bluuebunny/crossref_metadata_2025_split huggingface dataset:
KDR Activating Mutations in Human Angiosarcomas Are Sensitive to Specific Kinase Inhibitors
Authors: Antonescu Cristina R. , Yoshida Akihiko , Guo Tianhuo , Chang Ning-En , Zhang Lei , Agaram Narasimhan P. , Qin Li-Xuan , Brennan Murray F. , Singer Samuel , Maki Robert G. 
Published: September 2009

Abstract
Angiosarcomas (AS) represent a heterogeneous group of malignant vascular tumors occurring not only in different anatomic locations but also in distinct clinical settings, such as radiation or associated chronic lymphedema. Although representing only 1% to 2% of soft tissue sarcomas, vascular sarcomas provide unique insight into the general process of tumor angiogenesis. However, no molecular candidates have been identified to guide a specific therapeutic intervention. By expression profiling, AS show distinct up-regulation of vascular-specific receptor tyrosine kinases, including TIE1, KDR, SNRK, TEK, and FLT1. Full sequencing of these five candidate genes identified 10% of patients harboring KDR mutations. A KDR-positive genotype was associated with strong KDR protein expression and was restricted to the breast anatomic site with or without prior exposure to radiation. Transient transfection of KDR mutants into COS-7 cells showed ligand-independent activation of the kinase, which was inhibited by specific KDR inhibitors. These data provide a basis for the activity of vascular endothelial growth factor receptor–directed therapy in the treatment of primary and radiation-induced AS. [Cancer Res 2009;69(18):7175–9]
A Phase I Trial of Immunotherapy with Lapuleucel-T (APC8024) in Patients with Refractory Metastatic Tumors that Express HER-2/neu
Authors: Peethambaram Prema P. , Melisko Michelle E. , Rinn Kristine J. , Alberts Steven R. , Provost Nicole M. , Jones Lori A. , Sims Robert B. , Lin Lisa R. C. , Frohlich Mark W. , Park John W. 
Published: September 2009

AbstractPurpose: This study aimed to evaluate the safety of, immune response induced by, and efficacy of treatment with lapuleucel-T (APC8024) in patients with HER-2/neu–expressing tumors. Lapuleucel-T is an investigational active immunotherapy product consisting of autologous peripheral blood mononuclear cells, including antigen presenting cells, which are cultured ex vivo with BA7072, a recombinant fusion antigen consisting of portions of the intracellular and extracellular regions of HER-2/neu linked to granulocyte-macrophage colony-stimulating factor.Experimental Design: Patients with metastatic breast, ovarian, or colorectal cancer whose tumors expressed HER-2 were eligible. Patients underwent leukapheresis in week 0 and received lapuleucel-T infusions in weeks 0, 2, and 4. Patients who achieved a partial response or had stable disease through week 48 were eligible for re-treatment using the same protocol and dose as their initial treatment.Results: Eighteen patients were enrolled and treated. Patients showed an immune response to the immunizing antigen (BA7072) at week 8 compared with week 0 as measured by T lymphocyte proliferation and IFN-γ enzyme-linked immunospot assay. Therapy was well tolerated. The majority (94.7%) of adverse events associated with treatment were grade 1 or 2. Two patients experienced stable disease lasting &gt;48 weeks.Conclusions: Autologous active cellular immunotherapy with lapuleucel-T stimulated an immune response specific to the immunizing antigen and seemed to be well tolerated. Further clinical studies to assess the clinical benefit for patients with HER/2-neu–expressing breast, ovarian, and colorectal cancer are warranted. (Clin Cancer Res 2009;15(18):5937–44)
Impairment of Plasmacytoid Dendritic Cells for IFN Production by the Ligand for Immunoglobulin-Like Transcript 7 Expressed on Human Cancer Cells
Authors: Tsukamoto Nobuo , Okada Starlyn , Onami Yoko , Sasaki Yusuke , Umezawa Kazuo , Kawakami Yutaka 
Published: September 2009

