PubMed Health⌕ Search

Biomedical subjects

L Biancone

Publications and source records attributed to L Biancone.

At least 19 recordsLinked to original sources
PubMed2006

Antiangiogenic and immunomodulatory effects of rapamycin on islet endothelium: relevance for islet transplantation.

Donor intra-islet endothelial cells contribute to neovascularization after transplantation. Several factors may interfere with this process and ultimately influence islet engraftment. Rapamycin, a central immunosuppressant in islet transplantation, is an mTOR inhibitor that has been shown to inhibit cancer angiogenesis. The aim of this study was to evaluate the effects of rapamycin on islet endothelium. Rapamycin inhibited the outgrowth of endothelial cells from freshly purified human islets and the formation of capillary-like structures in vitro and in vivo after subcutaneous injection within Matrigel plugs into SCID mice. Rapamycin decreased migration, proliferation and angiogenic properties of human and mouse islet-derived endothelial cell lines with appearance of apoptosis. The expression of angiogenesis-related factors VEGF, alphaVbeta3 integrin and thrombospondin-1 on islet endothelium was altered in the presence of rapamycin. On the other hand, rapamycin decreased the surface expression of molecules involved in immune processes such as ICAM-1 and CD40 and reduced the adhesion of T cells to islet endothelium. Our results suggest that rapamycin exerts dual effects on islet endothelium inducing a simultaneous inhibition of angiogenesis and a down-regulation of receptors involved in lymphocyte adhesion and activation.

Angiogenesis Inhibitors↗
PubMed2005

Infliximab and newly diagnosed neoplasia in Crohn's disease: a multicentre matched pair study.

BACKGROUND AND AIMS: The widespread use of anti-tumour necrosis factor alpha antibody (Infliximab) in Crohn's disease (CD) raises concerns about a possible cancer risk in the long term. In a matched pair study, we assessed whether Infliximab is associated with an increased risk of neoplasia. METHODS: In a multicentre matched pair study, 404 CD patients treated with Infliximab (CD-IFX) were matched with 404 CD patients who had never received Infliximab (CD-C). Cases and controls were matched for sex, age (+/-5 years), site of CD, age at diagnosis (+/-5 years), immunosuppressant use, and follow up. New diagnoses of neoplasia from April 1999 to October 2004 were recorded. RESULTS: Among the 404 CD-IFX, neoplasia was diagnosed in nine patients (2.22%) while among the 404 CD-C, seven patients developed neoplasia (1.73%) (odds ratio 1.33 (95% confidence interval 0.46-3.84); p=0.40). The survival curve adjusted for patient year of follow up showed no differences between CD-IFX and CD-C (p=0.90; log rank test). In the CD-IFX group, there was one cholangiocarcinoma, three breast cancers, one skin cancer, one leukaemia, one laryngeal cancer, and two anal carcinomas. Among the 7/404 (1.73%) CD-C, there were three intestinal adenocarcinomas (two caecum, one rectum), one basalioma, one spinalioma, one non-Hodgkin's lymphoma, and one breast cancer. Age at diagnosis of neoplasia did not differ between groups (CD-IFX v CD-C: median 50 (range 40-70 years) v 45 (27-72); p=0.50). CONCLUSION: In our multicentre matched pair study, the frequency of a new diagnosis of neoplasia in CD patients treated with Infliximab was comparable with CD patients who had never received Infliximab.

Adolescent↗
PubMed2005

Appropriateness of immunosuppressive drugs in inflammatory bowel diseases assessed by RAND method: Italian Group for IBD (IG-IBD) position statement.

