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Biomedical subjects

R Rodriguez

Publications and source records attributed to R Rodriguez.

At least 37 records · Page 2Linked to original sources
PubMed2003

Reduced-intensity allogeneic stem cell transplantation for patients whose prior autologous stem cell transplantation for hematologic malignancy failed.

Autologous hematopoietic stem cell transplantation (autoSCT) is an effective treatment for patients with various hematologic malignancies. Despite the significant improvement in the overall outcome, disease progression after transplantation remains the major cause of treatment failure. With longer follow-up, therapy-related myelodysplasia/acute myelogenous leukemia is becoming an important cause of treatment failure. The prognosis for these 2 groups of patients is very poor. Allogeneic hematopoietic stem cell transplantation (alloSCT) is a potential curative treatment for these patients. However, the outcome with conventional myeloablative alloSCT after failed autoSCT is typically poor because of high transplant-related mortality. In an attempt to reduce the treatment-related toxicity, we studied a reduced-intensity conditioning regimen followed by alloSCT for patients with progressive disease or therapy-related myelodysplasia/acute myelogenous leukemia after autoSCT. This report describes the outcomes of 28 patients with hematologic malignancies who received a reduced-intensity alloSCT after having treatment failure with a conventional autoSCT. Fourteen patients received a hematopoietic stem cell transplant from a related donor and 14 from an unrelated donor. The conditioning regimen consisted of low-dose (2 Gy) total body irradiation with or without fludarabine in 4 patients and the combination of melphalan (140 mg/m(2)) and fludarabine in 24. Cyclosporine and mycophenolate mofetil were used for posttransplantation immunosuppressive therapy, as well as graft-versus-host disease (GVHD) prophylaxis, in all patients. All patients engrafted and had >90% donor chimerism on day 100 after SCT. Currently, 13 patients (46%) are alive and disease free, 7 patients (25%) developed disease progression after alloSCT, and 8 (32%) died of nonrelapse causes. Day 100 mortality and nonrelapse mortality were 25% and 21%, respectively. With a median follow-up of 24 months for surviving patients, the 2-year probabilities of overall survival, event-free survival, and relapse rates were 56.5%, 41%, and 41.9%, respectively. Six patients (21%) developed grade III to IV acute GVHD. Among 21 evaluable patients, 15 (67%) developed chronic GVHD. We conclude that (1) reduced-intensity alloSCT is feasible and has an acceptable toxicity profile in patients who have previously received autoSCT and that (2) although follow-up was short, a durable remission may be achieved in some patients who would otherwise be expected to have a poor outcome.

Adult↗
PubMed2003

Prognostic significance of the allelic loss of the BRCA1 gene in colorectal cancer.

BACKGROUND: Survival at the intermediate stage of colorectal cancer (CRC) is less predictable than in the early and advanced stages. Several genetic markers possibly involved in growth and progression of CRC can be used for prognosis. AIMS: This study investigated the proportion of allelic loss (loss of heterozygosity (LOH)) at the BRCA1 locus in sporadic CRC and its value in patient prognosis. PATIENTS AND METHODS: A total of 314 patients were investigated for LOH at the BRCA1 locus using polymerase chain reaction by means of three intragenic polymorphic microsatellite markers. Allelic losses were compared with clinicopathological characteristics of patients, recurrence rate, disease free survival (DFS), and overall survival. RESULTS: Twenty six patients were excluded because of microsatellite instability. Of the remaining 288 cases, 244 (84.7%) were informative, with 97 (39.8%) patients bearing BRCA1 LOH. Recurrence rate was higher in patients with LOH (p=0.0003), and DFS was 73.3% (SEM 5.7) at five years in patients without LOH, and 49.2% (7.1) in cases with positive allelic loss (p=0.0004). Retention of alleles at the BRCA1 locus was associated with a favourable DFS in stages I and II (p<0.05). The presence of LOH was also significantly associated with short overall survival (p=0.02). Multivariate analysis in the complete series showed that stage (p=0.006) and lymph node metastases (> or =4 nodes, p=0.0001; 1-3 nodes, p=0.038) were independent prognostic factors. However, multivariate study by stages revealed that BRCA1 LOH was an independent prognostic factor in stages I and II (p=0.001). CONCLUSIONS: BRCA1 LOH is a molecular alteration present in CRC, with unfavourable repercussions for overall survival, that could be considered as an outstanding independent prognostic factor in stages I and II.

