bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 523: Decrease of ARNT promotes cancer metastasis by activating the fibronectin/integrin β1/FAK axis
Authors: Huang Chi-Ruei , Lee Chung-Ta , Chang Kwang-Yu , Chang Wen-Chang , Chen Ben-Kuen 
Published: August 2015

Abstract
The aryl hydrocarbon receptor nuclear translocator (ARNT) is widely involved in regulating the tumorigenesis process by inducing genes that are involved in tumor growth and angiogenesis. Tumorigenesis usually involves normoxic conditions. However, the role of ARNT in tumor metastasis during normoxia remains unclear. Here, we demonstrated that ARNT protein levels were decreased in late stage human colorectal cancer using an immunohistochemical analysis. Stably silence of the ARNT protein promoted cancer cell migration and invasion, which was mediated by the activation of the fibronectin/integrin β1/FAK signaling axis. In addition, ARNT knockdown-induced migration and invasion was inhibited when ARNT was restored in cells. In a xenograft analysis of severe combined immunodeficiency mice, ARNT-knockdown inhibited tumor growth. However, when ARNT expression recovered, the tumor growth of ARNT-knockdown-induced metastatic lung colonies was significantly enhanced. Interestingly, chemotherapeutic drugs inhibited ARNT expression and promoted invasion of residual tumor cells. These results suggested that ARNT may play a positive role during tumor growth (either in early stage tumor growth or in metastatic organs), but plays a negative role in tumor migration and invasion. Therefore, the efficiency of ARNT-targeted therapy in different cancer stages should be carefully evaluated.
Citation Format: Chi-Ruei Huang, Chung-Ta Lee, Kwang-Yu Chang, Wen-Chang Chang, Ben-Kuen Chen. Decrease of ARNT promotes cancer metastasis by activating the fibronectin/integrin β1/FAK axis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 523. doi:10.1158/1538-7445.AM2015-523
Abstract 5241: Clinical relevance of circulating tumor DNA in plasma from pancreatic cancer patients
Authors: Tjensvoll Kjersti , Lapin Morten , Buhl Tove , Oltedal Satu , Berry Katrine Steen-Ottosen , Gilje Bjørnar , Søreide Jon Arne , Javle Millind , Nordgård Oddmund , Smaaland Rune 
Published: August 2015

Abstract
Background: Circulating tumor DNA (ctDNA) may originate from necrotic or apoptotic tumor cells in the primary tumor, metastatic lesions or in the circulation. There is evidence that the ctDNA level may reflect the total tumor burden in a patient. We wanted to investigate whether changes in the ctDNA level might be used to monitor disease progression in pancreatic cancer patients with locally or advanced disease. Methods: Blood samples (9 mL in EDTA tubes) were collected from 15 prospectively recruited patients with locally advanced and/or metastatic pancreatic cancer before initiation of treatment, and subsequently every month during chemotherapy. The samples were processed by LymphoprepTM (Axis Shield) density centrifugation before plasma DNA isolation using the QIAamp Circulating Nucleic Acid kit (Qiagen). A high-fidelity polymerase-based PNA clamp PCR method (Gilje et al., 2008, Oltedal et al., 2010) was then used for the detection of KRAS mutations in exon 12 and 13, as a surrogate marker for ctDNA. KRAS mutations have previously been reported to be present in &gt;90% of the pancreatic cancers. Plasma samples from 29 healthy individuals were also analysed as a reference group for the PNA clamp PCR method. The results were compared with conventional biochemical and radiological monitoring measures. Results: The majority of the patients (80%) had metastatic disease and they were treated either by gemcitabine or FOLFORINOX. Nine (60%) patients had a positive KRAS status in the plasma samples obtained before initiation of chemotherapy, indicating presence of ctDNA. Moreover, 11 of the 15 included patients had ≥2 follow-up samples, and in several of these patients the ctDNA level changed substantially during the course of chemotherapy. In total, 17/38 (44.7%) patient samples were positive for plasma DNA KRAS mutations during chemotherapy. Changes in the ctDNA level seemed to correspond both to radiological follow-up data and changes in CA19-9 for several patients. Analyses of the total plasma DNA fraction with regard to disease monitoring, gave more inconclusive results in this small pilot study. Conclusion: Our pilot study gives support to the hypothesis that ctDNA may be used as a marker for monitoring treatment efficacy and disease progression in pancreatic cancer patients. This will be further investigated.
