tbuckley/cabot-search huggingface dataset:
Association between asthma control trajectories in preschoolers and disease remission
Authors: Cristina Longo, Lucie Blais, Marni Brownell, Jacqueline M. Quail, Mohsen Sadatsafavi, Amélie Forget, Marc-André Turcot, Yao Nie, Wenbin Li, Hamid Tavakoli, Qier Tan, Yuxin Fan, Robert W. Platt, Francine M. Ducharme
Journal: European Respiratory Journal (2020)

Introduction Early disease morbidity has been associated with asthma persistence in wheezing preschoolers; however, whether asthma control trajectories shortly after diagnosis could influence remission is unknown. We examined the association between asthma control trajectories 2 years post-diagnosis in preschoolers and subsequent disease remission. Methods We conducted a multicentre population-based retrospective cohort study consisting of 48 687 children with asthma diagnosed before 5 years old and born between 1990 and 2013 in four Canadian provinces who had prolonged disease activity post-diagnosis. Prolonged disease activity was defined as one or more medical visits or medications for asthma every 6-month period for at least four of the six periods post-diagnosis. Follow-up began at 3 years post-diagnosis (at cohort entry). Remission was defined as 2 consecutive years without drug claims or medical visits for asthma or asthma-like conditions following cohort entry. Asthma control trajectories, ascertained over four 6-month periods following diagnosis using a validated index, were classified as: “controlled throughout”, “improving control”, “worsening control”, “out of control throughout” and “fluctuating control”. Adjusted Cox models estimated associations between asthma control trajectories and time to remission. A random effects meta-analysis summarised province-specific hazard ratios (HRs). Results The pooled remission rate was 8.91 (95% CI 8.80–9.02) per 100 person-years. Compared with children controlled throughout, poorer asthma control was associated with incrementally lower hazard ratios of remission in four other trajectories: improving control (HR 0.89, 95% CI 0.82–0.96), fluctuating control (HR 0.78, 95% CI 0.71–0.85), worsening control (HR 0.68, 95% CI 0.62–0.75) and out of control throughout (HR 0.52, 95% CI 0.45–0.59). Conclusions Asthma control trajectories 2 years following a diagnosis in preschoolers were associated with remission, highlighting the clinical relevance of documenting control trajectories in early life.
Author Correction: CAR-T cells targeting a nucleophosmin neoepitope exhibit potent specific activity in mouse models of acute myeloid leukaemia
Authors: Guozhu Xie, Nikola A. Ivica, Bin Jia, Yingzhong Li, Han Dong, Yong Liang, Douglas Brown, Rizwan Romee, Jianzhu Chen
Journal: Nature Biomedical Engineering (2020)
A reappraisal of the phylogenetic placement of the Aquilegia whole-genome duplication
Authors: Tao Shi, Jinming Chen
Journal: Genome biology (2020)

The accurate placement of an ancient whole-genome duplication (WGD) in relation to the lineage divergence is important. Here, we re-investigated the Aquilegia coerulea WGD and found it is more likely lineage-specific rather than shared by all eudicots.
ATM inhibition enhances cancer immunotherapy by promoting mtDNA leakage and cGAS/STING activation
Authors: Mengjie Hu, Min Zhou, Xuhui Bao, Dong Pan, Meng Jiao, Xinjian Liu, Fang Li, Chuan-Yuan Li
Journal: Journal of Clinical Investigation (2020)

