bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5306: Microparticles as novel prognostic markers in multiple myeloma
Authors: Rajeev Krishnan Sabna , Bebawy Mary , Brown Ross Duncan , Luk Frederick , Kwan Yiulam 
Published: August 2015

Abstract
Introduction: Multiple Myeloma (MM) is an incurable hematological malignancy affecting plasma cells marked by highly heterogeneous survival rates and confinement of the disease to bone marrow (BM). Relapse is a significant impediment in the clinical setting and the development of multidrug resistance (MDR) to therapy is the main cause of relapse. Currently, risk stratification to MM sub-groups and categorization of complete response to therapy are established on molecular and cytogenetic markers using bone marrow biopsies. We are exploring the clinical significance of plasma cell derived microparticles as a novel prognostic indicator in MM. Materials and Methods: We have analysed 79 de-identified MM patients and 24 normal subjects. Platelet free plasma was centrifuged and plasma cell derived MPs were identified and quantified by flow cytometry using Annexin V450, CD138 APC, anti-P-glycoprotein (P-gp)-FITC (17F9) in BD TruCount tubes. Platelet derived MPs were excluded from the analysis using CD41a-PE. All patient samples were compared to age-matched healthy volunteers. Western blot analysis was conducted on MP lysates probing for the presence of Lung-Resistance related Protein (LRP) and P-glycoprotein (P-gp). Morphology and the size of MP fraction from MM patients were investigated using scanning electron micrographs Results: The number of systemic MPs and CD138+MPs were found to be significantly higher in MM patient samples compared to the healthy volunteers. MDR markers (LRP & P-gp) were expressed on systemic MPs from relapsing MM patients. MPs from patients were spherical in shape and had smooth surface consistent with those isolated from the MM cell line OPM2.
Conclusions: There are elevated numbers of systemic MPs in all the 79 MM subjects (across all disease stages) compared to the healthy volunteers. The expressions of CD138 on MPs in the MM patients offer a sensitive assessment of disease progression and therapeutic outcome. Systemic MPs from MM patients carry a ‘snapshot’ of the less accessible bone marrow compartment and may provide a novel systemic ‘biosignature’ of MM progression and therapeutic outcome in the clinical setting. The MDR markers on systemic MPs may support dosage regimen and therapeutic decisions in MM clinical setting.
Acknowledgements: This project has ethical approval from Sydney Local Health District Human Research Ethics Committee (CRGH)- EC00118 # HREC/11/CRGH/223 (CH62/6/2011/150).
We would like to thank all the volunteers whom have contributed to this study.
Citation Format: Sabna Rajeev Krishnan, Mary Bebawy, Ross Duncan Brown, Frederick Luk, Yiulam Kwan. Microparticles as novel prognostic markers in multiple myeloma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5306. doi:10.1158/1538-7445.AM2015-5306
Abstract 5309: The role of aquaporin-1 as the prognostic factor for triple negative breast cancer
Authors: Lim Young Ah , Kim Lee-Su 
Published: August 2015

Abstract
Aquaporins(AQPs) area a large family of integral membrane water transport cannel proteins that facilitate the transport of water through the cell membrane. And in the subgroup of AQPs, AQP1 are expressed in many epithelia and endothelia such as kidney and lung. Recent studies revealed that AQPs were associated with human malignancies, since they are likely to play a role in the promotion of tumor progression and invasion. In this study, we evaluated the correlation with AQP1expression and invasive breast cancer, especially triple negative breast cancer(TNBC) and we analyzed AQP1 expression and the clinicopathologic factor. The present study was based on 277 patients of primary breast carcinomas who underwent surgery and treatment, presenting between Jan. 2003 and Dec. 2008. The immunohistochemical expression of AQP1 was investigated and compared with clinicopathologic factors. AQP1 expression was demonstrated in 17 tumors(6.1%) for all patinets. In 50 patients who were diagnosed with TNBC, 12 patients(24%) showed AQP1 expression. In the result, AQP1 expression was associated with TNBC. For all patients, AQP1 expression was associated with poor prognostic factor. In TNBC patients, AQP1 expression was not associated with prognostic factor. In consideration of AQP1 expression for TNBC patients, our results suggested AQP1 expression is a new prognostic factor of TNBC which is aggressive subgroup of breast carcinoma.
Note: This abstract was not presented at the meeting.
Citation Format: Young Ah Lim, Lee-Su Kim. The role of aquaporin-1 as the prognostic factor for triple negative breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5309. doi:10.1158/1538-7445.AM2015-5309
Abstract 5317: Preclinical evaluation of IQS019, a novel BCR kinase inhibitor, in in vitro and in vivo models of non-Hodgkin lymphoma
Authors: Balsas Patricia , Roldan Jocabed , Jimenez Laura , Rodriguez Vanina , de la Bellacasa Raimon Puig , Teixido Jordi , Matas-Cespedes Alba , Moros Alexandra , Martinez Antonio , Campo Elias , Borrell Jose I , Perez-Galan Patricia , Colomer Dolors , Roue Gael 
Published: August 2015

