Polymorphisms in base excision repair genes and thyroid cancer risk

We wish to thank Luisa Manso Oliveira, Lylliane Luz, Silvia Morgado Amaro and Maria Catarina Soveral for technical support. This study was supported by the Center for Research in Human Molecular Genetics (CIGMH), Projects PTDC/SAU-OSM/105572/2008, PTDC/SAU-ESA/102367/2008 and PTDC/QUI/67522/2006 from Fundacao para a Ciencia e Tecnologia (FCT) and Fundacao Calouste Gulbenkian (Grant 76438/2006). The grants to M. Pingarilho (SFRH/BD/22612/2005) from FCT are also acknowledgedThyroid cancer (TC) is the most frequent endocrine malignancy, accounting however for only 1-2\% of all human cancers, and tilt: best-established risk factor for TC is radiation exposure, particularly during childhood. Since the BER pathway seems to play an important role in the repair of DNA damage induced by IR and other genotoxicants, we carried out a hospital-based case-control study in order to evaluate the potential modifying role of 6 BER polymorphisms on the individual susceptibility to non-familial TC in 109 TC patients receiving iodine-131, and 217 controls matched for age ( 2 years), gender and ethnicity. Our results do not reveal a significant involvement of XRCCI Arg194Trp and Arg399Gln, OGGI Ser326Cys, APEXI Asp148Glu, MUTYH Gln335His and,PARPI Val762Ala polymorphisms on the individual susceptibility towards TC, mostly in aggreement with the limited available evidence. By histological stratification analyis, we observed that the association between the presence of heterozygozity in the MUTYH Gln335His polymorphism and TC risk almost reached significance for the papillary subtype of TC. This was the first time that the putative association between this polymorphism and TC susceptibility was evaluated. However, since the sample size was modest, the possibility of a type I error should not be excluded and this result should, therefore, be interpreted with caution. More in depth studies involving larger populations should be pursued in order to further clarify the potential usefulness of the MUTYH Gln335His genotype as a predictive biomarker of susceptibility to TC and the role of the remaining BER polymorphisms on TC susceptibility.publishersversionpublishe

Caracterización del movimiento fuerte en el emplazamiento de la presa de Itoiz

Se presenta en este trabajo una nueva caracterización del movimiento del suelo en la presa de Itoiz, consistente con la peligrosidad sísmica del emplazamiento. En primer lugar, proponemos una metodología con tres niveles de aproximación al movimiento esperado, que es después aplicada considerando las características particulares de la presa y su emplazamiento. Los cálculos de peligrosidad se realizan siguiendo la línea metodológica conocida como PSHA, con un método probabilista zonificado y formulando un árbol lógico que combina diferentes zonificaciones sísmicas y modelos de movimiento fuerte. La peligrosidad se representa en términos de la aceleración pico PGA y de las aceleraciones espectrales para periodos coincidentes con los de vibración de la presa, considerando dos estados de la misma correspondientes a presa vacía (T=0.1s) y presa con capacidad máxima de llenado (T=0.22 s). Se caracterizan los correspondientes movimientos para dos periodos de retorno, 975 años y 4975 años, asociados al sismo de proyecto y al sismo extremo, respectivamente. El efecto de sitio en el emplazamiento de la presa también fue tenido en cuenta. La metodología propuesta conduce a caracterizar el movimiento con tres niveles de detalle. En una primera etapa se obtienen los espectros de respuesta uniforme (UHS) para los dos niveles de movimiento referidos. Seguidamente se desarrolla un análisis de desagregación para obtener los sismos de control que previsiblemente pueden afectar mas a la presa. Estos se identifican como los que más contribuyen a los movimientos objeto dados por las aceleraciones espectrales de los dos periodos característicos, SA (0,1 s) y SA (0.22 s) y para los dos periodos de retorno de 975 y 4975 años asociados a lo sismos de proyecto y extremo. De ahí se obtienen los espectros de respuesta específicos para las cuatro combinaciones resultantes. Finalmente, se realiza una simulación del movimiento en el dominio del tiempo, obteniendo acelerogramas sintéticos mediante el método de número de onda discreto. Las simulaciones se realizaron considerando fuentes finitas en diferentes posiciones y evaluando el efecto de la directividad en las posibles fuentes consideradas. Se concluye destacando la importancia del efecto de directividad, en la caracterización del emplazamiento de la presa

