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Biomedical subjects

R Xu

Publications and source records attributed to R Xu.

At least 19 recordsLinked to original sources
PubMed2007

6q deletion in Waldenström macroglobulinemia is associated with features of adverse prognosis.

Fluorescence in situ hybridisation (FISH) is an effective technique for the cytogenetic analysis of Waldenström macroglobulinemia (WM), but the potential impact of molecular cytogenetics on disease evolution and as a prognostic marker is still unknown. Deletion of the long arm of chromosome 6 (6q-) is the most frequent cytogenetic abnormality in WM. This study analysed the prevalence of this aberration in 102 WM patients, and correlated it with disease characteristics. The incidence of 6q21 deletion was 7% by conventional cytogenetics and 34% when analysed by FISH (54% when cytoplasmic immunoglobulin M-FISH was used). Patients with deletion of 6q displayed features of adverse prognosis, such as higher levels of beta2-microglobulin and monoclonal paraprotein and a greater tendency to display anaemia and hypoalbuminemia. Interestingly, there was a correlation between the presence of 6q deletion and the International Staging System prognostic index (incidence of 6q- among patients stratified in stages 1, 2 and 3 was 24%, 42% and 67% respectively). Those patients diagnosed with smouldering WM who displayed the abnormality showed a trend to an earlier requirement of treatment. Finally, the survival analysis did not show differences between the two groups of patients, probably due to the short follow up of our series.

Adult↗
PubMed2006

A correlative study of NF-kappaB activity and cytokines expression in human chronic nasal sinusitis.

A growing body of literature suggests that cytokines play an important part in the pathogenesis of chronic nasal sinusitis. However, the mechanism by which the expression of cytokines in chronic nasal sinusitis is upregulated has not been well documented. The present study investigated the role of nuclear factor-kappa B (NF-kappaB) activation in upregulating the expression of interleukin-5, -6 and -8 (IL-5, IL-6 and IL-8). We titrated the levels of IL-5, IL-6 and IL-8 in nasal mucosa in 52 cases of chronic nasal sinusitis and 12 normal subjects using enzyme-linked immunosorbent assay. According to whether allergic rhinitis was associated or not, we subdivided the patients into the AR group (with allergic rhinitis) and the NAR group (without allergic rhinitis). Semi-quantitative reverse transcription-polymerase chain reaction and immunohistochemical staining were used to evaluate expression and activation of NF-kappaB P50 and P65 subunits in nasal mucosa. The correlation between activities of P50 and P65 and cytokines expression was analysed. Our results showed that IL-5, IL-6 and IL-8 in both the AR and NAR groups were strikingly elevated in comparison with the control group (all p < 0.01 for AR group; p < 0.05, 0.05, 0.01, respectively, for NAR group); and they were even higher in the AR group than those in the NAR group (p < 0.01, 0.05, 0.01, respectively). P50 and P65 mRNA levels in both AR and NAR groups were markedly greater than those in the control group (all p < 0.01); and the AR group had further higher levels as compared with the NAR group (both p < 0.05). Immunohistochemical study revealed that nucleus-positive rates of P50 and P65 in both AR and NAR groups were significantly higher than those of the control group (all p < 0.01), and they were much greater in the AR group in comparison with the NAR group (all p < 0.01). Pearson correlation analysis demonstrated that P50 and P65 nucleus-positive rates were closely correlated with IL-6 and IL-8 levels, but not IL-5, with a correlation coefficient of 0.49 for P50 and IL-6, 0.54 for P50 and IL-8, 0.61 for P65 and IL-6, and 0.66 for P65 and IL-8 (all p < 0.01). In conclusion, upregulated expression and activation of NF-kappaB P50 and P65 might be one of the mechanisms for induction of IL-6 and IL-8 expression in chronic nasal sinusitis. Association of allergic rhinitis with chronic nasal sinusitis further enhanced NF-kappaB activity, and subsequently lead to even stronger expression of IL-6 and IL-8. IL-5 expression appeared to be independent of NF-kappaB pathway in chronic nasal sinusitis.

Adult↗
PubMed2006

High-frequency promoter hypermethylation of the deleted in liver cancer-1 gene in multiple myeloma.

