Allogenic BMT for multiple myeloma (MM). The Italian experience.
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Adult↗
Biomedical subjects
M Grimaldi
Publications and source records attributed to M Grimaldi.
A human tumour-derived mutant p53 protein induces a p34cdc2 reversible growth arrest in fission yeast.
We have expressed wild-type and human tumour-derived mutant p53 cDNA genes in the fission yeast Schizosaccharomyces pombe. In the case of one mutant this resulted in a growth arrest of recipient yeast cells. In contrast, wild-type p53 and three other mutant proteins tested did not block outgrowth of colonies. Human and yeast cdc2 acted as functionally equivalent extragenic suppressors of the mutant-induced growth arrest allowing the establishment of viable p53 expressor strains. In cotransformation assays the mutant allele was found to be dominant over wt p53. Our results provide the first evidence of a functional relationship between p53 and p34cdc2 in an in-vivo system and suggest that the wide variety of mutant proteins present in human tumours may fall into functionally distinct subclasses.
Blotting, Northern↗
Stereochemical behavior of acyclic peptide-cation complexes.
The role of the beta-turns in the peptide interaction with several cations was investigated. In this work we report the solution studies of four linear peptides: Z-Aib-Aib-Aib-L-Val-OMe, Boc-D-aIle-L-Ile-D-aIle-L-Ile-OMe, Boc-L-Leu-L-Leu-L-Leu-L-Leu-OMe, and Boc-L-Phe-D-Phe-L-Phe-D-Phe-OMe. CD and 1H-nmr spectra reveal the presence of multiple ion-bonding equilibria. The stoichiometry and binding constant of the four peptides in the presence of Ca2+ ions in acetonitrile solution has been determined. Variable-temperature nmr spectra in the absence and in the presence of a large excess of cation have shown that the complexation process is not critically dependent on the conformation of the free peptide.
Amino Acid Sequence↗
Interleukin-1-beta modulation of prolactin secretion from rat anterior pituitary cells: involvement of adenylate cyclase activity and calcium mobilization.
Recent findings indicate that interleukin-1 beta (IL1 beta), a monokine secreted by stimulated macrophages and monocytes, modulates neuroendocrine functions in a manner similar to classical hormones. In this study we show that IL1 modulates PRL secretion, assessed by reverse hemolytic plaque assay, and describe the effect of the monokine on adenylate cyclase activity and calcium fluxes in rat normal pituitary cells. In basal and vasoactive intestinal peptide (VIP)-stimulated conditions, low doses of IL1 reduced the mean plaque area, a direct index of PRL secretion without affecting the percentage of PRL-secreting cells. Similarly, low concentrations of IL1 inhibited adenylate cyclase activity in both basal and VIP-stimulated conditions, while higher concentrations restored the enzymatic activity to the control value. IL1 also caused a biphasic effect on the free intracellular calcium increase induced by maitotoxin, a calcium channel activator, being inhibitory at low and stimulatory at high concentrations. The effects of IL1 on adenylate cyclase activity and calcium fluxes were reversed by preincubation of the monokine with its polyclonal antibody, thus confirming the specificity of the effects. In conclusion, our data show that IL1 modulates PRL secretion by acting directly on pituitary cells through interaction with the adenylate cyclase-cAMP system and calcium flux.
Adenylyl Cyclases↗
Adenosine and its analogue (-)-N6-R-phenyl-isopropyladenosine modulate anterior pituitary adenylate cyclase activity and prolactin secretion in the rat.
