Potential Role of Anti-interleukin (IL)-6 Drugs in the Treatment of COVID-19: Rationale, Clinical Evidence and Risks

The epidemic due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has been spreading globally, raising increasing concerns. This public health emergency has triggered a race to find medications to improve the prognosis of this disease. There is currently great interest in drug repositioning to manage SARS-CoV-2 infection, that is, the evaluation of the potential benefits of a drug that has already been proven safe and effective in humans for other approved indications. As interleukin-6 (IL-6) acts as a key driver of the inflammation associated with coronavirus disease 2019 (COVID-19), IL-6 and IL-6 receptor (IL-6R) inhibition appear to be promising targets for the treatment of COVID-19 patients. It is important to critically analyze the available evidence concerning the use of the available anti-IL-6 (siltuximab) and anti-IL-6R (tocilizumab and sarilumab) agents in COVID-19 patients, in terms of both benefit and risk. In this review, the pathogenesis of the cytokine storm induced by COVID-19, the role of IL-6 in this cytokine storm, the rationale for the use of anti-IL-6 agents, and key information on potential benefits and safety monitoring of these biologicals in COVID-19 patients is discussed

REPRESENTACIONES DE LOS JÓVENES ACERCA DE LA UNIVERSIDAD: PROCESO DE SELECCIÓN DE LA INSTITUCIÓN UNIVERSITARIA

Este informe se enmarca en el proyecto que desde hace dos años venimos desarrollando dentro del Departamento de Investigación de la Universidad Siglo 21, en Córdoba, Argentina. Hemos abordado a través de metodología cualitativa las representaciones que los jóvenes ingresantes a la Universidad tienen acerca de la misma y del estudio universitario. En el presente reporte exponemos una serie de ejes que, de acuerdo a nuestro análisis de los discursos relevados, dan cuenta de valoraciones emergentes al momento de evaluar la universidad pública en relación a la privada y viceversa. Nuestra intención es comprender y describir cuáles son las nociones entramadas en el análisis que los ingresantes realizan de una y otra institución, las cuales se ponen en juego al momento de optar y evaluar aquéllas

Improving Quality of Life in Older Adults Living at Home by a Moderate Exercise Training

Background: Physical activity is associated with a higher quality of life (QoL) in older adults, but there is no evidence whether its effects on healthy individuals or individuals with a mild disability performing a medium-intensity exercise program can be assessed. Objective: This randomized controlled trial aims to evaluate whether moderate exercise training can improve QoL, and whether this model is suitable for older adults with mild chronic diseases living in the community. Methods: 120 participants, randomized 1/1 to either perform a physical exercise protocol or to undergo a social program (control group), were recruited in a 12-week randomized controlled trial registered at ClinicalTrials.Gov (NCT03858114). QoL was measured through the Health-Related Quality of Life Survey Short Form - 12 items tool (SF-12). Results: The participants involved in the exercise-training program had a moderate QoL improvement, compared to those involved in cultural activities, who experienced no change or even a worsening of their QoL. However, the between-groups differences did not attain the statistically significant threshold, when globally assessed, F[1, 103] = 2.98, p = .087, nor when the analysis was restricted to the physical (F[1, 103] = 2.78, p = .099) or mental components (F[1, 103] = 3.83, p = .053). Conclusion: Data from this study are not conclusive, although suggestive of possible efficacy. An effort to collect a larger amount of evidence is advisable. Research published only as protocols, not providing final results, might be useful to demonstrate or reject the hypothesis that physical exercise improves QoL in older adults. On a heuristic level, the sum of results that are not conclusive individually might be decisive if meta-analyzed. (Randomized Controlled Blind trial NCT03858114)

Parp1 inhibitor and trabectedin combination does not increase tumor mutational burden in advanced sarcomas—a preclinical and translational study

SIMPLE SUMMARY: Immunotherapy has revolutionized cancer treatment, but not for all tumor types. Indeed, sarcomas are considered “immune-cold” tumors, which are relatively unresponsive to immunotherapy. One strategy to potentiate immunotherapy efficacy is to increase tumor immunogenicity, for instance by boosting the number of candidate targets (neoantigens) to be recognized by the immune system. Tumor mutational burden indicates the number of somatic mutations identified in the tumor and normalized per megabase. Tumor mutational burden is considered as an acceptable, measurable surrogate of tumor neoantigens. Here, we explored whether the combination of two DNA-damaging agents, trabectedin and olaparib, could increase tumor mutational burden in sarcomas, to prime subsequent immunotherapy. We found no variation in tumor mutational burden after trabectedin + olaparib in preclinical and clinical samples. Therefore, other aspects should be considered to increase sarcoma immunogenicity, by exploiting different pathways such as the potential modulation of the tumor microenvironment induced by trabectedin + olaparib. ABSTRACT: Drug-induced tumor mutational burden (TMB) may contribute to unleashing the immune response in relatively “immune-cold” tumors, such as sarcomas. We previously showed that PARP1 inhibition perpetuates the DNA damage induced by the chemotherapeutic agent trabectedin in both preclinical models and sarcoma patients. In the present work, we explored acquired genetic changes in DNA repair genes, mutational signatures, and TMB in a translational platform composed of cell lines, xenografts, and tumor samples from patients treated with trabectedin and olaparib combination, compared to cells treated with temozolomide, an alkylating agent that induces hypermutation. Whole-exome and targeted panel sequencing data analyses revealed that three cycles of trabectedin and olaparib combination neither affected the mutational profiles, DNA repair gene status, or copy number alterations, nor increased TMB both in homologous recombinant-defective and proficient cells or in xenografts. Moreover, TMB was not increased in tumor specimens derived from trabectedin- and olaparib-treated patients (5–6 cycles) when compared to pre-treatment biopsies. Conversely, repeated treatments with temozolomide induced a massive TMB increase in the SJSA-1 osteosarcoma model. In conclusion, a trabectedin and olaparib combination did not show mutagenic effects and is unlikely to prime subsequent immune-therapeutic interventions based on TMB increase. On the other hand, these findings are reassuring in the increasing warning of treatment-induced hematologic malignancies correlated to PARP1 inhibitor use

