DNA damage response-related alterations define the genetic background of patients with chronic lymphocytic leukemia and chromosomal gains

[EN]The presence of chromosomal gains other than trisomy 12 suggesting a hyperdiploid karyotype is extremely rare in chronic lymphocytic leukemia (CLL) and is associated with a dismal prognosis. However, the genetic mechanisms and mutational background of these patients have not been fully explored. To improve our understanding of the genetic underpinnings of this subgroup of CLL, seven CLL patients with several chromosomal gains were sequenced using a next-generation sequencing (NGS)-targeted approach. The mutational status of 54 genes was evaluated using a custom-designed gene panel including recurrent mutated genes observed in CLL and widely associated with CLL pathogenesis. A total of 21 mutations were detected; TP53 (42.8%), ATM (28.5%), SF3B1 (28.5%), and BRAF (28.5%) were the most recurrently mutated genes. Of these mutations, 61.9% were detected in genes previously associated with a poor prognosis in CLL. Interestingly, five of the seven patients exhibited alterations in TP53 or ATM (deletion and/or mutation), genes involved in the DNA damage response (DDR), which could be related to a high genetic instability in this subgroup of patients. In conclusion, CLL patients with several chromosomal gains exhibit high genetic instability, with mutations in CLL driver genes and high-risk genetic alterations involving ATM and/or TP53 genes

Exceedingly facile Ph−X activation (X=Cl, Br, I) with ruthenium(II) : Arresting kinetics, autocatalysis, and mechanisms

The ICIQ Foundation and The Spanish Government (Grant CTQ2011-25418 and the Severo Ochoa Excellence Accreditation 2014-2018 SEV-2013-0319) are thankfully acknowledged for support of this work. F.M.M. is grateful to the Government of Spain (MICINN) for the FPI Ph.D. Scholarship (BES-2012-054922). S.A.M. and D.M. thank the EPSRC for support through award EP/J010677/1.[(Ph3P)3Ru(L)(H)2] (where L=H2 (1) in the presence of styrene, Ph3P (3), and N2 (4)) cleave the Ph[BOND]X bond (X=Cl, Br, I) at RT to give [(Ph3P)3RuH(X)] (2) and PhH. A combined experimental and DFT study points to [(Ph3P)3Ru(H)2] as the reactive species generated upon spontaneous loss of L from 3 and 4. The reaction of 3 with excess PhI displays striking kinetics which initially appears zeroth order in Ru. However mechanistic studies reveal that this is due to autocatalysis comprising two factors: 1) complex 2, originating from the initial PhI activation with 3, is roughly as reactive toward PhI as 3 itself; and 2) the Ph[BOND]I bond cleavage with the just-produced 2 gives rise to [(Ph3P)2RuI2], which quickly comproportionates with the still-present 3 to recover 2. Both the initial and onward activation reactions involve PPh3 dissociation, PhI coordination to Ru through I, rearrangement to a η2-PhI intermediate, and Ph[BOND]I oxidative addition.Publisher PDFPeer reviewe

Crystal structure of the FAD-containing ferredoxin-NADP+ reductase from the plant pathogen Xanthomonas axonopodis pv. citri

We have solved the structure of ferredoxin-NADP(H) reductase, FPR, from the plant pathogen Xanthomonas axonopodis pv. citri, responsible for citrus canker, at a resolution of 1.5¿Å. This structure reveals differences in the mobility of specific loops when compared to other FPRs, probably unrelated to the hydride transfer process, which contributes to explaining the structural and functional divergence between the subclass I FPRs. Interactions of the C-terminus of the enzyme with the phosphoadenosine of the cofactor FAD limit its mobility, thus affecting the entrance of nicotinamide into the active site. This structure opens the possibility of rationally designing drugs against the X. axonopodis pv. citri phytopathogen

Analysis of Residual DSBs in Ataxia-Telangiectasia Lymphoblast Cells Initiating Apoptosis

