bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1733: Development of a novel blood plasma protein test for diagnosis of lung cancer
Authors: Streeper Robert T. , Izbicka Elzbieta , Diaz Armando , Campos David , Louden Christopher , Michalek Joel 
Published: August 2012

Abstract
Background: A blood test for detection of lung cancer (LC) could provide survival benefits in high-risk populations. We conducted a retrospective study as the next step of our effort to develop a test for diagnosis of non-small cell lung carcinoma (NSCLC), the most common form of LC, by measuring levels of protein biomarkers in plasma. Materials and Methods: We quantified levels of 106 proteinaceous biomarkers using multiplexed immunoassays of subjects a) diagnosed with stage I/II NSCLC, b) normal non-smoking controls, and c) normal heavy smoking controls (&gt; 10 p.y.). All groups consisted of Caucasian men and women (93 subjects each, ages range 45-87, Ave 59). The specimens were randomized and tested in a blinded manner. A support vector machine (SVM) algorithm, developed and tested in a pilot study, was used to identify differentially expressed biomarkers in the disease and control groups taking into account patients’ gender. Pathway analysis was applied to characterize pathology- and gender-specific patterns of biomarker expression. Results: In a recent pilot study we developed SVM models that classified subjects to NSCLC or normal using 59 plasma markers or subsets thereof, for both genders combined or separately. When data for both genders were analyzed together, SVM classified subjects to NSCLC or normal and identified 4 differentially expressed markers: EGF, sCD40 ligand, IL-8 and MMP-8; sensitivity (SE) 0.93 (95% CI: 0.88-0.96), specificity (SP) 0.87 (95% CI: 0.80-0.92). Considering the sexes separately, the differentially expressed best subset of markers for men (EGF, IL-8, sFAS, MMP-9 and PAI-1) had both SE and SP of 1.0. For women, the best subset of markers (EGF, sCD40 ligand and IL-8) also yielded SE and SP of 1.0. The present study has further confirmed and refined our earlier findings and expanded panels of diagnostic biomarkers for NSCLC with comparable sensitivities and specificities. Analysis of cellular pathways represented by the discriminatory biomarker signatures suggested a role of sex hormone-driven differences of NSCLC plasma biomarkers. Conclusions: The set of diagnostic biomarkers for NSCLC identified in this study holds significant promise for use in the early diagnosis of lung cancer and warrants validation of findings in other ethnic groups and for potentially confounding diseases in clinical studies.
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 1733. doi:1538-7445.AM2012-1733
Abstract 1737: Co-existence of positive MET FISH status with EGFR mutations signifies poor prognosis in lung adenocarcinoma
Authors: Kobayashi Naomi , Aragane Naoko , Nakamura Tomomi , Sato Akemi , Takeda Yuji , Mitsuoka Masahiro , Yamasaki Fumio , Hayashi Shinichiro , Sueoka Eisaburo , Kimura Shinya 
Published: August 2012

