tbuckley/cabot-search huggingface dataset:
LGG-18. MOLECULAR ALTERATIONS PREDICT RESPONSE TO CHEMOTHERAPY AND OUTCOME OF PEDIATRIC LOW-GRADE GLIOMA
Authors: Michal Zapotocky, Scott Ryall, Matthew Mistry, Anthony Arnoldo, Alvaro Lassaletta, Ana Guerreiro Stucklin, Rahul Krishnatry, Kohei Fukuoka, Peter Dirks, Vijay Ramaswamy, Ute Bartels, Annie Huang, Nataliya Zhukova, Eric Bouffet, Uri Tabori, Cynthia Hawkins
Journal: Neuro-Oncology (2017)

BACKGROUND: Pediatric low-grade glioma (pLGG) is the most common childhood brain tumor. Recently, alterations of the RAS/MAPK pathway have been identified as the major driver of PLGG however little is known about prognostic implications. DESIGN/METHODS: We undertook a large population based study of all pLGG diagnosed from 1985–2015. Detection of known pLGG-related fusions was evaluated by NanoString and point mutations BRAF-V600E and H3.3K27M were evaluated using QX200™Droplet Digital™PCR. Results were correlated with outcome and response to chemotherapy. RESULTS: BRAF was found to be altered (KIAA1549-BRAF or BRAF-V600E) in 57% of patients in our pLGG cohort with full clinical and molecular data (n=480). Other alterations accounted for 6% of cases (FGFR1-TACC1(n=9), MYBL1(n=5), H3.3K27M(n=10)). The remaining 37% pLGG cases did not harbor any of evaluated alterations. Additional 134 patients with neurofibromatosis-1(NF1) were included in survival analysis. Kaplan-Meier analysis revealed 10-year PFS 72.3% for NF1, 68.3% for all KIAA1549-BRAF, and 28.4% for BRAF-V600E(p<0.0001). Among other alterations, H3.3K27M delineated a poor prognostic group with behavior similar to high-grade glioma. All patients with FGFR1-TACC1 and MYBL1 were alive at the time of analysis despite several observed progressions. Furthermore, we evaluated whether differences in survival could be correlated with response to conventional therapy in 92 patients. Change in tumor size at 6 months of chemotherapy differed depending on alteration. 45% of patients with BRAF-KIAA1549 responded to first line chemotherapy, and only 7.5% progressed. Similarly, 35% of NF1 patients responded and none progressed. In contrast, only 15% BRAF-V600E responded and more than half of tumors exhibited growth after six months of chemotherapy. CONCLUSIONS: In contrast to BRAF-V600E, KIAA1549-BRAF defines a group of pLGG patients with excellent prognosis and response to chemotherapy similar to NF1. Biopsy should be mandated in order to predict outcome, response to chemotherapy and evaluate targets for novel therapies.
Circulating Lipoproteins: A Trojan Horse Guiding Squalenoylated Drugs to LDL-Accumulating Cancer Cells
Authors: Dunja Sobot, Simona Mura, Marie Rouquette, Branko Vukosavljevic, Fanny Cayre, Eric Buchy, Grégory Pieters, Sébastien Garcia-Argote, Maike Windbergs, Didier Desmaële, Patrick Couvreur
Journal: Molecular Therapy (2017)

Selective delivery of anticancer drugs to rapidly growing cancer cells can be achieved by taking advantage of their high receptor-mediated uptake of low-density lipoproteins (LDLs). Indeed, we have recently discovered that nanoparticles made of the squalene derivative of the anticancer agent gemcitabine (SQGem) strongly interacted with the LDLs in the human blood. In the present study, we showed both in vitro and in vivo that such interaction led to the preferential accumulation of SQGem in cancer cells (MDA-MB-231) with high LDL receptor expression. As a result, an improved pharmacological activity has been observed in MDA-MB-231 tumor-bearing mice, an experimental model with a low sensitivity to gemcitabine. Accordingly, we proved that the use of squalene moieties not only induced the gemcitabine insertion into lipoproteins, but that it could also be exploited to indirectly target cancer cells in vivo.
Genetic variation in transforming growth factor beta 1, serum levels and risk of colorectal neoplasia
Authors: Barbara Saltzman, Robert Decker, Andre Theriault, Lance Yokochi, Geoffrey Maiyoh, Jennifer Yamamoto, Loic Le Marchand
Journal: Cancer Research (2007)

