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Biomedical subjects

J Lee

Publications and source records attributed to J Lee.

At least 235 records · Page 13Linked to original sources
PubMed2001

CV706, a prostate cancer-specific adenovirus variant, in combination with radiotherapy produces synergistic antitumor efficacy without increasing toxicity.

Radiation is an effective means of treating localized prostate cancer. However, up to 40% of men with certain risk factors will develop biochemical failure 5 years after radiotherapy. CV706, a prostate cell-specific adenovirus variant, is currently in clinical trials for the treatment of recurrent organ-confined prostate cancer. We demonstrated previously that a single administration of CV706 at 5 x 10(8) particles/mm3 of tumor eliminated established tumors within 6 weeks in nude mouse xenografts (Rodriguez et al., Cancer Res. 57: 2559-2563, 1997). We now demonstrate that CV706-mediated cytotoxicity is synergistic with radiation. In vitro, addition of radiation to CV706 resulted in a synergistic increase of cytotoxicity toward the human prostate cancer cell line LNCaP and a significant increase of virus burst size, with no reduction in specificity of CV706-based cytopathogenicity for prostate cancer cells. In vivo, prostate-specific antigen (+) LNCaP xenografts of human prostate cancer were treated with CV706 (1 x 10(7) particles/mm3 of tumor), 10 Gy of single fraction local tumor radiation, or both. Tumor volumes of the group treated with CV706 or radiation was 97% or 120% of baseline 6 weeks after treatment. However, when the same dose of CV706 was followed 24 h later with the same dose of radiation, the tumor volume dropped to 4% of baseline at this time point and produced antitumor activity that was 6.7-fold greater than a predicted additive effect of CV706 and radiation. Histological analyses of tumors revealed that, compared with CV706 or radiation alone, combination treatment with two agents increased necrosis by 180% and 690%, apoptosis by 330% and 880%, and decreased blood vessel number by 1290% and 600%, respectively. Importantly, no increase in toxicity was observed after combined treatment when compared with CV706 or radiation alone. These data demonstrate that CV706 enhances the in vivo radioresponse of prostate tumors and support the clinical development of CV706 as a neoadjuvant agent with radiation for localized prostate cancer.

Adenoviridae↗
PubMed2001

Diptericin-like protein: an immune response gene regulated by the anti-bacterial gene induction pathway in Drosophila.

Insects produce various anti-microbial peptides in response to injury and infection. In Drosophila, diptericin has previously been studied as an anti-bacterial immune response gene. Here, we report the cloning of the diptericin-like protein (dptlp) gene as a paralog of Drosophila diptericin. By comparison of their sequences, we found that the dptlp gene has all of the functional domains conserved in the diptericin gene and other anti-bacterial proteins. The dptlp gene was rapidly induced by bacterial infections and showed different time-dependent gene expression patterns from those of diptericin. Like diptericin, dptlp was specifically produced from the fat body, and its expression was strictly dependent on bacterial infections. In addition, the dptlp gene expression was almost completely abolished in the imd mutant, which implicates that its expression is regulated by the anti-bacterial arm of the Drosophila innate immune regulatory pathways. In support of this, we found GATA, interferon consensus responding element, and kappa B binding sites, which is known to be important for the proper expression of anti-bacterial genes, in the proximal promoter region of the dptlp gene. Taken together, our findings support that dptlp is a novel anti-bacterial peptide whose expression is regulated by the anti-bacterial immune response mechanism.

Amino Acid Sequence↗
PubMed2001

Dual role of inflammatory stimuli in activation-induced cell death of mouse microglial cells. Initiation of two separate apoptotic pathways via induction of interferon regulatory factor-1 and caspase-11.

