tbuckley/cabot-search huggingface dataset:
Abstract 4369: Genome-wide copy number dependency analysis identifies partial copy loss of SF3B1 as a novel cancer vulnerability
Authors: Brenton R. Paolella, William J. Gibson, Laura M. Urbanski, John A. Alberta, Travis I. Zack, Pratiti Bandopadhayay, Caitlin A. Nichols, Pankaj K. Agarwalla, Meredith S. Brown, Rebecca Lamothe, Yong Yu, Peter S. Choi, Esther A. Obeng, Dirk Heckl, Benjamin L. Ebert, Guo Wei, Belinda Wang, William C. Hahn, Francisca Vazquez, Barbara A. Weir, Charles D. Stiles, Robin Reed, Rameen Beroukhim
Journal: Cancer Research (2016)

Abstract Genomic instability is a hallmark of cancer resulting in widespread somatic copy number alterations. We integrated a genome-scale shRNA viability screen and copy number profiles from 179 cancer cell lines to perform an unbiased analysis of copy-number associated gene-dependency interactions. We found most copy-number associated gene dependencies result from losses of genetic material rather than gains. Strikingly, the most enriched class of these dependencies was CYCLOPS (Copy-number alterations Yielding Cancer Liabilities Owing to Partial losS) genes. Hemizygous loss of CYCLOPS genes sensitizes cancer cells to their further suppression. One of the “top hits” from the analysis was the pre-mRNA splicing factor SF3B1, which is also frequently mutated in cancer. We then sought to evaluate SF3B1 as a CYCLOPS gene. Cancer cells with hemizygous SF3B1 copy-loss were uniquely sensitive to partial SF3B1 suppression by RNAi compared to cells with normal SF3B1 gene dosage. Mechanistically, cancer cells harboring partial SF3B1 copy-loss lack a reservoir of excess SF3b complex, a precursor complex of the U2 snRNP, which protects cells with normal SF3B1 copy number from cell death upon SF3B1 suppression. Our data highlight the prevalence of CYCLOPS dependencies in cancer and establish the spliceosome as a frequent CYCLOPS target. Further, these data indicate targeting wild-type SF3B1 as a novel cancer dependency in cells with hemizygous SF3B1 copy-loss. Citation Format: Brenton R. Paolella, William J. Gibson, Laura M. Urbanski, John A. Alberta, Travis I. Zack, Pratiti Bandopadhayay, Caitlin A. Nichols, Pankaj K. Agarwalla, Meredith S. Brown, Rebecca Lamothe, Yong Yu, Peter S. Choi, Esther A. Obeng, Dirk Heckl, Benjamin L. Ebert, Guo Wei, Belinda Wang, William C. Hahn, Francisca Vazquez, Barbara A. Weir, Charles D. Stiles, Robin Reed, Rameen Beroukhim. Genome-wide copy number dependency analysis identifies partial copy loss of SF3B1 as a novel cancer vulnerability. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4369.
Use of CA-125 Tests and Computed Tomographic Scans for Surveillance in Ovarian Cancer
Authors: Katharine M. Esselen, Angel M. Cronin, Kristin Bixel, Michael A. Bookman, Robert A. Burger, David E. Cohn, Mihaela Cristea, Jennifer J. Griggs, Charles F. Levenback, Gina Mantia-Smaldone, Larissa A. Meyer, Ursula A. Matulonis, Joyce C. Niland, Charlotte Sun, David M. O’Malley, Alexi A. Wright
Journal: JAMA Oncology (2016)

