bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional Genomic Analysis Identified Epidermal Growth Factor Receptor Activation as the Most Common Genetic Event in Oral Squamous Cell Carcinoma
Authors: Sheu Jim Jinn-Chyuan , Hua Chun-Hung , Wan Lei , Lin Ying-Ju , Lai Ming-Tsung , Tseng Hsien-Chang , Jinawath Natini , Tsai Ming-Hsui , Chang Nai-Wen , Lin Chin-Fen , Lin Chyi-Chyang , Hsieh Lie-Jiau , Wang Tian-Li , Shih Ie-Ming , Tsai Fuu-Jen 
Published: March 2009

Abstract
A 250K single-nucleotide polymorphism array was used to study subchromosomal alterations in oral squamous cell carcinoma (OSCC). The most frequent amplification was found at 7p11.2 in 9 of 29 (31%) oral cancer patients. Minimal genomic mapping verified a unique amplicon spanning from 54.6 to 55.3 Mb on chromosome 7, which contains SEC61G and epidermal growth factor receptor (EGFR). Results from fluorescence in situ hybridization, transcriptome, and immunohistochemistry analyses indicated that the expression level of EGFR, but not of SEC61G, was up-regulated and tightly correlated with DNA copy number in 7p11.2 amplified tumors. Among the members of the erbB family, EGFR (HER1) was found to be the most frequently amplified and highly expressed gene in both human and mouse oral tumors (P &lt; 0.01). Genes for downstream effectors of EGFR, including KRAS, mitogen-activated protein kinase 1, and CCND1, were also found amplified or mutated, which resulted in activation of EGFR signaling in 55% of OSCC patients. Head and neck squamous cancer cells with different EGFR expression levels showed differential sensitivity to antitumor effects of AG1478, a potent EGFR inhibitor. AG1478-induced EGFR inactivation significantly suppressed tumor development and progression in a mouse oral cancer model. Our data suggest that EGFR signaling is important in oral cancer development and that anti-EGFR therapy would benefit patients who carry the 7p11.2 amplicon in their tumors. [Cancer Res 2009;69(6):2568–76]
Immune-Induced Epithelial to Mesenchymal Transition In vivo Generates Breast Cancer Stem Cells
Authors: Santisteban Marta , Reiman Jennifer M. , Asiedu Michael K. , Behrens Marshall D. , Nassar Aziza , Kalli Kimberly R. , Haluska Paul , Ingle James N. , Hartmann Lynn C. , Manjili Masoud H. , Radisky Derek C. , Ferrone Soldano , Knutson Keith L. 
Published: March 2009

Abstract
The breast cancer stem cell (BCSC) hypotheses suggest that breast cancer is derived from a single tumor-initiating cell with stem-like properties, but the source of these cells is unclear. We previously observed that induction of an immune response against an epithelial breast cancer led in vivo to the T-cell–dependent outgrowth of a tumor, the cells of which had undergone epithelial to mesenchymal transition (EMT). The resulting mesenchymal tumor cells had a CD24−/loCD44+ phenotype, consistent with BCSCs. In the present study, we found that EMT was induced by CD8 T cells and the resulting tumors had characteristics of BCSCs, including potent tumorigenicity, ability to reestablish an epithelial tumor, and enhanced resistance to drugs and radiation. In contrast to the hierarchal cancer stem cell hypothesis, which suggests that breast cancer arises from the transformation of a resident tissue stem cell, our results show that EMT can produce the BCSC phenotype. These findings have several important implications related to disease progression and relapse. [Cancer Res 2009;69(7):2887–95]
FOXP3 Up-regulates p21 Expression by Site-Specific Inhibition of Histone Deacetylase 2/Histone Deacetylase 4 Association to the Locus
Authors: Liu Runhua , Wang Lizhong , Chen Guoyun , Katoh Hiroto , Chen Chong , Liu Yang , Zheng Pan 
Published: March 2009

