Senescence under appraisal: hopes and challenges revisited.

In recent years, cellular senescence has become the focus of attention in multiple areas of biomedical research. Typically defined as an irreversible cell cycle arrest accompanied by increased cellular growth, metabolic activity and by a characteristic messaging secretome, cellular senescence can impact on multiple physiological and pathological processes such as wound healing, fibrosis, cancer and ageing. These unjustly called 'zombie cells' are indeed a rich source of opportunities for innovative therapeutic development. In this review, we collate the current understanding of the process of cellular senescence and its two-faced nature, i.e. beneficial/detrimental, and reason this duality is linked to contextual aspects. We propose the senescence programme as an endogenous pro-resolving mechanism that may lead to sustained inflammation and damage when dysregulated or when senescent cells are not cleared efficiently. This pro-resolving model reconciles the paradoxical two faces of senescence by emphasising that it is the unsuccessful completion of the programme, and not senescence itself, what leads to pathology. Thus, pro-senescence therapies under the right context, may favour inflammation resolution. We also review the evidence for the multiple therapeutic approaches under development based on senescence, including its induction, prevention, clearance and the use of senolytic and senomorphic drugs. In particular, we highlight the importance of the immune system in the favourable outcome of senescence and the implications of an inefficient immune surveillance in completion of the senescent cycle. Finally, we identify and discuss a number of challenges and existing gaps to encourage and stimulate further research in this exciting and unravelled field, with the hope of promoting and accelerating the clinical success of senescence-based therapies

Annexin A1 Released in Extracellular Vesicles by Pancreatic Cancer Cells Activates Components of the Tumor Microenvironment, through Interaction with the Formyl-Peptide Receptors

Pancreatic cancer (PC) is one of the most aggressive cancers in the world. Several extracellular factors are involved in its development and metastasis to distant organs. In PC, the protein Annexin A1 (ANXA1) appears to be overexpressed and may be identified as an oncogenic factor, also because it is a component in tumor-deriving extracellular vesicles (EVs). Indeed, these microvesicles are known to nourish the tumor microenvironment. Once we evaluated the autocrine role of ANXA1-containing EVs on PC MIA PaCa-2 cells and their pro-angiogenic action, we investigated the ANXA1 paracrine effect on stromal cells like fibroblasts and endothelial ones. Concerning the analysis of fibroblasts, cell migration/invasion, cytoskeleton remodeling, and the different expression of specific protein markers, all features of the cell switching into myofibroblasts, were assessed after administration of wild type more than ANXA1 Knock-Out EVs. Interestingly, we demonstrated a mechanism by which the ANXA1-EVs complex can stimulate the activation of formyl peptide receptors (FPRs), triggering mesenchymal switches and cell motility on both fibroblasts and endothelial cells. Therefore, we highlighted the importance of ANXA1/EVs-FPR axes in PC progression as a vehicle of intercommunication tumor cells-stroma, suggesting a specific potential prognostic/diagnostic role of ANXA1, whether in soluble form or even if EVs are captured in PC

Mesoglycan connects Syndecan-4 and VEGFR2 through Annexin A1 and formyl peptide receptors to promote angiogenesis in vitro.

Mesoglycan is a mixture of glycosaminoglycans (GAG) with fibrinolytic effects and the potential to enhance skin wound repair. Here, we have used endothelial cells isolated from Wild Type (WT) and Syndecan-4 null (Sdc4-/-) C57BL/6 mice to demonstrate that mesoglycan promotes cell motility and in vitro angiogenesis acting on the co-receptor Syndecan-4 (SDC4). This latter is known to participate in the formation and release of extracellular vesicles (EVs). We characterized EVs released by HUVECs and assessed their effect on angiogenesis. Particularly, we focused on Annexin A1 (ANXA1) containing EVs, since they may contribute to tube formation via interactions with Formyl peptide receptors (FPRs). In our model, the bond ANXA1-FPRs stimulates the release of vascular endothelial growth factor (VEGF-A) that interacts with vascular endothelial receptor-2 (VEGFR2) and activates the pathway enhancing cell motility in an autocrine manner, as shown by Wound-Healing/invasion assays, and the induction of Endothelial to Mesenchymal Transition (EndMT). Thus, we have shown for the first time that mesoglycan exerts its pro-angiogenic effects in the healing process triggering the activation of the three interconnected molecular axis: mesoglycan-SDC4, EVs-ANXA1-FPRs and VEGF-A-VEGFR2

