tbuckley/cabot-search huggingface dataset:
Inhibition of Thioredoxin/Thioredoxin Reductase Induces Synthetic Lethality in Lung Cancers with Compromised Glutathione Homeostasis
Authors: Xiang Yan, Xiaoshan Zhang, Li Wang, Ran Zhang, Xingxiang Pu, Shuhong Wu, Lei Li, Pan Tong, Jing Wang, Qing H. Meng, Vanessa B. Jensen, Luc Girard, John D. Minna, Jack A. Roth, Stephen G. Swisher, John V. Heymach, Bingliang Fang
Journal: Cancer Research (2018)

Abstract Glutathione (GSH)/GSH reductase (GSR) and thioredoxin/thioredoxin reductase (TXNRD) are two major compensating thiol-dependent antioxidant pathways that maintain protein dithiol/disulfide balance. We hypothesized that functional deficiency in one of these systems would render cells dependent on compensation by the other system for survival, providing a mechanism-based synthetic lethality approach for treatment of cancers. The human GSR gene is located on chromosome 8p12, a region frequently lost in human cancers. GSR deletion was detected in about 6% of lung adenocarcinomas in The Cancer Genome Atlas database. To test whether loss of GSR sensitizes cancer cells to TXNRD inhibition, we knocked out or knocked down the GSR gene in human lung cancer cells and evaluated their response to the TXNRD inhibitor auranofin. GSR deficiency sensitized lung cancer cells to this agent. Analysis of a panel of 129 non–small cell lung cancer (NSCLC) cell lines revealed that auranofin sensitivity correlated with the expression levels of the GSR, glutamate-cysteine ligase catalytic subunit (GCLC), and NAD(P)H quinone dehydrogenase 1 (NQO1) genes. In NSCLC patient-derived xenografts with reduced expression of GSR and/or GCLC, growth was significantly suppressed by treatment with auranofin. Together, these results provide a proof of concept that cancers with compromised expression of enzymes required for GSH homeostasis or with chromosome 8p deletions that include the GSR gene may be targeted by a synthetic lethality strategy with inhibitors of TXNRD. Significance: These findings demonstrate that lung cancers with compromised expression of enzymes required for glutathione homeostasis, including reduced GSR gene expression, may be targeted by thioredoxin/thioredoxin reductase inhibitors.
Abstract 14477: Integrating Patient-Specific Cardiomyocyte Function With Population Multi-omics Identifies a Novel Arrhythmia Pathway
Authors: Kevin R Bersell, Tao Yang, Jonathan D Mosley, Andrew M Glazer, Jonathan D Brown, Courtney M Campbell, Charles C Hong, Quinn S Wells, Amanda N Johnson, Laura Short, Marcia A Blair, Elijah R Behr, Evmorfia Petropoulou, Yalda Jamshidi, Rob Gerszten, Mark D Benson, Ramachandran S Vasan, Qiong Yang, Gail P Jarvik, Bahram Namjou, Christian M Shaffer, Shan Parikh, Quanhu Sheng, Prince J Kannankeril, Thomas J Wang, Bjorn C Knollmann, Dan M Roden
Journal: Circulation (2017)

Introduction: In a family with Brugada Syndrome (BrS) and no mutation in the most common disease gene SCN5A, we identified a rare hypofunctional missense variant (G145R) in the transcription factor...
Circulating Cytokines Predict Immune-Related Toxicity in Melanoma Patients Receiving Anti-PD-1–Based Immunotherapy
Authors: Su Y. Lim, Jenny H. Lee, Tuba N. Gide, Alexander M. Menzies, Alexander Guminski, Matteo S. Carlino, Edmond J. Breen, Jean Y.H. Yang, Shila Ghazanfar, Richard F. Kefford, Richard A. Scolyer, Georgina V. Long, Helen Rizos
Journal: Clinical Cancer Research (2018)