Citation Format: Kjersti Tjensvoll, Morten Lapin, Tove Buhl, Satu Oltedal, Katrine Steen-Ottosen Berry, Bjørnar Gilje, Jon Arne Søreide, Millind Javle, Oddmund Nordgård, Rune Smaaland. Clinical relevance of circulating tumor DNA in plasma from pancreatic cancer patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5241. doi:10.1158/1538-7445.AM2015-5241
Abstract 5257: Immunohistochemical analysis and comprehensive hormone receptor profiling of uterine adenosarcomas at a single institution
Authors: Zechmeister Jenna R. , Huang Gloria S. , Karabakhtsian Rouzan , Schwartz Melissa , Prossnitz Eric R. , Goldberg Gary L. , Klobocista Merieme 
Published: August 2015

Abstract
Uterine adenosarcomas (AS) are rare uterine tumors with benign epithelium and a sarcomatous component which is typically low-grade. Those displaying sarcomatous overgrowth (AS+SO) behave in a more aggressive fashion and are associated with worse clinical outcomes. Immunohistochemistry performed on AS and AS+SO have shown a greater preponderance for estrogen receptor alpha (ERα) and progesterone receptor (PR) positivity in those with a low-grade sarcomatous component. Further studies showed an increased proliferative index (Ki-67) in AS+SO and confirmed loss of expression in ER/PR in addition to loss of CD10. Expression of estrogen receptor beta (ERβ), a classic estrogen receptor as well as G protein-coupled estrogen receptor (GPER), a receptor that interacts with estrogen independently of the classic receptors, has been reported in uterine carcinosarcomas and they are associated with advanced stage disease. We conducted this study to analyze the receptor status of ERβ and GPER in cases of uterine AS. An H-score was calculated as the product of intensity and the percentage of cells staining positive (0-100%), higher scores indicate increased intensity and a greater number of positive cells. Unpaired t-test was used to compare the mean H-scores of receptor expression between low-grade AS (LG-AS) and high-grade AS (HG-AS). Mean age of diagnosis was 59.4 ± 11.9 years, mean BMI of 34.2 ± 8.5, and median disease free survival was 18 months (range 2-113 months). There were 7 cases of LG-AS and 3 cases of HG-AS, 2 cases displayed SO. Seven cases were stage IA, two were IB and one stage IV. There was a significant difference (p = 0.01) between the mean H-score for ERα between LG-AS (203) and HG-AS (1.7), There was also a significant difference (p = 0.04) in mean H-score for PR between LG-AS (188.6) and HG-AS (18.3). ERβ and GPER expression were retained in the HG-AS at similar levels as in the LG-AS, thus there was no difference in mean H-scores. In one patient with HG-AS and recurrent disease after 2 years, the recurrent tumor remained negative for ERα and PR, and showed somewhat decreased ERβ expression. Although the sample size is small, this is the first report of comprehensive estrogen receptor profiling in this uncommon uterine tumor.
Citation Format: Jenna R. Zechmeister, Gloria S. Huang, Rouzan Karabakhtsian, Melissa Schwartz, Eric R. Prossnitz, Gary L. Goldberg, Merieme Klobocista. Immunohistochemical analysis and comprehensive hormone receptor profiling of uterine adenosarcomas at a single institution. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5257. doi:10.1158/1538-7445.AM2015-5257
Abstract 5258: Expression analysis of STEAP1 in breast cancer patients as therapeutic target
Authors: Mudalagiriyappa Chidananda , Pillai Sreeraj , Watson Mark , Aft Rebecca 
Published: August 2015

Abstract
Objective: The six transmembrane epithelial antigen of the prostate (STEAP1) is predominantly overexpressed in human prostate cancer. STEAP1 was first identified as a prostate-specific cell-surface antigen and found to be up-regulated in multiple cancer cell lines and in various cancers, including lung, bladder, colon and ovarian cancers. However no significant expression in normal tissue has been reported suggesting its potential use as a target for anti-STEAP1 immunotherapy. An anti-STEAP1 monoclonal antibody linked to an antimitotic agent is in Phase I clinical trials for prostate cancer patients. Microarray data from our lab suggested that STEAP1 is also highly expressed in human breast cancers. In this study we evaluate expression STEAP1 in primary tumors and the bone marrow from breast cancer patients as a therapeutic target for minimal residual disease.
