tbuckley/cabot-search huggingface dataset:
Human gut microbiome: hopes, threats and promises
Authors: Patrice D Cani
Journal: Gut (2018)

The microbiome has received increasing attention over the last 15 years. Although gut microbes have been explored for several decades, investigations of the role of microorganisms that reside in the human gut has attracted much attention beyond classical infectious diseases. For example, numerous studies have reported changes in the gut microbiota during not only obesity, diabetes, and liver diseases but also cancer and even neurodegenerative diseases. The human gut microbiota is viewed as a potential source of novel therapeutics. Between 2013 and 2017, the number of publications focusing on the gut microbiota was, remarkably, 12 900, which represents four-fifths of the total number of publications over the last 40 years that investigated this topic. This review discusses recent evidence of the impact of the gut microbiota on metabolic disorders and focus on selected key mechanisms. This review also aims to provide a critical analysis of the current knowledge in this field, identify putative key issues or problems and discuss misinterpretations. The abundance of metagenomic data generated on comparing diseased and healthy subjects can lead to the erroneous claim that a bacterium is causally linked with the protection or the onset of a disease. In fact, environmental factors such as dietary habits, drug treatments, intestinal motility and stool frequency and consistency are all factors that influence the composition of the microbiota and should be considered. The cases of the bacteria Prevotella copri and Akkermansia muciniphila will be discussed as key examples.
Incidence, morbidity and mortality of patients with achalasia in England: findings from a study of nationwide hospital and primary care data
Authors: Philip R Harvey, Tom Thomas, Joht S Chandan, Jemma Mytton, Ben Coupland, Neeraj Bhala, Felicity Evison, Prashant Patel, Krishnarajah Nirantharakumar, Nigel J Trudgill
Journal: Gut (2018)

Background Achalasia is an uncommon condition characterised by failed lower oesophageal sphincter relaxation. Data regarding its incidence, prevalence, disease associations and long-term outcomes are very limited. Methods Hospital Episode Statistics (HES) include demographic and diagnostic data for all English hospital attendances. The Health Improvement Network (THIN) includes the primary care records of 4.5 million UK subjects, representative of national demographics. Both were searched for incident cases between 2006 and 2016 and THIN for prevalent cases. Subjects with achalasia in THIN were compared with age, sex, deprivation tand smoking status matched controls for important comorbidities and mortality. Results There were 10 509 and 711 new achalasia diagnoses identified in HES and THIN, respectively. The mean incidence per 100 000 people in HES was 1.99 (95% CI 1.87 to 2.11) and 1.53 (1.42 to 1.64) per 100 000 person-years in THIN. The prevalence in THIN was 27.1 (25.4 to 28.9) per 100 000 population. Incidence rate ratios (IRRs) were significantly higher in subjects with achalasia (n=2369) compared with controls (n=3865) for: oesophageal cancer (IRR 5.22 (95% CI: 1.88 to 14.45), p&lt;0.001), aspiration pneumonia (13.38 (1.66 to 107.79), p=0.015), lower respiratory tract infection (1.33 (1.05 to 1.70), p=0.02) and mortality (1.33 (1.17 to 1.51), p&lt;0.001). The median time from achalasia diagnosis to oesophageal cancer diagnosis was 15.5 (IQR 20.4) years. Conclusion The incidence of achalasia is 1.99 per 100 000 population in secondary care data and 1.53 per 100 000 person-years in primary care data. Subjects with achalasia have an increased incidence of oesophageal cancer, aspiration pneumonia, lower respiratory tract infections and higher mortality. Clinicians treating patients with achalasia should be made aware of these associated morbidities and its increased mortality.
The EndoRotor, a novel tool for the endoscopic management of pancreatic necrosis
Authors: Sophia van der Wiel, Jan-Werner Poley, Marina Grubben, Marco Bruno, Arjun Koch
Journal: Endoscopy (2018)

