bluuebunny/crossref_metadata_2025_split huggingface dataset:
CAMTA1, a 1p36 Tumor Suppressor Candidate, Inhibits Growth and Activates Differentiation Programs in Neuroblastoma Cells
Authors: Henrich Kai-Oliver , Bauer Tobias , Schulte Johannes , Ehemann Volker , Deubzer Hedwig , Gogolin Sina , Muth Daniel , Fischer Matthias , Benner Axel , König Rainer , Schwab Manfred , Westermann Frank 
Published: March 2011

Abstract
A distal portion of human chromosome 1p is often deleted in neuroblastomas and other cancers and it is generally assumed that this region harbors one or more tumor suppressor genes. In neuroblastoma, a 261 kb region at 1p36.3 that encompasses the smallest region of consistent deletion pinpoints the locus for calmodulin binding transcription activator 1 (CAMTA1). Low CAMTA1 expression is an independent predictor of poor outcome in multivariate survival analysis, but its potential functionality in neuroblastoma has not been explored. In this study, we used inducible cell models to analyze the impact of CAMTA1 on neuroblastoma biology. In neuroblastoma cells that expressed little endogenous CAMTA1, its ectopic expression slowed cell proliferation, increasing the relative proportion of cells in G1/G0 phases of the cell cycle, inhibited anchorage-independent colony formation, and suppressed the growth of tumor xenografts. CAMTA1 also induced neurite-like processes and markers of neuronal differentiation in neuroblastoma cells. Further, retinoic acid and other differentiation- inducing stimuli upregulated CAMTA1 expression in neuroblastoma cells. Transciptome analysis revealed 683 genes regulated on CAMTA1 induction and gene ontology analysis identified genes consistent with CAMTA1-induced phenotypes, with a significant enrichment for genes involved in neuronal function and differentiation. Our findings define properties of CAMTA1 in growth suppression and neuronal differentiation that support its assignment as a 1p36 tumor suppressor gene in neuroblastoma. Cancer Res; 71(8); 3142–51. ©2011 AACR.
Overexpression of a Novel Activator of PAK4, the CDK5 Kinase–Associated Protein CDK5RAP3, Promotes Hepatocellular Carcinoma Metastasis
Authors: Mak Grace Wing-Yan , Chan Mandy Man-Lok , Leong Veronica Yee-Law , Lee Joyce Man-Fong , Yau Tai-On , Ng Irene Oi-Lin , Ching Yick-Pang 
Published: March 2011

Abstract
The CDK5 kinase regulatory subunit-associated protein 3 (CDK5RAP3 or C53/LZAP) regulates apoptosis induced by genotoxic stress. Although CDK5RAP3 has been implicated in cancer progression, its exact role in carcinogenesis is not well established. In this article, we report that CDK5RAP3 has an important prometastatic function in hepatocarcinogenesis. An examination of human hepatocellular carcinoma (HCC) samples revealed at least twofold overexpression of CDK5RAP3 transcripts in 58% (39/67) of HCC specimens when compared with corresponding nontumorous livers. CDK5RAP3 overexpression was associated with more aggressive biological behavior. In HCC cell lines, stable overexpression of CDK5RAP3 promoted, and small interfering RNA–mediated knockdown inhibited, tumorigenic activity and metastatic potential. We found that overexpression of CDK5RAP3 and p21-activated protein kinase 4 (PAK4) correlated in human HCCs, and that CDK5RAP3 was a novel binding partner of PAK4, and this binding enhanced PAK4 activity. siRNA-mediated knockdown of PAK4 in CDK5RAP3-expressing HCC cells reversed the enhanced cell invasiveness mediated by CDK5RAP3 overexpression, implying that PAK4 is essential for CDK5RAP3 function. Taken together, our findings reveal that CDK5RAP3 is widely overexpressed in HCC and that overexpression of CDK5RAP3 promotes HCC metastasis through PAK4 activation. Cancer Res; 71(8); 2949–58. ©2011 AACR.
Cdk2 is Required for Breast Cancer Mediated by the Low-Molecular-Weight Isoform of Cyclin E
Authors: Akli Said , Van Pelt Carolyn S. , Bui Tuyen , Meijer Laurent , Keyomarsi Khandan 
Published: March 2011