4118  In the normal intestinal epithelium, TGFβ1 acts as a growth inhibitor but in transformed cells it may act as a tumor promoter. Only limited information is available on genetic variation in the TGFβ1 gene and its relationship to circulating levels and risk of colorectal cancer. Preliminary evidence indicates that several single nucleotide polymorphisms (SNPs) in the TGFβ1 gene, including C-509T, L10P, and R25P, may be associated with altered circulating levels of TGFβ1. Other SNPs including G-800A and T263I are suspected to influence transcription or activation of TGFβ1 based on in vitro studies. To characterize associations of genetic variation (non-synonymous SNPs, tagSNPs and haplotypes with frequency >0.05) in TGFβ1 with risk of colorectal neoplasia, we conducted two case-controls studies (one screening-based study among 271 colorectal adenoma cases and 544 controls, and a population-based study of 535 colorectal adenocarcinoma cases and 656 controls) among Japanese Americans, Caucasians and Native Hawaiians in Hawaii. We genotyped 16 tagSNPs on the study participants based on a comprehensive examination of the linkage disequilibrium structure of the TGFβ1 gene that included a dense set of 29 SNPs and 2 haplotype blocks. Haplotypes within these blocks were estimated from the tagSNPs. Serum TGFβ-1 was measured by sandwich ELISA among the subjects of the adenoma study. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) adjusting for covariates.   The SNPs previously suggested to be functional, including G-800A, C-509T, L10P, R25P, and T263I, were not found to be associated with either adenoma or adenocarcinoma in our study. The number of variant G alleles for tagSNP rs6957 was associated with lower serum TGFβ1 (means, 95% CI, in ng/mL for AA=30.7, 29.6-31.7; AG=32.4, 31.0-33.8; GG=28.6, 25.1-32.0; p= 0.03) after adjusting for age and other factors. Carriers of the variant G allele for tagSNP rs11466345 had a significantly lower risk of adenocarcinoma (AG vs. AA, OR=0.9, 95% CI: 0.7, 1.2; GG vs. AA, OR= 0.4, 95% CI: 0.2-0.7, p-trend =0.01). The haplotype carrying these two variants was also statistically significantly associated with a reduced risk of adenocarcinoma (OR=0.3, 95% CI: 0.1-0.8). Although not statistically significant, the direction and magnitude of the association for this haplotype was similar for adenoma (OR=0.3, 95% CI: 0.1-1.2).  These results suggest that a specific haplotype in the 39 region of TGFβ1 is associated with genetic susceptibility to colorectal neoplasia. If this finding is reproduced, fine-mapping would be needed to identify the causal variant(s).
Genomic determinants of chronic myelomonocytic leukemia
Authors: B J Patel, B Przychodzen, S Thota, T Radivoyevitch, V Visconte, T Kuzmanovic, M Clemente, C Hirsch, A Morawski, R Souaid, C Saygin, A Nazha, B Demarest, T LaFramboise, H Sakaguchi, S Kojima, H E Carraway, S Ogawa, H Makishima, M A Sekeres, J P Maciejewski
Journal: Leukemia (2017)
GENE-15. CAVATICA- A PEDIATRIC GENOMIC CLOUD EMPOWERING DATA DISCOVERY THROUGH THE PEDIATRIC BRAIN TUMOR ATLAS
Authors: Pichai Raman, Angela J Waanders, Phillip B Storm, Jena V Lilly, Jennifer Mason, Allison P Heath, Alex S Felmeister, Anthony Cros, Yuankun Zhu, Leonard Sender, Michael Prados, Sabine Mueller, Rishi Lulla, Javad Nazarian, Adam C Resnick
Journal: Neuro-Oncology (2017)