Acute pancreatitis may run a severe course when pancreatic necrosis becomes infected, with mortality rates of up to 30 % [1] [2] [3]. Endoscopic drainage and ensuing necrosectomy have been shown to be effective in the management of pancreatic necrosis [4] [5]. One of the main limitations of endoscopic necrosectomy is the lack of dedicated and effective instruments to remove the necrotic tissue.
Methotrexate and BAFF interaction prevents immunization against TNF inhibitors
Authors: Samuel Bitoun, Gaetane Nocturne, Bineta Ly, Roman Krzysiek, Pierre Roques, Alain Pruvost, Audrey Paoletti, Juliette Pascaud, Pierre Dönnes, Kimberly Florence, Aude Gleizes, Agnes Hincelin-Mery, Matthieu Allez, Salima Hacein-Bey-Abina, Fabienne Mackay, Marc Pallardy, Roger Le Grand, Xavier Mariette
Journal: Annals of the Rheumatic Diseases (2018)

Objectives TNF inhibitors (TNFi) can induce anti-drug antibodies (ADA) in patients with autoimmune diseases (AID) leading to clinical resistance. We explored a new way of using methotrexate (MTX) to decrease this risk of immunisation. Methods We treated BAFF transgenic (BAFFtg) mice, a model of AID in which immunisation against biologic drugs is high, with different TNFi. We investigated the effect of a single course of MTX during the first exposure to TNFi. Wild-type (WT) and BAFFtg mice were compared for B-Cell surface markers involved in MTX-related purinergic metabolism, adenosine production and regulatory B-cells (Bregs). We translated the study to macaques and patients with rheumatoid arthritis from the ABIRISK cohort to determine if there was an interaction between serum BAFF levels and MTX that prevented immuniation. Results In BAFFtg but not in WT mice or macaques, a single course of MTX prevented immunisation against TNFi and maintained drug concentration for over 52 weeks. BAFFtg mice B-cells expressed more CD73 and CD39 compared to WT mice. MTX induced adenosine release from B cells and increased Bregs and precursors. Use of CD73 blocking antibodies reversed MTX-induced tolerance. In patients from the ABIRISK cohort treated with TNFi for chronic inflammatory diseases, high BAFF serum level correlated with absence of ADA to TNFi only in patients cotreated with MTX but not in patients on TNFi monotherapy. Conclusion MTX and BAFF interact in mice where CD73, adenosine and regulatory B cells were identified as key actors in this phenomenon. MTX and BAFF also interact in patients to prevent ADA formation.
EPEN-14. SUBGROUP-SPECIFIC THERAPY OPTIONS FOR CHILDHOOD SUPRATENTORIAL EPENDYMOMA
Authors: Vladimir Amani, Andrew Donson, Andrea Griesinger, Davis Witt, Jean Mulcahy Levy, Lindsey Hoffman, Todd Hankinson, Michael Handler, Rajeev Vibhakar, Kathleen Dorris, Nicholas Foreman
Journal: Neuro-Oncology (2018)

Treatment of ependymoma has changed little over the years and is essentially limited to surgery and radiation. Targeted therapy options have been hindered by limited preclinical testing. Our group has identified a variety of potential therapy options for ependymoma based on drug screening using novel human posterior fossa ependymoma cell lines with chromosome 1q gain. This preclinical approach identified 5-FU, retinoids and a subset of receptor tyrosine kinase inhibitors (RTKI) to be ependymoma-selective. Whether these agents were also effective in RELA fusion driven supratentorial ependymoma was not determined due to of a lack of available supratentorial ependymoma cell lines. Recently we were able to generate a novel supratentorial cell line harboring 1q+ as well as the RELA-C11orf95 fusion. This novel in vitro model was used to screen and assess ependymoma-selective drug sensitivity across a panel of 124 FDA-approved oncology drugs. Additionally, we are able to compare drug sensitivities between supratentorial and posterior fossa ependymoma. Our initial findings indicate that the two ependymoma subgroups respond to different therapy options with some overlap, notably RTKIs imatinib, axitinib and pazopanib. Conversely, 5-FU, a top hit in posterior fossa ependymoma, showed very little effect in the supratentorial model. This finding may explain the lack of response in supratentorial ependymoma tumors enrolled in early phase trials of 5-FU. Comparative drug screening of further supratentorial lines, and in vivo testing, will address the need for subgroup-stratified preclinical data to better inform design of clinical trials in ependymoma.
Omalizumab in patients with chronic spontaneous urticaria nonresponsive to H1‐antihistamine treatment: results of the phase <scp>IV</scp> open‐label <scp>SUNRISE</scp> study
Authors: F. Bérard, M.C. Ferrier Le Bouedec, L. Bouillet, Z. Reguiai, A. Barbaud, F. Cambazard, B. Milpied, B. Pelvet, I. Kasujee, H. Gharbi, J.P. Lacour
Journal: British Journal of Dermatology (2018)