Experimental procedures: RNA was isolated from primary tumor and non-malignant breast tissue. RNA was also isolated from bone marrow of state II and III breast cancer patients, healthy volunteers and breast cancer cell lines. STEAP1 expression was analyzed by nanostring nCounter and real time qRT-PCR using human specific probes. STEAP1 immunohistochemical (IHC) staining of human tissue was performed using standard IHC Protocol.
Results: STEAP1 mRNA was up-regulated in 77% of tumors (28/36) compared to the corresponding normal tissue. STEAP1 protein was expressed in 100% of tumors (8/8) and was absent in non-malignant breast tissue (7/7) by IHC staining. STEAP1 mRNA was not expressed normal BM, but was detected in 8% (6/74) of BM from patients with early stage breast cancer. Of patients with STEAP1 positive BM, 50% (3/6) had triple negative disease and 66% (4/6) developed recurrent disease (p = .028).
Conclusion: STEAP1 is expressed in human breast tumors and the BM of breast cancer patients. Expression of STEAP1 in the BM is significantly associated with the development of metastatic disease. Our data indicate that STEAP1 could serve as a therapeutic target for the treatment of minimal residual disease in breast cancer.
Citation Format: Chidananda Mudalagiriyappa, Sreeraj Pillai, Mark Watson, Rebecca Aft. Expression analysis of STEAP1 in breast cancer patients as therapeutic target. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5258. doi:10.1158/1538-7445.AM2015-5258
Abstract 5365: Alternating electric fields (TTFields) in combination with paclitaxel are therapeutically effective against ovarian cancer cells in vitro and in vivo
Authors: Munster Mijal , Roberts Christopher P. , Schmelz Eva M. , Giladi Moshe , Blat Roni , Schneiderman Rosa S. , Porat Yaara , Bomzon Zeev , Urman Noa , Itzhaki Aviran , Voloshin Sela Tali , Cahal Shay , Kirson Eilon D. , Weinberg Uri , Palti Yoram 
Published: August 2015

Abstract
Tumor Treating Fields (TTFields) are low intensity intermediate frequency alternating electric fields that disrupt mitosis. Our previous in vitro studies suggest that ovarian cancer cells are highly sensitive to TTFields treatment.
The goal of the present study was to evaluate the efficacy of the combined treatment of TTFields and paclitaxel against ovarian cancer cells in vitro and in vivo.
For in vitro studies, TTFields (1.75 V/cm) were applied for 72 hours using the inovitro system. The in vivo efficacy of the combined treatment was tested in C57Bl/6 mice, orthotopically injected with MOSE-L FFL luciferase positive cells. Finite Element Mesh (FEM) simulations were performed using the Sim4life software package (ZMT, Zurich, Switzerland) for the calculations of the electric fields intensities around the ovaries.
Our results demonstrate that in vitro application of 200 kHz TTFields led to a significant reduction in both the number of viable cells (44.6%) and the clonogenic potential (23.8%) as compared to untreated cells (p&lt;0.001). Further reduction in the number of viable cells was achieved when TTFields were combined with paclitaxel. In vivo, the combined treatment of TTFields and Paclitaxel led to a significant reduction in tumor luminescence (40%, p&lt;0.01) and in the tumor weight (55%, p&lt;0.05) as compared to untreated tumor bearing mice. FEM simulations demonstrated that electric fields intensities inside and in the vicinity of the ovaries of a real human anatomy model are about 1 and 2 V/cm RMS which is above the minimal threshold required for TTFields response.
Taken together these results demonstrate that the combined treatment of TTFields and paclitaxel could serve as an effective treatment against ovarian cancer. A clinical trial testing the efficacy of the combined modalities is now underway.