We have previously shown that mouse microglial cells undergo apoptosis upon inflammatory activation and that nitric oxide (NO) is the major autocrine mediator in this process (Lee, P., Lee, J., Kim, S., Yagita, H., Lee, M. S., Kim, S. Y., Kim, H., and Suk, K. (2001) Brain Res. 892, 380-385). Here, we present evidence that interferon regulatory factor-1 (IRF-1) and caspase-11 are the essential molecules in activation-induced cell death of microglial cells. The apoptogenic action of inflammatory stimuli such as lipopolysaccharide (LPS) and interferon-gamma (IFNgamma) was mediated through the induction of IRF-1 and caspase-11 expression in two separate events. Although IRF-1 was required for NO synthesis, caspase-11 induction was necessary for NO-independent apoptotic pathway. Microglial cells from IRF-1-deficient mice showed markedly decreased NO production, and they were partially resistant to apoptosis in response to LPS/IFNgamma but were sensitive to NO donor exposure. LPS/IFNgamma treatment resulted in the induction of caspase-11 followed by activation of caspase-11, -1, and -3. Inactivation of caspase-11 by the transfection of dominant-negative mutant or treatment with the caspase inhibitors rendered microglial cells partially resistant to LPS/IFNgamma-induced apoptosis. Inhibition of both NO synthesis and caspase-11 completely blocked LPS/IFNgamma-induced cytotoxicity. These results indicated that LPS/IFNgamma not only induced the production of cytotoxic NO through IRF-1 but also initiated the NO-independent apoptotic pathway through the induction of caspase-11 expression.

Animals↗
PubMed2001

Essential role for mammalian copper transporter Ctr1 in copper homeostasis and embryonic development.

The trace metal copper (Cu) plays an essential role in biology as a cofactor for many enzymes that include Cu, Zn superoxide dismutase, cytochrome oxidase, ceruloplasmin, lysyl oxidase, and dopamine beta-hydroxylase. Consequently, Cu transport at the cell surface and the delivery of Cu to intracellular compartments are critical events for a wide variety of biological processes. The components that orchestrate intracellular Cu trafficking and their roles in Cu homeostasis have been elucidated by the studies of model microorganisms and by the characterizations of molecular basis of Cu-related genetic diseases, including Menkes disease and Wilson disease. However, little is known about the mechanisms for Cu uptake at the plasma membrane and the consequences of defects in this process in mammals. Here, we show that the mouse Ctr1 gene encodes a component of the Cu transport machinery and that mice heterozygous for Ctr1 exhibit tissue-specific defects in copper accumulation and in the activities of copper-dependent enzymes. Mice completely deficient for Ctr1 exhibit profound growth and developmental defects and die in utero in mid-gestation. These results demonstrate a crucial role for Cu acquisition through the Ctr1 transporter for mammalian Cu homeostasis and embryonic development.

Animals↗
PubMed2001

Suppression of brain aging and neurodegenerative disorders by dietary restriction and environmental enrichment: molecular mechanisms.

Dietary restriction (reduced calorie intake with nutritional maintenance) can extend lifespan and may increase the resistance of the nervous system to age-related diseases including neurodegenerative disorders. An environment enriched in intellectual and physical activities can also allay many of the adverse effects of aging on the brain. The mechanisms underlying the beneficial effects of dietary restriction and environmental enrichment on the brain involve stimulation of the expression of neurotrophic factors and 'stress proteins'. The neurotrophic factors and stress proteins induced by dietary restriction may protect neurons by suppressing oxyradical production, stabilizing cellular calcium homeostasis and inhibiting a form of programmed cell death called apoptosis. Interestingly, dietary restriction and environmental enrichment also increase numbers of newly-generated neural cells in the adult brain suggesting that these behavioral modifications can increase the brain's capacity for plasticity and self-repair. A better understanding of the cellular and molecular mechanisms underlying these effects of diet and behavior on the brain is leading to novel therapeutic agents that mimick their beneficial effects.

Aging↗
PubMed2001

Altered sensitivity of CD81-deficient mice to neurobehavioral effects of cocaine.

