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Biomedical subjects

J Liebmann

Publications and source records attributed to J Liebmann.

At least 19 recordsLinked to original sources
PubMed2004

Disturbed balance of expression between XIAP and Smac/DIABLO during tumour progression in renal cell carcinomas.

Dysregulation of apoptosis plays an important role in tumour progression and resistance to chemotherapy. The X-linked inhibitor of apoptosis (XIAP) is considered to be the most potent caspase inhibitor of all known inhibitor of apoptosis-family members. Only recently, an antagonist of XIAP has been identified, termed Smac/DIABLO. To explore the relevance of antiapoptotic XIAP and proapoptotic Smac/DIABLO for tumour progression in renal cell carcinomas (RCCs), we analysed XIAP and Smac/DIABLO mRNA and protein expression in the primary tumour tissue from 66 RCCs of all major histological types by quantitative real-time PCR, Western blot and ELISA. X-linked inhibitor of apoptosis and Smac/DIABLO mRNA expression was found in all RCCs. Importantly, the relative XIAP mRNA expression levels significantly increased from early (pT1) to advanced (pT3) tumour stages (P=0.0002) and also with tumour dedifferentiation (P=0.04). Western blot analysis confirmed the tumour stage-dependent increase of XIAP expression on the protein level. In contrast, mRNA and protein expression levels of Smac/DIABLO did not significantly change between early and advanced tumour stages or between low and high tumour grades. Consequently, the mRNA expression ratio between antiapoptotic XIAP and proapoptotic Smac/DIABLO markedly increased during progression from early (pT1) to advanced (pT3) tumour stages. Moreover, RCCs confined within the organ capsule (pT1 and pT2) exhibited a significantly lower XIAP to Smac/DIABLO expression ratio when compared with RCCs infiltrating beyond the kidney (pT3; P=0.01). Thus, our investigation demonstrates that the delicate balance between XIAP and Smac/DIABLO expression is gradually disturbed during progression of RCCs, resulting in a relative increase of antiapoptotic XIAP over proapoptotic Smac/DIABLO, thereby probably contributing to the marked apoptosis resistance of RCC.

Apoptosis↗
PubMed2002

Differential subcellular localization of functionally divergent survivin splice variants.

Survivin is an inhibitor of apoptosis protein (IAP) that is markedly overexpressed in most cancers. We identified two novel functionally divergent splice variants, i.e. non-antiapoptotic survivin-2B and antiapoptotic survivin-deltaEx3. Because survivin-2B might be a naturally occurring antagonist of antiapoptotic survivin variants, we analyzed the subcellular distribution of these proteins. PSORT II analysis predicted a preferential cytoplasmic localization of survivin and survivin-2B, but a preferential nuclear localization of survivin-deltaEx3. GFP-tagged survivin variants confirmed the predicted subcellular localization and additionally revealed a cell cycle-dependent nuclear accumulation of survivin-deltaEx3. Moreover, a bipartite nuclear localization signal found exclusively in survivin-deltaEx3 may support cytoplasmic clearance of survivin-deltaEx3. In contrast to the known association between survivin and microtubules or centromeres during mitosis, no corresponding co-localization became evident for survivin-deltaEx3 or survivin-2B. In conclusion, our study provided data on a differential subcellular localization of functionally divergent survivin variants, suggesting that survivin isoforms may perform different functions in distinct subcellular compartments and distinct phases of the cell cycle.

Alternative Splicing↗
PubMed2001

Retinal pigment epithelial dysfunction in patients with pigment dispersion syndrome: implications for the theory of pathogenesis.

