bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1203: Therapeutic opportunities for anti-Met antibody (MetMAb) in breast cancer
Authors: Mark Merchant , Zheng Zhong , Peng Jing , Li Jun , Mai Elaine , Young Judy , Darlene Dela Cruz , Liu Jinfeng , Yauch Robert , Zha Jiping , Filvaroff Ellen 
Published: June 2012

Abstract
The hepatocyte growth factor (HGF)/Met pathway drives cell proliferation, survival, migration and invasion, which are hallmarks of cancer. Animal models and microarray data suggest that elevated expression of Met is a poor prognostic factor in breast tumors. Our evaluation of primary breast tumors and cell lines has confirmed that expression of Met is found predominantly in the basal sub-type, which includes estrogen receptor (ER), progesterone receptor (PR) and HER2 triple negative (3N) tumors as well as some HER2+ basal tumors. In a panel of 3N basal breast tumors, 96% (25/26) of samples express Met by enzyme-linked immunosorbant assay (ELISA), with 42% (11/26) positive by immuno-histochemistry (IHC). All of the samples were positive for HGF as determined by ECLA, with 32% (8/25) of these primary tumors showing robust staining by IHC. To further explore the biological response of basal breast cancers to HGF, a panel of basal breast cancer cell lines were evaluated in cell proliferation, migration and invasion assays. While most lines tested showed a modest response to HGF in proliferation assays, the migratory and invasive response to HGF was more robust. Assessment of signaling pathways and gene signatures was also performed to better understand the nature of Met signaling leading to biological outcomes. HGF responsive lines were evaluated for growth in transgenic SCID mice expressing human HGF. MetMAb, a potent HGF-blocking Met monovalent monoclonal antibody, acts to inhibit HGF-driven effects in basal breast cancer cell lines in vitro and xenograft growth in vivo. Taken together, these data suggest that Met can drive invasive growth of basal breast tumors, and that treatment with MetMAb, alone or in combination with standard of care, may be therapeutically beneficial in these tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1203. doi:10.1158/1538-7445.AM2011-1203
Abstract 1214: Single nucleotide polymorphism in HER family members increases susceptibility to human invasive cervical cancer
Authors: Ma Duanduan , Hovey Raymond , Zhang Zhengyan , Nguyen Loan , Borecki Ingrid , Rader Janet 
Published: June 2012

Abstract
Cervical cancer is the second-most common cancer among women worldwide (Parkin et al. 1999). Some studies address prognostic roles that different genes play after the development of cervical cancer. However, there is a lack of studies addressing polymorphisms in genes of normal tissues that influence susceptibility to cervical cancer prior to malignant transformation. Such studies could be pivotal in prevention and timely diagnosis. It is well-known that Human Papillomavirus (HPV) infection appears to be the primary causative factor for cervical cancer, but host factors must be crucial since only a fraction of HPV-infected women develop cervical cancer. HPV antigens are the ligands of HER family members, and the E5 protein may play a role in the early stage of HPV infection before transformation. Thus, we studied whether there are excessive parent-to-offspring transmissions of specific HER SNP variants in EGFR, ERBB2, ERBB3 and ERBB4, in cases of invasive cervical cancer (ICC) or cervical intraepithelial neoplasia grade 3 (CIN3). Based on single SNP TDT tests, we identified a significant association between ICC/CIN3 and rs11770506, which is located at intron1 of EGFR and in high linkage disequilibrium (LD) with multiple enhancers. Our study provides clues for the identification of vulnerable populations and will advance the development of early detection of ICC in appropriate populations.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1214. doi:10.1158/1538-7445.AM2011-1214
Abstract 1228: Resistance to discodermolide, a microtubule stabilizing agent and senescence inducer, is 4E-BP1 dependent
Authors: Chao Suzan K. , Lin Juan , Brouwer-Visser Jurriaan , McDaid Hayley M. , Horwitz Susan B. 
Published: June 2012