Aged↗
PubMed2003

An examination of daily activities and their scripts across the adult lifespan.

In two normative studies, we examined daily scripted activities from the perspective that scripts are frequency-based knowledge structures. In Study 1 individuals recorded their daily activities for 7 consecutive days. Fifteen activities that were reported with low, moderate, and high frequency were selected for Study 2, in which individuals generated a script for each activity. The 18 most frequently generated events from each script are reported, along with their centrality and distinctiveness rankings and the number of individuals reporting each event. Overall, the mean number of events generated increased with increasing script frequency, suggesting that script representations are subject to frequency effects. Also, we found a high level of consistency across the three age groups in the events generated in each script and in their corresponding rankings of centrality and distinctiveness. Finally, we found no evidence of age or gender bias in the frequency or recency of engaging in each of the scripted activities.

Activities of Daily Living↗
PubMed2003

Cellular determination in the anterior pituitary gland: PIT-1 and PROP-1 mutations as causes of human combined pituitary hormone deficiency.

In the anterior pituitary gland, five distinct hormone producing cell types are generated from common epithelial progenitor cells. This process of cellular determination is controlled by signaling molecules acting on transcription factors, which in turn regulate genes critical for the appearance of hormone producing cells. Two pituitary specific transcription factors, Pit-1 and Prop-1, which are required for generation of hormone producing cells in the anterior pituitary gland, have proved to be important in the cause of hypopituitarism in humans. Mutations in the human PIT-1 gene lead to a combined pituitary hormone deficiency characterized by lack of GH, PRL and TSH. Mutations in the PROP-1 gene, which are a more common cause of hypopituitarism, lead to a clinical phenotype characterized by GH, PRL, TSH, LH and FSH deficiency, and sometimes ACTH deficiency as well.

DNA-Binding Proteins↗
PubMed2003

Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide: players in innate and adaptive immunity.

Recent reports identified and described neural pathways, both hard-wiring and soluble mediators, that control and adjust the peripheral immune response. Immune organs are innervated by fibers rich in neurotransmitters and neuropeptides released in inflammatory conditions. Here we focus on the immunomodulatory role of two peptides, the vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase-activating polypeptide (PACAP). VIP/PACAP are present and released from both innervation and immune cells, particularly Th2 cells, and immune cells express receptors for VIP/PACAP. VIP/PACAP have a general anti-inflammatory effect, both in innate and adaptive immunity. In innate immunity, VIP/PACAP inhibit the production of pro-inflammatory cytokines and chemokines from macrophages, microglia and dendritic cells. In addition, VIP/PACAP reduce the expression of costimulatory molecules (particularly CD80 and CD86) on the antigen-presenting cells, and therefore reduce stimulation of antigen-specific CD4+ T cells. In terms of adaptive immunity, VIP/PACAP promote Th2-type responses, and reduce the pro-inflammatory Th1-type responses. Several of the molecular mechanisms involved in the inhibition of cytokine and chemokine expression, and in the preferential development and/or survival of Th2 effects, are discussed.

Adenylyl Cyclases↗
PubMed2002

The use of passive environmental TLDs in the operation of the Spanish early warning network 'REVIRA'.

