Identificación de determinantes genéticos y moleculares de la evolución y la respuesta a la quimioterapia del cáncer de mama mediante el análisis de fenotipos intermedios

[ES] El cáncer de mama es una enfermedad de génesis compleja, con un componente de genética cuantitativa que contribuye a la variabilidad en la susceptibilidad y en la evolución de la enfermedad entre individuos. La distinta respuesta a la quimioterapia entre pacientes con aparentemente la misma enfermedad es el resultado de diferencias en interacciones entre múltiples fenotipos intermedios que participan en el proceso patogénico del cáncer de mama. Muy a menudo, cada uno de estos fenotipos intermedios es a su vez un rasgo complejo que sigue un patrón de herencia de genética cuantiativa. En este trabajo, proponemos que el análisis de estos fenotipos intermedios podría ser una estrategia para explicar parte de la variabilidad en la evolución del cáncer de mama en presencia de quimioterapia y sin ella. Con este objetivo, hemos estudiado diferentes aspectos de la evolución tumoral sin tratamiento, y en respuesta a docetaxel y doxorrubicina, en poblaciones de ratones genéticamente heterogéneas con cáncer de mama HER2 positivo. A continuación, analizamos varios fenotipos de la biología tumoral como la presencia de distintas mutaciones oncogénicas, la longitud telomérica tumoral, la actividad de varias vías de señalización tumorales, la composición celular del tumor y su índice proliferativo. Hemos encontrado numerosas asociaciones entre estos parámetros tumorales y la evolución clínica de la enfermedad que sugieren que estos parámetros tumorales pudieron contribuir a la heterogeneidad en la evolución clínica observada en los ratones estudiados. Finalmente, hemos identificado un número de regiones genómicas donde las diferencias en el genotipo se asociaron con diferencias en la evolución clínica del tumor y en los fenotipos tumorales intermedios estudiados. Todas estas regiones podrían contener determinantes genéticos de la evolución del cáncer de mama sin tratamiento y de la respuesta a la quimioterapia con docetaxel y doxorrubicina

Identifying phenotypes involved in susceptibility to Schistosoma mansoni infection in F1B6CBA mice

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.Schistosomiasis is a disease with a strong genetic component influenced by socioeconomic and ecological factors. Epidemiological studies have identified several genetic regions involved in the schistosomiasis susceptibility. However, it is not well known what physiological traits are predisposing to the disease. The study of experimental infections in inbred mouse strains with variable genetic susceptibility to the disease offers a good opportunity to tackle this question. F1B6CBA hybrid between the most divergent strains was infected in order to characterize the immunophenotypes that correlate with the susceptibility of schistosomiasis disease in mice. Complete blood counts and immunophenotype were determined at 0, 3, 6, and 9 weeks post infection. Nine weeks after cercariae exposure, animals were perfused and worm recovery was assessed. A large number of hepatic lesions, a reduction in the eosinophil and basophil count in the acute phase of infection and the decreased number of monocytes, neutrophils and B-lymphocytes are phenotypes associated with increased susceptibility to S. mansoni infection.The present study was supported by a grant from the Areces Foundation (2010–13) and funding of the Junta de Castilla y Leon (Orden EDU/330/2008).Peer Reviewe