<h3>Importance</h3> A 2009 randomized clinical trial demonstrated that using cancer antigen 125 (CA-125) tests for routine surveillance in ovarian cancer increases the use of chemotherapy and decreases patients' quality of life without improving survival, compared with clinical observation. The Society of Gynecologic Oncology guidelines categorize CA-125 testing as optional and discourage the use of radiographic imaging for routine surveillance. To date, few studies have examined the use of CA-125 tests in clinical practice. <h3>Objectives</h3> To examine the use of CA-125 tests and computed tomographic (CT) scans in clinical practice before and after the 2009 randomized clinical trial and to estimate the economic effect of surveillance testing. <h3>Design, Setting, and Participants</h3> A prospective cohort of 1241 women with ovarian cancer in clinical remission after completion of primary cytoreductive surgery and chemotherapy at 6 National Cancer Institute–designated cancer centers between January 1, 2004, and December 31, 2011, was followed up through December 31, 2012, to study the use of CA-125 tests and CT scans before and after 2009. Data analysis was conducted from April 9, 2014, to March 28, 2016. <h3>Main Outcomes and Measures</h3> The use of CA-125 tests and CT scans before and after 2009. Secondary outcomes included the time from CA-125 markers doubling to retreatment among women who experienced a rise in CA-125 markers before and after 2009, and the costs associated with surveillance testing using 2015 Medicare reimbursement rates. <h3>Results</h3> Among 1241 women (mean [SD] age 59 [12] years; 1112 white [89.6%]), the use of CA-125 testing and CT scans was similar during the study period. During 12 months of surveillance, the cumulative incidence of patients undergoing 3 or more CA-125 tests was 86% in 2004-2009 vs 91% in 2010-2012 (<i>P</i> = .95), and the cumulative incidence of patients undergoing more than 1 CT scan was 81% in 2004-2009 vs 78% in 2010-2012 (<i>P</i> = .50). Among women whose CA-125 markers doubled (n = 511), there was no significant difference in the time to retreatment with chemotherapy before and after 2009 (median, 2.8 vs 3.5 months;<i>P</i> = .40). During a 12-month period, there was a mean of 4.6 CA-125 tests and 1.7 CT scans performed per patient, resulting in a US population surveillance cost estimate of $1 999 029 per year for CA-125 tests alone and $16 194 647 per year with CT scans added. <h3>Conclusions and Relevance</h3> CA-125 tests and CT scans are still routinely used for surveillance testing in patients with ovarian cancer, although their benefit has not been proven and their use may have significant implications for patients' quality of life as well as costs.
What Are the Facts About Autism Spectrum Disorders, Selective Serotonin Reuptake Inhibitors, and Assisted Reproductive Technology?
Authors: Daniel L. Coury
Journal: JAMA Pediatrics (2016)

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Abstract 383: In vitro effects of PI3K/mTOR inhibition in canine hemangiosarcoma
Authors: Alex A. Pyuen, Douglas H. Thamm
Journal: Cancer Research (2016)

Abstract While extremely rare in humans, hemangiosarcoma (HSA) accounts for nearly 2% of canine neoplasia, and is characterized by both aggressive local growth/invasion and a high rate of metastasis. Both canine and human HSA exhibit sustained aberrant PI3K/Akt/mTOR pathway signaling. The purpose of this study was to examine the in vitro effects of a novel dual PI3K/mTOR inhibitor, VDC-597, in canine HSA cells. Three canine HSA cell lines (DEN-HSA, CIN-HSA, and SB-HSA) were employed in multiple in vitro assays. Western analysis evaluated activation (phosphorylation) of key downstream pro-survival proteins in the PI3K/mTOR pathway. Changes in tumor cell growth/apoptosis were assessed using both bioreductive assays (Alamar Blue) and in vitro live-cell imaging (IncuCyte), in the presence and absence of doxorubicin, a standard-of-care cytotoxic drug for canine and human sarcomas, as well as in the presence and absence of U-0126, an inhibitor of the MEK pathway. Migration was assessed using both Boyden chamber and scratch assays, via live-cell imaging (IncuCyte). Matrigel invasion was assessed using traditional Boyden chambers. Finally, ELISA was utilized to quantify relative expression of vascular endothelial growth factor (VEGF). VDC-597 suppressed activation of both Akt and 4eBP1 in canine HSA cells in a dose- and time-dependent fashion, with an IC50 of approximately 0.3 uM, a concentration predicted to be clinically achievable based on preliminary early-phase canine and human studies. VDC-597 dose-dependently reduced proliferation, migration, invasion, and VEGF expression in HSA cells, while promoting tumor cell apoptosis. VDC-597 demonstrated additive antiproliferative effects when combined with doxorubicin and U-0126. Together, these results suggest that inhibitors of the PI3K/Akt/mTOR pathway may act against multiple components of the neoplastic process, including proliferation/apoptosis, chemosensitivity, invasion/migration and angiogenesis, and justify the evaluation of PI3K/mTOR inhibitors in canine, and eventually human, HSA. Experiments to examine the effect of VDC-597 in reducing tumor burden and metastasis in a rodent model are ongoing. Citation Format: Alex A. Pyuen, Douglas H. Thamm. In vitro effects of PI3K/mTOR inhibition in canine hemangiosarcoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 383.
The Research of Phenylhexyl Isothiocyanate’s Influence on p16 Gene Methylation of Leukaemia Cell
Authors: Bao-An Chen, Bei-ming Shou, Dong-rui Zhou, Delong Liu, Jia-hua Ding, Yun-Yu Sun, Jun Wang, Jian Cheng, Gang Zhao, Hui-hui Song, Wen Bao, Jue-qiong Wang, Peng Yuan, Xiao-ping Pei, Ning-na Chen, Xu-dong Ma, Zu-hong Lu, Quan-yi Lu, Yong-rong Lai, He Huang
Journal: Blood (2008)
Abstract 4458: Discovery of novel epigenetic biomarkers in premalignant/malignant oral cavity lesions by methylation arrays
Authors: Semra Demokan, Sevde Comert, Cansu Ozkoklesen, Murat Ulusan, Gulsum Ak, Canan Alatli, Nejat Dalay
Journal: Cancer Research (2016)