Omalizumab is approved as an add‐on therapy for the treatment of chronic spontaneous urticaria (CSU) in patients with inadequate response to H1‐antihistamine treatment. The urticaria control test (UCT) is a reliable, concise tool developed as an alternative to the 7‐day urticaria activity score (UAS7) – the standard for CSU disease activity assessment. This prospective, open‐label, phase IV study evaluated the efficacy and safety of omalizumab in French adult patients with CSU nonresponsive to H1‐antihistamine treatment. Patients [n =136; stratified 1 : 2 (with angio‐oedema : without angioedema)] received omalizumab 300 mg subcutaneously every 4 weeks for 12 weeks. Study assessments included UCT, UAS7, angio‐oedema activity score and d‐dimer levels (exploratory objective). At Week 12, 74·6% of the patients achieved disease control [UCT score ≥ 12 (primary endpoint)] and 67·7% of patients showed well‐controlled disease (UAS7 ≤ 6). There was a strong negative correlation between UCT score and UAS7 at Week 12 (Spearman's correlation coefficient −0·839). Mean plasma d‐dimer concentration was elevated at baseline (1002·1 ng mL−1) and decreased notably at Week 8 (455 ng mL−1). Among the nine patients with a very high baseline d‐dimer concentration (> 3000 ng mL−1), eight were responders (UAS7 ≤ 6) at Week 12. Omalizumab was efficacious in patients with CSU nonresponsive to H1‐antihistamines. The UCT was a reliable tool for disease assessment and the scores correlated well with UAS7. This study does not support the usefulness of d‐dimer to monitor long‐term disease prognosis in adult urticaria; however, it may indicate patients who respond to omalizumab.
Interrogation of nonconserved human adipose lincRNAs identifies a regulatory role of <i>linc-ADAL</i> in adipocyte metabolism
Authors: Xuan Zhang, Chenyi Xue, Jennie Lin, Jane F. Ferguson, Amber Weiner, Wen Liu, Yumiao Han, Christine Hinkle, Wenjun Li, Hongfeng Jiang, Sager Gosai, Melanie Hachet, Benjamin A. Garcia, Brian D. Gregory, Raymond E. Soccio, John B. Hogenesch, Patrick Seale, Mingyao Li, Muredach P. Reilly
Journal: Science Translational Medicine (2018)

Nonconserved linc-ADAL interacts with distinct cytoplasmic and nuclear factors to regulate human adipocyte differentiation and metabolism.
QOL-40. RADIATION DOSE EFFECT ON NEUROPSYCHOLOGICAL OUTCOME OF POSTERIOR FOSSA BRAIN TUMOR SURVIVORS
Authors: Jeffrey Tanedo, Sharon O’Neil, Katrina Huft, Aditi Tondulkar, Kenneth Wong, Arthur Olch, Jemily Malvar, Katherine Maina, Sinchai Tsao, Natasha Lepore, Mary Baron Nelson
Journal: Neuro-Oncology (2018)