Citation Format: Mijal Munster, Christopher P. Roberts, Eva M. Schmelz, Moshe Giladi, Roni Blat, Rosa S. Schneiderman, Yaara Porat, Zeev Bomzon, Noa Urman, Aviran Itzhaki, Tali Voloshin Sela, Shay Cahal, Eilon D. Kirson, Uri Weinberg, Yoram Palti. Alternating electric fields (TTFields) in combination with paclitaxel are therapeutically effective against ovarian cancer cells in vitro and in vivo. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5365. doi:10.1158/1538-7445.AM2015-5365
Abstract 5395: Anti-tumor activity of BMS-595, a novel CK2 kinase inhibitor
Authors: Rupnow Brent A. , Yu Chiang , Pabalan Jonathan G. , Roongta Urvashi V. , Lippy Jonathan S. , Dongre Ashok R. , Obermeier Mary T. , Fura Aberra , Elzinga Paul A. , Henley Benjamin J. , Fargnoli Joseph , Lee Francis Y. , Foster William R. , Tarby Christine M. , Fink Brian E. , Tokarski John S. , Gavai Ashvinikumar V. , Wong Tai W. , Hunt John T. , Vite Gregory D. , Purandare Ashok V. 
Published: August 2015

Abstract
The CK2 protein kinases are a small family of two highly related serine/threonine kinases composed of two catalytic subunits, α and α’, and a single β subunit. Numerous substrates have been reported for CK2 and these proteins are known to participate in diverse cellular processes, including cell signaling, transcription, DNA repair, apoptosis regulation and tumor suppression. Elevated CK2 expression and kinase activity has been observed in many cancer types. Further, mRNA knockdown and enzyme inhibition studies have demonstrated that many cancer cell lines are dependent on CK2 for growth and survival. To further evaluate CK2 kinases as targets for therapeutic intervention in cancer, we identified BMS-595, a potent and selective, ATP-competitive CK2 inhibitor. BMS-595 inhibits the in vitro proliferation of human colorectal and lung cancer cell lines with IC50s ranging from less than 10 nM to greater than 1 μM. In sensitive cell lines, anti-proliferative effects of BMS-595 and structurally related analogs strongly correlated with cellular CK2 kinase inhibition. Oral administration of BMS-595 to mice bearing colorectal cancer and lung cancer xenografts demonstrated pharmacodynamic effects and robust efficacy at tolerated doses. These studies confirm the dependence of a subset of human colon and lung cancer cell lines on CK2 activity for growth and demonstrate that pharmacologic inhibition of CK2 can produce anti-tumor efficacy at tolerated doses.
Citation Format: Brent A. Rupnow, Chiang Yu, Jonathan G. Pabalan, Urvashi V. Roongta, Jonathan S. Lippy, Ashok R. Dongre, Mary T. Obermeier, Aberra Fura, Paul A. Elzinga, Benjamin J. Henley, Joseph Fargnoli, Francis Y. Lee, William R. Foster, Christine M. Tarby, Brian E. Fink, John S. Tokarski, Ashvinikumar V. Gavai, Tai W. Wong, John T. Hunt, Gregory D. Vite, Ashok V. Purandare. Anti-tumor activity of BMS-595, a novel CK2 kinase inhibitor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5395. doi:10.1158/1538-7445.AM2015-5395
Abstract 5436: Targeting oncoproteins via disruption of proteostasis: Identification of oncoprotein destabilizing agents using luciferase tagged oncoproteins
Authors: Middleton Richard E. , Olsen Greg , McSweeney Russell , Lu Gang , Gao Wenhua , Roberts Justin , McKeown Michael R. , Bittinger Mark A. , Wong Kwok-Kin , Bradner James E. , Kaelin William G. 
Published: August 2015

Abstract
Since many oncoproteins are considered undruggable targets, we have developed and validated a new screening strategy to identify small molecules that inhibit oncoprotein activity by causing their degradation. Recently, the mechanism of action for the class of drugs known as immunomodulators (IMiDs; e.g. thalidomide, lenalidomide and pomalidomide) has uncovered a novel oncogene targeting strategy. IMiDs commandeer an E3 ligase complex that contains the E3 recognition subunit cereblon and divert its activity toward two transcription factors IKZF1 and IKZF3, which play critical roles in hematopoietic cells. This mechanism explains the efficacy of IMiDs in multiple myeloma and may translate into a general approach to target traditionally undruggable oncoproteins. We generated cell lines stably expressing IKZF1as a firefly luciferase fusion protein with coexpression of Renilla luciferase. A pilot HTS campaign was run to uncover novel drugs that can mimic the effects of IMiDs. A cell line expressing the MYC-firefly fusion protein was used for counter-screening. We used pomalidomide as our positive control and it reduced firefly luciferase signal ≈75% with no change in the renilla luciferase signals. This control resulted in a Z prime value typically &gt;0.5. The pilot screen of 3,850 compounds resulted in 39 “hits” that reduced firefly luciferase &gt;35%. More importantly, both thalidomide and lenalidomide were found to be active in the screen. Confirmation testing revealed that 75% of “hits” repeated, but also had activity in the MYC-firefly cell line. Actives were tested in western blots for their ability to decrease fusion protein abundance. Many active compounds did not reduce protein levels in western blots and represent nonspecific hits (e.g. luciferase inhibitor). In conclusion, we present a screening paradigm with the potential to uncover novel proteostasis disruptors by expressing luciferase tagged oncoproteins.
