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Biomedical subjects

M Serrano

Publications and source records attributed to M Serrano.

At least 37 records · Page 2Linked to original sources
PubMed2000

The cell cycle inhibitor p21 controls T-cell proliferation and sex-linked lupus development.

Here we show that the cell-cycle regulator p21 is involved in immune system function. T lymphocytes from p21-/- mice exhibit significant proliferative advantage over wild-type cells following prolonged stimulation, but not after primary activation. Consistent with this, p21-deficient mice accumulate abnormal amounts of CD4+ memory cells, and develop loss of tolerance towards nuclear antigens. Similar to human lupus, female p21-deficient mice develop antibodies against dsDNA, lymphadenopathy, and glomerulonephritis, leading to decreased viability. These data demonstrate a specialized role for p21 in the control of T-cell proliferation, tolerance to nuclear antigens, and female-prone lupus. These findings could be the basis for new therapeutic approaches to lupus.

Animals↗
PubMed2000

The INK4a/ARF locus in murine tumorigenesis.

The INK4a/ARF locus is regarded as one of the most important anti-tumoral defenses that mammalian organisms possess. The characterization of its two gene products, p16(INK4a) and p19(ARF), has provided a great insight on the functioning of the tumor suppressors Rb and p53, respectively. Present evidence indicates that the INK4a/ARF locus is transcriptionally activated by oncogenic stresses, resulting in cell-cycle arrest or apoptosis. Here, I review the evidence accumulated on the involvement of the INK4a/ARF locus in murine tumorigenesis. Also, I summarize the phenotype of the different transgenic mouse models based on the inactivation of the INK4a/ARF locus.

Alleles↗
PubMed1999

The downregulation of the pro-apoptotic protein Par-4 is critical for Ras-induced survival and tumor progression.

Inhibition of apoptosis is an important characteristic of oncogenic transformation. The Par-4 gene product has recently been shown to be upregulated in cells undergoing apoptotic cell death, and its ectopic expression was shown to be critical in apoptosis. We demonstrate that expression of oncogenic Ras promotes a potent reduction of Par-4 protein and mRNA levels through a MEK-dependent pathway. In addition, the expression of permanently active mutants of MEK, Raf-1 or zetaprotein kinase C but not of phosphatidylinositol 3-kinase (PI 3-kinase) is sufficient to decrease Par-4 levels. These effects are independent of p53, p16 and p19, and were detected not only in fibroblast primary cultures but also in NIH 3T3 and HeLa cells, indicating that they are not secondary to Ras actions on cell cycle regulation. Importantly, restoration of Par-4 levels to normal in Ras-transformed cells makes these cells sensitive to the pro-apoptotic actions of tumor necrosis factor-alpha under conditions in which PI 3-kinase is inhibited and also severely impairs colony formation in soft agar and tumor development in nude mice, as well as increases the sensitivity of these tumors to camptothecin. This indicates that the downregulation of Par-4 by oncogenic Ras is a critical event in tumor progression.

3T3 Cells↗
PubMed1999

Murine fibroblasts lacking p21 undergo senescence and are resistant to transformation by oncogenic Ras.

The cell-cycle inhibitor p21 is upregulated during senescence and upon induction of senescence-like arrest by oncogenic Ras. We have used primary fibroblasts derived from p21-null mice to evaluate the role of p21 in these processes. We find that primary p21-/- cells enter senescence and have a lifespan similar to wild-type cells. Upon immortalization, most wild-type and p21-/- cultures acquire alterations in either p53 or p16INK4a, further indicating that p21-deficiency is not sufficient by itself to allow immortalization. Primary p21-/- cells, like wild-type cells, respond to oncogenic Ras by accumulating p53 and p16INK4a, and by decreasing their proliferation rate. In agreement with this, p21-/- cells are refractory to neoplasic transformation by oncogenic Ras when compared to p53-/- cells. We conclude that, in murine fibroblasts, p21 is not essential neither for senescence nor for preventing neoplasic transformation by oncogenic Ras.

3T3 Cells↗
PubMed1999

Benign parotid hypertrophy on +HIV patients: limited late failures after external radiation.

