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Domenico Ribatti

Publications and source records attributed to Domenico Ribatti.

At least 37 records · Page 2Linked to original sources
PubMed2006

Bortezomib mediates antiangiogenesis in multiple myeloma via direct and indirect effects on endothelial cells.

Bone marrow angiogenesis plays an important role in the pathogenesis and progression in multiple myeloma. Recent studies have shown that proteasome inhibitor bortezomib (Velcade, formerly PS-341) can overcome conventional drug resistance in vitro and in vivo; however, its antiangiogenic activity in the bone marrow milieu has not yet been defined. In the present study, we examined the effects of bortezomib on the angiogenic phenotype of multiple myeloma patient-derived endothelial cells (MMEC). At clinically achievable concentrations, bortezomib inhibited the proliferation of MMECs and human umbilical vein endothelial cells in a dose-dependent and time-dependent manner. In functional assays of angiogenesis, including chemotaxis, adhesion to fibronectin, capillary formation on Matrigel, and chick embryo chorioallantoic membrane assay, bortezomib induced a dose-dependent inhibition of angiogenesis. Importantly, binding of MM.1S cells to MMECs triggered multiple myeloma cell proliferation, which was also abrogated by bortezomib in a dose-dependent fashion. Bortezomib triggered a dose-dependent inhibition of vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) secretion by the MMECs, and reverse transcriptase-PCR confirmed drug-related down-regulation of VEGF, IL-6, insulin-like growth factor-I, Angiopoietin 1 (Ang1), and Ang2 transcription. These data, therefore, delineate the mechanisms of the antiangiogenic effects of bortezomib on multiple myeloma cells in the bone marrow milieu.

Angiogenesis Inhibitors↗
PubMed2006

In vivo administered reserpine increases piecemeal degranulation in rat adrenal chromaffin cells.

The effects of the amine-depletory agent reserpine have been evaluated by transmission electron microscopy in chromaffin cells of the rat adrenal glands. The drug has been injected intraperitoneally in the animals at a dose of 0.5 mg/kg body weight in two administrations at 24-hr interval. The observed ultrastructural changes closely reminded of piecemeal degranulation (PMD), a slow and long-lasting secretory process previously described in normal and tumor pheochromocytes. Both adrenaline- and noradrenaline-storing cells presented the following microscopic features: high granule polymorphism, due to coexistence in the same cell of normal resting granules, granules with partially mobilized components, and large empty containers; absence of granule fusion; characteristic "haloed" pattern of residual secretory contents; great amount of 30-150 nm diameter, membrane-bound, electron-dense and -lucent vesicles, free in the cytoplasm or attached to granules; and multiple vesicles budding from the granule-limiting membranes. Morphometric analysis revealed that the frequency of all these microscopic parameters was found to be significantly increased in adrenal chromaffin cells from reserpinized rats in comparison to cells from control animals. These data suggest that reserpine, besides blocking the inward transport of catecholamines in chromaffin granules, might also stimulate a complex secretory reaction, which shares many common passages with bona fide PMD.

Adrenal Medulla↗
PubMed2006

Number of pericryptal fibroblasts correlates with density of distinct mast cell phenotypes in the crypt lamina propria of human duodenum: implications for the homeostasis of villous architecture.

Pericryptal fibroblasts (PFs), a class of myofibroblasts, have strongly been implicated in the regulation of villous structure because of their location close to crypts and their ability to secrete cytokines affecting intestinal epithelial cell proliferation and differentiation. Recently, mast cells (MCs) have also been involved in the homeostasis of villous architecture. As myofibroblasts arise in a wide variety of settings concurrently with a local increase in the number of tissue MCs, we calculated in this study the density of both PF and distinct pericryptal MC phenotypes in the mucosa of human duodenum showing normal, defective, or atrophic villous profiles. In addition, we evaluated the statistical association between PF-MC densities and each pattern of villous architecture. Finally, we correlated the density of PF with the density of pericryptal MC phenotypes. For this purpose, samples taken by endoscopy from 30 patients complaining of inflammatory bowel disorders were studied by immunohistochemistry. The densities of alpha-smooth muscle actin-positive PFs as well as tryptase-, chymase-, and c-kit-positive MCs were determined in the crypt lamina propria. Villous architecture was found to be significantly associated with the number of PFs and tryptase-, chymase-, c-kit-positive MCs in the lamina propria (ANOVA group effect P < 0.001). High density of both PFs and MCs was found in intestinal samples with normal villous morphology while lower densities were associated with defective or atrophic villous profiles (Tukey's test for multiple comparison P < 0.001). In addition, a significant correlation was found between PF density and the density of each pericryptal MC phenotype (vs. tryptase-positive MCs, r = 0.913; vs. chymase-positive MC, r = 0.905; vs. c-kit-positive MC, r = 0.927; P < 0.001 in all cases). This study provides morphological support for an important cooperation between PFs and MCs in maintaining normal villous architecture.

