Biomedical subjects

G Yang

Publications and source records attributed to G Yang.

At least 19 recordsLinked to original sources

PubMed2006

Cooperative effects of adenoviral vector-mediated interleukin 12 gene therapy with radiotherapy in a preclinical model of metastatic prostate cancer.

We investigated the potential benefits of combining adenoviral vector mediated in situ interleukin-12 (AdmIL-12) gene therapy with radiation therapy (XRT) to enhance therapeutic efficacy. In a metastatic mouse prostate cancer cell line, 178-2 BMA, AdmIL-12+XRT demonstrated enhanced therapeutic activities in vitro as determined by clonogenic survival, apoptosis, and mIL-12 levels. At the molecular level, increased expression of tumor necrosis factor-alpha mRNA was specific for the combined therapy. In a subcutaneous 178-2 BMA in vivo model, the combination of AdmIL-12+XRT produced statistically significant tumor growth suppression compared to control vector Adbetagal, Adbetagal XRT, or AdmIL-12 as monotherapy. In addition, significant prolongation of survival was demonstrated for the combination of AdmIL-12+XRT. The combination of AdmIL-12+XRT significantly suppressed both spontaneous and pre-established lung metastases, and led to a prolonged elevation of serum IL-12 and significantly increased natural killer (NK) activities. Importantly, in vivo depletion of NK cells resulted in significant attenuation of the antimetastatic activities of AdmIL-12 alone or AdmIL-12+XRT. These combined effects suggest that AdIL-12 gene therapy together with radiotherapy may achieve maximal tumor control (both local and systemic) in selected prostate cancer patients via radio-gene therapy induced local cytotoxicity and local and systemic antitumor immunity.

Adenoviridae↗

PubMed2006

Body weight and weight change in relation to blood pressure in normotensive men.

We examined blood pressure (BP) in association with weight change since age 20, body mass index (BMI) at different ages and fat distribution in normotensive individuals using baseline survey data collected in the Shanghai Men's Health Study, an ongoing population-based prospective cohort study of Chinese men aged 40-74 years. All anthropometric and BP measurements were performed by medical professionals. Included in this analysis were 25 619 men who had no prior history of hypertension, diabetes or cardiovascular disease, never took any antihypertensive medication and had both normal systolic BP (SBP) and diastolic BP (DBP) (<140/90 mm Hg). Both SBP and DBP increased linearly across the whole range of weight gain since age 20. The adjusted mean differences between the highest and the lowest quintiles of weight gain were 6.0 mm Hg (95% confidence interval (CI): 5.6, 6.5) for SBP and 3.9 (95% CI: 3.6, 4.2) for DBP. When accounting for BMI at age 20, the multivariate-adjusted odds ratio of prehypertension (SBP, 120-139 and/or DBP, 80-89 mm Hg) was 4.1 (95% CI: 3.7, 4.5; P for trend <0.0001) comparing the extreme quintiles of weight gain. Similar positive associations were also observed for BMI at age 40, current BMI, circumferences of the waist and hips and waist-to-hip ratio. In conclusion, these data suggest that weight gain since age 20 and elevated adiposity may contribute significantly to the rise in BP in normotensive individuals, emphasizing the importance of weight control throughout adulthood in preventing high BP.

Adult↗

PubMed2006

Disruption of the retinoblastoma pathway by small interfering RNA and ectopic expression of the catalytic subunit of telomerase lead to immortalization of human ovarian surface epithelial cells.

The risk of developing ovarian cancer is about 1% over a lifetime, but it is the most deadly gynecologic cancer, in part due to lack of diagnostic markers for early-stage disease and cell model system for studying early neoplastic changes. Most existing immortal human ovarian surface epithelial cells were achieved by using viral protein such as SV40 T/t antigen or E6/E7, which inactivate multiple cellular pathways. In the current study, we used a small interfering RNA (siRNA) against the retinoblastoma gene (pRb) and ectopic expression of human telomerase reverse transcriptase (hTERT) to immortalize the primary ovarian epithelial cell line OSE137 and two additional human ovarian surface epithelial cells. The immortalized OSE137 showed increased telomerase activity, lengthened telomeres, increased G2/M phase, altered cell-cycle regulatory proteins but nontumorigenic. As both Rb and hTERT pathways are commonly altered in human ovarian cancer and these genetic changes are faithfully modeled in these cells without using viral protein, these immortal cells represent an authentic in vitro model system with which to study the initiation and progression of human ovarian cancer.

