tbuckley/cabot-search huggingface dataset:
Abstract 2021: Identification of novel brachyury target genes in lung cancer
Authors: Yunping Hu, Wesley Hsu
Journal: Cancer Research (2016)

Abstract Lung cancer is the leading cause of cancer-related death worldwide. Previous studies have shown that the T-box transcription factor brachyury is commonly expressed in advanced lung cancer and is associated with a poor prognosis. The activation of brachyury promotes lung cancer progression, aggressiveness and resistance to conventional antitumor therapies. However, the mechanism by which brachyury drives lung cancer is unknown. Here we have sought to identify novel gene targets of brachyury to better understand the molecular pathogenesis of lung cancer. We used a bioinformatics approach and found a shortlist of putative potential brachyury target genes. We subsequently explored the modulation of candidate brachyury target genes in lung cancer. RNA interference analysis for lung cancer cell line H460 overexpressing brachyury demonstrated that fibroblast growth factor 8 (FGF8), MAS1 Proto-Oncogene G Protein-Coupled Receptor (MAS1) and Ran GTPase Activating Protein 1 (RANGAP1) played essential roles in cell growth, whereas transmembrane protein 37 (TMEM37) was involved in cell migration and invasion. ChIP-qPCR experiments confirmed the strong binding of brachyury to these functional target genes. Analysis of datasets derived from patients with lung cancer and a panel of lung cancer cell lines revealed that brachyury expression was positively correlated with FGF8, MAS1, RANGAP1 and TMEM37. In addition, the expression levels of FGF8, MAS1 and RANGAP1 were significantly associated with non-metastasis (early-stage and locally advanced lung cancer), whereas TMEM37 was associated with metastasis. Taken together, our findings suggest that brachyury may influence lung cancer progression and/or metastasis via direct regulation of FGF8, MAS1, RANGAP1 and TMEM37 expression. Identification of potential brachyury transcriptional targets provides novel insights into the molecular pathobiology of lung cancer. Citation Format: Yunping Hu, Wesley Hsu. Identification of novel brachyury target genes in lung cancer. [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 2021.
The role of adjuvant chemoradiotherapy (CRT) in Turkish patients with gastric carcinoma
Authors: M. Gumus, F. Dane, S. Kaya, M. A. Ozturk, P. F. Yumuk, B. M. Atasoy, G. Basaran, T. Salepci, M. Yaylaci, N. S. Turhal
Journal: Journal of Clinical Oncology (2007)

15159 Background: Increased disease free and overall survivals were seen in curatively resected patients with gastric and gastroesophageal adenocarcinoma treated with postoperative adjuvant CRT compared to surgery alone. There is no study analyzing the outcome of gastric cancer patients who received adjuvant CRT after curative resection in Turkish patients. Thus, we aimed to analyze the treatment outcome of postoperative CRT, and the prognostic significance of various parameters in these patients. Material Metod: Overall 130 patients with gastric cancer staged IB to IV(M0) were treated with chemoradiotherapy after curative resection, in two outpatient clinics in Istanbul. The chemotherapy consisted of fluorouracil 425 mg/m2 plus leucovorin 20 mg/m2 for 5 days, followed by 4500 cGy of radiotherapy for 5 weeks with fluorouracil (400 mg/m2) and leucovorin (20 mg/m2) on the first 4 days and the last 3 days of radiotherapy. Two 5-day cycles of chemotherapy with the doses used in the first cycle were given 4 weeks after the completion of radiotherapy. The demographic features and histopathological characteristics of the patients were analyzed as prognostic factors. Results: The median follow up was 13 months (range: 1–77) starting from surgery date. The median age was 58 years (range:33–75). About 28 % of the patients were female. ECOG performance score (PS) was =1 in 92.9 %, whereas it was 2 in the remaining 7.1%. Twenty-one patients had gastroesophageal junction and 109 had gastric primaries. The rates of T1, T2, T3, and T4 tumors were 3.8%, 26.9%, 61.5%, and 7.7%, respectively. A hundred and nine (83.8%) patients had regional node involvement. The 3 year disease free survival and overall survival for all patients were 50.1%, and 61.7%, respectively. The median overall survival was 54 months. In multivariate Cox regression analysis; nodal status (p: 0.003) was the only independent prognostic factor for overall survival. Tolerance was acceptable, and the main toxicity was related to gastrointestinal system. Conclusion: The adjuvant CRT after curative resection of gastric cancer was feasible, with acceptable toxicities in our Turkish patient population. No significant financial relationships to disclose.
Abstract LB-105: High-throughput target identification using CRISPR/Cas9
Authors: Chetana M. Revankar, Julia Braun, LaiYee Wong, Justin Wetter, Jian-Ping Yang, Namritha Ravinder, Jon Chesnut, David Piper
Journal: Cancer Research (2016)

