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Articles by J Wu
Total Records ( 15 ) for J Wu
  X Gong , W Ye , H Zhou , X Ren , Z Li , W Zhou , J Wu , Y Gong , Q Ouyang , X Zhao and X. Zhang

Acetylcholinesterase (AChE) expression may be induced during apoptosis in various cell types. Here, we used the C-terminal of AChE to screen the human fetal brain library and found that it interacted with Ran-binding protein in the microtubule-organizing center (RanBPM). This interaction was further confirmed by coimmunoprecipitation analysis. In HEK293T cells, RanBPM and AChE were heterogeneously expressed in the cisplatin-untreated cytoplasmic extracts and in the cisplatin-treated cytoplasmic or nuclear extracts. Our previous studies performed using morphologic methods have shown that AChE translocates from the cytoplasm to the nucleus during apoptosis. Taken together, these results suggest that RanBPM is an AChE-interacting protein that is translocated from the cytoplasm into the nucleus during apoptosis, similar to the translocation observed in case of AChE.

  K Kroenke , X Zhong , D Theobald , J Wu , W Tu and J. S. Carpenter

Background  The adverse impact of a high somatic symptom burden is well established for primary care and other noncancer populations with chronic medical disorders.

Methods  This study examines the impact of somatic symptom burden on disability and health care use in patients with cancer experiencing pain, depression, or both. We performed secondary analyses of baseline data from 405 patients with cancer enrolled in a telecare management trial for pain or depression. Somatic symptom burden was measured using a 22-item scale. Multivariable models were conducted to determine the association of somatic symptom burden with the Sheehan Disability Scale (SDS) score, the number of self-reported disability days in the past 3 months, and health care use. Models were adjusted for sociodemographic characteristics, medical comorbidity, and depression and pain severity.

Results  Somatic symptoms were highly prevalent, with 15 of the 22 symptoms reported by more than 50% of patients. The somatic symptom burden was similar across different types and phases of cancer. The mean SDS score (scored 0-10 [not at all disabled to unable to carry out any activities]) was 5.4, and the mean number of self-reported disability days in the past 4 weeks was 16.9. In multivariable models, somatic symptom burden was associated with SDS score (P < .001) and the likelihood of at least 14 disability days in the past 4 weeks (odds ratio, 1.51; 95% confidence interval, 1.19-1.92) but not with increased health care use.

Conclusions  The somatic symptom burden is high in patients with cancer who experience pain or depression. Given the strong association with disability and the high prevalence of many types of symptoms, recognizing and managing somatic symptoms may be important in improving quality of life and functional status regardless of type or phase of cancer.

Trial Registration Identifier: NCT00313573

  J Wu , F Nazemi , J Schofield , G Mirabella and A. M. F. Wong

Objective  To compare the effectiveness of patching plus telescopic magnification vs patching alone in treating refractory amblyopia.

Methods  Children aged 4 to 17 years who failed previous amblyopia treatment were recruited into this prospective study. Subjects were randomly assigned to either 30 minutes per day of patching of the fellow eye only (n = 7) or 30 minutes per day of patching of the fellow eye plus concurrent use of a telescope in the amblyopic eye (n = 8).

Main Outcome Measure  Best-corrected logMAR visual acuity score of the amblyopic eye after 17 weeks of treatment.

Results  Both treatment groups demonstrated significant improvement in visual acuity in the amblyopic eye after 17 weeks (P = .001). Improvements in the patching-only group were slightly greater over the course of treatment, but this difference was not statistically significant (P = .06). At 17 weeks, mean visual acuity improvement from baseline was 0.14 logMAR (SD, 0.13 logMAR) in the patching-only group and 0.06 logMAR (SD, 0.17 logMAR) in the patching plus telescope group (P = .11). The 17-week visual acuity was at least 0.2 logMAR and/or improved from baseline by at least 0.2 logMAR in 2 patients in the patching-only group and none in the patching plus telescope group (P = .08).

Conclusion  Treatment of refractory amblyopia in children using telescopic magnification did not appear to confer any additional benefits over patching alone.

Application to Clinical Practice  Occlusion and penalization remain the standard of care for patients with amblyopia and should remain the benchmark against which other treatments are compared in clinical trials for amblyopia therapy.

Trial Registration Identifier: NCT00970554

  C Taslim , J Wu , P Yan , G Singer , J Parvin , T Huang , S Lin and K. Huang

Motivation: Antibody-based Chromatin Immunoprecipitation assay followed by high-throughput sequencing technology (ChIP-seq) is a relatively new method to study the binding patterns of specific protein molecules over the entire genome. ChIP-seq technology allows scientist to get more comprehensive results in shorter time. Here, we present a non-linear normalization algorithm and a mixture modeling method for comparing ChIP-seq data from multiple samples and characterizing genes based on their RNA polymerase II (Pol II) binding patterns.

