End-to-End Automated Synthesis of C(sp3)-Enriched Drug-like Molecules via Negishi Coupling and Novel, Automated Liquid-Liquid Extraction.

Herein, we report an end-to-end process including synthesis, work-up, purification, and post-purification with minimal human intervention using Negishi coupling as a key transformation to increase Fsp3 in bioactive molecules. The main advantages of this protocol are twofold. First, the automated sequential generation of organozinc reagents from readily available alkyl halides offers a large diversity of alkyl groups to functionalize (hetero)aryl halide scaffolds via Pd-catalyzed Negishi coupling in continuous flow. Second, a fully automated liquid-liquid extraction has been developed and successfully applied for unattended operations. The workflow was completed with mass-triggered preparative high-performance liquid chromatography HPLC, providing an efficient production line of compounds with enriched sp3 character and better drug-like properties. The modular nature allows a smooth adaptation to a wide variety of synthetic methods and protocols and makes it applicable to any medchem laboratory.

¿Cómo entrenar una habilidad compleja en cirugía?: Evaluación cualitativa de una estrategia basada en simulación / How to train a complex skill in surgery: Qualitative evaluation of a simulation-based strategy

RESUMEN Antecedentes: el aprendizaje de tareas complejas en cirugía requiere la coordinación e integración de habilidades técnicas y no técnicas que impactan en el rendimiento de los equipos de trabajo. Objetivo: presentar la evaluación de una estrategia educativa basada en simulación para el entrena miento de una habilidad compleja en cirugía, desde la perspectiva de los participantes. Material y métodos: en 2019 se desarrolló un curso de 20 horas (6 horas virtuales y 14 presenciales). Participaron 10 profesionales de la salud. Como estrategia se diseñó la integración de actividades de resolución de casos, role playing, práctica con simuladores sintéticos y virtuales y simulación de alta fidelidad. Al finalizar se realizó un cuestionario sobre percepción de aprendizaje y cambios actitudi nales. Resultados: el 50% tuvo percepción de mejora de sus habilidades y conocimientos al finalizar el cur so. Sin embargo, cuando se preguntó por el impacto del curso sobre su actividad profesional, el 80% respondió niveles superiores al aprendizaje percibido. El 100% se refirió a la necesidad de mejorar habilidades no técnicas. Todos calificaron la experiencia como positiva o muy positiva, y con ganas de repetirla. Conclusión: la perspectiva de quienes participaron de este programa formativo da cuenta de la alta aceptación del método. El hacer conscientes las habilidades no técnicas durante la etapa de reflexión sugiere cambios no solo actitudinales sino sobre la autopercepción de eficacia. Creemos que la meto dología de entrenamiento de equipos basado en simulación tiene potencialidad de mejorar el rendi miento global y futuros estudios deberían estar orientados a ello.

ABSTRACT Background: Learning complex tasks in surgical requires the coordination and integration of technical and non-technical skills have an impact on the performance of work teams. Objective: The aim of this study is to report the results of a simulation-based educational strategy for training in complex surgical skills considering the participants' perceptions. Material and methods: In 2019, 10 healthcare professionals participated in a 20-hour course divided in 6 hours of online training and 14 hours of onsite training. The strategy designed included the inte gration of case resolution activities, role-playing, practice with synthetic and virtual simulators and high-fidelity simulation. At the end of the course, a questionnaire was administered to explore partici pants' perceptions on what they had learned and on their attitude changes. Results: Fifty percent of the participants perceived their skills and knowledge improved at the end of the course compared with their perception at the beginning of the course while 80% perceived the impact of the course on their professional activity was good or excellent. All the participants agreed with the need for improving non-technical skills. The experience was rated as positive or very positive by all participants, who were eager to repeat it. Conclusion: The participants' perceptions of this educational program demonstrates that this method is highly accepted. Raising awareness of non-technical skills during the reflection stage suggests the need for changes in attitude and in self-perception of efficacy. We believe that simulation-based tra ining offers the possibility of improving the overall performance of the surgical team. Future studies should focus on this goal.

Hydrogen Bonding Phase-Transfer Catalysis with Ionic Reactants: Enantioselective Synthesis of γ-Fluoroamines.

Ammonium salts are used as phase-transfer catalysts for fluorination with alkali metal fluorides. We now demonstrate that these organic salts, specifically azetidinium triflates, are suitable substrates for enantioselective ring opening with CsF and a chiral bis-urea catalyst. This process, which highlights the ability of hydrogen bonding phase-transfer catalysts to couple two ionic reactants, affords enantioenriched γ-fluoroamines in high yields. Mechanistic studies underline the role of the catalyst for phase-transfer, and computed transition state structures account for the enantioconvergence observed for mixtures of achiral azetidinium diastereomers. The N-substituents in the electrophile influence the reactivity, but the configuration at nitrogen is unimportant for the enantioselectivity.

