bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-281: The role of POU5F1B in prostate cancer.
Authors: Jiang Hongmei , Wang Man-Tzu , Nie Daotai 
Published: August 2014

Abstract
POU5F1B is the one of the pseudogenes of POU5F1 (also known as Oct3, Oct4) with protein-coding potential. It is localized on chromosome 8q24.21, inside of the 1.2 Mb “gene desert” between the FAM84B and the c-MYC gene, which is closely associated with prostate cancer risk. Recent studies showed that POU5F1B, but not POU5F1, is expressed in prostate tissue and is overexpressed in prostatic carcinoma, compared to normal prostatic tissue surrounding the carcinoma. However, the role of POU5F1B in prostate cancer is still unknown. Through in silico analysis of dataset HG-U95A, we found that POU5F1B expression is increased in prostate tumor and markedly increased in metastatic tumors. Western blot analysis revealed a marked increase in POU5F1B expression in prostate cancer cells when compared to non-tumorigenic RWPE-1 cells. To study the role of POU5F1B in prostate cancer, we cloned POU5F1B from prostate cancer cells, sequenced the amplicons, and found several polymorphism. We made pCDH-myc-POU5F1B constructs and expressed POU5F1B in prostate cancer cell lines LNCaP, DU145, and PC-3. Overexpression of POU5F1B in LNCaP, DU145 and PC3 cells can increase cell invasion using Boyden chamber assay. Overexpression of POU5F1B in LNCaP cells also promotes colony formation in soft agar. We also found that DU145 cells with POU5F1B overexpression lost cell-cell contact, compared to DU145-pCDH vector cells, and further found that CDH1 expression is downregulated in DU145-POU5F1B cells. Depletion of POU5F1B reduced the tumor forming ability of LNCaP cells in vivo. The data collectively suggest an important role of POU5F1B in prostate tumor formation and progression.
Citation Format: Hongmei Jiang, Man-Tzu Wang, Daotai Nie. The role of POU5F1B in prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-281. doi:10.1158/1538-7445.AM2013-LB-281
Abstract LB-305: Novel Rac1-GEF inhibitors as anticancer agents for aggressive tumors.
Authors: Cardama Georgina A. , Gonzalez Nazareno , Comin Maria Julieta , Turjanski Adrian G. , Alonso Daniel Fernando , Gomez Daniel Eduardo , Menna Pablo Lorenzano 
Published: August 2014

Abstract
Small GTPases of the Rho family, including Rac1, regulate fundamental cellular processes like actin cytoskeleton reorganization, cell migration and cell cycle progression. Rac1 has been associated with transformation, tumor progression and tumor cell migration in different type of cancers, including aggressive breast cancer and glioma. These proteins cycle between an active, GTP-bound state and an inactive, GDP-bound state. This cycle is highly regulated by many regulatory proteins, including activators such as guanine nucleotide exchange factors (GEFs).
We searched for Rac1 inhibitors able to interfere Rac1-GEF interaction using a docking-based virtual library screening approach. We selected ZINC69391 compound. This small-molecule was able to interfere Rac-Tiam1 and Rac-DOCK180 interaction in vitro and reduced Rac1-GTP intracellular levels but had no effect on the closely related Cdc42 GTPase. ZINC69391 also affected the activation of Pak1, one important Rac1 effector. This compound reduced cell migration, inhibited cell proliferation and arrested cell cycle progression in breast cancer cells and glioma cells. We also evaluated this compound in vivo and ZINC69391 was able to reduce 60% lung colonization in a breast cancer experimental metastasis model. We further evaluated novel analogs looking for more potent and specific Rac1 inhibitors. We synthesized a group of novel disubstituted guanidines and we screened these analogs in vitro. One of them, 1A-116 analog, showed to be more potent than the parental compound, reducing cancer cell proliferation and Rac1 activation at the low micromolar range. These data further confirm Rac1 GTPase as a valuable molecular target for anti-cancer therapies and drug development in breast cancer and glioma, where Rac1 presents a relevant role.
Citation Format: Georgina A. Cardama, Nazareno Gonzalez, Maria Julieta Comin, Adrian G. Turjanski, Daniel Fernando Alonso, Daniel Eduardo Gomez, Pablo Lorenzano Menna. Novel Rac1-GEF inhibitors as anticancer agents for aggressive tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-305. doi:10.1158/1538-7445.AM2013-LB-305
Abstract LB-33: TRPV1 suppresses intestinal tumorigenesis by negatively regulating EGFR signaling.
Authors: de Jong Petrus R. , Takahashi Naoki , Harris Alexandra R. , Lee Jihyung , Bertin Samuel , Raz Eyal 
Published: August 2014

