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Biomedical subjects

F Alves

Publications and source records attributed to F Alves.

At least 37 records · Page 2Linked to original sources
PubMed1999

Expression of granulocyte colony-stimulating factor- and granulocyte-macrophage colony-stimulating factor-associated signal transduction proteins of the JAK/STAT pathway in normal granulopoiesis and in blast cells of acute myelogenous leukemia.

Acute myelogenous leukemia (AML) is characterized by the malignant transformation of hematopoietic stem cells leading to dysregulated growth and differentiation of myeloid cells. Normally, proliferation and differentiation of myeloid cells are regulated by cytokines such as granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF). Abnormal signaling of the signal transduction pathway from the cytokine receptors via Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) might be involved in the pathogenesis of AML. We examined whether an abnormal expression of one of the four JAKs, STAT1, STAT3, STAT5, or the tyrosine phosphatase SHP-1, a negative regulator of this pathway, is associated with malignant transformation in AML. Analysis of the expression of proteins of the JAK/STAT pathway in normal myeloid cells at three stages of maturation revealed a strong expression of all proteins in CD34+ cells, whereas the level of the proteins was significantly lower in granulocytic precursors and mature neutrophils. Furthermore, during maturation the relation of the isoforms of STAT1 and STAT3 changed from predominantly alpha to predominantly beta. Leukemic blast cells from 25 patients and 12 cell lines showed a high level of STAT proteins and SHP-1, whereas a deficiency of at least one of the four JAKs was found in 10 of 25 patients. In primary AML blast cells a deficiency of three JAKs was more common in patients with an abnormal karyotype. In addition, a lack of JAK2 and Tyk2 protein was strongly associated with the FAB M2 phenotype. The proliferation rate in response to GM-CSF available in a small number of patients appears to be related to the JAK2 expression. Our data suggest that the degree of expression of G-CSF/GM-CSF receptor-associated proteins of the JAK/STAT pathway in normal myeloid cells is related with their clonogenic potential. STAT3 appears to be involved in early differentiation. Similar to CD34+ cells, it is likely that the high levels of STATs and SHP-1 found in leukemic cells reflects their proliferative activity, whereas a lack of members of the JAK family might lead to an inability to proliferate in response to G-CSF/GM-CSF described in a considerable percentage of AML blasts.

Antigens, CD34↗
PubMed1998

[HNPCC-associated stomach carcinomas display aggressive growth in orthotopic transplantation to the SCID mouse].

The accumulation of malignant tumors in a single family, as well as the early onset of the disease, are highly suggestive of a hereditary condition. The evidence of microsatellite instabilities suggest a disease that might be associated with the HNPCC-syndromee. In contrary to the favourable prognosis of colorectal cancer associated with the HNPCC-syndromee we found in our animal model a far more aggressive progression of the disease in patients with HNPCC-associated gastric carcinomas than in patients with sporadic gastric carcinomas. This observation is consistent with the clinical course. Therefore, gastric carcinomas that are associated with the HNPCC-syndromee seem to represent a separate group of HNPCC-associated carcinomas and may even represent another hereditary disease.

Animals↗
PubMed1998

[Pediatric Crohn's disease complications].

This case report describes our experience in treatment of a child with Crohn's disease involvement of ileocecal and sigmoid regions complicated with a severe abdominal wall abscess. A combined therapeutic approach of the acute episode was based on intestinal diversion, abscess drainage, antibiotherapy, nutritional support and post-operative immunosuppression with azathioprine. The definitive treatment of the ileocolonic involvement occurred 6 months after the acute episode and consisted of limited resection, multiple strictureplasties, primar" closure of ileosigmod fistula and undiversion. This operative procedure was followed by a short period of total parenteral nutrition and progressive re-establishment ofenteric nutritional support and immunosuppression. At 18 months follow-up, under low dose azathioprine revealed, a normal growth with a 20 Kg weight gain and 10 cm height gain, no evidence of fistula recurrence or restenosis and suggests the safety of strictureplasty in paediatric patients as a way to conserve as much small bowel as possible.

Abdominal Abscess↗
PubMed1997

The discoidin domain receptor tyrosine kinases are activated by collagen.