Abstract
Discodermolide is a microtubule stabilizing agent that induces accelerated cell senescence. A discodermolide-resistant cell line, AD32, was generated from the human lung cancer cell line A549. We hypothesize that the major resistance mechanism in these cells is escape from accelerated senescence. AD32 cells have decreased levels of 4E-BP1 mRNA and protein, relative to the parental discodermolide-sensitive A549 cells. Lentiviral-mediated re-expression of wild type 4E-BP1 in AD32 cells increased the proliferation rate and reverted resistance to discodermolide via restoration of discodermolide-induced accelerated senescence. Consistent with this, cell growth and response to discodermolide was confirmed in vivo using tumor xenograft models. Furthermore, re-introduction of a non-phosphorylatable mutant (Thr 37/46 Ala) of 4E-BP1 was able to partially restore sensitivity and enhance proliferation in AD32 cells, suggesting that these effects are independent of phosphorylation by mTORC1. Microarray profiling of AD32 resistant cells versus sensitive A549 cells, and subsequent unbiased gene ontology analysis, identified molecular pathways and functional groupings of differentially expressed mRNAs implicated in overcoming discodermolide-induced senescence. The most-statistically significant classes of differentially expressed genes included p53 signaling, G2/M checkpoint regulation and genes involved in the role of BRCA1 in the DNA damage response. Consistent with this, p53 protein expression was up-regulated and had increased nuclear localization in AD32 cells relative to parental A549 cells. Furthermore, the stability of p53 was enhanced in AD32 cells. Our studies propose a role for 4E-BP1 as a regulator of discodermolide-induced accelerated senescence.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1228. doi:10.1158/1538-7445.AM2011-1228
Abstract 1257: Tyrosine phosphorylation of mitochondrial pyruvate dehydrogenase kinase 1 is important for cancer metabolism
Authors: Chung Tae-Wook , Hitosugi Taro , Fan Jun , Wang Xu , Gu Ting-Lei , Roesel Johannes L. , Boggon Titus , Chen Zhuo (Georgia) , Khuri Fadlo R. , Kang Sumin , Chen Jing 
Published: June 2012

Abstract
Many tumor cells rely on aerobic glycolysis for their continued proliferation and survival, which is in part due to actively inhibited mitochondrial function. Myc and HIF-1 are believed to promote such inhibition by upregulating gene expression of pyruvate dehydrogenase kinase 1 (PDHK1), which phosphorylates and inactivates mitochondrial pyruvate dehydrogenase complex (PDC). However, how oncogenic signals activate PDHK1 to regulate cancer cell metabolism remains unclear. Here we report that oncogenic FGFR1 activates mitochondrial PDHK1 by tyrosine phosphorylation. FGFR1 directly phosphorylates PDHK1 at Y136, Y243 and Y244. Mutational, structural and biochemical studies revealed that phosphorylation at both Y243 and Y244, but not Y136 is required to promote ATP binding to PDHK1, which consequently facilitates PDHK1 binding to PDC scaffold to access substrate PDHA1. In contrast, Y136 phosphorylation may only function to enhance binding between PDHK1 and PDC. We also found that PDHK1 is commonly tyrosine phosphorylated by diverse oncogenic tyrosine kinases in different human cancers. Moreover, we generated cancer cells with stable knockdown of endogenous human PDHK1 and “rescue” expression of phosphorylation-deficient, catalytic hypomorph mouse PDHK1 mutants including Y134F and Y239/240F (mouse PDHK1 numberings correspond to human PDHK1 Y136F and Y243/244F, respectively). These “rescue” cancer cells demonstrated decreased cell proliferation under hypoxia, increased oxidative phosphorylation with decreased lactate production, and reduced tumor growth in xenograft nude mice.
Our findings suggest that tyrosine phosphorylation activates PDHK1 to inhibit mitochondrial function, providing a metabolic advantage for tumor growth. This represents a common, short-term molecular mechanism underlying the active inhibition of mitochondrial function in tumor cells, in addition to the chronic changes that are believed to be regulated by Myc and HIF-1. Moreover, inhibition of PDHK1 attenuates tumor growth, suggesting that PDHK1 may serve as a therapeutic target in cancer treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1257. doi:10.1158/1538-7445.AM2011-1257
Abstract 1265: Survival under glucose and serum deprivation is increased by DN-mutant p53 R175H in human melanoma: A possible gain of oncogenic function
Authors: Chavez-Perez Valery , Strasberg-Rieber Mary , Rieber Manuel 
Published: June 2012

