bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4264: PI3K/Akt/mTOR signaling modulation in solar UV-induced skin carcinogenesis.
Authors: Bermudez Yira , Stratton Steve P. , Curiel-Lewandrowski Clara , Hu Chengcheng , Bowden George T. , Saboda Kathylynn , Alberts David S. , Einspahr Janine G. 
Published: August 2014

Abstract
Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most common types of cancers. Since most BCC and SCC develop on sun-exposed areas of the body, chronic sun exposure is considered the main etiologic factor of these tumors. In vitro and in vivo studies have identified PI3K/Akt/mTOR signaling pathway as a solar light-activated pathway. However, little work has been done on studying the expression profiles of this pathway in humans. In the study herein, we evaluate the modulation of solar light-activated PI3K/Akt/mTOR signaling pathway in normal human skin and solar simulated light (SSL)-irradiated human skin to determine the expression profiles of upstream and downstream phosphorylated proteins Akt (Ser473), mTOR (Ser2448), S6 ribosomal protein (Ser235/236), and 4E-BP1 (Thr37/46). The study population consisted of individuals 18 years or older in general good health with skin types II-III. SSL irradiation at 2, 2.5, and 3 times minimal erythema dose (MED) were applied to unexposed skin. Punch biopsies were taken at baseline, 5 minutes, 1 h, 5 h, and 24 h post-irradiation and immediately fixed in 10% formalin. Tissues were evaluated by immunohistochemistry for the expression of phosphorylated proteins. Proliferating cell nuclear antigen (PCNA) and cleaved caspase 3 (Asp175) were evaluated as markers for keratinocyte proliferation and apoptosis, respectively. Induction of phosphorylated Akt was seen at 5 hours with a 2-fold increase in expression when compared to baseline. Expression of phosphorylated mTOR gradually increased with a peak at 24 hours (3-fold). Significant induction of phosphorylated S6 ribosomal protein was seen at 1 h (3-fold), 5 h (7-fold), and 24 h (10-fold) post SSL irradiation. Induction of phosphorylated 4E-BP1 was limited to the 24 h time point with an increase of 2-fold when compared to baseline. Our data corroborate in vitro and in vivo studies finding, which allow for better understanding of the expression profile patterns of phosphorylated proteins in the PI-3 kinase/Akt/mTOR pathway during exposure of physiological relevant solar-simulated light. Identification of key proteins in this pathway could lead to the use of these proteins as biomarkers and/or specific targets for the prevention and control of skin tumors.
Citation Format: Yira Bermudez, Steve P. Stratton, Clara Curiel-Lewandrowski, Chengcheng Hu, George T. Bowden, Kathylynn Saboda, David S. Alberts, Janine G. Einspahr. PI3K/Akt/mTOR signaling modulation in solar UV-induced skin carcinogenesis. [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 4264. doi:10.1158/1538-7445.AM2013-4264
Abstract 4290: c-Myc and Ras differentially regulate mitochondrial apoptotic priming and chemosensitivity.
Authors: Sarosiek Kristopher A. , Ni Chonghaile Triona , Karst Alison , Patel Luv , Drapkin Ronny , Letai Anthony 
Published: August 2014

Abstract
Successful treatment of most human cancers is dependent on tumor cell sensitivity to chemotherapy yet the basis for chemosensitivity is poorly understood. We have previously shown that a cancer's proximity to the apoptotic threshold, a property we call "apoptotic priming," governs its chemosensitivity in patients with multiple myeloma, ALL, AML and ovarian cancer. The genetic and molecular events that underlie the differential priming in tumors, however, are currently unknown. Utilizing in vitro ovarian, kidney and lung tumorigenesis models we find that oncogenes are powerful modulators of apoptotic priming and are consequently responsible for differential chemosensitivity. For example, forced expression of the c-Myc oncogene increases priming and chemosensitivity of immortalized normal epithelium. In contrast, Ras activation in isogenic cells dramatically decreases both priming and chemosensitivity. Our in vitro findings are validated by clinical observations. Apoptotic priming, an important determinant of patient outcomes, is modulated in contrasting manners by oncogenes.
Citation Format: Kristopher A. Sarosiek, Triona Ni Chonghaile, Alison Karst, Luv Patel, Ronny Drapkin, Anthony Letai. c-Myc and Ras differentially regulate mitochondrial apoptotic priming and chemosensitivity. [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 4290. doi:10.1158/1538-7445.AM2013-4290
Abstract 43: Detection of bladder cancer-associated gene methylation using next-gen bisulfite sequencing.
Authors: Dunn Andrew R. , Li Shuqiang , Fernandez Cecilia A. , Shuber Anthony P. 
Published: August 2014

