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Biomedical subjects

L Sanz

Publications and source records attributed to L Sanz.

At least 19 recordsLinked to original sources

Ordered quantization and the Ehrenfest time scale.

We propose a prescription to quantize classical monomials in terms of symmetric and ordered expansions of noncommuting operators of a bosonic theory. As a direct application of such quantization rules, we quantize a classically time evolved function O(q,p,t), and calculate its expectation value in coherent states. The result can be expressed in terms of the application of a classical operator that performs a Gaussian smoothing of the original function O evaluated at the center of the coherent state. This scheme produces a natural semiclassical expansion for the quantum expectation values at a short time scale. Moreover, since the classical Liouville evolution of a Gaussian probability density gives the same form for the classical statistical mean value, we can calculate the first-order correction in h entirely from the associated classical time evolved function. This allows us to write a general expression for the Ehrenfest time in terms of the departure of the centroid of the quantum distribution from the classical trajectory, provided we start with an initially coherent state for each subsystem. In order to illustrate this approach, we have calculated analytically the Ehrenfest time of a model with N-coupled nonlinear oscillators with nonlinearity of even order.

Journal Article↗

Clinical significance of the epidermal growth factor receptor and HER2 receptor in resectable gastric cancer.

BACKGROUND: Epidermal growth factor receptor (EGFR or HER1) and its homolog c-erbB-2 (HER2) are membrane receptors. Both EGFR and HER2 genes are overexpressed in a variety of solid human cancers and are related to poor prognosis of the patients. The objective of this work was to evaluate the EGFR and HER2 contents in resectable gastric cancer, their possible relationship with clinicopathologic parameters of tumors, and their prognostic significance. METHODS: This was a prospective analysis of 63 patients with resectable gastric carcinomas, with a mean follow-up period of 40.7 months. Membranous EGFR levels were examined by radioligand binding assays, and cytosolic HER2 levels were examined by means of an immunoenzymatic assay. RESULTS: There was a wide variability of EGFR (1-1,239 fmol/mg of protein) and HER2 (7-20,863 NHU/mg of protein) levels in tumors. There was no significant correlation between these levels and patient or tumor characteristics. However, high levels of EGFR and HER2 were significantly associated with a shorter overall survival period (P =.03 and P =.02, respectively). CONCLUSIONS: There is a wide variability in membranous EGFR levels and in cytosolic HER2 levels in gastric cancer, which seems to be related to the biological heterogeneity of these tumors. In addition, high tumor EGFR and HER2 levels were associated with an unfavorable outcome in patients with resectable gastric cancer.

Adenocarcinoma↗

Single-chain antibody-based gene therapy: inhibition of tumor growth by in situ production of phage-derived human antibody fragments blocking functionally active sites of cell-associated matrices.

Experimental evidence suggests that blocking the interactions between endothelial cells and extracellular matrix (ECM) components may provide a potent and general strategy to inhibit tumor neovascularization. Based on these considerations, we have focused our efforts on laminin, component of the vascular basement membrane of every tumor-associated vessel, which serves an essential role in tube formation. We screened anti-laminin single-chain antibody fragments (scFv) derived from a human phage-display library and identified one that blocks the formation of capillary-like structures in vitro. This scFv inhibits angiogenesis in vivo in the chick embryo chorioallantoic membrane assay and prevents the establishment and growth of subcutaneous tumors in mice, either when administered as bolus protein therapy or when produced locally by gene-modified tumor cells. Our work represents the first demonstration of a direct in vivo therapeutic effect of a single-chain antibody secreted by gene-modified mammalian cells. These results open the way for a new antibody-based gene therapy strategy of cancer.

Animals↗

Purification, crystallization and identification by X-ray analysis of a prostate kallikrein from horse seminal plasma.

The purification, crystallization and identification by X-ray diffraction analysis of a horse kallikrein is reported. The protein was purified from horse seminal plasma. Crystals belong to space group C2 and the structure was solved by the MIRAS method, with two heavy-atom derivatives of mercury and platinum. X-ray diffraction data to 1.42 A resolution were collected at the ESRF synchrotron-radiation source.

Amino Acid Sequence↗

Generation and characterization of recombinant human antibodies specific for native laminin epitopes: potential application in cancer therapy.

