Biomedical subjects

Michael Caligiuri

Publications and source records attributed to Michael Caligiuri.

6 recordsLinked to original sources

PubMed2006

Pharmacogenetics for off-patent antipsychotics: reframing the risk for tardive dyskinesia and access to essential medicines.

First-generation antipsychotics (FGAs) induce tardive dyskinesia, a debilitating involuntary hyperkinetic movement disorder, in 20-50% of individuals with a psychotic illness during chronic treatment. There is presently no curative treatment or definitive predictive test for tardive dyskinesia. The authors note that the three antipsychotic drugs enlisted in the most recent (14th) World Health Organization Model List of Essential Medicines--chlorpromazine, fluphenazine and haloperidol--belong to the FGA therapeutic class. In this regard, the need to choose between the competing objectives of ensuring global access to affordable and efficacious medicines, such as FGAs, and the formidable long-term risk for tardive dyskinesia, may create an ethical conundrum. Pharmacogenetics has thus far been conceptually framed as a tool to individualize therapy with new drugs under patent protection. However, the authors suggest that pharmacogenetics may also improve access to pharmacotherapy through the reintroduction of affordable second-line generic drugs or FGAs with suboptimal safety, as first-line therapy, in targeted subpopulations in whom they present a lower risk for tardive dyskinesia. To impact positively on global public health and distributive justice, a directory complementary to the essential medicines library--one that enlists the 'essential biomarkers' required for optimal pharmacotherapy--may benefit patients who do not have adequate access to new antipsychotic medications. This review discusses pharmacogenetic associations of tardive dyskinesia that are in part supported by meta-analyses and the oxidative stress-neuronal degeneration hypothesis.

Antipsychotic Agents↗

PubMed2005

The BRG1- and hBRM-associated factor BAF57 induces apoptosis by stimulating expression of the cylindromatosis tumor suppressor gene.

Mutation of BRG1, hBRM, and their associated factors, INI1 and BAF57, in primary human tumors has suggested that inactivation of human SWI/SNF (hSWI/SNF) complexes may be involved in neoplastic transformation. BT549 is an invasive human breast carcinoma cell line that lacks expression of BAF57, a key hSWI/SNF subunit that mediates interaction with transcriptional activators and corepressors. In this study we investigated the role of BAF57 in suppressing tumorigenesis by establishing BT549 stable cell lines that expresses full-length BAF57 protein. BT549 clones expressing BAF57 demonstrated marked phenotypic changes, slow growth kinetics, and restoration of contact inhibition. Altered growth was found to be due in part to cell cycle arrest and induction of apoptosis. Furthermore, microarray analysis revealed that BAF57-mediated cell death was associated with up-regulation of proapoptotic genes including the tumor suppressor familial cylindromatosis (CYLD), which was found to be a direct target of BAF57 as determined by chromatin immunoprecipitation analysis. Increased expression of CYLD in BT549 cells induced apoptosis, while its suppression by small interfering RNA inhibited cell death in BAF57 expressing BT549 cells. These findings demonstrate the importance of BAF57 in cell growth regulation and provide a novel link between hSWI/SNF chromatin remodelers and apoptosis.

Apoptosis↗

PubMed2004

EBV kidney allograft infection: possible relationship with a peri-graft localization of PTLD.

Post-transplant lymphoproliferative disorder (PTLD) is a grave complication of transplantation and the result of uncontrolled proliferation of B lymphocytes infected with Epstein-Barr virus (EBV). Herein we assess whether EBV infects renal grafts and whether there is a relationship between EBV kidney infection and PTLD. Allograft biopsies from 23 patients with PTLD were studied for the presence of EBV DNA and RNA (EBER-1, -2) by in situ hybridization and for CD21 by immunohistochemistry. Results were compared to 43 transplants from people without PTLD. EBV DNA and RNA were detected in 11/43 patients without PTLD (26%), and in 15/23 (65%) patients with PTLD (p = 0.004). EBV DNA and RNA localized to proximal tubular cells and these cells showed up-regulation of the EBV receptor CD21. EBV-infected allografts were noted in 12/12 patients with PTLD located near the allograft and in 3/11 (27%) of patients with PTLD distant from the graft. Multiple biopsies in eight patients showed that graft EBV infection can precede the diagnosis of PTLD by as long as 42 months. It is concluded that EBV can infect kidney allografts, and there appears to be a relationship between this infection and the presence of PTLD near the graft.

