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C Muro-Cacho

Publications and source records attributed to C Muro-Cacho.

14 recordsLinked to original sources
PubMed2002

An effective immunization and cancer treatment with activated dendritic cells transduced with full-length wild-type p53.

P53-based immunization is an attractive approach to cancer immunotherapy due to the accumulation of p53 protein in tumor, but not in normal cells. However, it was not known whether immune response against self-protein (p53) could be generated in vivo. Mouse dendritic cells (DCs) were transduced with adenoviral construct containing murine full-length wild-type p53 (Ad-p53). Repeated immunizations with these cells protected 60% of mice against challenge with MethA sarcoma cells bearing point mutations in p53 gene. Activation of DCs via ligation of CD40 significantly improved the results of immunization: all mice were protected against MethA sarcoma. The treatment of MethA tumor-bearing mice with activated Ad-p53-transduced DCs showed complete tumor rejection in four out of six mice. The specificity of antitumor immune response was confirmed by CTL assay. The analysis of phenotype and function of DCs demonstrated that the effect of CD40 ligation on these cells was enhanced by their infection with Ad-p53. The level of neutralizing anti-adenovirus antibody was moderately elevated in these mice. No signs of autoimmune reaction were evident during detailed pathological evaluation of treated mice. These data demonstrate that activated Ad-p53-infected DCs are able to break tolerance to this protein and can be used in immunotherapy of cancer.

Adenoviridae↗
PubMed2001

Identification of genetic alterations in the TGFbeta type II receptor gene promoter.

Modifications in the control sequences of tumor suppressor genes have been found to play a role in the activation or inactivation of these genes and may play an important role in tumorigenesis. For example, hypermethylation of CpG islands and promoter polymorphisms have been found to be involved in transcriptional repression. A decrease in the levels of expression of one such tumor suppressor gene, the TGFbeta type II receptor (TbetaR-II), has been associated with increased tumorigenicity in a number of human tumors. Genetic alterations have been described in several tumor types in the coding region of this gene. However, no comprehensive search for genetic alterations in the TbetaR-II promoter has been reported. Genetic alterations in the promoter of the TbetaR-II gene could inhibit binding of putative regulatory factors. For example, we have reported a A-364-G alteration in the TbetaR-II promoter, which results in decreased transcriptional activity. In this study, we analyzed the 1.0kb region upstream of the TbetaR-II transcriptional start site and found genetic alterations in 46% of the head and neck squamous cell carcinoma (SqCC) samples examined. The most frequent alteration was a G-875-A alteration, present in 41.6% of the samples. Analysis of normal healthy individuals showed a similar frequency of this alteration, suggesting that alterations within the TbetaR-II promoter are unlikely to account for the decreased expression of TbetaR-II in head and neck SqCC.

Base Sequence↗
PubMed2000

Cks1 mediates vascular smooth muscle cell polyploidization.

Vascular smooth muscle cells (VSMC) at capacitance arteries of hypertensive individuals and animals undergo dramatic polyploidization that contributes toward their hypertrophic phenotype. We report here the identification of a defective mitotic spindle cell cycle checkpoint in VSMC isolated from capacitance arteries of pre-hypertensive rats. These cells demonstrated a high predisposition to polyploidization in culture and failed to maintain cyclin B protein levels in response to colcemid, a mitotic inhibitor. Furthermore, this altered mitotic spindle checkpoint status was associated with the overexpression of Cks1, a Cdc2 adapter protein that promotes cyclin B degradation. Cks1 up-regulation, cyclin B down-regulation, and VSMC polyploidization were evidenced at the smooth muscle of capacitance arteries of genetically hypertensive and Goldblatt-operated rats. In addition, angiotensin II infusion dramatically increased Cks1 protein levels at capacitance arteries of normotensive rats, and angiotensin II treatment of isolated VSMC abrogated their ability to down-regulate Cks1 and maintain cyclin B protein expression in response to colcemid. Finally, transduction of VSMC from normotensive animals with a retrovirus that drives the expression of Cks1 was sufficient to alter their mitotic spindle cell cycle checkpoint status and promote unscheduled cyclin B metabolism, cell cycle re-entry, and polyploidization. These data demonstrate that Cks1 regulates cyclin B metabolism and ploidy in VSMC and may contribute to the understanding of the phenomena of VSMC polyploidization during hypertension.