Laminins are specific cellular regulators that directly and indirectly control activities such as cell attachment and migration, differentiation and polarity, proliferation and apoptosis, and protease expression. Considering the centrality of these issues to tumor progression, the generation of human-derived antibody fragments able to modulate laminin-regulated biological functions would allow the development of new strategies to improve treatment of cancer patients. In this report, we explore the use of phage display technology to isolate human anti-laminin antibody fragments. A library of single chain antibodies was selected using intact mouse laminin, and five different clones were identified. All the antibodies were specific for their cognate antigen, as revealed by lack of cross-reactivity with other components of the basement membranes. A more extensive characterization of the panel indicated that these antibodies recognize the native protein through conformational epitopes. All of them reduced tumor cell attachment to laminin, suggesting that domains of the laminin molecule that are recognized by these antibodies likely bind to cell-surface receptors. The antibody fragments bind to mouse, rat and human laminin. and show strong immunohistochemical reactivity with basement membranes in human and murine tissue sections. Their properties make them ideal candidates for in vivo applications.

Animals↗

Clinical course, treatment, and multivariate analysis of risk factors for pyogenic liver abscess.

BACKGROUND: Pyogenic liver abscess is a threatening condition. The purpose of this study was to audit the clinical behavior and to analyze the risk factors. METHODS: One hundred and thirty-three patients treated in five hospitals during the years 1985 to 1997 were studied. By univariate and multivariate analysis we tried to identify any risk factor associated with complicated clinical course and complicated-related clinical course, and with hospital mortality. RESULTS: Sixty-three patients (47%) were subjected to a percutaneous drainage, 45 (34%) were treated by open surgical drainage, and the remaining 25 cases (19%) received antibiotic therapy alone. Prognostic variables for a complicated clinical course were the presence of shock, low hemoglobin level, elevated prothrombin time, and polymicrobial infection. Shock, distress, low hemoglobin level, increased creatinine, and positive blood culture were significant predictors of a complicated-related clinical course. Concerning mortality, a biliary origin, shock, multiple abscesses, low hemoglobin level, and high concentration of blood urea nitrogen were independent predictors. CONCLUSIONS: Treatment of pyogenic liver abscesses should be tailored to each patient, however, the majority of them can be successfully treated with antibiotics and percutaneous methods. Those with signs of organ failure or septicemia should preferably be managed in the intensive care unit.

Anti-Bacterial Agents↗

Targeted disruption of the zetaPKC gene results in the impairment of the NF-kappaB pathway.

Here we have addressed the role that zetaPKC plays in NF-kappaB activation using mice in which this kinase was inactivated by homologous recombination. These mice, although grossly normal, showed phenotypic alterations in secondary lymphoid organs reminiscent of those of the TNF receptor-1 and of the lymphotoxin-beta receptor gene-deficient mice. The lack of zetaPKC in embryonic fibroblasts (EFs) severely impairs kappaB-dependent transcriptional activity as well as cytokine-induced phosphorylation of p65. Also, a cytokine-inducible interaction of zetaPKC with p65 was detected which requires the previous degradation of IkappaB. Although in zetaPKC-/- EFs this kinase is not necessary for IKK activation, in lung, which abundantly expresses zetaPKC, IKK activation is inhibited.

Acetylcysteine↗

Linear discrete population models with two time scales in fast changing environments I: autonomous case.

In this work we consider a structured population with groups and subgroups of individuals. The intra-group dynamics is assumed to be fast in comparison with the inter-group dynamics. We study linear discrete models where the slow dynamics is represented by a single matrix and the fast dynamics is described by means of the first k terms of a converging sequence of different matrices. The number k can be interpreted as the ratio between the two time scales. The aim of this work is to extend aggregation techniques to the case of fast changing environments. The main idea of aggregation is to build up a new system, with lower dimension, that summarizes the information concerning the fast process. This "aggregated" system provides essential information on the original one. It is shown that the asymptotic behavior of the original system can be approximated by the asymptotic behavior of the aggregated system when the ratio between the two time scales is large enough. We present an example of an age structured population in a patchy environment. The migration process is assumed to be fast in comparison with the demographic process. Numerical simulations illustrate that the asymptotic growth rate and the stable age distribution of the population in the original and the aggregated systems are getting closer as the ratio k increases.

Animals↗

The class II tumor-suppressor gene RARRES3 is expressed in B cell lymphocytic leukemias and down-regulated with disease progression.

The molecular pathogenesis of B cell chronic lymphocytic leukemia (B-CLL), the most common form of leukemia, remains unknown. We have used the mRNA differential display technique to analyze genes that may be involved in the development/progression of B-CLL. We have identified the tumor suppressor retinoic acid receptor responder 3 (RARRES3) as a B-CLL-related gene. RARRES3 maps to chromosome band 11q23, a region frequently deleted in lymphoproliferative disorders. To assess the potential involvement of RARRES3 in leukemogenesis, we examined 24 cases of B-CLL, 10 of acute lymphocytic leukemia (ALL) and five related cell lines by RT-PCR and sequence analyses. We report a correlation between RARRES3 down-regulation and B-CLL progression. We also found decreased RARRES3 gene levels in ALL cases and in the five cell lines studied. We did not find mutations in any of the leukemia samples assayed, including those with 11q23 deletion. These results indicate that RARRES3 may play a role in B-CLL progression.

