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Biomedical subjects

Everardo Cobos

Publications and source records attributed to Everardo Cobos.

16 recordsLinked to original sources
PubMed2006

Cancer initiation and progression: an unsimplifiable complexity.

BACKGROUND: Cancer remains one of the most complex diseases affecting humans and, despite the impressive advances that have been made in molecular and cell biology, how cancer cells progress through carcinogenesis and acquire their metastatic ability is still widely debated. CONCLUSION: There is no doubt that human carcinogenesis is a dynamic process that depends on a large number of variables and is regulated at multiple spatial and temporal scales. Viewing cancer as a system that is dynamically complex in time and space will, however, probably reveal more about its underlying behavioural characteristics. It is encouraging that mathematicians, biologists and clinicians continue to contribute together towards a common quantitative understanding of cancer complexity. This way of thinking may further help to clarify concepts, interpret new and old experimental data, indicate alternative experiments and categorize the acquired knowledge on the basis of the similarities and/or shared behaviours of very different tumours.

Algorithms↗
PubMed2006

Epidermolysis bullosa acquisita occurring in 2 patients with hepatitis C.

We report 2 patients with documented chronic hepatitis C infection and epidermolysis bullosa acquisita (EBA). Both patients clinically represent classic EBA, exhibiting skin fragility and blistering occurring both spontaneously and secondary to trauma, which heal with milia and scar formation. EBA often is a disease of altered immune status and debility. Further work is necessary to show whether hepatitis C plays a causative role in EBA in these 2 patients and in general.

Adult↗
PubMed2005

Immunological treatment of liver tumors.

Although multiple options for the treatment of liver tumors have often been described in the past, including liver resection, radiofrequency ablation with or without hepatic pump insertion, laparoscopic liver resection and the use of chemotherapy, the potential of immunotherapy and gene manipulation is still largely unexplored. Immunological therapy by gene manipulation is based on the interaction between virus-based gene delivery systems and dendritic cells. Using viruses as vectors, it is possible to transduce dendritic cells with genes encoding tumor-associated antigens, thus inducing strong humoral and cellular immunity against the antigens themselves. Both chemotherapy and radiation therapy have the disadvantage of destroying healthy cells, thus causing severe side-effects. We need more precisely targeted therapies capable of killing cancer cells while sparing healthy cells. Our goal is to establish a new treatment for solid liver tumors based on the concept of cytoreduction, and propose an innovative algorithm.

Algorithms↗
PubMed2005

Quantitative evaluation and modeling of two-dimensional neovascular network complexity: the surface fractal dimension.

BACKGROUND: Modeling the complex development and growth of tumor angiogenesis using mathematics and biological data is a burgeoning area of cancer research. Architectural complexity is the main feature of every anatomical system, including organs, tissues, cells and sub-cellular entities. The vascular system is a complex network whose geometrical characteristics cannot be properly defined using the principles of Euclidean geometry, which is only capable of interpreting regular and smooth objects that are almost impossible to find in Nature. However, fractal geometry is a more powerful means of quantifying the spatial complexity of real objects. METHODS: This paper introduces the surface fractal dimension (Ds) as a numerical index of the two-dimensional (2-D) geometrical complexity of tumor vascular networks, and their behavior during computer-simulated changes in vessel density and distribution. RESULTS: We show that Ds significantly depends on the number of vessels and their pattern of distribution. This demonstrates that the quantitative evaluation of the 2-D geometrical complexity of tumor vascular systems can be useful not only to measure its complex architecture, but also to model its development and growth. CONCLUSIONS: Studying the fractal properties of neovascularity induces reflections upon the real significance of the complex form of branched anatomical structures, in an attempt to define more appropriate methods of describing them quantitatively. This knowledge can be used to predict the aggressiveness of malignant tumors and design compounds that can halt the process of angiogenesis and influence tumor growth.

Computer Simulation↗
PubMed2005

FAM20: an evolutionarily conserved family of secreted proteins expressed in hematopoietic cells.

