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David George

Publications and source records attributed to David George.

18 recordsLinked to original sources
PubMed2006

Regulation of murine TGFbeta2 by Pax3 during early embryonic development.

Previously our laboratory identified TGFbeta2 as a potential downstream target of Pax3 by utilizing microarray analysis and promoter data base mining (Mayanil, C. S. K., George, D., Freilich, L., Miljan, E. J., Mania-Farnell, B. J., McLone, D. G., and Bremer, E. G. (2001) J. Biol. Chem. 276, 49299-49309). Here we report that Pax3 directly regulates TGFbeta2 transcription by binding to cis-regulatory elements within its promoter. Chromatin immunoprecipitation revealed that Pax3 bound to the cis-regulatory elements on the TGFbeta2 promoter (GenBanktrade mark accession number AF118263). Both TGFbeta2 promoter-luciferase activity measurements in transient cotransfection experiments and electromobility shift assays supported the idea that Pax3 regulates TGFbeta2 by directly binding to its cis-regulatory regions. Additionally, by using a combination of co-immunoprecipitation and chromatin immunoprecipitation, we show that the TGFbeta2 cis-regulatory elements between bp 741-940 and bp 1012-1212 bind acetylated Pax3 and are associated with p300/CBP and histone deacetylases. The cis-regulatory elements between bp 741 and 940 in addition to associating with acetylated Pax3 and HDAC1 also associated with SIRT1. Whole mount in situ hybridization and quantitative real time reverse transcription-PCR showed diminished levels of TGFbeta2 transcripts in Pax3(-/-) mouse embryos (whose phenotype is characterized by neural tube defects) as compared with Pax3(+/+) littermates (embryonic day 10.0; 30 somite stage), suggesting that Pax3 regulation of TGFbeta2 may play a pivotal role during early embryonic development.

Animals↗
PubMed2006

Proteasome inhibition induces both pro- and anti-cell death pathways in prostate cancer cells.

The proteasome-mediated protein degradation is critical for regulation of a variety of cellular processes, including cell cycle, cell death, differentiation and immune response. Proteasome inhibitors have recently been shown to be potent anti-cancer agents against a variety of cancer cells. Our study demonstrated that proteasome inhibitor MG132 (carbobenzoxy-L-leucyle-L-leucyl-L-leucinal) was a potent death-inducing agent for PC3 prostate cancer cells. MG132-induced cell death was partially inhibited by pan-caspase inhibitor zAVD-fmk and translational inhibitor cycloheximide. To understand the signaling pathways of proteasome inhibitor-induced cell death, we performed gene profiling study using Affymetrix human DNA microarrays to identify the genes whose expression was affected by proteasome inhibitor MG132 in PC3 cells. The genes with more than threefold increased expression induced by MG132 were functionally categorized into the following groups: heat shock and chaperone proteins, ubiquitination and protein degradation, transcription/translation factors, cell death and cell cycle arrest, signaling molecules and enzymes, and secreted cytokines. Among them, heat shock proteins and anti-oxidant enzymes may promote cell survival, while pro-death proteins such as GADD45B and STK17a may promote cell death. Interestingly, expression of a few autophagic genes was elevated by MG132 treatment. Furthermore, autophagy inhibitor 3-methyladenine partially inhibited MG132-induced cell death, indicating that autophagic cell death may contribute to MG132-induced cell death. Taken together, our results demonstrated that proteasome inhibition elicits activation of multiple signaling pathways in prostate cancer cells.

Amino Acid Chloromethyl Ketones↗
PubMed2006

Self-perceived loss of control and untreated dental decay in African American adults with and without sickle cell disease.