Abstract
DNA methylation profiling of bladder cancer specific gene promoters has been shown to be a sensitive and specific diagnostic tool for early- and late-stage bladder cancer. We have recently shown that a urine-based assay that combines DNA and protein biomarkers can accurately triage patients undergoing evaluation for bladder cancer. As part of this assay, hypermethylation of Twist1 and Nid2 is performed by conventional methylation-specific PCR (cMSP). To increase throughput and lower cost, we have now developed an approach to determine the methylation at single-base resolution of CpG sites using next generation bisulfite sequencing. In addition to Twist1 and Nid2, methylation of the Vimentin promoter, which has been shown to be associated with epithelial to mesenchymal transition (EMT) in bladder cancer, was also evaluated using this technique. To determine the sensitivity of this approach, amplification was performed on control bisulfite converted genomic DNA that was either enzymatically methylated or chemically unmethylated at CpG sites using non-methylation specific PCR. Twist1, Nid2 and Vimentin PCR products were subsequently used as template for emulsion PCR and sequenced using the Ion Torrent PGM. Methylation status was determined by aligning sequencing reads to unmethylated reference sequences. In this assay, 0.4% methylated DNA could be reliably detected in 10 ng of bisulfite converted DNA, more than doubling the sensitivity of the current assay as well as potentially generating a single-base resolution mapping of additional CpG sites not yet quantified for Twist1, Nid2 and Vimentin. The clinical performance of the Next-Gen bisulfite sequencing assays for Twist1, Nid2 and Vimentin is currently being tested using urine samples from patients with bladder cancer as well as from age matched individuals who present with hematuria but who are found to be cancer-free. The technique we have developed could be used to detect other hypermethylated genes in a variety of bodily fluids where percent methylation may be much lower than in tumor tissue samples.
Citation Format: Andrew R. Dunn, Shuqiang Li, Cecilia A. Fernandez, Anthony P. Shuber. Detection of bladder cancer-associated gene methylation using next-gen bisulfite sequencing. [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 43. doi:10.1158/1538-7445.AM2013-43
Abstract 4306: NAD(P)H:quinone oxidoreductase 1 (NQO1) regulates MAPK activation and cellular protection against chemical stress.
Authors: Patrick Brad A. , Jaiswal Anil K. 
Published: August 2014

Abstract
NAD(P)H: quinone oxidoreductase (NQO1) is a cytosolic redox-regulating enzyme modulated by Nrf2-mediated stress signaling pathways, with an established role in regulation of stress-related transcription factors. In these studies we investigate the role of NQO1 in regulation of mitogen-activated protein kinase (MAPK) signaling pathways. Quantitative PCR and western blot studies showed that constitutive levels of several MAPK members are upregulated in NQO1-null mouse skin as well as in skin-derived keratinocytes, relative to WT. However, though total protein levels are increased, inducibility of these kinases by known MAPK inducers such as EGF and benzo[a]pyrene (BP) is significantly decreased in NQO1-null cells. NQO1 regulation of MAPK signaling was confirmed by studies showing that NQO1 knockdown by siRNA led to decreased MAPK activation, and overexpression of NQO1 protein led to increased MAPK activation by EGF. Similarly, downregulation of activity via dicoumarol caused loss of ERK phosphorylation, while NQO1 activation via t-BHQ caused increased ERK phosphorylation, which was blocked by MAPK pathway-specific inhibitors. To investigate the functional role of MAPK deactivation in skin-derived keratinocytes, studies with BP and menadione showed that lack of NQO1 expression led to increased susceptibility to ROS generation, and that this ROS generation causes increased toxicity. Taken together, these results show a significant role for NQO1 in regulation of MAPK signaling pathways, which ultimately lead to protection against ROS-mediated apoptosis.
Citation Format: Brad A. Patrick, Anil K. Jaiswal. NAD(P)H:quinone oxidoreductase 1 (NQO1) regulates MAPK activation and cellular protection against chemical stress. [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 4306. doi:10.1158/1538-7445.AM2013-4306
Abstract 4315: Extracellular signal regulated kinase 5 inpathogenesis of malignant mesothelioma.
Authors: Shukla Arti , Miller Jill , Cason Christopher , Sayan Mutlay , MacPherson Maximilian , Beuschel Stacie , Mossman Brooke 
Published: August 2014

