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Biomedical subjects

P Mendez

Publications and source records attributed to P Mendez.

18 recordsLinked to original sources
PubMed2007

Gene expression of ERCC1 as a novel prognostic marker in advanced bladder cancer patients receiving cisplatin-based chemotherapy.

BACKGROUND: Customizing chemotherapy on the basis of chemosentitivity prediction may improve outcome in advanced bladder cancer patients. Since DNA damaging agents are the cornerstones of therapy, we hypothesized that levels of DNA repair genes could predict survival. PATIENTS AND METHODS: Messenger RNA expression levels of excision repair cross complementing 1 (ERCC1), breast cancer 1 (BRCA1), ribonucleotide reductase subunit M1 (RRM1) and caveolin-1 were determined by RT-PCR in tumor DNA from 57 advanced and metastatic bladder cancer patients treated with either gemcitabine/cisplatin or gemcitabine/cisplatin/paclitaxel (Taxol). Levels were correlated with survival, time to disease progression and chemotherapy response. RESULTS: Median survival was significantly higher in patients with low ERCC1 levels (25.4 versus 15.4 months; P = 0.03) (median follow-up 19 months). A trend towards longer time to progression was observed in patients with tumors expressing low levels of all markers. Levels of RRM1, BRCA1 and caveolin-1, however, failed to predict the survival and a clear link with chemotherapy response could not be established. On multivariate analysis with pretreatment prognostic factors, ERCC1 emerged as an independent predictive factor for survival. CONCLUSION: The results of the study indicate that ERCC1 may predict survival in bladder cancer treated by platinum-based therapy.

Adult↗
PubMed2006

Polymorphisms in DNA repair genes modulate survival in cisplatin/gemcitabine-treated non-small-cell lung cancer patients.

BACKGROUND: Impaired DNA repair capacity may favorably affect survival in cisplatin/gemcitabine-treated non-small-cell lung cancer (NSCLC) patients. We investigated the association of survival with genetic polymorphisms in X-ray repair cross-complementing group 1 and group 3 (XRCC3), xeroderma pigmentosum group D (XPD), excision repair cross-complementing group 1, ligase IV, ribonucleotide reductase, TP53, cyclooxygenase-2, interleukin-6, peroxisome proliferator-activated receptor gamma, epidermal growth factor, methylene-tetra-hydrofolate reductase and methionine synthase. PATIENTS AND METHODS: One hundred and thirty-five stage IV or IIIB (with malignant pleural effusion) NSCLC patients treated with cisplatin/gemcitabine from different hospitals of the Spanish Lung Cancer Group were genotyped for 14 different polymorphisms in 13 genes. Polymorphisms were detected by the TaqMan method, using genomic DNA extracted from baseline blood samples. RESULTS: Median survival was significantly increased in patients harboring XRCC3 241 MetMet: 16 months versus 10 months for patients with ThrMet and 14 months for those with ThrThr (P = 0.01). The risk of death ratio was significantly lower for MetMet than for ThrMet patients (hazard ratio, 0.43; P = 0.01). In the multivariate Cox model, XRCC3 241 remained an independent prognostic factor (hazard ratio: XRCC3 241 MetMet, 0.44; P = 0.01), and XPD 751 and XRCC1 399 also emerged as significant prognostic factors (hazard ratios: XPD 751 LysGln, 0.46, P = 0.03; XRCC1 399 ArgGln, 0.61, P = 0.04). No other association was observed between genotype and survival. CONCLUSION: XRCC3 241 MetMet is an independent determinant of favorable survival in NSCLC patients treated with cisplatin/gemcitabine. A simple molecular assay to determine the XRCC3 241 genotype can be useful for customizing chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

Epidermal growth factor receptor activating mutations in Spanish gefitinib-treated non-small-cell lung cancer patients.

