bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrated Molecular and Clinical Analysis of AKT Activation in Metastatic Melanoma
Authors: Davies Michael A. , Stemke-Hale Katherine , Lin E. , Tellez Carmen , Deng Wanleng , Gopal Yennu N. , Woodman Scott E. , Calderone Tiffany C. , Ju Zhenlin , Lazar Alexander J. , Prieto Victor G. , Aldape Kenneth , Mills Gordon B. , Gershenwald Jeffrey E. 
Published: December 2009

Abstract
Purpose: Activation of the phosphoinositide 3-kinase (PI3K)-AKT pathway has been implicated in melanoma based primarily on the prevalence of mutations in PTEN and NRAS. To improve our understanding of the regulation and clinical significance of the PI3K-AKT pathway in melanoma, we quantitatively measured the levels of phosphorylated AKT, its substrate GSK3α/β, and its negative regulator PTEN in clinical metastases. Results were compared with mutational status, clinical outcomes, and sites of metastasis.
Experimental Design: DNA and protein were isolated from dissected frozen melanoma metastases (n = 96). Activating mutations of BRAF, NRAS, AKT, PIK3CA, and KIT were detected by mass spectroscopy genotyping. Phosphorylated AKT (Ser473 and Thr308), P-GSK3α/β, and PTEN protein expression were measured by reverse-phase protein array. A panel of human melanoma cells lines (n = 58) was analyzed for comparison.
Results: BRAF-mutant tumors had higher levels of P-AKT-Ser473 (P = 0.01), P-AKT-Thr308 (P = 0.002), and P-GSK3α/β (P = 0.08) than NRAS-mutant tumors. Analysis of individual tumors showed that almost all tumors with elevated P-AKT had low PTEN levels; NRAS-mutant tumors had normal PTEN and lower P-AKT. Similar results were observed in melanoma cell lines. Stage III melanoma patients did not differ in overall survival based on activation status of the PI3K-AKT pathway. Brain metastases had significantly higher P-AKT and lower PTEN than lung or liver metastases.
Conclusions: Quantitative interrogation of the PI3K-AKT pathway in melanoma reveals unexpected significant differences in AKT activation by NRAS mutation and PTEN loss, and hyperactivation of AKT in brain metastases. These findings have implications for the rational development of targeted therapy for this disease. (Clin Cancer Res 2009;15(24):7538–46)
Differential Proteomics Identifies Protein Biomarkers That Predict Local Relapse of Head and Neck Squamous Cell Carcinomas
Authors: Schaaij-Visser Tieneke B.M. , Graveland A. Peggy , Gauci Sharon , Braakhuis Boudewijn J.M. , Buijze Marijke , Heck Albert J.R. , Kuik Dirk J. , Bloemena Elisabeth , Leemans C. René , Slijper Monique , Brakenhoff Ruud H. 
Published: December 2009

AbstractPurpose: The 5-year survival rates of head and neck squamous cell carcinomas (HNSCC) remain disappointing. HNSCCs develop in precursor fields of genetically altered cells that are often not completely resected when the tumor is excised, causing local relapse. These precursor fields are mostly recognized as dysplasia, but histologic grading cannot reliably predict malignant transformation. Our aim was to discover and validate protein biomarkers that can detect precursor fields and predict local relapse in HNSCC using immunostaining of surgical margins.Experimental Design: We compared paired and genetically characterized normal, precursor, and tumor tissues of eight patients by proteome analysis to identify differentially expressed proteins. The prognostic value of candidate protein biomarkers was evaluated by immunohistochemical analysis of 222 surgical margins of 46 HNSCC patients who developed local relapse or remained disease free. Significant associations were determined by Kaplan-Meier survival analysis and Cox-proportional hazards models.Results: Forty proteins showed significant differential expression (false discovery rate–corrected P &lt; 0.05). Most discriminative markers suited for immunostaining were keratin 4 and cornulin. Low expression in the surgical margins of keratin 4 (hazard ratio, 3.8; P = 0.002), cornulin (hazard ratio, 2.7; P = 0.025), and their combination (hazard ratio, 8.8; P = 0.0005) showed a highly significant association with the development of local relapse. Dysplasia grading had no prognostic relevance.Conclusions: Immunohistochemical assessment of keratin 4 and cornulin expression in surgical margins of HNSCC patients outperforms histopathologic grading in predicting the risk for local relapse. These markers can be used to initiate more frequent and lifelong surveillance of patients at high risk of local relapse, and enable selection for adjuvant treatment or tertiary prevention trials. (Clin Cancer Res 2009;15(24):7666–75)
Toll-Like Receptor Triggering and T-Cell Costimulation Induce Potent Antitumor Immunity in Mice
Authors: Westwood Jennifer A. , Haynes Nicole M. , Sharkey Janelle , McLaughlin Nicole , Pegram Hollie J. , Schwendener Reto A. , Smyth Mark J. , Darcy Phillip K. , Kershaw Michael H. 
Published: December 2009