Adolescent↗

Single and multiple pyogenic liver abscesses: etiology, clinical course, and outcome.

BACKGROUND: Pyogenic liver abscesses are uncommon but they still carry a high mortality rate when encountered. This study was undertaken to evaluate the differences in the clinical behaviour of patients with single and multiple abscesses. METHODS: From January 1985 to December 1997, 133 patients with this disease were treated in the surgical departments of five hospitals, 97 had a single abscess and 36 had multiple abscesses. Clinical features, methods of treatment, and outcome were assessed and compared in both types of abscesses. RESULTS: A biliary origin from ascending cholangitis was most frequently found in multiple abscesses (p = 0.007). Mean age and duration of symptoms were higher in multiple lesions (p = 0.03 and p = 0.001). High levels of alkaline phosphatase were more frequently seen in multiple abscesses than in solitary ones (p = 0.02). They were both most frequently located on the right side. Antibiotic therapy alone was most frequently used in multiple abscesses (p = 0.01). Mortality rate was also higher in this type of patients (p = 0.01). The abscess-related morbidity rate was higher in multiple lesions as well but the statistical difference was not significant. CONCLUSIONS: These results suggest that multiple liver abscesses comprise a disease of biliary origin, higher age, longer symptomatic periods, and also higher mortality rate than in single abscess.

Aged↗

The atypical PKC-interacting protein p62 channels NF-kappaB activation by the IL-1-TRAF6 pathway.

The atypical protein kinase C (aPKC)-interacting protein, p62, has previously been shown to interact with RIP, linking these kinases to NF-kappaB activation by tumor necrosis factor alpha (TNFalpha). The aPKCs have been implicated in the activation of IKKbeta in TNFalpha-stimulated cells and have been shown to be activated in response to interleukin-1 (IL-1). Here we demonstrate that the inhibition of the aPKCs or the down-regulation of p62 severely abrogates NF-kappaB activation by IL-1 and TRAF6, suggesting that both proteins are critical intermediaries in this pathway. Consistent with this we show that p62 selectively interacts with the TRAF domain of TRAF6 but not that of TRAF5 or TRAF2 in co-transfection experiments. The binding of endogenous p62 to TRAF6 is stimulus dependent, reinforcing the notion that this is a physiologically relevant interaction. Furthermore, we demonstrate that the N-terminal domain of TRAF6, which is required for signaling, interacts with zetaPKC in a dimerization-dependent manner. Together, these results indicate that p62 is an important intermediary not only in TNFalpha but also in IL-1 signaling to NF-kappaB through the specific adapters RIP and TRAF6.

Adaptor Proteins, Signal Transducing↗

HLA class I and class II allele distribution in the Peruvian population.

The distribution of HLA-A, -B, -C, -DRB1 and -DQB1 alleles in the Peruvian population was studied and compared with those of other populations in order to provide further information about their anthropological origin. Our data are consistent with the Mestizo character of this population. In terms of genetic distance Peruvians are closest to Bolivians, which is in agreement with the geographical location and the cultural and anthropological background of the two human groups. Several HLA-B alleles originally described in genetically isolated Amerindian tribes are also present in the sample studied here. This fact and the reported finding of these alleles in several Amerindian groups suggests that they were present in the first wave of humans that populated South America (Paleoindians) before they split to give rise to the different South American tribes.

Asian People↗

The disulfide bond pattern of catrocollastatin C, a disintegrin-like/cysteine-rich protein isolated from Crotalus atrox venom.

The disulfide bond pattern of catrocollastatin-C was determined by N-terminal sequencing and mass spectrometry. The N-terminal disintegrin-like domain is a compact structure including eight disulfide bonds, seven of them in the same pattern as the disintegrin bitistatin. The protein has two extra cysteine residues (XIII and XVI) that form an additional disulfide bond that is characteristically found in the disintegrin-like domains of cellular metalloproteinases (ADAMs) and PIII snake venom Zn-metalloproteinases (SVMPs). The C-terminal cysteine-rich domain of catrocollastatin-C contains five disulfide bonds between nearest-neighbor cysteines and a long range disulfide bridge between CysV and CysX. These results provide structural evidence for a redefinition of the disintegrin-like and cysteine-rich domain boundaries. An evolutionary pathway for ADAMs, PIII, and PII SVMPs based on disulfide bond engineering is also proposed.

Amino Acid Motifs↗

Correlation of central venous pressure with Doppler waveform of the common femoral veins.

