bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2569: Disruption of ceramide glycosylation restores p53-dependent apoptosis in p53 mutant drug-resistant cancer cells: Alternative splicing determines the feature of p53 activity
Authors: Patwardhan Gauri A. , Gupta Vineet , Hsia Shaochung , Gu Xin , Jazwinski Michal , Liu Yong-Yu 
Published: February 2011

Abstract
Mutation of tumor suppressor p53 is frequently detected in many different types of cancers. p53 mutants acts as oncogenic proteins preventing programmed cell death and promoting cancer progression. Restoration of p53 that is to increase the expression of wild-type p53 and to eliminate mutant expression can substantially increase the efficacy of chemotherapy and stop malignant progression. However, incomplete understanding the molecular mechanism underlying p53 gene regulation limits the success in p53 restoration. We, for the first time, report that disruption of ceramide glycosylation restores p53 dependent-apoptosis in p53 mutant drug-resistant cancer cells. A lose of 21 base-pair in the mRNA of exon-5 can result in the accumulation of mutant p53 and cells insensitiveness to induced-apoptosis in human NCI/ADR-RE ovarian cancer cells. We found that treatment of mixed-backbone oligonucleotide against human glucosylceramide synthase (MBO-asGCS) increased the levels of wild-type p53 mRNA (containing the 21 bp in exon-5) and protein of wild-type p53 in dose-dependent manner (50-200 nM). In response to doxorubicin-induced DNA damage, phosphorylated p53 (Ser15 in the exon-5) was significantly increased, that in turn increased the protein levels of p21 and Bax, and apoptosis (52% vs. 3%) after MBO-asGCS treatment compared to control in NCI/ADR-RE cells. Silencing of GCS using MBO-asGCS (1 mg/kg) restored wild-type p53 expression and substantially sensitizes NCI/ADR-RE tumors to doxorubicin-induced apoptosis in vivo (10 mice per group), as compared to MBO-scramble control or other treatments. In contrast, introduction of GCS gene in NCI-ADR-RE cells reduces wild-type p53 expression and p53-depedent apoptosis. Further mechanic studies indicated that increased ceramide after GCS silencing modulates the function of SRp30a (ASF/SF2) regulating alternative pre-mRNA splicing. Increasing endogenous ceramide by inhibition of its glycosylation using PDMP or enhanced its production using sphingomylinase promoted wild-type p53 expression at the levels of mRNA, protein and phosphorylation; decreasing ceramide by inhibition of ceramide synthesis using fumonisin (FB1) repressed wild-type p53 expression. Present study indicates that cancer cells marked with mutant p53 phenotype are capable of expressing functional p53; ceramide glycosylation is one molecular mechanism that shifts expression to wild-type form of p53 at alternative splicing of post-transcription processing. MBO-asGCS, a specific agent silencing GCS restores p53-dependent apoptosis in cancer cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2569.
Abstract 258: Molecular features and functional consequence of CD44 activation by a novel recurrent IGH translocation t(11;14) (p13;q32) in mature B-cell lymphoid neoplasm
Authors: Chen Yun-Wen , Hu Xiao-Tong , Liang Anthony C.T. , Wong Michelle L.Y. , Au Wing-Yan , Wong Kai-Yau , Choi William W.L. , Wan Thomas S.K. , Chu Kent-Man , Chim Chor Sang , Chan Li Chong , Kwong Yok-Lam , Liang Raymond H.S. , Srivastava Gopesh 
Published: February 2011

