bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4560: A new IGF-1-integrated Child-Pugh score to risk-stratify patients with hepatocellular carcinoma
Authors: Kaseb Ahmed O. , Xiao Lianchun , Hassan Manal M. , Shah Neeraj , Rashid Asif , Abbruzzese James L. , Morris Jeffrey 
Published: August 2012

Abstract
Purpose The Child-Pugh (CP) system is the major tool for assessing the underlying liver condition and guiding therapy decisions in hepatocellular carcinoma (HCC) patients. It is itself relatively quantitative and uses five empirically selected variables, including hepatic encephalopathy and ascites, which are clinically difficult to grade and may vary in severity according to medical management of patients. Insulin-like growth factor-1 (IGF-1) is produced predominantly in the liver, and hence reflects its synthetic function. Our study objective was to build a new CP score by integrating plasma IGF-1 level into the CP parameters to refine its prognostic stratification ability. Patients and Methods We prospectively collected plasma samples and clinical data from 310 individuals with HCC. IGF-1 levels were measured by ELISA and recursive partitioning was used to identify optimal cut points and IGF-1 ranges, using training and validation sets, and established the cut-off values of IGF-1 arranged so as to define the three distinct groups of IGF-1 with increasing liver function severity; A=1, B=2, and C=3. We then constructed the new score by replacing points from ascites and encephalopathy with plasma IGF-1 points; the new score points = 4-11. Finally, we performed log rank test for both systems, and also compared their prognostic abilities using concordance index (c-index). Results Compared with CP system, the new system (c -index = 0.608) improves the capacity in predicting OS and refined the stratification of all classes of the original CP (c-index = 0.573), (p value = 0.0029). Conclusion Replacing ascites and encephalopathy by plasma IGF-1 significantly improved prediction of OS and prognostic stratification of the conventional CP system. After external validation, the new scoring system may become the standard of care in guiding therapy decisions and stratifying HCC patients in clinical trials.
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 4560. doi:1538-7445.AM2012-4560
Abstract 4563: Monotherapy with a tumor-targeting mutant of Salmonella typhimurium inhibits human glioma in an orthotopic model in nude mice
Authors: Momiyama Masashi , Zhao Ming , Hiroshima Yukihiko , Suetsugu Atsushi , Tome Yasunori , Mii Sumiyuki , Yano Shuya , Bouvet Michael , Chishima Takashi , Endo Itaru , Hoffman Robert M. 
Published: August 2012

Abstract
Malignant glioma tumors are the most common primary central nervous system tumors. Despite the multidisciplinary approach to treatment, prognosis remains poor. In this study, we demonstrated that the Salmonella typhimurium A1-R tumor-targeting strain can inhibit and eradicate human glioma in an orthotopic nude mouse model. S. typhimuirum A1-R was administered by injection through a craniotomy open-window or intravenously in nude mice. To establish the model, 2×105 U87-RFP human glioma cells were injected stereotactically into the mouse brain through the craniotomy open window. Two weeks after glioma-cell implantation, mice were treated with S. typhimurium A1-R (2×107 CFU / 200 αl intravenous injection [i.v.] or 1×106 CFU / 1 αl intracranial injection [i.c.]) once a week for 3 weeks. Brain tumors were observed by fluorescence imaging through the craniotomy open window over time. S. typhimurium A1-R, administered i.c., inhibited brain tumor growth 7.6-fold compared with untreated mice (p = 0.009) and improved survival 73% (p = 0.001). Two of ten mice appeared to have their tumors eradicated. In contrast, intravenous administration of S. typhimurium A1-R was not effective. The craniotomy open window enabled observation of tumor growth in the brain in real time in both treated and untreated mice. The results of the present study demonstrate that bacterial therapy of brain cancer is a novel, effective and safe treatment strategy in a highly treatment-resistance cancer.
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 4563. doi:1538-7445.AM2012-4563
Abstract 4564: Dysregulated p15 in urothelial carcinoma of the upper urinary tract
Authors: Ho Pei-Yin , Tsai Yu-Chieh , Huang Chao-Yuan , Chung Shiu-Dong , Yang Hsin-Yi , Peng Hsiang-Chi , Lin Ching-Hung , Lai Ming-Kuen 
Published: August 2012