The effect of adenosine and its analogue (-)-N6-R-phenylisopropyladenosine (PIA) on both anterior pituitary adenylate cyclase activity and prolactin secretion was examined in the rat. Adenosine inhibited basal adenylate cyclase activity in a dose-dependent manner and also reduced the stimulation of the enzyme by vasoactive intestinal peptide (VIP). Likewise, in primary cultures of anterior pituitary cells, adenosine decreased prolactin secretion in both basal and VIP-stimulated conditions. In perifusion experiments, adenosine also inhibited prolactin release in both basal and TRH-stimulated conditions. PIA produced a biphasic pattern of response of basal adenylate cyclase activity, being inhibitory at low and stimulatory at high concentrations. In VIP-stimulated conditions, low concentrations of PIA inhibited both adenylate cyclase activity and prolactin release from primary cultures of pituitary cells, while no additive stimulatory effect was seen at high concentrations. Similarly, low concentrations of PIA reduced both basal and TRH-stimulated prolactin release from perifused pituitaries, while increasing PIA concentrations restored prolactin release. These data show that adenosine affects basal and stimulated prolactin secretion from anterior pituitary cells. Adenosine receptors seem to be coupled to the adenylate cyclase system in the anterior pituitary gland, suggesting a possible relationship between the effect of adenosine on adenylate cyclase activity and prolactin secretion.
Adenosine↗
p53 interacts with p34cdc2 in mammalian cells: implications for cell cycle control and oncogenesis.
The p53 gene product has been implicated in both human and animal tumorigenesis. p53 complexes with the transforming proteins encoded by several different DNA tumour viruses. We demonstrate that human p53 is phosphorylated by the mammalian p34cdc2 kinase in vitro and coprecipitates with p34cdc2 in vivo. Our observations suggest that phosphorylation of p53 by p34cdc2 kinase may regulate the known activities of p53 in the initiation steps of DNA replication in mammalian cells.
Amino Acid Sequence↗
How maitotoxin increases cytosolic calcium levels?
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Calcium↗
Interleukin 1 beta inhibition of TRH-stimulated prolactin secretion and phosphoinositides metabolism.
The effect of interleukin 1 beta on prolactin secretion and on phosphoinositide turnover in anterior pituitary cells was evaluated. Interleukin 1 beta significantly inhibited TRH-stimulated prolactin secretion assessed by the reverse hemolytic plaque assay. In particular, the cytokine reduced the percentage of plaque forming cells, the plaque mean area, the large plaques percentage. TRH-stimulated inositol phosphate production was also significantly inhibited by interleukin 1 beta. This study shows that interleukin 1 beta reduces TRH-induced prolactin secretion through a direct action on pituitary cell, and attenuates the TRH-stimulated phosphoinositide breakdown. This latter effect may suggest that the reduced lactotropes sensitivity to TRH action may be partially due to interleukin 1 beta inhibition of phosphatidylinositol breakdown.
Animals↗
Somatostatin inhibition of adenylate cyclase activity in different brain areas.
Somatostatin receptors have been identified in different brain areas but the characterization of their postreceptor effect is still lacking. In this study we analyze the somatostatin effect on adenylate cyclase activity in different brain regions, namely frontal cortex, striatum, hypothalamus and hippocampus. Somatostatin inhibited basal adenylate cyclase activity in all brain areas, being maximally effective in the frontal cortex (-42%). Moreover, somatostatin inhibited both dopamine- and norepinephrine-stimulated adenylate cyclase activity in the examined cerebral regions showing a higher effectiveness than in basal conditions. VIP stimulation of adenylate cyclase was also reduced by somatostatin. The peptide inhibited by 50% forskolin-stimulated (10 nM to 10 microM) enzyme activity in frontal cortex and hypothalamus (in hippocampus the inhibition reached only -25%) showing a non-competitive pattern of inhibition. Finally, pertussis toxin pretreatment abolished the somatostatin inhibition of forskolin-stimulated frontal cortex adenylate cyclase activity. These results show that brain somatostatin receptors are coupled in an inhibitory way with adenylate cyclase enzyme that may represent one of the postreceptor mechanisms mediating the somatostatin modulation of brain functions.
Adenylyl Cyclases↗
Dissection of the T antigen/mouse p53 complex and its inhibitory effects on viral origin-directed DNA replication in vivo and in vitro.
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Animals↗
Unchanging clinical picture of coeliac disease presentation in Campania, Italy.