Abstract
BACKGROUND.- To help counteract tumor development, the p53 tumor suppressor protein functions to preserve genomic stability, when inhibiting cell cycle progression or inducing senescence or apoptosis. However, cancer-associated dominant-negative (DN) p53 mutations can override the tumor suppressor functions of wt p53, through possible gain-of oncogenic functions including those increasing resistance to metabolic stress. OBJECTIVES.- Since hypoglycemia and growth factor shortage may intermittently occur in the microenvironment of poorly vascularized tumors, this report investigated whether metabolic restriction (glucose deprivation and low serum supplementation), unequally influence the survival of genetically-matched human C8161 melanoma harbouring wt or DN-R175H mutant p53.(Strasberg-Rieber, M. et al. Clin. Cancer Res.7(2001)1446). RESULTS.- Cell death by prolonged metabolic restriction increased oxidative stress, since it was counteracted by the anti-oxidant N-acetylcysteine. Melanoma cells harbouring the DN-mutant p53 R175H were more resistant to cell death induced by shorter metabolic restriction. DPI, a NADPH oxidase inhibitor of superoxide generation counteracted the greater resistance of glucose-deprived mutant p53 cells, by altering expression of mitochondrial Mn-SOD∼SOD2. Pyruvate preferentially protected from DPI treatment under metabolic restriction, restoring levels of MnSOD. CONCLUSIONS. our results suggests that tumor cell death in response to anti-glycolytic treatment, may be antagonized by DN-mutant p53R175H.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1265. doi:10.1158/1538-7445.AM2011-1265
Abstract 128: MicroRNA-23b acts as an oncogenic microRNA in renal cancer
Authors: Zaman Mohd Saif , Deng Guoren , Shahryari Varahram , Saini Sharanjot , Majid Shahana , Singh Kamaldeep , Sandhu Herman , Chang Inik , Tanaka Yuichiro , Dahiya Rajvir 
Published: June 2012

Abstract
The North American region has the highest rates of renal cancers in the entire world. MicroRNAs are small noncoding RNAs that play important roles in numerous cellular processes including development, proliferation, and apoptosis. miR-23b is part of a cluster of miRNAs which includes among others miR-24-1, miR-27b and miR-30a. Recent studies have demonstrated that miR-23b plays different roles in different organs of the body. This led us to speculate its role in urological cancers in general and renal cancer in particular. In the current study we observe the role of miR-23b in renal cancer. The expression of miR-23b was checked in 30 pairs of renal cancer and normal tissues. The samples included three different types of renal cancer tissues, clear cell, papillary and tubular. 55% of clear cell carcinoma and all tubular samples showed high expression of miR-23b as compared to the normal. Interestingly, papillary carcinoma showed a contrasting result in which miR-23b levels were found to be down regulated in almost 90% of the samples. The expression in renal cancer cell lines, A498, ACHN, Caki-1 and Caki-2 was found to be significantly higher as compared to the normal cell line HK-2. The chemo preventive agent Genistein (25µM for 96 hours) was able to reduce the expression of miR-23b in A498 cells by more than 50%. Inhibition of miR-23b expression by the anti-miR-23b antagonist in A498 cells resulted in a significant increase in apoptosis, as detected through flow cytometry analysis. In contrast over expression of mir-23b in A498 cells resulted in a decrease in apoptosis. No significant effect on cell cycle was observed in either over expressing or inhibiting miR-23b in A498 cells. Cell viability assays also did not show any major effect due to the inhibition of expression of miR-23b. Moreover, the expression of miR-23b was correlated with 5 year survival rate of patients. For patients with low levels of miR-23b, 85% of patients survived after 5 years of operation, whereas in case of high expression of miR-23b only 50% survived. Our data suggests that miR-23b acts as an oncogenic mi-RNA in renal cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 128. doi:10.1158/1538-7445.AM2011-128
Abstract 129: miR-345 is a novel tumor suppressor microRNA in pancreatic cancer
Authors: Srivastava Sanjeev K. , Singh Seema , Bhardwaj Arun , Grizzle William E. , Singh Ajay P. 
Published: June 2012