Results: We apply a two-step non-linear normalization method based on locally weighted regression (LOESS) approach to compare ChIP-seq data across multiple samples and model the difference using an Exponential-NormalK mixture model. Fitted model is used to identify genes associated with differential binding sites based on local false discovery rate (fdr). These genes are then standardized and hierarchically clustered to characterize their Pol II binding patterns. As a case study, we apply the analysis procedure comparing normal breast cancer (MCF7) to tamoxifen-resistant (OHT) cell line. We find enriched regions that are associated with cancer (P < 0.0001). Our findings also imply that there may be a dysregulation of cell cycle and gene expression control pathways in the tamoxifen-resistant cells. These results show that the non-linear normalization method can be used to analyze ChIP-seq data across multiple samples.

  A. M. M Frankemolle , J Wu , A. M Noecker , C Voelcker Rehage , J. C Ho , J. L Vitek , C. C McIntyre and J. L. Alberts

Deep brain stimulation in the subthalamic nucleus is an effective and safe surgical procedure that has been shown to reduce the motor dysfunction of patients with advanced Parkinson’s disease. Bilateral subthalamic nucleus deep brain stimulation, however, has been associated with declines in cognitive and cognitive–motor functioning. It has been hypothesized that spread of current to nonmotor areas of the subthalamic nucleus may be responsible for declines in cognitive and cognitive–motor functioning. The aim of this study was to assess the cognitive–motor performance in advanced Parkinson’s disease patients with subthalamic nucleus deep brain stimulation parameters determined clinically (Clinical) to settings derived from a patient-specific computational model (Model). Data were collected from 10 patients with advanced Parkinson’s disease bilaterally implanted with subthalamic nucleus deep brain stimulation systems. These patients were assessed off medication and under three deep brain stimulation conditions: Off, Clinical or Model based stimulation. Clinical stimulation parameters had been determined based on clinical evaluations and were stable for at least 6 months prior to study participation. Model-based parameters were selected to minimize the spread of current to nonmotor portions of the subthalamic nucleus using Cicerone Deep Brain Stimulation software. For each stimulation condition, participants performed a working memory (n-back task) and motor task (force tracking) under single- and dual-task settings. During the dual-task, participants performed the n-back and force-tracking tasks simultaneously. Clinical and Model parameters were equally effective in improving the Unified Parkinson’s disease Rating Scale III scores relative to Off deep brain stimulation scores. Single-task working memory declines, in the 2-back condition, were significantly less under Model compared with Clinical deep brain stimulation settings. Under dual-task conditions, force tracking was significantly better with Model compared with Clinical deep brain stimulation. In addition to better overall cognitive–motor performance associated with Model parameters, the amount of power consumed was on average less than half that used with the Clinical settings. These results indicate that the cognitive and cognitive–motor declines associated with bilateral subthalamic nucleus deep brain stimulation may be reversed, without compromising motor benefits, by using model-based stimulation parameters that minimize current spread into nonmotor regions of the subthalamic nucleus.

  T Holopainen , H Huang , C Chen , K. E Kim , L Zhang , F Zhou , W Han , C Li , J Yu , J Wu , G. Y Koh , K Alitalo and Y. He

The angiopoietin-1 (Ang1)/Tie2 signaling pathway is known to play an important role in the regulation of vascular maturation and maintenance of vessel integrity. In this study, we have investigated the effect of systemic Tie2 activation or inhibition on tumor growth and metastasis. We found that treatment with Ang1 delivered via an adenoviral vector promoted s.c. implanted tumor metastasis to the lungs. Ang1 treatment did not significantly increase vascular density in the tumors but induced enlargement of blood vessels in both the tumor and normal tissues, which increased tumor cell dissemination into the blood circulation. Ang1 also enhanced the formation of metastatic foci in the lungs when tumor cells were injected into the circulation via the tail vein. The effect of Ang1 on metastasis was validated by a simultaneous treatment with a soluble form of Tie2 (sTie2), which led to the suppression of Ang1-induced increase of tumor metastasis. Furthermore, using a highly metastatic tumor model, we confirmed that systemic treatment with sTie2 suppressed tumor metastasis to the lungs and lymph nodes, whereas tumor-associated angiogenesis and lymphangiogenesis were not significantly affected. This suggests that the Ang1/Tie2 signals contribute to tumor progression by increasing vascular entry and exit of tumor cells to facilitate tumor dissemination and establishment of metastases. [Cancer Res 2009;69(11):4656–64]