INTRODUCTION: Despite the explosion of biological therapies, the old immunosuppressants continue to play a pivotal role in the management of inflammatory bowel diseases. AIM: To assess the appropriateness of immunosuppressants-azathioprine, 6-mercaptopurine, methotrexate, cyclosporine A, tacrolimus (FK506), mycophenolate mofetil and thalidomide-in the treatment of inflammatory bowel disease by using RAND/University of California Appropriateness Method. METHODS: The RAND method consists of a combination of evidence from the literature and experts' opinions. Appropriateness has been defined to mean that the expected health benefit exceeds the expected negative consequences by a sufficiently wide margin. A panel of 10 experts from the Italian Group for Inflammatory Bowel Disease has rated, in two rounds, on a scale from 1 to 9, the appropriateness of each indication selected by the Promoter Centre, on the basis of their own clinical experience. An indication was considered appropriate if the median of the panelists' ratings fell within the area 7-9, inappropriate in the area 1-3 and uncertain in the area 4-6. A total of 2781 indications were grouped into 13 categories (mild to moderate Crohn's disease; severe Crohn's disease; fistulizing Crohn's disease; steroid-dependant and -resistant Crohn's disease; maintenance of remission induced by medical treatment in Crohn's disease; maintenance of remission induced by surgery in Crohn's disease; mild to moderate ulcerative colitis; severe ulcerative colitis; steroid-dependant and -resistant ulcerative colitis; maintenance of remission induced by medical treatment in ulcerative colitis; extra-intestinal manifestations in inflammatory bowel disease; pregnancy and inflammatory bowel disease; azathioprine-resistant or -intolerant inflammatory bowel disease patients). RESULTS: Of the 2781 scenarios, 212 (7.6%) were rated appropriate, 645 (23.2%) uncertain and 1924 (69.2%) inappropriate. The most relevant results were: in steroid-dependant or -resistant Crohn's disease, azathioprine, 6-mercaptopurine and methotrexate were defined as appropriate in 25 (86.2%) and 14 (48.3%) of the 29 scenarios respectively; in Crohn's disease, azathioprine and 6-mercaptopurine were defined as appropriate combined with Infliximab (bridge therapy); in steroid-dependant or -resistant ulcerative colitis, azathioprine and 6-mercaptopurine were defined as appropriate in 45 (77.6%) out of 58 scenarios, while methotrexate was defined appropriate only after previous azathioprine failure; in severe ulcerative colitis, cyclosporine A was defined as appropriate only after previous failure with steroids; in azathioprine-intolerant or -resistant inflammatory bowel disease patients, methotrexate was appropriate in 20 (66.7%) out of 30 scenarios; it is inappropriate to stop azathioprine treatment before conception in the presence of active disease. The use of FK506, mycophenolate mofetil and Thalidomide resulted as inappropriate or uncertain. CONCLUSIONS: Results of this study show that only azathioprine, 6-mercaptopurine and methotrexate are appropriate in the treatment of inflammatory bowel diseases. Cyclosporine A was found to be appropriate only in severe ulcerative colitis after the failure of steroids. FK506, mycophenolate mofetil and Thalidomide resulted as inappropriate but experience with these agents is somewhat limited.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2005

Infliximab in the treatment of Crohn's disease: predictors of response in an Italian multicentric open study.

BACKGROUND: Almost 20% of patients with active Crohn's disease are refractory to conventional therapy. Infliximab is a treatment of proven efficacy in this group of patients and it is not clear which variables predict a good response. AIMS.: To evaluate the role of infliximab looking at the predictors of response in a large series of patients with Crohn's disease. PATIENTS AND METHODS: Five hundred and seventy-three patients with luminal refractory Crohn's disease (Crohn's Disease Activity Index (CDAI)>220-400) (312 patients) or with fistulising disease (190 patients) or both of them (71 patients) were treated with a dose of 5 mg/kg in 12 Italian referral centres. The primary endpoints of the study were clinical response and clinical remission for luminal refractory and fistulising disease. We evaluated at univariable and multivariable analysis the following variables: number of infusions, sex, age at diagnosis, smoking habit, site of disease, previous surgery, extraintestinal manifestations and concomitant therapies, and type of fistulas. RESULTS: Patients with luminal refractory disease: 322 patients (84.1%) had a clinical response and 228 (59.5%) reached clinical remission. Patients with fistulising disease: 187 patients (72%) had a reduction of 50% of the number of fistulas and in 107 (41%) a total closure of fistulas was observed. For luminal disease, single infusion (OR 0.49, 95% CI 0.28-0.86) and previous surgery (OR 0.53, 95% CI 0.30-0.93) predicted a worse response for fistulising disease. Other fistulas responded worse than perianal fistulas (OR 0.57, 95% CI 0.303-1.097). CONCLUSION: In Crohn's disease infliximab is effective in luminal refractory and in fistulising disease. A single infusion and previous surgery predicted a worse response in luminal disease whereas perianal fistulas predicted a better response than other type of fistulas.