Abstract
The intestinal epithelium is the most rapidly self-renewing tissue. This dynamic process is mainly driven by Wnt, Notch and EGFR signaling in the crypts of Lieberkühn. These signaling pathways are negatively regulated by multiple control mechanisms to restrain intestinal epithelial cell (IEC) turnover and thereby reduce the risk of oncogenic transformation. Here we report a novel homeostatic feedback loop, intrinsic to IEC, between the EGFR and a member of the transient receptor potential (TRP) ion channel family. We identified that TRP vanilloid 1 (TRPV1), a polymodal pain receptor, is expressed by IEC and that this channel negatively regulates EGFR-induced cell proliferation in vivo. Intestinal crypt cultures (organoids) from Trpv1-/- mice showed hyperproliferation, crypt elongation and a reduced requirement for exogenous EGF compared to WT controls. Importantly, genetic deletion of Trpv1 increased the intestinal tumor load in multiple intestinal neoplasia (Apc+/min) mice, which was reversed by EGFR kinase inhibitor treatment. Continuous oral administration of a dietary TRPV1 agonist, capsaicin, suppressed intestinal tumorigenesis in Apc+/min mice in a TRPV1-dependent manner. In addition we found that capsaicin worked synergistically with a COX2 inhibitor, celecoxib, in the prevention of intestinal neoplasia development in these mice. Mechanistically, we show that TRPV1 is activated by EGFR signaling through phospholipase C (PLC). TRPV1 signaling subsequently restrains EGFR signaling through Ca2+-dependent triggering of protein tyrosine phosphatase (PTP) activity. Together, these findings suggest an intrinsic mechanism that exerts negative feedback on EGFR signaling through Ca2+ channel TRPV1 that thereby acts as a tumor suppressor in the intestinal epithelium.
Citation Format: Petrus R. de Jong, Naoki Takahashi, Alexandra R. Harris, Jihyung Lee, Samuel Bertin, Eyal Raz. TRPV1 suppresses intestinal tumorigenesis by negatively regulating EGFR signaling. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-33. doi:10.1158/1538-7445.AM2013-LB-33
Abstract LB-35: Site specific activation of AKT protects cells from death induced by glucose deprivation .
Authors: Gao Meng , Liang Jiyong , Lu Yiling , Guo Huifang , German Peter , Bai Shanshan , Jonasch Eric , Yang Xingsheng , Mills Gordon B. , Ding Zhiyong 
Published: August 2014

Abstract
The serine/threonine kinase AKT is a key mediator of cancer cell survival. We demonstrate that transient glucose deprivation modestly induces AKT phosphorylation at both Thr308 and Ser473. In contrast, prolonged glucose deprivation induces selective AKT phosphorylation at Thr308 and phosphorylation of a distinct subset of AKT downstream targets leading to cell survival under metabolic stress. Glucose deprivation-induced AKT Thr308 phosphorylation is dependent on PDK1 and PI3K but not EGFR or IGF1R. Prolonged glucose-deprivation induces the formation of a complex of AKT, PDK1, and the GRP78 chaperone protein, directing phosphorylation of AKT at Thr308 but not Ser473. Our results reveal a novel mechanism of AKT activation under prolonged metabolic stress that protects cells from metabolic stress. The selective activation of AKT phosphorylation at Thr308 that occurs during prolonged nutrient deprivation may provide an unexpected opportunity for the development and implementation of drugs targeting cell metabolism and aberrant AKT signaling.
Citation Format: Meng Gao, Jiyong Liang, Yiling Lu, Huifang Guo, Peter German, Shanshan Bai, Eric Jonasch, Xingsheng Yang, Gordon B. Mills, Zhiyong Ding. Site specific activation of AKT protects cells from death induced by glucose deprivation . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-35. doi:10.1158/1538-7445.AM2013-LB-35
Abstract LB-44: A novel PUMA inhibitor protects against chemotherapy-induced intestinal injury without compromising tumor response.
Authors: Leibowitz Brian J. , Li Mei , Wei Liang , Zhang Lin , Yu Jian 
Published: August 2014

