tbuckley/cabot-search huggingface dataset:
TLR7/8 regulates type I and type III interferon signalling in rhinovirus 1b-induced allergic asthma
Authors: Jasmin Krug, Alexander Kiefer, Julia Koelle, Tytti Vuorinen, Paraskevi Xepapadaki, Barbara Stanic, Mircea T. Chiriac, Mübeccel Akdis, Theodor Zimmermann, Nikolaos G. Papadopoulos, Susetta Finotto
Journal: European Respiratory Journal (2020)

Introduction Interferon (IFN) responses have been reported to be defective in rhinovirus (RV)-induced asthma. The heterodimeric receptor of type I IFN (IFN-α/β) is composed of IFN-αR1 and IFN-αR2. Ligand binding to the IFN-α/β receptor complex activates signal transducer and activator of transcription (STAT) proteins STAT1 and STAT2 intracellularly. Although type III IFN (IFN-λ) binds to a different receptor containing IFN-λR1 and interleukin-10R2, its triggering leads to activation of the same downstream transcription factors. Here, we analysed the effects of RV on IFN type I and III receptors, and asked about possible Toll-like receptor 7/8 (TLR7/8) agonist R848-mediated IFN-αR1 and IFN-λR1 regulation. Methods We measured IFN-α, IFN-β and IFN-λ and their receptor levels in peripheral blood mononuclear cell (PBMC) supernatants and cell pellets stimulated with RV1b and R848 in two cohorts of children with and without asthma recruited at pre-school age (PreDicta) and at primary school age (AGENDAS) as well as in cell supernatants from total lung cells isolated from mice. Results We observed that R848 induced IFN-λR mRNA expression in PBMCs of healthy and asthmatic children, but suppressed IFN-αR mRNA levels. In murine lung cells, RV1b alone and together with R848 suppressed IFN-αR protein in T-cells compared with controls and in total lung IFN-λR mRNA compared with RV1b infection alone. Conclusions In PBMCs from pre-school age children, IFN-αR mRNA was reduced and IFN-λR1 mRNA was induced upon treatment with the TLR7/8 agonist R848, thus suggesting new avenues for induction of antiviral immune responses in paediatric asthma.
TAMI-36. CONNEXIN 43 BLOCKADE INHIBITS PROLIFERATION IN IDH1-MUTANT GLIOMA CELLS
Authors: Lisa Melamed, Christine Lee, Hiroaki Nagashima, Julie Miller, Hiroaki Wakimoto, Daniel Cahill
Journal: Neuro-Oncology (2020)

Abstract IDH1-mutant gliomas are characteristically sensitive to NAD+ depletion. It is known that NAD+ can move between cells through gap junctions, which provides an opportunity for treatments that prevent NAD+ sharing across tumor cells, effectively decreasing available NAD+. Previous studies have also shown the role of connexin 43 (Cx43) in mediating communication in glioma cell networks and have identified Cx43 as a potential mediator of temozolomide resistance in glioma. We hypothesized that blocking Cx43 would prevent intercellular NAD+ sharing in IDH-mutant gliomas, causing tumor cells to be more vulnerable to metabolic NAD+ depletion via nicotinamide phosphoribosyltransferase (NAMPT) inhibitors and temozolomide (TMZ) treatment. Here, we show that blockade of Cx43 with α-connexin carboxyl-terminal (ACT1) is able to inhibit growth of patient-derived IDH1-mutant tumor cells. ACT1 sensitizes cells to TMZ and inhibits growth of IDH1-mutant gliomas via an NAD-dependent mechanism. We also found that ACT1 can be used in combination with other NAD-depleting drugs, such as NAMPT inhibitors, to enhance its effect and provide a viable therapeutic window. Overall, our results suggest that ACT1 may enhance the efficacy of treatments for IDH1-mutant tumors by blocking metabolic buffering through tumor cell gap junctions.