PURPOSE: Although 8-10 Gy of external radiation therapy for +HIV associated parotid hypertrophy has achieved high response rates, the responses were transient with only 1/12 of patients retaining cosmetic control at median follow-up procedures of 9.5 months. Retreatment for failures after 8-10 Gy has also been unsatisfactory. Having shown that 24 Gy of external radiation therapy for benign parotid hypertrophy produced more durable cosmetic control than 8-10 Gy, we now report on longer follow-up periods on a group of patients receiving 24 Gy. MATERIALS AND METHODS: Twenty +HIV patients with clinical and radiographic evidence of lymphoepithelial lesions of the parotid were treated with 24 Gy of external radiation therapy using daily 1.5 Gy fractions; parallel opposed technique and 6 MV photons were used in 19 patients, and unilateral electron treatment was performed for one patient. RESULTS: With a mean follow-up period of 24 months, the cosmetic control appears durable. We have had no late failures past 24 months. Two patients have complained of modest xerostomia. There was no correlation with size of the cyst and eventual cosmetic result. CONCLUSIONS: Twenty-four Gy produces durable parotid control for HIV associated lymphoepithelial lesions of the parotid glands in +HIV patients. Failures after 2 years are uncommon and the side effects have been tolerable.

Female↗
PubMed1999

Candidate vaccine antigens and genes in Pasteurella multocida.

Pasteurella multocida is the causative agent of fowl cholera and other diseases of production animals. Isolates are classified into five groups based on capsular antigens and into 16 serotypes based on LPS antigens. Strains causing fowl cholera are most frequently designated A:1, A:3 or A:4. Whole cell bacterins can provide some degree of protection, but only against the homologous LPS serotype. There is good evidence that cross-protective antigens are expressed only under in vivo conditions. Empirically derived, live, attenuated vaccines can protect against heterologous serotypes, but because the basis for attenuation is undefined, reversion to virulence is not uncommon. Work in our laboratory is aimed at using a variety of approaches to identify potential protective antigens or virulence genes to be used as candidates for attenuating mutations or as the basis for vaccine antigen delivery systems. The gene encoding an outer membrane protein, Oma87, which is a homologue of the D15 protective antigen of Haemophilus influenzae, was cloned and sequenced. Rabbit antiserum prepared against recombinant Oma87 could passively protect mice against infection. Type 4 fimbriae form the basis of vaccines against ovine footrot and bovine keratoconjunctivitis. We have identified type 4 fimbriae on the surface of P. multocida, purified the fimbrial subunit protein, PtfA, and determined its N-terminal amino acid sequence. Subsequent cloning of the ptfA gene and its inactivation will now be used to assess the importance of type 4 fimbriae in virulence. There has long been anecdotal evidence for the importance of capsule in virulence, but unequivocal genetic evidence for such a role is lacking. We have cloned and characterised the capsule biosynthetic locus in P. multocida A:1 and identified four bex genes involved in capsule transport and genes encoding enzymes involved in the biosynthesis and transfer of the N-acetyl glucosamine and glucuronic acid components of the capsule. It has been suggested that the low concentration of available iron in vivo acts as an environmental cue for expression of cross-protective antigens. Accordingly, we have cloned and characterised the gene encoding transferrin binding protein, Tbpl, so that its role in immunity and virulence can be investigated. Although P. multocida is not normally considered haemolytic, we have observed haemolysis under anaerobic conditions. Standard library construction and screening resulted in the identification of the mesA gene which encodes an esterase enzyme resulting in a haemolytic phenotype under anaerobic conditions. Virulence studies with mesA- mutants were performed to assess its role in pathogenesis. Using a promoterless phoA gene vector system, the cloning of proteins homologous to known surface proteins of other species as well as proteins unique to P. multocida, allowing their potential as vaccine components to be assessed.

Amino Acid Sequence↗
PubMed1999

Mouse p73 gene maps to the distal part of chromosome 4 and might be involved in the progression of gamma-radiation-induced T-cell lymphomas.

We have isolated and sequenced a DNA fragment of about 12 kb that comprises exons 5-14 of the mouse p73 gene. We have identified four polymorphic markers, and one of them has been used to genetically map p73 to the distal part of chromosome 4. Previously, we have reported that gamma-radiation-induced T-cell lymphomas undergo frequent loss of heterozygosity around marker D4Mit205b at the distal part of chromosome 4. Based on this, we have performed loss of heterozygosity analysis in a set of T-cell lymphomas, and we have found allelic losses of p73 in 32.6% (16 of 49) of the tumors analyzed. Interestingly, allelic losses occur concurrently at both p73 and D4Mit205b, thus suggesting that p73 could be specifically inactivated in radiation-induced T-cell lymphomas.

Alleles↗
PubMed1999

Role of ethylene and abscisic acid in physicochemical modifications during melon ripening.

