bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mutations in BRAF and KRAS Converge on Activation of the Mitogen-Activated Protein Kinase Pathway in Lung Cancer Mouse Models
Authors: Ji Hongbin , Wang Zhenxiong , Perera Samanthi A. , Li Danan , Liang Mei-Chih , Zaghlul Sara , McNamara Kate , Chen Liang , Albert Mitchell , Sun Yanping , Al-Hashem Ruqayyah , Chirieac Lucian R. , Padera Robert , Bronson Roderick T. , Thomas Roman K. , Garraway Levi A. , Jänne Pasi A. , Johnson Bruce E. , Chin Lynda , Wong Kwok-Kin 
Published: May 2007

Abstract
Mutations in the BRAF and KRAS genes occur in ∼1% to 2% and 20% to 30% of non–small-cell lung cancer patients, respectively, suggesting that the mitogen-activated protein kinase (MAPK) pathway is preferentially activated in lung cancers. Here, we show that lung-specific expression of the BRAF V600E mutant induces the activation of extracellular signal–regulated kinase (ERK)-1/2 (MAPK) pathway and the development of lung adenocarcinoma with bronchioloalveolar carcinoma features in vivo. Deinduction of transgene expression led to dramatic tumor regression, paralleled by dramatic dephosphorylation of ERK1/2, implying a dependency of BRAF-mutant lung tumors on the MAPK pathway. Accordingly, in vivo pharmacologic inhibition of MAPK/ERK kinase (MEK; MAPKK) using a specific MEK inhibitor, CI-1040, induced tumor regression associated with inhibition of cell proliferation and induction of apoptosis in these de novo lung tumors. CI-1040 treatment also led to dramatic tumor shrinkage in murine lung tumors driven by a mutant KRas allele. Thus, somatic mutations in different signaling intermediates of the same pathway induce exquisite dependency on a shared downstream effector. These results unveil a potential common vulnerability of BRAF and KRas mutant lung tumors that potentially affects rational deployment of MEK targeted therapies to non–small-cell lung cancer patients. [Cancer Res 2007;67(10):4933–9]
Hint1 Inhibits Growth and Activator Protein-1 Activity in Human Colon Cancer Cells
Authors: Wang Lin , Zhang Yujing , Li Haiyang , Xu Zhiheng , Santella Regina M. , Weinstein I. Bernard 
Published: May 2007

Abstract
There is accumulating evidence that histidine triad (HIT) nucleotide-binding protein 1 (HINT1), a member of the evolutionary highly conserved HIT protein super family, is a novel tumor suppressor. However, the mechanism of action of HINT1 with respect to tumor suppression is not known. In the present study, we found that a series of human colon cancer cell lines displayed various levels of expression of HINT1, with a very low level in SW480 cells. This cell line also displayed partial methylation of the promoter region of the Hint1 gene, and treatment of these cells with 5-azadeoxycitidine increased expression of Hint1 mRNA and protein. Therefore, the decreased expression of HINT1 in SW480 cells seems to be due to epigenetic silencing. Increased expression of HINT1 in these cells, using a retrovirus vector (pLNCX2) that encodes either wild-type (WT) Hint1 or a point mutant (His112/Asn112) of Hint1, inhibited the proliferation of SW480 cells. Because of the important role of the activator protein-1 (AP-1) transcription factor in cancer cells, we examined possible effects of HINT1 on AP-1 transcription factor activity in SW480 cells transfected with an AP-1-luciferase reporter. We found that cotransfection with a pHA-Hint1 plasmid DNA significantly inhibited this activity. Studies with inhibitors indicated that AP-1 activity in SW480 cells requires the activity of c-Jun NH2-terminal kinase (JNK) 2 and not JNK1. Cotransfection with the Hint1 plasmid DNA also inhibited AP-1-luciferase reporter activity in WT mouse embryo fibroblast (MEF) studies, and studies with JNK1 deleted or JNK2 deleted MEFs confirmed the essential role for JNK2, but not JNK1, in mediating AP-1 activity. Recent studies indicate that the protein plenty of SH3 (POSH) provides a scaffold that enhances JNK activity. We found that cotransfection of a plasmid DNA encoding POSH stimulated the phosphorylation of c-Jun and also AP-1 reporter activity, and cotransfection with Hint1 inhibited both of these activities. Furthermore, coimmunoprecipitation studies provided evidence that HINT1 forms an in vivo complex with POSH and JNK. These results suggest that HINT1 inhibits AP-1 activity by binding to a POSH-JNK2 complex, thus inhibiting the phosphorylation of c-Jun. This effect could contribute to the tumor suppressor activity of HINT1. [Cancer Res 2007;67(10):4700–8]
Regulation of Helicobacter pylori cagA Expression in Response to Salt
Authors: Loh John T. , Torres Victor J. , Cover Timothy L. 
Published: May 2007