BACKGROUND: North American and Japanese non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) activation via tyrosine kinase (TK) mutations respond dramatically to gefitinib treatment. To date, however, the frequency and effect of EGFR TK mutations have not been examined in European patients. PATIENTS AND METHODS: Eighty-three Spanish advanced NSCLC patients who had progressed after chemotherapy, were treated with compassionate use of gefitinib. Patients were selected on the basis of available tumor tissue. Tumor genomic DNA was retrieved from paraffin-embedded tissue obtained by laser capture microdissection. EGFR mutations in exons 19 and 21 were examined by direct sequencing. RESULTS: EGFR mutations were found in 10 of 83 (12%) of patients. All mutations were found in adenocarcinomas, more frequently in females (P=0.007) and non-smokers (P=0.01). Response was observed in 60% of patients with mutations and 8.8% of patients with wild-type EGFR (P=0.001). Time to progression for patients with mutations was 12.3 months, compared with 3.6 months for patients with wild-type EGFR (P=0.002). Median survival was 13 months for patients with mutations and 4.9 months for those with wild-type EGFR (P=0.02). CONCLUSIONS: EGFR TK mutational analysis is a novel predictive test for selecting lung adenocarcinoma patients for targeted therapy with EGFR TK inhibitors.

Adult↗
PubMed2003

Serum DNA as a tool for cancer patient management.

PURPOSE: Genetic analysis has shown that cell-free circulating DNA in plasma or serum of cancer patients shares similar genetic alterations to those described in the corresponding tumor. One of the most important alterations involved in carcinogenesis is aberrant promoter methylation. The interest in this field has grown due to the implementation of the methylation-specific PCR (MSP) assay. The main objective of this study is to analyze the methylation status of different genes in tumor and serum DNA obtained at the time of surgery in two different tumor models (glioblastoma [GBM] and non-small-cell lung cancer [NSCLC]) and their relationship to clinico-pathological characteristics and response to chemotherapy. MATERIAL AND METHODS: Using MSP assay, we assessed the methylation status of MGMT, RASSF1A, p16, DAPK, TMS-1 in tumor and serum DNA obtained at time of surgery or stereotactic biopsy from 28 GBM patients and from 51 NSCLC patients. RESULTS: In GBM patients, the prevalence of MGMT, p16, DAPK, and RASSF1A promoter methylation was 38.1%, 66.7%, 52.4%, 57.1%, respectively, in glioma tissue, and 39.3%, 53.6%, 34.3%, 50%, respectively, in serum. A high correlation between methylation in tumor and serum (Spearman test p = 0.0001) was observed. In NSCLC patients, RASSF1A, DAPK and TMS-1 were methylated in 34%, 45% and 35% tumors, respectively, and in 34%, 40% and 34% serum, respectively. A good correlation was found between alterations found in tumor and serum (Spearman test p = 0.0001). CONCLUSIONS: The study of serum or plasma DNA has opened new roads for translational research and new strategies for molecular diagnosis. Due to the similarities of alterations found in serum DNA and primary tumor, we can use this tool to calculate the risk of local or distant recurrence and its relationship with survival and its value in patient follow-up to evaluate response to therapy.

Adult↗
PubMed2002

Rapid stimulation of the PI3-kinase/Akt signalling pathway in developing midbrain neurones by oestrogen.

Oestrogen promotes the differentiation of neurones in the central nervous system. In the rodent midbrain, the maturation of dopaminergic neurones appears to be under oestrogen control. This is supported by the fact that dopaminergic cells contain nuclear oestrogen receptors-alpha/beta (ER). Second, aromatase is transiently expressed in the developing midbrain. In previous studies, we have shown that oestrogen increases dopamine synthesis and plasticity of dopamine cells. These effects are transmitted through classical nuclear ER but require also the stimulation of nonclassical signalling pathways involving the activation of membrane receptors. This study attempted to identify nonclassical oestrogen-dependent signalling cascades which might be stimulated downstream of membrane ERs. Using cultured mouse midbrain cells, we could demonstrate by Western blotting, that oestrogen rapidly phosphorylates Akt, a kinase which is implicated in the phosphatidylinositol 3 (PI3)-kinase pathway. This effect was only seen in midbrain neurones but not astrocytes. Oestrogen-induced Akt phosphorylation was time- and dose-dependent, showing highest responses after 30 min and at a steroid concentration of 10(-8) and 10(-6) M. Immunocytochemistry for phosphorylated Akt (pAkt) demonstrated that pAkt is predominantly found in a nuclear/perinuclear position and that oestrogen exposure increased the number of pAkt-positive cells. To investigate the mechanisms which are involved in transmitting oestrogen effects on the cellular level, cells were treated with antagonists for distinct signalling pathways. The application of the nuclear ER antagonist ICI 182 780 did not abolish the oestrogen-induced Akt phosphorylation. In contrast, interrupting intracellular calcium signalling with BAPTA completely prevented this effect. The PI3-kinase inhibitor LY294002 also inhibited the activation of Akt by oestrogen. Our study clearly indicates that oestrogen can rapidly stimulate the PI3-kinase/Akt signalling cascade in differentiating midbrain neurones. This effect requires the intermediate activation of calcium-dependent signalling pathways. In conclusion, oestrogen effects in the developing midbrain appear to be connected with the PI3-kinase/Akt signalling mechanism.