Abstract Purpose: The incidence of the oral squamous cell carcinoma (OSCC) is around 50% of all head and neck cancer (HNC), the sixth most common type of cancer in the world. Aberrant hyper/hypo-methylation in the promoter region of some known or putative tumor suppressor/protoonco-genes occurs frequently during the development of various cancers including OSCC. Both of genetic and environmental factors play roles in the carcinogenesis of malignant lesions. Etiological factors predisposing to OSCC are smoking, alcohol and tobacco consumption, snuffuse, viral factors, chronic irritation, iron and various vitamin deficiencies, poor oral hygiene and diseases such as syphilis. Despite the advances in cancer diagnosis and treatment, the 5-year survival rate of OSCC patients is poor and because of advanced stage of disease, it has high mortality and morbidity. Another the most important ethiological factor of OSCC is oral premalignant lesions (OPML), since OPML is related with malignant transformation. In our study, we included three different OPML associated with different risks of leading to malignancy: Oral leukoplakia has a high risk of conversion into malignancy, whereas oral lichen planus and oral lichenoid dysplasia are associated with lower risk. We aimed to investigate the epigenetic characterization of OSCC and OPML relative to the epigenetic changes in these groups. Experimental Design: Tumor and corresponding healthy tissues from 12 and 10 Turkish patients with OPML and OSCC, respectively were collected. The samples were analyzed histopatologically and after DNA extraction and bisulfite modification, methylation patterns of the samples were investigated by using the Illumina Infinium HumanMethylation450 (450K) BeadChip array. Results: According to our preliminary results obtained from the methylation array experiments, CpG regions in the UOX, ABCC12, FCRLB, ABL2, LGR6 and SLC22A18 genes were found unmethylated while CpGs located in YPEL-3 were highly methylated (p&amp;lt;0.005). Conclusion: We concluded the UOX, ABCC12, FCRLB, ABL2, LGR6, SLC22A18 and YPEL-3 may be potential biomarker candidate genes playing role in the transformation mechanism of OPML/OSCC. In the further studies, we will compare the methylation patterns between OPML subgroups to discriminate the potential candidates. *This study was supported by the Scientific and Technological Research Council of Turkey (TUBITAK-SBAG-114S497). Citation Format: Semra Demokan, Sevde Comert, Cansu Ozkoklesen, Murat Ulusan, Gulsum Ak, Canan Alatli, Nejat Dalay. Discovery of novel epigenetic biomarkers in premalignant/malignant oral cavity lesions by methylation arrays. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4458.
Analysis of patients (pts) with pathological (p-) stage I (T1> 2 cm) non small cell lung cancer (NSCLC) who were excluded from clinical trial of adjuvant chemotherapy.
Authors: Yasushi Goto, Hiroyuki Sakurai, Sakae Okumura, Yasuhisa Ohde, Norihiko Ikeda, Hiroyuki Ito, Yukinori Sakao, Hiroshi Date, Motohiro Yamashita, Kiyotaka Yoh, Tomoyuki Hishida, Takehito Shukuya, Kazuya Takamochi, Yasuo Ohashi, Masahiro Tsuboi, Hideo Kunitoh
Journal: Journal of Clinical Oncology (2016)