Abstract One of the major challenges of the drug discovery process is the identification of novel, validated targets, whose pharmacological modulation may yield the desired therapeutic outcomes. The use of CRISPR (clustered regularly interspaced short palindromic repeat)-associated Cas9 nuclease and guide RNA can potentially impact the entire drug discovery process from generation of models based on clinical findings through to the target identification. The ability of CRISPR/Cas9, to efficiently and precisely edit a cell's DNA and introduce a complete genetic knockout, while minimizing off-target effects, offers an improved approach to target identification. Moreover, the ability to scale this approach through the generation of genome wide CRISPR libraries, coupled with the use of lentiviral delivery methods enables high-throughput (HTP) loss-of-function screens to be performed rapidly and identify genes whose activity is important for the specific endpoint being measured. For example, in this study, we have used CellSensor® cell lines targeting various signaling pathways (AP-1, c-Fos and NF-kB) to identify key targets critical to these pathways. Transcription factors like AP-1, c-Fos and NF-kB have shown to play an important role in cancer initiation and progression. Using the key signaling molecules along these pathways as controls we have data that supports HTP target identification. Furthermore, we will present our results from screening of a subset of a CRISPR library targeting 160 different kinases. Eventually, we plan to screen the entire CRISPR library targeting 750 kinases with 4 gRNA per gene against each of these signaling pathways. Similar screenings can be performed using other functional assay formats, like the cell health assays or high content imaging. These screenings can provide a wealth of data on the normal functioning of a target and in turn, should yield better validated targets for progression into full drug discovery. Ultimately, the hits from the HTP screenings can be followed up by using CRISPR technology to generate animal knockout models that would support translating the screen to the pre-clinical trials. This in turn could provide better correlation to the clinical setting and thereby reduce candidate drug attrition. Citation Format: Chetana M. Revankar, Julia Braun, LaiYee Wong, Justin Wetter, Jian-Ping Yang, Namritha Ravinder, Jon Chesnut, David Piper. High-throughput target identification using CRISPR/Cas9. [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 LB-105.
Crizotinib vs chemotherapy in <i>ALK</i>+ advanced non-small cell lung cancer (NSCLC): Final survival results from PROFILE 1007.
Authors: Alice Tsang Shaw, Pasi A. Janne, Benjamin Besse, Benjamin J. Solomon, Fiona Helen Blackhall, D. Ross Camidge, Tony Mok, Vera Hirsh, Judith Robin Scranton, Anna Polli, Yiyun Tang, Keith D. Wilner, Dong-Wan Kim
Journal: Journal of Clinical Oncology (2016)

9066 Background: PROFILE 1007 demonstrated superior PFS with crizotinib vs standard-of-care chemotherapy in patients (pts) with ALK+ advanced NSCLC previously treated with 1 prior platinum-based regimen. Here, we present final OS and updated safety data from this study. Methods: In this ongoing open-label phase 3 trial (NCT00932893), pts were randomized (1:1) to crizotinib 250 mg PO BID or chemotherapy (pemetrexed 500 mg/m2 or docetaxel 75 mg/m2, IV q3w). Pts with PD (per independent radiological review) on chemotherapy could cross over to crizotinib in a separate study. The Kaplan-Meier method was used to estimate OS, 1-sided stratified log-rank tests to compare survival curves, and stratified Cox regression models to estimate HRs. Results: 347 pts were randomized: 173 to crizotinib (172 treated), 174 to chemotherapy (171 treated). At data cutoff (Aug 31, 2015), 13 (8%) and 0 pts randomized to crizotinib and chemotherapy, respectively, were on treatment. Median treatment duration (range) was 48 wk (1–263) and 13 wk (3–162) and median duration of follow-up was 51.0 and 53.1 mo in the crizotinib and chemotherapy arms, respectively. There was a numerical, but not statistically significant, improvement in the secondary endpoint of OS for crizotinib vs chemotherapy (HR: 0.85; 95% CI: 0.66−1.10; P = 0.11; median 21.7 and 21.9 mo). 154 pts (89%) randomized to chemotherapy subsequently received crizotinib as follow-up systemic therapy. OS analysis with adjustment for crossover is in progress. The most common all-causality AEs (any grade) with crizotinib were diarrhea (62%), vision disorder (62%), and nausea (60%) and with chemotherapy were nausea (36%), fatigue (36%), and decreased appetite (27%). Grade 5 treatment-related AEs (TRAEs) were reported in 3 pts and 1 pt with crizotinib and chemotherapy, respectively. Treatment discontinuations associated with TRAEs were reported in 6% of pts on crizotinib and 12% on chemotherapy. Conclusions: In this randomized study, which allowed crossover to crizotinib, there was a numerical improvement in OS for crizotinib vs chemotherapy that did not reach statistical significance. Crizotinib has a distinct and generally tolerable safety profile. Clinical trial information: NCT02511184.
Comparison of clinical features and outcomes in patients with extraskeletal versus skeletal localized Ewing sarcoma: A report from the Children’s Oncology Group.
Authors: Thomas Cash, Elizabeth McIlvaine, Mark D. Krailo, Stephen L. Lessnick, Elizabeth R. Lawlor, Nadia N. Laack, Joel Sorger, Neyssa Marina, Holcombe E. Grier, Linda Granowetter, Richard B. Womer, Steven G. DuBois
Journal: Journal of Clinical Oncology (2015)