Abstract
Dysregulation of an oncogene by translocation to Ig locus is a common event in the pathogenesis of most non-Hodgkin's lymphoma. Using inverse-PCR, CD44 on 11p13 was identified as a novel translocation partner of IgH in 9 of 114 cases of gastric, non-gastric extranodal, follicular and nodal diffuse large B-cell lymphomas (DLBCLs) analyzed. IgHSμ/CD44 translocation juxtaposes the enhancer of IgHSμ to the 5’ regulatory region of CD44 in a tail-to-head orientation, leading to the removal of exon 1 of CD44. Sequencing analysis showed microhomology sequences at the junction breakpoints of all the IGHSμ/CD44 translocations, suggesting that these translocations were the results of illegitimate switch recombination facilitated by homologous sequences present on both chromosomes. By interphase-FISH using home-grown CD44 dual-color break-apart probes (consisting of BACs RP4-607I7 and RP4-683L5), breakage at the CD44 locus in each of the nine IGHSμ/CD44 translocation-positive cases was confirmed. By 5’ RACE analysis, fusion Iμ-CD44ΔEx1 hybrid transcripts (with a splicing of the Iμ exon upstream of Sμ to exon 2 of CD44), were identified in all the nine lymphomas with IGHSμ/CD44 translocations. Notably, these translocations were detected exclusively in GCB-type DLBCLs. However, CD44 mRNA was minimally or not expressed in CD10+ microdissected reactive GCB cells. The IGHSμ/CD44 translocation substitute Sμ for the CD44 promoter and remove exon 1 of CD44, resulting in over-expression of the Iμ-CD44 hybrid transcript which encodes for a new CD44 variant lacking leader peptide sequence but retaining a unique C-terminus (CD44ΔEx1). The Iμ-CD44ΔEx1 ORF would encode for the CD44ΔEx1 protein starting from the ATG at nucleotide 254 with strong Kozak sequence. The new CD44ΔEx1 variant showed some similarity to CD44v5, but it lacked the leader peptide. The IGHSμ/CD44 translocation was detected in patients with advanced-stage disease (stages III and IV). When overexpressed in vitro in the CD44-negative GCB-DLBCL cell line BJAB, the CD44ΔEx1-GFP was localized to the cytoplasm and nucleus, while CD44s-GFP (standard form) was localized to the plasma membrane. The ectopic expression of CD44ΔEx1 in BJAB cells enhanced the cell proliferation rate and its clonogenic ability. These findings indicate a possible pathogenic role of the recurrent translocation in several malignant B-cell lymphomas.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 258.
Abstract 2587: In vitro plasma stability of human anti-CD70 antibody drug conjugate, MDX-1203
Authors: Sung Janette , Vemuri Kavitha , Passmore David , Tatum Andrea , Kempe Tom , Brams Peter , Derwin Dan , Thevanayagam Lourdes , Srinivasan Mohan , Huber Mary , Rao Chetana , Zhang Allen , Cong Charlie , Sufi Bilal , Gangwar Sanjeev , Deshpande Shrikant , Rangan Vangipuram S. 
Published: February 2011

Abstract
MDX-1203 is a human anti-CD70 antibody conjugated to a pro-drug containing DNA alkylating cytotoxic Drug A. Drug A is composed of the anti-tumor compound Drug B, containing an ester linked protecting group, and a maleimide containing cleavable peptide linker designed to facilitate conjugation to the antibody. Mechanism of action of ADCs involve antibody mediated tumor specific delivery, cellular uptake, and intracellular pro-drug release and activation. Understanding the stability of the peptide linker as well as the pro-drug in various plasma matrices is critical for the development of successful ADC therapeutic. We have generated mouse monoclonal antibodies that specifically recognize either the intact Drug A or Drug A without the protecting group. Using these antibodies, an ELISA method was developed to study in vitro plasma stability of pro-drug in MDX-1203. Our results indicate that the plasma stability of ester linked protecting group varies significantly depending on the animal species probably due to variation in the level of plasma esterase activity. In order to determine the peptide linker stability, a radiolabeled MDX-1203 with 14C radiolabel on Drug A was made. A Thin Layer Chromatography method was developed to determine the in vitro plasma stability of the peptide linker in different plasma matrices. Our results indicate that the peptide linker in MDX-1203 is stable at 37o C up to 6 days. Based on these experimental data, we propose a model for stability of the peptide linker as well as the pro-drug in MDX-1203 in various plasma matrices.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2587.
Abstract 2593: Telomerase-specific oncolytic virotherapy for osteosarcoma
Authors: Kawashima Hiroyuki , Li Guidong , Ogose Akira , Endo Naoto , Kuwano Ryozo , Urata Yasuo , Fujiwara Toshiyoshi 
Published: February 2011