Displasia fibrosa de la tibia en paciente con neurofibromatosis tipo 1

Introduction: fibrous dysplasia is a metabolic bone disease characterized by an accelerated bone resorption, resulting in a bone with less mechanical resistance. It is considered a nonneoplasticdisorder that simulates a bone tumor. The origin of this disease remains uncertain, although genetic or environmental factors are implicated in its etiology. It is among the rarest onset of neurofibromatosis type 1. Case report:a 7-year-old schoolgirl with a history of neurofibromatosis type 1, who attended the Orthopedics Emergency Room at Pepe Portilla Provincial Pediatric Hospital in Pinar del Río, with a pathological fracture of the left tibia. A diagnosis of fibrous bone dysplasia secondary to neurofibromatosis type 1 was completed and immobilization treatment was initiated. Conclusions:fibrous bone dysplasia is a rare indicator of neurofibromatosis type 1. This condition has several types of presentation, which depends on the prognosis and the evolution of patients. Its treatment includes several objectives and the alternative of its management depends on several factors.Introducción: la displasia fibrosa es una enfermedad metabólica ósea caracterizada por una acelerada reabsorción ósea que resulta en un hueso de menor resistencia mecánica. Se considera como trastorno no neoplásico que simula un tumor óseo. El origen de esta enfermedad sigue siendo incierto, aunque se postulan factores genéticos o medioambientales como implicados en su etiología. Se encuentra entre las manifestaciones poco frecuentes de la neurofibromatosis tipo 1.Presentación del caso: se presentó el caso de una escolar de 7 años de edad, con antecedentes de neurofibromatosis tipo 1, que acudió a consulta de Ortopedia del Cuerpo de Guardia del Hospital Pediátrico Provincial “Pepe Portilla” de Pinar del Río, con fractura patológica de la tibia izquierda. Se realizó diagnóstico de una displasia fibrosa ósea secundaria a neurofibromatosis tipo 1 y se inició tratamiento inmovilizador.Conclusiones: la displasia fibrosa ósea es una manifestación poco frecuente de la neurofibromatosis tipo 1. Dicha afección posee varias formas de presentación, de lo que dependerá el pronóstico y la evolución de los pacientes. Su tratamiento comprende varios objetivos y la elección del mismo depende de varios factores

Resultados del diagnóstico prenatal de defectos congénitos en el Policlínico “Raúl Sánchez Rodríguez”

Introducción: las enfermedades genéticas son casi siempre graves y discapacitantes. En Cuba los medios más efectivos de prevención se basan en el asesoramiento genético y diagnóstico precoz. Los programas de diagnóstico prenatal han contribuido de forma significativa a la detección y prevención de enfermedades genéticas y defectos congénitos.   Objetivo: describir los resultados del diagnóstico prenatal de defectos congénitos en el Policlínico “Raúl Sánchez Rodríguez” durante el período 2009 al 2016.   Método: se realizó un estudio observacional, descriptivo de corte transversal en el Policlínico “Raúl Sánchez Rodríguez” durante el periodo comprendido de enero de 2009 a diciembre de 2016. El universo estuvo constituido por 4 469 gestantes, de las cuales se seleccionó una muestra de 71, que corresponde a las embarazadas que presentaron algún defecto congénito en su gestación. Los datos se obtuvieron mediante los registros estadísticos del Centro Provincial de Genética Médica y el Policlínico “Raúl Sánchez Rodríguez”.   Resultados: un total de 71 defectos congénitos fueron diagnosticados mediante ultrasonografía prenatal. Predominaron, en orden de frecuencia, los cardiovasculares (15). En todos los casos se ofreció asesoramiento genético a la pareja, lo que permitió que en el 81,7 % de los casos se decidiera la interrupción voluntaria de la gestación. El 94,4 % de los defectos diagnosticados fueron confirmados al nacer o por anatomía patológica.   Conclusiones: el programa de detección precoz de defectos congénitos fue capaz de diagnosticar un alto porcentaje de ellos. En todos los casos se brindó asesoramiento genético, teniendo en cuenta los principios básicos y normativas del mismo

Estado clínico-oncológico de pacientes incluidos en el ensayo clínico RANIDO tratados con Racotumomab o Nimotuzumab

