bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3232: Oligonucleotide-selective sequencing (OS-Seq): a rapid and efficient targeting technology for ultra-deep detection of cancer mutations and rearrangements.
Authors: Hopmans Erik S. , Natsoulis Georges , Buenrostro Jason , Grimes Sue , Bell John , Ji Hanlee P. 
Published: August 2014

Abstract
Somatic mutations, chromosomal rearrangements and other genomic aberrations in cancer genomes are critical events in the development of cancer and increasingly used in identifying oncogenic events that may be indicators for targeted therapies. For rapid and high accuracy analysis of targeted candidate genes and regions from cancer genomes, we developed OS-Seq that can be used to simultaneously discover cancer point mutations, copy number variants and rearrangements. For this new sequencing technology, we re-engineer the immobilized oligonucleotide primer lawn on a solid phase support (e.g. Illumina flow cell) with capture “primer-probes” such that it functions for both genomic target capture and sequencing (Myllykangas et al. 2011, Nature Biotech). As a result, in a matter of days we can rapidly sequence target regions in cancer genomes. We designed an in-silico exome capture probe set, enabling rapid design of disease-specific targeted capture primer probe sets. Subsequently, we designed assays to cover 313 and 1,400 cancer genes. Using the 313-gene assay targeting 5,000 exons, we can routinely sequence cancer genomes with on-target coverage greater than 500X, including for the entire length of exons as large as 1 Mb regions. Using a smaller gene set we have established coverage depths over 8,000 that enables the investigation of tumor evolution via mutations with low allelic fractions. In addition, we have designed OS-Seq assays for characterizing loci that are involved in rearrangements. We design capture probes positioned on opposing strands upstream and downstream of suspected rearrangement breakpoints and by localized assembly were able to confirm certain rearrangements, including a long deletion and inversions. For our current studies, we are using OS-Seq to identify cancer mutations in colorectal adenocarcinoma and determine the extent of genetic heterogeneity prevalent in these tumors. OS-Seq provides high-depth, high quality cancer genome sequence data, opening the door to potential diagnostic analysis of cancer genetic heterogeneity as seen in tumor evolution and cancer rearrangements.
Citation Format: Erik S. Hopmans, Georges Natsoulis, Jason Buenrostro, Sue Grimes, John Bell, Hanlee P. Ji. Oligonucleotide-selective sequencing (OS-Seq): a rapid and efficient targeting technology for ultra-deep detection of cancer mutations and rearrangements. [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 3232. doi:10.1158/1538-7445.AM2013-3232
Abstract 3236: Molecular characterization of lung tumors based on metabolomic profiling.
Authors: Sappington Daniel R. , Helms Scott , Dhakal Ishwori B. , Siegel Eric R. , Bartter Thaddeus , Boysen Gunnar 
Published: August 2014

Abstract
Lung cancer is the leading cause of cancer-related deaths in US. For the majority of patients (70%), the extent of the disease precludes complete surgical resection and treatment relies solely on radiation, chemotherapy or a combination of both. Unfortunately, these treatments improve survival only minimally and are accompanied by considerable adverse side effects. Despite immense research efforts over the last 20 years, the mean survival of lung cancer patients has only increased by 13 days. This relatively poor mean survival is attributed to inadequate therapy selection. Current therapy selection is mainly based on the histopathologic examination of needle biopsies obtained during bronchoscopy. There is growing concern that these classifications and stratification are insufficient to predict treatment response of individual tumors. To complement current histopathological-based tumor classification, we investigated the suitability of metabolomics to improve tumor classification. Therefore, metabolomic profiles were obtained from various lung cancer cell-lines. Data were analyzed for molecular features characteristic for cell-lines derived from adenocarcinoma (AdenoCa) or squamous cell carcinoma (SqCCa). Data analyses revealed 78 features that are capable of clearly separating AdenoCa, SqCCa, and lung fibroblasts from each other. Subsequently, the studies were extended to specimen from 30 lung cancer patients. Similar to the cell-line experiments, metabolomic profiles were obtained and analyzed for characteristic features of patients with AdenoCa, SqCCa, or non-malignant specimen. The analysis of the human specimen revealed 21 unique features that are potentially suitable biomarkers for tumor classification. Our data suggest that metabolomic profiling is a promising approach to classify and distinguish between individual tumor cell-lines and to distinguish patients with AdenoCa from patients with SqCCa.