Abstract
Purpose: Plasmacytoid dendritic cells (pDC) are specialized cells to produce type I IFN. Infiltration of pDCs in cancer tissues that have impaired ability to produce IFN-α has been suggested to play immunosuppressive roles in tumor immunity. To identify potential mechanisms causing pDC impairment in the cancer microenvironment, expression of immunoglobulin-like transcript 7 ligands (ILT7L), which inhibits pDC production of type I IFNs on the surface of various human cancer and noncancer cells, was examined.
Experimental Design: To detect unidentified ILT7L, reporter cells, which express green fluorescent protein on interaction with ILT7L, were constructed. ILT7L expression on various human cancer cell lines as well as various noncancerous stromal cells and immune cells was examined. Cytokines and signals involved in the ILT7L expression were also investigated.
Results: ILT7L was detected on all of the various types of human cancer cell lines tested. IFN-α, IFN-β, IFN-γ, tumor necrosis factor-α, interleukin-1β, transforming growth factor-β, lipopolysaccharide, and imiquimod induced ILT7L expression on cancer and noncancer cells. High ILT7L-expressing cancer cells inhibited production of IFN-α and tumor necrosis factor-α by pDC stimulated with CpG. ILT7L does not appear to be a member of classic or nonclassic HLAs. Additionally, NF-κB and mammalian target of rapamycin are involved in regulating ILT7L expression.
Conclusions: ILT7L expression on cancer cells may be one of the mechanisms for impairment of pDCs in the cancer microenvironment. ILT7/ILT7L signaling may normally enable a negative immune response feedback following viral infection. Intervention of the ILT7L/ILT7 system may be useful for enhancing antitumor immunity as well as antiviral immunity. (Clin Cancer Res 2009;15(18):5733–43)
Report from the Radiation Therapy Committee of the Southwest Oncology Group (SWOG): Research Objectives Workshop 2008
Authors: Okunieff Paul , Kachnic Lisa A. , Constine Louis S. , Fuller Clifton D. , Gaspar Laurie E. , Hayes Daniel F. , Hooks Jean , Ling Clifton , Meyskens Frank L. , Philip Philip A. , Raben David , Smalley Stephen R. , Swanson Gregory P. , Teicher Beverly A. , Thomas Charles R. , Vikram Bhadrasain , Zelefsky Michael J. , Baker Laurence H. 
Published: September 2009

Abstract
Strategic planning for the Radiation Therapy Committee of the Southwest Oncology Group (SWOG) is comprehensively evaluated every six years in an effort to maintain a current and relevant scientific focus, and to provide a standard platform for future development of protocol concepts. Participants in the 2008 Strategic Planning Workshop included clinical trial experts from multiple specialties, industry representatives from both pharmaceuticals and equipment manufacturers, and basic scientists. High-priority research areas such as image-guided radiation therapy for control of limited metastatic disease, analysis of biomarkers for treatment response and late toxicity, assessment of novel agents in combination with radiation, standardization of radiation target delineation, and the assessment of new imaging techniques to individualize cancer therapy, were discussed. Research priorities included clinical study designs featuring translational end points that identify patients most likely to benefit from combined modality therapy; intervention including combination radiation with standard chemotherapy; radiation with radiosensitizing molecular-targeted therapies; and stereotactic radiation for treatment of patients with regard to asymptomatic metastasis and radiation-induced tumor autoimmunity. The Committee concluded that the future research opportunities are among the most exciting to have developed in the last decade, and work is in progress to embark on these plans. (Clin Cancer Res 2009;15(18):5663–70)
Molecular Analysis of Endometrial Tumorigenesis: Importance of Complex Hyperplasia Regardless of Atypia
Authors: Nieminen Taina T. , Gylling Annette , Abdel-Rahman Wael M. , Nuorva Kyösti , Aarnio Markku , Renkonen-Sinisalo Laura , Järvinen Heikki J. , Mecklin Jukka-Pekka , Bützow Ralf , Peltomäki Päivi 
Published: September 2009