NCOG-25. EFFICACY OF ANTICONVULSANT THERAPY IN GLIOMA PATIENTS
Authors: Ravi Medikonda, Kisha Patel, Laura Saleh, Siddhartha Srivastava, Christina Jackson, Aditya Mohan, Pavan Shah, Jon Weingart, Chetan Bettegowda, Gary Gallia, Henry Brem, Michael Lim
Journal: Neuro-Oncology (2020)

Abstract Gliomas account for 30% of primary brain tumors and can frequently present with seizures. There are few guidelines for usage of anticonvulsant therapy in glioma patients. Some clinicians utilize anticonvulsant therapy in all glioma patients as a means of prophylaxis, whereas other clinicians prescribe anticonvulsant therapy only in patients that experience seizures. In this single-institution retrospective cohort study, we evaluate the effect of commonly prescribed anticonvulsant levetiracetam on incidence of post-operative seizures and overall survival in primary glioma patients. 436 patients met the inclusion criteria for this study. 35% of patients presented with a pre-operative seizure and 63% of patients received pre-operative Levetiracetam. The incidence of a seizure within 1 year of tumor resection was 31%. On multivariate logistic regression analysis of patient pre-operative clinical and imaging characteristics, it was found that only a pre-operative seizure (p = 0.02) significantly increased the odds of a post-operative seizure within 1 year of tumor resection. Neither pre-operative levetiracetam (p = 0.31), intra-operative levetiracetam (p = 0.59), or post-operative levetiracetam (p = 0.75) significantly reduced the odds of a post-operative seizure. Using a cox proportional hazards model, pre-operative levetiracetam (p = 0.11), intra-operative levetiracetam (p = 0.34), and post-operative levetiracetam (p = 0.88) do not significantly affect overall survival. Our findings reveal that glioma patients are often prescribed anticonvulsant medication regardless of whether they have had a pre-operative seizure. Most patients also receive anti-convulsant medication in the peri-operative and post-operative setting regardless of whether they have had pre-operative or immediate post-operative seizures. Use of pre-operative or intra-operative levetiracetam as a prophylactic measure does not impact the incidence of post-operative seizures. Furthermore, anti-convulsant therapies do not demonstrate a survival benefit in our study. These results provide a rationale for re-evaluating the use of anti-convulsant medications in glioma patients that do not have seizure symptoms.
NCOG-72. DIFFERENTIAL EFFECTS OF SURGERY AND CHEMOTHERAPY ON CHILDREN WITH POSTERIOR FOSSA BRAIN TUMORS
Authors: Sofia Dhanani, Sharon O’Neil, Jeffrey Tanedo, Jemily Malvar, Benita Tamrazi, Jonathan Finlay, Francesca Trane, Vidya Rajagopalan, Natasha Lepore, Mary Baron Nelson
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Few neuroimaging studies of children with brain tumors treated with chemotherapy without radiation exist, and the neuropsychological effects of chemotherapy remain unclear. We aimed to differentiate the effects of surgery and chemotherapy on brain microstructure and cognition. METHODS Twenty-eight children with a history of posterior fossa tumor (17 treated with surgery alone; 11 treated with surgery + chemotherapy), and 21 sibling controls (n= 49) underwent diffusion tensor imaging (DTI) and neuropsychological assessment a mean of 4.5 (surgery group) to 9 years (surgery + chemotherapy group) after treatment. Psychometric measures focused on general intelligence, executive functions, processing speed, learning and memory, and social-emotional functioning. Age at diagnosis and time since diagnosis were covariates in the analyses. Group differences in DTI findings and psychometric scores, and correlations between psychometric scores and DTI results were examined. RESULTS Mean fractional anisotropy (FA) in the prefrontal cortex, white matter tracts, hippocampus, putamen, globus pallidus, thalamus, and pons were significantly (z≥ 2SD) lower in children treated with surgery + chemotherapy compared to those treated with surgery alone. In neuropsychological evaluation, the patient groups differed only in receptive vocabulary (p= 0.05), with children treated with surgery + chemotherapy scoring lower. Both patient groups scored lower than healthy sibling controls on measures of visuoconstructional reasoning (p= 0.02) and delayed visual (p= 0.02) and spatial memory (p= 0.01). Lower FA in the uncinate fasciculus and higher FA in the right thalamus associated with higher scores on general intelligence (p= 0.003, p= 0.002), and higher FA in the right thalamus associated with higher scores on spatial learning (p= 0.01) and memory (p= 0.01) in children treated with surgery + chemotherapy. CONCLUSIONS Chemotherapy is associated with injury to the microstructure of white and gray matter and neuropsychological deficits not seen in children with posterior fossa tumors treated with surgery alone.
EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood
Authors: Michael Weller, Martin van den Bent, Matthias Preusser, Emilie Le Rhun, Jörg C. Tonn, Giuseppe Minniti, Martin Bendszus, Carmen Balana, Olivier Chinot, Linda Dirven, Pim French, Monika E. Hegi, Asgeir S. Jakola, Michael Platten, Patrick Roth, Roberta Rudà, Susan Short, Marion Smits, Martin J. B. Taphoorn, Andreas von Deimling, Manfred Westphal, Riccardo Soffietti, Guido Reifenberger, Wolfgang Wick
Journal: Nature Reviews Clinical Oncology (2020)

Abstract In response to major changes in diagnostic algorithms and the publication of mature results from various large clinical trials, the European Association of Neuro-Oncology (EANO) recognized the need to provide updated guidelines for the diagnosis and management of adult patients with diffuse gliomas. Through these evidence-based guidelines, a task force of EANO provides recommendations for the diagnosis, treatment and follow-up of adult patients with diffuse gliomas. The diagnostic component is based on the 2016 update of the WHO Classification of Tumors of the Central Nervous System and the subsequent recommendations of the Consortium to Inform Molecular and Practical Approaches to CNS Tumour Taxonomy — Not Officially WHO (cIMPACT-NOW). With regard to therapy, we formulated recommendations based on the results from the latest practice-changing clinical trials and also provide guidance for neuropathological and neuroradiological assessment. In these guidelines, we define the role of the major treatment modalities of surgery, radiotherapy and systemic pharmacotherapy, covering current advances and cognizant that unnecessary interventions and expenses should be avoided. This document is intended to be a source of reference for professionals involved in the management of adult patients with diffuse gliomas, for patients and caregivers, and for health-care providers.
MBRS-32. TOPOISOMERASE II β INDUCES NEURONAL, BUT NOT GLIAL, DIFFERENTIATION IN MEDULLOBLASTOMA
Authors: Hiroaki Miyahara, Manabu Natsumeda, Junichi Yoshimura, Yukihiko Fujii, Akiyoshi Kakita, Yasushi Iwasaki, Mari Yoshida
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND We previously reported that Gli3, which was a downstream molecule of Sonic Hedgehog signal, induced neuronal and/or glial differentiation in some types of medulloblastoma (desmoplastic/nodular medulloblastoma and medulloblastoma with extensive nodularity), and patients of medulloblastoma with neuronal differentiation showed favorable prognosis, but those with glial differentiation tended to show miserable prognosis (Miyahara H, Neuropathology, 2013). This time, we focused on Topoisomerase II β (Top2β), which was reported to induce neuronal differentiation and inhibit glial differentiation, and examined the expression of Top2β in medulloblastomas with neuronal and glial differentiations. METHODS We assessed the expression of Top2β, NeuN, and GFAP using triple fluorescent immunostaining method in medulloblastoma samples with both neuronal and glial differentiations. Furthermore, the expression of Top2β, H3K4me2, and H3K27me3 were also assessed, because Top2βwas positively or negatively regulated by H3K4me2 and H3K27me3, respectively. RESULTS Many large nuclei in the nodules, in which differentiated cells were seen, was visualized by Top2β. The Top2β signals were seen in NeuN+ cells but not GFAP+ cells. H3K4me2 signals were visualized in Top2β+ large nuclei, but H3K27me3 and NeuN+ large nuclei were distributed independently. CONCLUSIONS These results indicate that Top2β may be a molecule associated with neuronal, but not glial, differentiation of medulloblastoma cells. Drugs targeting histone modification enzymes such as EZH2 inhibitors are possible therapeutic targets as a differentiation-inducing therapy for medulloblastoma.
GCT-18. CLINICAL FEATURES OF GERM CELL TUMORS IN CHILDREN
Authors: Nayuta Higa
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Here, we discuss the presentation, histology, therapy, and outcome of germ cell tumors in children. METHODS Treatment outcome and management was assessed for children diagnosed with germ cell tumors from 2007 to 2017 at Kagoshima University. RESULTS Twenty-six patients (20 boys, 6 girls) with a mean age of 11.5 ± 4.9 years were included in this study. Patient tumor types included: germinoma (n = 19); immature teratoma (n = 3); yolk sac tumor (n = 3); choriocarcinoma (n = 1); embryonal carcinoma (n = 1). The most common patient clinical features were headache and vomiting associated with hydrocephalus. The median follow-up period was 96.5 months. Tumor location was pineal (n=9), bifocal (n=6), suprasellar (n = 5), basal ganglia (n=2), frontal lobe (n=2), and cerebellum (n=2). Surgical procedures included stereotactic biopsy (n=13), endoscopic third ventriculostomy and biopsy (n=8), and tumor decompression (n=5). All patients with germ cell tumors underwent adjuvant chemotherapy and radiation therapy; patients with germinoma or immature teratoma were still alive, while patients with embryonal carcinoma, yolk sac tumor, or choriocarcinoma had poor prognosis with a median survival of 16 months. CONCLUSIONS Patients with germinoma had a relatively good prognosis, while patients with embryonal carcinoma, yolk sac tumor, or choriocarcinoma had a poor prognosis. A multidisciplinary approach including surgical strategy based on location, appropriate radiation planning, and chemotherapy is needed for effective treatment and improved outcomes.
