Gαq activation modulates autophagy by promoting mTORC1 signaling.

The mTORC1 node plays a major role in autophagy modulation. We report a role of the ubiquitous Gαq subunit, a known transducer of plasma membrane G protein-coupled receptors signaling, as a core modulator of mTORC1 and autophagy. Cells lacking Gαq/11 display higher basal autophagy, enhanced autophagy induction upon different types of nutrient stress along with a decreased mTORC1 activation status. They are also unable to reactivate mTORC1 and thus inactivate ongoing autophagy upon nutrient recovery. Conversely, stimulation of Gαq/11 promotes sustained mTORC1 pathway activation and reversion of autophagy promoted by serum or amino acids removal. Gαq is present in autophagic compartments and lysosomes and is part of the mTORC1 multi-molecular complex, contributing to its assembly and activation via its nutrient status-sensitive interaction with p62, which displays features of a Gαq effector. Gαq emerges as a central regulator of the autophagy machinery required to maintain cellular homeostasis upon nutrient fluctuations.We thank Paula Ramos, Susana Rojo-Berciano, and Laura López for helpful technicalassistance. Dr. Marta Cruces (Universidad Autónoma de Madrid, Spain) for herinvaluable help regarding the liver explants experiments, Dr. Badford Berk (University ofRochester, NY, USA) for providing the GFP-Flag-PB1-p62 plasmid, Drs. Stefan Offer-manns and Nina Wettschureck (Max-Planck-Institute for Heart and Lung Research,Germany) for providing Tie2-CreERT2; Gnaq f/f; Gna11−/−[EC-q/11-KO) mice, andDr. Guzmán Sánchez for scientific advice. We thank also Ricardo Ramos from theGenomic facility of Fundación Parque Científico de Madrid (Universidad Autónoma deMadrid, Spain) and Gemma Rodríguez-Tarduchy from the Genomic facility of theInstituto de Investigaciones Biomédicas“Alberto Sols”for their help with cell linesauthentication. The help from CBMSO Animal Care, Flow Cytometry, Electron andOptical and Confocal Microscopy facilities is also acknowledged. This work was sup-ported by Ministerio de Economía; Industria y Competitividad (MINECO) of Spain(grant SAF2017-84125-R to F.M.), (grant BFU2017-83379-R to A.M.A.), Instituto deSalud Carlos III (PI18/01662 to CR, co-funded with European FEDER contribution),CIBERCV-Instituto de Salud Carlos III, Spain (grant CB16/11/00278 to F.M., co-fundedwith European FEDER contribution), Fundación Ramón Areces (to C.R. and F.M.) andPrograma de Actividades en Biomedicina de la Comunidad de Madrid-B2017/BMD-3671-INFLAMUNE to F.M. and NIH grants AG021904 and AG038072 to A.M.C. Wealso acknowledge the support of a Contrato para la Formación del Profesorado Uni-versitario (FPU13/04341) and (FPU14/06670), an EMBO short-term fellowship (ASTF600-2016). We also acknowledge institutional support to the CBMSO from FundaciónRamón Areces.S

Evaluación de la respuesta eritropoyética en pacientes con eritroblastopenia congénita (Anemia de Blackfan-Diamond) tras suplementación dietética con L-Leucina

La anemia de Blackfan-Diamond (ABD), o eritroblastopenia congénita arregenerativa, se caracteriza por fallo eritrocitario, anormalidades congénitas y predisposición a neoplasias. De extremadamente baja prevalencia. Se pretende evaluar la respuesta eritropoyética al tratamiento con L-Leucina en los pacientes con anemia de Blackfan-Diamond como nueva diana terapéutica

Pectoralis major myocutaneous flap for faringeal defects reconstruction. Case report