  Z Fu , M Wang , M Gucek , J Zhang , J Wu , L Jiang , R. E Monticone , B Khazan , R Telljohann , J Mattison , S Sheng , R. N Cole , G Spinetti , G Pintus , L Liu , F. D Kolodgie , R Virmani , H Spurgeon , D. K Ingram , A. D Everett , E. G Lakatta and J. E. Van Eyk

Advancing age induces aortic wall thickening that results from the concerted effects of numerous signaling proteins, many of which have yet to be identified. To search for novel proteins associated with aortic wall thickening, we have performed a comprehensive quantitative proteomic study to analyze aortic proteins from young (8 months) and old (30 months) rats and identified 50 proteins that significantly change in abundance with aging. One novel protein, the milk fat globule protein epidermal growth factor 8 (MFG-E8), increases 2.3-fold in abundance in old aorta. Transcription and translation analysis demonstrated that aortic MFG-E8 mRNA and protein levels increase with aging in several mammalian species including humans. Dual immunolabeling shows that MFG-E8 colocalizes with both angiotensin II and monocyte chemoattractant protein (MCP)-1 within vascular smooth muscle cells (VSMCs) of the thickened aged aortic wall. Exposure of early passage VSMCs from young aorta to angiotensin II markedly increases MFG-E8 and enhances invasive capacity to levels observed in VSMCs from old rats. Treatment of VSMCs with MFG-E8 increases MCP-1 expression and VSMCs invasion that are inhibited by the MCP-1 receptor blocker vCCI. Silencing MFG-E8 RNA substantially reduces MFG-E8 expression and VSMCs invasion capacity. The data indicate that arterial MFG-E8 significantly increases with aging and is a pivotal relay element within the angiotensin II/MCP-1/VSMC invasion signaling cascade. Thus, targeting of MFG-E8 within this signaling axis pathway is a potential novel therapy for the prevention and treatment of the age-associated vascular diseases such as atherosclerosis.

  S Chandar , L. S Yeo , C Leimena , J. C Tan , X. H Xiao , V Nikolova Krstevski , Y Yasuoka , M Gardiner Garden , J Wu , S Kesteven , L Karlsdotter , S Natarajan , A Carlton , S Rainer , M. P Feneley and D. Fatkin

Rationale: Mutations in the LMNA gene, which encodes the nuclear lamina proteins lamin A and lamin C, are the most common cause of familial dilated cardiomyopathy (DCM). Mechanical stress-induced apoptosis has been proposed as the mechanism underpinning DCM in lamin A/C–deficient hearts, but supporting in vivo evidence has been lacking.

Objective: Our aim was to study interventions to modify mechanical stress in heterozygous Lmna knockout (Lmna+/–) mice.

Methods and Results: Cardiac structure and function were evaluated before and after exercise training, thoracic aortic constriction, and carvedilol treatment. Lmna+/– mice develop adult-onset DCM with relatively more severe disease in males. Lmna+/– cardiomyocytes show altered nuclear morphology and perinuclear desmin organization, with enhanced responses to hypo-osmotic stress indicative of cytoskeletal instability. Despite these structural defects that provide a template for mechanical stress-induced damage, young Lmna+/– mice subjected to 6 weeks of moderate or strenuous exercise training did not show induction of apoptosis or accelerated DCM. In contrast, regular moderate exercise attenuated DCM development in male Lmna+/– mice. Sustained pressure overload generated by thoracic aortic constriction depressed ventricular contraction in young wild-type and Lmna+/– mice with no sex or genotype differences in the time-course or severity of response. Treatment of male Lmna+/– mice from 12 to 40 weeks with the β-blocker, carvedilol, prevented the dilatation and contractile dysfunction that was observed in placebo-treated mice.

Conclusions: These data suggest that factors other than mechanical stress-induced apoptosis contribute to DCM and provide the first demonstration that regular moderate exercise and carvedilol can modify disease progression in lamin A/C–deficient hearts.

  J Wu and S. Furber

A multicast routing infrastructure is proposed as a core feature of SpiNNaker, a massively parallel computer for the real-time simulation of large-scale spiking neural networks. The infrastructure is implemented using a communications router, based on an event-driven routing scheme, on each multicore processing node in the system. The design considerations emphasize the difference between the requirements of neural network communications and those of conventional computer networks and on-chip networks. The focus of the design is on neural modelling flexibility, power-efficiency, fault-tolerance and the communication throughput of the router.