Abstract
Purpose: Endometrial carcinoma (EC) is common in the population and the most frequent extracolonic malignancy in hereditary nonpolyposis colorectal carcinoma (HNPCC)/Lynch syndrome. We characterized precursor lesions of endometrioid EC to identify markers of malignant transformation and tumor progression.
Experimental Design: Serial specimens of normal endometrium, simple hyperplasia, complex hyperplasia without atypia, complex hyperplasia with atypia, and endometrial carcinoma obtained during a 10-year surveillance of DNA mismatch repair (MMR) gene mutation carriers (together 110 samples) were molecularly profiled and compared with a sporadic reference series of endometrial specimens taken for nonmalignant reasons (62 samples).
Results: Among MMR gene mutation carriers, decreased MMR protein expression was present in 7% in normal endometrium, 40% in simple hyperplasia, 100% in complex hyperplasia without atypia, 92% in complex hyperplasia with atypia, and 100% in endometrial carcinoma. Microsatellite instability frequencies were lower (6%, 17%, 67%, 38%, and 64%, respectively). Among 24 tumor suppressor genes, the number of methylated loci increased from normal endometrium to simple hyperplasia to complex hyperplasia (complex hyperplasia without atypia/complex hyperplasia with atypia) in both Lynch syndrome and reference series. The most frequently methylated genes were CDH13, RASSF1A, and GSTP1. In MMR gene mutation carriers, MMR and methylation defects appeared up to 12 years before endometrial carcinoma.
Conclusions: Molecular changes in endometrial tissue are detectable several years before endometrial carcinoma in genetically predisposed individuals. Abnormal MMR and methylation classify normal endometrium and simple hyperplasia into one category and complex hyperplasia without atypia, complex hyperplasia with atypia, and endometrial carcinoma into another, suggesting that, contrary to a traditional view, complex hyperplasia without atypia and complex hyperplasia with atypia are equally important as precursor lesions of endometrial carcinoma. (Clin Cancer Res 2009;15(18):5772–83)
Tramadol and Flurbiprofen Depress the Cytotoxicity of Cisplatin via Their Effects on Gap Junctions
Authors: He Bo , Tong Xuhui , Wang Lingzhi , Wang Qin , Ye Hua , Liu Bing , Hong Xiaoting , Tao Liang , Harris Andrew L. 
Published: September 2009

AbstractPurpose: Cancer patients are often concurrently treated with analgesics and antineoplastic drugs, yet the influence of analgesic agents on therapeutic activity of antineoplastic drugs is largely unexplored. This study investigates the effects of three commonly used analgesics, which produce analgesia by different mechanisms, on cytotoxicity induced by cisplatin, a widely used antitumor agent, and the relation between those effects and modulation of gap junction function by the analgesics.Experimental Design: The role of gap junctions in the modulation of cisplatin toxicity is explored by manipulation of connexin expression, and gap junction presence and function, using clinically relevant concentrations of the analgesics and cisplatin.Results: Short-term exposure of transformed cells to cisplatin reduced the clonogenic survival in low-density cultures (without gap junction formation) and in high density (with gap junction formation), but the toxic effect was greater at high density. In the absence of connexin expression or with block of connexin channels, cell density had no effect on cisplatin toxicity. Tramadol and flurbiprofen, but not morphine, significantly reduced cisplatin cytotoxicity, but this effect required functional gap junctions between the cells. Tramadol and flurbiprofen inhibited dye-coupling through gap junctions, but morphine did not.Conclusions: The results suggest that the density dependence of cisplatin toxicity is mediated by gap junctions. They further indicate that tramadol and flurbiprofen depress cisplatin cytotoxicity through inhibition of gap junction activity, and more generally, that agents that depress junctional communication can counteract the effects of antitumor agents. (Clin Cancer Res 2009;15(18):5803–10)
Recombinant adeno-associated virus encoding Epstein-Barr virus latent membrane proteins fused with heat shock protein as a potential vaccine for nasopharyngeal carcinoma
Authors: Pan Jianqing , Zhang Qin , Zhou Jianfeng , Ma Ding , Xiao Xiao , Wang Dao Wen 
Published: September 2009