Children with brain tumors treated with cranial irradiation experience significant cognitive late effects. Cranial irradiation followed by posterior fossa boost results in high doses of radiation to the thalamus, hippocampus and putamen, structures critical to cognitive functioning. Twenty-three children (mean 12 years of age) with a history of posterior fossa tumor (13 treated with surgery, chemotherapy and cranial irradiation; 10 treated with surgery and chemotherapy) underwent neuroimaging, neurocognitive and psychosocial assessment 3.7 to 8.8 years after treatment. The putamen, thalamus and hippocampus were manually segmented in the radiation treatment group and the dose to each structure was calculated. Differences in patient demographics and medical history among patients in each treatment group were evaluated using the χ2 test (for categorical variables) and t-test (for continuous variables). Linear regression was utilized to examine differences in neuropsychological test scores and QOL measures among the two treatment groups. Time off treatment was a significant predictor of verbal comprehension standard index score and BRIEF® metacognition index for survivors in both treatment groups, before correction for multiple comparisons. There were no significant differences on psychometric scores between the two groups after Bonferroni correction, and no significant correlation of structural radiation dose to scores; however, there was wide range of abilities from impaired to superior in both groups in this small sample.
QOL-35. EXPRESSIVE WRITING FOR ADOLESCENTS WITH BRAIN TUMOR: A CASE STUDY
Authors: Sofia Anzeneder, Domitilla Elena Secco, Angela Mastronuzzi, Anna Rita Colasanti, Simonetta Gentile
Journal: Neuro-Oncology (2018)

The study aimed at exploring (1) whether expressive writing (EW) affects well-being of adolescents with brain tumor; (2) whether EW effects are moderated by the time of EW with respect to medical therapy and baseline levels of emotional wellbeing; and (3) what are language mechanisms underlying EW effects. Four of 12 patients with brain tumor aged 11-18 years, contacted at the Rome Pediatric Hospital Bambino Gesù, participated and completed all evaluations prior to, immediately and one month after an intervention composed of four writings one week apart. EW effects were evaluated with the Pediatric Quality of Life Inventory, Child Behavior Checklist, and Adolescent Coping Orientation for Problem Experiences questionnaires. Linguistic analysis of the psycho-physical processes underlying the expressive narration was performed with the Linguistic Inquiry and Word Count Program. Descriptive statistics for each case showed (1) amelioration trends in perceived quality of life, internalized symptoms and coping skills in three of four participants; (2) carry-over of these EW benefits in patients out-of-treatment and with higher baseline levels of emotional wellbeing; (3) differentiated patterns of change, across writings, of linguistic variables reflecting biological, cognitive, emotional and social processes. Results suggest that EW may be a feasible and cost-effective way to obtain psycho-physical benefits, though clinically non-relevant, in patients who have advantageous baseline conditions. Mechanisms underlying the beneficial effect of EW on emotional states and coping skills seem a progressive balancing of cognitive and social processes and the activation of embodied simulation. Future replication studies with larger cohort of patients are needed.
Liver metastases from esophageal carcinoma
Authors: D. Kostov
Journal: Annals of Oncology (2018)

Introduction: Hepatectomy for liver metastases from esophageal squamous cell carcinoma (LMESCC) remains controversial. We aimed at assessing the surgical results, clinicopathological features of LMEC and prognostic factors. Methods: The outcome of 8 consecutive patients with synchronous (n = 3) or metachronous (n = 5) LMEC was retrospectively analyzed. Curatively, initial hepatectomies such as segmentectomy and hemihepatectomy or non-anatomical limited liver resection less extensive than segmentectomy followed complete primary esophageal cancer (EC) resections. Results: Median survival time was 12 months (range, 8 - 22 months). The actuarial overall 12-, 36-, and 60-month survival rates after hepatectomy were 87.5% (n = 7), 37.5% (n = 3), and 12.5% (n = 1), respectively. In multivariate analysis, absent EC adventitia invasion-hazard ratio (HR) 1; 95% confidence interval (CI) 1.4 - 8.4; P = 0.040; solitary LM-HR 1; 95% CI 1.4 - 12.0; P = 0.004, and curative liver resection with negative resection margin (R0)-HR 1, 95% CI 1.2 - 15.0; P = 0.002 were independent prognostic factors. Conclusion: Surgery of LMESCC is a good indication in well-selected patients with an absent EC adventitia invasion of primary tumor, single LMEC and attainment of R0 liver resection. For most LMESCC patients, however, there are no other therapeutic modalities. Thus, systemic radiochemotherapy remains the best hope for a longer patient's survival and an improved individual quality of life.
PDTM-07. DETECTION OF IDH1 R132H MOSAICISM IN ANAPLASTIC ASTROCYTOMA PATIENTS
Authors: Sulgi Lee, Miriam Bornhorst, Eshini Panditharatna, Madhuri Kambhampati, Javad Nazarian
Journal: Neuro-Oncology (2018)