Abstract
PUMA is a BH3-only member of the Bcl2 family that is a critical mediator of apoptosis in response to a variety of stimuli, and plays a particularly strong role in gastrointestinal and hematopoietic stem cell apoptosis following radiation. In this study we found that PUMA-dependent apoptosis mediates gastrointestinal injury induced by chemotherapeutic agents, indicating its critical role in DNA damage induced intestinal injury. PUMA neutralizes all known anti-apoptotic Bcl-2 family members through high-affinity interactions with its BH3 domain, thus facilitating activation of the intrinsic apoptotic pathway. Based on these interactions, we devised a pharmacophore model to mimic them, with the goal being a small molecule that prevents PUMA interaction with Bcl-2 family proteins. In silico screening of the ZINC 8.0 database yielded 142 potential compounds, 13 of which had favorable toxicity profiles. Extensive in vitro testing further narrowed the list to two lead compounds, one of which demonstrated significant in vivo activities. This lead compound significantly protected the intestinal stem cells from apoptosis induced by Irinotecan (CPT-11) and 5-Fluorouracil (5-FU). Utilizing a Lewis Lung Carcinoma (LLC) syngeneic tumor model, we found that treatment of C57/B6 mice with the experimental PUMA inhibitor (I.P.) significantly decreased CPT-11-induced apoptosis in the intestinal crypt base, similarly to that observed in PUMA KO animals. This treatment significantly preserved intestinal morphology and decreased weight loss in tumor bearing mice. Further, we found that administration of the PUMA inhibitor did not alter the tumor response to CPT-11. These findings suggest the feasibility of retaining the efficacy of chemotherapy while mitigating GI adverse effects with a small molecule. Further experiments will determine the inhibitor's pharmacokinetics and pharmacodynamics, as well as its mechanisms of action in vivo.
Citation Format: Brian J. Leibowitz, Mei Li, Liang Wei, Lin Zhang, Jian Yu. A novel PUMA inhibitor protects against chemotherapy-induced intestinal injury without compromising tumor response. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-44. doi:10.1158/1538-7445.AM2013-LB-44
Abstract LB-46: C/EBPα acts as tumor suppressor in lung cancer by inhibiting the proto-oncogene Bmi-1.
Authors: Levantini Elena , Basseres Daniela S. , Zhang Wen Cai , Welner Robert S. , Alberich-Jorda' Meritxell , Yong Kol Jia , Thakkar Bhavin M. , Zhang Junyan , Battelli Chiara , Hetherington Christopher J. , Ye Min , O'Brien Karen , Magli Maria Cristina , Loh Marie , Nga Min En , Pang Yin Huei , Borczuk Alain C. , Varticovski Lyuba , Kocher Olivier , Zhang Pu , Soo Ross A. , Lim Bing , Halmos Balazs , Tenen Daniel G. 
Published: August 2014

Abstract
C/EBPα gene expression is frequently lost in non-small cell lung cancer, suggesting it acts as a tumor suppressor. Here, we generated an inducible lung-specific mouse model of C/EBPα deletion (C/EBPαLung-Δ mice) that develops lung adenocarcinomas. We observed that C/EBPα excision results in upregulation of Bmi-1, and that tumor initiation strictly depends on Bmi-1 gene dosage, as C/EBPαLung-Δ mice carrying only one functional Bmi-1 allele escape tumorigenesis. Accordingly, C/EBPα negative human adenocarcinomas show elevated Bmi-1 expression, in line with our observation that C/EBPα acts as tumor suppressor in lung cells by directly inhibiting Bmi-1 transcription. Furthermore, pharmacological inhibition of Bmi-1 impairs the ability of C/EBPα null adenocarcinoma cells to form tumors in xenografts. Overall, we have identified Bmi-1 as a critical therapeutic target in those patients carrying abnormal C/EBPα function.
Citation Format: Elena Levantini, Daniela S. Basseres, Wen Cai Zhang, Robert S. Welner, Meritxell Alberich-Jorda’, Kol Jia Yong, Bhavin M. Thakkar, Junyan Zhang, Chiara Battelli, Christopher J. Hetherington, Min Ye, Karen O'Brien, Maria Cristina Magli, Marie Loh, Min En Nga, Yin Huei Pang, Alain C. Borczuk, Lyuba Varticovski, Olivier Kocher, Pu Zhang, Ross A. Soo, Bing Lim, Balazs Halmos, Daniel G. Tenen. C/EBPα acts as tumor suppressor in lung cancer by inhibiting the proto-oncogene Bmi-1. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-46. doi:10.1158/1538-7445.AM2013-LB-46
Abstract LB-6: Non-covalent assembly of meso-tetra-4-pyridyl porphine with single-stranded DNA to form nano-sized complexes with pH-dependent DNA release and anti-tumor activity.
Authors: Gmeiner William H. , Ghosh Supratim , Ucer Kamil B. , Williams Richard T. , D'Agostino Ralph , Grant Ken , Sirintrapun Joseph , Thomas Michael , Hantgan Roy , Bharadwaj Manish 
Published: August 2014

