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Biomedical subjects

Domenico Ribatti

Publications and source records attributed to Domenico Ribatti.

At least 19 recordsLinked to original sources
PubMed2007

The contribution of Gianni Bonadonna to the history of chemotherapy.

The history of cancer chemotherapy and of the discipline of medical oncology has been that of drug discovery. The pioneering discoveries of the early days of chemotherapy have allowed the development of a paradigm for drug discovery that persists, with modifications to the present day. This review article summarizes the seminal work of the Italian scientist Gianni Bonadonna on the treatment of breast cancer and Hodgkin's disease.

Antineoplastic Agents↗
PubMed2007

A portrait of Aristotle as an anatomist: historical article.

Aristotle is principally known as a theoretical philosopher and logician but he was also an eminent natural scientist. In particular, he should be considered probably the first anatomist in the modern sense of this term and the originator of anatomy as a special branch of knowledge. Although it seems certain that he did not perform dissections of human adult cadavers, he examined human fetal material and, above all, made systematic analysis of animal bodies. His contribution to comparative anatomy, as well as to human anatomy, was enormous. He founded the anatomical discipline on precise descriptive and scientific ground. He also coined a series of technical terms, which are still in use in the modern nomenclature. His observational skill was astounding. Although many of his physiological concepts turned out to be wrong, still his structural description of organs and body parts was often first-rank. The present study will chiefly focus on Aristotle's anatomical work and will provide only essential mention of his complex physiological and philosophical doctrine. The main purpose of this article is indeed to offer to today's anatomists a systematic account of the extraordinary achievements of this great pioneer of our discipline.

Anatomy↗
PubMed2006

The discovery of endothelial progenitor cells. An historical review.

Although the earliest sites of hematopoietic cell and endothelial cell differentiation in the yolk sac blood islands were identified about 100 years ago, cells with hemangioblast properties have not yet been identified in vivo. Endothelial cells differentiate from angioblasts in the embryo and from endothelial progenitor cells, mesoangioblasts and multipotent adult progenitor cells in the adult bone marrow. Endothelial progenitor cells (EPC) were initially described by Asahara et al. [Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997;275:964-7.], and the past few years have seen a rapid expansion of our knowledge of EPC biology. Prior to the discovery of this cell type, new vessel formation was believed to occur to proliferation of existing endothelial cells. These findings have overturned the previous dogma that vasculogenesis can only occur during embryogenesis. Questions persist regarding their functional characteristics, as well as the precise panel of cell surface markers that define this cell population.

Animals↗
PubMed2006

The fundamental contribution of Jan C. Waldenström to the discovery and study of the so-called "Waldenström macroglobulinemia".

Waldenström macroglobulinemia may be said to be characterized cheifly by two features: (1) a striking increase in IgM globulin of the "monoclonal gammapathy" type and (2) an abnormal bone marrow characterized by either a leukemic or leukemic-like picture, in which lymphocytes of various types are prominent. All the other features, hemorrhagic, hemolytic, rheologic (viscosity syndrome) must be considered as secondary manifestations. This historical review article summarizes the fundamental contribution of Jan Costa Waldenström to the discovery and study of this lymphoproliferative disorder.

History, 20th Century↗
PubMed2006

Expression and functions of the vascular endothelial growth factors and their receptors in human basophils.

Angiogenesis is a multistep complex phenomenon critical for several inflammatory and neoplastic disorders. Basophils, normally confined to peripheral blood, can infiltrate the sites of chronic inflammation. In an attempt to obtain insights into the mechanism(s) underlying human basophil chemotaxis and its role in inflammation, we have characterized the expression and function of vascular endothelial growth factors (VEGFs) and their receptors in these cells. Basophils express mRNA for three isoforms of VEGF-A (121, 165, and 189) and two isoforms of VEGF-B (167 and 186). Peripheral blood and basophils in nasal polyps contain VEGF-A localized in secretory granules. The concentration of VEGF-A in basophils was 144.4 +/- 10.8 pg/10(6) cells. Immunologic activation of basophils induced the release of VEGF-A. VEGF-A (10-500 ng/ml) induced basophil chemotaxis. Supernatants of activated basophils induced an angiogenic response in the chick embryo chorioallantoic membrane that was inhibited by an anti-VEGF-A Ab. The tyrosine kinase VEGFR-2 (VEGFR-2/KDR) mRNA was expressed in basophils. These cells also expressed mRNA for the soluble form of VEGFR-1 and neuropilin (NRP)1 and NRP2. Flow cytometric analysis indicated that basophils express epitopes recognized by mAbs against the extracellular domains of VEGFR-2, NRP1, and NRP2. Our data suggest that basophils could play a role in angiogenesis and inflammation through the expression of several forms of VEGF and their receptors.

