tbuckley/cabot-search huggingface dataset:
Raising awareness of the health effects of environmental exposures
Authors: Anna Trakoli
Journal: BMJ (2019)

The research by von Ehrenstein and colleagues on prenatal and infant exposure to ambient pesticides and autism spectrum disorder in children is a welcome and timely addition to environmental health research.1

The technological advances of recent decades have seen an exponential growth in the number of environmental hazards, which is unmatched by research on their effects on health. The health …
LGG-11. ESTABLISHMENT OF A HUMAN 3-DIMENSIONAL LOW-GRADE GLIOMA TUMOR MODEL IN INDUCED PLURIPOTENT STEM CELL DERIVED BRAIN ORGANOIDS
Authors: Annabelle Bahr, David Capper, Olaf Witt, Till Milde, Florian Selt, Juliane Buhl, Harald Stachelscheid, Pablo Hernáiz Driever
Journal: Neuro-Oncology (2019)

INTRODUCTION: Low-grade glioma (LGG) are the most common pediatric brain tumors. Preclinical models are still scarce. We used human induced pluripotent stem cell (hiPSC) derived brain organoids for human LGG disease modeling. METHODS: Brain organoids were generated from hiPSC cells using the STEMdiff™ Cerebral Organoid Kit (Stem Cell Technologies), based on the Lancaster et al. (Nature, 2013). LGG tumor spheres were generated from pilocytic astrocytoma cells DKFZ-BT66. High-grade glioma (HGG) tumor spheres were derived from U-87 cells. Brain organoids were co-cultured with either LGG or HGG tumor spheres. Co-cultures were formalin-fixed and paraffin-embedded for H&E and immunohistochemistry for analysis. RESULTS: Neuronal rosettes in the brain organoids represented immature and proliferating progenitor cells which were positive for MIB1. From day 30 to day 45, numbers of mature neurons expressing MAP2 increased. Organoids were focally expressing GFAP and S-100. After co-culturing tumor spheres with brain organoids (size ratio 1:1) we observed a partial or complete fusion of both tissues within the first three days. Red fluorescent protein expressing LGG cells migrated into the organoids. Their morphology resembled bipolar astrocytes and they invaded without destroying the normal organoid architecture. LGG cells strongly expressed MAP2 showing their differentiated character. In contrast, U-87 HGG cells massively spread around the organoids and showed a highly proliferating and invading biology. It was not possible to clearly discern remaining organoid tissue from HGG cells. Furthermore, we found a high rate of apoptotic cells. Co-cultured U-87 cells only expressed MIB1, especially in the outer cell layers, and no mature glial markers. CONCLUSIONS: We established the first human 3-dimensional LGG model in developing brain organoids, that allows animal free 3D LGG research. To better characterize the inter- and intracellular biology we will apply single-cell analysis.
Receptor‐Interacting Protein Kinase 3 Deficiency Recruits Myeloid‐Derived Suppressor Cells to Hepatocellular Carcinoma Through the Chemokine (C‐X‐C Motif) Ligand 1–Chemokine (C‐X‐C Motif) Receptor 2 Axis
Authors: Yi‐Ming Li, Zhen‐Yu Liu, Jian‐Chao Wang, Jing‐Min Yu, Zhu‐Chun Li, Hai‐Jiao Yang, Juan Tang, Zhi‐Nan Chen
Journal: Hepatology (2019)