Abstract
OBJECTIVE: To investigate tumorigenic characteristics of upper urinary tract urothelial carcinoma (UTUC) by evaluating genomic alterations and protein expression of p15, located in 9p21, in primary tumors and in the morphologically normal pelvis of UTUC patients. METHODS: 10 pairs of tumor and pelvis tissues were submitted for comparative genomic hybridization (CGH) to examine chromosome abberations. Western blotting assays were performed to compare the fold change of p15 expression between another 16 pairs of tumor and normal tissues. Immunohistochemistry was conducted to determine the presence of p15-positive tumor cells and staining intensity in 53 tumor tissues, including 26 superficial and 27 invasive tumors. The Student's t-test and Chi-square test were applied to explore the correlation between the p15 expression and clinicopathologic parameters of UTUC patients. RESULTS AND CONCLUSIONS: CGH revealed incomplete 9p21 in 70% of UTUC tumors, including 3 low-grade and 7 high-grade cases. Results of Western blotting assays showed high frequencies (75%) of p15 downregulation (fold change &gt; 1.5) in UTUC tissues compared to their normal pelvis control. Immunohistochemistry results indicated that superficial tumors had lower p15 expression than invasive tumors (p=0.002). In patients with tumor metastases, local recurrence or distal recurrence, the p15 expression level was significantly increased in UTUC tissues (p=0.038, 0.01 and 0.017, respectively). Taken together, our data suggest that the decreased expression of p15 may be an important step in early neoplastic transformation of the urothelium of upper urinary tract and, during tumor progression, p15 may be up-regulated by other molecules, such as SP-1.
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 4564. doi:1538-7445.AM2012-4564
Abstract 4565: Prediction of prognosis by the combination of mutation and methylation in colorectal cancer
Authors: Iida Satoru , Kato Shunsuke , Ishiguro Megumi , Ishikawa Toshiaki , Matsuyama Takatoshi , Kobayashi Hirotoshi , Higuchi Tetsuro , Uetake Hiroyuki , Sugihara Kenichi 
Published: August 2012

Abstract
Colorectal cancer (CRC) is among the most common types of cancer in both men and women and is associated with high mortality, particularly at advanced stages. Markers for defining individual risk signatures in CRC patients are of great clinical value, as they may allow for targeted therapies to improve outcomes in CRC patients. Epigenetic alteration such as promoter hypermethylation of gene, as well as genetic abnormality such as gene mutation, occurs frequently during the pathogenesis of human cancers. Recent studies exhibit the increasing observations that both epigenetic and genetic changes combine to determine the phenotype of cancer. Thus, in the present study, we examined KRAS and PIK3CA mutations and the methylation status of BNIP3, SFRP1, and Dkk1, and analyzed the correlation between these molecular alterations and the clinicopathological features of CRC. We aimed to clarify whether a combination of genetic and epigenetic alterations can be used to classify CRC patients in relation to their clinicopathological features and outcomes. Tissue samples from 122 CRC patients who underwent surgical resection were examined. The methylation status of SFRP1 and Dkk1 and the sequences of exon 1 of KRAS gene and exons 9 and 20 of the PIK3CA gene were determined by methylation specific PCR and direct sequencing, respectively, using genomic DNA extracted from paraffin-embedded blocks. Correlation between these factors and clinicopathologic findings/patients survival were examined. As a result, there was a significant correlation between KRAS mutation and BNIP3 (p=0.0004) or Dkk1 (p=0.0009) methylation but not SFRP1 (p=0.114). Although SFRP1 and Dkk1 methylation showed no associations with disease specific survival (DSS) and other clinicopathological findings in CRC patients, BNIP3 was associated with poor DSS (p=0.0149). In CRC without both KRAS and PIK3CA mutation, patients with two or three methylated genes had poorer overall survival compared to those with no or one methylated genes (p=0.0017). To contrary, in the cases of at least one or more mutations, patients with two or three methylated genes tended to have better survival than patients with no methylation. Classifying CRC based on BNIP3, SFRP1, and Dkk1 methylation status and KRAS and PIK3CA mutation may be a clinically powerful predictor of patient outcome.
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 4565. doi:1538-7445.AM2012-4565
Abstract 4682: Compensatory activation of alternative DNA repair pathways following exposure to the PARP Inhibitor ABT-888 in vitro and in patients with solid malignancies
Authors: Gao Li , Duan Wenrui , Wu Xin , Chen Alice , Otterson Gregory A. , Villalona Miguel A. 
Published: August 2012