The aim of this cross-sectional study was to investigate the association between self-perceived loss of control as measured by dental external locus of control summary scores, with the amount of untreated dental decay in African American adults with sickle cell disease (SCD) and African Americans adults without SCD. The sample included 102 subjects with SCD and 103 subjects without SCD matched on age, sex, and recruitment location (mean age of all subjects 35.4 years, 55.6% female). Subjects with SCD in the highest quartile for dental external locus of control summary scores had 2.58-fold (CI 1.05, 6.34) as much untreated decay as those in the lowest quartile (p<.05) in multivariable analysis using the negative binomial regression model. For subjects without SCD, those in the highest quartile for dental external locus of control summary scores had 3.00-fold (CI 1.38, 6.49) as much untreated decay as those in the lowest quartile (p<.05) using similar analysis. This study showed that higher dental external locus of control is associated with increased untreated tooth decay, both for African Americans with and without SCD and that the magnitude of the association did not differ across groups.

Adolescent↗
PubMed2006

Association between elevated depressive symptoms and clinical disease severity in African-American adults with sickle cell disease.

OBJECTIVE: The purpose of this cross-sectional study was to examine the association between elevated depressive symptoms and the clinical severity of sickle cell disease (SCD) using African-American adults with and without SCD. STUDY DESIGN: The population consisted of 102 African-American adults with SCD, diagnosed using hemoglobin electrophoresis, individually matched on age (+/-5 years), gender and recruitment location to 103 African-American adults without SCD (mean age of all subjects was 35.4 years, 55.6% female). Logistic regression was used to examine the association between SCD clinical severity and elevated depressive symptoms in bivariate and multivariable analyses. RESULTS: The prevalence of elevated depressive symptoms as measured using the 10-item Center for Epidemiological Studies Depression Scale (CES-D) was 38.6% in those with SCD, compared to 27.5% in those without SCD; however, this difference was not statistically significant (p>0.05). Compared to African Americans without SCD, African Americans with SCD were less educated, had lower incomes, and were more likely to be unemployed or disabled (p<0.01). The odds of having elevated depressive symptoms were 1.78 (CI: 0.94, 3.38) for those with high clinical SCD severity compared to those without SCD in bivariate analysis and 1.37 (CI: 0.62, 3.02) in multivariable analysis after adjusting for socioeconomic factors. CONCLUSIONS: The reported relationship between elevated depressive symptoms and SCD may be a result of the adverse economic conditions associated with SCD.

Adolescent↗
PubMed2006

Clinical evaluation of an all-ceramic restorative system: 24-month report.

PURPOSE: To clinically evaluate an all-ceramic restorative system (Finesse All-Ceramic) when used in conjunction with an ultra-low fusing porcelain (Finesse) using bonded esthetic resin cements (Enforce & Calibra). METHODS: 40 posterior and anterior crowns, 20 all-ceramic inlays and onlays, and 26 veneers were placed in 43 patients. Standard ceramic preparations were performed followed by conventional polyvinylsiloxane (Aquasil) impression techniques using cord retraction. The bonded resin cement was used to place the restorations following manufacturer's instructions. A majority of restorations (95-100%) were evaluated to be optimal at baseline (B), 6, 12, and 24 months using a modified Ryge criteria for the following categories: color match, marginal adaptation, porcelain staining, secondary caries, postoperative sensitivity, and retention. RESULTS: There were sufficient shades available to obtain desired esthetic result with 98% of all restorations being rated Alfa for shade match to Vita Lumin shade guide. The overall 2-year success rate (inlay/onlays, crowns, and veneers) was 98.75%.

Dental Marginal Adaptation↗
PubMed2005

The two major subspecies of Fusobacterium necrophorum have distinct leukotoxin operon promoter regions.