Actins↗
PubMed2006

Development of the blood-brain barrier: a historical point of view.

Although there has been considerable controversy since the observation by Ehrlich more than 100 years ago that the brain did not take up dyes from the vascular system, the concept of an endothelial blood-brain barrier (BBB) was confirmed by the unequivocal demonstration that the passage of molecules from blood to brain and vice versa was prevented by endothelial tight junctions (TJs). There are three major functions implicated in the term "BBB": protection of the brain from the blood milieu, selective transport, and metabolism or modification of blood- or brain-borne substances. The BBB phenotype develops under the influence of associated brain cells, especially astrocytic glia, and consists of complex TJs and a number of specific transport and enzyme systems that regulate molecular traffic across the endothelial cells. The development of the BBB is a complex process that leads to endothelial cells with unique permeability characteristics due to high electrical resistance and the expression of specific transporters and metabolic pathways. This review article summarizes the historical background underlying our current knowledge of the cellular and molecular mechanisms involved in the development and maintenance of the BBB.

Anatomy↗
PubMed2006

Diogenes of Apollonia: a pioneer in vascular anatomy.

Diogenes of Apollonia was a pre-Socratic philosopher who lived in the 5th century BC and provided the first systematic and fairly truthful account of blood vessel architecture in man. This article presents Diogenes' report and comments on the most significant passages of his vascular description. It also discusses the magnitude of Diogenes' contribution to shape early theories regarding blood vessel physiology. What emerges from this portrait is the figure of an eclectic spirit, who remarkably influenced the development of leading concepts in vascular anatomy and biology.

Anatomy↗
PubMed2006

Mondino de' Liuzzi and his Anothomia: a milestone in the development of modern anatomy.

Mondino's Anothomia was written in Bologna around 1316. This book is the intellectual legacy of one of the fathers of human anatomy, and probably represents a collection of lessons given by the author at the Studium in Bologna. Mondino's Anothomia witnesses a profound renewal of the mode of understanding and teaching human anatomy through direct observation of dissected corpses. This book enjoyed an extraordinarily large dissemination in the whole of Europe, thanks to many extant manuscripts and printed editions. In this article, we present some selected passages from this remarkable book to let today's anatomists know how great was the descriptive skill of this medieval scientist, a pioneer in the anatomical discipline.

Anatomy↗
PubMed2006

Serum levels of syndecan-1 in B-cell chronic lymphocytic leukemia: correlation with the extent of angiogenesis and disease-progression risk in early disease.

