bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2590: A novel use of E2f and Cdk inhibitors to prevent RB-null tumours in genetically engineered models of retinoblastoma
Authors: McCurdy Sean R. , Aman Ahmed , Livne-Bar Izhar , Sangwan Monika , Chen Danian , Al-awar Rima , Bremner Rod 
Published: August 2012

Abstract
Over the past few decades, extensive mouse and human genetics have implicated deregulated E2f and Cdk activity in cell exit escape and tumorigenesis. In flies, activating E2f or Cdk causes temporary abnormal division, but both must be induced for long-term aberrant proliferation - a hallmark in benign tumor-prone lesions. Almost invariably, defects in the Rb-E2f or Cip/Kip Cdk inhibitor (CKI)-Cdk2/1 cell cycle regulatory pathways occur together in human cancer. Despite this, little is known in regards to whether dual activation is an obligate feature for tumor susceptibility at initiation in vivo. In human retinoblastoma, homozygous RB1 inactivation is sufficient to initiate the disease. However, mouse retinoblastoma requires inactivation of both Rb1 and one of its family members (p107 or p130). Like pRb, p107 and p130 are best known as E2f inhibitors. Unexpectedly, the additional loss of p107 does not elevate E2f targets follow Rb loss. Instead, Rb/p107-deficient cells induce the E3 ubiquitin ligase Skp2 and activate Cdk2 in vivo. Strikingly, Cdk2 activity tightly correlates with susceptibility to retinoblastoma in our mouse models. Compiling this data, tumorigenesis may have two distinct steps: (1) Rb loss initiates abnormal division, and (2) the additional loss of p107 or, as we have found, p27kip1, both of which lead to Cdk2 activation is required to engender cancer susceptibility. Together, E2f and Cdk dual axes activity is essential for retinoblastoma initiation. To test this notion pharmaceutically, we treated retinoblastoma-prone mice with a Cdk or E2f small molecule inhibitor during the birth period of suspected cancer cell-of-origin. Strikingly, one-week exposure to an inhibitor of either axes curtailed retinoblastoma in Rb/p107- null and Rb/p27-null retinas. These therapeutic successes were achieved without disrupting normal proliferation. Thus, E2f inhibitors, untested in vivo, or Cdk inhibitors, largely unproven as therapeutics, may be ideal chemopreventative agents.
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 2590. doi:1538-7445.AM2012-2590
Abstract 2656: Predictors of bloodstream infection associated with permanently implantable venous port in solid cancer patients
Authors: Chen I-Chun , Hsu Chiun , Chien Shu-Fen , Kao Hsiang-Fong , Chang Sin-Yuan , Hu Fu-Chang , Chen Yee-Chun , Yeh Kun-Huei 
Published: August 2012

Abstract
Background There is no literature for stratification of permanent implantable venous ports (Port-A) related bloodstream infection (BSI) in solid cancer patients. We conduct this study to characterize the risk factors of BSI associated with the use of Port-A (PABSI) in solid cancer patients. Methods The study is done in a teaching hospital in Taiwan. Solid cancer patients who were implanted with a Port-A for systemic anti-cancer therapies were prospectively followed for the occurrence of PABSI, defined as BSI without other identifiable infection foci. Patients with PABSI during the follow-up period constitute the case cohort (N = 58) and 174 patients were randomly selected from those without BSI as the control cohort. PABSI risk score was developed by Cox proportional hazards model. Results 416 patients were registered (Table 1). Eighty-eight PABSI episodes occurred in 58 patients, with an incidence of 1.05 per 1000 catheter-days. All but one patient had stage 4 cancer. Independent predictors of PABSI occurrence included neutropenia (HR = 3.86, 95% CI = 1.75-8.50), total parental nutrition (TPN) (HR = 3.51, 95% CI = 1.86-6.63), chronic steroid use (HR = 7.01, 95% CI = 2.78-17.65), invasive procedure (HR = 3.00, 95% CI = 1.29-6.98), postoperative antibiotics (HR = 2.61, 95% CI = 1.43-4.75), and preoperative antibiotics (HR = 0.38, 95% CI = 0.17-0.83). A PABSI risk score, with a cut-off value of 0 (sensitivity 88.5%, specificity 64.3%), was defined for stage 4 cancer patients as follows: neutropenia, +1.350; TPN, +1.256; chronic steroid use, +1.947; preoperative antibiotics, –0.970; postoperative antibiotics, +0.959; and invasive procedure, +1.098. The median PABSI-free survival was 4.47 months for patients with score β0 but not reached for patients with score &lt; 0 (p &lt; 0.0001). Conclusions The PABSI risk score can help define high-risk groups in solid cancer patients and may help design future preventive strategies. Presence of any risk factor would render patients as high risk.

