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Biomedical subjects

M Pastor

Publications and source records attributed to M Pastor.

At least 19 recordsLinked to original sources
PubMed2006

The "El Alamo" project (1990-1997): two consecutive hospital-based studies of breast cancer outcomes in Spain.

BACKGROUND: The "Alamo" project is a retrospective analysis of 14,854 patients diagnosed of breast cancer between 1990 and 1997 in 50 Spanish hospitals. METHODS: Alamo I (AI) consisted of 4,532 patients diagnosed with breast cancer between 1990 and 1993. Data were collected in 2000. Alamo II (AII) consisted of 10,322 patients diagnosed between 1994 and 1997. Data were collected in 2003. RESULTS: At presentation, there were (AI vs. AII) 17.6% vs. 24.3% at stage I; 55.5% vs. 53.1% at stage II; 18.7% vs. 15% at stage III; 7.2% vs. 5.9 at stage IV. Median age was 57 (AI) vs. 58 years (AII) and 65.9% vs. 67.2% (AI vs. AII) were post-menopausal. Firstline treatment for disease stages I, II and III was surgery in 91% of patients in both studies. Breast conserving surgery rate increased from 20.2% (AI) to 32.7% (AII). Adjuvant systemic treatments were administered to 87.6% (AI) and 92.8% (AII) of patients. Recurrence rate diminished from 36.6% (AI) to 22.5% (AII) and the 9-year survival rate increased from 63.2% (95% CI: 61.5-64.9) to 70.1% (95% CI: 68.5-71.8). CONCLUSION: Breast cancer outcomes in Spain have improved from 1990-1993 to 1994-1997, likely because of breast cancer screening program implementation and new therapies.

Adult↗
PubMed2002

Towards the establishment of a permanent colony of Drosophila in the International Space Station: hardware tests and adaptation of techniques.

Our group has the long-term goal of establishing a permanent colony of Drosophila melanogaster in the International Space Station (ISS) to study its long-term adaptation to this unusual environment. We are currently building an enhanced version of an automatic cultivation unit (ESE1) in which we can grow flies with minimal crew involvement. We are working on a fixation unit as well. We are also adapting current protocols to maintain fixed animals during at least three months, the minimal refurbishment shuttle flight time, with minimal handling and maximal automatization, that can be used for inmuno-cytochemistry, ultrastructure or molecular experiments.

Journal Article↗
PubMed2001

De novo hepatitis B after liver transplantation from hepatitis B core antibody-positive donors in an area with high prevalence of anti-HBc positivity in the donor population.

Transmission of hepatitis B virus (HBV) infection from donors who are negative for hepatitis B surface antigen (HBsAg-) but positive for antibody to hepatitis B core antigen (anti-HBc+) has been reported. However, previous studies were generally performed in geographic regions with a low prevalence of anti-HBc positivity in the liver donor population. The aims of this study are (1) to assess the risk for de novo hepatitis B in recipients of livers from anti-HBc+ donors in an area of high prevalence of anti-HBc positivity in the donor population, and (2) to analyze the risk factors for acquisition of HBV infection from anti-HBc+ donors. The transplantation experience of a single center between 1995 and 1998 was reviewed. Thirty-three of 268 liver donors (12%) were HBsAg- and anti-HBc+ during the study period. The proportion of anti-HBc+ donors increased with age; it was lowest (3.6%) in donors aged 1 to 20 years and highest (27.1%) in donors aged older than 60 years. Of the 211 HBsAg- recipients with 3 months or more of HBV serological follow-up, 30 received a liver from an anti-HBc+ donor and 181 received a liver from an anti-HBc- donor. Hepatitis B developed in 15 of 30 recipients (50%) of livers from anti-HBc+ donors but in only 3 of 181 recipients (1.7%) of livers from anti-HBc- donors (P < .0001). None of the 4 recipients who were antibody to HBsAg (anti-HBs)+ at the time of transplantation developed HBV infection after receiving a liver from an anti-HBc+ donor compared with 15 of 26 recipients (58%) who were anti-HBs- (P =.10). None of the 5 anti-HBc+ recipients developed hepatitis B compared with 15 of 25 anti-HBc- recipients (60%; P = 0.04). Child-Pugh score was significantly higher in recipients of livers from anti-HBc+ donors who developed HBV infection than in those who did not (9 +/- 2 v 7 +/- 1; P =.03). In our area, testing liver donors for anti-HBc is mandatory, particularly in older donors. With such information available, anti-HBc+ donors can be safely directed to appropriate recipients, mainly those with anti-HBs and/or anti-HBc at the time of transplantation. In the current era of donor shortage, this policy would allow adequate use of such donors.