Base Sequence↗

PubMed2006

IFITM1 plays an essential role in the antiproliferative action of interferon-gamma.

Interferon-gamma (IFN-gamma) is a pleiotropic cytokine involved in antiproliferative and anti-virus responses, immune surveillance and tumor suppression. These biological responses to IFN-gamma are mainly mediated by the regulation of gene expression. It has been reported that growth-inhibitory role of IFN-gamma is dependent on activation of signal transducers and activators of transcription 1 (STAT1); however, the molecular basis downstream of STAT1 remains unclear. Here, we report that an IFN-gamma-induced gene, interferon-induced transmembrane protein 1 (IFITM1), plays a key role in the antiproliferative action of IFN-gamma. Overexpression of IFITM1 negatively regulated cell growth, whereas suppression of IFITM1 blocked the antiproliferative effect of IFN-gamma, accelerated the cell growth rate and conferred tumorigenicity to a non-malignant hepatocyte in nude mice. Further, IFITM1 could inhibit the activity of extracellular signal-regulated kinase, enhance the transcriptional activity of p53 and stabilize the p53 protein by inhibiting p53 phosphorylation on Thr55. Suppression of p53 reduced the growth-inhibitory capacity of both IFITM1 and IFN-gamma. Therefore, these findings indicated that the antiproliferative action of IFN-gamma requires the induction of IFITM1, and provided a crosstalk between two well-known signaling mediators, STAT1 and p53, both of which play critical roles in tumor suppression.

Adult↗

PubMed2006

Nature of signals that initiate the immune response during Wallerian degeneration of peripheral nerves.

Monocyte chemoattractant protein-1 is produced by Schwann cells during Wallerian degeneration of a peripheral nerve and contributes to a selective accumulation of macrophages in the degenerating segment. An in vitro preparation has been developed to analyze the molecules from axons and non-neuronal cells in nerves that stimulate an increased production of monocyte chemoattractant protein-1 mRNA by Schwann cells. For this purpose, Schwann cells obtained from neonatal rats were maintained in culture, exposed to putative molecular stimuli and analyzed for their content of monocyte chemoattractant protein-1 mRNA. Under basal conditions, the concentration of monocyte chemoattractant protein-1 in Schwann cells was low. Freeze-killed fragments or homogenates of nerve (or brain) but not viable nerve or freeze-killed muscle were effective in inducing monocyte chemoattractant protein-1 mRNA. The inductive activity was abolished by heating. Results of dialysis of supernatants of nerve homogenates indicate that a protein or proteins of 1-10 kDa were capable of stimulating synthesis of monocyte chemoattractant protein-1 by Schwann cells. Also, the activity in nerve homogenates was partially inhibited by antibodies to Toll-like receptor-4. The observations suggest that a non-secreted protein is released from disintegrating axons to initiate the innate immune response that characterizes Wallerian degeneration.

Animals↗

PubMed2006

Histone deacetylase inhibitors induce the degradation of the t(8;21) fusion oncoprotein.

The t(8;21) chromosomal translocation that generates the fusion oncoprotein RUNX1-ETO predominates in leukemia patients of the French-American-British (FAB) class M2 subtype. The oncoprotein has the capacity to promote expansion of hematopoietic stem/progenitor cells and induces leukemia in association with other genetic alterations. Here, we show that RUNX1-ETO undergoes degradation in response to treatment with histone deacetylase inhibitors, one of which, depsipeptide (DEP), is currently undergoing phase II clinical testing in a variety of malignancies. These compounds induce turnover of RUNX1-ETO without affecting the stability of RUNX1-ETO partner proteins. In addition, RUNX1-ETO physically interacts with heat shock protein 90 (HSP90). DEP treatment interrupts the association of RUNX1-ETO with HSP90 and induces proteasomal degradation of RUNX1-ETO. DEP and the HSP90 antagonist 17-allylamino-geldanamycin (17-AAG) both triggered RUNX1-ETO degradation, but without any additive or cooperative effects. These findings may stimulate the development of more rational and effective approaches for treating t(8;21) patients using histone deacetylase inhibitors or HSP90 inhibitors.