OBJECTIVE: To test the hypothesis that the retinal pigment epithelial/photoreceptor complex is affected in patients with pigment dispersion syndrome and/or in patients with pigmentary glaucoma. METHODS: Electro-oculograms were recorded from patients with pigment dispersion syndrome, pigmentary glaucoma, ocular hypertension, and primary open-angle glaucoma and from control subjects. Electro-oculograms were recorded during 15 minutes of dark adaptation followed by 15 minutes of light adaptation. For each subject, dark-trough amplitudes, dark-trough latencies, light-peak amplitudes, light-peak latencies, and ratios of the light-peak amplitude to the dark-trough amplitude (Arden ratios) were calculated. RESULTS: A 1-way analysis of variance of the Arden ratios indicated significant differences among the groups of subjects. Results of a post hoc Newman-Keuls test revealed that the mean Arden ratios of patients with pigment dispersion syndrome and patients with pigmentary glaucoma were significantly lower than the mean ratios of the controls, the patients with primary open-angle glaucoma, and those with ocular hypertension. CONCLUSIONS: The results provide support for the hypothesis that the integrity of the retinal pigment epithelial/photoreceptor complex is affected in patients with pigment dispersion syndrome and in those with pigmentary glaucoma. Congenital and/or structural abnormalities of the retinal pigment epithelial/photoreceptor complex should be considered when models of the etiology of pigment dispersion syndrome are proposed.

Adult↗
PubMed1999

Hemodynamic effect of the nitroxide superoxide dismutase mimics.

Reactive oxygen species play critical roles in a number of physiologic and pathologic processes. Nitroxides are stable free radical compounds that possess superoxide dismutase (SOD) mimetic activity and have been shown to protect against the toxicity of reactive oxygen species in vitro and in vivo. Tempol, a cell-permeable hydrophilic nitroxide, protects against oxidative stress and also is an in vitro and in vivo radioprotector. In the course of evaluating the pharmacology and toxicity of the nitroxides, Tempol and another nitroxide, 3-carbamoyl-PROXYL (3-CP), were administered intravenously in various concentrations to miniature swine. Tempol caused dose-related hypotension accompanied by reflex tachycardia and increased skin temperature. Invasive hemodynamic monitoring with Swan Ganz catheterization (SGC) confirmed the potent vasodilative effect of Tempol. However, 3-CP had no effect on porcine blood pressure. The hemodynamic effects of Tempol and 3-CP are discussed in the context of differential catalytic rate constants for superoxide disumation that may impact systemic nitric oxide (NO) levels and lead to vasodilation. These findings are consistent with a role for the superoxide ion in the modulation of blood pressure and have potential implications for the systemic use of nitroxides.

Animals↗
PubMed1999

Kinetic and static fixation methods in automated threshold perimetry.

PURPOSE: Static fixation is the standard method for stabilizing the eye during automated perimetry. Kinetic fixation is an alternative for fixation control in which the eye follows a moving target. This study was conducted to evaluate the fixation accuracy of static and kinetic fixation perimetry and to determine their ability to detect the absolute scotoma of the physiologic blind spot. METHODS: The 71 patients with early glaucomatous field loss (mean age 65 years) and 45 control subjects (mean age 57 years) recruited from five clinical sites underwent threshold testing on the Dicon perimeter (kinetic fixation; Vismed, San Diego, CA) and Humphrey Field Analyzer (static fixation). The frequency of Heijl-Krakau fixation catch-trial errors was used as an indicator of fixation accuracy, and the measured sensitivity at the physiologic blind spot was used as an indicator of perimetric accuracy. RESULTS: In patients with glaucoma, the frequency of fixation errors was significantly greater for kinetic fixation (17.2%) than for static fixation (10.2%). In the control group, the frequency of fixation errors also was significantly greater for kinetic fixation (27.5%) than for static fixation (12.6%). The threshold at the presumed location of the blind spot (15 degrees temporal, 3 degrees inferior from fixation) was 14.8 dB using kinetic fixation versus 4.0 dB with static fixation in patients with glaucoma, and 18.5 dB using kinetic fixation versus 2.5 dB using static fixation in the control group. CONCLUSION: Relative to static fixation, kinetic fixation was associated with fixation inaccuracy and underestimation of the absolute scotoma at the physiologic blind spot.