Adolescent↗
PubMed2001

Comparative binding energy (COMBINE) analysis of human neutrophil elastase inhibition by pyridone-containing trifluoromethylketones.

The complexes of human neutrophil elastase with a series of 40 N3-substituted trifluoromethylketone-based pyridone inhibitors have been modelled. The series spans three orders of magnitude in inhibition constants despite the fact that it was originally developed in an attempt to improve the oral activity of a lead compound. Ligand-receptor interaction energies calculated using molecular mechanics did not correlate well with the experimental activities. A good correlation with activity was found, however, when a COMBINE analysis of the same data was carried out, which allowed a quantitative interpretation of the modelled complexes. The essence of this method is to partition the ligand-receptor interaction energies into individual residue-based van der Waals and electrostatic contributions, and to subject the resulting energy matrix to partial least squares analysis. Incorporation of two additional descriptors representing the electrostatic energy contributions to the partial desolvation of both the receptor and the ligands improved the QSAR model, as did the replacement of the distance-dependent electrostatic contributions with solvent-screened electrostatic interactions calculated by numerically solving the Poisson-Boltzmann equation. The model was validated both internally (cross-validation) and externally, using a set of twelve 6-phenyl-pyridopyrimidine analogs. The analysis reveals the subtle interplay of binding forces which occurs within the enzyme active site and provides objective information that can be interpreted in the light of the receptor structure. This information, gained from a series of real compounds, can be easily translated into 3D real or virtual database queries in the search for more active derivatives.

Humans↗
PubMed2001

Adverse effects of azathioprine in the treatment of inflammatory bowel disease.

OBJECTIVE: To know the type, frequency and time course for the occurrence of adverse events in our series of patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine. PATIENTS AND METHOD: 92 consecutive patients were treated with azathioprine. 70 of them (55 Crohn's disease, 14 ulcerative colitis and 1 undetermined colitis) were suitable for analysis. RESULTS: We observed 23 adverse reactions in 21 patients. Adverse events were as follows: haematological 11.4%, digestive intolerance 11.4%, infection 7.1%, and pancreatitis 2.8%. The prevalence was increased among ulcerative colitis patients (57.8 vs. 21.8%) (p = 0.02). There were no statistical differences in the prevalence of adverse events respective of the age, gender or location of disease. Digestive intolerance and pancreatitis occurred within the first 6 months of therapy, whereas haematological side effects occurred between 3 months and 4 years after therapy onset. Early occurrence (but not late occurrence) was associated with thiopurine methyltransferase (TMPT) activity levels. All infections took place between 8 months and 5 years of treatment. Azathioprine was definitively withdrawn due to side effects in 9 cases (12.8%). CONCLUSIONS: The frequency of adverse events in our study is similar to that reported in previous studies. Azathioprine withdrawal is required in almost half of the cases because of toxicity. Frequency of side effects is increased in patients with ulcerative colitis. The variability in time course makes clinical-biological monitoring mandatory.

Adult↗
PubMed2000

GRid-INdependent descriptors (GRIND): a novel class of alignment-independent three-dimensional molecular descriptors.