  J. G Bromer , J Wu , Y Zhou and H. S. Taylor

Diethylstilbestrol (DES) is a nonsteroidal estrogen that induces developmental anomalies of the female reproductive tract. The homeobox gene HOXA10 controls uterine organogenesis, and its expression is altered after in utero DES exposure. We hypothesized that an epigenetic mechanism underlies DES-mediated alterations in HOXA10 expression. We analyzed the expression pattern and methylation profile of HOXA10 after DES exposure. Expression of HOXA10 is increased in human endometrial cells after DES exposure, whereas Hoxa10 expression is repressed and shifted caudally from its normal location in mice exposed in utero. Cytosine guanine dinucleotide methylation frequency in the Hoxa10 intron was higher in DES-exposed offspring compared with controls (P = 0.017). The methylation level of Hoxa10 was also higher in the caudal portion of the uterus after DES exposure at the promoter and intron (P < 0.01). These changes were accompanied by increased expression of DNA methyltransferases 1 and 3b. No changes in methylation were observed after in vitro or adult DES exposure. DES has a dual mechanism of action as an endocrine disruptor; DES functions as a classical estrogen and directly stimulates HOXA10 expression with short-term exposure, however, in utero exposure results in hypermethylation of the HOXA10 gene and long-term altered HOXA10 expression. We identify hypermethylation as a novel mechanism of DES-induced altered developmental programming.

  Temple The MGC Project Team , D. S Gerhard , R Rasooly , E. A Feingold , P. J Good , C Robinson , A Mandich , J. G Derge , J Lewis , D Shoaf , F. S Collins , W Jang , L Wagner , C. M Shenmen , L Misquitta , C. F Schaefer , K. H Buetow , T. I Bonner , L Yankie , M Ward , L Phan , A Astashyn , G Brown , C Farrell , J Hart , M Landrum , B. L Maidak , M Murphy , T Murphy , B Rajput , L Riddick , D Webb , J Weber , W Wu , K. D Pruitt , D Maglott , A Siepel , B Brejova , M Diekhans , R Harte , R Baertsch , J Kent , D Haussler , M Brent , L Langton , C. L.G Comstock , M Stevens , C Wei , M. J van Baren , K Salehi Ashtiani , R. R Murray , L Ghamsari , E Mello , C Lin , C Pennacchio , K Schreiber , N Shapiro , A Marsh , E Pardes , T Moore , A Lebeau , M Muratet , B Simmons , D Kloske , S Sieja , J Hudson , P Sethupathy , M Brownstein , N Bhat , J Lazar , H Jacob , C. E Gruber , M. R Smith , J McPherson , A. M Garcia , P. H Gunaratne , J Wu , D Muzny , R. A Gibbs , A. C Young , G. G Bouffard , R. W Blakesley , J Mullikin , E. D Green , M. C Dickson , A. C Rodriguez , J Grimwood , J Schmutz , R. M Myers , M Hirst , T Zeng , K Tse , M Moksa , M Deng , K Ma , D Mah , J Pang , G Taylor , E Chuah , A Deng , K Fichter , A Go , S Lee , J Wang , M Griffith , R Morin , R. A Moore , M Mayo , S Munro , S Wagner , S. J.M Jones , R. A Holt , M. A Marra , S Lu , S Yang , J Hartigan , M Graf , R Wagner , S Letovksy , J. C Pulido , K Robison , D Esposito , J Hartley , V. E Wall , R. F Hopkins , O Ohara and S. Wiemann

Since its start, the Mammalian Gene Collection (MGC) has sought to provide at least one full-protein-coding sequence cDNA clone for every human and mouse gene with a RefSeq transcript, and at least 6200 rat genes. The MGC cloning effort initially relied on random expressed sequence tag screening of cDNA libraries. Here, we summarize our recent progress using directed RT-PCR cloning and DNA synthesis. The MGC now contains clones with the entire protein-coding sequence for 92% of human and 89% of mouse genes with curated RefSeq (NM-accession) transcripts, and for 97% of human and 96% of mouse genes with curated RefSeq transcripts that have one or more PubMed publications, in addition to clones for more than 6300 rat genes. These high-quality MGC clones and their sequences are accessible without restriction to researchers worldwide.

