Lipodystrophy associated with nevirapine-containing antiretroviral therapies.
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Adult↗
Biomedical subjects
R Lau
Publications and source records attributed to R Lau.
Dendritic cell secretion of IL-15 is induced by recombinant huCD40LT and augments the stimulation of antigen-specific cytolytic T cells.
Dendritic cells (DC) are professional antigen-presenting cells which stimulate strong proliferative and cytolytic T cell responses. Stimulation of CD40 on dendritic cells by its ligands and anti-CD40 antibodies induces maturation and enhances DC stimulatory ability. In order to understand the mechanism by which ligand:CD40 interactions augment DC function, we assessed the role of T cell stimulatory cytokines IL-12 and IL-15 in the function of DC stimulated with soluble trimeric CD40L, a recombinant fusion protein incorporating three covalently linked extracellular CD40L domains (huCD40LT). Peripheral blood derived DC treated with huCD40LT and/or IFN-gamma were used to stimulate T cell responses in vitro to specific antigens. DC treated with huCD40LT or IFN-gamma/huCD40LT stimulated enhanced T cell proliferation to CASTA, a soluble protein from C. albicans, induced T cells with augmented antigen-specific lysis, and increased the yield of antigen-specific IFN-gamma-producing T cells. IL-15 production by DC was enhanced in cultures treated with huCD40LT and correlated with expansion of antigen-specific cytolytic T cells. Addition of a neutralizing anti-IL-15 monoclonal antibody inhibited the expansion of viral and tumor antigen-specific T cells stimulated by IFN-gamma and huCD40LT-treated DC. In contrast, this enhanced stimulatory ability of DC did not appear to depend on synthesis of IL-12 since huCD40LT treatment stimulated the generation of antigen-specific cytokine producing and cytolytic T cells without increased IL-12 production. Addition of anti-IL-12 monoclonal antibody did not inhibit expansion of these cells. These data suggest that production of IL-15 but not IL-12 is an important factor in the enhanced immunostimulatory ability of huCD40LT-treated DC.
Antigens↗
Open-label comparison of the antiemetic efficacy of single intravenous doses of dolasetron mesylate in pediatric cancer patients receiving moderately to highly emetogenic chemotherapy.
BACKGROUND: Nausea and vomiting are among the most unpleasant adverse side effects of cancer therapy. PROCEDURE: An open-label dose-escalation study was conducted to assess the appropriate intravenous dose of dolasetron for pediatric patients undergoing chemotherapy. Patients received dolasetron in single intravenous doses of 0.6 (n = 10), 1.2 (n = 12), 1.8 (n = 12), or 2.4 (n = 12) mg/kg 30 min before receiving emetogenic chemotherapy. Pharmacokinetic parameters were evaluated at each dose level and efficacy was evaluated over the first 24 hr following the administration of dolasetron. RESULTS: A complete response was achieved in 10% of patients given 0.6 mg/kg, 25% of patients given 1. 2 mg/kg, 67% of patients given 1.8 mg/kg, and 33% of patients given 2.4 mg/kg. Peak plasma concentrations (Cmax) were observed between 0. 33 and 0.75 hr following dolasetron infusion. Cmax and area under plasma concentration-time (AUC) increased with larger doses of dolasetron, while terminal disposition half-life (t1/2) and apparent clearance (Clapp) were not significantly changed with respect to dose. For 1.8-mg/kg dolasetron, the t1/2 was 4.98 hr and the maximum plasma concentration (tmax) 0.47 hr. Adverse events were mild to moderate. No serious events occurred. Conclusions. This study suggests that a single intravenous dose of 1.8 mg/kg is the optimum single intravenous dose for controlling chemotherapy-induced emesis in pediatric patients.
Adolescent↗
Comparison of cutting efficiency and instrumentation of curved canals with nickel-titanium and stainless-steel instruments.
The cutting efficiency and the effects of instrumentation on curved canal shape of both stainless-steel and nickel-titanium nonstandardized ProFile Series 29 hand instruments and stainless-steel Flexoreamer were investigated under standardized conditions. Concerning cutting efficiency in rotary motion, the Flexoreamer had significantly (p < 0.01) greater cutting efficiency than stainless-steel ProFiles and nickel-titanium ProFiles. Changes in the canal shape differed significantly between the different instruments at all measuring points (p < 0.001). After instrumentation with Flexoreamers with inclusion of two half-sizes (#17 and #22), there were fewer undesirable changes in canal shape compared with both stainless-steel and nickel-titanium ProFile Series 29 instruments. In this study, it seemed that flexible stainless-steel instruments with noncutting tips were superior to the nonstandardized ProFile Series 29 instruments with regard to cutting efficiency and instrumentation of curved canals.