Fusobacterium necrophorum, a gram-negative, non-spore-forming anaerobe, is a normal inhabitant of the alimentary tract of animals and humans. Two types of F. necrophorum, subspecies necrophorum (biotype A) and funduliforme (biotype B), have been recognized, which differ morphologically, biochemically and biologically. The organism is an opportunistic pathogen that causes numerous necrotic conditions (necrobacillosis) such as bovine hepatic abscesses and ruminant foot abscesses. Subspecies necrophorum strains are considered to be more virulent for cattle and have been shown to produce greater amounts of leukotoxin than subspecies funduliforme strains. The leukotoxin operon of F. necrophorum consists of three genes (lktBAC) of which the leukotoxin structural gene (lktA) is the second gene in the operon. In this study, the promoter regions of the leukotoxin operons from the two subspecies were identified and their nucleotide sequence compared. The promoter regions were found to differ in sequence, in length of the sequence between the upstream determinant (oppF) and the first gene of the leukotoxin operon (lktB), and in promoter strength as assayed in Escherichia coli host cells.

Animals↗
PubMed2005

Microarray analysis of postictal transcriptional regulation of neuropeptides.

Unlike adults, kainic acid (KA)-induced status epilepticus (SE) in immature rats causes neither cell death nor recurrent spontaneous seizures. To elucidate the mechanisms of these distinct responses, transcriptional changes in neuropeptides were examined following KA-induced SE. We aimed to determine whether neuropeptides with anticonvulsant/neuroprotective properties were preferentially increased in immature rats while those with a proconvulsant/neurotoxic role were elevated to a greater extent in mature rats. We used high-density oligonucleotide gene arrays and directly compared transcriptional regulation of seven select neuropeptides at P15 and P30 over five time points. Total RNAs were isolated from hippocampi of 12 animals and pooled to hybridize to triplicate Affymetrix Genechips. Microarray results were validated by real-time quantitative RT-PCR (qRT-PCR). Independent individual RNA samples were purified for triplicate runs of qRT-PCR. Neuropeptides are significantly regulated by seizures in both immature and mature hippocampus. The magnitude of increase is significantly higher at P30 compared with that at P15, not only for neuropeptides with neurotoxic/proconvulsant properties but also for those with neuroprotective/ anticonvulsant properties. Galanin is induced at 24 h only in P30 rats. CST shows high expression in immature hippocampus and is further increased after KA-induced SE only in P15. The expression trends seen in the microarray data are confirmed by qRT-PCR for all six neuropeptides analyzed. CST might play a neuroprotective role in immature rats, and its overexpression might prevent neuronal loss after seizure in adults. Also, suppression of tachykinin and corticotropin-releasing hormone might be effective in alleviating seizure-induced neuronal damage.

Animals↗
PubMed2004

Efficacy and safety evaluation of human reovirus type 3 in immunocompetent animals: racine and nonhuman primates.

PURPOSE: Human reovirus type 3 has been proposed to kill cancer cells with an activated Ras signaling pathway. The purpose of this study was to investigate the efficacy of reovirus in immunocompetent glioma animal models and safety/toxicity in immunocompetent animals, including nonhuman primates. EXPERIMENTAL DESIGN: Racine glioma cells 9L and RG2 were implanted s.c. or intracranially in Fisher 344 rats with or without reovirus antibodies, followed by treatment of reovirus. To study whether reovirus kills contralateral tumors in the brain and to determine viral distribution, we established an in situ dual tumor model followed by reovirus intratumoral inoculation only into the ipsilateral tumor. To evaluate neurotoxicity/safety of reovirus, Cynomolgus monkeys and immunocompetent rats were given intracranially with reovirus, and pathological examination and/or behavioral studies were done. Viral shedding and clinical biochemistry were systematically studied in monkeys. RESULTS: Intratumorally given reovirus significantly suppressed the growth of both s.c. and intracranially tumors and significantly prolonged survival. The presence of reovirus-neutralizing antibodies did not abort the reovirus' antitumor effect. Reovirus inhibited glioma growth intracranially in the ipsilateral but not the contralateral tumors; viral load in ipsilateral tumors was 15 to 330-fold higher than the contralateral tumors. No encephalitis or behavioral abnormalities were found in monkeys and rats given reovirus intracranially. No treatment-related clinical biochemistry changes or diffuse histopathological abnormality were found in monkeys inoculated intracranially with Good Manufacturing Practice prepared reovirus. Microscopic changes were confined to the region of viral inoculation and were dose related, suggesting reovirus intracranially was well tolerated in nonhuman primates. CONCLUSIONS: These data show the efficacy and safety of reovirus when it is used in the treatment of gliomas in immunocompetent hosts. Inoculation of reovirus into the brain of nonhuman primates did not produce significant toxicities.

