tbuckley/cabot-search huggingface dataset:
Graft-versus-host disease of the CNS is mediated by TNF upregulation in microglia
Authors: Nimitha R. Mathew, Janaki M. Vinnakota, Petya Apostolova, Daniel Erny, Shaimaa Hamarsheh, Geoffroy Andrieux, Jung-Seok Kim, Kathrin Hanke, Tobias Goldmann, Louise Chappell-Maor, Nadia El-Khawanky, Gabriele Ihorst, Dominik Schmidt, Justus Duyster, Jürgen Finke, Thomas Blank, Melanie Boerries, Bruce R. Blazar, Steffen Jung, Marco Prinz, Robert Zeiser
Journal: Journal of Clinical Investigation (2019)

Acute graft-versus-host disease (GVHD) can affect the central nervous system (CNS). The role of microglia in CNS-GVHD remains undefined. In agreement with microglia activation, we found that profound morphological changes and MHC-II and CD80 upregulation occurred upon GVHD induction. RNA sequencing–based analysis of purified microglia obtained from mice with CNS-GVHD revealed TNF upregulation. Selective TNF gene deletion in microglia of Cx3cr1creER Tnffl/– mice reduced MHC-II expression and decreased CNS T cell infiltrates and VCAM-1+ endothelial cells. GVHD increased microglia TGF-β–activated kinase-1 (TAK1) activation and NF-κB/p38 MAPK signaling. Selective Tak1 deletion in microglia using Cx3cr1creER Tak1fl/fl mice resulted in reduced TNF production and microglial MHC-II and improved neurocognitive activity. Pharmacological TAK1 inhibition reduced TNF production and MHC-II expression by microglia, Th1 and Th17 T cell infiltrates, and VCAM-1+ endothelial cells and improved neurocognitive activity, without blocking graft-versus-leukemia effects. Consistent with these findings in mice, we observed increased activation and TNF production of microglia in the CNS of GVHD patients. In summary, we prove a role for microglia in CNS-GVHD, identify the TAK1/TNF/MHC-II axis as a mediator of CNS-GVHD, and provide a TAK1 inhibitor–based approach against GVHD-induced neurotoxicity.
A randomized controlled phase III study of VB-111 combined with bevacizumab vs bevacizumab monotherapy in patients with recurrent glioblastoma (GLOBE)
Authors: Timothy F Cloughesy, Andrew Brenner, John F de Groot, Nicholas A Butowski, Leor Zach, Jian L Campian, Benjamin M Ellingson, Laurence S Freedman, Yael C Cohen, Noa Lowenton-Spier, Tamar Rachmilewitz Minei, Shifra Fain Shmueli, Patrick Y Wen, Nicholas Avgeropoulos, Joseph Beck, Tara Benkers, Felix Bokstein, Andrew Brenner, Eric Burton, Nicholas Butowski, Jian Campian, Jose Carrillo, Timothy Cloughesy, John de Groot, Paula De Robles, Jan Drappatz, Irine Dunbar, Karen Fink, Morris Groves, Xiaosi Han, Hormigo Adila, Randy Jensen, Agnieszka Kowalska, Pyriya Kumthekar, Mijung Lee, Glenn Lesser, Alexander Lossos, Rimas Lukas, David Macdonald, Aaron Mammoser, Laszlo Mechtler, Nimish Mohile, Seema Nagpal, Garth Nicholas, Teri Kreisl, Edward Pan, Scott Peak, Michael Pearlman, James Perry, Richard Peterson, David Piccioni, Henry Robins, Lara Ronan, Michael Salacz, David Schiff, David Tran, Leor Zach, Tzahala Tzuk-Shina, Tobias Walbert, Patrick Wen, Shlomit Youst
Journal: Neuro-Oncology (2019)