Hormonal metabolism associated with fruit ripening in two cantaloupe muskmelon cultivars, Talma and Manta, has been studied. The ethylene crisis began on day 33 after fruit set, reaching the maximum values of internal ethylene concentration and ethylene production rate on day 35 after fruit set. This was the optimum moment for consumption as shown by the higher content in soluble solids, ripening index, sensory analysis, and color parameter values. The b parameter and the b/a quotient values in peel were good indicators of the maturity stage, the optimum moment for harvesting being about day 33 after fruit set (when autocatalytic ethylene synthesis has begun), with values of 20 and 5 for the b parameter and b/a quotient, respectively. In both cultivars, free 1-aminocyclopropane-1-carboxylic acid (ACC) content increased until day 35 after fruit set and conjugated ACC increased in postclimacterium. The increase in both ACC-synthase and ACC-oxidase activities together could be responsible for the climacteric ethylene production. Significant differences in the abscisic acid evolution in Talma and Manta cultivars were reached, and also a possible stimulation of ethylene by this hormone could be established.

Abscisic Acid↗
PubMed1999

Prostacyclin: its pathogenic role in essential hypertension and the class effect of ACE inhibitors on prostaglandin metabolism.

Angiotensin-converting enzyme inhibitors (ACEI) block degradation of bradykinin, and bradykinin stimulates prostacyclin synthesis. Therefore, we set out to determine whether the effects of ACE inhibitors on prostaglandin production in essential hypertensive patients are class effects or are dependent on ACE inhibitor structure. In addition, we studied whether hypertensives show an impaired capacity to synthesize vasodilator prostaglandins. To address these questions, we compared the effects of captopril (sulfhydryl-containing inhibitor), enalapril and ramipril (carboxyl-containing inhibitors) and fosinopril (phosphoryl-containing inhibitor) on blood pressure and urinary excretion of 6-keto-prostaglandin (PG) F1-alpha (the breakdown product of prostacyclin) in 44 mild-to-moderate essential hypertensive subjects before and 8 weeks after administration of an ACEI. We also studied prostacyclin excretion in 15 normotensive healthy controls. Levels of urinary 6-keto-PGF1-alpha (pg/ml) were measured by specific radioimmunoassay. Hypertensive subjects showed a lower excretion of 6-keto-PGF1-alpha than normotensive controls (212+/-147 vs 353+/-98 pg/ml, p < 0.001). All ACEI induced a significant decrease in MAP and increased the rate of excretion of the prostacyclin metabolite: C, 211+/-200 to 338+/-250 pg/ml, p < 0.05; E, 202+/-133 to 296+/-207 pg/ml, p < 0.05; R, 205+/-127 to 342+/-211 pg/ml, p < 0.05; F, 235+/-128 to 347+/-241 pg/ml, p < 0.05. In hypertensives (n = 44) the decrease in blood pressure correlated negatively with the rise in 6-keto-PGF1-alpha excretion (r = -0.51, p < 0.001). These data suggest that impaired prostacyclin biosynthesis in hypertensive patients could account for haemodynamic changes leading to the hypertensive state. Moreover, the hypotensive mechanisms of ACEI may be mediated by an increase in prostacyclin production; this effect seems to be class-dependent.

6-Ketoprostaglandin F1 alpha↗
PubMed1999

Dynamical regimes in the dissipative particle dynamics model.

We discuss theoretically the behavior of the velocity autocorrelation function in the dissipative particle dynamics (DPD) model. Two dynamical regimes are identified depending on the dimensionless model parameters. For low values of the dimensional friction, a mean field behavior is observed in which the kinetic theory for the DPD model provides good predictions. For high values of the friction, collective hydrodynamic effects are dominant. We have performed numerical simulations that validate the theory presented.

Journal Article↗
PubMed1999

A Bacillus subtilis secreted protein with a role in endospore coat assembly and function.