Syndecan-1 is a transmembrane proteoglycan generally not expressed in mature B-cell neoplasias like chronic lymphocytic leukemia (CLL). Moreover, information dealing with the evaluation of soluble syndecan-1 in CLL are lacking. We measured syndecan-1 concentrations in serum drawn at the time of diagnosis from 67 B-cell CLL patients (Binet stage A, 46; stage B, 7; stage C, 14). For this purpose a syndecan-1 enzyme-linked immunosorbent assay (ELISA, Diaclone, Besancon, France) was used. Detectable levels of syndecan-1 were found in all patients, although serum concentrations were significantly lower in CLL patients in comparison to age- and sex-matched controls (P = 0.02; Mann-Whitney test). No correlation was found with Binet clinical stages (P = 0.796), beta2-microglobulin (P = 0.923), hemoglobin level (P = 0.605), platelet count (P = 0.992) and lymphocyte doubling time (P = 0.709). Only an association with absolute peripheral blood lymphocytosis (PBL) (P = 0.01) and LDH (P = 0.05) could be detected. Serum levels of syndecan-1 did not parallel those of several angiogenic cytokines such as vascular endothelial growth factor (VEGF) (P = 0.963), basic fibroblastic growth factor (FGF-2) (P = 0.216), angiogenin (P = 0.478), metalloproteinase-9 (MMP-9) (P = 0.125) as well as bone marrow (BM) microvessel density (P = 0.110). The same applied with adhesion molecules such as CD54 (P = 0.233), CD108 (P = 0.799), CD44 (P = 0.816) and CD31 (P = 0.508). Interestingly, the inverse correlation (r = -0.4967; P = 0.03) between serum concentrations of syndecan-1 and plasma levels of stromal derived growth factor-1 (SDF-1) is in keeping with the different function, respectively, pro- and anti-apoptotic, of these molecules. In 46 Binet stage A patients, serum levels of syndecan-1 were further evaluated as a dichotomous variable with respect to progression-free survival (PFS), an end-point surrogate for overall survival in early B-cell CLL. The best separation of curves was seen with a cut-off point at the median value of syndecan-1 (i.e. 36.5 pg/ml). Median PFS was not reached in the patient group with low syndecan-1, compared to a median of 34 months observed in the remaining patients (P = 0.018; HR = 0.208; 95% CI = 0.115 - 0.816). At the multivariate analysis performed including variables significant in the univariate analysis [i.e. PBL (P = 0.03) and syndecan-1 (P = 0.01)], only syndecan-1 retained a trend of significance (P = 0.08). Despite the pro-angiogenic activity of syndecan-1 which mediates FGF-2 binding and activity, no correlation with either angiogenic cytokines or the extent of BM angiogenesis was found in CLL. The inverse correlation with plasma levels of SDF-1 suggests an involvement in the processes leading to apoptosis. Finally, our results highlight the involvement of syndecan-1 in the mechanisms of disease-progression of early CLL.

Adult↗
PubMed2006

Microvascular density and endothelial area correlate with Ki-67 proliferative rate in the canine non-Hodgkin's lymphoma spontaneous model.

Experimental and clinical data indicate that tumor progression and malignancy are associated with increased angiogenesis and higher Ki-67 proliferation rate. Furthermore, increased angiogenesis and higher Ki-67 proliferation rate are associated with a poor prognosis, in both solid and hematological malignancies. However, no data have been published concerning the relationship between angiogenesis and Ki-67 proliferation rate in canine non-Hodgkin's lymphoma (NHL), a neoplasm that shares several biological and clinical characteristics with human NHL. This study has evaluated the relationship between angiogenesis and Ki-67 proliferation rate in a series of 58 canine NHL. Results showed that microvascular density (MVD), endothelial area (EA) and Ki-67 (MIB-1) are significantly correlated and that all the above indexes paralleled with the malignancy degree of NHL. These data suggest a biological link between angiogenesis and Ki-67 proliferation rate in canine NHL, which represents an interesting model to study the role of angiogenesis and proliferative activity as inter-species pathways of tumoral malignancy and biological aggressiveness.

Animals↗
PubMed2006

The fundamental contribution of Robert A. Good to the discovery of the crucial role of thymus in mammalian immunity.

Robert Alan Good was a pioneer in the field of immunodeficiency diseases. He and his colleagues defined the cellular basis and functional consequences of many of the inherited immunodeficiency diseases. His was one of the groups that discovered the pivotal role of the thymus in the immune system development and defined the separate development of the thymus-dependent and bursa-dependent lymphoid cell lineages and their responsibilities in cell-mediated and humoral immunity.

Agammaglobulinemia↗
PubMed2006

Genetic and epigenetic mechanisms in the early development of the vascular system.

The cardiovascular system plays a critical role in vertebrate development and homeostasis. Vascular development is a highly organized sequence of events that requires the correct spatial and temporal expression of specific sets of genes leading to the development of a primary vascular network. There have been intensive efforts to determine the molecular mechanisms regulating vascular growth and development, and much of the rationale for this has stemmed from the increasing clinical importance and therapeutic potential of modulating vascular formation during various disease states.

Animals↗
PubMed2006

Serum insulin-like growth factor is not elevated in patients with early B-cell chronic lymphocytic leukemia but is still a prognostic factor for disease progression.

