Showing papers by "Hebron University published in 2003"

ZD1839, a specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, induces the formation of inactive EGFR/HER2 and EGFR/HER3 heterodimers and prevents heregulin signaling in HER2-overexpressing breast cancer cells.

Abstract: Purpose: ZD1839 is a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR) that has shown clinical activity against EGFR-expressing tumors. Our aim was to explore the effects of ZD1839 in breast cancer cell lines expressing different levels of EGFR and the closely related HER2 receptor. Experimental Design: We studied the growth-inhibitory effects of ZD1839 in a series of breast carcinoma cell lines. In HER2-overexpressing BT-474 breast cancer cells, we studied the effects of ZD1839 on cell growth and heterodimerization of receptors under basal and ligand-stimulated conditions. Results: ZD1839 was an equally potent inhibitor of growth in breast cancer cells expressing high levels of EGFR and HER2. In BT-474 breast cancer cells, ZD1839 abolished EGF- and heregulin-induced activation of ErbB receptors and downstream signaling molecules. Because ZD1839 does not inhibit the HER2 tyrosine kinase in vitro , and because heregulin is a ligand that activates HER2 by binding to HER3 and HER4 but does not bind to the EGFR, our findings suggested that ZD1839 interfered with HER2 function in intact cells. Searching for mechanisms, we report that ZD1839 induces the formation of inactive unphosphorylated EGFR/HER2 and EGFR/HER3 heterodimers. Furthermore, ZD1839 completely abolishes basal and heregulin-induced formation of active phosphorylated HER2/HER3 heterodimers. Conclusions : ZD1839 inhibits the growth of HER2-overexpressing breast cancer cells, possibly by sequestration of HER2 and HER3 receptors in an inactive heterodimer configuration with the EGFR. Our findings suggest that there is a strong rationale to conduct clinical trials of ZD1839 in patients with HER2-overexpressing breast tumors.

Phase II trial of antiepidermal growth factor receptor antibody C225 in patients with advanced renal cell carcinoma.

Abstract: Fifty-five patients with metastatic renal cell carcinoma (RCC) were treated on a multicenter, single-arm Phase II trial. Patients received single-agent Cetuximab (C225) administered by intravenous infusion at a loading dose of 400 or 500 mg/m2 followed by weekly maintenance doses at 250 mg/m2. None of the patients treated with C225 achieved either a complete or partial response. The median time to progression was 57 days. The most frequently reported grade 3 or 4 toxicity treatment-related adverse events were acne (17%) and rash or dry skin (4%). The lack of clinical response or suggestion of prolonging time to progression compared to historical data with interferon-alfa supports no further study of single-agent C225 in patients with metastatic RCC.

Association between inflammatory mediators and the fibrinolysis system in infectious pleural effusions.

Abstract: The response of the fibrinolytic system to inflammatory mediators in empyema and complicated parapneumonic pleural effusions is still uncertain. We prospectively analysed 100 patients with pleural effusion: 25 with empyema or complicated parapneumonic effusion, 22 with tuberculous effusion, 28 with malignant effusion and 25 with transudate effusion. Inflammatory mediators, tumour necrosis factor-α (TNF-α), interleukin-8 (IL-8) and polymorphonuclear elastase, were measured in serum and pleural fluid. Fibrinolytic system parameters, plasminogen, tissue-type plasminogen activator (t-PA) and urokinase PA, PA inhibitor type 1 (PAI 1) and PAI type 2 concentrations and PAI 1 activity, were quantified in plasma and pleural fluid. The Wilcoxon signed-rank test was used to compare plasma and pleural values and to compare pleural values according to the aetiology of the effusion. The Pearson correlation coefficient was used to assess the relationship between fibrinolytic and inflammatory markers in pleural fluid. Significant differences were found between pleural and plasma fibrinolytic system levels. Pleural fluid exudates had higher fibrinolytic levels than transudates. Among exudates, tuberculous, empyema and complicated parapneumonic effusions demonstrated higher pleural PAI levels than malignant effusions, whereas t-PA was lowest in empyema and complicated parapneumonic pleural effusions. PAI concentrations correlated with TNF-α, IL-8 and polymorphonuclear elastase when all exudative effusions were analysed, but the association was not maintained in empyema and complicated parapneumonic effusions. A negative association found between t-PA and both IL-8 and polymorphonuclear elastase in exudative effusions was strongest in empyema and complicated parapneumonic effusions. Blockage of fibrin clearance in empyema and complicated parapneumonic effusions was associated with both enhanced levels of PAIs and decreased levels of t-PA.