Two mammalian receptor tyrosine kinases (DDR1 and DDR2) have extracellular domains closely related to a D. discoideum lectin, discoidin, required for cell aggregation. Here, we show that the mammalian DDR receptors bind and are activated by specific types of collagen. Stimulation of DDR receptor tyrosine kinase activity requires the native triple-helical structure of collagen and occurs over an extended period of time. Collagen activation of DDR1 induces phosphorylation of a docking site for the Shc phosphotyrosine binding domain, whose presence is controlled by alternative splicing. Activation of DDR2 by collagen results in the up-regulation of matrix metalloproteinase-1 expression. These results suggest that the discoidin-related DDR tyrosine kinases are novel collagen receptors with the potential to control cellular responses to the extracellular matrix.

Amino Acid Sequence↗
PubMed1995

Colon carcinoma kinase-4 defines a new subclass of the receptor tyrosine kinase family.

Complementary DNA (cDNA) encoding a novel member of the receptor tyrosine kinase (RTK) family has been isolated from colon carcinoma tissue. Colon carcinoma kinase 4 (CCK-4) mRNA is highly expressed in human lung tissue and at lower levels in the thyroid gland and ovary. While no mRNA was found in human adult colon tissues, expression varied remarkably in colon carcinoma-derived cell lines. CCK-4 cDNA encodes a chicken KLG-related, 1071 amino acid-long transmembrane glycoprotein containing several genetic alterations within the RTK consensus sequences. These define CCK-4 as a catalytically inactive member of the RTK family of proteins and, in analogy to HER3, suggest a potentially tumor-characteristic role as a signal amplifier or modulator for an as yet unidentified kinase-competent partner.

Adult↗
PubMed1995

Distinct structural characteristics of discoidin I subfamily receptor tyrosine kinases and complementary expression in human cancer.

Mammary carcinoma kinase 10 (MCK-10) and colon carcinoma kinase 2 (CCK-2) constitute a subclass of receptor tyrosine kinases characterized by a discoidin I motif in the extracellular domain and a large cytoplasmic juxtamembrane (JM) region. While the ectodomain structure suggests a common role in cell aggregation, the JM domains of MCK-10 and CCK-2 are structurally most divergent and display features that suggest an involvement in signal generation and definition. MCK-10 occurs in at least three isoforms, which contain alternatively spliced consensus sequences for internalization and SH3 domain interaction. The presence of the 37 amino acid insert affects receptor autophosphorylation and changes ectodomain glycosylation. Proteolytic cleavage within the extracellular domain of MCK-10 generates a membrane-anchored kinase domain and releases a soluble ectodomain fragment including the discoidin I homology domain. CCK-2 and MCK-10 expression was found in connective and epithelial tissues, respectively, which in cancers of epithelial origin results in mutually exclusive expression in stroma and tumor cells, indicating a possible involvement of this class of RTKs in tumor invasion.

Amino Acid Sequence↗
PubMed1993

Putrescine uptake in rat pancreatic acini: effect of secretagogues and growth factors.

Polyamines [putrescine (Put), spermidine, and spermine] are normal cellular constituents that can modulate cellular proliferation and differentiation in a number of tissue and cell types. Transport is one of the mechanisms that control intracellular polyamine content. The present investigation explores the influence of cholecystokinin (CCK), other secretagogues [carbachol, bombesin, vasoactive intestinal polypeptide (VIP)], insulin, insulin-like growth factor 1 (IGF-1), and epidermal growth factor (EGF) on Put uptake in rat pancreatic acini. Insulin, IGF-1, and EGF stimulated Put uptake by 30-40%. Insulin did not enhance intracellular metabolism of Put. In contrast, CCK and the other secretagogues inhibited this transport system by 40-50% of control (VIP by 23% only). Further investigations of the inhibitory effect of CCK revealed that the maximal uptake rate of Put (Vmax) shifted from 346 pmol [14C]Put/mg DNA-min (control) to 265 pmol [14C]Put/mg DNA-min (100 pM CCK), whereas the Km was only moderately influenced. Augmented Put efflux as well as increased production of endogenous Put (possibly induced by CCK) did not contribute to this change in transport kinetics. In addition, the inhibition of Put uptake induced by CCK was specific and dose dependent up to 100 pM. CCK at 1,000 pM exerted only minor inhibition (20% of control). Incubation with the Ca-ionophore A 23187 did not influence Put accumulation, whereas treatment with the phorbol ester phorbol 12-myristate-13-acetate led to enhanced Put uptake (30-40%). Pretreatment of the acini with 1 mM ouabain led to a reduction of Put uptake by 43%.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Role of polyamines in glucocorticoid effects on pancreatic acinar AR42J cell growth and differentiation.