Adult↗
PubMed2005

A novel diagnostic tool for detecting functional patency of the small bowel: the Given patency capsule.

BACKGROUND AND STUDY AIMS: The current visualization of small-bowel strictures using traditional radiological methods is associated with high radiation doses and false-negative results. These methods do not always reveal small-bowel patency for solids. The aim is to assess the safety of the Given patency system and its ability to detect intestinal strictures in patients with strictures that are known or suspected radiologically. MATERIALS AND METHODS: The Given patency capsule is composed of lactose, remains intact in the gastrointestinal tract for 40-100 hours post ingestion, and disintegrates thereafter. A total of 34 patients with small-bowel stricture were prospectively enrolled; 30 had a previous diagnosis of Crohn's disease, three had adhesion syndrome and in one ischemic enteritis was suspected. Of the patients, 15 (44.1 %) had previously undergone surgery. Following ingestion, the capsule was monitored for integrity and transit time, using a specially designed Given scanner and also radiologically. Seventeen patients had been enrolled with the intent of using the patency capsule as a preliminary test in patients with small-bowel strictures before undergoing video capsule endoscopy. RESULTS: 30 patients (88.2 %) retrieved the capsule in the stool; it was intact in 20 (median transit time 22 hours), and disintegrated in 10 patients (median transit time 53 hours). Six patients complained of abdominal pain which disappeared within 24 hours. The scanner successfully indicated the presence of the capsule in 94 % of cases. Ten patients underwent video capsule endoscopy following the patency capsule examination; in all of these the video capsule passed through the small-bowel stricture. CONCLUSIONS: This feasibility study has shown that the Given patency capsule is a safe, effective, and convenient tool for assessment of functional patency of the small bowel. It can indicate functional patency even in cases where traditional radiology indicates stricture.

Adult↗
PubMed2005

Technetium-99m-HMPAO labeled leukocyte single photon emission computerized tomography (SPECT) for assessing Crohn's disease extent and intestinal infiltration.

OBJECTIVES: Scintigraphy using radiolabeled leukocytes is a useful technique for assessing intestinal infiltration in Crohn's disease (CD). However, limits of planar images include overlapping activity in other organs and low specificity. To investigate the usefulness of (99m)Tc-HMPAO (hexametyl propylene amine oxime) labeled leukocyte single photon emission computerized tomography (SPECT) for assessing CD lesions, in comparison with planar images. METHODS: Twenty-two inflammatory bowel disease patients (19 CD; 2 ulcerative colitis, UC; 1 ileal pouch) assessed by conventional endoscopy or radiology were enrolled. Leukocytes were labeled with (99m)Tc-HMPAO. SPECT images were acquired at 2 h and planar images at 30 min and 2 h. Bowel uptake was quantitated in nine regions (score 0-3). RESULTS: Both SPECT and planar images detected a negative scintigraphy (score 0) in the UC patient with no pouchitis and a positive scintigraphy (score 1-3) in the 21 patients showing active inflammation by conventional techniques. SPECT showed a higher global score than planar images (0.71 +/- 0.09 vs 0.30 +/- 0.05; p < 0.001), and in particular in the right iliac fossa (p= 0.003), right and left flank (p < 0.001; p= 0.02), hypogastrium (p= 0.002), and mesogastrium (p < 0.001). SPECT provided a better visualization and a higher uptake than planar images in patients with ileal and ileocolonic CD (6.45 +/- 0.82 vs 2.8 +/- 0.55, p < 0.001; 5.5 +/- 1.6 vs 2.6 +/- 0.7, p= 0.03), and with perianal CD (6.6 +/- 1.6 vs 3.4 +/- 1.2; p= 0.03). CONCLUSIONS: (99m)Tc-HMPAO labeled leukocyte SPECT provides a more detailed visualization of CD lesions than planar images. This technique may better discriminate between intestinal and bone marrow uptake, thus being useful for assessing CD lesions within the pelvis, including perianal disease.