Abstract
MET, which is located in 7q31, is a receptor tyrosine kinase for hepatocyte growth factor. Overexpression of MET has been reported in various malignancies and is associated with cell proliferation, inhibition of apoptosis, and metastasis. MET amplification has been reported to contribute to acquired resistance to epidermal growth factor tyrosine kinase inhibitors (EGFR-TKI) in non-small cell lung cancer(NSCLC), being observed among 5-10% of those patients. Therefore, MET gene alterations could be both prognostic and predictive. To evaluate MET gene copy number, fluorescence in situ hybridization (FISH), real-time PCR, and comparative genomic hybridization (CGH) have been used. The results of real-time PCR do not directly reflect cancer cells. CGH is not suitable for the evaluation of a large number of specimens due to cost. Therefore, FISH is the most practical method for evaluation of MET gene copy number. However, the frequency of positive cases varies due to a lack of standardized criteria. We evaluated MET gene copy number in lung adenocarcinoma and its association with clinicopathological characteristics. FISH was applied to evaluate high MET gene copy number and true amplification in 138 lung adenocarcinoma patients using two criteria: the Cappuzzo scoring system and PathVysion. MET positive cases according to the Cappuzzo scoring system evidenced both aneuploidy and true amplification, whereas PathVysion revealed only amplification. Proportion of MET FISH positive cases was 15% and 4% determined by the Cappuzzo system and PathVysion, respectively. PathVysion demonstrated higher frequencies of MET FISH positives among men and smokers and evidenced no MET FISH positives in patients with bronchioloalveolar carcinoma, which is recognized as pure lepidic growth without invasion of stroma, blood vessels, or pleura. Prognosis was significantly associated with MET FISH positive only as defined by the PathVysion system (gene amplification), not by the Cappuzzo system. However, progression-free survival time of patients with both EGFR mutations and MET FISH positive defined by the Cappuzzo scoring system was significantly shorter than with EGFR mutations alone. These results suggest that MET FISH is a potential prognostic factor and co-existence of EGFR mutation and MET FISH positive status evidences poorer prognosis compared to EGFR mutation alone, which is consistent with the results of in vitro experiments.
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 1737. doi:1538-7445.AM2012-1737
Abstract 174: Keratin 8 and 18 knockdown increases cisplatin-induced apoptosis and invasive potential through claudin1/PI3K/NFkB up-regulation in epithelial carcinoma cells
Authors: Fortier Anne-Marie , Cadrin Monique , Asselin Éric 
Published: August 2012

Abstract
Keratins are epithelial-specific intermediate filament (IF) proteins, which are expressed in a tissue-specific manner. As part of the cytoskeleton, keratins are important for the mechanical stability and integrity of epithelial cells and tissues. Moreover, a number of keratins are involved in intracellular signalling pathways which regulate response to injuries and non-mechanical stresses, cell growth, cell death and cancer progression. Keratins 8 and 18 (K8/18) are typically co-expressed as the primary keratin pair in simple epithelial cells and their expression are maintained during malignant transformation, hence their use as diagnostic marker in tumor pathology. However, in recent years different studies have shown that IF should not be considered only as markers proteins but also as regulators of cancer cell signaling and that they might play an active role in malignant transformation. In the present study, we addressed the question as to whether K8/18 expression affects tumor fate and behaviour. Our results show that K8/18 stable knockdown using shRNA increases cisplatin sensitivity in three different epithelial cancer cell lines. Indeed, western blot analysis of caspases activation and flow cytometry analysis of AnnexinV/PI staining show that K8/18 knockdown sensitizes cells to cisplatin-induce apoptosis. Increased FasL expression and FasR membrane targeting suggest that apoptosis is enhanced via the death receptor pathway. Moreover, using in vitro wound healing and transwell invasion assays, we observed that K8/18-knockdowned cancer cells display an increased cellular motility and invasion. Interestingly, we observed that these cells present higher PIP3 levels in the plasma membrane as determined by both fluorescence microscopy and flow cytometry analysis. Consequently, the K8/18-shRNA clones show PI3K/Akt/PKC/NFkB pathways hyperactivation and increased MMP-9 expression. Furthermore, these processes are shown to be partially regulated by the tight junction's protein claudin-1, which is highly increased in K8/18-shRNA clones. To our knowledge, these results represent the first indication that K8/18 can influence the phenotype of epithelial cancer cells. Knockdown of K8/18 increases cisplatin sensitivity and invasive potential of epithelial cancer cell lines through the regulation of different cell signaling pathways, involving claudin-1 dependent PI3K activation and NFkB transcription activity. These results support the hypothesis that modulation of K8/18 expression plays an active role in cancer progression.
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 174. doi:1538-7445.AM2012-174
Abstract 1756: Downregulation of topoisomerase IIα by all-trans retinoic acid in human cervical carcinoma cells
Authors: Li Xiaoting , Fu Shilong , Shen XIn , Zhou Donghu , Jiang Apei , Han Suping , Feng Qing 
Published: August 2012

