bluuebunny/crossref_metadata_2025_split huggingface dataset:
KIT Mutations Induce Intracellular Retention and Activation of an Immature Form of the KIT Protein in Gastrointestinal Stromal Tumors
Authors: Tabone-Eglinger Séverine , Subra Frédéric , El Sayadi Hiba , Alberti Laurent , Tabone Eric , Michot Jean-Philippe , Théou-Anton Nathalie , Lemoine Antoinette , Blay Jean-Yves , Emile Jean-François 
Published: April 2008

Abstract
Purpose: Gastrointestinal stromal tumors (GIST) are frequently associated with gain-of-function mutations of KIT, which can be inhibited by imatinib both in vitro and in vivo. The survival of patients with GIST, following imatinib therapy, has been correlated with the nature of mutations but not with KIT expression.
Experimental Design: Subcellular localization, activation, and trafficking of the mature and the immature forms of KIT were investigated in GIST samples and in NIH3T3 cells infected with two different GIST-type exon 11–mutated human KIT cDNA.
Results: Paranuclear dot expression of KIT was more frequent in GISTs with homozygous KIT mutations than in those with heterozygous (P = 0.01) or no mutations (P &lt; 0.01). Activation of the immature 125 kDa form of KIT was detected in most GISTs with KIT mutations but not in GISTs without KIT mutations. In NIH3T3 cells, mutant KIT was mainly retained within endoplasmic reticulum and Golgi compartments in an immature constitutively phosphorylated form, whereas the wild-type KIT was expressed at the plasma membrane, in a mature nonphosphorylated form. Imatinib-induced inhibition of the phosphorylation of immature and mature mutant KIT proteins resulted in the restoration of KIT expression at the cell surface.
Conclusions: These results show that GIST-type KIT mutations induce an activation-dependent alteration of normal maturation and trafficking, resulting in the intracellular retention of the activated kinase within the cell. These observations likely account for the absence of correlation between response to imatinib and KIT expression using immunohistochemistry and may deserve to be investigated in other tyrosine kinase–activated tumors.
Loss of Complex I due to Mitochondrial DNA Mutations in Renal Oncocytoma
Authors: Mayr Johannes A. , Meierhofer David , Zimmermann Franz , Feichtinger Rene , Kögler Christian , Ratschek Manfred , Schmeller Nikolaus , Sperl Wolfgang , Kofler Barbara 
Published: April 2008

Abstract
Purpose: Many solid tumors exhibit abnormal aerobic metabolism characterized by increased glycolytic capacity and decreased cellular respiration. Recently, mutations in the nuclear encoded mitochondrial enzymes fumarate hydratase and succinate dehydrogenase have been identified in certain tumor types, thus demonstrating a direct link between mitochondrial energy metabolism and tumorigenesis. Although mutations in the mitochondrial genome (mitochondrial DNA, mtDNA) also can affect aerobic metabolism and mtDNA alterations are frequently observed in tumor cells, evidence linking respiratory chain deficiency in a specific tumor type to a specific mtDNA mutation has been lacking.
Experimental Design: To identify mitochondrial alterations in oncocytomas, we investigated the activities of respiratory chain enzymes and sequenced mtDNA in 15 renal oncocytoma tissues.
Results: Here, we show that loss of respiratory chain complex I (NADH/ubiquinone oxidoreductase) is associated with renal oncocytoma. Enzymatic activity of complex I was undetectable or greatly reduced in the tumor samples (n = 15). Blue Native gel electrophoresis of the multisubunit enzyme complex revealed a lack of assembled complex I. Mutation analysis of the mtDNA showed frame-shift mutations in the genes of either subunit ND1, ND4, or ND5 of complex I in 9 of the 15 tumors.
Conclusion: Our data indicate that isolated loss of complex I is a specific feature of renal oncocytoma and that this deficiency is frequently caused by somatic mtDNA mutations.
Inhibiting Fatty Acid Synthase for Chemoprevention of Chemically Induced Lung Tumors
Authors: Orita Hajime , Coulter Jonathan , Tully Ellen , Kuhajda Francis P. , Gabrielson Edward 
Published: April 2008

