Overcoming Paradoxical Kinase Priming by a Novel MNK1 Inhibitor

Inhibidor de MNK1; OncologíaInhibidor de MNK1; OncologiaMNK1 inhibitor; OncologyTargeting the kinases MNK1 and MNK2 has emerged as a valuable strategy in oncology. However, most of the advanced inhibitors are acting in an adenosine triphosphate (ATP)-competitive mode, precluding the evaluation of different binding modes in preclinical settings. Using rational design, we identified and validated the 4,6-diaryl-pyrazolo[3,4-b]pyridin-3-amine scaffold as the core for MNK inhibitors. Signaling pathway analysis confirmed a direct effect of the hit compound EB1 on MNKs, and in line with the reported function of these kinases, EB1 only affects the growth of tumor but not normal cells. Molecular modeling revealed the binding of EB1 to the inactive conformation of MNK1 and the interaction with the specific DFD motif. This novel mode of action appears to be superior to the ATP-competitive inhibitors, which render the protein in a pseudo-active state. Overcoming this paradoxical activation of MNKs by EB1 represents therefore a promising starting point for the development of a novel generation of MNK inhibitors.This work was supported by the Instituto de Salud Carlos III (PI17/02247), (PI20/01687), and CIBERONC (CB16/12/00363). S.R.y.C. acknowledges support from the Generalitat de Catalunya (2017-9015-385045). E. Bou-Petit thanks the Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya (2017 FI_B2 00139) and the European Social Funds for her predoctoral fellowship

Evaluation of nine serological rapid tests for the detection of SARS-CoV-2

Objetivo. Evaluar la capacidad operativa de nueve pruebas serológicas rápidas para detectar la respuesta de anticuerpos IgM/IgG en el suero de pacientes con SARS-CoV-2 en diferentes etapas clínicas. Métodos. Se diseñó un estudio transversal de las pruebas serológicas rápidas para comparar su rendimiento respecto del diagnóstico del SARS-CoV-2. Se utilizaron en total 293 muestras, inclusive muestras de suero de pacientes negativos, asintomáticos y sintomáticos. Resultados. La sensibilidad de las pruebas evaluadas fue baja y moderada en las muestras de suero del grupo de pacientes asintomáticos y en el grupo de pacientes con menos de 11 días desde el inicio de los síntomas. La especificidad de las pruebas de anticuerpos anti-SARS-CoV-2 varió entre 86,5%-99% para la IgM y 86,5%-99,5% para la IgG. La sensibilidad y la razón de verosimilitud (likelihood ratio) fueron diferentes según los grupos de estudio. La utilidad de estas pruebas se limita a los pacientes sintomáticos y su sensibilidad es superior al 85% después de 11 días de la aparición de los síntomas. Conclusiones. Las pruebas serológicas no son una estrategia adecuada para la identificación de los pacientes asintomáticos y presintomáticos. Las pruebas serológicas rápidas para la detección de anticuerpos específicos anti-SARS-CoV-2 pueden ser utilizadas como ayuda diagnóstica, pero el diagnóstico debe ser confirmado por RT-PCR. Las pruebas rápidas deben reservarse para los pacientes con síntomas que duren más de 11 días.Objective. To evaluate the operative capacity of nine serological rapid tests to detect the IgM/IgG antibodies response in serum from patients with SARS-CoV-2 in different clinical stages. Methods. A cross-sectional study of serological rapid tests was designed to compare the performance of the evaluated immunochromatographic tests for the diagnosis of SARS-CoV-2. A total of 293 samples was used, including negatives, asymptomatic, and symptomatic serum samples. Results. The sensitivity of the evaluated tests was low and moderate in the groups of asymptomatic serum samples and the group of serums coming from patients with less than 11 days since the onset of the symptoms. The specificity for the anti-SARS-CoV-2 antibodies tests ranged between 86.5%-99% for IgM and 86.5%-99.5% for IgG. The sensitivity and the likelihood ratio were different according to the study groups. The usefulness of these tests is restricted to symptomatic patients and their sensitivity is greater than 85% after 11 days from the appearance of symptoms. Conclusions. Serological tests are not an adequate strategy for the identification of asymptomatic and pre-symptomatic patients. Serological rapid tests for the detection of specific anti-SARS-CoV-2 antibodies can be used as a diagnostic aid, but diagnosis must be confirmed by RT-PCR. Rapid tests should be reserved for patients with symptoms lasting more than 11 days

Study protocol of a randomized controlled trial to assess safety of teleconsultation compared with face-to-face consultation: the ECASeT study

