PubMed Health⌕ Search

Biomedical subjects

S Fiorentino

Publications and source records attributed to S Fiorentino.

11 recordsLinked to original sources
PubMed2005

Disruption of T cell regulatory pathways is necessary for immunotherapeutic cure of T cell acute lymphoblastic leukemia in mice.

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. In recent years, the outcome has been globally improved by current therapies, but it remains poor in patients with high, persistent residual disease following the first course of chemotherapy, prompting evaluation of the possible beneficial effects of immunotherapy protocols. In this study, we hypothesized that the disruption of two immunoregulatory pathways controlling the auto-reactive T cell response might synergize with dendritic cell-based immunotherapy of the disease, which is considered to be poorly immunogenic. In this study, we used TAL1xLMO1 leukemia cells adoptively transferred in mice, to generate murine leukemia with poorly immunogenic cells as a model for human T-ALL. Subsequently, these animals were treated with several different immunotherapeutic protocols. We compared the efficiency of a classical, dendritic cell-based immunotherapy (injection of dendritic cells loaded with tumor-derived antigenic products), to a combined treatment associating injection of antigen-loaded dendritic cells and disruption of the two immunoregulatory pathways: CD25+ suppressive T cells and cytotoxic T lymphocyte-associated antigens (CTLA-4). We show that this combined treatment resulted in cure, concomitantly with in vivo generation of immune memory, and TNF-alpha secretion. This study demonstrates that the disruption of these two immunoregulatory pathways synergized with immunostimulation by dendritic cells loaded with tumor-derived antigens, and paves the way for the testing of this combination in clinical trials.

Animals↗
PubMed1999

Altered ex vivo balance between CD28+ and CD28- cells within HIV-specific CD8+ T cells of HIV-seropositive patients.

The CD8+CD28- cell population in the blood of HIV-infected individuals is considerably expanded. Yet the cause of this expansion is not clear. The recent demonstration of identical TCR-rearranged genes in CD8+CD28+ and CD8+CD28- expanded T cells of HIV-seropositive patients supports the hypothesis that these two subpopulations are phenotypic variants of the same lineage. To further elucidate the precise relationship between them, we measured the fraction of CD28+ and CD28- T cell subsets in IFN-gamma-producing CD8+ T cells by intracellular staining and cytofluorometry as a functional test for ex vivo recognition of epitopes derived from HIV-1, Epstein-Barr virus (EBV) and influenza virus. HIV-specific CD8+ T cells were predominantly CD28 in all the eight HIV-seropositive subjects tested. In contrast, the anti-EBV and anti-influenza CD8+ T cells were mainly CD28+ in these patients as well as in HIV-seronegative individuals. This supports the notion that the CD8 CD28 hyperlymphocytosis observed in HIV infection is due mainly to chronic activation and differentiation of HIV-specific memory CD8+CD28+ T cells into terminally differentiated CD8+CD28-lymphocytes, because of intense HIV-1 replication and without any important bystander activation. This clarification of the mechanisms underlying the CD8+CD28- expansion in HIV-induced pathogenesis may have important therapeutic implications.

CD28 Antigens↗
PubMed1997

Tartronates: a new generation of drugs affecting bone metabolism.

In the search for a new class of bone-sparing agents for treating osteopenic disorders, we hypothesized that tartronic acid derivatives, sharing the chemical characteristics both of bisphosphonates and of Gla residues contained in matrix proteins such as osteocalcin, could positively affect bone metabolism. A series of tartronates was therefore tested for their ability to affect bone metabolism. In vitro resorption tests were performed examining pit formation by freshly isolated rat and rabbit osteoclasts plated onto bone slices and exposed to the drugs for 48 h. Tartronates bearing a linear side-chain (DF 1222 and DF 1363A) were the most effective in inhibiting pit excavation in the pM-nM range. Tartronates did not affect osteoclast viability, number, adhesion, or tartrate resistant acid phosphatase activity. Transient cell retraction was observed in osteoclasts plated onto glass and exposed to DF 1222. The maximal effect was seen in cells treated for 4 h at a concentration of 1 pM. DF 1222 accelerated mineralization in cultures of periosteal cells without affecting other osteoblast-like functions. This product was therefore tested in vivo in ovariectomized mice. Bone mass in femur was evaluated, by ash gravimetry, 21 days after ovariectomy. Unfortunately, DF 1222, the most active of tartronates in vitro, was inactive in this test because of its high hydrophilicity and the subsequent too short residence time. On the contrary, its tetrahydropyranyl ether derivative, DF 1363A, endowed with a significantly higher lipophilicity, showed a dose-dependent bone-sparing effect when administered subcutaneously at 10, 30, and 100 mg/kg/die, thus confirming the activity seen in in vitro tests. Because of their feasible parallel effect on both bone resorption and formation, tartronate derivatives may be tested to candidate this class of products for clinical studies.

Animals↗
PubMed1996

Delayed virus-specific CD8+ cytotoxic T lymphocyte activity in an HIV-infected individual with high CD4+ cell counts: correlations with various parameters of disease progression.