Abstract
Malignant mesothelioma (MM) is a neoplastic disease of the pleural, peritoneal or pericardial cavity. Currently, there is no therapy for MM as it is resistant to most of the common chemotherapies and therefore, there is a need for new treatment strategies. In the present study we demonstrated that ERK5 is important in MM tumor growth and can potentially be targeted in combination with the chemotherapeutic drugs for more effective treatment. Human MM cell lines exhibit constitutive activation of ERK5.
Addition of doxorubicin to these MM cell lines resulted in further activation of ERK5. ERK5 silencing by small hairpin RNA (shERK5) increased DOX-induced cell death and DOX retention in human MM cells. In addition, shERK5 MM lines exhibited both attenuated colony formation on soft agar and invasion of MM cells in vitro. Most importantly, injection of shERK5 MM cell lines into SCID mice showed significant reduction in tumor growth using both subcutaneous and intraperitoneal models. Finally, use of doxorubicin and cisplatin in combination with ERK5 inhibition showed further reduction in tumor weight and volume in the IP model of tumor growth, proving our hypothesis that ERK5 inhibition in combination with chemotherapeutic drugs is a beneficial strategy for combination therapy in MM patients. This work is supported by Mesothelioma
Applied Research Foundation (AS), NIEHS-RO1ES021110 (AS) and T32 ES07122 (BM) grants.
Citation Format: Arti Shukla, Jill Miller, Christopher Cason, Mutlay Sayan, Maximilian MacPherson, Stacie Beuschel, Brooke Mossman. Extracellular signal regulated kinase 5 inpathogenesis of malignant mesothelioma. [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 4315. doi:10.1158/1538-7445.AM2013-4315
Abstract 4328: Phenotypic selection for identification of functional antibodies and development of high throughput screening assays.
Authors: Hay Carl , Rust Steven , Sult Erin , Clarke Lori , Rosenthal Kim , Guillard Sandrine , Lowne David , Flynn Matt , Jermutus Lutz , Minter Ralph , Hollingsworth Robert , Sachsenmeier Kris 
Published: August 2014

Abstract
Discovery of therapeutic antibodies requires the continued identification of tractable targets, and we have employed a phenotypic screening strategy to this end. In this study, antibodies from phage display libraries were screened for their abilities to inhibit MDA-MB-231 (‘triple negative’) breast cancer cells. The screening cascade included tests for specific cell binding, antibody internalization, and cytotoxicity as an antibody-drug conjugate. Targets of these antibodies then were identified using immunoprecipitation and mass spectrometry, and confirmed by showing diminished antibody binding after siRNA-mediated knockdown of the putative target gene. One target was identified as NT5E (also known as CD73), a 5’-ectonucleotidase. NT5E catalyzes the conversion of adenosine monophosphate to adenosine, and its function has been linked with immunity, angiogenesis, and cancer. To screen for additional inhibitors of this target, a novel, high-throughput ectonucleotidase assay was developed. NT5E activity is typically assayed either by high performance liquid chromatography or by quantification of free phosphate using malachite green, and neither of these methods is suitable for high-throughput screening. One inhibitory antibody was found to significantly slow growth of MDA-MB-231 xenograft tumors in mice. In summary, our phenotypic screening approach provides a mechanism for rapidly discovering and evaluating new antibody targets and is being used to accelerate the discovery of new cancer drugs.
Citation Format: Carl Hay, Steven Rust, Erin Sult, Lori Clarke, Kim Rosenthal, Sandrine Guillard, David Lowne, Matt Flynn, Lutz Jermutus, Ralph Minter, Robert Hollingsworth, Kris Sachsenmeier. Phenotypic selection for identification of functional antibodies and development of high throughput screening assays. [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 4328. doi:10.1158/1538-7445.AM2013-4328
Abstract 4329: Novel HER2 targeting antibody-drug conjugates based on DNA-interacting duocarmycin and an unique linker technology with great potential in breast cancer and NSCLC.
Authors: Dokter Wim , Beusker Patrick , Verheijden Gijs , Ubink Ruud , van der Lee Miranda , van den Dobbelsteen Diels , Goedings Peter , Lemmens Jacques , de Groot Vincent , Timmers Marco 
Published: August 2014

