tbuckley/cabot-search huggingface dataset:
Comparative Effectiveness of Radical Prostatectomy Versus External Beam Radiation Therapy Plus Brachytherapy in Patients with High-risk Localized Prostate Cancer
Authors: Sebastian Berg, Alexander P. Cole, Marieke J. Krimphove, Junaid Nabi, Maya Marchese, Stuart R. Lipsitz, Joachim Noldus, Toni K. Choueiri, Adam S. Kibel, Quoc-Dien Trinh
Journal: European Urology (2018)
PDTM-15. IDENTIFICATION AND CHARACTERIZATION OF WILMS’ TUMOR PROTEIN IN PEDIATRIC MIDLINE GLIOMAS
Authors: Sulgi Lee, Madhuri Kambhampati, Sridevi Yadavilli, Heather Gordish-Dressman, Mariarita Santi, Conrad Cruz, Roger Packer, Isabel Almira-Suaurez, Eugene Hwang, Javad Nazarian
Journal: Neuro-Oncology (2018)

Pediatric midline gliomas, especially those associated with the pons, known as diffuse intrinsic pontine gliomas (DIPGs) are deadly pediatric brain cancer that makes up 10–15% of all central nervous system (CNS) tumors in children. Its anatomical location and infiltrative nature makes it one of the most challenging tumors to treat. Targeted therapies are gaining more interest in CNS tumors. Identification of tumor associated antigens is one of many requirements in developing an effective targeted therapy. Wilms’ tumor protein (WT1) has been ranked number 1 cancer immunotherapy target by National Cancer Institute. Many types of solid tumors have been shown to express WT1 and it is being examined as one of potential immunotherapeutic targets. Here we validated WT1 as a potential tumor associated antigen in pediatric diffuse midline gliomas using formalin fixed paraffin embedded (FFPE) tumor and adjacent healthy specimens, fresh frozen post-mortem tissues and patient-derived DIPG primary cell lines. Our immunohistochemistry (IHC) staining of patient FFPE specimens showed strong WT1 immunoreactivity in tumor compared to adjacent normal tissue. Western blot of tumor tissues and cell lines were performed to further validate WT1 levels in the tumors versus adjacent healthy tissues. Interestingly, tumors showed cytoplasmic expression of WT1. In addition, H3.1K27M subtype gliomas showed weak to absent WT1 immunoreactivity compared to strong to moderate in H3.3K27M subtypes. Western blots also validated the differential expression of the protein. Our study suggests that WT1 is a potential tumor specific antigen in pediatric midline gliomas, which can be utilized for targeted therapies such as immunotherapy.
Abstract 18253: Reliance on Electrocardiogram Computer Algorithm Interpretation to Activate ST Elevation Myocardial Infarction Processes of Care and Initiate Reperfusion Therapy: Impact on False Activation
Authors: Mohammad Al-akchar, Frank V Aguirre, Hadi Mahmaljy, Joseph Venturini, Stephanie Besser, Jenny Chambers, Sachin Goel, Varadendra Panchamukhi, Rohan Kalathiya, Raed Al-Dallow, Atman Shah, James K Liao
Journal: Circulation (2017)

Background: Rapid clinical assessment and accurate ECG interpretation are requisites to ensure expeditious initiation of reperfusion therapy in patients (pts) with presumed ST elevation myocardial ...
DRES-19. THE MECHANISMS OF RESISTANCE TO TEMOZOLOMIDE IN GLIOMA CELLS
Authors: Shigeo Ohba, Yuichi Hirose
Journal: Neuro-Oncology (2018)

