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1.
J Urol ; 207(2): 284-292, 2022 Feb.
Article in English | MEDLINE | ID: mdl-34547921

ABSTRACT

PURPOSE: The incidence and risk factors for metachronous upper tract urothelial carcinoma (UTUC) following radical cystectomy (RC) remain incompletely defined, which has limited the ability to individualize postoperative surveillance. MATERIALS AND METHODS: A retrospective review of 2 institutional registries was performed to identify patients undergoing RC for urothelial carcinoma. Multivariable Cox proportional hazard models for metachronous post-RC UTUC were developed in one institutional data set and validated in the second institutional data set. A post-RC UTUC risk score was then developed from these models. RESULTS: A total of 3,170 RC patients were included from the training cohort and 959 RC patients from the validation cohort. At a median followup after RC of 4.6 years (IQR 2.1-8.7), 167 patients were diagnosed with UTUC. On multivariable analysis in the training cohort, risk factors for metachronous UTUC were the presence of positive urothelial margin (HR 2.60, p <0.01), history of bacillus Calmette-Guérin treatment prior to RC (HR 2.20, p <0.01), carcinoma in situ at RC (HR 2.01, p <0.01) and pre-RC hydronephrosis (HR 1.48, p=0.04). These factors had similar discriminative capacity in the training and validation cohorts (C-statistic 0.71 and 0.73, respectively). A UTUC risk score was developed with these variables which stratified patients into low (0 points), intermediate (1-3 points), and high risk (4+ points) for post-RC UTUC, with respective 5-year UTUC-free survivals of 99%, 96%, 89% in the training cohort and 98%, 96%, and 91% in the validation cohort. CONCLUSIONS: We developed and validated a risk score for post-RC UTUC that may optimize UTUC surveillance protocols after RC.


Subject(s)
Carcinoma, Transitional Cell/epidemiology , Kidney Neoplasms/epidemiology , Neoplasms, Second Primary/epidemiology , Ureteral Neoplasms/epidemiology , Urinary Bladder Neoplasms/therapy , Aged , Carcinoma, Transitional Cell/therapy , Cystectomy , Female , Follow-Up Studies , Humans , Incidence , Kidney Neoplasms/diagnosis , Male , Middle Aged , Neoadjuvant Therapy , Neoplasms, Second Primary/diagnosis , Postoperative Period , Registries/statistics & numerical data , Retrospective Studies , Risk Assessment/methods , Risk Factors , Ureteral Neoplasms/diagnosis , Ureteroscopy/statistics & numerical data , Urinary Bladder Neoplasms/pathology
2.
Int J Impot Res ; 19(2): 167-75, 2007.
Article in English | MEDLINE | ID: mdl-16871270

ABSTRACT

Fifty partial and non-responders (Clinical Global Impression-Sexual Function (CGI-SF) score>2), out of 76 men who completed a 6-week, double-blind, placebo-controlled trial of sildenafil treatment for serotonergic antidepressant-associated sexual dysfunction, were eligible for an additional 6-week trial of open-label sildenafil (50 mg adjustable to 100 mg) under the same protocol, with blind maintained to initial assignment. Participation (double-blind and open-label) required major depressive disorder in remission (MDD-R) and continuing antidepressant medication. Forty-three entered open-label study: 16/17 initially randomized to sildenafil (sildenafil/sildenafil) and 27/33 initially randomized to placebo (placebo/sildenafil). Thirty-five of 43 (81%) achieved full response (CGI-SF

Subject(s)
Antidepressive Agents/adverse effects , Erectile Dysfunction/drug therapy , Phosphodiesterase Inhibitors/therapeutic use , Piperazines/therapeutic use , Sexual Dysfunctions, Psychological/drug therapy , Sulfones/therapeutic use , Antidepressive Agents/therapeutic use , Double-Blind Method , Erectile Dysfunction/chemically induced , Erectile Dysfunction/psychology , Humans , Male , Purines/therapeutic use , Selective Serotonin Reuptake Inhibitors/adverse effects , Selective Serotonin Reuptake Inhibitors/therapeutic use , Sexual Dysfunctions, Psychological/chemically induced , Sildenafil Citrate , Treatment Outcome
3.
Dev Biol (Basel) ; 113: 53-7; discussion 113-4, 2003.
Article in English | MEDLINE | ID: mdl-14620852