Review of a promising new agent—pemetrexed disodium

Abstract: Pemetrexed disodium (ALIMTa, [pemetrexed], LY231514; Eli Lilly and Company; Indianapolis, IN), a novel antifolate antimetabolite with multiple enzyme targets involved in both pyrimidine and purine synthesis, has entered clinical trials due to its favorable pleclinical profile. Many studies utilizing the drug, as a single or combination agent, are currently ongoing, including Phase III trials in mesothelioma, nonsmall cell lung carcinoma (NSCLC) and pancreatic cancer. Promising feasibility and activity data have been obtained with pemetrexed in combination with platinum compounds and gemcitabine. The supplementation with daily oral folate could reduce the incidence of hematologic toxicities while preserving the antitumor activity of pemetrexed.

Metallothionein expression in the central nervous system of multiple sclerosis patients.

Abstract: Multiple sclerosis (MS) is a major chronic demyelinating and inflammatory disease of the central nervous system (CNS) in which oxidative stress likely plays a pathogenic role in the development of myelin and neuronal damage. Metallothioneins (MTs) are antioxidant proteins induced in the CNS by tissue injury, stress and some neurodegenerative diseases, which have been postulated to play a neuroprotective role. In fact, MT-I+II-deficient mice are more susceptible to developing experimental autoimmune encephalomyelitis (EAE), and treatment of Lewis rats with Zn-MT-II reduces EAE severity. We show here that, as in EAE, MT-I+II proteins were expressed in brain lesions of MS patients. Cells expressing MT-I+II were mainly astrocytes and activated monocytes/macrophages. Interestingly, the levels of MT-I+II were slightly increased in the inactive MS lesions in comparison with the active lesions, suggesting that MTs may be important in disease remission.

Gene expression profiling of egfr positive cancer

Abstract: The present invention concerns prognostic markers associated with EGFR positive cancer. In particular, the invention concerns prognostic methods based on the molecular characterization of gene expression in paraffin-embedded, fixed tissue samples of EGFR-expressing cancer, which allow a physician to predict whether a patient is likely to respond well to treatment with an EGFR inhibitor.

Two-Dimensional Basin Flow with Irregular Bottom Configuration

Abstract: Two-dimensional flow from a point or line source is simulated in an irrigated basin with a nonlevel soil surface; the goal is to predict the distribution uniformity of infiltrated depths. The zero-inertia approximation to the equations of motion allows computation in both wet and dry areas. A fully implicit, nonlinear finite-difference scheme is developed for the solution, but practical numerical considerations suggest local linearization instead. Both isotropic and anisotropic resistance to flow are considered. Results in basins with irregular bottom configurations and small inflows show stream advance confined to the lowest elevations in the basin.

Lack of evidence of foetal microchimerism in female Spanish patients with systemic sclerosis.

Abstract: Our objective was to study the presence of microchimerism in a series of 47 female Spanish patients with scleroderma (SSc) and to compare with a control group. Polymerase chain reaction was used to identify Y-chromosome sequences in DNA extracted from peripheral blood cells.Y-chromosome sequences were found in DNA from peripheral blood cells in four out of 47 (8.5%) patients with scleroderma (two limited and two diffuse) and in two out of 40 (5%) healthy women (no statistical differenceswere found). When we compared SSc patients and healthy controls who had had at least one male child, four out of 29 (13.7%) and two out of 26 (7.6%) had microchimerism respectively (no statistically significant differences were found). Patients with both scleroderma and persistent microchimerism had had a male offspring. Foetal microchimerism does not seem to play a major role in most cases of female Spanish patients with SSc.

Liver transplantation for hilar cholangiocarcinoma: Spanish experience.

Abstract: Introduction. Palliative treatment for nondisseminated irresectable hilar cholangiocarcinoma (HCC) carries a 0% 5-year survival rate. The role of orthotopic liver transplantation (OLT) in these patients is controversial because the survival rate is lower than that for other indications for transplantation and the lack of available donor organs. The aim of this paper was to review the Spanish experience in OLT for HCC and identify prognostic factors for survival. Methods. We retrospectively reviewed 36 patients undergoing OLT for HCC over 13 years. Results. The actuarial survival rate at 1, 3, and 5 years was 82%, 53%, and 30%, respectively. The main cause of death was tumor recurrence (53%). In the univariate analysis, the factors for a poor prognosis were vascular invasion (P .001) namely 0% survival at 3 years when present versus 63% and 35% at 3 and 5 years, respectively, when it was not; and stages III to IVA (P .05), namely 15% survival at 5 years versus 47% for stages I to II. Lymph node and perineural invasion also reduce survival. In the multivariate analysis, the factors for poor prognosis included vascular invasion (P .01) and stages III to IVA (P .01). Conclusions. OLT for nondisseminated irresectable HCC has higher survival rates at 3 and 5 years than palliative treatments, especially with initial stage tumors, which means that more information is needed to better select cholangiocarcinoma patients for transplantation.