Citation Format: Daniel R. Sappington, Scott Helms, Ishwori B. Dhakal, Eric R. Siegel, Thaddeus Bartter, Gunnar Boysen. Molecular characterization of lung tumors based on metabolomic profiling. [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 3236. doi:10.1158/1538-7445.AM2013-3236
Abstract 3251: Blockade of HIF-1 with a small molecule inhibitor WP1066 in melanoma.
Authors: Jayakumar Arumugam , Rauvolfova Jana , Bao Hanying , Fokt Izabela , Skora Stanislaw , Heimberger Amy , Priebe Waldemar 
Published: August 2014

Abstract
WP1066 was shown to exert its potent inhibitory activity against several types of human cancer including melanoma in vitro and in vivo via suppression of JAK2/STAT3/STAT5 activation. However, if there is any other additional molecular mechanism(s) by which WP1066 generates its anti-tumor effects remain largely unknown. Here, we report a novel function for WP1066 in inducing the degradation of both HIF-1α and HIF-1β subunits in human melanoma cells. We found constitutive activation of HIF-1α and an increased expression of hexokinase II, a down target of HIF-1α, in normoxia in 6/6 of melanoma cell lines, but not in other tumor types. Both hypoxia and cobalt chloride, a transition metal that mimics hypoxia, further increased HIF-1α protein accumulation in a time-dependent manner in WM35 and SKMEL-1 melanoma cells. WP1066 selectively decreased the constitutive and hypoxia and cobalt chloride induced increase in the level of HIF-1α in a dose-dependent manner with a half-life (T1/2) of ∼13, ∼10, and ∼10 min in WM35 cells. Moreover, WP1066 decreased the T1/2 of HIF-1α following cycloheximide treatment from ∼13 to ∼7 min suggesting that WP1066 induced HIF-1α instability is not mediated via inhibition of its translation. Further, inhibition of HIF-1α protein accumulation by WP1066 was not abolished in the presence of MG132 and proteasome inhibitor I, a potent inhibitor of the 26S proteasome, suggesting that the 26S proteasome-system is not responsible for WP1066-induced HIF-1α instability. Immunoprecipitation, confocal microscopy, and cellular fractionation analyses revealed that WP1066 induced ubiquitinylation, aggregation and degradation of HIF-1α in WM35 cells. Finally, WP1066 directly inhibits activity of rhUSP5 and rUCH-L1. Altogether, our study identified a novel function for WP1066 in inducing HIF-1 instability that may also contribute to the anti-cancer effects of WP1066 in human melanoma.
Citation Format: Arumugam Jayakumar, Jana Rauvolfova, Hanying Bao, Izabela Fokt, Stanislaw Skora, Amy Heimberger, Waldemar Priebe. Blockade of HIF-1 with a small molecule inhibitor WP1066 in melanoma. [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 3251. doi:10.1158/1538-7445.AM2013-3251
Abstract 3253: A novel small-molecule inhibitor of Stat3 induces antitumor cell effects in human glioma and breast cancer cells.