Animals↗
PubMed2004

The PSI Gantry 2: a second generation proton scanning gantry.

PSI is still the only location in which proton therapy is applied using a dynamic beam scanning technique on a very compact gantry. Recently, this system is also being used for the application of intensity-modulated proton therapy (IMPT). This novel technical development and the success of the proton therapy project altogether have led PSI in Year 2000 to further expand the activities in this field by launching the project PROSCAN. The first step is the installation of a dedicated commercial superconducting cyclotron of a novel type. The second step is the development of a new gantry, Gantry 2. For Gantry 2 we have chosen an iso-centric compact gantry layout. The diameter of the gantry is limited to 7.5 m, less than in other gantry systems (approximately 10-12 m). The space in the treatment room is comfortably large, and the access on a fixed floor is possible any time around the patient table. Through the availability of a faster scanning system, it will be possible to treat the target volume repeatedly in the same session. For this purpose, the dynamic control of the beam intensity at the ion source and the dynamic variation of the beam energy will be used directly for the shaping of the dose.

Cyclotrons↗
PubMed2003

Gene expression profiling reveals a highly specialized genetic program of plasma cells.

The formation of terminally differentiated plasma cells represents the critical final step in B-cell differentiation. In this study, utilizing oligonucleotide microarray analysis, we describe the highly specialized genetic profile exhibited by terminally differentiated plasma cells. A total of 1476 known genes were differentially expressed by plasma cells compared with B cells. Plasma cells displayed an up-regulation, induction, or a selective retention of a unique constellation of transcription factors, including members of the AP-1, nuclear factor-kappaB (NF-kappaB), nuclear factor of activated T cells (NFAT), and octamer binding factor families. Interestingly, plasma cells also displayed a down-regulation of several RNA polymerase I- related factors, consistent with terminal differentiation, and exhibited a down-regulation of the TATA box binding protein. Furthermore, plasma cells displayed alterations in multiple components of the Wnt and Notch signaling pathways and showed a unique pattern of apoptosis and proliferation-associated genes. Unexpectedly, plasma cells displayed an up-regulation of 2 factors normally associated with microenvironmental positioning of neuronal cells, reelin and neuropilin-1. These results supply insight into the developmental genetics of plasma cell differentiation and provide a foundation for further analysis of plasma cell biology.

Animals↗
PubMed2002

Interaction of the extracellular domain of the epidermal growth factor receptor with gangliosides.

Ganglioside GM3 inhibits epidermal growth factor (EGF)-dependent cell proliferation in a variety of cell lines. Both in vitro and in vivo, this glycosphingolipid inhibits the kinase activity of the EGF receptor (EGFR). Furthermore, membrane preparations containing EGFR can bind to GM3-coated surfaces. These data suggest that GM3 may interact directly with the EGFR. In this study, the interaction of gangliosides with the extracellular domain (ECD) of the EGFR was investigated. The purified human recombinant ECD from insect cells bound directly to ganglioside GM3. The ganglioside interaction site appears to be distinct from the EGF-binding site. In agreement with previous reports on the effects of specific gangliosides on EGFR kinase activity, the ECD preferentially interacted with GM3. The order of relative binding of other gangliosides investigated was as follows: GM3 GM2, GD3, GM4 > GM1, GD1a, GD1b, GT1b, GD2, GQ1b > lactosylceramide. These data suggest that NeuAc-lactose is essential for binding and that any sugar substitution reduces binding. In agreement with the specificity of soluble ECD binding to gangliosides, GM3 specifically inhibited EGFR autophosphorylation. Identification of a ganglioside interaction site on the ECD of the EGFR is consistent with the hypothesis that endogenous GM3 may function as a direct modulator of EGFR activity.