CD81, also known as target of the antiproliferative antibody, is known to be expressed in astrocytes and involved in cell adhesion and, recently, we demonstrated its induction exclusively in the accumbens following cocaine. In the present study, the sensitivity of CD81-deficient mice to behavioral effects of cocaine was evaluated. It was found that CD81-deficient mice exhibited altered sensitivity to cocaine as assessed in the place preference conditioning paradigm and locomotor activity. This deficit in place preference conditioning was not accompanied by a deficit in acquisition or retention of water maze behavior. In addition, CD81 knockout mice exhibited higher levels of nucleus accumbens dopamine as compared to their controls. These observations are discussed in the context of the role of CD81 in cocaine-mediated behaviors.

Animals↗
PubMed2001

Study of tau decays to six pions and a neutrino.

The tau decays to six-pion final states have been studied with the CLEO detector at the Cornell Electron Storage Ring. The measured branching fractions are B(tau(-)-->2pi(-)pi(+)3pi(0)nu(tau)) = (2.2+/-0.3+/-0.4)x10(-4) and B(tau(-)-->3pi(-)2pi(+)pi(0)nu(tau)) = (1.7+/-0.2+/-0.2)x10(-4). A search for substructure in these decays shows that they are saturated by intermediate states with eta or omega mesons. We present the first observation of the decay tau(-)-->2pi(-)pi(+)omega(nu)tau and the branching fraction is measured to be (1.2+/-0.2+/-0.1)x10(-4). The measured branching fractions are in good agreement with the isospin expectations but somewhat below the conserved-vector-current predictions.

Journal Article↗
PubMed2001

Activation-induced cell death of rat astrocytes.

Inflammatory activation of astrocytes has been implicated in various neurodegenerative diseases. The elimination of activated astrocytes by apoptosis or the deactivation may be the mechanisms for auto-regulation of activated astrocytes. To test the possibility of apoptotic elimination of activated astrocytes, we examined a potential correlation between activation state of astrocytes and their viability using C6 rat glial cells and rat primary astrocyte cultures exposed to a variety of inflammatory stimuli such as lipopolysaccharide, interferon-gamma, and tumor necrosis factor-alpha. Nitric oxide production was measured to evaluate inflammatory activation of astrocytes. We found that: (i) the activation of astrocytes by the combination of lipopolysaccharide and inflammatory cytokines, but not by either alone, led to nitric oxide production followed by apoptotic cell death; (ii) the amount of nitric oxide produced by activated astrocytes was inversely proportional to the viability of the cells; (iii) inhibition of nitric oxide synthase by N-monomethyl L-arginine blocked death of activated astrocytes; and (iv) nitric oxide donors induced apoptosis of astrocytes in a caspase-dependent manner. Taken collectively, our results suggest that activated astrocytes produce nitric oxide as an autocrine mediator of caspase-dependent apoptosis, and this type of programmed cell death of astrocytes may be the underlying mechanism for the auto-regulation of inflammatory activation of astrocytes.

Animals↗
PubMed2001

Drosophila phosphoinositide-dependent kinase-1 regulates apoptosis and growth via the phosphoinositide 3-kinase-dependent signaling pathway.

Phosphoinositide-dependent kinase-1 (PDK-1) is a central mediator of the cell signaling between phosphoinositide 3-kinase (PI3K) and various intracellular serine/threonine kinases including Akt/protein kinase B (PKB), p70 S6 kinases, and protein kinase C. Recent studies with cell transfection experiments have implied that PDK-1 may be involved in various cell functions including cell growth and apoptosis. However, despite its pivotal role in cellular signalings, the in vivo functions of PDK-1 in a multicellular system have rarely been investigated. Here, we have isolated Drosophila PDK-1 (dPDK-1) mutants and characterized the in vivo roles of the kinase. Drosophila deficient in the dPDK-1 gene exhibited lethality and an apoptotic phenotype in the embryonic stage. Conversely, overexpression of dPDK-1 increased cell and organ size in a Drosophila PI3K-dependent manner. dPDK-1 not only could activate Drosophila Akt/PKB (Dakt1), but also substitute the in vivo functions of its mammalian ortholog to activate Akt/PKB. This functional interaction between dPDK-1 and Dakt1 was further confirmed through genetic analyses in Drosophila. On the other hand, cAMP-dependent protein kinase, which has been proposed as a possible target of dPDK-1, did not interact with dPDK-1. In conclusion, our findings provide direct evidence that dPDK-1 regulates cell growth and apoptosis during Drosophila development via the PI3K-dependent signaling pathway and demonstrate our Drosophila system to be a powerful tool for elucidating the in vivo functions and targets of PDK-1.

