Thrombolysis - Although certain risk factors have been associated with morbidity and mortality, validated emergency department (ED) derived risk prediction models specific...