bluuebunny/crossref_metadata_2025_split huggingface dataset:
INVESTIGATION OF RADIOLUNATE RELATIONS IN NORMAL AND FRACTURED WRISTS
Authors: Broadbent M. R. , Stevenson I. , MacEachern C. , Johnstone A. J. 
Published: February 2010

As the distal radius fracture is one of the most commonly encountered upper limb injuries, the aim of this study was to provide a quick and easy method to aid in the assessment of fractured wrists, both pre- and post-fixation, by utilising the relationship of the radial shaft and the lunate. A retrospective analysis on 100 consecutive patients with normal wrist radiographs was performed. The results demonstrated that the variations of radiolunate anatomy followed a normal distribution. The normal anatomical relationship was then described. A second part to the study consisted of reviewing our method of radiocarpal analysis on a cohort of patients who had sustained a distal radius fracture. Carpal alignment pre- and post-fixation was measured, with the results demonstrating that by using this assessment method, it was possible with a quick glance of the radiograph, to determine whether satisfactory correction of the fracture had been achieved.
MAGNETOPOLARON IN A CYLINDRICAL QUANTUM DOT
Authors: TCHOFFO M. , FAI L. C. , ISSOFA N. , KENFACK S. C. , DIFFO J. T. , MODY ASHOK 
Published: February 2010

We examine the magnetopolaron state in a cylindrical quantum dot with a transverse parabolic potential and a high rectangular potential well in the longitudinal direction. The quadratic dependence of the magnetopolaron energy versus Fröhlich electron–phonon coupling constant for different cyclotron radii and constant structure radius is modulated by a logarithmic function seems to depend on the Fröhlich coupling constant. The same law is seen in the case of magnetopolaron energy versus Fröhlich electron–phonon coupling constant for different structure radii and constant cyclotron radius. The energies are seen to be lifted in different fashions in the case of the structure and cyclotron radii. The high degrees of confinement (or high magnetic field) lead to an enhancement in the effective electron–phonon coupling that in turn brings about the possibility that in spite of weak polar coupling as in GaAS say, the polaron problem may also have strong-coupling counterparts arising from confinement or magnetic field effects. The polaron mass increases with increasing Fröhlich electron–phonon coupling constant. The dependence seems to be fourth-order law of the Fröhlich coupling constant modulated by a logarithmic function.
The Neurofibromatosis Type 1 Tumor Suppressor Controls Cell Growth by Regulating Signal Transducer and Activator of Transcription-3 Activity In vitro and In vivo
Authors: Banerjee Sutapa , Byrd Jonathan N. , Gianino Scott M. , Harpstrite Scott E. , Rodriguez Fausto J. , Tuskan Robert G. , Reilly Karlyne M. , Piwnica-Worms David R. , Gutmann David H. 
Published: February 2010

Abstract
Neurofibromatosis type 1 (NF1) is a common cancer predisposition syndrome in which affected individuals develop benign and malignant nerve tumors. The NF1 gene product neurofibromin negatively regulates Ras and mammalian target of rapamycin (mTOR) signaling, prompting clinical trials to evaluate the ability of Ras and mTOR pathway inhibitors to arrest NF1-associated tumor growth. To discover other downstream targets of neurofibromin, we performed an unbiased cell-based high-throughput chemical library screen using NF1-deficient malignant peripheral nerve sheath tumor (MPNST) cells. We identified the natural product, cucurbitacin-I (JSI-124), which inhibited NF1-deficient cell growth by inducing apoptosis. We further showed that signal transducer and activator of transcription-3 (STAT3), the target of cucurbitacin-I inhibition, was hyperactivated in NF1-deficient primary astrocytes and neural stem cells, mouse glioma cells, and human MPNST cells through Ser727 phosphorylation, leading to increased cyclin D1 expression. STAT3 was regulated in NF1-deficient cells of murine and human origin in a TORC1- and Rac1-dependent manner. Finally, cucurbitacin-I inhibited the growth of NF1-deficient MPNST cells in vivo. In summary, we used a chemical genetics approach to reveal STAT3 as a novel neurofibromin/mTOR pathway signaling molecule, define its action and regulation, and establish STAT3 as a tractable target for future NF1-associated cancer therapy studies. Cancer Res; 70(4); 1356–66
Prolactin Inhibits BCL6 Expression in Breast Cancer through a Stat5a-Dependent Mechanism
Authors: Tran Thai H. , Utama Fransiscus E. , Lin Justin , Yang Ning , Sjolund Ashley B. , Ryder Amy , Johnson Kevin J. , Neilson Lynn M. , Liu Chengbao , Brill Kristin L. , Rosenberg Anne L. , Witkiewicz Agnieszka K. , Rui Hallgeir 
Published: February 2010