Abstract
Oncolytic adenoviruses are being developed as novel antitumor therapeutics and currently undergoing clinical trial. Telomelysin (OBP-301) is a type 5 adenovirus that contains the replication cassette in which the human telomerase reverse transcriptase promoter drives expression of the E1 genes, and shows telomerase specific replication and cell killing effect. We previously demonstrated that the expression of coxsackie-adenovirus receptor (CAR) is high in osteosarcoma compared with the other mesenchymal tumors, and moreover, many investigators have been reported that telomerase expression predicts the unfavorable outcome in osteosarcoma. The present investigation analyzed that the selective replication and antitumor effects of Telomelysin using 8 osteosarcoma and 1 normal dermal fibroblast cell lines in vitro as well as in vivo by using athymic mice carrying xenografts. At first, all cell lines were used to examine the mRNA expression of CAR and hTERT, and 3 osteosarcoma cell lines and 1 normal fibroblast cell were chosen for Telomelysin infection. Selective E1A and E1B expression were shown in osteosarcoma cells by quantitative real-time RT-PCR and Western blot analysis, but not in normal cells such as human dermal fibroblasts. Telomelysin replicated efficiently and induced marked cell death in osteosarcoma cells, whereas replication as well as cytotoxicity was highly attenuated in normal fibroblast cells lacking telomerase activity. Expression of cleaved caspase, PARP and LC-3 I, II after Telomelysin infection was tested by Western blot, however the mechanism of induction of cell death could not be revealed in this time. For in vivo evaluation, nu/nu mice xenografted with NOS10 human osteosarcoma cell received intratumoral injection of 107 plaque-forming units of Telomelysin, and resulted in a significant inhibition of tumor growth and long-term survival in all treated mice. Moreover, selective replication of Telomelysin in tumor cell was also demonstrated by anti-E1A immunohistochemistly, and induction of apoptosis was observed by TUNEL staining. Our results suggest that the hTERT promoter confers competence for selective replication of Telomelysin in osteosarcoma cells, and the outcome has important implications for tumor-specific oncolytic chemovirotherapies for human osteosarcomas.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2593.
Abstract 2595: Vesicular stomatitis virus as a treatment for colorectal cancer
Authors: Stewart John H. , Ahmed Maryam , Northrup Scott A. , Lyles Douglas S. 
Published: February 2011

Abstract
Introduction: Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States. Despite progress in many aspects of combating colorectal cancer, the cause of death in nearly a third of all patients is metastatic disease. Vesicular stomatitis virus (VSV) is an attractive candidate as an oncolytic virus for the treatment of CRC due to its potent ability to induce apoptosis. Our group has generated a genetically engineered recombinant VSV containing an M protein mutation (rM51R) to enhance its tumor selectivity while preserving its oncolytic effects. As an extension of these findings, we hypothesized that oncolytic VSV can effectively treat CRC cells and therefore serve as an oncolytic therapy for the treatment of metastatic CRC.
Methods: We compared the cytolytic effects of wild type (rwt) and M51R VSV in RKO, HCT116 and Lovo CRC cell lines via MTS assays. We initially sought to determine if CRC cells were susceptible to the oncolytic effects of VSV in single-cycle and multiple-cycle infection conditions. Viral protein synthesis and the production of viral progeny by CRC cell lines was quantified by S35 methionine labeling and viral plaque assays respectively. RKO tumor xenografts were established in athymic nude mice and injected with 108 pfu of M51R VSV.
Results: We found that CRC cells display differential sensitivity to oncolytic VSV. RKO and HCT116 CRC cells were very sensitive to the oncolytic effects of both rwt and M51R viruses at 48 hours after both single and multiple-cycle infections. On the other hand, Lovo cells were somewhat resistant to VSV-induced cell killing under identical treatment conditions. All CRC cell lines supported the production of viral progeny with the peak viral production occurring at 36 hours after single and multiple-cycle infections with rwt and M51R VSV. Treatment of RKO xenografts with M51R VSV resulted in stabilization of tumor size relative to untreated controls after 21 days.
Conclusions: These findings suggest that M51R VSV is a good candidate oncolytic virus for the treatment of metastatic colorectal cancer. Our future work will focus on defining the proportion of colorectal cancers that are susceptible to the oncolytic effects of VSV. In addition, we will identify molecular targets that may enhance the therapeutic efficacy of M51R VSV.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2595.
Abstract 2596: Targeted delivery of doxorubicin conjugated with anti-matriptase antibody to treat multiple myeloma
Authors: Bertino Joseph R. , Lin Siang-Yo , Lin Chen-Yong 
Published: February 2011