Combination PD-1 and CTLA-4 inhibitor therapy has dramatically improved the survival of patients with advanced melanoma but is also associated with significant immune-related toxicities. This study sought to identify circulating cytokine biomarkers of treatment response and immune-related toxicity.The expression of 65 cytokines was profiled longitudinally in 98 patients with melanoma treated with PD-1 inhibitors, alone or in combination with anti-CTLA-4, and in an independent validation cohort of 49 patients treated with combination anti-PD-1 and anti-CTLA-4. Cytokine expression was correlated with RECIST response and immune-related toxicity, defined as toxicity that warranted permanent discontinuation of treatment and administration of high-dose steroids.Eleven cytokines were significantly upregulated in patients with severe immune-related toxicities at baseline (PRE) and early during treatment (EDT). The expression of these 11 cytokines was integrated into a single toxicity score, the CYTOX (cytokine toxicity) score, and the predictive utility of this score was confirmed in the discovery and validation cohorts. The AUC for the CYTOX score in the validation cohort was 0.68 at PRE [95% confidence interval (CI), 0.51-0.84; P = 0.037] and 0.70 at EDT (95% CI, 0.55-0.85; P = 0.017) using ROC analysis.The CYTOX score is predictive of severe immune-related toxicity in patients with melanoma treated with combination anti-CTLA-4 and anti-PD-1 immunotherapy. This score, which includes proinflammatory cytokines such as IL1a, IL2, and IFNα2, may help in the early management of severe, potentially life-threatening immune-related toxicity.See related commentary by Johnson and Balko, p. 1452.
58 Measuring pyloric function using the functional lumen imaging probe
Authors: S Bligh, P Park, M Bergstrom, J Arroyo, BP McMahon
Journal: Gut (2017)

Background  Manometric studies are known to be inadequate in evaluating tone and opening patterns of digestive sphincters. The functional lumen imaging probe (FLIP) evolved as an important tool in evaluating sphincteric regions in the gastrointestinal tract.  Aim  To evaluate the potential for this technique in a pilot study on a human volunteer to  1. Evaluate the efficiency and efficacy of placing and measuring with the probe endoscopically. 2. Demonstrate if the shape and function of the pylorus could be measured using this device. 3. Evaluate the effect of the administration of a pro-kenetic drug on the function of the pylorus.  Method  One subject volunteered for the procedure as the probe is already approved for diagnostic use in the gastrointestinal tract. The EndoFLIP system (Crospon, Galway, Ireland) was set up as previously described using probe model EF-353. An Olympus therapeutic endoscope was inserted as per normal upper gastrointestinal investigation. The probe was inserted into the endoscope biopsy channel and positioned straddling the pylorus. Distension measurements were made with probe volumes of 20 ml, 30 ml and 40 ml before and after the administration of 10 mg of metoclopramide (Primperan).  Results  Activity dramatically changed in the pylorus after Primperan. The narrowest region the sphincter measured using the minimum cross sectional (CSAmin) area was relatively inactive and stable before the drug but after the CSAmin varied significantly during the 20 s measurement window, indicating changes in activity.  Conclusions  The FLIP system can successfully measure distensibility in the pylorus and these measurements may be useful in determining proper function in the region.
COMP-24. UTILIZING MACHINE LEARNING METHODS FOR SEGMENTATION AND CLASSIFICATION OF BRAIN TUMORS BASED ON CONVENTIONAL MRI
Authors: Moran Artzi, Idan Bressler, Dafna Ben Bashat
Journal: Neuro-Oncology (2018)

