Otorrhea from lateral extension of a retropharyngeal abscess.
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Drainage↗
Biomedical subjects
D J Lee
Publications and source records attributed to D J Lee.
Coimmunization with IFN-gamma or IL-2, but not IL-13 or IL-4 cDNA can enhance Th1-type DNA vaccine-induced immune responses in vivo.
As we explore the potential improvements to the current DNA vaccine strategies, it may be desirable to investigate methods to improve the level of resulting immune responses. One strategy is the use of cytokine cDNA as molecular adjuvants for DNA-based vaccines. Codelivery of these molecular adjuvants consisting of expression plasmid encoding for cytokines with DNA vaccine constructs is an effective method to modulate the magnitude and direction (humoral or cellular) of the immune responses. We have previously reported on the immunomodulatory effects of codelivering cDNA for interleukin-2 (IL-2) and IL-4 as molecular adjuvants for DNA-based vaccines. In this report, we extend these finding and compare the immunomodulatory effects of IL-2 and IL-4 with those of cDNA for prototypical Thl-type cytokine interferon-y (IFN-gamma) and Th2-type cytokine IL-13. We observed that distinct antigen-specific immune modulation can be achieved by the coinjection of IFN-gamma or IL-13 genes with DNA immunogen cassettes. We observed that IFN-gamma is a strong driver of Thl immune responses. Furthermore, in contrast to previous reports on their similarities in biologic activities, IL-13 and IL-4 cDNA coimmunizations modulated vaccine-induced immune responses differently in this model. Overall, these results further support the potential utility of this strategy as an important tool for the development of vaccines and immune therapies.
Adjuvants, Immunologic↗
Modulation of antigen-specific humoral responses in rhesus macaques by using cytokine cDNAs as DNA vaccine adjuvants.
An important limitation of DNA immunization in nonhuman primates is the difficulty in generating high levels of antigen-specific antibody responses; strategies to enhance the level of immune responses to DNA immunization may be important in the further development of this vaccine strategy for humans. We approached this issue by testing the ability of molecular adjuvants to enhance the levels of immune responses generated by multicomponent DNA vaccines in rhesus macaques. Rhesus macaques were coimmunized intramuscularly with expression plasmids bearing genes encoding Th1 (interleukin 2 [IL-2] and gamma interferon)- or Th2 (IL-4)-type cytokines and DNA vaccine constructs encoding human immunodeficiency virus Env and Rev and simian immunodeficiency virus Gag and Pol proteins. We observed that the cytokine gene adjuvants (especially IL-2 and IL-4) significantly enhanced antigen-specific humoral immune responses in the rhesus macaque model. These results support the assumption that antigen-specific responses can be engineered to a higher and presumably more desirable level in rhesus macaques by genetic adjuvants.
Adjuvants, Immunologic↗
Gamma knife radiosurgery as a primary treatment for prolactinomas.
OBJECT: The purpose of this study was to estimate the efficacy of gamma knife radiosurgery (GKS) in controlling tumor growth and endocrinopathy associated with prolactinomas. METHODS: Between 1993 and 1997, 164 of 469 patients with pituitary adenomas treated by GKS harbored prolactinomas. The dose to the tumor margin ranged from 9 to 35 Gy (mean 31.2 Gy), and the visual pathways were exposed to a dose of less than 10 Gy. The mean tumor diameter was 13.4 mm. The mean follow-up time for 128 cases was 33.2 months (range 6-72 months). Tumor control was observed in all but two patients who underwent surgery 18 and 36 months, respectively, after GKS. Clinical cure was achieved in 67 cases. Clinical improvement was noted with a decrease in the hyperprolactinemia after GKS. Nonetheless, in 31 (29%) of 108 patients who were followed for more than 2 years no improvement in serum prolactin levels was demonstrated, although this could be normalized by bromocriptine administration after treatment. Nine infertile women became pregnant 2 to 13 months after GKS and all gave birth to normal children. There was no visual deterioration related to GKS. Five women experienced premature menopause. In these patients there was subtotal disappearance of the tumor and an empty sella developed. CONCLUSIONS: Gamma knife radiosurgery as a primary treatment for prolactinomas can be safe and effective both for controlling tumor growth and for normalization of prolactin hypersecretion. A higher margin dose (> or = 30 Gy) seemed to be associated with a better clinical outcome. Gamma knife radiosurgery may make prolactinomas more sensitive to the bromocriptine.
Humans↗
Prevalence of usual-corrected binocular distance visual acuity impairment in Hispanic and non-Hispanic adults.