Automated open-access liquid chromatography high resolution mass spectrometry to support drug discovery projects.

The need of a continuous productivity increases in medicinal chemistry laboratories of the pharmaceutical industry motivated the development, over the years, of new software solutions to enable Open-Access in many analytical techniques such as NMR or LC, among others, to characterize and assess the purity of new molecules. These approaches have been widely spread in LC with low resolution MS systems, but similar automated platforms have been rather less explored with high resolution MS. In this work, an improved Automated Open-Access methodology on an UHPLC with DAD coupled to ESI and quadrupole time-of-flight MS system is described. Detailed reports from standard UHPLC-MS runs containing chromatograms and different spectra (MS with different fragmentation) are automatically sent to the chemists. High resolution MS data is typically achieved within ± 1 mDa mass accuracy regardless of sample concentration. Upon training, chemists log-in samples into the system by selecting appropriate methods, being able to interpret the results by themselves in 95% of the cases. The instrument is working unattended, except for a limited number of samples (5%) which require more complex experiments. To the best of our knowledge, this is the first time a completely automated Open-Access LC-HRMS approach has been implemented for medicinal chemists of a pharmaceutical industry.

Computationally Guided Identification of Allosteric Agonists of the Metabotropic Glutamate 7 Receptor.

The metabotropic glutamate 7 (mGlu7) receptor belongs to the group III of mGlu receptors. Since the mGlu7 receptor can control excitatory neurotransmission in the hippocampus and cortex, modulation of the receptor may have therapeutic benefit in several CNS diseases. However, mGlu7 remains relatively unexplored among the eight known mGlu receptors partly because of the limited availability of tool compounds to interrogate its potential therapeutic utility. Here we report the discovery of a new class of mGlu7 allosteric agonists. Hits originating from virtual screening were followed up with further analogue searching and screening, leading to a novel series of mGlu7 allosteric agonists. Guided by docking into a structural model of the mGlu7 receptor the initial hit 5 was successfully optimized to analogues with comparable potencies and more attractive drug-like attributes than AMN082.

Visible-Light-Induced Nickel-Catalyzed Negishi Cross-Couplings by Exogenous-Photosensitizer-Free Photocatalysis.

The merging of photoredox and transition-metal catalysis has become one of the most attractive approaches for carbon-carbon bond formation. Such reactions require the use of two organo-transition-metal species, one of which acts as a photosensitizer and the other one as a cross-coupling catalyst. We report herein an exogenous-photosensitizer-free photocatalytic process for the formation of carbon-carbon bonds by direct acceleration of the well-known nickel-catalyzed Negishi cross-coupling that is based on the use of two naturally abundant metals. This finding will open new avenues in cross-coupling chemistry that involve the direct visible-light absorption of organometallic catalytic complexes.

Discovery of N-(Pyridin-4-yl)-1,5-naphthyridin-2-amines as Potential Tau Pathology PET Tracers for Alzheimer's Disease.

A mini-HTS on 4000 compounds selected using 2D fragment-based similarity and 3D pharmacophoric and shape similarity to known selective tau aggregate binders identified N-(6-methylpyridin-2-yl)quinolin-2-amine 10 as a novel potent binder to human AD aggregated tau with modest selectivity versus aggregated ß-amyloid (Aß). Initial medicinal chemistry efforts identified key elements for potency and selectivity, as well as suitable positions for radiofluorination, leading to a first generation of fluoroalkyl-substituted quinoline tau binding ligands with suboptimal physicochemical properties. Further optimization toward a more optimal pharmacokinetic profile led to the discovery of 1,5-naphthyridine 75, a potent and selective tau aggregate binder with potential as a tau PET tracer.

Identification of a novel orally bioavailable phosphodiesterase 10A (PDE10A) inhibitor with efficacy in animal models of schizophrenia.

We report the continuation of a focused medicinal chemistry program aimed to further optimize a series of imidazo[1,2-a]pyrazines as a novel class of potent and selective phosphodiesterase 10A (PDE10A) inhibitors. In vitro and in vivo pharmacokinetic and pharmacodynamic evaluation allowed the selection of compound 25a for its assessment in preclinical models of psychosis. The evolution of our medicinal chemistry program, structure-activity relationship (SAR) analysis, as well as a detailed pharmacological profile for optimized lead 25a are described.