Animals↗
PubMed2001

Interactions of estrogens and insulin-like growth factor-I in the brain: implications for neuroprotection.

Data from epidemiological studies suggest that the decline in estrogen following menopause could increase the risk of neurodegenerative diseases. Furthermore, experimental studies on different animal models have shown that estrogen is neuroprotective. The mechanisms involved in the neuroprotective effects of estrogen are still unclear. Anti-oxidant effects, activation of different membrane-associated intracellular signaling pathways, and activation of classical nuclear estrogen receptors (ERs) could contribute to neuroprotection. Interactions with neurotrophins and other growth factors may also be important for the neuroprotective effects of estradiol. In this review we focus on the interaction between insulin-like growth factor-I (IGF-I) and estrogen signaling in the brain and on the implications of this interaction for neuroprotection. During the development of the nervous system, IGF-I promotes the differentiation and survival of specific neuronal populations. In the adult brain, IGF-I is a neuromodulator, regulates synaptic plasticity, is involved in the response of neural tissue to injury and protects neurons against different neurodegenerative stimuli. As an endocrine signal, IGF-I represents a link between the growth and reproductive axes and the interaction between estradiol and IGF-I is of particular physiological relevance for the regulation of growth, sexual maturation and adult neuroendocrine function. There are several potential points of convergence between estradiol and IGF-I receptor (IGF-IR) signaling in the brain. Estrogen activates the mitogen-activated protein kinase (MAPK) pathway and has a synergistic effect with IGF-I on the activation of Akt, a kinase downstream of phosphoinositol-3 kinase. In addition, IGF-IR is necessary for the estradiol induced expression of the anti-apoptotic molecule Bcl-2 in hypothalamic neurons. The interaction of ERs and IGF-IR in the brain may depend on interactions between neural cells expressing ERs with neural cells expressing IGF-IR, or on direct interactions of the signaling pathways of alpha and beta ERs and IGF-IR in the same cell, since most neurons expressing IGF-IR also express at least one of the ER subtypes. In addition, studies on adult ovariectomized rats given intracerebroventricular (i.c.v.) infusions with antagonists for ERs or IGF-IR or with IGF-I have shown that there is a cross-regulation of the expression of ERs and IGF-IR in the brain. The interaction of estradiol and IGF-I and their receptors may be involved in different neural events. In the developing brain, ERs and IGF-IR are interdependent in the promotion of neuronal differentiation. In the adult, ERs and IGF-IR interact in the induction of synaptic plasticity. Furthermore, both in vitro and in vivo studies have shown that there is an interaction between ERs and IGF-IR in the promotion of neuronal survival and in the response of neural tissue to injury, suggesting that a parallel activation or co-activation of ERs and IGF-IR mediates neuroprotection.

Animals↗
PubMed2001

Photon shielding for a positron emission tomography suite.