Recovery of dialysis patients with COVID-19 : health outcomes 3 months after diagnosis in ERACODA

Background. Coronavirus disease 2019 (COVID-19)-related short-term mortality is high in dialysis patients, but longer-term outcomes are largely unknown. We therefore assessed patient recovery in a large cohort of dialysis patients 3 months after their COVID-19 diagnosis. Methods. We analyzed data on dialysis patients diagnosed with COVID-19 from 1 February 2020 to 31 March 2021 from the European Renal Association COVID-19 Database (ERACODA). The outcomes studied were patient survival, residence and functional and mental health status (estimated by their treating physician) 3 months after COVID-19 diagnosis. Complete follow-up data were available for 854 surviving patients. Patient characteristics associated with recovery were analyzed using logistic regression. Results. In 2449 hemodialysis patients (mean ± SD age 67.5 ± 14.4 years, 62% male), survival probabilities at 3 months after COVID-19 diagnosis were 90% for nonhospitalized patients (n = 1087), 73% for patients admitted to the hospital but not to an intensive care unit (ICU) (n = 1165) and 40% for those admitted to an ICU (n = 197). Patient survival hardly decreased between 28 days and 3 months after COVID-19 diagnosis. At 3 months, 87% functioned at their pre-existent functional and 94% at their pre-existent mental level. Only few of the surviving patients were still admitted to the hospital (0.8-6.3%) or a nursing home (∼5%). A higher age and frailty score at presentation and ICU admission were associated with worse functional outcome. Conclusions. Mortality between 28 days and 3 months after COVID-19 diagnosis was low and the majority of patients who survived COVID-19 recovered to their pre-existent functional and mental health level at 3 months after diagnosis

Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial

Background: The EMPA KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population. Methods: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1·73 m2, or 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ≥40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1·73 m2, or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110. Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2·0 years (IQR 1·5–2·4). Prespecified subgroupings by primary kidney disease included 2057 (31·1%) participants with diabetic kidney disease, 1669 (25·3%) with glomerular disease, 1445 (21·9%) with hypertensive or renovascular disease, and 1438 (21·8%) with other or unknown causes. Kidney disease progression occurred in 384 (11·6%) of 3304 patients in the empagliflozin group and 504 (15·2%) of 3305 patients in the placebo group (hazard ratio 0·71 [95% CI 0·62–0·81]), with no evidence that the relative effect size varied significantly by primary kidney disease (pheterogeneity=0·62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1·37 mL/min per 1·73 m2 per year (95% CI 1·16–1·59), representing a 50% (42–58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all >0·1). Interpretation: In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease. Funding: Boehringer Ingelheim, Eli Lilly, and UK Medical Research Council