AbstractPurpose: Fatty acid synthase (FAS) is overexpressed in lung cancer, and we have investigated the potential use of FAS inhibitors for chemoprevention of lung cancer.Experimental Design: Expression of FAS was evaluated in preinvasive human lung lesions (bronchial squamous dysplasia and atypical adenomatous hyperplasia) and in murine models of lung tumorigenesis [4-(methylnitrosamino)-I-(3-pyridyl)-1-butanone–induced and urethane-induced lung tumors in A/J mice]. Then, the ability of pharmacologic inhibitors of FAS to prevent development of the murine tumors was investigated. Finally, the effect of the FAS inhibitor treatment of levels of phosphorylated Akt in the murine tumors was evaluated by immunohistochemistry.Results: Immunohistochemical studies show that human bronchial dysplasia and atypical adenomatous hyperplasia express high levels of FAS compared with normal lung tissues, suggesting that FAS might be a target for intervention in lung carcinogenesis. FAS is also expressed at high levels in chemically induced murine lung tumors, and the numbers and sizes of those murine tumors are significantly reduced by treating carcinogen-exposed mice with pharmacologic inhibitors of FAS, C75 and C93. C93 treatment is associated with reduced levels of phosphorylated Akt in tumor tissues, suggesting that inhibition of this signal transduction pathway might be involved in the chemopreventative activity of this compound.Conclusions: We conclude that increased levels of FAS are common in human preinvasive neoplasia of the lung. Based on studies in mouse models, it seems that inhibiting FAS is an effective strategy in preventing and retarding growth of lung tumors that have high expression of this enzyme.
Therapeutic Significance of Elevated Tissue Transglutaminase Expression in Pancreatic Cancer
Authors: Verma Amit , Guha Sushovan , Diagaradjane Parmeswaran , Kunnumakkara Ajaikumar B. , Sanguino Angela M. , Lopez-Berestein Gabriel , Sood Anil K. , Aggarwal Bharat B. , Krishnan Sunil , Gelovani Juri G. , Mehta Kapil 
Published: April 2008

Abstract
Purpose: Tissue transglutaminase (TG2) is a multifunctional protein that is implicated in development of drug resistance and metastasis. Therefore, we examined therapeutic targeting of TG2 for inhibiting growth and metastasis of in vivo growing pancreatic ductal adenocarcinoma (PDAC) in nude mice.
Experimental Design: We implanted Panc-28 pancreatic cancer cells to induce orthotopic PDAC tumors in nude mice and determined the efficacy of liposomal TG2 small interfering RNA (siRNA) either alone or in combination with gemcitabine.
Results: We show that down-regulation of endogenous TG2 by siRNA could effectively block the growth of PDAC. Moreover, down-regulation of TG2 significantly enhanced the therapeutic efficacy of gemcitabine against PDAC and inhibited metastatic spread of the disease. The antitumor activity was related to inhibition of proliferation, angiogenesis, and Akt phosphorylation.
Conclusion: siRNA-mediated down-regulation of TG2 represents a promising therapeutic approach for improved treatment of PDAC.
Ornithine Decarboxylase G316A Genotype Is Prognostic for Colorectal Adenoma Recurrence and Predicts Efficacy of Aspirin Chemoprevention
Authors: Hubner Richard A. , Muir Kenneth R. , Liu Jo-Fen , Logan Richard F.A. , Grainge Matthew J. , Houlston Richard S. ,   Members of the UKCAP Consortium
Published: April 2008