High grade brain tumors and brain metastasis are the two most common malignant brain tumors in adults. There is high clinical importance for differentiating between the two, as well as for sub-classification of metastases based on their origin, since medical staging, surgical planning, and therapeutic decisions are vastly different for each tumor type. MRI is the modality of choice for the assessment of patients with brain tumors. However, in many cases, differentiation between the tumor types may be challenging due to their similar appearance on MRI. The aim of this study was to develop an automatic method for segmentation and classification of brain tumors based on conventional MRI. A retrospective analysis of 439 MRI data sets: 212 from patients with high grade glioma and 227 from patients with brain metastasis of breast, lung and other origins, was performed. Data include post contrast 3D T1 weighted images acquired at 1.5/3.0 Tesla MRI and clinical information including age, weight and gender. Following preprocessing and automatic segmentation of the enhancing tumor, several features were extracted: bag of features, first and second order statistical, morphological and wavelet features. The classifiers were trained in a 5-fold manner on 80% of the dataset and tested on the remaining 20% of the dataset. Sensitivity, specificity and accuracy were calculated. Best classification results obtained when classifying between high grade brain tumors and brain metastasis, using quadratic SVM classifier with mean accuracy=0.85, sensitivity=0.82 and specificity=0.87. Classifying brain metastases by their origin achieved best results with cosin KNN classifier with mean specificity=0.85 but low sensitivity=0.46. The proposed study demonstrates the use of machine learning methods for automatic segmentation and classification of brain tumors based on conventional MRI. Such methods may have great clinical importance in assisting in the diagnosis of new patients.
RTHP-21. CHARACTERIZATION OF RADIATION THERAPY EFFECTS ON CEREBRAL VASCULATURE IN PEDIATRIC BRAIN TUMOR SURVIVORS
Authors: Sivakami Avadiappan, Melanie Morrison, Angela Jakary, Erin Felton, Sabine Mueller, Janine Lupo
Journal: Neuro-Oncology (2018)

Although cranial Radiation Therapy (RT) plays an important role in the treatment of pediatric brain tumors, it is often associated with significant long-term side effects such as cognitive decline and vascular injury in the form of cerebral microbleeds (CMBs). Understanding the evolution of CMBs and the effect of their presence on surrounding vascular integrity could serve as a risk factor for evaluating the severity of radiation related injury in these children. The goal of this study was to explore the effects of RT on arterial structure, including how arterial thickness changes based on proximity to CMBs of varying sizes. 17 patients (ages 10–24) treated with whole-brain or whole-ventricular RT for pediatric brain tumors 2 months to 16 years prior to imaging, and 3 non-irradiated control patients (ages 14–26) were scanned on a 7 Tesla MRI scanner using a novel simultaneous MRA-SWI acquisition that enables visualization of arteries, veins, and CMBs all on one image. Arterial radii were quantified from segmented vessels and the resulting distribution of vessel radii thickness was correlated with clinical information and CMB burden. Individual CMB size was related to the distance from the nearest vessel. Overall, normalized arterial volume decreased as a function of time since RT. The fraction of small arteries increased with time since RT up to 2 years, after which a decreasing trend was observed. All CMBs were located closer to veins than arteries. Although larger CMBs were initially farther away from the nearest vein, over time CMBs far from surrounding vasculature varied in size. These results suggest that after a CMB forms, the surrounding vasculature narrows and eventually recedes. Current work is investigating the spatial distribution of these findings throughout the brain and how they relate to measured cognitive deficits in these children.
To switch or not to switch: results of a nationwide guideline of mandatory switching from originator to biosimilar etanercept. One-year treatment outcomes in 2061 patients with inflammatory arthritis from the DANBIO registry
Authors: Bente Glintborg, Anne Gitte Loft, Emina Omerovic, Oliver Hendricks, Asta Linauskas, Jakob Espesen, Kamilla Danebod, Dorte Vendelbo Jensen, Henrik Nordin, Emil Barner Dalgaard, Stavros Chrysidis, Salome Kristensen, Johnny Lillelund Raun, Hanne Lindegaard, Natalia Manilo, Susanne Højmark Jakobsen, Inger Marie Jensen Hansen, Dorte Dalsgaard Pedersen, Inge Juul Sørensen, Lis Smedegaard Andersen, Jolanta Grydehøj, Frank Mehnert, Niels Steen Krogh, Merete Lund Hetland
Journal: Annals of the Rheumatic Diseases (2018)