The objects of this prospective study were to determine the nature of the flow in the right femoral vein and to correlate the flow velocity with the venous pressure measured in the right atrium. We performed 236 pulsed Doppler ultrasonographic examinations in 1 year on patients with a venous catheter with the distal tip in the right atrium. In the Doppler wave readouts we analyzed wave frequency, velocity components, and relationships among them and the existence of pulsatile flow. These parameters were then compared to the right atrium pressure. We investigated the correlation between the atrium pressure and the flow velocity obtained from the Doppler waveforms of the common femoral veins, obtaining a significant correlation (P<0.0001) with the following: the atrium systolic wave a, the atrium diastolic wave v, the pulsatility ratio (PR = Vmin/Vmax) and the pulsatility index (PI = [Vmax - Vmin] /Vavg). The receiver operating characteristic showed that the pulsed Doppler ultrasonography is not a sensitive technique in diagnosis high atrium pressures. In addition, both cardiac and respiratory phasicity of the venous wave was observed. A significant inverse relation was found between the pulsatile flow and high atrium pressure. Nonetheless, the low sensitivity of this technique does not allow the use of pulsatile Doppler ultrasonography in the common femoral vein for diagnosing increases of the atrium pressure.

Adolescent↗

The interaction of p62 with RIP links the atypical PKCs to NF-kappaB activation.

The two members of the atypical protein kinase C (aPKC) subfamily of isozymes (zetaPKC and lambda/iotaPKC) are involved in the control of nuclear factor kappaB (NF-kappaB) through IKKbeta activation. Here we show that the previously described aPKC-binding protein, p62, selectively interacts with RIP but not with TRAF2 in vitro and in vivo. p62 bridges the aPKCs to RIP, whereas the aPKCs link IKKbeta to p62. In this way, a signaling cascade of interactions is established from the TNF-R1 involving TRADD/RIP/p62/aPKCs/IKKbeta. These observations define a novel pathway for the activation of NF-kappaB involving the aPKCs and p62. Consistent with this model, the expression of a dominant-negative mutant lambda/iotaPKC impairs RIP-stimulated NF-kappaB activation. In addition, the expression of either an N-terminal aPKC-binding domain of p62, or its C-terminal RIP-binding region are sufficient to block NF-kappaB activation. Furthermore, transfection of an antisense construct of p62 severely abrogates NF-kappaB activation. Together, these results demonstrate that the interaction of p62 with RIP serves to link the atypical PKCs to the activation of NF-kappaB by the TNFalpha signaling pathway.

Adaptor Proteins, Signal Transducing↗

Variables aggregation in a time discrete linear model.

In this work we extend approximate aggregation methods to deal with a very general linear time discrete model. Approximate aggregation consists in describing some features of the dynamics of a general system in terms of the dynamics of a reduced system governed by a few global variables. We present a time discrete model for a structured population (i.e., the population is subdivided in subpopulations) in which we can distinguish two processes of a general nature and whose corresponding time scales are very different from each other. We transform the general system to make the global variables appear and obtain the reduced system. These global variables are, for each subpopulation, a certain linear combination of the corresponding state variables. We show that, under quite general conditions, the asymptotic behavior of the reduced system can be known in terms of the corresponding behavior for the reduced system. The general method is applied to aggregate a multiregional Leslie model in which the demographic process is supposed to be fast with respect to migration.

Canada↗

Characterisation of the conformational and quaternary structure-dependent heparin-binding region of bovine seminal plasma protein PDC-109.

PDC-109, the major heparin-binding protein of bull seminal plasma, binds to sperm choline lipids at ejaculation and modulates capacitation mediated by heparin. Affinity chromatography on heparin-Sepharose showed that polydisperse, but not monomeric, PDC-109 displayed heparin-binding capability. We sought to characterise the surface topology of the quaternary structure-dependent heparin-binding region of PDC-109 by comparing the arginine- and lysine-selective chemical modification patterns of the free and the heparin-bound protein. A combination of reversed-phase peptide mapping of endoproteinase Lys-C-digested PDC-109 derivatives and mass spectrometry was employed to identify modified and heparin-protected residues. PDC-109 contains two tandemly arranged fibronectin type II domains (a, Cys24-Cys61; b, Cys69-Cys109). The results show that six basic residues (Lys34, Arg57, Lys59, Arg64, Lys68, and Arg104) were shielded from reaction with acetic anhydride and 1,2-cyclohexanedione in heparin-bound PDC-109 oligomers. In the 1H-NMR solution structures of single fibronectin type II domains, residues topologically equivalent to PDC-109 Arg57 (Arg104) and Lys59 lay around beta-strand D on the same face of the domain. In full-length PDC-109, Arg64 and Lys68 are both located in the intervening polypeptide between domains a and b. Our data suggest possible quaternary structure arrangements of PDC-109 molecules to form a heparin-binding oligomer.

Acetic Anhydrides↗