DNA damage response and breast cancer development: Possible therapeutic applications of ATR, ATM, PARP, BRCA1 inhibition.

Breast cancer is the most common and significant cancers in females regarding the loss of life quality. Similar to other cancers, one of the etiologic factors in breast cancer is DNA damage. A plethora of molecules are responsible for sensing DNA damage and mediating actions which lead to DNA repair, senescence, cell cycle arrest and if damage is unbearable to apoptosis. In each of these, aberrations leading to unrepaired damage was resulted in uncontrolled proliferation and cancer. Another cellular function is autophagy defined as a process eliminating of unnecessary proteins in stress cases involved in pathogenesis of cancer. Knowing their role in cancer, scholars have tried to develop strategies in order to target DDR and autophagy. Further, the interactions of DDR and autophagy plus their regulatory role on each other have been focused simultaneously. The present review study has aimed to illustrate the importance of DDR and autophagy in breast cancer according to the related studies and uncover the relation between DDR and autophagy and its significance in breast cancer therapy.

Pro-apoptotic properties and mitochondrial functionality in platelet-like-particles generated from low Aspirin-incubated Meg-01 cells.

Long-term therapy with low Aspirin (ASA) dose is basis to prevent thrombotic acute events. However, the anti-platelet mechanisms of ASA remain not completely known. The aim was to analyze if in vitro exposure of human megakaryocytes to low ASA concentration may alter the apoptotic features of the newly formed platelets. Cultured Meg-01 cells, a human megakaryoblastic cell line, were stimulated to form platelets with 10 nmol/L phorbol 12-myristate-13-acetate (PMA) in the presence and absence of ASA (0.33 mmol/L). Results revealed that platelet-like particles (PLPs) derived from ASA-exposed Meg-01 cells, showed higher content of pro-apoptotic proteins Bax and Bak than PLPs from non-ASA incubated Meg-01 cells. It was accompanied of reduced cytochrome C oxidase activity and higher mitochondrial content of PTEN-induced putative kinase-1 in PLPs from ASA-incubated Meg-01 cells. However, only after calcium ionophore A23187 stimulation, caspase-3 activity, the cytosolic cytochrome C content, and reduction of mitochondrial membrane potential were higher in PLPs from ASA-incubated megakaryocytes than in those from Meg-01 without ASA. Nitric oxide synthase 3 content was higher in PLPs from ASA-exposed Meg-01 cells than in PLPs from non-ASA incubated Meg-01 cells. The L-arginine antagonist, NG-Nitro-L-arginine Methyl Ester, reduced caspase-3 activity in A23187-stimulated PLPs generated from ASA-incubated Meg-01 cells. As conclusions exposure of megakaryocyte to ASA promotes that the newly generated PLPs have, under stimulating condition, higher sensitivity to go into apoptosis than those PLPs generated from Meg-01 cells without ASA. It could be associated with differences in mitochondrial functionality and NO formation.

El reto de comenzar a impartir cuidados paliativos en una facultad de medicina. ¿Es útil esta materia para los futuros médicos? / The challenge of begining to teach palliative care in medical school. Will this be useful for future doctors?

INTRODUCCIÓN Y OBJETIVO: Impartir la materia de cuidados paliativos a nivel universitario se ha iniciado hace pocos años, con un progresivo aumento de las universidades donde este hecho está ocurriendo. En nuestro caso llevamos 2 cursos haciéndolo, con la sensación de ser algo positivo para nuestros alumnos. Quisimos valorar si nuestros alumnos adquirían los adecuados conocimientos científicos que se presuponen al impartir la asignatura, pero además conocer hasta qué punto llegaban a percibir esos otros aspectos que hacen peculiar a la medicina paliativa y que tanto ayudan en la relación médico-paciente-familia. Material y MÉTODO: Definimos la muestra como todos los alumnos de la facultad de medicina de quinto curso que cursan la materia de cuidados paliativos durante los cursos académicos 2013-2014 y 2014-2015. Antes de la intervención completaron un test de 8 ítems sobre conocimientos básicos de cuidados paliativos (preguntas cerradas). Posteriormente a la intervención se completó otro test con las mismas preguntas cerradas a las que se añadieron 6 cuestiones abiertas en las que se exploran también sus opiniones y actitudes respecto a los cuidados paliativos. RESULTADOS: De los alumnos matriculados en los 2 años en la asignatura acudieron a clases, y por tanto realizaron el test de preintervención, 102 y el test postintervención 105. La edad media fue de 23,16 años (±2,25). El 67% fueron mujeres y el 33% hombres. Sesenta y siete (65,6%) no conocían lo que son los cuidados paliativos al iniciar el curso. Las entidades clínicas que asociaban con más frecuencia a los cuidados paliativos antes de iniciar la materia fueron el cáncer de pulmón 95 (93%) y de colon 90 (88%), variando los resultados en el test al finalizar el curso. Los profesionales de medicina y enfermería (100%) son los más referidos, otros se incluyen o aumenta su número tras la intervención. Los conocimientos teóricos muestran un aumento en las respuestas afirmativas, así como las preguntas que hacen referencias a aspectos más generales. CONCLUSIONES: Existe una mejora en los conocimientos teóricos que deben asimilar los alumnos de esta área de la medicina. Además la mayoría de los alumnos participantes muestran actitudes de mejora tras impartir la materia en aspectos fundamentales de cuidados paliativos