Glioblastoma is one of the most aggressive tumors in the central nervous system tumors, with 5-year survival rates of less than 10%. The standard therapy for glioblastomas is maximal safe resection, followed by radiation therapy and chemotherapy with temozolomide (TMZ). One of the reasons of the worse prognosis is the acquisition of resistance to TMZ. TMZ is a DNA-methylating agent, delivering a methyl group to DNA (O6-guanine, N7-guanine and N3-adenine). The primary cytotoxic lesion, O6-methylguanine, mispairs with thymine, leading to futile DNA mismatch repair (MMR), formation of double strand breaks and eventual cell death, in the absence of O6-methylguanine DNA methyltransferase (MGMT). To clarify the mechanisms of resistance to TMZ and to find the way to overcome the resistance to TMZ, several clones of TMZ-resistant U251 were obtained and analyzed. #3 clone showed G2 arrest after TMZ exposure and this arrest was abrogated sooner compared to parental U251. TMZ did not induce G2 arrest in #8 clone. The expression of MGMT was not found in U251 parental cells, #3 cells nor #8 cells. The ability of homologous recombination (HR) was increased in #3 clone, and by suppression of HR, #3 resistant clone was resensitized to TMZ, however #8 was not. The protein levels of MSH6, which was associated with MMR, was reduced in #8 clone. PARP inhibitor resensitized #8 clone to TMZ, inducing apoptosis. Inhibition of HR or base excision repair was suggested to be a useful strategy to resensitize TMZ-resistant gliomas with higher HR or with MMR dysfunction to TMZ, respectively.
EXTH-56. CLINICALLY DELIVERABLE DEEP BRAIN STIMULATOR GENERATED ELECTRICAL FIELDS HAVE PROFOUND EFFECTS ON GLIOBLASTOMA MULTIFORME CELL LINES
Authors: Joshua Branter, Maria de, los Angeles, Estevez Cebrero, Richard Grundy, Surajit Basu, Stuart Smith
Journal: Neuro-Oncology (2018)

Phase III trials of the Optune system which utilises Tumour Treating Fields (TTFields) have shown positive results in both primary, and recurrent adult Glioblastoma multiforme (GBM) patients. These results have given strength to the feasibility of electromagnetic fields as a therapy for brain tumour patients. Here we present the repurposing deep brain stimulation (DBS) electrodes as a novel delivery system of therapeutic electric fields to GBM cell lines. Medtronic DBS electrodes were inserted into cell culture flasks and delivered clinically relevant electric fields over a range of frequencies and intensities to our panel of GBM cell lines. The effects of DBS treatment on cell viability, cell cycling, long-term effects of treatment, as well as genome-wide expression via microarray were analysed. GBM cells were also treated in a combinational fashion with mitotic inhibitors to enhance efficacy. DBS electric fields negatively affect cell proliferation and viability of our commercial and primary GBM cell lines over a range of clinically relevant DBS settings. The magnitude of these effects were dependent upon frequency, intensity and the number of DBS leads. Cells treated with DBS were re-seeded and growth rates were compared to non-treated cells. The treated cells experienced up to 50% slower growth rates following treatment. Cell cycle analysis revealed that DBS treated cells have significant levels of G0 phase accumulation relative to control flasks. The effects of electrotreatment on gene expression will be discussed. Efficacy of DBS may be increased with the addition of paclitaxel and mebendazole. DBS treatment has demonstrated efficacy against our array of GBM cell lines. The treatments offers an alternative electric fields treatment to TTFields, which has different mechanisms of action at the cellular level and this is reflected in our data.
COMP-07. COMPARATIVE MOLECULAR LIFE HISTORY OF SPONTANEOUS CANINE AND HUMAN GLIOMA
Authors: Samirkumar Amin, Beth Boudreau, Juan Emmanuel Martinez-Ledesma, Kevin Anderson, Hoon Kim, Kevin Johnson, Peter Dickinson, Rebecca Packer, Amanda Taylor, John Rossmeisl, Amy Heimberger, Jonathan Levine, Roel Verhaak
Journal: Neuro-Oncology (2018)

Sporadic glioma occurs in companion dogs at frequencies comparable to humans. Genomic characterization of canine glioma has a distinct merit, in that age distribution at the time of diagnosis implies a pediatric disease while the animals are in the adult stage of life. This creates an opportunity to compare relative timing of driver events to that of human glioma, and to evaluate the importance of host context in the presence of driver alterations. Second, breed-specific elevated cancer risk enables increased sensitivity to the characterization of evolutionary conserved mammalian mutational processes in gliomagenesis. We performed whole genome, exome, transcriptome and methylation sequencing on 188 canine tumor and germline samples. As in human adult gliomas, we found frequently occurring alterations in Tp53 pathway, cell cycle pathway (Cdk4, Cdkn2a), and receptor tyrosine kinases (Egfr, Pdgfrα) in canine glioma. Common R132 mutations in the Idh1 gene reflected a remarkable and species-agnostic but cancer-specific driving effect. Frequent whole chromosome gains were observed in syntenic regions of chromosome 13, harboring Pdgfrα and Myc, but we found notable absence of 1p/19q co-deletion and Tert promoter mutations. We calculate mutational processes and highlight ones related to DNA damage repair and transcriptional strand bias in both species. We also estimate mutational rate and relative timing of mutations, and compare those to human glioma in mapping life history of glioma, i.e., are canine glioma more similar to adult or pediatric human glioma? We found coding mutation rate on the lower end of human adult glioma cases but with a broader spectrum (0.3–3 per MB), while subset of cases having mutations found in human pediatric cancer drivers, e.g., Kmt2c, Setd2, Bcor. In bringing together a large canine glioma genomic sequencing dataset and comparing to human glioma, our study provides unique insights into glioma etiology and the chronology of glioma-causing somatic alterations.
ACTR-38. A PHASE I TRIAL OF AFATINIB AND RADIOTHERAPY (RT) WITH OR WITHOUT TEMOZOLOMIDE (TMZ) IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA (GBM)
Authors: Frank Saran, Allan James, Catherine McBain, Sarah Jefferies, Fiona Harris, Agnieszka Cseh, Karine Pemberton, Jennifer Schaible, Shaun Bender, Michael Brada
Journal: Neuro-Oncology (2018)