Abstract
BCL6 is a transcriptional repressor that recognizes DNA target sequences similar to those recognized by signal transducer and activator of transcriptions 5 (Stat5). BCL6 disrupts differentiation of breast epithelia, is downregulated during lactation, and is upregulated in poorly differentiated breast cancer. In contrast, Stat5a mediates prolactin-induced differentiation of mammary epithelia, and loss of Stat5 signaling in human breast cancer is associated with undifferentiated histology and poor prognosis. Here, we identify the mammary cell growth factor prolactin as a potent suppressor of BCL6 protein expression in human breast cancer through a mechanism that requires Stat5a, but not prolactin-activated Stat5b, MEK-ERK, or PI3K-AKT pathways. Prolactin rapidly suppressed BCL6 mRNA in T47D, MCF7, ZR75.1, and SKBr3 breast cancer cell lines, followed by prolonged reduction of BCL6 protein levels within 3 hours. Prolactin suppression of BCL6 was enhanced by overexpression of Stat5a but not Stat5b, was mimicked by constitutively active Stat5a, but did not require the transactivation domain of Stat5a. Stat5 chromatin immunoprecipitation demonstrated physical interaction with a BCL6 gene regulatory region, and BCL6 transcript repression required histone deacetylase activity based on sensitivity to trichostatin A. Functionally, BCL6 overexpression disrupted prolactin induction of Stat5 reporter genes. Prolactin suppression of BCL6 was extended to xenotransplant tumors in nude mice in vivo and to freshly isolated human breast cancer explants ex vivo. Quantitative immunohistochemistry revealed elevated BCL6 in high-grade and metastatic breast cancer compared with ductal carcinoma in situ and nonmalignant breast, and cellular BCL6 protein levels correlated negatively with nuclear Stat5a (r = −0.52; P &lt; 0.001) but not with Stat5b. Loss of prolactin-Stat5a signaling and concomitant upregulation of BCL6 may represent a regulatory switch facilitating undifferentiated histology and poor prognosis of breast cancer. Cancer Res; 70(4); 1711–21
Efficient Tumor Targeting with High-Affinity Designed Ankyrin Repeat Proteins: Effects of Affinity and Molecular Size
Authors: Zahnd Christian , Kawe Martin , Stumpp Michael T. , de Pasquale Christine , Tamaskovic Rastislav , Nagy-Davidescu Gabriela , Dreier Birgit , Schibli Roger , Binz H. Kaspar , Waibel Robert , Plückthun Andreas 
Published: February 2010