Analysis of Variance↗
Hydroxyurea-induced nail pigmentation in HIV patients.
Hydroxyurea (HU), a cytotoxic agent used in myeloproliferative disorders, has recently been introduced as an adjunct to combination anti-retroviral therapy. We describe abnormal nail pigmentation in four HIV-seropositive patients treated with HU and discuss the likely factors associated with its development.
Adult↗
Generation of melanoma-specific cytotoxic T lymphocytes by dendritic cells transduced with a MART-1 adenovirus.
Dendritic cells (DC) are potent stimulators of primary T cell responses. In this study, we demonstrate that DC, genetically engineered to express the MART-1/Melan-A (MART-1) tumor-associated Ag, express MART-1 mRNA and protein, correctly process and present the HLA-A2.1-restricted immunodominant MART-1 peptide (MART-1(27-35)), and serve as potent stimulators of MART-1-specific CTL in vitro. A replication-defective E1-deleted adenovirus (AdV) was constructed that expresses MART-1 (AdVMART1). Transduced DC produce full length MART-1 mRNA as well as MART-1 protein. AdVMART1 does not significantly down-regulate cell surface class I expression despite having an intact E3 region. Transduction of an HLA-A2-positive/MART-1-negative cell line with AdVMART1 renders these cells sensitive to lysis by CTL specific for the MART-1(27-35) immunodominant peptide. In addition, DC transduced with AdVMART1 stimulated MART-1(27-35)-specific tumor-infiltrating lymphocytes to synthesize IFN-gamma. Finally, AdVMART1-transduced DC were able to generate MART-1(27-35) peptide-specific, class I-restricted CTL in PBL cultures from normal donors. This study supports the use of tumor Ag-engineered DC in genetic immunotherapy.
Adenoviridae↗
Herpes zoster infection in HIV-seropositive patients associated with highly active antiretroviral therapy.
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Anti-HIV Agents↗
Lack of cisplatin-ranitidine kinetic interactions: in vivo study in children, and in vitro study using dog renal brush border membrane vesicles.
The interactions between cisplatin and organic ions have been extensively investigated in animal models for the potential to reduce cisplatin cellular uptake and resultant nephrotoxicity. To further investigate the beneficial interaction clinically, we studied the effects of the organic cation, ranitidine, on the renal handling of cisplatin in children. In parallel, we examined the effects of cisplatin on the uptake kinetics of organic cations and anions by brush border membrane vesicles (BBMV) prepared from dog renal cortex. The results indicate that: 1) there is no measurable effect of ranitidine on renal clearance of cisplatin in children; and 2) BBMV uptake of anionic p-aminohippurate, but not cationic N-methylnicotinamide, is inhibited by cisplatin at concentrations of <1 mM. These findings suggest that cisplatin may not share transport systems with organic cations to a clinically significant degree. Assuming that renal tubular transport is a prerequisite for cisplatin nephrotoxicity, the lack of apparent kinetic interactions between cisplatin and organic cations may preclude clinical use of organic cations as a modality to prevent cisplatin nephrotoxicity.
Adolescent↗
Adenovirus-mediated p53 gene delivery potentiates the radiation-induced growth inhibition of experimental brain tumors.
Patients with malignant gliomas continue to have very poor prognosis even after surgical resection, radiation and chemotherapy. Because these tumors often have alterations in the p53 tumor suppressor gene, which plays a key role in the cellular response to DNA damaging agents, we investigated the role of p53 gene therapy in conjunction with ionizing radiation in a rat brain tumor model. Exposure of cultured rat 9L gliosarcoma cells, which contain a mutant p53 gene, to a recombinant adenovirus-vector bearing the wild-type p53 gene (Adp53), induced apoptosis within 24 hours. Although ionizing radiation had no additional effect on apoptosis within this time frame, it caused G1 arrest in non-apoptotic cells after Adp53 therapy. In contrast, wild-type 9L cells demonstrated little G1 arrest after X-irradiation. When animals bearing brain tumors were irradiated after intratumoral Adp53 injections, more than 85% reduction in tumor size was noted. Moreover, the group of rats receiving both radiation and Adp53 therapy had a significant increase in survival as compared to animals receiving either therapy alone. These results support the use of p53 gene therapy as an adjunct to radiation in treatment of malignant brain tumors.
Adenoviridae↗
In vivo therapy of hepatocellular carcinoma with a tumor-specific adenoviral vector expressing interleukin-2.