3-Phosphoinositide-Dependent Protein Kinases↗
PubMed2001

A cell-based assay system for monitoring NF-kappaB activity in human HaCat transfectant cells.

A cell-based assay system for monitoring NF-kappaB activity was developed to determine the influence of activated NF-kappaB in human HaCaT cells. The pNF-kappaB-SEAP-NPT plasmid that permits expression of the secretory alkaline phosphatase (SEAP) reporter gene in response to the NF-kappaB activity and contains the neomycin phosphotransferase (NPT) gene for geneticin resistance in host cells was constructed and transfected into the human keratinocyte cell line HaCaT. Human HaCaT transfectant cells were demonstrated to secrete the SEAP enzyme into the culture medium in a time-dependent manner until 72 h. NF-kappaB activities were measured by the SEAP reporter gene assay using a fluorescence detection method. HaCaT cell transfectants treated with antioxidants [e.g., N-acetyl-l-cysteine and vitamin C] showed reduction of NF-kappaB activity in a time- and concentration-dependent manner, whereas phorbol 12-myristate 13-acetate known as a stimulator of NF-kappaB expression increased NF-kappaB activity in a time- and concentration-dependent manner. This assay system could be used to determine the quantitative measurement of NF-kappaB activity in the human skin and allow the screening of anti-inflammatory agents for dermatological purpose from various synthetic chemicals and natural products.

Anti-Inflammatory Agents↗
PubMed2001

fucosyltransferase1 and H-type complex carbohydrates modulate epithelial cell proliferation during prostatic branching morphogenesis.

The prostate undergoes branching morphogenesis dependent on paracrine interactions between the prostatic epithelium and the urogenital mesenchyme. To identify cell-surface molecules that function in this process, monoclonal antibodies raised against epithelial cell-surface antigens were screened for antigen expression in the developing prostate and for their ability to alter development of prostates grown in serum-free organ culture. One antibody defined a unique expression pattern in the developing prostate and inhibited growth and ductal branching of cultured prostates by inhibiting epithelial cell proliferation. Expression cloning showed that this antibody binds fucosyltransferase1, an alpha-(1,2)-fucosyltransferase that synthesizes H-type structures on the complex carbohydrate modifications of some proteins and lipids. The lectin UEA I that binds H-type 2 carbohydrates also inhibited development of cultured prostates. These data demonstrate a previously unrecognized role for fucosyltransferase1 and H-type carbohydrates in controlling the spatial distribution of epithelial cell proliferation during prostatic branching morphogenesis. We also show that fucosyltransferase1 is expressed by epithelial cells derived from benign prostatic hyperplasia or prostate cancer; thus, fucosyltransferase1 may also contribute to pathological prostatic growth. These data further suggest that rare individuals who lack fucosyltransferase1 (Bombay phenotype) should be investigated for altered reproductive function and/or altered susceptibility to benign prostatic hyperplasia and prostate cancer.

Androgens↗
PubMed2001

Ester and hydroxamate analogues of methionyl and isoleucyl adenylates as inhibitors of methionyl-tRNA and isoleucyl-tRNA synthetases.

The structure activity relationship on a series of ester and hydroxamate analogues of methionyl and isoleucyl adenylate has been investigated through introducing linkers between the 1'-position of ribose and adenine surrogates as methionyl-tRNA, and isoleucyl-tRNA synthetase inhibitors, respectively. The results indicate that ester analogue 23 was found to be a potent inhibitor of Escherichia coli methionyl-tRNA synthetase, and its interaction with the active site was proposed by a molecular modeling study.

Adenosine↗
PubMed2001

Vanilloid and isovanilloid analogues as inhibitors of methionyl-tRNA and isoleucyl-tRNA synthetases.

