Synthesis of substituted indazole acetic acids by N−N bond forming reactions

Herein, we report on the discovery and development of novel cascade N−N bond forming reactions for the synthesis of rare indazole acetic acid scaffolds. This approach allows for convenient synthesis of three distinct indazole acetic acid derivatives (unsubstituted, hydroxy, and alkoxy) by heating 3-amino-3-(2-nitroaryl)propanoic acids with an appropriate nucleophile/solvent under basic conditions. The reaction tolerates a range of functional groups and electronic effects and, in total, 23 novel indazole acetic acids were synthesized and characterized. This work offers a valuable strategy for the synthesis of useful scaffolds for drug discovery programs

La Cuevona de Avín (Avín, Asturias, North Spain): A new Late Pleistocene site in the lower valley of the River Güeña

The archaeological investigations carried out in the last twenty years in the Lower Valley of the River Güeña (Asturias, central part of northern Spain) have documented different prehistoric sites, particularly with Middle and Upper Palaeolithic occupations. This paper presents the first results of the archaeological excavation carried out in the cave of La Cuevona de Avín. From the systematic study of the biotic and abiotic remains, a total of three occupation phases (Phases 1 to 3) have been determined, dated in the Late Pleistocene. The lithic studies indicate the use of local raw materials (mainly quartzite), but also regional ones (different types of flint) in the whole sequence. Retouched implements are typologically representative only during the Upper Magdalenian (Phase II) and use-wear analysis indicates the manufacture and use of artefacts in situ during this phase. Archaeozoological studies reveal continuity in subsistence strategies throughout the sequence, noting specialization in red deer hunting during the Azilian (Phase I), and more diversified prey in the older phases of the sequence. © 2022 The Author(s

Inhibitory Kappa B Kinase α (IKKα) Inhibitors That Recapitulate Their Selectivity in Cells against Isoform-Related Biomarkers

© 2017 American Chemical Society. IKKβ plays a central role in the canonical NF-kB pathway, which has been extensively characterized. The role of IKKα in the noncanonical NF-kB pathway, and indeed in the canonical pathway as a complex with IKKβ, is less well understood. One major reason for this is the absence of chemical tools designed as selective inhibitors for IKKα over IKKβ. Herein, we report for the first time a series of novel, potent, and selective inhibitors of IKKα. We demonstrate effective target engagement and selectivity with IKKα in U2OS cells through inhibition of IKKα-driven p100 phosphorylation in the noncanonical NF-kB pathway without affecting IKKβ-dependent IKappa-Bα loss in the canonical pathway. These compounds represent the first chemical tools that can be used to further characterize the role of IKKα in cellular signaling, to dissect this from IKKβ and to validate it in its own right as a target in inflammatory diseases

Women's Education Level, Maternal Health Facilities, Abortion Legislation and Maternal Deaths: A Natural Experiment in Chile from 1957 to 2007

The aim of this study was to assess the main factors related to maternal mortality reduction in large time series available in Chile in context of the United Nations' Millennium Development Goals (MDGs).Time series of maternal mortality ratio (MMR) from official data (National Institute of Statistics, 1957-2007) along with parallel time series of education years, income per capita, fertility rate (TFR), birth order, clean water, sanitary sewer, and delivery by skilled attendants were analysed using autoregressive models (ARIMA). Historical changes on the mortality trend including the effect of different educational and maternal health policies implemented in 1965, and legislation that prohibited abortion in 1989 were assessed utilizing segmented regression techniques.During the 50-year study period, the MMR decreased from 293.7 to 18.2/100,000 live births, a decrease of 93.8%. Women's education level modulated the effects of TFR, birth order, delivery by skilled attendants, clean water, and sanitary sewer access. In the fully adjusted model, for every additional year of maternal education there was a corresponding decrease in the MMR of 29.3/100,000 live births. A rapid phase of decline between 1965 and 1981 (-13.29/100,000 live births each year) and a slow phase between 1981 and 2007 (-1.59/100,000 live births each year) were identified. After abortion was prohibited, the MMR decreased from 41.3 to 12.7 per 100,000 live births (-69.2%). The slope of the MMR did not appear to be altered by the change in abortion law.Increasing education level appears to favourably impact the downward trend in the MMR, modulating other key factors such as access and utilization of maternal health facilities, changes in women's reproductive behaviour and improvements of the sanitary system. Consequently, different MDGs can act synergistically to improve maternal health. The reduction in the MMR is not related to the legal status of abortion

Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress

The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors

Guía clínica para el diagnóstico y seguimiento de la distrofia miotónica tipo 1, DM1 o enfermedad de Steinert

La enfermedad de Steinert o distrofia miotónica tipo 1 (DM1), (OMIM 160900) es la miopatía más prevalente en el adulto. Es una enfermedad multisistémica con alteración de prácticamente todos los órganos y tejidos y una variabilidad fenotípica muy amplia, lo que implica que deba ser atendida por diferentes especialistas que dominen las alteraciones más importantes. En los últimos anos ˜ se ha avanzado de manera exponencial en el conocimiento de la enfermedad y en su manejo. El objetivo de la guía es establecer recomendaciones para el diagnóstico, el pronóstico, el seguimiento y el tratamiento de las diferentes alteraciones de la DM1. Esta guía de consenso se ha realizado de manera multidisciplinar. Se ha contado con neurólogos, neumólogos, cardiólogos, endocrinólogos, neuropediatras y genetistas que han realizado una revisión sistemática de la literatura. Se recomienda realizar un diagnóstico genético con cuantificación precisa de tripletes CTG. Los pacientes con DM1 deben seguir control cardiológico y neumológico de por vida. Antes de cualquier cirugía con anestesia general debe realizarse una evaluación respiratoria. Debe monitorizarse la presencia de síntomas de disfagia periódicamente. Debe ofrecerse consejo genético a los pacientes con DM1 y a sus familiares. La DM1 es una enfermedad multisistémica que requiere un seguimiento en unidades especializadas multidisciplinares

Esclerosis múltiple, maternidad y cuestiones relacionadas con el género

Resumen: Antecedentes: La esclerosis múltiple (EM) es una enfermedad en cuyo curso influyen el género, los factores hormonales y el embarazo. Objetivos: Realizar un análisis de la influencia de esos factores para aportar información sobre los mecanismos etiopatogénicos involucrados en la enfermedad. Métodos: Revisión exhaustiva de publicaciones científicas (búsqueda en la base de datos PubMed utilizando los términos: esclerosis múltiple, EM, EAE, embarazo, factores hormonales, tratamiento y términos relacionados), de los avances presentados en una reunión organizada por el Comité Europeo para el Tratamiento e Investigación de Esclerosis Múltiple (ECTRIMS), celebrado en marzo de 2013 en Londres, así como de las recomendaciones de reconocidos expertos internacionales. Resultados y conclusiones: Se ofrecen recomendaciones para el asesoramiento y la gestión de personas con EM antes de la concepción, durante el embarazo y después del parto. Se comentan también los conocimientos actuales sobre el efecto del tratamiento en la madre, el feto y el recién nacido. Realizamos recomendaciones para investigaciones futuras a fin de subsanar deficiencias de conocimiento y aclarar incoherencias de los datos actualmente disponibles. Abstract: Background: The course of multiple sclerosis (MS) is influenced by sex, pregnancy and hormonal factors. Aims: To analyse the influence of the above factors in order to clarify the aetiopathogenic mechanisms involved in the disease. Methods: We conducted a comprehensive review of scientific publications in the PubMed database using a keyword search for ‘multiple sclerosis’, ‘MS’, ‘EAE’, ‘pregnancy’, ‘hormonal factors’, ‘treatment’, and related terms. We reviewed the advances presented at the meeting held by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in March 2013 in London, as well as recommendations by international experts. Results and conclusions: We provide recommendations for counselling and treating women with MS prior to and during pregnancy and after delivery. Current findings on the effects of treatment on the mother, fetus, and newborn are also presented. We issue recommendations for future research in order to address knowledge gaps and clarify any inconsistencies in currently available data. Palabras clave: Esclerosis múltiple, Patofisiología, Embarazo, Sexo, Hormonas, Tratamiento, Keywords: Multiple sclerosis, Pathophysiology, Pregnancy, Sex, Hormones, Treatmen