Four hundred and sixty-three new diagnoses of coeliac disease in children were made during 1973 to 1986 in our department. The distribution of new diagnoses per year did not show any decreasing trend in the period 1973 to 1986. No changing trend in breast feeding attitudes was found in the region during the same period. Analysis of the clinical pattern showed a constant distribution of age at diagnosis, onset of first symptoms and nature of symptoms throughout the period studied. These data suggest that coeliac disease is predominantly genetically determined and its expression is modulated by individual and environmental factors. The stability of the observed prevalence of the disease is parallel to the unchanging pattern of breast feeding attitudes in the region.
Adolescent↗
Predictive value of hormonal profiles before stimulation for in vitro fertilization.
Ovarian responses to stimulation for in vitro fertilization by clomiphene citrate menotropins have been correlated to the hormonal profiles determined during spontaneous cycles. The authors found 80% of high plasmatic luteinizing hormone (LH) and/or androgens levels associated with an inappropriated response: premature LH surge, multifollicular ovarian response, or dissociated cystic response, versus only 11% with appropriated responses. High plasmatic follicle-stimulating hormone existed in 71% of the no response group. Detryptoréline, a luteinizing hormone-releasing hormone agonist associated with menotropins, in a "short procedure" maintained the adequate responses and suppressed premature LH surges. The no response group was moderately improved, as were multifollicular and dissociated cystic response groups. Hormonal profiles could be useful predictive factors of the ovarian response for adaptation on the first procedure of stimulation.
Adult↗
Early prediction of relapse during gluten challenge in childhood celiac disease.
Thirty-seven children, in whom celiac disease had been diagnosed because of flat mucosa on a gluten-containing diet and recovery on a gluten-free diet, were challenged with gluten powder, 10 g/day, in addition to an otherwise gluten-free diet. A small intestinal biopsy was performed before the challenge; clinical symptoms, a 1-h blood xylose test, and gliadin antibody measurement were used to establish the timing of the confirmatory biopsy. All but one case relapsed within 205 days (mode, 60 days). In no case was the relapse clinically evident. Raised levels of gliadin antibodies, a fall in xylose absorption, or both predicted the relapse in 37%, 7%, and 57% of cases, respectively. Evaluated individually, each test gave a considerable rate of false negative results. Discriminant coefficients produced for each test were used to compute a score that allowed the classification of patients into relapse/no relapse categories with a good degree of accuracy. The discriminant score rose sharply after only 15 days of challenge, indicating that it is possible to predict the relapse long before any clinical symptom appears.
Antibodies↗
Improvement of Durie & Salmon staging for multiple myeloma by adding platelet count as a stratifying variable: a multivariate regression analysis of 163 untreated patients.
The presenting clinical features of 163 previously untreated patients with multiple myeloma were correlated with survival duration using univariate and multivariate regression analyses. The univariate proportional hazard analysis ranked the parameters in the following order of importance: platelet count, haemoglobin level (Hb), tumour cell mass stage, lytic bone lesions, creatinine and age. When the individual contribution of each variable was assessed by multivariate regression analysis, platelet count was confirmed to be the dominant feature for prognosis, while clinical stage provided additional information. The introduction of platelet count could then be used to improve the discriminating power of Durie & Salmon staging, by allowing separation of the high-risk group (stages II and III) into a smaller subgroup (22%) of thrombocytopenic patients (less than 150 x 10(9) platelets/l) whose risk of death was actually very high (median survival: 9 months) and a larger subgroup (46%) of patients with normal platelet count and intermediate or standard risk (median survival: 48 months).
Humans↗
High-dose chemoradiotherapy and allogenic bone marrow transplantation in multiple myeloma.
