Pharmacological activation of SIRT6 triggers lethal autophagy in human cancer cells

Sirtuin 6 (SIRT6) is a member of the NAD+-dependent class III deacetylase sirtuin family, which plays a key role in cancer by controlling transcription, genome stability, telomere integrity, DNA repair, and autophagy. Here we analyzed the molecular and biological effects of UBCS039, the first synthetic SIRT6 activator. Our data demonstrated that UBCS039 induced a time-dependent activation of autophagy in several human tumor cell lines, as evaluated by increased content of the lipidated form of LC3B by western blot and of autophagosomal puncta by microscopy analysis of GFP-LC3. UBCS039-mediated activation of autophagy was strictly dependent on SIRT6 deacetylating activity since the catalytic mutant H133Y failed to activate autophagy. At the molecular level, SIRT6-mediated autophagy was triggered by an increase of ROS levels, which, in turn, resulted in the activation of the AMPK-ULK1-mTOR signaling pathway. Interestingly, antioxidants were able to completely counteract UBCS039-induced autophagy, suggesting that ROS burst had a key role in upstream events leading to autophagy commitment. Finally, sustained activation of SIRT6 resulted in autophagy-related cell death, a process that was markedly attenuated using either a pan caspases inhibitor (zVAD-fmk) or an autophagy inhibitor (CQ). Overall, our results identified UBCS039 as an efficient SIRT6 activator, thereby providing a proof of principle that modulation of the enzyme can influence therapeutic strategy by enhancing autophagy-dependent cell death

Ligand-based drug repurposing strategy identified SARS-CoV-2 RNA G-quadruplex binders

The single-stranded RNA genome of SARS-CoV-2 contains some G-quadruplex-forming G-rich elements which are putative drug targets. Here, we performed a ligand-based pharmacophore virtual screening of FDA approved drugs to find candidates targeting such RNA structures. Further in silico and in vitro assays identified three drugs as emerging SARS-CoV-2 RNA G-quadruplex binders

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Telomere Targeting Approaches in Cancer: Beyond Length Maintenance

Telomeres are crucial structures that preserve genome stability. Their progressive erosion over numerous DNA duplications determines the senescence of cells and organisms. As telomere length homeostasis is critical for cancer development, nowadays, telomere maintenance mechanisms are established targets in cancer treatment. Besides telomere elongation, telomere dysfunction impinges on intracellular signaling pathways, in particular DNA damage signaling and repair, affecting cancer cell survival and proliferation. This review summarizes and discusses recent findings in anticancer drug development targeting different “telosome” components

Telomere Targeting Approaches in Cancer: Beyond Length Maintenance

Telomeres are crucial structures that preserve genome stability. Their progressive erosion over numerous DNA duplications determines the senescence of cells and organisms. As telomere length homeostasis is critical for cancer development, nowadays, telomere maintenance mechanisms are established targets in cancer treatment. Besides telomere elongation, telomere dysfunction impinges on intracellular signaling pathways, in particular DNA damage signaling and repair, affecting cancer cell survival and proliferation. This review summarizes and discusses recent findings in anticancer drug development targeting different “telosome” components

Diagnosis and treatment of ALT tumors: is Trabectedin a new therapeutic option?

Abstract Telomeres are specialized nucleoprotein structures responsible for protecting chromosome ends in order to prevent the loss of genomic information. Telomere maintenance is required for achieving immortality by neoplastic cells. While most cancer cells rely on telomerase re-activation for linear chromosome maintenance and sustained proliferation, a significant population of cancers (10–15%) employs telomerase-independent strategies, collectively referred to as Alternative Lengthening of Telomeres (ALT). ALT mechanisms involve different types of homology-directed telomere recombination and synthesis. These processes are facilitated by loss of the ATRX or DAXX chromatin-remodeling factors and by abnormalities of the telomere nucleoprotein architecture. Although the functional consequences of telomerase and ALT up-regulation are similar in that they both prevent overall telomere shortening in tumors, these telomere maintenance mechanisms (TMMs) differ in several aspects which may account for their differential prognostic significance and response to therapy in various tumor types. Therefore, reliable methods for detecting telomerase activity and ALT are likely to become an important pre-requisite for the use of treatments targeting one or other of these mechanisms. However, the question whether ALT presence can confer sensitivity to rationally designed anti-cancer therapies is still open. Here we review the latest discoveries in terms of mechanisms of ALT activation and maintenance in human tumors, methods for ALT identification in cell lines and human tissues and biomarkers validation. Then, original results on sensitivity to rational based pre-clinical and clinical anti-tumor drugs in ALT vs hTERT positive cells will be presented