Introduction: RANIDO is a clinical trial extended to primary health care with the objective of assessing the efficiency of Cuban biotechnology products Racotumomab and Nimotuzumab for the treatment of non-small cell lung cancer.Objective: to characterize the patients from the clinical and oncological assessments included in the RANIDO clinical trial treated with Racotumomab and Nimotuzumab in Pinar del Río between January 2013 and January 2018.Methods: observational, descriptive and cross-sectional study carried out at Raúl Sánchez Rodríguez University Polyclinic between 2013 and 2018. The target group comprised 33 patients, working with the totality of them. The information was collected from the clinical records. Descriptive statistical methods were applied.Results: male patients prevailed (63,6 %). The age group from 60 to 69 years old predominated (57,6 %). Adenocarcinoma (54,5 %) was the predominant histopathological type. Stage IIIB was the most frequent at diagnosis (54,5 %); the disease in progression was the response to the standard oncological treatment (48.5 %). Most patients survived between 12-17 months (42,4%); the overall survival rate was 18,6 months.Conclusions: a greater number of adults were found after the sixth decade of life and of the male sex; who were affected in greater percentage by epidermoid carcinoma and detected in advanced stages of the disease. With the immunotherapy, favorable results were obtained in the treatment of patients with advanced stages of the disease, which turned into an increase in their survival.Introducción: RANIDO es un ensayo clínico extendido hasta la atención primaria de salud con el objetivo de evaluar la eficacia de los productos biotecnológicos cubanos Racotumomab y Nimotuzumab para el tratamiento del cáncer de pulmón de células no pequeñas.Objetivo: caracterizar clínico-oncológicamente a los pacientes incluidos en el ensayo clínico RANIDO tratados con Racotumomab y Nimotuzumab en Pinar del Río entre enero de 2013 y enero de 2018.Métodos: estudio observacional, descriptivo y de corte transversal en el Policlínico Universitario “Raúl Sánchez Rodríguez” entre 2013 y 2018. El universo lo constituyeron 33 pacientes, trabajándose con la totalidad. La información fue extraída de las historias clínicas. Se emplearon métodos de estadística descriptiva.Resultados: el 63,6 % de los pacientes fueron del sexo masculino. Predominó el grupo etario de 60 a 69 años (57,6 %). El adenocarcinoma (54,5 %) fue el tipo histopatológico predominante. El estadio IIIB fue el más frecuente al diagnóstico (54,5 %); la enfermedad en progresión constituyó la respuesta al tratamiento oncoespecífico usual (48,5 %). La mayoría de los pacientes sobrevivieron entre 12 y 17 meses (42,4 %); la media de supervivencia global fue de 18,6 meses.Conclusiones: Se encontró mayor número de adultos pasados la sexta década de vida y del sexo masculino; afectados en mayor porciento por el carcinoma epidermoide y detectados en estadíos avanzados de la enfermedad. Con la inmunoterapia se obtuvieron resultados favorables en el tratamiento de los pacientes con estadios avanzados de la enfermedad, lo que se tradujo en un aumento de su supervivencia

Caracterización del adulto mayor hemodializado en el Hospital General Docente “Abel Santamaría Cuadrado”, 2016-2017

