Live and let die: signaling AKTivation and UPRegulation dynamics in SARS-CoVs infection and cancer

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for the coronavirus disease 2019 (COVID-19) pandemic. Of particular interest for this topic are the signaling cascades that regulate cell survival and death, two opposite cell programs whose control is hijacked by viral infections. The AKT and the Unfolded Protein Response (UPR) pathways, which maintain cell homeostasis by regulating these two programs, have been shown to be deregulated during SARS-CoVs infection as well as in the development of cancer, one of the most important comorbidities in relation to COVID-19. Recent evidence revealed two way crosstalk mechanisms between the AKT and the UPR pathways, suggesting that they might constitute a unified homeostatic control system. Here, we review the role of the AKT and UPR pathways and their interaction in relation to SARS-CoV-2 infection as well as in tumor onset and progression. Feedback regulation between AKT and UPR pathways emerges as a master control mechanism of cell decision making in terms of survival or death and therefore represents a key potential target for developing treatments for both viral infection and cancer. In particular, drug repositioning, the investigation of existing drugs for new therapeutic purposes, could significantly reduce time and costs compared to de novo drug discovery.Fil: Suaya, Mariana. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Biociencias, Biotecnología y Biología Traslacional; ArgentinaFil: Sánchez, Gonzalo Manuel. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Biociencias, Biotecnología y Biología Traslacional; ArgentinaFil: Vila, Antonella Sofía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Biociencias, Biotecnología y Biología Traslacional; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Amante, Analia. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Biociencias, Biotecnología y Biología Traslacional; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Cotarelo, María. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Biociencias, Biotecnología y Biología Traslacional; ArgentinaFil: García Carrillo, Mercedes. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Biociencias, Biotecnología y Biología Traslacional; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Blaustein, Matíaa. Universidad de Buenos Aires; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Biociencias, Biotecnología y Biología Traslacional; Argentin

Arginine transport is impaired in C57Bl/6 mouse macrophages as a result of a deletion in the promoter of slc7a2 (CAT2) and Leishmania infection is reduced

Host genetic factors play a crucial role in immune response. To determine whether the differences betweenC57Bl/6 and BALB-C mice are due only to the production of cytokines by T-helper 1 cells or T-helper 2 cells,we obtained bone marrow–derived macrophages from both strains and incubated them with these cytokines.Although the induction of Nos2 and Arg1 was similar in the 2 strains, infectivity to Leishmania major differed,as did macrophage uptake of arginine, which was higher in BALB-C macrophages. The levels of interferon γ–and interleukin 4–dependent induction of the cationic amino acid transporter SLC7A2 (also known as “cationicamino acid transporter 2,” or “CAT2”) were decreased in macrophages from C57Bl/6 mice. This reductionwas a result of a deletion in the promoter of one of the 4 AGGG repeats. These results demonstrate that theavailability of arginine controls critical aspects of macrophage activation and reveal a factor for susceptibility to Leishmania infection

Genetic variation in NDFIP1 modifies the metabolic patterns in immune cells of multiple sclerosis patients

Autoinmunidad; Marcadores genéticos; Trastornos neurológicosAutoimmunitat; Marcadors genètics; Trastorns neurològicsAutoimmunity; Genetic markers; Neurological disordersOne of the 233 polymorphisms associated with multiple sclerosis (MS) susceptibility lies within the NDFIP1 gene, and it was previously identified as eQTL in healthy controls. NDFIP1 shows interesting immune functions and is involved in the development of the central nervous system. We aimed at studying the NDFIP1 variant on activation and metabolism of immune cells. NDFIP1 mRNA and protein expression were assessed in PBMCs by qPCR and western blot in 87 MS patients and 84 healthy controls genotyped for rs4912622. Immune activation after PHA stimulation was evaluated by CD69 upregulation, and metabolic function of both basal and PHA-activated lymphocytes was studied by Seahorse Xfp-Analyzer. In minor-allele homozygous controls but not in patients, we found higher NDFIP1 expression, significantly reduced protein levels, and CD69 upregulation in B- and T-cells. PBMCs from minor-allele homozygous controls showed significantly higher basal mitochondrial respiration and ATP production compared to major-allele carriers, while minor-allele homozygous patients showed significantly lower metabolic activity than carriers of the major allele. In conclusion, we describe associations in minor-allele homozygous controls with lower levels of NDFIP1 protein, CD69 upregulation, and raised mitochondrial activity, which are not replicated in MS patients, suggesting a NDFIP1 differential effect in health and disease.This work was supported by the projects PI16/01259 and PI20/01634, integrated in the Plan Nacional de I + D + I, AES 2013–2016 and 2017–2020; funded by the ISCIII and co-funded by the European Regional Development Fund (ERDF) "A way to make Europe”. LEP is recipient of a contract from “REEM: Red Española de Esclerosis Múltiple” (RETICS-REEM RD16/0015/0013; www.reem.es). AGJ and JAZ hold contracts from the program “Promoción de empleo joven y garantía juvenil-CAM” (PEJ2018-003125-A and PEJD-2019-PRE/SAL-16662)