ABSTRACT

Various types of structural variants have been observed in recombinant DNA - derived products. These isoforms include variations in post translational carbohydrate modifications where variations in site occupancy or unoccupied sites may occur. In addition, varying degrees of C-terminal processing and N-terminal substitutions have been observed. Isoforms may also be generated during processing and can include aggregated and/or chemically modified forms of the protein. Sophisticated analytical techniques exist for the identification and characterization of these structural variants. Several strategies have been used to isolate or enrich the isoform before molecular characterization. However, the effect these structural variations have on the biological activity of the product is less well understood. This may, in part, be due to the specificity and variability of the bioassay employed. This presentation describes the isolation and characterization of specific molecular isoforms for a monoclonal antibody product as well as an assessment of effects on biological activity.


Subject(s)
Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/immunology , Recombinant Proteins/chemistry , Animals , Antibodies, Monoclonal/metabolism , Drug Industry/methods , Electrophoresis , Humans , Mass Spectrometry , Protein Isoforms , Protein Processing, Post-Translational , Recombinant Proteins/genetics , Recombinant Proteins/immunology , Recombinant Proteins/metabolism
4.
J Biomol Tech ; 14(4): 247-69, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14715884

ABSTRACT

Fully characterizing the interactions involving biomolecules requires information on the assembly state, affinity, kinetics, and thermodynamics associated with complex formation. The analytical technologies often used to measure biomolecular interactions include analytical ultracentrifugation (AUC), isothermal titration calorimetry (ITC), and surface plasmon resonance (SPR). In order to evaluate the capabilities of core facilities to implement these technologies, the Association of Biomolecular Resource Facilities (ABRF) Molecular Interactions Research Group (MIRG) developed a standardized model system and distributed it to a panel of AUC, ITC, and SPR operators. The model system was composed of a well-characterized enzyme-inhibitor pair, namely bovine carbonic anhydrase II (CA II) and 4-carboxybenzenesulfonamide (CBS). Study participants were asked to measure one or more of the following: (1) the molecular mass, homogeneity, and assembly state of CA II by AUC; (2) the affinity and thermodynamics for complex formation by ITC; and (3) the affinity and kinetics of complex formation by SPR. The results from this study provide a benchmark for comparing the capabilities of individual laboratories and for defining the utility of the different instrumentation.


Subject(s)
Carbonic Anhydrase II/chemistry , Sulfonamides/chemistry , Animals , Calorimetry, Differential Scanning , Carbonic Anhydrase II/drug effects , Cattle , Enzyme Inhibitors/pharmacology , Kinetics , Molecular Weight , Sulfonamides/pharmacology , Surface Plasmon Resonance , Thermodynamics , Ultracentrifugation
5.
Pharmacoeconomics ; 19(10): 973-82, 2001.
Article in English | MEDLINE | ID: mdl-11735668

ABSTRACT

The American healthcare market is currently estimated at more than 900 billion US dollars with double digit rising costs per year. Psychotropic agent costs have more than kept pace with market increases. Medication acquisition costs are an obvious focus for limiting costs in various care systems. Restrictive formularies are a common method of attempting to limit costs. To support our opinion that a single agent is ill advised, we explored the available evidence on the intended and unintended consequences of having a single or exclusive selective serotonin reuptake inhibitor (SSRI) on a formulary. Central to this position is an assumption of the interchangeability of SSRIs; we examined the evidence for and against this through a model to determine the probability of interchangeability. We conclude that the practice of having a single SSRI on the formulary for a healthcare plan seems ill founded. Patients who switch antidepressants remain in treatment 50% longer and cost approximately 50% more to treat in a more costly treatment setting. Giving the primary care physician several antidepressant choices can provide more options to continue treatment of his or her patient in the less expensive primary care setting. In terms of cost containment, formulary restrictions are far more likely to have the opposite effect.