Abstract
p21 loss has been implicated in conferring oncogenic activity to known tumor suppressor gene KLF4 and cancer drug tamoxifen. Regulators of p21, therefore, play critical roles in tumorigenesis. Here, we report that X-linked tumor suppressor FOXP3 is essential for p21 expression in normal epithelia and that lack of FOXP3 is associated with p21 down-regulation in breast cancer samples. A specific FOXP3 binding site in the intron 1 is essential for p21 induction by FOXP3. FOXP3 specifically inhibited binding of histone deacetylase 2 (HDAC2) and HDAC4 to the site and increased local histone H3 acetylation. Short hairpin RNA silencing of either HDAC2 or HDAC4 is sufficient to induce p21 expression. Our data provides a novel mechanism for transcription activation by FOXP3 and a genetic mechanism for lack of p21 in a large proportion of breast cancer. [Cancer Res 2009;69(6):2252–9]
Aurora A Regulates Prometaphase Progression by Inhibiting the Ability of RASSF1A to Suppress APC-Cdc20 Activity
Authors: Song Su Jung , Song Min Sup , Kim Soon Jung , Kim So Yeon , Kwon Seung Hae , Kim Jhin Gook , Calvisi Diego F. , Kang Dongmin , Lim Dae-Sik 
Published: March 2009

AbstractThe Aurora (Ipl) kinase family plays important roles in the regulation of mitosis and tumorigenesis. The tumor suppressor RASSF1A controls mitotic progression by regulating anaphase-promoting complex (APC)-Cdc20 activity and microtubule stability, but the mechanism by which this action is regulated has not been previously established. Here, we show that Aurora A and B associate with and phosphorylate RASSF1A on serine 203 in vivo at different times and in different subcellular compartments during mitosis. Notably, both depletion of Aurora A by RNA interference and expression of a nonphosphorylatable RASSF1A (S203A) mutant gene led to a marked delay in prometaphase progression. This is likely because of the failure of RASSF1A to dissociate from Cdc20, constitutive inhibition of APC-Cdc20, and accumulation of mitotic cyclins. In contrast, the delay in prometaphase progression caused by Aurora A depletion was largely normalized by phosphomimetic RASSF1A (S203D). Finally, RASSF1A phosphorylation on serine 203 was up-regulated in Aurora A–overexpressing human tumors. These findings indicate that Aurora A plays a critical role in RASSF1A-APC-Cdc20 regulatory mechanisms that control normal prometaphase progression and that are involved in tumorigenesis. [Cancer Res 2009;69(6):2314–23
Associations between Single Nucleotide Polymorphisms in Double-Stranded DNA Repair Pathway Genes and Familial Breast Cancer
Authors: Sehl Mary E. , Langer Lucy R. , Papp Jeanette C. , Kwan Lorna , Seldon Joyce L. , Arellano Geovanni , Reiss Jean , Reed Elaine F. , Dandekar Sugandha , Korin Yael , Sinsheimer Janet S. , Zhang Zuo-Feng , Ganz Patricia A. 
Published: March 2009

Abstract
Purpose: DNA damage recognition and repair play a major role in risk for breast cancer. We investigated 104 single nucleotide polymorphisms (SNP) in 17 genes whose protein products are involved in double-stranded break repair (DSBR).
Experimental Design: We used a case-control design. Both the case individuals affected with breast cancer or with both breast and ovarian cancers and the controls had similar familial risk of breast cancer and were participants in a high-risk cancer registry.
Results: We found that 12 of the polymorphisms are associated with breast or breast and ovarian cancers, most notably rs16888927, rs16888997, and rs16889040, found in introns of RAD21, suggesting that SNPs in other genes in the DSBR pathway in addition to BRCA1 and BRCA2 may affect breast cancer risk.
Conclusions: SNPs within or near several DSBR DNA repair pathway genes are associated with breast cancer in individuals from a high-risk population. In addition, our study reemphasizes the unique perspective that recruitment of cases and controls from family cancer registries has for gene discovery studies.
Enhanced Antitumor Efficacy of a DR5-Specific TRAIL Variant over Recombinant Human TRAIL in a Bioluminescent Ovarian Cancer Xenograft Model
Authors: Duiker Evelien W. , de Vries Elisabeth G.E. , Mahalingam Devalingam , Meersma Gert Jan , Boersma-van Ek Wytske , Hollema Harry , Lub-de Hooge Marjolijn N. , van Dam Go M. , Cool Robbert H. , Quax Wim J. , Samali Afshin , van der Zee Ate G.J. , de Jong Steven 
Published: March 2009

