Martin-Navarro C.M.,University of La Laguna |
Lorenzo-Morales J.,University of La Laguna |
Machin R.P.,University of Las Palmas de Gran Canaria |
Lopez-Arencibia A.,University of La Laguna |
And 6 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2013
Acanthamoeba is an opportunistic pathogen in humans, whose infections most commonly manifest as Acanthamoeba keratitis or, more rarely, granulomatous amoebic encephalitis. Although there are many therapeutic options for the treatment of Acanthamoeba, they are generally lengthy and/or have limited efficacy. Therefore, there is a requirement for the identification, validation, and development of novel therapeutic targets against these pathogens. Recently, RNA interference (RNAi) has been widely used for these validation purposes and has proven to be a powerful tool for Acanthamoeba therapeutics. Ergosterol is one of the major sterols in the membrane of Acanthamoeba. 3-Hydroxy-3- methylglutaryl-coenzyme A (HMG-CoA) reductase is an enzyme that catalyzes the conversion of HMG-CoA to mevalonate, one of the precursors for the production of cholesterol in humans and ergosterol in plants, fungi, and protozoa. Statins are compounds which inhibit this enzyme and so are promising as chemotherapeutics. In order to validate whether this enzyme could be an interesting therapeutic target in Acanthamoeba, small interfering RNAs (siRNAs) against HMG-CoA were developed and used to evaluate the effects induced by the inhibition of Acanthamoeba HMG-CoA. It was found that HMG-CoA is a potential drug target in these pathogenic free-living amoebae, and various statins were evaluated in vitro against three clinical strains of Acanthamoeba by using a colorimetric assay, showing important activities against the tested strains. We conclude that the targeting of HMG-CoA and Acanthamoeba treatment using statins is a novel powerful treatment option against Acanthamoeba species in human disease. Copyright © 2013, American Society for Microbiology. All Rights Reserved. Source
Caldes Llopis T.,Laboratorio Of Oncologia Molecular
Revisiones en Cancer | Year: 2011
Colorectal cancer (CRC) is one of the most common neoplasms and a leading cause of death related to cancer worldwide. Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant inherited cancer susceptibility syndrome which confers an increased risk for colorectal cancer and endometrial cancer at a young age. It also entails an increased risk of a variety of other tumors, such as ovarian, gastric, uroepithelial and biliary tract cancer. The underlying pathogenic mutation lies in one of the five known DNA mismatch repair genes (MSH2, MLH1, PMS1, PMS2 and MSH6). An accurate algorithm is essential for effective molecular diagnosis of hereditary colorectal cancer (CRC). MSI analysis and immunostaining for MLH1, MSH2 and MSH6 were used for detecting MMR deficiency in the patients. This study suggests that both analyses are useful for selecting high-risk patients because most MLH1, MSH2 and MSH6 gene carriers will be detected by this two-step approach. This practical method should have immediate application to the clinical work out of patients with inherited colorectal cancer syndromes. Copyright © 2011 Aran Ediciones, s. l. Source
Segui N.,Catalan Institute of Nanoscience and Nanotechnology |
Mina L.B.,Autonomous University of Barcelona |
Lazaro C.,Catalan Institute of Nanoscience and Nanotechnology |
Sanz-Pamplona R.,Catalan Institute of Nanoscience and Nanotechnology |
And 30 more authors.
Gastroenterology | Year: 2015
Identification of genes associated with hereditary cancers facilitates management of patients with family histories of cancer. We performed exome sequencing of DNA from 3 individuals from a family with colorectal cancer who met the Amsterdam criteria for risk of hereditary nonpolyposis colorectal cancer. These individuals had mismatch repair-proficient tumors and each carried nonsense variant in the FANCD2/FANCI-associated nuclease 1 gene (FAN1), which encodes a nuclease involved in DNA inter-strand cross-link repair. We sequenced FAN1 in 176 additional families with histories of colorectal cancer and performed in vitro functional analyses of the mutant forms of FAN1 identified. We detected FAN1 mutations in approximately 3% of families who met the Amsterdam criteria and had mismatch repair-proficient cancers with no previously associated mutations. These findings link colorectal cancer predisposition to the Fanconi anemia DNA repair pathway, supporting the connection between genome integrity and cancer risk. © 2015 AGA Institute. Source
De Garibay G.R.,Laboratorio Of Oncologia Molecular |
Diaz A.,Laboratorio Of Oncologia Molecular |
Gavina B.,Laboratorio Of Oncologia Molecular |
Romero A.,Laboratorio Of Oncologia Molecular |
And 9 more authors.