Identification of genetic determinants associated with susceptibility and therapeutic efficacy in Philadelphia-negative Myeloproliferative Neoplasms

Poster presented at the Scientific Toxomics Meeting, 28 September 2015, Lisbon, Portugal

The role of base excision repair polymorphisms in individual susceptibility to Philadelphia-negative myeloproliferative neoplasms

Poster presented at the 6th International Conference on Myeloproliferative Neoplasms. European School of Haematology, Estoril, 2014

The role of apoptosis polymorphisms in individual susceptibility to Philadelphia-negative myeloproliferative neoplasms

Poster presented at the 18th Annual Reunion of Sociedade Portuguesa de Genética Humana. Lisboa, 2014

Usefulness of sputum gram stain for etiologic diagnosis in community-acquired pneumonia: a systematic review and meta-analysis

Background: implementation of sputum Gram stain in the initial assessment of community-acquired pneumonia (CAP) patients is still controversial. We performed a systematic review and meta-analysis to investigate the usefulness of sputum Gram stain for defining the etiologic diagnosis of CAP in adult patients. Methods: we systematically searched the Medline, Embase, Science Direct, Scopus and LILACS databases for full-text articles. Relevant studies were reviewed by at least three investigators who extracted the data, pooled them using a random effects model, and carried out quality assessment. For each bacterium (Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and Gram-negative bacilli), pooled sensitivity, specificity, positive and negative likelihood ratios were reported. Results: after a review of 3539 abstracts, 20 articles were included in the present meta-analysis. The studies included yielded 5619 patients with CAP. Pooled sensitivity and pooled specificity of sputum Gram stain were 0.59 (95% CI, 0.56-0.62) and 0.87 (95% CI, 0.86-0.89) respectively for S. pneumoniae, 0.78 (95% CI, 0.72-0.84) and 0.96 (95% CI, 0.94-0.97) for H. influenzae, 0.72 (95% CI, 0.53-0.87) and 0.97 (95% CI, 0.95-0.99) for S. aureus, and 0.64 (95% CI, 0.49-0.77) and 0.99 (95% CI, 0.97-0.99) for Gram-negative bacilli. Conclusion: Sputum Gram stain test is sensitive and highly specific for identifying the main causative pathogens in adult patients with CAP

Antimicrobial activity of prophage endolysins against critical Enterobacteriaceae antibiotic-resistant bacteria

Enterobacteriaceae species are part of the 2017 World Health Organization antibiotic-resistant priority pathogens list for development of novel medicines. Multidrug-resistant Klebsiella pneumoniae is an increasing threat to public health and has become a relevant human pathogen involved in life-threatening infections. Phage therapy involves the use of phages or their lytic endolysins as bioagents for the treatment of bacterial infectious diseases. Gram-negative bacteria have an outer membrane, making difficult the access of endolysins to the peptidoglycan. Here, three endolysins from prophages infecting three distinct Enterobacterales species, Kp2948-Lys from K. pneumoniae, Ps3418-Lys from Providencia stuartii, and Kaer26608-Lys from Klebsiella aerogenes, were purified and exhibited antibacterial activity against their specific bacterium species verified by zymogram assays. These three endolysins were successfully associated to liposomes composed of dimyristoyl phosphatidyl choline (DMPC), dioleoyl phosphatidyl ethanolamine (DOPE) and cholesteryl hemisuccinate (CHEMS) at a molar ratio (4:4:2), with an encapsulation efficiency ranging from 24 to 27%. Endolysins encapsulated in liposomes resulted in higher antibacterial activity compared to the respective endolysin in the free form, suggesting that the liposome-mediated delivery system enhances fusion with outer membrane and delivery of endolysins to the target peptidoglycan. Obtained results suggest that Kp2948-Lys appears to be specific for K. pneumoniae, while Ps3418-Lys and Kaer26608-Lys appear to have a broader antibacterial spectrum. Endolysins incorporated in liposomes constitute a promising weapon, applicable in the several dimensions (human, animals and environment) of the One Health approach, against multidrug-resistant Enterobacteriaceae.F.F.V. was funded by Fundação para a Ciência e a Tecnologia (FCT) through a project grant (PTDC/BTM-SAL/28978/2017) that supported this work. The work is partially supported by National funds from FCT, projects UIDB/04138/2020, UIDP/04138/2020, UIDB/00211/2020 and UIDB/04046/2020 (DOI https://doi.org/10.54499/UIDB/0404 6/2020)info:eu-repo/semantics/publishedVersio