Anaplastic astrocytomas are aggressive cancers of glial cells that present poor prognosis and high recurrence. Heterozygous mutations in IDH1 and IDH2 genes are common in the patients with anaplastic astrocytomas and glioblastomas. In the majority of cases, if not all, the IDH mutations seen in patients with brain tumors have been heterozygous somatic mutations. Patients with Ollier disease and Maffucci syndrome, which are rare enchondromatosis syndromes, have been shown to carry mosaic mutations of IDH1 or IDH2 in non-neoplastic tissues but no patients with anaplastic astrocytoma have been shown to carry such mosaicism. Here, we present two siblings with high grade astrocytoma with IDH1 R132H mutation. Our analysis of IDH1 R132H mutations in the siblings’ tumors and non-neoplastic tissues, including healthy regions of the brain, cheek cells and primary teeth has identified IDH1 R132H mosaicism, using digital PCR system. IDH1 R132H mutant allelic frequencies ranging from 0.01% to 0.64% were detected in teeth, cheek cells and non-tumorous brain tissue. The findings were confirmed by next-generation sequencing with similar single nucleotide variation frequencies. Our study demonstrated an example of IDH1 R132H mosaicism in anaplastic astrocytoma patients, which could have gone unnoticed by traditional sequencing technologies.
Brain Somatic Mutations in MTOR Disrupt Neuronal Ciliogenesis, Leading to Focal Cortical Dyslamination
Authors: Sang Min Park, Jae Seok Lim, Suresh Ramakrishina, Se Hoon Kim, Woo Kyeong Kim, Junehawk Lee, Hoon-Chul Kang, Jeremy F. Reiter, Dong Seok Kim, Hyongbum (Henry) Kim, Jeong Ho Lee
Journal: Neuron (2018)
DIPG-66. THE H3K27M MUTATION CAUSES WIDE-RANGING CHANGES MEDIATING DIPG TUMORIGENESIS
Authors: Rakeb Lemma, John DeSisto, Patrick Flannery, Bridget Sanford, Ilango Balakrishnan, Krishna Madhavan, Bethany Veo, Jean Mulcahy Levy, Nicholas Foreman, Rajeev Vibhakar, Kenneth Jones, Sujatha Venkataraman, Adam Green
Journal: Neuro-Oncology (2018)