Abstract
Slow-clearing, tumor-targeting proteins such as monoclonal antibodies typically exhibit high tumor accumulation but low tissue contrast, whereas intermediate-sized proteins such as scFvs show faster clearance but only moderate tumor accumulation. For both, tumor targeting does not seem to improve further above an optimal affinity. We show here that with very small high-affinity proteins such as designed ankyrin repeat proteins (DARPins), these limits can be overcome. We have systematically investigated the influence of molecular mass and affinity on tumor accumulation with DARPins with specificity for HER2 in SK-OV-3.ip nude mouse xenografts. DARPins with a mass of 14.5 kDa and affinities between 270 nmol/L and 90 pmol/L showed a strong correlation of tumor accumulation with affinity to HER2, with the highest affinity DARPin reaching 8% ID/g after 24 hours and 6.5% ID/g after 48 hours (tumor-to-blood ratio &gt;60). Tumor autoradiographs showed good penetration throughout the tumor mass. Genetic fusion of two DARPins (30 kDa) resulted in significantly lower tumor accumulation, similar to values observed for scFvs, whereas valency had no influence on accumulation. PEGylation of the DARPins increased the circulation half-life, leading to higher tumor accumulation (13.4% ID/g after 24 hours) but lower tumor-to-blood ratios. Affinity was less important for tumor uptake of the PEGylated constructs. We conclude that two regimes exist for delivering high levels of drug to a tumor: small proteins with very high affinity, such as unmodified DARPins, and large proteins with extended half-life, such as PEGylated DARPins, in which the importance of affinity is less pronounced. Cancer Res; 70(4); 1595–605
Epigenetic Downregulation of Mitogen-Activated Protein Kinase Phosphatase MKP-2 Relieves Its Growth Suppressive Activity in Glioma Cells
Authors: Waha Anke , Felsberg Jörg , Hartmann Wolfgang , von dem Knesebeck Anna , Mikeska Thomas , Joos Stefan , Wolter Marietta , Koch Arend , Yan Pearlly S. , Endl Elmar , Wiestler Otmar D. , Reifenberger Guido , Pietsch Torsten , Waha Andreas 
Published: February 2010

Abstract
Critical tumor suppression pathways in brain tumors have yet to be fully defined. Along with mutational analyses, genome-wide epigenetic investigations may reveal novel suppressor elements. Using differential methylation hybridization, we identified a CpG-rich region of the promoter of the dual-specificity mitogen-activated protein kinase phosphatase-2 gene (DUSP4/MKP-2) that is hypermethylated in gliomas. In 83 astrocytic gliomas and 5 glioma cell lines examined, hypermethylation of the MKP-2 promoter was found to occur relatively more frequently in diffuse or anaplastic astrocytomas and secondary glioblastomas relative to primary glioblastomas. MKP-2 hypermethylation was associated with mutations in TP53 and IDH1, exclusive of EGFR amplification, and with prolonged survival of patients with primary glioblastoma. Expression analysis established that promoter hypermethylation correlated with reduced expression of MKP-2 mRNA and protein. Consistent with a regulatory role, reversing promoter hypermethylation by treating cells with 5-aza-2′-deoxycytidine increased MKP-2 mRNA levels. Furthermore, we found that glioblastoma cell growth was inhibited by overexpression of exogenous MKP-2. Our findings reveal MKP-2 as a common epigenetically silenced gene in glioma, the inactivation of which may play a significant role in glioma development. Cancer Res; 70(4); 1689–99
Acquired Resistance of Non–Small Cell Lung Cancer Cells to MET Kinase Inhibition Is Mediated by a Switch to Epidermal Growth Factor Receptor Dependency
Authors: McDermott Ultan , Pusapati Raju V. , Christensen James G. , Gray Nathanael S. , Settleman Jeff 
Published: February 2010

Abstract
Cancer cells harboring MET amplification display striking sensitivity to selective small molecule inhibitors of MET kinase, prompting their clinical evaluation. Similar to the experience with traditional therapeutics, most patients responding to treatment with such molecular targeted therapeutics ultimately relapse with drug-resistant disease. In this study we modeled acquired resistance to experimental MET kinase inhibitor PF2341066 in MET-amplified non–small cell lung carcinoma (NSCLC) cell lines to identify drug resistance mechanisms that may arise in clinic. We found that activation of the epidermal growth factor receptor (EGFR) pathway emerges as a resistance mechanism in MET-amplified cells after prolonged exposure to PF2341066. Whereas combined inhibition of MET and EGFR kinases in MET-dependent NSCLC cells did not enhance their initial sensitivity to PF2341066, this combination dramatically suppressed the eventual emergence of drug-resistant clones after prolonged drug exposure. Conversely, activation of the EGFR pathway increased the yield of PF2341066-resistant clones, confirming the significance of this pathway in conferring resistance. Our findings support an intimate relationship between the EGFR and MET signaling pathways in NSCLC, and they suggest that combination treatment with MET and EGFR kinase inhibitors may be beneficial in MET-amplified NSCLC by reducing selection for drug resistant clones. Cancer Res; 70(4); 1625–34
Hormonal Regulation and Distinct Functions of Semaphorin-3B and Semaphorin-3F in Ovarian Cancer
Authors: Joseph Doina , Ho Shuk-Mei , Syed Viqar 
Published: February 2010

