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  • 1
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    TANK-binding kinase 1 (TBK1) controls cell survival through PAI-2/serpinB2 and transglutaminase 2 [Cell Biology] (2012)
    National Academy of Sciences
    Details
    Publication Date: 2012-01-25
    Description: The decision between survival and death in cells exposed to TNF relies on a highly regulated equilibrium between proapoptotic and antiapoptotic factors. The TNF-activated antiapoptotic response depends on several transcription factors, including NF-κB and its RelA/p65 subunit, that are activated through phosphorylation-mediated degradation of IκB inhibitors, a process controlled by the IκB kinase complex. Genetic studies in mice have identified the IκB kinase-related kinase TANK-binding kinase 1 (TBK1; also called NAK or T2K) as an additional regulatory molecule that promotes survival downstream of TNF, but the mechanism through which TBK1 exerts its survival function has remained elusive. Here we show that TBK1 triggers an antiapoptotic response by controlling a specific RelA/p65 phosphorylation event. TBK1-induced RelA phosphorylation results in inducible expression of plasminogen activator inhibitor-2 (PAI-2), a member of the serpin family with known antiapoptotic activity. PAI-2 limits caspase-3 activation through stabilization of transglutaminase 2 (TG2), which cross-links and inactivates procaspase-3. Importantly, Tg2−/− mice were found to be more susceptible to apoptotic cell death in two models of TNF-dependent acute liver injury. Our results establish PAI-2 and TG2 as downstream mediators in the antiapoptotic response triggered upon TBK1 activation.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 2
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    Recurrence risk score based on the specific activity of CDK1 and CDK2 predicts response to neoadjuvant paclitaxel followed by 5-fluorouracil, epirubicin and cyclophosphamide in breast cancers (2012)
    Oxford University Press
    Details
    Publication Date: 2012-04-03
    Description: Background: We established the cell cycle profiling (C2P) assay for specific activity (SA; activity/expression) of cyclin-dependent kinases (CDKs). C2P risk score (C2P-RS) based on CDK1 and CDK2 SAs was significantly associated with relapse in breast cancer (BC). This study was conducted to investigate the predictive value of C2P-RS for neoadjuvant chemotherapy (NAC). Patients and methods: Among 124 eligible patients, 122 were treated with weekly paclitaxel followed by 5-fluorouracil, epirubicin and cyclophosphamide (P-FEC) and 2 were treated with paclitaxel monotherapy. C2P-RS was determined via C2P using frozen biopsy samples before NAC. Results: Negative estrogen receptor (ER), negative progesterone receptor (PR), positive human epidermal growth factor receptor 2 (HER2), high Ki-67 expression and intermediate + high C2P-RS were significantly associated with high pathological complete response (pCR) rates compared with positive ER (30% versus 9%), positive PR (25% versus 6%), negative HER2 (34% versus 11%), low Ki-67 expression (24% versus 7%) or low C2P-RS (24% versus 9%), respectively. The combination of C2P-RS and Ki-67 had a stronger impact on pCR than each parameter alone, and a multivariate analysis showed that the combination was an independent predictor of pCR (odds ratio 3.3, 95% confidence interval 1.1–9.5). Conclusions: C2P-RS was significantly associated with pCR after P-FEC and may be a useful predictor for chemotherapy in BCs.