Abstract
We have generated cleavable linker-duocarmycin payloads that previously have been shown to be highly stable in human plasma and to cause excellent in vitro and in vivo efficacy when conjugated to antibodies directed against multiple targets in different models. In our HER2 program, we have used these linker-duocarmycin payloads to generate HER2-targeting antibody-drug conjugates (ADCS) and prepare these for FIM studies. HER2 is a validated target in breast (BC) and gastric cancer (GC) that is currently used to target trastuzumab towards HER2-positive BC and GC tumors. We have generated a set of cysteine-coupled ADCs using newly developed duocarmycins conjugated to a therapeutic HER2/neu antibody. In vitro studies with the anti-Her2 ADCs showed that compared to the naked Ab, the ADCs tested have gained a more than 100-fold potency and more than two-fold efficacy in cell killing capacity. Studies in HER2 positive and negative cell lines indicated that cytotoxicity was HER2- mediated. HER2 binding and ADCC activity was not affected by conjugation. Single dose and multiple dose xenograft studies in mice using a human HER2-positive breast cancer cell line showed dose-dependent anti-tumor activity of the ADCs in vivo. Patient-derived xenografts (PDx) using primary tumors from HER2-positive breast cancer and NSCLC patients demonstrated the ability of the ADC to induce complete remission of tumors that remained unresponsive to the naked Ab trastuzumab. Also taken into account toxicology studies in rodents and cynomolgous monkeys, we conclude that we have generated a new class of HER2-based ADCs that have great potential to become effective treatment for HER2-positive tumors, including breast cancer and NSCLC. From a series of compounds, a preclinical candidate was selected that is currently being prepared for Phase I clinical trials that will start in 2014.
Citation Format: Wim Dokter, Patrick Beusker, Gijs Verheijden, Ruud Ubink, Miranda van der Lee, Diels van den Dobbelsteen, Peter Goedings, Jacques Lemmens, Vincent de Groot, Marco Timmers. Novel HER2 targeting antibody-drug conjugates based on DNA-interacting duocarmycin and an unique linker technology with great potential in breast cancer and NSCLC. [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 4329. doi:10.1158/1538-7445.AM2013-4329
Abstract 433: mTOR overexpression is associated with radio-resistance and worse prognosis of cervical cancer.
Authors: Nishimura Masato , Yoshida Kanako , Furumoto Hiroyuki , Irahara Minoru 
Published: August 2014

Abstract
mTOR is an important factor for cell proliferation. It is reported that overexpression of mTOR is associated with poor prognosis in many cancers. We examined mTOR expression in cervical cancer and association with clinico-pathological findings. 34 patients were examined about mTOR expression by immuno-histochemistry. The result was classified into 3 categories, i.e negative, weak positive and strong positive. 25 patients were treated with concurrent chemoradiotherapy, 8 ptients were treated with hysterectomy and one patient was treated with chemotherapy as main treatment. Overexpression of mTOR was recognized in 24(71%) patients. The frequency of parametrial invasion and lymphnode metastasis in mTOR positive and negative were 17/24 (71%) versus 3/10 (30%) (p=0.027) and 14/24 (58%) versus 2/10 (20%) (p=0.041). In 25 cases treated with radiotherapy, mTOR overexpression was seen in 19 cases (76%). Averages of tumor diameter in mTOR positive and negative cases were 4.8 cm and 5.0cm respectively (n.s). In 5 local recurrent cases treated with chemo-radiotherpy, tumor diameters of pre-treatment were 0, 3.5, 5.5, 7 and 7cm. Small tumor was included in local recurrence in mTOR positive cases. It is suggested that mTOR overexpression promotes lymphnode and parametrial metastasis and is associated with radio-resistance. In case of mTOR overexpression, we need to consider treatment by hysterectomy if the tumor is resectable or usage of mTOR inhibitor at chemo-radiation, and control of mTOR expression is important in treatment of cervical cancer.
Citation Format: Masato Nishimura, Kanako Yoshida, Hiroyuki Furumoto, Minoru Irahara. mTOR overexpression is associated with radio-resistance and worse prognosis of cervical 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 433. doi:10.1158/1538-7445.AM2013-433
Abstract 4337: Selection of DNA aptamers for an ovarian cancer cell line using high-throughput sequencing.
Authors: Whelan Rebecca J. , Kapur Arvinder , Felder Mildred , Nie Jeff , Patankar Manish S. 
Published: August 2014