Subject(s)
Depressive Disorder/drug therapy , Depressive Disorder/economics , Selective Serotonin Reuptake Inhibitors/economics , Selective Serotonin Reuptake Inhibitors/therapeutic use , Formularies as Topic , Humans
7.
Clin Immunol ; 98(2): 164-74, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11161972

ABSTRACT

Keliximab, a Primatized IgG1 CD4 mAb, was reconfigured to an IgG4 antibody. The gamma4 constant region was further modified by substituting glutamic acid for serine at position 235 in the CH2 domain (IgG4-E), to remove residual binding to Fcgamma receptors, and substitution of serine with proline at position 228 in the hinge region (IgG4-PE) for greater stability. Pharmacokinetic analysis in rats gave a t(1/2) of approximately 4 days for IgG4-E and 9 days for IgG4-PE, consistent with a greater stability of the IgG4-PE molecule. The effects on T cell subsets were assessed in chimpanzees given escalating doses of IgG4-PE: 0.05 mg/kg on Day 16, 1.5 mg/kg dose on Day 43, and 15 mg/kg on Day 85. Receptor modulation was observed at the two highest doses, but no depletion of T cells at any dose. The in vitro and in vivo results demonstrate the potential of this IgG4-PE mAb for use in human trials.


Subject(s)
Antibodies, Monoclonal/chemistry , CD4 Antigens/immunology , CD4-Positive T-Lymphocytes/drug effects , Immunoglobulin Fc Fragments/chemistry , Immunoglobulin G/chemistry , Lymphocyte Depletion , Pan troglodytes/immunology , Amino Acid Substitution , Animals , Antibodies, Monoclonal/genetics , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/pharmacokinetics , Antibody Affinity , Arthritis, Rheumatoid/therapy , Binding Sites , CD4-Positive T-Lymphocytes/immunology , Cloning, Molecular , Genes, Immunoglobulin , Humans , Immunoglobulin Constant Regions/genetics , Immunoglobulin Fc Fragments/genetics , Immunoglobulin Fc Fragments/immunology , Immunoglobulin G/genetics , Immunoglobulin G/immunology , Immunoglobulin Heavy Chains/genetics , Immunosuppression Therapy/methods , Macaca fascicularis , Male , Mutagenesis, Site-Directed , Polymerase Chain Reaction , Protein Denaturation , Rats , Rats, Sprague-Dawley , Receptors, IgG/metabolism , Structure-Activity Relationship
8.
Proc Natl Acad Sci U S A ; 97(16): 9026-31, 2000 Aug 01.
Article in English | MEDLINE | ID: mdl-10922058

ABSTRACT

HIV infection is initiated by the selective interaction between the cellular receptor CD4 and gp120, the external envelope glycoprotein of the virus. We used analytical ultracentrifugation, titration calorimetry, and surface plasmon resonance biosensor analysis to characterize the assembly state, thermodynamics, and kinetics of the CD4-gp120 interaction. The binding thermodynamics were of unexpected magnitude; changes in enthalpy, entropy, and heat capacity greatly exceeded those described for typical protein-protein interactions. These unusual thermodynamic properties were observed with both intact gp120 and a deglycosylated and truncated form of gp120 protein that lacked hypervariable loops V1, V2, and V3 and segments of its N and C termini. Together with previous crystallographic studies, the large changes in heat capacity and entropy reveal that extensive structural rearrangements occur within the core of gp120 upon CD4 binding. CD spectral studies and slow kinetics of binding support this conclusion. These results indicate considerable conformational flexibility within gp120, which may relate to viral mechanisms for triggering infection and disguising conserved receptor-binding sites from the immune system.