OBJECTIVES: The purpose of this study was to perform comparative analyses of the population-based prevalence of usual-corrected binocular distance visual acuity impairment among Hispanics and non-Hispanics in the United States. METHODS: Data from the Hispanic Health and Nutrition Examination Survey (HHANES), 1982-1984, and the National Health and Nutrition Examination Augmentation Survey I (NHANES I-A), 1974-1975, were analyzed to investigate the epidemiology of usual-corrected binocular distance acuity in adults 25 to 74 years of age among Cuban-Americans (N=396), Mexican-Americans (N=1,381), Puerto Ricans (N=513), African-Americans (N=250), and non-Hispanic white Americans (N=2, 660). Binocular distance acuity was assessed using Sloan Letters or Landolt Rings with the participants wearing their corrective lenses, if any. RESULTS: Prevalences of 20/50 or worse usual-corrected binocular distance acuity were 3.5%, 4.6%, and 6.6% for Cuban-Americans, Mexican-Americans, and Puerto Ricans, respectively, in the HHANES; and 7.7% and 4.1% for African-Americans and non-Hispanic whites, respectively, in the NHANES I-A. Within the HHANES, after adjustment for gender and age, Puerto Rican adults were found to have a significantly higher prevalence of visual impairment (20/50 or worse) and were significantly less likely to become unimpaired with usual correction than Cuban-American adults. Within the NHANES I-A, African-Americans were found to have a higher prevalence of visual impairment (20/50 or worse) and were significantly less likely to become unimpaired with usual correction than non-Hispanic whites. Higher prevalences of visual impairment (20/50 or worse) were associated with increasing age for all ethnic groups. After controlling for age, odds of usual-corrected visual impairment (20/50 or worse) were significantly higher in women than in men for Cuban-Americans and Mexican-Americans (odds ratios: 4.5 and 2.6, respectively). CONCLUSIONS: The results from this study suggest that compared to other Hispanic groups and non-Hispanic whites, Puerto Rican and African-American adults may not be receiving similar eye care services and/or may have more severe eye diseases.
Adult↗
Sphingosine 1-phosphate induces angiogenesis: its angiogenic action and signaling mechanism in human umbilical vein endothelial cells.
Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid metabolite abundantly stored in platelets and released upon platelet activation. Recently, S1P has been postulated for its potential roles in angiogenesis. In this study, we provided several lines of evidence showing that S1P has angiogenic activity. In vitro, S1P stimulated DNA synthesis and chemotactic motility of human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner, reaching a near maximum at 1 microM. S1P also significantly induced tube formation of HUVECs on Matrigel. Matrigel plug assay in mice revealed that S1P promotes angiogenesis in vivo. In addition, exposure of HUVECs to S1P led to rapid activation of extracellular signal-regulated kinases (ERKs) and p38 mitogen-activated protein kinase (p38 MAPK) in a pertussis toxin (PTX)-sensitive manner. Notably, HUVEC migration and tube formation in response to S1P were completely blocked by pretreatment with PTX. Further, the MEK inhibitor U0126 markedly inhibited S1P-induced tube formation but S1P-induced migration was not affected by inhibition of ERK and p38 MAPK. Taken together, these results indicate that S1P induces angiogenesis predominantly via G(i) protein-coupled receptors in endothelial cells and suggest that S1P may act as an important modulator of platelet-induced angiogenesis.
Animals↗
In vivo priming by DNA injection occurs predominantly by antigen transfer.
DNA vaccines can stimulate both humoral and cytolytic immune responses. Although bone marrow-derived elements present the expressed Ag, the mechanisms for acquiring immunogenic peptides have yet to be fully elucidated. APCs may become directly transfected by plasmid DNA or process extracellular proteins produced by other transfected cells. Using a transactivating plasmid system and bone marrow chimeras, we show that both mechanisms appear to be involved; however, the bulk of the immune response is dependent on expression of Ag by nonlymphoid tissues and transfer to APCs. These in vivo studies are the first to define the role of transfected nonlymphoid cells in generating Ag for presentation by bone marrow-derived APCs after needle injection with plasmid DNA.
Animals↗
Structure of the enabled/VASP homology 1 domain-peptide complex: a key component in the spatial control of actin assembly.
The Enabled/VASP homology 1 (EVH1; also called WH1) domain is an interaction module found in several proteins implicated in actin-based cell motility. EVH1 domains bind the consensus proline-rich motif FPPPP and are required for targeting the actin assembly machinery to sites of cytoskeletal remodeling. The crystal structure of the mammalian Enabled (Mena) EVH1 domain complexed with a peptide ligand reveals a mechanism of recognition distinct from that used by other proline-binding modules. The EVH1 domain fold is unexpectedly similar to that of the pleckstrin homology domain, a membrane localization module. This finding demonstrates the functional plasticity of the pleckstrin homology fold as a binding scaffold and suggests that membrane association may play an auxiliary role in EVH1 targeting.