The Influence of Patient Experience with Healthcare on the Health-Related Quality of Life of People Living with HIV: An Observational Cross-Sectional Survey

[Abstract] Introduction Patient experience is central to the quality of healthcare delivery, showing positive associations with several outcome measures. The main objectives of this study are to analyze the influence of patient experience on the health-related quality of life in people living with HIV and the role played by treatment complexity and clinical care. Methods We conducted a cross-sectional survey with 467 patients with HIV. We used the Instrument for Evaluation of the Experience of Chronic Patients and the Health-related Quality of Life Questionnaire (EQ-5D-5L). We analyzed a predictive model through the partial least squares (PLS) method. Results The patient self-management scores showed the highest positive relationship with the patient’s health-related quality of life (β = 0.24, β = 0.32, p  50 years old (p < 0.05). Conclusions Patient experience mainly influenced the health-related quality of life of older people living with HIV. The treatment and clinical care complexity played an important role in degrading the patients' experience and their quality of life. More integrated care would benefit the health-related quality of life of people living with HIV

HPV knowledge and vaccine acceptability: a survey-based study among parents of adolescents (KAPPAS study)

Background: Human papillomavirus (HPV) infection is recognized as one of the major causes of infection-related cancer worldwide. In Spain, the HPV vaccination program started in 2007 and until 2022, it targeted 12-year-old girls. Methods: This was a cross-sectional, multicenter survey-based research carried out at 24 pediatric offices to describe HPV knowledge and vaccine acceptability in parents of children aged between 9 and 14 years-old in Spain. Parents were randomly selected from the medical records following specific quotas to ensure representativeness. The survey included five sections that aim to collect information about sociodemographic characteristics, knowledge of HPV, knowledge and acceptability of vaccines in general, HPV vaccination knowledge and HPV vaccine acceptability. Each section was constituted by a number of close questions with different answer options. Specific scores were assigned to each possible answer to these questions. Based on these scores, four composite variables were created to assess HPV knowledge, HPV vaccine knowledge, HPV vaccine acceptability and vaccines knowledge and acceptability in general. A latent class analysis was performed to identify different group of respondents according to their HPV vaccine acceptability. Results: A total of 1405 valid surveys were included, with 86.19% of the respondents being mothers. The mean score of HPV knowledge was 28.92 out of 40 (maximum value) (95% CI 28.70-29.20) and the mean score of HPV vaccine acceptability was 3.37 out of 5 (maximum value). One third of parents still need more information to take a final decision about HPV vaccination in their children. Parents perceived that females were more likely to become infected than males and tended to associate HPV infection mainly with cervical cancer, showing a. a lack of information about other HPV-related diseases affecting males. Conclusions: This study results highlight the need for future actions and educational initiatives to raise awareness of HPV consequences in both genders and to contribute to achieving the elimination of HPV-related diseases beyond cervical cancer.Funding: This study has been funded and sponsored by MSD Spain. Acknowledgements: Investigators of the KAPPAS study: Magdalena Aga (CS Repélega); Isabel Cañabate (CS Churriana); Cynthia Crespo (CAP Montclar); Mara Garcés (CS Nazaret); Ana Belén López (IHP Córdoba); Gema Belén López (IHP Córdoba); María Martín (CS La Cala de Mijas); Abián Montesdeoca (CS Guanarteme); Ana María Nocea (CS Condes de Barcelona); Mª Belén Panizo (CS Illescas); Lizeth Peña (CS Pla Vinalopó); Victoria Planelles (CS Paiporta); Almudena Sánchez (CAP Les Hortes); Eva Suarez (CS Burriana II); Isabel Úbeda (CS L’Eliana); Edelmiro Verges (CS Binissalem, CS Alaro). Editorial assistance and medical writing support were provided by Esther Tapia, PhD and Adelphi Targis, S

Lipopolysaccharide-induced apoptosis of macrophages determines the up-regulation of concentrative nucleoside transporters Cnt1 and Cnt2 through tumor necrosis factor-alpha-dependent and -independent mechanisms

