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Articles by J Shen
Total Records ( 5 ) for J Shen
  J. C Umhau , R Momenan , M. L Schwandt , E Singley , M Lifshitz , L Doty , L. J Adams , V Vengeliene , R Spanagel , Y Zhang , J Shen , D. T George , D Hommer and M. Heilig
 

Context  Acamprosate is approved for the treatment of alcoholism, but its mechanism of action remains unclear. Results of animal studies suggest that a persistent hyperglutamatergic state contributes to the pathogenesis of alcoholism and that acamprosate may exert its actions by intervening in this process. Human translation of these findings is lacking.

Objective  To examine whether acamprosate modulates indices of central glutamate levels in recently abstinent alcohol-dependent patients as measured using proton nuclear magnetic resonance spectroscopy (1H-MRS).

Design  A 4-week, double-blind, placebo-controlled, randomized controlled experimental medicine study, with 1H-MRS measures obtained on days 4 and 25.

Setting  An inpatient research unit at the NIH Clinical Center.

Patients  Thirty-three patients who met the DSM-IV criteria for alcohol dependence and who were admitted for medically supervised withdrawal from ongoing alcohol use.

Intervention  Four weeks of acamprosate (initial oral loading followed by 1998 mg daily) or matched placebo, initiated at the time of admission.

Main Outcome Measures  The glutamate to creatine ratio as determined using single-voxel 1H-MRS in the anterior cingulate. Exploratory neuroendocrine, biochemical, and behavioral outcomes were also collected, as were safety- and tolerability-related measures.

Results  There was a highly significant suppression of the glutamate to creatine ratio across time by acamprosate (time x treatment interaction: F1,29 = 13.5, P < .001). Cerebrospinal fluid levels of glutamate obtained in a subset of patients 4 weeks into abstinence were uncorrelated with the MRS measures and unaffected by treatment but were strongly correlated (R2 = 0.48, P < .001) with alcohol dependence severity. Other exploratory outcomes, including repeated dexamethasone–corticotropin-releasing hormone tests, and psychiatric ratings were unaffected. Among tolerability measures, gastrointestinal symptoms were significantly greater in acamprosate-treated individuals, in agreement with the established profile of acamprosate.

Conclusion  The MRS measures of central glutamate are reduced across time when acamprosate therapy is initiated at the onset of alcohol abstinence.

Trial Registration  clinicaltrials.gov Identifier: NCT00106106

  J Shen , U. M Chandrasekharan , M. Z Ashraf , E Long , R. E Morton , Y Liu , J. D Smith and P. E. DiCorleto
 

Rationale: Multiple protein kinases have been implicated in cardiovascular disease; however, little is known about the role of their counterparts: the protein phosphatases.

Objective: To test the hypothesis that mitogen-activated protein kinase phosphatase (MKP)-1 is actively involved in atherogenesis.

Methods and Results: Mice with homozygous deficiency in MKP-1 (MKP-1–/–) were bred with apolipoprotein (Apo)E-deficient mice (ApoE–/–) and the 3 MKP-1 genotypes (MKP-1+/+/ApoE–/– ; MKP-1+/–/ApoE–/– and MKP-1–/–/ApoE–/–) were maintained on a normal chow diet for 16 weeks. The 3 groups of mice exhibited similar body weight and serum lipid profiles; however, both MKP-1+/– and MKP-1–/– mice had significantly less aortic root atherosclerotic lesion formation than MKP-1+/+ mice. Less en face lesion was observed in 8-month-old MKP-1–/– mice. The reduction in atherosclerosis was accompanied by decreased plasma levels of interleukin-1 and tumor necrosis factor , and preceded by increased antiinflammatory cytokine interleukin-10. In addition, MKP-1–null mice had higher levels of plasma stromal cell–derived factor-1a, which negatively correlated with atherosclerotic lesion size. Immuno-histochemical analysis revealed that MKP-1 expression was enriched in macrophage-rich areas versus smooth muscle cell regions of the atheroma. Furthermore, macrophages isolated from MKP-1–null mice showed dramatic defects in their spreading/migration and impairment in extracellular signal-regulated kinase, but not c-Jun N-terminal kinase and p38, pathway activation. In line with this, MKP-1–null atheroma exhibited less macrophage content. Finally, transplantation of MKP-1–intact bone marrow into MKP-1–null mice fully rescued the wild-type atherosclerotic phenotype.