BACKGROUND: Hematopoiesis is a complex developmental process controlled by a large number of factors that regulate stem cell renewal, lineage commitment and differentiation. Secreted proteins, including the hematopoietic growth factors, play critical roles in these processes and have important biological and clinical significance. We have employed representational difference analysis to identify genes that are differentially expressed during experimentally induced myeloid differentiation in the murine EML hematopoietic stem cell line. RESULTS: One identified clone encoded a previously unidentified protein of 541 amino acids that contains an amino terminal signal sequence but no other characterized domains. This protein is a member of family of related proteins that has been named family with sequence similarity 20 (FAM20) with three members (FAM20A, FAM20B and FAM20C) in mammals. Evolutionary comparisons revealed the existence of a single FAM20 gene in the simple vertebrate Ciona intestinalis and the invertebrate worm Caenorhabditis elegans and two genes in two insect species, Drosophila melanogaster and Anopheles gambiae. Six FAM20 family members were identified in the genome of the pufferfish, Fugu rubripes and five members in the zebrafish, Danio rerio. The mouse Fam20a protein was ectopically expressed in a mammalian cell line and found to be a bona fide secreted protein and efficient secretion was dependent on the integrity of the signal sequence. Expression analysis revealed that the Fam20a gene was indeed differentially expressed during hematopoietic differentiation and that the other two family members (Fam20b and Fam20c) were also expressed during hematcpoiesis but that their mRNA levels did not vary significantly. Likewise FAM20A was expressed in more limited set of human tissues than the other two family members. CONCLUSIONS: The FAM20 family represents a new family of secreted proteins with potential functions in regulating differentiation and function of hematopoietic and other tissues. The Fam20a mRNA was only expressed during early stages of hematopoietic development and may play a role in lineage commitment or proliferation. The expansion in gene number in different species suggests that the family has evolved as a result of several gene duplication events that have occurred in both vertebrates and invertebrates.

Amino Acid Sequence↗
PubMed2005

Repression and coactivation of CCAAT/enhancer-binding protein epsilon by sumoylation and protein inhibitor of activated STATx proteins.

CCAAT/enhancer-binding protein epsilon (C/EBPepsilon) is a neutrophil-specific transcription factor whose activity is controlled by juxtaposed activating and regulatory domains. We previously determined that the function of the major regulatory domain (RD1) in C/EBPepsilon was dependent on the integrity of a five-amino acid motif that was identical to the recognition site for members of the small ubiquitin-like modifier (SUMO) family of ubiquitin-related proteins. We show here that the SUMO attachment site (the regulatory domain motif) is necessary and sufficient both for the intrinsic inhibitory function of RD1 and for coactivation by PIASxalpha and PIASxbeta, two members of the protein inhibitor of activated STAT (PIAS) family of SUMO E3 ligases. PIASxbeta was a more potent coactivator than PIASxalpha of both full-length C/EBPepsilon and fusion proteins containing the N-terminal portion of C/EBPepsilon, whereas PIASxalpha was more active on fusion proteins containing a heterologous activation domain. Two modes of coactivation were observed, one that was dependent on the integrity of the RING finger (RF) domain and was shared by both PIASxalpha and PIASxbeta and a second mode that was independent of the RF and was only observed with PIASxbeta. Sumoylation of C/EBPepsilon was enhanced by coexpression of PIASxalpha, suggesting that this modification is associated with the enhanced activity of the target protein. These results suggest that a complex interplay of accessory factors, including SUMO and PIAS proteins, modulates the activity of C/EBPepsilon.

Amino Acid Motifs↗
PubMed2005

Use and specificity of breast cancer antigen/milk protein BA46 for generating anti-self-cytotoxic T lymphocytes by recombinant adeno-associated virus-based gene loading of dendritic cells.

Antigen-targeted immunotherapy is an emerging treatment for breast cancer. However, useful breast cancer antigens are only found in a subset of cancer patients. BA46, also known as lactadherin, is a membrane-associated glycoprotein that is expressed in most breast cancer cells but not in general hematopoietic cell populations. Moreover, it is much more difficult to generate CTLs against self-antigens. We wished to determine if the use of recombinant adeno-associated virus (rAAV) type 2 vectors for gene-loading of dendritic cells (DCs) could generate rapid, effective cytotoxic T lymphocytes (CTLs) against BA46. We were able to demonstrate that AAV/BA46/Neo-loading of DCs resulted in: (1) BA46 expression in DCs, (2) chromosomal integration of the AAV/BA46/Neo vector within DCs, (3) strong, rapid BA46-specific, MHC class I-restricted CTLs in only 1 week, (4) T-cell populations with significant interferon-gamma (IFN-gamma) expression but low IL-4 expression, (5) high CD80 and CD86 expression in DCs, and (6) high CD8:CD4 and CD8:CD56 T cell ratios. These data suggest that rAAV-loading of DCs may be useful for immunotherapeutic protocols against self-antigens in addition to viral antigens and that the BA46 antigen is potentially appropriate for cell-mediated immunotherapeutic protocols addressing ductal breast cancer.

Antibodies↗
PubMed2004

Determination of the serum matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in patients with either advanced small-cell lung cancer or non-small-cell lung cancer prior to treatment.

