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Biomedical subjects

Javier de Oca

Publications and source records attributed to Javier de Oca.

8 recordsLinked to original sources
PubMed2006

Tumor thymidylate synthase 1494del6 genotype as a prognostic factor in colorectal cancer patients receiving fluorouracil-based adjuvant treatment.

PURPOSE: The purpose of this study was to analyze the value of germline and tumor thymidylate synthase (TS) genotyping as a prognostic marker in a series of colorectal cancer patients receiving adjuvant fluorouracil (FU) -based treatment. PATIENTS AND METHODS: One hundred twenty-nine colorectal cancer patients homogeneously treated with FU plus levamisole or leucovorin in the adjuvant setting were included. TS enhancer region, 3R G > C single nucleotide polymorphism (SNP), and TS 1494del6 polymorphisms were assessed in both fresh-frozen normal mucosa and tumor. Mutational analyses of TS and allelic imbalances were studied in all primary tumors and in 18 additional metachronic metastases. TS protein immunostaining was assessed in an expanded series of 214 tumors. Multivariate Cox models were adjusted for stage, differentiation, and location. RESULTS: Tumor genotyping (frequency of allelic loss, 26%) showed that the 3R/3R genotype was associated with a better outcome (hazard ratio [HR] = 0.38; 95% CI, 0.16 to 0.93; P = .020 for the recessive model). 3R G > C SNP genotyping did not add prognostic information. Tumor TS 1494del6 allele (frequency of allelic loss, 36%) was protective (for each allele with the deletion, based on an additive model, HR = 0.42; 95% CI, 0.22 to 0.82; P = .0034). Both polymorphisms were in strong linkage disequilibrium (D' = 0.71, P < .001), and the 3R/-6 base pair (bp) haplotype showed a significant overall survival benefit compared with the most prevalent haplotype 2R/+6bp (HR = 0.42; 95% CI, 0.20 to 0.85; P = .017). No TS point mutation was detected in primary tumors or metastases. TS protein immunostaining was not associated with survival or any of the genotypes analyzed. CONCLUSION: Tumor TS 1494del6 genotype may be a prognostic factor in FU-based adjuvant treatment of colorectal cancer patients.

Adult↗
PubMed2005

Apoptosis inhibition plays a greater role than necrosis inhibition in decreasing bacterial translocation in experimental intestinal transplantation.

BACKGROUND: During small-bowel transplantation, necrosis and apoptosis are involved in the destruction of intestinal epithelial cells. This study was conducted to assess which mode of cell death plays a greater role as a trigger of the bacterial translocation (BT) associated with intestinal transplantation. METHODS: The following experimental groups were studied: sham, Tx (intestinal transplantation), Tx + poly (ADP-ribose) synthetase (PARS) inhibitor 3-aminobenzamide (3-AB), and Tx + caspase inhibitor Z-VAD-fmk. Histological analysis, caspase-3 activity, DNA fragmentation, and BT were measured in tissue samples after transplantation. RESULTS: During intestinal transplantation, apoptosis and necrosis both increased, showing graft injury and high levels of BT. Rats treated with 3-AB showed histological protection of the transplanted graft and a tendency toward lower BT despite the existence of high apoptosis levels. The rats treated with Z-VAD showed histological protection of the transplanted graft and decreased levels of caspase-3 and DNA fragmentation. The Tx + Z-VAD group showed the lowest levels of BT in all tissues. CONCLUSIONS: In small intestinal transplantation, both apoptosis and cell necrosis give rise to histological injury and BT. Apoptosis inhibition and necrosis inhibition treatments protect intestinal grafts from ischemia/reperfusion injury; Z-VAD supplementation has a greater effect on BT prevention than does administration of the PARS inhibitor 3-AB.

Amino Acid Chloromethyl Ketones↗
PubMed2005

A comprehensive analysis of phase I and phase II metabolism gene polymorphisms and risk of colorectal cancer.

OBJECTIVES: Sporadic colorectal cancer (CRC) is considered a multifactorial disease where multiple exposures interact with the individual genetic background resulting in risk modulation. We performed an association study aimed to investigate the role of single nucleotide polymorphisms (SNPs) within genes of phase I (CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2D6, CYP2E1, CYP2C9, CYP2C19, CYP3A4, ADH2, EPHX1) and phase II of the xenobiotic metabolism (ALDH2, COMT, GSTA2, GSTA4, GSTM1, GSTM3, GSTP1, GSTT2, MTHFR, NAT1, NAT2, NQO1, MnSOD2, SULT1A1, TPMT). METHODS: We genotyped 377 cases and 326 controls, by use of an oligonucleotide micro-array and the arrayed primer extension technique (APEX). RESULTS: N-acetyl-transferase 1 'rapid' phenotype and CYP1A2 -164C>A carriers were associated with increased risk of CRC, confirming data reported in previous studies. Interestingly, homozygotes for allele 48G within CYP1B1, a variant with an increased activity towards several substrates including sex hormones, were at increased risk (OR=2.81, 95% CI 1.32-5.99). Moreover, CYP1A1 SNPs T461N and -1738A>C were associated with a reduced risk of cancer (OR=0.52; 95% CI 0.31-0.88 and OR=0.69, 95% CI 0.50-0.94 for carriers, respectively). CONCLUSIONS: The present data suggest a role for CYP1B1 and CYP1A1 as new candidate genes in the etiology of CRC and confirm the carcinogenic role of aromatic amines metabolism for colorectum.

Case-Control Studies↗
PubMed2004

[Survival and recurrence in the multidisciplinary approach of colorectal cancer].