Diffuse intrinsic pontine glioma (DIPG) is a nearly uniformly fatal pediatric brain tumor. 80% of DIPGs harbor a mutation (K27M) in genes encoding histones H3.1 or H3.3. We aimed to clarify the role of this mutation in tumorigenesis. We transduced adult glioblastoma, pediatric glioblastoma, and DIPG cell lines (AM38, GBM1 and DIPG10 respectively) wild-type for H3.1 and H3.3 with a lentivirus-packaged H3K27M plasmid. We studied changes in the stably transduced cells compared to wild-type cells using western blot, a proliferation assay, a murine orthotopic xenograft model, RNA sequencing, karyotyping, and an inflammatory kinase assay. We observed a decrease in H3K27me3, an increase in H2AK119 ubiquitination and H3K27 acetylation, and an increase in proliferation rate, both in cell culture and an orthotopic xenograft model, in H3K27M relative to matched wild-type lines. Additionally, H3K27M cells exhibited a reduction in p16 or p53 protein expression, an increase in chromosomal abnormalities/fragmentation, and cytokine changes, including downregulation of the immune cell recruiter MCP-1, and upregulation of the proangiogenic factor VEGF. Geneset enrichment analysis showed H3K27M cell lines exhibited a more mesenchymal expression profile (GBM1: NES=4.84, FDR=0.0; DIPG10: NES=2.24, FDR=0.004), and greater expression of tumor invasiveness genes (GBM1: NES=5.52, FDR=0.0; DIPG10: NES=4.68, FDR=0.0), hallmark inflammatory response genes (NES=2.37, FDR=0.006; DIPG10: NES=3.49, FDR=0.0), and epithelial-to-mesenchymal transition genes (GBM1: NES=4.07, FDR=0.0; DIPG10: NES=4.06, FDR=0.0). The presence of H3K27M causes epigenetic, chromosomal, inflammatory, immunomodulatory, and gene expression changes that provide these cells a selective growth advantage over time. These findings raise several potential treatment strategies.
IMMU-28. DECIPHERING THE AT/RT LIGANDOME
Authors: Ana Marcu, Nico Trautwein, Stefan Stevanovic, Pascal Johann, Antje Technau, Johanna Lager, Camelia-Maria Monoranu, Lisa Henkel, Jürgen Krauß, Martin Ebinger, Martin Schuhmann, Ulrich Thomale, Torsten Pietsch, Matthias Wölfl, Paul Gerhardt Schlegel, Michael Frühwald, Florian Oyen, Yair Reisner, Hans-Georg Rammensee, Matthias Eyrich
Journal: Neuro-Oncology (2018)

Atypical teratoid/rhabdoid tumors (AT/RTs) are commonly regarded as immunologically cold tumors, as they rank among malignancies with the lowest mutational load. However, low mutational burden is not necessarily correlated with poor immunogenicity, as tumor-exclusive peptides bound in the tumor cell’s MHC represent potential targets for immune responses. Indeed, in a first set of n=17 AT/RT samples we could determine by immunohistochemistry that 1.8% of all cells within the tumors were T-cells. MHC class I, class II, and PD-L1 was expressed on 12.9%, 3%, and 5.1% of the tumor cells, respectively. To investigate whether the ligandome of AT/RTs contained tumor-exclusive peptides we then analyzed 23 centrally reviewed AT/RTs using LC-MS and subsequent bioinformatical validation. In 14 (61%) and 21 (91%) of the 23 patients, tumor-exclusive peptides were identified (59 MHC class I and 153 class II peptides in total). Of these, 47/109 peptides were exclusive for one tumor, demonstrating the high individuality of the AT/RT ligandome. Representative examples of these ligandome peptides proved to be immunogenic in T-cell priming assays. Mutation analysis revealed a median of 11 (range 1-166) tumor-specific mutations dispersed over the entire genome. In silico MHC-binding prediction showed that these neoantigenic peptides had a similar binding affinity compared to their ligandome counterparts. In conclusion, tumor-exclusive ligandome peptides can be identified in the vast majority of AT/RT patients. In silico and in vitro analyses qualify them as suitable candidates for personalized cancer vaccines.
Antibody-mediated inhibition of FXIIa blocks downstream bradykinin generation
Authors: Helen Cao, Mark Biondo, Hadi Lioe, Samantha Busfield, Veronika Rayzman, Bernhard Nieswandt, Konrad Bork, Leonard C. Harrison, Priscilla Auyeung, Henriette Farkas, Dorottya Csuka, Matthias Pelzing, Steve Dower, Michael J. Wilson, Andrew Nash, Marc W. Nolte, Con Panousis
Journal: Journal of Allergy and Clinical Immunology (2018)
LGG-35. IDENTIFICATION OF SETD2 MUTATION IN AN AGGRESSIVE PILOCYTIC ASTROCYTOMA PRESENTING AS AN INFLAMMATORY OPTIC NERVE LESION
Authors: Robyn Gartrell, Lenore Omesi, Andrew Silverman, Ashley Campbell, Neil Feldstein, Yvonne Saenger, Mahesh Mansukhani, George Zanazzi, Peter Canoll, Michael Kazim, James Garvin
Journal: Neuro-Oncology (2018)