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 2656. doi:1538-7445.AM2012-2656
Abstract 2675: CXCL12 (SDF-1) and its truncation products in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) receiving ON 01910.Na (Rigosertib) in phase I trials
Authors: Cho Sool Y. , Navada Shyamala C. , Silverman Lewis R. , Holland James F. , Roboz John 
Published: August 2012

Abstract
CXCL12 (stromal cell-derived factor, SDF-1), is an 8 kDa peptide chemokine. The interaction between CXCL12 and its receptor, CXCR4, plays a pivotal role in the trafficking of hematopoietic stem cells between bone marrow and peripheral blood. The CXCL12/CXCR4 axis may play a role in the pathogenesis of myeloid neoplasms. We developed a technique for the determination of intact (full length) CXCL12 and its protease(s)-induced truncation products in plasma from patients with myeloproliferative neoplasms (Cancer Res., 70, 3402, 2010). In the present work, we are extending our observations to the myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). CXCL12 concentrations in normal subjects were 16.6 ± 9.4 ng/mL (n=10). In primary myelofibrosis (PMF), the concentrations were 5.8 ± 4.0 ng/mL (n=15), and in polycythemia vera (PV) 7.9 ± 3.6 ng/mL (n=21). Now we report that in MDS/AML, the concentrations are 2.2 ± 2.1 ng/mL (n=8). In normal subjects, truncation products, due to proteolysis, were not detectable (≥ 1.0 ng/mL). The loss of 2, 3, 4, and 5 amino acids (aa) from CXCL12 were confirmed by molecular masses measured using electrospray ionization mass spectrometry. Quantification was completed with synthetic standards. In MDS/AML patients the concentration of the truncation product corresponding to −2 aa (KP removed),-3 aa (KPV removed), −4 aa (KPVS removed) and −5 aa (KPVSL removed) were 2.7 ± 3.2 ng/mL, 2.4 ± 2.1 ng/mL, 3.8 ± 3.0 ng/mL, and 2.5 ± 2.4 ng/mL, respectively. The total concentration of all truncation products was 11.3 ± 5.8 ng/mL. For comparison, the concentration of total truncation products was 28.7 ± 19.9 for PMF, and 31.1 ± 7.8 for PV. Patients with these myeloid malignancies have lower CXCL12 concentrations compared to normal controls and high concentrations of proteolytic truncation products which are absent in normal plasma. Of the 8 patients with MDS (n=3) and AML (n=5), treated with continuous infusion of ON 01910.Na (rigosertib), 650 - 1,700 mg/m2, in a Phase I dose escalation study, 4 patients attained a partial or complete bone marrow remission according to International Working Group criteria. The concentration of intact CXCL12 rose at 72 h in responding patients, whereas those who failed to respond had a decrease. These data suggest that monitoring intact CXCL12 and its truncation products may provide a marker of response to treatment with ON 01910.Na, as well as insight into the role of the CXCL12/CXCR4 axis in the pathobiology of these bone marrow diseases.
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 2675. doi:1538-7445.AM2012-2675
Abstract 268: Regulation of the UDP-glucuronosyltransferases (UGTs) by UV exposure in human melanocytes
Authors: Dellinger Ryan W. , Ahmed Amelia S. , Duong Priscilla H. , Meyskens Frank L. 
Published: August 2012