CAVATICA (cavatica.org) was developed to address the lack of open access large scale pediatric cancer genomic datasets for the research community. As the first of its kind pediatric genomic portal, CAVATICA empowers data upload, sharing, and creation of pipelines, data, algorithms, visualizations, and hypotheses. Building upon the need for pediatric brain tumor genome dataset, the Pediatric Brain Tumor Atlas was founded in late 2016, a concerted multi-institution effort by the Children's Brain Tumor Consortium (CBTTC) and the Pacific Pediatric Neuro-Oncology Consortium. The goal of the Pediatric Brain Tumor Atlas is to characterize and deeply profile a newly defined cohort of brain tumor samples across diverse histopathologies via a combination of whole exome sequencing, whole genome sequencing, RNA sequencing and limited proteomic analysis. CAVATICA is positioned to support integrative analysis and open access to data alongside shared computation and algorithms that empower users to further integrate and analyze their own uploaded data. Additionally, CAVATICA provides further portal access to dbGaP approved users to TCGA and other NCI datasets hosted by the NCI's Cancer Genomics' Cloud. By committing to the rapid release of these large pediatric brain tumor data and their deposition in CAVATICA's cloud-based environment supporting shared pipelines, computation, and visualizations, PNOC and the CBTTC's collaborating membership are seeking to provide a centralized, collaborative rapid discovery environment for researchers to engage new discovery and data reuse. An additional component of this research application ecosystem, the data generated by the Pediatric Brain Tumor Atlas within CAVATICA will also link with PedcBioPortal (PedcBioPortal.org), a data visualization and analysis application further integrating across additional public and deposited datasets. In summary, CAVATICA will empower data discovery and hypothesis generation for the Pediatric Brain Tumor Atlas.
Visual Acuity Change over 12 Months in the Prospective Progression of Atrophy Secondary to Stargardt Disease (ProgStar) Study
Authors: Xiangrong Kong, Rupert W. Strauss, Artur V. Cideciyan, Michel Michaelides, José-Alain Sahel, Beatriz Munoz, Mohamed Ahmed, Ann M. Ervin, Sheila K. West, Janet K. Cheetham, Hendrik P.N. Scholl
Journal: Ophthalmology (2017)
EPND-05. LYSINE SPECIFIC DEMETHYLASE-1 (LSD-1) INHIBITOR SYC-836 IN COMBINATION WITH RADIATION PROLONGS ANIMAL SURVIVAL IN PATIENT-DERIVED ORTHOTOPIC XENOGRAFT (PDOX) MODEL OF POSTERIOR FOSSA EPENDYMOMA
Authors: Sibo Zhao, Huiyuan Zhang, Lin Qi, Holly Lindsay, Yuchen Du, Mari Kogiso, Frank Braun, Sarah Injac, Lazlo Perlaky, Donald W. Parsons, Murali Chintagumpala, Adekunle Adesina, Yongcheng Song, Xiao-Nan Li
Journal: Neuro-Oncology (2017)

BACKGROUND: Recent molecular subgrouping of ependymoma (EPN) has identified one group, posterior fossa A (PFA), to have one of the worst prognosis and driven by epigenetic changes, suggesting targeting epigenetic changes in PFA EPN can potentially be effective. In this study, we examined the therapeutic efficacy of SYC-836, a novel LSD-1 inhibitor compound developed at Baylor College of Medicine, in PDOX models of posterior fossa EPN. METHODS: To examine in vitro anti-tumor activities, paired primary cultured cells (both as attached cells and neurospheres) from a posterior fossa EPN cell line (ICb-4423EPN) were subjected to SYC-836 at various concentrations (0-25uM). Cell viability and proliferation were measured over 14 days. To validate the drug’s in vivo efficacy, two established posterior fossa EPN PDOX models, ICb-4423EPN and ICb-2002EPN, were utilized. 40 eight weeks old SCID mice per model were implanted with tumor cells and divided into 4 treatment groups each: 1) control, 2) radiation, 3) SYC-836 only, and 4) combination (radiation + SYC-836). Animal survival times were analyzed using log rank analysis. Changes of histone lysine methylation were examined through western hybridization. RESULTS: SYC-836 demonstrated effective cell killing in vitro in both time- and dose-dependent manner. In vivo experiment was completed in 1 of the 2 EPN PDOX models with the second model ongoing. There were no survival benefit with either XRT only (P=0.205) or SYC-836 only (P=0.186) when compared to the control group; however, when used in combination, the treatment strategy lead to significant improvement in animal survival (P=0.004). SYC-836 was well tolerated in mice. CONCLUSION: Our data showed that combining SYC-836 with current standard therapy of radiation synergistically prolongs animal survival significantly. SYC-836 may have a role in the clinical setting by either reducing radiation dosages, or be an adjuvant agent to other chemotherapy drugs in our treatment approach for ependymoma.
Risk of infection following colonoscopy and sigmoidoscopy in symptomatic patients
Authors: Jiun-Nong Lin, Chang-Bi Wang, Chih-Hui Yang, Chung-Hsu Lai, Hsi-Hsun Lin
Journal: Endoscopy (2017)