Receptor‐interacting protein kinase 3 (RIP3) is the core regulator that switches cell death from apoptosis to necrosis. However, its role in tumor immunity is unknown. In this study, decreased RIP3 expression was observed in patients with hepatocellular carcinoma (HCC), which correlates with myeloid‐derived suppressor cell (MDSC) accumulation. Moreover, RIP3 is a prognosis factor for patients with HCC. We further found that RIP3 knockdown results in an increase of MDSCs and a decrease of interferon gamma–positive (IFN‐γ + ) cluster of differentiation 8–positive (CD8 + ) tumor‐infiltrating lymphocytes (IFN‐γ + CD8 + T cells) in hepatoma tissues, thus promoting immune escape and HCC growth in immunocompetent mice. By phosphorylating P65 Ser536 and promoting phosphorylated P65 Ser536 nuclear translocation, RIP3 knockdown increases the expression of chemokine (C‐X‐C motif) ligand 1 (CXCL1) in HCC cells. RIP3 knockdown induces MDSC recruitment through the CXCL1–chemokine (C‐X‐C motif) receptor 2 (CXCR2) axis. Furthermore, a CXCR2 antagonist substantially suppresses MDSC chemotaxis and HCC growth in RIP3 knockout mice. Conclusion : RIP3 deficiency is an essential factor directing MDSC homing to HCC and promoting CXCL1/CXCR2‐induced MDSC chemotaxis to facilitate HCC immune escape and HCC progression; blocking the CXCL1–CXCR2 chemokine axis may provide an immunological therapeutic approach to suppress progression of RIP3 deficiency HCC.
LRP1-upregulated nanoparticles for efficiently conquering the blood-brain barrier and targetedly suppressing multifocal and infiltrative brain metastases
Authors: Qian Guo, Qiuning Zhu, Tongtong Miao, Jing Tao, Xiufeng Ju, Zhenglong Sun, Hui Li, Guoqiang Xu, Huabing Chen, Liang Han
Journal: Journal of Controlled Release (2019)
Phase Ib evaluation of a self-adjuvanted protamine formulated mRNA-based active cancer immunotherapy, BI1361849 (CV9202), combined with local radiation treatment in patients with stage IV non-small cell lung cancer
Authors: Alexandros Papachristofilou, Madeleine M. Hipp, Ute Klinkhardt, Martin Früh, Martin Sebastian, Christian Weiss, Miklos Pless, Richard Cathomas, Wolfgang Hilbe, Georg Pall, Thomas Wehler, Jürgen Alt, Helge Bischoff, Michael Geißler, Frank Griesinger, Karl-Josef Kallen, Mariola Fotin-Mleczek, Andreas Schröder, Birgit Scheel, Anke Muth, Tobias Seibel, Claudia Stosnach, Fatma Doener, Henoch S. Hong, Sven D. Koch, Ulrike Gnad-Vogt, Alfred Zippelius
Journal: Journal for ImmunoTherapy of Cancer (2019)

Preclinical studies demonstrate synergism between cancer immunotherapy and local radiation, enhancing anti-tumor effects and promoting immune responses. BI1361849 (CV9202) is an active cancer immunotherapeutic comprising protamine-formulated, sequence-optimized mRNA encoding six non-small cell lung cancer (NSCLC)-associated antigens (NY-ESO-1, MAGE-C1, MAGE-C2, survivin, 5T4, and MUC-1), intended to induce targeted immune responses.We describe a phase Ib clinical trial evaluating treatment with BI1361849 combined with local radiation in 26 stage IV NSCLC patients with partial response (PR)/stable disease (SD) after standard first-line therapy. Patients were stratified into three strata (1: non-squamous NSCLC, no epidermal growth factor receptor (EGFR) mutation, PR/SD after ≥4 cycles of platinum- and pemetrexed-based treatment [n = 16]; 2: squamous NSCLC, PR/SD after ≥4 cycles of platinum-based and non-platinum compound treatment [n = 8]; 3: non-squamous NSCLC, EGFR mutation, PR/SD after ≥3 and ≤ 6 months EGFR-tyrosine kinase inhibitor (TKI) treatment [n = 2]). Patients received intradermal BI1361849, local radiation (4 × 5 Gy), then BI1361849 until disease progression. Strata 1 and 3 also had maintenance pemetrexed or continued EGFR-TKI therapy, respectively. The primary endpoint was evaluation of safety; secondary objectives included assessment of clinical efficacy (every 6 weeks during treatment) and of immune response (on Days 1 [baseline], 19 and 61).Study treatment was well tolerated; injection site reactions and flu-like symptoms were the most common BI1361849-related adverse events. Three patients had grade 3 BI1361849-related adverse events (fatigue, pyrexia); there was one grade 3 radiation-related event (dysphagia). In comparison to baseline, immunomonitoring revealed increased BI1361849 antigen-specific immune responses in the majority of patients (84%), whereby antigen-specific antibody levels were increased in 80% and functional T cells in 40% of patients, and involvement of multiple antigen specificities was evident in 52% of patients. One patient had a partial response in combination with pemetrexed maintenance, and 46.2% achieved stable disease as best overall response. Best overall response was SD in 57.7% for target lesions.The results support further investigation of mRNA-based immunotherapy in NSCLC including combinations with immune checkpoint inhibitors.ClinicalTrials.gov identifier: NCT01915524 .
Maternal Glycemic Control in Type 1 Diabetes and the Risk for Preterm Birth
Authors: Jonas F. Ludvigsson, Martin Neovius, Jonas Söderling, Soffia Gudbjörnsdottir, Ann-Marie Svensson, Stefan Franzén, Olof Stephansson, Björn Pasternak
Journal: Annals of Internal Medicine (2019)