10051 Background: The prognostic significance of having extraskeletal Ewing sarcoma (EES) using modern chemotherapy protocols is unknown. The purpose of this study was to compare the clinical characteristics and outcomes for patients with extraskeletal and skeletal Ewing sarcoma. Methods: Patients had localized Ewing sarcoma and were treated on two consecutive protocols using 5-drug chemotherapy (INT-0154 and AEWS0031). Patients were analyzed based on having an extraskeletal (n = 213) or skeletal (n = 826) site of tumor origin. Patient characteristics were compared using Wilcoxon rank sum, Fisher exact, and chi-square tests. Event-free survival (EFS) was estimated using the Kaplan-Meier method and compared using the log-rank test. Relapse, death, or second malignancy were considered events. Results: Age of diagnosis and sex did not differ according to tissue of origin. Patients with EES were less likely to be white (80.8% vs. 87.7%; p = 0.02), and were less likely to have tumors > 8cm (22.3% vs. 36.3%; p = 0.01) compared to patients with skeletal Ewing sarcoma. There was a trend to suggest superior EFS for patients with EES compared to skeletal tumors (hazard ratio 1.34; p = 0.053). Among patients with extraskeletal tumors, the EFS was inferior for those patients who were not white (p = 0.005) and who were > 18 years of age (p = 0.02). The distribution of event types experienced by each group did not differ. Conclusions: Clinical characteristics differ between patients with extraskeletal and skeletal localized Ewing sarcoma and outcomes may be superior for patients with EES. The origin of these differences requires further investigation.
Hematopoietic Stem Cell Transplantation for Patients with Refractory Cytopenia of Childhood
Authors: Daisuke Hasegawa, Shinsuke Hirabayashi, Shizuka Watanabe, Yuji Zaike, Masahiro Tsuchida, Atsuko Masunaga, Ayami Yoshimi, Asahito Hama, Seiji Kojima, Masafumi Ito, Tatsutoshi Nakahata, Atsushi Manabe
Journal: Blood (2014)
Abstract 3693: Oligomerization status of p53 serves as an indicator of sensistivity of p53 wildtype tumors to the therapeutic combination of DNA damaging agent and checkpoint inhibitor
Authors: Pawan Puli, Robert Lipski, Aime A. Levesque
Journal: Cancer Research (2016)