European Journal of Human Genetics | Year: 2013
Fanconi anemia is a genetically heterogeneous autosomal recessive disorder characterized by development abnormalities, bone marrow failure, and childhood cancers. Compelling evidence indicates a common genetic basis for FA and breast/ovarian cancer susceptibility. Recently, biallelic germ-line mutations in SLX4 have been demonstrated to cause a previously unknown FA subtype (FA-P). We address the role of SLX4/FANCP in breast/ovarian cancer susceptibility by conducting a comprehensive mutation scanning in 486 index cases from non-BRCA1/BRCA2 multiple-case breast and/or ovarian cancer families (non-BRCA1/2 families) from Spain. We detected one unequivocal loss-of-function mutation (p.Glu1517X). In addition, one missense change (p.Arg372Trp) predicted to be pathogenic by in silico analysis co-segregates with disease in one family. Overall, the study indicates that SLX4 mutation screening will have a very low impact (if any) in the genetic counseling of non-BRCA1/2 families. © 2013 Macmillan Publishers Limited. All rights reserved. Source
Blay P.,Instituto Universitario Of Oncologia Del Principado Of Asturias Iuopa |
Santamaria I.,Laboratorio Of Oncologia Molecular |
Pitiot A.S.,Laboratorio Of Oncologia Molecular |
Luque M.,Servicio de Oncologia Medica |
And 6 more authors.
BMC Cancer | Year: 2013
Background: The prevalence of BRCA1 and BRCA2 mutations in Spain is heterogeneous and varies according to geographical origin of studied families. The contribution of these mutations to hereditary breast and ovarian cancer has not been previously investigated in Asturian populations (Northern Spain).Methods: In the present work, 256 unrelated high-risk probands with breast and/or ovarian cancer from families living in Asturias were analyzed for the presence of a BRCA1 or BRCA2 gene mutation from October 2007 to May 2012. The entire coding sequences and each intron/exon boundaries of BRCA1/2 genes were screened both by direct sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA).Results: A total of 59 families (23%) were found to carry a pathogenic germ line mutation, 39 in BRCA1 and 20 in BRCA2. Twenty nine additional families (12%) carried an unknown significance variant. We detected 28 distinct pathogenic mutations (16 in BRCA1 and 12 in BRCA2), of which 3 mutations in BRCA1 (c.1674delA, c.1965C>A and c.2900_2901dupCT) and 5 in BRCA2 (c.262_263delCT, c.2095C>T, c.3263dupC, c.4030_4035delinsC, c.8042_8043delCA) had not been previously described.The novel mutations c.2900_2901dupCT in BRCA1 and c.4030_4035delinsC in BRCA2 occurred in 8 and 6 families respectively and clustered in two separated small geographically isolated areas suggesting a founder effect. These 2 mutations, together with the Galician BRCA1 mutation c.211A>G (9 families), and the common BRCA1 mutation c.3331_3334delCAAG (6 families), account for approximately 50% of all affected families. By contrast, very frequent mutations in other Spanish series such as the BRCA1 Ashkenazi founder mutation c.68_69delAG, was found in only one family.Conclusions: In this study we report the BRCA1 and BRCA2 spectrum of mutations and their geographical distribution in Asturias, which largely differ from other areas of Spain. Our findings may help design a first step recurrent mutation panel for screening high-risk breast and/or ovarian cancer families from this specific area. © 2013 Blay et al.; licensee BioMed Central Ltd. Source