Colitis, Ulcerative↗
PubMed2004

Rofecoxib and early relapse of inflammatory bowel disease: an open-label trial.

BACKGROUND: The safety and efficacy of selective cyclo-oxygenase-2 inhibitors in inflammatory bowel disease are under investigation. AIM: To assess, in a prospective, open-label trial, the efficacy and safety of rofecoxib (12.5 mg/day) in inflammatory bowel disease patients and controls. METHODS: The inflammatory bowel disease group included 45 inactive patients (25 Crohn's disease; 20 ulcerative colitis) with associated arthralgia. The control group included 30 dyspeptic patients. The efficacy and safety of rofecoxib were assessed in inflammatory bowel disease patients and controls before and after treatment (range, 3 days to 3 months). RESULTS: In inflammatory bowel disease, nine of the 45 patients (20%) required rofecoxib withdrawal due to gastrointestinal symptoms inducing clinical relapse, which subsided on drug discontinuation. The percentage of patients requiring rofecoxib discontinuation was comparable in patients with Crohn's disease and ulcerative colitis (20% vs. 20%), but was higher in inflammatory bowel disease patients than in controls (20% vs. 3%; P < 0.001). In inflammatory bowel disease, arthralgia relief was reported by 32 patients (71%): complete relief by eight patients (18%) and partial relief by 24 (53%). Thirteen patients (29%) reported no benefit. A comparable percentage of inflammatory bowel disease patients and controls reported arthralgia relief (71% vs. 70%). CONCLUSIONS: Rofecoxib appears to control arthralgia in almost two-thirds of inflammatory bowel disease patients. Side-effects requiring drug discontinuation are observed, however, in almost one-quarter of patients.

Adult↗
PubMed2003

Review article: maintenance treatment of Crohn's disease.

The aetiology of Crohn's disease is unknown and therefore no curative treatments are available for the disease. The natural history of Crohn's disease is characterized by recurrent flare-ups of symptoms. Several drug treatments are effective in inducing clinical remission. However, no drug treatments are available in order to prevent clinical relapses, although several drug regimens may delay clinical flare-ups. Crohn's disease treatment for maintaining clinical remission needs to be tailored in relation to specific characteristics of each patient. The frequency of clinical relapse indeed shows marked variations in subgroups of patients, as the likelyhood of relapse is higher in patients in clinical remission for less than 6 months. Treatment strategies for maintaining remission may therefore differ among inactive patients. In chronically active, steroid-dependent or steroid-refractory Crohn's disease patients immunomodulatory drugs (azathioprine 2-2.5 mg/kg by mouth, 6-mercaptopurine 1-1.5 mg/kg by mouth, or methotrexate 15-25 mg/i.m./week) should be added to oral mesalazine (2.4 g/day), while in long-term inactive Crohn's disease patients mesalazine alone may be effective in delaying relapse. Recently, treatment with anti-tumour necrosis factor-alpha monoclonal antibodies (Infliximab or CDP571) has shown efficacy in delaying relapse in responsive patients. One other issue which needs to be considered before selecting drug treatments for maintaining remission in Crohn's disease, is that Crohn's disease activity is currently assessed on the basis of standard clinical scores which may not appropriately reflect the biological activity of the disease. Clinical remission as defined by standardized scores may include heterogeneous subgroups of patients showing different endoscopic and histological activity or persistence of activated immunocompetent cells within the gut. Several sub-clinical markers of relapse have indeed been reported in quiescent Crohn's disease, although their usefulness in clinical practice in currently uncertain.

Adrenal Cortex Hormones↗
PubMed2002

Cytoskeletal proteins and resident flora.