Animals↗
PubMed2002

Immunophenotypic differences between uveal and cutaneous melanomas.

OBJECTIVE: To determine the immunophenotypic differences between uveal and cutaneous melanomas, employing standard melanoma markers as well as p75 neurotrophin receptor (p75NTR) and microphthalmia transcription factor (MITF). DESIGN: Fifteen uveal melanomas (5 spindle, 5 epithelioid, and 5 mixed uveal subtypes) were immunolabeled with a panel of antibodies that included S100, tyrosinase, melan-A, HMB-45 and HMB-50 combination, MITF, and p75NTR. The results were tabulated on the basis of intensity and pervasiveness of the labeling and compared with a prior study on cutaneous spindle and epithelioid melanomas. RESULTS: In contrast to its strong labeling of cutaneous melanomas, S100 immunolabeling of uveal melanomas was weak and variable. p75NTR, known to differentiate spindle from epithelioid melanomas of the skin, did not immunolabel uveal melanomas. HMB-45, HMB-50, tyrosinase, melan-A, and MITF immunolabeled all uveal melanomas strongly, irrespective of the histologic subtype, but not cutaneous melanomas. Microphthalmia transcription factor was especially clear in its labeling of uveal melanomas. CONCLUSIONS: Although cutaneous and uveal melanomas share many molecular markers in common, there are differences between the 2 types of melanoma. First, the level of expression of S100 differs between cutaneous and uveal melanomas. Second, while cutaneous melanomas can be further subdivided into spindle and epithelioid types based on their immunophenotype, the uveal melanomas cannot.

Antigens, Neoplasm↗
PubMed2002

Clinical-pathological study of levodopa complications.

We sought to determine the continued benefit and the pattern of motor complications of long-term levodopa treatment in Parkinson's disease. Patients were evaluated between 1968 and 1996. Only those who had an adequate levodopa trial and in whom autopsy revealed Lewy body Parkinson's disease were included. Total levodopa and mean daily dose were calculated in each case. Dyskinesia, wearing-off and on-off were collectively classified as motor adverse effects and reported as cumulative incidence. Forty-two patients (male, 30; female, 12) with mean 15.9 years of illness and 9.1 years follow-up received on average 500-mg levodopa daily over 9.8 years. Seventeen of 21 patients assessed during the last 18 months of life reported some motor benefit. Adverse effects were seen in 71.4% of patients. The most common was dyskinesia, in 61.9%; wearing-off in 35.7%; and on-off in 16.7% of patients. The earliest adverse effect was dyskinesia and the last to emerge was on-off. Isolated dyskinesia was seen in 35.7% and wearing-off in 7.1% of patients; 15.5% of patients developed dyskinesia after 2.6 years and 31% after 6.4 years on levodopa. We concluded that levodopa benefit declined and adverse effects increased with time. Dyskinesia was the earliest and the most common isolated adverse effect.

Aged↗
PubMed2002

Progressive supranuclear palsy diagnosis and confounding features: report on 16 autopsied cases.