BackgroundThe use of remote consultation modalities has exponentially grown in the past few years, particularly since the onset of the COVID-19 pandemic. Although a huge body of the literature has described the use of phone (tele) and video consultations, very few of the studies correspond to randomized controlled trials, and none of them has assessed the safety of these consultation modalities as the primary objective. The primary objective of this trial was to assess the safety of remote consultations (both video and teleconsultation) in the follow-up of patients in the hospital setting.MethodsMulticenter, randomized controlled trial being conducted in four centers of an administrative healthcare area in Catalonia (North-East Spain). Participants will be screened from all individuals, irrespective of age and sex, who require follow-up in outpatient consultations of any of the departments involved in the study. Eligibility criteria have been established based on the local guidelines for screening patients for remote consultation. Participants will be randomly allocated into one of the two study arms: conventional face-to-face consultation (control) and remote consultation, either teleconsultation or video consultation (intervention). Routine follow-up visits will be scheduled at a frequency determined by the physician based on the diagnostic and therapy of the baseline disease (the one triggering enrollment). The primary outcome will be the number of adverse reactions and complications related to the baseline disease. Secondary outcomes will include non-scheduled visits and hospitalizations, as well as usability features of remote consultations. All data will either be recorded in an electronic clinical report form or retrieved from local electronic health records. Based on the complications and adverse reaction rates reported in the literature, we established a target sample size of 1068 participants per arm. Recruitment started in May 2022 and is expected to end in May 2024.DiscussionThe scarcity of precedents on the assessment of remote consultation modalities using randomized controlled designs challenges making design decisions, including recruitment, selection criteria, and outcome definition, which are discussed in the manuscript.Trial registrationNCT05094180. The items of the WHO checklist for trial registration are available in Additional file 1. Registered on 24 November 2021

Analysis of antimicrobial susceptibility and virulence factors in Helicobacter pylori clinical isolates

BACKGROUND: In this study, we evaluated the prevalence of primary resistance of Brazilian H. pylori isolates to metronidazole, clarithromycin, amoxicillin, tetracycline, and furazolidone. In addition, the vacA, iceA, cagA and cagE genotypes of strains isolated from Brazilian patients were determined and associated with clinical data in an effort to correlate these four virulence markers and antibiotic resistance. METHODS: H. pylori was cultured in 155 H. pylori-positive patients and MICs for metronidazole, clarithromycin, amoxicillin, tetracycline, and furazolidone were determined by the agar dilution method. Genomic DNA was extracted, and allelic variants of vacA, iceA, cagA and cagE were identified by the polymerase chain reaction. RESULTS: There was a strong association between the vacA s1/cagA -positive genotype and peptic ulcer disease (OR = 5.42, 95% CI 2.6–11.3, p = 0.0006). Additionally, infection by more virulent strains may protect against GERD, since logistic regression showed a negative association between the more virulent strain, vacA s1/cagA-positive genotype and GERD (OR = 0.26, 95% CI 0.08–0.8, p = 0.03). Resistance to metronidazole was detected in 75 patients (55%), to amoxicillin in 54 individuals (38%), to clarithromycin in 23 patients (16%), to tetracycline in 13 patients (9%), and to furazolidone in 19 individuals (13%). No significant correlation between pathogenicity and resistance or susceptibility was detected when MIC values for each antibiotic were compared with different vacA, iceA, cagA and cagE genotypes. CONCLUSION: The analysis of virulence genes revealed a specific association between H. pylori strains and clinical outcome, furthermore, no significant association was detected among pathogenicity and resistance or susceptibility

Genome-wide association study identifies Sjögren’s risk loci with functional implications in immune and glandular cells