Abstract
Helicobacter pylori infection and a high dietary salt intake are risk factors for the development of gastric adenocarcinoma. In this study, we tested the hypothesis that high salt concentrations might alter gene expression in H. pylori. Transcriptional profiling experiments indicated that the expression of multiple H. pylori genes, including cagA, was regulated in response to the concentrations of sodium chloride present in the bacterial culture medium. Increased expression of cagA in response to high salt conditions was confirmed by the use of transcriptional reporter strains and by immunoblotting. H. pylori CagA is translocated into gastric epithelial cells via a type IV secretion pathway, and on entry into target cells, CagA undergoes tyrosine phosphorylation and causes multiple cellular alterations. Coculture of gastric epithelial cells with H. pylori grown under high salt conditions resulted in increased tyrosine-phosphorylated CagA and increased secretion of interleukin-8 by the epithelial cells compared with coculture of the cells with H. pylori grown under low salt conditions. Up-regulation of H. pylori cagA expression in response to high salt concentrations may be a factor that contributes to the development of gastric adenocarcinoma. [Cancer Res 2007;67(10):4709–15]
Tumor Suppressor Activity of CCAAT/Enhancer Binding Protein α Is Epigenetically Down-regulated in Head and Neck Squamous Cell Carcinoma
Authors: Bennett Kristi L. , Hackanson Björn , Smith Laura T. , Morrison Carl D. , Lang James C. , Schuller David E. , Weber Frank , Eng Charis , Plass Christoph 
Published: May 2007

Abstract
Tumor suppressor CCAAT enhancer binding protein α (C/EBPα) is a transcription factor involved in cell cycle control and cellular differentiation. In a recent study, microarray expression profiling on head and neck squamous cell carcinoma (HNSCC) samples identified significant C/EBPα down-regulation, correlating with poor prognosis. However, the mechanisms of C/EBPα down-regulation remained elusive. C/EBPα has been previously found to provide an antiproliferative role in lung cancer, and our laboratory showed that its down-regulation involves epigenetic mechanisms. This prompted us to investigate the involvement of epigenetics in down-regulating C/EBPα in HNSCC. Here, we show that C/EBPα is down-regulated in HNSCC by loss of heterozygosity and DNA methylation, but not by gene mutation. We found a consistently methylated upstream regulatory region (−1,399 bp to −1,253 bp in relation to the transcription start site) in 68% of the HNSCC tumor samples, and DNA demethylation using 5-aza-2′-deoxycytidine treatment was able to significantly restore C/EBPα mRNA expression in the HNSCC cell lines we tested. In addition, C/EBPα overexpression in a HNSCC cell line (SCC22B) revealed its ability to provide tumor suppressor activity in HNSCC in vitro and in vivo. In conclusion, we showed for the first time not only that C/EBPα has tumor suppressor activity in HNSCC, but also that it is down-regulated by DNA promoter methylation. [Cancer Res 2007;67(10):4657–64]
Suicide Gene Therapy of Human Colon Carcinoma Xenografts Using an Armed Oncolytic Adenovirus Expressing Carboxypeptidase G2
Authors: Schepelmann Silke , Ogilvie Lesley M. , Hedley Douglas , Friedlos Frank , Martin Janet , Scanlon Ian , Chen Ping , Marais Richard , Springer Caroline J. 
Published: May 2007