AbstractNasopharyngeal carcinoma (NPC) is a common cancer in Southern China and EBV is the most important pathogenesis. In this study, we explore the potential that a recombinant adeno-associated virus (rAAV) carrying a fusing gene containing heat shock protein as an adjuvant, EBV latent membrane proteins (LMP1 and LMP2) CTL epitope DNA as a vaccine prevents NPC. The tumor vaccine was devised by constructing a chimeric gene which contained EBV LMPs CTL epitope DNA fused with the heat shock protein gene as a tumor vaccine delivered via rAAV. Our results show that this vaccine can eliminate tumors in syngeneic animals and induce CTL activity in vitro. Taken together, the data suggest that this chimeric gene delivered by rAAV has potential as a NPC vaccine for prevention and therapy. [Mol Cancer Ther 2009;8(9):2754–61]
Nuclear factor κB inhibitors alleviate and the proteasome inhibitor PS-341 exacerbates radiation toxicity in zebrafish embryos
Authors: Daroczi Borbala , Kari Gabor , Ren Qing , Dicker Adam P. , Rodeck Ulrich 
Published: September 2009

AbstractInflammatory changes are a major component of the normal tissue response to ionizing radiation, and increased nuclear factor κB (NF-κB) activity is an important mediator of inflammatory responses. Here, we used zebrafish embryos to assess the capacity of two different classes of pharmacologic agents known to target NF-κB to modify radiation toxicity in the vertebrate organism. These were proteasome inhibitors, including lactacystin, MG132, and PS-341 (Bortezomib/VELCADE), and direct inhibitors of NF-κB activity, including ethyl pyruvate (EP) and the synthetic triterpenoid CDDO-TFEA (RTA401), among others. The proteasome inhibitors either did not significantly affect radiation sensitivity of zebrafish embryos (MG132, lactacystin) or rendered zebrafish embryos more sensitive to the lethal effects of ionizing radiation (PS-341). Radiosensitization by PS-341 was reduced in fish with impaired p53 expression or function but not associated with enhanced expression of select p53 target genes. In contrast, the direct NF-κB inhibitors EP and CDDO-TFEA significantly improved overall survival of lethally irradiated zebrafish embryos. In addition, direct NF-κB inhibition reduced radiation-induced apoptosis in the central nervous system, abrogated aberrations in body axis development, restored metabolization and secretion of a reporter lipid through the gastrointestinal system, and improved renal clearance compromised by radiation. In contrast to amifostine, EP and CDDO-TFEA not only protected against but also mitigated radiation toxicity when given 1 to 2 hours postexposure. Finally, four additional IκB kinase inhibitors with distinct mechanisms of action similarly improved overall survival of lethally irradiated zebrafish embryos. In conclusion, inhibitors of canonical pathways to NF-κB activation may be useful in alleviating radiation toxicity in patients. [Mol Cancer Ther 2009;8(9):2625–34]
Modulation of transcription by the peroxisome proliferator-activated receptor δ–binding RNA aptamer in colon cancer cells
Authors: Kwak Hoyun , Hwang Injoo , Kim Jee Ho , Kim Mee Young , Yang Ji Sun , Jeong Sunjoo 
Published: September 2009