Animals↗
PubMed2000

Factors affecting survival for floor-of-mouth carcinoma.

OBJECTIVES: The treatment of extensive floor-of-mouth carcinoma has remained a challenging problem for head and neck surgeons. We have reviewed our experience in the surgical management of floor-of-mouth cancer in an attempt to identify factors influencing survival. METHODS: A total of 144 patients with cancer involving the floor of the mouth were treated between March 1988 and November 1995. A retrospective chart review was conducted that captured information including clinical staging, therapeutic modalities, pathologic findings, and patient follow-up. Factors affecting survival were assessed by nonparametric analysis and analysis of variance. RESULTS: There was no statistical significance for the effects of vascular invasion (P = 0.4019), lymphatic invasion (P = 0.3430), bone invasion (P = 0.1548), or positive margins (P = 0.1113) on survival. Extranodal extension and recurrent disease were strongly suggestive of influencing survival but were not statistically significant (P = 0.0650 and P = 0.0504, respectively). Nodal disease significantly affected survival (P = 0.0138) but did not affect recurrence (P = 0.451). CONCLUSION: Mean survival for this cohort was 30.6 months. Positive node status significantly affected mean overall survival in this series, whereas extracapsular disease did not. These data suggest that aggressive surgical management of neck disease is mandated to maximize survival.

Adult↗
PubMed2000

Akt1/PKB upregulation leads to vascular smooth muscle cell hypertrophy and polyploidization.

Vascular smooth muscle cells (VSMCs) at capacitance arteries of hypertensive individuals and animals undergo marked age- and blood pressure-dependent polyploidization and hypertrophy. We show here that VSMCs at capacitance arteries of rat models of hypertension display high levels of Akt1/PKB protein and activity. Gene transfer of Akt1 to VSMCs isolated from a normotensive rat strain was sufficient to abrogate the activity of the mitotic spindle cell-cycle checkpoint, promoting polyploidization and hypertrophy. Furthermore, the hypertrophic agent angiotensin II induced VSMC polyploidization in an Akt1-dependent manner. These results demonstrate that Akt1 regulates ploidy levels in VSMCs and contributes to vascular smooth muscle polyploidization and hypertrophy during hypertension.

Angiotensin II↗
PubMed1999

Transforming growth factor beta receptors in verrucous and squamous cell carcinoma.

OBJECTIVES: To study the intracellular location of transforming growth factor beta type II receptors (TbetaR-II) in verrucous carcinoma (VC) and squamous cell carcinoma (SqCC), and to evaluate their role in the biological behavior of both neoplasias. DESIGN: Ten VC and 10 well-differentiated SqCC specimens were analyzed by immunohistochemistry and in situ hybridization for the expression and intracellular location of TbetaR-II. Receptor expression was evaluated in areas of invasion and in areas of transformation of VC into SqCC. TbetaR-II expression was compared with expression of the type I receptor (TbetaR-I). SUBJECTS: Formalin-fixed, paraffin-embedded tissue sections from VCs and well-differentiated SqCCs, operated on at the H. L. Moffitt Cancer Center and Research Institute from May 1987 to January 1998, were selected for the study. INTERVENTIONS: None. RESULTS: While in all VCs TbetaR-II was found to be located along the membrane of the neoplastic keratinocytes, TbetaR-II expression in SqCC was observed predominantly in a cytoplasmic location. This cytoplasmic location of TbetaR-II was also seen in areas of transition from VC to SqCC. Expression of TbetaR-I was found in a cytoplasmic location in both tumor types. CONCLUSIONS: The membranous location of TbetaR-II in VC exposes the receptor to the growth inhibitory control of TGF-beta and may explain why VC tumors are less aggressive clinically. The marked reduction of membranous TbetaR-II and their predominant cytoplasmic location diminishes TGF-beta growth inhibition and may contribute to the transformation of VC into the more aggressive SqCC.

Activin Receptors, Type I↗
PubMed1998

Intraoperative gamma probe-directed biopsy of asymptomatic suspected bone metastases.