Global incidence and prevalence of differentiated thyroid cancer in childhood: systematic review and meta-analysis

ObjectiveDifferentiated thyroid cancer (DTC) is rare in childhood and adolescence although it represents the most frequent endocrine malignancy in this population. DTC includes both papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC). Most pediatric DTCs are PTCs, while FTCs are rare. To date, no systematic reviews on the global epidemiology of pediatric and adolescent DTC have been published. This systematic review and meta-analysis aims to estimate the overall incidence and prevalence of DTCs in patients aged 0–19 years.MethodsThe systematic research was conducted from January 2000 to December 2021 through MEDLINE via PubMed, Cochrane Library, and Embase databases. Two separate meta-analyses were performed for PTC and FTC.ResultsAfter the selection phase, a total of 15 studies (3,332 screened) met the inclusion criteria and are reported in the present systematic review. Five studies were conducted in Europe, five in North America, two in South America, one in Asia, one reported data for 49 countries and territories across the five continents, and one from both the USA and Africa. Most of the studies (n = 14) reported data obtained from national registries, and only one provided information collected from hospital medical records. Beyond the actual trend over time, our study reported a pooled global incidence rate (IR) of PTC and FTC in the pediatric age of 0.46 (95% CI: 0.33–0.59) and 0.07 (95% CI: 0.02–0.12) per 100,000 person-years, respectively. The highest IRs were recorded among Caucasian girls, and the lowest in black or other races/ethnicities.ConclusionOur data confirm that DTC in the pediatric population is a rare condition. The pooled IRs of the studies included in this meta-analysis are ~0.5 for PTC, which is the most common histological type when both genders and all age groups are considered. The implementation of a prospective international registry on pediatric DTC, as part of the wider European Registries for Rare Endocrine Conditions, has been recently proposed. In addition to providing relevant information on the clinical behavior of this rare disease, standardization of data collection will be pivotal to fill current gaps and allow an accurate estimation of the real incidence and risk factors of DTC

Active elderly and health-can moderate exercise improve health and wellbeing in older adults? Protocol for a randomized controlled trial

Abstract Background: Aging is marked by a progressive rise in chronic diseases with an impact on social and healthcare costs. Physical activity (PA) may soothe the inconveniences related to chronic diseases, has positive effects on the quality of life and biological rhythms, and can prevent the decline in motor functions and the consequent falls, which are associated with early death and disability in older adults. Methods: We randomized 120 over-65 males and females into groups of similar size and timing and will give each either moderate physical activity or cultural and recreational activities. Being younger than 65 years, inability to participate in physical activity for any medical reason, and involvement in a massive program of physical exercise are the exclusion criteria. The primary outcome measures are quality of life, walking speed, and postural sway. Participants are tested at baseline, post-treatment, and 6-month (24 weeks) and 12-month (48 weeks) follow-ups. Discussion: This study aims at improving the quality of life, wellness, and cognitive functioning in the elderly through a low-cost affordable program of moderate physical activity. Given the growing aging of the world population and the social and economic burden of disability in the elderly, our results might have a major impact on future practices

Understanding the political motivations that shape Rwanda’s emergent developmental state

Twenty years after its horrific genocide, Rwanda has become a model for economic development. At the same time, its government has been criticized for its authoritarian tactics and use of violence. Missing from the often-polarized debate are the connections between these two perspectives. Synthesizing existing literature on Rwanda in light of a combined year of fieldwork, we argue that the GoR is using the developmental infrastructure to deepen state power and expand political control. We first identify the historical pressures that have motivated the Rwanda Patriotic Front (RPF) to re-imagine the political landscape. Sectarian unrest, political rivalry, wider regional insecurity, and aid withdrawal have all pressured the RPF to identify growth as strategic. However, the country’s political transformation extends beyond a prioritisation of growth and encompasses the reordering of the social and physical layout of the territory, the articulation of new ideologies and mindsets, and the provision of social services and surveillance infrastructure. Growth and social control go hand in hand. As such, the paper’s main contribution is to bring together the two sides of the Rwandan debate and place the country in a broader sociological literature about the parallel development of capitalist relations and transformations in state power

REST Controls Self-Renewal and Tumorigenic Competence of Human Glioblastoma Cells

The Repressor Element 1 Silencing Transcription factor (REST/NRSF) is a master repressor of neuronal programs in non-neuronal lineages shown to function as a central regulator of developmental programs and stem cell physiology. Aberrant REST function has been associated with a number of pathological conditions. In cancer biology, REST has been shown to play a tumor suppressor activity in epithelial cancers but an oncogenic role in brain childhood malignancies such as neuroblastoma and medulloblastoma. Here we examined REST expression in human glioblastoma multiforme (GBM) specimens and its role in GBM cells carrying self-renewal and tumorigenic competence. We found REST to be expressed in GBM specimens, its presence being particularly enriched in tumor cells in the perivascular compartment. Significantly, REST is highly expressed in self-renewing tumorigenic-competent GBM cells and its knock down strongly reduces their self-renewal in vitro and tumor-initiating capacity in vivo and affects levels of miR-124 and its downstream targets. These results indicate that REST contributes to GBM maintenance by affecting its self-renewing and tumorigenic cellular component and that, hence, a better understanding of these circuitries in these cells might lead to new exploitable therapeutic targets