BACKGROUND: Deleted in liver cancer-1 (DLC-1) is a tumour suppressor gene that is inactive in liver carcinogenesis. It encodes a rho-guanosine triphosphatase-activating protein (rho-GAP) and maps to one of the deleted regions (8p21.3-22). Little is known, however, about the methylation status of the DLC-1 promoter in myeloma cells. AIM: To identify whether methylation of DLC-1 was associated in pathogenesis of multiple myeloma. METHODS: Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect DLC-1 transcripts in RPMI 8226, U266, OPM-2 and XG-2 cell lines. The methylation status was determined by methylation-specific PCR followed by bisulphite DNA sequencing in these four cell lines and in the bone marrow of 14 patients with multiple myeloma and 4 normal patients. DLC-1 mRNA expression in cells with or without treatment with 5-aza-deoxycytidine (5-aza-CdR) or trichostatin A (TSA) was investigated by real-time RT-PCR. RESULTS: RPMI 8226 and U266 showed complete methylation and XG-2 showed partial methylation. DLC-1 was expressed only in OPM-2 cell lines that showed no methylation. DLC-1 methylation was shown in 11 of 14 (78%) patients with multiple myeloma and none of the normal controls. The exposure of cell lines to 5-aza-CdR or TSA resulted in the up regulation of DLC-1 gene expression. CONCLUSIONS: DLC-1 methylation is often present in multiple myeloma and has a key role in DLC-1 silencing.

Azacitidine↗
PubMed2006

Persistent organic pollutants in moss as bioindicators of atmospheric pollution in Singapore.

Moss samples were collected from the island of Singapore and analysed for a range of organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs). Although all compounds analysed have been banned from use in Singapore, they were detected in all samples collected. Among the hexachlorocyclohexanes (HCH), beta-HCH was the most dominant isomer, while trans-chlorane was found to be the most dominant cyclodiene pesticide. High levels (79.12 ng g(-1)) of PCBs were detected in mosses collected from a nearby island due to active accumulation of pollutants associated with boat emissions. Significant spatial variations in the levels of organic pollutants in Singapore were largely absent, indicating that air masses moving over the island deposit OCPs and PCBs in a uniform pattern. A comparison of moss pollutant levels with available data from Czech Republic showed that dichlorodiphenyldichloroethylene (p,p'-DDE), dichlorodiphenyltrichloroethane (p,p'-DDT) and PCB levels in Singapore are the highest. The presence of these compounds suggests that they are still used in the region and are environmentally recalcitrant.

Air Pollutants↗
PubMed2006

Overexpression of von Hippel-Lindau tumor suppressor protein and antisense HIF-1alpha eradicates gliomas.

The von Hippel-Lindau tumor suppressor protein (pVHL) suppresses tumor formation by binding the alpha subunits of hypoxia-inducible-factors responsible for stimulating tumor angiogenesis and glycolysis, and targeting them for ubiquitination and proteasomal destruction. Loss of pVHL leads to tumorigenesis and development of sporadic renal cell carcinomas and central nervous system hemangioblastomas. In the present study, we investigated whether engineered overexpression of pVHL in C6 glioma cells, which already express endogenous pVHL, would suppress the tumorigenicity of this particular tumor cell type. C6 cells overexpressing VHL displayed a reduced growth rate (70% inhibition) compared to the parental cell line when subcutaneously implanted in athymic (nu/nu) mice. Growth inhibition was associated with a 50% reduction in the number of tumor vessels and a 60% increase in tumor cell apoptosis, due in part to downregulation of HIF-1, VEGF, and the antiapoptotic factor Bcl-2, respectively. Gene transfer of VHL suppressed the growth of established C6 gliomas, and synergized with antisense HIF-1 to completely eradicate tumors. The data suggest that VHL gene therapy and/or agents that increase VHL expression could have utility in the treatment of gliomas, particularly when combined with agents that inhibit the expression or function of HIF-1.

Animals↗
PubMed2006

Characterization of a novel DRB1*14 allele (DRB1*1449) in the Han-Chinese population.

We report here a novel human leukocyte antigen (HLA) allele, DRB1*1449, in the Han-Chinese population. The nature of the new allele was confirmed by the sequencing-based typing (SBT) method. Genomic DNA and six subclones containing DNA fragment of DRB1 exon 2 were sequenced in both forward and reverse directions. The exon 2 nucleotide sequence of DRB1*1449 is closely related to DRB1*1432 allele based on sequence homology. It has four nucleotide (nt) substitutions at positions 71, 196, 244 and 245 in exon 2, which lead to changes of amino acid sequences. The serological assignment of DRB1*1449 is DR14 based on the serological HLA typing result. This novel allele might be a result of recombination between DRB1*1402 and DRB1*140101 like alleles, which are very common among Chinese population.

Alleles↗
PubMed2006

Recent advances in the treatment of colon cancer.