Actins↗
Rheumatoid factor B cell tolerance via autonomous Fas/FasL-independent apoptosis.
Normal individuals do not express the high-affinity autoantibodies specific for self-IgG (rheumatoid factors, RF) that are commonly seen in rheumatoid arthritis patients. Studies of transgenic mice expressing a human IgM rheumatoid factor have shown that one mechanism by which higher affinity RF B cells are tolerized to IgG is through abortive RF B cell activation followed by deletion in the absence of T cell help. We show that RF B cell deletion occurs through an intrinsic apoptotic mechanism that is independent of the Fas/FasL pathway and does not involve active killing by T cells, as it occurs in RAG-1-deficient RF transgenic mice to the same extent as in the parental RF transgenic line.
Animals↗
Confirmation of translocated gastrointestinal bacteria in a neonatal model.
PURPOSE: The hypothesis that enteric bacteria translocate from the gastrointestinal (GI) tract to extraintestinal sites has been extensively studied. However, definitive evidence that spontaneous bacterial translocation and dissemination from the GI tract to extraintestinal sites occur in a neonatal model has been lacking. The aim of this study was to confirm this phenomenon by tracking enterally administered, plasmid-labeled bacteria to extraintestinal sites. MATERIALS AND METHODS: Escherichia coli 07:K1 (E. coli K1) with and without a nontransferable, ampicillin resistance plasmid (pGEM-7) were used in this study. Newborn New Zealand white rabbit pups were separated into three treatment groups: transformed E. coli K1 (E. coli K1 + pGEM-7, n = 20), nontransformed E. coli K1 (n = 12), and control pups (no bacteria, n = 7). Pups were enterally fed 10% Formulac solution supplemented with a suspension of bacteria respective to their group. After the pups fed twice daily for 2 days, representative tissue specimens from the small bowel (SB), mesenteric lymph nodes (MLNs), spleen (SPL), and liver (LIV) were aseptically harvested and tested for culture growth in ampicillin-supplemented medium. RESULTS: Positive growths of plasmid-induced ampicillin-resistant bacteria were detected in tissue specimens harvested from rabbits fed transformed E. coli K1, but were not detected in the other groups. CONCLUSION: This experiment demonstrated conclusively that transformed E. coli K1 fed to healthy rabbit pups spontaneously translocated from the intestinal lumen and subsequently disseminated to the mesenteric lymph nodes, spleen, and liver.
Animals↗
Sociodemographic correlates of visual acuity impairment in Hispanic children and adolescents.
Sociodemographic correlates of visual impairment were examined in 6- to 19-year-old Hispanic children and adolescents using data from the Hispanic Health and Nutrition Examination Survey. Mexican American and Puerto Rican children whose parents had 0 to 6 years of education were more likely to remain visually impaired even when tested with their glasses or contact lenses, if any (i.e., with usual correction) than children whose parents reported 12 to 17 years of education. Mexican Americans residing below versus at or above the poverty line were more likely to remain visually impaired even with the usual correction. Mexican Americans enrolled in the Medicaid program or who were without health insurance were more likely to remain visually impaired than Mexican Americans with private health insurance. When tested without glasses or contact lenses, Cuban Americans and Mexican Americans born outside of the mainland United States had lower rates of visual impairment compared to those born in the United States; however, children in this latter group were more likely to remain visually impaired with usual correction than U.S.-born Mexican Americans. These findings suggest that Hispanic children from economically disadvantaged households and those born outside the United States may not be receiving optimal eye care that could improve visual function.
Journal Article↗
Protein-protein interactions between native Ro52 and immunoglobulin G heavy chain.
Using a yeast two-hybrid system to search for proteins interacting with Ro52 autoantigen, we identified a novel protein-protein interaction. Two different cDNA clones, which interacted with Ro52 in the yeast two-hybrid system, were identified and isolated from a human B-cell library. Surprisingly, both clones encoded the heavy chain of human IgG1. The expression of both HIS3 and beta-galactosidase reporter genes in yeast suggested that the interaction between Ro52 and IgG occurred in vivo. In vitro studies utilizing recombinant Ro52 and purified immunoglobulins indicated that the interaction was immunoglobulin class and subclass specific. Ro52 interacted with IgG1 and IgG4, but not with IgG2, IgG3, IgA or IgM. Ro52 could also precipitate IgG directly from serum. The identified cDNA clones did not include the variable region of IgG, which suggested a non-classical interaction independent of antibody specificity. We further mapped the domain of Ro52 responsible for this interaction to the C-terminus rfp-like region. In conclusion, our data support an unusual interaction between native Ro52 and IgG. The potential biological significance of this unusual protein-protein interaction is discussed.