Abstract
Peroxisome proliferator-activated receptor δ (PPAR-δ), one of three PPAR subtypes, is a lipid-sensing nuclear receptor that has been implicated in multiple processes, including inflammation and cancer. To directly establish the role of PPAR-δ in colon cancer development and progression, we selected high-affinity RNA aptamers and expressed them in several colon cancer cell lines. Nuclear-expressed aptamers efficiently inhibited PPAR-δ–dependent transcription from a synthetic peroxisome proliferator response element–driven luciferase reporter. PPAR-δ–specific aptamers suppressed transcription from natural promoters of vascular endothelial cell growth factor-A and cyclooxygenase-2. Moreover, vascular endothelial cell growth factor-A and cyclooxygenase-2 mRNA levels were significantly reduced by the PPAR-δ–specific aptamers in colon cancer cells. Most significantly, HCT116 colon cancer cells with high-level expression of PPAR-δ–specific aptamers exhibited a striking loss of tumorigenic potential. Further study on these RNA aptamers could provide an opportunity to modulate PPAR-δ–mediated colon cancer development and progression. Taken together, our results establish an important role for PPAR-δ in transcription of tumor-promoting genes, which can be specifically modulated by high-affinity RNA intramers in colon cancer cells. The RNA intramers may be further developed as specific inhibitors for cancer therapeutic strategies. [Mol Cancer Ther 2009;8(9):2664–73]
EpCAM-targeted delivery of nanocomplexed siRNA to tumor cells with designed ankyrin repeat proteins
Authors: Winkler Johannes , Martin-Killias Patricia , Plückthun Andreas , Zangemeister-Wittke Uwe 
Published: September 2009

Abstract
Specific delivery to tumors and efficient cellular uptake of nucleic acids remain major challenges for gene-targeted cancer therapies. Here we report the use of a designed ankyrin repeat protein (DARPin) specific for the epithelial cell adhesion molecule (EpCAM) as a carrier for small interfering RNA (siRNA) complementary to the bcl-2 mRNA. For charge complexation of the siRNA, the DARPin was fused to a truncated human protamine-1 sequence. To increase the cell binding affinity and the amount of siRNA delivered into cells, DARPin dimers were generated and used as fusion proteins with protamine. All proteins expressed well in Escherichia coli in soluble form, yet, to remove tightly bound bacterial nucleic acids, they were purified under denaturing conditions by immobilized metal ion affinity chromatography, followed by refolding. The fusion proteins were capable of complexing four to five siRNA molecules per protamine, and fully retained the binding specificity for EpCAM as shown on MCF-7 breast carcinoma cells. In contrast to unspecific LipofectAMINE transfection, down-regulation of antiapoptotic bcl-2 using fusion protein complexed siRNA was strictly dependent on EpCAM binding and internalization. Inhibition of bcl-2 expression facilitated tumor cell apoptosis as shown by increased sensitivity to the anticancer agent doxorubicin. [Mol Cancer Ther 2009;8(9):2674–83]
Combinatorial efficacy of anti-CS1 monoclonal antibody elotuzumab (HuLuc63) and bortezomib against multiple myeloma
Authors: van Rhee Frits , Szmania Susann M. , Dillon Myles , van Abbema Anne M. , Li Xin , Stone Mary K. , Garg Tarun K. , Shi JuMei , Moreno-Bost Amberly M. , Yun Rui , Balasa Balaji , Ganguly Bishwa , Chao Debra , Rice Audie G. , Zhan Fenghuang , Shaughnessy John D. , Barlogie Bart , Yaccoby Shmuel , Afar Daniel E.H. 
Published: September 2009