Sjögren’s disease is a complex autoimmune disease with twelve established susceptibility loci. This genome-wide association study (GWAS) identifies ten novel genome-wide significant (GWS) regions in Sjögren’s cases of European ancestry: CD247, NAB1, PTTG1-MIR146A, PRDM1-ATG5, TNFAIP3, XKR6, MAPT-CRHR1, RPTOR-CHMP6-BAIAP6, TYK2, SYNGR1. Polygenic risk scores yield predictability (AUROC = 0.71) and relative risk of 12.08. Interrogation of bioinformatics databases refine the associations, define local regulatory networks of GWS SNPs from the 95% credible set, and expand the implicated gene list to >40. Many GWS SNPs are eQTLs for genes within topologically associated domains in immune cells and/or eQTLs in the main target tissue, salivary glands.Research reported in this publication was supported by the National Institutes of Health (NIH): R01AR073855 (C.J.L.), R01AR065953 (C.J.L.), R01AR074310 (A.D.F.), P50AR060804 (K.L.S.), R01AR050782 (K.L.S), R01DE018209 (K.L.S.), R33AR076803 (I.A.), R21AR079089 (I.A.); NIDCR Sjögren’s Syndrome Clinic and Salivary Disorders Unit were supported by NIDCR Division of Intramural Research at the National Institutes of Health funds - Z01-DE000704 (B.W.); Birmingham NIHR Biomedical Research Centre (S.J.B.); Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy – EXC 2155 – Projektnummer 390874280 (T.W.); Research Council of Norway (Oslo, Norway) – Grant 240421 (TR.R.), 316120 (M.W-H.); Western Norway Regional Health Authority (Helse Vest) – 911807, 912043 (R.O.); Swedish Research Council for Medicine and Health (L.R., G.N., M.W-H.); Swedish Rheumatism Association (L.R., G.N., M.W-H.); King Gustav V’s 80-year Foundation (G.N.); Swedish Society of Medicine (L.R., G.N., M.W-H.); Swedish Cancer Society (E.B.); Sjögren’s Syndrome Foundation (K.L.S.); Phileona Foundation (K.L.S.). The Stockholm County Council (M.W-H.); The Swedish Twin Registry is managed through the Swedish Research Council - Grant 2017-000641. The French ASSESS (Atteinte Systémique et Evolution des patients atteints de Syndrome de Sjögren primitive) was sponsored by Assistance Publique-Hôpitaux de Paris (Ministry of Health, PHRC 2006 P060228) and the French society of Rheumatology (X.M.).publishedVersio

El futuro después del COVID-19

El libro reúne ensayos de 27 autoras y autores en el contexto del inicio de la pandemia del Covid-19. Plantea diagnósticos, analiza dimensiones sociales, políticas y culturales. Y ofrece un panorama plural del debate en un momento de emergencia.Fil: Follari, Roberto Agustin. Universidad Nacional de Cuyo; Argentina. Universidad Nacional de la Patagonia "San Juan Bosco"; ArgentinaFil: Canelo, Paula Vera. Universidad Nacional de San Martín. Instituto de Altos Estudios Sociales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Saavedra 15. Centro de Innovación de los Trabajadores. Universidad Metropolitana para la Educación y el Trabajo. Centro de Innovación de los Trabajadores; ArgentinaFil: Sztulwark, Diego. Universidad de Buenos Aires; ArgentinaFil: Palermo, Vicente Antonio. Universidad de Buenos Aires. Facultad de Ciencias Sociales. Instituto de Investigaciones "Gino Germani"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: González, Horacio. Universidad de Buenos Aires; Argentina. Universidad Nacional de Rosario; ArgentinaFil: Tokatlian, Juan Gabriel. Universidad de San Andrés; Argentina. Universidad Nacional de Colombia; Colombia. Universidad de los Andes; ColombiaFil: Forster, Ricardo. Universidad Nacional de Córdoba; ArgentinaFil: Fidanza, Eduardo. Academia Nacional de Periodismo; ArgentinaFil: Boron, Atilio Alberto. Universidad de Buenos Aires. Facultad de Ciencias Sociales. Instituto de Estudios de América Latina y el Caribe; Argentina. Universidad Nacional de Avellaneda; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Sociales; ArgentinaFil: Segato, Rita Laura. Unesco; Argentina. Universidad de Brasilia; BrasilFil: Rebón, Julián. Universidad de Buenos Aires. Centro de Estudios Avanzados; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Sociales. Instituto de Investigaciones "Gino Germani"; Argentina. Consejo Latinoamericano de Ciencias Sociales; ArgentinaFil: Svampa, Maristella Noemi. Universidad Nacional de La Plata; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Viale, Enrique. Asociación Argentina de Abogados Ambientalistas; ArgentinaFil: Carreiras, Helena. Instituto Universitario de Lisboa; Portugal. Instituto de Defensa Nacional de Portugal; PortugalFil: Malamud, Andrés. University of Maryland; Estados Unidos. Max-planck-institut Für Europäische Rechtsgeschichte.; AlemaniaFil: Sarlo Sabajanes, Beatriz Ercilia. Columbia University; Estados Unidos. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Barrancos, Dora Beatriz. Universidad de Buenos Aires. Facultad de Filosofía y Letras. Instituto Interdisciplinario de Estudios de Género; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Waisbord, Silvio Ricardo. The George Washington University; Estados Unidos. University of Pennsylvania; Estados UnidosFil: Casullo, María Esperanza. Universidad Nacional de Río Negro; Argentina. University of Richmond; Estados Unidos. University Brown; Estados UnidosFil: Mignolo, Walter. University of Duke; Estados UnidosFil: Valdettaro, Sandra Catalina. Universidad Nacional de Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Humanidades y Artes. Centro de Estudios Culturales Urbanos; ArgentinaFil: Alarcon, Cristian Francisco. Universidad Nacional de San Martín; ArgentinaFil: López, María Pia Luján. No especifíca;Fil: Moreno, María. No especifíca;Fil: Maffía, Diana. Universidad de Buenos Aires. Facultad de Filosofía y Letras; ArgentinaFil: Giunta, Andrea Graciela. Universidad de Buenos Aires. Facultad de Filosofía y Letras. Instituto de Teoría e Historia del Arte "Julio E. Payró"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Cabezón Cámara, Gabriela. University of California at Berkeley; Estados Unidos. Universidad Nacional de las Artes; ArgentinaFil: Grimson, Alejandro. Universidad Nacional de San Martín. Instituto de Altos Estudios Sociales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Intrafamilial variability in SLC6A1-related neurodevelopmental disorders