Abstract
The UDP-glucuronosyltransferase (UGT) family of enzymes catalyzes the glucuronidation of a variety of endogenous compounds such as bilirubin and steroid hormones, as well as xenobiotics including chemotherapeutic agents and environmental carcinogens. Glucuronidation of these substrates inactivates them by making them more hydrophilic and easily excreted. UGTs are expressed primarily in the liver, but are also expressed in several extra-hepatic tissues including prostate, breast, colon, lung, brain, kidney, bladder and ovary. We have demonstrated that three UGT family members (UGT2B7, UGT2B10 and UGT2B15) are normally expressed in human melanocytes isolated form neonatal foreskin. Further, we screened several primary and metastatic melanoma cells lines for UGT expression. Interestingly, of all the melanoma cell lines screened only WM115, a primary melanoma, had UGT expression. Again, only UGT2B7, UGT2B10 and UGT2B15 were detected. UGT expression was not detected in another primary melanoma cell line, WM3211, or in any of the four metastatic melanoma cell line assayed suggesting that loss of UGT expression occurs during melanoma progression. To elucidate if ultraviolet (UV) light could be the underlying cause to the disappearance of UGTs in melanoma progression, human melanocytes were subjected to UV-B radiation at low and high (sunburn) doses. Melanocytes were collected at 1, 5 and 24 Hrs post UV-B treatment and UGT expression was analyzed by quantitative real-time PCR. Expression of UGT2B7, UGT2B10 and UGT2B15 all was significantly reduced in response to both low and high dose UV-B. In general, loss of UGT expression was observed even at 1 hour after exposure, reached maximal low levels at 5 hours and started to return to normal levels at 24 hours post exposure. We hypothesize that reduction of UGT expression in melanocytes following a sunburn would increase an individuals risk for melanoma since the UGTs detoxify environmental carcinogens. This hypothesis is consistent with a causative role for UV in melanoma in which ‘classical’ UV-induced DNA damage is not observed; a problem that has long puzzled investigators.
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 268. doi:1538-7445.AM2012-268
Abstract 2682: New diagnostic and therapeutic target KU-MEL9 for chronic myeloid leukemia (CML)
Authors: Matsushita Maiko , Suzuki Takuma , Tsutsumida Naoya , Iijima Shiro , Tsukamoto Nobuo , Kawakami Yutaka , Matsuki Eri , Okamoto Shinichiro , Hattori Yutaka 
Published: August 2012

Abstract
Overall survival of patients with chronic myeloid leukemia (CML) has dramatically changed over past ten years by the introduction of targeted therapy with tyrosine kinase inhibitors (TKIs). However, it has been reported that more than half of patients eventually relapse after the cessation of TKIs, suggesting that CML cells including leukemic stem cell (LSC) cannot be completely eradicated by TKIs. To this end, the identification of targets expressed in LSC is crucial for developing highly effective therapies for CML. In this study, we evaluated the gene expression of cancer testis antigen KU-MEL9, which was found in melanoma research, in a variety of human cell lines. This gene was highly expressed in several cell lines of hematological malignancies including CML and multiple myeloma (MM). We then investigated the gene expression of KU-MEL9 in bone marrow samples from 20 CML patients by standard RT-PCR method. Gene expression of KU-MEL9 were found in 17 patients (85%), and correlated with the expression of BCR-ABL fusion gene in most of the cases. On the other hand, 6 samples from normal donors didn't express this gene. In 2 CML patients who achieved a molecular remission with imatinib, the expression of KU-MEL9 gene was still observed, although BCR-ABL gene was not detected. It suggested that KU-MEL9 was expressed in residual CML cells including LSC and could be a more sensitive biomarker for CML patients. We also examined the possibility of KU-MEL9 being as a target of cytotoxic T cells (CTL) for immunotherapy to eradicate remaining LSCs after TKI treatment. Although this study had limited number of patient sample, KU-MEL9 may be a useful target for diagnosis and treatment for CML patients.
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 2682. doi:1538-7445.AM2012-2682
Abstract 2684: Imaging lung colony formation by osteosarcoma cells expressing αv integrin-GFP in nude mice
Authors: Tome Yasunori , Sugimoto Naotoshi , Yano Shuya , Momiyama Masashi , Maehara Hiroki , Tsuchiya Hiroyuki , Tomita Katsuro , Kanaya Fuminori , Bouvet Michael , Hoffman Robert M. 
Published: August 2012