Cell Line, Tumor↗

PubMed2006

HER2 signaling modulates the equilibrium between pro- and antiangiogenic factors via distinct pathways: implications for HER2-targeted antibody therapy.

We determined the impact of HER2 signaling on two proangiogenic factors, vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8), and on an antiangiogenic factor, thrombospondin-1 (TSP-1). Re-expression of HER2 in MCF-7 and T-47D breast cancer cells that endogenously express low levels of HER2 resulted in elevated expression of VEGF and IL-8 and decreased expression of TSP-1. Inhibition of HER2 with a humanized anti-HER2 antibody (trastuzumab, or Herceptin) or a retrovirus-mediated small interfering RNA against HER2 (siHER2) decreased VEGF and IL-8 expression, but increased TSP-1 expression in BT474 breast cancer cells that express high levels of HER2. These in vitro results were further evaluated by treatment of BT474 xenografts in immunosuppressed mice with trastuzumab. Trastuzumab inhibited growth of BT474 xenografts and decreased microvascular density associated with downregulation of VEGF and IL-8 and with upregulation of TSP-1 expression. Inhibiting the PI3K-AKT pathway decreased VEGF and IL-8 expression. AKT1 overexpession increased VEGF and IL-8 expression, but did not increase TSP-1 expression. A p38 kinase inhibitor, SB203580, instead blocked TSP-1 expression and a p38 activator, MKK6, increased TSP-1 expression. Trastuzumab stimulated sustained p38 activation and SB203580 attenuated the TSP-1 upregulation induced by trastuzumab. HER2 signaling therefore influences the equilibrium between pro- and antiangiogenic factors via distinct signaling pathways. Trastuzumab inhibits angiogenesis and tumor growth, at least in part, through activation of the HER2-p38-TSP-1 pathway and inhibition of the HER2-PI3K-AKT-VEGF/IL-8 pathway.

Animals↗

PubMed2006

Adenoviral vector-mediated RTVP-1 gene-modified tumor cell-based vaccine suppresses the development of experimental prostate cancer.

We previously identified a novel p53 target gene, RTVP-1, that possesses unique cytotoxic and immunostimulatory activities which make it potentially useful for cancer gene therapy. To test the therapeutic potential of RTVP-1 in a gene-modified tumor cell-based vaccine model, we used an adenoviral vector capable of efficient transduction and expression of RTVP-1 (AdRTVP-1), together with a highly metastatic mouse prostate cancer cell line (178-2 BMA). A vaccine was prepared with 178-2 BMA cells transduced with AdRTVP-1 or a control adenoviral vector expressing beta-galactosidase (Adbetagal). After irradiation of the cells, syngeneic 129/Sv mice were vaccinated three times at weekly intervals. After 3 weeks, they were challenged with orthotopic 178-2 BMA cells. After 21 days, fewer than 60% of the RTVP-1-cell-vaccinated mice developed tumors compared to 100% of the control mice. The RTVP-1-cell vaccine significantly reduced primary tumor wet weight compared with control Adbetagal-cell vaccine (P<0.0001 at 7 and 14 days). Experimental metastasis to lung was also significantly reduced (P=0.0377), and survival significantly increased (P=0.0002). In addition, significantly increased NK and CTL activities were demonstrated in the AdRTVP-1-cell-vaccinated mice. These findings indicate that RTVP-1 gene-modified cell-based vaccines may be useful in the prevention of recurrent prostate cancer.

Adenoviridae↗

PubMed2006

Use of body mass index to identify obesity-related metabolic disorders in the Chinese population.

