Antiproliferative effect of lonidamine on a human glioblastoma multiforme cell line

Recent data from phase II trials have shown that lonidamine (LND) is effective in the treatment of tumors of various histogenesis, including gliomas. In the present work, we tested the antiproliferative effect of LND on a human glioblastoma cell line (LI) in different culture conditions. When LI are cultured in their standard conditions, a reduction of cell growth is seen after 3 days of treatment with 10(-4) M LND. It reaches 70% with respect to control after 6 days and is statistically significant. LND is ineffective at the other concentrations tested. In more stringent culture conditions, 10(-4) M LND determines a higher inhibition of cell proliferation both after 3 and 6 days of exposure, while other doses of LND are unable to affect cell growth.     

Pertussis toxin-sensitive GTP-binding proteins regulate activation-induced apoptotic cell death of human natural killer cells

Apoptosis of natural killer (NK) cells can be induced by non-specific physical damage (UV irradiation, heat shock) or by simultaneous ligation of the CD 16 and the interleukin-2 receptor (IL-2R) molecules, but not with either anti-CD 16 or IL-2 alone. Whereas blockade of GTP-binding protein (G protein)-mediated signal transduction using ADP-ribosylating bacterial toxins or the GTPase-resistant GTP analog guanosine 5′-0-(3-thiotriphosphate (GTPγS) does not affect non-specific induction of NK cell apoptosis, such interventions do inhibit induction of apoptosis by anti-CD16/IL-2. The G proteins involved in the regulation of activation-induced NK apoptosis are sensitive to pertussis toxin (PTX) and to the non-specific GTP analog GTPγS but not to cholera toxin, Pseudomonas exotoxin A or diphtheria toxin. A pertussis toxin mutant that lacks ADP-ribosylating activity, but conserves the membrane translocating and T cell-mitogenic effects of the native molecule, fails to inhibit NK apoptosis. To exert their apoptosis-inhibitory effect, PTX and GTPγS must be employed before cells are activated. Later addition has no effect, suggesting the implication of G proteins in the transmission of apoptosis-inducing signals, but not in the effector stage of apoptosis. Pre-incubation with PTX or GTPγS does not affect the activation of NK cells by CD 16 cross-linking, IL-2 stimulation - or both, as assessed by the induction of CD69 expression, protein tyrosine phosphorylation and calcium mobilization. Moreover, neither PTX nor GTPγS compromise the effector function of NK cells or the susceptibility of target cells to NK-mediated lysis. These data suggest apoptosis as a novel mechanism by which NK responses may be controlled in vivo, as well as an experimental and therapeutical strategy to counteract endogenous down-regulation of NK responses.     

Inhibition of prolactin and aldosterone secretion by the dopamine derivative ibopamine

Summary In 7 patients with congestive heart failure acute oral administration of ibopamine, a new dopamine derivative, induced a significant decrease in serum prolactin and aldosterone without affecting serum growth hormone or cortisol. The Metoclopramide-induced secretion of prolactin and aldosterone was blunted in 6 patients pretreated with 200 mg ibopamine. The data are consistent with a dopaminergic effect of ibopamine due to a peripheral action, probably on D-2 receptors.     

Efficacy of adjuvant CYVADIC chemotherapy in early-stage uterine sarcomas: results of long-term follow-up

Data on adjuvant chemotherapy in early-stage uterine sarcomas are conflicting and most often based on small patient groups with relatively short duration of follow-up. Approximately 60% of patients present with stage I disease with an overall 5-year survival of 30-50% when treated with surgery alone. This study examines the efficacy and results of long-term follow-up of a multiagent chemotherapy regimen of cyclophosphamide, vincristine, doxorubicin, and dacarbazine (CYVADIC) as adjuvant treatment for patients with stage I uterine sarcoma. Between 1982 and 1999, 24 evaluable patients with completely staged uterine sarcomas received adjuvant multiagent chemotherapy with vincristine sulfate (1mg /m(2)) on days 1 and 4, doxorubicin (40 mg /m(2)) and cyclophosphamide (400 mg /m(2)) on day 2, and dacarbazine (200 mg /m(2)) on days 1 through 4 for a total of nine monthly cycles or until recurrence of disease was documented. Survival distributions were calculated by the Kaplan-Meier method, and statistical significance was determined with the log-rank test. Factors significant on univariate analysis were analyzed in a multivariate fashion using Cox proportional hazards model. The histologic distribution of patients was 46% leiomyosarcoma, 33% mixed mullerian tumors, 13% stromal sarcomas, 4% adenosarcomas, and 4% hemangiosarcoma. The patients received 206 of a planned 216 cycles of chemotherapy. The median follow-up of the patient population was 93 months (range 11-213 months). Eight patients (33%) developed recurrent disease. The median time to recurrence was 19 months (range 7-184 months). The estimated survival for the entire group was 88, 75, and 69% at 2, 5, and 15 years, respectively. Factors that did not affect survival included age, histology, and tumor grade. Four patients required dose reductions secondary to grade 2-3 toxicities (hematologic). Grade 1 neurotoxicity was observed in six patients (25%) and grade 2 neurotoxicity in one patient (4%). Adjuvant CYVADIC chemotherapy appears to be safe and well tolerated in patients with stage I uterine sarcomas. Our data provide information on the longest duration of follow-up ever reported and suggests that CYVADIC may have a potential role in the adjuvant treatment of early-stage uterine sarcoma.     

Wyatt v. Stickney: a consent decree

On September 22, 1986, Judge Myron Thompson issued a consent decree in the Wyatt v. Stickney litigation. The settlement occurred 14 years after Judge Frank M. Johnson, Jr. rendered his landmark decision in this case. The consent decree included termination of the court's active supervision of the state's mental health system, termination of the receivership, and termination of the court monitor's powers. The state agreed to adhere to Wyatt standards, maintain Title XIX accreditation, continue deinstitutionalization efforts, and develop an internal advocacy and quality assurance program. Mechanisms are also to be put in place to apprise the plaintiffs' attorneys of progress in these efforts.     

Protein bound folates in liver of castrated rats

The effect of castration and testosterone treatment on the distribution of [3H] radioactive and endogenous bound folates in hepatic cytosolic folate binding proteins (FBP-C) has been studied in rats. The distribution of [3H] radioactive bound folates in these FBP's shows no significant difference in the three experimental group animals. On the contrary a significant decrease in the amount of endogenous bound folates is observed in castrated if compared with control rats, particularly marked for FBP-CI and FBP-CII bound folates. The testosterone treatment of castrated rats partially restores bound folate levels. The decrease of bound folates in castrated rats might be ascribable to a lower availability of longer-chain forms, almost the ones that bind to FBP's; however lower binding protein content and/or lower affinity for ligands cannot be excluded.     

Identifying weak signals in the presence of noise: A new method of locating potential ligand contact residues in immunoglobulin-related molecules

We develop and apply a new method for estimating the locations of hypervariable residues in immunoglobulin-related molecules. The method differs from the standard introduced by Wu and Kabat in two essential ways: (1) we take explicit account of the type of substitution at a given position, rather than just the total number of substitutions, and (2) we use an explicit statistical decision criterion for classifying a site into either the complementarity determining or framework category. Simulations indicate that the method is reliable with relatively little data, approximately 5% of the sites being misclassified when 10 sequences are aligned. The method is applied to immunoglobulin light chains and to class 1 and class 2 products of the major histocompatibility complex.