Amino Acid Sequence↗
Radiologic and histopathologic changes after Gamma Knife radiosurgery for acoustic schwannoma.
Gamma knife radiosurgery (GKRS) is a widely used treatment option for acoustic schwannomas, 3 cm in diameter or less. Between May 1990 and February 1998, 102 acoustic tumors in 101 patients were treated with GKRS. There are 77 patients with a follow-up period of more than six months (mean 55, range 7 to 90 months). Seventy (91%) of these tumors have remained unchanged or reduced in volume. After GKRS there was an increase in volume in seven cases. In four the volume increase affected solid tumour. Among these, three patients were in stable condition and are being observed. One of these patients developed brain stem compression symptoms and was operated. In another three cases, cysts with multiple septa developed medial to the tumor and compressed the brain stem and fourth ventricle, thus necessitating post-GKRS surgery. In these three patients, MRI had shown loss of central contrast enhancement followed by its return. Histological findings at surgery before and after GKRS were compared for these four tumours. In spite of the MRI changes, there were no definite histological findings after GKRS which could be attributed to radiation induced changes. The development of cysts occurred after the treatment of larger tumors.
Adolescent↗
Intracellular adhesion molecule-1 modulates beta-chemokines and directly costimulates T cells in vivo.
The potential roles of adhesion molecules in the expansion of T cell-mediated immune responses in the periphery were examined using DNA immunogen constructs as model antigens. We coimmunized cDNA expression cassettes encoding the adhesion molecules intracellular adhesion molecule-1 (ICAM-1), lymphocyte function associated-3 (LFA-3), and vascular cell adhesion molecule-1 (VCAM-1) along with DNA immunogens, and we analyzed the resulting antigen-specific immune responses. We observed that antigen-specific T-cell responses can be enhanced by the coexpression of DNA immunogen and adhesion molecules ICAM-1 and LFA-3. Coexpression of ICAM-1 or LFA-3 molecules along with DNA immunogens resulted in a significant enhancement of T-helper cell proliferative responses. In addition, coimmunization with pCICAM-1 (and more moderately with pCLFA-3) resulted in a dramatic enhancement of CD8-restricted cytotoxic T-lymphocyte responses. Although VCAM-1 and ICAM-1 are similar in size, VCAM-1 coimmunization did not have any measurable effect on cell-mediated responses. These results suggest that ICAM-1 and LFA-3 provide direct T-cell costimulation. These observations are further supported by the finding that coinjection with ICAM-1 dramatically enhanced the level of interferon-gamma (IFN-gamma) and beta-chemokines macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta, and regulated on activation normal T-cell expression and secreted (RANTES) produced by stimulated T cells. Through comparative studies, we observed that ICAM-1/LFA-1 T-cell costimulatory pathways are independent of CD86/CD28 pathways and that they may synergistically expand T-cell responses in vivo.
AIDS Vaccines↗
Multimodality therapy of patients with locally advanced squamous cell cancer of the head and neck: preliminary results of two pilot trials using paclitaxel and cisplatin.
Chemotherapy has been integrated into the initial treatment of patients with locally advanced squamous cell cancer of the head and neck to improve locoregional control and survival. Two strategies for improving these outcomes are the use of new, potentially more effective drugs either with concurrent radiotherapy or as induction regimens. Because of its inherent activity against squamous cell cancer of the head and neck and its radiation-sensitizing properties, paclitaxel may be a valuable agent in the treatment of this patient population. We describe the preliminary results of two trials that evaluated the combination of paclitaxel and cisplatin in patients with locally advanced disease: a phase I trial of weekly paclitaxel and cisplatin with concurrent postoperative radiation therapy in patients with high-risk disease and a phase I/II trial of paclitaxel as a 96-hour infusion in combination with cisplatin as induction therapy. These studies identified tolerable doses of paclitaxel and cisplatin administered in these settings, with apparent clinical activity. These trials formed the basis for subsequent evaluation of induction paclitaxel and cisplatin followed by definitive radiotherapy and concurrent weekly paclitaxel and cisplatin plus radiotherapy.
Adult↗
Presentation of peptide antigens by mouse CD1 requires endosomal localization and protein antigen processing.