BACKGROUND: Radioisotope bone scanning is frequently used in staging malignancies. However, false-positive results are common, and biopsy is usually required. In the absence of plain radiographic abnormalities or local symptoms, localization of the area of abnormal tracer activity at the time of open rib or sternum biopsy may be difficult. It often requires resection of a large portion of one or more ribs or the sternum to assure that biopsy of the target area was performed. In this setting, a small gamma probe underwent evaluation as an aid to precise intraoperative localization of increased tracer activity in the target bone. METHODS: Ten patients with asymptomatic suspected osseous chest metastases by radioisotope bone scanning but with normal plain radiographs underwent open biopsy of 13 ribs and 1 sternum. Six to 12 hours before operation, each received an intravenous injection of 28 mCi of technetium-99m oxidronate. The hand-held, pencil-sized gamma probe in a sterile sleeve was used to localize the area of greatest activity in the target bone, once the bone was exposed through a small incision. Biopsy of a 3-cm length of rib or portion of sternum was performed. In the first two rib biopsies, an intraoperative radiograph with a radiopaque marker on the rib confirmed that the correct rib was selected for biopsy. Intraoperative radiographs were not done on later cases. RESULTS: The mean ratio of hot spot activity on the targeted rib to background counts on adjacent ribs was 1.65 +/- 0.22 (range, 1.35 to 2.05), and the difference was easily discernible intraoperatively. The ratio of hot spot activity on the sternum was somewhat lower (1.22), but the target area was still easy to detect. An abnormal diagnosis to account for the increased tracer activity was found in each of the 13 ribs and 1 sternal biopsy in all 10 patients: metastatic squamous cell carcinoma (1 rib), metastatic prostatic adenocarcinoma (1 rib), lymphoma (2 ribs), localized hypercellular marrow (1 rib), medullary fibrosis/Paget's disease of the bone (2 ribs), localized fibrosis/granulation tissue (1 rib), enchondroma (3 ribs), and chondroma (2 ribs, 1 sternum). The difference in background counts to hot spot activity was best with injection of the tracer 6 hours before operation. CONCLUSIONS: The intraoperative use of gamma counting is an easy, highly accurate aid (100% sensitivity) to localize areas of abnormal radioisotope uptake in suspected asymptomatic rib and sternal metastases. Use of this technique obviates the need to obtain intraoperative localizing radiographs to confirm accurate rib identification, thereby decreasing operative time.

Adenocarcinoma↗
PubMed1997

Expression of adrenomedullin and its receptor in normal and malignant human skin: a potential pluripotent role in the integument.

Adrenomedullin (AM) is a multifunctional peptide involved in a variety of physiological functions, including growth regulation and antimicrobial activity. We have determined by immunohistochemistry and in situ hybridization that AM and its receptor are present in all the epithelial cells of the normal skin, including keratinocytes of the epidermis and hair follicles, as well as cells of the glands and secretory ducts. We also have detected AM in the sweat, by RIA. In addition, AM and its receptor were found in skin tumors of different histologies. The presence of AM and its receptor in normal and neoplastic skin was confirmed by RT-PCR and Western blot analysis performed on cell extracts from human skin cell lines. Radiolabeled AM bound to specific sites in cultured cells with a Kd of 9 nM. This binding was blocked by the addition of cold AM but not by related peptides such as AM 22-52, pro-AM 20 N-terminal peptide, calcitonin gene-related peptide, calcitonin gene-related peptide 8-37, or amylin. Finally, exposure to synthetic AM resulted in an increase of thymidine intake by skin cells. These results implicate AM as a potential player in skin defense against infectious microorganisms and as a possible autocrine growth factor in normal skin physiology and tumor development.

Adrenomedullin↗
PubMed1994

Infection and immunoregulation of T lymphocytes by parainfluenza virus type 3.

Human parainfluenza virus type 3 (HPIV3) is a major cause of disease in newborns and infants. It also has a striking potential to reinfect individuals throughout their lives, suggesting that HPIV3 does not induce lifelong immunity; however, the operative mechanism for the failure to prevent reinfection is not known. We have assessed the potential of the virus to infect nontransformed human T lymphocytes and have found that T cells are readily infected by the virus. Productive infection requires activation of the T cells and results in a marked inhibition of proliferation. Furthermore, our results indicate that exposure to the virus, even without overt expression of viral proteins as detected by immunohistology, profoundly alters the functional capacity of the T cells. The capacity of the virus to regulate T-lymphocyte function may play an important role in the failure of the virus to induce lifelong immunity.