Adult↗
PubMed2006

Bone morphogenic protein antagonist Drm/gremlin is a novel proangiogenic factor.

Angiogenesis plays a key role in various physiologic and pathologic conditions, including tumor growth. Drm/gremlin, a member the Dan family of bone morphogenic protein (BMP) antagonists, is commonly thought to affect different processes during growth, differentiation, and development by heterodimerizing various BMPs. Here, we identify Drm/gremlin as a novel proangiogenic factor expressed by endothelium. Indeed, Drm/gremlin was purified to homogeneity from the conditioned medium of transformed endothelial cells using an endothelial-cell sprouting assay to follow protein isolation. Accordingly, recombinant Drm/gremlin stimulates endothelial-cell migration and invasion in fibrin and collagen gels, binds with high affinity to various endothelial cell types, and triggers tyrosine phosphorylation of intracellular signaling proteins. Also, Drm/gremlin induces neovascularization in the chick embryo chorioallantoic membrane. BMP4 does not affect Drm/gremlin interaction with endothelium, and both molecules exert a proangiogenic activity in vitro and in vivo when administered alone or in combination. Finally, Drm/gremlin is produced by the stroma of human tumor xenografts in nude mice, and it is highly expressed in endothelial cells of human lung tumor vasculature when compared with non-neoplastic lung. Our observations point to a novel, previously unrecognized capacity of Drm/gremlin to interact directly with target endothelial cells and to modulate angiogenesis.

Amino Acid Sequence↗
PubMed2006

Soul, mind, brain: Greek philosophy and the birth of neuroscience.

The nature of "soul" and the source of "psychic life", the anatomical seat of cognitive, motor and sensory functions, and the origin of neural diseases were broadly debated by ancient Greek scientists since the earliest times. Within the space of few centuries, speculation of philosophers and medical thinkers laid the foundations of modern experimental and clinical neuroscience. This review provides a brief history of the leading doctrines on the essence of soul and the properties of mind professed by Greek philosophers and physicians as well as the early attempts to localize brain faculties and to explain neural disorders.

Brain↗
PubMed2006

Targeting liposomal chemotherapy via both tumor cell-specific and tumor vasculature-specific ligands potentiates therapeutic efficacy.

Neuroblastoma, the most common solid tumor of infancy derived from the sympathetic nervous system, continues to present a formidable clinical challenge. Sterically stabilized immunoliposomes (SIL) have been shown to enhance the selective localization of entrapped drugs to solid tumors, with improvements in therapeutic indices. We showed that SIL loaded with doxorubicin (DXR) and targeted to the disialoganglioside receptor GD(2) [aGD(2)-SIL(DXR)] led to a selective inhibition of the metastatic growth of experimental models of human neuroblastoma. By coupling NGR peptides that target the angiogenic endothelial cell marker aminopeptidase N to the surface of DXR-loaded liposomes [NGR-SL(DXR)], we obtained tumor regression, pronounced destruction of the tumor vasculature, and prolonged survival of orthotopic neuroblastoma xenografts. Here, we showed good liposome stability, long circulation times, and enhanced time-dependent tumor accumulation of both the carrier and the drug. Antivascular effects against animal models of lung and ovarian cancer were shown for formulations of NGR-SL(DXR). In the chick embryo chorioallantoic assay, NGR-SL(DXR) substantially reduced the angiogenic potential of various neuroblastoma xenografts, with synergistic inhibition observed for the combination of NGR-SL(DXR) with aGD(2)-SIL(DXR). A significant improvement in antitumor effects was seen in neuroblastoma-bearing animal models when treated with the combined formulations compared with control mice or mice treated with either tumor- or vascular-targeted liposomal formulations, administered separately. The combined treatment resulted in a dramatic inhibition of tumor endothelial cell density. Long-term survivors were obtained only in animals treated with the combined tumor- and vascular-targeted formulations, confirming the pivotal role of combination therapies in treating aggressive metastatic neuroblastoma.