Abstract It is well established that cell cycle arrest in response to treatment with DNA damaging agents can be abrogated in p53-defective cells by treatment with the Chk1 inhibitors, but our more recent studies have shown that some p53 wild-type tumors are also sensitive to checkpoint abrogation. Two possible explanations are cytoplasmic sequestration of p53 or a defect in p53 oligomerization. In this study, we investigated the DNA damage response and UCN-01 sensitivity of two p53 wildtype neuroblastoma cell lines: SK-N-SH, and SH-SY5Y. In order to determine the responses of these cells to DNA damage, the cells were treated with concentrations of SN38 ranging from 0-30 ng/ml. Both lines arrested in G2, S, or G1 depending upon SN38 concentration and displayed an increase in p53 levels with increasing SN38. Additionally, p53 was phosphorylated on serine 15 and serine 20 following SN38 treatment in all three cell lines, suggesting that p53 is active. In order to determine whether these cells are susceptible to UCN-01-mediated abrogation of cell cycle arrest, cell were treated with 3 ng/ml SN38 for 24 hours, followed by 25 nM UCN-01 for 6 and 24 hours. The SK-N-SH showed now sensitivity to UCN-01 treatment whereas the SH-SY5Y abrogated S arrest within 6 hours and abrogated G2 arrest within 24 hours. We also analyzed the oligomerization status of p53 using glutaraldehyde crosslinking. The SK-N-SH cells possessed levels of p53 dimers and tetramers similar to what has previously been reported in p53 wildtype MCF10A cells. The SH-SY5Y, however, had extremely low levels of dimers and tetramers. Consistent with this, only SK-N-SH showed activation of p21waf1 and repression of cyclin B in response to SN38 treatment. Previous studies have reported cytoplasmic sequestration as a mechanism of p53 inactivation in p53 wildtype neuroblastomas. In order to determine the sub-cellular distribution of p53, we prepared nuclear and cytoplasmic extracts. Both the SK-N-SH and SH-SY5Y had primarily nuclear p53. The results of this study suggest that oligomerization status may serve as an indicator of sensitivity of p53 wildtype tumors to the therapeutic combination of DNA damage agent and checkpoint inhibitor. Citation Format: Pawan Puli, Robert Lipski, Aime A. Levesque. Oligomerization status of p53 serves as an indicator of sensistivity of p53 wildtype tumors to the therapeutic combination of DNA damaging agent and checkpoint inhibitor. [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 3693.
Diagnosing primary ciliary dyskinesia: an international patient perspective
Authors: Laura Behan, Audrey Dunn Galvin, Bruna Rubbo, Sarah Masefield, Fiona Copeland, Michele Manion, Bernhard Rindlisbacher, Beatrice Redfern, Jane S. Lucas
Journal: European Respiratory Journal (2016)

Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterised by progressive sino-pulmonary disease, with symptoms starting soon after birth. A European Respiratory Society (ERS) Task Force aims to address disparities in diagnostics across Europe by providing evidence-based clinical practice guidelines. We aimed to identify challenges faced by patients when referred for PCD diagnostic testing. A patient survey was developed by patient representatives and healthcare specialists to capture experience. Online versions of the survey were translated into nine languages and completed in 25 countries. Of the respondents (n=365), 74% were PCD-positive, 5% PCD-negative and 21% PCD-uncertain/inconclusive. We then interviewed 20 parents/patients. Transcripts were analysed thematically. 35% of respondents visited their doctor more than 40 times with PCD-related symptoms prior to diagnostic referral. Furthermore, the most prominent theme among interviewees was a lack of PCD awareness among medical practitioners and failure to take past history into account, leading to delayed diagnosis. Patients also highlighted the need for improved reporting of results and a solution to the “inconclusive” diagnostic status. These findings will be used to advise the ERS Task Force guidelines for diagnosing PCD, and should help stakeholders responsible for improving existing services and expanding provision for diagnosis of this rare disease.
Abstract 2682: Sympathetic activation alters the bone vasculature: implication for osteotropic breast cancer metastasis
Authors: Patrick L. Mulcrone, J. Preston Campbell, Ana Lia Anbinder, Julie A. Sterling, Florent Elefteriou
Journal: Cancer Research (2016)