We evaluated 16 (15 men, 1 woman) autopsy-verified progressive supranuclear palsy (PSP) cases during 31 years (1969-2000) for clinical diagnosis and the course of the disease. The onset was gait difficulty or postural instability in 9 (56.3%), general motor slowing in 3 (18.8%), and tremor in 2. One case had onset with cognitive decline and 1 as hemidystonia. Four cases had supranuclear ophthalmoplegia (SNO) at the first assessment and were diagnosed as PSP. By last assessment, PSP diagnosis was made in 4 additional cases, but in 8 (50%) who never manifested ophthalmoplegia (mean 9.8 years after onset), PSP diagnosis was not made. Other manifestations included bulbar symptoms in 13 (81.3%), and cognitive impairment in 10 (62.5%) during the course of illness. Fifteen cases received levodopa, amantadine, anticholinergics, dopamine agonists, and selegiline in different combinations with symptomatic benefit in 9 of 15 (60%). Five had some improvement on levodopa alone and 3 showed more improvement when a dopamine agonist was added to levodopa. In general, the benefit was minimal and occurred only early in the course of illness. The mean age at onset was 63.7 (range, 53-85) years. Mean duration at PSP diagnosis was 4.8 (range, 2-11) years. Mean survival was 8.6 (range, 3-24) years and mean age at death was 72.3 (range, 60-89) years. When the different diagnostic criteria recommended in the literature were used, the accuracy of clinical diagnosis did not improve substantially.

Aged↗
PubMed2002

Engraftment assessment in human and mouse liver tissue after sex-mismatched liver cell transplantation by real-time quantitative PCR for Y chromosome sequences.

Transplanted hepatocytes can engraft, proliferate, and function permanently in host animals. After one cell infusion, however, engrafted hepatocytes constitute only between 1 in 200 to 1 in 3,000 host liver cells. Although transplanted cells can be identified using biochemical and molecular techniques, more accurate methods are needed to evaluate interventions that could improve cell engraftment rates. Real-time polymerase chain reaction (PCR) was done using primers and probes complementary to human testis determining gene (SRY) and mouse testis-specific Y-encoded protein (TSPY) pseudogene. Tissue samples from human or mouse recipients of liver cell transplantation were used to determine the test ability to detect transplanted cell DNA. Real-time PCR for the human SRY and mouse TSPY were species- and sex-specific. These two tests were sensitive in the detection of male DNA. Test sensitivity was consistently found at minimum 1:10,000 of male and female DNA mixing curve in both human SRY and mouse TSPY assays. The optimal amount of sample DNA per reaction to produce the highest sensitivity was 300 ng to 1 microg. Real-time PCR gave similar results whether standard male-female mixtures were prepared from liver cells or mononuclear cells. Engraftment of male liver cells in female liver tissues in mice and humans ranging from 0.125% to 0.257% was successfully measured using this method. Real-time PCR for SRY and TSPY affords a specific, sensitive, and reproducible tool for chimerism analysis in transplanted human and mouse liver tissues. This method could be used to optimize current models of cell transplantation.

Animals↗
PubMed2002

Clinical evaluation of a 15% in-office hydrogen peroxide tooth-whitening touch-up agent.

The success of tooth whitening has increased public demand for quicker results of the tooth-whitening process. More and more patients are opting for in-office treatments, if available, to expedite the process, and they are looking for ways to re-whiten quickly when they feel their teeth have reverted from their after-treatment results. This article will discuss the use of a commercially available product as a touch-up procedure for patients who had been previously treated with a 2-week carbamide peroxide whitening regimen.

Adolescent↗
PubMedDate not supplied

The association between sickle cell disease and dental caries in African Americans.

This study sought to determine whether there was an association between sickle cell disease (SCD) and dental caries in African-American adults. A sample of 102 African-American adult patients with SCD from Washington, D.C., and Baltimore, Maryland, were matched to 103 African-American adult subjects, who did not have SCD. The match was by age, gender and recruitment location. Each subject underwent a standardized oral examination as well as an interview to ascertain risk factors for dental caries. For individuals with incomes of less than dollars 15,000, subjects with SCD had more decayed (10.36 versus 1.58) and fewer filled (2.86 versus 8.45) surfaces compared to subjects without SCD with both differences being statistically significant (p<0.05) after adjusting for age and gender. The results suggest that low-income African Americans with SCD may be at increased risk for dental caries and are less likely to receive treatment with a restoration.

Adult↗