Abstract
Cyclin E activates Cdk2, controls centrosome duplication, and regulates histone gene transcription. Cyclin E is deregulated in cancer and appears as low-molecular-weight (LMW) isoforms that correlate strongly with decreased survival in breast cancer patients. Transgenic mice overexpressing LMW-cyclin E have increased incidence of mammary tumors and distant metastasis when compared with mice that had full-length cyclin E. To specifically test the requirement for Cdk2 in LMW-cyclin E–mediated mammary tumorigenesis, we generated transgenic mice, which expressed LMW-cyclin E in a Cdk2-deficient background. We found that mammary gland development proceeds relatively normally in these animals, indicating that Cdk2 kinase activity is largely dispensable for this process. However, Cdk2-deficient mice were completely resistant to LMW-cyclin E–mediated mammary tumors. Cdk2 wild-type or heterozygous mice succumbed to mammary tumors with mean latencies of 16 and 19.5 months, respectively, but Cdk2 nullizygous littermates did not display tumors through 24 months. Similarly, continuous administration of two different Cdk inhibitors significantly delayed LMW-cyclin E–induced mammary tumor progression. Triple transgenic mice generated in a p53 heterozygous background also displayed no tumors. Finally, we found that Cdk2 silencing induced cell death in LMW-overexpressing breast cancer cell lines, but not in cell lines lacking LMW expression. Our findings establish a requirement for Cdk2 in LMW-cyclin E–mediated mammary tumorigenesis, arguing that human breast tumors overexpressing LMW-cyclin E are prime candidates for anti-Cdk2 therapy. Cancer Res; 71(9); 3377–86. ©2011 AACR.
Molecular Karyotypes of Hodgkin and Reed–Sternberg Cells at Disease Onset Reveal Distinct Copy Number Alterations in Chemosensitive versus Refractory Hodgkin Lymphoma
Authors: Slovak Marilyn L. , Bedell Victoria , Hsu Ya-Hsuan , Estrine Dolores B. , Nowak Norma J. , Delioukina Maria L. , Weiss Lawrence M. , Smith David D. , Forman Stephen J. 
Published: March 2011

AbstractPurpose: To determine the recurring DNA copy number alterations (CNA) in classical Hodgkin lymphoma (HL) by microarray-based comparative genomic hybridization (aCGH) using laser capture microdissected CD30+ Hodgkin and Reed–Sternberg (HRS) cells.Experimental Design: Archived tissues from 27 CD30+ HL plus control samples were analyzed by DNA microarrays. The HL molecular karyotypes were compared with the genomic profiles of germinal center B cells and treatment outcome (chemotherapy responsive vs. primary refractory disease).Results: Gains and losses observed in more than 35% of HL samples were localized to 22 and 12 chromosomal regions, respectively. Frequent gains (&gt;65%) were associated with growth and proliferation, NF-κB activation, cell-cycle control, apoptosis, and immune and lymphoid development. Frequent losses (&gt;40%) observed encompassed tumor suppressor genes (SPRY1, NELL1, and ID4, inhibitor of DNA binding 4), transcriptional repressors (TXNIP, thioredoxin interacting protein), SKP2 (S-phase kinase-associated protein 2; ubiquitin ligase component), and an antagonist of NF-κB activation (PPARGC1A). In comparison to the germinal center profiles, the most frequent imbalances in HL were losses in 5p13 (AMACR, GDNF, and SKP2), and gains in 7q36 (SHH, sonic hedgehog homolog) and 9q34 (ABL1, CDK9, LCN2, and PTGES). Gains (&gt;35%) in the HL chemoresponsive patients housed genes known to regulate T-cell trafficking or NF-κB activation (CCL22, CX3CL1, CCL17, DOK4, and IL10), whereas the refractory samples showed frequent loss of 4q27 (interleukin; IL21/IL2) and 17p12, and gain of 19q13.3 (BCL3/RELB).Conclusion: We identified nonrandom CNAs in the molecular karyotypes of classical HL. Several recurring genetic lesions correlated with disease outcome. These findings may be useful prognostic markers in the counseling and management of patients and for the development of novel therapeutic approaches in primary refractory HL. Clin Cancer Res; 17(10); 3443–54. ©2011 AACR.
The Histone Methyltransferase and Putative Oncoprotein MMSET Is Overexpressed in a Large Variety of Human Tumors
Authors: Hudlebusch Heidi Rye , Santoni-Rugiu Eric , Simon Ronald , Ralfkiær Elisabeth , Rossing Henrik Holm , Johansen Jens Vilstrup , Jørgensen Mette , Sauter Guido , Helin Kristian 
Published: March 2011