Evaluation of the Urban Weather Generator model in arid and tropical climates: applications in Mendoza, Argentina and Campinas, Brazil

Los modelos climáticos son indispensables para la predicción del clima y para comprender las complejas interacciones entre el uso del suelo y la atmósfera. En este contexto, el trabajo tiene como objetivo investigar la sensibilidad del modelo urbano de balance energético, denominado Urban Weather Generator v4.1 (UWG) a la aplicación de distintas estrategias de mitigación de la isla de calor urbana, a distintas condiciones climáticas, y analizar su capacidad de representar las condiciones micro climáticas de una situación urbana particular. El estudio de caso se llevó a cabo en un barrio social bajo dos contextos climáticos: clima desértico ?BWk, Köppen- (ciudad de Mendoza-Argentina) y clima tropical ?Cwa, Köppen- (ciudad de Campinas-Brasil). Para cada clima fueron simulados doce escenarios que modifican sus parámetros morfo-materiales (nivel de albedo de los materiales, presencia y ausencia de vegetación y densidad edilicia). Los resultados mostraron que la temperatura del aire que predice el modelo UWG no es significativamente sensible a los cambios resultantes de la aplicación de distintas estrategias en contextos urbanos de igual densidad edilicia, sin embargo, sí muestra sensibilidad a la variación de la densidad edilicia (ΔTa ≤ 1.3°C) y del contexto climático. La mayor sensibilidad del modelo UWG se registró sobre las temperaturas superficiales de los diferentes elementos de la envolvente urbana, a la modificación de distintas estrategias y contextos climáticos. La máxima diferencia de temperatura superficial fue registrada en el escenario con alto albedo de la ciudad de la ciudad de Mendoza, con una disminución de temperatura superficial de techos de 28°C en alta densidad.Climate models are indispensable tools for predicting and understanding the complex interactions between urban land use and atmosphere. This paper presents an analysis of the sensitivity the Urban Weather Generator v4.1 (UWG) model for two Latin American cities. A social housing neighborhood was used as a case study and tested in two climatic contexts: desert climate -BWk, Köppen- (Mendoza-Argentina) and tropical climate -Cwa, Köppen- (Campinas-Brazil). For each climate, twelve scenarios were simulated modifying three morpho-material parameters: the albedo of materials, the presence and absence of vegetation and the building density. The results showed that the air temperature predicted by the UWG model is not significantly sensitive to the changes resulting from the application of different strategies in urban contexts of equal building density, and it does show sensitivity to the variation of the building density and the climatic context (ΔTa ≤ 1.3 ° C). However, the model shows greater sensitivity to the application of different strategies and changing climatic conditions in terms of the value of surface temperatures of the different elements of the urban envelope - walls, ceilings and floors. The maximum difference in surface temperature was estimated for the high albedo scenario in the city of Mendoza, with a decrease of 28°C in the surface temperature of roofs.Fil: Alchapar, Noelia Liliana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Ambiente, Hábitat y Energía; ArgentinaFil: Correa, Erica. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Ambiente, Hábitat y Energía; ArgentinaFil: Pezzuto Cotrim, Cláudia. Pontificia Universidad Catolica de Sao Paulo.; BrasilFil: Salvati Agnese. Brunel University; Reino UnidoVI Congreso Latinoamericano de Simulación de EdificiosMendozaArgentinaInternational Building Performance Simulation AssociationUniversidad Nacional de Cuyo.Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Ambiente, Hábitat y Energí

BRCA2 deletion induces alternative lengthening of telomeres in telomerase positive colon cancer cells

BRCA1/2 are tumor suppressor genes controlling genomic stability also at telomeric and subtelomeric loci. Their mutation confers a predisposition to different human cancers but also sensitivity to antitumor drugs including poly(ADP-ribose) polymerase (PARP) inhibitors and G-quadruplex stabilizers. Here we demonstrate that BRCA2 deletion triggers TERRA hyperexpression and alternative lengthening mechanisms (ALT) in colon cancer cells in presence of telomerase activity. This finding opens the question if cancer patients bearing BRCA2 germline or sporadic mutation are suitable for anti-telomerase therapies, or how ALT activation could influence the short or long-term response to anti-PARP inhibitors or anti-G-quadruplex therapies