Abstract
We have designed a targeted systemic suicide gene therapy that combines the advantages of tumor-selective gene expression, using the human telomerase promoter (hTERT), with the beneficial effects of an oncolytic adenovirus to deliver the gene for the prodrug-activating enzyme carboxypeptidase G2 (CPG2) to tumors. Following delivery of the vector (AdV.hTERT-CPG2) and expression of CPG2 in cancer cells, the prodrug ZD2767P was administered for conversion by CPG2 to a cytotoxic drug. This system is sometimes termed gene-directed enzyme prodrug therapy (GDEPT). Here, we have shown that it is applicable to 10 human colorectal carcinoma cell lines with a direct correlation between viral toxicity and CPG2 production. SW620 xenografts were selected for analysis and were significantly reduced or eradicated after a single administration of AdV.hTERT-CPG2 followed by a prodrug course. The oncolytic effect of adenovirus alone did not result in DNA cross-links or apoptosis, whereas DNA cross-links and apoptosis occurred following prodrug administration, showing the combined beneficial effects of the GDEPT system. The apoptotic regions extended beyond the areas of CPG2 expression in the tumors, indicative of significant bystander effects in vivo. Higher concentrations of vector particles and CPG2 were found in the AdV.hTERT-CPG2 plus prodrug–treated tumors compared with the virus alone, showing an unexpected beneficial and cooperative effect between the vector and GDEPT. This is the first time that a tumor-selective GDEPT vector has been shown to be effective in colorectal carcinoma and that apoptosis and significant bystander effects have been identified as the mechanisms of cytotoxicity within the tumor. [Cancer Res 2007;67(10):4949–55]
Hu/Mu ProtIn Oligonucleotide Microarray: Dual-Species Array for Profiling Protease and Protease Inhibitor Gene Expression in Tumors and Their Microenvironment
Authors: Schwartz Donald R. , Moin Kamiar , Yao Bin , Matrisian Lynn M. , Coussens Lisa M. , Bugge Thomas H. , Fingleton Barbara , Acuff Heath B. , Sinnamon Mark , Nassar Hind , Platts Adrian E. , Krawetz Stephen A. , Linebaugh Bruce E. , Sloane Bonnie F. 
Published: May 2007

Abstract
Proteolysis is a critical regulatory mechanism for a wide variety of physiologic and pathologic processes. To assist in the identification of proteases, their endogenous inhibitors, and proteins that interact with proteases or proteolytic pathways in biological tissues, a dual-species oligonucleotide microarray has been developed in conjunction with Affymetrix. The Hu/Mu ProtIn microarray contains 516 and 456 probe sets that survey human and mouse genes of interest (proteases, protease inhibitors, or interactors), respectively. To investigate the performance of the array, gene expression profiles were analyzed in pure mouse and human samples (reference RNA; normal and tumor cell lines/tissues) and orthotopically implanted xenografts of human A549 lung and MDA-MB-231 breast carcinomas. Relative gene expression and “present-call” P values were determined for each probe set using dChip and MAS5 software, respectively. Despite the high level of sequence identity of mouse and human protease/inhibitor orthologues and the theoretical potential for cross-hybridization of some of the probes, &gt;95% of the “present calls” (P &lt; 0.01) resulted from same-species hybridizations (e.g., human transcripts to human probe sets). To further assess the performance of the microarray, differential gene expression and false discovery rate analyses were carried out on human or mouse sample groups, and data processing methods to optimize performance of the mouse and human probe sets were identified. The Hu/Mu ProtIn microarray is a valuable discovery tool for the identification of components of human and murine proteolytic pathways in health and disease and has particular utility in the determination of cellular origins of proteases and protease inhibitors in xenograft models of human cancer. (Mol Cancer Res 2007;5(5):443–54)
Gα12/13 Basally Regulates p53 through Mdm4 Expression
Authors: Kim Mi-Sung , Lee Sang Min , Kim Won Dong , Ki Sung Hwan , Moon Aree , Lee Chang Ho , Kim Sang Geon 
Published: May 2007

Abstract
Gα12/13, which belongs to the Gα12 family, participates in the regulation of diverse physiologic processes. In view of the control of Gα12/13 in cell proliferation, this study investigated the role of Gα12/13 in the regulation of p53 and mdm4. Immunoblotting and immunocytochemistry revealed that p53 was expressed in control embryonic fibroblasts and was largely localized in the nuclei. Gα12 deficiency decreased p53 levels and its DNA binding activity, accompanying p21 repression with Bcl2 induction, whereas Gα13 deficiency exerted weak effects. Gα12 or Gα13 deficiency did not change p53 mRNA expression. ERK1/2 or Akt was not responsible for p53 repression due to Gα12 deficiency. Mdm4, a p53-stabilizing protein, was repressed by Gα12 deficiency and to a lesser extent by Gα13 deficiency, whereas mdm2, PTEN, β-catenin, ATM, and Chk2 were unaffected. p53 accumulation by proteasomal inhibition during Gα12 deficiency suggested the role of Gα12 in p53 stabilization. Constitutively active Gα12 (Gα12QL) or Gα13 (Gα13QL) promoted p53 accumulation with mdm4 induction in MCF10A cells. p53 accumulation by mdm4 overexpression, but no mdm4 induction by p53 overexpression, and small interfering RNA knockdown verified the regulatory role of mdm4 for p53 downstream of Gα12/13. In control or Gα12/Gα13-deficient cells, genotoxic stress led to p53 accumulation. At concentrations increasing the flow cytometric pre-G1 phase, doxorubicin or etoposide treatment caused serine phosphorylations in Gα12−/− or Gα12/13−/− cells, but did not induce mdm4. Gα12/13QL transfection failed to phosphorylate p53 at serines. Our results indicate that Gα12/13 regulate basal p53 levels via mdm4, which constitutes a cell signaling pathway distinct from p53 phosphorylations elicited by genotoxic stress. (Mol Cancer Res 2007;5(5):473–84)
The Effect of the Galápagos Islands on the Equatorial Pacific Cold Tongue
Authors: Karnauskas Kristopher B. , Murtugudde Raghu , Busalacchi Antonio J. 
Published: May 2007