Adult↗
PubMed1994

Role of lymphoid organs in the pathogenesis of human immunodeficiency virus (HIV) infection.

The pathogenic mechanisms of HIV disease are multifactorial and multi-phasic. The common denominator of the disease is the profound immunosuppression that occurs in the vast majority of infected patients. Studies in lymphoid tissues in HIV disease have provided considerable insight into the pathogenic processes involved from the earliest phases of infection through the advanced stages. Following primary infection, virus is disseminated throughout the body and seeds the lymphoid tissue where its replication is only incompletely suppressed and where a reservoir of virus is established. Extracellular virus is trapped within the FDC of the lymph node germinal centers and serves as a source of infection for cells which reside in or migrate through the lymph node throughout the course of infection even during the early and often prolonged asymptomatic period. Eventually, the architecture of the lymphoid tissue is destroyed, compounding the immune dysfunction that results from the depletion of CD4+ T cells. In this regard, the lymphoid tissue of LTNPs is relatively intact and viral burden and replication is considerably lower in the peripheral blood and lymph node mono-nuclear cells of LTNPs than in individuals whose disease progresses. Cytokines probably play a major role in the modulation of HIV expression in the milieu of the lymphoid tissue. Further understanding of the pathogenic mechanisms operative in the lymphoid tissues of HIV-infected individuals will have important implications in the design of therapeutic strategies involving both antiretroviral and immunomodulatory approaches.

Apoptosis↗
PubMedDate not supplied

Alpha1-adrenergic receptors and their significance to chemical-induced nephrotoxicity--a brief review.

Stimulation of alpha-adrenergic receptors by cold stress or adrenergic agents has been shown to potentiate the toxicity of numerous toxicants. Several lines of evidence indicate that this interaction is dependent on glutathione depression and increased cytosolic Ca2+ concentrations produced by alpha1-adrenergic compounds. In this report, evidence is provided in support of the mechanism of adrenoreceptor-mediated potentiation of nephrotoxicity. Alpha1-adrenergic agonists are shown to potentiate the toxicity of nephrotoxicants that exert their toxic effects via glutathione conjugation or Ca2+ deregulation. This review summarizes the effects of the alpha1-adrenergic agonist, phenylephrine, at enhancing the toxicity of 2-bromohydroquinone, 1,2-dibromoethane, and cis-diammineplatinum(II) dichloride.

Animals↗
PubMedDate not supplied

Cell proliferation and apoptosis during development and aging of the rabbit corpus luteum.

Corpora lutea (CL) are endocrine ovarian structures that regulate fundamental reproductive events in mammals. The functional lifespan of these structures is finite as CL regress and cease secreting progesterone after species-dependent intervals during nonfertile postovulatory cycles or pregnancy. The signals that regulate CL aging are poorly understood. This study investigates cell growth and programmed cell death or apoptosis in corpora lutea of New Zealand White rabbits. To study cell growth, CL were obtained at various postovulatory days (POD) from animals injected with the deoxyribonucleic acid (DNA) precursor analog bromodeoxyuridine (BUdR). The BUdR-labeled cells were identified by avidin-biotin-complex immunocytochemistry, and the mean proliferation index area computed by image analysis. Apoptotic cells were scored and further identified by in situ demonstration of DNA fragmentation. Proliferation in parenchymal, stromal, and endothelial CL cells was significantly elevated at POD 3, 5, 18, and 21 and highest at POD 3 (P < 0.001). The number of apoptotic cells was elevated (P < 0.001) at POD 18 and 21, while 1 percent or less of CL cells were apoptotic at POD 3, 5, and 12. Apoptosis was accompanied by shrinkage or vacuolization of CL cells and increased mean number (P < 0.001) of heterophilic leucocytes at POD 18. These data demonstrate that cell growth is more intense during early luteal development and that cell deletion via apoptosis plays an important role in CL regression. The role of paracrine signals such as microphagic cytokines in CL aging remains to be elucidated.

Animals↗