Characterization of the HDAC/PI3K inhibitor CUDC-907 as a novel senolytic.

The accumulation of senescent cells has an important role in the phenotypical changes observed in ageing and in many age-related pathologies. Thus, the strategies designed to prevent these effects, collectively known as senotherapies, have a strong clinical potential. Senolytics are a type of senotherapy aimed at specifically eliminating senescent cells from tissues. Several small molecule compounds with senolytic properties have already been identified, but their specificity and range of action are variable. Because of this, potential novel senolytics are being actively investigated. Given the involvement of HDACs and the PI3K pathway in senescence, we hypothesized that the dual inhibitor CUDC-907, a drug already in clinical trials for its antineoplastic effects, could have senolytic effects. Here, we show that CUDC-907 was indeed able to selectively induce apoptosis in cells driven to senesce by p53 expression, but not when senescence happened in the absence of p53. Consistent with this, CUDC-907 showed senolytic properties in different models of stress-induced senescence. Our results also indicate that the senolytic functions of CUDC-907 depend on the inhibitory effects of both HDACs and PI3K, which leads to an increase in p53 and a reduction in BH3 pro-survival proteins. Taken together, our results show that CUDC-907 has the potential to be a clinically relevant senolytic in pathological conditions in which stress-induced senescence is involved.

Duration of viable SARS-CoV-2 shedding from respiratory tract in different human hosts and its impact on isolation discontinuation polices revision; a narrative review.

BACKGROUND: The duration of viable viral shedding is important to be defined in regards of viral transmission in SARS-CoV-2 infection with the backdrop of the current worldwide effort for revising isolation polices and establishing the duration of infectiousness. METHODS: In this review we searched databases including Medline and google scholar for research articles published between January 2020 and January 2022. We included case reports, case series, cross sectional, cohort, and randomized control trials that reported the duration of shedding of viable SARS-CoV-2 virus. After evaluating the criteria for inclusion, 32 articles (2721 patients) were included. RESULT: This review showed that the median for the last day of successful viral isolation was 11 (8.5-14.5 95% CI) , 20 (9.0-57.5 95 %CI), 20 (9.0-103 95 %CI) for the general population, critical patients and immunocompromised individuals, respectively, with significant association between prolonged viral shedding, disease severity (P-Value 0.024) and immunosuppressive status (P-Value 0.023).The corresponding higher cutoff of CTv to culturable virus ranged between 26.25 and 34.00 (95% confidence interval) with median of 30.5, and higher values were observed when critical (25.0-37.37 95 %CI) and immunocompromised patients (20.0-37.82 95 %CI) have been excluded, this deviation did not represent a statistical significance (P-Value 0.997 and 0.888) respectively. CONCLUSION: Our review highlights that repeating SARS-CoV-2 viral RNA test solely in recovering patients has no importance in determining infectivity and emphasizes the individualization of de-isolation decisions based on the host factors and a combined symptom and testing-based approaches with the later benefiting most of correlation with recently introduced rapid antigen test. Our finding in the review also opposes the most recent CDC Guidance on shortening isolation duration in term of the last days of viable transmissible virus, therefore caution should be considered when revising such protocols.

Too early for admission? A Telemedicine follow up comparison of mild COVID-19 patients from the Emergency Department and Clinics.

OBJECTIVE: Mildly symptomatic COVID-19 patients may seek medical attention either in the Emergency Department (ED) or Ambulatory Clinics (AC). However, it is unclear if ED patients have different characteristics and outcomes than AC patients when discharged under telemedicine surveillance, which we explored in this study. METHODS: Patients with mild or asymptomatic COVID-19 disease referred to a multidisciplinary Telemedicine clinical service (TM-CS) program in an urban tertiary-care hospital, between June 2020 and February 2021, were evaluated. Those referred from ED were labeled "ED Group" and ones from AC as "AC Group." Their characteristics, clinical features and outcomes including telemedicine parameters, subsequent ED visits, hospital admission, oxygen requirements, intensive care unit (ICU) admission, and mortality were compared. RESULTS: Out of 1132 confirmed non-admitted COVID-19 patients, 526 with mild (89%) or asymptomatic (11%) disease were enrolled in TM-CS. Majority of these were referred from ED (n = 370; 70%) and rest (n = 156, 30%) from the AC. Patients in the ED group compared to AC group, had higher BMI (28.9 vs. 27.5), higher Charlson Comorbidity Index (1.4 vs. 0.9), and higher incidence of comorbidities (50% vs. 22%), P ≤ 0.01. However, there were no differences in the ED and AC groups in subsequent ED visits (26% vs. 24%), hospital admission (18% vs. 15%), oxygen requirements (5% vs. 4%), ICU admission (1% vs. 2%), and mortality (0.3% vs. 0.6%), respectively (P > 0.40). CONCLUSION: Significant number of mild COVID-19 patients head to the ED for initial assistance but have similar outcomes to AC patients. TM-CS could be a safe alternative for follow-up monitoring of these patients.