Bacterial endospores are encased in a complex protein coat, which confers protection against noxious chemicals and influences the germination response. In Bacillus subtilis, over 20 polypeptides are organized into an amorphous undercoat, a lamellar lightly staining inner structure, and an electron-dense outer coat. Here we report on the identification of a polypeptide of about 30 kDa required for proper coat assembly, which was extracted from spores of a gerE mutant. The N-terminal sequence of this polypeptide matched the deduced product of the tasA gene, after removal of a putative 27-residue signal peptide, and TasA was immunologically detected in material extracted from purified spores. Remarkably, deletion of tasA results in the production of asymmetric spores that accumulate misassembled material in one pole and have a greatly expanded undercoat and an altered outer coat structure. Moreover, we found that tasA and gerE mutations act synergistically to decrease the efficiency of spore germination. We show that tasA is the most distal member of a three-gene operon, which also encodes the type I signal peptidase SipW. Expression of the tasA operon is enhanced 2 h after the onset of sporulation, under the control of sigmaH. When tasA transcription is uncoupled from sipW expression, a presumptive TasA precursor accumulates, suggesting that its maturation depends on SipW. Mature TasA is found in supernatants of sporulating cultures and intracellularly from 2 h of sporulation onward. We suggest that, at an early stage of sporulation, TasA is secreted to the septal compartment. Later, after engulfment of the prespore by the mother cell, TasA acts from the septal-proximal pole of the spore membranes to nucleate the organization of the undercoat region. TasA is the first example of a polypeptide involved in coat assembly whose production is not mother cell specific but rather precedes its formation. Our results implicate secretion as a mechanism to target individual proteins to specific cellular locations during the assembly of the bacterial endospore coat.

Bacillus subtilis↗
PubMed1999

Other cancers in patients with gastric MALT lymphoma.

Patients with Hodgkin's disease and nodal non-Hodgkin's lymphomas seem to have an excess risk for other cancers. A high incidence of other cancers has also been found in some series of patients with gastric MALT lymphomas. In a series of 136 patients with gastric MALT lymphomas the occurrence and features of other cancers have been described. In order to evaluate their occurrence statistically (excluding skin cancers) standard incidence ratios (SRI) have been calculated, using the incidence rates of a Cancer Registry in Spain as a reference. A Cox's multivariate proportional hazard model was fitted in order to evaluate the influence of age, sex, histological grade and treatment with chemotherapy or chemotherapy plus radiotherapy in the development of other non-skin cancers occurring after the diagnosis of MALT lymphoma. Other cancers were detected in 16 of the 136 patients (11.7%); the other cancer was detected prior to MALT gastric lymphoma in 6 patients (4.41%), concomitantly in 4 (2.9%) and after diagnosis of the lymphoma in 6 (4.41%). Other cancers occurred in 14.4% of the male and in 8.3% of the female patients; in 12% of the patients with low grade and in 11% of the patients with high grade lymphomas. Of the 6 cancers that occurred after diagnosis of the gastric lymphoma, 3 did in the 80 patients (3.7%) that had been treated with chemotherapy, 1 in the 3 cases (33%) treated with chemotherapy and radiotherapy and 2 in the 53 patients (3.7%) who had not received chemotherapy or radiotherapy. The most frequent other cancers were lymphoid neoplasms and gastric carcinoma. There was not an excess of other cancers in the whole cohort or in the sex or histological grade strata. There was an excess close to significance (SIR =2.59; 95% CI:0.98-6.88) in the patients under 50 years of age. In the Cox's analysis, age, sex, histological grade and treatment did not influence the occurrence of other cancers after the diagnosis of lymphoma. In conclusion, in patients with gastric MALT lymphoma other cancers also occur. An excess incidence was not demonstrated, although it may exist in patients under 50 years. Of special importance is the occurrence of gastric cancer that appears concomitantly or after gastric lymphoma.

Adenocarcinoma↗
PubMed1999

[Massive epistaxis associated with trauma. An indication for superselective angiography and embolization. Clinical case].

We report a 23 years old male admitted to the hospital after a fall from a great altitude with severe trauma. During the second week of hospitalization he presented a severe nosebleed that did not respond to conventional tamponade. A selective angiography was performed and the branches of the internal maxillary artery were embolized in two occasions, stopping the bleeding. The patient was discharged from the hospital after 71 days of hospitalization.

Adult↗
PubMed1998

Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling.

Oncogenic Ras transforms immortal rodent cells to a tumorigenic state, in part, by constitutively transmitting mitogenic signals through the mitogen-activated protein kinase (MAPK) cascade. In primary cells, Ras is initially mitogenic but eventually induces premature senescence involving the p53 and p16(INK4a) tumor suppressors. Constitutive activation of MEK (a component of the MAPK cascade) induces both p53 and p16, and is required for Ras-induced senescence of normal human fibroblasts. Furthermore, activated MEK permanently arrests primary murine fibroblasts but forces uncontrolled mitogenesis and transformation in cells lacking either p53 or INK4a. The precisely opposite response of normal and immortalized cells to constitutive activation of the MAPK cascade implies that premature senescence acts as a fail-safe mechanism to limit the transforming potential of excessive Ras mitogenic signaling. Consequently, constitutive MAPK signaling activates p53 and p16 as tumor suppressors.

Animals↗