GBM is the most frequent primary CNS tumor. RT + TMZ represents first-line therapy. ErbB pathway dysregulation contributes to GBM pathogenesis; EGFR activation is associated with RT resistance. This 3 + 3 dose-escalation study assessed afatinib, an irreversible ErbB family blocker, with RT ± TMZ in newly diagnosed GBM. Patients with MGMT promoter methylation received afatinib (20, 30, 40 mg/day) + RT + TMZ for 6 weeks (RT period), then afatinib 40 mg/day + TMZ for 6 months, then afatinib 40 mg/day until progression/undue adverse events (AEs; Regimen M). Those with unmethylated MGMT promoter received RT + afatinib then afatinib (Regimen U). Primary endpoint was maximum tolerated dose (MTD) of afatinib + RT ± TMZ; secondary endpoints were safety, pharmacokinetics and antitumor activity. Thirty-six patients were enrolled (M, 20; U, 16). In regimen M, 1/6 (20 mg), 0/6 (30 mg) and 2/5 (40 mg) evaluable patients had dose-limiting toxicities (DLTs) in the RT period (two Grade 4 thrombocytopenia, one Grade 3 vomiting); MTD of afatinib + RT + TMZ was 30 mg/day. In regimen U, 0/3 (20 mg) and 1/6 (40 mg) evaluable patients had DLTs (Grade 3 diarrhea); MTD of afatinib + RT was 40 mg/day. Common treatment-related AEs were diarrhea, rash, fatigue, nausea and thrombocytopenia; 80% and 75% had Grade 3 AEs in M and U. Pharmacokinetic evaluation suggested that afatinib with RT ± TMZ had no influence on afatinib exposure. Five patients in M and one in U had an objective response. Five patients (M, 4; U, 1) were long-term responders to afatinib (>12 months treatment); two had available tumor samples. Both had MGMT promoter methylation; one had a PTPN11 mutation, the other focal EGFR amplification with concomitant EGFRvIII allele amplification. Afatinib + RT ± TMZ appears tolerable; preliminary biomarker analysis may indicate patients likely to have long-term responses.
CBMT-11. PEROXISOMAL FATTY ACID OXIDATION IN GLIOBLASTOMA DURING HYPOXIA
Authors: Laura Caflisch, Aleksandra Gruslova, Michael Garcia, Alessia Lodi, Stefano Tiziani, Andrew J. Brenner
Journal: Neuro-Oncology (2018)

Peroxisomal fatty acid oxidation (FAO) offers some unique metabolic advantages compared to mitochondrial FAO that may be important to cancer cells adapting to chronic hypoxia exacerbated by anti-angiogenic treatment. When peroxisomal FAO is dominant, the resulting low FADH2/NADH ratio allows for more efficient oxygen utilization and lower oxidative stress production during oxidative phosphorylation. Our previous findings suggest cells from tumors treated with bevacizumab are more sensitive to peroxisomal FAO inhibition. The current study further examines changes in peroxisomes, mitochondria, and their FAO pathways, and their roles in adaptation to hypoxia and anti-angiogenic treatment. Peroxisomal number was determined by electron microscopy. Gene expression was determined by QT-PCR. Metabolomic analysis by NMR/MRS revealed glioblastoma cells under chronic hypoxia (2–5 weeks) likely utilize less mitochondrial FAO and showed signs of increased oxidative stress. In some cell lines we observed that chronic hypoxic cells were more sensitive to treatment with a peroxisomal FAO inhibitor, particularly in an anti-angiogenic resistant tumor cell line. Increased expression (RQ>2) of the genes ACADVL, ACADS, and DECR2, suggests an increase in mitochondrial FAO for very long and short fatty acids and increase in peroxisomal FAO for unsaturated fatty acids. There were higher overall levels of peroxisomes in the anti-angiogenic resistant tumor cell line and lower levels of mitochondria in hypoxia compared to normoxia for cell lines which were sensitive to peroxisomal FAO inhibition (p<.05). Both chronic hypoxia in vitro and through anti-angiogenic treatment appear to produce changes in peroxisome and mitochondria levels and FAO pathways which we are currently further characterizing with additional cell lines and animal experiments.
Abstract #4664: Implication of ATM-/ATR-Chk1-E2F1-dependent up-regulation of ribonucleotide reductase R2 (RRM2) in DNA damage response
Authors: Yongwei Zhang, Tamara Jones, Scott Martin, Natasha Caplen, Yves Pommier
Journal: Cancer Research (2009)