Abstract
Purpose: The chemopreventive activity of aspirin in colorectal neoplasia may be explained in part by its effect on polyamine metabolism. The ornithine decarboxylase (ODC) G316A polymorphism affects polyamine metabolism through altered expression of ODC. We investigated the influence of ODC G316A on the chemopreventive activity of aspirin in colorectal adenoma (CRA) recurrence.
Experimental Design: We genotyped ODC G316A in 546 individuals in the United Kingdom Colorectal Adenoma Prevention trial of aspirin for CRA recurrence prevention and pooled our findings with data from two other randomized intervention trials.
Results: The United Kingdom Colorectal Adenoma Prevention participants with homozygous ODC 316AA genotype were at reduced CRA recurrence risk [relative risk (RR), 0.43; 95% confidence interval (95% CI), 0.16-1.15], particularly if also exposed to aspirin (RR, 0.24; 95% CI, 0.03-1.71). In the pooled analysis of 2,207 individuals, those with homozygous ODC 316AA genotype were at significantly reduced CRA recurrence risk (RR, 0.68; 95% CI, 0.47-0.99). Following stratification by genotype and aspirin exposure, individuals with homozygous wild-type or heterozygous genotypes derived modest benefit from aspirin (RR, 0.85; 95% CI, 0.72-1.01), whereas in those with both ODC 316AA genotype and aspirin exposure recurrence risk was halved (RR, 0.52; 95% CI, 0.29-0.91).
Conclusion: The ODC G316A genotype is prognostic for CRA recurrence and predictive of an enhanced response to aspirin in preventing recurrence. This variant has the potential to be a clinically useful genetic marker to identify individuals likely to derive the greatest benefit from aspirin chemoprevention.
Clinical Significance of High Mobility Group A2 in Human Gastric Cancer and Its Relationship to let-7 MicroRNA Family
Authors: Motoyama Kazuo , Inoue Hiroshi , Nakamura Yoshito , Uetake Hiroyuki , Sugihara Kenichi , Mori Masaki 
Published: April 2008

Abstract
Purpose: The high mobility group A2 (HMGA2) nonhistone chromosomal protein can modulate transcription by altering chromatin architecture. HMGA2 is highly expressed during embryogenesis and in various benign and malignant tumors. Recent studies report that HMGA2 is negatively regulated by the let-7 microRNA (miRNA) family. However, no studies have examined the clinical significance of HMGA2 and its relationship to the let-7 miRNA family in gastric cancer.
Experimental Design: Using quantitative real-time reverse transcription–PCR, we analyzed HMGA2 expression with respect to various clinicopathologic factors in 110 patients with gastric cancer. We also did an association study comparing HMGA2 expression and let-7 miRNA family expression in gastric cancer.
Results: Expression of HMGA2 in cancerous tissues was significantly higher than in noncancerous tissues (P &lt; 0.05). Elevated HMGA2 expression was significantly correlated with serosal invasion (P &lt; 0.05) and poor clinical prognosis (P &lt; 0.05). A multivariate analysis showed that HMGA2 expression status was an independent prognostic factor (P &lt; 0.05). An inverse correlation between HMGA2 and let-7a was found in gastric cancer cell lines (P = 0.08). The expressions of let-7a, let-7b, and let-7c in gastric cancer patients with low HMGA2 expression were significantly higher than those with high HMGA2 expression (P &lt; 0.05).
Conclusions: High expression of HMGA2 in gastric cancer correlates with tumor invasiveness and is an independent prognostic factor. Furthermore, our findings suggest that HMGA2 is negatively regulated by the let-7 miRNA family in human gastric cancer.
Cyclooxygenase-2 dependent and independent antitumor effects induced by celecoxib in urinary bladder cancer cells
Authors: Dhawan Deepika , Jeffreys Antonella Borgatti , Zheng Rong , Stewart Jane C. , Knapp Deborah W. 
Published: April 2008

