bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2681: Multicolor imageable orthotopic tumorgraft models of human patient pancreatic cancer
Authors: Suetsugu Atsushi , Katz Matthew H.G. , Fleming Jason B. , Hassanein Mohamed K. , Moriwaki Hisataka , Bouvet Michael , Saji Shigetoyo , Hoffman Robert M. 
Published: August 2012

Abstract
In order to help develop more effective treatment for pancreatic cancer, we developed a multicolor imageable orthotopic mouse model for individual human pancreatic-cancer patients. Pancreatic cancer patient tumor specimens were initially established in SCID-NOD mice. The tumors were then passaged orthotopically into transgenic nude mice expressing GFP in almost every tissue. Both the primary tumors and resultant metastasis acquired GFP stroma and could be imaged by GFP fluorescence. GFP stroma included cancer-associated fibroblasts (CAFs). Further passage to nude mice expressing RFP in almost all tissues resulted in tumors and metastasis acquiring RFP stroma in addition to their GFP stroma, including CAFs. Further passage to transgenic nude mice expressing CFP in almost all tissues resulted in tumors and metastasis acquiring CFP stroma in addition to RFP and GFP stroma including CAFs. The model can be used to image primary and metastatic progression of patient pancreatic tumors, study acquisition of stroma and to test both standard and novel cancer- and stroma-targeting agents. The imageable tumor-graft model should prove valuable for treatment evaluation of individual cancer patients, as well as for evaluation of experimental therapeutics targets in the tumor or the tumor microenvironment such as cancer-associated fibroblasts (CAFs).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2681. doi:1538-7445.AM2012-2681
Abstract 2687: Imaging sub-cellular dynamics of proliferating intra- and extra-vascular cancer cells
Authors: Suetsugu Atsushi , Digman Michelle , Aguilar Jose A. , Jiang Ping , Hassanein Mohamed , Moriwaki Hisataka , Bouvet Michael , Saji Shigetoyo , Gratton Enrico , Hoffman Robert M. 
Published: August 2012

Abstract
In order to visualize nuclear-cytoplasmic dynamics during intravascular cancer cell-proliferation and extravasation, green fluorescent protein (GFP) was expressed in the cytoplasm of HT-1080 human fibrosarcoma cells, and red fluorescent protein (m-Cherry), linked to histone H2B, was expressed in the nucleus. Nuclear m-Cherry expression enabled visualization of nuclear dynamics, whereas simultaneous cytoplasmic GFP expression enabled visualization of nuclear-cytoplasmic ratios as well as simultaneous cell and nuclear shape changes. Thus, total cellular dynamics can be visualized in the living dual-color cells in real time. The cell cycle position of individual living cells was readily visualized by the nuclear-cytoplasmic ratio and nuclear morphology. Real-time induction of apoptosis was observed by nuclear size changes and progressive nuclear fragmentation. Intra- and extra-vascular mitotic cells were visualized by imaging after injection of the cancer cells in the epigastric cranials vein in an abdominal flap. After one hour, round and elongated cancer cells were observed in the vessel. Three hours after injection, invadopodia of the cancer cells was observed. Five hours after injection, dual-color cancer cells began to divide within the vessel. By 10 hours, some intra-vascular cancer cells underwent apoptosis. Deformed new blood vessels in the tumor were observed 10 days later. Extravascular cancer cells were dividing in the tumor at day 14. The subcellular in vivo imaging approach described here provides new visual targets for trafficking, extravasating and invading cancer cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2687. doi:1538-7445.AM2012-2687
Abstract 269: A novel mechanism of p21 induction by oxaliplatin in p53 deficient cancer cells
Authors: Xu Weiguo , Li Dawei 
Published: August 2012