Abstract
Purpose: Multiple myeloma SET (Suppressor of variegation, Enhancer of zeste, and Trithorax) domain (MMSET) is a histone lysine methyltransferase deregulated in a subgroup of multiple myelomas with the t(4;14)(p16;q32) translocation and poor prognosis. With the aim of understanding, if MMSET can be involved in other types of cancer we investigated the expression of MMSET protein in different types of human tumors.
Experimental Design: A monoclonal antibody against MMSET was developed and immunohistochemical staining of tissue microarrays (TMA) containing a large number of tumor samples (n = 3774) and corresponding normal tissues (n = 904) was carried out. Further validations of MMSET expression were carried out on independent, tumor-specific sets of TMAs for urinary bladder (n = 1293) and colon cancer (n = 1206) with corresponding clinicopathological data and long-term follow-up.
Results: MMSET protein was highly expressed in different tumor types compared to normal counterparts. Particular frequent and/or high MMSET expression was found in carcinomas of the gastrointestinal tract (stomach, colon, anal canal), small cell lung carcinoma, tumors of the urinary bladder, female genitals, and skin. In bladder cancer, MMSET expression correlated with tumor aggressiveness. In contrast, MMSET expression was associated with good prognostic factors in colon cancer and was more pronounced in early stages of colon carcinogenesis (dysplasias) than in adenocarcinomas. However, colon cancer patients with high MMSET levels showed a worse 5-year survival.
Conclusions: Our data suggest that MMSET has a broader role in cancer than previously anticipated, and further analysis might qualify it as a prognostic marker and a target for the development of therapy against several types of cancer. Clin Cancer Res; 17(9); 2919–33. ©2011 AACR.
Synergistic Effect between Erlotinib and MEK Inhibitors in KRAS Wild-Type Human Pancreatic Cancer Cells
Authors: Diep Caroline H. , Munoz Ruben M. , Choudhary Ashish , Von Hoff Daniel D. , Han Haiyong 
Published: March 2011

Abstract
Purpose: The combination of erlotinib and gemcitabine has shown a small but statistically significant survival advantage when compared with gemcitabine alone in patients with advanced pancreatic cancer. However, the overall survival rate with the erlotinib and gemcitabine combination is still low. In this study, we sought to identify gene targets that, when inhibited, would enhance the activity of epidermal growth factor receptor (EGFR)-targeted therapies in pancreatic cancer cells.
Experimental Design: A high-throughput RNA interference (RNAi) screen was carried out to identify candidate genes. Selected gene hits were further confirmed and mechanisms of action were further investigated using various assays.
Results: Six gene hits from siRNA screening were confirmed to significantly sensitize BxPC-3 pancreatic cancer cells to erlotinib. One of the hits, mitogen-activated protein kinase (MAPK) 1, was selected for further mechanistic studies. Combination treatments of erlotinib and two MAP kinase kinase (MEK) inhibitors, RDEA119 and AZD6244, showed significant synergistic effect for both combinations (RDEA119–erlotinib and AZD6244–erlotinib) compared with the corresponding single drug treatments in pancreatic cancer cell lines with wild-type KRAS (BxPC-3 and Hs 700T) but not in cell lines with mutant KRAS (MIA PaCa-2 and PANC-1). The enhanced antitumor activity of the combination treatment was further verified in the BxPC-3 and MIA PaCa-2 mouse xenograft model. Examination of the MAPK signaling pathway by Western blotting indicated effective inhibition of the EGFR signaling by the drug combination in KRAS wild-type cells but not in KRAS mutant cells.
Conclusions: Overall, our results suggest that combination therapy of an EGFR and MEK inhibitors may have enhanced efficacy in patients with pancreatic cancer. Clin Cancer Res; 17(9); 2744–56. ©2011 AACR.
Randomized Double-Blind Trial of Sulindac and Etodolac to Eradicate Aberrant Crypt Foci and to Prevent Sporadic Colorectal Polyps
Authors: Takayama Tetsuji , Nagashima Hiroyuki , Maeda Masahiro , Nojiri Shuichi , Hirayama Michiaki , Nakano Yoichiro , Takahashi Yasuo , Sato Yasushi , Sekikawa Hitoshi , Mori Mitsuru , Sonoda Tomoko , Kimura Tetsuo , Kato Junji , Niitsu Yoshiro 
Published: March 2011