Objectives Real-world evidence on effectiveness of switching to biosimila r etanercept is scarce. In Denmark, a nationwide guideline of mandatory switch from 50 mg originator (ETA) to biosimilar (SB4) etanercept was issued for patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (AxSpA) in 2016. Clinical characteristics and treatment outcomes were studied in ETA-treated patients, who switched to SB4 (switchers) or maintained ETA (non-switchers). Retention rates were compared with that of a historic cohort of ETA-treated patients. Switchers who resumed ETA treatment (back-switchers) were characterised. Methods Observational cohort study based on the DANBIO registry. Treatment retention was explored by Kaplan-Meier plots and Cox regression (crude, adjusted). Results 1621 (79%) of 2061 ETA-treated patients switched to SB4. Disease activity was unchanged 3 months’ preswitch/postswitch. Non-switchers often received 25 mg ETA (ETA 25 mg pens/syringes and powder solution were still available). One-year adjusted retention rates were: non-switchers: 77% (95% CI: 72% to 82%)/switchers: 83% (79% to 87%)/historic cohort: 90% (88% to 92%). Patients not in remission had lower retention rates than patients in remission, both in switchers (crude HR 1.7 (1.3 to 2.2)) and non-switchers (2.4 (1.7 to 3.6)). During follow-up, 120 patients (7% of switchers) back-switched to ETA. Back-switchers’ clinical characteristics were similar to switchers, and reasons for SB4 withdrawal were mainly subjective. Conclusion Seventy-nine per cent of patients switched from ETA to SB4. After 1 year, adjusted treatment retention rates were lower in switchers versus the historic ETA cohort, but higher than in non-switchers. Withdrawal was more common in patients not in remission. The results suggest that switch outcomes in routine care are affected by patient-related factors and non-specific drug effects.
NIMG-57. IMAGING FEATURES OF POLYMORPHOUS LOWGRADE NEUROEPITHELIAL TUMOR OF THE YOUNG (PLNTY)
Authors: Derek R Johnson, Caterina Giannini, Timothy Kaufmann, Jonathan Morris
Journal: Neuro-Oncology (2018)

Polymorphous lowgrade neuroepithelial tumor of the young (PLNTY) is a recently described epileptogenic tumor. The imaging features of PLNTY are not well characterized, as the largest published series included only 7 patients with available CT or MR imaging. IRB-approved retrospective review of patients diagnosed with PLNTY at Mayo Clinic Rochester (MCR) or via the MCR consultative pathology practice between 01/2015 and 03/2018 with available CT and/or MR imaging. Eight patients with PLNTY met inclusion criteria for this study. Median age was 15 years (range 5 - 59 years), and 7 patients (88%) were female. Six tumors (75%) were temporal and 2 (25%) were extratemporal in location. MR imaging was available for review in all patients, and CT imaging was available in 5 patients (63%). Four of five (80%) of cases with CT imaging demonstrated dense tumoral calcification, and two of the three (66%) MR-only cases showed focal hypointensity on GRE sequences, likely reflecting calcification. Overall, 6/8 (75%) of cases demonstrated definite or probable calcification on imaging. Tumors were generally heterogeneous on FLAIR and T2-weighted images with hyperintense tumor tissue outside the region of calcification. T1-weighted images were likewise heterogeneous, with 2/8 (25%) of tumors demonstrating enhancement on post-gadolinium imaging. DISCUSSION: In this imaging series, the largest reported for patients with PLNTY, dense tumoral calcification and temporal lobe localization were common features, while enhancement was relatively rare. The high rate of tumoral calcification is distinct from other epileptogenic tumors seen in young patients, and may be a useful marker for pre-operative diagnosis.
Vaccines as an Integral Component of Cancer Immunotherapy
Authors: Jeffrey Schlom, James L. Gulley
Journal: JAMA (2018)

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RTHP-34. CRANIOSPINAL IRRADIATION (CSI) AS PART OF RE-IRRADIATION (RT2) FOR CHILDREN WITH RECURRENT INTRACRANIAL EPENDYMOMA
Authors: Derek Tsang, Louise Murray, Vijay Ramaswamy, Uri Tabori, Ute Bartels, Annie Huang, Eric Bouffet, Normand Laperriere
Journal: Neuro-Oncology (2018)