Abstract
Purpose: Recombinant human tumor necrosis factor-related apoptosis-inducing ligand (rhTRAIL) is clinically evaluated as novel anticancer drug. rhTRAIL-DR5, a rhTRAIL variant that specifically binds to DR5 receptor, has recently been developed. We investigated whether rhTRAIL-DR5 is more efficient than rhTRAIL in combination with cisplatin in DR5-expressing human A2780 ovarian cancer cells.
Design: Effect of cisplatin alone or in combination with rhTRAIL or rhTRAIL-DR5 on DR5 surface expression, apoptosis, and cell survival of A2780 was measured. Biodistribution analysis was done in mice with 125I-rhTRAIL administered intravenously versus intraperitoneally. Antitumor efficacy of rhTRAIL-DR5 versus rhTRAIL was determined in an intraperitoneally growing bioluminescent A2780 xenograft model.
Results: Cisplatin strongly enhanced DR5 surface expression. Both rhTRAIL and rhTRAIL-DR5 in combination with cisplatin induced high levels of caspase-3 activation, apoptosis, and cell kill, with rhTRAIL-DR5 being most potent. Intraperitoneal administration of 125I-rhTRAIL resulted in a 1.7-fold higher area under the curve in serum, increased tumor exposure, and more caspase-3 activation in the tumor than intravenous administration. Intraperitoneal administration of rhTRAIL-DR5 delayed A2780 tumor progression, reflected in a mean light reduction of 68.3% (P = 0.015), whereas rhTRAIL or rhTRAIL-DR5 plus cisplatin resulted in 85% (P = 0.003) and 97% (P = 0.002) reduction compared with A2780 tumor progression in vehicle-treated animals. Combination of rhTRAIL-DR5 with cisplatin was more effective than cisplatin alone (P = 0.027).
Conclusion: rhTRAIL-DR5 was superior over rhTRAIL in vitro and in vivo against DR5-expressing ovarian cancer also in combination with cisplatin. Intraperitoneal administration of rhTRAIL-DR5 warrants further exploration in ovarian cancer.
Enhancement of Lexatumumab-Induced Apoptosis in Human Solid Cancer Cells by Cisplatin in Caspase-Dependent Manner
Authors: Wu Xiu-Xian , Kakehi Yoshiyuki 
Published: March 2009

Abstract
Purpose: This study was designed to evaluate the apoptotic effect of mapatumumab or lexatumumab, human agonistic antibodies that target the tumor necrosis factor–related apoptosis-inducing ligand receptor 1 (TRAIL-R1) and receptor 2 (TRAIL-R2), in combination with chemotherapeutic agents, against human solid cancer cells.
Experimental Design: Cytotoxicity was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Synergy was assessed by isobolographic analysis.
Results: Treatment of ACHN human renal cell carcinoma cells with cisplatin combined with mapatumumab did not overcome resistance to these agents. However, treatment with cisplatin in combination with lexatumumab had a synergistic cytotoxicity. Synergy was also achieved in six primary renal cell carcinoma cell cultures. Lexatumumab and cisplatin also synergistically enhanced apoptosis. Pretreatment with cisplatin followed by lexatumumab resulted in high cytotoxicity compared with the reverse sequence. Cisplatin significantly increased TRAIL-R2 expression at both the mRNA and the protein levels. Furthermore, the combination of lexatumumab and cisplatin significantly enhanced caspase-8 activity, Bid cleavage, up-regulation of Bax, cytochrome c release, and caspase-9, caspase-6, and caspase-3 activities. Importantly, the activation of caspase-8 was significantly abrogated by the specific inhibitors of caspase-9, caspase-6, and caspase-3. Furthermore, combination-induced cytotoxicity was significantly suppressed by the DR5:Fc chimeric protein and the specific inhibitors of caspase-8, caspase-9, caspase-6, and caspase-3. A similar effect was observed in prostate cancer, bladder cancer, lung cancer, and cervical cancer cells.
Conclusions: Cisplatin sensitizes solid cancer cells to lexatumumab-induced apoptosis by potentiation of the extrinsic and intrinsic apoptotic pathways that lead to amplification of caspase activation, particularly caspase-8, suggesting the combination treatment of solid cancers with cisplatin and lexatumumab might overcome their resistance.
Tie2 in Tumor Endothelial Signaling and Survival: Implications for Antiangiogenic Therapy
Authors: Tsai Jeff H. , Lee William M.F. 
Published: March 2009