Abstract
Survival of patients with multiple myeloma (MM) has been significantly improved owing to the advances in new therapeutics for the patients in the past decade; however, the disease remains incurable. New or improved therapeutic agents are therefore urgently needed. Matriptase, a membrane-bound serine type II protease, is overexpressed in B- cell lymphoma, multiple myeloma and epithelial carcinomas. Due to the overexpression of matriptase in multiple myeloma in combination with the limited distribution of the enzyme in epithelial-containing tissues, we have designed and generated an anti-matriptase monoclonal antibody (M24) conjugated to doxorubicin (DOX) for selectively targeting MM cells. The immunoconjugate (M24-DOX) is as potent as free doxorubicin to inhibit the growth of MM cells. Significantly, bone marrow-derived mesenchymal stromal cells that do not express matriptase, were insensitive to the immunoconjugate, whereas free DOX showed cytotoxicity. More importantly, compared to free DOX, target delivery of doxorubicin by the matriptase antibody significantly reduced the toxicity toward cardiomyocytes that lack maptriptase expression. Following exposure of MM cells to M24-DOX, the immunoconjugate was rapidly internalized, and was mainly localized within nuclei. Moreover, after 24-hour incubation, over 90% of the free DOX was released from the conjugate within the cells. Targeting matriptase, expressed on myeloma cells, should increase the effectiveness and therapeutic index of doxorubicin and improve the treatment of patients with multiple myeloma.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2596.
Abstract 2600: Effect of green tea intake on pharmacokinetics of oral etoposide in cancer patients
Authors: Nagai Shunji , Fujiwara Yutaka , Ishizuka Naoki , Ishihara Mikiya , Itoh Kuniaki , Ogasawara Naomi , Nakajima Hikaru , Fuse Hiroe , Matsubara Nobuaki , Mukai Hirofumi , Yamaguchi Takeshi , Mukohara Toru , Minami Hironobu 
Published: February 2011

Abstract
BACKGROUND: Habitual consumption of green tea has been epidemiologically correlated with low risk of cancer. Among various constituents of green tea, catechins are experimentally suggested to have benefitial activity. Especially, (-)-epigallocatechin gallate (EGCG) is the most bioactive constituent. Decreased activation of carcinogenic compounds by inhibition CYP3A4 is proposed as one of mechanisms of anticarcinogenic effect. Green tea is one of the most popular beverages in Japan and Asian countries, and patients often take drugs with green tea beverages. Co-administration of oral cancer medicine which is metabolized by CYP3A4 with green tea may cause harmful interactions. PURPOSE: We investigated the effect of green tea beverage intake on pharmacokinetics of etoposide in an open label, single-dose, randomized, two-way crossover study. METHODS: Patients with various cancers were randomly assigned to receive an etoposide 50-mg capsule either with 600mL green tea beverage or 600mL of water, separated by at least 72-hours washout period. Blood samples were collected for 24 hours. Etoposide concentrations in plasma were determined by high performance liquid chromatography. Plasma pharmacokinetic parameters, including area under the curve (AUC), maximum concentration (Cmax) and elimination half-life (t1/2) were calculated by non-compartment analysis using WinNonlin software.
RESULTS: Twenty-five cancer patients (11 males, 14 females; median (range) age, 63 years (46 to 81 years)) participated in this study. Co-administration with green tea resulted in an unexpected decrease by 24.8% in the AUC (p= 0.0003) of etoposide (Table). Carry-over effect was denied.
CONCLUSION: Green tea reduces rather than increases exposure to orally administered etoposide.Mean pharmacokinetic parameters of etoposideParameters Water Green teaP-valueAUC 337.61257.45P=0.0003(mg*min/ml) Cmax (mcg/ml) 2.97252.1284P=0.0004t1/2 (h) 7.43116.7696P=0.0771
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2600.
Abstract 2603: A critical role of Gβγ in breast tumor growth and metastasis
Authors: Tang Xiaoyun , Henry Michael , Chen Songhai 
Published: February 2011

