Biomedical subjects
Publications and source records attributed to E Espinosa.
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To characterize natriuretic peptide receptor (NPr) gene expression in human tissues, we cloned portions of the cDNAs codifying for NPr with guanylyl cyclase activity (NPr-A and NPr-B) and without guanylyl cyclase activity (NPr-C). Total RNA was extracted from samples taken at surgery from normal human tissues. NPr-A and NPr-B cDNAs obtained from lung as well as NPr-C cDNA obtained from renal cortex were cloned, characterized, and used for comparative Northern analysis. NPr-A mRNA (approximately 4 kb) was most abundant in adipose tissue (8 patients) independently on the site of sampling, whereas it was approximately 2.5-fold and 5-fold less abundant, respectively, in kidney (either renal cortex or papilla from 3 patients) and adrenal (4 patients), known target tissues of natriuretic peptides. NPr-C mRNAs (approximately 7.7 and 6.8 kb) had a similar tissue distribution but the highest levels were found in renal tissue and only very low expression levels were found in adrenals (approximately 20-fold lower than renal cortex). The ratio of NPrA versus NPr-C mRNA levels were highest in adrenal and lowest in renal tissue. NPr-B mRNA (approximately 4 kb), which encodes the receptor for the C-type natriuretic peptide, had a different and wide tissue distribution, including expression in ileum and liver, with the highest levels in venous and prostatic tissue. These results indicate that, in humans, different patterns of NPr expression with different NPr-A/NPr-C mRNA level ratios, are present in known target tissues of natriuretic peptides. "Non-classic" target tissues, such as the adipose one, maximally expressed NPr-A and also NPr-C, suggesting that natriuretic peptides may have wider functional activities than those previously demonstrated.
A phase II study was performed to assess the efficacy and toxicity of the combination of cisplatin (CDDP) and tamoxifen (TAM) in patients with metastatic malignant melanoma (MM). A total of 31 consecutive previously untreated patients with unresectable measurable MM were given 100 mg/m2 CDDP every 21 days and 60 mg TAM every 12 h daily. All courses were given on an outpatient basis. A total of 119 courses of treatment were given. In all, 5 of the 31 patients (16%) had an objective response (95% confidence interval 5.3-34%) and 2 (6%) achieved a clinical complete response. The median duration of response was 7 months. The main side effect was gastrointestinal: 13% of the patients experienced grade 3/4 nausea/vomiting. Hematological or neurological toxicities were mild and rare. In conclusion, the combination CDDP-TAM has limited activity in MM, although its toxicity is tolerable. Our results do not allow us to recommend its use for the treatment of MM.
In 26 acute promyelocytic leukaemia (APL) patients treated with all-trans retinoic acid (ATRA), 23% had platelet counts between 459 and 800 x 10(9)/I during treatment. These values, observed between days 28 and 45 of ATRA treatment, were transient and asymptomatic. We report two APL cases with platelet counts > 1000 x 10(9)/I during ATRA therapy who were treated with recombinant interferon alpha. In both cases ATRA doses were not modified, no complications secondary to thrombocytosis were seen, and they subsequently achieved complete remission. It is suggested that IL-6 may play an important role in the pathogenesis of the thrombocytosis induced by ATRA. To our knowledge, this is the first report of thrombocytosis occurring during ATRA treatment.
We performed a phase II study to assess the efficacy and toxicity of the cisplatin-UFT-leucovorin (LV) combination in patients with advanced non-small-cell lung cancer (NSCLC). Twenty-five patients with measurable disease who had not received prior chemotherapy were entered into the trial. The therapeutic regimen consisted of cisplatin 90 mg/m(2) and i.v. LV 500 mg/m(2) on day 1, followed by oral UFT 390 mg/m(2)/day (in two doses on days 1 through 14. Patients also received oral LV 15 mg/12 h on days 2 through 14. Seventeen patients required reduced doses of UFT (200 mg/m(2) due to toxicity. Courses were repeated every 28 days for a minimum of three per patient. Three of 25 patients (12%) achieved a partial response (95% CI: 2.6 to 32.2%), two with 390 mg/m(2)/day and one with 200 mg/m(2)/day of UFT. The main side effects were hematological and gastrointestinal. In the courses including 390 mg/m(2)/day of UFT, grade 3-4 toxicity was leucopenia in 18% of the courses, nausea/vomiting in 27%, and diarrhea and epigastralgia in 13% each. Grade 3-4 toxicities for 200 mg/m(2)/day of UFT were leucopenia 2%, nausea/vomiting 9% and diarrhea 7%. In conclusion, this regimen cannot be recommend for the treatment of advanced NSCLC due to its low response rate and high toxicity.