Abstract
Transitional cell carcinoma of the urinary bladder is the second most common genitourinary malignancy in people in the United States. Cyclooxygenase-2 (COX-2) is overexpressed in bladder cancer. COX-2 inhibitors have had antitumor activity against bladder cancer, but the mechanisms of action are unclear. Clinically relevant concentrations of COX-2 inhibitors fail to inhibit proliferation in standard in vitro assays. In pilot experiments, different culture conditions [standard monolayer, modified monolayer, soft agar, collagen, and poly(2-hydroxyethyl methacrylate)–coated plates] were assessed to determine conditions suitable for the study of COX inhibitor growth-inhibitory effects. This was followed by studies of the effects of clinically relevant concentrations of a selective COX-2 inhibitor (celecoxib) on urinary bladder cancer cell lines (HT1376, TCCSUP, and UMUC3). Celecoxib (≤5 μmol/L) inhibited proliferation of COX-2–expressing HT1376 cells in soft agar and modified monolayer cell culture conditions in a COX-2–dependent manner. COX-2 expression, however, did not always correlate with response to celecoxib. TCCSUP cells that express COX-2 were minimally affected by celecoxib, and UMUC3 cells that lack COX-2 expression were modestly inhibited by the drug. When UMUC3Cox-2/Tet cells overexpressing COX-2 under the control of tetracycline-inducible promoter were treated with celecoxib in modified monolayer cell culture, growth inhibition was found to be associated with changes in the expression of pRb. Not surprisingly, the proliferation of all cell lines was inhibited by excessively high concentrations of celecoxib. In conclusion, the modified culture conditions allowed detection of COX-2–dependent and COX-2–independent growth-inhibitory activity of celecoxib in urinary bladder cancer cells. [Mol Cancer Ther 2008;7(4):897–904]
A selective small molecule inhibitor of c-Met, PHA-665752, reverses lung premalignancy induced by mutant K-ras
Authors: Yang Yanan , Wislez Marie , Fujimoto Nobukazu , Prudkin Ludmila , Izzo Julie G. , Uno Futoshi , Ji Lin , Hanna Amy E. , Langley Robert R. , Liu Diane , Johnson Faye M. , Wistuba Ignacio , Kurie Jonathan M. 
Published: April 2008

Abstract
The c-Met receptor tyrosine kinase has been implicated in cellular transformation induced by mutant Ras, a commonly activated proto-oncogene in non-small cell lung cancer (NSCLC). However, the role of c-Met has not been defined in K-ras-mutant NSCLC, a disease for which no effective targeted therapeutic options currently exist. To acquire a greater understanding of its role, we used genetic and pharmacologic approaches to inhibit c-Met in mice and cultured cells. In KrasLA1 mice, which develop premalignant lung lesions that progress to multifocal lung adenocarcinomas owing to somatic mutations in K-ras, c-Met was expressed in multiple cell types within premalignant lung lesions, and high concentrations of HGF were detected in bronchoalveolar lavage samples. Short-term treatment with PHA-665752, a c-Met inhibitor, decreased the numbers of premalignant lung lesions and induced apoptosis in tumor cells and vascular endothelial cells within lesions. In cell culture, PHA-665752 induced apoptosis of a lung adenocarcinoma cell line derived from KrasLA1 mice (LKR-13) and a murine lung endothelial cell line (MEC). c-Met depletion by siRNA transfection induced apoptosis of MECs but not LKR-13 cells. Collectively, these findings suggest that apoptosis was an on-target effect of PHA-665752 in MECs but not in LKR-13 cells. We conclude that PHA-665752 inhibited lung tumorigenesis in KrasLA1 mice and may provide a novel therapeutic approach to the prevention of K-ras-mutant NSCLC. [Mol Cancer Ther 2008;7(4):952–60]
The T790M “gatekeeper” mutation in EGFR mediates resistance to low concentrations of an irreversible EGFR inhibitor
Authors: Godin-Heymann Nadia , Ulkus Lindsey , Brannigan Brian W. , McDermott Ultan , Lamb Jennifer , Maheswaran Shyamala , Settleman Jeffrey , Haber Daniel A. 
Published: April 2008