Abstract
Semaphorins comprise a family of molecules that influence neuronal growth and guidance. Class-3 semaphorins, semaphorin-3B (SEMA3B) and semaphorin-3F (SEMA3F), illustrate their effects by forming a complex with neuropilins (NP-1 or NP-2) and plexins. We examined the status and regulation of semaphorins and their receptors in human ovarian cancer cells. A significantly reduced expression of SEMA3B (83 kDa), SEMA3F (90 kDa), and plexin-A3 was observed in ovarian cancer cell lines when compared with normal human ovarian surface epithelial cells. The expression of NP-1, NP-2, and plexin-A1 was not altered in human ovarian surface epithelial and ovarian cancer cells. The decreased expression of SEMA3B, SEMA3F, and plexin-A3 was confirmed in stage 3 ovarian tumors. The treatment of ovarian cancer cells with luteinizing hormone, follicle-stimulating hormone, and estrogen induced a significant upregulation of SEMA3B, whereas SEMA3F was upregulated only by estrogen. Cotreatment of cell lines with a hormone and its specific antagonist blocked the effect of the hormone. Ectopic expression of SEMA3B or SEMA3F reduced soft-agar colony formation, adhesion, and cell invasion of ovarian cancer cell cultures. Forced expression of SEMA3B, but not SEMA3F, inhibited viability of ovarian cancer cells. Overexpression of SEMA3B and SEMA3F reduced focal adhesion kinase phosphorylation and matrix metalloproteinase-2 and matrix metalloproteinase-9 expression in ovarian cancer cells. Forced expression of SEMA3F, but not SEMA3B in ovarian cancer cells, significantly inhibited endothelial cell tube formation. Collectively, our results suggest that the loss of SEMA3 expression could be a hallmark of cancer progression. Furthermore, gonadotropin- and/or estrogen-mediated maintenance of SEMA3 expression could control ovarian cancer angiogenesis and metastasis. Mol Cancer Ther; 9(2); 499–509
Integrative Analysis of Proteomic Signatures, Mutations, and Drug Responsiveness in the NCI 60 Cancer Cell Line Set
Authors: Park Eun Sung , Rabinovsky Rosalia , Carey Mark , Hennessy Bryan T. , Agarwal Roshan , Liu Wenbin , Ju Zhenlin , Deng Wanleng , Lu Yiling , Woo Hyun Goo , Kim Sang-Bae , Cheong Jae-Ho , Garraway Levi A. , Weinstein John N. , Mills Gordon B. , Lee Ju-Seog , Davies Michael A. 
Published: February 2010