Abstract
Constitutive activation of B-cell receptor (BCR) signaling is a hallmark of several B-cell non-Hodgkin lymphoma (B-NHL), including diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL). Despite the promising clinical activity of the first BCR kinase inhibitors in some of these entities, the design of new compounds is warranted to improve the survival of B-NHL patients who are poorly responsive, and/or who eventually develop resistance to current BCR-targeting therapies. In this context, we recently described the synthesis of IQS019, a 4-aminopyrido[2,3-d]pyrimidine with improved inhibition pattern against the three BCR-related kinases Lyn, Syk and Btk, when compared to reference BCR kinase inhibitors. Here, by assessing the activity of IQS019 in a panel of 21 human cell lines and 17 primary samples representative of the main B-NHL subtypes, we show that doses of IQS019 in the micromolar range allowed to a rapid and dose-dependent de-phosphorylation of both constitutive and Ig-activated Syk, Lyn and Btk in CLL, MCL, FL and DLBCL cell lines and CLL primary cultures. IQS019 treatment impairs cell proliferation and CXCL12-dependent cell migration, and leads to the induction of caspase-dependent apoptosis. Of interest, in CLL primary cells, these effects were independently of IGVH mutational status. In xenotransplant mouse models of MCL and FL, daily dosing of 2 mg/kg IQS019 for two weeks demonstrated to be safe for the animals and allowed to a 50-60% reduction in tumor outgrowth and glucose uptake, together with a 52% decrease in cell infiltration into the spleen (p &lt; 0.05). These effects were accompanied by a significant (p &lt; 0.05) downregulation of p-Syk, p-Lyn and p-Btk, and consequent mitotic arrest and induction of apoptosis in human malignant B cells. Altogether, these results define the BCR kinase inhibitor IQS019 as a potential candidate in antitumor therapy against a variety of B-NHL subtypes with aberrant activation of BCR pathway.
Citation Format: Patricia Balsas, Jocabed Roldan, Laura Jimenez, Vanina Rodriguez, Raimon Puig de la Bellacasa, Jordi Teixido, Alba Matas-Cespedes, Alexandra Moros, Antonio Martinez, Elias Campo, Jose I Borrell, Patricia Perez-Galan, Dolors Colomer, Gael Roue. Preclinical evaluation of IQS019, a novel BCR kinase inhibitor, in in vitro and in vivo models of non-Hodgkin lymphoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5317. doi:10.1158/1538-7445.AM2015-5317
Abstract 5324: Selective Inhibition of HDAC6 regulates preferential cytotoxicity in cancer cells by modulating p53 and Hsp90 stability
Authors: Kwon So Hee 
Published: August 2015