    Print ISSN: 0923-7534
    Electronic ISSN: 1569-8041
    Topics: Medicine
    Published by Oxford University Press
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  • 3
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    Aberrant L1CAM Expression in Anaplastic Thyroid Carcinoma (2012)
    The American Association for Cancer Research (AACR)
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    Publication Date: 2012-06-11
    Description: Purpose: Anaplastic thyroid carcinoma (ATC) is one of the most invasive human cancers and has a poor prognosis. Molecular targets of ATC that determine its highly aggressive nature remain unidentified. This study investigated L1 cell adhesion molecule (L1CAM) expression and its role in tumorigenesis of ATCs. Experimental Design: Expression of L1CAM in thyroid cancer was evaluated by immunohistochemical analyses of tumor samples from patients with thyroid cancer. We investigated the role of L1CAM in proliferation, migration, invasion, and chemoresistance using short hairpin RNA (shRNA) knockdown experiments in human ATC cell lines. Finally, we evaluated the role of L1CAM on tumorigenesis with ATC xenograft assay in a nude mouse model. Results: L1CAM expression was not detectable in normal follicular epithelial cells of the thyroid or in differentiated thyroid carcinoma. In contrast, analysis of ATC samples showed specifically higher expression of L1CAM in the invasive area of the tumor. Specific knockdown of L1CAM in the ATC cell lines, FRO and 8505C, caused a significant decrease in the proliferative, migratory, and invasive capabilities of the cells. Suppression of L1CAM expression in ATC cell lines increased chemosensitivity to gemcitabine or paclitaxel. Finally, in an ATC xenograft model, depletion of L1CAM markedly reduced tumor growth and increased the survival of tumor-bearing mice. Conclusions: We report that L1CAM is highly expressed in the samples taken from patients with ATCs. L1CAM plays an important role in determining tumor behavior and chemosensitivity in cell lines derived from ATCs. Therefore, we suggest that L1CAM may be an important therapeutic target in patients with ATCs. Clin Cancer Res; 18(11); 3071–8. ©2012 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
    Published by The American Association for Cancer Research (AACR)
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  • 4
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    Extranodal natural killer/T-cell lymphoma from skin or soft tissue: suggestion of treatment from multinational retrospective analysis (2012)
    Oxford University Press
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    Publication Date: 2012-09-26
    Description: Background Clinical features and outcomes of extranodal natural killer/T-cell lymphoma (ENKL) arising from extranasal sites are not fully understood. The purpose of this study was to study the prognosis and treatment outcome of skin/soft tissue primary ENKL. Patients and methods This multicenter retrospective study included 48 patients with skin/soft tissue primary ENKL diagnosed from 1993 to 2010. Results Patients with Ann Arbor stage I, T1–2N0M0 by International Society for Cutaneous Lymphomas–European Organization of Research and Treatment of Cancer TNM (tumour–node–metastasis) stage, International prognostic index score of 0–1, and a Korean prognostic index (KPI) score of 0–1 were associated with better survival. Four of five patients with T1–2N0M0 disease achieved complete response with radiation alone. In disseminated disease, only 6 of 13 patients responded to anthracycline-containing chemotherapy, and all the two patients receiving SMILE showed response. Conclusion In conclusion, we identified the prognostic value of KPI, and we suggest a treatment recommendation according to the TNM (tumour–node–metastasis) stage. Radiotherapy with/without chemotherapy seemed to be optimal in localized disease. In advanced stages, a more aggressive treatment regimen with newer agents should be sought.
    Print ISSN: 0923-7534
    Electronic ISSN: 1569-8041
    Topics: Medicine
    Published by Oxford University Press
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  • 5
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    Probing spin-charge relation by magnetoconductance in one-dimensional polymer nanofibers (2012)
    American Physical Society (APS)
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    Publication Date: 2012-10-13
    Description: Author(s): A. Choi, K. H. Kim, S. J. Hong, M. Goh, K. Akagi, R. B. Kaner, N. N. Kirova, S. A. Brazovskii, A. T. Johnson, D. A. Bonnell, E. J. Mele, and Y. W. Park Polymer nanofibers are one-dimensional organic hydrocarbon systems containing conducting polymers where the nonlinear local excitations such as solitons, polarons, and bipolarons formed by the electron-phonon interaction were predicted. Magnetoconductance (MC) can simultaneously probe both the spin ... [Phys. Rev. B 86, 155423] Published Fri Oct 12, 2012
    Keywords: Surface physics, nanoscale physics, low-dimensional systems
    Print ISSN: 1098-0121
    Electronic ISSN: 1095-3795
    Topics: Physics
    Published by American Physical Society (APS)
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  • 6
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    Attenuation-based Automatic Tube Voltage Selection and Tube Current Modulation for Dose Reduction at Contrast-enhanced Liver CT [Gastrointestinal Imaging] (2012)
    The Radiological Society of North America (RSNA)
    In: Radiology
    Details
    Publication Date: 2012-10-24