Abstract
p21(CDKN1A) is a well known cyclin-dependent kinase (cdk) inhibitor. As a critical cell cycle checkpoint of p53 mediated DNA damage response, p21 interferes with cyclin-CDK2 complex, blocking cell cycle at the G1/S interface, thus reducing the risk of DNA damaged cells transforming to cancer cells. Activation of p21 checkpoint by therapeutic agent is often associated with cancer cell cycle arrest and effective tumor suppression. However, many cancer lost wild type p53 while p21 in these cells maintains at a low level. In these cells p21 transcription is mainly controlled by p53-independent mechanisms through various cis-acting elements and these type of cancer are often more likely to resist chemo treatment. In search of effective therapeutic agents against p53 negative and drug resistant cancers we used SKOV3, a p53 deficient cancer cell line, to assess the ability of common therapeutic drugs to induce p21 expression. Promoter-reporter assays suggest p21 promoter is significantly stimulated by Oxaliplatin in SKOV3 cells compared with most common drugs used in chemotherapy. Through the promoter deletion analysis we identified a previously unreported Oxaliplatin responsive cis-acting element located between −237 to −220bp in the p21 promoter. Genomic DNA functional element analysis using ENCODE (Encyclopedia of DNA Elements) Consortium suggests that a vertebrate-conserved element overlaps well with the newly discovered Oxaliplatin responsive element. This conserved promoter element is required for the effective induction of p21 promoter activity by Oxaliplatin and such induction is positively related to drug induced S-phase cell cycle arrest. Finally, the ability of p21 induction of chemotherapy drugs is well correlated with their effectiveness of reducing SKOV3 xenograft tumors in nude mice.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 269. doi:1538-7445.AM2012-269
Abstract 2690: Evaluation of the hemostatic status in patients with prostate cancer using thromboelastography and tissue factor- microparticles
Authors: Toukh Mazen , Black Angela , Siemens Robert D. , Othman Maha 
Published: August 2012

Abstract
Coagulopathy is reported as the second most common cause of death from cancers, particularly prostate cancer. DVT and pulmonary embolism are two major thrombotic complications in prostate cancer and the risk is even higher with chemotherapy and hormonal therapy. Thromboelastography (TEG) is a global hemeostatic test that detects and specifies the type of coagulopathy encountered through a vesicoelastic trace that reflects the kinetics of the clot from the initial fibrin thread till and fibrinolysis. We performed a hemostatic study in 27 patients (age range 59-88 years) diagnosed with prostate cancer at various stages (metastatic and non-metastatic) as compared to a control group (n=9) matching the same age range and with -ve pathology for prostate cancer. The study included whole blood TEG and flow cytometry analysis of microprticles (MPs) in plasma using Annexin V- FITC and anti-tissue factor - PE. Analysis of the data revealed hypercoagulable state in all patients except two who were maintained on coumadin as prophylaxis for previous DVT. Hypercoagulability was indicated by shorter R time, increased alpha angle, MA and clot index. The mean values for TEG parameters in the patients were: R: 6.01 vs 9.8 minutes in the control group, alpha angle: 68.3 vs 53.1 degrees in controls, MA: 69.3 vs 57.9 mm in controls, and CI: 3.32 vs 0.7 in controls. Paired student t test showed significant differences as regards R time (P=0.009), MA (p=0.053) and CI (P=0.051). Microparticle assay revealed significant elevation in the number of microparticles carrying tissue factor in the patient group compared to the control group (p=0.05). The mean plasma TF-MPs in patient group was 5,142 MPs/uL compared to 2,914 MPs/ uL in the control group suggesting a link between elevated tissue factor and hypercoagulability observed in these patients. To our knowledge, this is the first report for the use of TEG in patients with prostate cancer. TEG is a relatively simple test that uses a small volume of blood and can be a useful tool for evaluation of patients’ thrombotic potential and may help identification of those who may require anticoagulant prophylaxis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2690. doi:1538-7445.AM2012-2690
Abstract 2691: A randomized Phase III study comparing the efficacy of Bacillus Calmette Guérin strain Tice versus Connaught for immunotherapy of non-muscle invasive bladder cancer
Authors: Rentsch Cyrill A. , Birkhäuser Frédéric , Studer Urs E. , Albert Matthew L. , Thalmann George N. 
Published: August 2012