Animals↗
PubMed2006

Cutting edge: IL-1beta mediates the proangiogenic activity of osteopontin-activated human monocytes.

Inflammation plays an important role in the onset of angiogenesis. In the present study, we show that osteopontin (OPN), a proinflammatory mediator involved in tissue repair, induces IL-1beta up-regulation in human monocytes. This was accompanied by the enhanced production of TNF-alpha, IL-8, and IL-6, a decreased release of IL-10, and increased p38 phosphorylation. The supernatants of OPN-treated monocytes were highly angiogenic when delivered on the chick embryo chorioallantoic membrane. The angiogenic response was completely abrogated by a neutralizing anti-IL-1 Ab, thus indicating that this cytokine represents the major proangiogenic factor expressed by OPN-activated monocytes. Accordingly, rIL-1beta mimicked the proangiogenic activity of OPN-treated monocyte supernatants, and IL-1R (type I) was found to be expressed in the chorioallantoic membrane. In conclusion, OPN-activated monocytes may contribute to the onset of angiogenesis through a mechanism mediated by IL-1beta.

Animals↗
PubMed2006

Effect of bortezomib on human neuroblastoma cell growth, apoptosis, and angiogenesis.

BACKGROUND: Bortezomib is a selective and reversible inhibitor of the 26S proteasome that shows potent antitumor activity in vitro and in vivo against several human cancers of adulthood. No data are available on bortezomib activity against human pediatric neuroblastoma. METHODS: Ten neuroblastoma cell lines and suspensions of primary neuroblastoma cells from three patients were tested for sensitivity to bortezomib. Colony formation, cell proliferation, cell cycle progression, and apoptosis were evaluated by a clonogenic assay and by measuring 3H-thymidine incorporation, bromodeoxyuridine uptake, DNA fragmentation, and phosphatidylserine exposure and propidium iodide staining, respectively. Angiogenesis was assessed by the chick embryo chorioallantoic membrane (CAM) assay. Two mouse xenograft models that mimic the growth and spread of neuroblastoma in humans were used to examine in vivo sensitivity of neuroblastoma to bortezomib. All statistical tests were two-sided. RESULTS: Bortezomib inhibited proliferation and colony formation of neuroblastoma cell lines in a time- and dose-dependent manner. The mean bortezomib concentration that caused 50% inhibition of growth was 6.1 nM (95% confidence interval [CI] = 0.9 to 11.3 nM) at 72 hours. Bortezomib-treated neuroblastoma cells were arrested at G2/M and underwent apoptosis (mean percentage of apoptotic cells in four neuroblastoma cell lines treated with 20 nM bortezomib for 24 hours ranged from 20% to 35%, and caspases were activated by two- to fivefold with respect to untreated cells). Similar results were obtained for primary neuroblastoma cells exposed to bortezomib. Bortezomib inhibited angiogenesis in CAMs stimulated by conditioned medium from neuroblastoma cell lines, by neuroblastoma xenografts, and by primary neuroblastoma biopsy specimens (microvessel area: 2.9 x 10(-2) mm2, 95% CI = 1.8 x 10(-2) to 3.8 x 10(-2) mm2 in CAMs treated with biopsy specimens alone and 1.3 x 10(-2) mm2, 95% CI = 1 x 10(-2) to 1.5 x 10(-2) mm2 in CAMs treated with biopsy specimens plus bortezomib, P = .024). In both mouse models, mice treated with bortezomib lived statistically significantly longer than control mice (mean survival time in the pseudometastatic model: 74.2 versus 50.3 days, P<.001; mean survival time in the orthotopic model: 72.3 versus 50.6 days, P<.001). CONCLUSIONS: Bortezomib is an effective inhibitor of neuroblastoma cell growth and angiogenesis. These findings provide the rationale for further clinical investigation of bortezomib in pediatric neuroblastoma.