Novel approaches are needed to boost the efficacy of immune checkpoint blockade (ICB) therapy. Ataxia telangiectasia mutated (ATM) protein plays a central role in sensing DNA double-stranded breaks (DSBs) and coordinating their repair. Recent data indicated that ATM might be a promising target to enhance ICB therapy. However, the molecular mechanism involved has not been clearly elucidated. Here, we show that ATM inhibition could potentiate ICB therapy by promoting cytoplasmic leakage of mitochondrial DNA (mtDNA) and activation of the cGAS/STING pathway. We show that genetic depletion of ATM in murine cancer cells delayed tumor growth in syngeneic mouse hosts in a T cell–dependent manner. Furthermore, chemical inhibition of ATM potentiated anti–PD-1 therapy of mouse tumors. ATM inhibition potently activated the cGAS/STING pathway and enhanced lymphocyte infiltration into the tumor microenvironment by downregulating mitochondrial transcription factor A (TFAM), which led to mtDNA leakage into the cytoplasm. Moreover, our analysis of data from a large patient cohort indicated that ATM mutations, especially nonsense mutations, predicted for clinical benefits of ICB therapy. Our study therefore provides strong evidence that ATM may serve as both a therapeutic target and a biomarker to enable ICB therapy.
ATRT-01. UPREGULATION OF PROTEIN SYNTHESIS AND PROTEASOME DEGRADATION CONFERS SENSITIVITY TO PROTEASOME INHIBITOR BORTEZOMIB IN MYC-ATYPICAL TERATOID/RHABDOID TUMORS
Authors: Minh-Huy Tran, Kuo-Sheng Wu, Che-Chang Chang, Tai-Tong Wong
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Atypical teratoid rhabdoid tumors (ATRTs) are among the most malignant brain tumors in early childhood and remain incurable. Myc-ATRT is driven by the Myc oncogene, which directly controls the intracellular protein synthesis rate. Proteasome inhibitor bortezomib (BTZ) was approved by the Food and Drug Administration as a primary treatment for multiple myeloma. This study aimed to determine whether the upregulation of protein synthesis and proteasome degradation in Myc-ATRTs increases tumor cell sensitivity to BTZ. METHODS We performed differential gene expression and gene set enrichment analysis on matched primary and recurrent patient-derived xenograft (PDX) samples from an infant with ATRT. The expressions of proteasome-encoding genes were compared among this paired model as well as between the 24 human ATRT samples and normal brain tissues. The antitumor effect of BTZ was evaluated in three human Myc-ATRT cell lines (PDX-derived tumor cell line Re1-P6, BT-12, and CHLA-266) and in the orthotopic xenograft models of Re1-P6 cell. RESULTS Concomitant upregulation of the Myc pathway, protein synthesis, and proteasome degradation were identified in recurrent ATRTs. In ATRTs, the proteasome-encoding genes were highly expressed compared with in normal brain tissues, correlated with the malignancy of tumor cells, and were essential for tumor cell survival. BTZ inhibited proliferation and induced apoptosis through the accumulation of p53 in in vitro drug tests. Furthermore, BTZ inhibited tumor growth and prolonged survival in Myc-ATRT orthotopic xenograft mice. CONCLUSIONS Our findings suggest that BTZ may be a promising targeted therapy for Myc-ATRTs.
DIPG-50. A NOVEL ORTHOTOPIC PATIENT-DERIVED XENOGRAFT MODEL OF RADIATION-INDUCED GLIOMA
Authors: Jacqueline Whitehouse, Meegan Howlett, Jason Stanley, Hilary Hii, Santosh Valvi, Christine White, Chelsea Mayoh, Marie Wong, Brooke Strowger, Jason Dyke, Mark Cowley, Nicholas Gottardo, Raelene Endersby
Journal: Neuro-Oncology (2020)

Abstract Diffuse midline glioma (DMG) can arise as a primary tumour but also as a consequence of radiation therapy (RT) in survivors of other paediatric brain tumours. Radiation-associated gliomas are molecularly distinct from primary gliomas and have poorer overall survival. We report a case of radiation-associated DMG following treatment for medulloblastoma, and the development of a matched patient-derived xenograft (PDX) model. A four-year-old boy diagnosed with medulloblastoma was treated with surgical resection, RT and chemotherapy (COG:CCG-99701-Arm B). Eleven years post-diagnosis, the patient relapsed with radiation-associated DMG, participated in a Phase I clinical trial (COG:ACNS0927), and passed away eight months later. Tumour tissue collected at autopsy was intracranially implanted into immunodeficient mice and serially transplanted in vivo. Immunohistochemistry demonstrated both the primary DMG and PDXs expressed PDGFR-alpha and PTEN, were H3K27me3-positive, and had undetectable levels of p53. Sequencing revealed an activating mutation in PI3-kinase (H1047L) and variants of unknown significance in GRK4, FLG, BAZ2A, and CRTC3. DNA methylation array of the PDX demonstrated 1p loss, which is not typically associated with primary DMG, and broad deletion within 9p including CDKN2A/B, MTAP and multiple interferon genes. The methylation profile did not significantly classify with other tumours in the Molecular Neuropathology database (molecularneuropathology.org/mnp). We describe the first reported PDX model of radiation-associated DMG following medulloblastoma, which recapitulates the patient disease and is molecularly distinct from primary DMG. Interrogation of this model through RNA and whole genome sequencing presents a valuable opportunity to better understand and identify novel therapeutic vulnerabilities against this currently incurable disease.
Melflufen and Dexamethasone in Heavily Pretreated Relapsed and Refractory Multiple Myeloma
Authors: Paul G. Richardson, Albert Oriol, Alessandra Larocca, Joan Bladé, Michele Cavo, Paula Rodriguez-Otero, Xavier Leleu, Omar Nadeem, John W. Hiemenz, Hani Hassoun, Cyrille Touzeau, Adrián Alegre, Agne Paner, Christopher Maisel, Amitabha Mazumder, Anastasios Raptis, Jan S. Moreb, Kenneth C. Anderson, Jacob P. Laubach, Sara Thuresson, Marcus Thuresson, Catriona Byrne, Johan Harmenberg, Nicolaas A. Bakker, María-Victoria Mateos
Journal: Journal of Clinical Oncology (2020)

Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly and selectively releases alkylating agents into tumor cells. The phase II HORIZON trial evaluated the efficacy of melflufen plus dexamethasone in relapsed and refractory multiple myeloma (RRMM), a population with an important unmet medical need.
Comparison of Subcutaneous Injection Versus Intravenous Infusion of Cytarabine for Induction Therapy in Young Adult Acute Myeloid Leukemia: Results of a Prospective, Multicenter, Noninferiority, Randomized Trial
Authors: Huafeng Wang, LU LIU, Jianfeng Zhou, Jianyong Li, Ying Lu, Jianping Shen, Chunyan Ji, Tong Chen, Kang Yu, Hanyun Ren, Yan Li, Dengju Li, Ying Chen, Shaolei Zang, Bin Liang, Sijing Kang, Jinghan Wang, Wei Cheng, Haitao Meng, Wen-Juan Yu, Yanhong Tong, Honghu Zhu, Jie Jin
Journal: Blood (2020)
Optimizing Hemodynamics in Cardiac Resynchronization Therapy by Left Ventricular Pacing Site: You Find Only What You Are Looking For**Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Nicolas Derval, Pierre Jaïs
Journal: Journal of the American College of Cardiology (2010)
Transtelephonic Versus Remote Monitoring of Cardiovascular Implantable Electronic Devices: Is One Approach to Be Preferred?⁎⁎Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Mark H. Schoenfeld
Journal: Journal of the American College of Cardiology (2009)
TBIO-21. Lnc-TALC PROMOTES O6-METHYLGUANINE-DNA METHYLTRANSFERASE EXPRESSION VIA REGULATING THE C-MET PATHWAY BY COMPETITIVELY BINDING WITH miR-20b-3p
Authors: Pengfei Wu, Jinquan Cai, Qun Chen
Journal: Neuro-Oncology (2020)

Abstract Long noncoding RNAs (lncRNAs) have emerged as new regulatory molecules implicated in diverse biological processes, including therapeutic resistance. However, the mechanisms underlying lncRNA-mediated temozolomide (TMZ) resistance in glioblastoma (GBM) remain largely unknown. To illustrate the role of lncRNA in TMZ resistance, we induce TMZ resistant GBM cells, perform a lncRNA microarray of the parental and TMZ-resistant cells, and find an unreported lncRNA in GBM, lnc-TALC (temozolomide-associated lncRNA in glioblastoma recurrence), correlated with TMZ resistance via competitively binding miR-20b-3p to facilitate c-Met expression. A phosphorylated AKT/FOXO3 axis regulated lnc-TALC expression in TMZ-resistant GBM cells. Furthermore, lnc-TALC increased MGMT expression by mediating the acetylation of H3K9, H3K27 and H3K36 in MGMT promoter regions through the c-Met/Stat3/p300 axis. In clinical patients, lnc-TALC is required for TMZ resistance and GBM recurrence. Our results reveal that lnc-TALC in GBM could serve as a therapeutic target to overcome TMZ resistance, enhancing the clinical benefits of TMZ chemotherapy.
COVD-25. THE PARADOXICAL EFFECTS OF COVID-19 ON CANCER CARE IN THE NEURO-ONCOLOGY SETTING
Authors: Nicole Cort, Alex Broom, Katherine Kenny, Alexander Page, Jennifer Durling, Casey Brown, Eric Lipp, David Ashley, Kyle Walsh, Margaret Johnson, Mustafa Khasraw
Journal: Neuro-Oncology (2020)