Abstract
Introduction: For almost forty years now, adjuvant immunotherapy with intravesical Bacillus Calmette Guérin (BCG) is standard of care in the treatment of non-muscle invasive bladder cancer (NMIBC). The question whether the choice of the different available BCG strains used for treatment influences treatment outcome is still under debate. We report on a randomized phase III study comparing the two most commonly used strains in Europe and the USA. Patients and Methods: This study was performed under approval of the Cantonal Ethical Committee of Bern, Switzerland, to evaluate recurrence free survival in patients treated with BCG as the primary end-point. Between 1998 and 2010 149 patients (n=149) were recruited. Patients underwent transurethral resection of all visible bladder tumors or random bladder biopsies in case of a solely positive bladder wash cytology. TaG3 and T1G3 tumors underwent a second resection to confirm non-muscle invasive disease. Two to 15 days after surgery, patients were either randomized to receive six weekly intravesical instillations with 2-8x108 CFU OncoTice ® (BCG Tice) or 6.6-19.2 x108 CFU ImmuCyst ® (BCG Connaught) dissolved in 50 ml of saline according to manufacturers recommendations. Patients were followed in 3-monthly intervals for 3yrs, then in 6-monthly intervals by cystoscopy and bladder wash cytology. Relapses were confirmed by histology after transurethral surgery. Cox regression analysis and Log rank tests served for statistical analysis. Results: Gender, age, tumor stage and grade were well balanced between the two treatment arms (p=0.38). Median follow up was 25 months (range: 0.3-136). Side effects did not differ between the two treatment arms (p=0.42). Age and gender did not have an impact on treatment response (p=0.71). Five year recurrence-free survival for all patients was 61%. Patients treated with Connaught had significantly less recurrences than patients treated with OncoTice (p&lt;0.002). Five year recurrence-free survival was 75% and 46% for Connaught and Tice treated patients, respectively. Median recurrence-free survival was 28 months (range: 0.6-136) for Connaught and 22 months (range: 0.3-122) for Tice treated patients. Progression-free and overall survivals were not significantly different between the two treatment arms. Conclusions: The choice of the BCG strain impacts on treatment outcome and favors the use of BCG Connaught over Tice in the treatment of NMIBC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2691. doi:1538-7445.AM2012-2691
Abstract 2720: Sym004, a novel anti-EGFR antibody mixture augments radiation response in human lung and head and neck cancer models
Authors: Huang Shyhmin , Armstrong Eric A. , Kragh Michael , Pedersen Mikkel W. , Harari Paul M. 
Published: August 2012

Abstract
Sym004* is a newly developed EGFR targeting agent that is a mixture of two anti-EGFR antibodies directed against distinct epitopes on domain III of EGFR. In contrast to existing anti-EGFR antibodies, Sym004 induces rapid and efficient EGFR internalization and degradation. In the current study, we examine the capacity of Sym004 to augment radiation response in lung cancer and head and neck (H&N) cancer model systems. We examined the anti-proliferative effect of Sym004 confirming 40∼60% growth inhibition by Sym004 across a variety of lung and H&N cancer cell lines. Using clonogenic survival analysis, we identified that Sym004 potently increased cell kill by up to 10-fold following 9 Gy radiation exposure. Immunoblot analysis showed down-regulation of MAPK and AKT pathways, as well as changes in several key proteins involved in cell cycle progression, DNA damage repair and apoptosis. Flow cytometric analysis confirmed a significant increase of cells in S phase 24 hrs following 6 Gy radiation in control cells. However, treatment with Sym004 preceding radiation induced a significant G1 and G2 arrest accompanied by a reduction in S phase. Interestingly, we found a significant increase in apoptosis 48 hrs after radiation. These results suggest that Sym004 arguments radiation response via the induction of cell cycle arrest followed by the induction of apoptosis and cell death likely reflecting inhibitory effects on DNA damage repair. Finally, using single dose or fractionated radiation experiments in human tumor xenograft models, we found that the combination of Sym004 and radiation resulted in a significant delay in tumor regrowth and superior anti-tumor effects than treatment with drug or radiation alone. Taken together, these data reveal the strong capacity of Sym004 to augment radiation response in lung and H&N cancers. The unique action mechanism of Sym004 warrants further investigation as a promising EGFR targeting agent combined with radiotherapy in cancer therapy. (*Pedersen et al., Cancer Res 70:588∼597, 2010)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2720. doi:1538-7445.AM2012-2720
Abstract 2721: MEHD7945A, dual specific antibody against EGFR and HER3, augments radiation response in head and neck squamous cell carcinoma
Authors: Li Chunrong , Huang Shyhmin , Armstrong Eric A. , Sliwkowski Mark X. , Amler Lukas C. , Harari Paul M. 
Published: August 2012