Influence of polarity on the scalability and reproducibility of solvent-free microwave-assisted reactions.

Organic reactions performed in the absence of solvent in domestic ovens without appropriate temperature control are generally considered as not reproducible, particularly when different instruments are used. For this reason, reproducibility has historically been one of the major issues associated with Microwave-Assisted Organic Synthesis (MAOS) especially when domestic ovens are involved. The lack of reproducibility limits the general applicability and the scale up of these reactions. In this work several solvent-free reactions previously carried out in domestic ovens have been translated into a single-mode microwave reactor and then scaled up in a multimode oven. The results show that most of these reactions, although not considered as reproducible, can be easily updated and applied in microwave reactors using temperature-controlled conditions. Furthermore, computational calculations can assist to explain and/or predict whether a reaction will be reproducible or not.

Cancer en el adolescente a proposito de nuestra experiencia (224 pacientes) / Cancer in adolescents our experience with 224 patients

El cáncer es una enfermedad de rara ocurrencia en pediatría y adolescencia (10-19 años). Casi el 70 % de las neoplasias ocurren en pacientes menores de 5 años. Presentamos nuestra experiencia sobre 224 pacientes adolescentes con una enfermedad neoplásica no hematológica. El 61 % correspondieron al sexo masculino. La incidencia relativa de las neoplasias fue: tumores del sistema nerviosos central 30,5 %, sarcomas de partes blandas 22,7 %, tumores de hueso 18,1 %, tumores germinales 11,8 %, carcinomas 6,3 %, nefroblastoma 2,9 % y neuroblastoma 0,9 %.Comparando dos periodos diferentes (1984-89 y 1990-99) la sobrevida libre de enfermedad (SLE) a 48 meses fue de 39,4 % (45/114) y 81,8 % (90/110), respectivamente mientras que 49 % y 35,5 % presentaron secuelas, respectivamente. La adaptación social posterior a la curación orgánica de la enfermedad mostró que solo 4/135 pacientes (2,9 %) están en la Universidad; el grupo mas numerosos correspondió a aquellos con instrucción primaria incompleta (42,2 % versus 33 %). El 37 % y 53,3 % respectivamente, trabajan (intermitentemente) y el 13,3 % y el 15,5 % han formado pareja. De estos últimos 20 pacientes, el 35 % tiene 10 hijos; 6 son mujeres y 3 tenían tumores pelvianos, dos de ellas de ovario (tumores germinales).

Cancer en el adolescente a proposito de nuestra experiencia (224 pacientes) / Cancer in adolescents our experience with 224 patients

El cáncer es una enfermedad de rara ocurrencia en pediatría y adolescencia (10-19 años). Casi el 70 % de las neoplasias ocurren en pacientes menores de 5 años. Presentamos nuestra experiencia sobre 224 pacientes adolescentes con una enfermedad neoplásica no hematológica. El 61 % correspondieron al sexo masculino. La incidencia relativa de las neoplasias fue: tumores del sistema nerviosos central 30,5 %, sarcomas de partes blandas 22,7 %, tumores de hueso 18,1 %, tumores germinales 11,8 %, carcinomas 6,3 %, nefroblastoma 2,9 % y neuroblastoma 0,9 %.Comparando dos periodos diferentes (1984-89 y 1990-99) la sobrevida libre de enfermedad (SLE) a 48 meses fue de 39,4 % (45/114) y 81,8 % (90/110), respectivamente mientras que 49 % y 35,5 % presentaron secuelas, respectivamente. La adaptación social posterior a la curación orgánica de la enfermedad mostró que solo 4/135 pacientes (2,9 %) están en la Universidad; el grupo mas numerosos correspondió a aquellos con instrucción primaria incompleta (42,2 % versus 33 %). El 37 % y 53,3 % respectivamente, trabajan (intermitentemente) y el 13,3 % y el 15,5 % han formado pareja. De estos últimos 20 pacientes, el 35 % tiene 10 hijos; 6 son mujeres y 3 tenían tumores pelvianos, dos de ellas de ovario (tumores germinales)

Reproducibility and scalability of solvent-free microwave-assisted reactions: from domestic ovens to controllable parallel applications.

The heating of different parallel arrays in domestic ovens offers the possibility to perform multiple reactions in one irradiation experiment, blending the advantages of microwave heating technology and parallel chemistry. However, they are usually performed without an appropriate temperature control; thus, reproducibility becomes a major issue limiting the application of such reactions. This is exemplified when working at a different scales or using different instruments. For the first time a typical solvent-free reaction described in a domestic oven has been reproduced in monomode reactor, scaled up in a controlled multimode oven and reproduced in parallel, 24 reactions were carried out in a well plate. Parallel reactions were performed in a Weflon multiwell plate to assure identical conditions for each individual reaction. As many reactions under microwave irradiation have been performed in solvent-free conditions, this result opens new possibilities in reproducibility, scalability and combinatorial chemistry and permits to take advantage of many synthetic procedures described in domestic ovens.