Adult↗
PubMed1998

High-resolution ultrasound biomicroscopy of the pars plana and peripheral retina.

OBJECTIVE: This study aimed to evaluate the ability and role of ultrasound biomicroscopy in imaging the peripheral retina, pars plana, and anterior choroid. DESIGN: The study design was a case series. PARTICIPANTS: Seventeen eyes of 17 patients with a variety of clinical diagnoses involving the anterior portion of the posterior segment were studied. INTERVENTION: High-frequency (50 MHz), high-resolution (50 microns) ultrasound biomicroscopy was performed. RESULTS: Ultrasound biomicroscopy was capable of imaging the peripheral retina, pars plana, and anterior choroid. Images had features consistent with known histopathology. Retinoschisis consisted of one thin hyper-reflective echo and could be differentiated from a retinal detachment, which was thicker and formed a bilayered echo. A choroidal effusion could be identified as an echolucent space within the suprachoroidea, whereas a choroidal hemorrhage was moderately echodense. Inflammatory diseases, such as a sarcoid granuloma, pars planitis, and Harada's disease, were characterized by different forms of uveal thickening. A ciliochoroidal nevus was internally hyporeflective and could be measured accurately and localized. CONCLUSIONS: Imaging of the peripheral retina, pars plana, and anterior choroid is possible with ultrasound biomicroscopy and may aid in the diagnosis and management of pathology involving this region.

Adolescent↗
PubMed1998

Phase I study of paclitaxel as a radiation sensitizer in the treatment of mesothelioma and non-small-cell lung cancer.

PURPOSE: To determine the maximum-tolerated dose (MTD) and dose-limiting toxicities of paclitaxel with concurrent thoracic irradiation in patients with malignant pleural mesothelioma and locally advanced non-small-cell lung cancer (NSCLC) using a 120-hour continuous infusion regimen. A secondary objective was to assess the effect of paclitaxel on the cell cycle through serial tumor biopsies. PATIENTS AND METHODS: Paclitaxel was administered as a 120-hour (5-day) continuous infusion repeated every 3 weeks during the course of radiation therapy. The starting dose of paclitaxel was 90 mg/m2. Doses were escalated at 15-mg/m2 increments in successive cohorts of three patients. In NSCLC patients, radiation was delivered to the primary tumor and regional lymph nodes for a total tumor dose of 6,120 cGy. In mesothelioma patients, hemithoracic irradiation was delivered as the initial treatment field with a conedown to the tumor volume for a total dose of 5,760 to 6,300 cGy. Tumor biopsies were obtained, if possible, before and during paclitaxel treatment. RESULTS: Thirty patients were entered onto this study through three dose levels (from 90 mg/m2 to 120 mg/m2). The MTD was determined to be 105 mg/m2. The dose-limiting toxicity was grade 4 neutropenia (two patients). Grade 2 gastrointestinal (GI) toxicity (nausea and vomiting) was also observed at 120 mg/m2. Three of 30 patients developed a hypersensitivity reaction. Six patients had grade 2 lung injury manifested by a persistent cough that required antitussives. Five patients underwent tumor biopsies. None of the patients showed a significant block of cells in mitosis (G2/M) after paclitaxel infusion. CONCLUSION: The MTD of paclitaxel, when administered as a 120-hour continuous infusion with concurrent radiotherapy, was determined to be 105 mg/m2. The dose-limiting toxicity was neutropenia. Continuous infusion paclitaxel administered with large field irradiation of the lung is well tolerated and deserves continued evaluation.

Adult↗
PubMed1998

The role of nitric oxide chemistry in cancer treatment.

Over the last decade the role of nitric oxide (NO) in various disease states has become apparent. In cancer, NO plays a variety of roles which are at times contradictory. On one hand, NO is involved in different etiological mechanisms as well as promoting tumor growth. Yet, NO derived from leukocytes plays a seminal role in their tumoricidal activity. In cancer treatment, NO also has diverse effects. Whereas in vitro, NO can enhance the cytotoxic efficacy of some chemotherapeutic agents as well as radiation, NO donors can provide whole body protection against these same agents. This manuscript will discuss some mechanisms involved with NO and cancer treatment modalities and the potential application of these findings to cancer therapy.