Authors: Yue Peibin , Haftchenary Sina , Gunning Patrick T. , Turkson James 
Published: August 2014

Abstract
Constitutive activation of Stat3, a member of signal transducer and activator of transcription (Stat) family of proteins, occurs with a high frequency in human tumors and contributes to carcinogenesis and tumor progression. Compelling evidence shows aberrant activation of Stat3 constitutes a point of convergence in oncogenic tyrosine kinase signaling, functioning as a master regulator of events crucial for tumorigenesis and malignant progression. We present a series of novel small-molecules that abrogate constitutive activation of Stat3 in human tumors, including glioma and breast cancer. The small-molecule, SH5-07, inhibits in vitro Stat3 DNA-binding activity, with IC50 value of 3.9 μM. Further, treatment with SH5-07 induces dose-dependent inhibition of constitutively-active Stat3 in human glioma U251MG and U373MG and breast cancer MDA-MB-231 cells. Moreover, treatment with low micromolar SH5-07 of U251MG, U373MG, and MDA-MB-231 cells blocks constitutive Stat3 phosphorylation, DNA-binding, and transcriptional activities by as early as 30 minutes. Furthermore, the inhibition of aberrantly-active Stat3 by SH5-07 blocks the anchorage-dependent and independent growth, survival, migration, and invasion in vitro of human glioma and breast cancer cells. Data together indicates SH5-07 is a promising small-molecule Stat3 inhibitor and a suitable drug candidate for clinical development.
Citation Format: Peibin Yue, Sina Haftchenary, Patrick T. Gunning, James Turkson. A novel small-molecule inhibitor of Stat3 induces antitumor cell effects in human glioma and breast cancer cells. [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 3253. doi:10.1158/1538-7445.AM2013-3253
Abstract 3262: Targeting PI3K-coupled MEK/ERK pathway for therapy in pediatric B-cell acute lymphocytic leukemia.
Authors: Wang Xiang , Li Ben-shang , Ding Li-xia , Liang Chris , Ding Jian , Meng Ling-hua 
Published: August 2014

Abstract
Acute lymphoblastic leukemia (ALL) is the most common hematological malignancy diagnosed in children and B cell type is prevalent among pediatric ALL. At present, cytotoxic agents are the major components for chemotherapy against ALL, which are limited by their severe side effects. PI3Kδ was found to be over activated in most B cell type leukemia, and one of its inhibitor CAL-101 (GS-1101) is in active clinical trials for B cell type acute or chronic leukemia with promising outcomes. However, the mechanism of action of PI3Kδ inhibitor against B-ALL needs to be further studied to optimize the therapeutic success. Herein, for the first time we found that blockade of PI3K-coupled MEK/ERK pathway by a novel PI3Kδ selective inhibitor X-370 is essential for its efficacy against B cell acute lymphocytic leukemia. X-370, which was obtained through rational design and screening displayed potent activity against PI3Kδ (IC50=7 nM), while sparing class II/III PI3Ks as well as a panel of protein kinases representative of the human kinome. X-370 selectively blocked constitutively activated and stimuli-induced PI3Kδ signaling among four isoforms of class I PI3Ks. X-370 abrogated both Akt and Erk signaling in human B cell leukemia cells, which is accompanied with induction of cell cycle arrest and apoptosis. Mechanism studies revealed that X-370 obstructed PDK1 from binding to and/ or phosphorylating MEK in a PI3Kδ-dependent manner. Accordingly, forced expression of constitutively activated MEK attenuated the antiproliferative activity of X-370. Furthermore, X-370 preferentially inhibited the survival of primary B-ALL cells containing PI3Kδ-coupled Erk phosphorylation, which were obtained from pediatric B-ALL patients.
In summary, with a novel PI3Kδ selective inhibitor X-370, we found that inhibition of PI3Kδ led to abrogation of ERK signaling via an atypical PI3K/ PDK1/ MEK/ Erk signaling cascade. Inhibition of PI3Kδ-coupled Erk by a PI3Kδ inhibitor may predict its efficacy against B cell acute lymphocytic leukemia. These findings support the rationale for clinical testing of PI3Kδ inhibitor for the treatment of pediatric B-ALL and provide insight to optimize therapeutic strategy for such treatment.
Citation Format: Xiang Wang, Ben-shang Li, Li-xia Ding, Chris Liang, Jian Ding, Ling-hua Meng. Targeting PI3K-coupled MEK/ERK pathway for therapy in pediatric B-cell acute lymphocytic leukemia. [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 3262. doi:10.1158/1538-7445.AM2013-3262
Abstract 3294: Apoptotic effect of thymus extract plus Lactobacillus kefiri P-IF on human myeloid leukemia (HL60/AR) cancer cells.