Abstract
Purpose: On the basis of the results of our preliminary trial suggesting that aberrant crypt foci (ACF) could be eradicated by short-term administration of sulindac, in the present study, we explored the feasibility of using ACF as surrogate markers for chemoprevention of colorectal cancer.
Experimental design: Randomly assigned to sulindac (300 mg daily), etodolac (400 mg daily), and placebo groups were 189 subjects without polyps or who had undergone polypectomy. Drugs were administered for 2 months. ACF in the rectal region were counted by magnifying endoscopy. Occurrence of polyps was evaluated at 12 months. A planned interim analysis was conducted.
Results: ACF number at 2 months was significantly suppressed in the sulindac group (P = 0.0075), but not in the etodolac group (P = 0.73). In the sulindac group, the numbers of adenomas plus hyperplastic polyps (total polyps) and adenomas at 12 months were significantly (P = 0.02) and marginally (P = 0.064) lower, respectively, in comparison with the placebo group; no such difference was observed in the etodolac group. In analysis of only polypectomized subjects, the numbers of total polyps and adenomas in the sulindac group were even more markedly lower, with P values of 0.014 and 0.034, respectively. A similar tendency was confirmed by analyses of the incidence of polyps at 12 months. Suppression rates of total polyps and adenomas in ACF responders to sulindac were significantly greater than in nonresponders. In all groups, compliance was more than 90% and no intolerable adverse effects were observed.
Conclusions: ACF may be useful as surrogate lesions for chemoprevention of colorectal cancer. Clin Cancer Res; 17(11); 3803–11. ©2011 AACR.
Global Gene Expression Profiling and Validation in Esophageal Squamous Cell Carcinoma and Its Association with Clinical Phenotypes
Authors: Su Hua , Hu Nan , Yang Howard H. , Wang Chaoyu , Takikita Mikiko , Wang Quan-Hong , Giffen Carol , Clifford Robert , Hewitt Stephen M. , Shou Jian-Zhong , Goldstein Alisa M. , Lee Maxwell P. , Taylor Philip R. 
Published: March 2011

Abstract
Purpose: Esophageal squamous cell carcinoma (ESCC) is an aggressive tumor with poor prognosis. Understanding molecular changes in ESCC will enable identification of molecular subtypes and provide potential targets for early detection and therapy.
Experimental Design: We followed up a previous array study with additional discovery and confirmatory studies in new ESCC cases by using alternative methods. We profiled global gene expression for discovery and confirmation, and validated selected dysregulated genes with additional RNA and protein studies.
Results: A total of 159 genes showed differences with extreme statistical significance (P &lt; E-15) and 2-fold differences or more in magnitude (tumor/normal RNA expression ratio, N = 53 cases), including 116 upregulated and 43 downregulated genes. Of 41 genes dysregulated in our prior array study, all but one showed the same fold change directional pattern in new array studies, including 29 with 2-fold changes or more. Alternative RNA expression methods validated array results: more than two thirds of 51 new cases examined by real-time PCR (RT-PCR) showed 2-fold differences or more for all seven genes assessed. Immunohistochemical protein expression results in 275 cases which were concordant with RNA for five of six genes.
Conclusion: We identified an expanded panel of genes dysregulated in ESCC and confirmed previously identified differentially expressed genes. Microarray-based gene expression results were confirmed by RT-PCR and protein expression studies. These dysregulated genes will facilitate molecular categorization of tumor subtypes and identification of their risk factors, and serve as potential targets for early detection, outcome prediction, and therapy. Clin Cancer Res; 17(9); 2955–66. ©2011 AACR.
Intra–Lymph Node Prime-Boost Vaccination against Melan A and Tyrosinase for the Treatment of Metastatic Melanoma: Results of a Phase 1 Clinical Trial
Authors: Ribas Antoni , Weber Jeffrey S. , Chmielowski Bartosz , Comin-Anduix Begonya , Lu David , Douek Michael , Ragavendra Nagesh , Raman Steve , Seja Elizabeth , Rosario Darlene , Miles Sabrina , Diamond David C. , Qiu Zhiyong , Obrocea Mihail , Bot Adrian 
Published: March 2011