e20018 Background: From Nov. 2008 to Dec. 2013, JCOG0707, the phase III randomized study of adjuvant chemotherapy for the pts with completely resected, p-stage I (T1 > 2 cm) NSCLC, accrued 963 cases. The monitoring in Jun. 2013 showed the combined overall survival (OS) of the 2 arms far exceeded initial presumption, with 4-year OS of 91.6%. We undertook the survey of pts excluded from the clinical trial during the same period. Methods: Pts’ characteristics, tumor profiles, reasons for non-enrollment to a trial, actual post-surgical therapy, and outcomes of pts with completely resected, p-stage I (T1 > 2 cm) NSCLC were surveyed at each institution. Accrual rates to the trial, as well as the reasons for exclusion and patterns of care, were analyzed according to pts background and institutions. Results: Of the 48 institutions that took part in JCOG0707, 34 (enrolling 917 or 95.2% of JCOG0707 cases) participated in the survey, and 5006 pts were registered. Among them, 2617 pts (52.3%) fulfilled the eligibility criteria of JCOG0707, but were not enrolled mainly due to patients’ decline (69.2%), or decision by attending physicians (20.5%). Therefore, JCOG0707 enrolled 917/3534 (25.9%) of the eligible and 917/5923 (15.5%) of all pts. The other 2389 (47.7%) were ineligible for JCOG0707, due to concomitant malignancy (33.4%), attending physicians’ clinical judgment (22.2%), delay of recovery from surgery (16.2%) or age limitation (12.2%). Proportion of trial participation differed widely by institutions (4.1 to 46.1%), and was not correlated with total number of pts (r2= 0.003) or number of eligible cases (r2= 0.046) at each institution. It declined after the adverse events-associated temporary suspension of accrual from May to Jul. 2011 (20.1 to 12.6%). No adjuvant chemotherapy was given to 3338 pts (66.7%), and 1550 (31.0%) received standard UFT treatment. Conclusions: Only a minority of candidate pts, even when they met the eligibility criteria, were accrued to JCOG0707. The “excluded” cases were treated with observation only or standard therapy. Further analysis of the population, including OS, would be needed to define the external validity of the randomized trial. Clinical trial information: UMIN000015732.
Abstract 933: Protein kinase a regulation of malignant brain tumor migration
Authors: Jennifer N. Ausland, Robert H. Newman, Patrick M. Martin
Journal: Cancer Research (2016)

Abstract Glioblastoma multiforme (GBM) is the most common and deadly type of primary brain tumor, accounting for over 13,000 new cases in the U.S. annually and a two-year survival rate of &amp;lt; 5%. GBMs are highly invasive and classified by the World Health Organization as a grade IV astrocytoma. Recent studies have shown that protein kinase A (PKA), a key regulator of signal transduction and various biological functions, is essential for maintaining polarity during cell migration and that localized activation of PKA at the leading edge is an early event in directional cell migration of other cell types. Though PKA has previously been shown to promote proliferation and migration in lung, colorectal, adrenocortical, and prostate cancer cell lines, the molecular mechanisms that link PKA activity with GBM physiology remain unclear. Wound healing assays in human GBM cell lines U-251 MG, U-87 MG and A172, demonstrated that GBM cell migration increased following the addition of 20 μM epidermal growth factor (EGF). Similar results were found with 5 μM treatment of the adenylate cyclase activator, forskolin, and inhibited by pre-treatment with 10 μM of the PKA inhibitor, H89. In order to assay the amount of PKA activity, we measured the phosphorylation of cAMP response element binding protein (CREB) in these cell lines. Western blot studies revealed an increase in CREB phosphorylation in cells treated with EGF and forskolin. Phosphorylation of CREB was decreased with the addition of H89 treatment. Our western blot analysis supports our wound healing data demonstrating a correlation between increased PKA-mediated CREB phosphorylation and migration in the absence of serum. Taken together, these data suggest that PKA activation by EGF is involved in GBM cell migration. Moreover, our findings describe a mechanism by which PKA regulates the migration of human brain tumors. Citation Format: Jennifer N. Ausland, Robert H. Newman, Patrick M. Martin. Protein kinase a regulation of malignant brain tumor migration. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 933.
Abstract 3467: Moderate-intensity exercise to reduce radiation therapy-related fatigue in black breast cancer patients: A feasibility trial
Authors: Chiranjeev Dash, Mary Mills, Vivian Watkins, Pamela Randolph-Jackson, Claudine Isaacs, Kepher Makambi, Lucile L. Adams-Campbell
Journal: Cancer Research (2016)