Background and study aims Previous studies describing the incidence of infection after colonoscopy and sigmoidoscopy are limited. The aim of this study was to determine the incidence of infection, and to propose a nomogram to predict the probability of infection following colonoscopy and sigmoidoscopy in symptomatic patients. Patients and methods A nationwide retrospective study was conducted by analyzing the National Health Insurance Research Database of Taiwan. The incidence of infection within 30 days after colonoscopy and sigmoidoscopy was assessed and compared with a control group matched at a ratio of 1:1 based on age, sex, and the date of examination. Results In all, 112 543 patients who underwent colonoscopy or sigmoidoscopy and 112 543 matched patients who did not undergo these procedures were included. The overall incidence of infection within 30 days after colonoscopy and sigmoidoscopy was 0.37 %, which was significantly higher than that of the control group (0.04 %; P < 0.001). Diverticulitis, peritonitis, and appendicitis were the most common infections. Patients who underwent colonoscopy or sigmoidoscopy had a 9.38-fold risk of infection (95 % confidence interval, 6.81 - 12.93; P < 0.001) compared with the control group. The predicted infection-free rates of the nomogram were closely aligned with the actual infection-free rates, with a bootstrapping concordance index of 0.763. Conclusions Colonoscopy and sigmoidoscopy are associated with an increased risk of infection, which may occur after these procedures. Our nomogram may provide clinicians with an easy tool to evaluate the risk of infection after colonoscopy and sigmoidoscopy in symptomatic patients.
Abstract #1688: Pathways conferring sensitivity to etoposide and other topoisomerase II targeting agents
Authors: Alexander Stepanov, Jeffrey Berk, Kisley Sinha, John Nitiss
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

Topoisomerase II (Top2) is the principal target for highly active anticancerdrugs. Etoposide, anthracyclines and other clinically active agents have been termed Top2 poisons, because the drugs generate DNA damage by trapping the enzyme when it is covalently bound to DNA. Our previous work has demonstrated that many DNA repair proteins that are required for repair of double strand breaks arising from ionizing radiation. These include all components of the two major double strand break repair pathways (homologous recombination and NHEJ), repair nucleases such as Rad2, Tdp1, and Mms4/Mus81, proteins involved in checkpoint responses, as well as other proteins whose role in DNA repair remains less certain. We have carried out a genome wide screen in the yeast S. cerevisiae to identify additional proteins that alter etoposide sensitivity. A novel aspect of our screening procedure was the use of an artificialtranscriptional repressor that blocks the expression of several yeast genes that are involved in the efflux of small molecules. We identified more than 50 genes that confer hypersensitivity to etoposide that had not been previously identified in genome wide screens of genes important for surviving DNA damage. All gene deletions identified in the primary screen were verified using an independent assay that tests sensitivity to an intercalating Top2 targeting drug. Therefore, all of the identified genes are likely to be important for surviving Top2 mediated DNA damage. We have identified several pathways that are critical for surviving exposure to etoposide. One pathway, which includes previously identified repair genes, is important for repairing double strand breaks that occur during S phase. This result supports the hypothesis that double strand breaks induced during replication are important for cell killing by Top2 targeting drugs. We also identified several genes that are involved in ubiquitination and proteasome mediated degradation. These results are consistent with the hypothesis that degradation of Top2 by the proteasome plays an important role in repairing Top2 mediated damage. Finally, we also identified several unexpected classes of proteins. One group includes several ribosomal proteins. We suggest that the ribosomal proteins may be important in modulating translational responses to DNA damage or cellular stress. Although the genes described here were identified in yeast, many of these genes have homologs in mammalian cells and are likely to be important in the sensitivity of mammalian cells to etoposide and other Top2 targeting agents. Current experiments are assessing this hypothesis.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1688.
MONARCH 1, A Phase II Study of Abemaciclib, a CDK4 and CDK6 Inhibitor, as a Single Agent, in Patients with Refractory HR+/HER2− Metastatic Breast Cancer
Authors: Maura N. Dickler, Sara M. Tolaney, Hope S. Rugo, Javier Cortés, Véronique Diéras, Debra Patt, Hans Wildiers, Clifford A. Hudis, Joyce O'Shaughnessy, Esther Zamora, Denise A. Yardley, Martin Frenzel, Andrew Koustenis, José Baselga
Journal: Clinical Cancer Research (2017)