Traditional methods for performing 3D-QSAR rely upon an alignment step that is often time-consuming and can introduce user bias, the resultant model being dependent upon and sensitive to the alignment used. There are several methods which overcome this problem, but in general the necessary transformations prevent a simple interpretation of the resultant models in the original descriptor space (i.e. 3D molecular coordinates). Here we present a novel class of molecular descriptors which we have termed GRid-INdependent Descriptors (GRIND). They are derived in such a way as to be highly relevant for describing biological properties of compounds while being alignment-independent, chemically interpretable, and easy to compute. GRIND are obtained starting from a set of molecular interaction fields, computed by the program GRID or by other programs. The procedure for computing the descriptors involves a first step, in which the fields are simplified, and a second step, in which the results are encoded into alignment-independent variables using a particular type of autocorrelation transform. The molecular descriptors so obtained can be used to obtain graphical diagrams called "correlograms" and can be used in different chemometric analyses, such as principal component analysis or partial least-squares. An important feature of GRIND is that, with the use of appropriate software, the original descriptors (molecular interaction fields) can be regenerated from the autocorrelation transform and, thus, the results of the analysis represented graphically, together with the original molecular structures, in 3D plots. In this respect, the article introduces the program ALMOND, a software package developed in our group for the computation, analysis, and interpretation of GRIND. The use of the methodology is illustrated using some examples from the field of 3D-QSAR. Highly predictive and interpretable models are obtained showing the promising potential of the novel descriptors in drug design.

Butyrophenones↗
PubMed2000

GRID/CPCA: a new computational tool to design selective ligands.

We present a computational procedure aimed at understanding enzyme selectivity and guiding the design of drugs with respect to selectivity. It starts from a set of 3D structures of the target proteins characterized by the program GRID. In the multivariate description proposed, the variables are organized and scaled in a different way than previously published methodologies. Then, consensus principal component analysis (CPCA) is used to analyze the GRID descriptors, allowing the straightforward identification of possible modifications in the ligand to improve its selectivity toward a chosen target. As an important new feature the computational method is able to work with more than two target proteins and with several 3D structures for each protein. Additionally, the use of a 'cutout tool' allows to focus on the important regions around the active site. The method is validated for a total number of nine structures of the three homologous serine proteases thrombin, trypsin, and factor Xa. The regions identified by the method as being important for selectivity are in excellent agreement with available experimental data and inhibitor structure-activity relationships.

Algorithms↗
PubMed2000

VolSurf: a new tool for the pharmacokinetic optimization of lead compounds.

A method for the modeling and prediction of pharmacokinetic properties based on computed molecular interaction fields and multivariate statistics has been investigated in different experimental datasets. The program VolSurf was used to correlate 3D molecular structures with physico-chemical and pharmacokinetic properties. In membrane partitioning, VolSurf produced a two-component model explaining 94% of the total variation with a predictive q(2) of 0.90. This result was achieved without conformational sampling and without any quantum-chemical calculation. For the prediction of blood-brain barrier penetration the VolSurf model was able to predict the BBB profile for most of the drugs in the external prediction set. In Caco-2 and MDCK permeation experiments, VolSurf was used with success to establish statistical models and to predict the behaviour of new compounds. The method thus appears as a valuable new property filter in virtual screening and as a novel tool in optimizing the pharmacokinetic profile of pharmaceutically relevant compounds.

Animals↗
PubMed2000

3D-QSAR methods on the basis of ligand-receptor complexes. Application of COMBINE and GRID/GOLPE methodologies to a series of CYP1A2 ligands.

Many heterocyclic amines (HCA) present in cooked food exert a genotoxic activity when they are metabolised (N-oxidated) by the human cytochrome P450 1A2 (CYP1A2h). In order to rationalize the observed differences in activity of this enzyme on a series of 12 HCA, 3D-QSAR methods were applied on the basis of models of HCA-CYP1A2h complexes. The CYP1A2h enzyme model has been previously reported and was built by homology modeling based on cytochrome P450 BM3. The complexes were automatically generated applying the AUTODOCK software and refined using AMBER. A COMBINE analysis on the complexes identified the most important enzyme-ligand interactions that account for the differences in activity within the series. A GRID/GOLPE analysis was then performed on just the ligands, in the conformations and orientations found in the modeled complexes. The results from both methods were concordant and confirmed the advantages of incorporating structural information from series of ligand-receptor complexes into 3D-QSAR methodologies.