A recombinant adenovirus (AdVAFP1-IL2) containing the murine alpha-fetoprotein (AFP) promoter was constructed to direct hepatocellular carcinoma (HCC)-specific expression of the human interleukin-2 (IL-2) gene. In vitro testing of AdVAFP1-IL2 showed HCC-specific IL-2 gene expression three to four orders of magnitude higher in AFP-producing HCC lines compared to non-AFP producing non-HCC lines. The in vivo efficacy and tumor specificity of AdVAFP1-IL2 was evaluated compared to AdVCMV-IL2 (in which the IL-2 gene is driven by the strong constitutive cytomegalovirus promoter) in the treatment of established human HCC (Hep 3B/Hep G2) xenografts growing in CB-17/SCID mice. Intratumoral injection of AdV resulted in growth retardation and regression in a majority of established hepatomas, but with a much wider therapeutic index and less systemic toxicity using the AFP vector. This study illustrates the superiority of using transcriptionally targeted recombinant AdV vectors in cytokine-based gene therapy.
Adenoviridae↗
Genetic immunization for the melanoma antigen MART-1/Melan-A using recombinant adenovirus-transduced murine dendritic cells.
Dendritic cells (DCs) are professional antigen-presenting cells that process and present antigenic peptides and are capable of generating potent T-cell immunity. A murine tumor model was developed to evaluate methods of genetic immunization to the human MART-1/Melan-A (MART-1) melanoma antigen. A poorly immunogenic murine fibrosarcoma line (NFSA) was stably transfected with the MART-1 gene. This transfected tumor [NFSA(MART1)] grows progressively in C3Hf/Kam/Sed (H-2k) mice. Partial protection against a challenge with NFSA(MART1) could be achieved with i.m. injections of a MART-1 expression plasmid or with systemic administration of an adenovirus vector expressing MART-1. However, superior protection was achieved when granulocyte macrophage colony-stimulating factor/interleukin-4-differentiated murine DCs transduced with an adenovirus vector expressing MART-1 were used for immunization. Both partial and complete protection could be achieved with i.v. administration of MART-1-engineered DCs. Splenocytes from immunized mice contained MHC class 1-restricted CTLs specific for MART-1. This preclinical model of genetic immunization supports a therapeutic strategy for human melanoma.
Adenoviridae↗
Cloning and analysis of MART-1/Melan-A human melanoma antigen promoter regions.
The MART-1/Melan-A human melanoma tumor antigen can be recognized by T lymphocytes and appears to be involved in tumor regression. To study the transcriptional regulation of this important gene, the 5' untranslated (UT) region of the MART-1/Melan-A gene was cloned and sequenced. Human melanoma cell lines were screened for MART-1/Melan-A mRNA expression. Primer extension and northern analysis were performed to confirm the mRNA size and start site. Several overlapping fragments of 5'UT were isolated from genomic DNA by polymerase chain reaction (PCR) from the previously described sequence for an additional 700 bp upstream. The fragments isolated (ranging from 838 bp to 160 bp in length) were used to drive luciferase reporter gene expression in melanoma and non-melanoma cell lines. Tissue-specific promoter activity was found in a 233-bp fragment of 5' UT with an average index of induction of 35 fold. The 233-bp MART-1/Melan-A promoter does not appear to have cytokine (IL-2, IL-4, IL-7, GM-CSF, TNF-alpha or IFN-gamma) responsive elements when studied in transient transfection assays.
Antigens, Neoplasm↗
Drug interactions with zileuton.
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Anti-Inflammatory Agents, Non-Steroidal↗
Sound alters visual motion perception.
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Auditory Perception↗
Transduction of murine and human tumors using recombinant adenovirus vectors.
BACKGROUND: Most cytokine-based cancer gene therapy clinical trials have used labor-intensive, retrovirus-mediated strategies resulting in unpredictable gene expression. Recombinant AdV vectors were evaluated for easier, more reproducible gene transfer into 12 human melanoma, 2 murine fibrosarcomas, and 8 other tumor cell lines. METHODS: AdV vectors contained a reporter (Escherichia coli beta-galactosidase or firefly luciferase) or cytokine gene (human interleukin-2 [IL-2] or IL-7). Transduction efficiencies and expression levels were assessed by histochemical staining, flow cytometry, polymerase chain reaction, fluorometry, and enzyme-linked immunosorbent assay. Tumorigenicity was determined by subcutaneous injection of cells into syngeneic mice. RESULTS: All cell lines studied were transduced with AdV. Most cell lines exhibited 100% transduction efficiencies (by flow cytometry) at multiplicities of infection (MOI) epsilon 10. Gene expression correlated linearly with MOI, but a cytopathic effect was observed at MOI > 100 with all vectors. Nanogram gene expression levels were routinely achieved. Irradiation (30 Gy) minimally affected expression levels. Tumorigenicity of AdV-IL-2-transduced fibrosarcoma cells in mice was inversely related to IL-2 production. A majority of mice that rejected their tumor challenge were immune to tumor rechallenge. CONCLUSIONS: E1-deleted AdV vectors may prove useful in generating tumor vaccines ex vivo with high, transient cytokine expression levels.