Abstract COVID-19 has caused ongoing interruptions to healthcare systems worldwide, shifting care to virtual platforms, and placing significant economic and logistical burdens on clinical practice. The pandemic has created uncertainty in delivering the standard of care, both in areas of cancer diagnosis and treatment, especially within neuro-oncology. Due to the pandemic, care and operational planning goals have shifted to infection prevention, modifying recommendations to decrease viral transmission and increasing telemedicine use, potentially creating a burden on implementing evidence-based medicine. These dynamics have since begun to redefine traditional practice and research regimens, impacting the comprehensive care that cancer patients can and should receive; and the enduring consequences for the delivery of healthcare. The impact of COVID-19 on oncology practice and trials might endure well beyond the short- to mid-term of the active pandemic. Therefore, these shifts must be accompanied by improved training and awareness, enhanced infrastructure, and evidence-based support to harness the positives and offset the potential negative consequences of the impacts of COVID-19 on cancer care. To address these paradoxical effects, we will conduct iterative, qualitative (face-to-face/video conference) interviews with neuro-oncology clinical and research professionals and adult brain tumor patients receiving care during the pandemic. We will capture unique aspects of oncology care: the lived, subjective, situated, and contingent accounts of patients and medical professionals, especially during a pandemic. We will also specifically compare the impact of telehealth during the pandemic on delivery of care to complex neuro-oncology patients. A summary of this in-depth, qualitative approach will result in a sophisticated understanding of neuro-oncology care on the frontline at a time of crisis, as experienced during a pandemic, to articulate best practices for future implementation.
RADT-25. EVALUATING LYMPHOCYTE COUNTS IN NEWLY DIAGNOSED GLIOBLASTOMA PATIENTS RECEIVING CHEMORADIATION
Authors: Lubna Hammoudeh, Mary Jane Lim-Fat, Daniel Cagney, Ayal A Aizer, Shyam Tanguturi, Nils Arvold, Jose Mcfaline-Figueroa, Ugonma Chukwueke, David Reardon, Eudocia Lee, Lakshmi Nayak, Mikael Rinne, Keith Ligon, Patrick Wen, Brian Alexander, Rifaquat Rahman
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Glioblastoma (GBM) patients are treated with chemotherapy, radiation therapy (RT) and often corticosteroids, which can all contribute to lymphopenia. We examined lymphopenia with respect to incidence, predictors, and association with progression-free survival (PFS) and overall survival (OS). METHODS We reviewed 349 newly diagnosed adult GBM patients treated at our institution in the temozolomide (TMZ) era with available lymphocyte and RT records. Data was reviewed from diagnosis through the chemoradiation (CRT) phase, defined as the period upto 6 weeks after RT. Linear regression and Cox proportional hazards modeling were used to evaluate outcomes. RESULTS Median age was 60 years (range, 19-90); 86% had KPS ≥ 70, 30% had gross total resection (GTR), and 91% received TMZ. Prior to RT, 60% (205/341) patients had a lymphocyte measurement &amp;lt; 1.0 x 1000 cells [K]/μL and 15% (50/341) had &amp;lt; 0.5 K/μL. During the CRT phase of therapy, 83% (270/324) had at least one lymphocyte measurement &amp;lt; 1.0 K/μL, 42% (135/324) &amp;lt; 0.5 K/μL, and 5% (16/324) &amp;lt; 0.2 K/μL. Older age was associated with lower lymphocytes pre-RT, while subtotal resection, TMZ use, and RT dose was associated with lower lymphocyte counts during CRT (p&amp;lt; 0.05). On multivariable analysis (MVA), age (AHR 1.03, p&amp;lt; 0.01), KPS &amp;gt; 70 (AHR 0.35, p&amp;lt; 0.01), MGMT status (AHR 0.47, p&amp;lt; 0.01), GTR (AHR 0.67, p=0.03), TMZ (AHR 0.27, p&amp;lt; 0.01) and lymphopenia during CRT (AHR 1.80, p&amp;lt; 0.01) were significantly associated with OS. Pre-RT lymphocyte level was associated with PFS on UVA (HR 0.81, p=0.03) but not on MVA (p=0.27). Lymphocyte count during CRT was not associated with PFS (p=0.24). CONCLUSION Lymphopenia is common in GBM, and chemoradiation-related lymphopenia was associated with inferior OS relative to patients without lymphopenia. Further characterization of the mechanism and optimal treatment of patients with lymphopenia are warranted to improve outcomes.
Single cell analysis of CD4 T cell differentiation reveals three major cell states and progressive acceleration of proliferation (vol 17, 103, 2016)
Authors: Valentina Proserpio, Andrea Piccolo, Liora Haim-Vilmovsky, Gozde Kar, Tapio Lonnberg, Valentine Svensson, Jhuma Pramanik, Kedar Nath Natarajan, Weichao Zhai, Xiuwei Zhang, Giacomo Donati, Melis Kayikci, Jurij Kotar, Andrew Nj McKenzie, Ruddy Montandon, Kylie R James, Daniel Fernandez-Ruiz, William R Heath, Ashraful Haque, Oliver Billker, Steven Woodhouse, Pietro Cicuta, Mario Nicodemi, Sarah A Teichmann
Journal: Genome biology (2016)
LGG-15. PEDIATRIC LOW-GRADE GLIOMAS IN SAUDI ARABIA: RETROSPECTIVE ANALYSIS OF CHILDREN WITH LOW-GRADE GLIOMAS TREATED IN KING FAHAD MEDICAL CITY KFMC- SINGLE INSTITUTIONAL EXPERIENCE
Authors: Fahad Alammar, Musa Alharpi, Maqsood Ahmad, Ayman Al-Banyan, Fahad E Alotaibi, Wafa Al Shakweer, Malak Abedalthagafi, Nahla Ali Mobark
Journal: Neuro-Oncology (2020)