Abstract
Cervical cancer remains a threatening disease to women worldwide. Topoisomerase IIα is a novel proliferation marker for cervical cancer diagnosis, therapy and prognosis. Understanding of the regulation of topoisomerase IIα would facilitate prevention and therapy of cervical cancer. In the present study, a significant repression of topoisomerase IIα level in stage Ib of squamous cervical carcinoma tissue was observed in patients with chemotherapeutic treatment, suggesting topoisomerase IIα is a target for chemotherapeutic drugs. All-trans-retinoic acid (ATRA), a chemopreventive agent, was shown to suppress both endogenous and exogenous topoisomerase IIα protein but not mRNA expression in human cervical carcinoma HeLa cells. Cycloheximide (CHX) prior to ATRA treatment augmented the topoisomerase IIα instability. ATRA induced the degradation of topoisomerase IIα via the proteasome pathway but not lysosome pathway. Ubiquitination was involved in this ATRA-induced topoisomerase IIα degradation. The ATRA-induced topoisomerase IIα repression occurred only in cell nucleus. Interestingly, overexpression of topoisomerase IIα enhanced cyclin D1 expression and caused HeLa cells de-differentiation while knockdown of topoisomerase IIα resulted in the cells differentiation and decreased cyclin D1. ATRA suppressed drug resistant protein P-gp while the typical topoisomerase II inhibitor etoposide did not. The molecular therapeutic implication of ATRA in cervical cancer therapy is discussed.
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 1756. doi:1538-7445.AM2012-1756
Abstract 1761: Breast cancers with compromised DNA repair exhibit selective sensitivity to elesclomol-induced oxidative DNA damage
Authors: Alli Elizabeth , Ford James M. 
Published: August 2012

Abstract
Hereditary breast cancers due to germline mutations in BRCA1 and sporadic breast cancers of the basal-like subtype are often triple-negative, i.e. lack expression of estrogen and progesterone receptors and lack overexpression/amplification of the HER2/neu oncogene. Given that the triple-negative status of these cancers renders them relatively insensitive to existing “targeted” therapy, improved treatment options are needed. We tested a panel of cell lines that represent the different molecular subtypes of breast cancer for sensitivity to elesclomol, an experimental therapeutic that produces elevated levels of oxidative DNA damage, using the MTT assay. We found that both BRCA1-mutated and basal-like breast cancer cell lines with defective base-excision DNA repair (BER) were markedly more sensitive to elesclomol than cell lines that represent the normal breast or other subtypes of breast cancer with proficient BER. We also assessed sensitivity to elesclomol in breast cancer cell lines that were stably transduced with shRNA to OGG1, a BER glycosylase required for the repair of the most common type of oxidative DNA damage. Two different cell lines with decreased levels of OGG1 (shOGG1A, 50% knock-down; shOGG1B, 20% knock-down) were more sensitive to elesclomol (IC50 = 0.04nM and 0.3nM, respectively) compared to two different isogenic control cell lines (IC50 = 2nM and 3nM, respectively). Taken together, these data suggest that compromised repair of oxidative DNA damage by BER represents a functional target for elesclomol. Overall, BRCA1-mutated and/or basal-like breast cancers may benefit from treatment regimens that include elesclomol.
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 1761. doi:1538-7445.AM2012-1761
Abstract 1764: Changes in apoptotic gene expression in human leukemia cells treated with the anticancer drug Laromustine
Authors: Kaye Emily G. , Gross Kayla M. , Bellairs Jo , Dale Lindsay E. , Gallagher Catherine , Sher Emily V. , Robinson Kristen N. , Rice Kevin P. 
Published: August 2012