To investigate drug mechanisms of action and identify molecular targets for the development of rational drug combinations, we are conducting synthetic siRNA-based RNAi screens to identify genes whose silencing affects anti-cancer drug responses. One such screen indicated that the silencing of RRM1 and RRM2, which encode the large and small subunits of the human ribonucleotide reductase (RNR) complex respectively, markedly enhances the cytotoxicity of the Topoisomerase 1 (Top1) inhibitor camptothecin (CPT). Silencing of RRM2 was also found to enhance DNA damage as measured by \#947;-H2AX. Further studies showed that CPT up-regulates both RRM1 and RRM2 mRNA and protein levels, and induces the nuclear translocation of RRM2. The Checkpoint kinase 1 (Chk1) was also up-regulated and activated in response to CPT. CHEK1 down-regulation by siRNA and small molecule inhibition of Chk1 activity blocked induction of RRM2 by CPT. CHEK1 siRNA also suppressed E2F1 up-regulation by CPT, and silencing of E2F1 suppressed the up-regulation of RRM2. Silencing of ATR or ATM, and inhibition of ATM activity by KU-55933 blocked Chk1 activation and RRM2 up-regulation. This study links the function of known components of CPT-induced DNA damage response with proteins required for the synthesis of dNTPs, presumably in preparation for DNA repair. Specifically, we propose that, upon DNA damage, Chk1 activation, mediated by ATM and ATR, regulates RRM2 expression through the E2F1 transcription factor. Up-regulation in RRM2 levels, coupled with its nuclear recruitment suggests an active role for RNR in the cellular response to CPT-mediated DNA damage that could potentially be exploited as strategy for enhancing the efficacy of Top 1 inhibitors.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4664.
Genomes reveal marked differences in the adaptive evolution between orangutan species
Authors: Maja P. Mattle-Greminger, Tugce Bilgin Sonay, Alexander Nater, Marc Pybus, Tariq Desai, Guillem de Valles, Ferran Casals, Aylwyn Scally, Jaume Bertranpetit, Tomas Marques-Bonet, Carel P. van Schaik, Maria Anisimova, Michael Krützen
Journal: Genome biology (2018)

Integrating demography and adaptive evolution is pivotal to understanding the evolutionary history and conservation of great apes. However, little is known about the adaptive evolution of our closest relatives, in particular if and to what extent adaptions to environmental differences have occurred. Here, we used whole-genome sequencing data from critically endangered orangutans from North Sumatra (Pongo abelii) and Borneo (P. pygmaeus) to investigate adaptive responses of each species to environmental differences during the Pleistocene.Taking into account the markedly disparate demographic histories of each species after their split ~ 1 Ma ago, we show that persistent environmental differences on each island had a strong impact on the adaptive evolution of the genus Pongo. Across a range of tests for positive selection, we find a consistent pattern of between-island and species differences. In the more productive Sumatran environment, the most notable signals of positive selection involve genes linked to brain and neuronal development, learning, and glucose metabolism. On Borneo, however, positive selection comprised genes involved in lipid metabolism, as well as cardiac and muscle activities.We find strikingly different sets of genes appearing to have evolved under strong positive selection in each species. In Sumatran orangutans, selection patterns were congruent with well-documented cognitive and behavioral differences between the species, such as a larger and more complex cultural repertoire and higher degrees of sociality. However, in Bornean orangutans, selective responses to fluctuating environmental conditions appear to have produced physiological adaptations to generally lower and temporally more unpredictable food supplies.
Zinc Transporter 8 Autoantibodies (ZnT8A) and a Type 1 Diabetes Genetic Risk Score Can Exclude Individuals With Type 1 Diabetes From Inappropriate Genetic Testing for Monogenic Diabetes
Authors: Kashyap A. Patel, Michael N. Weedon, Beverley M. Shields, Ewan R. Pearson, Andrew T. Hattersley, Timothy J. McDonald
Journal: Diabetes Care (2018)