Animals↗
PubMed1997

Cultured blood dendritic cells retain HIV-1 antigen-presenting capacity for memory CTL during progressive HIV-1 infection.

Dendritic cells (DC) are potent APC that may be involved in the pathogenesis of HIV-1 infection. We studied the APC function of DC from HIV-1-infected subjects that were derived from monocyte-depleted PBMC by culture in human IL-4 and human granulocyte-macrophage CSF. The cultured cells from the HIV-1-infected subjects had similar morphology and phenotype of mature DC (CD80 = 41 +/- 8%, CD86 = 77 +/- 5%, CD40 = 87 +/- 6%, CD1a = 1 +/- 1%) to DC cultured from seronegative subjects. The yield of these DC was lower than from HIV-1-seronegative subjects (4 +/- 0% vs 11 +/- 2%, p < 0.01), and the lower DC yields correlated with lower numbers of blood CD4+ T cells (r = 0.60, p < 0.01) and higher plasma viral load (r = -0.49, p < 0.01). DC from HIV-1-infected subjects were infected with recombinant vaccinia virus vectors expressing Gag, Pol, and Env and were able to stimulate equal or higher levels of MHC class I-restricted, anti-HIV-1 memory CTL (CTLm) than were similarly treated, autologous B lymphocyte cell lines. DC pulsed with peptides representing HIV-1 CTL epitopes stimulated higher levels of anti-HIV-1 CTLm responses than did DC infected with the vaccinia virus-HIV-1 constructs. Allogeneic, MHC class I-matched DC also stimulated anti-HIV-1 CTLm activity in cells from HIV-1-infected subjects. DC from early and late stages of HIV-1 infection had a similar ability to activate CTLm specific for targets expressing either HIV-1 genes via vaccinia virus vectors or HIV-1 immunodominant synthetic peptides. However, DC from either early or late stages of HIV-1 infection could not overcome the defect in anti-HIV-1 CTLm response in advanced infection.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Nitric oxide enhancement of melphalan-induced cytotoxicity.

The effects of the diatomic radical, nitric oxide (NO), on melphalan-induced cytotoxicity in Chinese hamster V79 and human MCF-7 breast cancer cells were studied using clonogenic assays. NO delivered by the NO-releasing agent (C2H5)2N[N(O)NO]- Na+ (DEA/NO; 1 mM) resulted in enhancement of melphalan-mediated toxicity in Chinese hamster V79 lung fibroblasts and human breast cancer (MCF-7) cells by 3.6- and 4.3-fold, respectively, at the IC50 level. Nitrite/nitrate and diethylamine, the ultimate end products of DEA/NO decomposition, had little effect on melphalan cytotoxicity, which suggests that NO was responsible for the sensitization. Whereas maximal sensitization of melphalan cytotoxicity by DEA/NO was observed for simultaneous exposure of DEA/NO and melphalan, cells pretreated with DEA/NO were sensitized to melphalan for several hours after NO exposure. Reversing the order of treatment also resulted in a time-dependent enhancement in melphalan cytotoxicity. To explore possible mechanisms of NO enhancement of melphalan cytotoxicity, the effects of DEA/NO on three factors that might influence melphalan toxicity were examined, namely NO-mediated cell cycle perturbations, intracellular glutathione (GSH) levels and melphalan uptake. NO pretreatment resulted in a delayed entry into S phase and a G2/M block for both V79 and MCF-7 cells; however, cell cycle redistribution for V79 cells occurred after the cells returned to a level of cell survival, consistent with treatment with melphalan alone. After 15 min exposure of V79 cells to DEA/NO (1 mM), GSH levels were reduced to 40% of control values; however, GSH levels recovered fully after 1 h and were elevated 2 h after DEA/NO incubation. In contrast, DEA/NO (1 mM) incubation did not reduce GSH levels significantly in MCF-7 cells (approximately 10%). Melphalan uptake was increased by 33% after DEA/NO exposure in V79 cells. From these results enhancement of melphalan cytotoxicity mediated by NO appears to be complex and may involve several pathways, including possibly alteration of the repair of melphalan-induced lesions. Our observations may give insights for improving tumour kill with melphalan using either exogenous or possibly endogenous sources of NO.