INTRODUCTION AND OBJECTIVE: The teaching of palliative care has begun recently in certain universities. In our case, we have given two courses with positive outcome. We want to investigate if our students were able to acquire the necessary skills of basic palliative care and if they also appreciate the aspects of the bedside manner needed for our practice. Material and method: We prepared a survey to be taken by fifth year medical students undertaking our palliative care course during the academic years 2003-2014 and 2014-2015. The survey was carried out before the first class was taught (pre-intervention test) and after completing the course (post-intervention test). RESULTS: A total of 102 students undertook the pre-intervention test and 105 the post-intervention test. The average age of the students was 23.16 years (+/- 2.25). Sixty-seven percent were female and 33% male. A total of 67 (65.6%) had no idea of the meaning of palliative care when they started the course. They associated lung cancer 95 (93%) and colon cancer 90 (88%) as the most common diseases treated by palliative care at first, and changed their opinion after taking the course. They identified doctors and nurses (100%) as the only professionals that practiced palliative care; however, they identified other professionals involved after the course. The students also acquired more theoretical knowledge on concluding the course as well as acquiring more general knowledge of palliative care. CONCLUSIONS: We have seen an improvement in the medical knowledge that a medical student should have about palliative care. We have also seen that the students acquired a better bedside manner and better communication skills in talking to patients and their relatives

HLA-DMB in Amerindians: Specific linkage of DMB*01:03:01/DRB1 alleles.

BACKGROUND: HLA-DMB proteins are important for intracellular microbial metabolism in order other major histocompatibility complex (MHC) molecules present peptides to lymphocytes. In addition, HLA-DMB alleles have been found linked to diseases in some ethnic groups and HLA-DMB molecules may be important to explain HLA disease association. OBJECTIVE: To detect HLA-DMB alleles profile in Amerindians for the first time and compare them to other populations. This will establish the bases to study HLA-DMB linkage to disease in Amerindians. METHOD: A group of 168 voluntary Amerindians have been typed for HLA-DMB alleles. They have been characterized both, by genetic and genealogical bases. Cloning and automated HLA-DMB DNA (exons 2, 3 and 4) sequencing have been performed for allele assignation. RESULTS: HLA-DMB*01:01:01 and HLA-DMB*01:03:01 show the highest frequencies. These have been compared to other World wide populations. HLA-DMB*01:03:01 is tightly associated to certain specific HLA-DRB1 alleles in Amerindians. CONCLUSION: The specific Amerindian HLA-DMB allele frequencies and their linkage disequilibrium with other MHC alleles may be crucial to determine HLA-DMB World wide variation, evolution and specific linkage to disease in Amerindians and other populations.

Inmunodeficiencias congénitas del receptor de antígeno de los linfocitos T / Congenital T-cell receptor immunodeficiencies

Las inmunodeficiencias humanas del TCR son enfermedades autosómicas recesivas con baja prevalencia, caracterizadas por un defecto de expresión del TCR asociado a una linfopenia T selectiva (más leve en el caso de CD3γ, TCRα o CD247, o grave en el caso de CD3δ o CD3¿). La ausencia congénita de componentes del TCR tiene un impacto diferencial en el desarrollo y función de los linfocitos T, que depende de la cadena del TCR afectada y de la especie, siendo en algunos casos diferente en los pacientes humanos en comparación con los modelos en ratones. El estudio del inmunofenotipo mediante citometría de flujo, junto con los estudios moleculares, proporciona información esencial para el diagnóstico y el tratamiento, que continúa siendo a día de hoy el trasplante de progenitores hematopoyéticos en los casos asociados a inmunodeficiencia grave (AU)

T-cell receptor (TCR) immunodeficiencies of humans are low-prevalence autosomal recessive diseases characterized by impaired surface TCR expression and selective T lymphopenia (milder in CD3γ, TCRα or CD247 deficiency, and severe in individuals lacking CD3δ or CD3¿). The congenital absence of TCR components has a differential impact on T-cell development and function depending on the affected TCR chain and on the species, with human patients being, in some cases, rather different from mouse counterparts. The study of the immunophenotype by flow cytometry, along with molecular analyses, provides essential information for diagnosis and treatment, which is still to date the transplant of hematopoietic progenitors in severe immunodeficiency associated cases(AU)

A pathway of double-strand break rejoining dependent upon ATM, Artemis, and proteins locating to gamma-H2AX foci.

The hereditary disorder ataxia telangiectasia (A-T) is associated with striking cellular radiosensitivity that cannot be attributed to the characterized cell cycle checkpoint defects. By epistasis analysis, we show that ataxia telangiectasia mutated protein (ATM) and Artemis, the protein defective in patients with RS-SCID, function in a common double-strand break (DSB) repair pathway that also requires H2AX, 53BP1, Nbs1, Mre11, and DNA-PK. We show that radiation-induced Artemis hyperphosphorylation is ATM dependent. The DSB repair process requires Artemis nuclease activity and rejoins approximately 10% of radiation-induced DSBs. Our findings are consistent with a model in which ATM is required for Artemis-dependent processing of double-stranded ends with damaged termini. We demonstrate that Artemis is a downstream component of the ATM signaling pathway required uniquely for the DSB repair function but dispensable for ATM-dependent cell cycle checkpoint arrest. The significant radiosensitivity of Artemis-deficient cells demonstrates the importance of this component of DSB repair to survival.