OBJECTIVES: Insulin-like growth factor 1 (IGF-1) is an important growth and anti-apoptotic factor for the cancer cells in several malignancies and in multiple myeloma recent studies support the hypothesis of a role for IGF-1 in disease progression; however, clinico-biological relevance of IGF-1 was never studied in B-cell chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: Using a quantitative sandwich immunoassay technique (ELISA) (Quantikine, Human IGF-1 and IGFBP-3, R&D Systems), we measured the concentration of IGF-1 and its major binding protein IGF-binding protein 3 (IGFBP-3) in serum drawn at the time of diagnosis from 77 Binet stage A CLL patients. RESULTS: Either IGF-1 or IGFBP-3 were significantly decreased compared with healthy age- and sex-matched controls (P < 0.0001 for both; Mann-Whitney test). Serum levels of IGF-1 and IGFBP-3 paralleled each other (P = 0.002); in contrast, no significant correlation was found between serum levels of IGF-1 and clinico-hematological variables including age (P = 0.253), sex (P = 0.270), Rai clinical substages (P = 0.140), lactate dehydrogenase (P = 0.956), beta2-microglobulin (P = 0.368), lymphocyte count (P = 0.703) and lymphocyte doubling time (LDT, P = 0.233). When correlation were attempted with circulating levels of angiogenic cytokines such as vascular endothelial growth factor (P = 0.971), basic fibroblastic growth factor (P = 0.695), angiogenin (P = 0.282) or adhesion molecules such as vascular cell adhesion molecule-1 (P = 0.318), intercellular adhesion molecule-1 (P = 0.883) and platelet endothelial cell adhesion molecule-1 (P = 0.772) similar results were found. Serum levels of IGF-1 were further evaluated as a dichotomous variable with respect to progression-free survival (PFS), an endpoint surrogate for overall survival in early B-cell CLL. The best separation of curves was seen with the cutoff point at the 75th percentile of IGF-1 levels (i.e., 93 pg/mL). Median PFS was 63 months in the patient group with low IGF-1, compared with a median PFS of 40 months in the remaining patients (P = 0.03). In the multivariate analysis performed including variables significant at univariate analysis [i.e. Rai substage (P = 0.002); LDT (P = 0.004), IGF-1 (P = 0.01)], only Rai substage retained prognostic significance (P = 0.006). However, after removing from analysis LDT (only six of 77 had an LDT < 12 months), either IGF-1 or Rai substage entered the model at a significant level (P = 0.03 and P = 0.01, respectively). CONCLUSIONS: IGF-1 did not correlate with markers of tumor burden or clinical status in CLL thus suggesting that levels of this cytokine do not reflect the intrinsic malignancy of disease. Results of the present study highlight, however, its involvement in mechanisms of disease progression in early CLL.

Age Factors↗
PubMed2006

Vascular endothelial growth factor (VEGF) as a target of bevacizumab in cancer: from the biology to the clinic.

Angiogenesis is important in the growth and progression of solid tumours. The main pro-angiogenic factor, namely vascular endothelial growth factor (VEGF), also known as vascular permeability factor, is a potent angiogenic cytokine that induces mitosis and also regulates the permeability of endothelial cells. The soluble isoform of VEGF is a dimeric glycoprotein of 36-46 kDa, induced by hypoxia and oncogenic mutation and it binds to two specific tyrosine-kinase receptors: VEGF-1 (flt-1) and VEGF-2 (KDR/flk1). An increase in VEGF expression in tumour tissue or some blood compartments (i.e. serum or plasma) has been found in solid and haematological malignancies of various origins and is associated with metastasis formation and poor prognosis. Bevacizumab, a recombinant humanised monoclonal antibody developed against VEGF, binds to soluble VEGF, preventing receptor binding and inhibiting endothelial cell proliferation and vessel formation. Pre-clinical and clinical studies have shown that bevacizumab alone or in combination with a cytotoxic agent decreases tumour growth and increases median survival time and time to tumour progression. Bevacizumab is the first anti-angiogenetic treatment approved by the American Food and Drug Administration in the first-line treatment of metastatic colorectal cancer. It has shown preliminary evidence of efficacy for breast, non-small-cell lung, pancreatic, prostate, head and neck and renal cancer as well as haematological malignancies. Common toxicities associated with bevacizumab include hypertension, proteinuria, bleeding episodes and thrombotic events. This review summarises the critical role of VEGF and discusses the data available on bevacizumab, from the humanisation of its parent murine monoclonal antibody (mAb) A.4.6.1 to its use in cancer clinical trials.

Amino Acid Sequence↗
PubMed2006

An image analysis of the spatial distribution of perivascular mast cells in human melanoma.