Colorectal cancer is one of the leading causes of cancer-related deaths worldwide. Although surgical resection is still the only treatment capable of curing colon cancer, adjuvant therapy continues to play an important role in preventing recurrence and metastasis. In recent years remarkable progress has been made in the treatment of colon cancer. This review discusses recent advances in adjuvant therapy for colon cancer, including chemotherapy, immunotherapy, antiangiogenic therapy and apoptosis induction. In the meantime, molecular therapy is also elucidated in the above methods. All these new advances will provide new promises for patients of colon cancer.

Colonic Neoplasms↗
PubMed2005

Binding of sodium dodecyl sulfate and hexaethylene glycol mono-n-dodecyl ether to the block copolymer L64: electromotive force, microcalorimetry, surface tension, and small angle neutron scattering investigations of mixed micelles and polymer/micellar surfactant complexes.

The interactions of sodium dodecyl sulfate (SDS) with the triblock copolymer L64 (EO13-PO30-EO13) and hexaethylene glycol mono-n-dodecyl ether (C12EO6) were studied using electromotive force, isothermal titration microcalorimetry, differential scanning microcalorimetry, and surface tension measurements. In certain regions of binding, mixed micelles are formed, and here we could evaluate an interaction parameter using regular solution theory. The mixed micelles of L64 with both SDS and C12EO6 exhibit synergy. When L64 is present in its nonassociated state, it forms polymer/micellar SDS complexes at SDS concentrations above the critical aggregation concentration (cac). The cac is well below the critical micellar concentration (cmc) of pure SDS, and a model suggesting how bound micelles are formed at the cac in the presence of a polymer is described. The interaction of nonassociated L64 with C12EO6 is a very rare example of strong binding between a nonionic surfactant and a nonionic polymer, and C12EO6/L64 mixed micelles are formed. We also carried out small angle neutron scattering measurement to determine the structure of the monomeric polymer/micellar SDS complex, as well as the mixed L64/C12EO6 aggregates. In these experiments, contrast matching was achieved by using the h and d forms of SDS, as well as C12EO6. During the early stages of the formation of polymer-bound SDS micelles, SDS aggregates with aggregation numbers of approximately 20 were found and such complexes contain 4-6 bound L64 monomers. The L64/C12EO6 data confirmed the existence of mixed micelles, and structural information involving the composition of the mixed micelle and the aggregation numbers were evaluated.

Journal Article↗
PubMed2005

TRAIL-induced apoptosis in gliomas is enhanced by Akt-inhibition and is independent of JNK activation.

Patients with malignant gliomas have a poor prognosis and new treatment paradigms are needed against this disease. TRAIL/Apo2L selectively induces apoptosis in malignant cells sparing normal cells and is hence of interest as a potential therapeutic agent against gliomas. To determine the factors that modulate sensitivity to TRAIL, we examined the differences in TRAIL-activated signaling pathways in glioma cells with variable sensitivities to the agent. Apoptosis in response to TRAIL was unrelated to DR5 expression or endogenous p53 status in a panel of 8 glioma cell lines. TRAIL activated the extrinsic (cleavage of caspase-8, caspase-3 and PARP) and mitochondrial apoptotic pathways and reduced FLIP levels. It also induced caspase-dependent JNK activation, which did not influence TRAIL-induced apoptosis. Because the pro-survival PI3K/Akt pathway is highly relevant to gliomas, we assessed whether Akt could protect against TRAIL-induced apoptosis. Pretreatment with SH-6, a novel Akt inhibitor, enhanced TRAIL-induced apoptosis, suggesting a protective role for Akt. Conversely, TRAIL induced caspase-dependent cleavage of Akt neutralizing its anti-apoptotic effects. These results demonstrate that TRAIL-induced apoptosis in gliomas involves both activation of death pathways and downregulation of survival pathways. Additional studies are warranted to determine the therapeutic potential of TRAIL against gliomas.

Apoptosis↗
PubMed2005

Skewed T-cell receptor BV14 and BV16 expression and shared CDR3 sequence and common sequence motifs in synovial T cells of rheumatoid arthritis.

T-lymphocytes play an important role in rheumatoid arthritis (RA). In this study, we evaluated the hypothesis that common T-cell receptor (TCR) structural features may exist among infiltrating T cells of different RA patients, if the TCR repertoire is shaped by interaction with common self or microbial antigens in the context of susceptible HLA genes in RA. Synovial lesion tissue (ST), synovial fluid (SF) and blood specimens from RA patients and controls were analyzed for TCR V gene repertoire by real-time PCR. There was highly skewed BV14 and BV16 usage in synovial T cells of RA as opposed to those of controls, which was accompanied with a trend for correlation between skewed BV16 and DRB1(*)0405. Immunoscope analysis of the V-D-J region of ST-derived T cells demonstrated oligoclonal and polyclonal expansion of BV14(+) and BV16(+) T cells. Detailed characterization using specific BV and BJ primers further revealed common clonotypes combining the same BV14/BV16, BJ and CDR3 length. DNA cloning and sequence analysis of the clonotypes confirmed identical CDR3 sequences and common CDR3 sequence motifs among different RA patients. The findings are important in the understanding of BV gene skewing and CDR3 structural characteristics among synovial infiltrating T cells of RA.