We previously found that glucocorticoids inhibit growth and increase differentiation in rat pancreatic acinar AR42J cells. In the current study, we examined the role of polyamines in these effects. Treatment of AR42J cells with the ornithine decarboxylase (ODC) inhibitor difluoromethylornithine (DFMO) inhibited DNA synthesis. Thus polyamines are required for AR42J cell growth. However, we have previously shown that dexamethasone (Dex) increased AR42J cell ODC activity and mRNA levels. In the current study, we found that Dex treatment increased cellular putrescine levels. These increases in ODC and putrescine occurred during Dex-induced inhibition of DNA synthesis. Therefore, in AR42J cells, ODC activity and polyamine levels are not strictly growth related. To examine the requirement for glucocorticoid induction of ODC activity in glucocorticoid stimulation of differentiation, we examined the effects of DFMO on amylase gene expression and cholecystokinin binding. DFMO reduced cell amylase content while having little effect on mRNA levels in both Dex-treated and untreated cells. In contrast, DFMO had little effect on control CCK binding but inhibited the Dex-induced increase. Thus polyamines are necessary for growth and glucocorticoid-induced differentiation of AR42J cells; however, effects of glucocorticoids on AR42J cell growth and differentiation are not mediated by effects on ODC.

Amylases↗
PubMed1992

Putrescine uptake and metabolism in isolated rat pancreatic acini.

In addition to de novo synthesis, polyamine uptake is one of the major mechanisms in the regulation of intracellular polyamine concentrations. The aim of the present study was to investigate the uptake of putrescine (PUT) in isolated rat pancreatic acini and its further metabolic transformation. PUT accumulation was nearly linear over 60 min, showed saturation kinetics with an apparent Km of 3 x 10(-5) M and a Vmax of 346 pmol [14C]-PUT/min/mg DNA and decreased with decreasing temperature. Potassium cyanide (KCN) and dinitrophenol (DNP) inhibited PUT uptake. In the absence of a transmembrane Na+ gradient, PUT uptake decreased by 50%. After 60 min of incubation, 31% of the accumulated [14C]-PUT was metabolized. PUT uptake was stimulated by several amino acids, except for lysine, by decreasing the apparent Km for PUT uptake. PUT accumulation was reduced by spermidine (0.1 mM) by about 90%. Acetylated polyamines had only a minor effect. The release of radioactive material from prelabelled acini was only 10-20% after 90 min.

Amino Acids↗
PubMed1991

Changes in plasma, erythrocyte, and urinary magnesium with prolonged swimming exercise.

Erythrocyte, plasma and urinary magnesium were observed in a group of 8 well-trained swimmers and in a group of 10 untrained subjects before, 2 minutes after and 30 minutes after a swimming test. After effort, plasma Mg (pMg) decreased significantly in both groups. Erythrocyte and urinary Mg variations were not significant in this study. PMg decrease after effort was more important in the swimmers group than in the untrained group (12% versus 6% after 2 minutes; 21% versus 4% after 30 minutes). The observed fall in plasma Mg concentration after exercise cannot be explained by a shift into erythrocytes during exercise, since the Mg content of these blood cells did not suffer significant alterations. The possible causes of the observed phenomena are discussed.

Adolescent↗
PubMed1990

Polyamines in pancreatic growth.

This chapter reviews available data concerning the role of polyamines in pancreatic growth. Like in many other mammalian cells stimulation of pancreatic proliferation by trophic factors is associated with an early increase in ornithine decarboxylase (ODC) activity with consequent putrescine formation. ODC and putrescine play probably an important role in the initiation but not maintenance of pancreatic growth. The application of the specific ODC inhibitor alpha-difluoromethylornithine (DFMO) alone is not sufficient to judge the role of polyamines in pancreatic growth. For that purpose a combination of substances which inhibit ODC (DFMO) and polyamine oxidase (N1,N4-bisallenylputrescine) and/or S-adenosylmethionine-decarboxylase (SAM-DC) simultaneously has to be investigated. Ideally polyamines from dietary sources and intestinal bacterial flora should be abolished. The uptake of polyamines from the circulation has still to be considered. Studies will be presented proving that though ODC is completely inhibited by DFMO putrescine is still formed via spermidine/spermine N1-acetyltransferase (SAT). The fast increase of ODC in response to growth stimulating factors like cholecystokinin (CCK) is regulated at a pretranslational level by increasing ODC mRNA.