Subject(s)
CD4 Antigens/metabolism , HIV Envelope Protein gp120/metabolism , Animals , CHO Cells , Circular Dichroism , Cricetinae , Kinetics , Protein Binding , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Surface Plasmon Resonance , Thermodynamics
10.
Methods Enzymol ; 323: 207-30, 2000.
Article in English | MEDLINE | ID: mdl-10944754

ABSTRACT

This chapter has described a bioenergetic analysis of the interaction of sCD4 with an IgG1 and two IgG4 derivatives of an anti-sCD4 MAb. The MAbs have identical VH and VL domains but differ markedly in their CH and CL domains, raising the question of whether their antigen-binding chemistries are altered. We find the sCD4-binding kinetics and thermodynamics of the MAbs are indistinguishable, which indicates rigorously that the molecular details of the binding interactions are the same. We also showed the importance of using multiple biophysical methods to define the binding model before the bioenergetics can be appropriately interpreted. Analysis of the binding thermodynamics and kinetics suggests conformational changes that might be coupled to sCD4 binding by these MAbs are small or absent.


Subject(s)
Antibodies, Monoclonal/chemistry , CD4 Antigens/chemistry , CD4 Antigens/immunology , Immunoglobulin G/chemistry , Binding Sites, Antibody , Calorimetry/methods , Calorimetry, Differential Scanning/methods , Genetic Variation , Humans , Immunoglobulin Fab Fragments/chemistry , Immunoglobulin Fc Fragments/chemistry , Immunoglobulin Heavy Chains/chemistry , Immunoglobulin Light Chains/chemistry , Kinetics , Macromolecular Substances , Microchemistry/methods , Models, Molecular , Protein Conformation , Protein Denaturation , Surface Plasmon Resonance/methods , Thermodynamics
12.
J Biol Chem ; 275(1): 472-8, 2000 Jan 07.
Article in English | MEDLINE | ID: mdl-10617641

ABSTRACT

The interaction of the catalytic subunit of herpes simplex virus DNA polymerase with the processivity subunit, UL42, is essential for viral replication and is thus a potential target for antiviral drug discovery. We have previously reported that a peptide analogous to the C-terminal 36 residues of the catalytic subunit, which are necessary and sufficient for its interaction with UL42, forms a monomeric structure with partial alpha-helical character. This peptide and one analogous to the C-terminal 18 residues specifically inhibit UL42-dependent long chain DNA synthesis. Using multidimensional (1)H nuclear magnetic resonance spectroscopy, we have found that the 36-residue peptide contains partially ordered N- and C-terminal alpha-helices separated by a less ordered region. A series of "alanine scan" peptides derived from the C-terminal 18 residues of the catalytic subunit were tested for their ability to inhibit long-chain DNA synthesis and by circular dichroism for secondary structure. The results identify structural aspects and specific side chains that appear to be crucial for interacting with UL42. These findings may aid in the rational design of new drugs for the treatment of herpesvirus infections.


Subject(s)
DNA-Directed DNA Polymerase/chemistry , Exodeoxyribonucleases , Herpesvirus 1, Human/enzymology , Peptide Fragments/chemistry , Viral Proteins/chemistry , Amino Acid Sequence , Cold Temperature , DNA-Directed DNA Polymerase/genetics , DNA-Directed DNA Polymerase/metabolism , Molecular Sequence Data , Nuclear Magnetic Resonance, Biomolecular , Peptide Fragments/genetics , Peptide Fragments/metabolism , Protein Binding , Protein Structure, Secondary , Structure-Activity Relationship , Ultracentrifugation , Viral Proteins/genetics , Viral Proteins/metabolism
13.
Biochemistry ; 38(45): 14843-50, 1999 Nov 09.
Article in English | MEDLINE | ID: mdl-10555966