This paper provides information on the effects of distance and attenuation in lead sheet and gypsum board of the 0.511 MeV photon produced by positron annihilation. Exposure rates are projected external to an adult injected with 185 MBq (5 mCi) of 18F in a fluorodeoxyglucose solution and for the same activity in a small unshielded container. These data have been applied to estimate the shielding requirements for the Positron Emission Tomography (PET) suite operated by the Nuclear Medicine Department of Our Lady of the Lake Regional Medical Center. To assure that exposures are as low as reasonably achievable, lead was added to the walls of the room where the 18F is stored, handled, and injected into the patients. The PET scanner is installed in a room that formerly contained a Computerized Axial Tomography scanner; the existing 1.6 mm of lead sheet was left in place even though it is not required for personnel protection. During the initial phase of operation, a shield test program was conducted to estimate annual exposures to personnel inside and outside the suite. Projection of measured rates over a year of operation demonstrate that whole body doses are well below regulatory limits.

Adult↗
PubMed2000

Molecular identification and epidemiological tracing of Pasteurella multocida meningitis in a baby.

We report a case of Pasteurella multocida meningitis in a 1-month-old baby exposed to close contact with two dogs and a cat but without any known history of injury by these animals. 16S rRNA gene sequencing of the isolate from the baby allowed identification at the subspecies level and pointed to the cat as a possible source of infection. Molecular typing of Pasteurella isolates from the animals, from the baby, and from unrelated animals clearly confirmed that the cat harbored the same P. multocida subsp. septica strain on its tonsils as the one isolated from the cerebrospinal fluid of the baby. This case stresses the necessity of informing susceptible hosts at risk of contracting zoonotic agents about some basic hygiene rules when keeping pets. In addition, this study illustrates the usefulness of molecular methods for identification and epidemiological tracing of Pasteurella isolates.

Animals↗
PubMed1999

In vitro scanning saturation mutagenesis of all the specificity determining residues in an antibody binding site.

For the first time, each specificity determining residue (SDR) in the binding site of an antibody has been replaced with every other possible single amino acid substitution, and the resulting mutants analyzed for binding affinity and specificity. The studies were conducted on a variant of the 26-10 antidigoxin single chain Fv (scFv) using in vitro scanning saturation mutagenesis, a new process that allows the high throughput production and characterization of antibody mutants [Burks,E.A., Chen,G., Georgiou,G. and Iverson,B.L. (1997) Proc. Natl Acad. Sci. USA, 94, 412-417]. Single amino acid mutants of 26-10 scFv were identified that modulated specificity in dramatic fashion. The overall plasticity of the antibody binding site with respect to amino acid replacement was also evaluated, revealing that 86% of all mutants retained measurable binding activity. Finally, by analyzing the physical properties of amino acid substitutions with respect to their effect on hapten binding, conclusions were drawn regarding the functional role played by the wild-type residue at each SDR position. The reported results highlight the value of in vitro scanning saturation mutagenesis for engineering antibody binding specificity, for evaluating the plasticity of proteins, and for comprehensive structure-function studies and analysis.

Amino Acids↗
PubMed1997

Correlation between bronchoalveolar lavage (BAL) fluid cell lysate histamine content and BAL fluid eosinophil count in atopic and nonatopic asthmatics.

We have compared the bronchoalveolar lavage fluid (BAL) cellular composition and the BAL cell lysate histamine content (fluorometric assay) in 28 stable mild to moderate asthmatics (atopic n = 18 and intrinsic n = 10) and 11 control subjects. When compared to control subjects, the whole group of asthmatics had a higher proportion of BAL eosinophils (p < 0.01) and metachromatic cells (p < 0.05). The BAL cell lysate histamine was increased in atopic (p < 0.05) and intrinsic asthmatics (p < 0.05) in comparison with control subjects. In the whole group of asthmatics, the BAL cell lysate histamine content correlated with the percentage of BAL eosinophils (r = 0.58, p < 0.01). This relationship was significant in both atopic (r = 0.48, p < 0.05) and intrinsic (r = 0.70, p < 0.05) asthmatics. For the whole group of asthmatics, both the BAL cell lysate histamine and the percentage of BAL eosinophils inversely correlated with the percent predicted FEV1 (r = -0.42, p < 0.05; r = -0.51, p < 0.05). We conclude that an increased BAL cell lysate histamine content correlates with airway eosinophilic infiltration and lung function impairment in mild to moderate atopic and intrinsic asthmatics. This suggests that BAL mast cells play a key role in recruiting eosinophils in the airways of asthmatics irrespective of the presence of an atopic status.