Abstract
PARP inhibitors are being developed with the hope of inhibiting base excision repair in tumor cells following DNA insult. They do so by inhibiting poly ADP-ribose polymerase-1(PARP-1) which plays an important role in the repair of single-stranded DNA (ssDNA) breaks. Although some PARP inhibitors have been shown to suppress its target at safely achievable concentrations in humans, mono-therapy with these agents is generally not able to induce responses. The compensatory effect of alternative repair pathways, including., homologous recombination (HR) repair, nucleotide excision repair (NER), among others, could potentially be responsible for this lack of effect. Examples of HR repair proteins include those involved in the Fanconi Anemia/BRCA pathway and for NER, the ERCC proteins. We performed Western immunoblot analysis to evaluate the expression level of PAR, Fanconi Anemia D2, ERCC1 and beta-actin proteins in the human cancer cell lines H1299 (lung) and MDA-MB-231(breast) following exposure to the PARP inhibitor ABT-888 (veliparib). The expression level of these protein was also evaluated in human peripheral blood mononuclear cells (PBMCs) obtained from consenting patients with advanced solid malignancies participating in a dose escalation trial with ABT-888, as monotherapy or in combination with mitomycin C. PAR protein level was reduced at 6 hours post ABT-888 exposure (5μM) and maintained at low levels through 48 hours in the H1299 and MDA-MB-231cancer cells. However FANCD2 and ERCC1 protein expression was elevated simultaneously in these cancer cells post ABT-888. Similarly, FANCD2 and ERCC1 protein levels increased in the PBMCs of 22 patients analyzed following ABT-888 as a single agent (n=12) or in combination with mitomycin C (n=10). These results confirm that ABT888 can inhibit its target PAR expression both in cancer cells and patients’ PBMCs. However, our results also show that ABT-888 up-regulates homologous recombination (HR) and nucleotide excision repair (NER) pathways, which have the potential of resulting in not only resistance to the antitumor effect of ABT-888, but also in decreasing the effect of DNA targeting cytotoxic chemotherapy when combined with isolated PARP inhibition. It is plausible that cancers with defective FA or NER pathways, which are incapable of mounting a compensatory response, would represent a better target for ABT-888 alone or in combination with DNA targeted cytotoxic chemotherapy. Experiments aimed to evaluate this notion are underway. The potential role of other compensatory repair mechanisms also merit further investigation.
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 4682. doi:1538-7445.AM2012-4682
Abstract 4684: Synthetic lethal interaction between EGFR and PARP inhibition
Authors: Whitley Alexander , Nowsheen Somaira , Cooper Tiffiny , LoBuglio Albert , Bonner James , Yang Eddy S. 
Published: August 2012