Recent observations demonstrate that enteropathogenetic and enterohaemorrhagic bacteria, as well as other non enteropathogenetic bacteria (Listeria, Coxiella Burnetii), may subvert the host cell cytoskeleton. Models from enteropathogenic bacteria demonstrate that cytoskeletal proteins are required for bacteria binding to the enterocytes and that they play a role in the immune response of the host to intestinal bacteria. The cytoskeletal protein family Tropomyosins is present in all eukaryotic cells, with multiple isoforms regulated by multiple genes. Of the different Tropomyosin isoforms, TM5 has been shown to be expressed in colonic and jejunal epithelial cells, while TM1 in colonic and jejunal smooth muscle. In vitro studies have shown the presence of serum and mucosal IgG against TM5 in almost two thirds of patients with ulcerative colitis, suggesting: a. a possible autoimmune response to Tropomyosin in these patients; b. the hypothesis that the development of pouchitis may be related to the expression of TM5 in the ileal pouch; c. the use of probiotics in the treatment of pouchitis. Overall, the new expression of cytoskeletal proteins on the cell surface appears to be possibly induced by several mechanisms, including intestinal bacteria and apoptosis. The expression of cytoskeletal proteins on the cell surface may induce tolerance or autoimmune response on target cells. Further investigations are, however needed on the possible role of cytoskeletal proteins in human diseases.

Cytoskeletal Proteins↗
PubMed2002

Resident bacterial flora and immune system.

The "controlled inflammation" of the normal human gut is a closely controlled phenomenon and any change in the cell type number and/or functions, including the release of soluble mediators can lead to an "uncontrolled" inflammation. The physiological inflammation in the human gut plays a crucial role in maintaining a local immune response that is appropriate, efficiently protective and which respects the gut structure and function. The intestinal mucosa represents a considerable proportion of the human immune system. Disregulation of the mucosal immune response can switch a "controlled" toward an "uncontrolled" intestinal inflammation. A key role in the maintenance of an adequate balance between antigenic stimulation and host immune response is played by the immunoregulatory molecules released by activated immunocytes in the human gut. The role of the host immune system in the maintenance of an adequate balance between luminal antigens, including the resident bacterial flora and host immune response, is strongly supported by animal models of uncontrolled intestinal inflammation. Besides the aetiology of inflammatory bowel disease, luminal antigens (including food, viral and bacterial antigens) contribute to the maintenance of the inflammatory process in inflammatory bowel disease, by stimulating the immunocompetent cells in the intestinal mucosa. Of the luminal antigens, the resident bacterial flora seems to play a major role in the development of animal models of "uncontrolled" intestinal inflammation. Recent evidence also suggest that bacterial flora can modulate the function of the intestinal mucosal cells. These observations support the role of the intestinal bacterial flora in the induction of an uncontrolled inflammation in the human gut, leading to tissue damage. Probiotics, defined as living micro-organisms which, when taken in appropriate amounts, improve the health status, have been proposed in the treatment of inflammatory bowel disease, but their mechanisms of action still remain to be fully elucidated.

Anti-Bacterial Agents↗
PubMed2002

Review article: monitoring the activity of Crohn's disease.

Crohn's disease is characterized by a chronic inflammation of the intestine of unknown aetiology. One of the main problems when treating patients with Crohn's disease, is the identification of patients undergoing early clinical relapse, for timely treatment and the possible prevention of complications. No sub-clinical markers are currently available that predict relapse during remission. Several parameters have been proposed for this purpose. Although none have proven useful, growing evidence suggests a possible benefit in the clinical management of Crohn's disease. Among these, we may identify: clinical behaviour, the characteristics of the host, clinical activity, markers of intestinal inflammation and markers of immune activation. In particular, the possible relationship between cytokine pattern and the clinical behaviour of Crohn's disease has been addressed. Overall, these observations suggest that mucosal immune activation is a feature of Crohn's disease, and may persist in the form of activated immunocompetent cells during remission. On the basis of this evidence, studies are currently investigating whether the down-regulation of immune activation markers is associated with clinical remission in Crohn's disease. It has been shown that higher mucosal levels of TNF-alpha and an increased state of activation of lamina propria mononuclear cells in patients with inactive Crohn's disease, are significantly associated with an earlier clinical relapse of the disease. These observations suggest that a persistent local immune activation during remission may represent a marker of early clinical relapse of Crohn's disease.