Conclusion: These findings demonstrate that chronic deficiency of MKP-1 leads to decreased atherosclerosis via mechanisms involving impaired macrophage migration and defective extracellular signal-regulated kinase signaling.

  W Wu , W Zhang , R Qiao , D Chen , H Wang , Y Wang , S Zhang , G Gao , A Gu , J Shen , J Qian , W Fan , L Jin , B Han and D. Lu
 

Purpose: Platinum agents cause DNA cross-linking and adducts. Xeroderma pigmentosum group D (XPD) plays a key role in the nucleotide excision repair pathway of DNA repair. Genetic polymorphisms of XPD may affect the capacity to remove the deleterious DNA lesions in normal tissues and lead to greater treatment-related toxicity. This study aimed to investigate the association of three polymorphisms of XPD at codons 156, 312, and 711, with the occurrence of grade 3 or 4 toxicity in advanced non–small cell lung cancer patients.

Experimental Design: We used matrix-assisted laser desorption/ionization time-of-flight mass spectrometry to genotype the three polymorphisms in 209 stage III and IV non–small cell lung cancer patients treated with platinum-based chemotherapy.

Results: The variant homozygotes of XPD p.Arg156Arg (rs238406) polymorphism were associated with a significantly increased risk of grade 3 or 4 hematologic toxicity (adjusted odds ratios, 3.24; 95% confidence interval, 1.35-7.78; P for trend = 0.009), and, more specifically, severe leukopenia toxicity (P for trend = 0.005). No statistically significant association was found for the three polymorphisms and grade 3 or 4 gastrointestinal toxicity. Consistent with these results of single-locus analysis, both the haplotype and the diplotype analyses revealed a protective effect of the haplotype "CG" (in the order of p.Arg156Arg-p.Asp312Asn) on the risk of grade 3 or 4 hematologic toxicity.

Conclusions: This investigation, for the first time, provides suggestive evidence of an effect of XPD p.Arg156Arg polymorphism on severe toxicity variability among platinum-treated non–small cell lung cancer patients.

  N. E Sounni , K Dehne , L van Kempen , M Egeblad , N. I Affara , I Cuevas , J Wiesen , S Junankar , L Korets , J Lee , J Shen , C. J Morrison , C. M Overall , S. M Krane , Z Werb , N Boudreau and L. M. Coussens
  Nor E. Sounni, Kerstin Dehne, Leon van Kempen, Mikala Egeblad, Nesrine I. Affara, Ileana Cuevas, Jane Wiesen, Simon Junankar, Lidiya Korets, Jake Lee, Jennifer Shen, Charlotte J. Morrison, Christopher M. Overall, Stephen M. Krane, Zena Werb, Nancy Boudreau, and Lisa M. Coussens

Innate regulatory networks within organs maintain tissue homeostasis and facilitate rapid responses to damage. We identified a novel pathway regulating vessel stability in tissues that involves matrix metalloproteinase 14 (MMP14) and transforming growth factor beta 1 (TGFβ1). Whereas plasma proteins rapidly extravasate out of vasculature in wild-type mice following acute damage, short-term treatment of mice in vivo with a broad-spectrum metalloproteinase inhibitor, neutralizing antibodies to TGFβ1, or an activin-like kinase 5 (ALK5) inhibitor significantly enhanced vessel leakage. By contrast, in a mouse model of age-related dermal fibrosis, where MMP14 activity and TGFβ bioavailability are chronically elevated, or in mice that ectopically express TGFβ in the epidermis, cutaneous vessels are resistant to acute leakage. Characteristic responses to tissue damage are reinstated if the fibrotic mice are pretreated with metalloproteinase inhibitors or TGFβ signaling antagonists. Neoplastic tissues, however, are in a constant state of tissue damage and exhibit altered hemodynamics owing to hyperleaky angiogenic vasculature. In two distinct transgenic mouse tumor models, inhibition of ALK5 further enhanced vascular leakage into the interstitium and facilitated increased delivery of high molecular weight compounds into premalignant tissue and tumors. Taken together, these data define a central pathway involving MMP14 and TGFβ that mediates vessel stability and vascular response to tissue injury. Antagonists of this pathway could be therapeutically exploited to improve the delivery of therapeutics or molecular contrast agents into tissues where chronic damage or neoplastic disease limits their efficient delivery.

  J Shen , S. S Rathore , L Khandan and J. E. Rothman
 

Whittling away SNARE complex components reveals essential domains for Munc18-1–mediated membrane fusion.

 
 
 
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