As required by different international agreements, the regulatory body in Spain (Consejo de Seguridad Nuclear) implemented in 1992 a national automatic network (REVIRA) that continuously monitors radiation levels in order to give early warning of incidents having potential transboundary implications. The detector for environmental gamma-radiation dose rate is an active instrument based on a Geiger-Müller counter. However, the use of passive environmental dosemeters provides an additional low-cost dose estimate with an independent centralised calibration and even better basic features than active instruments. Since 1999, all 25 REVIRA stations have been monitored with passive TL environmental dosemeters based on LiF:Mg,Cu,P and operated according to the procedures established at Ciemat. This paper presents the obtained results and the further analysis considering differences in aspects such as photon energy response, inherent background or response to cosmic rays. The benefits of the use of passive environmental dosemeters in early warning networks are discussed.

Air Pollution, Radioactive↗
PubMed2002

Epidermal growth factor receptor targeting of replication competent adenovirus enhances cytotoxicity in bladder cancer.

PURPOSE: We evaluated the delivery and oncolytic potential of targeted replication competent adenoviruses in bladder cancer lines. MATERIALS AND METHODS: Seven established human bladder cancer tumor lines (5637, SW800, TCCsup, J82, Scaber, T24 and 253J) were studied for the expression of integrins alpha(v)beta3, alpha(v)beta5, Coxsackievirus and adenovirus receptor, epidermal growth factor receptor (EGF-R) and epithelial cell adhesion molecule antigens using flow cytometry analysis. Bispecific single chain Fv fragments were used to target replication deficient luciferase reporter adenovirus to EGF-R (425-s11) or to epithelial cell adhesion molecule (C28-s11) antigens. Moreover, a fiber modified adenovirus targeting alpha(v)-integrins was studied. Replication competent serotype-5 adenoviruses attenuated to replicate specifically in retinoblastoma pRb (Ad5-d24) or p53 deficient (Ad5-d55K) cells were tested in vitro for oncolytic properties. RESULTS: Low to absent Coxsackievirus and adenovirus receptor expression was found in 5 of the 7 tumor lines (SW800, J82, T24, 5637 and Scaber). EGF-R expression was found in all cell lines, whereas elevated epithelial cell adhesion molecule expression was seen in 3 (5637, Scaber and TCCsup), alpha(v)beta3-integrin was found in 1 (Scaber) and alpha(v)beta5-integrin was found in 3 (TCCsup, 253J and T24). EGF-R targeting using 425-s11 improved transgene expression in all cell lines from 2.1 to 12.5 times over nontargeted viruses. Epithelial cell adhesion molecule and integrin targeting was inferior to EGF-R targeting with a maximal increase in transgene expression of 2 times for epithelial cell adhesion molecule in 5637cells and 1.6 times for integrin targeting in T24 cells. Comparison of the wild-type replication competent virus with conditionally replicating adenoviruses (Ad5-d55K and Ad5-d24) showed superior oncolytic activity for the latter 2 in all lines. Furthermore, improved cytotoxicity (29% to 33%) was obtained in 4 of the 7 lines after pre-incubation of Ad5-d24 with 425-s11. CONCLUSIONS: EGF-R directed bispecific single chain antibodies enhance adenovirus mediated transgene expression and oncolysis in bladder cancer lines.

Adenoviridae↗
PubMed2002

Detection of epithelial tumour RNA in the plasma of colon cancer patients is associated with advanced stages and circulating tumour cells.