Abstract
A HDAC6-selective inhibitor is a promising new therapeutic agent for cancer treatment, but its precise mechanisms of actions are not well understood. In particular, the relevance of p53 for HDAC6 inhibitor-induced effects has not been fully elucidated. Here, we show that a γ-lactam based HDAC inhibitor A452 selectively inhibits HDAC6 catalytic activity in vivo and in vitro. A452 causes cell death as well as growth inhibition of transformed cells not observed in normal cells. A452 exhibits differential cytotoxicity for wild-type (wt) and mutant p53 (mutp53) human colorectal cancer cells. Interestingly, A452 shows different mechanisms of action of modulating p53 in cancer cells. A452 increases wtp53 by destabilizing MDM2 and MDMX. In contrast, A452 causes mutp53 destabilization by inhibiting complex formation between Hsp90 and hyperstable mutp53, which is a hallmark of p53 mutation and cancer cell-specific. A452 also chemosensitizes cancer cells differing in p53 status for chemotherapy due to its ability to degrade mutp53 and stabilize wtp53. Intriguingly, acetylation of Hsp90 by A452 results in its degradation as well as inactivation of its chaperone activity. Furthermore, A452 effectively suppresses cell migration and invasion. These results demonstrate that A452 is a specific HDAC6 inhibitor and requires for p53 and Hsp90 for inducing anticancer action. Therefore, these results suggest that therapeutic targeting of HDAC6 may represent a new way to treat cancers expressing mutant forms of p53.
Citation Format: So Hee Kwon. Selective Inhibition of HDAC6 regulates preferential cytotoxicity in cancer cells by modulating p53 and Hsp90 stability. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5324. doi:10.1158/1538-7445.AM2015-5324
Abstract 5325: A c-Kit targeting antibody-drug conjugate is efficiently metabolized and activated inside cancer cell lines and xenograft tumors
Authors: Hong Erica , Qiu Qifeng , Wu Rui , Wilhelm Alan , Whiteman Kathleen , Pinkas Jan , Erickson Hans , Abrams Tinya , Schleyer Siew 
Published: August 2015

Abstract
We have developed an antibody-drug conjugate (ADC) targeting the c-Kit receptor tyrosine kinase, which is selectively expressed on the cell surface of various tumors including gastrointestinal tumors (GIST), small cell lung cancer (SCLC) and acute myelogenous leukemia (AML). The ADC consists of a humanized c-Kit-binding monoclonal antibody (c-Kit-Ab) covalently attached to a maytansinoid tubulin inhibitor, DM1, via a non-cleavable linker, SMCC. Like other ADCs, the c-Kit ADC is a pro-drug that is activated upon metabolism inside cells. Its target-mediated internalization and lysosomal degradation generates active maytansinoid metabolites that bind and inhibit microtubule dynamics. To understand the activation of the ADC, we studied the kinetics and efficiency of its metabolism in cancer cells and xenograft tumor models. Using radiolabeled ADC and c-Kit-Ab, we followed the formation of metabolites in SCLC and AML cells and in SCLC tumors, as well as in engineered cell lines that express various mutant forms of c-Kit.
We found that the ADC and c-Kit-Ab are efficiently metabolized in c-Kit-positive cancer cells irrespective of the mutational status or the activation state of c-Kit. The degradation half-life of c-Kit-Ab is 3-fold lower than that observed for T-DM1 and SGN35, indicating a faster rate of activation. Moreover, cell surface repopulation with c-Kit is highly efficient after ADC-mediated internalization, allowing multiple rounds of ADC recruitment and activation. Interestingly, cell surface repopulation of c-Kit is more rapid for cells with a c-Kit mutation than those with wild-type c-Kit, leading to generation of greater levels of active metabolites in cells with mutant c-Kit. This may lead to better targeting of the c-Kit-mutated cancer cells over normal cells with wild-type c-Kit, which may improve the safety of the c-Kit ADC.
Consistent with the in vitro findings, the ADC was found to undergo efficient metabolism in tumors in vivo. While tumor localization of the ADC over a non-targeting conjugate is similar to that observed with T-DM1 and SAR3419, its tumor-specific formation of active metabolites is 3-fold greater. Thus, the c-Kit-targeting ADC is particularly efficient at achieving high levels of active metabolites inside c-Kit-positive tumor cells, consistent with its robust efficacy in mouse xenograft models.
Citation Format: Erica Hong, Qifeng Qiu, Rui Wu, Alan Wilhelm, Kathleen Whiteman, Jan Pinkas, Hans Erickson, Tinya Abrams, Siew Schleyer. A c-Kit targeting antibody-drug conjugate is efficiently metabolized and activated inside cancer cell lines and xenograft tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5325. doi:10.1158/1538-7445.AM2015-5325
Abstract 5334: Oncolytic Newcastle disease virus: armed but not dangerous
Authors: Carroll Danielle K. , Harper James , Burke Shannon , Travers Jon , Franks Ruth , Navarro Christel , Cheng Xing , Wilkinson Robert W. , Jin Hong 
Published: August 2015