Abstract
The mucin, MUC16, facilitates metastasis and immuneprotection of ovarian tumors. Therefore, agents that effectively target MUC16 expressing ovarian cancer cells will be useful for diagnostic and therapeutic applications. Here, we have utilized the Cell-based Systematic Evolution of Ligands by Exponential Enrichment (cell-SELEX) approach to generate high affinity single-stranded DNA (ssDNA) aptamers as agents for detection and treatment of MUC16-positive ovarian tumors. An ssDNA aptamer library composed of ∼100 trillion sequences was subjected to ten iterative rounds of negative and positive selection using the MUC16-knockdown and MUC16-positive ovarian cancer cell line, OVCAR-3. Aptamers from each round were amplified by asymmetric PCR and subjected to high throughput NextGen sequencing. Eight ssDNA aptamers enriched through the selection process were identified by bioinformatics analysis and their selectivity and affinity for MUC16-positive cells was determined by flow cytometry. Two of these aptamers (Apt-1 and Apt-8) showed significant binding to the MUC16-positive OVCAR-3 with a Kd of 24 and 28 nM, respectively. In contrast, Apt-1 and Apt-8 only weakly recognized the MUC16-knockdown OVCAR-3 cells. M-Fold analysis indicated that Apt-1 and Apt-8 had defined secondary structures resulting from ordered base pairing of the ssDNA. The inclusion of NextGen sequencing techniques has therefore allowed rapid identification of theranostic aptamers from an exhaustive library of ssDNA sequences. This study provides a streamlined method for development of theranostic aptamers that can be used to recognize and target MUC16 expressing ovarian cancer cells.
Citation Format: Rebecca J. Whelan, Arvinder Kapur, Mildred Felder, Jeff Nie, Manish S. Patankar. Selection of DNA aptamers for an ovarian cancer cell line using high-throughput sequencing. [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 4337. doi:10.1158/1538-7445.AM2013-4337
Abstract 4350: Low frequencies of SF3B1 mutations indicate SF3B1 inhibitor as a novel moleculartargeted drug for colorectal cancer.
Authors: Yamano Tomoki , Nakajima Hidenori , Tsuda Satoshi , Kubo Shuji , Hamanaka Mie , Kobayashi Masayoshi , Yamagishi Daisuke , Kuno Takashi , Tsukamoto Kiyoshi , Tamamoto Astuko , Noda Masafumi , Matsubara Nagahide , Hoon Dave SB , Tomita Naohiro 
Published: August 2014

Abstract
Purpose: FR901464 (FR) is an antitumor agent that specifically binds to and inhibits the function of splicing factor 3B subunit 1 (SF3B1). Higher frequencies of SF3B1 gene mutations and their relevance to cancer progression have been shown in studies of hematological malignancies.
We assessed the frequencies of SF3B1 gene mutations in colorectal cancer (CRC) and the correlation of SF3B1 mutations and FR sensitivity in CRC.
Experimental Design: We measured FR sensitivity in CRC cell lines to establish FR-resistant clones and performed DNA sequencing of all
25 SF3B1 exons in nine CRC cell lines, FR-resistant clones, and 16 CRC patients.
On the basis our results, we performed further DNA sequencing in 80 CRC patients.
Results: The FR IC50 values in all CRC cell lines were &lt; 1ng/ml. Six FR-resistant clones were established: three from DLD1, two from HCT116, and one from LoVo cells. The FR IC50 of the FR-resistant clones was &gt; 500-fold greater than that of their parental cells, although the IC50 of oxaliplatin or 5-fuluorouracil were the same. We found nonsense mutations in exon 10 of DLD1 cells and no significant mutations in the other samples. All the FR-resistant clones had the missense mutations in codon 1073 of exon 22. We found no mutation in exons 10, 22, and 12-15, which were previously reported in hematological malignancies in 80 CRC patients.
Conclusion: Our data indicated the usefulness of the SF3B1 inhibitor as a novel molecular targeted drug for CRC and the other malignancies without codon 1073 mutations.
Citation Format: Tomoki Yamano, Hidenori Nakajima, Satoshi Tsuda, Shuji Kubo, Mie Hamanaka, Masayoshi Kobayashi, Daisuke Yamagishi, Takashi Kuno, Kiyoshi Tsukamoto, Astuko Tamamoto, Masafumi Noda, Nagahide Matsubara, Dave SB Hoon, Naohiro Tomita. Low frequencies of SF3B1 mutations indicate SF3B1 inhibitor as a novel moleculartargeted drug for colorectal 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 4350. doi:10.1158/1538-7445.AM2013-4350