Abstract
Laromustine is an experimental anticancer drug that has been tested in the clinic against acute myelogenous leukemia and glioblastoma multiforme. In the body, Laromustine's cytotoxic effects are a result of two cogenerated electrophiles, a 2-chloroethylating species that can cause lethal DNA damage and methylisocyanate, which carbamoylates sulfydryl groups in proteins. The mechanism by which Laromustine kills cancer cells likely includes apoptosis. In order to further investigate this phenomenon, the extent to which Laromustine affects cultured human promyelocytic (HL-60) cells’ use of 88 genes relating to this cell death pathway was examined using quantitative real-time reverse transcriptase PCR. Cultured cells were treated with drug for six hours before harvesting mRNA for analysis. The expression of a subset of the tested genes emerged as significantly different in cells treated with Laromustine as compared to control cells. Included among these genes are: TNFRSF10D, TNFRSF17, CD40LG, TRAF4, and BAG3. The expression of BAG3, whose encoded protein is also known as CAIR-1 or Bis, was increased by more than two orders of magnitude in HL-60 cells exposed to Laromustine. By forming a complex with heat shock protein 70 (Hsp70), it is thought that BAG3 promotes anti-apoptotic activity by interfering with protein chaperoning and cytochrome-c release. It is possible that a pathway involving BAG3 could be a mechanism by which cells attempt to counter the effects of Laromustine exposure. Other apoptotic markers are also reported, including activation of caspase-3 and caspase-7, cleavage of poly(ADP-ribose) polymerase, and staining of annexin V.
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 1764. doi:1538-7445.AM2012-1764
Abstract 1765: Potent antitumor BO-1922, derivative of indolizino[6,7-b]indole, against human colon, lung, and pancreatic cancers in xenograft model
Authors: Su Tsann-Long , Tala Satishkumar , Chaniyara Ravi , Chen Chi-Wei , Lee Te-Chang , Chou Ting-Chao 
Published: August 2012

Abstract
Our previously studies demonstrated that bis(hydroxymethyl)cyclopenta[a]indenes, which bear a bis(hydroxymethyl)pyrrolidine pharmacophore, exhibited potent antitumor activity in inhibiting various human tumor xenografts. We also demonstrated that these agents showed strong synergistic therapeutic efficacy in combination with arsenic trioxide (ATO) against acquire or inherited MDR human tumors in xenograft model (human lung H460 or bladder cancer resistant to cisplatin NTUB1/P). Based on these findings, we have recently synthesized a series of 1,2-bis(hydroxymethyl)indolizino[6,7-b]indols and their bis(alkylcarbomate) derivatives for antitumor evaluation. These new agents were easily prepared starting from L-tryptophane in 5 steps. The in vitro cytotoxicity studies showed that the newly synthesized derivatives possessed a broad spectrum of anticancer activity against human lymphoblastic leukemia and various solid tumor cell growth in vitro. Of these analogues, 1,2-bis(hydroxymethyl)-3,6-dimethylindolizino[6,7-b]indole (BO-1922) was selected for further antitumor studies. We found that this agent displayed potent therapeutic efficacy against human colon cancer HT-29, lung adenocarcinoma lung A549, and primary pancreatic adenocarcinoma BX-PC3 xenografts. The antitumor activity of BO-1922 was compared with Irinotecan (CPT-11) in animal xenograft model. It revealed that BO-1922 is more potent than CPT-11 against human colon cancer HT-29 xenograft; complete tumor suppression on day 20 after mice treated with BO-1922 (25 mg/kg, QD×4, intravenous injection), while, tumor relapsed on day 9 after mice treated with CPT-11 (60 mg/kg, Q2D×3, iv. inj.). Under the same drug administration conditions (dosage and schedule), BO-1922 is as potent as CPT-11 against lung cancer A549 and pancreatic cancer BX-PC3 xenografts. Although the bodyweight of all drug treated mice recovered after ceasing of treatment, it was found that BO-1922 is less toxic to the host based on the average body-weight loss. The alkaline agarose gel shifting assay showed that this agent is able to induce DNA double strand cross-linking. Flow cytomeric assay revealed that BO-1922 induced cell cycle arrest at G1/S phase in non-small cell lung carcinomas H1299. These results suggest that BO-1922 is a promising candidate for clinical application and is currently undergoing preclinical studies.
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 1765. doi:1538-7445.AM2012-1765
Abstract 1768: Enhanced cytotoxicity and apoptosis of cisplatin by p53-reactivating small molecule RITA in head and neck cancer
Authors: Ryu Chang Hwan , Ryu In Sun , Park Gi Cheol , Choi Jun Young , Park Jung Je , Roh Jong-Lyel 
Published: August 2012