  N Sidell , Y Feng , L Hao , J Wu , J Yu , M. A Kane , J. L Napoli and R. N. Taylor

Vascular endothelial growth factor (VEGF) and endometrial angiogenesis play a critical role in successful embryonic implantation. Despite many studies of the effects of estrogen and progesterone on VEGF expression, its focal regulation at the site of implantation is unknown. Retinoic acid (RA) has been reported to regulate VEGF in a variety of cell types. Because localized RA synthesis occurs within the periimplantation endometrium, we tested the possibility that RA regulates VEGF production in endometrial stromal cells. Using primary and telomerase-immortalized human endometrial stromal cells, we determined that RA alone did not alter constitutive levels of VEGF production, but markedly amplified secretion when the cells were cotreated with activators of VEGF gene transcription (12-O-tetradecanoyl phorbol-13-acetate, TPA; TGF-β; and IL-1β). Whereas TPA or TGF-β alone stimulated VEGF promoter activity and up-regulated mRNA levels, significant protein secretion was detected only after RA was added to the culture systems. Analysis of retinoids in secretory phase endometrial biopsies indicated that endogenous RA accumulated at concentrations sufficient to induce VEGF secretion. Polyribosome profile analysis showed that the addition of RA to transcriptional activators of VEGF shifted the translational suppressed VEGF mRNA transcripts into larger polyribosome complexes engaged in active translation. Although the precise mechanism(s) of the RA effect remains to be defined, it appears to be mediated by reactive oxygen species; the antioxidant N-acetylcysteine inhibited RA+TPA-stimulated secretion of VEGF by more than 80%. Together, our results demonstrate that in human endometrial stromal cells, RA can combine with transcriptional activators of VEGF to augment VEGF secretion through a translational mechanism of action mediated by reactive oxygen species. These findings suggest a link between the spatiotemporal changes of retinoid synthesis in the periimplantation stroma and the capacity to quickly up-regulate focal VEGF secretion needed to induce early angiogenic events of pregnancy.

  J Wu , G. H Lyons , R. D Graham and M. F. Fenech

A supranutritional intake of selenium (Se) may be required for cancer prevention, but an excessively high dose could be toxic. Therefore, the effect on genome stability of seleno-L-methionine (Se-met), the most important dietary form of Se, was measured to determine its bioefficacy and safety limit. Peripheral blood lymphocytes were isolated from six volunteers and cultured with medium supplemented with Se-met in a series of Se concentrations (3, 31, 125, 430, 1880 and 3850 µg Se/litre) while keeping the total methionine (i.e. Se-met + L-methionine) concentration constant at 50 µM. Baseline genome stability of lymphocytes and the extent of DNA damage induced by 1.5-Gy -ray were investigated using the cytokinesis-block micronucleus cytome assay after 9 days of culture in 96-microwell plates. High Se concentrations (≥1880 µg Se/litre) caused strong inhibition of cell division and increased cell death (P < 0.0001). Baseline frequency of nucleoplasmic bridges and nuclear buds, however, declined significantly (P trend < 0.05) as Se concentration increased from 3 to 430 µg Se/litre. Se concentration (≤430 µg Se/litre) had no significant effect on baseline frequency of micronuclei and had no protective effect against genome damage induced by exposure to 1.5-Gy -ray irradiation. In conclusion, Se, as Se-met, may improve genome stability at concentrations up to 430 µg Se/litre, but higher doses may be cytotoxic. Therefore, a cautious approach to supplementation with Se-met is required to ensure that optimal genome health is achieved without cytotoxic effects.

  X Huang , X Bai , Y Cao , J Wu , M Huang , D Tang , S Tao , T Zhu , Y Liu , Y Yang , X Zhou , Y Zhao , M Wu , J Wei , D Wang , G Xu , S Wang , D Ma and J. Zhou

Angiogenesis is increasingly recognized as an important prognosticator associated with the progression of lymphoma and as an attractive target for novel modalities. We report a previously unrecognized mechanism by which lymphoma endothelium facilitates the growth and dissemination of lymphoma by interacting with circulated T cells and suppresses the activation of CD4+ T cells. Global gene expression profiles of microdissected endothelium from lymphoma and reactive lymph nodes revealed that T cell immunoglobulin and mucin domain–containing molecule 3 (Tim-3) was preferentially expressed in lymphoma-derived endothelial cells (ECs). Clinically, the level of Tim-3 in B cell lymphoma endothelium was closely correlated to both dissemination and poor prognosis. In vitro, Tim-3+ ECs modulated T cell response to lymphoma surrogate antigens by suppressing activation of CD4+ T lymphocytes through the activation of the interleukin-6–STAT3 pathway, inhibiting Th1 polarization, and providing protective immunity. In a lymphoma mouse model, Tim-3–expressing ECs promoted the onset, growth, and dissemination of lymphoma by inhibiting activation of CD4+ T cells and Th1 polarization. Our findings strongly argue that the lymphoma endothelium is not only a vessel system but also a functional barrier facilitating the establishment of lymphoma immune tolerance. These findings highlight a novel molecular mechanism that is a potential target for enhancing the efficacy of tumor immunotherapy and controlling metastatic diseases.

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