Abstract
Signaling through the Tie2 receptor on endothelial cells has been shown to play an important role in normal and pathologic vascular development. We generated K1735 murine melanoma tumor cells that inducibly express soluble Tie2 receptor (Tie2Ex) to study the effects of inhibiting Tie2 signaling on tumor vasculature. Tie2Ex induction rapidly decreased AKT activation but not extracellular signal-regulated kinase (ERK) activation in tumor endothelial cells as detected by immunostaining. This was accompanied by an increase in endothelial cell TUNEL staining but no change in Ki-67 expression. Together with a decrease in the percentage of perfused vessels, this suggested that tumor vessel regression and impaired vascular function rather than angiogenesis inhibition was responsible for the delay in tumor growth following Tie2Ex treatment. However, Tie2Ex failed to inhibit the growth of larger, more established K1735 tumors. These tumors were additionally treated with sorafenib, a multikinase inhibitor that inhibits tumor endothelial cell ERK activation but not AKT activation. Combining Tie2Ex and sorafenib decreased both endothelial cell AKT and ERK activation, decreased endothelial cell survival and proliferation, and significantly inhibited growth of the more established tumors. These studies indicate that activity of specific signaling pathways and prosurvival effects are brought about by Tie2 activation in tumor endothelial cells, and knowledge of the effects of Tie2 inhibition can lead to development of more effective therapeutic regimens for inhibiting tumor neovascularization. (Mol Cancer Res 2009;7(3):300–10)
Estimation of Gamma Raindrop Size Distribution Parameters: Statistical Fluctuations and Estimation Errors
Authors: Mallet Cécile , Barthes Laurent 
Published: March 2009

Abstract
The gamma distribution is often used to characterize raindrop size distributions (DSDs). However, the estimation of measured raindrop distributions suffers from the shortcomings of statistical sampling errors, which become increasingly significant when the collecting surface of the measuring instrument and the integration time are small. Different estimators of the three parameters (N0*, μ, and Dm) that characterize a normalized gamma distribution have been computed from simulated DSD. A database has been established, containing 22 950 simulated DSDs, corresponding to a wide set of various rainfall situations. Moment, least squares, and maximum likelihood estimators have been evaluated. Error measurement considerations are discussed, in particular the difficulty encountered in measuring small drops (diameter &lt;0.5 mm) with a disdrometer. Modified estimation approaches are proposed to compensate for the lack of small drops accounted for by real measurements. For each of the different methods, systematic error analysis is performed, and the estimation error is quantified in terms of its bias and standard deviation. The sensitivity of the various methods to instrumental characteristics is also evaluated. A case study is run to highlight correlation effects in the estimated DSD parameters, resulting from the use of various retrieval techniques.
Finally, a criterion is derived that enables the hypothesis of gamma-distributed DSD to be tested. When applied to real data recorded by an optical disdrometer, this criterion shows that approximately 91% of DSDs are of the gamma type. Real gamma DSDs are then used to compare adapted maximum likelihood estimators with the more commonly used methods.
The Role of Long-Term Trends in Seasonal Predictions: Implication of Global Warming in the NCEP CFS
Authors: Cai Ming , Shin Chul-Su , van den Dool H. M. , Wang Wanqiu , Saha S. , Kumar A. 
Published: March 2009