PURPOSE: To evaluate outcomes in children with relapsed intracranial ependymoma who received focal initial radiotherapy (RT1) and subsequently underwent RT2 with or without CSI. 32 patients under age 18 were identified in this retrospective review. Patients with distant relapse received craniospinal irradiation (CSI) as part of RT2. Prior to 2012, those with local relapse were treated with 54 Gy focal RT2 (1.8 Gy/fraction). From 2012 onwards, our practice changed to include 23.4–36 Gy CSI, followed by boost RT2 to all sites of resected or gross disease (CSI+RT2). The Kaplan-Meier method was used to calculate overall survival (OS) and freedom-from-progression (FFP); groups were compared using the log-rank test. Median follow-up was 5.5 years. Of 10 patients with distant relapse after RT1, 2-year OS and FFP were 66.7% (95% CI 28.2–87.8) and 22.2% (95% CI 3.4–51.3); amongst this group, there were no 5-year survivors. Of 22 patients with local-only recurrence after RT1, use of CSI (n = 7, median age 8.4 at RT2) was associated with a statistically significant improvement in FFP (5-year probability 83.3% [95% CI 27.3–97.5] with CSI+RT2 vs. 15.6% [95% CI 2.6–38.7] with focal RT2, p = 0.025). In those with posterior fossa (PF) ependymoma and local-only recurrence after RT1 (n = 16), 5-year FFP was 100% (95% CI 100-100) with CSI+RT2 vs. 10.4% (95% CI 0.6–36.4, p = 0.034) with focal RT2. There was no OS difference between those who received CSI+RT2 vs. focal RT2 (5-year OS; all tumour locations: 80.0% [95% CI 20.4–96.9] vs. 43.1% [95% CI 17.9–66.2], respectively, p = 0.24; PF subgroup: 100% [95% CI 100-100] vs. 36.7% [95% CI 11.3–63.0], respectively; p = 0.093). There were no cases of radiation necrosis attributable to RT2. Re-irradiation with CSI is a safe and effective approach to control recurrent disease in children with ependymoma.
COMP-20. THE NON-INVASIVE DETECTION OF GLIOBLASTOMA-DERIVED CELL-FREE DNA IN PLASMA USING NEXT-GENERATION SEQUENCING AND AN UNTARGETED VARIANT SEARCH
Authors: Hunter Underhill, Sabine Hellwig, David Nix, Preetida Bhetariya, Carrie Fuertes, Gabor Marth, Howard Colman, Mary Bronner, Randy Jensen
Journal: Neuro-Oncology (2018)