Arthritis, Rheumatoid↗
PubMed2005

Increased production of reactive oxygen species contributes to motor neuron death in a compression mouse model of spinal cord injury.

STUDY DESIGN: Experimental laboratory investigation of the role and pathways of reactive oxygen species (ROS)-mediated motor neuron cell death in a mouse model of compression spinal cord injury. OBJECTIVES: To analyze ROS-mediated oxidative stress propagation and signal transduction leading to motor neuron apoptosis induced by compression spinal cord injury. SETTING: University of Louisville Health Science Center. METHODS: Adult C57BL/6J mice and transgenic mice overexpressing SOD1 were severely lesioned at the lumbar region by compression spinal cord injury approach. Fluorescent oxidation, oxidative response gene expression and oxidative stress damage markers were used to assay spinal cord injury-mediated ROS generation and oxidative stress propagation. Biochemical and immunohistochemical analyses were applied to define the ROS-mediated motor neuron apoptosis resulted from compression spinal cord injury. RESULTS: ROS production was shown to be elevated in the lesioned spinal cord as detected by fluorescent oxidation assays. The early oxidative stress response markers, NF-kappaB transcriptional activation and c-Fos gene expression, were significantly increased after spinal cord injury. Lipid peroxidation and nucleic acid oxidation were also elevated in the lesioned spinal cord and motor neurons. Cytochrome c release, caspase-3 activation and apoptotic cell death were increased in the spinal cord motor neuron cells after spinal cord injury. On the other hand, transgenic mice overexpressing SOD1 showed lower levels of steady-state ROS production and reduction of motor neuron apoptosis compared to that of control mice after spinal cord injury. CONCLUSION: These data together provide direct evidence to demonstrate that the increased production of ROS is an early and likely causal event that contributes to the spinal cord motor neuron death following spinal cord injury. Thus, antioxidants/antioxidant enzyme intervention combined with other therapy may provide an effective approach to alleviate spinal cord injury-induced motor neuron damage and motor dysfunction.

Animals↗
PubMed2005

Segmentation of intestinal gland images with iterative region growing.

A region growing algorithm for segmentation of human intestinal gland images is presented. The initial seeding regions are identified based on the large vacant regions (lumen) inside the intestinal glands by fitting with a very large moving window. The seeding regions are then expanded by repetitive application of a morphological dilate operation with a much smaller round window structure set. False gland regions (nongland regions initially misclassified as gland regions) are removed based on either their excessive ages of active growth or inadequate thickness of dams formed by the strings of goblet cell nuclei sitting immediately outside the grown regions. The goblet cell nuclei are then identified and retained in the image. The gland contours are detected by applying a large moving round window fitting to the enormous empty exterior of the goblet cell nucleus chains in the image. The assumptions based on real intestinal gland images include the closed chain structured goblet cell nuclei that sit side-by-side with only small gaps between the neighbouring nuclei and that the lumens enclosed by the goblet cell nucleus chains are most vacant with only occasional run-away nuclei. The method performs well for most normal and abnormal intestinal gland images although it is less applicable to cancer cases. The experimental results show that the segmentations of the real microscopic intestinal gland images are satisfactorily accurate based on the visual evaluations.

Adenocarcinoma↗
PubMed2005

A novel HLA allele, DRB1*1609, identified in the Chinese Han population*.

A novel human leucocyte antigen-DRB1*16 (HLA-DRB1*16) allele (DRB1*1609) has been identified by sequencing-based typing (SBT) in Chinese Han population. This new allele has identical nucleotide sequence to DRB1*160101 in exon 2, except for a single-nucleotide substitution from A to T at position 127. This change leads to an amino acid change from tyrosine to phenylalanin at residue 47 (Y47F). SBT was performed for cloned DRB1*16-specific polymerase chain reaction fragment. The serological phenotype of DRB1*1609 is equivalent to DR16 antigen.

Alleles↗
PubMed2004

Increased oxidative stress is associated with chronic intermittent hypoxia-mediated brain cortical neuronal cell apoptosis in a mouse model of sleep apnea.