OBJECTIVE: To identify the body mass index (BMI; in kg/m2) cutoff that predicts the risk for obesity-related metabolic disorders for the Chinese population. DESIGN: Community-based cross-sectional survey. SETTING: Rural regions of Jiangxi and Anhui provinces and an urban community of Jing'an District of Shanghai, China. SUBJECTS: Five hundred and twenty-nine non-pregnant, non-lactating urban and rural adults, aged 20-64 years without diagnosed diabetes. RESULTS: Subjects were divided into two groups: with or without obesity-related metabolic disorders, which was defined as having at least one of the following: hypertension, insulin resistance, high plasma triacylglycerol, low-density lipoprotein-cholesterol or glucose. Gender-specific multiple logistic regression analysis demonstrated a significant dose-response relationship between BMI and obesity-related metabolic disorders, after adjusting for potential confounders. The lowest BMI interval associated with significant risk for both men and women (odds ratios of 2.67 and 3.46, respectively) was that of 22.5-24.4. Receiver-operating characteristic (ROC) curve analysis indicated that a BMI cutoff of 23 had the best combination of sensitivity and specificity and the shortest distance in the ROC curve, with positive and negative predictive values of 0.6-0.7 in both genders. CONCLUSIONS: A BMI cutoff of 23 might be appropriate for use in identification of high risk of obesity-related metabolic disorders and serve as a public health action threshold in the Chinese population. SPONSORSHIP: Center of a Livable Future, John Hopkins Bloomberg School of Public Health.

Adult↗

PubMed2006

Cerium and boron chemistry in doped borosilicate glasses examined by EELS.

Spatially resolved measurements of boron coordination and cerium valency in a doped borosilicate glass with crystalline nano-precipitates are described. The fine structure of the boron K-edge and the white-line ratio of the cerium M-edge doublet were evaluated from EELS line scans. Due to high beam sensitivity it was found that reliable boron-coordination measurements in some of the glasses studied required extrapolation of results acquired after different periods of irradiation back to a zero-irradiation. However, borosilicates that contained heavy alkali atoms were found to suffer very little structural change. The Ce valency of a 4% (molar) doped alkali-borosilicate glass was found to be mixed +III/+IV in the glass matrix and purely +IV (indicative of CeO2) in the precipitates. A significant dependency of the valence results on the data processing method was found and explained.

Journal Article↗

PubMed2006

Retrovirus molecular conjugates: a versatile and efficient gene transfer vector system for primitive human hematopoietic progenitor cells.

In principle, transient nongenetic modification of a noninfectious gene transfer virus enabling a one time infection and transduction of human cells could eliminate the risk of formation of replication competent virus. Formation of a molecular conjugate vector by conjugation of noninfective ecotropic murine Moloney leukemia virus to polylysine (eMMLV-PL) enabled high-efficiency transduction of human HPC using in vitro and in vivo assays. Xenotransplanted NOD-SCID mice durably expressed the transgene in human leukocytes and human progenitor cells with eMMLV-PL achieving three-fold increased transduction efficiency when directly compared to optimized amphotropic MMLV (aMMLV) transduction. Both aMMLV and eMMLV assembled conjugate vectors showed similar transduction efficiency indicating predominant polylysine-mediated uptake. Integration of retroviral sequences was determined from individual human HPC recovered from eMMLV-PL-xenotransplanted animals. This simple and versatile concept of conjugate gene transfer vectors has the potential to enhance transduction efficiency as well as to improve certain safety aspects of human gene therapy. Moreover, because it permits effective cellular internalization of particles, this concept of molecular conjugates can be used as research tool to investigate the interactions of otherwise noninfectious viruses or modified viral particles at the genomic level.

Animals↗

PubMed2006

Changes and relations of circulating visfatin, apelin, and resistin levels in normal, impaired glucose tolerance, and type 2 diabetic subjects.

Visfatin and apelin are two novel adipocyte- secreted hormone proposed to link obesity with insulin resistance. In this study we investigated whether plasma visfatin and apelin levels were altered in normal, impaired glucose tolerance, and type 2 diabetic subjects. We also assessed the association between plasma visfatin, or apelin and body composition, metabolic parameters, and resistin concentrations in these subjects. The visfatin levels of fasting and 2-h post-glucose load were found to be significantly decreased in diabetics compared with the controls ( P<0.05). In contrast, basal apelin levels were significantly increased in the IGT and diabetic subjects compared with the controls ( P<0.05 and P<0.01). The apelin levels of 2-h post-glucose load were significantly higher than the basal levels in every group (all P<0.05). Fasting plasma visfatin was found to correlate positively and significantly with BMI, WHR, and fasting plasma resistin, but negatively with HbA1c and 2 h OGTT glucose. Multiple regression analysis showed that WHR, HbA1c, 2 h OGTT glucose were independent related factors influencing plasma visfatin levels. Fasting plasma apelin levels correlated positively with HOMA-IR, BMI, TC, LDL-C, FBG and Fasting plasma insulin. Multiple regression analysis also showed that HOMA-IR, BMI, and TC were independent related factors influencing plasma apelin levels. The present work indicates the potential link of visfatin and apelin with the pathogenesis of insulin resistance and T2DM.