Abstract
Oncolytic viruses are live, replication-competent viruses that infect and/or replicate selectively in tumour cells leading to the destruction of the infected cell. Cell lysis occurs as a natural consequence of the viral life cycle and released virions can infect and kill neighbouring tumour cells leading to an amplified therapeutic effect. Oncolysis has the added benefit of releasing multiple tumour antigens that may further induce an immune-mediated therapeutic response.
Newcastle Disease Virus (NDV) is an avian paramyxovirus, which has proven safety and demonstrated efficacy against a variety of preclinical cancer models and in PhI clinical studies as an oncolytic agent, oncolysate or whole cell vaccine. Using reverse genetics, we have generated a recombinant strain of NDV that overcomes environmental and regulatory concerns uncoupling oncolytic potency and avian pathogenicity. Furthermore we have enhanced the immune modulatory properties of
NDV by engineering the virus to express granulocyte/macrophage colony-stimulating factor (GM-CSF). We have evaluated the biological characteristics of recNDVGM-CSF in vivo and in vitro. RecNDVGM-CSF
selectively replicates in and kills a wide variety of human and mouse tumour cell lines. Additionally NDV infection of cancer cells results in the increased production and secretion of pro-inflammatory cytokines and chemokines which are able to recruit mediators of both the innate and adaptive immune responses. NDV is a potent activator of the type I interferon response and is also able to directly activate many immune cell types. In vivo, using a range of syngeneic and xenograft models we have demonstrated that NDV treatment has profound anti-tumour activity. In a
HT1080 fibrosarcoma xenograft model a single administration (intra-tumoural or systemic) was able to cure 80% of tumour bearing mice. In syngeneic mouse tumour models, NDV treatment causes profound changes in the immune suppressive microenvironment and can result in long-lasting anti-tumour immune responses.
The inherent properties of NDV (self-propagation, tumour-selective replication, and immunostimulatory properties) coupled with the ability to genetically engineer NDV to express therapeutic transgenes may provide a multi-modal attack on the tumour, delivering greater benefit to patients.
Citation Format: Danielle K. Carroll, James Harper, Shannon Burke, Jon Travers, Ruth Franks, Christel Navarro, Xing Cheng, Robert W. Wilkinson, Hong Jin. Oncolytic Newcastle disease virus: armed but not dangerous. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5334. doi:10.1158/1538-7445.AM2015-5334
Abstract 5348: The extracellular domain of thrombomodulin induces erythroid differentiation and hampers proliferation of human leukemia cells in vitro and in vivo
Authors: Ikezoe Takayuki , Yang Jing , Nishioka Chie , Honda Goichi , Yokoyama Akihito 
Published: August 2015

Abstract
Thrombomodulin (TM) is a glycosylated type I transmembrane molecule with multiple domains that include an NH2-terminal lectin-like region, six tandem epidermal growth factor (EGF)-like structures, an O-glycosylation site-rich domain, a transmembrane domain, and a cytoplasmic tail domain. TM is ubiquitously expressed on endothelial cells and acts as an anticoagulant via generation of activated protein C. Recombinant human soluble thrombomodulin (rTM) comprises the active, extracellular domain of TM, and inactivates coagulation. Use of rTM for the treatment of disseminated intravascular coagulation was approved in Japan in 2008. We previous showed that exposure of acute promyelocytic leukemia or acute myelomonocytic leukemia cells to rTM induced myeloid differentiation and growth arrest in vitro (Exp Hemat. 2012, Leuk Res. 2012). The present study found that exposure of K562 and KU812 cell lines that were derived from chronic myeloid leukemia cells to rTM increased expression of cell surface glycophorin CD235a in association with upregulation of GATA1 mRNA, indicating a differentiation of leukemia cells toward erythroid lineage. Interestingly, treatment of K562 bearing immunodeficient mice with rTM significantly decreased number of K562 cells infiltrating in liver and prolonged their survival compared to mice who received control diluent. These observations shed light on a novel function of TM in hematopoietic cells.
Note: This abstract was not presented at the meeting.
Citation Format: Takayuki Ikezoe, Jing Yang, Chie Nishioka, Goichi Honda, Akihito Yokoyama. The extracellular domain of thrombomodulin induces erythroid differentiation and hampers proliferation of human leukemia cells in vitro and in vivo. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5348. doi:10.1158/1538-7445.AM2015-5348
Abstract 5352: Mesenchymal stem cell as delivery carrier for prodrug gene therapy against colorectal cancer cell
Authors: Salehi Nasrin , Peng Ching-An 
Published: August 2015