17 patients with multiple myeloma (MM) received marrow transplants from their HLA-matched, MLC-negative sibling donors. 9 patients had progressive disease not responding to conventional treatments, while the other 8 patients were rated as responders. The most frequently used conditioning regimen consisted of total body irradiation and high-dose, multi-agent chemotherapy with cyclophosphamide plus either oral melphalan (5 cases) or BCNU (1 case) on both these drugs (7 cases). 12 patients were evaluable for response to BTM: 7 of them (6 responders and 1 with advanced refractory MM) entered complete remission, while 5 had a sustained decrease in tumor mass that ranged between 72% and 93%. 11 patients died of transplant-related causes, 1 of them with signs of progressive disease. The remaining 6 patients are alive and 5 of them maintain a complete remission status 4 to 67 (median 36) months after BMT. It is concluded that therapeutic benefits of transplantation in MM are still offset by the high mortality related to the procedure. A more accurate selection of patients who would most benefit from BMT and performing transplant at an earlier phase of the disease are warranted before major advances can be made in the cure of these patients.
Adult↗
Allogeneic bone marrow transplantation for multiple myeloma.
Seventeen patients received marrow transplants from their HLA-matched, MLC-negative, sibling donors. Nine patients had progressive disease not responding to conventional treatments, while the other 8 patients were rated as responders. The most frequently used conditioning regimen consisted of total body irradiation and high-dose multi-agent chemotherapy with cyclophosphamide plus either oral melphalan (5 cases) or BCNU (1 case) on both these drugs (7 cases). Twelve patients were valuable for response to BTM: 7 of them (6 responders and 1 with advanced refractory MM) entered complete remission, while 5 had sustained decrease in tumor mass that ranged between 72% and 93%. Eleven patients died of transplant-related causes, 1 of them with signs of progressive disease. The remaining 6 patients are alive and 5 of them maintain a complete remission status 4 to 67 (median 36) months after BMT.
Adult↗
Effect of interleukin 1 beta on transducing mechanisms in 235-1 clonal pituitary cells. Part I: Modulation of adenylate cyclase activity.
In the present study we evaluated the effect of interleukin 1-beta on adenylate cyclase activity in 235-1 pituitary cell line. The dose-response curve of interleukin 1 beta effect on adenylate cyclase activity showed a significant inhibition of basal enzyme activity at 1 pM concentration, while the inhibition of forskolin stimulated adenylate cyclase activity was more pronounced and evident at both 0.01 and 1 pM concentrations. The action of the monokine on basal enzyme activity was almost completely reverted by polyclonal anti interleukin 1 beta antibody. The incubation of the cells for 48h with interleukin 1 beta showed a different pattern of response. The inhibitory effect of interleukin 1 beta on adenylate cyclase activity disappeared, while the highest concentration of interleukin 1 beta tested, caused a meaningful stimulation of adenylate cyclase activity which is not present in acute condition. These data show that interleukin 1-beta interacts with the cAMP-generating system in the 235-1 clonal pituitary cells.
Adenylyl Cyclases↗
Effect of interleukin 1 beta on transducing mechanisms in 235-1 clonal pituitary cells. Part II: Modulation of calcium fluxes.
In the present study we investigated the effect of the interleukin 1 beta on intracellular free calcium concentrations in 235-1 cell line both in basal conditions and after stimulation by the calcium channel activator maitotoxin. Interleukin 1 beta (from 0.01 pM to 10 nM) was unable to significantly affect basal cytosolic free calcium levels in acute conditions. The preincubation of these cells with interleukin 1 beta for 48h modulates maitotoxin stimulation of calcium fluxes without modifying basal intracellular free calcium levels. Low concentrations of interleukin 1 beta (0.01 pM, 1 pM) caused a marked reduction of intracellular free calcium concentrations increase induced by maitotoxin while higher doses of the monokine potentiated maitotoxin stimulation of calcium fluxes. The specificity of interleukin 1 beta effect was tested by means of polyclonal anti-interleukin 1 beta antibody (titer 1:100) which significantly abolished the inhibitory effect of interleukin 1 beta on free cytosolic calcium levels. These results show that a long lasting interaction of interleukin 1 beta with its receptor is able to influence voltage-sensitive calcium channels activation induced by maitotoxin in 235-1 cells.
Animals↗