AbstractPurpose: To determine the antitumor activity of a novel combination of two immunomodulatory agents that simultaneously direct multiple components of immunity against cancer.Experimental Design: We combined the Toll-like receptor agonist CpG 1826 with a T-cell costimulatory antibody specific for CD137 in an optimal treatment route and dosing schedule against established tumors in two mouse models. Mechanistic insight was gained using gene-deficient mice and cell-depleting antibodies.Results: The combination was shown to eradicate tumors in a large proportion of mice. Crucial roles for CD8+ T cells, natural killer cells, and IFNs were shown. CpG and anti-CD137 injection led to activation of dendritic cells and optimal expansion of activated T cells in the blood. Macrophages were not necessary for therapeutic effect, and indeed depletion of macrophages in vivo enhanced therapy leading to tumor rejection in 100% of mice, which has not been previously reported in the immunotherapeutic setting. Long-term surviving mice were resistant to tumor rechallenge, demonstrating immunologic memory. In addition, we show, for the first time, that mice lacking B cells have a total loss of a recall response against tumor, suggesting a role for B cells in the induction of antitumor immunologic memory.Conclusion: This study provides support for the use of a novel combination of immunomodulatory agents stimulating multiple facets of immunity for the effective immunotherapy of cancer. (Clin Cancer Res 2009;15(24):7624–33)
Angiotensin type 2 receptor–mediated apoptosis of human prostate cancer cells
Authors: Li Hongwei , Qi Yanfei , Li Chengyao , Braseth Leah N. , Gao Yongxin , Shabashvili Arseniy E. , Katovich Michael J. , Sumners Colin 
Published: December 2009

Abstract
Angiotensin II (Ang II) type 1 receptor blocking drugs have been shown to inhibit the growth of prostate cancer cells and delay the development of prostate cancer. Functional Ang II type 2 receptors (AT2R) are present in these cells and inhibit growth induced by epidermal growth factor. The present studies report apoptosis of prostate cancer cells induced by AT2R overexpression. A recombinant adenoviral vector expressing AT2R (Ad-G-AT2R-EGFP) was transduced into prostate cancer cells, including androgen-independent (DU145 and PC3) and androgen-dependent cell lines (LNCaP). Following AT2R transduction, apoptosis was analyzed by terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling staining and caspase-3 activity assays. The results indicate that increased expression of AT2R alone induced apoptosis in the prostate cancer lines, an effect that did not require Ang II. AT2R overexpression in DU145 cells induced inhibition of proliferation, a significant reduction of S-phase cells, and an enrichment of G1-phase cells. The data also indicate that overexpression of AT2R led to apoptosis via an extrinsic cell death signaling pathway that is dependent on activation of p38 mitogen-activated protein kinase, caspase-8, and caspase-3. Finally, the apoptosis induced by AT2R overexpression is partially dependent on the activation of p53, but not on p21. The observations presented here suggest that the ability of increased AT2R expression to induce apoptosis in prostate cancer cells may have potential therapeutic implications for this disease, and suggest that AT2R is a promising novel target gene for prostate cancer gene therapy. [Mol Cancer Ther 2009;8(12):3255–65]
G-quadruplex ligand SYUIQ-5 induces autophagy by telomere damage and TRF2 delocalization in cancer cells
Authors: Zhou Wen-Jun , Deng Rong , Zhang Xiao-Yue , Feng Gong-Kan , Gu Lian-Quan , Zhu Xiao-Feng 
Published: December 2009

Abstract
Agents stabilizing G-quadruplexes have the potential to destroy the functional structure of telomere and could therefore act as antitumor agents. We previously reported that SYUIQ-5 could stabilize G-quadruplex, induce senescence, and inhibit c-myc gene promoter activity. In this study, we showed that SYUIQ-5 inhibited proliferation of CNE2 and HeLa cancer cells, triggered a rapid and potent telomere DNA damage response characterized by the formation of telomeric foci γ-H2AX, and obviously induced autophagy with the features of increased LC3-II and a punctuated pattern of YFP-LC3 fluorescence. These phenomena may primarily depend on the delocalization of TRF2 from telomere, which was further degraded by proteasomes. Furthermore, overexpression of TRF2 inhibited SYUIQ-5–induced γ-H2AX expression. Also, ATM was activated following SYUIQ-5 treatment. The pretreatment with ATM inhibitor ku55933 and ATM siRNA effectively reduced the production of γ-H2AX and LC3-II. ATM knockdown partially antagonized the anticancer effects of SYUIQ-5. Moreover, inhibition of autophagy by short hairpin RNA against the autophagy-related gene ATG5 attenuated the cytotoxicity of SYUIQ-5. These results indicated that SYUIQ-5 triggered potent telomere damage through TRF2 delocalization from telomeres, and eventually induced autophagic cell death in cancer cells. Our findings exhibit a novel mechanism that is responsible for the antitumor effects of SYUIQ-5. [Mol Cancer Ther 2009;8(12):3203–13]
Basal c-Jun NH2-terminal protein kinase activity is essential for survival and proliferation of T-cell acute lymphoblastic leukemia cells
Authors: Cui Jian , Wang Qingyang , Wang Jing , Lv Ming , Zhu Ning , Li Yan , Feng Jiannan , Shen Beifen , Zhang Jiyan 
Published: December 2009

Abstract
Hyperactivation of c-Jun NH2-terminal protein kinase (JNK) has been found in various malignant lymphocytes and inhibition of JNK activity leads to cell cycle arrest and apoptosis. However, the role of JNK activity in the oncogenic growth of T-cell acute lymphoblastic leukemia (T-ALL) cells remains largely unknown. Here, we report that treatment of T-ALL cells with JNK inhibitors led to cell cycle arrest and apoptosis and increased sensitivity to Fas-mediated apoptosis, whereas weak ectopic expression of MKK7-JNK1 fusion protein, which shows constitutive JNK activity, in T-ALL cells resulted in accelerated cell cycle progression and resistance to Fas-mediated apoptosis. The protein levels of c-Myc and Bcl-2 were reduced in the presence of JNK inhibitors but were enhanced with MKK7-JNK1. Small interfering RNA against JNK1, but not JNK2, exhibited similar effects to JNK inhibitors. These findings suggest that targeting JNK, especially JNK1 isoform, may have some important therapeutic implications in the treatment of T-ALL. Further exploration revealed that JNK protein and basal JNK activity in T-ALL cells showed aberrant subcellular localization, but no hyperactivation of JNK was observed. Thus, our work suggests that there might be novel mechanism(s) other than hyperactivation underlying the protumorigenic role of JNK activity. [Mol Cancer Ther 2009;8(12):3214–22]
Hepatocyte Nuclear Factor-4–Independent Synthesis of Coagulation Factor VII in Breast Cancer Cells and Its Inhibition by Targeting Selective Histone Acetyltransferases
Authors: Koizume Shiro , Yokota Naho , Miyagi Etsuko , Hirahara Fumiki , Nakamura Yoshiyasu , Sakuma Yuji , Yoshida Akira , Kameda Yoichi , Tsuchiya Eiju , Ruf Wolfram , Miyagi Yohei 
Published: December 2009

Abstract
Tissue factor/coagulation factor VII (fVII) complex formation on the surface of cancer cells plays important roles in cancer biology, such as cell migration and invasion, angiogenesis, and antiapoptotic effects. We recently found that various cancer cells ectopically synthesize fVII, resulting in activation of cell motility and invasion. Here, we characterized mechanisms of hepatic and ectopic fVII (FVII) gene expression to identify molecular targets enabling selective inhibition of the ectopic expression. Unlike hepatic expression, hepatocyte nuclear factor-4 binding to the promoter is not required for ectopic FVII expression, although Sp1 binding is essential. Furthermore, we found novel nuclear targets of basal hepatocytic and ectopic FVII expression. Notably, histone acetyltransferases p300 and cyclic AMP–responsive element binding protein–binding protein (CBP) are exclusively recruited to the promoter region of the FVII gene specifically in breast cancer cells. We further show that curcumin, a dietary compound, can selectively inhibit ectopic fVII expression by targeting p300/CBP activity. These results suggest a strategy to inhibit ectopic fVII-induced tumor progression without impairment of the physiologic hemostatic process. (Mol Cancer Res 2009;7(12):1928–36)
Topographic Patterns of Cartilage Lesions in Knee Osteoarthritis
Authors: Bae Won C. , Payanal Melanie M. , Chen Albert C. , Hsieh-Bonassera Nancy D. , Ballard Brooke L. , Lotz Martin K. , Coutts Richard D. , Bugbee William D. , Sah Robert L. 
Published: December 2009

Objective: Treatments for articular cartilage lesions could benefit from characterization of lesion patterns and their progression to end-stage osteoarthritis. The objective of this study was to identify, quantitatively, topographic patterns of cartilage lesions in the human knee. Design: Photographs were taken of 127 unilateral distal femora (from 109 cadavers and 18 arthroplasty remnants) with full-thickness cartilage lesions. Using digital image analysis, the lesions were localized, and normalized lesion size was determined for the patellofemoral groove (PFG) and the lateral and medial femoral condyles (LFC and MFC, respectively). Samples were classified into patterns using cluster analysis of the lesion size at each compartment. For each pattern, maps showing the extent and frequency of lesions were created. Results: Four main patterns (a-d) were identified (each P < 0.001), with the lesion size varying from small (a) to large in distinct regions (b-d). Pattern b had a predominant lesion (23% area) in the MFC and smaller (<3%) lesions elsewhere. Pattern c had predominant lesions in the LFC (19%) and MFC (10%). Pattern d had a predominant lesion in the PFG (15%) and smaller lesions in the MFC (6%) and LFC (2%). The subpatterns of a (a1-a3) had relatively small lesions, with similarity between a2 and b and between a3 and d. Conclusion: The present methods facilitated quantitative identification of distinct topographic patterns of full-thickness cartilage lesions, based on lesion size and location. These results have implications for stratifying osteoarthritis patients using precise quantitative methods and, with additional longitudinal data, targeting cartilage treatments.
Induction of myeloproliferative disorder and myelofibrosis by thrombopoietin receptor W515 mutants is mediated by cytosolic tyrosine 112 of the receptor
Authors: Pecquet Christian , Staerk Judith , Chaligné Ronan , Goss Valerie , Lee Kimberly A. , Zhang Xiaowu , Rush John , Van Hees Joanne , Poirel Hélène A. , Scheiff Jean-Marie , Vainchenker William , Giraudier Stéphane , Polakiewicz Roberto D. , Constantinescu Stefan N. 
Published: December 2009

Abstract
Constitutively active JAK2V617F and thrombopoietin receptor (TpoR) W515L/K mutants are major determinants of human myeloproliferative neoplasms (MPNs). We show that a TpoRW515 mutation (W515A), which we detected in 2 myelofibrosis patients, and the Δ5TpoR active mutant, where the juxtamembrane R/KW515QFP motif is deleted, induce a myeloproliferative phenotype in mouse bone marrow reconstitution experiments. This phenotype required cytosolic Y112 of the TpoR. Phosphotyrosine immunoprofiling detected phosphorylated cytosolic TpoR Y78 and Y112 in cells expressing TpoRW515A. Mutation of cytosolic Y112 to phenylalanine prevented establishment of the in vivo phenotype and decreased constitutive active signaling by Δ5TpoR and TpoRW515A, especially via the mitogen-activated protein (MAP)–kinase pathway, without decreasing Janus kinase 2 (JAK2) activation. In contrast, mutation of cytosolic Y78 to phenylalanine enhanced the myeloproliferative syndrome induced by the TpoRW515 mutants, by enhancing receptor-induced JAK2 activation. We propose that TpoR cytosolic phosphorylated Y112 and flanking sequences could become targets for pharmacologic inhibition in MPNs.
Survival impact of lung transplantation for COPD
Authors: Lahzami S. , Bridevaux P.O. , Soccal P.M. , Wellinger J. , Robert J.H. , Ris H.B. , Aubert J.D. 
Published: December 2009

Chronic obstructive pulmonary disease (COPD) is the primary indication for lung transplantation (LTx), but survival benefit is still under debate. We analysed the survival impact of LTx in COPD with a new approach, using the BODE (body mass index, airway obstruction, dyspnoea, exercise capacity) index.We retrospectively reviewed 54 consecutive lung transplants performed for COPD. The pre-transplant BODE score was calculated for each patient and a predicted survival was derived from the survival functions of the original BODE index validation cohort. Predicted and observed post-transplant survival was then compared.In the subgroups with a BODE score ≥7 and <7, a majority of patients (66% and 69%, respectively) lived for longer after LTx than predicted by their individual BODE index. The median survival was significantly improved in the entire cohort and in the subgroup with a BODE score ≥7. 4 yrs after LTx a survival benefit was only apparent in patients with a pre-transplant BODE score of ≥7.In conclusion, while a majority of COPD patients had an individual survival benefit from LTx regardless of their pre-transplant BODE score, a global survival benefit was seen only in patients with more severe disease. This supports the use of the BODE index as a selection criteria for LTx candidates.
Usual interstitial pneumonia in rheumatoid arthritis-associated interstitial lung disease
Authors: Kim E. J. , Elicker B. M. , Maldonado F. , Webb W. R. , Ryu J. H. , Van Uden J. H. , Lee J. S. , King T. E. , Collard H. R. 
Published: December 2009

Interstitial lung disease is a common manifestation of rheumatoid arthritis; however, little is known about factors that influence its prognosis. The aim of the present study was to determine whether or not the usual interstitial pneumonia pattern found on high-resolution computed tomography (HRCT) is of prognostic significance in rheumatoid arthritis-associated interstitial lung disease (RA-ILD).Patients with RA-ILD were identified retrospectively (n = 82). The relationship of a definite usual interstitial pneumonia pattern on HRCT to survival was determined and compared to that in a cohort of patients with radiologically diagnosed idiopathic pulmonary fibrosis (n = 51).A definite usual interstitial pneumonia pattern was seen in 20 (24%) out of 82 patients with RA-ILD. These patients showed worse survival than those without this pattern (median survival 3.2versus6.6 yrs), and a similar survival to those with idiopathic pulmonary fibrosis. On multivariate analysis, a definite usual interstitial pneumonia pattern on HRCT was associated with worse survival (hazard ratio of 2.3). Analysis of specific HRCT features demonstrated that traction bronchiectasis and honeycomb fibrosis were associated with worse survival (hazard ratio of 2.6 and 2.1, respectively). Female sex (hazard ratio of 0.30) and a higher baseline diffusing capacity of the lung for carbon monoxide (hazard ratio of 0.96) were associated with better survival.A definite usual interstitial pneumonia pattern on HRCT has important prognostic implications in RA-ILD.
Graded contrast echocardiography in pulmonary arteriovenous malformations
Authors: Parra J. A. , Bueno J. , Zarauza J. , Fariñas-Alvarez C. , Cuesta J. M. , Ortiz P. , Zarrabeitia R. , Pérez del Molino A. , Bustamante M. , Botella L. M. , Delgado M. T. 
Published: December 2009

To compare the results of transthoracic contrast echocardiography (TTCE) adding a grading scale with the results of thoracic computed tomography (CT) in order to optimise the use of both techniques.95 patients with hereditary haemorrhagic telangiectasia (HHT) were examined with TTCE and thoracic CT to detect pulmonary arteriovenous malformations (PAVMs). According to previous studies, TTCE was divided into a four grade scale depending on the degree of opacification of the left ventricle after the administration of a contrast agent.Of the 95 patients (50.5% female; mean age 46 yrs), none with normal or grade 1 TTCE had detectable PAVMs on thoracic CT. Shunts of grades 2, 3 and 4 were associated with PAVMs according to thoracic CT in 25, 80, and 100% of the cases. There was a statistically significant association between the TTCE grade and the detection of a PAVM by thoracic CT. There were also statistically significant associations between TTCE grade and the cardiac cycle when the contrast was first visible in the left atrium, and size of the feeding artery.Graded TTCE and timing of left atrium opacification may be useful techniques in selecting HHT patients for PAVM screening with thoracic CT scans.
Exhaled nitric oxide predicts control in patients with difficult-to-treat asthma
Authors: Pérez-de-Llano L. A. , Carballada F. , Castro Añón O. , Pizarro M. , Golpe R. , Baloira A. , Vázquez Caruncho M. , Boquete M. 
Published: December 2009

We aimed to evaluate the accuracy of baseline exhaled nitric oxide fraction (FeNO) to recognise individuals with difficult-to-treat asthma who have the potential to achieve control with a guideline-based stepwise strategy.102 consecutive patients with suboptimal asthma control underwent stepwise increase in the treatment with maximal fluticasone/salmeterol combination dose for 1 month. Then, those who remained uncontrolled received oral corticosteroids for an additional month.With this approach, 53 patients (52%) gained control. Those who achieved control were more likely to have positive skin results (60.4%versus34%; p = 0.01), positive bronchodilator test (57.1%versus35.8%; p = 0.02) and peak expiratory flow variability ≥20% (71.1%versus49.1%; p = 0.04). Conversely, depression was more frequent in those who remained uncontrolled (18.4 %versus43.4 %; p = 0.01). AnFeNOvalue ≥30 ppb demonstrated a sensitivity of 87.5% (95% CI 73.9–94.5%) and a specificity of 90.6% (95% CI 79.7–95.9%) for the identification of responsive asthmatics.The current results suggest thatFeNOcan identify patients with difficult-to-treat asthma and the potential to respond to high doses of inhaled corticosteroids or systemic steroids.