Rifabutin encapsulated in liposomes exhibits increased therapeutic activity in a model of disseminated tuberculosis

Tuberculosis (TB) is a leading cause of death amongst infectious diseases. The low permeation of antimycobacterial agents and their difficult access to infected macrophages necessitate long-term use of high drug doses. Liposomes preferentially accumulate in macrophages, increasing the efficacy of antibiotics against intracellular parasites. In the present work, several rifabutin (RFB) liposomal formulations were developed and characterised and their in vivo profile was compared with free RFB following intravenous administration. With the RFB liposomal formulations tested, higher concentrations of the antibiotic were achieved in liver, spleen and lungs 24h post administration compared with free RFB. The concentration of RFB in these organs was dependent on the rigidity of liposomal lipids. The liposomal RFB formulation prepared with dipalmitoyl phosphatidylcholine:dipalmitoyl phosphatidylglycerol (DPPC:DPPG) was the most effective and was selected for biological evaluation in a mouse model of disseminated TB. Compared with mice treated with free RFB, mice treated with the DPPC:DPPG RFB formulation exhibited lower bacterial loads in the spleen (5.53 log(10) vs. 5.18 log(10)) and liver (5.79 log(10) vs. 5.41 log(10)). In the lung, the level of pathology was lower in mice treated with encapsulated RFB. These results suggest that liposomal RFB is a promising approach for the treatment of extrapulmonary TB in human immunodeficiency virus co-infected patients.This work was supported by grants from FCT (POCTI/FCB/36416/99) and from the Health Services of FCG. Fellowships were granted by FCT (SFRH/BD/9624/2002- GABBA Program to A. Cruz and SFRH/BD/15911/2005 to A.G. Fraga

Mercados municipales de Zapopan

Documento final del Proyecto de Aplicación Profesional en el que se presenta una investigación realizada en tres mercados del ayuntamiento de Zapopan: San Isidro, Francisco Sarabia y Tesistán. El objetivo de la investigación fue identificar las problemáticas, hacer propuestas y colaborar en la planeación de estrategias para mejorar las condiciones de los mercados y lograr un impacto positivo que se vea reflejado en las ventas. Para la investigación, se visitaron los mercados y se aplicaron encuestas a los locatarios, consumidores y administradores. La muestra que se usó para sacar el número de encuestas fue infinita con un nivel de confianza del 90 por ciento y un índice de error del 5 por ciento. En este proyecto trabajaron alumnos de las licenciaturas en Mercadotecnia, Administración de Empresas y Administración Financiera.ITESO, A.C

Germline MUTYH (MYH) mutations in Portuguese individuals with multiple colorectal adenomas

Germinal mutations in the base excision repair (BER) gene MUTYH (MYH) have recently been described in association with predisposition to multiple colorectal adenomas and cancer. In contrast to the classic dominant condition of familial adenomatous polyposis (FAP) due to germinal mutations in the APC gene, the MYH polyposis is an autosomal recessive disease. The identification of individuals affected by MYH polyposis brings new and important implications for the diagnostic, screening, genetic counseling, follow up and therapeutic options in these patients. In this study, screening for germinal mutations in the MYH gene was performed in 53 Portuguese individuals with multiple colorectal adenomas or classic adenomatous polyposis, in whom no mutation had been identified in the APC gene. The results revealed the presence of biallelic germline MYH mutations in 21 patients. In addition, we here report 3 mutations (c.340T>C [p.Y114H]; c.503G>A [p.R168H]; and c.1186_1187insGG [p.E396fsX437]) which, to our knowledge, have not been previously describe