Variability of breathing pattern during inspiratory elastic load

La ventilación pulmonar en humanos tiene una variabilidad respiración a respiración no lineal, compleja y caótica. El objetivo del trabajo fue: caracterizar la variabilidad del patrón respiratorio en perros (n: 8) anestesiados respirando bajo carga elástica umbral (CEU) inspiratoria (7 a 50 cm H2O). Con el flujo, presión traqueal y esofágica, se analizaron: tiempo inspiratorio (Ti), ritmo [tiempo espiratorio (Te); tiempo total (Ttot), y Ti/Ttot] e impulso central (Vt/Ti), variables relacionadas [volumen corriente (Vt) y ventilación pulmonar (Ve)]. Se determinaron: variabilidad grosera (varianzas), oscilaciones de baja frecuencia (análisis espectral) y memoria a corto plazo (análisis de autocorrelación). La CEU produjo disminución de la varianza de medias en Te, Ttot, Vt y Vt/Ti (p < 0.05). La media de las varianzas del Ti/Ttot aumentó (p < 0.005) y disminuyó para el Vt y el Vt/Ti (p < 0.05). En general, el porcentaje de oscilaciones de baja frecuencia (OB%) disminuyó (p < 0.02). Durante CEU alta, las variables de ritmo no cambiaron el porcentaje de registros con autocorrelación (AU%), pero el Vt y variables relacionadas disminuyeron los AU% (p < 0.005). Hubo correlación positiva (r: 0.955, p < 0.001) entre OB% y AU% en Vt y variables relacionadas, pero las variables de ritmo no mostraron correlación. En conclusión: La CEU indujo un patrón respiratorio más monótono. La memoria a corto plazo disminuyó en la fase inspiratoria y aumentó en la espiratoria. Estos cambios ocurrieron bajo anestesia, sugiriendo que ciertas estructuras suprapontinas pueden no ser imprescindibles para la generación de estos cambios.In humans, lung ventilation exhibits breath-to-breath variability and dynamics that are nonlinear, complex and chaotic. Our objective was to characterize the breathing pattern variational activity in anesthetized dogs (n: 8) breathing through threshold inspiratory elastic load (7 to 50 cm H2O). Starting from flow signal and tracheal and esophageal pressures, we analyzed inspiratory time (Ti), timing (expiratory time, Te; total time, Ttot; and Ti/Ttot) and central drive (Vt/Ti) and variables related to it (tidal volume, Vt and pulmonary ventilation, Ve). We measured gross variability (variances), low frequency oscillations (spectral analysis), and short term memory (autocorrelation analysis). Loading decreased variance of the mean values of Te, Ttot, Vt and Vt/Ti (p < 0.05); the mean of variances for Ti/Ttot increased (p < 0.005) while it decreased for Vt and Vt/Ti (p < 0.05). In general, percent of data recordings with low frequency oscillations (OB%) decreased (p < 0.02). During heavy load, timing parameters percent of data recordings with autocorrelations (AU%) did not change, but Vt and its related parameters decreased their AU% (p < 0.005). There was a positive correlation (r: 0.955, p < 0.001) between the existence of low frequency oscillations and autocorrelations for Vt and its related parameters, while timing variables did not show such a correlation. In conclusion, threshold elastic load induced a monotonous respiratory pattern. The short term memory decreased during inspiratory stage while increased during expiratory stage. These changes occurred during anesthesia suggesting that certain suprapontine structures may not be obligatory to induce them.Fil: D'Negri, Carlos E.. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Pessolano, Fernando A.. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: de Vito, Eduardo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentin

Respiratory domain of revised amyotrophic lateral sclerosis: Functional Rating Scale