This study was undertaken to examine the relationship between circulating matrix metalloproteinase (MMP-9) and tissue inhibitor of matrix metalloproteinase (TIMP-1) in our patients with either advanced small-cell lung cancer (SCLC) or non-small-cell lung cancer (NSCLC) prior to treatment. Thirty-one male and female patients with either stage III or IV NSCLC and 17 with either stage III or IV SCLC were compared to 117 age matched non-smoking controls of both sexes. Prior to any treatment of the patient, a baseline serum sample was obtained from each of the patients for the determination of circulating MMP-9 and TIMP-1 by ELISA. The results indicate that both MMP-9 and TIMP-1 are elevated in the serum of lung cancer patients when compared to the controls. This observation was true for both SCLC and NSCLC. However, the mean values for both MMP-9 and TIMP-1 in the two tumors were not different from each other. The natural physiological relationship between MMP-9 and the inhibitor TIMP-1 was lost in both SCLC and NSCLC, indicative of abnormal alterations by the tumor. The data from this study suggests that advanced lung cancer does alter the normal circulatory pattern of MMP-9 and TIMP-1. This could aid in the processes of tumor invasion and/or metastasis.

Adult↗
PubMed2004

Is the circulating urokinase plasminogen activator upregulated by the circulating p105 fraction of the HER-2/neu proto-oncogene in patients with cervical cancer?

It has been suggested that urokinase plasminogen activator (uPA) in cancer cells is upregulated by the p185 kD form of the HER-2/neu oncogene. This study was performed to see if the extracellular domain of HER-2/neu, the p105 fraction, which is found in the circulation, has any regulatory influence on uPA in patients with cervical cancer. Levels of uPA and p105 HER-2/neu were determined in blood from age-matched controls and patients with early and advanced cervical cancer. In the patients with cervical cancer, samples were obtained before treatment only. No significant increase in either uPA or HER-2/neu was seen in the patients before their treatment for cervical cancer. Additionally, correlation analysis of circulating uPA and HER-2/neu against each other in both the controls and cervical cancer indicated no relationship except in early stage disease. It appears that circulating uPA and HER-2/neu are not altered in patients with cervical cancer, either early or advanced stages. The upregulation of uPA by HER-2/neu seen in cancer cells in vitro appears to occur in vivo in early stage cervical cancer.

Adult↗
PubMed2003

Initial management of immune thrombocytopenic purpura in adults: a randomized controlled trial comparing intermittent anti-D with routine care.

We conducted a randomized clinical trial in adults with a new diagnosis of ITP and a platelet count <30000/muL to test the hypothesis that initial intermittent treatment with anti-D may avoid or defer the need for splenectomy when compared to current routine care (glucocorticoid treatment, followed by splenectomy). Splenectomy was to be performed in the anti-D group if patients failed to respond to three consecutive anti-D treatments given within 10 days. The incidences of splenectomy were 14 of 37 (38%) in the routine care group and 14 of 33 (42%) in the anti-D group (absolute risk reduction = 4.6% in favor of the routine care group, 95% CI, -18.4 to 27.6%). However, splenectomy was performed prematurely, not according to the protocol, in 11 of 14 patients in the anti-D group. The median time to splenectomy was 36 days (range, 9-78) in the routine care group and 112 days (range, 19-558) in the anti-D group (P = 0.045 at 100 days after randomization, P = 0.840 at 1 year after randomization, using log-rank analysis). Patients in the anti-D group were treated with prednisone for fewer days (70 days) compared to the routine care group (112 days, P = 0.01). No major bleeding events occurred. In this study, initial treatment of patients with intermittent anti-D initially deferred splenectomy. Whether our aggressive regimen of anti-D could have prevented splenectomy if it had been adhered to in all patients remains uncertain. However, compliance with this anti-D regimen was not feasible for many patients and/or their physicians.

Adult↗
PubMed2003

Pretreatment determination of the serum urokinase plasminogen activator and its soluble receptor in advanced small-cell lung cancer or non-small-cell lung cancer.

This study was undertaken to evaluate the circulating urokinase plasminogen activator (uPA), and its soluble receptor (suPAR) in patients with either small-cell lung cancer (SCLC) or non-small-cell lung cancer (NSCLC). Thirty-one male and female patients with stage III or IV NSCLC and 17 with stage III or IV SCLC were compared to 138 age-matched non-smoking controls of both sexes. Before any treatment was undertaken, serum was obtained and evaluated for its content of uPA and suPAR with enzyme-linked immunosorbent assay. The results indicated a wide variation in serum uPA content that was not significant, while extremely significant increases in suPAR were found. The natural physiologic relationship between uPA and its receptor was lost in both SCLC and NSCLC, which could indicate abnormal alterations of uPA suPAR, suggesting these factors aid in the process of invasion and metastasis of lung cancer.

Biomarkers, Tumor↗
PubMed2002

Mapping gene expression patterns during myeloid differentiation using the EML hematopoietic progenitor cell line.