BACKGROUND: Although circulating tumour DNA has been detected in patients with different types of cancer, little is known of free RNA in cancer patients. AIMS: We investigated the presence of RNA from epithelial tumours in plasma from patients with colorectal carcinomas, and its correlation with tumour characteristics and circulating tumour cells. METHODS: beta-actin mRNA was analysed to assess the viability of plasma RNA in samples from 53 patients with colonic cancer and 25 controls. Subsequently, nested primers were used to detect the presence of cytokeratin 19 (CK19) and carcinoembryonic antigen (CEA) RNA in the same samples. Nine clinicopathological parameters were studied to correlate the molecular and clinical parameters. Additionally, we investigated for micrometastases in blood in 18 of these patients and in 10 of the controls samples. RESULTS: All samples had detectable quantities of beta-actin RNA. In the controls, one case (4%) was positive for CEA and five (20%) for CK19 RNA; of the 53 patients, 17 cases (32%) were positive for CEA and 39 (73.6%) for CK19 RNA. This was statistically significant (p=0.000001). Advanced stages (p=0.03) and soluble CEA status (p=0.03) were associated with the presence of CEA, CK19, or both RNAs in plasma. Lymph node metastases (p=0.06) and vascular invasion (p=0.07) were almost significant. On the basis of these results, we examined the possible presence of micrometastases in blood in several of these patients. The presence of plasma tumour RNA was found to be associated with circulating tumour cells in blood (p=0.04). CONCLUSIONS: Epithelial tumour RNA is detectable in plasma from colon cancer patients. This molecular event is associated with advanced stages and circulating tumour cells. Our results could offer new approaches in the diagnosis and monitoring of colon cancer.

Actins↗
PubMed2001

Spatio-temporal patterns of brain magnetic activity during a memory task in Alzheimer's disease.

The brain magnetic activity patterns in a high load probe-letter (targets and distractors) memory task were examined in patients with Alzheimers's disease (AD) and elderly controls. Control subjects showed a higher number of activity sources over the temporal and parietal cortex between 400 and 700 ms after stimulus onset. However, AD patients showed a higher number of sources over the frontal motor areas, including Broca's and the insula. The number of activity sources on the left parietal areas in response to the target stimuli predicted the AD score oncognitive (MMSE, CAMCOG) and functional staging (FAST) scales. These results suggest that a high information load reveals a deficient functioning of phonological store and reduced task-related activity in temporal and parietal areas, manifesting in a rapid information trace decay. The increased levels of activity in motor areas may reflect a compensatory strategy in an attempt to facilitate rehearsal speed.

Aged↗
PubMed2001

DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis.

Cancer cells have aberrant patterns of DNA methylation including hypermethylation of gene promoter CpG islands and global demethylation of the genome. Genes that cause familial cancer, as well as other genes, can be silenced by promoter hypermethylation in sporadic tumors, but the methylation of these genes in tumors from kindreds with inherited cancer syndromes has not been well characterized. Here, we examine CpG island methylation of 10 genes (hMLH1, BRCA1, APC, LKB1, CDH1, p16(INK4a), p14(ARF), MGMT, GSTP1 and RARbeta2) and 5-methylcytosine DNA content, in inherited (n = 342) and non-inherited (n = 215) breast and colorectal cancers. Our results show that singly retained alleles of germline mutated genes are never hypermethylated in inherited tumors. However, this epigenetic change is a frequent second "hit", associated with the wild-type copy of these genes in inherited tumors where both alleles are retained. Global hypomethylation was similar between sporadic and hereditary cases, but distinct differences existed in patterns of methylation at non-familial genes. This study demonstrates that hereditary cancers "mimic" the DNA methylation patterns present in the sporadic tumors.

Breast Neoplasms↗
PubMed2001

Tyrosine residues in phospholipase Cgamma 2 essential for the enzyme function in B-cell signaling.

Phospholipase Cgamma (PLCgamma) isoforms are regulated through activation of tyrosine kinase-linked receptors. The importance of growth factor-stimulated phosphorylation of specific tyrosine residues has been documented for PLCgamma1; however, despite the critical importance of PLCgamma2 in B-cell signal transduction, neither the tyrosine kinase(s) that directly phosphorylate PLCgamma2 nor the sites in PLCgamma2 that become phosphorylated after stimulation are known. By measuring the ability of human PLCgamma2 to restore calcium responses to the B-cell receptor stimulation or oxidative stress in a B-cell line (DT40) deficient in PLCgamma2, we have demonstrated that two tyrosine residues, Tyr(753) and Tyr(759), were important for the PLCgamma2 signaling function. Furthermore, the double mutation Y753F/Y759F in PLCgamma2 resulted in a loss of tyrosine phosphorylation in stimulated DT40 cells. Of the two kinases that previously have been proposed to phosphorylate PLCgamma2, Btk, and Syk, purified Btk had much greater ability to phosphorylate recombinant PLCgamma2 in vitro, whereas Syk efficiently phosphorylated adapter protein BLNK. Using purified proteins to analyze the formation of complexes, we suggest that function of Syk is to phosphorylate BLNK, providing binding sites for PLCgamma2. Further analysis of PLCgamma2 tyrosine residues phosphorylated by Btk and several kinases from the Src family has suggested multiple sites of phosphorylation and, in the context of a peptide incorporating residues Tyr(753) and Tyr(759), shown preferential phosphorylation of Tyr(753).

