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Biomedical subjects

C Rivas

Publications and source records attributed to C Rivas.

At least 19 recordsLinked to original sources
PubMed2007

Outcome of patients with acute promyelocytic leukemia failing to front-line treatment with all-trans retinoic acid and anthracycline-based chemotherapy (PETHEMA protocols LPA96 and LPA99): benefit of an early intervention.

To determine prognosis of acute promyelocytic leukemia (APL) failing to front-line therapy with all-trans retinoic acid (ATRA) and anthracyclines, outcome of 52 patients (32 M/20 F; age: 37, 3-72) included in PETHEMA trials LPA96 and LPA99 who presented with either molecular failure (MOLrel, n=16) or hematological relapse (HEMrel, n=36) was analyzed. Salvage therapy consisted of ATRA and high-dose ara-C-based chemotherapy (HDAC) in most cases (83%), followed by stem-cell transplantation (autologous, 18; allogeneic, 10; syngeneic, 1). Fourteen patients with MOLrel (88%) achieved second molecular complete response (molCR), whereas 81% HEMrel patients responded to second-line treatment, with 58% molCR. After median follow-up of 45 months, four MOLrel and 18 HEMrel patients, respectively, experienced a second relapse. Outcome after MOLrel compared favorably to HEMrel, with longer survival (5-year survival: 64+/-14 vs 24+/-8%, P=0.01) and lower relapse risk (5-year relapse risk: 30+/-13 vs 64+/-9%; P=0.044). Additionally, age <or=40 and male gender were favorable variables for survival, whereas molecular response predicted longer leukemia-free survival. In conclusion, early institution of salvage therapy at molecular failure, before onset of hematological relapse, is beneficial in APL. Moreover, given the poor outcome of HEMrel managed with ATRA and HDAC, use of alternative therapeutic strategies in this setting is warranted.

Adolescent↗
PubMed2006

Impact of protein kinase PKR in cell biology: from antiviral to antiproliferative action.

The double-stranded RNA-dependent protein kinase PKR is a critical mediator of the antiproliferative and antiviral effects exerted by interferons. Not only is PKR an effector molecule on the cellular response to double-stranded RNA, but it also integrates signals in response to Toll-like receptor activation, growth factors, and diverse cellular stresses. In this review, we provide a detailed picture on how signaling downstream of PKR unfolds and what are the ultimate consequences for the cell fate. PKR activation affects both transcription and translation. PKR phosphorylation of the alpha subunit of eukaryotic initiation factor 2 results in a blockade on translation initiation. However, PKR cannot avoid the translation of some cellular and viral mRNAs bearing special features in their 5' untranslated regions. In addition, PKR affects diverse transcriptional factors such as interferon regulatory factor 1, STATs, p53, activating transcription factor 3, and NF-kappaB. In particular, how PKR triggers a cascade of events involving IKK phosphorylation of IkappaB and NF-kappaB nuclear translocation has been intensively studied. At the cellular and organism levels PKR exerts antiproliferative effects, and it is a key antiviral agent. A point of convergence in both effects is that PKR activation results in apoptosis induction. The extent and strength of the antiviral action of PKR are clearly understood by the findings that unrelated viral proteins of animal viruses have evolved to inhibit PKR action by using diverse strategies. The case for the pathological consequences of the antiproliferative action of PKR is less understood, but therapeutic strategies aimed at targeting PKR are beginning to offer promising results.

Animals↗
PubMed2005

Identification of a nuclear export signal in the KSHV latent protein LANA2 mediating its export from the nucleus.

LANA2 is a latent protein detected in Kaposi's sarcoma-associated herpesvirus (KSHV)-infected B cells that inhibits p53-dependent transcriptional transactivation and apoptosis and PKR-dependent apoptosis, suggesting an important role in the transforming activity of the virus. It has been reported that LANA2 localizes into the nucleus of both KSHV-infected B cells and transiently transfected HeLa cells. In this study, we show that LANA2 is a nucleocytoplasmic shuttling protein that requires a Rev-type nuclear export signal located in the C-terminus to direct the protein to the cytoplasm, through an association with the export receptor CRM1. In addition, a functional protein kinase B (PKB)/Akt phosphorylation motif partially overlapping with the nuclear export signal was identified. Nuclear exclusion of LANA2 was negatively regulated by the phosphorylation of threonine 564 by Akt. The ability of LANA2 to shuttle between nucleus and cytoplasm has implications for the function of this viral protein.