IntroductionPhenotypic spectrum of SLC6A1-related neurodevelopmental disorders (SLC6A1-NDD) includes intellectual disability (ID), autistic spectrum disorders (ASD), epilepsy, developmental delay, beginning from early infancy or after seizure onset, and other neurological features such as hypotonia and movement disorders. Data on familial phenotypic heterogeneity have been rarely reported, thus in our study we aimed to investigate intrafamilial phenotypic variability in families with SLC6A1 variants.MethodsWe collected clinical, laboratory and genetic data on 39 individuals, including 17 probands, belonging to 13 families harboring inherited variants of SLC6A1. Data were collected through an international network of Epilepsy and Genetic Centers.ResultsMain clinical findings in the whole cohort of 39 subjects were: (a) epilepsy, mainly presenting with generalized seizures, reported in 71% of probands and 36% of siblings or first/second-degree relatives. Within a family, the same epilepsy type (generalized or focal) was observed; (b) ID reported in 100% and in 13% of probands and siblings or first/second-degree relatives, respectively; (c) learning disabilities detected in 28% of the SLC6A1 carriers, all of them were relatives of a proband; (d) around 51% of the whole cohort presented with psychiatric symptoms or behavioral disorders, including 82% of the probands. Out of the 19 patients with psychiatric symptoms, ASD were diagnosed in 40% of them; (e) neurological findings (primarily tremor and speech difficulties) were observed 38.5% of the whole cohort, including 10 probands. Our families harbored 12 different SLC6A1 variants, one was a frameshift, two stop-gain, while the remaining were missense. No genotype–phenotype associations were identified.DiscussionOur study showed that first-or second-degree relatives presented with a less severe phenotype, featuring mainly mild intellectual and/or learning disabilities, at variance with the probands who suffered from moderate to severe ID, generalized, sometimes intractable, epileptic seizures, behavioral and psychiatric disorders. These findings may suggest that a proportion of individuals with mild SLC6A1-NDD might be missed, in particular those with an older age where genetic testing is not performed. Further studies on intrafamilial phenotypic variability are needed to confirm our results and possibly to expand the phenotypic spectrum of these disorders and benefit genetic counseling

A qué sabe el norte?

Libro que compila saberes de las recetas ancestrales y sabores tradicionales de la gastronomía Nortesantandereana, recopila 3 rutas de turismo gastronómico que conjuga 30 municipios de norte de santander y más de 300 tipos de sopas, platos fuertes y postres.Book that compiles knowledge of ancestral recipes and traditional flavors of gastronomy Nortesantandereana, compiles 3 routes of gastronomic tourism that brings together 30 municipalities of northern Santander and more than 300 types of soups, main dishes and desserts.Ruta del durazno y el agua -- Ruta del oro negro -- Ruta del río y la gran convención -- Las mujeres de la independencia -- Honrando a nuestros portadores del saber -- A qué sabe el norte-recetarioPrimera ediciónna230 página

2021 DORIS definition of remission in SLE: final recommendations from an international task force.

OBJECTIVE: To achieve consensus on a definition of remission in SLE (DORIS). BACKGROUND: Remission is the stated goal for both patient and caregiver, but consensus on a definition of remission has been lacking. Previously, an international task force consisting of patient representatives and medical specialists published a framework for such a definition, without reaching a final recommendation. METHODS: Several systematic literature reviews were performed and specific research questions examined in suitably chosen data sets. The findings were discussed, reformulated as recommendations and voted on. RESULTS: Based on data from the literature and several SLE-specific data sets, a set of recommendations was endorsed. Ultimately, the DORIS Task Force recommended a single definition of remission in SLE, based on clinical systemic lupus erythematosus disease activitiy index (SLEDAI)=0, Evaluator's Global Assessment <0.5 (0-3), prednisolone 5 mg/day or less, and stable antimalarials, immunosuppressives, and biologics. CONCLUSION: The 2021 DORIS definition of remission in SLE is recommended for use in clinical care, education, and research including clinical trials and observational studies