Abstract
We report here imaging the behavior of αv integrin linked to GFP in osteosarcoma cells which are colonizing the lung of nude mice. 143B osteosarcoma cells expressing αv integrin-GFP were generated by transfection of an αv integrin-GFP vector. Confocal microscopy with the FV1000 (Olympus Corp., Tokyo, Japan) demonstrated that αv integrin immunofluorescence staining colocalized with αv integrin-GFP fluorescence. To generate pulmonary colonies, osteosarcoma cells, stably expressing αv integrin-GFP, were injected intravenously (1×106) via the tail vein of nude mice. Eight weeks after injection, both lungs were harvested and observed by confocal microscopy within 1 hour after harvesting. Scattered-expression of αv integrin-GFP was observed in the pulmonary osteosarcoma colonies. In contrast, osteosarcoma cells strongly expressed αv integrin-GFP when aligned along the edge of colonies and around blood vessels. Expression of αv integrin-GFP can be imaged in lung metastasis which will allow further understanding of its role in this process.
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 2684. doi:1538-7445.AM2012-2684
Abstract 2686: Methioninase S-phase block of cancer cells imaged in real time by cell-cycle-specific fluorescence reporters
Authors: Yano Shuya , Li Shukuan , Han Qinghong , Tan Yuying , Fujiwara Toshiyoshi , Hoffman Robert M. 
Published: August 2012

Abstract
A general feature of cancer cells is their elevated requirement for methionine compared to normal cells, which may be due to excessive methylation reactions in cancer cells since methionine is the global source of cellular methyl groups. When deprived of methionine, cancer cells undergo a cell-cycle arrest in late S-phase. The recombinant bacterial enzyme, methionine β, α-lyase (methioninase or METase) degrades methionine very efficiently and effects an S-phase block selectively in cancer cells. In order to image the kinetics of cell cycle arrest of cancer cells due to deprivation of methionine by METase, cancer cells were engineered to express cell cycle-dependent fluorescent proteins using fluorescent ubiquitination-based cell cycle indicator (FUCCI) whereby cancer cells express Azami-green only in S-phase and Kusabira-orange only in G1. Thus, each cancer could be followed in real time as it becomes blocked in S-phase after METase treatment. FUCCI imaging demonstrated that cancer cells could remain in S-phase for 5 days before starting to die which indicates a new type of cancer cell dormancy. The use of METase treatment and cell-cycle specific fluorescent reporters provide a unique opportunity to image and study the cancer cell cycle and the consequences and advantages of an S-phase block in 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 2686. doi:1538-7445.AM2012-2686
Abstract 2744: Identification of synergistic effect of autophagy inhibitors and resveratrol on BRCA1 mutant cancer cells
Authors: Vazquez-Ortiz Guelaguetza , Chisholm Cristine L. , Huang Ruili , Li Cuiling , Xu Xiaoling , Rui-Hong Wang , Deng Chuxia 
Published: August 2012