Abstract
Pancreatic cancer is a highly lethal malignancy due to late diagnosis, rapid progression and lack of effective therapies for treatment. In majority of cases, the disease is diagnosed at a stage when it is locally advanced or has already metastasized to distant organs. In that scenario, chemotherapy is considered as an option, but the effects are usually modest due to chemo-resistance. Hence, there is an urgent need to identify novel diagnostic/therapeutic targets for effective management of this malignancy. MicroRNAs (miRNAs) have received significant attention as a new class of non-coding-RNAs engaged in the regulation of gene expression. It is now evident that miRNAs exhibit differential expression in cancer and play important roles in the disease processes. According to recently published studies, a number of miRNAs are differentially expressed in pancreatic cancer, including miR-345, which is among the top aberrantly-expressed genes exhibiting significant downregulation. miR-345 has remained an understudied miRNA with no report on its functional role in pancreatic cancer. Here, we show that miR-345 is differentially-expressed in pancreatic cancer cell lines with relatively more downregulated expression in poorly-differentiated cancer cells. Ectopic overexpression of miR-345 in two poorly-differentiated pancreatic cancer cell lines, Panc1 and MiaPaCa, diminished their growth, clonogenicity, motility and invasion, and enhanced cell-cell interaction. miR-345-overexpressing cells had distinguishable morphological differences and an increased expression of epithelial (E-cadherin) and loss of mesenchymal markers (N-cadherin, vimentin, twist, slug and snail) as compared to the control cells. Furthermore, our data showed that miR-345-overexpressing pancreatic cancer cells were more sensitive to gemcitabine-cytotoxicity as compared to the control cells. Altogether, our findings demonstrate novel tumor suppressive roles of miR-345 in pancreatic cancer and indicate that miR-345 downregulation may be one of the mechanisms underlying the chemo-resistance of pancreatic cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 129. doi:10.1158/1538-7445.AM2011-129
Abstract 1292: Pharmacokinetics of CPX-351: A nano-scale liposomal fixed molar ratio of cytarabine-daunorubicin (Cyt:Daun) in patients with advanced leukemia
Authors: Feldman Eric J. , Lancet Jeffrey E. , Kolitz Jonathan E. , Trang John M. , Mayer Lawrence D. , Swenson Chris E. , Chiarella Michael T. , Louie Arthur C. 
Published: June 2012

Abstract
Background: CPX-351 is a liposomal formulation that co-encapsulates Cyt and Daun enabling delivery of both drugs at a synergistic 5:1 molar ratio. A Phase I study in advanced AML patients demonstrated substantial efficacy with complete remissions (CRs) and acceptable safety. The MTD was 101 units/m2. One unit of CPX-351 contains 1 mg Cyt and 0.44mg of Daun. Here we examine the PK of CPX-351 as a function of dose, inter-patient variability and patient characteristics in order to identify potential PD relationships. Methods: 35 male and female patients with advanced hematologic malignancies were included in the PK portion of this Phase I trial and received 24, 32, 43, 57, 76, 101, or 134 units/m2 of CPX-351 by IV infusion over 90 minutes on Days 1, 3, and 5. Validated LC/MS/MS assays were used for determination of total plasma Cyt and Daun. PK parameters [Cmax, AUC, t1/2, Vss, CL, Cmax/Dose, AUC/Dose] were determined on Days 1 and 5. Results: Mean Cyt and Daun PK parameters are presented in the table below. No significant differences were observed in t1/2, Vss, CL, Cmax/Dose, or AUC/Dose among dose groups on either study day, although some drug accumulation was observed from day 1 to day 5. Cyt and Daun PK parameters were not correlated with patient gender, age or race. Incidence of non-hematologic toxicity increased with dose and systemic exposure. CRs were observed in patients receiving doses of 32-134 units/m2 of CPX-351. The responses at 101 units/m2 and above appear to be more durable. The Cyt:Daun molar ratio remained near 5:1 for up to 48 hours on both study days for all dose levels. Conclusions: Cyt and Daun delivered in CPX-351 exhibited linear single dose and multiple dose PK and low inter-patient variability in plasma concentrations within dose groups. CPX-351 provides predictable, extended systemic exposure of elevated Cyt:Daun concentrations near a 5:1 molar ratio. The 100 unit/m2 dose is undergoing testing in Phase II studies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1292. doi:10.1158/1538-7445.AM2011-1292
Abstract 1302: Delayed elimination of SN-38 and prolonged neutropenia in cancer patients with severe renal failure requiring dialysis who receive irinotecan
Authors: Fujita Ken-Ichi , Sunakawa Yu , Miwa Keisuke , Akiyama Yuko , Sugiyama Minako , Kawara Kaori , Ishida Hiroo , Yamashita Keishi , Mizuno Keiko , Saji Shigehira , Ichikawa Wataru , Yamamoto Wataru , Nagashima Fumio , Miya Toshimichi , Narabayashi Masaru , Ando Yuichi , Hirose Takashi , Sasaki Yasutsuna 
Published: June 2012