Cough hypersensitivity and suppression in COPD
Authors: Peter S.P. Cho, Hannah V. Fletcher, Irem S. Patel, Richard D. Turner, Caroline J. Jolley, Surinder S. Birring
Journal: European Respiratory Journal (2020)

Cough reflex hypersensitivity and impaired cough suppression are features of chronic refractory cough (CRC). Little is known about cough suppression and cough reflex hypersensitivity in cough associated with chronic obstructive pulmonary disease (COPD). This study investigated the ability of patients with COPD to suppress cough during a cough challenge test in comparison to patients with CRC and healthy subjects. This study also investigated whether cough reflex hypersensitivity is associated with chronic cough in COPD.Participants with COPD (n=27) and CRC (n=11) and healthy subjects (n=13) underwent capsaicin challenge tests with and without attempts to self-suppress cough in a randomised order over two visits, 5 days apart. For patients with COPD, the presence of self-reported chronic cough was documented, and objective 24-h cough frequency was measured.Amongst patients with COPD, those with chronic cough (n=16) demonstrated heightened cough reflex sensitivity compared to those without chronic cough (n=11): geometric mean±sd capsaicin dose thresholds for five coughs (C5) 3.36±6.88 µmol·L-1versus 44.50±5.90 µmol·L-1, respectively (p=0.003). Participants with CRC also had heightened cough reflex sensitivity compared to healthy participants: geometric mean±sd C5 3.86±5.13 µmol·L-1versus 45.89±3.95 µmol·L-1, respectively (p<0.001). Participants with COPD were able to suppress capsaicin-evoked cough, regardless of the presence or absence of chronic cough: geometric mean±sd capsaicin dose thresholds for 5 coughs without self-suppression attempts (C5) and with (CS5) were 3.36±6.88 µmol·L-1versus 12.80±8.33 µmol·L-1 (p<0.001) and 44.50±5.90 µmol·L-1versus 183.2±6.37 µmol·L-1 (p=0.006), respectively. This was also the case for healthy participants (C5 versus CS5: 45.89±3.95 µmol·L-1versus 254.40±3.78 µmol·L-1, p=0.033), but not those with CRC, who were unable to suppress capsaicin-evoked cough (C5 versus CS5: 3.86±5.13 µmol·L-1versus 3.34±5.04 µmol·L-1, p=0.922). C5 and CS5 were associated with objective 24-h cough frequency in patients with COPD: ρ= -0.430, p=0.036 and ρ= -0.420, p=0.041, respectively.Patients with COPD-chronic cough and CRC both had heightened cough reflex sensitivity but only patients with CRC were unable to suppress capsaicin-evoked cough. This suggests differing mechanisms of cough between patients with COPD and CRC, and the need for disease-specific approaches to its management.
ケニアにおける生殖,母親,新生児および小児保健の進展と優先事項:2015か国の事例研究へのカウントダウン【Powered by NICT】
Authors: Keats Emily C, Ngugi Anthony, Macharia William, Akseer Nadia, Khaemba Emma Nelima, Bhatti Zaid, Rizvi Arjumand, Tole John, Bhutta Zulfiqar A
Journal: The Lancet Global Health (2017)
Abstract 12563: Retrospective Analysis of Cardiovascular Events With the Use of Immune Checkpoint Inhibitors
Authors: Tushar Tarun, Brian P Bostick, Deepa Baswaraj, Nishchayjit Basra, Meeshal Khan, Trent Bickel
Journal: Circulation (2020)

Introduction: Immune checkpoint inhibitors have emerged as a promising, novel therapy for multiple malignancies. Immune-related adverse reactions pose a serious concern with use of these agents and reportedly involve multiple organ systems, notably cardiotoxicity. Early identification and management of these adverse events is essential in the prevention of morbidity and mortality. Hypothesis: Immune checkpoint inhibitors cause multiple cardiotoxic effects, and patients with prior cardiac history have a higher likelihood of cardiotoxicity. Methods: 1. A retrospective analysis of 150 patients was performed who had received immunotherapy with either the cytotoxic T lymphocyte associated antigen 4 inhibitors (CTLA4) or with the programmed cell death inhibitors (PD1) or programmed death-ligand 1 (PD-L1) inhibitors for a period of two years at a Tertiary health Care from 7/1/2016-6/30/2018. 2. Patients' cardiac diagnoses prior to the initiation of therapy were noted and included, including history of heart failure, coronary artery disease, atrial fibrillation, and sudden cardiac arrest. 3. Patients’ clinic visits and hospitalizations with admitting and discharge diagnosis, electrocardiogram, echocardiogram, troponin T, and NT-proBNP were reviewed. Results: 6% of patients had new onset heart failure (both preserved and reduced), 1.3% had evidence of myocardial infarction, 2% had new atrial fibrillation with rapid ventricular rate, and 0.6% had fulminant myocarditis. Of patients with new cardiac events, 60% had a history of cardiac disease, which was significantly higher than in patients without (p&lt; 0.05). There were no age or sex differences between the groups with and without cardiotoxicity. Conclusion: Immunotherapy with immune checkpoint inhibitors have broadened the horizon for treatment of multiple solid and hematological malignancies. Nonetheless, new adverse effects on multiple organ systems, specifically cardiac involvement, occur with these therapies, which are important and potentially detrimental toxicities. Patients with a history of prior cardiovascular disease have higher likelihood to develop cardiotoxicity.