Binding Sites↗
PubMed2000

Identification of peptides that neutralize bacterial endotoxins using beta-hairpin conformationally restricted libraries.

Bacterial endotoxins are the major mediator of septic shock; therefore, endotoxin-neutralizing molecules could have biomedical applications. The septic shock cascade relies in a series of molecular recognition processes. The large contact-surface described for the interacting macromolecules, in most cases, prevents the identification of small molecules that could modulate such recognition events. Here we report on a beta-hairpin conformationally restricted combinatorial library that has been generated and screened towards the identification of new peptides that neutralize bacterial endotoxins. Starting with a de novo designed linear peptide that shows a beta-hairpin structure population of around 30%, (Ramirez-Alvarado, M., Blanco, F. J. and Serrano, L. Nat. Struc. Biol., 7, 604-612 (1996)), we selected four positions to build up a combinatorial library of 20(4) sequences. Deconvolution of the library reduced such a sequence complexity to 8 defined sequences. The newly identified peptides have a biological activity equivalent to that reported for peptides derived from natural endotoxin-binding proteins.

Amino Acid Sequence↗
PubMed2000

Natural history of clinically compensated hepatitis C virus-related graft cirrhosis after liver transplantation.

The natural history of clinically compensated hepatitis C virus (HCV) cirrhosis after liver transplantation is unknown. This information is relevant to transplant centers to improve the management of these patients and decide the optimal timing for retransplantation. The aims of the study were (1) to describe the natural history of patients with HCV-cirrhosis transplants in a center with annual liver biopsies, and (2) to determine predictors for clinical decompensation, retransplantation, and mortality rates. A total of 49 patients with HCV-graft cirrhosis, 39 clinically compensated at histologic diagnosis of cirrhosis (post-liver transplantation cirrhosis) were included and followed up for 1 year (15 days-3.5 years). All patients tested were infected with genotype 1b. Predictive variables included histologic activity index (HAI) at post-liver transplantation cirrhosis, liver function tests, age, sex, and maintenance immunosuppression. Eighteen of 39 patients developed at least 1 episode of decompensation after a median of 7.8 months (4 days-2.6 years; 93% ascites). The cumulative probability of decompensation was 8%, 17%, and 42% at 1, 6, and 12 months, respectively. Graft and patient survival rates were 100%, 85%, and 71% and 100%, 92%, and 74% at 1, 6, and 12 months, respectively. Patient survival rates dropped significantly once decompensation developed (93%, 61%, and 41% at 1, 6, and 12 months, respectively). Variables associated with decompensation, retransplantation, and mortality rate included a high Child-Pugh score (>A), low levels of albumin at post-liver transplantation cirrhosis, and a short interval between liver transplantation and post-liver transplantation cirrhosis. The natural history of clinically compensated HCV-graft cirrhosis is shortened when compared with immunocompetent patients. If retransplantation is considered, it should be performed promptly once decompensation develops.

Adult↗
PubMed2000

[Comparative analysis of viral load by bDNA HCV RNA-2.0 and amplicor HCV monitor in patients with hepatitis C infection].