Altres ajuts: This work was funded by grants from Consejo de Seguridad Nuclear (CSN 2012-0001) and EURATOM (Dark.Risk GA323216). Laia Hernandez is supported by the Universitat Autònoma de Barcelona Ph.D. programme fellowshipIn order to examine the relationship between accumulation of residual DNA double-strand breaks (DSBs) and cell death, we have used a control and an ATM (Ataxia-Telangiectasia Mutated) defective cell line, as Ataxia-Telangiectasia (AT) cells tend to accumulate residual DSBs at long times after damage infliction. After irradiation, AT cells showed checkpoint impairment and a fraction of cells displayed an abnormal centrosome number and tetraploid DNA content, and this fraction increased along with apoptosis rates. At all times analyzed, AT cells displayed a significantly higher rate of radiation-induced apoptosis than normal cells. Besides apoptosis, 70-85% of the AT viable cells (TUNEL-negative) carried ≥10 γ H2AX foci/cell, while only 12-27% of normal cells did. The fraction of AT and normal cells undergoing early and late apoptosis were isolated by flow cytometry and residual DSBs were concretely scored in these populations. Half of the γ H2AX-positive AT cells undergoing early apoptosis carried ≥10 γ H2AX foci/cell and this fraction increased to 75% in late apoptosis. The results suggest that retention of DNA damage-induced γ H2AX foci is an indicative of lethal DNA damage, as cells undergoing apoptosis are those accumulating more DSBs. Scoring of residual γ H2AX foci might function as a predictive tool to assess radiation-induced apoptosis

Mechanostability of the Single-Electron-Transfer Complexes of Anabaena Ferredoxin-NADP+ Reductase

The complexes formed between the flavoenzyme ferredoxin-NADP+ reductase (FNR; NADP+=nicotinamide adenine dinucleotide phosphate) and its redox protein partners, ferredoxin (Fd) and flavodoxin (Fld), have been analysed by using dynamic force spectroscopy through AFM. A strategy is developed to immobilise proteins on a substrate and AFM tip to optimise the recognition ability. The differences in the recognition efficiency regarding a random attachment procedure, together with nanomechanical results, show two binding models for these systems. The interaction of the reductase with the natural electron donor, Fd, is threefold stronger and its lifetime is longer and more specific than that with the substitute under iron-deficient conditions, Fld. The higher bond probability and two possible dissociation pathways in Fld binding to FNR are probably due to the nature of this complex, which is closer to a dynamic ensemble model. This is in contrast with the one-step dissociation kinetics that has been observed and a specific interaction described for the FNR:Fd complex

Boletín oficial de la provincia de León: Num. 116 (26/03/1897)

Copia digital. Valladolid : Junta de Castilla y León. Consejería de Cultura y Turismo, 2011-201

Prognostic implications of comorbidity patterns in critically ill COVID-19 patients: A multicenter, observational study

Background The clinical heterogeneity of COVID-19 suggests the existence of different phenotypes with prognostic implications. We aimed to analyze comorbidity patterns in critically ill COVID-19 patients and assess their impact on in-hospital outcomes, response to treatment and sequelae. Methods Multicenter prospective/retrospective observational study in intensive care units of 55 Spanish hospitals. 5866 PCR-confirmed COVID-19 patients had comorbidities recorded at hospital admission; clinical and biological parameters, in-hospital procedures and complications throughout the stay; and, clinical complications, persistent symptoms and sequelae at 3 and 6 months. Findings Latent class analysis identified 3 phenotypes using training and test subcohorts: low-morbidity (n=3385; 58%), younger and with few comorbidities; high-morbidity (n=2074; 35%), with high comorbid burden; and renal-morbidity (n=407; 7%), with chronic kidney disease (CKD), high comorbidity burden and the worst oxygenation profile. Renal-morbidity and high-morbidity had more in-hospital complications and higher mortality risk than low-morbidity (adjusted HR (95% CI): 1.57 (1.34-1.84) and 1.16 (1.05-1.28), respectively). Corticosteroids, but not tocilizumab, were associated with lower mortality risk (HR (95% CI) 0.76 (0.63-0.93)), especially in renal-morbidity and high-morbidity. Renal-morbidity and high-morbidity showed the worst lung function throughout the follow-up, with renal-morbidity having the highest risk of infectious complications (6%), emergency visits (29%) or hospital readmissions (14%) at 6 months (p<0.01). Interpretation Comorbidity-based phenotypes were identified and associated with different expression of in-hospital complications, mortality, treatment response, and sequelae, with CKD playing a major role. This could help clinicians in day-to-day decision making including the management of post-discharge COVID-19 sequelae. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd

Prognostic implications of comorbidity patterns in critically ill COVID-19 patients: A multicenter, observational study

Background: The clinical heterogeneity of COVID-19 suggests the existence of different phenotypes with prognostic implications. We aimed to analyze comorbidity patterns in critically ill COVID-19 patients and assess their impact on in-hospital outcomes, response to treatment and sequelae. Methods: Multicenter prospective/retrospective observational study in intensive care units of 55 Spanish hospitals. 5866 PCR-confirmed COVID-19 patients had comorbidities recorded at hospital admission; clinical and biological parameters, in-hospital procedures and complications throughout the stay; and, clinical complications, persistent symptoms and sequelae at 3 and 6 months. Findings: Latent class analysis identified 3 phenotypes using training and test subcohorts: low-morbidity (n=3385; 58%), younger and with few comorbidities; high-morbidity (n=2074; 35%), with high comorbid burden; and renal-morbidity (n=407; 7%), with chronic kidney disease (CKD), high comorbidity burden and the worst oxygenation profile. Renal-morbidity and high-morbidity had more in-hospital complications and higher mortality risk than low-morbidity (adjusted HR (95% CI): 1.57 (1.34-1.84) and 1.16 (1.05-1.28), respectively). Corticosteroids, but not tocilizumab, were associated with lower mortality risk (HR (95% CI) 0.76 (0.63-0.93)), especially in renal-morbidity and high-morbidity. Renal-morbidity and high-morbidity showed the worst lung function throughout the follow-up, with renal-morbidity having the highest risk of infectious complications (6%), emergency visits (29%) or hospital readmissions (14%) at 6 months (p<0.01). Interpretation: Comorbidity-based phenotypes were identified and associated with different expression of in-hospital complications, mortality, treatment response, and sequelae, with CKD playing a major role. This could help clinicians in day-to-day decision making including the management of post-discharge COVID-19 sequelae.Financial support was provided by Instituto de Salud Carlos III (CIBERESUCICOVID, COV20/00110), co-funded by Fondo Europeo de Desarrollo Regional (FEDER), “Una manera de hacer Europa”, Centro de Investigación Biomédica en Red − Enfermedades Respiratorias (CIBERES) and Donation Program “estar preparados”, UNESPA, Madrid, Spain. JdB acknowledges receiving financial support from Instituto de Salud Carlos III (ISCIII; Miguel Servet 2019: CP19/00108), cofunded by the European Social Fund (ESF), “Investing in your future”. DdGC acknowledges receiving financial support from Instituto de Salud Carlos III (ISCIII; Miguel Servet 2019: CP20/00041), co-funded by the European Social Fund (ESF), “Investing in your future”. AC acknowledges receiving financial support from Instituto de Salud Carlos III (ISCIII; Sara Borrell 2021: CD21/00087).Peer ReviewedArticle signat per 71 autors/es: Iván D. Benítez (a,b,1), Jordi de Batlle (a,b,1), Gerard Torres (a,b), Jessica Gonzáalez (a,b), David de Gonzalo-Calvo (a,b), Adriano D.S. Targa (a,b), Clara Gort-Paniello (a,b), Anna Moncusí-Moix (a,b), Adrián Ceccato (b,c), Laia Fernández-Barat (b,d), Ricard Ferrer (b,e), Dario Garcia-Gasulla (f), Rosario Menéndez (b,g), Anna Motos (b,d), Oscar Peñuelas (b,h), Jordi Riera (b,e), Jesús F. Bermejo-Martin (b,i), Yhivian Peñasco (j), Pilar Ricart (k), María Cruz Martin Delgado(l), Luciano Aguilera(m), Alejandro Rodríguez(n), Maria Victoria Boado Varela (o), Fernando Suarez-Sipmann (p), Juan Carlos