We have recently shown that the detection of monogenic diabetes in a population can be improved by excluding individuals with type 1 diabetes (T1D) identified by having low C-peptide levels and/or the presence of GAD autoantibodies (GADA) or IA-2 autoantibodies (IA-2A) in the Using pharmacogeNetics to Improve Treatment in Early-onset Diabetes (UNITED) study (1). Since completion of the study, there are now two new tests that also robustly identify T1D: zinc transporter 8 autoantibodies (ZnT8A) (2) and the T1D genetic risk score (T1D GRS) (3,4). It is not known the extent to which the addition of these new tests will improve the diagnostics (1). Autoantibodies assessment was performed at recruitment. The median duration of diabetes at recruitment was 7.4 years (interquartile range [IQR] 2.5–17.3). GADA and IA-2A were measured as previously described (1). ZnT8A was measured by ELISA (RSR Ltd, Cardiff, U.K.) on a Dynex DS2 ELISA robot (Dynex, Preston, U.K.). The RSR ZnT8A ELISA is capable of detecting and quantifying autoantibodies specific to R325 or to W325, or to residue 325 nonspecific variants. We used >99th centile of a control population ( n = 1,559, age range …
IMMU-39. FIRST-IN-KIND T CELLS CARRYING A CHIMERIC ANTIGEN RECEPTOR AGAINST AN EXTRACELLULAR MATRIX PROTEIN TARGET GLIOBLASTOMA CELLS AND SHOW ANTI-TUMOR EFFICACY
Authors: Sadhak Sengupta, Mohan Nandhu, Sharon Longo, Sudarshana Sengupta, John Longo, Prakash Sampath, Mariano Viapiano
Journal: Neuro-Oncology (2018)

and PD-1/IDO1 inhibitors, with and without the anxiety inhibiting pharmacologic, propranolol.While there was no difference in OS between subjects treated with IgG control or propranolol, alone, 60% of mice treated with all four agents survived long-term, whereas only 30% survived long-term with trimodal immunotherapy, alone (P=0.001).CONCLUSIONS: Given the association between higher anxiety levels, and an increased mortality rate among cancer patients in the U.S., these data suggest that, inhibiting stress-signaling pathways may synergize to improve immunotherapeutic efficacy, specifically improved likelihood of sustained response, for patients with malignant glioma.
DDIS-05. PATIENT DERIVED NEUROSPHERE CULTURES IDENTIFY NOVEL CHEMOVULNERABILITIES IN GLIOBLASTOMA
Authors: Darren Finlay, Tao Long, Harshil Dhruv, Michael Berens, Kristiina Vuori
Journal: Neuro-Oncology (2018)

3-dimensional (3D) cell culture systems are increasingly used in biomedical research due to their recapitulation of tumor architecture, including pertinent nutrient and oxygen gradients, and a requisite drug penetration through multiple cell layers. Deployment of patient derived models of cancer (PDMC) propagated in defined media (serum-free) heightens clinical relevance of drug activity over that of long-term established cell lines, with an expectation of greater preclinical prediction of efficacy in patients. Indeed 3D tumor models retain the genomic heterogeneity and “stem-like” properties of the original tumors. Here we report results from screening 3D neurosphere cultures of 24 different glioblastoma (GBM) PDMC with focused, clinically-relevant, drug collections. In addition to uncovering patient-specific agents (Precision Medicine), the approach uncovers sub-stratification of GBM into novel chemosensitive groups. Specifically, cases dichotomize into instances of sensitivity to targeted agents such as proteasome inhibitors or those of growth factor signaling (e.g. TGFβ pathway modulators), although many novel targets are also identified. We further employ genomic and gene expression analyses to characterize said groups with a view to illustrating these chemovulnerabilities to detect the relevant signaling pathways’ therapeutic intervention points. In sum, using clinically-relevant PDMCs and 3D culture systems, we can identify drugs and novel targets relevant to individual patients. Once further validated, genomic characterization of new patient cultures could be used to predict sensitivity to certain perturbagens, making a case for evidence-based precision medicine. As current GBM treatment options are particularly limited, this approach may help provide insights for optimal use of available therapeutics.