Cisplatin (P) and 5-fluorouracil (5FU) have demonstrated activity for the treatment of squamous cell carcinoma of the esophagus. Previous studies have shown that leucovorin (L) may potentiate the antitumoral activity of 5FU, so we tested the combination P-5FU-L in 31 patients with inoperable squamous cell esophageal carcinoma. Chemotherapy consisted of P 20 mg/m2 in 4 h, followed by L 200 mg/m2 in 2 h and 5FU 600 mg/m2 in 18 h. This schedule was repeated for 5 days every 4 weeks. The treatment plan included three courses of chemotherapy followed by radiotherapy. The overall response rate was 58% (95% CI = 39-76%), with one complete remission (3%), and 61% of patients reported an improvement in dysphagia. Gastrointestinal toxicity was the main side effect: grade 3-4 mucositis appeared in 19% of patients, grade 3-4 nausea/vomiting in 13%, and grade 3-4 diarrhea in 6.5%. There was one toxic death caused by neutropenia and sepsis. Nineteen patients received local radiotherapy after chemotherapy, which increased the overall response rate to 63% (5% complete responses). Dysphagia improved in 75% of them. The median survival for all patients was 11 months. This study shows that sequential therapy with P-5FU-L and radiotherapy achieves a high response rate as well as adequate symptomatic relief in patients with inoperable esophageal cancer. The results justify further evaluation of P-5FU-L in patients with earlier-stage disease.
OBJECTIVES: Cardiovascular disease is rare in premenopausal women, but increases after the menopause when hormone replacement therapy reduces coronary events. Vascular smooth muscle cell (SMC) proliferation and migration occur in atherosclerosis, restenosis and venous graft disease. We studied the effects of 17 beta-estradiol on SMC proliferation and migration. METHODS: SMC were cultured from saphenous veins of postmenopausal women and age-matched men. Cell growth was determined by 3H-thymidine incorporation and cell counting. Migration of SMC was assessed in 4-well chambers. SMC were seeded in one corner and PDGF-BB in filter paper glued onto the opposite wall. RESULTS: PDGF-BB (5 ng/ml for 24 h) similarly stimulated 3H-thymidine incorporation in female (511 +/- 57%; n = 8) and male (528 +/- 62%; n = 12) SMC. This was reduced by 17 beta-estradiol (10(-8)-10(-6) M; female 313 +/- 52%; male 337 +/- 54%; P < 0.05). PDGF-BB increased the number of SMC (P < 0.0001 at 10 days) obtained from females (153 +/- 3%; n = 5) and males (150 +/- 4%; n = 5), which was inhibited by 17 beta-estradiol (10(-6) M; female 134 +/- 7%; male 128 +/- 5%; P < 0.05). Similar results were obtained with basic fibroblast growth factor. In contrast to 17 beta-estradiol, another steroid (dexamethasone) had no effects on 3H-thymidine incorporation in these cells stimulated with PDGF-BB, PDGF-BB (0.01-1 ng) stimulated SMC migration (P < 0.05) which was inhibited by 17 beta-estradiol (10(-10)-10(-6) M; n = 5; P < 0.005). CONCLUSION: 17 beta-Estradiol inhibits growth-factor-induced SMC proliferation and migration regardless of gender. These effects of 17 beta-estradiol may contribute to its cardiovascular protective properties in postmenopausal women during replacement therapy.
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A polarized split-valence wavefunction was computed for the H3PO4 molecule at its neutron crystallographic valence geometry, and the wavefunction was used to map the molecular electron-density distribution and to simulate X-ray crystal structure factors for both static, at-rest and dynamic thermally averaged structures. The thermal vibrational averaging was approximated using anisotropic mean-square atomic displacements from approximately 300 K neutron diffraction data. The simulated X-ray data were used to test pseudoatom multipole modeling of the valence electron-density distribution, in particular, radial modeling of the M valence shell of the P atom, and deconvolution of the nonspherical density features from anisotropic vibrational smearing.