Introduction: chronic kidney disease is considered a growing socio-economic and public health problem for all systems worldwide.Objective: characterize hemodialysis older adults at “Abel Santamaria Cuadrado” General Teaching Hospital during 2016-2017.Method: an observational, descriptive cross-sectional study was conducted, the target group was made up of the 139 patients suffering from chronic kidney disease who underwent hemodialysis treatment in the period study, the sample included 53 older adult patients, the data obtained was stored in a database for further analysis and processing, using descriptive statistics to present the results obtained.Results: male sex predominated (66 %), the age group from 65 to 69 (37,7 %). Hypertension was the cause of the utmost prevalence (41,5 %), the type vascular access for hemodialysis most applied in patients was the central venous catheter (60 %), and cardiovascular disease was the clinical characteristic associated with a morbidity and mortality rate of higher incidence (50,9 %). Cardiovascular diseases prevailed as the main causes of death (17 %). Conclusions: older adults with hemodialysis treatment suffered from diabetes mellitus and/or hypertension as the principal comorbidities, which constitute at the same time, the triggering causes of the disease. The use of central venous catheter was common as a venous access. Cardiovascular diseases constituted the principal causes of mortality.Introducción: la enfermedad renal crónica se considera un creciente problema socioeconómico y de salud pública para todos los sistemas de salud a nivel mundial.Objetivo: caracterizar los adultos mayores hemodializado en el Hospital General Docente “Abel Santamaría Cuadrado” entre 2016 y 2017.Método: se realizó un estudio observacional, descriptivo de corte transversal. El universo estuvo conformado por los 139 pacientes con enfermedad renal crónica que recibieron tratamiento de hemodiálisis en el período de estudio, quedando constituida la muestra por 53 pacientes adultos mayores. Los datos obtenidos se almacenados en una base de datos, para su posterior análisis y procesamiento, recurriéndose a la estadística descriptiva para la presentación de los resultados obtenidos.Resultados: predominó el sexo masculino 66 %) y el grupo atareo de 65 a 69 años (37,7 %). La hipertensión arterial fue la causa de mayor prevalencia (41,5 %), el tipo de acceso vascular para hemodiálisis más empleado en los pacientes fue el catéter venoso central (60 %), la enfermedad cardiovascular fue el aspecto clínico asociado a morbimortalidad de mayor prevalencia (50,9 %). Predominaron las enfermedades cardiovasculares como principal causa de los fallecidos (17 %).Conclusiones: los adultos mayores que recibieron hemodiálisis sufrían de diabetes mellitus y/o hipertensión arterial como principales comorbilidades, las cuales constituyeron a la ves las causas desencadenantes de la enfermedad. Fue común el empleo del catéter venoso central como acceso venoso. Las enfermedades cardiovasculares constituyeron las principales causas de mortalidad

Evolutionary origins of metabolic reprogramming in cancer

Metabolic changes that facilitate tumor growth are one of the hallmarks of cancer. These changes are not specific to tumors but also take place during the physiological growth of tissues. Indeed, the cellular and tissue mechanisms present in the tumor have their physiological counterpart in the repair of tissue lesions and wound healing. These molecular mechanisms have been acquired during metazoan evolution, first to eliminate the infection of the tissue injury, then to enter an effective regenerative phase. Cancer itself could be considered a phenomenon of antagonistic pleiotropy of the genes involved in effective tissue repair. Cancer and tissue repair are complex traits that share many intermediate phenotypes at the molecular, cellular, and tissue levels, and all of these are integrated within a Systems Biology structure. Complex traits are influenced by a multitude of common genes, each with a weak effect. This polygenic component of complex traits is mainly unknown and so makes up part of the missing heritability. Here, we try to integrate these different perspectives from the point of view of the metabolic changes observed in cancer.This work was supported in JPL’s lab by Grant PID2020-118527RB-I00 funded by MCIN/AEI/10.13039/501100011039; Grant PDC2021-121735-I00 funded by MCIN/AEI/10.13039/501100011039 and by the “European Union Next Generation EU/PRTR.”, the Regional Government of Castile and León (CSI234P18 and CSI144P20). SCLl was the recipient of a Ramón y Cajal research contract from the Spanish Ministry of Economy and Competitiveness and was supported by grant RTI2018-094130-B-100 funded by MCIN/AEI/10.13039/501100011039 and by “ERDF A way of making Europe.” RCC and AJN are funded by fellowships from the Spanish Regional Government of Castile and León. NGS is a recipient of an FPU fellowship (MINECO/FEDER). MJPB is funded by grant PID2020-118527RB-I00 funded by MCIN/AEI/10.13039/501100011039. J.C. is partially supported by grant GRS2139/A/20 (Gerencia Regional de Salud de Castilla y León) and by the Instituto de Salud Carlos III (PI18/00587 and PI21/01207), co-financed by FEDER funds, and by the “Programa de Intensificación” of the ISCIII, grant number INT20/00074. We thank Phil Mason for English language support

