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        Actions of Prostaglandins on Human Nucleus Pulposus Metabolism Inferred by Cyclooxygenase 2 Inhibition of Cytokine Activated Cells

        Nam Vo,Brandon Couch,Joon Lee,Gwendolyn Sowa,James Kang,Studer Rebecca 대한척추신경외과학회 2020 Neurospine Vol.17 No.1

        Objective: Low back pain is frequently treated with nonsteroidal anti-inflammatory drugs (NSAIDs), but little is known about intervertebral disc metabolism of the prostaglandins that are diminished by these drugs. Hence, this study aimed at delineating prostaglandin actions in cytokine activated disc cells by comparing the response of nucleus pulposus (NP) cells to the pro-inflammatory cytokine interleukin (IL)-1β with and without cyclooxygenase 2 (COX-2) inhibition. Methods: NP cells cultured in alginate beads were activated with IL-1β±the COX-2 inhibitor Sc-58125. Media harvested from cultured cells were analyzed for prostaglandin E2 (PGE2), prostaglandin F2 alpha (PGF2α), IL-6, and matrix metalloproteinase (MMP)-3 by enzymelinked immunosorbent assay and nitric oxide by Griess Reaction. Gene expression along with proteoglycan, collagen, and total protein synthesis were also measured. Results: IL-1β increased culture media PGE2 and PGF2α, but decreased proteoglycan and collagen syntheses as well as mRNA expression of the matrix genes aggrecan, versican, collagen I, and collagen II. COX-2 inhibition partially rescued proteoglycan and collagen syntheses and collagen I mRNA, but decreased collagen II mRNA IL-1β activated NP cells. COX-2 inhibition initially enhanced and subsequently reduced IL-1β induced inducible nitric oxide synthase, without altering medium nitrite. IL-1β induction of MMP-3 mRNA was increased by COX-2 inhibition at 24 and 48 hours. Conclusion: COX-2 inhibition alters the response of NP cells to IL-1β, suggesting IL-1β action on disc cells is mediated at least in part through COX-2 and its prostaglandins. COX-2 inhibition produces minimal effects on several key catabolic mediators, with the exception of MMP-3. Blocking COX-2 might be beneficial for maintaining disc matrix since it provides an overall rescue of IL-1 induced loss of matrix protein synthesis.

      • KCI등재

        Rabbit Annulus Fibrosus Cells Express Neuropeptide Y, Which Is Influenced by Mechanical and Inflammatory Stress

        Malcolm E. Dombrowski,Adam S. Olsen,Nicholas Vaudreuil,Brandon K. Couch,Qing Dong,Michelle Tucci,Joon Y. Lee,Nam V. Vo,Gwendolyn Sowa 대한척추신경외과학회 2020 Neurospine Vol.17 No.1

        Objective: Rabbit annulus fibrosus (AF) cells were exposed to isolated or combined mechanical and inflammatory stress to examine the expression of neuropeptide Y (NPY). This study aims to explore the ability of AF cells to produce NPY in response to mechanical and inflammatory stress. Methods: Lumbar AF cells of 6- to 8-month-old female New Zealand white rabbits were harvested and exposed to combinations of inflammatory (interleukin-1β) and mechanical (6% or 18%) tensile stress using the Flexcell System. NPY concentrations were measured in the media via enzyme-linked immunosorbent assay. The presence of NPY receptor-type 1 (NPY-1R) in AF cells of rabbit intervertebral discs was also analyzed via immunohistochemistry and immunofluorescence. Results: Exposure to inflammatory stimuli showed a significant increase in the amount of NPY expression compared to control AF cells. Mechanical strain alone did not result in a significant difference in NPY expression. While combined inflammatory and mechanical stress did not demonstrate an increase in NPY expression at low (6%) levels of strain, at 18% strain, there was a large—though not statistically significant—increase in NPY expression under conditions of inflammatory stress. Lastly, immunofluorescence and immunohistochemistry of AF cells and tissue, respectively, demonstrated the presence of NPY-1R. Conclusion: These findings demonstrate that rabbit AF cells are capable of expressing NPY, and expression is enhanced in response to inflammatory and mechanical stress. Because both inflammatory and mechanical stress contribute to intervertebral disc degeneration (IDD), this observation raises the potential of a mechanistic link between low back pain and IDD.

      • KCI등재

        Spine Fractures of Patients with Ankylosing Spondylitis and Diffuse Idiopathic Skeletal Hyperostosis: Fracture Severity and Injury-Related Mortality at a Level I Trauma Center

        Chen Stephen Ryan,Munsch Maria Amelia,Chen Joseph,Couch Brandon Keith,Wawrose Richard Alan,Oyekan Anthony Abimbade,Adjei Joshua,Donaldson William F.,Lee Joon Yung,Shaw Jeremy DeWitt 대한척추외과학회 2023 Asian Spine Journal Vol.17 No.3