X-ray diffraction data for H3PO4 crystals have been measured to dmin = 0.46 A resolution, and used to model the electron-density distribution with the hydrogen structure of the crystals adopted from an earlier neutron diffraction analysis. The molecule is asymmetric in the crystal with site symmetry 1 (C1), but the local symmetries of the pseudoatomic densities are, within experimental error, equivalent as they would be under idealized 3m (C3v) molecular symmetry. Although the experimental analysis entailed substantial problems with absorption and extinction corrections, the static deformation density from the experiment agrees very well with that from a polarized split-valence molecular orbital wavefunction for an isolated molecule with the crystallographic molecular geometry. Hydrogen bonding in the crystal polarizes the molecule's P==O acceptor group towards P(+)--O-, and appears to relocalize the lone-pair density of the P--OH donor groups. Crystal data: anhydrous orthophosphoric acid, H3PO4, M(r) = 98.00, room temperature, P2(1)/c, a = 5.7572 (13), b = 4.8310 (17), c = 11.5743 (21) A, beta = 95.274 (12) degrees, V = 320.55 (25) A3, Z = 4, dx = 2.030 mg mm-3, mu = 0.660 mm-1 for lambda(Mo K alpha) = 0.7107 A, F(000) = 200 e-, R(parallel F) = 0.026 for 3512 unique reflections.
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We have studied 91 patients with SS genotype, 44 children and 47 adults. Excluding the Cameroon and atypical haplotypes, the distribution in the children's sample exhibited 43% Benin, 38% Bantu, and 3% Senegal. In adults, the sample exhibited 46% Benin, 30% Bantu, and 9% Senegal (chi 2: 13.511, 2 df, P = 0.001). When the whole sample of 198 chromosomes (SS, SC, and S/beta thal) is considered, we find that the beta s chromosome is linked 51% to the Benin haplotype, 41% with the Bantu, and 8% with the Senegal. After adjusting for the different frequencies of beta s in Africa, these numbers would predict the port of origin to be 16% from Atlantic West Africa, 37.3% from Central West Africa, and 46% from Bantu-speaking Africa. This is in direct contradiction with the historical record that establishes a higher percentage from Bantu-speaking Africa (55%) and a much lower percentage from Senegal (3.4%). The overall conclusions from these findings is that there is a loss of Bantu haplotypes in sickle cell syndromes in Cuba, particularly among adults, and that there is an excess of Senegal haplotype, also among adults. These differences might reflect the differential survival and severity of the sickle cell disease linked to these haplotypes.
A phase II study was performed to assess the efficacy and toxicity of the combination of 5-fluorouracil (5-FU), leucovorin (LV), etoposide, and cisplatin (FLEP) in patients with advanced gastric carcinoma. A total of 46 consecutive, previously untreated patients with unresectable, measurable gastric carcinoma were treated with 300 mg/m2 LV, 100 mg/m2 etoposide, 500 mg/m2 5-FU, and 30 mg/m2 cisplatin on days 1-3 every 28 days. All courses were given on an outpatient basis. A total of 169 courses of treatment were given. In all, 18 of the 46 patients (39%) had an objective response [95% confidence interval (CI), 25%-54%] and 2 (4%) patients experienced a clinical complete response. The median duration of response was 5 months. The main side effects were hematological and gastrointestinal. Grade 3-4 toxicity was encountered as follows: leukopenia, in 9.5% of the courses; anemia, in 3%; thrombocytopenia, in 3%; nausea/vomiting, in 4%; and diarrhea, in 5%. Hospitalization due to fever and granulocytopenia was required in 5 patients, 3 of whom died of sepsis. In conclusion, FLEP shows moderate activity in patients with advanced gastric carcinoma, albeit at the cost of a high degree of toxicity. For this reason we do not recommend its use.
PURPOSE: The possibility of increasing the efficiency of an in vitro fertilization system (IVF) for Swiss OF1 mice was studied. The experimental protocol proposed analyzed the use of FSH as a superovulatory inducing hormone in comparison to traditional PMSG treatment. At the same time, the quality of IVF-derived embryos was evaluated both in vitro, with culture in CZB medium and fixation in advanced stages of development, and in vivo, by transfer to female recipients. RESULTS: Treatment with FSH induced a much higher ovulation number compared PMSG (64.26 vs 33.85; P < 0.01). With this gonadotropin, IVF provided a positive tendency to normal fecundation (67.76 vs 64.72; P < 0.1) and a much lower index of abnormal division in embryos (10.57 vs 15.11; P < 0.05). The viability of embryos obtained from donors treated with hormones was similar, although differences did exist regarding embryo origin: those obtained following natural fertilization showed a higher developmental capacity from in vivo (P < 0.05) and in vivo (P < 0.05). CONCLUSIONS: We conclude that FSH is an improved superovulation alternative treatment in comparison to PMSG for IVF. It provides a higher number of embryos with the same in vitro and in vivo viability as those obtained from PMSG.