Abstract
Monoclonal antibody (mAb) therapy for multiple myeloma, a malignancy of plasma cells, has not been clinically efficacious in part due to a lack of appropriate targets. We recently reported that the cell surface glycoprotein CS1 (CD2 subset 1, CRACC, SLAMF7, CD319) was highly and universally expressed on myeloma cells while having restricted expression in normal tissues. Elotuzumab (formerly known as HuLuc63), a humanized mAb targeting CS1, is currently in a phase I clinical trial in relapsed/refractory myeloma. In this report we investigated whether the activity of elotuzumab could be enhanced by bortezomib, a reversible proteasome inhibitor with significant activity in myeloma. We first showed that elotuzumab could induce patient-derived myeloma cell killing within the bone marrow microenvironment using a SCID-hu mouse model. We next showed that CS1 gene and cell surface protein expression persisted on myeloma patient-derived plasma cells collected after bortezomib administration. In vitro bortezomib pretreatment of myeloma targets significantly enhanced elotuzumab-mediated antibody-dependent cell-mediated cytotoxicity, both for OPM2 myeloma cells using natural killer or peripheral blood mononuclear cells from healthy donors and for primary myeloma cells using autologous natural killer effector cells. In an OPM2 myeloma xenograft model, elotuzumab in combination with bortezomib exhibited significantly enhanced in vivo antitumor activity. These findings provide the rationale for a clinical trial combining elotuzumab and bortezomib, which will test the hypothesis that combining both drugs would result in enhanced immune lysis of myeloma by elotuzumab and direct targeting of myeloma by bortezomib. [Mol Cancer Ther 2009;8(9):2616–24]
A novel target for treatment of chordoma: signal transducers and activators of transcription 3
Authors: Yang Cao , Schwab Joseph H. , Schoenfeld Andrew J. , Hornicek Francis J. , Wood Kirkham B. , Nielsen G. Petur , Choy Edwin , Mankin Henry , Duan Zhenfeng 
Published: September 2009

Abstract
A major obstacle in the effective treatment of chordoma is that there are no identifiable biomarkers capable of predicting prognosis. Recent research has indicated that signal transducers and activators of transcription (Stat3) may be an important prognostic marker in some cancers, but its role in chordoma tumors has not been elucidated. In this study, the expression of Stat3 was evaluated in chordoma tissue microarray that contains 70 chordoma samples. Cells in the tissue microarray showed nuclear staining for phosphorylated Stat3 in all instances. The level of phosphorylated Stat3 expression correlated with the survival and severity of the disease. Three chordoma cell lines were exposed to SD-1029, a novel inhibitor of Stat3 activation. MTT assay showed that the growth of all chordoma cell lines was inhibited by SD-1029. The expression of Stat3 signaling cascade was inhibited in all chordoma cell lines after treatment with SD-1029. The cytotoxicity of the combination of SD-1029 and chemotherapeutic drugs is significantly better than either agent alone. Phosphorylation of Stat3 in chordoma cells in vitro and cellular proliferation in three-dimensional culture were inhibited by SD-1029. In conclusion, the Stat3 pathway is constitutively activated in chordomas and the level of expression may serve as a predictor for prognosis. Blockade of the Stat3 pathway represents a potential strategy for future treatment. [Mol Cancer Ther 2009;8(9):2597–605]
Activate and resist: L576P-KIT in GIST
Authors: Conca Elena , Negri Tiziana , Gronchi Alessandro , Fumagalli Elena , Tamborini Elena , Pavan Giovanni Maria , Fermeglia Maurizio , Pierotti Marco A. , Pricl Sabrina , Pilotti Silvana 
Published: September 2009

Abstract
L576P is a rare KIT mutation often reported in cancers other than gastrointestinal stromal tumors (GIST). In GISTs, it correlates with features linked to an aggressive phenotype, eventually resulting in secondary mutations. In vitro findings point out that L576P/KIT is constitutively activated, and shows poor imatinib sensitivity. In this work, histological, immunohistochemical, and biochemical analyses, coupled with mutational-molecular analysis and fluorescence in situ hybridization, were applied to surgical specimens. In parallel, the affinities of wild-type, L576P/KIT, and Δ559/KIT for imatinib were estimated by in silico studies. Despite imatinib treatment and the apparent clinical-imaging response, the detected histological response was very low. KIT resulted, expressed and activated in absence of secondary mutations, BRAF/NRAS mutations, and KIT/PDGFRA gene alterations. Computer modeling proved that L576P/KIT is two times less sensitive than the wild-type counterpart and considerably less affine to imatinib than the sensitive Δ559/KIT. Accordingly, the modeling evidence strongly supports the lack of tumoral regression we observed at the histological level. [Mol Cancer Ther 2009;8(9):2491–5]