BACKGROUND: Two standardized techniques, Quantiplex (bDNA-2.0) and Amplicor Monitor have been evaluated for the quantification of virus load of HCV with these objectives: a) determinate the relationship between virus load and genotype, and b) evaluate the virus load in serial serum samples and in patients with normal or slightly increased liver enzymes in an area with a high prevalence of genotype 1. RESULTS: A significant correlation of 0.7 (p < 0.0001) in virus load has been observed by both methods, but the virus load is smaller by Monitor than by Quantiplex and does not depend on genotype. The relationship Monitor/Quantiplex is smaller in patients with non-1 genotype than in patients with genotype 1a (p = 0.01) and 1b (p = 0.005). Virus characteristics are similar in patients with normal or slightly increased enzymes than in patients with high enzymes. Virus load by both methods is not related to the age, sex, know duration of the infection, transmission manner of the infection neither to the histologic activity index. CONCLUSION: The virus load not depends on genotype. The determination of virus load in a single serum sample adequately reflects the virus load are in several serum samples in patients with chronic HCV infection. The genotype and the virus load are similar in patients with normal enzymes than in patients with high enzymes.

Adult↗
PubMed2000

[Azathioprine and 5-ASA in the prevention of postoperative recurrence of Crohn's disease].

Recurrence of Crohn's disease (CD) lesions in the neo-ileum after apparently curative resection frequently occurs after surgery. The most appropriate prophylactic treatment has not been clearly defined. This study evaluated the efficacy of 5-ASA and azathioprine in decreasing postoperative recurrence and analysed the presence of variables associated with recurrence. Thirty-nine patients (mean age 32.8 years, range 18-61) with a history of ileal or ileocecal surgical resection were studied. They received 5-ASA (3 mg/day) or azathioprine (50 mg/day) immediately after the operation and for 2 years thereafter. Patients were followed clinically (Crohn's disease activity index) and serologically every 3 months and by imaging methods every 6 months. The latter included colonoscopy with ileoscopy and if not available, small bowel barium or ultrasonographic study. Laboratory tests included ESR, C-reactive protein, white blood cell and platelet count, fibrinogen and albumin. The end-point evaluated included clinical recurrence (CR), serological recurrence (SR: alteration of at least three of the above-mentioned variables) and morphologic recurrence (MR: endoscopic recurrence > 1 according to Rutgeerts score or radiological or ultrasonographic recurrence). Eighteen patients received azathioprine and 21 received 5-ASA. Thirty-four patients were evaluated. The cumulative proportion of patients with recurrence was 29% (CR), 35% (SR) and 50% (MR). Statistical analysis did not show significant differences between the two groups. Twenty-seven patients completed the 2-year study (11 in the azathioprine group and 16 in the 5-ASA group). Crude relapse rates were 37% (CR), 44% (SR) and 69% (MR) in the 5-ASA group and 36% (CR), 45% (SR) and 64% (MR) in the azathioprine group. No statistically significant differences were observed between groups. No variables associated with recurrence were detected. In conclusion, treatment does not prevent a high percentage of postsurgical recurrence. 5-ASA (3 g/day) and azathioprine (50 mg/day) showed similar efficacy in the prevention of recurrence.

Adolescent↗
PubMed1999

Long-term results after combined modality treatment for non-metastatic osteosarcoma.

Since the introduction of multimodality treatment, the prognosis of patients with high-grade non-metastatic osteosarcoma has significantly improved. A retrospective review was performed to assess the long-term results of this approach in a single centre setting, and to investigate the impact of potential clinical prognostic factors. Between 1985 and 1993, 35 patients with stage II-A and II-B osteosarcoma underwent preoperative chemotherapy (high-dose methotrexate), wide surgery, and adjuvant chemotherapy (cisplatin-doxorubicin/bleo-mycin-cyclophosphamide-dactinomycin) (modified T-10A protocol). There were 19 males and 16 females. Median patient age was 17 y (range 12-42). Primary tumour sites were the extremities (83%) and axial bones (17%). In spite of an unfavourable grade 3-4 histologic response rate to high-dose methotrexate of 12%, 31 (88%) patients were able to undergo limb-sparing surgery and 28 (80%) were rendered disease free after the planned therapy. Median follow-up was 8 y. The actuarial overall survival and disease-free survival rates were 64% and 49% at 5 y, and 59% and 49% at 10 y, respectively. Tumour size and primary site were significant prognostic factors for survival in univariate analyses. In conclusion, long-term survival after combined modality treatment can be achieved in more than 60% of patients with localised osteosarcoma, including non-appendicular lesions. Limb-sparing surgery is a realistic goal for most cases. The prognostic value of tumour necrosis and the efficacy of neoadjuvant chemotherapy should be interpreted according to individual high-dose methotrexate scheduling.