Abstract
A growing body of evidence indicates the involvement of G protein coupled receptors (GPCRs) in the process of breast tumor development, including tumor growth, invasion and metastasis. Targeting GPCRs has been proposed as a novel adjuvant strategy in cancer treatment. However, this approach faces many significant hurdles due in part to the involvement of multiple GPCRs in tumor progression. Thus, there is a need for an alternative approach that targets a signaling mechanism common to these receptors. GPCRs such as lysophosphatidic acid (LPA) receptors, thrombin receptors and the chemokine receptor CXCR4 transmit signals through multiple classes of heterotrimeric G proteins, which consist of Gα and Gβγ subunits. There are four major classes of Gα subunits (Gαi, Gαs, Gαq and Gα12/13) that regulate distinct activities of different effectors. Although there are 5 Gβ and 12 Gγ isoforms, different combination of Gβγ complexes appear to regulate a similar profile of downstream effectors. We therefore reason that Gβγ-dependent signaling may represent a point of signal convergence from multiple GPCRs that can be targeted for the therapeutic of breast tumor. In this study, we evaluated the role of Gβγ in breast tumor progression. Our data show that blocking Gβγ signaling with small molecular inhibitors alleviated breast tumor cell proliferation and GPCR-stimulated cell migration in vitro, suggesting that Gβγ is critical for breast tumor progression. Consistent with these findings, overexpression of Gβγ scavengers, the C-terminal tail of G protein-coupled receptor kinase 2 (GRK2-ct) or Gαt, in breast tumor cells suppressed tumor cell growth both in 2D and 3D culture, and abolished LPA- and SDF1α-stimulated cell migration. Additional studies indicate that Gβγ mediates GPCR-simulated activation of PI3K, PLCβ and MAPK, which in turn contribute to breast tumor cell growth and migration. Finally, by inducible expression of Gαt in MDA-MB-231 cells, we provided evidence that Gβγ signaling promotes tumor cell growth and lung metastasis in mouse xenograft models. Taken together, our data demonstrate that Gβγ plays a critical role in breast tumor progression. These findings suggest that targeting Gβγ-dependent signaling may represent a novel therapeutic approach for breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2603.
Abstract 2611: Cisplatin negatively affects CNS progenitor cells and behavior in the adult mouse
Authors: Ana Nunes T. , Han Ruolan , Sprentall Kelcie , Santoni Ornella , Noble Mark 
Published: February 2011

Abstract
Patients that are treated with chemotherapy exhibit long term changes in cognitive function, decreasing quality of life (Van Dam et al 1998). Although much work has been done characterizing these changes in the patient, there is little research on the possible cellular changes. Additionally, little has been done studying the effects of a single chemotherapeutic agent on cognitive function. Our laboratory has previously shown that chemotherapy, including cisplatin, decreases neural progenitor cell division and increases cell death in the mouse brain (Dietrich et al 2006; Han et al., 2008). Here, we have studied the effects of cisplatin on CNS progenitor cells and also on behavior. We found that cisplatin negatively affects progenitor cells throughout the CNS: progenitor cells migrating from the subventricular zone to the olfactory bulb, the olfactory epithelium, the dentate gyrus of the hippocampus and the corpus callosum. The subventricular zone, rostral migratory stream and olfactory bulb all showed increases in cell death and decreases in the neuroblast population. This change in progenitor cell numbers remained significant compared to vehicle control for as long as six months. In the olfactory epithelium, we found a significant decrease in proliferation of olfactory receptor neuron (ORN) progenitor cells. There was also a decrease in proliferation and an increase in cell death in the oligodendrocyte precursor cell (OPC) population of the corpus callosum and in the dentate gyrus. Using a fixed interval-60s operant schedule we examined the effects of cisplatin on performance. This schedule allows for the operant response rate to vary widely without altering the rate of reinforcement. When compared to the vehicle control, we found significant changes in response rate. These findings demonstrate that even in the absence of underlying cancer, cisplatin has adverse effects on CNS progenitor cells in multiple regions and negatively impacts behavioral outcomes. This work provides animal models of potential value in developing treatments to prevent the neurotoxic side effects of cisplatin, thus improving quality of life in recipients of this therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2611.