Introduction: Pharyngocutaneous fistula after total laryngectomy (TL) remains a hardly frequent complication especially after radiotherapy. When conservative measures fail, reconstructive procedures are necessary. Our institution has adopted the pharyngeal interposition graft (PIG) using a pectoralis major myocutaneous flap (PMMC), which has adequate blood flow, for treatment post-irradiation pharyngocutaneous fistula. Description: We present a case-patient with a pharyngocutaneous fistula after TL that requires an externsive reconstruction by PMMC flap and the important role of hyperbaric oxygen therapy in the management of radiation-induced injury. Conclusions: In this era of microvascular reconstruction, the PMMC flap can safely be used for reconstruction of head and neck defects, providing cover to pharyngeal repair following salvage laryngectomy in patients who are high risk for free flaps after organ preservation protocols or patiens with a history of vascular disease.Introducción: La fístula faringocutánea post-laringectomía total (LT) continúa siendo una complicación frecuente luego de esta intervención especialmente tras tratamiento radioterápico. Cuando fracasan las medidas conservadoras, es necesario recurrir a cirugía reconstructiva. En nuestro centro se utiliza el colgajo miocutáneo de pectoral mayor (CMPM), que asegura un flujo sanguíneo adecuado para el tratamiento fístulas post-irradiación. Descripción: Presentamos un paciente con una fístula faringocutánea tras LT que requirió una amplia reconstrucción mediante CMPM asimismo discutiremos el importante papel que juega el tratamiento con oxígeno hiperbárico en el manejo de las consecuencias post-radioterapia. Conclusión: En la era de la reconstrucción microvascular, el PMMC puede ser utilizado para la reconstrucción de grandes defectos de cabeza y cuello, consiguiendo una adecuada cobertura tras protocolos de preservación de órgano o pacientes con historia de enfermedad vascular

Población mayor, Calidad de Vida y redes de apoyo: demanda y prestación de cuidados en el seno familiar

Esta investigación ha recibido el 2º Premio Caja Madrid de Investigación Social - Edición 2008El trabajo se enfoca desde la doble complementariedad de metodologías cuantitativa y cualitativa, al usar, respectivamente, datos de la encuesta sobre Calidad de Vida de los mayores no institucionalizados en la Comunidad de Madrid –CadeViMa- (diseñada y elaborada por el equipo de investigación en el año 2005), así como Entrevistas en Profundidad a mayores dependientes y Grupos de Discusión a familiares cuidadores (realizados en abril-mayo de 2007)

B-cell regeneration profile and minimal residual disease status in bone marrow of treated multiple myeloma patients

© 2021 by the authors.B-cell regeneration during therapy has been considered as a strong prognostic factor in multiple myeloma (MM). However, the effects of therapy and hemodilution in bone marrow (BM) B-cell recovery have not been systematically evaluated during follow-up. MM (n = 177) and adult (≥50y) healthy donor (HD; n = 14) BM samples were studied by next-generation flow (NGF) to simultaneously assess measurable residual disease (MRD) and residual normal B-cell populations. BM hemodilution was detected in 41 out of 177 (23%) patient samples, leading to lower total B-cell, B-cell precursor (BCP) and normal plasma cell (nPC) counts. Among MM BM, decreased percentages (vs. HD) of BCP, transitional/naïve B-cell (TBC/NBC) and nPC populations were observed at diagnosis. BM BCP increased after induction therapy, whereas TBC/NBC counts remained abnormally low. At day+100 postautologous stem cell transplantation, a greater increase in BCP with recovered TBC/NBC cell numbers but persistently low memory B-cell and nPC counts were found. At the end of therapy, complete response (CR) BM samples showed higher CD19− nPC counts vs. non-CR specimens. MRD positivity was associated with higher BCP and nPC percentages. Hemodilution showed a negative impact on BM B-cell distribution. Different BM B-cell regeneration profiles are present in MM at diagnosis and after therapy with no significant association with patient outcome.This work has been supported by the International Myeloma Foundation-Black Swan Research Initiative, the EuroFlow Consortium (grant LSHB-CT-2006-018708); Centro de Investigación Biomédica en Red de Cáncer (CIBER-ONC; Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Madrid, Spain and FONDOS FEDER), numbers: CB16/12/00400, CB16/12/00233, CB16/12/00369, CB16/12/00489 and CB16/12/00480; grant from Bilateral Cooperation Program between Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-CAPES (Brasília/Brazil) and Dirección General de Políticas Universitárias (DGPU)-Ministério de Educación, Cultura y Deportes (Madrid/Spain) number DGPU 311/15; Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro of Brazil (FAPERJ) numbers: E26/110.105/2014 and E26/102.191/2013; grant from Conselho Nacional de Desenvolvimento Científico e Tecnológico of Brazil (CNPQ), number: 400194/2014-7. R.M.d.P. was supported by a grant from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES/DGPU), number: 000281/2016-06 and CAPES/PROEX 641/2018, Brazil; Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro of Brazil (FAPERJ) number: E01/200/537/2018