Electron and Positron Scattering Cross Sections from CO\u3csub\u3e2\u3c/sub\u3e: A Comparative Study over a Broad Energy Range (0.1−5000 eV)

In this Review, we present a comparative study between electron and positron scattering cross sections from CO2 molecules over a broad impact energy range (0.1−5000 eV). For electron scattering, new total electron scattering cross sections (e-TCS) have been measured with a high resolution magnetically confined electron beam transmission system from 1 to 200 eV. Dissociative electron attachment processes for electron energies from 3 to 52 eV have been analyzed by measuring the relative O−anion production yield. In addition, elastic, inelastic, and total scattering cross section calculations have been carried out in the framework of the Independent Atom Model by using the Screening Corrected Additive Rule, including interference effects (IAM-SCARI). Based on the previous cross section compilation from Itikawa (J. Phys. Chem. Ref. Data, 2002, 31, 749−767) and the present measurements and calculations, an updated recommended e-TCS data set has been used as reference values to obtain a self-consistent integral cross section data set for the elastic and inelastic (vibrational excitation, electronic excitation, and ionization) scattering channels. A similar calculation has been carried out for positrons, which shows important differences between the electron scattering behavior: e.g., more relevance of the target polarization at the lower energies, more efficient excitation of the target at intermediate energies, but a lower total scattering cross section for increasing energies, even at 5000 eV. This result does not agree with the charge independence of the scattering cross section predicted by the first Born approximation (FBA). However, we have shown that the inelastic channels follow the FBA’s predictions for energies above 500 eV while the elastic part, due to the different signs of the scattering potential constituent terms, remains lower for positrons even at the maximum impact energy considered here (5000 eV). As in the case of electrons, a self-consistent set of integral positron scattering cross sections, including elastic and inelastic (vibrational excitation, electronic excitation, positronium formation, and ionization) channels is provided. Again, to derive these data, positron scattering total cross sections based on a previous compilation from Brunger et al. (J. Phys. Chem. Ref. Data, 2017, 46, 023102) and the present calculation have been used as reference values. Data for the main inelastic channels, i.e. direct ionization and positronium formation, derived with this procedure, show excellent agreement with the experimental results available in the literature. Inconsistencies found between different model potential calculations, both for the elastic and inelastic collision processes, suggest that new calculations using more sophisticated methods are required

A Comparative Study over a Broad Energy Range (0.1-5000 eV)