Purpose: The phase II MONARCH 1 study was designed to evaluate the single-agent activity and adverse event (AE) profile of abemaciclib, a selective inhibitor of CDK4 and CDK6, in women with refractory hormone receptor-positive (HR+), HER2- metastatic breast cancer (MBC).Experimental Design: MONARCH 1 was a phase II single-arm open-label study. Women with HR+/HER2- MBC who had progressed on or after prior endocrine therapy and had 1 or 2 chemotherapy regimens in the metastatic setting were eligible. Abemaciclib 200 mg was administered orally on a continuous schedule every 12 hours until disease progression or unacceptable toxicity. The primary objective of MONARCH 1 was investigator-assessed objective response rate (ORR). Other endpoints included clinical benefit rate, progression-free survival (PFS), and overall survival (OS).Results: Patients (n = 132) had a median of 3 (range, 1-8) lines of prior systemic therapy in the metastatic setting, 90.2% had visceral disease, and 50.8% had ≥3 metastatic sites. At the 12-month final analysis, the primary objective of confirmed objective response rate was 19.7% (95% CI, 13.3-27.5; 15% not excluded); clinical benefit rate (CR+PR+SD≥6 months) was 42.4%, median progression-free survival was 6.0 months, and median overall survival was 17.7 months. The most common treatment-emergent AEs of any grade were diarrhea, fatigue, and nausea; discontinuations due to AEs were infrequent (7.6%).Conclusions: In this poor-prognosis, heavily pretreated population with refractory HR+/HER2- metastatic breast cancer, continuous dosing of single-agent abemaciciclib was well tolerated and exhibited promising clinical activity. Clin Cancer Res; 23(17); 5218-24. ©2017 AACR.
Abstract 255: Modulation Of Cardiac Macrophages As A Strategy For Infarct Healing
Authors: Inthirai Somasuntharam, Sheridan Carroll, Milton Brown, Andres Garcia, Michael Davis
Journal: Circulation Research (2013)

Heart failure is the leading cause of death in the developed world and myocardial infarction (MI) is the most common cause. Macrophages are key cells that orchestrate the initial inflammatory as well as later stage wound healing responses following MI. These functions are carried out by pro-inflammatory (M1) and reparative (M2) macrophages respectively. Optimal healing response after MI requires a balancing act of the biphasic macrophage response, so as to not prolong inflammatory signals detrimental to wound healing. Taking advantage of the fact that interleukin-4 (IL-4) activates macrophages towards M2, we hypothesize that delivering IL-4 to the post-MI heart can alter the ratio of M2 to M1 macrophages in the infarct area and induce a better healing response. In this study, we validate our approach in vitro and perform in vitro optimization of a suitable delivery system. RAW 264.7 macrophages were stimulated with IL-4 (10ng/uL) or LPS/IFN-γ (100ng/mL and 10ng/mL) for 24h and gene expression markers (qPCR) and Nitric Oxide (NO) levels (Griess assay) analyzed as indication of M1or M2 activation. Mouse aortic endothelial cells were treated with conditioned media from these cells for 24h and tube formation assessed on matrigel. A bioactive, protease-cleavable polyethylene glycol (PEG) hydrogel delivery system was evaluated for release of functional IL-4 to LPS-activated macrophages. Empty or IL-4 encapsulating hydrogel was placed on a trans-well above LPS-stimulated macrophages. Collagenase I at 0.1mg/mL was applied over 48h to degrade the gels and release IL-4 (n≥3 and p&lt;0.05 considered significant by one-way ANOVA). We demonstrate that IL-4 significantly upregulates M2 markers (MRC-1 and Arg-1) while IFN-γ and LPS upregulate M1 markers (NO and TNF-alpha). We observe enhanced tube density in endothelial cells treated with M2 media while M1 inhibited tube formation. Hydrogel release study shows a significant reduction in NO levels of LPS-stimulated macrophages when IL-4 is released, demonstrating that IL-4 is released from the gel in its bioactive form. In conclusion, we show that macrophages can indeed respond to changing stimuli and adopt distinct activation types and our PEG based hydrogel could be a potential delivery system for in vivo IL-4 delivery.
Wound Healing: Silk Fibroin Biomaterial Shows Safe and Effective Wound Healing in Animal Models and a Randomized Controlled Clinical Trial (Adv. Healthcare Mater. 10/2017)
Authors: Wei Zhang, Longkun Chen, Jialin Chen, Lingshuang Wang, Xuexian Gui, Jisheng Ran, Guowei Xu, Hongshi Zhao, Mengfeng Zeng, Junfeng Ji, Li Qian, Jianda Zhou, Hongwei Ouyang, Xiaohui Zou
Journal: Advanced Healthcare Materials (2017)

Silk fibroin is a natural protein derived from Bombyx mori cocoons, and shows potential in tissue repair applications due to its excellent biomedical properties. The silk fibroin film, developed by Xiaohui Zou, Hongwei Ouyang, and co-workers from Zhejiang University in article number 1700121, is a highly transparent, biocompatible, air-permeable, waterproof and bacteria barrier scaffold. It significantly reduces the time to wound healing and incidence of adverse events compared to commercial dressing.