Adult↗

PubMed2006

Salicylate- and quinine-induced tinnitus and effects of memantine.

CONCLUSION: Memantine, an antiglutamatergic drug, has been proposed as a treatment for tinnitus. OBJECTIVES: The purpose of this study was to determine if memantine would prevent salicylate-induced tinnitus. Local field potentials were also recorded from auditory cortex to determine what effect salicylate, memantine, and the combination of both drugs would have on evoked potential amplitudes. MATERIALS AND METHODS: Schedule induced polydipsia-avoidance conditioning was used to identify the doses of salicylate or quinine that reliably induced tinnitus in rats. Rats were trained to lick for water during quiet intervals and avoid licking during sound intervals. RESULTS: Rats injected with saline or a low dose of sodium salicylate or quinine failed to develop tinnitus-like behaviors. However, high doses of salicylate (150-300 mg/kg/day) or quinine (100-150 mg/kg/day) greatly reduced licks-in-quiet, behavior consistent with the presence of tinnitus. Licks-in-quiet increased slightly when memantine (1.5 or 3 mg/kg/day) was co-administered with salicylate; however, the effect was not statistically significant or dose-dependent. These results indicate that memantine does not completely suppress salicylate-induced tinnitus. Cortical auditory evoked potential amplitude increased after salicylate treatment; co-administration of memantine failed to block this salicylate-induced increase.

Analgesics, Non-Narcotic↗

PubMed2006

HLA-A, -B, and -DRB1 polymorphism defined by sequence-based typing of the Han population in Northern China.

DNA typing for human leukocyte antigen (HLA)-A, -B and -DRB1 was performed using polymerase chain reaction-sequence-based typing method on 618 randomly selected healthy individuals of the Han population in Northern China. Allele frequencies and haplotypes were statistically analyzed. A total of 84 HLA-A alleles, 143 B alleles, and 122 DRB1 alleles were detected, and 853 A-B-DRB1 haplotypes, 473 A-B haplotypes, and 551 B-DRB1 haplotypes were statistically inferred. Statistical analysis of three-locus haplotypes showed that A*0207-B*4601-DRB1*0901 (3.06%) was the most predominant. Gene frequencies and haplotypic associations within HLA-A, -B, and -DRB1 loci were determined at a high-resolution (four digit) allelic level and should provide useful information in anthropology, bone marrow donor registry, legal medicine, and disease association studies.

Alleles↗

PubMed2006

Photorhabdus virulence cassettes confer injectable insecticidal activity against the wax moth.

Two recently sequenced genomes of the insect-pathogenic bacterium Photorhabdus and a large Serratia entomophila plasmid, pADAP, have phage-related loci containing putative toxin effector genes, designated the "Photorhabdus virulence cassettes" (PVCs). In S. entomophila, the single plasmid PVC confers antifeeding activity on larvae of a beetle. Here, we show that recombinant Escherichia coli expressing PVC-containing cosmids from Photorhabdus has injectable insecticidal activity against larvae of the wax moth. Electron microscopy showed that the structure of the PVC products is similar to the structure of the antibacterial R-type pyocins. However, unlike these bacteriocins, the PVC products of Photorhabdus have no demonstrable antibacterial activity. Instead, injection of Photorhabdus PVC products destroys insect hemocytes, which undergo dramatic actin cytoskeleton condensation. Comparison of the genomic organizations of several PVCs showed that they have a conserved phage-like structure with a variable number of putative anti-insect effectors encoded at one end. Expression of these putative effectors directly inside cultured cells showed that they are capable of rearranging the actin cytoskeleton. Together, these data show that the PVCs are functional homologs of the S. entomophila antifeeding genes and encode physical structures that resemble bacteriocins. This raises the interesting hypothesis that the PVC products are bacteriocin-like but that they have been modified to attack eukaryotic host cells.