Funding Information: This study has been partially supported by the Spanish Ministerio de Ciencia e Innovación (Project PID2019-104727RB-C21) and the Spanish Ministerio de Universidades (Project PRX21/00340). Work performed at Lawrence Berkeley National Laboratory was supported by the US Department of Energy, Office of Science, Division of Chemical Sciences of the Office of Basic Energy Sciences, under Contract DE-AC02-05CH11231. M.H. was supported by the US Department of Energy Office of Science, Basic Energy Sciences under Award No. DE-SC0019482. P.L.V. acknowledges the Portuguese National Funding Agency (FCT) through Research Grants CEFITEC (UIDB/00068/2020) and PTDC/FIS-AQM/31281/2017. The work is part of COST Action CA18212 - Molecular Dynamics in the GAS phase (MD-GAS). Publisher Copyright: © 2022 American Chemical Society.In this Review, we present a comparative study between electron and positron scattering cross sections from CO2 molecules over a broad impact energy range (0.1-5000 eV). For electron scattering, new total electron scattering cross sections (e-TCS) have been measured with a high resolution magnetically confined electron beam transmission system from 1 to 200 eV. Dissociative electron attachment processes for electron energies from 3 to 52 eV have been analyzed by measuring the relative O- anion production yield. In addition, elastic, inelastic, and total scattering cross section calculations have been carried out in the framework of the Independent Atom Model by using the Screening Corrected Additive Rule, including interference effects (IAM-SCARI). Based on the previous cross section compilation from Itikawa (J. Phys. Chem. Ref. Data, 2002, 31, 749-767) and the present measurements and calculations, an updated recommended e-TCS data set has been used as reference values to obtain a self-consistent integral cross section data set for the elastic and inelastic (vibrational excitation, electronic excitation, and ionization) scattering channels. A similar calculation has been carried out for positrons, which shows important differences between the electron scattering behavior: e.g., more relevance of the target polarization at the lower energies, more efficient excitation of the target at intermediate energies, but a lower total scattering cross section for increasing energies, even at 5000 eV. This result does not agree with the charge independence of the scattering cross section predicted by the first Born approximation (FBA). However, we have shown that the inelastic channels follow the FBA's predictions for energies above 500 eV while the elastic part, due to the different signs of the scattering potential constituent terms, remains lower for positrons even at the maximum impact energy considered here (5000 eV). As in the case of electrons, a self-consistent set of integral positron scattering cross sections, including elastic and inelastic (vibrational excitation, electronic excitation, positronium formation, and ionization) channels is provided. Again, to derive these data, positron scattering total cross sections based on a previous compilation from Brunger et al. (J. Phys. Chem. Ref. Data, 2017, 46, 023102) and the present calculation have been used as reference values. Data for the main inelastic channels, i.e. direct ionization and positronium formation, derived with this procedure, show excellent agreement with the experimental results available in the literature. Inconsistencies found between different model potential calculations, both for the elastic and inelastic collision processes, suggest that new calculations using more sophisticated methods are required.publishersversionpublishe

Strategy for the identification of the tumor intrinsic QTL determining the response to treatment of ERBB2 breast cancer

Resumen del póster presentado al VII Simposium Bases Biológicas del Cáncer y Terapias Personalizadas, celebrado en el Centro de Investigación del Cáncer (CIC-IBMCC) del 21 al 22 de mayo de 2015.-- et al.Este póster ha ganado el 1er premio en el Concurso de Pósters de Oncología Básica y Traslacional en Oncología para Jóvenes Investigadores, celebrado durante el VII Simposium Bases Biológicas del Cáncer y Terapias Personalizadas.An essential aspect of breast cancer is its different evolution among patients with the same histopathological disease. Moreover, cancer is a tissue growing in the context of a complex organism, thus it can be identified two main sources of variability responsible for the disease behavior: intrinsic and extrinsic factors which act, respectively, mainly inside the tumor cells and outside them at local or systemic levels. Our aim is to identify intrinsic factors to the tumor cells responsible for the different responses of breast cancer to chemotherapy with Doxorubicin and Docetaxel. For this purpose, we collected tumors developed in a cohort of genetically heterogeneous mice from a backcross between a resistant strain to breast cancer (C57BL/6) and a susceptible one (FVB) which overexpress the cNeu/ErbB2 protooncogene controlled by the MMTV promoter. The backcross mice were genotyped by SNP analysis. To identify tumor intrinsic factors controlling the response to chemotherapy, we transplanted 125 tumors collected from the backcross mice into singenic F1-C57/FVB mice to remove variability coming from the host compartments. Each tumor was transplanted into two F1 recipient mice; each one was treated with Doxorubicin or Docetaxel, and we studied tumor response to treatment. Linkage analysis permits us to identify QTL (Quantitative Trait Loci) controlling susceptibility to mammary cancer and evolution of the disease in the backcross population, and the specific intrinsic QTL associated with different chemotherapy responses in the F1 mice. Moreover, we are studying molecular and signalling pathways that control chemotherapy responses and the QTL associated with them. The identification of breast cancer susceptibility genes and their pathways associated with different response to chemotherapy will be important for the prediction of human breast cancer evolution during therapy, and to learn about the mechanisms involved in resistance to chemotherapy, thus it would help to develop new preventive and therapeutic strategies.Peer Reviewe