        Study Design: Retrospective review of prospectively collected cohort.Purpose: To identify differences in treatment and mortality of spine fractures in patients with ankylosing conditions of the spine. Overview of Literature: Ankylosing spondylitis (AS) and diffuse idiopathic skeletal hyperostosis (DISH) are the two most common etiologies of ankylosing spinal disorder (ASD). However, studies on the treatment and outcomes of spine fractures in AS and DISH patients remain few.Methods: Patients presenting with a spine fracture were diagnosed with AS or DISH at a single tertiary care center between 2010 and 2019. We excluded those who lacked cross-sectional imaging or fractures occurring at spinal segments affected by ankylosis, as well as polytraumatized patients. Patient demographics, injury mechanism, fracture level, neurologic status, treatment, and 1-year mortality were recorded. Computed tomography imaging was reviewed by two independent readers and graded according to the indicated AO Spine Injury Classification System. Differences in fracture severity, treatment method, and mortality were examined using Student t -tests, chi-square tests, and two-proportion Z-tests with significance set to p <0.05.Results: We identified 167 patients with spine fracture diagnosed with AS or DISH. Patients with AS had more severe fractures and more commonly had surgery than patients with DISH (p <0.001). Despite these differences, 1-year mortality did not significantly differ between AS and DISH patients (p =0.14).Conclusions: Although patients with AS suffered more severe fractures compared to DISH and more frequently underwent surgery for these injuries, outcomes and 1-year mortality did not differ significantly between the two groups. For patients with ASDs and fractures, outcomes appear similar regardless of treatment modality. Consequently, there may be an opportunity for critical reappraisal of operative indications in ASD and a larger role for nonoperative management in these challenging patients.

      • Assessment of variation in immunosuppressive pathway genes reveals <i>TGFBR2</i> to be associated with prognosis of estrogen receptor-negative breast cancer after chemotherapy

        Lei, Jieping,Rudolph, Anja,Moysich, Kirsten B,Rafiq, Sajjad,Behrens, Sabine,Goode, Ellen L,Pharoah, Paul PD,Seibold, Petra,Fasching, Peter A,Andrulis, Irene L,Kristensen, Vessela N,Couch, Fergus J,Ham BioMed Central 2015 Breast cancer research Vol.17 No.-

        <P><B>Introduction</B></P><P>Tumor lymphocyte infiltration is associated with clinical response to chemotherapy in estrogen receptor (ER) negative breast cancer. To identify variants in immunosuppressive pathway genes associated with prognosis after adjuvant chemotherapy for ER-negative patients, we studied stage I-III invasive breast cancer patients of European ancestry, including 9,334 ER-positive (3,151 treated with chemotherapy) and 2,334 ER-negative patients (1,499 treated with chemotherapy).</P><P><B>Methods</B></P><P>We pooled data from sixteen studies from the Breast Cancer Association Consortium (BCAC), and employed two independent studies for replications. Overall 3,610 single nucleotide polymorphisms (SNPs) in 133 genes were genotyped as part of the Collaborative Oncological Gene-environment Study, in which phenotype and clinical data were collected and harmonized. Multivariable Cox proportional hazard regression was used to assess genetic associations with overall survival (OS) and breast cancer-specific survival (BCSS). Heterogeneity according to chemotherapy or ER status was evaluated with the log-likelihood ratio test.</P><P><B>Results</B></P><P>Three independent SNPs in <I>TGFBR2</I> and <I>IL12B</I> were associated with OS (<I>P</I> <10<SUP>−3</SUP>) solely in ER-negative patients after chemotherapy (267 events). Poorer OS associated with <I>TGFBR2</I> rs1367610 (G > C) (per allele hazard ratio (HR) 1.54 (95% confidence interval (CI) 1.22 to 1.95), <I>P</I> = 3.08 × 10<SUP>−4</SUP>) was not found in ER-negative patients without chemotherapy or ER-positive patients with chemotherapy (<I>P</I> for interaction <10<SUP>−3</SUP>). Two SNPs in <I>IL12B</I> (r<SUP>2</SUP> = 0.20) showed different associations with ER-negative disease after chemotherapy: rs2546892 (G > A) with poorer OS (HR 1.50 (95% CI 1.21 to 1.86), <I>P</I> = 1.81 × 10<SUP>−4</SUP>), and rs2853694 (A > C) with improved OS (HR 0.73 (95% CI 0.61 to 0.87), <I>P</I> = 3.67 × 10<SUP>−4</SUP>). Similar associations were observed with BCSS. Association with <I>TGFBR2</I> rs1367610 but not <I>IL12B</I> variants replicated using BCAC Asian samples and the independent Prospective Study of Outcomes in Sporadic versus Hereditary Breast Cancer Study and yielded a combined HR of 1.57 ((95% CI 1.28 to 1.94), <I>P</I> = 2.05 × 10<SUP>−5</SUP>) without study heterogeneity.</P><P><B>Conclusions</B></P><P><I>TGFBR2</I> variants may have prognostic and predictive value in ER-negative breast cancer patients treated with adjuvant chemotherapy. Our findings provide further insights into the development of immunotherapeutic targets for ER-negative breast cancer.</P><P><B>Electronic supplementary material</B></P><P>The online version of this article (doi:10.1186/s13058-015-0522-2) contains supplementary material, which is available to authorized users.</P>

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