Agammaglobulinaemia Tyrosine Kinase↗
PubMed2001

A phase I trial of CV706, a replication-competent, PSA selective oncolytic adenovirus, for the treatment of locally recurrent prostate cancer following radiation therapy.

CV706 is a prostate-specific antigen (PSA)-selective, replication-competent adenovirus that has been shown to selectively kill human prostate cancer xenografts in preclinical models. To study the safety and activity of intraprostatic delivery of CV706, a Phase I dose-ranging study for the treatment of patients with locally recurrent prostate cancer after radiation therapy was conducted. Twenty patients in five groups were treated with between 1 x 10(11) and 1 x 10(13) viral particles delivered by a real-time, transrectal ultrasound-guided transperineal technique using a three-dimensional plan. The primary end point was the determination of treatment-related toxicity. Secondary objectives included evaluation of the antitumor activity of CV706 and monitoring for other correlates of antineoplastic action. In this study, CV706 was found to be safe and was not associated with irreversible grade 3 or any grade 4 toxicity. No grade >1 alterations in liver function tests associated with CV706 administration were observed. Posttreatment prostatic biopsies and detection of a delayed "peak" of circulating copies of virus provided evidence of intraprostatic replication of CV706. The study defined the timing of CV706 shedding into blood and urine as well as the appearance of circulating Ad5 neutralizing antibodies. Finally, this study documents the serum PSA response of treated patients and reveals a dose response showing that all five patients who achieved a > or =50% reduction in PSA were treated with the highest two doses of CV706. This study represents the first clinical translation of a prostate-specific, replication-restricted adenovirus for the treatment of prostate cancer. Taken together, this study documents that intraprostatic delivery of CV706 can be safely administered to patients, even at high doses, and the data also suggest that CV706 possesses enough clinical activity, as reflected by changes in serum PSA, to warrant additional clinical and laboratory investigation.

Adenoviridae↗
PubMed2001

Transduction and apoptosis induction in the rat prostate, using adenovirus vectors.

Proapoptotic adenovirus vectors offer great promise for the treatment of cancer and nonmalignant conditions. Benign prostate hyperplasia (BPH) is a common nonmalignant enlargement of the prostate that involves epithelial, stromal, and smooth muscle components of the gland. We tested the hypothesis that an adenovirus vector expressing Fas ligand can be used to induce apoptosis in the prostate. We analyzed the efficiency of transduction and apoptosis induction in primary cultures of human prostate cells after adenovirus-mediated gene transfer. Efficient transduction was observed in primary prostate epithelial cells. Stromal and smooth muscle cells were more difficult to transduce, as no coxsackie-adenovirus receptor (CAR) expression was detectable on these cells. However, transduction was achieved in these cells when the multiplicity of infection was increased to 100 focal-forming units per cell, or when the vectors were delivered as calcium phosphate precipitates. Infection of all three primary prostate cell types with an adenovirus vector that expresses Fas ligand (AdFasL/G) resulted in rapid apoptosis. Direct injection of the rat prostate with an adenovirus vector carrying luciferase resulted in substantial luciferase expression. TUNEL analysis demonstrated that AdFasL/G administration induced low-level apoptosis in prostatic epithelial cells throughout the gland. As a first step toward enhancing the efficiency of prostate transduction in vivo, we tested an adenovirus vector that was engineered to have an expanded tropism. This vector, AdZ.F2K(pK7), was 10- to 500-fold more efficient than unmodified vectors in transducing prostate epithelial, smooth muscle, and stromal cells in culture. Moreover, AdZ.F2K(pK7) was more efficient than an unmodified vector at transducing the rat prostate in vivo, although the effect was dose dependent.