Adenoviridae↗
Cytotoxic aldehydes as possible markers for childhood cancer.
Concentrations of 22 known aldehydes (byproducts of lipid peroxidation), 5 acyloins, free and total carnitine and acylcarnitines were measured in plasma and urine obtained from pediatric patients with various forms of cancer before any treatment, and following treatment with doxorubicin or daunorubicin. Aldehydes, before the initiation of chemotherapy, were significantly elevated in cancer patients compared to controls. Aldehydes such as hexanal, heptanal, and malondialdehyde were strikingly higher in samples from cancer patients, while trans 4-cis-4-decenal was the prominent aldehyde in the blood of controls. In addition, in each form of cancer the pattern of aldehydes appeared to be unique when compared to controls, or to others forms of cancer. In cancer patients receiving chemotherapy there was a general trend toward a reduction 24 h after both the first and after the fifth doxorubicin dose. These changes however were not significant statistically due to large inter-patient variation. Free and total plasma carnitine levels remained in the normal range, and there were no abnormal acylcarnitines detected in urine. Possible hypotheses to explain the elevations in aldehydes, and the reasons for the changed aldehyde profiles in different forms of cancer are discussed.
Adolescent↗
Crystal structure of the kinesin motor domain reveals a structural similarity to myosin.
Kinesin is the founding member of a superfamily of microtubule based motor proteins that perform force-generating tasks such as organelle transport and chromosome segregation. It has two identical approximately 960-amino-acid chains containing an amino-terminal globular motor domain, a central alpha-helical region that enables dimer formation through a coiled-coil, and a carboxy-terminal tail domain that binds light chains and possibly an organelle receptor. The kinesin motor domain of approximately 340 amino acids, which can produce movement in vitro, is much smaller than that of myosin (approximately 850 amino acids) and dynein (1,000 amino acids), and is the smallest known molecular motor. Here, we report the crystal structure of the human kinesin motor domain with bound ADP determined to 1.8-A resolution by X-ray crystallography. The motor consists primarily of a single alpha/beta arrowhead-shaped domain with dimensions of 70 x 45 x 45 A. Unexpectedly, it has a striking structural similarity to the core of the catalytic domain of the actin-based motor myosin. Although kinesin and myosin have virtually no amino-acid sequence++ identity, and exhibit distinct enzymatic and motile properties, our results suggest that these two classes of mechanochemical enzymes evolved from a common ancestor and share a similar force-generating strategy.
Adenosine Diphosphate↗
In vivo trafficking of adoptively transferred interleukin-2 expanded tumor-infiltrating lymphocytes and peripheral blood lymphocytes. Results of a double gene marking trial.
Adoptive immunotherapy with tumor-infiltrating lymphocytes (TIL) and IL-2 appears to produce dramatic regressions in patients with metastatic melanoma and renal cancer. However, the in vivo mechanism of TIL function is not known. We conducted an UCLA Human Subject Protection Committee, Recombinant DNA Advisory Committee, and FDA-approved clinical trial using genetically-marked TIL to test the hypothesis that these cells have unique, tumor-specific in vivo trafficking patterns. TIL and PBL (as a control effector cell population) were isolated and expanded in parallel in vitro in IL-2-containing medium for 4-6 wk. During the expansion, TIL and PBL were separately transduced with the amphotropic retroviral vectors LNL6 and G1Na. Transduced TIL and PBL were coinfused into patients and their respective numbers measured in tumor, peripheral blood, and normal tissues; integrated provirus could be quantitated and distinguished by DNA PCR. Nine patients were treated (six melanoma, three renal) and received between 4.5 x 10(8) and 1.24 x 10(10) total cells. Both "marked" TIL and PBL could be detected circulating in the peripheral blood, in some patients for up to 99 d after infusion. Marked TIL and/or PBL could be detected in tumor biopsies in six of nine patients as early as day 6 and as late as day 99 after infusion. No convincing pattern of preferential trafficking of TIL vs. PBL to tumor was noted. Moreover, concurrent biopsies of muscle, fat, and skin demonstrated the presence of TIL/PBL in comparable or greater numbers than in tumor in five patients. The results of this double gene marking trial provide interesting insights into the life span and trafficking of adoptively transferred lymphocytes, but do not support the hypothesis that TIL specifically traffic to tumor deposits.
Adult↗