ABSTRACT

The essential bacterial cell division protein FtsZ (filamentation temperature-sensitive protein Z) is a distant homologue to the eukaryotic cytoskeletal protein tubulin. We have examined the GTP hydrolytic activity of Escherichia coli FtsZ using a real-time fluorescence assay that monitors phosphate production. The GTPase activity shows a dramatic, nonlinear dependence on FtsZ concentration, with activity only observed at enzyme concentrations greater than 1 microM. At 5 microM FtsZ, we have determined a K(m) of 82 microM GTP and a V(max) of 490 nmol of P(i) min(-1) (mg of protein)(-1). Hydrolysis of GTP requires Mg(2+) and other divalent cations substitute only poorly for this requirement. We have compared the concentration dependence of FtsZ GTPase activity with the oligomeric state by use of analytical ultracentrifugation and chemical cross-linking. Equilibrium analytical ultracentrifugation experiments show that FtsZ exists as 68% dimer and 13% trimer at 2 microM total protein concentration. Chemical cross-linking of FtsZ also shows that monomer, dimer, trimer, and tetramer species are present at higher (>2 microM) FtsZ concentrations. However, as shown by analytical centrifugation, GDP-bound FtsZ is significantly shifted to the monomeric state, which suggests that GTP hydrolysis regulates polymer destabilization. We also monitored the effect of nucleotide and metal ion on the secondary structure of FtsZ; nucleotide yielded no evidence of structural changes in FtsZ, but both Mg(2+) and Ca(2+) had significant effects on secondary structure. Taken together, our results support the hypothesis that Mg(2+)-dependent GTP hydrolysis by FtsZ requires oligomerization of FtsZ. On the basis of these results and structural comparisons with the alpha-beta tubulin dimer, GTP is likely hydrolyzed in a shared active site formed between two monomer subunits.


Subject(s)
Bacterial Proteins/metabolism , Cytoskeletal Proteins , GTP Phosphohydrolases/metabolism , GTP-Binding Proteins/metabolism , Cell Cycle , Enzyme Activation , Escherichia coli , Kinetics , Magnesium/metabolism , Phosphates/metabolism , Polymers/metabolism , Spectrometry, Fluorescence , Ultracentrifugation
15.
Psychiatr Serv ; 50(10): 1351-3, 1999 Oct.
Article in English | MEDLINE | ID: mdl-10506306

ABSTRACT

The authors present a method for modeling cost data on three selective serotonin reuptake inhibitors (SSRIs)-fluoxetine, paroxetine, and sertraline-from a large clinical outcomes study in a university-affiliated mental health center. Using data from 2,779 patients, average drug cost per day was calculated based on the percentage of patients on each daily dose of each medication. Given no overall significant difference between the SSRIs in effectiveness, the actual average cost per day determined by dose distribution was $1.79 for fluoxetine, $1.41 for paroxetine, and $1.21 for sertraline (using halved 100 mg tablets). The results suggest that cost can serve as one measure to help guide choice of medications.


Subject(s)
Fluoxetine/economics , Mental Health Services/economics , Paroxetine/economics , Selective Serotonin Reuptake Inhibitors/economics , Sertraline/economics , Dose-Response Relationship, Drug , Fluoxetine/therapeutic use , Follow-Up Studies , Humans , Mental Disorders/drug therapy , Paroxetine/therapeutic use , Retrospective Studies , Selective Serotonin Reuptake Inhibitors/therapeutic use , Sertraline/therapeutic use
16.
J Clin Psychiatry ; 60(9): 574-9, 1999 Sep.
Article in English | MEDLINE | ID: mdl-10520974