Pozo-Laderas (q), Jordi Solé-Violan (r), Maite Nieto (s), Mariana Andrea Novo (t), José Barberán (u), Rosario Amaya Villar (v), José Garnacho-Montero (w), Jose Luis García-Garmendia (x), José M. Gómez (y), José Ángel Lorente (b,h), Aaron Blandino Ortiz (z), Luis Tamayo Lomas (aa), Esther López-Ramos (ab), Alejandro Úbeda (ac), Mercedes Catalán-González (ad), Angel Sánchez-Miralles (ae), Ignacio Martínez Varela (af), Ruth Noemí Jorge García (ag), Nieves Franco (ah), Víctor D. Gumucio-Sanguino (ai), Arturo Huerta Garcia (aj), Elena Bustamante-Munguira (ak), Luis Jorge Valdivia (al), Jesús Caballero (am), Elena Gallego (an), Amalia Martínez de la Gándara (ao), Álvaro Castellanos-Ortega (ap), Josep Trenado (aq), Judith Marin-Corral (ar), Guillermo M Albaiceta (b,as), Maria del Carmen de la Torre (at), Ana Loza-Vázquez (au), Pablo Vidal (av), Juan Lopez Messa (aw), Jose M. Añon (b,ax), Cristina Carbajales Pérez (ay), Victor Sagredo (az), Neus Bofill (ba), Nieves Carbonell (bb), Lorenzo Socias(bc), Carme Barberá (bd), Angel Estella (be), Manuel Valledor Mendez (bf), Emili Diaz (bg), Ana López Lago (bh), Antoni Torres (b,d) and Ferran Barbé (a,b*), on behalf of the CIBERESUCICOVID Project (COV20/00110, ISCIII)2 // (a) Translational Research in Respiratory Medicine, University Hospital Arnau de Vilanova and Santa Maria, IRBLleida, Lleida, Spain; (b) CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain; (c) Critical Care Center, ParcTaulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Sabadell, Spain; (d) Department of Pneumology, Hospital Clinic of Barcelona; August Pi i Sunyer Biomedical Research Institute−IDIBAPS, University of Barcelona, Barcelona, Spain; (e) Intensive Care Department, Vall d’Hebron Hospital Universitari. SODIR Research Group, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain; (f) Barcelona Supercomputing Center (BSC), Barcelona, Spain; (g) Pulmonology Service, University and Polytechnic Hospital La Fe, Valencia, Spain; (h) Hospital Universitario de Getafe, Madrid, Spain; Universidad Europea, Madrid, Spain; (i) Hospital Universitario Río Hortega de Valladolid, Valladolid, Spain; Group for Biomedical Research in Sepsis (BioSepsis), Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain; (j) Servicio de Medicina Intensiva, Hospital Universitario Marqués de Valdecilla, Santander, Spain; (k) Servei de Medicina Intensiva, Hospital Universitari Germans Trias, Badalona, Spain; (l) Hospital Universitario Torrejón-Universidad Francisco de Vitoria, Madrid, Spain; (m) Servicio de Anestesiología y Reanimación, Hospital Universitario Basurto, Bilbao, Spain; (n) Critical Care Department, Hospital Joan XXIII, Tarragona, Spain; (o) Servicio de Medicina Intensiva, Hospital de Cruces, Baracaldo, Vizcaya, Spain; (p) Intensive Care Unit, Hospital Universitario La Princesa, Madrid, Spain; (q) UGC-Medicina Intensiva, Hospital Universitario Reina Sofia, Instituto Maimonides IMIBIC, Córdoba, Spain; (r) Critical Care Department, Hospital Dr. Negrín Gran Canaria, Las Palmas, Gran Canaria, Spain. Universidad Fernando Pessoa, Canarias, Spain; (s) Hospital Universitario de Segovia, Segovia, Spain; (t) Servei de Medicina Intensiva, Hospital Universitari Son Espases, Palma de Mallorca, Illes Balears, Spain; (u) Hospital Universitario HM Montepríncipe, Universidad San Pablo-CEU, Madrid, Spain; vIntensive Care Clinical Unit, Hospital Universitario Virgen de Rocío, Sevilla, Spain; (w) Intensive Care Clinical Unit, Hospital Universitario Virgen Macarena, Seville, Spain; (x) Intensive