Adult-onset subacute sclerosing panencephalitis: clinico-pathological findings in 2 new cases.

Abstract: Subacute sclerosing panencephalitis (SSPE), an uncommon disease usually affecting children and adolescents, is caused by persistent measles infection that progresses to chronic infection with fatal outcome. The debut of this disease in adults is rare, with a small number of cases in the medical literature. This article presents the clinical, radiologic and post-mortem neuropathologic findings in 2 new cases of women with SSPE (1 of them during pregnancy), which showed very atypical clinical characteristics, presentation and evolution. The influence of pregnancy on the course of the disease was unfavorable, in keeping with earlier reports. Our patients showed a very prolonged biphasal clinical course, with a period of disease-free remission that lasted several years. Histological study disclosed features of inflammatory disease associated with others of a neurodegenerative nature, such as the formation of neurofibrillary tangles, which would relate SSPE with other tauopathies.

Liver transplantation for peripheral cholangiocarcinoma: Spanish experience

Abstract: Introduction Palliative treatment for nondisseminated unresectable peripheral cholangiocarcinoma (PCC) carries a 0% 5-year survival rate. The role of orthotopic liver transplantation (OLT) in these patients is controversial because the survival rate is lower than with other indications for transplantation and the lack of available donor organs. The aim of this paper was to review the Spanish experience in OLT for PCC to identify prognostic factors for survival. Methods We retrospectively reviewed 23 patients undergoing OLT in Spain for PCC over a period of 13 years. Results The actuarial survival rates were 77%, 65%, and 42% at 1, 3, and 5 years, respectively. The main cause of death was tumor recurrence (35%). Prognotic factors for an adverse outcome were pTNM classification (P Conclusions OLT for nondisseminated irresectable PCC displays higher survival rates at 3 and 5 years than palliative treatments, especially for tumors in the initial stages, which means that more information is needed to help better select PCC patients for transplantation.

Encapsulation of nickel(II) and copper(II) by a tetraazamacrocyclic ligand

Abstract: A tetraazamacrocyclic ligand, L, containing six non-equivalent benzene rings, derived from the condensation of benzil with 1,2- diaminobenzene, has been isolated and its complexes [MLCl2] (M = Ni2+ and Cu2+) prepared and characterized by elemental analysis, i.r., u.v.–vis., e.p.r. spectral studies, magnetic moments, redox potentials and conductivity measurements. The complexes have axially elongated octahedral geometries with two axial chlorines, and adopt the trans-configuration. These studies also indicate the covalent nature and the high-spin octahedral structure for these complexes. A cyclic voltammetric investigation reveals that the complexes exhibit a single one-electron redox couple, as anticipated for a copper(II) complex (Cu2+/Cu+) and a single two-electron redox couple for a nickel(II) complex (Ni2+/Ni0). The electrochemical processes are considered quasi-reversible. Antimicrobial activities of the ligand and the complexes have been tested against Bacillus megaterium and Candida tropicallis.

OC207: In utero therapy for congenital diaphragmatic hernia

Abstract: Objective: The purpose of this study was to evaluate the clinical value of the uterine artery color Doppler at 23 week’s gestation in predicting adverse perinatal outcomes in unselected population. Methods: Uterine artery Doppler assessment was carried out at 22–25 week’s gestation in singleton pregnancies attending routine antenatal care. The mean pulsatility index (PI) was calculated and the predictive value of an average PI above 95th centiles in the detection of poor outcome was determined. Results: Transvaginal color Doppler examination was performed in 1350 consecutive singleton pregnancies and a complete outcome information was obtained in 1110 (83%) pregnancies. The median PI was 1.02 and the 95th centile was 1.57. Poor outcome, defined as preeclampsia, fetal growth restriction (FGR), abruption placenta and preterm delivery before 34 week’s, occurred in 143 (12.9%) pregnant women. The incidence of preeclampsia and FGR was 4.6% and 5.2%, respectively. The sensitivity of the mean PI above 95th centile for poor perinatal outcome was 26%, and for preeclampsia was 33%. Although, there were few cases with adverse perinatal outcome born before 35 week’s in our series (20 cases with just 6 preeclamptic pregnancies), the respective sensitivities for total adverse outcome and preeclampsia requiring delivery before 34 week’s was 45% (9 out of 20 cases) and 67% (4 out of 6 cases), respectively. Conclusions: Transvaginal uterine artery Doppler using as a screening test between 22–25 week’s identifies most of the pregnant women who develop severe adverse perinatal outcomes before 34 week’s of gestation. Supported by Fondecyt No 1020080.