Animals↗
PubMed1990

Acute and chronic effects of cyclosporine A on pancreatic polyamine metabolism and pancreatic adaptation.

The present study was designed to investigate the effects of acute and chronic application of the immunosuppressive agent cyclosporine A (CsA) on pancreatic polyamine metabolism as well as pancreatic growth of rats in vivo. Seven to ten animals per group were treated with either the synthetic trypsin inhibitor camostate (FOY-305, 200 mg/kg b.wt. p.o. twice a day), CsA (10 mg/kg b.wt. p.o. once a day), camostate plus CsA, or oil as control, and animals were killed after 8 h, 1, 5 and 14 days. Feeding of camostate resulted in a significant increase of the measured parameters in the following time-course: cholecystokinin (CCK), 8 h; ornithine decarboxylase (ODC), 8 h: putrescine, 8 h; S-adenosylmethionine decarboxylase (SAM-DC), 1 day; pancreatic weight, 1 day; protein content, 5 days; spermidine, 5 days; RNA, 5 days; and DNA, 14 days. Simultaneous treatment with CsA resulted in a significant inhibition of camostate-induced increases in ODC, SAM-DC as well as putrescine and spermidine and furthermore caused a nearly complete inhibition of the increase of all trophic parameters, while CCK plasma levels were not altered. Counterregulatory mechanisms to maintain the intracellular polyamine pool as known after application of specific inhibitors of enzymes of the polyamine metabolism (i.e. DFMO) were not observed. Therefore we conclude that CsA does not directly interact with the polyamine metabolism, but rather with the second messenger system or any other intracellular mechanism, that is activated after stimulation with CCK before the polyamine metabolism is induced.

Acetyltransferases↗
PubMed1988

Ornithine decarboxylase and polyamine biosynthesis in pancreatic adaptation.

This study was designed to investigate the role of ornithine decarboxylase (ODC) and polyamines in pancreatic adaptation. Cholecystokinin (CCK) is well-known to be a potent trophic stimulus on the pancreas. On the other hand, the oral application of the synthetic trypsin inhibitor camostate results in an extensive release of endogenous CCK in rats. alpha-difluoromethylornithine (DFMO), an irreversible and specific inhibitor of ODC, was applied simultaneously to elucidate the essential role of polyamines in pancreatic growth. Camostate feeding (200 mg/kg b.wt. orally twice a day) resulted in a rapid elevation of ODC activity already after 2 hours, reaching a maximum after 6 hours (about 200fold above controls) followed by a significant increase in putrescine after 4 hours and spermidine after 24 hours while spermine remained unchanged. The trophic parameters increased as expected in following time-course: thymidine kinase (12 hours), DNA polymerase (12 hours), protein (24 hours), pancreatic weight (24 hours) and DNA (5 days). DFMO (2% in drinking water + 3 x 300 mg/kg b.wt. i.p. during daytime) was not able to prevent but significantly delayed and reduced the camostate-induced increase in ODC and polyamines as well as the trophic parameters. These data indicate an essential role for ODC and polyamines in camostate-induced pancreatic growth and hormonal mediated pancreatic adaptation.

Animals↗
PubMed1988

Changes in serum and erythrocyte magnesium and blood lipids after distance swimming.

The effect of a 30 min. swimming exercise (freestyle) on plasma magnesium and other biochemical variables was assessed on 6 well trained swimmers. Blood samples were taken before, right after, 30 min. and 24 hours after exercise. Serum Mg concentration decreased significantly during exercise, returning to base line 24 hours after. Erythrocyte content in Mg did not show any significant changes. Plasma total cholesterol level decreased significantly 30 min. after exercise. A significant positive correlation found at rest between plasma Mg levels and plasma total H.D.L. cholesterol disappeared after exercise but was observed again 24 hours later.

Adolescent↗