Animals↗
PubMed2006

The structure of the vascular network of tumors.

Tumor blood vessels display many structural and functional abnormalities. Their unusual leakiness, potential for rapid growth and remodeling, and expression of distinctive surface molecules mediate the dissemination of tumor cells in the bloodstream and maintain the tumor microenvironment. Like normal blood vessels, they consist of endothelial cells, mural cells and their enveloping basement membrane. Common features, irrespective of their origin, size and growth pattern, are absent hierarchy, formation of large-caliber sinusoidal vessels and markedly heterogeneous density. This review will focus on the factors influencing this heterogeneity.

Animals↗
PubMed2006

Angiogenesis and anti-angiogenesis in hepatocellular carcinoma.

Experimental and clinical data indicate that in human hepatocellular carcinoma (HCC) tumor progression is associated with angiogenesis and that an increase in microvascular density is associated with a poor prognosis. This review summarizes the literature concerning the relationship between angiogenesis and progression in HCC. It is becoming increasingly evident that agents which interfere with blood vessel formation also block tumor progression. Accordingly, anti-angiogenic tumor therapy has gained much interest in preclinical and clinical assessments. The recent applications of anti-angiogenic agents which interfere or block HCC progression are reviewed.

Angiogenesis Inhibitors↗
PubMed2006

Glycated fibroblast growth factor-2 is quickly produced in vitro upon low-millimolar glucose treatment and detected in vivo in diabetic mice.

Angiogenesis impairment in hyperglycemic patients represents a leading cause of severe vascular complications of both type-1 and -2 diabetes mellitus (DM). Angiogenesis dysfunction in DM is related to glycemic control; however, molecular mechanisms involved are still unclear. Fibroblast growth factor-2 (FGF-2) is a potent angiogenic factor and, according to previous evidence, may represent a key target of molecular modifications triggered by high-sugar exposure. Therefore, the purpose of this study was to investigate whether short incubation with hyperglycemic levels of glucose affected FGF-2 and whether glucose-modified FGF-2 was detectable in vivo. Biochemical analyses carried out with SDS-PAGE, fluorescence emission, mass-spectrometry, immunoblot, and competitive ELISA experiments demonstrated that human FGF-2 undergoes a rapid and specific glycation upon 12.5-50 mm glucose exposure. In addition, FGF-2 exposed for 30 min to 12.5 mm glucose lost mitogenic and chemotactic activity in a time- and dose-dependent manner. Under similar conditions, binding affinity to FGF receptor 1 was dramatically reduced by 20-fold, as well as FGF receptor 1 and ERK-1/2 phosphorylation, and FGF-2 lost about 45% of angiogenic activity in two different in vivo angiogenic (Matrigel and chorioallantoic-membrane) assays. Such glucose-induced modification was specific, because other angiogenic growth factors, namely platelet-derived growth factor BB and placental-derived growth factor were not significantly or markedly less modified. Finally, for the first time, glycated-FGF-2 was detected in vivo, in tissues from hyperglycemic nonobese diabetic mice, in significantly higher amounts than in normoglycemic mice. In conclusion, hyperglycemic levels of glucose may strongly affect FGF-2 structure and impair its angiogenic features, and endogenous glycated-FGF-2 is present in diabetic mice, indicating a novel pathogenetic mechanism underlying angiogenesis defects in DM.

Animals↗
PubMed2006

In vitro and in vivo proposal of an artificial esophagus.