Abstract
This paper analyzes long-term surface air temperature trends in a 25-yr (1982–2006) dataset of retrospective seasonal climate predictions made by the NCEP Climate Forecast System (CFS), a model that has its atmospheric greenhouse gases fixed at the 1988 concentration level. Although the CFS seasonal forecasts tend to follow the observed interannual variability very closely, there exists a noticeable time-dependent discrepancy between the CFS forecasts and observations, with a warm model bias before 1988 and a cold bias afterward except for a short-lived warm bias during 1992–94. The trend from warm to cold biases is likely caused by not including the observed increase in the anthropogenic greenhouse gases in the CFS, whereas the warm bias in 1992–94 reflects the absence of the anomalous aerosols released by the 1991 Mount Pinatubo eruption. Skill analysis of the CFS seasonal climate predictions with and without the warming trend suggests that the 1997–98 El Niño event contributes significantly to the record-breaking global warmth in 1998 whereas the record-breaking warm decade since 2000 is mainly due to the effects of the increased greenhouse gases. Implications for operational seasonal prediction will be discussed.
Initial therapy in multiple myeloma: investigating the new treatment paradigm
Authors: Kettle Jacob K , Finkbiner Karen L , Klenke Susan E , Baker Ronald D , Henry Dave W , Williams Casey B 
Published: March 2009

The development of three novel chemotherapeutic agents — thalidomide, lenalidomide, and bortezomib — has resulted in a fundamental shift in the management of multiple myeloma. Despite this tremendous advancement, the selection of initial treatment must still be made with a degree of uncertainty as a true standard therapy has yet to be established. Although challenging, the relative abundance of therapeutic options, when taken into consideration with unique patient characteristics, creates the potential for individualization of care. For patients eligible for autologous stem cell transplantation, various combinations of novel agents with dexamethasone or traditional chemotherapy have supplanted the previous standard regimen consisting of vincristine, doxorubicin, and dexamethasone. In elderly patients or others that are deemed ineligible for the transplant procedure, the addition of a novel agent to melphalan-prednisone has demonstrated significant improvements in response rates. Due to the immaturity of the available data, it is perhaps best to regard the era of novel agents with a degree of rational enthusiasm, as the ultimate impact on patient care remains undetermined. Although further research is clearly implicated, recent advancements have resulted in significant progress toward obtaining optimum outcomes in a historically challenging disease.
Retrospective review of hemoglobin and/or hematocrit levels with occurrence of thrombosis in cancer patients treated with erythropoiesis stimulating agents
Authors: Fullmer Amber C , Miller Rickey 
Published: March 2009

Background. No data exists that directly compares hemoglobin and hematocrit levels between cancer patients with and without occurrence of thrombosis during treatment with erythropoiesis stimulating agents (ESAs). Objective. To determine the association of hemoglobin and hematocrit levels with the occurrence of thrombosis in cancer patients treated with ESAs. Methods. A retrospective case-control study approved by the Institutional Review Board was conducted on cancer patients billed for epoetin or darbepoetin between 1 July 2002 and 30 June 2007. Cases were defined as patients billed for thrombosis while controls were defined as patients not billed for thrombosis. Results. Sixteen patients had an occurrence of thrombosis (cases) and were matched to 16 patients that did not have an occurrence of thrombosis (controls) based on age, sex, and cancer type. The mean peak hemoglobin levels for cases and controls were 12.6 ± 1.2 g/dL versus 12.6 ± 1.4 g/dL (p = 0.9). The mean peak hematocrit levels for cases and controls were 37.3 ± 3.8% versus 37.9 ± 4.3% (p = 0.8). For the 16/586 (2.7%) patients with thrombosis, the mean hemoglobin and hematocrit at time of thrombosis were 9.6 ± 1.0 g/dL and 28.9 ± 3.1%. A significant identifiable risk factor for thrombosis between the cases and controls was history of thrombosis 31.3% versus 0% (p = 0.04). Conclusion. There was no statistical difference in peak hemoglobin and hematocrit levels between patients with thrombosis and those without thrombosis. Further study is warranted to determine if these levels are true risk factors for thrombosis.
Encephalopathy secondary to capecitabine chemotherapy: a case report and discussion
Authors: Tipples Karen , Kolluri Rajeev B , Raouf Sherif 
Published: March 2009