Abstract
Porphyrin-based nanomaterials frequently require non-physiological conditions to promote non-covalent assembly limiting therapeutic utility. In the present studies, we demonstrate that single-stranded DNA (ssDNA) modulates non-covalent assembly of meso-tetra-4-pyridyl porphine (MTP) and that the resulting porphyrin:DNA nano-sized complexes (PDN) are stable indefinitely in aqueous solution under physiologically relevant conditions and undergo pH-dependent DNA release under moderately acidic conditions (pH 5.1) that protonate the pyridyl nitrogens of MTP. The biological utility of pH-dependent DNA release from PDN was demonstrated by endosomal release of DNA in cancer cells. PDN formation is DNA-dependent with the ratio of porphyrin:DNA being approximately two DNA nucleobases per porphyrin consistent with half the pyridyl side chains of MTP interacting with DNA nucleobases. Raman spectra display surface-enhanced features for the porphyrin in the context of PDN consistent with π-π stacking of porphyrins and DNA nucleobases being a principal driving force for PDN assembly, a result also consistent with enhanced PDN dissociation in more hydrophobic solvent systems. PDN produce reactive oxygen species (ROS) in a light-dependent manner under conditions that favor dissociation, such as in hydrophobic environments as occurs upon endocytosis or in the presence of hydrophobic solvents. PDN induce light-dependent cytotoxicity in vitro and anti-tumor activity towards bladder cancer xenografts in vivo. Light-dependent, PDN-mediated cell death resulted from ROS-mediated localized membrane damage with mass spectrometry confirming the generation of the lipid peroxidation products9- and 13-hydroxy octadecanoic acid. Our results demonstrate that PDN have properties useful for therapeutic applications, including cancer treatment.
Citation Format: William H. Gmeiner, Supratim Ghosh, Kamil B. Ucer, Richard T. Williams, Ralph D'Agostino, Ken Grant, Joseph Sirintrapun, Michael Thomas, Roy Hantgan, Manish Bharadwaj. Non-covalent assembly of meso-tetra-4-pyridyl porphine with single-stranded DNA to form nano-sized complexes with pH-dependent DNA release and anti-tumor activity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-6. doi:10.1158/1538-7445.AM2013-LB-6
Abstract LB-73: Circulating tumor cells with the invasive phenotype predict progression free survival and overall survival in preoperative patients diagnosed with advanced epithelial ovarian cancer.
Authors: Chen Wen-Tien , Zhao Qiang , Dong Huan , Yang Jie , Zhang Qiao , Fan Tina , Golightly Marc G. , Dessio Whitney C. , Madajewicz Stefan , Henretta Melissa , Pearl Michael L. 
Published: August 2014