Background: Maternal type 1 diabetes (T1D) has been linked to preterm birth and other adverse pregnancy outcomes. How these risks vary with glycated hemoglobin (or hemoglobin A1c [HbA1c]) levels is unclear. Objective: To examine preterm birth risk according to periconceptional HbA1c levels in women with T1D. Design: Population-based cohort study. Setting: Sweden, 2003 to 2014. Patients: 2474 singletons born to women with T1D and 1 165 216 reference infants born to women without diabetes. Measurements: Risk for preterm birth (<37 gestational weeks). Secondary outcomes were neonatal death, large for gestational age, macrosomia, infant birth injury, hypoglycemia, respiratory distress, 5-minute Apgar score less than 7, and stillbirth. Results: Preterm birth occurred in 552 (22.3%) of 2474 infants born to mothers with T1D versus 54 287 (4.7%) in 1 165 216 infants born to mothers without diabetes. The incidence of preterm birth was 13.2% in women with a periconceptional HbA1c level below 6.5% (adjusted risk ratio [aRR] vs. women without T1D, 2.83 [95% CI, 2.28 to 3.52]), 20.6% in those with a level from 6.5% to less than 7.8% (aRR, 4.22 [CI, 3.74 to 4.75]), 28.3% in those with a level from 7.8% to less than 9.1% (aRR, 5.56 [CI, 4.84 to 6.38]), and 37.5% in those with a level of 9.1% or higher (aRR, 6.91 [CI, 5.85 to 8.17]). The corresponding aRRs for medically indicated preterm birth (n = 320) were 5.26 (CI, 3.83 to 7.22), 7.42 (CI, 6.21 to 8.86), 11.75 (CI, 9.72 to 14.20), and 17.51 (CI, 14.14 to 21.69), respectively. The corresponding aRRs for spontaneous preterm birth (n = 223) were 1.81 (CI, 1.31 to 2.52), 2.86 (CI, 2.38 to 3.44), 2.88 (CI, 2.23 to 3.71), and 2.80 (CI, 1.94 to 4.03), respectively. Increasing HbA1c levels were associated with the study's secondary outcomes: large for gestational age, hypoglycemia, respiratory distress, low Apgar score, neonatal death, and stillbirth. Limitation: Because HbA1c levels were registered annually at routine visits, they were not available for all pregnant women with T1D. Conclusion: The risk for preterm birth was strongly linked to periconceptional HbA1c levels. Women with HbA1c levels consistent with recommended target levels also were at increased risk. Primary Funding Source: Swedish Diabetes Foundation.
Plasma-Based Circulating MicroRNA Biomarkers for Chronic Thromboembolism Pulmonary Hypertension
Authors: A. T. Fabro, H. R. Crunivel, P. D. Leao, S. S. Batah, A. L. Santos, J. R. Machado-Rugulo, A. I. de Padua, J. Baddini-Martinez, C. A. Rainho, H. H. Yoo, V. L. Capelozzi
Journal: American Journal of Respiratory and Critical Care Medicine (2018)
Modeling and Surveillance of Reporting Delays of Mosquitoes and Humans Infected With West Nile Virus and Associations With Accuracy of West Nile Virus Forecasts
Authors: Nicholas B. DeFelice, Ruthie Birger, Nathaniel DeFelice, Alexandra Gagner, Scott R. Campbell, Christopher Romano, Michael Santoriello, Jennifer Henke, Jeremy Wittie, Barbara Cole, Cameron Kaiser, Jeffrey Shaman
Journal: JAMA Network Open (2019)