DIPG-25. KETOGENIC DIET IN DIFFUSE INTRINSIC PONTINE GLIOMA IN CHILDREN: A RETROSPECTIVE STUDY INVESTIGATING THE FEASIBILITY
Authors: Alexandre Perez, Janak Nathan, Moatasem El-Ayadi, Christian Korff, Marc Ansari, André von Bueren
Journal: Neuro-Oncology (2020)

Abstract PURPOSE Diffuse Intrinsic Pontine Glioma (DIPG) is one of the most devastating diseases amongst children with cancer, thus novel strategies are urgently needed. We aimed to retrospectively evaluate the feasibility of the carbohydrate restricted ketogenic diet (KD) in DIPG patients. METHODS Searches of MEDLINE and Embase identified four publications meeting the inclusion criteria (diagnosis of DIPG and exposition to a KD ≥ 3 months). One additional case was identified by contact with experts. The minimal feasibility criteria were defined as the ability to use the KD for ≥ 3 months. Individual patient data were extracted from the publications or obtained from investigators. RESULTS Five patients (males, n=3; median age 4.4 years; range, 2.5–17 years) met the inclusion criteria (one patient – identified and not included - was on KD &amp;lt; 3 months due to disease progression). Further feasibility analyses showed a duration of the KD of ≥ 3 months and less than 7 months (n=2), &amp;gt; 7 months and less than 1 year (n= 2), and two years (n=1), respectively. CONCLUSION These results – based on a small patient population – suggest that the KD appears to be a feasible treatment option for children with DIPG. The potential duration of the KD is limited by the aggressive clinical behavior of DIPG. The safety analysis is currently being retrospectively assessed. These data should encourage further studies on a larger scale; ideally assessing the impact of the KD in DIPG patients in a randomized controlled trial.
Respiratory medicine curriculum in Portuguese family medicine training: A Delphi study
Authors: P.M. Teixeira, F. Lemos, J. Yaphe, L. Alves, J.C. de Sousa
Journal: Pulmonology (2020)

Respiratory diseases (RD) constitute a significant part of the workload of family physicians. There is no consensus on what family doctors should know in this area but established methods for achieving consensus may help to overcome this. The purpose of the study was to obtain a national consensus on the required knowledge and skills in respiratory medicine for family medicine trainees after vocational training. A Delphi study was conducted via e-mail with a diverse panel of experts. We developed a Learning Curriculum Framework (LCF) with 399 items adapted from the Royal Australasian College of Physicians — Respiratory Medicine Advanced Training Curriculum. The LCF was submitted to the experts in two rounds for consensus. Consensus was considered for items that had an agreement of 80% in the classifications above 4 on a scale of importance that ranged from 1 (not important) to 5 (very important). Consensus was obtained for 159 items (38.8%). These included structure and function of the respiratory tract (0.6%), presenting problems (21.4%), diagnosis (7.5%), interventions and prevention (11.3%), COPD-emphysema (12.6%), tumours (3.1%), infections (10.7%), tuberculosis (5.7%), HIV (1.3%), thromboembolic disease (2.5%), pleural-pulmonary disease (3.1%), pregnancy (0.6%) and sleep disorders (3.8%). Items on iatrogenic diseases and respiratory research did not reach consensus. Consensus on the respiratory medicine curriculum may contribute to further development of the vocational training curriculum in Portugal. This approach may help teachers in other countries in Europe to develop curricula for respiratory medicine and other areas of general practice.