Abstract
Purpose: Circulating tumor cells (CTCs) might function as prognostic markers for monitoring and assessing therapy efficacy ex vivo. This study aimed to measure overall population of CTCs based on expression of epithelial lineage (Epi) markers and the subpopulation of CTCs with the invasive phenotype (iCTCs) in preoperative patients for prognosis of advanced Epithelial Ovarian Cancer (EOC).
Experimental Design: CTCs and iCTCs enriched by the Cell Adhesion Matrix (CAM)-coated devices from 122 preoperative patients were identified as Epi+ nucleic acid (NA)+ hematopoietic lineage (HL)- cells and CAM uptake (CAM+) Epi+ NA+ HL- cells, respectively. CTCs and iCTCs were enumerated using multiplex flow cytometry, validated by microscopy, and correlated with overall survival (OS) and progression-free survival (PFS).
Results: iCTCs were detected in 0/39 (0%) benign patients, 5/11 (45.5%) Stage I, 2/4 (50%) Stage II, 41/43 (95.3%) Stage III and 16/16 (100%) stage IV patients (P-value &lt;0.001). However, healthy (n=48) and benign women had noticeable CTCs (mean=10 and 3 CTCs/1.0-mL blood, respectively), and large variation (IQR=24.5 and 30 CTCs/1.0-mL blood, respectively), although CTCs were significantly different across different stage groups. Kaplan-Meier estimates of OS at 5 years in the iCTC positive and negative groups were 15.4% (95% CI, 7.2% to 26.3%) and 94% (95% CI, 82.5% to 98%), respectively. The PFS in the iCTC positive group was also significantly lower than that in the negative group (P-value &lt;0.001). In multivariable Cox models, iCTCs were independently predictive of OS (P-value &lt;0.001) and provided predictive power for disease recurrence independent of diagnostic disease stages, age, debulking status and platinum sensitivity.
Conclusion: CTCs show the expression of heterogeneous epithelial antigens with potential biologic relevance. Co-expression of epithelial antigens and invasiveness of iCTCs in preoperative patients provides prognosis of advanced EOC that could help tailor appropriate therapy.
Citation Format: Wen-Tien Chen, Qiang Zhao, Huan Dong, Jie Yang, Qiao Zhang, Tina Fan, Marc G. Golightly, Whitney C. Dessio, Stefan Madajewicz, Melissa Henretta, Michael L. Pearl. Circulating tumor cells with the invasive phenotype predict progression free survival and overall survival in preoperative patients diagnosed with advanced epithelial ovarian cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-73. doi:10.1158/1538-7445.AM2013-LB-73
Abstract LB-89: A combined epigenetic and genetic biomarker panel for detection of lung cancer.
Authors: Wang Michael X. , Guo Dan , Andersen Mary , Guntur Vamsi 
Published: August 2014

Abstract
Introduction: Lung cancer is the leading cause of cancer-related deaths in human. However, there is no valid screening procedure or test available at the present time. Although National Lung Screening Trial (NLST) demonstrated, for the first time, that low-dose helical CT screening in high-risk population reduced lung cancer mortality by 20%, the procedure is associated with over 95% false positive results (Aberle DR et al. N Engl J Med. 2011, 365:395). A confirmatory test is urgently needed. We have been developing a combined epigenetic and genetic molecular biomarker panel to verify the presence of lung cancer on the blood samples. Methods: Lung cancer cell lines NCI-H69 (small cell carcinoma), NCI-H1299 and NCI-H460 (large cell lung cancer), NCI-H1781 and A549 (adenocarcinoma), NCI- H358 (bronchioalveolar carcinoma) and NCI-H520 (squamous cell carcinoma) were obtained from ATCC (Manassas, VA). Blood samples of patients with lung cancer (n=105) and non-cancer patients were collected at MU Health Care System with an IRB approval. Genomic DNA was extracted from cell lines, mononuclear cell fraction and plasma using QIAamp DNA mini kit and circulating nucleic acid kit (QIAGEN, Valencia, CA), respectively. Isolated DNAs were digested with 4 methylation sensitive restriction enzymes followed by PCR for DNA methylation assay. Genomic DNAs were also subject to allele-specific PCR for PT53, EGFR and BRAF gene mutation assay. All PCR reactions were carried out in an iQ5 Real-time PCR system (Bio-Rad, Hercules, CA). Results: Specific CGI DNA methylation of HOXA7, HOXA6 and PCDHGA12A was detected in all lung cancer cell lines except NCI-H1299 in HOXA7. Only NCI-H460 was positive for EGFR L858R mutation. Among patient blood samples, HOXA7 methylation was detectable in 9 out of 105 patient mononuclear cell DNAs, but neither in patient plasma nor in non-cancer patients or normal blood control DNAs. EGFR L858R mutation was detected in only 4 lung cancer patient DNA samples. The sensitivity of HOXA7 DNA methylation assay, determined by serial dilutions of cancer cell DNA into normal DNA, was 0.1%. Conclusion: A combined epigenetic DNA methylation and genetic mutation panel could be utilized for lung cancer detection or verification in patient blood sample.
Citation Format: Michael X. Wang, Dan Guo, Mary Andersen, Vamsi Guntur. A combined epigenetic and genetic biomarker panel for detection of lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-89. doi:10.1158/1538-7445.AM2013-LB-89