    Description: Purpose: To retrospectively determine whether the combined use of automatic tube voltage selection (ATVS) and automatic tube current modulation (ATCM) can effectively reduce radiation dose at contrast material–enhanced liver computed tomography (CT) while maintaining acceptable image quality compared with the use of ATCM alone. Materials and Methods: This study was approved by an institutional review board, and informed consent was waived. Three hundred fourteen consecutive patients suspected of having liver disease were divided into three groups. In two groups, both ATVS and ATCM were used (group A1, n = 97; group A2, n = 101) but with different contrast gain settings; in one group, only ATCM with a fixed tube potential of 120 kV (group B, n = 116) was used. Weighted volume CT dose index and dose–length product, contrast-to-noise ratios (CNRs), and mean image noise were assessed. Qualitative analysis was performed by two board-certified radiologists and one radiology resident. Statistical analysis was performed by using the one-way analysis of variance test, two-tailed paired t test, Kruskal-Wallis test, and noninferiority test. Results: In groups A1 and A2, a significant dose reduction was obtained compared with that in group B ( P 〈 .0001). The mean dose reduction was 20% in group A1 and 31% in group A2. Furthermore, CNRs were significantly higher in groups A1 and A2 than in group B ( P 〈 .0001). Despite the higher image noise in groups A1 and A2, the overall image quality was acceptable. Conclusion: Compared with the use of ATCM alone, the combined use of ATVS and ATCM allowed reduction of radiation exposure while maintaining good image quality at contrast-enhanced liver CT. © RSNA, 2012 Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12112434/-/DC1
    Keywords: Computed Tomography, Gastrointestinal Radiology
    Print ISSN: 0033-8419
    Electronic ISSN: 1527-1315
    Topics: Medicine
    Published by The Radiological Society of North America (RSNA)
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  • 7
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    Clinicopathological analysis of GATA3-positive breast cancers with special reference to response to neoadjuvant chemotherapy (2012)
    Oxford University Press
    Details
    Publication Date: 2012-11-20
    Description: Background The aim of this study was to investigate the clinicopathological characteristics of GATA binding protein 3 (GATA3)-positive breast cancers as well as the association of GATA3 expression with response to chemotherapy. Patients and methods Tumor specimens obtained before neoadjuvant chemotherapy [paclitaxel followed by 5-fluorouracil/epirubicin/cyclophosphamide)] from breast cancer patients ( n  = 130) were subjected to immunohistochemical and mutational analysis of GATA3 and DNA microarray gene expression analysis for intrinsic subtyping. Results Seventy-four tumors (57%) were immunohistochemically positive for GATA3. GATA3-positive tumors were significantly more likely to be lobular cancer, estrogen receptor (ER)-positive, progesterone receptor (PgR)-positive, Ki67-negative, and luminal A tumors. Somatic mutations were found in only three tumors. Pathological complete response (pCR) was observed in 8 (11%) GATA3-positive tumors and in 22 (39%) GATA3-negative tumors. Multivariate analysis showed that tumor size, human epidermal growth factor receptor 2 (HER2), and GATA3 were independent predictors of pCR. Conclusions GATA3-positive breast cancers showed luminal differentiation characterized by high ER expression and were mostly classified as luminal-type tumors following intrinsic subtyping. Interestingly, GATA3 was an independent predictor of response to chemotherapy, suggesting that GATA3 might be clinically useful as a predictor of a poor response to chemotherapy.
    Print ISSN: 0923-7534
    Electronic ISSN: 1569-8041
    Topics: Medicine
    Published by Oxford University Press
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  • 8
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    A public resource for clinical use of genomes [Genetics] (2012)
    National Academy of Sciences
    Details
    Publication Date: 2012-07-25
    Description: Rapid advances in DNA sequencing promise to enable new diagnostics and individualized therapies. Achieving personalized medicine, however, will require extensive research on highly reidentifiable, integrated datasets of genomic and health information. To assist with this, participants in the Personal Genome Project choose to forgo privacy via our institutional review board- approved “open consent” process. The contribution of public data and samples facilitates both scientific discovery and standardization of methods. We present our findings after enrollment of more than 1,800 participants, including whole-genome sequencing of 10 pilot participant genomes (the PGP-10). We introduce the Genome-Environment-Trait Evidence (GET-Evidence) system. This tool automatically processes genomes and prioritizes both published and novel variants for interpretation. In the process of reviewing the presumed healthy PGP-10 genomes, we find numerous literature references implying serious disease. Although it is sometimes impossible to rule out a late-onset effect, stringent evidence requirements can address the high rate of incidental findings. To that end we develop a peer production system for recording and organizing variant evaluations according to standard evidence guidelines, creating a public forum for reaching consensus on interpretation of clinically relevant variants. Genome analysis becomes a two-step process: using a prioritized list to record variant evaluations, then automatically sorting reviewed variants using these annotations. Genome data, health and trait information, participant samples, and variant interpretations are all shared in the public domain—we invite others to review our results using our participant samples and contribute to our interpretations. We offer our public resource and methods to further personalized medical research.