Introduction. Capecitabine is an oral prodrug of 5-fluorouracil (5-FU) chemotherapy and is licenced for the treatment of breast and gastrointestinal cancers. Multifocal inflammatory leukoencephalopathy has been associated with intravenous 5-FU, but only a few cases of capecitabine-induced encephalopathy have been reported. Setting. We describe here a case of encephalopathy following administration of Epirubicin/ Cisplatin/Capecitabine chemotherapy, review those cases previously described and suggest recommendations for management. Results. Symptoms of neurotoxicity from 5-FU and capecitabine usually include confusion, ataxia, nystagmus, dysarthria, sensory loss, and memory loss. Withdrawal of the drug generally leads to improvement of symptoms and steroids are of only questionable benefit. Conclusion. Patients on fluouropyrimidine drugs with new neurological symptoms should be investigated with brain MRI scan and the drug should be withdrawn until symptoms resolve. Dihydropyrimidine dehydrogenase deficiency should be excluded and ideally an alternative chemotherapy regime sought. We would encourage reporting of such incidences to gain a clearer picture of the incidence and optimal management. J Oncol Pharm Practice (2009) 15: 237—239.
Anticoagulation and antiplatelet therapy, and gastrointestinal endoscopy
Authors: Székely Hajnal , Tulassay Zsolt 
Published: March 2009

Az utóbbi évtizedben az antikoaguláns és thrombocytaaggregáció-gátló készítmények alkalmazása a különböző szív- és érrendszeri, illetve vérképző szervi betegségekben széles körűvé vált. Ezek a készítmények a thromboemboliás események kockázatának csökkentését szolgálják, ugyanakkor növelik az emésztőrendszeri vérzés lehetőségét. Az endoszkópos beavatkozások során az antikoagulálás felfüggesztése, ezáltal a thromboemboliás szövődmények kialakulásának kockázata minden esetben gondosan mérlegelendő a kezelés folytatásával járó fokozott vérzés kockázatával. Ideiglenes antikoagulálásra szoruló betegeknél (például a mélyvénás thrombosis eseteiben) az elektív endoszkópos beavatkozások későbbi időpontra halasztandók. Kis vérzési kockázatú endoszkópos vizsgálatok előtt (például diagnosztikus vizsgálatok biopsziával) nem szükséges az antikoaguláns kezelés módosítása vagy felfüggesztése. Fokozott vérzési kockázattal járó beavatkozások eseteiben (mint például a polypectomia és a sphincterotomia) egyéni megítélés szükséges; az orális antikoaguláns kezelés felfüggesztése javasolt áthidaló heparinnal vagy a nélkül (a thromboemboliás kockázat függvényében). A thrombocytaaggregáció-gátló készítmények (aszpirin, clopidogrel, ticlopidin) szintén fokozhatják az emésztőrendszeri endoszkópos beavatkozásokkal járó vérzés kockázatát. Felső pánendoszkópia előtt nem szükséges a kezelés felfüggesztése. Egyéb vizsgálatok előtt 4–7 nappal (a szív- és érrendszeri kockázat függvényében) megszakítható a kezelés. Ha az aszpirint elsődleges megelőzésre alkalmaztuk, polypectomia után 14 nappal, sphincterotomiát követően 10 nappal állítható vissza. A másodlagos megelőzés eseteiben a beavatkozást követően egy héttel folytatandó az aszpirin adagolása.