Adult↗

PubMed2004

Functional brain asymmetries during visuomotor tracking.

This study examined brain asymmetries elicited during visuomotor tracking. Thirty-two healthy participants performed a fixed gaze, dynamic, pinch force, visuomotor tracking task during a functional magnetic resonance imaging study. The dynamic task required the subject to press a rubber bulb with the thumb to trace a cosine square wave varying in force amplitude from 0-500 cN and having a frequency of 1.5 Hz. Response hand order and direction of the stimulus presentation (right-to-left or left-to-right) were permuted across participants. Two forms of functional cerebral asymmetry were observed, hemispheric specialization and homologous lateralized response. The superior portion of the right middle frontal gyrus and the left supplementary motor area appeared specialized for VM tracking regardless of response hand used or stimulus movement direction. Lateralized effects appeared in the primary sensorimotor hand area, putamen, parietal operculum/posterior insula, dentate nucleus of the cerebellum, precuneus, and middle occipital gyrus. These lateralized areas of activation surfaced when either response hand or direction of stimulus movement was manipulated. The VM task used in this study activated asymmetrical neural activity in the vertically organized skelotomotor system and in sensory systems involving visual attention or proprioception.

Adult↗

PubMed2003

The role of STAT1 in viral sensitization to LPS.

The phenomenon of endotoxin sensitization by virus infection is well documented but not yet well understood. Infection by virtually any viral agent will quickly induce expression of type I interferons (IFN-alpha/beta), and type II IFN-gamma production will follow as NK cells and T cells are activated. It has been well established that type II IFN pretreatment can intensify the effects of endotoxin. We have recently demonstrated that type I IFN induction by lymphocytic choriomeningitis virus (LCMV) infection dramatically increases TNF-alpha production following LPS treatment, and that this sensitization by type I IFN is STAT1 dependent. Taken together these data suggest that the STAT1-mediated, MyD88-independent, arm of the LPS signaling pathway plays an important role in endotoxin toxicity, and that this pathway mediates a major component of virus-enhanced LPS sensitization.

Animals↗

PubMed2002

A phase I trial of escalating doses of trastuzumab combined with daily subcutaneous interleukin 2: report of cancer and leukemia group B 9661.

PURPOSE: The purpose of this study was to determine the toxicity of escalating doses of trastuzumab when combined with a fixed dose regimen of interleukin (IL)-2. EXPERIMENTAL DESIGN: Eligible patients had nonhematological malignancies for which standard therapy did not exist or was no longer effective and had tumors that overexpressed HER2. IL-2 was initially administered at a dose of 1.25 million IU/m(2) (low dose) s.c. daily except for 3 days every 2 weeks, when it was given at a dose of 15 million IU/m(2) (intermediate dose). These doses were reduced to 1.0 million and 12 million IU/m(2) after the first 18 patients. Trastuzumab was administered i.v. just before the first intermediate IL-2 dose and was escalated in cohorts of six or more patients from 1 mg/kg every 2 weeks to 8 mg/kg weekly. In vitro cytotoxicity testing was performed with patient peripheral blood mononuclear cells and HER2-overexpressing cell lines. RESULTS: Forty-five patients were treated. Dose-related toxicity from trastuzumab was not observed. IL-2-related toxicities such as fever, chills, and fatigue were less common with the reduced doses of IL-2. There were two grade 3 and three grade 4 pulmonary reactions. Four major responses were observed, all in breast cancer patients treated with trastuzumab doses of at least 4.0 mg/kg. Although IL-2 produced expansion of natural killer cell subsets, there was no correlation between in vitro cytotoxicity and clinical response. CONCLUSIONS: A regimen of IL-2 combined with trastuzumab is feasible, and response numbers are encouraging. Further testing of this regimen is warranted if the pulmonary toxicity can be ameliorated.

Adult↗