Biomarkers↗
PubMed2002

Immunoregulation in the gut: success and failures in human disease.

In normal conditions, human gut mucosa is infiltrated with a large number of mononuclear cells. This is a reflection of the fact that human intestine is continuously subjected to a massive stimulation by luminal antigens. This state of "physiological" inflammation is a tightly controlled phenomenon, as several mucosal cells interact to generate and maintain an appropriate local immune response. Changes in cell type number and/or function, including the release of soluble mediators, have been associated with the development of chronic inflammatory diseases, such as Crohn's disease (CD) and ulcerative colitis (UC), the two major forms of inflammatory bowel disease. Evidence also indicates that the type of inflammatory response occurring in the intestine of patients with CD differs from that in UC, and this probably reflects distinct pathways of immune activation. In CD mucosa, a Th1 response with high IL-12 and IFNgamma production prevails, while in UC a humoral immunity appears to be predominant. Despite this, CD and UC share downstream inflammatory events, characterised by high levels of inflammatory cytokines, free radicals, matrix-degrading enzymes and growth factors.

CD4-Positive T-Lymphocytes↗
PubMed2002

Teaching technology with technology: computer assisted lessons in the medical school the first Italian experience in nephrology and dialysis.

BACKGROUND: Dialysis is often neglected in academic teaching. At the University of Torino, Italy, teaching Nephrology (4th year of Medical School) consists of 21 hours of formal lessons, 10 hours/student of interactive lessons (4/10 dedicated to dialysis) and 10 optional lessons (3 regarding dialysis). Interactive and optional lessons widely employ computer assisted teaching. Aim of the study was to evaluate student satisfaction on this approach. METHODS: Student satisfaction was assessed on 4 sample lessons (166 students), by two short dedicated questionnaires (0-10 scale, open questions). RESULTS: High scores were given to the dialysis lessons (median 8/10). Computer assisted interface (median 8/10, range 6-10) was of help in check of knowledge in real time (86%), enhancing participation (61%); 62% suggest extending this experience to selected courses, 38% to all. CONCLUSIONS: Medical students consider dialysis an important part of the academic teaching of Nephrology; new interfaces may help to enhance student satisfaction.

Adult↗
PubMed2002

[Daily dialysis: evaluation of the first year of experience at home and in a limited care center].

BACKGROUND: Among self dialysis treatments, daily dialysis is encountering a growing interest. Aim of this study was to evaluate results of the first year of daily dialysis in our Center. METHODS: Since November 1998, twelve patients started daily dialysis. One patient started RRT on daily dialysis; one patient was in training; 8 were on home dialysis, 3 in the limited care center. Selection of patients was performed according to wide acceptance criteria as for age (range 33-61 years), dialysis follow-up (range 1-23 years), comorbidity (=/>1 comorbid factor present in 8). Dialysis schedule consisted of 6 sessions per week (2-3 hours), blood flow 250-320 ml/min, individualized dialysate. Occasional shift to 3-4 times per week were allowed for logistic or working reasons. RESULTS: Results were analyzed taking into account patient satisfaction and main clinical parameters. In 9/12 the choice of treatment resulted from both clinical reasons and patient preferences, while in 3 was due to clinical indications (1/3 dropped out). The main reasons of choice were logistic or research of the best treatment. The most common fears regarded fistula and needle puncturing. Despite the time unconvenience, the rapidly regained well being was the reason for choosing this treatment. Also in this relatively short follow-up the favorable results reported as for weight gain, blood pressure control and metabolic pattern are confirmed. The few side effects were multifactorial (fistula thrombosis after blood pressure normalization, 2 recurrences of atrial fibrillation). CONCLUSIONS: In conclusion, daily dialysis resulted also in our centre as a promising alternative even in difficult patients.