Abstract
Patients with non–small cell lung cancer (NSCLC) harboring activating mutations in the epidermal growth factor receptor (EGFR) kinase domain tend to respond well to the tyrosine kinase inhibitors, gefitinib and erlotinib. However, following clinical response, these patients typically relapse within a year of treatment. In many cases, resistance is caused by an acquired secondary EGFR kinase domain mutation, T790M. In vitro studies have shown that a new class of EGFR-irreversible inhibitors could overcome the resistance conferred by T790M. Clinical trials are under way to examine the efficacy of one of these inhibitors, HKI-272, in patients with NSCLC who initially responded to gefitinib/erlotinib and subsequently relapsed. To anticipate the possibility that patients who respond to irreversible inhibitors will develop secondary resistance to such inhibitors, as has been seen in other similar settings, we modeled acquired resistance to the dual EGFR/HER2-irreversible tyrosine kinase inhibitor HKI-272 in a NSCLC cell culture model. We found that HKI-272–resistant clones fall into two biochemical groups based on the retention of EGFR phosphorylation in the presence of the drug. Cells that retain phosphorylated EGFR have acquired the secondary mutation T790M. Moreover, HKI-272 can overcome T790M resistance only at suprapharmacologic concentrations. We further model mutations at EGFR C797 as a mechanism of resistance to irreversible EGFR inhibitors and show that although these mutants are resistant to the irreversible inhibitor, they retain erlotinib sensitivity. Our findings suggest that HKI-272 treatment at maximally tolerated dosing may lead to the emergence of T790M-mediated resistance, whereas treatment with a more potent irreversible inhibitor could yield a resistance mutation at EGFR C797. [Mol Cancer Ther 2008;7(4):874–9]
Aberrant Crypt Foci in the Adenoma Prevention with Celecoxib Trial
Authors: Cho Nancy L. , Redston Mark , Zauber Ann G. , Carothers Adelaide M. , Hornick Jason , Wilton Andrew , Sontag Stephen , Nishioka Norman , Giardiello Francis M. , Saltzman John R. , Gostout Chris , Eagle Craig J. , Hawk Ernest T. , Bertagnolli Monica M. 
Published: April 2008

Abstract
Aberrant crypt foci (ACF) are the earliest visible neoplastic lesions in the colorectum. The natural history of these lesions and their role in the adenoma-carcinoma sequence are unknown. We studied ACF in a subset of patients randomized to placebo (n = 17), celecoxib (200 mg twice daily; n = 15), or celecoxib (400 mg twice daily; n = 13) in the Adenoma Prevention with Celecoxib (APC) trial. Magnification chromoendoscopy was done to identify, count, and biopsy ACF within the rectum at baseline and after 8 to 12 months of treatment. A total of 655 ACF were identified in 45 patients. We examined 70 of these ACF histologically, and all 70 were nondysplastic. Cohort characteristics and APC trial treatment results for substudy patients were similar to those of the overall APC trial. There was no significant modulation of ACF by celecoxib (versus placebo; P = 0.77). Immunohistochemical comparison of ACF with adjacent normal mucosa showed that ACF had an increased proliferative index as determined by Ki-67 (P &lt; 0.0001), but lacked other features of neoplasia such as increased cyclooxygenase-2 expression and microvessel density, nuclear localization of β-catenin, or decreased expression of the tumor suppressors SMAD4, Estrogen Receptor α, or MGMT. Only baseline SMAD4 expression in ACF correlated with posttreatment adenoma recurrence (independent of treatment arm; P = 0.01). The presence or number of nondysplastic ACF did not correlate with a higher risk of synchronous advanced or recurrent adenomas. Our overall results indicated that nondysplastic ACF were not accurate surrogate endpoint biomarkers of recurrent colorectal adenomas in the APC trial.
Difluoromethylornithine Plus Sulindac for the Prevention of Sporadic Colorectal Adenomas: A Randomized Placebo-Controlled, Double-Blind Trial
Authors: Meyskens Frank L. , McLaren Christine E. , Pelot Daniel , Fujikawa-Brooks Sharon , Carpenter Philip M. , Hawk Ernest , Kelloff Gary , Lawson Michael J. , Kidao Jayashri , McCracken John , Albers C. Gregory , Ahnen Dennis J. , Turgeon D. Kim , Goldschmid Steven , Lance Peter , Hagedorn Curt H. , Gillen Daniel L. , Gerner Eugene W. 
Published: April 2008