<h3>Importance</h3> West Nile virus (WNV) is the leading cause of domestically acquired arboviral disease. <h3>Objective</h3> To develop real-time WNV forecasts of infected mosquitoes and human cases. <h3>Design, Setting, and Participants</h3> Real-time forecasts of WNV in 4 geographically dispersed locations in the United States were generated using a WNV model-inference forecasting system previously validated with retrospective data. Analysis was performed to evaluate how observational reporting delays of mosquito WNV assay results and human medical records were associated with real-time forecast accuracy. <h3>Exposures</h3> Mosquitoes positive for WNV and human cases. <h3>Main Outcomes and Measures</h3> Delays in reporting mosquito WNV assay results and human medical records and the association of these delays with real-time WNV forecast accuracy. <h3>Results</h3> Substantial delays in data reporting exist for both infected mosquitoes and human WNV cases. For human cases, confirmed data (n = 37) lagged behind the onset of illness by a mean (SD) of 5.5 (2.3) weeks (range, 2-14 weeks). These human case reporting lags reduced mean forecast accuracy for the total number of human cases over the season in 110 simulated outbreaks for 2 forecasting systems by 26% and 14%, from 2 weeks before to 3 weeks after the predicted peak of infected mosquitoes. This period is the time span during which 47% of human cases are reported. Of 7064 mosquito pools, 500 (7%) tested positive; the reporting lag for these data associated with viral testing at a state laboratory was a mean (SD) of 6.6 (2.6) days (range, 4-11 days). This reporting lag was associated with decreased mean forecast accuracy for the 3 mosquito infection indicators, timing, magnitude, and season, by approximately 5% for both forecasting systems. <h3>Conclusions and Relevance</h3> Delays in reporting human WNV disease and infected mosquito information are associated with difficulties in outbreak surveillance and decreased real-time forecast accuracy. Infected mosquito lags were short enough that skillful forecasts could still be generated for mosquito infection indicators, but the human WNV case lags were too great to support accurate forecasting in real time. Forecasting WNV is potentially an important evidence-based decision support tool for public health officials and mosquito abatement districts; however, to operationalize real-time forecasting, more resources are needed to reduce human case reporting lags between illness onset and case confirmation.
Image Gallery: Peculiar subungual localization of a second primary melanoma during <scp>BRAF</scp> inhibitors treatment for metastatic melanoma: case report
Authors: A. Ventura, R. Pitocco, A. Di Stefani, C. Cota, D. Spallone, L. Bianchi, G. Spallone
Journal: British Journal of Dermatology (2019)
Tracking spending on malaria by source in 106 countries, 2000–16: an economic modelling study
Authors: Annie Haakenstad, Anton Connor Harle, Golsum Tsakalos, Angela E Micah, Tianchan Tao, Mina Anjomshoa, Jessica Cohen, Nancy Fullman, Simon I Hay, Tomislav Mestrovic, Shafiu Mohammed, Seyyed Meysam Mousavi, Molly R Nixon, David Pigott, Khanh Tran, Christopher J L Murray, Joseph L Dieleman
Journal: The Lancet Infectious Diseases (2019)

Sustaining achievements in malaria control and making progress toward malaria elimination requires coordinated funding. We estimated domestic malaria spending by source in 106 countries that were malaria-endemic in 2000-16 or became malaria-free after 2000.
TTPAL Promotes Colorectal Tumorigenesis by Stabilizing TRIP6 to Activate Wnt/β-Catenin Signaling
Authors: Hongyan Gou, Jessie Qiaoyi Liang, Lijing Zhang, Huarong Chen, Yanquan Zhang, Rui Li, Xiaohong Wang, Jiafu Ji, Joanna H. Tong, Ka-Fai To, Joseph J.Y. Sung, Francis K.L. Chan, Jing-Yuan Fang, Jun Yu
Journal: Cancer Research (2019)