Abstract
A reduced-gravity ocean general circulation model of the tropical Pacific Ocean is used to determine potential improvements to the simulated equatorial Pacific cold tongue region through choices in horizontal resolution and coastline geometry—in particular, for the Galápagos Islands. Four simulations are performed, with identical climatological forcing. Results are compared between model grids with and without the Galápagos Islands, with coarse and fine resolutions. It is found that properly including the Galápagos Islands results in the obstruction of the Equatorial Undercurrent (EUC), which leads to improvements in the simulated spatial structure of the cold tongue, including a basinwide warming of up to 2°C in the east-central Pacific. The obstruction of the EUC is directly related to the improvements east of the Galápagos Islands, and for the basinwide reduction of the tropical cold bias through an equatorial dynamical adjustment. The pattern of SST warming resulting from the inclusion of the Galápagos Islands is similar to that of the known cold biases in ocean models and the current National Oceanic and Atmospheric Administration Climate Forecast System. It is thought that such an improvement would have a considerable impact on the ability of coupled ocean–atmosphere and ocean–ecosystem models to produce realistic clouds, precipitation, surface ocean bioproductivity, and carbon cycling in the tropical Pacific Ocean.
Interpreting Eddy Fluxes
Authors: Eden Carsten , Greatbatch Richard J. , Olbers Dirk 
Published: May 2007

Abstract
A generalization of the transformed Eulerian and temporal residual means is presented. The new formulation uses rotational fluxes of buoyancy, and the full hierarchy of statistical density moments, to reduce the cross-isopycnal eddy flux to the physically relevant component associated with the averaged water mass properties. The resulting eddy-induced diapycnal diffusivity vanishes for adiabatic, statistically steady flow, and is related to either the growth or decay of mesoscale density variance and/or the covariance between small-scale forcing (mixing) and density fluctuations, such as that associated with the irreversible removal of density variance by dissipation. The relationship between the new formulation and previous approaches is described and is illustrated using results from an eddying channel model. The formalism is quite general and applies to all kinds of averaging and to any tracer (not just density).
RETRACTED: Targeting MEK induces myeloma-cell cytotoxicity and inhibits osteoclastogenesis
Authors: Tai Yu-Tzu , Fulciniti Mariateresa , Hideshima Teru , Song Weihua , Leiba Merav , Li Xian-Feng , Rumizen Matthew , Burger Peter , Morrison Aileen , Podar Klaus , Chauhan Dharminder , Tassone Pierfrancesco , Richardson Paul , Munshi Nikhil C. , Ghobrial Irene M. , Anderson Kenneth C. 
Published: May 2007

This article has been retracted: please see Elsevier's Article Correction, Retraction and Removal Policy Article withdrawal | Elsevier policy.
Tai Y-T, Fulciniti M, Hideshima T, Song W, Leiba M, Li X-F, Rumizen M, Burger P, Morrison A, Podar K, Chauhan D, Tassone P, Richardson P, Munshi NC, Ghobrial IM, Anderson KC. Targeting MEK induces myeloma-cell cytotoxicity and inhibits osteoclastogenesis. Blood 2007;110(5):1656-1663.
This article has been retracted at the request of the Editors and authors.
Within the paper, image issues were identified in Figures 1, 4, and 6. Images within these figures show duplication, modification, or unmarked splices.
The authors state that these figures cannot be used to support the conclusions of the paper.
Authors Tai, Fulciniti, Song, Li, Morrison, Chauhan, Tassone, Ghobrial, and Anderson approve the retraction. Authors Hideshima, Leiba, Rumizen, Burger, Podar, Richardson, and Munshi did not respond.
Identification of hot regions in protein-protein interactions by sequential pattern mining
Authors: Hsu Chen-Ming , Chen Chien-Yu , Liu Baw-Jhiune , Huang Chih-Chang , Laio Min-Hung , Lin Chien-Chieh , Wu Tzung-Lin 
Published: May 2007