Abstract
Preclinical studies of chemoprevention drugs given in combination at low doses show remarkable efficacy in preventing adenomas with little additional toxicities, suggesting a strategy to improve risk to benefit ratios for preventing recurrent adenomas. Three hundred seventy-five patients with history of resected (≥3 mm) adenomas were randomly assigned to receive oral difluoromethylornithine (DFMO) 500 mg and sulindac 150 mg once daily or matched placebos for 36 months, stratified by use of low-dose aspirin (81 mg) at baseline and clinical site. Follow-up colonoscopy was done 3 years after randomization or off-study. Colorectal adenoma recurrence was compared among the groups with log-binomial regression. Comparing the outcome in patients receiving placebos to those receiving active intervention, (a) the recurrence of one or more adenomas was 41.1% and 12.3% (risk ratio, 0.30; 95% confidence interval, 0.18-0.49; P &lt; 0.001); (b) 8.5% had one or more advanced adenomas, compared with 0.7% of patients (risk ratio, 0.085; 95% confidence interval, 0.011-0.65; P &lt; 0.001); and (c) 17 (13.2%) patients had multiple adenomas (&gt;1) at the final colonoscopy, compared with 1 (0.7%; risk ratio, 0.055; 0.0074-0.41; P &lt; 0.001). Serious adverse events (grade ≥3) occurred in 8.2% of patients in the placebo group, compared with 11% in the active intervention group (P = 0.35). There was no significant difference in the proportion of patients reporting hearing changes from baseline. Recurrent adenomatous polyps can be markedly reduced by a combination of low oral doses of DFMO and sulindac and with few side effects.
Advanced Rain/No-Rain Classification Methods for Microwave Radiometer Observations over Land
Authors: Seto Shinta , Kubota Takuji , Takahashi Nobuhiro , Iguchi Toshio , Oki Taikan 
Published: April 2008

Abstract
Seto et al. developed rain/no-rain classification (RNC) methods over land for the Tropical Rainfall Measuring Mission (TRMM) Microwave Imager (TMI). In this study, the methods are modified for application to other microwave radiometers. The previous methods match TMI observations with TRMM precipitation radar (PR) observations, classify the TMI pixels into rain pixels and no-rain pixels, and then statistically summarize the observed brightness temperature at the no-rain pixels into a land surface brightness temperature database. In the modified methods, the probability distribution of brightness temperature under no-rain conditions is derived from unclassified TMI pixels without the use of PR. A test with the TMI shows that the modified (PR independent) methods are better than the RNC method developed for the Goddard profiling algorithm (GPROF; the standard algorithm for the TMI) while they are slightly poorer than corresponding previous (PR dependent) methods. M2d, one of the PR-independent methods, is applied to observations from the Advanced Microwave Scanning Radiometer for Earth Observing Satellite (AMSR-E), is evaluated for a matchup case with PR, and is evaluated for 1 yr with a rain gauge dataset in Japan. M2d is incorporated into a retrieval algorithm developed by the Global Satellite Mapping of Precipitation project to be applied for the AMSR-E. In latitudes above 30°N, the rain-rate retrieval is compared with a rain gauge dataset by the Global Precipitation Climatology Center. Without a snow mask, a large amount of false rainfall due to snow contamination occurs. Therefore, a simple snow mask using the 23.8-GHz channel is applied and the threshold of the mask is optimized. Between 30° and 60°N, the optimized snow mask forces the miss of an estimated 10% of the total rainfall.
Settling of Particles beneath Water Waves
Authors: Eames Ian 
Published: April 2008

AbstractConsidered here is the motion of small particles beneath irrotational water waves. The added mass and inertial forces are shown to be an important role in the mean transport of particles. To leading order, particles are transported with a mean horizontal Stokes drift velocity and sediment with their terminal fall velocity. The combination of a settling velocity and a mean drift transports particles a finite distance forward from their point of release.