Animals↗
PubMed1997

Acute renal failure in a patient receiving treatment with suramin.

Suramin has demonstrated modest activity against prostate cancer and is being investigated in clinical trials. We describe a patient with metastatic prostate cancer who developed nonoliguric renal failure during treatment with suramin. Other potential causes of renal failure were not present in our patient and his renal function gradually recovered with the cessation of suramin treatment. Acute renal failure should be recognized as a potential complication of suramin treatment.

Acute Kidney Injury↗
PubMed1996

The effect of various nitric oxide-donor agents on hydrogen peroxide-mediated toxicity: a direct correlation between nitric oxide formation and protection.

The role that nitric oxide (NO) plays in various degenerative and disease states has remained a mystery since its discovery as a biological messenger, prompting the question, "NO, friend or foe?" Some reports have suggested that NO is cytotoxic, and yet others have shown that it possesses protective properties against reactive oxygen species (ROS). Many studies have used various NO donor complexes arriving at seemingly different conclusions. This report will address the effects of various NO donor compounds on ROS-mediated toxicity. Consistent with our previous study, the NO donor compound, DEA/NO ((C2H5)2N[N(O)NO]-Na+), afforded protection against hydrogen peroxide-mediated cytotoxicity in V79 Chinese hamster lung fibroblasts at concentrations as low as 10 microM DEA/NO. Furthermore, a survey of other NO donor complexes revealed that some either protected or potentiated hydrogen peroxide-mediated cytotoxicity. 3-Morpholinosynodiomine.HCl (SIN-1) and sodium nitroprusside (SNP) enhanced hydrogen peroxide-mediated cytotoxicity, while S-nitrosoglutathione (GSNO), and S-nitroso-N-acetylpenicillamine (SNAP) afforded protection. Electrochemical detection of NO in cell culture medium revealed that neither 1000 microM SIN-1 nor SNP yielded appreciable NO concentrations (<0.3 microM). In contrast, DEA/NO, SNAP, and GSNO yielded fluxes of NO >1.0 microM. Thus, a direct correlation between inhibition of hydrogen peroxide cytotoxicity and NO production was observed: agents that release NO during hydrogen peroxide treatment afford significant protection, whereas agents that do not release NO do not protect. Similar results were observed for NO donors studied when hypoxanthinesolidusxanthine oxidase was used as the source for ROS, although the S-nitrosothiol agents were much less protective. These results demonstrate that NO possesses properties which protect against ROS toxicity and demonstrate how the use of different NO donor compounds can lead to different conclusions about the role that NO can play in the cytotoxicity of ROS.

Animals↗
PubMed1996

Personal computer-based 3-dimensional ultrasound biomicroscopy of the anterior segment.

OBJECTIVE: To develop a practical, inexpensive system for 3-dimensional ultrasound biomicroscopic imaging of the anterior segment with a commercially available high-frequency ultrasound imager and a personal computer. METHODS: Sequential, high-frequency, ultrasound biomicroscopic images of the anterior segment were obtained with a motorized scanning control arm designed in our imaging laboratory. Images were acquired by a personal computer-based video capture device. Ultrasound slice data were then reconstructed as 3-dimensional volumetric images by a personal computer and commercially available software. RESULTS: Four 3-dimensional visualization formats were developed to enhance the clinical utility of high-frequency ultrasound. Rotational animation sequences were created that detailed the extent and anatomy of a filtering bleb, intraocular lens subluxation, focal angle closure from an iridociliary cyst, intraocular foreign bodies, and an iris tumor. CONCLUSIONS: Three-dimensional, high-frequency ultrasound of the anterior segment enhances our ability to visualize spatial relationships between adjacent anatomic structures. The low cost and ease of use of this system make widespread clinical application practical.