Crosslinking of the B-cell receptor (BCR) for antigen to low-affinity receptors for IgG (Fc gamma RII) inhibits B-cell activation induced by BCR aggregation. The cell-triggering properties of the BCR depend on tyrosine-containing activation motifs (TAM), in the intracytoplasmic domain of its Ig alpha and Ig beta subunits. TAMs also account for the cell-triggering capabilities of the T-cell receptor (TCR) for antigen, in T lymphocytes, and of the high-affinity receptor for IgE (Fc epsilon RI), in mast cells. Using as a model, rat basophilic leukemia cells (RBL-2H3) stably transfected with cDNA encoding wild-type or mutated murine or human Fc gamma RIIB and chimeric molecules having the intracytoplasmic domain of the FcR gamma subunit or of TCR-CD3 zeta subunit, we found that the inhibitory properties of Fc gamma RII are neither restricted to B cells nor to BCR-dependent cell activation, but can be extended to other cells and, as a general rule, to TAM-dependent cell activation.
The standard therapy for advanced non-small cell lung cancer (NSCLC) remains to be defined. The poor results from chemotherapy have favored the search for prognostic factors that help identify patients more likely to respond. Our objective was to find factors related to response, the duration of response, and overall survival in patients with advanced NSCLC. We reviewed the clinical records of 292 patients with non-operable NSCLC, all of whom had a good performance status and had received chemotherapy. Ninety percent were male and the median age was 59 years. The therapeutic regimens included MACC (methotrexate, adriamycin, cyclophosphamide and CCNU), cisplatin + vindesine or etoposide, MIP (mitomycin, ifosfamide and cisplatin) and MVP (mitomycin, vindesine and cisplatin). In the multivariate analysis, a normal albumin level and the inclusion of cisplatin were related to the achievement of a response (40% if both favorable factors were present). No factors appeared related to the duration of response. The following factors were predictive for survival: weight loss, performance status, lymphocyte count, albumin level, number of metastases and the presence of bone metastases. We conclude that the albumin level identifies a group of patients with advanced NSCLC who are more likely to respond to cisplatin-containing chemotherapy.
A phase II study was performed to assess the efficacy and toxicity of UFT (tegafur-uracil in the molar ratio 1:4) modulated with leucovorin (LV) in previously untreated patients with advanced colorectal carcinoma (CRC). 79 patients with measurable advanced colorectal cancer (CRC) and no prior chemotherapy were included. 75 patients were evaluable for toxicity and response. The regimen consisted of LV 500 mg/m2 administered intravenously on day 1, followed by oral UFT 390 mg/m2 on days 1-14. Patients received oral LV 15 mg every 12 h on days 2-14. Treatment was repeated every 28 days for a minimum of four courses per patient. Three hundred and ninety-eight cycles of chemotherapy were delivered (median five per patient). 7 patients (9%) had a complete response, and 22 a partial response for an overall response rate of 39%. Mild gastrointestinal toxicity was dose limiting: grade 3-4 diarrhoea appeared in 9% of patients. Other grade 3-4 toxicities were nausea/vomiting and mucositis in 4% of patients, gastric pain and leucopenia in 3%. Oral UFT modulated by oral LV is active in advanced CRC and can be administered on an outpatient basis with no significant toxicity requiring hospitalisation. Given its excellent tolerance profile and low toxicity, the regimen should be thoroughly studied and compared with 5-fluorouracil modulated by LV.
The cell-triggering properties of BCR, TCR and FcR depend on structurally related immunoreceptor tyrosine-based activation motifs (ITAMs). Fc gamma RIIB have no ITAM and do not trigger cell activation. When coaggregated to BCR, they inhibit B cell activation. We show here that, when coaggregated to these receptors, Fc gamma RIIB inhibit Fc epsilon RI-, Fc gamma RIIA-, and TCR-dependent cell activation. Inhibition also affected cell activation by single ITAMs, in isolated FcR or TCR subunits. The same tyrosine-based inhibitory motif (ITIM), which is highly conserved in murine and human Fc gamma RIIB and that was previously shown to inhibit BCR-dependent B cell activation, was required to regulate TCR- and FcR-dependent cell activation. Our findings endow Fc gamma RIIB, and thus IgG antibodies, with general immunoregulatory properties susceptible to act on all ITAM-containing receptors.