Abstract
Aberrations in oncogenes and tumor suppressors frequently affect the activity of critical signal transduction pathways. To analyze systematically the relationship between the activation status of protein networks and other characteristics of cancer cells, we did reverse phase protein array (RPPA) profiling of the NCI60 cell lines for total protein expression and activation-specific markers of critical signaling pathways. To extend the scope of the study, we merged those data with previously published RPPA results for the NCI60. Integrative analysis of the expanded RPPA data set revealed five major clusters of cell lines and five principal proteomic signatures. Comparison of mutations in the NCI60 cell lines with patterns of protein expression showed significant associations for PTEN, PIK3CA, BRAF, and APC mutations with proteomic clusters. PIK3CA and PTEN mutation enrichment were not cell lineage-specific but were associated with dominant yet distinct groups of proteins. The five RPPA-defined clusters were strongly associated with sensitivity to standard anticancer agents. RPPA analysis identified 27 protein features significantly associated with sensitivity to paclitaxel. The functional status of those proteins was interrogated in a paclitaxel whole genome small interfering RNA (siRNA) library synthetic lethality screen and confirmed the predicted associations with drug sensitivity. These studies expand our understanding of the activation status of protein networks in the NCI60 cancer cell lines, demonstrate the importance of the direct study of protein expression and activation, and provide a basis for further studies integrating the information with other molecular and pharmacological characteristics of cancer. Mol Cancer Ther; 9(2); 257–67
Aurora Kinase Inhibitors - Rising Stars in Cancer Therapeutics?
Authors: Dar Altaf A. , Goff Laura W. , Majid Shahana , Berlin Jordan , El-Rifai Wael 
Published: February 2010

Abstract
Standard therapeutic approaches of cytotoxics and radiation in cancer are not only highly toxic, but also of limited efficacy in treatment of a significant number of cancer patients. The molecular analysis of the cancer genomes have shown a remarkable complexity and pointed to key genomic and epigenomic alterations in cancer. These discoveries are paving the way for targeted therapy approaches. However, although there are a large number of potential targets, only a few can regulate key cellular functions and intersect multiple signaling networks. The Aurora kinase family members (A, B, and C) are a collection of highly related and conserved serine-threonine kinases that fulfill these criteria, being key regulators of mitosis and multiple signaling pathways. Alterations in Aurora kinase signaling are associated with mitotic errors and have been closely linked to chromosomal aneuploidy in cancer cells. Several studies have shown amplification and/or overexpression of Aurora kinase A and B in hematologic malignancies and solid tumors. Over the past several years, Aurora kinases have become attractive targets. Several ongoing clinical trials and bench-based research are assessing the unique therapeutic potential of Aurora-based targeted therapy. Mol Cancer Ther; 9(2); 268–78
Resistance to ErbB2 Tyrosine Kinase Inhibitors in Breast Cancer Is Mediated by Calcium-Dependent Activation of RelA
Authors: Xia Wenle , Bacus Sarah , Husain Intisar , Liu Leihua , Zhao Sumin , Liu Zuguo , Moseley M. Arthur , Thompson J. Will , Chen Franklin L. , Koch Kevin M. , Spector Neil L. 
Published: February 2010

Abstract
The widespread clinical use of therapies targeting the ErbB2 receptor tyrosine kinase oncogene represents a significant advance in breast cancer treatment. However, the development of therapeutic resistance represents a dilemma limiting their clinical efficacy, particularly small-molecule tyrosine kinase inhibitors that block ErbB2 autophosphorylation and activation. Here, we show that lapatinib (GW572016), a highly selective, small-molecule inhibitor of the ErbB2 and epidermal growth factor receptor tyrosine kinases, which was recently approved for the treatment of advanced-stage ErbB2+ breast cancer, unexpectedly triggered a cytoprotective stress response in ErbB2+ breast cancer cell lines, which was mediated by the calcium-dependent activation of RelA, the prosurvival subunit of NF-κB. Abrogation of lapatinib-induced RelA activation using either small interfering RNA constructs or an intracellular calcium chelator enhanced the apoptotic effects of lapatinib in parental ErbB2+ breast cancer cells and overcame therapeutic resistance to lapatinib in ErbB2+ breast cancer lines that had been rendered resistant to lapatinib through chronic exposure to the drug, mimicking the clinical setting. In addition, analysis of changes in phospho-RelA expression in sequential clinical biopsies from ErbB2+ breast cancers treated with lapatinib monotherapy revealed marginally statistically significant differences between responders and nonresponders, which was consistent with our preclinical findings. Elucidating the regulation of RelA by lapatinib in ErbB2+ breast cancers, and showing its role in the development of therapeutic resistance to lapatinib, identifies another therapeutic target to overcome or prevent the onset of resistance to lapatinib in some women with ErbB2+ breast cancers. Mol Cancer Ther; 9(2); 292–9
ASCL1 Regulates the Expression of the CHRNA5/A3/B4 Lung Cancer Susceptibility Locus
Authors: Improgo Ma. Reina D. , Schlichting Nicolette A. , Cortes Roxana Y. , Zhao-Shea Rubing , Tapper Andrew R. , Gardner Paul D. 
Published: February 2010