Abstract
Purpose: We prospectively examined the effects of severe renal failure on the pharmacokinetics and toxicity of irinotecan.
Experimental Design: The pharmacokinetics of irinotecan, SN-38 and SN-38 glucuronide (SN-38G), and irinotecan-induced toxicity in 3 cancer patients with severe renal failure (creatinine clearance [Ccr] ≤20 mL/min) who were undergoing dialysis and received 100 mg/m2 irinotecan as monotherapy were compared with those in 5 cancer patients with normal renal function (Ccr ≥60 mL/min). To ensure that the subjects had similar genetic backgrounds of UDP-glucuronosyltransferase (UGT) 1A1, patients with UGT1A1*1/*1, *1/*6, or *1/*28 were enrolled.
Results: The estimated terminal elimination rate constant of SN-38 in patients undergoing dialysis was about one tenth that in patients with normal renal function (P=0.025). Consequently, the estimated t1/2 of SN-38 in patients with severe renal failure was roughly 10 times longer than that in patients without renal failure (P=0.025). About 50% of SN-38 was dialyzed with a 2.1-m2 dialysis membrane, whereas 27% was dialyzed with a 1.5-m2 membrane. All patients with severe renal failure experienced neutropenia (grade 2, 3 or 4 at nadir). In two of them experienced grade 2 or 3 neutropenia, the second irinotecan infusion was delayed 10 or 20 days by the prolonged neutropenia.
Conclusions: Our results showed that the elimination of SN-38 was significantly delayed in patients with severe renal failure as compared with patients with normal renal function. We demonstrated SN-38 was partly dialyzed. The prolonged neutropenia was seen in patients with severe renal failure.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1302. doi:10.1158/1538-7445.AM2011-1302
Abstract 1305: Fulvestrant induces the expression/activity of UGT1A4 in HepG2 cells: potential interactions with other therapeutic agents
Authors: Edavana Vineetha Koroth , Dhakal Ishwori B. , Yu Xinfeng , Williams Suzanne , Kadlubar Susan A. 
Published: June 2012

Abstract
Fulvestrant (Faslodex™) is a pure antiestrogen that has been shown to be effective in treating estrogen receptor (ER) positive tumors that are resistant to selective estrogen receptor modulators (SERMs) such as tamoxifen. Currently, clinical trials investigating the utility of adding fulvestrant to other therapeutics are being conducted. While co-administration of these drugs has not been shown to affect cytochrome P450-mediated metabolism of either drug, effects of co-administration on Phase II metabolism (i.e. glucuronidation) have not been explored.
We demonstrated that fulvestrant up-regulates expression of UDP glucuronosyltransferase (UGT) 1A4, the major enzyme responsible for the direct conjugation and subsequent elimination of many therapeutic drugs. Endogenous mRNA expression levels of UGT1A4 in HepG2 cells were induced 4.5-fold by fulvestrant treatment in this ERα-expressing cell line. Treatment with fulvestrant upregulated UGT1A4 in a time- (0-72 hours) and concentration-(0-250 nM) dependent manner and silencing ERα with specific siRNA abolished UGT1A4 up regulation. The role of a Sp1 binding site (−1906 to -1901 base pairs), known to be critical for the induction of UGT1A4 transcriptional activity by estradiol, was examined in relation to fulvestrant-mediated induction of UGT1A4. Electrophoretic mobility shift assays were performed using these nuclear extracts and UGT1A4/Sp1 probe. Fulvestrant-treated HepG2 nuclear extract formed multiple shifted bands that appear to represent homomultimeric complexes of Sp1 with UGT1A4/Sp1 probe. This binding ability was partially blocked by mithramycin, a known inhibitor of Sp1 binding to DNA.
While these in vitro assays indicate that fulvestrant administration could influence the disposition of other UGT1A4 substrates, the clinical significance of these findings is unclear. Further studies are needed to assess the effects of fulvestrant administration on the disposition of drugs that are substrates of UGT1A4, including anastrozole, clozapine, imipramine, irinotecanl, amotrigine, meperidine, midazolam, nicotine, olanzapine, SN-38 and tamoxifen.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1305. doi:10.1158/1538-7445.AM2011-1305