Abstract
The HER receptor family members (EGFR, HER2, HER3 and HER4) play an important role in tumorigenesis. High EGFR expression levels correlate with poor prognosis and resistance to therapy for many epithelial tumors. Combining EGFR inhibition with radiation has been extensively studied in head and neck squamous cell carcinoma (HNSCC). Increasing evidence implicates HER3 as a key mediator of response and resistance to EGFR targeted therapies. We therefore examined the capacity of a dual specific antibody MEHD7945A, that can simultaneously target EGFR and HER3, to modulate radiation response in HNSCC. We characterized 10 HNSCC cell lines for their EGFR and HER3 expression. Immunoblot analysis confirmed that MEHD7945A significantly inhibited basal and radiation-induced EGFR and HER3 phosphorylation and downstream MAPK and AKT signaling. MEHD7945A consistently inhibited tumor cell growth in culture ranging from 30∼80%. The growth inhibitory effect of MEHD7945A was more potent than that observed with anti-EGFR or anti-HER3 antibody alone. Using clonogenic survival assay, we found that MEHD7945A significantly enhanced radiosensitivity in HNSCC cells. Once again, this effect of MEHD7945A was more potent than that observed with anti-EGFR or anti-HER3 antibodies. Treatment with MEHD7945A and radiation induced cell cycle arrest in G1 and G2 phases. Tumor cells eventually processed to apoptosis without successful DNA damage repair, as reflected by increased apoptotic populations detected by AnnexinV/PI staining. In addition, an increase of nuclear γ-H2AX foci was observed in cells receiving combination MEHD7945A and radiation. We administered MEHD7945A systemically to athymic mice bearing human tumor xenografts. Using single dose and fractionated radiation schedules, we observed that combined MEHD7945A and radiation was significantly more potent than single modality treatment to induce HNSCC tumor growth inhibition. These in vitro and in vivo results indicate that MEHD7945A can sensitize cells to radiation and inhibit HNSCC tumor growth, suggesting the potential of MEHD7945A as a radiation sensitizer for future clinical investigations.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2721. doi:1538-7445.AM2012-2721
Abstract 2722: Active recruitment of immune effector cells mediates in vivo tumor growth inhibition by enavatuzumab, an antibody to human TWEAK receptor
Authors: Ye Shiming , Fox Melvin , Belmar Nicole , Sho Mien , Chao Debra T. , Choi Donghee , Fang Yuni , Zhao Vivian , Keller Stephen , Starling Gary C. , Culp Patricia A. 
Published: August 2012