ABSTRACT

BACKGROUND: This investigation focuses on the 3 most frequently used selective serotonin reuptake inhibitors (SSRIs) (paroxetine, fluoxetine, sertraline) and examines the rate of medication switches as a measure of effectiveness. We answer 2 questions: (1) What is the likelihood that a patient starting treatment with an SSRI will complete treatment with the same agent? and (2) Depending on the initial SSRI agent used, do patients switch at different frequencies? METHOD: A retrospective chart review was performed on 2779 patients treated in a university outpatient clinic from March 1995 to January 1997. Of these, 263 patients given antidepressants were randomly selected: 214 were prescribed SSRIs; 24, novel antidepressants; and 25, tricyclic antidepressants. RESULTS: There was no significant difference in rate of switching between the different classes of antidepressant (p = .1) nor between drugs within the SSRI class (p = .513). When medication change was the independent factor, significant differences between the groups were total time in treatment and number of visits (p < .001 and p = .011, respectively). Age, education, and Clinical Global Impressions-Severity of Illness scale scores (admission, discharge, and change) were not significantly different between the groups. CONCLUSION: Approximately 25% of patients started with an SSRI will switch to another antidepressant in the course of their treatment. The SSRIs appear to be equivalent in effectiveness. They are not interchangeable, because patients who discontinue one SSRI for lack of tolerability or response can generally be treated effectively with another.


Subject(s)
Fluoxetine/therapeutic use , Mental Disorders/drug therapy , Paroxetine/therapeutic use , Selective Serotonin Reuptake Inhibitors/therapeutic use , Sertraline/therapeutic use , Adolescent , Adult , Aged , Antidepressive Agents, Tricyclic/therapeutic use , Anxiety Disorders/drug therapy , Drug Administration Schedule , Female , Humans , Male , Medical Records , Middle Aged , Mood Disorders/drug therapy , Retrospective Studies , Sampling Studies , Treatment Outcome
17.
Psychiatr Serv ; 50(8): 1076-8, 1999 Aug.
Article in English | MEDLINE | ID: mdl-10445658

ABSTRACT

In an open study, sildenafil (Viagra) was prescribed for nine women outpatients who reported sexual dysfunction induced by antidepressant medication, primarily selective serotonin reuptake inhibitors. A 50 mg dose of sildenafil was prescribed, and patients were instructed to take it approximately one hour before sexual activity. They were told to increase the dose to 100 mg on the next occasion if they experienced a partial response or a lack of response to sildenafil. The nine patients, all of whom had experienced either anorgasmia or delayed orgasm with or without associated disturbances, reported significant reversal of sexual dysfunction, usually with the first dose of 50 mg of sildenafil.


Subject(s)
Antidepressive Agents/adverse effects , Depressive Disorder/drug therapy , Phosphodiesterase Inhibitors/therapeutic use , Piperazines/therapeutic use , Sexual Dysfunctions, Psychological/chemically induced , Sexual Dysfunctions, Psychological/drug therapy , Adult , Ambulatory Care , Antidepressive Agents/therapeutic use , Drug Administration Schedule , Female , Humans , Middle Aged , Phosphodiesterase Inhibitors/administration & dosage , Piperazines/administration & dosage , Purines , Selective Serotonin Reuptake Inhibitors/adverse effects , Selective Serotonin Reuptake Inhibitors/therapeutic use , Sex Factors , Sildenafil Citrate , Sulfones , Treatment Outcome
18.
Nurs Econ ; 17(2): 91-5, 1999.
Article in English | MEDLINE | ID: mdl-10410027

ABSTRACT

The authors describe an elegant goal-driven program designed to prepare new nursing graduates to function optimally on a hospital unit by focusing first on their security and affiliative needs [belonging], and subsequently on their professional skill and knowledge acquisition. This developmental program has both a clear timeline and structure as well as well defined role expectations for the experienced RN guide/mentor, the orientee, and the unit's nurse manager and staff. The guide/mentors are carefully selected and prepared for their new roles as well. Shared goal-setting sessions are held weekly, along with three major evaluations during the first 90 days, with less frequent updates throughout the following year. This frequent feedback, reinforcement, and fine-tuning of goals allows the new graduate to gradually take on the full work load by the end of week 12 without feeling as overwhelmed or inadequate as those who are less carefully developed.