Next generation flow for minimally-invasive blood characterization of MGUS and multiple myeloma at diagnosis based on circulating tumor plasma cells (CTPC)

© The Author(s) 2018.Here, we investigated for the first time the frequency and number of circulating tumor plasma cells (CTPC) in peripheral blood (PB) of newly diagnosed patients with localized and systemic plasma cell neoplasms (PCN) using next-generation flow cytometry (NGF) and correlated our findings with the distinct diagnostic and prognostic categories of the disease. Overall, 508 samples from 264 newly diagnosed PCN patients, were studied. CTPC were detected in PB of all active multiple myeloma (MM; 100%), and smoldering MM (SMM) patients (100%), and in more than half (59%) monoclonal gammopathy of undetermined significance (MGUS) cases (p <0.0001); in contrast, CTPC were present in a small fraction of solitary plasmacytoma patients (18%). Higher numbers of CTPC in PB were associated with higher levels of BM infiltration and more adverse prognostic features, together with shorter time to progression from MGUS to MM (p <0.0001) and a shorter survival in MM patients with active disease requiring treatment (p ≤ 0.03). In summary, the presence of CTPC in PB as assessed by NGF at diagnosis, emerges as a hallmark of disseminated PCN, higher numbers of PB CTPC being strongly associated with a malignant disease behavior and a poorer outcome of both MGUS and MM.This work has been supported by the International Myeloma Foundation-Black Swan Research Initiative and the EuroFlow Consortium; Centro de Investigación Biomédica en Red de Cáncer (CIBER-ONC; Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Madrid, Spain and FONDOS FEDER), numbers: CB16/12/00400, CB16/12/00369, CB16/12/00489 and CB16/12/00233; grant SA079U14 from the Consejería de Educación, Junta de Castilla y León, Valladolid, Spain and; grant DTS15/00119 from Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Madrid, Spain. Acuerdo de colaboración con Fundación de Hemoterapia y Hemodonación de Castilla y León, Valladolid, Spain. This study was also supported by the Qatar National Research Fund (QNRF) Award No. 7-916-3-237, the AACR-Millennium Fellowship in Multiple Myeloma Research (15-40-38-PAIV), ERA-NET TRANSCAN-2 (iMMunocell), by a 2017 Leonardo Grant (BZG10931) for Researchers and Cultural Creators, BBVA Foundation, and the European Research Council (ERC) 2015 Starting Grant (MYELOMANEXT)

Genetic and environmental factors related to the development of myopic maculopathy in Spanish patients