Adult↗
PubMed1995

Regulation of histamine release from human bronchoalveolar lavage mast cells by stem cell factor in several respiratory diseases.

We investigated the effects of stem cell factor (SCF) on histamine release (HR) from human bronchoalveolar lavage (BAL) mast cells. BAL cells were recovered from lavage performed in patients undergoing clinical bronchoscopy. SCF (0.02-20 ng/ml), which is by itself a poor secretagogue (mean +/- SEM HR: 3.7 +/- 0.9%; n = 27), strongly enhanced HR induced by anti-IgE in a concentration-related manner. Significant potentiation began at 0.2 ng/ml (30 +/- 10%; p < 0.05; n = 12) and reached a plateau at 2 ng/ml (40 +/- 10%; P < 0.01 at 2 ng/ml and 45 +/- 10%; P < 0.01 at 20 ng/ml; n = 12). In contrast, SCF failed to enhance HR induced by calcium ionophore A23187. Among the BAL cell samples initially unresponsive to anti-IgE (55% of samples), 36% (10/28) were converted to responders if the cells were shortly preincubated with SCF. In 25% of samples (7/27), SCF (20 ng/ml) caused direct HR of 10 +/- 2.1%. The mast cells which released histamine when challenged with SCF also secreted higher levels of histamine in response to anti-IgE and calcium ionophore than those nonresponsive to SCF. While interleukin (IL)-3 and IL-5 (20 ng/ml) were unable to modulate immunologic HR, GM-CSF (20 ng/ml) produced significant potentiation (P < 0.05), which was, however, smaller than that observed with SCF.(ABSTRACT TRUNCATED AT 250 WORDS)

Adjuvants, Immunologic↗
PubMed1991

Inhibition of complement activity in murine leprosy.

NIH mice infected with Mycobacterium lepraemurium (MLM) show a marked depression in their levels of hemolytic complement that is proportional to the degree of infection. The defect affects more the activation of complement through the classical pathway (CPW) than the activation of complement through the alternative pathway. Although this low activity of CPW-complement may be due to different causes (complement consumption by the infecting microorganism, lack of biosynthesis of complement components, or the presence of complement inhibitory factors), our results seem to support the last possibility. The generation of factors in the infected animals that inhibit the autologous activity of complement as the infection goes on reduces the risk of complement-mediated tissue damage and prolongs the survival time of the host, a wise strategy on the part of the MLM to assure its own survival as a parasite.

Animals↗
PubMed1985

Squamous cell carcinoma of the head and neck in patients under 40 years of age.

Between 1960 and 1983, 63 of 3,489 patients treated for squamous cell carcinoma of the head and neck at the University of Iowa Hospitals and Clinics, Iowa City, were under the age of 40 years. Malignancies in these patients occurred in the oral cavity (41%), pharynx (28%), larynx (25%), and other sites (6%). One third of the patients were females and half the patients were smokers. Approximately 50% of the patients presented with a cervical mass. Management consisted of surgery, radiation, or a combination of the two. Actuarial five-year survival for the entire group was 67%. The best prognosis was for patients with cancer of the larynx, while the poorest was for those with cancer of the pharynx.

Adolescent↗
PubMed1979

Symptomatic coccidioidomycosis following a severe natural dust storm. An outbreak at the Naval Air Station, Lemoore, Calif.

Eighteen newly diagnosed cases of symptomatic cocidioidomycosis developed two to four weeks following exposure to a severe natural dust storm. The population at risk consisted of 26,000 residents of the San Joaquin Valley with access to health care at the Naval Hospital, Lemoore, Calif. Eight patients were white, and ten were nonwhite. The number of cases per 100,000 was estimated to be 36 for the white group and 254 for the nonwhite group. The disease was disseminated in four patients, and all were from the nonwhite group. One patient with disseminated disease, a black man, died. These data suggest that nonwhites may be relatively more susceptible to acquiring primary disease, in addition to developing disseminated disease. Dust storms of this magnitude must be considered a threat to health for populations living within areas endemic for coccidioidomycosis.

ABO Blood-Group System↗