Subject(s)
Education, Nursing, Continuing/organization & administration , Inservice Training/organization & administration , Nursing Staff, Hospital/education , Nursing Staff, Hospital/psychology , Staff Development/organization & administration , Clinical Competence/standards , Curriculum , Feedback , Goals , Humans , Job Description , Mentors/psychology , Nursing, Supervisory/organization & administration , Personnel Loyalty , Program Evaluation , Socialization
19.
J Clin Psychiatry ; 60(1): 33-5, 1999 Jan.
Article in English | MEDLINE | ID: mdl-10074875

ABSTRACT

OBJECTIVE: To evaluate the effect of sildenafil on iatrogenic serotonergic antidepressant-induced sexual dysfunction. METHOD: Four outpatients (2 men, 2 women) who developed sexual dysfunction (erectile impotence, anorgasmia) during treatment with a serotonin reuptake inhibitor antidepressant for psychiatric disorder were selected. Each subject was initially prescribed sildenafil 50 mg to be taken approximately 1 hour before sexual activity. The dose was increased to 100 mg for a partial or failed response. RESULTS: Four cases are detailed in case report fashion. All 4 had rapid reversal of their sexual dysfunction, usually with the first dose. Reversal equates to 1 successful use of sildenafil in each of 2 patients and 3 uses in 2 patients. CONCLUSION: Sildenafil may be an effective treatment for serotonergic antidepressant-induced sexual dysfunction and deserves further evaluation in randomized placebo-controlled studies.


Subject(s)
Depressive Disorder/drug therapy , Enzyme Inhibitors/therapeutic use , Piperazines/therapeutic use , Selective Serotonin Reuptake Inhibitors/adverse effects , Sexual Dysfunctions, Psychological/chemically induced , Sexual Dysfunctions, Psychological/drug therapy , Adult , Ambulatory Care , Drug Administration Schedule , Female , Humans , Iatrogenic Disease , Male , Middle Aged , Purines , Selective Serotonin Reuptake Inhibitors/therapeutic use , Sildenafil Citrate , Sulfones , Treatment Outcome
20.
J Biol Chem ; 273(42): 27548-56, 1998 Oct 16.
Article in English | MEDLINE | ID: mdl-9765287

ABSTRACT

Herpesvirus entry mediator (HVEM), a member of the tumor necrosis factor (TNF) receptor family, mediates herpesvirus entry into cells during infection. Upon overexpression, HVEM activates NF-kappaB and AP-1 through a TNF receptor-associated factor (TRAF)-mediated mechanism. Using an HVEM-Fc fusion protein, we screened soluble forms of novel TNF-related proteins derived from an expressed sequence tag data base. One of these, which we designated HVEM-L, specifically bound to HVEM-Fc with an affinity of 44 nM. This association was confirmed with soluble and membrane forms of both receptor and ligand. HVEM-L mRNA is expressed in spleen, lymph nodes, macrophages, and T cells and encodes a 240-amino acid protein. A soluble, secreted form of the protein stimulates proliferation of T lymphocytes during allogeneic responses, inhibits HT-29 cell growth, and weakly stimulates NF-kappaB-dependent transcription.


Subject(s)
Antineoplastic Agents/metabolism , Growth Substances/metabolism , Membrane Proteins/metabolism , Receptors, Tumor Necrosis Factor/metabolism , Receptors, Virus/metabolism , Tumor Necrosis Factor-alpha/metabolism , Amino Acid Sequence , Antineoplastic Agents/pharmacology , Bacterial Proteins/metabolism , Gene Expression Regulation , Growth Inhibitors/metabolism , Growth Inhibitors/pharmacology , Growth Substances/pharmacology , HT29 Cells/drug effects , Humans , Ligands , Lymphocyte Culture Test, Mixed , Membrane Proteins/genetics , Membrane Proteins/pharmacology , Molecular Sequence Data , NF-kappa B/metabolism , Protein Binding , Receptors, Tumor Necrosis Factor, Member 14 , Recombinant Fusion Proteins/metabolism , Recombinant Fusion Proteins/pharmacology , Sequence Homology, Amino Acid , T-Lymphocytes/drug effects , Tissue Distribution , Transcription Factor AP-1/metabolism , Tumor Necrosis Factor Ligand Superfamily Member 14 , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/pharmacology
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