Abstract
Tobacco contains a variety of carcinogens as well as the addictive compound nicotine. Nicotine addiction begins with the binding of nicotine to its cognate receptor, the nicotinic acetylcholine receptor (nAChR). Genome-wide association studies have implicated the nAChR gene cluster, CHRNA5/A3/B4, in nicotine addiction and lung cancer susceptibility. To further delineate the role of this gene cluster in lung cancer, we examined the expression levels of these three genes as well as other members of the nAChR gene family in lung cancer cell lines and patient samples using quantitative reverse transcription-PCR. Overexpression of the clustered nAChR genes was observed in small-cell lung carcinoma (SCLC), an aggressive form of lung cancer highly associated with cigarette smoking. The overexpression of the genomically clustered genes in SCLC suggests their coordinate regulation. In silico analysis of the promoter regions of these genes revealed putative binding sites in all three promoters for achaete-scute complex homolog 1 (ASCL1), a transcription factor implicated in the pathogenesis of SCLC, raising the possibility that this factor may regulate the expression of the clustered nAChR genes. Consistent with this idea, knockdown of ASCL1 in SCLC, but not in non-SCLC, led to a significant decrease in expression of the α3 and β4 genes without having an effect on any other highly expressed nAChR gene. Our data indicate a specific role for ASCL1 in regulating the expression of the CHRNA5/A3/B4 lung cancer susceptibility locus. This regulation may contribute to the predicted role that ASCL1 plays in SCLC tumorigenesis. Mol Cancer Res; 8(2); 194–203
High-dose cyclophosphamide as single-agent, short-course prophylaxis of graft-versus-host disease
Authors: Luznik Leo , Bolaños-Meade Javier , Zahurak Marianna , Chen Allen R. , Smith B. Douglas , Brodsky Robert , Huff Carol Ann , Borrello Ivan , Matsui William , Powell Jonathan D. , Kasamon Yvette , Goodman Steven N. , Hess Allan , Levitsky Hyam I. , Ambinder Richard F. , Jones Richard J. , Fuchs Ephraim J. 
Published: February 2010

AbstractBecause of its potent immunosuppressive yet stem cell–sparing activity, high-dose cyclophosphamide was tested as sole prophylaxis of graft-versus-host disease (GVHD) after myeloablative allogeneic bone marrow transplantation (alloBMT). We treated 117 patients (median age, 50 years; range, 21-66 years) with advanced hematologic malignancies; 78 had human leukocyte antigen (HLA)–matched related donors and 39 had HLA-matched unrelated donors. All patients received conventional myeloablation with busulfan/cyclophosphamide (BuCy) and T cell–replete bone marrow followed by 50 mg/kg/d of cyclophosphamide on days 3 and 4 after transplantation. The incidences of acute grades II through IV and grades III through IV GVHD for all patients were 43% and 10%, respectively. The nonrelapse mortality at day 100 and 2 years after transplantation were 9% and 17%, respectively. The actuarial overall survival and event-free survivals at 2 years after transplantation were 55% and 39%, respectively, for all patients and 63% and 54%, respectively, for patients who underwent transplantation while in remission. With a median follow-up of 26.3 months among surviving patients, the cumulative incidence of chronic GVHD is 10%. These results suggest that high-dose posttransplantation cyclophosphamide is an effective single-agent prophylaxis of acute and chronic GVHD after BuCy conditioning and HLA-matched BMT (clinicaltrials.gov no. NCT00134017).