Abstract Background Ofranergene obadenovec (VB-111) is an anticancer viral therapy that demonstrated in a phase II study a survival benefit for patients with recurrent glioblastoma (rGBM) who were primed with VB-111 monotherapy that was continued after progression with concomitant bevacizumab. Methods This pivotal phase III randomized, controlled trial compared the efficacy and safety of upfront combination of VB-111 and bevacizumab versus bevacizumab monotherapy. Patients were randomized 1:1 to receive VB-111 1013 viral particles every 8 weeks in combination with bevacizumab 10 mg/kg every 2 weeks (combination arm) or bevacizumab monotherapy (control arm). The primary endpoint was overall survival (OS), and secondary endpoints were objective response rate (ORR) by Response Assessment in Neuro-Oncology (RANO) criteria and progression-free survival (PFS). Results Enrolled were 256 patients at 57 sites. Median exposure to VB-111 was 4 months. The study did not meet its primary or secondary goals. Median OS was 6.8 versus 7.9 months in the combination versus control arm (hazard ratio, 1.20; 95% CI: 0.91–1.59; P = 0.19) and ORR was 27.3% versus 21.9% (P = 0.26). A higher rate of grades 3–5 adverse events was reported in the combination arm (67% vs 40%), mainly attributed to a higher rate of CNS and flu-like/fever events. Trends for improved survival with combination treatment were seen in the subgroup of patients with smaller tumors and in patients who had a posttreatment febrile reaction. Conclusions In this study, upfront concomitant administration of VB-111 and bevacizumab failed to improve outcomes in rGBM. Change of treatment regimen, with the lack of VB-111 monotherapy priming, may explain the differences from the favorable phase II results. Clinical trials registration NCT02511405
Disruptive anti-IgE inhibitors prevent mast cell–dependent early airway response in viable atopic lung tissue
Authors: Sharon Jiménez Delgado, Susann Dehmel, Elaine Twisterling, Judy Wichmann, Danny Jonigk, Gregor Warnecke, Peter Braubach, Hans-Gerd Fieguth, Ludwig Wilkens, Franziska Dahlmann, Franz-Josef Kaup, Alexander Eggel, Sascha Knauf, Katherina Sewald, Armin Braun
Journal: Journal of Allergy and Clinical Immunology (2019)
Association of lung immune prognostic index (LIPI) with survival of first line immune checkpoint inhibitors single agent or in combination with chemotherapy in untreated advanced NSCLC patients
Authors: F. Blanc-Durand, E. Auclin, D. Planchard, S. Ponce Aix, L. Hendriks, I.G. Sullivan, D. Saravia, B. Routy, R. Lopez Castro, S. Pilotto, F. Aboubakar, E. Kassouf, A. Rodriguez, A. Amores Martin, M.V. Bluthgen, B. Duchemann, C. Caramella, E. Nadal, B. Besse, L. Mezquita
Journal: Annals of Oncology (2019)
Lipid, Lipoproteins, C-Reactive Protein, and Hemostatic Factors at Baseline in the Diabetes Prevention Program
Journal: Diabetes Care (2005)

OBJECTIVE—Individuals with impaired glucose tolerance (IGT) appear to be at increased risk for cardiovascular disease (CVD) due at least in part to an increased prevalence of risk factors. We evaluated lipid, lipoprotein, C-reactive protein (CRP), fibrinogen, and tissue plasminogen activator (tPA) levels at study entry in the largest multiethnic cohort of participants with IGT described, namely in the Diabetes Prevention Program (DPP). RESEARCH DESIGN AND METHODS—Measurements were performed at the baseline visit of 3,819 randomized participants of the DPP. Among 3,622 participants who were not taking lipid-lowering medicines, cardiovascular risk factors were analyzed in relation to demographic, anthropometric, and metabolic measures. Major determinants of risk factors were assessed in multivariate analysis. RESULTS—Over 40% of participants had elevated triglyceride, LDL cholesterol, and CRP levels and reduced HDL cholesterol levels. Men had higher triglyceride and tPA and lower HDL cholesterol concentrations and smaller LDL particle size than women, whereas women had higher CRP and fibrinogen levels. African Americans had less dyslipidemia but higher fibrinogen levels, and Asian Americans had lower CRP and fibrinogen levels than Caucasians and Hispanics. The surrogate measure of insulin resistance (homeostasis model assessment of insulin resistance [HOMA-IR]) had the strongest association with HDL cholesterol, triglyceride, and tPA levels and LDL particle size. BMI had the greatest influence on CRP and fibrinogen levels. Using median splits of indexes of insulin resistance and insulin secretion (insulin-to-glucose ratio), participants with greater insulin resistance had a more adverse CVD risk-factor profile, whereas insulin secretion had little influence on risk factors. CONCLUSIONS—The pattern of CVD risk factors in participants with IGT in the DPP exhibits substantial heterogeneity and is significantly influenced by race, sex, and age, as well as by obesity, glucose, and insulin measures. The degree of insulin resistance, as reflected by HOMA-IR, showed the greatest association with the cardiovascular risk factors.
Long-term follow-up of patients with mantle cell lymphoma (MCL) treated with the selective Bruton’s tyrosine kinase inhibitor tirabrutinib (GS/ONO-4059)
Authors: Simon A. Rule, Guillaume Cartron, Christopher Fegan, Franck Morschhauser, Lingling Han, Siddhartha Mitra, Gilles Salles, Martin J. S. Dyer
Journal: Leukemia (2019)