Abstract
Purpose: The goal of this study was to test the safety and activity of a therapeutic vaccine, MKC1106-MT, in patients with metastatic melanoma.
Experimental Design: MKC1106-MT comprises a plasmid (pMEL-TYR) and two peptides (E-MEL and E-TYR), corresponding to Melan A and tyrosinase, administered by intra–lymph node injection in a prime-boost sequence. All 18 patients were HLA-A*0201 positive and received a fixed priming dose of plasmid and a low or a high peptide dose. Enumeration of antigen-specific T cells was done prior to and throughout the treatment. Patients who did not exhibit disease progression remained on study and could receive up to eight cycles of treatment.
Results: The MKC1106-MT regimen was well tolerated and resulted in an overall immune response rate of 50%. The treatment showed disease control, defined as stable disease that lasted for 8 weeks or more in 6 of 18 (33%) of the patients: 14% and 46% in the low and high peptide dose, respectively. Interestingly, four patients, all with tumor burden largely confined to lymph nodes and Melan A–specific T cells at baseline, showed durable disease control associated with radiologic evidence of tumor regression. There was no noticeable correlation between the expansion of antigen-specific T cells in blood and the clinical outcome; yet, there was evidence of active tumor-infiltrating lymphocytes (TIL) in two regressing lesions.
Conclusions: MKC1106-MT showed immunogenicity and evidence of disease control in a defined patient population. These findings support further development of this investigational agent and the concept of therapeutic vaccination in metastatic melanoma. Clin Cancer Res; 17(9); 2987–96. ©2011 AACR.
Clinical Outcomes in Patients With the Concomitant Use of Clopidogrel and Proton Pump Inhibitors After Percutaneous Coronary Intervention
Authors: Harjai Kishore J. , Shenoy Chetan , Orshaw Pam , Usmani Samer , Boura Judy , Mehta Rajendra H. 
Published: March 2011

Background—
The concomitant use of proton pump inhibitors (PPIs) with clopidogrel is suspected to be associated with an adverse impact on clinical outcomes in patients with coronary artery disease. We sought to evaluate whether the use of PPIs with clopidogrel was associated with worse clinical outcomes after percutaneous coronary intervention (PCI) compared with the use of clopidogrel alone.

Methods and Results—
We studied 2651 consecutive patients discharged alive after coronary stenting for stable or unstable coronary artery disease between 2001 and 2007. All patients received aspirin indefinitely and a thienopyridine for 1 to 12 months. Patients were categorized into 2 groups: those taking a PPI [PPI (+), n=751] and those not taking a PPI [PPI (−), n=1900] at discharge. The primary end points were the 6-month incidence of major adverse cardiovascular events (MACE) (composite of death, myocardial infarction, target vessel revascularization, and stent thrombosis) and net adverse clinical events (NACE) (composite of MACE and thrombolysis in myocardial infarction major or minor bleeding), which were evaluated using propensity-adjusted Cox regression analysis. In addition, propensity-matched analysis was performed in 685 pairs of patients. The PPI (+) group was older and had more comorbid conditions than the PPI (−) group. In propensity-adjusted as well as propensity-matched analyses, the use of PPIs was not associated with an increased risk of MACE or NACE.

Conclusions—
The use of PPIs with dual antiplatelet therapy was not associated with any adverse influence on MACE or NACE after PCI.
Impact of a Depression Care Management Program for Hospitalized Cardiac Patients
Authors: Huffman Jeff C. , Mastromauro Carol A. , Sowden Gillian , Fricchione Gregory L. , Healy Brian C. , Januzzi James L. 
Published: March 2011

Background—
Depression is independently associated with poor outcomes among patients with acute cardiac disease. Collaborative care depression management programs have been used in outpatients to improve depression outcomes, but such a program had never been initiated in the hospital or used for patients with a wide range of cardiac illnesses.

Methods and Results—

This was a prospective, randomized trial of a low-intensity, 12-week collaborative care program versus usual care for 175 depressed patients hospitalized for acute coronary syndrome, arrhythmia, or heart failure. Study outcomes, assessed using mixed regression models to compare groups at 6 weeks, 12 weeks, and 6 months, included mental health (depression, cognitive symptoms of depression, anxiety, and mental health-related quality of life) and medical (physical health-related quality of life, adherence to medical recommendations, and cardiac symptoms) outcomes. Collaborative care subjects (n=90) had significantly greater improvements on all mental health outcomes at 6 and 12 weeks, including rates of depression response (collaborative care, 59.7% versus usual care 33.7%; odds ratio, 2.91;
P
=0.003 at 6 weeks; 51.5% versus 34.4%; odds ratio, 2.02;
P
=0.04 at 12 weeks), though these effects decreased after intervention. At 6 months, intervention subjects had significantly greater self-reported adherence and significantly reduced number and intensity of cardiac symptoms.

Conclusions—
Among patients with a broad range of cardiac diagnoses, a collaborative care depression management program initiated during hospitalization led to significant improvements in multiple clinically important mental health outcomes and had promising effects on relevant medical outcomes after intervention.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00847132.