Adult↗
PubMed1995

Enhanced glutathione peroxidase expression protects cells from hydroperoxides but not from radiation or doxorubicin.

Both radiation and anthracycline antibiotics may produce reactive oxygen species to cause cytotoxicity, and it has been suggested that some cellular antioxidant enzymes may be important for resistance to these agents. The human breast adenocarcinoma cell line MCF-7WT has a low level of glutathione peroxidase (GPX) activity. We have transfected MCF-7WT cells with a plasmid that contains the cDNA for human GPX under the transcriptional control of the human metallothionein IIA promoter. One transfected clone, MCF-GPX-6, contained multiple copies of GPX cDNA/cell and, after exposure to heavy metals, expressed a level of GPX enzyme activity that was 40-fold higher than that present in MCF-7WT cells and comparable to the GPX activity contained in the doxorubicin-resistant MCF-7DOX cell line. No differences in levels of glutathione, catalase, superoxide dismutase, glutathione S-transferase, or glutathione reductase were noted in MCF-GPX-6 cells compared to MCF-7WT cells. MCF-GPX-6 cells were relatively resistant to hydrogen peroxide and tert-butylhydroperoxide compared to MCF-7WT cells, e.g., exposure of both cell lines to 750 microM H2O2 for 1 h resulted in a relative surviving fraction of 0.07 for MCF-7WT and 0.35 for MCF-GPX-6 cells. However, no difference in sensitivity to either radiation or doxorubicin was noted between MCF-7WT and MCF-GPX-6 cells. These results suggest that GPX is not important for the development of cellular resistance to either radiation or doxorubicin.

Antibiotics, Antineoplastic↗
PubMed1995

Nitric oxide (NO) protects against cellular damage by reactive oxygen species.

Since the discovery of nitric oxide (NO) as an endogenously formed radical, its effect on numerous physiological processes has been intensively investigated. Some studies have suggested NO to be cytotoxic while others have demonstrated it protective under various biological conditions. Though NO shows minimal cytotoxicity to a variety mammalian cell cultures, it does modulate the toxicity of some agents such as reactive oxygen species. Often, NO is generated in the presence of these reactive oxygen species in response to foreign pathogens or under various pathophysiological conditions. We will show that NO can play a protective role under oxidative stress resulting from superoxide, hydrogen peroxide and alkyl peroxides. It was found by measuring the time-concentration profiles of NO released from various NO donor compounds that only microM levels of NO were required for protection against the toxicity of these reactive species. It was found that there are several chemical reactions which may account for these protective effects such as NO preventing heme oxidation, inhibition of Fenton-type oxidation of DNA, and abatement of lipid peroxidation. Taken together, NO at low concentrations clearly protects against peroxide-mediated toxicity.

Animals↗
PubMed1995

Radiation reaction recall following simvastatin therapy: a new observation.

A 60-year-old woman was treated postoperatively for carcinoma of the gall bladder with a split course of radiotherapy. The tumour dose (TD) was 61.2 Gy in 34 fractions delivered by an anterior and two lateral wedge fields with 60Co; the Dmax was 70% of TD for the anterior field and 150% of the TD at the thin edge of the wedges. She also underwent 5-FU and leucovorin chemotherapy. No skin reaction was seen during radiotherapy or in 1 year of follow-up. A year after radiotherapy she was treated for hypercholesterolaemia by simvastatin. Within 2-3 days a severe skin and subcutaneous reaction developed in the lateral radiation fields but not in the anterior field. To our knowledge, recall of skin radiation reaction after simvastatin therapy has not been previously reported.

Anticholesteremic Agents↗