As aminoacyl adenylate surrogates, a series of methionyl and isoleucyl phenolic analogues containing bioisosteric linkers mimicking ribose have been investigated. Inhibition of synthesized compounds to the aminoacylation reaction by the corresponding Escherichia coli methionyl-tRNA and isoleucyl-tRNA synthetases indicated that 18 was found to be a potent inhibitor of isoleucyl-tRNA synthetase. A molecular modeling study demonstrated that in 18, isovanillate and hydroxamate served as proper surrogates for adenine and ribose in isoleucyl adenylate, respectively.

Adenine↗
PubMed2001

Mesenchymal factor bone morphogenetic protein 4 restricts ductal budding and branching morphogenesis in the developing prostate.

The budding of the urogenital sinus epithelium into the surrounding mesenchyme signals the onset of prostate morphogenesis. The epithelial and mesenchymal factors that regulate ductal budding and the ensuing process of ductal growth and branching are not fully known. We provide evidence that bone morphogenetic protein 4 (BMP4) is a mesenchymal factor that regulates ductal morphogenesis. The Bmp4 gene was most highly expressed in the male urogenital sinus from embryonic day 14 through birth, a period marked by formation of main prostatic ducts and initiation of ductal branching. From an initial wide distribution throughout the prostatic anlage of the urogenital sinus, Bmp4 expression became progressively restricted to the mesenchyme immediately surrounding the nascent prostatic ducts and branches. Exogenous BMP4 inhibited epithelial cell proliferation and exhibited a dose-dependent inhibition of ductal budding in urogenital sinus tissues cultured in vitro. Adult Bmp4 haploinsufficient mice exhibited an increased number of duct tips in both the ventral prostate and coagulating gland. Taken together, our data indicate that BMP4 is a urogenital sinus mesenchymal factor that restricts prostate ductal budding and branching morphogenesis.

Animals↗
PubMed2001

Chemotherapy for human immunodeficiency virus-associated non-Hodgkin's lymphoma in combination with highly active antiretroviral therapy.

PURPOSE: This study investigated the efficacy, toxicity, and pharmacokinetic interactions resulting from simultaneous combination chemotherapy and highly active antiretroviral therapy (HAART) for patients with human immunodeficiency virus (HIV)-associated non-Hodgkin's lymphoma (NHL). In addition, the effects on viral load, CD4 counts, and opportunistic infections were examined with the use of combination chemotherapy combined with HAART. PATIENTS AND METHODS: Sixty-five patients with previously untreated and measurable disease at any stage of HIV-associated NHL of intermediate or high grade were entered onto this study at 17 different centers. The first 40 patients entered onto the study received reduced doses of cyclophosphamide and doxorubicin, combined with vincristine and prednisone (modified CHOP [mCHOP]), whereas the subsequent 25 patients entered onto the study received full doses of CHOP combined with granulocyte colony-stimulating factor (G-CSF). All patients also received stavudine, lamivudine, and indinavir. RESULTS: The complete response rates were 30% and 48% among patients who received mCHOP and full-dose CHOP combined with HAART, respectively. Grade 3 or 4 neutropenia occurred in 25% of patients receiving mCHOP and 12% of those receiving full-dose CHOP combined with G-CSF (25% v 12%). There were similar numbers of patients with grade 3 or 4 hyperbilirubinemia (12% and 17%), constipation and abdominal pain (18% and 17%), and transaminase elevation (48% and 52%) on the modified and full-dose arms of the study, respectively. Doxorubicin clearance and indinavir concentration curves were similar among patients on this study and historical controls, whereas cyclophosphamide clearance was 1.5-fold reduced as compared with control values. Human immunodeficiency virus (HIV) load declined from a median baseline value of 29,000 copies/mL to a median minimum value on therapy of 500 copies/mL. CONCLUSION: Either modified-dose or full-dose CHOP chemotherapy for HIV-NHL, delivered with HAART, is effective and tolerable.

Adult↗