Authors: Ghoneum Mamdooh H. , Henary Mark , Seto Yoshikazu 
Published: August 2014

Abstract
Apoptosis involves a cascade of biochemical events that is tightly regulated. Induction of apoptosis in tumor cells is a promising approach to curing cancer. Therefore, new and safe treatment methods that maximize cancer cells apoptosis are therefore highly sought after. In this study, we examined the effect of gross thymus extract (GTE) combined with freeze dried, heat-killed Lactobacillus kefiri P-IF in the induction of apoptosis in human multidrug-resistant (MDR) myeloid leukemia (HL60/AR) cells in vitro and evaluated the mechanism underlying its effect. L. kefiri P-IF is a specific strain of lactic acid bacteria that has a unique DNA sequence and PET scans show a 99.6% homology with regular kefiris. To identify any synergistic effect of these two products, tumor cells were cultured for three days with 1) GTE at a concentration of 1.25 mg/ml or 2) L.kefiri P-IF at a concentration of 1.25 mg/ml or 3) a combination of both products at the same concentrations. The apoptotic response was assessed by propidium iodide assay and expression of Bcl2, anti-apoptotic protein, was determined by flow cytometry. Results showed that GTE and L.kefiri P-IF induced apoptosis in HL60/AR cells; GTE caused 37% apoptosis while L.kefiri P-IF caused 17% apoptosis, as compared to 7% for control cancer cells without treatment. When cancer cells were cultured in the presence of both GTE and L.kefiri P-IF, 60% apoptosis of cancer cells was detected. This data was confirmed by giemsa stained cytospin preparation. The synergistic apoptotic effect was associated with decreased expression of Bcl2. MFC: 74, 68, 61 and 50 for control untreated cells, GTE, L.kefiri P-IF and GTE + kefiri P-IF respectively. Atomic Force Microscopy studies were performed and showed clear signs of apoptotic cancer cells including membrane blebbing. These results demonstrate that GTE + L.kefiri P-IF induces apoptosis on cancer cells that exceed the effect of either agent alone, and this agent may represent a new class of adjuvants for the treatment of leukemia. GTE (Thymax) was provided by the YS Nature Company, Tokyo, Japan; L.kefiri P-IF was provided by Paitos Co., Ltd. Yokohama, Kanagawa, Japan.
Citation Format: Mamdooh H. Ghoneum, Mark Henary, Yoshikazu Seto. Apoptotic effect of thymus extract plus Lactobacillus kefiri P-IF on human myeloid leukemia (HL60/AR) cancer cells. [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 3294. doi:10.1158/1538-7445.AM2013-3294
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 330A: Differential expression of angiogenic genes in invasive high grade serous ovarian carcinomas.
Authors: Siamakpour- Reihani Sharareh , Jiang Chen , Turner Taylor , Owzar Kouros , Berchuck Andrew , Dewhirst Mark , Alvarez Secord Angeles 
Published: August 2014

Abstract
Our objective is to establish quantifiable and reproducible biomarkers that can aid in prognosis, and predicting treatment outcome in invasive high-grade serous ovarian cancer (HGSC). The goal of this project is to identify genomic determinants that affect the tumor angiogenesis as defined by microvascular density (MVD) count. Our central hypothesis is: differences in angiogenic gene expression profiles are associated with variations in MVD. This is a retrospective pilot study. Under an approved IRB protocol, between 1988 and 2001, sixty five snap frozen invasive serous ovarian cancer tissue samples were gathered at Duke University Medical Center. RNA from those samples were extracted and analyzed by the Affymetrix U133A microarray. Fifty-one of those samples belonged to patients with HGSC. MVD counts were determined for those samples using CD31 and CD105. CD31 and 105 are markers of proliferating endothelial cells and neoangiogenesis. Approximately 285 probe sets (associated with 148 genes) involved in angiogenesis and vasculogenesis were screened. Association between the gene expression levels and MVD counts based on a continuous variable and overall survival of the patients were evaluated. Our results indicate that: i) median CD105-MVD and CD31-MVD counts were 30 and 33, respectively; ii) there was a marginal association between CD105-MVD and overall survival (p-value =0.045) and CD31-MVD and overall survival (OS) (p-value =0.028); iii) CUL7, a member of CULLIN family of ubiquitin ligases, is associated with overall survival of the HGSC patients. Higher expression levels of CUL7 is related to worsening of OS (p-value= 8.17E−05); iv) a stronger association between CD105-MVD count and CUL7 expression (p-value= 0.001), compared to the association between CD31-MVD count and CUL7 expression (p-value= 0.024). In conclusion: CUL 7 has previously been implicated as an antiapoptotic oncogene and a P53 suppressor. Mutations in CUL7 have been linked to abnormal vasculogenesis. CUL2, another member of CULLIN family of ubiquitin ligases has also been implicated in the activity of Hypoxia-Inducible Factor (HIFα) and vasculogenesis. In this study we report that higher expression of CUL7 is significantly associated with worsening of the OS of patients with HGSC. These are considered preliminary results which need to be further verified and validated in an independent data set in future studies.