BACKGROUND AND OBJECTIVE: Colorectal cancer is one of the most frequent causes of death in the general population. Our aim was to analyze our experience in the multidisciplinary approach of colorectal carcinoma during a three year period. PATIENTS AND METHOD: Between January 1996 and December 1998, we studied prospectively 807 patients with colorectal cancer. The epidemiology, treatment and outcome(recurrence and survival) were analyzed. The minimum follow-up was 3 years. RESULTS: There were 598 colon (65.5%) and 279 rectal (34.5%) tumors in all the series. Surgical treatment was elective in 84% and urgent in 16%, and was considered radical in 598 cases (74.1%). Chemotherapy or radiotherapy was administered in 49.6% and 18.3% patients, respectively. The overall 3-year survival was as follows: stage I 97.5%, stage II 90.6%, stage III 75.2%, and stage IV 12.6%. The 3-year free-disease survival was as follows: in colon cancer 97.8% for stage I, 87.3% for stage II, and 71.4% for stage III; and in rectal cancer 96.8% for stage I, 85.1% for stage II, and 75.4% for stage III. During the follow-up 124 patients (20.7%) developed recurrence: local (2.8%), systemic (15.9%) or both (2%). The three-year survival in operated patients with liver metastases was 61.9%. CONCLUSIONS: We have observed adequate survival and recurrence rates which are the result are of systematic protocols established by a multidisciplinary team.

Adult↗
PubMed2004

Administration of nitric oxide with caspase inhibitors minimizes bacterial translocation in experimental intestinal transplantation.

BACKGROUND: Bacterial translocation (BT) has been suggested to be responsible for the high incidence of infections occurring after small-bowel transplantation (Trp). Nitric oxide (NO) and apoptosis could affect cell demise. The aim of this study was to asses whether supplementation of University of Wisconsin (UW) solution with NO donors and apoptosis inhibitors can abolish BT in Trp. METHODS: The following experimental groups were studied: sham, Trp, intestinal transplantation, Trp+spermine NONOate (NONOs), and Trp+NONOs+caspase inhibitor Z-Val-Ala-Asp(Ome)-fluoromethylketone(Z-VAD-fmk). Histologic analysis, caspase-3 activity, DNA fragmentation, and BT from graft to mesenteric lymph nodes, liver, and spleen were measured in tissue samples after transplantation. RESULTS: During intestinal transplantation, apoptosis and necrosis were increased, showing graft injury and high levels of BT. The rats treated with NONOs showed a histologic protection of transplanted graft and a decrease in BT despite caspase-3 and DNA fragmentation-inducing effects. Administration of caspase inhibitor Z-VAD to NONOs-treated rats reversed the NO apoptosis-inducing effects and showed the lowest levels of BT in all tissues. CONCLUSIONS: Exogenous administration of NO associated with the inhibition of apoptosis maintains the graft in optimal conditions in terms of BT and improves the histology of the graft after intestinal transplantation in rats.

Adenosine↗
PubMed2003

Association of common polymorphisms in inflammatory genes interleukin (IL)6, IL8, tumor necrosis factor alpha, NFKB1, and peroxisome proliferator-activated receptor gamma with colorectal cancer.

Animal models and epidemiological observations suggest that a continuous inflammatory condition predisposes to colorectal cancer (CRC), but the roles of different elements participating in inflammatory responses have been little investigated in relation to CRC. We have studied the association between single nucleotide polymorphisms in the interleukin (IL)-6 (-174 G>C), IL8 (-251T>A), tumor necrosis factor alpha (-308G>A), and PPARG (Pro12Ala) genes and the risk of CRC in a group of 377 cases and 326 controls from Barcelona, Spain. These genes are known to be important for inflammation of the colorectum and common allelic variants have been shown to have a biological effect. The PPARG Ala12 and IL8-251A genotypes are associated with reduced risk of disease (0.56, 95% CI, 0.37-0.85, P = 0.0056, and 0.70, 95% CI, 0.50-0.99, P = 0.043, respectively), whereas the IL6-174C genotype is associated with increased risk (1.53, 95% CI, 1.12-2.09, P = 0.0073). We also studied a single nucleotide polymorphism in intron 11 of the NFKB1 gene (rs1020759), which probably lacks any functional role, and found no significant association with the disease. This is the first report that IL6, IL8, and PPARG genes are important in relation to inflammation-related risk of sporadic CRC.

Aged↗
PubMed2003

Long-term results of ileal pouch-anal anastomosis in Crohn's disease.

The unexpected diagnosis of Crohn's disease (CD) after restorative proctocolectomy is a relatively frequent occurrence. We report a retrospective analysis of the long-term development of patients with an ileal pouch-anal anastomosis (IPAA) in whom the definitive anatomopathological diagnosis was CD, and compare their development with that of patients in whom the diagnosis of ulcerative colitis (UC) was confirmed. We reviewed the clinical data of 112 patients with an IPAA. The definitive diagnosis was CD in 12, and UC in the rest. The mean follow-up period was 76 months (range 12 to 192). We analyzed and compared the epidemiologic and clinical data, postoperative complications, functional results, anxiety, and quality of life in the two groups. Postoperative morbidity and the degree of satisfaction were similar in the two groups. The test showed a lower level of anxiety and higher quality of life in patients with CD. Of all the functional parameters studied, only urgency of defecation presented a higher risk in the CD group (HR: 4.13, CI: 1.41-12.04, p = 0.027). Despite the fact that a diagnosis of CD is currently considered a contraindication for an IPAA, some patients with secondary diagnosis of CD have good functional outcome and quality of life after restorative proctocolectomy. Closure of the temporary ileostomy may be justified in these patients.

Adolescent↗