Adult↗
PubMed2001

Immunotoxins containing recombinant anti-CTLA-4 single-chain fragment variable antibodies and saporin: in vitro results and in vivo effects in an acute rejection model.

Immunotoxins containing recombinant human-derived single-chain fragment variable (scFv) reagents (83 and 40) against CTLA-4 (CD152) linked to saporin, a ribosome-inactivating protein, were prepared and tested on CD3/CD28-activated T lymphocytes, MLRs, CTLA-4-positive cell lines, and hemopoietic precursors. Immunotoxins induced apoptosis in activated T lymphocytes and were able to specifically inhibit MLR between T lymphocytes and dendritic cells. The 83-saporin immunotoxin also inhibited the T cell activation in an MLR between T lymphocytes and an EBV-positive lymphoblastoid B cell line. Toxicity tests on hemopoietic precursors showed little or no effects in inhibiting colonies' growth. As the 83 scFv Ab was reactive also with activated mouse T lymphocytes, 83-saporin was tested in a model of tumor rejection consisting of C57BL/6 mice bearing a murine H.end endothelioma cell line, derived from DBA/2 mice. The lymphoid infiltration due to the presence of the tumor was reduced to a high extent, demonstrating that the immunotoxin was actually available and active in vivo. Thus, taking the results altogether, this study might represent a new breakthrough for immunotherapy, showing the possibility of targeting CTLA-4 to kill activated T cells, using conjugates containing scFv Abs and type 1 ribosome-inactivating protein.

Abatacept↗
PubMed2001

HIV type 1 Tat protein is a survival factor for Kaposi's sarcoma and endothelial cells.

The HIV-1 Tat protein has been directly implicated in the pathogenesis of AIDS-related Kaposi's sarcoma (KS); however, its effects on KS spindle-shaped and endothelial cell apoptosis are largely unexplored. Since susceptibility to apoptosis is relevant for tumor development and response to therapy, we investigated the effects of Tat on KS and endothelial cell survival from apoptosis. The effect of Tat was evaluated in three KS cell lines (KS-imm, KS-C1, and KS-L3) exposed to the chemotherapy agent vincristine, currently used for the treatment of this tumor, and in human umbilical vein-derived endothelial cells (HUVECs) induced to undergo apoptosis by serum withdrawal. Apoptosis was assessed by enzymatic assays, microscopic examination of chromatin and cytoskeleton, evaluation of plasma membrane integrity and subdiploid DNA content, TUNEL assays, and measurement of caspase-3 activity. Tat, in a dose-dependent manner, protected the three KS cell lines and HUVECs from apoptosis induced by vincristine or serum starvation, respectively. This effect appeared to be independent of modulation of Fas, Bcl-2, or Bax expression. In contrast, Tat upregulated Bcl-X(L) expression and induced a relevant decrease in caspase-3 activity in vincristine-treated KS cells. Taken together, these results suggest that the HIV-1 Tat protein may factor KS development and progression by sustaining endothelial and transformed cell survival.

Apoptosis↗
PubMed2001

Tat-induced platelet-activating factor synthesis contributes to the angiogenic effect of HIV-1 Tat.

This study shows that human umbilical cord vein-derived endothelial cells (HUVEC) stimulated with HIV-1 Tat synthesized platelet-activating factor (PAF), a phospholipid mediator of inflammation that possesses angiogenic properties. The synthesis of PAF by HUVEC stimulated with Tat was dose and time dependent. Moreover, in vitro experiments were performed to evaluate whether migration of HUVEC induced by Tat was dependent on the synthesis of PAF. It was found that the cell motility induced by Tat was inhibited by WEB 2170, a specific PAF receptor antagonist. In vivo, the neoangiogenesis induced by Tat was also inhibited by WEB 2170 in a murine model, in which matrigel subcutaneously injected was used as substratum for angiogenesis. These results suggest that the synthesis of PAF by endothelial cells mediates, at least in part, the angiogenic activity of Tat by promoting the endothelial cell migration.

Angiogenesis Inducing Agents↗