Abstract
Purpose: Dysregulation of the epidermal growth factor receptor (EGFR) family is a hallmark of many cancers. Although targeting of EGFR family has improved outcomes, many patients ultimately fail this therapy. PARP inhibitors (PARPi) have gained recent attention due to their unique selectivity in killing homologous recombination (HR)-deficient tumors while maintaining minimal toxicity in normal tissues. We have previously shown that EGFR inhibition induces synthetic lethality with PARPi in head and neck squamous cell carcinomas (HNSCCs) in vitro by attenuating DNA repair pathways. In this study, we validated these observations in vivo in HNSCCs xenografts. Importantly, we also tested this strategy in other EGFR dysregulated cancers. Methods: Cervical, breast, and head and neck cancer cell lines were used in this study. DNA damage and repair were assessed by immunofluorescence staining of cells for γ-H2AX, Rad51, and DNA-Pk foci and/or chromosomally integrated HR and nonhomologous end-joining based GFP reporter assays. Cell viability was determined via colony formation and ATPlite assays. Tumor growth delay was assessed in mice bearing tumor xenografts. Results: Combined EGFR and PARP inhibition resulted in the greatest tumor growth delay versus either agent alone in mice bearing head and neck tumor xenografts (9 week tumor growth delay when compared to PARPi alone, 3 week tumor growth delay when compared to EGFR inhibitor alone). This correlated with persistent γ-H2AX foci indicative of unresolved DNA damage. Interestingly, this combination was also effective in other EGFR dysregulated tumors. Human cervical and breast cancer cells exhibited enhanced cytotoxicity with EGFR and PARP inhibition compared to either agent alone (80-99% cytotoxicity with combination vs 0-20% with either agent alone). Similar to head and neck cancer, susceptibility to PARPi induced by EGFR inhibition was associated with deficient NHEJ- and HR-mediated DNA repair and subsequent persistence of DNA damage. Conclusions: Thus, by generating a DNA repair deficit, EGFR inhibition can induce synthetic lethality with PARP inhibition. This can be an innovative treatment strategy for tumors with dysregulated EGFR signaling.
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 4684. doi:1538-7445.AM2012-4684
Abstract 4689: Stabilization of PARP-DNA complexes plays a critical role for the cytotoxic effects of the PARP inhibitors, veliparib and oliparib
Authors: Pommier Yves G. , Murai Junko , Takeda Shunichi 
Published: August 2012

Abstract
Poly(ADPribose) (PAR) polymerase (PARP) inhibitors are in clinical trials with alkylating agents such as temozolomide and topoisomerase I (Top1) inhibitors such as camptothecin derivatives (topotecan and irinotecan). To elucidate the mechanism of action of PARP inhibitors and how they synergize with alkylating agents and Top1 inhibitors, we compared genetic PARP knockout versus chemical inhibition with the PARP inhibitor. DNA alkylation damage was assayed by treating wild type (WT) and PARP knockout chicken DT40 cells with methyl methane sulfonate (MMS) in the presence of oliparib or veliparib. Notably, PARP inhibitors produced a much greater cytotoxicity than knocking out the PARP gene in cells treated with low MMS concentrations that are not cytotoxic in WT cells. Moreover, knocking out PARP eliminated the cytotoxicity of the PARP inhibitors even in the absence of MMS treatment. These results suggested that PARP inhibitors not only act by abrogating the catalytic activity of PARP and blocking PAR polymer formation but also by poisoning PARP. To further investigate this possibility, we measured PARP binding to DNA. Accordingly, we found that both oliparib and veliparib trap PARP on cellular DNA. By contrast, in the case of Top1 inhibitors, the potentiation by PARP inhibitors was no greater than knocking out PARP. Together, these results demonstrate that oliparib and veliparib act primarily as catalytic PARP inhibitors for Top1-linked DNA damage, whereas, in the case of base damage, oliparib and veliparib also act by preventing the removal of PARP complexes from DNA, probably as a result of defective PARP auto-PARylation, thereby converting base damage and DNA nicks into tight PARP-DNA complexes.
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 4689. doi:1538-7445.AM2012-4689
Abstract 4690: PARP inhibition increases sensitivity to cisplatin in ERCC1-low non-small cell lung cancers
Authors: Cheng Haiying , Zhang Zhenfeng , Borczuk Alain , Powell Charles A. , Halmos Balazs 
Published: August 2012