Chronic intermittent hypoxia (CIH), as occurs in obstructive sleep apnea (SA), is associated with substantial cortico-hippocampal damage leading to impairments of neurocognitive, respiratory and cardiovascular functions. Previous studies in a rat model have shown that CIH increases brain cortical neuronal cell death. However, the molecular events leading to CIH-mediated neuronal cell death remain largely undefined. The oscillation of O2 concentrations during CIH remarkably mimics the processes of ischemia/re-oxygenation and could therefore increase cellular production of reactive oxygen species (ROS). We extended the CIH paradigm to a mouse model of SA to identify the molecular mechanisms underlying cortical neuronal cell death. A significant increase of ROS production in mouse brain cortex and cortical neuronal cells was detected by fluorescent oxidation assays upon exposure of mice to CIH, followed by increased expression of oxidative stress response markers, c-Fos, c-Jun and NF-kappaB in mouse brain cortex, as revealed by immunohistochemical and LacZ reporter assays respectively. Long-term exposure of mice to CIH increased the levels of protein oxidation, lipid peroxidation and nucleic acid oxidation in mouse brain cortex. Furthermore, exposure of mice to CIH induced caspase-3 activation and increased some cortical neuronal cell apoptosis. On the other hand, transgenic mice overexpressing Cu,Zn-superoxide dismutase exposed to CIH conditions had a lower level of steady-state ROS production and reduced neuronal apoptosis in brain cortex compared with that of normal control mice. Taken together, these findings suggest that the increased ROS production and oxidative stress propagation contribute, at least partially, to CIH-mediated cortical neuronal apoptosis and neurocognitive dysfunction.

Animals↗
PubMed2003

Gene therapy for new bone formation using adeno-associated viral bone morphogenetic protein-2 vectors.

Previous reports have suggested that bone morphogenetic protein (BMP) gene therapy could be applied for in vivo bone regeneration. However, these studies were conducted either using immunodeficient animals because of immunogenicity of adenovirus vectors, or using ex vivo gene transfer technique, which is much more difficult to handle. Adeno-associated virus (AAV) is a replication-defective virus without any association with immunogenicity and human disease. This study was conducted to investigate whether orthotopic new bone formation could be induced by in vivo gene therapy using AAV-based BMP2 vectors. To test the feasibility of this approach, we constructed an AAV vector carrying human BMP2 gene. Mouse myoblast cells (C2C12) transduced with this vector could produce and secrete biologically active BMP2 protein and induce osteogenic activity, which was confirmed by ELISA and alkaline phosphatase activity assay. For in vivo study, AAV-BMP2 vectors were directly injected into the hindlimb muscle of immunocompetent Sprague-Dawley rats. Significant new bone under X-ray films could be detected as early as 3 weeks postinjection. The ossification tissue was further examined by histological and immunohistochemical analysis. This study is, to our knowledge, the first to establish the feasibility of AAV-based BMP2 gene therapy for endochondral ossification in immunocompetent animals.

Animals↗
PubMed2002

Dopamine D2L receptor knockout mice display deficits in positive and negative reinforcing properties of morphine and in avoidance learning.

The dopamine D2 receptor (D2) is implicated in drug addiction, learning and memory. Two isoforms of the D2 receptor, termed D2L (long form) and D2S (short form), have been identified. We previously generated mice lacking D2L (D2L-/-), but expressing functional D2S. In this study, we investigated the role of D2L in the positive and negative reinforcing properties of abused drugs and electrical stimuli, using D2L-/- mice as a model system. Mice were trained in three associative learning tasks: conditioned place preference to morphine and cocaine, conditioned place aversion to naloxone-precipitated morphine withdrawal, and active avoidance. D2L-/- mice, like wild type mice, developed a place preference to cocaine. In contrast to wild type mice, D2L-/- mice did not develop a place preference to morphine, nor did they attain a place aversion to morphine withdrawal. D2L-/- mice also failed to acquire avoidance behavior in response to electrical stimuli. There were no significant differences between D2L-/- and wild type mice in mu-opioid receptor density, morphine-induced locomotor stimulation and morphine withdrawal symptoms. These results suggest that D2L may have a greater impact than D2S on the rewarding aspects of morphine, and the aversive properties of morphine withdrawal and electrical stimulus. These findings also suggest that the presence of D2L is critical in the acquisition (learning) and/or retention (memory) of context-stimulus associations in certain situations. On the other hand, D2L is not essential for the rewarding aspects of cocaine and for the development of morphine dependence. Thus, these studies reveal distinct functional roles of D2L and/or D2S in drug addiction and avoidance learning, which may lead to a better understanding of the neurobiological basis underlying these behaviors.

Animals↗