Endocrine and immunological alterations during cancer processes.

An immunological deficit is often associated with cancer processes. Because cortisol has an important immunosuppressive activity and it is strictly involved in stress responses, we examined its serum levels in colorectal cancer patients and its relationships with peripheral lymphocyte counts. Cortisol circadian rhythm and total and CD4+ lymphocytes were determined in 40 patients. The rate of patients with an altered cortisol circadian rhythm was 28%, and it was significantly more frequent in patients with nodal involvement (P < 0.005) and with metastatic spread (P < 0.005). Patient ratio with total lymphocytes assessment decrease was 30%. There was no correlation between lymphocytopenia and alteration of cortisol circadian rhythm. Data suggest a significant adrenal glands rhythm modification during cancer processes, associated with poor prognostic factors. Cortisol levels and lymphocytopenia seem not to be related. The origins of these alterations are unknown. They may favor or result from cancer spread.

Fetal rhabdomyomatous nephroblastoma: report of 14 cases confirming chemotherapy resistance.

The authors retrospectively reviewed their experience with 14 cases of fetal rhabdomyomatous nephroblastoma (15.6% of all renal tumors seen in the 1984-1998 period), analyzing the diagnostic and treatment approach as well outcome. Mean age at presentation was 27 months; 10 (71%) patients were younger than 36 months (5 of these were less than 12 months) at diagnosis. Three patients had bilateral tumors. One case was extrarenal. Nine patients received preoperative chemotherapy after fine-needle aspiration biopsy. The response was null in five children and mild in three; in the remaining one the tumor increased in size. The only patient showing greater than 50% tumor shrinkage was the one treated with radiotherapy. Postoperative treatment according to staging followed the SIOP protocol. In the follow-up (mean 59.5 months) of 12 patients, 6 were in stages 1-2: 4 are alive and free of disease and 2 died (one due to intractable local recurrence and the other in complete clinical remission). All six patients presenting in advanced stages died (four due to disease progression and two due to complications while in complete clinical remission). Patients with fetal rhabdomyomatous nephroblastoma presenting with distant metastatic disease and high stage have unfavorable outcomes, confirming data from the literature indicating that chemotherapy is not as effective as in other variants of nephroblastoma. New protocols are needed to overcome this situation, for which surgery appears the only truly effective option.

[Von Recklinghausen's disease and intestinal neurofibromatosis: a case report]. / Malattia di von Recklinghausen e neurofibromatosi intestinale: presentazione di un caso.

We report the case of a patient with von Recklinghausen's disease, who was admitted with a diagnosis of acute abdomen due to small bowel neurofibromatosis. The patient was submitted to an abdominal CT scan that showed a homogeneous round lesion, with a regular margin, probably belonging to the small bowel and with the appearance of a benign lesion that probably caused an intestinal intussusception. The patient was submitted to a surgical procedure that mainly consisted in multiple small bowel resections. The histopathological examination confirmed the benign nature of the lesions. About one third of patients affected by von Recklinghausen's disease present involvement of the bowel, but only 5% of them are symptomatic. The intestinal tumours are usually neurofibromas and are mainly localized in the jejunum. However, there have also been reports of stromal, nervous and endocrine tumours and even other tumours not belonging to these categories, including adenocarcinoma. The overall incidence of intestinal malignancy in patients with von Reckilnghausen's disease is about 10%. The surgical operation, as well as the histopathological and immunochemical examination of the intestinal lesions are of crucial importance for the treatment of the complications of intestinal neurofibromatosis and for the treatment and diagnosis of malignancy.

Synthesis and cytotoxic activity of pyridazino[1',6':1,2]pyrido[3,4-b]indol-5-inium derivatives as anti-cancer agents.

Several new pyridazino[1',6':1,2]pyrido[3,4-b]indol-5-inium derivatives were synthesised from beta-carboline derivatives and their cytotoxic activity and effect on the cell cycle were evaluated against L1210 cancer cells.