Abstract Copy number alterations are crucial for the development of colorectal cancer. Our whole-genome analysis identified tocopherol alpha transfer protein-like (TTPAL) as preferentially amplified in colorectal cancer. Here we demonstrate that frequent copy number gain of TTPAL leads to gene overexpression in colorectal cancer from a Chinese cohort (n = 102), which was further validated by a The Cancer Genome Atlas (TCGA) cohort (n = 376). High expression of TTPAL was significantly associated with shortened survival in patients with colorectal cancer. TTPAL promoted cell viability and clonogenicity, accelerated cell-cycle progression, inhibited cell apoptosis, increased cell migration/invasion ability in vitro, and promoted tumorigenicity and cancer metastasis in vivo. TTPAL significantly activated Wnt signaling and increased β-catenin activation and protein expression of cyclin D1 and c-Myc. Coimmunoprecipitation followed by mass spectrometry identified thyroid receptor–interacting protein 6 (TRIP6) as a direct downstream effector of TTPAL. Depletion of TRIP6 significantly abolished the effects of TTPAL on cell proliferation and Wnt activation. Direct binding of TTPAL with TRIP6 in the cytoplasm inhibited ubiquitin-mediated degradation of TRIP6 and, subsequently, increased levels of TRIP6 displaced β-catenin from the tumor suppressor MAGI1 via competitive binding. This sequence of events allows β-catenin to enter the nucleus and promotes oncogenic Wnt/β-catenin signaling. In conclusion, TTPAL is commonly overexpressed in colorectal cancer due to copy number gain, which promotes colorectal tumorigenesis by activating Wnt/β-catenin signaling via stabilization of TRIP6. TTPAL overexpression may serve as an independent new biomarker for the prognosis of patients with colorectal cancer. Significance: TTPAL, a gene preferentially amplified in colorectal cancer, promotes colon tumorigenesis via activation of the Wnt/β-catenin pathway.
Impact of adjuvant chemotherapy on oncologic outcomes following radical nephroureterectomy for patients with pT3NanyM0 upper tract urothelial carcinoma: A retrospective cohort study
Authors: Wan Song, Jae Yong Jeong, Hwang Gyun Jeon, Seong Il Seo, Seong Soo Jeon, Han Yong Choi, Hyun Moo Lee, Hyun Hwan Sung
Journal: International Journal of Surgery (2019)
Abstract 14671: Acute Right Ventricular Failure After Successful Opening of Chronic Total Occlusion in Right Coronary Artery
Authors: Masataka Kawana, Anson Lee, David H Liang, Alan Yeung
Journal: Circulation (2016)

A 76 year-old man with history of coronary artery disease and recent aortic valve replacement for severe aortic stenosis was referred for an elective PCI with a drug eluting stent (DES) in mid-LCX, and serial lesions in the RCA with CTO of the distal segment that was opened with 3 DES. Final angiographic result was excellent, and he was monitored in recovery unit. 6 hours later, he developed acute left shoulder and chest pain, and ECG showed ST segment elevation in inferolateral leads. He was loaded with prasugrel and emergently taken back to the cath lab with assumed in-stent thrombosis; however, coronary angiogram showed patent stents in RCA and LCX and no significant disease in LAD. Limited TTE in the cath lab showed no evidence of pericardial effusion. He was transferred to CCU with IABP, where he required increasing amount of inotrope, continued to have chest pain, and had a sharp rise in troponin. Further TTE examination showed a large mass measuring 3.5 x 6cm along the space between epicardium and ...
ATRT-08. SMARCB1 LOSS INTERACTS WITH NEURAL DIFFERENTIATION STATE TO GENERATE CELL TYPE-SPECIFIC PHENOTYPES
Authors: Alison Parisian, Tomoyuki Koga, Frank Furnari
Journal: Neuro-Oncology (2019)

