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Hospital de Órbigo, Spain

Poveda E.,Charles III University of Madrid | Anta L.,Charles III University of Madrid | Blanco J.L.,Hospital Clinic | Casado J.L.,Hospital Ramon y Cajal | And 6 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2010

The presence of resistance mutations in patients failing tipranavir or darunavir was examined at the national drug resistance database of the Spanish AIDS Research Network. Although mutations emerging during tipranavir and darunavir failures differed considerably, cross-resistance was found in up to half of the patients tested. Interestingly, mutation 54L, which is associated with tipranavir hypersusceptibility, was selected in half of the darunavir failures. Thus, resistance testing seems mandatory to ensure the benefit of the sequential use of these drugs. Copyright © 2010, American Society for Microbiology. All Rights Reserved.

Tippin B.L.,University of California at Los Angeles | Kwong A.M.,University of California at Los Angeles | Inadomi M.J.,University of California at Los Angeles | Lee O.J.,University of California at Los Angeles | And 11 more authors.
Cancer Medicine | Year: 2014

Our earlier work showed that knockout of hematopoietic prostaglandin D synthase (HPGDS, an enzyme that produces prostaglandin D2) caused more adenomas in ApcMin/+ mice. Conversely, highly expressed transgenic HPGDS allowed fewer tumors. Prostaglandin D2 (PGD2) binds to the prostaglandin D2 receptor known as PTGDR (or DP1). PGD2 metabolites bind to peroxisome proliferator-activated receptor γ (PPARG). We hypothesized that Ptgdr or Pparg knockouts may raise numbers of tumors, if these receptors take part in tumor suppression by PGD2. To assess, we produced ApcMin/+ mice with and without Ptgdr knockouts (147 mice). In separate experiments, we produced ApcMin/+ mice expressing transgenic lipocalin-type prostaglandin D synthase (PTGDS), with and without heterozygous Pparg knockouts (104 mice). Homozygous Ptgdr knockouts raised total numbers of tumors by 30-40% at 6 and 14 weeks. Colon tumors were not affected. Heterozygous Pparg knockouts alone did not affect tumor numbers in ApcMin/+ mice. As mentioned above, our Pparg knockout assessment also included mice with highly expressed PTGDS transgenes. ApcMin/+ mice with transgenic PTGDS had fewer large adenomas (63% of control) and lower levels of v-myc avian myelocytomatosis viral oncogene homolog (MYC) mRNA in the colon. Heterozygous Pparg knockouts appeared to blunt the tumor-suppressing effect of transgenic PTGDS. However, tumor suppression by PGD2 was more clearly mediated by receptor PTGDR in our experiments. The suppression mechanism did not appear to involve changes in microvessel density or slower proliferation of tumor cells. The data support a role for PGD2 signals acting through PTGDR in suppression of intestinal tumors. © 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd..

Jurado J.C.,Hospital Universitario Canarias | Aznar P.R.,Hospital de Manises | Martinez R.F.,Hospital de Cabuenes | Fernandez I.P.,Hospital de Cabuenes | And 5 more authors.
Advances in Therapy | Year: 2011

Hormone treatment is one of the key strategies in the management of metastatic breast cancer. Aromatase inhibitors (AI) have been extensively studied in this setting. This section summarizes the key data regarding the use of AI in advanced breast cancer. In postmenopausal women, AI are the first line of treatment for untreated patients, or those who had prior AI treatment and progress after 12 months of adjuvant therapy. A longer disease-free interval and absence of visceral disease is associated with a better response. If tumors recur in less than 12 months, it is recommended that tamoxifen (TAM) or the estrogen-receptor antagonist fulvestrant (FUL) treatment be initiated. In the second-line setting, the best option after progression is the administration of either FUL or TAM. In the third- line setting, reintroduction of AI is considered an acceptable option. In premenopausal women who have not received prior treatment or who have progressed after 12 months following adjuvant treatment, it is recommended to initiate therapy with a combination of TAM and a luteinizing hormone-releasing hormone (LHRH) analog. If there is treatment failure with the use of this combination, megestrol acetate or an LHRH agonist plus an AI may be reasonable alternatives. Intensive research is ongoing to understand the mechanisms of resistance to hormone therapy. In human epidermal growth factor receptor 2 positive-patients, combinationswith HER2 antagonists are associated with significant clinical activity. © © Springer Healthcare 2011.

Pey A.L.,University of Granada | Salido E.,Hospital Universitario Canarias | Sanchez-Ruiz J.M.,University of Granada
Amino Acids | Year: 2011

The G170R variant of the alanine:glyoxylate aminotransferase (AGT) is the most common pathogenic allele associated to primary hyperoxaluria type I (PH1), leading to mitochondrial mistargeting when combined with the P11L and I340M polymorphisms (minor allele; AGTLM). In this work, we have performed a comparative analysis on the conformation, unfolding energetics and interaction with molecular chaperones between AGTwt, AGTLM and AGTLRM (G170R in the minor allele) proteins. Our results show that these three variants share similar conformational and functional properties as folded dimers. However, kinetic stability analyses showed a &1,000-fold increased unfolding rate for apo-AGTLRM compared to apo-AGTwt, as well as a reduced folding efficiency upon expression in Escherichia coli. Pyridoxal 50-phosphate (PLP)-binding provided a 4-5 orders of magnitude enhancement of the kinetic stability for all variants, suggesting a role for kinetic stabilization in pyridoxineresponsive PH1. Conformational studies at mild acidic pH and moderate guanidium concentrations showed the formation of a molten-globule-like unfolding intermediate in all three variants, which do not reactivate to the native state and strongly interact with Hsc70 and Hsp90 chaperones. Additional expression analyses in a mammalian cell-free system at neutral pH showed enhanced interaction of AGTLRM with Hsc70 and Hsp90 proteins compared to AGTwt, suggesting kinetic trapping of the mutant by chaperones along the folding process. Overall, our results suggest that mitochondrial mistargeting of AGTLRM may involve the presentation of AGT partially folded states to the mitochondrial import machinery by molecular chaperones, which would be facilitated by the low native state kinetic stability (partially corrected by PLP binding) and kinetic trapping during folding of the AGTLRM variant with molecular chaperones. © Springer-Verlag 2010.

Hernandez-Fernaud J.R.,Max Planck Institute of Biochemistry | Salido E.C.,Hospital Universitario Canarias
FEBS Journal | Year: 2010

Mutations in the alanine-glyoxylate aminotransferase gene (AGXT) are responsible for primary hyperoxaluria type I, a rare disease characterized by excessive hepatic oxalate production that leads to renal failure. A deeper understanding of the changes in the metabolic pathways secondary to the lack of AGXT expression is needed in order to explore substrate depletion as a therapeutic strategy to limit oxalate production in primary hyperoxaluria type I. We have developed an Agxt knockout (AgxtKO) mouse that reproduces some key features of primary hyperoxaluria type I. To improve our understanding of the metabolic adjustments subsequent to AGXT deficiency, we performed a proteomic analysis of the changes in expression levels of various subcellular fractions of liver and kidney metabolism linked to the lack of AGXT. In this article, we report specific changes in the liver and kidney proteome of AgxtKO mice that point to significant variations in gluconeogenesis, glycolysis and fatty acid pathways. Journal compilation © 2010 FEBS. No claim to original German government works.

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