AbstractBackgroundIdentification of protein interacting sites is an important task in computational molecular biology. As more and more protein sequences are deposited without available structural information, it is strongly desirable to predict protein binding regions by their sequences alone. This paper presents a pattern mining approach to tackle this problem. It is observed that a functional region of protein structures usually consists of several peptide segments linked with large wildcard regions. Thus, the proposed mining technology considers large irregular gaps when growing patterns, in order to find the residues that are simultaneously conserved but largely separated on the sequences. A derived pattern is called a cluster-like pattern since the discovered conserved residues are always grouped into several blocks, which each corresponds to a local conserved region on the protein sequence.ResultsThe experiments conducted in this work demonstrate that the derived long patterns automatically discover the important residues that form one or several hot regions of protein-protein interactions. The methodology is evaluated by conducting experiments on the web server MAGIIC-PRO based on a well known benchmark containing 220 protein chains from 72 distinct complexes. Among the tested 218 proteins, there are 900 sequential blocks discovered, 4.25 blocks per protein chain on average. About 92% of the derived blocks are observed to be clustered in space with at least one of the other blocks, and about 66% of the blocks are found to be near the interface of protein-protein interactions. It is summarized that for about 83% of the tested proteins, at least two interacting blocks can be discovered by this approach.ConclusionThis work aims to demonstrate that the important residues associated with the interface of protein-protein interactions may be automatically discovered by sequential pattern mining. The detected regions possess high conservation and thus are considered as the computational hot regions. This information would be useful to characterizing protein sequences, predicting protein function, finding potential partners, and facilitating protein docking for drug discovery.
A population study of the minicircles in Trypanosoma cruzi: predicting guide RNAs in the absence of empirical RNA editing
Authors: Thomas Sean , Martinez LL Isadora Trejo , Westenberger Scott J , Sturm Nancy R 
Published: May 2007

AbstractBackgroundThe structurally complex network of minicircles and maxicircles comprising the mitochondrial DNA of kinetoplastids mirrors the complexity of the RNA editing process that is required for faithful expression of encrypted maxicircle genes. Although a few of the guide RNAs that direct this editing process have been discovered on maxicircles, guide RNAs are mostly found on the minicircles. The nuclear and maxicircle genomes have been sequenced and assembled forTrypanosoma cruzi, the causative agent of Chagas disease, however the complement of 1.4-kb minicircles, carrying four guide RNA genes per molecule in this parasite, has been less thoroughly characterised.ResultsFifty-four CL Brener and 53 Esmeraldo strain minicircle sequence reads were extracted fromT. cruziwhole genome shotgun sequencing data. With these sequences and all publishedT. cruziminicircle sequences, 108 unique guide RNAs from all knownT. cruziminicircle sequences and two guide RNAs from the CL Brener maxicircle were predicted using a local alignment algorithm and mapped onto predicted or experimentally determined sequences of edited maxicircle open reading frames. For half of the sequences no statistically significant guide RNA could be assigned. Likely positions of these unidentified gRNAs inT. cruziminicircle sequences are estimated using a simple Hidden Markov Model. With the local alignment predictions as a standard, the HMM had an ~85% chance of correctly identifying at least 20 nucleotides of guide RNA from a given minicircle sequence. Inter-minicircle recombination was documented. Variable regions contain species-specific areas of distinct nucleotide preference. Two maxicircle guide RNA genes were found.ConclusionThe identification of new minicircle sequences and the further characterization of all published minicircles are presented, including the first observation of recombination between minicircles. Extrapolation suggests a level of 4% recombinants in the population, supporting a relatively high recombination rate that may serve to minimize the persistence of gRNA pseudogenes. Characteristic nucleotide preferences observed within variable regions provide potential clues regarding the transcription and maturation ofT. cruziguide RNAs. Based on these preferences, a method of predictingT. cruziguide RNAs using only primary minicircle sequence data was created.