Abstract
Over 200,000 new breast cancer cases are diagnosed in the US each year, with 5% of cases caused by mutations in BRCA1 (Breast cancer associated gene 1). Mutation carries have a lifetime risk of up to 80% for developing breast cancer. Current treatment options are limited and often do not lead to cure. We showed previously that treatment with resveratrol, although initially reduced more the tumor size in BRCA1 mutant (mt) tumors, with respect to BRCA1 wild-type (wt) in mice, tumors continued to grow after prolonged treatment. To identify small molecules that can be repurposed and synergize the killing effect of resveratrol in BRCA1-mt tumors, we screened the NCGC Pharmaceutical Collection in which, more than 52% are drugs approved for human or animal use by FDA, and the rest are drugs approved in other countries or in clinical trial. Using a high-throughput cell viability assay by measuring intracellular ATP content, we identified the inhibitory effect of 43 compounds that exhibited synergy with resveratrol (Res) with efficacy&gt;50% and potency &lt;35uM. We further analyzed 4 of them, cantharidin, chloroquine, amodiaquin and colchicine for in vivo study. Utilizing BRCA1-mt breast tumor implant models in aythymic mice reveal that mice treated with combination therapy (Drug + Res) exhibit significantly reduced tumor volumes and increased survival rate compared with mice on monotreatment and this effect was even more significant when compared to wt-BRCA1. Also, some mammary tumors developed in the BRCA1 mammary tissue specific mutant mice exhibited a total regression with combination therapy. In order to identify a shared molecular and biochemical change which make BRCA1-mt cancer cells more susceptible to the combination treatment, we found that these compounds inhibit autophagy at different levels, targeting the mTOR/AKT pathway at different levels and/or inhibiting the fusion between the lysosome and the phagosome producing strong vacuolization in the cytoplasm during treatment, increasing LC3-II in a Beclin independent manner, followed by a faster induction of apoptosis on the BRCA mutant cells. This approach offers the potential to combat breast cancer cells and sensitize BRCA1 deficient cells to more effective treatments.
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 2744. doi:1538-7445.AM2012-2744
Abstract 2751: Protective effects of phenylaminoethyl selenide (PAESe) on doxorubicin-induced cardiotoxicity in vitro and in vivo
Authors: Kang Jeong Yeon , Costyn Leah J. , Nagy Tamas , Cowan Elizabeth A. , Oldham Charlie D. , May Sheldon W. , Arnold Robert D. 
Published: August 2012

Abstract
Anthracyclines are potent anticancer agents that are effective in the treatment of acute leukemia, non-Hodgkin's lymphomas, breast, ovarian and lung cancers, but their clinical use is hampered by dose-limiting cardiotoxicity mediated by free radicals generation. We determined the ability of phenyl-2-aminoethyl selenide (PAESe), a novel antioxidant, to reduce doxorubicin (DOX)-induced cardiotoxicity. Growth inhibitory effects of PAESe on human breast carcinoma (BT-474) and prostate adenocarcinoma (PC-3) cells were determined alone and in combination with two clinically used anticancer agents, DOX, a topoisomerase-2 antagonist known to generate reactive oxygen species (ROS), and vincristine (a tubulin binding agent) and a known oxidant, tert-butylhydroperoxide (TBHP). Conventional growth inhibitory assays, i.e., sulforhodamine B (SRB) and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium-bromide (MTT) staining, were used to determine in vitro activity. Treatment effect on intracellular formation of ROS was also determined by quantifying the oxidation of a cell-permeant indicator H2DCFDA. The effect of PAESe on cardiomyocytes was determined in NCr (nu/nu) mice with DOX (5 mg/kg), PAESe (10 mg/kg), concomitant (DOX & PAESe) therapy, and saline controls were administered by tail vein injections weekly over 12 weeks. Histopathological examination was performed to look for evidence of cardiotoxicity. PAESe did not alter the growth of BT-474 or PC-3 cells up to 10 uM. However, co-administration of PAESe decreased the oxidative-mediated cytotoxicity of TBHP in a dose-dependent manner, but had limited to no effect on vincristine or DOX antitumor activity. Further, PAESe decreased the formation of intracellular ROS from TBHP and DOX in a dose-dependent manner. Histological examination showed PAESe decreased short-term DOX-mediated infiltration of neutrophils and macrophages into the myocardium and more chronic evidence of necrotic foci, suggesting PAESe decreased early and late myocardial damage following initial and prolonged DOX treatments, unlike other antioxidants. Concomitant administration of PAESe did not alter the antitumor activity of DOX in vivo, nor did it reduce treatment mediated weight-loss associated with DOX. These data suggest that PAESe may be used in combination with DOX to preserve its antitumor activity, but decrease free radical generation and cardiotoxicity associated with use of anthracyclines.
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 2751. doi:1538-7445.AM2012-2751