Citation Format: Richard E. Middleton, Greg Olsen, Russell McSweeney, Gang Lu, Wenhua Gao, Justin Roberts, Michael R. McKeown, Mark A. Bittinger, Kwok-Kin Wong, James E. Bradner, William G. Kaelin. Targeting oncoproteins via disruption of proteostasis: Identification of oncoprotein destabilizing agents using luciferase tagged oncoproteins. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5436. doi:10.1158/1538-7445.AM2015-5436
Abstract 5445: Dual-color immunohistochemistry assays for measuring Aiolos and Ikaros proteins in multiple myeloma patient samples
Authors: Ren Yan , Wang Maria , Couto Suzana , Hansel Donna , Gandhi Anita K. , Hagner Patrick , Thakurta Anjan , Chopra Rajesh , Breider Mike 
Published: August 2015

Abstract
IMiDs® immunomodulatory drugs Lenalidomide (LEN) and Pomalidomide (POM) are antineoplastic agents that have a significant clinical impact in the treatment of patients with multiple myeloma (MM). Recent studies indicate that the anti-proliferative activity of LEN and POM in MM cells is associated with ubiquitination and degradation of the Ikaros family zinc finger protein transcription factors, Aiolos (IKZF3) and Ikaros (IKZF1), the substrates of the Cereblon (CRBN)-dependent Cullin 4 E3-ligase complex. Measurement of Aiolos and Ikaros protein levels in MM patient samples is critical for future correlative studies. Here we describe the development and validation of dual IHC Aiolos/CD138 and Ikaros/CD138 assays using the highly specific Aiolos rabbit monoclonal antibody CGN-9-9-7, and a commercial Ikaros rabbit polyclonal antibody H-100 in combination with a commercial CD138 antibody. Aiolos and Ikaros immunoreactivity in CD138+ MM cells is scored using the semi-quantitative H-score method. H-scores range from 0 to 300 and are the sum of the products of the percentage of tumor cells (0-100%) and the intensity of staining (0-3). The assays were specific and detected high Aiolos and Ikaros expression in the positive control OCI-Ly10 lymphoma cell line, and low Aiolos and Ikaros levels in POM treated OCI-Ly10 cells. These results were confirmed via Western Blot analysis of Aiolos and Ikaros expression data in these cells lines. Assay precision was examined via staining serial sections of the same MM tumor across three different days and deemed acceptable. The dual IHC assays were used to evaluate bone marrow core biopsies or aspirate clots from 22 MM patients and H-scores were determined by a board-certified pathologist. The dual IHC assays detected a wide range of Aiolos or Ikaros immunoreactivity in the 22 MM cases, with nuclear H-scores ranging from 10 to 260 for Aiolos and 40 to 240 for Ikaros. In conclusion, the dual Aiolos/CD138 and Ikaros/CD138 IHC assays were developed to provide a specific and reliable semi-quantitative method to evaluate Aiolos and Ikaros protein levels in both bone marrow core biopsies and clots from MM patients. These assays are currently being used in clinical trials to assess the importance of Aiolos and Ikaros as biomarkers in MM patients treated with IMiDs® immunomodulatory drugs.
Citation Format: Yan Ren, Maria Wang, Suzana Couto, Donna Hansel, Anita K. Gandhi, Patrick Hagner, Anjan Thakurta, Rajesh Chopra, Mike Breider. Dual-color immunohistochemistry assays for measuring Aiolos and Ikaros proteins in multiple myeloma patient samples. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5445. doi:10.1158/1538-7445.AM2015-5445