Atypical teratoid rhabdoid tumors (ATRT) are challenging pediatric brain tumors which are predominantly associated with inactivation of the gene SMARCB1. As SMARCB1 is a conserved subunit of the chromatin remodeling BAF complex, we hypothesize that the effect of its loss of function is influenced by the epigenetic landscape of the cell in which deletion occurs, resulting in constrained age of onset and tissue specificity of tumor formation. To address this question and identify potential interactions between SMARCB1 loss and the process of neural development, we generated a model of ATRT using an inducible SMARCB1 loss of function system in human induced pluripotent stem cells (iPSCs) which were used to form cerebral organoids. We have identified substantial differences in the downstream effects of SMARCB1 loss depending on differentiation state and have identified neural cell types which are particularly vulnerable to SMARCB1 loss. Our results suggest that SMARCB1 loss likely interacts with processes of neural development for ATRT tumorigenesis.
Electronic clinical decision support system (eCDSS) in the management of asthma: from theory to practice
Authors: Jean Bousquet
Journal: European Respiratory Journal (2019)

Controlling symptoms while minimising the side-effects of treatment is the main aim of asthma management. If a patient's asthma stabilises, the clinician should then consider stepping down the treatment [1]. In practice, the implementation of step-down or step-up strategies includes 1) the use of risk prediction, 2) tools to support shared decision-making and 3) communication between clinicians and patients about risk. Major contributors to poor asthma control include the following evidence-based care gaps [2]: 1) monitoring of control, resulting in the under-recognition of suboptimal control, 2) adjustment of medication, and 3) delivery of an asthma action plan. Electronic decision support systems may improve asthma control <http://ow.ly/UoAe30o6IEC>
Sustained imaging response and hearing preservation with low-dose bevacizumab in sporadic vestibular schwannoma
Authors: Matthias A Karajannis, Mari Hagiwara, Mark Schreyer, Sofia Haque
Journal: Neuro-Oncology (2019)

Sustained imaging response and hearing preservation with low-dose bevacizumab in sporadic vestibular schwannomaBevacizumab (BEV) is effective in reducing tumor volume and improving hearing in a subset of neurofibromatosis type 2 (NF2) patients with vestibular schwannoma (VS).Recent prospective clinical trial data demonstrated imaging and hearing response rates of 57% and 36%, respectively, in NF2-related VS patients, 1 and therapeutic benefit is not maintained after discontinuation of drug.It is not currently known whether sporadic VS may also respond to bevacizumab.We report sustained treatment response to low-dose bevacizumab in an adult female patient with progressive sporadic VS.She was diagnosed at age 47 years when a brain MRI obtained after a fall disclosed a right cerebellopontine angle tumor consistent with a VS.Her past medical history is relevant for deafness in the left ear since early childhood, presumably due to mumps and/or administration of ototoxic antibiotics.Imaging surveillance revealed slow continued progression of the VS, and she subsequently developed progressive hydrocephalus requiring placement of a ventriculoperitoneal shunt.She declined surgery or radiation therapy for treatment of her progressive VS due to concern for the risk of hearing loss in her remaining ear.After informed consent, she began treatment with off-label BEV at a dose of 10 mg/kg every 2 weeks.Response assessments included MRIs of the brain with tumor volumetrics as previously described, 2 as well as audiograms.At pretreatment baseline, tumor volume was 8.56 cc, with normal hearing in the right ear.She had an excellent imaging response to therapy, which was maintained with stepwise reduction of BEV to a low dose of 2.5 mg/kg every 4 weeks to limit the risk of toxicity 3 (Fig. 1).She tolerated therapy well, with no BEV-related toxicity such as hypertension or proteinuria.Most recent tumor volume measured 2.76 cc, which represents a 67.8% shrinkage from pretreatment baseline.She currently continues on therapy for 33+ months, with no evidence of any BEV-related toxicity, and maintaining normal hearing in the right ear.Mean apparent diffusional coefficient (ADC) calculated from diffusion-weighted imaging was 1267 mm 2 /s at baseline and declined to 1050 mm 2 /s after 2 months of treatment,