A mutual spatial and functional relationship occurs between mast cells (MCs) and endothelial cells and the density of MCs is highly correlated with the extent of tumor angiogenesis. The aim of this study was to investigate the pattern of MCs around the blood vessels in melanoma samples by means of an approach derived from spatial statistics, based on the analysis of the distribution of the distances of MCs from vessels to objectively establish if the two structures (MCs and vessels) are distributed independently over the studied area or if they displayed any kind of spatial association. Results showed that a higher number of vessels and MCs can be observed in melanoma as compared with samples from common acquired nevi (control group). The percent of area covered by vessel profiles was significantly higher in the melanoma group than the control group and the MC density was also significantly different; the melanoma group showing a number of MCs per unit area twice as high as the number measured in the control group. Furthermore, in the melanoma group, MCs were closer to each other and to the vessels. In fact, both the mean distance from vessels and the mean distance from the nearest cell profile were significantly lower than in the control group. This close association between MCs and the endothelium does not necessarily imply a participation of MCs in angiogenic processes, but might rather indicate that MCs are involved in the maintenance reaction necessary for the long lasting functional integrity of the endothelium.

Adult↗
PubMed2006

Dense-core granules in neuroendocrine cells and neurons release their secretory constituents by piecemeal degranulation (review).

The term piecemeal degranulation (PMD) refers to a slow releasing process mediated by vesicular transport of stored secretory granule contents. This form of cell secretion was first proposed for basophils, mast cells and eosinophils, but evidence has begun to accumulate that PMD also occurs in dense-core granules of neuroendocrine cells and neurons. This review summarizes the electron-microscopic evidence that has been gathered in support of this view and also discusses the possible physiological significance of PMD in this class of secretory organelles in comparison with 'full fusion' and 'kiss-and-run' exocytosis.

Animals↗
PubMed2006

Urotensin-II and its receptor (UT-R) are expressed in rat brain endothelial cells, and urotensin-II via UT-R stimulates angiogenesis in vivo and in vitro.

Urotensin-II (UII), along its receptor UT-R, is widely expressed in the cardiovascular system, where it exerts regulatory actions under both physiological and pathological conditions. Real-time PCR and immunocytochemistry demonstrated the expression of UII and UT-R as mRNA and protein in rat neuromicrovascular endothelial cells (NECs). UII did not affect the proliferation rate of cultured NECs, but exerted a strong angiogenic action in both an in vitro assay on Matrigel and an in vivo assay on chorioallantoic membrane. The angiogenic effect of UII was similar to that of FGF-2, and was abolished by the UT-R antagonist Palosuran. Collectively, our findings allow us to include UII in the group of cytokines (e.g. endothelin-1 and adrenomedullin), which are expressed in endothelial cells and exert a pro-angiogenic effect acting in an autocrine-paracrine manner.

Animals↗
PubMed2005

Synergistic inhibition of human neuroblastoma-related angiogenesis by vinblastine and rapamycin.

The aim of this study was to evaluate the synergistic antiangiogenic effect of low dose of vinblastine (VBL) and rapamycin (RAP) in neuroblastoma (NB). Both in vitro (endothelial cells proliferation assay; TUNEL assay; phosphatidylserine exposure and cell cycle analysis) and in vivo (chick embryo chorioallantoic membrane, CAM) assays were used. Each compound alone was able to induce a significant dose- and time-response inhibition of in vitro endothelial cells (EC) growth. Interaction index evaluation indicates that a synergistic effect was found when both drugs were combined at very low doses. Comparable effects were obtained when EC were preincubated with conditioned medium (CM) derived from the human NB cell line HTLA-230. Morphological changes were induced by each drug, and their combination resulted in a clear and stronger effect. Apoptosis was demonstrated by the TUNEL assay and confirmed by Annexin V-FITC staining of EC treated with VBL, showing an increase in the percentage of cells with a G2-M and sub-G1 DNA content, whereas in those treated with RAP a block in the G1 cell fraction and inhibition of progression to the S phase were observed. Here too, the combination resulted in a synergistic cell cycle arrest and induction of apoptosis. Similar results were obtained in vivo with the CAM assay. The angiogenic responses induced by HTLA-230-derived CM, NB tumor xenografts, and human NB biopsy specimens were inhibited by each drug and more significantly by their combination. The observation that these well-known drugs display synergistic effects as antiangiogenics when administered frequently at very low dose may be of significance in the designing of new ways of treating NB.

Animals↗