OBJECTIVE: The detailed examination of the molecular events that control the early stages of myeloid differentiation has been hampered by the relative scarcity of hematopoietic stem cells and the lack of suitable cell line models. In this study, we examined the expression of several myeloid and nonmyeloid genes in the murine EML hematopoietic stem cell line. METHODS: Expression patterns for 19 different genes were examined by Northern blotting and RT-PCR in RNA samples from EML, a variety of other immortalized cell lines, and purified murine hematopoietic stem cells. Representational difference analysis (RDA) was performed to identify differentially expressed genes in EML. RESULTS: Expression patterns of genes encoding transcription factors (four members of the C/EBP family, GATA-1, GATA-2, PU.1, CBFbeta, SCL, and c-myb) in EML were examined and were consistent with the proposed functions of these proteins in hematopoietic differentiation. Expression levels of three markers of terminal myeloid differentiation (neutrophil elastase, proteinase 3, and Mac-1) were highest in EML cells at the later stages of differentiation. In a search for genes that were differentially expressed in EML cells during myeloid differentiation, six cDNAs were isolated. These included three known genes (lysozyme, histidine decarboxylase, and tryptophan hydroxylase) and three novel genes. CONCLUSION: Expression patterns of known genes in differentiating EML cells accurately reflected their expected expression patterns based on previous studies. The identification of three novel genes, two of which encode proteins that may act as regulators of hematopoietic differentiation, suggests that EML is a useful model system for the molecular analysis of hematopoietic differentiation.

3T3 Cells↗
PubMed2002

Acute myeloid leukaemia arising from a patient with untreated essential thrombocythaemia.

Acute myeloid leukaemia (AML) is an uncommon complication of patients with essential thrombocythaemia (ET). We report a patient with ET which progressed into AML and who had only received a few days of therapy with hydroxyurea (HU) when diagnosed with ET. This is extremely rare, as in large series no patients who were left untreated for their ET developed this complication. This case supports the theory that AML transformation can be part of the natural history of ET in some cases.

Bone Marrow Transplantation↗
PubMedDate not supplied

Gamma-radiation upregulates MHC class I/II and ICAM-I molecules in multiple myeloma cell lines and primary tumors.

The gamma-irradiation of normal cells causes an increased synthesis of specific proteins. However, few studies have described the effects of high doses of irradiation on the expression of cell surface antigens in tumor cells. This study analyzed the effects of high doses of gamma-irradiation on the surface antigen expression of Major Histocompatability Complex (MHC) class I/II and intercellular adhesion molecule-1 (ICAM-I) in human multiple myeloma (MM) cell lines ARP-1, ARK-RS, and 10 MM primary tumors. The expression of surface antigens was evaluated by fluorescence-activated cell sorter analysis at different time points, following the exposure to high doses of gamma-irradiation. Doses of 10,000 and 15,000 cGy were not sufficient to totally block cell replication in both cell lines and primary tumors; cell replication was able to be inhibited completely only at 18,000 cGy. Lower doses (10,000 cGy) and lethal doses of irradiation (i.e., 15,000 and 18,000 cGy) increased the expression of all surface antigens present on the cells before irradiation. Essentially, such upregulation was shown to be dose dependent, with higher radiation doses resulting in higher antigen expression. Furthermore, when the kinetics of this upregulation were studied 3 and 6 d after irradiation, there was a constant increase in antigen expression in MM cells. These findings suggest that upregulation of costimulatory molecules, such as of MHC class I/II antigens and ICAM-I molecules in MM patients treated by gamma-radiation, can increase the immunogenicity of the tumor cells. In light of these findings, radiotherapy combined with immunotherapy might be considered in relapsing patients after receiving the standard treatment.

Antigens, Neoplasm↗
PubMedDate not supplied

The circulating urokinase plasminogen activator (uPA) and its soluble receptor (suPAR) are not up-regulated by the circulating P105 fraction of the HER-2/neu proto-oncogene: in vivo evidence from patients with advanced non-small cell lung cancer (NSCLC).

It has been suggested that uPA in cancer cells is up regulated by the p 185 kD form of the HER-2/neu oncogene. We elected to see if the extra cellular domain of HER-2/neu, the p 105 fraction, which is found in the circulation, has any regulatory influence on uPA or uPAR in those patients with NSCLC Levels of uPA, uPAR and p 105 HER-2/neu were determined in blood from age-matched controls and patients with advanced NSCLC. In the patients with NSCLC, samples were obtained before and following treatment. A large increase in both uPA and uPAR compared to controls was seen in the patients prior to treatment. The uPAR level post-treatment decreased from pre-treatment values, which is favorable. There was a significant increase in uPA and a decrease in HER-2/neu in the post-treatment time frame. Additionally, correlation analysis of circulating uPAR, uPA and HER-2/neu against each other in both the controls and treatment groups indicated no relationship. It appears that circulating uPA and uPAR are elevated in NSCLC patients. The up-regulation of uPA by HER-2/neu seen in lung cancer cells in vitro is apparently lost in the blood in vivo as is evidenced by the lack of correlation between them which is also true for the receptor as well.

Carcinoma, Non-Small-Cell Lung↗