Abstract
Overexpression of MDM2 inactivates the tumor suppressive function of p53 and a small-molecule reactivation of p53 and induction of tumor cell apoptosis (RITA) disrupts the MDM2-p53 interaction. We evaluated whether the restoration of p53 function by RITA enhances cytotoxicity and apoptosis of cisplatin in head-and-neck cancer (HNC). RITA was tested in four human HNC cell lines differing in TP53 status. In vitro and in vivo growth suppression, cell cycle arrest, apoptosis after RITA treatment individually or in combination with cisplatin were assessed. RITA induced prominent accumulation and reactivation of p53 in a wild-type TP53-bearing tumor cell line. RITA showed maximal growth suppression in tumor cells showing MDM2-dependent p53 degradation. RITA upregulated p21, BAX, and cleavage of caspase-3 but the p53-dependent apoptosis was blocked by pifithrin-μ. Strong induction of apoptosis rather than G2-phase arrest was observed along with increased dose of RITA. In combination therapy, RITA enhanced the growth inhibition and apoptosis of HNC by cisplatin in vitro and in vivo. Our data suggest that the restoration of p53 tumor suppressive function by RITA enhances cytotoxicity and apoptosis of cisplatin, which may offer an attractive strategy for treating HNC.
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 1768. doi:1538-7445.AM2012-1768
Abstract 1777: Antitumor effect of PM01183 in a human pancreatic adenocarcinoma orthotopic model
Authors: Cespedes M Virtudes , Guillén M José , Mangues Ramon , Gallardo Alberto , Alamo P , Casanova I , Cuevas Carmen , Aviles Pablo 
Published: August 2012

Abstract
Background: Pancreatic ductal adenocarcinoma is the fourth cause of death in the Western world and, despite the advances in cancer therapies, limited therapeutic benefit (palliating symptoms, better quality of life) may be offered to patients: the overall 5-year survival rate remains &lt; 5%. PM01183 is a new synthetic tetrahydroisoquinoline alkaloid that binds to selected DNA sequences and promotes apoptosis by inducing double-strand breaks at nanomolar concentrations. Confirmed antitumor clinical activity was observed at the recommended dose level of PM01183 in the first-in-human Phase I study in patients with advanced/refractory solid tumors. Currently, PM01183 clinical development includes Phase II single agent trials (pancreas, breast and platinum-resistant/refractory ovarian) as well as Phase I trials in combination (with doxorubicin and gemcitabine) and in advanced acute leukemia. The in vivo antitumor activity of PM01183 was investigated in the human NP9 pancreatic orthotopic model Material and Methods: Athymic nude female mice were orthotopically implanted with luciferase-expressing NP9Luc tumors. Fifteen days after implantation, tumor bearing mice were randomly allocated (N=12 /group) into either PM01183 (at 0.18 mg/kg), gemcitabine (at 180 mg/kg) or control (placebo) groups. Treatments were initiated (Day 0) and administered for 3 consecutive weeks (q7dx3; days 0, 7, 14). Response to treatment was assessed on Day 7 (short-term) by bioluminescence imaging (BLI), and by survival evaluation (long-term): mice were sacrificed when their tumor diameters reached ca. 2 cm or when they became moribund. Statistical differences between groups were determined using two-tailed Mann-Whitney U test and by analysis of the Kaplan-Meier curve. Results: Results showed that PM01183 (q7dx3 at 0.18 mg/kg) induced statistically significant tumor reduction compared to placebo-treated animals by BLI analysis (P= 0.006) on Day 7. Reductions in tumor size were associated to changes in survival median times: PM01183 treatment significantly increased the survival time compared to either gemcitabine- (P= 0.003) or placebo-treated (P= 0.0001) animals. Conclusion: PM01183 demonstrated in vivo antitumor activity in a human pancreatic orthotopic model (NP9), as reflected by metabolic, size-related and survival rate.
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 1777. doi:1538-7445.AM2012-1777