This 4-year longitudinal study monitored the temporal association between the HIV-specific cytotoxic T lymphocyte (CTL) response and the control viremia in an individual infected with human immunodeficiency virus type (HIV-1). At the beginning of the study, this asymptomatic individual with a high CD4+ cell count showed no HIV-specific cytotoxic activity after polyclonal in vitro restimulation with autologous PHA-blasts, unlike most HIV-seropositive individuals. Anti-HIV CTLs were detected only in the last year of the study, both after in vitro restimulation and directly ex vivo. This was correlated with the inversion of the CD4+/CD8+ ratio, essentially due to increased numbers of CD8+CD28- T lymphocytes. The HIV-specific cytolytic activity was mediated by this CD28+CD28- subpopulation. The amount of HIV-1 provirus in peripheral blood mononuclear cells (PBMCs) did not change during the study, but the HIV RNA in plasma increased and virus was isolated from PBMCs only at the time when HIV-specific CTL activity was detected. This suggests overall that the HIV-1 replication was low in this individual, with a transient increase that could have reached the threshold for CTL reactivation, and was perhaps controlled thereby.

CD28 Antigens↗
PubMed1996

Predominant involvement of CD8+CD28- lymphocytes in human immunodeficiency virus-specific cytotoxic activity.

Distinct functional CD8+ T-cell populations have been observed during human immunodeficiency virus (HIV) infection. One of these functions is the inhibition of viral replication by a noncytotoxic mechanism, which was shown to be mediated by the CD8+CD28+ subpopulation. On the other hand, CD8+ T cells exert an HIV-specific cytotoxic activity. The present study shows that CD8+CD28- lymphocytes display this HIV-specific cytotoxic activity, which is detectable immediately after the cells are purified from peripheral blood. The CD28- population is also able to proliferate and to retain its cytotoxic activity after in vitro restimulation with autologous blast cells. Finally, HIV-specific cytotoxic T cells can be obtained in vitro from the CD8+CD28+ population.

CD28 Antigens↗
PubMedDate not supplied

Ketoprofen lysine salt inhibits disuse-induced osteopenia in a new non-traumatic immobilization model in the rat.

Immobilization and the consequent unloading can cause osteopenia both in humans and in animals due to an increased bone resorption and a parallel reduction in bone formation. Non-steroidal anti-inflammatory drugs (NSAIDs), and in particular the aryl propionic acids, are described to prevent bone loss by inhibiting the cyclo-oxygenase activity. In this study we evaluated the role of a classical aryl propionic acid, ketoprofen lysine salt (KLS), in a new model of disuse-induced osteoporosis in the rat. Tail immobilization evoked a time-dependent bone loss in the caudal vertebral bodies, measured densitometrically as a reduction of bone mineral density (BMD) and content (BMC). KLS was administered once daily for 10 days by subcutaneous route at 0.5 mg kg-1, a dose lower than that effective to elicit an anti-inflammatory response. In these conditions, KLS completely abolished BMD and BMC decrease observed in the caudal vertebrae after 10-day immobilization, without affecting bone mass in normal (non-immobilized) rats. These results suggest that KLS can exert, besides to its anti-inflammatory effect, an anti-resorptive activity on bone that could be useful in the prevention of disuse-induced osteopenia.

Animals↗
PubMedDate not supplied

Cyclooxygenase inhibitors are potent sensitizers of prostate tumours to hyperthermia and radiation.

It has previously been demonstrated that hyperthermia can activate prostaglandin synthesis and that prostaglandins are protective against hyperthermia. This study examined the use of inhibitors of prostaglandin synthesis on the response of prostate tumours to hyperthermia. The non-steroidal anti-inflammatory drugs (NSAID) ibuprofen and sulindac, known cyclooxygenase inhibitors that inhibit prostaglandin production, were effective hyperthermia sensitizers and augmented growth delay of DU-145 and PC-3 prostate tumours to combined radiation and hyperthermia treatment protocols. Pre-treatment of mice with ibuprofen and sulindac at hyperthermia sensitizing doses resulted in significant (p < 0.01) inhibition of hyperthemia-induced serum prostaglandin E2. These findings indicate that NSAID may have both sensitizing effects on prostate tumour growth and may function by inhibiting prostaglandin synthesis.

Animals↗
PubMedDate not supplied

[Operative risk. Patient evaluation, informed consent].

It is mandatory, the Authors say, to obtain a previous and definite consent before the patient undergoes the operation. Moreover the patient shall be well acquainted about the risk connected to the operation before he gives his consent. On the contrary, as already confirmed by the Italian Supreme Court of Justice, the consent shall not be valid and the Doctors could be found guilty of "psychic violence". Finally the Authors, to evaluate the probable risks liked to the operation, use scales as ASA and prognostic indexes as SAPS to avoid appraisage too subjective.

Humans↗
PubMedDate not supplied

[Superselective monolateral subarachnoid anesthesia in saphenectomy by long stripping].

The authors describe a recent anaesthetic technique: the subarachnoid monolateral superselective anaesthesia. Currently they use it in the surgical operation of "long stripping" saphenectomy. They argue on the utility of codifying this technique for its numberless advantages and discuss on the opportunity to perform day-hospital saphenectomy.

Anesthesia, Spinal↗