Abstract Background: Fatigue is an important side-effect of radiation therapy (RT) for treatment of early stage breast cancer. Evidence on the efficacy of physical activity (PA) interventions in reducing fatigue among Black cancer patients undergoing RT is lacking. In a randomized controlled trial we tested the efficacy of a structured PA intervention, coinciding with the start of RT, in reducing cancer-related fatigue among Black patients undergoing RT for breast cancer. Methods: We randomly assigned 30 Black, sedentary, RT-naïve, non-pregnant patients diagnosed with stage 0-IIIA breast cancer who had completed adjuvant or neo-adjuvant chemotherapy and were scheduled for RT to the PA intervention (n = 15) and control groups (n = 15). PA intervention was an 8-week structured, moderate-intensity aerobic exercise regimen (75 minutes/week) using PEDLARS (portable stationary cycle ergometers) concurrent with RT. Fatigue was measured by using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) survey, a 13-item scale whose score ranges from 0 to 52 with a higher score denoting lower fatigue. We used ANCOVA to compare fatigue levels between the groups at T8 weeks after adjusting for baseline (T0) fatigue levels. We also compared change in fatigue scores (T8 weeks - T0) using 2-sample t-tests. All tests were double-sided with alpha = 0.05. Results: 27 women completed baseline and follow-up assessments. After adjusting for baseline fatigue scores, intervention group participants reported lower fatigue at T8 weeks than the control group (42.53 vs. 37.12; P = 0.17). Intervention group participants improved their fatigue scores at T8 weeks compared to T0 (mean change +1.3) but the control group did not (mean change -1.91; P = 0.42). Conclusion: Although statistically not significant, moderate-intensity exercise regimen among Black breast cancer patients undergoing RT was associated with lower RT-associated fatigue. This trial demonstrated the feasibility and acceptability of conducting a randomized clinical trial of a moderate-intensity exercise program among women initiating RT for breast cancer. Citation Format: Chiranjeev Dash, Mary Mills, Vivian Watkins, Pamela Randolph-Jackson, Claudine Isaacs, Kepher Makambi, Lucile L. Adams-Campbell. Moderate-intensity exercise to reduce radiation therapy-related fatigue in black breast cancer patients: A feasibility trial. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3467.
Abstract 1322: Folate receptor-targeted lipid coated albumin nanoparticles (F-LCAN) for therapeutic delivery of RX-0201 (Archexin®), an antisense oligonucleotide against Akt-1
Authors: Hong Li, Xinwei Cheng, Yang Liu, Young Bok Lee, Deog Joong Kim, Chang-ho Ahn, Robert J. Lee
Journal: Cancer Research (2016)

Abstract Akt-1 is a protein kinase that contributes to cancer progression by promoting proliferation and inhibiting apoptosis of tumor cells. RX-0201 (Archexin®), a 20-mer phosphorothioate antisense oligonucleotide that inhibits the expression of Akt-1, is currently in a Phase IIa clinical trial for metastatic renal cancer. To further improve the efficacy of RX-0201, folate receptor-targeted lipid coated albumin nanoparticles containing RX-0201 (F-LCAN-RX-0201) were synthesized and evaluated for Akt-1 inhibition and antitumor activity. These nanoparticles are composed of DOTAP/soyPC/TPGS/folate-PEG-DSPE (25:70:4:1), a cationic human serum albumin-pentaethylenehexamine (HSA-PEHA) conjugate, and RX-0201. F-LCAN-RX-0201 had a particle size of 108.6±5.8 nm, zeta potential of 10.5±3.2 mV and 71.5% antisense loading efficiency. F-LCAN-RX-0201 in folate receptor-expressing KB cells inhibited cell growth at IC50 of 11.9 ± 4.0 μM while free RX-0201 did not show significant cytotoxicity at concentration up to 250 μM. Cellular uptake and Akt-1 inhibition of F-LCAN-RX-0201 was greater than the non-targeted LCAN-RX-0201 and was partially blocked by excess free folate. Pharmacokinetic studies showed that F-LCAN-RX-0201 had a longer half-life than that of free RX-0201 (30 ± 4 min vs 10 ± 2 min). In a KB xenograft tumor model, F-LCAN-RX-0201 exhibited higher tumor suppressive activity compared to the non-targeted LCAN-RX-0201 at 16 mg/kg (as a RX-0201 amount) without body weight changes. Moreover, the antitumor activity of F-LCAN-RX-0201 at a dose of 16mg/kg (as a RX-0201 amount) was similar to free RX-0201 at a dose of 90mg/kg. In conclusion, LCAN is a highly effective formulation for therapeutic delivery of antisense agents and F-LCAN-RX-0201 could be a potential therapeutic agent for tumors with increased folate-receptor expression. Citation Format: Hong Li, Xinwei Cheng, Yang Liu, Young Bok Lee, Deog Joong Kim, Chang-ho Ahn, Robert J. Lee. Folate receptor-targeted lipid coated albumin nanoparticles (F-LCAN) for therapeutic delivery of RX-0201 (Archexin®), an antisense oligonucleotide against Akt-1. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1322.