Active Transport, Cell Nucleus↗
PubMed2005

Characterization of MDGA1, a novel human glycosylphosphatidylinositol-anchored protein localized in lipid rafts.

We report the characterization of the novel human protein MDGA1 encoded by MDGA1 (MAM domain containing glycosylphosphatidylinositol anchor-1) gene, firstly termed as GPIM. MDGA1 has been mapped to 6p21 and it is expressed in human tissues and tumors. The deduced polypeptide consists of 955 amino acids and exhibits structural features found in different types of cell adhesion molecules (CAMs), such as the presence of both immunoglobulin domains and a MAM domain or the capacity to anchor to the cell membrane by a GPI (glycosylphosphatidylinositol) motif. Our results demonstrate that human MDGA1 (hMDGA1) is localized in the membrane of eukaryotic cells. The protein follows the secretion pathway and finally it is retained in the cell membrane by a GPI anchor, susceptible to be cleavaged by phospholipase C (PI-PLC). Moreover, our results reveal that hMDGA1 is localized specifically into membrane microdomains known as lipid rafts. Finally, as other proteins of the secretory pathway, hMDGA1 undergoes other post-translational modification consisting of N-glycosylation.

Amino Acid Motifs↗
PubMed2005

Differential expression of NF-kappaB pathway genes among peripheral T-cell lymphomas.

Nuclear factor kappa B (NF-kappaB) is one important pathway in T-cell proliferation and survival. In a previously reported microarray study, we found NF-kappaB pathway genes differentially expressed between peripheral (PTCL) and lymphoblastic lymphomas. Here, we investigated the expression of NF-kappaB pathway genes using cDNA microarrays in a group of 62 PTCL and in reactive lymph nodes. We found two different subgroups of PTCL based on the expression of NF-kappaB pathway genes. One-third of PTCL showed clearly reduced expression of NF-kappaB genes, while the other group was characterized by high expression of these genes. This distinction was found among all T-cell lymphoma categories analyzed (PTCL unspecified, angioimmunoblastic, cutaneous and natural killer/T lymphomas) with the exception of anaplastic lymphomas (ALCL), which were characterized by reduced NF-kappaB expression in anaplastic cells. Quantitative RT-PCR and immunohistochemical analysis of NF-kappaB-p65 protein confirmed these differences among PTCL subgroups. Importantly, we found that differentiation between NF-kappaB-positive and -negative PTCL could be of clinical interest. The expression profile associated to reduced expression of NF-kappaB genes was significantly associated with shorter survival of patients and seems to be an independent prognostic factor in a multivariate analysis.

Adult↗
PubMed2005

Clozapine prevents apoptosis and enhances receptor-dependent respiratory burst in human neutrophils.

The present study was undertaken to determine if the antipsychotic drug clozapine (CLZ) in the concentration range 2-50 microM can rescue polymorphonuclear cells (PMNs) from undergoing apoptosis. Our results indicate that 20 microM CLZ can rescue PMNs both from UVB-accelerated (28.0% vs. 45.9% for control without CLZ; P < 0.05) and from spontaneous (35.8% vs. 57.6%; P < 0.05) apoptosis whereas 50 microM CLZ could rescue PMNs from spontaneous (34.3% vs. 57.6%; P < 0.05) apoptosis only. Furthermore, since apoptosis has been reported to involve the impairment of PMN function, we evaluated the effects of CLZ on respiratory burst in UVB-irradiated and in unirradiated PMNs. When 20 or 50 microM CLZ-pretreated PMNs were aged in a culture during 4 h, the luminol-dependent chemiluminescence (CL) response was 3-fold (P < 0.01) and 2.5-fold (P < 0.05) increased, respectively, by subsequent exposure to serum opsonized zymosan (OZ). When 50 microM-pretreated PMNs were either UVB-irradiated or unirradiated, the CL response was 2.6-fold (P < 0.05) and 3.3-fold (P < 0.05) increased, respectively, after subsequent exposure to formyl-methionyl-leucyl-phenylalanine (fMLP). In contrast, the degree of enhancement was negligible upon subsequent exposure to ionomycin or phorbol myristate acetate (PMA). When incubation times were extended up to 22 h, the CL response induced by OZ in 20 microM CLZ-treated PMNs had a 4.9-fold increase (P < 0.001). This priming effect could be reverted when 20 microM CLZ-treated PMNs (aged 4 h in culture) were coincubated for 5 min with the protein tyrosine kinase inhibitor genistein as well as with the phosphatidylinositol 3-kinase (PI3-K) inhibitor wortmannin. These findings suggest that CLZ primes respiratory burst and prevents PMN apoptosis as a consequence of tyrosine phosphorylation- and PI3-K activation-dependent signal transduction pathways.