Mouse CD1(mCD1) molecules have been reported to present two types of antigens: peptides or proteins and the glycolipid alpha-galactosylceramide. Here, we demonstrate that a protein antigen, chicken ovalbumin (Ova), must be processed to generate peptides presented by mCD1 to CD8(+) T cells. The processing and mCD1-mediated presentation of chicken Ova depend on endosomal localization because inhibitors of endosomal acidification and endosomal recycling pathways block T cell reactivity. Furthermore, a cytoplasmic tail mutant of mCD1, which disrupts endosomal localization, has a greatly reduced capacity to present Ova to mCD1 restricted cells. Newly synthesized mCD1 molecules, however, are not required for Ova presentation, suggesting that molecules recycling from the cell surface are needed. Because of these data showing that mCD1 trafficks to endosomes, where it can bind peptides derived from exogenous proteins, we conclude that peptide antigen presentation by mCD1 is likely to be a naturally occurring phenomenon. In competition assays, alpha-galactosylceramide did not inhibit Ova presentation, and presentation of the glycolipid was not inhibited by excess Ova or the peptide epitope derived from it. This suggests that, although both lipid and peptide presentation may occur naturally, mCD1 may interact differently with these two types of antigens.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Concurrent tirapazamine and radiotherapy for advanced head and neck carcinomas: a Phase II study.
PURPOSE: To evaluate the efficacy and toxicity of tirapazamine, a hypoxic cytotoxin, combined with conventional radiotherapy (RT) for advanced head and neck carcinomas. MATERIALS AND METHODS: From Oct. 1994 to Nov. 1996, 40 patients with stage III or IV carcinomas of the head and neck were enrolled in a Phase II trial to receive conventional RT (70 Gy in 7 weeks) with concurrent tirapazamine (159 mg/m2 intravenously, 3 times per week for 12 doses). One patient subsequently withdrew from the protocol treatment, and was excluded from analyses. Among the 39 cases, the primary sites were located in the oropharynx (n = 28), supraglottic larynx (n = 6), or hypopharynx (n = 5). Twenty-seven patients had T3 or T4, and 27 had N2 or N3 disease. RESULTS: Thirty-two (82%) patients received full 12 drug doses. Thirty-two patients (82%) received full 70 Gy of RT. The most frequent drug toxicities were muscle cramps (77%) and nausea/vomiting (62%), usually grade 1 or 2. Overall, 13 patients (33%) experienced grade 3 or 4 drug-related toxicities. No excessive RT-associated acute normal tissue reactions were observed. With a median follow-up of 13 months, the 1-year and 2-year local control rate was 64% and 59% respectively. CONCLUSION: The tirapazamine regimen was well tolerated with a compliance rate of 82%. The toxicity of RT with concurrent tirapazamine was acceptable in treating advanced head and neck carcinomas. The disease control trend was encouraging. Further clinical studies are warranted.
Adult↗
Distinguishing second primary tumors from lung metastases in patients with head and neck squamous cell carcinoma.
BACKGROUND: In patients with head and neck squamous cell carcinoma (HNSCC), a squamous cell carcinoma (SCC) in the lung represents either another primary tumor or a metastasis. This distinction greatly influences patient prognosis and could guide treatment strategies, but the nature of a solitary lung nodule is often difficult to discern by use of standard clinical and histologic parameters. Comparison of genetic alterations in the tumors could resolve this dilemma. METHODS: We compared paired tumors from 16 patients with HNSCC and a solitary lung SCC for loss (i.e., deletion) of loci on chromosomal arms 3p and 9p. Losses at these loci occur early during neoplastic transformation of the respiratory tract. DNA from microdissected tumors and normal tissues was subjected to polymerase chain reaction-based microsatellite analysis. An effort was also made to distinguish primary lung cancers from lung metastases on the basis of clinical and histopathologic features. RESULTS: In most cases, comparison of genetic alterations clarified the relationship between the lung tumor and the primary HNSCC. The paired tumors from 10 patients had concordant patterns of loss at all loci suggesting metastatic spread, whereas three paired tumors had discordant patterns of loss at all loci suggesting independent tumor origin. These observations were supported by the clinical and pathologic findings. CONCLUSIONS/IMPLICATIONS: In patients with HNSCC and a solitary SCC in the lung, microsatellite analysis provides a rapid genetic approach for discerning clonal relationships. In such patients, we found that a solitary SCC in the lung more likely represents a metastasis than an independent lung cancer. Microsatellite analysis could potentially be applied to any patient with multiple tumors, where tumor relationships are not clear on clinical, radiographic, or even histopathologic grounds.
Adult↗