Abstract
Gene-directed enzyme prodrug therapy (GDEPT) is an approach that delivers a suicidal gene to cancer cells for the expression of prodrug-activating enzyme which converts prodrug into cytotoxic drug. One of the major impediments of GDEPT is to have the therapeutic gene specifically target on cancer cells prior to the administration of prodrug. Among various gene delivery methods, mesenchymal stem cells (MSCs) have emerged as potential carriers for gene delivery. They exhibit remarkable tumor-tropic and low immunogenic capacities. In this study, MSCs was engineered to express thymidine phosphorylase (TP) which has the capability of converting the prodrug doxifluridine into toxic 5-fluorouracil. TP expression in the MSCs post-transfection of TP cDNA was confirmed by immunoblotting analysis and its activity was determined by spectrophotometric assay. Our results showed the anticancer effectiveness of human HT29 colorectal adenocarcinoma cells co-cultured with TP-expressing MSCs was enhanced with the addition of various dosages of doxifluridine.
Citation Format: Nasrin Salehi, Ching-An Peng. Mesenchymal stem cell as delivery carrier for prodrug gene therapy against colorectal cancer cell. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5352. doi:10.1158/1538-7445.AM2015-5352
Abstract 5354: The guilty bystander model for electrochemotherapy of cancer: Verification in vitro
Authors: Lambert W Clark , Tsongalis Gregory J. , Gagna Claude E. , Lambert Muriel W. 
Published: August 2015

Abstract
Electroporation (EPR) is the induction of pores in cellular membranes in cells by application of a short application of a high voltage, low amperage electric current. If the cells are immersed in a solution containing a large molecule which is normally impervious to this membrane, it may be introduced into the cells in this manner. Electrochemotherapy (ECT) is a clinical procedure in which a drug, such as bleomicin or cisplatin, is introduced into the blood of or intratumorally into an animal or human subject by intravenous injection followed by application of a short high dose, low amperage electric current into a neoplasm after a delay enabling the drug to reach the neoplasm through the bloodstream or by other means. ECT is normally used for palliative care in human subjects, however there are now a number of reports, numbering well over 10, of unexpected complete clearance of neoplasms following ECT. Many of these reports have come from university centers in Europe and elsewhere. Although ECT is not yet approved in the USA, we believe that these reports can no longer be ignored. We and others have used EPR in culture to introduce large molecules into cells for experimental purposes for decades. Even under the controlled experimental conditions we have employed, however, the proportion of cells into which these molecules have been introduced has been well below 100 per cent. To account for the clearance of some tumors by ECT, in which the proportion of cells in which drug is introduced would be expected to be lower than for EPR, we have proposed a “Guilty Bystander Model”, in which cells adjacent to neoplastic cells into which drug has been introduced are also cleared. To test this model in vitro, we optimized conditions for EPR but were unable to produce more than 88 per cent introduction of labeled large molecules into lymphoblastoid cells (GM 1989A, derived from a healthy 33 year old Caucasian male, and GM 3999, derived from a healthy 8 year old Caucasian female), even under conditions which reduced cell viability from 99 per cent to 79 per cent. Increasing voltage produced a marked loss of viability. We conclude that EPR does not produce 100 per cent introduction of large molecules into human cells, even under optimized conditions in vitro, and that there must remain neoplastic cells in tumors treated by ECT that are eliminated by means other than introduction of the drug.
Citation Format: W Clark Lambert, Gregory J. Tsongalis, Claude E. Gagna, Muriel W. Lambert. The guilty bystander model for electrochemotherapy of cancer: Verification in vitro. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5354. doi:10.1158/1538-7445.AM2015-5354