Virtualmente todos los pacientes con esclerosis lateral amiotrófica tendrán disnea, que es quizá el síntoma más penoso de esta devastadora enfermedad. El objetivo de este estudio fue correlacionar la dimensión respiratoria de la escala ALSFRS-R, la capacidad vital forzada y las presiones estáticas máximas bucales. Se estudiaron prospectivamente 20 pacientes consecutivos sin disnea durante 24 meses. El puntaje total de la escala ALSFRS-R disminuyó de 34.3 ± 10.3 a 22.1 ± 8.0 (p = 0.0325); la contribución de la dimensión respiratoria fue insignificante. En quienes refirieron disnea (n: 12), la capacidad vital forzada cayó un 41 ± 21 % del valor inicial pero con similar caída (46 ± 23%), 8 pacientes no refirieron disnea. La correlación entre la escala ALSFRS-R con la capacidad vital forzada (litros) fue r: 0.73, (p = 0.0016) y con la presión inspiratoria máxima (cm H2O), r: 0.84, p = 0.0038. La correlación entre la capacidad vital forzada (%) con la disnea fue rs: 0.23, p = 0.1400. La correlación de la disnea con la presión inspiratoria máxima (%) fue rs: 0.58, p = 0.0300 y con la presión espiratoria máxima (%), rs: 0.49, p = 0.0400. La dimensión respiratoria de la escala ALSFRS-R no permitió predecir el grado de deterioro funcional respiratorio. Esto sugiere que dicha dimensión no reemplaza a las mediciones funcionales respiratorias y, debido a que la insuficiencia respiratoria puede no ser evidente, la realización de dichas pruebas provee una base objetiva de seguimiento y permite planear medidas con anticipación.2O), r: 0.84, p = 0.0038. La correlación entre la capacidad vital forzada (%) con la disnea fue rs: 0.23, p = 0.1400. La correlación de la disnea con la presión inspiratoria máxima (%) fue rs: 0.58, p = 0.0300 y con la presión espiratoria máxima (%), rs: 0.49, p = 0.0400. La dimensión respiratoria de la escala ALSFRS-R no permitió predecir el grado de deterioro funcional respiratorio. Esto sugiere que dicha dimensión no reemplaza a las mediciones funcionales respiratorias y, debido a que la insuficiencia respiratoria puede no ser evidente, la realización de dichas pruebas provee una base objetiva de seguimiento y permite planear medidas con anticipación.s: 0.58, p = 0.0300 y con la presión espiratoria máxima (%), rs: 0.49, p = 0.0400. La dimensión respiratoria de la escala ALSFRS-R no permitió predecir el grado de deterioro funcional respiratorio. Esto sugiere que dicha dimensión no reemplaza a las mediciones funcionales respiratorias y, debido a que la insuficiencia respiratoria puede no ser evidente, la realización de dichas pruebas provee una base objetiva de seguimiento y permite planear medidas con anticipación.s: 0.49, p = 0.0400. La dimensión respiratoria de la escala ALSFRS-R no permitió predecir el grado de deterioro funcional respiratorio. Esto sugiere que dicha dimensión no reemplaza a las mediciones funcionales respiratorias y, debido a que la insuficiencia respiratoria puede no ser evidente, la realización de dichas pruebas provee una base objetiva de seguimiento y permite planear medidas con anticipación.Virtually all patients with amyotrophic lateral sclerosis will complain of dyspnea, which is perhaps the most distressing symptom of this devastating disease. The objective was to correlate respiratory domain of ALSFRS-R with forced vital capacity and maximal static pressures in the mouth. We designed a prospective study in 20 consecutive patients without dyspnea during 24 months. The global decline of ALSFRS-R was from 34.3 ± 10.3 to 22.1 ± 8.0 (p = 0.0325), the contribution of respiratory domain was irrelevant. Those who referred dyspnea (n: 12), forced vital capacity fell 41 ± 21% of the initial value but with similar value of fall (46 ± 23%) 8 patients did not referred dyspnea. Total score of ALSFRS-R correlated with forced vital capacity (litres), r: 0.73, p = 0.0016 and maximal inspiratory pressure (cm H2 O), r: 0.84, p = 0.0038, but the fall of the forced vital capacity (%) did not correlate with dyspnea (rs : 0.23, p = 0.1400). There was a moderate correlation between dyspnea and maximal inspiratory pressure (%), rs : 0.58, p = 0.0300 and between dyspnea and maximal expiratory pressure (%), rs : 0.49, p = 0.0400. We concluded that the respiratory functional deterioration could not be predicted using respiratory domain of ALSFRS-R. This suggests that respiratory domain of this scale does not replace to respiratory function testing measurements and, due to the respiratory insufficiency could not be clinically evident; performing pulmonary function tests provides an objective view and permit to make anticipatory actions.Fil: Lima, Sandra E.. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Pessolano, Fernando A.. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Monteiro, Sergio G.. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: de Vito, Eduardo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentin