bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heat Shock Protein 90-Sheltered Overexpression of Insulin-Like Growth Factor 1 Receptor Contributes to Malignancy of Thymic Epithelial Tumors
Authors: Breinig Marco , Mayer Philipp , Harjung Andreas , Goeppert Benjamin , Malz Mona , Penzel Roland , Neumann Olaf , Hartmann Arndt , Dienemann Hendrik , Giaccone Giuseppe , Schirmacher Peter , Kern Michael André , Chiosis Gabriela , Rieker Ralf Joachim 
Published: March 2011

Abstract
Purpose: The underlying molecular mechanisms of thymic epithelial malignancies (TEMs) are poorly understood. Consequently, there is a lack of efficacious targeted therapies and patient prognosis remains dismal, particularly for advanced TEMs. We sought to investigate protumorigenic mechanism relevant to this understudied cancer.
Experimental Design: Recently established cell lines derived from thymic epithelial tumors were used as a model system. The antitumor activity of specific heat shock protein 90 (Hsp90) inhibitors was investigated by an analysis of cell viability, cell cycle, and apoptosis using MTT-assays and flow cytometry. Western blotting was used to investigate the altered expression of Hsp90 clients. Pharmacological inhibitors against select Hsp90 clients, as well as RNAi, were employed to test the relevance of each client independently. Tissue microarray analysis was performed to match the in vitro findings with observations obtained from patient-derived samples.
Results: Hsp90 inhibition significantly reduces cell viability of thymic carcinoma cells, induces cell cycle arrest and apoptosis, and blocks invasiveness. Hsp90 inhibition triggers the degradation of multiple oncogenic clients, for example insulin-like growth factor 1 receptor (IGF-1R), CDK4, and the inactivation of PI3K/Akt and RAF/Erk signaling. Mechanistically, the IGF/IGF-1R–signaling axis contributes to the establishment of the antiapoptotic phenotype of thymic cancer cells. Finally, IGF-1R is overexpressed in advanced TEMs.
Conclusions: We have unraveled a novel protumorigenic mechanism in TEMs, namely Hsp90-capacitated overexpression of IGF-1R, which confers apoptosis evasion in malignant thymic epithelial cells. Our data indicate that Hsp90 inhibition, which simultaneously blocks multiple cancer hallmarks, represents a therapeutic strategy in TEMs that may merit evaluation in clinical trials. Clin Cancer Res; 17(8); 2237–49. ©2011 AACR.
Phase I Dose-Escalation Study and Biomarker Analysis of E7080 in Patients with Advanced Solid Tumors
Authors: Yamada Kazuhiko , Yamamoto Noboru , Yamada Yasuhide , Nokihara Hiroshi , Fujiwara Yutaka , Hirata Taizo , Koizumi Fumiaki , Nishio Kazuto , Koyama Noriyuki , Tamura Tomohide 
Published: March 2011

Abstract
Purpose: E7080, an oral multitargeted receptor tyrosine kinase inhibitor, has antiangiogenic and antitumor activity. This Phase I study investigated maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK), pharmacodynamics (PD), and efficacy in patients with advanced solid tumors.
Experimental Design: In this sequential, dose-escalation, open-label study E7080 was administered orally twice daily in a 2-week-on/1-week-off cycle. Plasma angiogenic proteins, circulating endothelial cells (CEC) and circulating progenitor cells (CEP) were measured for biomarker analysis.
Results: Twenty-seven patients (median age 53 years, performance status 0/1) were enrolled. E7080 was escalated from 0.5 to 1, 2, 4, 6, 9, 13, 16, and 20 mg bid by conventional 3-patient cohorts. During cycle 1, no grade 3/4 toxicity was observed up to 13 mg bid. DLTs included grade 3 AST/ALT increase in 1 patient at 16 mg bid and grade 3 platelet count decrease in 2 patients at 20 mg bid. The MTD of 13 mg bid was determined. After repeated doses, Cmax and area under the plasma concentration–time curve increased in a dose-dependent manner. After 14 days' treatment, c-kit(+) CEPs and CECs significantly decreased in cycle 1, but c-kit(−) CEPs and CECs did not. Change from baseline in c-kit(+) CEC ratio in cycle 1 and baseline SDF1α, c-kit(+) CEPs and c-kit(+) CEP ratio significantly correlated with the E7080 therapeutic effect.
Conclusion: E7080 has manageable toxicity up to 13 mg bid when administered in a 2-week-on/1-week-off cycle and shows preliminary activity for durable disease control. Biomarker analysis suggested antiangiogenic activity correlated with antitumor activity in patients with a wide range of solid tumors. Clin Cancer Res; 17(8); 2528–37. ©2011 AACR.
Aberrant Methylation of the X-Linked Ribosomal S6 Kinase RPS6KA6 (RSK4) in Endometrial Cancers
Authors: Dewdney Summer B. , Rimel BJ , Thaker Premal H. , Thompson Dominic M , Schmidt Amy , Huettner Phyllis , Mutch David G. , Gao Feng , Goodfellow Paul J. 
Published: March 2011

Abstract
Purpose: Effective treatments for advanced endometrial cancer are lacking. Novel therapies that target specific pathways hold promise for better treatment outcomes with less toxicity. Mutation activation of the FGFR2/RAS/ERK pathway is important in endometrial tumorigenesis. RPS6KA6 (RSK4) is a putative tumor suppressor gene and is a target of the ERK signaling pathway. We explored the role of RSK4 in endometrial cancer.
Experimental Design: We showed that RSK4 is expressed in normal endometrial tissue and is absent or much reduced in endometrial cancer. On the basis of previous reports on methylation in other cancers, we hypothesized that the absence of RSK4 transcript is associated with epigenetic silencing rather than mutation. We determined the methylation and expression status of RSK4 in primary endometrial cancers and cell lines and the effects of treatment with a demethylating agent. The relationship between RSK4 methylation and clinicopathologic features was assessed.
Results: RSK4 is frequently hypermethylated in endometrial cancer cells lines and in primary endometrial cancer compared with normal endometrial tissue. RSK4 methylation was significantly associated with tumor grade, with higher grade tumors having lower levels of methylation (P = 0.03). RSK4 methylation levels were not associated with other clinical variables. We did find that RSK4 methylation was significantly correlated with expression in primary endometrial tumors and in cell lines. Reactivation of RSK4 by 5-azacytidine was successfully performed showing 8- to more than 1,200-fold increases in transcript levels.
Conclusion: RSK4 appears to be epigenetically silenced in endometrial cancer as evidenced by hypermethylation. Its role as a suppressor in endometrial cancer, however, remains uncertain. Clin Cancer Res; 17(8); 2120–9. ©2011 AACR.
(−)-Gossypol Suppresses the Growth of Human Prostate Cancer Xenografts via Modulating VEGF Signaling–Mediated Angiogenesis
Authors: Pang Xiufeng , Wu Yuanyuan , Wu Yougen , Lu Binbin , Chen Jing , Wang Jieqiong , Yi Zhengfang , Qu Weijing , Liu Mingyao 
Published: March 2011

Abstract(−)-Gossypol, a natural BH3-mimetic and small-molecule Bcl-2 inhibitor, shows promise in ongoing phase II clinical trials for human cancers. However, whether (−)-gossypol plays functional roles in tumor angiogenesis has not been directly elucidated yet. In this study, we showed that (−)-gossypol dose dependently inhibited the expression of VEGF, Bcl-2, and Bcl-xL in human prostate cancer cells (PC-3 and DU 145) and primary cultured human umbilical vascular endothelial cells (HUVEC) in vitro. Notably, the growth of human prostate tumor PC-3 xenografts in mice was significantly suppressed by (−)-gossypol at a dosage of 15 mg/kg/d. This inhibitory action of (−)-gossypol in vivo was largely dependent on suppression of angiogenesis in the solid tumors, where VEGF expression and microvessel density were remarkably decreased. Furthermore, (−)-gossypol inhibited VEGF-induced chemotactic motility and tubulogenesis in HUVECs and human microvascular endothelial cells and suppressed microvessel sprouting from rat aortic rings ex vivo. When examined for the mechanism, we found that (−)-gossypol blocked the activation of VEGF receptor 2 kinase with the half maximal inhibitory concentration of 2.38 μmol/L in endothelial cells. Consequently, the phosphorylation of key intracellular proangiogenic kinases induced by VEGF was all suppressed by the treatment, such as Src family kinase, focal adhesion kinase, extracellular signal-related kinase, and AKT kinase. Taken together, the present study shows that (−)-gossypol potently inhibits human prostate tumor growth through modulating VEGF signaling pathway, which further validates its great potential in clinical practice. Mol Cancer Ther; 10(5); 795–805. ©2011 AACR.
Regulatory Approval of Cancer Risk-Reducing (Chemopreventive) Drugs: Moving What We Have Learned into the Clinic
Authors: Meyskens Frank L. , Curt Gregory A. , Brenner Dean E. , Gordon Gary , Herberman Ronald B. , Finn Olivera , Kelloff Gary J. , Khleif Samir N. , Sigman Caroline C. , Szabo Eva 
Published: March 2011

Abstract
This article endeavors to clarify the current requirements and status of regulatory approval for chemoprevention (risk reduction) drugs and discusses possible improvements to the regulatory pathway for chemoprevention. Covering a wide range of topics in as much depth as space allows, this report is written in a style to facilitate the understanding of nonscientists and to serve as a framework for informing the directions of experts engaged more deeply with this issue. Key topics we cover here are as follows: a history of definitive cancer chemoprevention trials and their influence on the evolution of regulatory assessments; a brief review of the long-standing success of pharmacologic risk reduction of cardiovascular diseases and its relevance to approval for cancer risk reduction drugs; the use and limitations of biomarkers for developing and the approval of cancer risk reduction drugs; the identification of individuals at a high(er) risk for cancer and who are appropriate candidates for risk reduction drugs; business models that should incentivize pharmaceutical industry investment in cancer risk reduction; a summary of scientific and institutional barriers to development of cancer risk reduction drugs; and a summary of major recommendations that should help facilitate the pathway to regulatory approval for pharmacologic cancer risk reduction drugs. Cancer Prev Res; 4(3); 311–23. ©2011 AACR.
δ-Tocopherol Is More Active than α- or γ-Tocopherol in Inhibiting Lung Tumorigenesis In Vivo
Authors: Li Guang-Xun , Lee Mao-Jung , Liu Anna B. , Yang Zhihong , Lin Yong , Shih Weichung J. , Yang Chung S. 
Published: March 2011

Abstract
In contrast to strong epidemiologic, preclinical, and secondary clinical evidence for vitamin E (tocopherols) in reducing cancer risk, large-scale clinical cancer-prevention trials of α-tocopherol have been negative. This vexing contrast helped spur substantial preclinical efforts to better understand and improve the antineoplastic activity of tocopherol through, for example, the study of different tocopherol forms. We previously showed that the γ-tocopherol–rich mixture (γ-TmT) effectively inhibited colon and lung carcinogenesis and the growth of transplanted lung-cancer cells in mice. We designed this study to determine the relative activities of different forms of tocopherol in a xenograft model, comparing the anticancer activities of δ-tocopherol with those of α- and γ-tocopherols. We subcutaneously injected human lung cancer H1299 cells into NCr nu/nu mice, which then received α-, γ-, or δ-tocopherol or γ-TmT in the diet (each at 0.17% and 0.3%) for 49 days. δ-Tocopherol inhibited tumor growth most strongly. γ-Tocopherol and γ-TmT (at 0.3%) also inhibited growth significantly, but α-tocopherol did not. δ-Tocopherol also effectively decreased oxidative DNA damage and nitrotyrosine formation and enhanced apoptosis in tumor cells; again, γ-tocopherol also was active in these regards but less so, and α-tocopherol was not. Each supplemented diet increased serum levels of its tocopherol – up to 45 μmol/L for α-tocopherol, 9.7 μmol/L for γ-tocopherol, and 1.2 μmol/L for δ-tocopherol; dietary γ- or δ-tocopherol, however, decreased serum α-tocopherol levels, and dietary α-tocopherol decreased serum levels of γ-tocopherol. Each dietary tocopherol also increased its corresponding side-chain–degradation metabolites, with concentrations of δ-tocopherol metabolites greater than γ-tocopherol and far greater than α-tocopherol metabolites in serum and tumors. This study is the first in vivo assessment of δ-tocopherol in tumorigenesis and shows that δ-tocopherol is more active than α- or γ-tocopherol in inhibiting tumor growth, possibly through trapping reactive oxygen and nitrogen species and inducing apoptosis; δ-tocopherol metabolites could contribute significantly to these results. Cancer Prev Res; 4(3); 404–13. ©2011 AACR.
The Next Phase of Chemoprevention Research
Authors: Cohen Ezra E.W. , Schilsky Richard L. 
Published: March 2011

Abstract
Phase 0 clinical trials are meant to explore mechanism of action, pharmacokinetics, pharmacodynamics, or biodistribution of investigational compounds in an efficient manner with relatively few subjects. Phase 0 designs have been applied sparingly in cancer research, but this issue of the journal provides an example of their utility reported by Reid and colleagues (beginning on page 347). Indeed, aspects of the phase 0 design lend themselves well to chemoprevention research, suggesting that this approach will become more common in the near future. Cancer Prev Res; 4(3); 293–5. ©2011 AACR.
Reflections on the Spread of Metastasis to Cancer Prevention
Authors: Taketo Makoto Mark 
Published: March 2011

Abstract
Most patients with a lethal cancer die of metastasis, the control of which deserves to be one of the most urgent missions of cancer treatment. For some subsets of colorectal cancer, metastasis is stimulated by chemokines or Notch signaling at early stages that coincide with the inflammatory phase of postoperative wound healing. This temporary phase may provide a unique opportunity for “metastasis prevention,” because some novel agents have been developed that target such chemokine receptors or Notch signaling. Cancer Prev Res; 4(3); 324–8. ©2011 AACR.
The Sine Qua Non of Discovering Novel Biomarkers for Early Detection of Ovarian Cancer: Carefully Selected Preclinical Samples
Authors: Jacobs Ian , Menon Usha 
Published: March 2011

Abstract
This perspective discusses reports by Cramer and colleagues (beginning on page 365 in this issue of the journal) and Zhu and colleagues (beginning on page 375), which provide the first systematic and reliable comparison of a large number of candidate biomarkers for the early detection of ovarian cancer in a sample set well-suited for this purpose. This research has important implications for the future design of cancer biomarker studies. Cancer Prev Res; 4(3); 299–302. ©2011 AACR.
Challenges Related to Developing Serum-Based Biomarkers for Early Ovarian Cancer Detection
Authors: Mai Phuong L. , Wentzensen Nicolas , Greene Mark H. 
Published: March 2011

Abstract
In this issue of the journal, Cramer and colleagues and Zhu and colleagues report carefully designed phase 3 assessments of candidate ovarian cancer screening biomarkers. The main conclusion is that CA-125 remains the “best of a bad lot”; the new candidates have fallen short of expectations. We review factors impeding the development of an effective ovarian cancer screening strategy, highlight the requirements related to validating proposed screening biomarkers, and emphasize the risks from premature clinical applications of unvalidated tests, all underscoring the need for new research strategies. Cancer Prev Res; 4(3); 303–6. ©2011 AACR.
Endothelial Grb2-Associated Binder 1 Is Crucial for Postnatal Angiogenesis
Authors: Zhao Jinjing , Wang Weiye , Ha Chang Hoon , Kim Ji Young , Wong Chelsea , Redmond Eileen M. , Hamik Anne , Jain Mukesh K. , Feng Gen-Sheng , Jin Zheng Gen 
Published: March 2011

Objective—
Grb2-associated binder 1 (Gab1), a scaffolding adaptor protein, plays an important role in transmitting key signals that control cell growth, differentiation, and function from multiple tyrosine kinase receptors. The study was designed to investigate the role of endothelial Gab1 in angiogenesis and its underlying molecular mechanisms.

Methods and Results—
Using Cre-Lox recombination technology, we generated endothelial-specific Gab1 knockout (Gab1-ecKO) mice. Gab1-ecKO mice are viable and showed no obvious developmental defects in the vascular system. To analyze the role of Gab1 in postnatal angiogenesis, we used hindlimb ischemia and Matrigel plug models. We found that loss of endothelial Gab1 in mice dramatically impaired postnatal angiogenesis. Gab1-ecKO mice had impaired ischemia-initiated blood flow recovery, exhibited reduced angiogenesis, and were associated with marked limb necrosis. We further observed significant endothelial cell (EC) death in the ischemic hindlimb of Gab1-ecKO mice. Matrigel plug assay showed that hepatocyte growth factor (HGF)–mediated angiogenesis was inhibited in Gab1-ecKO mice. In vitro studies showed that Gab1 was required for HGF-induced EC migration, tube formation, and microvessel sprouting. Mechanistically, HGF stimulated Gab1 tyrosine phosphorylation in ECs, leading to activation of extracellular regulated MAP kinase 1/2 and Akt, which are angiogenic and survival signaling.

Conclusion—
Gab1 is essential for postnatal angiogenesis through mediating angiogenic and survival signaling.
A Critical Analysis of the Scientific Evidence Behind International Guidelines Related to Cardiac Arrhythmias
Authors: Roos Markus , Brodbeck Jeannette , Sarkozy Andrea , Battista Chierchia Gian , De Asmundis Carlo , Brugada Pedro 
Published: March 2011

Background—
Guidelines have become very important in assisting with decision making in clinical practice. However, few studies have analyzed the level of evidence (LOE) underlying guidelines critically. This study aims to assess the accuracy of the referenced literature that has led to recommendations with a level of evidence A (LOE-A) rating.

Methods and Results—
The latest updates of the practice guidelines related to arrhythmia posted on the European Society of Cardiology (ESC) web site were analyzed. The referenced literature for LOE-A recommendation was analyzed to reassess the proposed grading scheme for LOE-A. Furthermore, the clearly defined positive (Class I) and negative (Class III) recommendations with correctly referenced LOE-A were assessed. A median of 5.4% of all recommendations per guideline (interquartile range 4.9% to 9.7%) were categorized as LOE-A, but only 3.7% (IQR 3.4% to 4.9%) were accurately referenced as LOE-A. In total, 27 of 698 recommendations (median 1.2% per guideline [IQR 0.95% to 3.7%]) were correctly referenced as Class I or III LOE-A recommendations implying definite evidence-based positive or negative conclusion.

Conclusions—
Our findings raise the question of the accuracy of LOE-A in medical guidelines in general and highlight the importance of a critical use of all recommendations. Moreover, they underline the need for improving the guideline-writing process. Further randomized double-blinded and/or crossover-designed studies should focus on areas with a gap in the evidence, such as existing but not yet convincing (LOE-B) or conflicting (Class II) evidence.
Preprocedural Clinical Parameters Determining Perimitral Conduction Time During Mitral Isthmus Line Ablation
Authors: Miyazaki Shinsuke , Shah Ashok J. , Liu Xingpeng , Jadidi Amir S. , Nault Isabelle , Wright Matthew , Forclaz Andrei , Linton Nick , Xhaët Olivier , Rivard Lena , Derval Nicolas , Knecht Sébastien , Sacher Frédéric , Hocini Mélèze , Jaïs Pierre , Haïssaguerre Michel 
Published: March 2011

Background—
Achievement of complete conduction block across left mitral isthmus (MI) is challenging. Anticipation of perimitral conduction time (PMCT) associated with MI block may expedite this procedure. We evaluated the relationship between the preprocedural variables and the quantum of PMCT in patients with bidirectionally blocked MI.

Methods and Results—
We reviewed clinical and echocardiographic parameters in 290 consecutive patients with confirmed bidirectional MI block during atrial fibrillation (AF) ablation. PMCT was defined as the temporal delay to the latest of the double potentials on the line of block while pacing posteroseptal to it in the left atrium (LA). LA size and type of AF significantly influenced PMCT in multivariate analysis. A cumulative score based on LA size (0≦45 mm; 1>45 mm) and type of AF (0: paroxysmal; 1=nonparoxysmal) ranged from 0 to 2. PMCT was directly correlated to the cumulative score (0: 169 ms; n=78; 95% confidential interval, 156 to 181); 1: 187 ms; n=103; 95% confidential interval, 178 to 196; 2: 209 ms; n=109; 95% confidential interval, 200 to 217). In 61 patients who underwent AF ablation twice, the difference between 2 PMCT values was <30 ms in 75% patients. Another consecutive 143 patients with and without MI block after at least 15 minutes of radiofrequency application were analyzed. Perimitral conduction delay <130 ms ruled out bidirectional MI block. Perimitral conduction delay >173 ms predicted bidirectional block with an accuracy of 86%.

Conclusions—
LA size and AF type significantly influence PMCT in patients undergoing successful MI ablation. These parameters can be used to predict the time value associated with MI block, preprocedurally.
Chromosome 9p21 Haplotypes and Prognosis in White and Black Patients With Coronary Artery Disease
Authors: Gong Yan , Beitelshees Amber L. , Cooper-DeHoff Rhonda M. , Lobmeyer Maximilian T. , Langaee Taimour Y. , Wu Jun , Cresci Sharon , Province Michael A. , Spertus John A. , Pepine Carl J. , Johnson Julie A. 
Published: March 2011

Background—
Although numerous single-nucleotide polymorphisms (SNPs) in chromosome 9p21 have been associated with coronary artery disease (CAD) and incident myocardial infarction (MI) in whites, there are limited and conflicting reports on the association of this locus with prognosis in whites with existing CAD and no reports in blacks or Hispanics. We investigated the hypothesis that 9p21 polymorphisms are associated with increased risk for adverse cardiovascular outcomes in patients with documented CAD.

Methods and Results—

We studied the association of 155 chromosome 9p21 SNPs with adverse outcomes among hypertension patients with CAD of multiple races/ethnicities in INVEST-GENES (the International Verapamil SR Trandolapril Study Genetic Substudy) (n=1460 and n=5979 for 2 SNPs) with replication testing of 4 SNPs in the INFORM (Investigation of Outcomes From Acute Coronary Syndrome) study (n=714) of patients with acute coronary syndromes. In INVEST, the haplotype comprising the risk allele for the widely reported 9p21 SNPs was associated with better prognosis in whites (odds ratio [OR], 0.72; 95% CI, 0.57 to 0.92;
P
=0.0085) but not in blacks (OR, 1.21; 95% CI, 0.68 to 1.24;
P
=0.52) or Hispanics (OR, 0.96; 95% CI, 0.65 to 1.44;
P
=0.86). A less commonly reported linkage disequilibrium block was associated with worse prognosis in INVEST in both whites (OR, 1.52; 95% CI, 1.20 to 1.93;
P
=0.0006) and blacks (OR, 4.11; 95% CI, 1.55 to 10.88;
P
=0.004).

Conclusions—
Our findings suggest that previously reported chromosome 9p21 SNPs, which predict incident CAD, are not associated with higher risk for adverse outcomes in patients with established CAD. The less commonly reported linkage disequilibrium block warrants further investigation.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00133692.