Abstract Pediatric Low-grade gliomas (PLGGs) are extremely heterogeneous tumors and account for approximately 35% of childhood brain tumors. This retrospective study on 55 newly diagnosed children (&amp;lt;14 ys) with pathologically confirmed LGG from 2006 to 2016 aimed to review demographic data, clinical and therapeutic aspects and treatment outcome of PLGGs in children in Saudi Arabia. RESULTS: 33 (60.0%) males,22 (40.0%) females, median age at diagnosis 68 months. Pilocytic astrocytoma was the most common pathological diagnosis 42 (76.4%) location of tumor was Infratentorial in 30 patients (54.0%) and Supratentorial in 24 patients (43.2%), 19 patients (34.6%) had total surgical excision, 10 (18.2%) subtotal resection, 20 (36.4%) partial excision and 6 (10.9%) had biopsy only; After initial Surgery 30 patients (54.5%) required adjuvant chemotherapy of whom 14 patients (46.7%) experienced a treatment failure event, 25 patients (45.5%) who were initially observed post surgery 6 patients (24%) of them had relapse /progression and required further therapy. Only 2 patients (3.6%) received radiotherapy due to uncontrolled progression first line chemotherapy carboplatin and vincristine (CV) regimen was tolerated, Carboplatin allergic reactions developed in 21.1% of patients. Median follow-up of 6.49 years, the median time of relapse/ progression was 2.85 years The 5-year overall survival (OS) rates and progression free survival for all patients were 92.2 %, and 63.3% respectively. This study was to document the outcome of pediatric LGG in Saudi Arabia and to serve as a guideline for the future management with incorporation of molecular studies on pediatric LGGs which may help improve the outcome for Saudi children with LGG.
IMMU-41. HIGH-THROUGHPUT RETRIEVAL OF THERAPEUTIC T CELL RECEPTORS FROM GLIOMA
Authors: Katharina Lindner, Chin Leng Tan, Matthias Bozza, Khwab Sanghvi, Isabel Poschke, Richard Harbottle, Andreas von Deimling, Wolfgang Wick, Felix Sahm, Michael Platten, Edward W Green, Lukas Bunse
Journal: Neuro-Oncology (2020)

Abstract Gliomas are tumors with low mutational burden with the majority of them being resistant to checkpoint inhibition due to few immunogenic antigens. Multicenter vaccine trials targeting personalized neoantigens in gliomas demonstrated feasibility and illustrated the challenges of retrieving neoepitope-specific T cells based on the prediction of immunogenic neoepitopes. Here we took an entirely different T cell-centric approach and established a single cell sequencing-based high-throughput T cell receptor (TCR) retrieval platform, exploiting the therapeutic potential of spontaneous intratumoral T cell clonotypes for the development of adoptive cell therapy. We conducted direct ex vivo TCR single cell sequencing from freshly sorted human glioma-infiltrating T cell samples. High fidelity PCR was established to clone TCRs from single cell libraries directly into episomal expression vectors further optimized for T cell therapy. In parallel to standard therapy, patient-derived xenografts were developed and characterized. Tumor-reactivity of retrieved TCRs was demonstrated against patient-derived cell lines. Collectively, we provide a novel sequencing-based platform for high-throughput identification and validation of endogenous glioma-targeting TCRs and demonstrate their therapeutic applicability.
Readmission and Death After Initial Hospital Discharge Among Patients With COVID-19 in a Large Multihospital System
Authors: John P. Donnelly, Xiao Qing Wang, Theodore J. Iwashyna, Hallie C. Prescott
Journal: JAMA (2020)

This study describes reasons for readmission, use of ICU interventions during readmission, and proportions of death after initial hospital discharge of COVID-19 patients from US Veterans Affairs (VA) hospitals in March-June 2020.
Cardiac Magnetic Resonance in the World of the Cardiac Electrophysiologist: The Road to Real-Time Cardiac Magnetic Resonance⁎⁎Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.
Authors: Anil Pandit, Nassir F. Marrouche
Journal: JACC. Cardiovascular imaging (2009)