Investigación psicofisiologica de las imagenes mentales / Psychophysiological research on mental pictures

En este trabajo se realiza un estudio de los tipos de imágenes de vigilia y de sueño que surgen en sujetos de experimentación bajo condiciones de privación sensorial a la vez que se les administra un estímulo sonoro, especialemtne un ritmo cardíaco electrónicamente obtenido, que actúa como inductor propioceptivo. Simultaneamente se toma um registro polisomnográfico con el fin de realizar una correlación entre el momento que surgen estas imágenes y los estados de conciencia que los fundan. El estudio permite una reelaboración del proceso de maduración y de formación de las imágenes en la mente, un replanteo semiológico de los tipos de imágenes, a la vez que una mayor comprensión de las funciones del yo durante el dormir, el soñar y durante las fases de transición hipnagógico-hipnopómpico. Finalmentea se toma en cuenta la importancia que tiene la relación interpersonal entre los sujetos y el equipo de investigación y su encuadre, el cual llega a modificar las características de los trazados de sueño

Investigación psicofisiologica de las imagenes mentales / Psychophysiological research on mental pictures

En este trabajo se realiza un estudio de los tipos de imágenes de vigilia y de sueño que surgen en sujetos de experimentación bajo condiciones de privación sensorial a la vez que se les administra un estímulo sonoro, especialemtne un ritmo cardíaco electrónicamente obtenido, que actúa como inductor propioceptivo. Simultaneamente se toma um registro polisomnográfico con el fin de realizar una correlación entre el momento que surgen estas imágenes y los estados de conciencia que los fundan. El estudio permite una reelaboración del proceso de maduración y de formación de las imágenes en la mente, un replanteo semiológico de los tipos de imágenes, a la vez que una mayor comprensión de las funciones del yo durante el dormir, el soñar y durante las fases de transición hipnagógico-hipnopómpico. Finalmentea se toma en cuenta la importancia que tiene la relación interpersonal entre los sujetos y el equipo de investigación y su encuadre, el cual llega a modificar las características de los trazados de sueño (AU)

Evolución en el diagnóstico y tratamiento quirúrgico de las atresias de las vías biliares extrahepáticas: nuestra experiencia / Evolution in diagnosis and surgical treatment of the extrahepatic bile duct atresia: our experience

En este trabajo exponemos la experiencia de trece años de nuestro grupo multidisciplinario e interinstitucional. Ya que esta enfermedad representa uno de los integrantes del síndrome de colestasis en el lactante, comenzamos por referirnos al mismo, para continuar con la patología que nos ocupa especificamente. Efectuamos consideraciones acerca de su diagnóstico, de la importancia de la anatomía patológica en el mismo y de sus diagnósticos diferenciales. Nos referimos a la evolución que siguió nuestro grupo en todos estos temas, muchos de los cuales recibieron aportes originales de nuestra parte. Luego de ésto, pasamos a considerar el tema central: la discusión del tratamiento quirúrgico para la solución de esta patología. Consideramos sus antecedentes, los aportes que hemos realizado al mismo, nuestra conducta en el pre-, intra- y postoperatorio, la descripción de las técnicas quirúrgicas que utilizamos, las complicaciones postoperatorias, inmediatas y alejadas, y el tratamiento médico postoperatorio de apoyo; presentamos luego nuestra casuística con su seguimiento correspondiente. Finalmente, y a modo de conclusión, proponemos las conductas que creemos más convenientes para el manejo de esta afección en el futuro inmediato. (AU)

Evolución en el diagnóstico y tratamiento quirúrgico de las atresias de las vías biliares extrahepáticas: nuestra experiencia / Evolution in diagnosis and surgical treatment of the extrahepatic bile duct atresia: our experience

En este trabajo exponemos la experiencia de trece años de nuestro grupo multidisciplinario e interinstitucional. Ya que esta enfermedad representa uno de los integrantes del síndrome de colestasis en el lactante, comenzamos por referirnos al mismo, para continuar con la patología que nos ocupa especificamente. Efectuamos consideraciones acerca de su diagnóstico, de la importancia de la anatomía patológica en el mismo y de sus diagnósticos diferenciales. Nos referimos a la evolución que siguió nuestro grupo en todos estos temas, muchos de los cuales recibieron aportes originales de nuestra parte. Luego de ésto, pasamos a considerar el tema central: la discusión del tratamiento quirúrgico para la solución de esta patología. Consideramos sus antecedentes, los aportes que hemos realizado al mismo, nuestra conducta en el pre-, intra- y postoperatorio, la descripción de las técnicas quirúrgicas que utilizamos, las complicaciones postoperatorias, inmediatas y alejadas, y el tratamiento médico postoperatorio de apoyo; presentamos luego nuestra casuística con su seguimiento correspondiente. Finalmente, y a modo de conclusión, proponemos las conductas que creemos más convenientes para el manejo de esta afección en el futuro inmediato.