Androstadienes↗
PubMed2004

Abundance of IFN-alpha and IFN-gamma mRNA in blood of resistant and susceptible chickens infected with Marek's disease virus (MDV) or vaccinated with turkey herpesvirus; and MDV inhibition of subsequent induction of IFN gene transcription.

The effects of the very virulent RB-1B strain of Marek's disease virus (MDV) and turkey herpesvirus (HVT), a vaccinal strain, on abundance of IFN mRNA in the blood were investigated. MDV and HVT infection did not change the circulating level of IFN-gamma mRNA 1 and 7 days p.i., but they increased IFN-alpha mRNA levels slightly in genetically susceptible (to tumour development) B(13)/B(13) chickens. The total number of circulating leukocytes was unchanged and increase in message was accompanied by an increase in circulating CD8alpha(+) and MHC Class II(+) cells. On the contrary, both viruses slightly increased IFN-gamma transcripts and decreased IFN-alpha transcripts in genetically resistant B(21)/B(21) chickens. Further, oncogenic MDV was able to block the response to inactivated Newcastle disease virus, a potent inducer of IFN, in both chicken lines. The inhibiting effect on transcription was present for both IFN at days 1 and 7 p.i. in susceptible B(13)/B(13) chickens, but only at day 7 p.i. in resistant B(21)/B(21) chickens. By contrast, non-oncogenic HVT did not interfere with induction of either message at one day p.i. and MDV had a more suppressive effect than HVT on IFN gene transcription 7 days p.i. in B(21)/B(21) chickens. Thus, the strong ability of MDV to block induction of IFN gene transcription detected in the blood as soon as one day after infection in susceptible chickens, as opposed to resistant chickens, not only causes immunosuppression but also may be related to the virus's oncogenicity.

Animals↗
PubMed2004

Case report: MRI in the diagnosis of testicular Leydig cell tumour.

We report the appearance of three cases of Leydig cell tumours on MRI. This imaging method showed well-defined and peripheral intratesticular tumours displaying marked and homogeneous enhancement when contrast medium was used. This latter finding was only observed in Leydig cell tumours when they were compared in a series of 104 patients with different scrotal pathologies.

Adult↗
PubMed2003

Inflammatory pseudotumor of the spleen in a patient with human immunodeficiency virus infection: a case report and review of the literature.

Inflammatory pseudotumor of the spleen (IPS) is a rarely described benign tumoral lesion of unknown etiology and pathogenesis. Diagnosis is complex as clinical manifestations and imaging features are indistinguishable from lymphoproliferative disorders and other malignancies of the spleen. Human immunodeficiency virus (HIV) infection is often combined with several malignancies including non-Hodgkin's lymphoma and Kaposi's sarcoma. However, no HIV infection-associated IPS has been reported so far. We report and discuss a case of IPS in an HIV-infected woman who presented with abdominal pain and multiple lesions in the spleen.

Adult↗
PubMed2003

[Lymphoma of the nasal cavity, clinical and anatomo-pathologic considerations].