Care Unit, Hospital San Juan de Dios del Aljarafe, Bormujos, Sevilla, Spain; (y) Hospital General Universitario Gregorio Marañon, Madrid, Spain; (z) Servicio de Medicina Intensiva, Hospital Universitario Ramón y Cajal, Madrid, Spain; (aa) Critical Care Department, Hospital Universitario Río Hortega de Valladolid, Valladolid, Spain; (ab) Servicio de Medicina Intensiva, Hospital Universitario Príncipe de Asturias, Madrid, Spain; (ac) Servicio de Medicina Intensiva, Hospital Punta de Europa, Algeciras, Spain; (ad) Department of Intensive Care Medicine, Hospital Universitario 12 de Octubre, Madrid, Spain; (ae) Hospital de Sant Joan d’Alacant, Alacant, Spain; (af) Critical Care Department, Hospital Universitario Lucus Augusti, Lugo, Spain; (ag) Intensive Care Department, Hospital Nuestra Señora de Gracia, Zaragoza, Spain; (ah) Hospital Universitario de Móstoles, Madrid, Spain; (ai) Department of Intensive Care. Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Barcelona, Spain. Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain; (aj) Pulmonary and Critical Care Division; Emergency Department, Clínica Sagrada Família, Barcelona, Spain; (ak) Department of Intensive Care Medicine, Hospital Clínico Universitario Valladolid, Valladolid, Spain; (al) Hospital Universitario de León, León, Spain; (am) Critical Care Department, Hospital Universitari Arnau de Vilanova; IRBLleida, Lleida, Spain; (an) Unidad de Cuidados Intensivos, Hospital Universitario San Pedro de Alcántara, Cáceres, Spain; (ao) Department of Intensive Medicine, Hospital Universitario Infanta Leonor, Madrid, Spain; (ap) Servicio de medicina intensiva. Hospital Universitario y Politécnico La Fe, Valencia, Spain; (aq) Servicio de Medicina Intensiva, Hospital Universitario Mútua de Terrassa, Terrassa, Barcelona, Spain; (ar) Critical Care Department, Hospital del Mar-IMIM, Barcelona, Spain; (as) Departamento de Biología Funcional. Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo; Instituto de Investigación Sanitaria del Principado de Asturias, Hospital Central de Asturias, Oviedo, Spain; (at) Hospital de Mataró de Barcelona, Spain; (au) Unidad de Medicina Intensiva, Hospital Universitario Virgen de Valme, Sevilla, Spain; (av) Complexo Hospitalario Universitario de Ourense, Ourense, Spain; (aw) Complejo Asistencial Universitario de Palencia, Palencia, Spain; (ax) Servicio de Medicina Intensiva. Hospital Universitario La Paz, IdiPAZ, Madrid, Spain; (ay) Intensive Care Unit, Hospital Álvaro Cunqueiro, Vigo, Spain; (az) Hospital Universitario de Salamanca, Salamanca, Spain; (ba) Department of Physical Medicine and Rehabilitation, Hospital Verge de la Cinta, Tortosa, Tarragona, Spain; (bb) Intensive Care Unit, Hospital Clínico y Universitario de Valencia, Valencia, Spain; (bc) Intensive Care Unit, Hospital Son Llàtzer, Palma de Mallorca, Illes Balears, Spain; (bd) Hospital Santa Maria; IRBLleida, Lleida, Spain; (be) Intensive Care Unit, University Hospital of Jerez. Medicine Department University of Cadiz. INiBICA, Spain; (bf) Hospital Universitario San Agustín, Asturias, Spain; (bg) Department of Medicine, Universitat Autónoma de Barcelona (UAB); Critical Care Department, Corporació Sanitària Parc Taulí, Sabadell, Barcelona, Spain; (bh) Department of Intensive care Medicine, Complejo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, SpainPostprint (published version

Boletín oficial de la provincia de León: Num. 17 (08/02/1915)

Copia digital. Valladolid : Junta de Castilla y León. Consejería de Cultura y Turismo, 2011-201