    Keywords: Inaugural Articles
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 9
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    Predictors for Neoatherosclerosis: A Retrospective Observational Study From the Optical Coherence Tomography Registry [Original Articles] (2012)
    American Heart Association (AHA)
    Details
    Publication Date: 2012-09-19
    Description: Background— Recent studies have reported development of neoatherosclerosis (NA) inside the stents several years after stent implantation. The aim of this study was to determine the predictors for NA using optical coherence tomography. Methods and Results— From a total of 1080 patients who underwent optical coherence tomography, we identified 179 stents in 151 patients in which the mean neointimal thickness was 〉100 µm. The presence of lipid-laden neointima or calcification inside the stents was defined as NA in the present study. Patient characteristics, stent type, and time since stent implantation (stent age) were compared between stents with or without NA. Univariable and multivariable logistic regression analyses were used to assess the independent predictors. In univariate analysis, stent age ≥48 months (Odds ratio [OR], 4.48; [95% CI 2.68-9.65]; P 〈0.001), drug-eluting stents (OR, 2.66; [95% CI, 1.38–5.16]; P =0.004), age ≥65 years (OR, 1.91; [95% CI, 1.05–3.44]; P =0.032), current smoking (OR, 2.30; [95% CI, 1.10–4.82]; P =0.024), chronic kidney disease (OR, 4.17; [95% CI, 1.42–12.23]; P =0.009), and angiotensin-converting enzyme inhibitors or angiotensin II receptor blockade use (OR, 0.42; [95% CI, 0.22–0.80]; P =0.008) were significant predictors. In multivariate analysis, stent age ≥48 months, all subtypes of drug-eluting stent, current smoking, chronic kidney disease, and angiotensin-converting enzyme inhibitors/angiotensin II receptor blockade use remained independent predictors for NA. Conclusions— In addition to the stent type and the stent age, patient characteristics, including current smoking, chronic kidney disease, and angiotensin-converting enzyme inhibitors/angiotensin II receptor blockade, were associated with the presence of NA. This result may support the importance of secondary prevention after stent implantation.
    Keywords: Restenosis, Catheter-based coronary interventions: stents, Coronary imaging: angiography/ultrasound/Doppler/CC
    Print ISSN: 1941-9651
    Electronic ISSN: 1942-0080
    Topics: Medicine
    Published by American Heart Association (AHA)
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  • 10
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    FOXO1 impairs whereas statin protects endothelial function in diabetes through reciprocal regulation of Kruppel-like factor 2 (2012)
    Oxford University Press
    Details
    Publication Date: 2012-12-22
    Description: Aims Krüppel-like factor 2 (KLF2) is implicated as a key molecule maintaining endothelial function. This study was designed to evaluate the reciprocal regulation of KLF2 by the forkhead transcription factor FOXO1, and the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor atorvastatin, in hyperglycaemic conditions. Methods and results Exposure of human umbilical vein endothelial cells to 30 mM glucose activated FOXO1 and suppressed KLF2. These effects were reversed by FOXO1 small interfering RNA. Adenoviral transfection of constitutively active FOXO1 suppressed KLF2 expression. Interestingly, atorvastatin inhibited FOXO1 by increasing phosphorylation and also by inhibiting nuclear localization and replenished KLF2 in high-glucose conditions. This effect of atorvastatin was attenuated by mevalonate. Chromatin immunoprecipitation analysis demonstrated that glucose increased whereas atorvastatin decreased FOXO1 binding to the promoter region of the KLF2 gene. In the vessels of Otsuka Long-Evans Tokushima Fatty rats, animal models of type 2 diabetes, FOXO1 was activated and KLF2 was suppressed, and this was reversed by atorvastatin treatment. The arteries from Otsuka Long-Evans Tokushima Fatty rats showed impairment of endothelium-dependent vasodilatation, and both atorvastatin and KLF2 gene therapies restored it. Conclusions Suppression of KLF2 by FOXO1 may be a plausible mechanism of diabetic endothelial dysfunction. High-glucose-induced, FOXO1-mediated KLF2 suppression was reversed by atorvastatin, suggesting that intensive statin treatment could be a therapeutic option in diabetic vascular dysfunction.
    Print ISSN: 0008-6363
    Electronic ISSN: 1755-3245
    Topics: Medicine
    Published by Oxford University Press
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