Detection of tumor-derived circulating cell-free DNA (ccfDNA) in plasma from glioblastoma patients remains elusive. The vast intra-tumor genetic heterogeneity of glioblastoma has limited targeted searches using a priori molecular profiling from a focal tissue sample. Recent data supports the isolation of shorter ccfDNA fragments relative to ccfDNA’s principal mononucleosomal peak (< 150 bp vs. 167 bp, respectively) to both enrich for tumor-derived ccfDNA and reduce false positives associated with next-generation sequencing (NGS). Here, we sought to determine if size selection affords detection of glioblastoma-derived ccfDNA. The ccfDNA from 11 healthy controls and 10 glioblastoma patients was molecularly barcoded, PCR amplified, and short ccfDNA fragments (< 150 bp) isolated using an automated gel-based technology. Both the original and size-selected ccfDNA samples were capture enriched using a custom-designed, glioblastoma-targeted NGS panel (128 genes, 128 kb) followed by paired-end sequencing. A consensus sequence was determined for each group of PCR duplicates with an identical barcode. The number of PCR duplicates used to derive a consensus sequence has been termed family size (FS). Non-reference alleles (NRAs) from consensus sequences in exons were tabulated. In healthy controls, there was a 15-fold reduction (P < 0.001) in NRAs (i.e., false positives) in the short ccfDNA fraction at FS ≥ 20 compared to FS ≥ 1. At FS ≥ 20 in the short ccfDNA fraction, there were significantly more NRAs in glioblastoma patients (i.e., potential tumor-derived variants) compared to healthy controls (1,065 ± 406 vs. 174 ± 75 NRAs, respectively; P < 0.001). In glioblastoma patients, there were significantly more NRAs in the short ccfDNA fraction compared to the original unselected ccfDNA sample at FS ≥ 20 (1,065 ± 406 vs. 165 ± 135 NRAs, respectively; P < 0.001). Selection for short ccfDNA fragments coupled with molecular barcoding detects glioblastoma-derived ccfDNA through concomitant improvements in both sensitivity and specificity during untargeted searches employing panel-based NGS.
A randomized, controlled double-blind study comparing the efficacy and safety of dose-ranging voclosporin with placebo in achieving remission in patients with active lupus nephritis
Authors: Brad H. Rovin, Neil Solomons, William F. Pendergraft, Mary Anne Dooley, James Tumlin, Juanita Romero-Diaz, Lidia Lysenko, Sandra V. Navarra, Robert B. Huizinga, Ihar Adzerikho, Elena Mikhailova, Natalya Mitkovskaya, Sergey Pimanov, Nikolay Soroka, Boris Iliev Bogov, Boriana Deliyska, Valentin Ikonomov, Eduard Tilkiyan, Ruth Almeida, Fernando Jimenez, Faud Teran, Irma Tchokhonelidze, Nino Tsiskarishvili, Maynor Herrera Mendez, Nilmo Noel Chavez Perez, Arturo Reyes Loaeza, Sergio Ramon Gutierrez Urena, Juanita Romero Diaz, Rodolfo Araiza Casillas, Magdalena Madero Rovalo, Stanislaw Niemczyk, Antoni Sokalski, Andrzej Wiecek, Marian Klinger, Olga V. Bugrova, Tatiana M. Chernykh, Tatiana R. Kameneva, Lidia V. Lysenko, Tatiana A. Raskina, Olga V. ReshEtko, Natalia N. Vezikova, Tatiana V. Kropotina, Adelya N. Maksudova, Vyacheslav Marasaev, Vladimir A. Dobronravov, Ivan Gordeev, Ashot M. EssAian, Alexey Frolov, Rosa Jelacic, Dragan Jovanovic, Branka Mitic, Gordana Pekovic, Milan Radovic, Goran Radunovic, Patricia Carreira, Federico Diaz Gonzalez, Xavier Fulladosa, Eduardo Ucar, Shamila De Silva, Chula Herath, Anura Hewageegana, Abdul Latiff Mohamed Nazar, A.W.M. Wazil, Iryna Dudar, Olga Godlevska, Svitlana Korneyeva, ViktoriIa Vasylets, Nataliya Sydor, Mykola Kolesnyk, Samir V. Parikh, Nancy Olsen, Ellen M. Ginzler, James A. Tumlin, Amit Saxena, Ramesh Saxena, Richard Alan Lafayette, William Franklin Pendergraft, Amber S. Podoll, Annie A. Arrey-Mensah, Michael Bubb, Jennifer Grossman, Alejandro I. Oporta, Alireza Nami, Md. Mujibur Rahman, Syed Atiqul Haq, Tak Mao Daniel Chan, Mok Mo Yin Temy, Harold Michael P. Gomez, James Bermas, Bernadette Heizel Reyes, Llewellyn T. Hao, Linda Charmaine Roberto, Eric Amante, Sandra V. Navarra, Allan E. Lanzon, Jung-Yoon Choe, Tae Young Kang, Yon Su Kim, Seung-Geun Lee, Ji Soo Lee, Jason Choo Chon Jun, Archana Vasudevan, Shue-Fen Luo, Tien-Tsai Cheng, Bancha Satirapoj, Kajohnsak Noppakun
Journal: Kidney International (2018)