Artificial materials and autologous tissues used for esophageal reconstruction often induce complications like stenosis and leakage at long-term follow-up. This study evaluates the possibility to obtain in vitro an implantable tissue-engineered esophagus composed of homologous esophageal acellular matrix and autologous smooth muscle cells (SMCs). Acellular matrices obtained by detergent-enzymatic method did not present any major histocompatibility complex marker and expressed bFGF as protein, showing angiogenic activity in vivo on the chick embryo chorioallantoic membrane (CAM). Moreover, they supported cell adhesion, and inasmuch as just after 24 h from seeding, the scaffold appeared completely covered by SMCs. To verify the biocompatibility of our constructs, defects created in the porcine esophageal wall were covered using homologous acellular matrices with and without cultures of autologous SMCs. At 3 week from surgery, the patches composed of only acellular matrices showed a more severe inflammatory response and were negative for alpha-smooth muscle actin immunostaining. In contrast, the cell-matrix implants presented ingrowth of SMCs, showing an early organization into small fascicules. Collectively, these results suggest that patches composed of homologous esophageal acellular matrix and autologous SMCs may represent a promising tissue-engineering approach for the repair of esophageal injuries.

Animals↗
PubMed2006

Mast cells in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic disease of joints that is characterized by inflammation, abnormal cellular and humoral immune responses, and synovial hyperplasia. Mast cells (MCs) are involved in several of these inflammatory and immune events. MC-derived mediators induce edema, destroy connective tissue, and are involved in lymphocyte chemotaxis and infiltration and in pathological fibrosis of RA joints. Moreover, MCs are involved in angiogenesis during RA, and their proteolytic activity results in cartilage destruction and bone remodeling. Lastly, MCs could be a target in the treatment of RA.

Arthritis, Rheumatoid↗
PubMed2006

Loss of inhibitory semaphorin 3A (SEMA3A) autocrine loops in bone marrow endothelial cells of patients with multiple myeloma.

Vascular endothelial growth factor165 (VEGF165) and semaphorin3A (SEMA3A) elicit pro- and antiangiogenic signals respectively in endothelial cells (ECs) by binding to their receptors VEGFR-2, neuropilin-1 (NRP1), and plexin-A1. Here we show that the VEGF165-driven angiogenic potential of multiple myeloma (MM) ECs is significantly higher than that of monoclonal gammopathy of undetermined significance (MGUS) ECs (MGECs) and human umbilical vein (HUV) ECs. This is probably due to a constitutive imbalance of endogenous VEGF165/SEMA3A ratio, which leans on VEGF165 in MMECs but on SEMA3A in MGECs and HUVECs. Exogenous VEGF165 induces SEMA3A expression in MGECs and HUVECs, but not in MMECs. Moreover, by counteracting VEGF165 activity as efficiently as an anti-VEGFR-2 antibody, exogenous SEMA3A restrains the over-angiogenic potential of MMECs. Our data indicate that loss of endothelial SEMA3A in favor of VEGF165 could be responsible for the angiogenic switch from MGUS to MM.

Bone Marrow Cells↗
PubMed2006

Sonographic quantitative evaluation of scrotal veins in healthy subjects: normative values and implications for the diagnosis of varicocele.

OBJECTIVES: To define the normative values of scrotal vein diameters, investigate the eventual presence and characteristics of scrotal reflux in healthy subjects, and describe its implication for the diagnosis of scrotal varicocele. METHODS: Color-Doppler ultrasonography was performed on a population of 145 healthy, symptomless subjects, with clinical examinations and semen analyses within normal limits. RESULTS: The upper limit of the scrotal veins diameter (3.7-3.8mm) exceeds values presently employed for a diagnosis of varicocele. Furthermore, a high percentage of healthy subjects (53%) were found to have reflux in the scrotal veins, currently considered one of the criteria for diagnosing varicocele, especially in its subclinical form. CONCLUSIONS: To reduce the risk of misinterpretations between the various specialists involved in Color-Doppler ultrasonography and urologists, quantitative data of the scrotal veins (i.e., maximum diameter and the presence, velocity, and duration of reflux) should be described in reports of sonographic examinations performed for scrotal varicocele.

Adult↗