Adenoviridae↗
PubMed2001

Allele varepsilon4 of apolipoprotein E gene is less frequent in Down syndrome patient of the Sicilian population and has no influence on the grade of mental retardation.

We evaluated the allele (and genotype frequencies in 60 Down syndrome (DS), 25 mothers and 57 controls from Sicily and its relation with mental retardation. DS patients and sex ratio (M:F) was 22.1+/-10.5 and 1.14, respectively. Allele varepsilon4 and varepsilon3 frequencies were respectively lower (P=0.015) and higher (P=0.005) in DS patients compared to controls. Genotype varepsilon3/varepsilon4 and varepsilon3/varepsilon3 were less (P=0.03) and more frequent (P=0.001) in DS patients, with respective odd ratios of 0.31 (CI at 95%: 0.18-0.49) and of 4.4 (CI at 95%: 3.4-5.7). No difference of allele (distribution was found in function of the grades of mental retardation according to DMS-IV. Our results show that the implication of Apo-E4 in the pathogenesis of Alzheimer disease cannot be extrapolated in that of dementia of DS.

Adolescent↗
PubMed2001

Real time fluorescence imaging of PLC gamma translocation and its interaction with the epidermal growth factor receptor.

The translocation of fluorescently tagged PLC gamma and requirements for this process in cells stimulated with EGF were analyzed using real time fluorescence microscopy applied for the first time to monitor growth factor receptor--effector interactions. The translocation of PLC gamma to the plasma membrane required the functional Src homology 2 domains and was not affected by mutations in the pleckstrin homology domain or inhibition of phosphatidylinositol (PI) 3-kinase. An array of domains specific for PLC gamma isoforms was sufficient for this translocation. The dynamics of translocation to the plasma membrane and redistribution of PLC gamma, relative to localization of the EGF receptor and PI 4,5-biphosphate (PI 4,5-P(2)), were shown. Colocalization with the receptor was observed in the plasma membrane and in membrane ruffles where PI 4,5-P(2) substrate could also be visualized. At later times, internalization of PLC gamma, which could lead to separation from the substrate, was observed. The data support a direct binding of PLC gamma to the receptor as the main site of the plasma membrane recruitment. The presence of PLC gamma in membrane structures and its access to the substrate appear to be transient and are followed by a rapid incorporation into intracellular vesicles, leading to downregulation of the PLC activity.

Animals↗
PubMed2001

Muscular function and bone mass after knee arthroplasty.

We report a study of 28 women with severe primary gonarthrosis followed for 1 year. Variations in bone mineral density and in functional behaviour of knee extensors and flexors were studied before and after implantation of uncemented total knee prosthesis. A functional deficit was noted in the extensor apparatus, which increased in the first 6 months following surgery. This strength was not improved 1 year following the arthroplasty, but it was more efficient as shown by the reduction of muscle fatigue. Flexor strength was conserved and a pathological muscle balance was maintained, reaching maximum efficiency over a smaller joint range.

Aged↗
PubMed2001

A cavernous haemangioma of breast in male: radiological-pathological correlation.

Vascular tumours of the breast are especially rare in men, and a majority of them are angiosarcomas. In fact, we found only four cases of haemangioma in males in the literature. We present a case of cavernous haemangioma in a male aged 48 years, and which commenced as a palpable mass. We performed differential diagnosis and radiological-pathological correlation. We established the correct classification of this case histologically, and decided on the definitive therapeutic approach.

Biopsy, Needle↗