Citation Format: Sharareh Siamakpour- Reihani, Chen Jiang, Taylor Turner, Kouros Owzar, Andrew Berchuck, Mark Dewhirst, Angeles Alvarez Secord. Differential expression of angiogenic genes in invasive high grade serous ovarian carcinomas. [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 330A. doi:10.1158/1538-7445.AM2013-330A
Abstract 3342: Characterization and targeting of BRIT1 deficiency in liver cancer.
Authors: Liang Yulong , Yu Lihou , Zhang Dongxiao , Gao Hong , Lin Shiaw-Yih , Li Kaiyi 
Published: August 2014

Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide, and there are no safe and effective therapeutic agents yet to treat HCC after diagnosis. However, in HCC, genomic instability is the major remarkable hallmark, especially in the tumors at the late stage and metastatic tumors.
Thus, we wonder if targeting genomic instability can inhibit tumor growth in
HCC. BRIT1/MCPH1 has been identified to be one of the key DNA damage and repair proteins, which harbors three BRCT domains, conserved in BRCA1 and some other proteins involved in DNA damage response pathways. Our previous studies and other reports have illustrated
BRIT1’s essential roles in mitotic and meiotic homologous recombination DNA repair and maintaining genomic stability, which functions through interacting with BRCA2/Rad51 and/or chromatin structure remodeling protein SWI/SNF. Recently, we identified that BRIT1 is aberrantly expressed in ∼25% of HCC samples (n=28).
In these samples, the locus of BRIT2 gene showed notable loss of heterogeneity (nearly
50%). We also found a somatic mutation in BRIT1, which occurred in the splicing donor site of intro 10 in the BRIT1 gene, leading to a truncated protein.
Functional analysis showed that this mutation can cause failure of foci formation of BRIT1 under irradiation. Importantly, given that BRIT1-deficient cells exhibited defective DNA repair described above, our in vitro studies showed that the BRIT1-low expressing HCC cells HepG2 and Hep3B are more sensitive to olaparib, the inhibitor of poly(ADP-ribose) polymerase (PARPi), compared to the BRIT1-proficient cell SNU-449, which was determined by WST-1 and colony formation assays.
Furthermore, we also test the inhibitory effect of olaparib in the xenograft mouse model, and found that PARPi can significantly suppress tumor growth of Hep3B xenografts. Collectively, our results clearly demonstrate that
BRIT1 is mutated or aberrantly expressed in HCC, and targeting BRIT1 deficiency by PARP inhibitors may lead to novel and effective targeted therapies to treat BRIT1-deficient
HCC.
Citation Format: Yulong Liang, Lihou Yu, Dongxiao Zhang, Hong Gao, Shiaw-Yih Lin, Kaiyi Li. Characterization and targeting of BRIT1 deficiency in liver 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 3342. doi:10.1158/1538-7445.AM2013-3342
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.