Animals↗

PubMed2006

Building capacity for tobacco control research and policy.

The Fogarty International Center (FIC) initiative, "International Tobacco and Health Research Capacity Building Program" represents an important step in US government funding for global tobacco control. Low- and middle-income countries of the world face a rising threat to public health from the rapidly escalating epidemic of tobacco use. Many are now parties to the Framework Convention on Tobacco Control (FCTC) and capacity development to meet FCTC provisions. One initial grant provided through the FIC was to the Institute for Global Tobacco Control (IGTC) at the Johns Hopkins Bloomberg School of Public Health (JHSPH) to support capacity building and research programmes in China, Brazil, and Mexico. The initiative's capacity building effort focused on: (1) building the evidence base for tobacco control, (2) expanding the infrastructure of each country to deliver tobacco control, and (3) developing the next generation of leaders as well as encouraging networking throughout the country and with neighbouring countries. This paper describes the approach taken and the research foci, as well some of the main outcomes and some identified challenges posed by the effort. Individual research papers are in progress to provide more in-depth reporting of study results.

Brazil↗

PubMed2005

Spine loading as a function of lift frequency, exposure duration, and work experience.

BACKGROUND: Physiological and psychophysical studies of the effects of lifting frequency have focused on whole-body measurements of fatigue or subjective acceptance of the task and have not considered how spine loads may change as a function of lift frequency or lift time exposure. Our understanding of biomechanical spine loading has been extrapolated from short lifting bouts to the entire work day and may have led us to incorrect assumptions. The objective of this project was to document how spine loading changes as a function of experience, lift frequency, and lift duration while repetitively lifting over the course of an 8-h workday. METHODS: Twelve novice and twelve experienced manual materials handlers performed repetitive, asymmetric lifts at different load and lift frequency levels throughout an 8-h exposure period. Compression, anterior-posterior shear, and lateral shear were evaluated over the lifting period using an EMG-assisted biomechanical model. RESULTS: Spinal loads increased after the first 2 h of lifting exposure regardless of the lift frequency. Loading was also greater for the inexperienced subjects compared to experienced lifters. The greatest spine loads occurred at those lift frequencies and weights to which the workers were unaccustomed. INTERPRETATION: Increases in spine loading were tracked back to the changes in muscle recruitment patterns that typically involved increased muscle coactivation. The results emphasize the importance of previous motor programming in defining spine loads during repetitive lifting. These results indicate a very different influence of frequency and lift time exposure compared to physiologic and psychophysical assessments. This study has shown that it is not sufficient to extrapolate from short lift periods to extended exposure periods if the biomechanical loading implications of the task are of interest.

Adult↗

PubMed2005

High diversity of the chicken growth hormone gene and effects on growth and carcass traits.

The chicken growth hormone (cGH) gene plays a crucial role in controlling growth and metabolism, leading to potential correlations between cGH polymorphisms and economic traits. In this study, DNA from four divergent chicken breeds were screened for single nucleotide polymorphisms (SNPs) in the cGH gene using denaturing high-performance liquid chromatography and sequencing. A total of 46 SNPs were identified, of which 4 were in the 5' untranslated region, 1 in the 3' untranslated region, 5 in exons (two of which are nonsynonymous), with the remaining 36 in introns. The nucleotide diversity in the cGH gene ( theta = 2.7 x 10(-3)) was higher than that reported for other chicken genes, even within the same breeds. The associations of five of these SNPs and their haplotypes with chicken growth and carcass traits were determined using polymerase chain reaction-restriction fragment length polymorphism analysis in a F2 resource population cross of two of the four chicken breeds (White Recessive Rock and Xinghua). This analysis shows that, among other correlations, G+1705A was significantly associated with body weight at all ages measured, shank length at three of four ages measured, and average daily gain within weeks 0 to 4. Thus, this cGH polymorphism, or another polymorphism that is in linkage disequilibrium with G+1705A, appears to correspond to a significant growth-related quantitative trait locus difference between the two breeds used to construct the resource population.

Animals↗