Sorafenib, Rapamycin, and Venetoclax Attenuate Doxorubicin-Induced Senescence and Promote Apoptosis in HCT116 Cells

Emerging evidence has shown that the therapy-induced senescent growth arrest in cancer cells is of durable nature whereby a subset of cells can reinstate proliferative capacity. Promising new drugs named senolytics selectively target senescent cells and commit them into apoptosis. Accordingly, senolytics have been proposed as adjuvant cancer treatment to cull senescent tumor cells, and thus, screening for agents that exhibit senolytic properties is highly warranted. Our study aimed to investigate three agents, sorafenib, rapamycin, and venetoclax for their senolytic potential in doxorubicin-induced senescence in HCT116 cells. HCT116 cells were treated with one of the three agents, sorafenib (5 µM), rapamycin (100 nM), or venetoclax (10 µM), in the absence or presence of doxorubicin (1 µM). Senescence was evaluated using microscopy-based and flow cytometry-based Senescence-associated-β-galactosidase staining (SA-β-gal), while apoptosis was assessed using annexin V-FITC/PI, and Muse caspase-3/-7 activity assays. We screened for potential genes through which the three drugs exerted senolytic-like action using the Human Cancer Pathway Finder PCR array. The three agents reduced doxorubicin-induced senescent cell subpopulations and significantly enhanced the apoptotic effect of doxorubicin compared with those treated only with doxorubicin. The senescence genes IGFBP5 and BMI1 and the apoptosis genes CASP7 and CASP9 emerged as candidate genes through which the three drugs exhibited senolytic-like properties. These results suggest that the attenuation of doxorubicin-induced senescence might have shifted HCT116 cells to apoptosis by exposure to the tested pharmacological agents. Our work argues for the use of senolytics to reduce senescence-mediated resistance in tumor cells and to enhance chemotherapy efficacy

The t copula with Multiple Parameters of Degrees of Freedom: Bivariate Characteristics and Application to Risk Management

The t copula is often used in risk management as it allows for modelling tail dependence between risks and it is simple to simulate and calibrate. However, the use of a standard t copula is often criticized due to its restriction of having a single parameter for the degrees of freedom (dof) that may limit its capability to model the tail dependence structure in a multivariate case. To overcome this problem, grouped t copula was proposed recently, where risks are grouped a priori in such a way that each group has a standard t copula with its specific dof parameter. In this paper we propose the use of a grouped t copula, where each group consists of one risk factor only, so that a priori grouping is not required. The copula characteristics in the bivariate case are studied. We explain simulation and calibration procedures, including a simulation study on finite sample properties of the maximum likelihood estimators and Kendall's tau approximation. This new copula can be significantly different from the standard t copula in terms of risk measures such as tail dependence, value at risk and expected shortfall. Keywords: grouped t copula, tail dependence, risk management

Residents\u27 perceptions of smart energy metres

Smart metres are a form of expert system with performance features beyond energy‐consumption record keeping, to include monitoring, analysing, and estimating metre readings. Although smart metres have great capabilities, this technology is still in its infancy in many developing countries, and little is known about the kinds of risks associated with smart metres from residents\u27 perspectives. This research therefore aims to fill this gap by examining the influence of four different types of perceived risk on residents\u27 intentions to use smart metres in Jordan. By following a quantitative approach, 242 survey responses were tested by using structural equation modelling–partial least squares. The statistical results indicated that perceived security and technical risks have a significant and negative impact on residents\u27 intentions to use smart metres. However, perceived privacy and health risks, surprisingly, were found to have no significant negative influence on intention to use. Theoretical and practical implications are indicated, and directions of future research are subsequently specified

Rebuilding the health care system in Afghanistan: an overview of primary care and emergency services

Developing nations have many challenges to the growth of emergency medical systems. This development in Afghanistan is also complicated by many factors that plague post-conflict countries including an unstable political system, poor economy, poor baseline health indices, and ongoing violence. Progress has been made in Afghanistan with the implementation of the Basic Package of Health Service (BPHS) by the Ministry of Public Health in an effort to provide healthcare that would have the most cost-effective impact on common health problems. Trauma and trauma-related disability were both identified as priorities under the BPHS, and efforts have begun to address these problems. Most of the emergency care delivered in Afghanistan is provided by the military sector and non-governmental organizations. Security, lack of infrastructure, economic hardship, difficult access to healthcare facilities, poor healthcare facility conditions, and lack of trained healthcare providers, especially women, are all problems that need to be addressed. The long-term goal of quality healthcare for all Afghan citizens will only be met by a combination of specific goal-oriented projects, foreign aid, domestic responsibility, and time

Anti-cancer effects and mechanism of actions of aspirin analogues in the treatment of glioma cancer