Adolescent↗
PubMed1999

ESHAP is an active regimen for relapsing Hodgkin's disease.

BACKGROUND: Refractory or relapsing Hodgkin's disease is associated with a poor prognosis. There is no widely accepted salvage chemotherapy regimen for these patients. However, the addition of high-dose chemotherapy followed by autologous hematopoietic transplantation (AHT) has proven of benefit to them. A prospective clinical trial was carried out to evaluate the efficacy and toxicity of ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin). PATIENTS AND METHODS: Twenty-two patients with refractory (5) or relapsing Hodgkin's disease (17) were entered and scheduled to receive three courses of ESHAP. Patients suitable for AHT were then given high-dose chemotherapy with CBV (cyclophosphamide, carmustine, and etoposide) plus AHT, whereas responding, non-AHT-suitable patients completed six ESHAP courses. RESULTS: Nine patients achieved complete responses and seven partial responses (overall response rate 73%) with ESHAP. Grade 3-4 myelotoxicity was seen in 13 patients (59%). Nine patients received CBV plus AHT. At a median follow-up time of 50 months (range 6-96), seven patients (32%) are alive and disease-free. Three patients died of toxic effects of ESHAP (1) or CBV (2). Actuarial overall survival and disease-free survival were 35% and 27% at three years. CONCLUSIONS: ESHAP is an active regimen for relapsing Hodgkin's disease, with myelosuppression as its dose-limiting toxicity. An increased risk of treatment-related mortality when it is combined with high-dose chemotherapy can not be ruled out.

Adolescent↗
PubMed1999

[The effect of iron depletion on the response to interferon treatment in patients with chronic hepatitis C. Pilot study].

UNLABELLED: It has been reported that increase in serum ferritin levels and/or in hepatic iron content is associated with a poor response to interferon treatment in patients with chronic hepatitis C (CH-C). AIM: To determinate whether iron depletion by phlebotomy (PB) increases the response to interferon therapy in chronic hepatitis C. PATIENTS AND METHODS: We have evaluated 12 patients with CH-C (genotype 1b = 11, 1a = 1), increased ALT levels, positive serum VHC-RNA and increased serum ferritin levels (> 220 ng/ml), including 8 previously non responders to interferon therapy and 4 naive subjects. Phlebotomies were performed weekly (mean number per patient: 6, range: 5-12) until serum ferritin levels were < 100 ng/ml, followed by interferon treatment (3MU thrice weekly for 3-12 months depending on the response). RESULTS: Multiple regression analysis showed that serum ferritin levels were not related to serum ALT levels (p = 0.18) or viral load (p = 0.06). Serum ALT levels decreased significantly post-PB (58 U/l, range: 35-141 U/l) as compared to pretreatment levels (164 U/l, range: 51-216 U/l, p < 0.006) and normalized in two subjects. HCV-RNA was positive in one of the latter and negative in the other. Eleven of the twelve patients did not respond to interferon after three months of therapy (increased serum ALT levels in 10 subjects and positive HCV RNA in 11). One additional patient, who had not been treated previously with interferon and had low pretreatment viral load, had a sustained response after 12 months of interferon therapy. Viral load did not decreased either with PB or following interferon treatment. By contrast, serum ferritin levels did not increase with interferon treatment or during the 6 month follow-up period. CONCLUSIONS: Decreasing serum ferritin levels by phlebotomies does not increase HCV erradication rate after interferon treatment. Sustained response to interferon therapy is an infrequent event and is more dependent on viral factors (viral load and genotype).

Adult↗