High myopia and the subsequent degenerative changes of the retina, choroid, and sclera, known as myopic maculopathy (MM), are a serious visual problem in many Asian countries, and are beginning to be so in the south of Europe, especially in the Mediterranean. It is therefore necessary to carry out genetic and environmental studies to determine the possible causes of this disease. This study aims to verify if the genetic factors that have been most related to Asian populations are also associated in two Spanish cohorts. Eight SNPs from six genes (PAX6,SCO2,CCDC102B,BLID,chromosome 15q14, andCOL8A1) along with demographic, ophthalmic and environmental factors were analysed in two cohorts from a total of 365 highly myopic subjects and 177 control subjects. The genetic analysis showed thatCOL8A1SNP rs13095226 was associated with the development of choroidal neovascularization (CNV) and also seems to play an important role in the increase of axial length. The SNP rs634990 ofchromosome 15q14also showed a significant association with MM, although this was lost after the Bonferroni correction. Additional demographic and environmental factors, namely age, sex, smoking status, and pregnancy history, were also found to be associated with MM and CNV in this population

A cluster-randomized trial of hydroxychloroquine for prevention of Covid-19

Background: current strategies for preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are limited to nonpharmacologic interventions. Hydroxychloroquine has been proposed as a postexposure therapy to prevent coronavirus disease 2019 (Covid-19), but definitive evidence is lacking. Methods: we conducted an open-label, cluster-randomized trial involving asymptomatic contacts of patients with polymerase-chain-reaction (PCR)-confirmed Covid-19 in Catalonia, Spain. We randomly assigned clusters of contacts to the hydroxychloroquine group (which received the drug at a dose of 800 mg once, followed by 400 mg daily for 6 days) or to the usual-care group (which received no specific therapy). The primary outcome was PCR-confirmed, symptomatic Covid-19 within 14 days. The secondary outcome was SARS-CoV-2 infection, defined by symptoms compatible with Covid-19 or a positive PCR test regardless of symptoms. Adverse events were assessed for up to 28 days. Results: the analysis included 2314 healthy contacts of 672 index case patients with Covid-19 who were identified between March 17 and April 28, 2020. A total of 1116 contacts were randomly assigned to receive hydroxychloroquine and 1198 to receive usual care. Results were similar in the hydroxychloroquine and usual-care groups with respect to the incidence of PCR-confirmed, symptomatic Covid-19 (5.7% and 6.2%, respectively; risk ratio, 0.86 [95% confidence interval, 0.52 to 1.42]). In addition, hydroxychloroquine was not associated with a lower incidence of SARS-CoV-2 transmission than usual care (18.7% and 17.8%, respectively). The incidence of adverse events was higher in the hydroxychloroquine group than in the usual-care group (56.1% vs. 5.9%), but no treatment-related serious adverse events were reported. Conclusions: postexposure therapy with hydroxychloroquine did not prevent SARS-CoV-2 infection or symptomatic Covid-19 in healthy persons exposed to a PCR-positive case patient. (Funded by the crowdfunding campaign YoMeCorono and others; BCN-PEP-CoV2 ClinicalTrials.gov number, NCT04304053.)

The genetic ancestry of American Creole cattle inferred from uniparental and autosomal genetic markers

Cattle imported from the Iberian Peninsula spread throughout America in the early years of discovery and colonization to originate Creole breeds, which adapted to a wide diversity of environments and later received influences from other origins, including zebu cattle in more recent years. We analyzed uniparental genetic markers and autosomal microsatellites in DNA samples from 114 cattle breeds distributed worldwide, including 40 Creole breeds representing the whole American continent, and samples from the Iberian Peninsula, British islands, Continental Europe, Africa and American zebu. We show that Creole breeds differ considerably from each other, and most have their own identity or group with others from neighboring regions. Results with mtDNA indicate that T1c-lineages are rare in Iberia but common in Africa and are well represented in Creoles from Brazil and Colombia, lending support to a direct African influence on Creoles. This is reinforced by the sharing of a unique Y-haplotype between cattle from Mozambique and Creoles from Argentina. Autosomal microsatellites indicate that Creoles occupy an intermediate position between African and European breeds, and some Creoles show a clear Iberian signature. Our results confirm the mixed ancestry of American Creole cattle and the role that African cattle have played in their development