Six cases of high-grade lymphoma affecting the nasal cavity are presented. Their main symptoms were nasal obstruction, epistaxis and rhinorrea. Clinical exploration showed an ulcerated lesion in four patients (all of them T/NK cell lymphomas) and an exofitic tumour in the other two (B cell lymphomas). Pathology was diagnostic for high grade lymphoma in all the six cases, immunohistochemical studies revealed that the atypical cells were T/NK in 4 cases and B in the other two cases. Genotypic analysis was done looking for rearrangement of the genes for Ig H or T-cell receptors. In situ hybridisation was done to detect Epstein-Barr virus RNA. Malignant lymphomas arising in the nasal cavity are unusual, its major prognostic factor is the clinical stage at presentation. To perform an early diagnosis this neoplasia must be suspected in the presence of an exofitic tumour (B cell lymphoma) or necrotic and ulcerated lesion (T/NK cell lymphoma).

Adolescent↗
PubMed2003

The latency protein LANA2 from Kaposi's sarcoma-associated herpesvirus inhibits apoptosis induced by dsRNA-activated protein kinase but not RNase L activation.

Kaposi's sarcoma-associated herpesvirus (KSHV) uses several strategies to counteract the interferon (IFN) system. In this study, the relationship of the protein LANA2 from KSHV to the IFN-activated protein kinase (PKR) and 2-5A system was analysed. It was found that LANA2 could not abrogate apoptosis or RNA degradation mediated by the 2-5A system. However, expression of LANA2 inhibited apoptosis triggered by PKR. LANA2 also counteracted the PKR-mediated inhibition of protein synthesis and partially blocked PKR-induced phosphorylation of eIF-2alpha. Analysis of PKR-induced activation of caspases 3 and 9 revealed that LANA2 abrogated activation of caspase 3 but not of caspase 9. These findings show that LANA2 is able to interfere with downstream events triggered by PKR. Hence, LANA2 should be considered as a KSHV defence protein against IFN.

2',5'-Oligoadenylate Synthetase↗
PubMed2003

Antioxidant properties of dipyridamole as assessed by chemiluminescence.

The ability of dipyridamole (DIP) to scavenge oxygen metabolites generated by either activated human neutrophils (PMNs) or cell-free systems using luminol(s)- and lucigenin-enhanced chemiluminescence was investigated. In the presence of DIP (15-50 microM) a dose-dependent inhibition period was seen in phorbol myristate acetate (PMA)-stimulated PMNs as assayed by isoluminol-enhanced chemiluminescence (ILCL) with horseradish peroxidase (HRP). Although such a lag period was not observed in the absence of HRP, 50 microM DIP inhibited extracellular ILCL by more than 50%. Intracellular luminol-enhanced chemiluminescence (LCL) as assayed in either PMA- or in ionomycin-activated PMNs was not affected by dipyridamole (15-50 microM). In cell-free systems, DIP produced concentration-dependent inhibition in H2O2-(45% at 50 microM), OH- (40%, at 0.1 microM) and HOCl-(20% at 10 microM). Both absorbance and fluorescence scans revealed that DIP is able to react with equimolar quantities of either H202 or HOCl. These results suggest that DIP scavenges reactive oxygen species (ROS) presumably secreted by activated human PMNs in the following decreasing order: *OH > HOCl > H2O2 >> O2-.

Acridines↗
PubMed2002

Increase in alcohol related deaths: is hepatitis C a factor?

AIM: To evaluate recent trends in alcohol related deaths in the UK and to consider possible causative factors. DESIGN: Observational retrospective study of the database of the Office for National Statistics, alcohol consumption data reported by the General Household Survey, and other published data. SETTING: England, 1993-9. RESULTS: Deaths for each million of the population from alcohol related illness increased by 59% in men and 40% in women over the years 1993 to 1999. One subgroup of alcohol related deaths, ICD 571.3 (alcoholic liver damage unspecified), showed a 243% increase in men aged 40 to 49 years over the same period. Figures for younger men, and women in all age groups, showed less pronounced increases. There has been no associated rise in alcohol intake. There has been an increase in the incidence of hepatitis C virus (HCV) infection in recent years, and alcohol consumption in HCV positive individuals accelerates the progression to cirrhosis. Circumstantial evidence links the rise in HCV infection to the use of illicit drugs in the 1970s and 1980s, among those currently aged 40 to 59 years. CONCLUSIONS: The recent increase in alcohol related deaths cannot be solely explained by a change in drinking habits. It is suggested that this probably results from the rapid progression of alcoholic cirrhosis in people who have acquired HCV infection through intravenous drug use. Alcohol consumption in HCV positive individuals is firmly linked with a poor outcome.