Abstract
Enavatuzumab (PDL192) is a humanized anti-TWEAK receptor antibody currently under clinical evaluation for the treatment of solid malignancies. Enavatuzumab is postulated to exert its potent anti-tumor activity in xenograft models through two distinct mechanisms of action: direct inhibition of tumor cell growth and Fc-mediated function. The goal of this study was to elucidate the role of immune effector cells in Fc-mediated function. The initial evidence for a role of effector cells was obtained in a subset of tumor xenograft mouse models which responded to enavatuzumab but did not respond to a version of enavatuzumab containing a mutation in the FcαRIII binding region. Subsequent analysis of circulating effector cells showed increased expression of activation markers DX5 and CD27 on monocyte-like cells (CD45+CD11bHigh) and DX5 on NK-like cells (CD45+CD11bLow) after enavatuzumab treatment in xenograft models dependent on Fc-FcR interactions for enavatuzumab efficacy. The involvement of effector cells was further confirmed by immunohistochemistry, which revealed strong infiltration of CD45+ effector cells into tumor xenografts in responding models, but minimal infiltration in non-responders. Consistent with the in vivo xenograft studies, human effector cells migrated towards enavatuzumab-treated tumor cells in vitro. Effector cells preferentially migrated toward in vivo responsive tumor cells, and the majority of migratory cells were monocytes and NK cells. Conditioned media from enavatuzumab-treated tumor cells also induced migration, and contained elevated levels of cytokines/chemokines, including IL8 and MCP-1. The presence of an anti-MCP-1 neutralizing antibody in enavatuzumab-treated tumor cell conditioned medium significantly blocked effector cell migration, suggesting that MCP-1 might be responsible for effector cell migration triggered by enavatuzumab. We also observed elevated levels of human MCP-1 in the serum of both enavatuzumab-treated xenograft mouse models and in a subset of patients from the enavatuzumab Phase I clinical study. In summary, in vivo and in vitro studies suggest that enavatuzumab exerts its potent anti-tumor activity, in part, by actively recruiting effector cells and activating effectors to kill tumor cells. In addition, enavatuzumab-induced chemokines may be potential pharmacodynamic biomarkers and warrant further evaluation in clinical studies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2722. doi:1538-7445.AM2012-2722
Abstract 2725: Preclinical development of an Fc-enhanced anti-B7-H3 monoclonal antibody with potent anti-tumor activity
Authors: Loo Deryk T. , Alderson Ralph , Chen Francine , Huang Ling , Zhang Wenjun , Gorlatov Sergey , Burke Steve , Ciccarone Valentina , Li Hua , Yang Yinhua , Son Thomas , Chen Yan , Li Jonathan , Rillema Jill , Licea Monica , Liang Tony , Mather Jennie P. , Koenig Scott , Stewart Stanford J. , Johnson Syd , Bonvini Ezio , Moore Paul 
Published: August 2012

Abstract
Antigens that are tumor-specific or over-expressed on cancer cells represent opportunities for developing target-specific antibody-based therapeutics. Utilizing a non-target-biased intact cell-based immunization approach, we have generated greater than 1600 mAbs to cell-surface proteins that are expressed on cancer cells. A subset of the mAbs exhibit differential reactivity to tumor cells compared to normal cells. One of the differentially expressed proteins identified was B7-H3 (also referred to as CD276). B7-H3 is a member of the B7 family of immune regulatory proteins. Over-expression of B7-H3 has been correlated with disease severity and outcome in a growing number of cancer types, and several lines of evidence support a functional role for B7-H3 in cancer. In this report we describe the development of a humanized anti-B7-H3 mAb, designated MGA271, which bears an engineered Fc domain that imparts enhanced antibody-dependent cellular cytotoxicity (ADCC) through increased affinity for the human activating Fc-gamma receptor IIIA (CD16A) and decreased affinity for the human inhibitory Fc-gamma receptor IIB (CD32B). MGA271 displays strong reactivity to multiple tumors including kidney, prostate, pancreatic, breast, colon, gastric and ovarian cancer as well as melanoma, but limited reactivity toward normal human tissues. Independently of the donor's CD16A genotype, MGA271 mediates ADCC in vitro against human tumor cell lines representing these tumor types, as well as to human lung and gastrointestinal cell lines that exhibit properties of cancer stem cells. MGA271 exhibits potent anti-tumor activity toward B7-H3-expressing tumor xenografts in mice knocked-out for the murine CD16 gene and transgenic for the low affinity allele of human CD16A. Single- and repeat-dose toxicology studies were carried out in cynomolgus monkeys and no significant test article-related safety findings were observed. Taken together, these data support the clinical development of MGA271 for the treatment of patients who have B7-H3-expressing cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2725. doi:1538-7445.AM2012-2725