Abstract Emotional stresses chronically activate the Hypothalamic-Pituitary-Adrenal axis and the sympathetic nervous system (SNS), and have been associated with the progression and recurrence of breast cancer, as well as with reduced survival of breast cancer patients. We observed that isoproterenol (ISO), a β1/2 adrenergic receptor (βAR) agonist used to mimic sympathetic activation, induced the expression of Vegfa in mouse bone in vivo and in osteoblast cultures in vitro. Because VEGF is pro-angiogenic, and tumor cells depend on the vasculature to form distant metastases, we hypothesized that SNS chronic activation may increase bone marrow vascular density via an effect on β2AR-expressing osteoblasts, thus promoting the possibility of metastatic breast cancer establishment in the skeleton. To address this question, we measured the formation of CD31+ vessels in femurs in vivo by histomorphometric analyses, following daily ISO treatment of adult mice for 6 weeks. Vessel number was significantly increased by ISO treatment in WT mouse femurs, and this effect was blunted in mice lacking the β2AR. Further supporting our hypothesis, we found that the conditioned media (CM) from MC3T3 osteoblasts treated with ISO augmented blood vessel formation in an ex vivo metatarsal assay as compared to the CM of PBS-treated osteoblasts. Lastly, the CM of ISO-treated MC3T3 osteoblasts promoted primary bone endothelial cell tube formation, and inhibition of Vegf:Vegfr2 interaction with the antibody mcr84 reduced this formation. These results suggest that the effect of chronic stress on metastatic breast cancer cell establishment in the skeleton may be mediated in part due to changes in the bone microenvironment, specifically an increase in osteoblastic VEGF that changes host bone marrow vascular density. Citation Format: Patrick L. Mulcrone, J. Preston Campbell, Ana Lia Anbinder, Julie A. Sterling, Florent Elefteriou. Sympathetic activation alters the bone vasculature: implication for osteotropic breast cancer metastasis. [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 2682.
Abstract LB-169: Ovarian cancer cells selectively release exosomes containing tumor suppressor miRNAs to maintain SRC-mediated oncogenic activities
Authors: Mohammed H. Rashed, Pinar Kanlikilicer, Cristian Rodriguez Aguayo, Nashwa N. Kabil, Martin Pichler, Recep Bayraktar, Emine Bayraktar, Cristina Ivan, Rahul Mitra, George A. Calin, Anil K. Sood, Mohamed F. Abd-Ellah, Gouda K. Helal, Gabriel Lopez Berestein
Journal: Cancer Research (2016)

Abstract Exosomes have emerged as an important mediator of diverse biological functions including tumor cell progression, invasion, immune escape, and cell-to-cell communication, through the release of molecules such as mRNAs, microRNAs, and proteins. Ovarian cancer (OC) is one of the lethal cancers with extensive local invasion, metastasis, and poor diagnosis. Thus, finding novel targets for OC therapy are urgently needed. Here, we isolated 30-140 nm exosomes from the supernatant of one normal and six different OC cells. In addition, RNAs were isolated from cells and exosomes, and profiles of two miRNA fractions were obtained using affymetrix microarray analysis. By comparing signal intensities of microarray data and validation using RT-PCR analysis, we found that miR-940 was abundant in exosomes from SKOV3IP1, HeyA8, and HeyA8-MDR. Ectopic expression of miR-940 inhibited proliferation, colony formation, invasion, migration, induced G0/G1 cell cycle arrest, and apoptosis in OC. Overexpression of miR-940 also inhibited tumor cell growth in vivo. The target gene of miRNA-940 and the downstream pathway were further investigated using several target prediction algorithms. We identified specific targeting sites for miR-940 in the 3’-untranslated region (3’-UTR) of SRC. We then experimentally validated miR-940 as a direct regulator of SRC using cell transfection and luciferase assays, and showed that miR-940 inhibited SRC expression at mRNA and protein levels. Following this reduction, the activity of proteins downstream of SRC, such as FAK, paxillin and Akt were also reduced. Collectively, our results suggest that OC cells selectively secreted the tumor suppressive miR-940 into the extracellular environment via exosomes, to maintain their invasiveness and tumorigenic phenotype. Citation Format: Mohammed H. Rashed, Pinar Kanlikilicer, Cristian Rodriguez Aguayo, Nashwa N. Kabil, Martin Pichler, Recep Bayraktar, Emine Bayraktar, Cristina Ivan, Rahul Mitra, George A. Calin, Anil K. Sood, Mohamed F. Abd-Ellah, Gouda K. Helal, Gabriel Lopez Berestein. Ovarian cancer cells selectively release exosomes containing tumor suppressor miRNAs to maintain SRC-mediated oncogenic activities. [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 LB-169.
Primary Linneg/CD45neg/CD271pos/PDGFRαlow/Neg Stroma Stem Cells In Adult Human Bone Marrow Show a Distinct Molecular Signature and Potent Hematopoiesis-Supporting Function
Authors: Hongzhe Li, Dimitra Zacharaki, Roshanak Ghazanfari, Marja Ekblom, Simón Méndez-Ferrer, Stefan Scheding
Journal: Blood (2013)
TARC Predicts PET-Normalization and Event Free Surival in Relapsed/Refractory Hodgkin Lymphoma Patients Treated with Brentuximab Vedotin
Authors: Alison J Moskowitz, Sun Cho, Martin Fleisher, Kaitlin M Woo, Zhigang Zhang, Stephanie Fox, Susan J McCall, Heiko Schoder, Joachim Yahalom, Craig H Moskowitz
Journal: Blood (2015)