In murine bone marrow macrophages, lipopolysaccharide (LPS) induces apoptosis through the autocrine production of tumor necrosis factor-alpha (TNF-alpha), as demonstrated by the fact that macrophages from TNF-alpha receptor I knock-out mice did not undergo early apoptosis. In these conditions LPS up-regulated the two concentrative high affinity nucleoside transporters here shown to be expressed in murine bone marrow macrophages, concentrative nucleoside transporter (CNT) 1 and 2, in a rapid manner that is nevertheless consistent with the de novo synthesis of carrier proteins. This effect was not dependent on the presence of macrophage colony-stimulating factor, although LPS blocked the macrophage colony-stimulating factor-mediated up-regulation of the equilibrative nucleoside transport system es. TNF-alpha mimicked the regulatory response of nucleoside transporters triggered by LPS, but macrophages isolated from TNF-alpha receptor I knock-out mice similarly up-regulated nucleoside transport after LPS treatment. Although NO is produced by macrophages after LPS treatment, NO is not involved in these regulatory responses because LPS up-regulated CNT1 and CNT2 transport activity and expression in macrophages from inducible nitric oxide synthase and cationic amino acid transporter (CAT) 2 knock-out mice, both of which lack inducible nitric oxide synthesis. These data indicate that the early proapoptotic responses of macrophages, involving the up-regulation of CNT transporters, follow redundant regulatory pathways in which TNF-alpha-dependent- and -independent mechanisms are involved. These observations also support a role for CNT transporters in determining extracellular nucleoside availability and modulating macrophage apoptosis

cuidArt: Art Project of the Health Department of Dénia

Con esta iniciativa pionera en España, desarrollada por parte de la empresa DKV Seguros, se busca que la presencia del arte llene el Hospital de Dénia y forme un entorno mas humanizado. Así, junto a la Colección DKV: Arte y Salud, se muestra un importante proyecto escultórico, así como la intervención pictórica mural llevada a cabo en el área de Pediatría y desarrollada por un reconocido colectivo de Urban Art. Además, el proyecto cuenta con una Sala de Exposiciones dentro del propio hospital, que bajo el leivmotiv de Arte y Salud, programará exposiciones anuales, de producción propia y también en colaboración con distintas entidades públicas y privadas. Todo este proyecto se completa con un programa de actividades para pacientes de las distintas áreas del hospital: hemodiálisis, quimioterapia, psiquiatría y pediatría. Durante la semana se desarrollan talleres de teatro, musicoterapia y arteterapia, así como diversas intervenciones murales efímeras mientras los pacientes están recibiendo sus tratamientos. Un programa de arte al servicio de la salud, donde la humanización del entorno, el dialogo entre las diferentes disciplinas del arte y la medicina, serán la base de desarrollo del proyecto.With this initiative, pioneer in Spain, developed by DKV Seguros, the hospital is imbued with art in order to make a more humanized environment. This way, with DKV Collection: Art and Health, an important sculpture project is held as well as the wall paintings in the pediatric area, developed by an important Urban Art group. Besides, the project has an Exhibition Room, which, under the slogan of Art and Health, will hold annual exhibitions of self production as well as exhibitions in collaboration with different public and private institutions. This whole project is completed with a program of activities for patients of different areas: hemodialysis, chemotherapy, psychiatry and pediatrics. During the week drama workshops, music therapy and art therapy activities are developed at the hospital, as well as ephemeral wall paintings while patients are receiving their treatments. It is an art program at the service of health, where the humanization of the environment, the dialogue between different art disciplines and medicine will be the foundation upon which this project will be developed

Cuidart: proyecto de arte del departamento de salud de Dénia

Con esta iniciativa pionera en España, desarrollada por parte de la empresa DKV Seguros, se busca que la presencia del arte llene el Hospital de Dénia y forme un entorno mas humanizado. Así, junto a la Colección DKV: Arte y Salud, se muestra un importante proyecto escultórico, así como la intervención pictórica mural llevada a cabo en el área de Pediatría y desarrollada por un reconocido colectivo de Urban Art. Además, el proyecto cuenta con una Sala de Exposiciones dentro del propio hospital, que bajo el leivmotiv de Arte y Salud, programará exposiciones anuales, de producción propia y también en colaboración con distintas entidades públicas y privadas. Todo este proyecto se completa con un programa de actividades para pacientes de las distintas áreas del hospital: hemodiálisis, quimioterapia, psiquiatría y pediatría. Durante la semana se desarrollan talleres de teatro, musicoterapia y arteterapia, así como diversas intervenciones murales efímeras mientras los pacientes están recibiendo sus tratamientos. Un programa de arte al servicio de la salud, donde la humanización del entorno, el dialogo entre las diferentes disciplinas del arte y la medicina, serán la base de desarrollo del proyecto