Adult↗
PubMed2001

BCR-ABL and interleukin 3 promote haematopoietic cell proliferation and survival through modulation of cyclin D2 and p27Kip1 expression.

Although it is evident that BCR-ABL can rescue cytokine-deprived hematopoietic progenitor cells from cell cycle arrest and apoptosis, the exact mechanism of action of BCR/ABL and interleukin (IL)-3 to promote proliferation and survival has not been established. Using the pro-B cell line BaF3 and a BaF3 cell line stably overexpressing BCR-ABL (BaF3-p210), we investigated the proliferative signals derived from BCR-ABL and IL-3. The results indicate that both IL-3 and BCR-ABL target the expression of cyclin Ds and down-regulation of p27(Kip1) to mediate pRB-related pocket protein phosphorylation, E2F activation, and thus S phase progression. These findings were further confirmed in a BaF3 cell line (TonB.210) where the BCR-ABL expression is inducible by doxycyclin and by using the drug STI571 to inactivate BCR-ABL activity in BaF3-p210. To establish the functional significance of cyclin D2 and p27(Kip1) expression in response to IL-3 and BCR-ABL expression, we studied the effects of ectopic expression of cyclin D2 and p27(Kip1) on cell proliferation and survival. Our results demonstrate that both cyclin D2 and p27(Kip1) have a role in BaF3 cell proliferation and survival, as ectopic expression of cyclin D2 is sufficient to abolish the cell cycle arrest and apoptosis induced by IL-3 withdrawal or by BCR-ABL inactivation, while overexpression of p27(Kip1) can cause cell cycle arrest and apoptosis in the BaF3 cells. Furthermore, our data also suggest that cyclin D2 functions upstream of p27(Kip1), cyclin E, and cyclin D3, and therefore, plays an essential part in integrating the signals from IL-3 and BCR-ABL with the pRB/E2F pathway.

Animals↗
PubMed2001

BCR-ABL-expressing cells transduced with the HSV-tk gene die by apoptosis upon treatment with ganciclovir.

The potential efficacy of prodrug activation of a transduced suicide gene in a cancer cell may be impaired or enhanced by oncoproteins produced by that cell. In the context of a gene therapy protocol for chronic myeloid leukemia (CML) we examined whether the Bcr-Abl fusion protein would have either of these effects. Thus, the mechanism of cell killing by transfer of herpes simplex virus thymidine kinase (HSV-tk) and subsequent ganciclovir (GCV) treatment was examined in pre-B (TonB210.1) cells and myeloid cells (32D) and in their BCR-ABL-expressing counterparts. HSV-tk-transduced cell lines, either in the presence or in the absence of BCR-ABL expression, became susceptible to GCV at concentrations which were nontoxic to the nontransduced cells. This susceptibility was represented by apoptotic cell death in all cases. Apoptosis was observed after 24 h of treatment with GCV in the tk-transduced parental cells and in the BCR-ABL-expressing TonB210.1 cells but only after a delay of more than 24 h in the 32Dp210 cells compared to 32D. Cell death in the BCR-ABL-expressing clones was preceded by S- and G2/M-phase cell cycle arrest. Activation of FAS/APO-1 and caspase-8 was observed in all the tk-transduced cell lines after GCV treatment. However, the caspase-8 inhibitor Z-IETD-FMK only partially abrogated tk/GCV-induced apoptosis. A possible role for inhibition of Bcl-2 or Bcl-x(L) expression in the apoptosis induced by GCV was observed in the tk-transduced TonB210.1 cells but not in the 32D or 32Dp210 cells. The data demonstrate that expression of the Bcr-Abl oncoprotein does not block the apoptosis induced by the HSV-tk/GCV system, suggesting that this suicide gene therapy strategy could be considered for the treatment of CML in blast crisis.

Animals↗