Abstract
Platinum compounds are the foundation of chemotherapy regimens for non-small cell lung cancer (NSCLC) but nevertheless response rates are disappointing and response duration is limited. Tumor expression of ERCC1, a key enzyme in nucleotide excision repair, may correlate with clinical response to platinum agents. Inhibition of poly(ADP-ribose) polymerases (PARPs), enzymes essential for base excision repair, enhances platinum sensitivity in BRCA-associated breast and ovarian cancers. We hypothesized that combining PARP inhibition with platinum compounds for tumors with low ERCC1 expression, may be an approach to optimize platinum-based therapy for NSCLC. In primary lung tumor specimens and NSCLC cell lines, PARP1 was found to be a mainly nuclear protein with higher expression in tumor cells as compared to normal counterparts. Drug combination experiments revealed that olaparib (PARP inhibitor) selectively synergized with cisplatin in ERCC1-low HCC827 and PC9 but not in ERCC1-high A549 and H157 lung cancer cells. Similar data were obtained with an alternative PARP inhibitor, veliparib (ABT-888). Moreover, siRNA-mediated knockdown of ERCC1 in ERCC1-high A549 and H157 cells increased sensitivities of both cisplatin and olaparib. Mechanistic studies further indicated that PARP inhibition alone or in combination with cisplatin led to cell cycle arrest in the G2/M phase, via activation of the DNA damage checkpoint pathways involving γH2AX, checkpoint kinase 1 and p53. These data suggest that there is a synthetically lethal relationship between PARP inhibition and ERCC1 loss in NSCLC that could be exploited for novel therapeutic approaches in lung cancer therapy based on tumor ERCC1 expression.
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 4690. doi:1538-7445.AM2012-4690
Abstract 4691: Rationale for combining PARP inhibitors with topotecan or irinotecan: taking advantage of the alternative DNA repair pathways involving XPF-ERCC1 and PARP-TDP1
Authors: Zhang Yongwei , Regairaz Marie , Seiler Jennifer , Agama Keli , Doroshow James , Pommier Yves 
Published: August 2012

Abstract
Poly(ADP-Ribose) (PAR) polymerase (PARP) inhibitors represent an important class of novel anticancer agents. The present study explores the molecular rationale for combining veliparib (ABT-888) with camptothecin (CPT) and its clinical derivatives, topotecan and irinotecan. ABT-888 inhibited PAR induction by CPT and increased CPT-induced cell killing and DNA damage measured by histone gamma-H2AX and comet assays. Notably, increased DNA breaks by ABT-888 was not associated with a corresponding increase of topoisomerase I cleavage complexes (Top1cc). Also, ABT-888 failed to further enhance the gamma-H2AX response in tyrosyl-DNA-phosphodiesterase (TDP1) knockout cells, which indicates that PARP inhibition no longer enhances Top1-induced DNA damage once TDP1 is inactivated. To explore alternative endonuclease pathway for the repair of Top1cc upon PARP inhibition, we tested the role of the 3′-flap endonuclease XPF-ERCC1. XPF-ERCC1 inactivation reduced the ABT-888-induced gamma-H2AX response both in non-replicating and replicating cells, and further enhanced the antiproliferative effect of ABT-888 in CPT-treated cells. Together, our findings demonstrate that XPF-ERCC1 acts as an alternative endonuclease pathway for the repair of Top1-induced DNA damage. Its function becomes critical when the PARP-TDP1 excision repair pathway is inactivated. Our study suggests the rationale for combining Top1 and PARP inhibitors in tumors with XPF-ERCC1 deficiency.
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 4691. doi:1538-7445.AM2012-4691