INTRODUCTION: In the past 25 years only modest advancements in glioma treatment have been made, with patient prognosis and median survival time following diagnosis only increasing from 3 to 7 months. A substantial body of clinical and preclinical evidence has suggested a role for aspirin in the treatment of cancer with multiple mechanisms of action proposed including COX 2 inhibition, down regulation of EGFR expression, and NF-κB signaling affecting Bcl-2 expression. However, with serious side effects such as stroke and gastrointestinal bleeding, aspirin analogues with improved potency and side effect profiles are being developed. METHOD: Effects on cell viability following 24 hr incubation of four aspirin derivatives (PN508, 517, 526 and 529) were compared to cisplatin, aspirin and di-aspirin in four glioma cell lines (U87 MG, SVG P12, GOS – 3, and 1321N1), using the PrestoBlue assay, establishing IC50 and examining the time course of drug effects. RESULTS: All compounds were found to decrease cell viability in a concentration and time dependant manner. Significantly, the analogue PN517 (IC50 2mM) showed approximately a twofold increase in potency when compared to aspirin (3.7mM) and cisplatin (4.3mM) in U87 cells, with similar increased potency in SVG P12 cells. Other analogues demonstrated similar potency to aspirin and cisplatin. CONCLUSION: These results support the further development and characterization of novel NSAID derivatives for the treatment of glioma

The role of left and right hemispheres in the comprehension of idiomatic language: an electrical neuroimaging study

<p>Abstract</p> <p>Background</p> <p>The specific role of the two cerebral hemispheres in processing idiomatic language is highly debated. While some studies show the involvement of the left inferior frontal gyrus (LIFG), other data support the crucial role of right-hemispheric regions, and particularly of the middle/superior temporal area. Time-course and neural bases of literal vs. idiomatic language processing were compared. Fifteen volunteers silently read 360 idiomatic and literal Italian sentences and decided whether they were semantically related or unrelated to a following target word, while their EEGs were recorded from 128 electrodes. Word length, abstractness and frequency of use, sentence comprehensibility, familiarity and cloze probability were matched across classes.</p> <p>Results</p> <p>Participants responded more quickly to literal than to idiomatic sentences, probably indicating a difference in task difficulty. Occipito/temporal N2 component had a greater amplitude in response to idioms between 250-300 ms. Related swLORETA source reconstruction revealed a difference in the activation of the left fusiform gyrus (FG, BA19) and medial frontal gyri for the contrast idiomatic-minus-literal. Centroparietal N400 was much larger to idiomatic than to literal phrases (360-550 ms). The intra-cortical generators of this effect included the left and right FG, the left cingulate gyrus, the right limbic area, the right MTG (BA21) and the left middle frontal gyrus (BA46). Finally, an anterior late positivity (600-800 ms) was larger to idiomatic than literal phrases. ERPs also showed a larger right centro-parietal N400 to associated than non-associated targets (not differing as a function of sentence type), and a greater right frontal P600 to idiomatic than literal associated targets.</p> <p>Conclusion</p> <p>The data indicate bilateral involvement of both hemispheres in idiom comprehension, including the right MTG after 350 ms and the right medial frontal gyrus in the time windows 270-300 and 500-780 ms. In addition, the activation of left and right limbic regions (400-450 ms) suggests that they have a role in the emotional connotation of colourful idiomatic language. The data support the view that there is direct access to the idiomatic meaning of figurative language, not dependent on the suppression of its literal meaning, for which the LIFG was previously thought to be responsible.</p

Rehabilitation Care at the Time of Coronavirus Disease-19 (COVID-19) Pandemic: A Scoping Review of Health System Recommendations

Purpose: The coronavirus disease-19 (COVID-19) was declared a pandemic by the World Health Organization in March 2020. COVID-19, caused by SARS-CoV-2 has imposed a significant burden on health care systems, economies, and social systems in many countries around the world. The provision of rehabilitation services for persons with active COVID-19 infection poses challenges to maintaining a safe environment for patients and treating providers. Materials and Methods: Established frameworks were used to guide the scoping review methodology. Medline, Embase, Pubmed, CINAHL databases from inception to August 1, 2020, and prominent rehabilitation organizations\u27 websites were searched. Study Selection: We included articles and reports if they were focused on rehabilitation related recommendations for COVID-19 patients, treating providers, or the general population. Data Extraction: Pairs of team members used a pre-tested data abstraction form to extract data from included full-text articles. The strength and the quality of the extracted recommendations were evaluated by two reviewers using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. Results: We retrieved 6,468 citations, of which 2,086 were eligible for review, after duplicates were removed. We excluded 1,980 citations based on title and abstract screening. Of the screened full-text articles, we included all 106 studies. A summary of recommendations is presented. We assessed the overall evidence to be strong and of fair quality. Conclusion: The rehabilitation setting, and processes, logistics, and patient and healthcare provider precaution recommendations identified aim to reduce the spread of SARS-CoV-2 infection and ensure adequate and safe rehabilitation services, whether face-to-face or through teleservices. The COVID-19 pandemic is rapidly changing. Further updates will be needed over time in order to incorporate emerging best evidence into rehabilitation guidelines

New Whole Earth Telescope observations of CD-24 7599: steps towards δ Scuti star seismology

92 h of new Whole Earth Telescope observations have been acquired for the δ Scuti star CD-24 7599. All the seven pulsation modes reported by Handler et al. are confirmed. However, significant amplitude variations which are not caused by beating of closely spaced frequencies occurred within two years. Analysing the combined data of both WET runs, we detect six further pulsation modes, bringing the total number up to 13. We also examine our data for high-frequency pulsations similar to those exhibited by rapidly oscillating Ap stars, but we do not find convincing evidence for variability in this frequency domai