Recent therapeutic advances for mantle cell lymphoma (MCL) include inhibitors of Bruton's tyrosine kinase (BTK), a critical component in the B-cell receptor signaling pathway [1,2].Remarkably, approximately two thirds of patients with relapsed/refractory (R/R) MCL treated with ibrutinib, the first-in-class BTK inhibitor, achieve a durable response [3][4][5].However, ibrutinib treatment also commonly produces off-target adverse events (AEs) such as bleeding, atrial fibrillation, diarrhea, and infection.Second-generation BTK inhibitors with greater selectivity include tirabrutinib (GS/ONO-4059), acalabrutinib, and .In 2017, acalabrutinib received FDA
Nilotinib Effects on Safety, Tolerability, and Potential Biomarkers in Parkinson Disease
Authors: Fernando. L. Pagan, Michaeline L. Hebron, Barbara Wilmarth, Yasar Torres-Yaghi, Abigail Lawler, Elizabeth E. Mundel, Nadia Yusuf, Nathan J. Starr, Muhammad Anjum, Joy Arellano, Helen H. Howard, Wangke Shi, Sanjana Mulki, Tarick Kurd-Misto, Sara Matar, Xiaoguang Liu, Jaeil Ahn, Charbel Moussa
Journal: JAMA Neurology (2019)

This study evaluated nilotinib safety and its effects on biomarkers as a potential disease-modifying drug in Parkinson disease.To assess nilotinib effects on safety and pharmacokinetics and measure the change in exploratory biomarkers in patients with moderately severe Parkinson disease.This was a single-center, phase 2, randomized, double-blind, placebo-controlled trial with 300 patients approached in clinic; of these, 200 declined to participate, 100 were screened, 25 were excluded, and 75 were randomized 1:1:1 into placebo; nilotinib, 150-mg; or nilotinib, 300-mg groups. Recruitment started on May 17, 2017, and ended April 28, 2018, and follow-up ended August 10, 2019. Parkinson disease was confirmed according to the UK Brain Bank diagnostic criteria and symptoms were stabilized with use of optimal levodopa and/or dopamine agonists and other medications used in Parkinson disease.Nilotinib vs placebo, administered orally once daily for 12 months followed by a 3-month washout period.It was hypothesized that nilotinib is safe and can be detected in the cerebrospinal fluid, where it alters exploratory biomarkers via inhibition of Abelson tyrosine kinase and potentially improves clinical outcomes.Of the 75 patients included in the study, 55 were men (73.3%); mean (SD) age was 68.4 (8.2) years. Doses of 150 or 300 mg of nilotinib were reasonably safe, although more serious adverse events were detected in the nilotinib (150 mg: 6 [24%]; 300 mg: 12 [48%]) vs placebo (4 [16%]) groups. The 150-mg nilotinib group showed an increase in cerebrospinal fluid levels of the dopamine metabolites homovanillic acid (159.80nM; 90% CI, 7.04-312.60nM; P = .04) and 3,4-dihydroxyphenylacetic acid (4.87nM; 90% CI, 1.51-8.23nM; P = .01), and the 300-mg nilotinib group showed an increase in 3,4-dihydroxyphenylacetic acid (7.52nM; 90% CI, 2.35-12.69nM; P = .01). The nilotinib 150-mg but not the nilotinib 300-mg group demonstrated a reduction of α-synuclein oligomers (-0.04 pg/mL; 90% CI, -0.08 to 0.01 pg/mL; P = .03). A significant reduction of hyperphosphorylated tau levels was seen in the nilotinib 150-mg (-10.04 pg/mL; 90% CI, -17.41 to -2.67 pg/mL; P = .01) and nilotinib 300-mg (-12.05 pg/mL; 90% CI, -19.21 to -4.90 pg/mL; P = .01) groups.In this study, nilotinib appeared to be reasonably safe and detectable in the cerebrospinal fluid. Exploratory biomarkers were altered in response to nilotinib. Taken together, these data will guide the development of a phase 3 study to investigate the effects of nilotinib therapy in patients with Parkinson disease.ClinicalTrials.gov identifier: NCT02954978.
Interferon-inducible MX2 is a host restriction factor of hepatitis B virus replication
Authors: Yong-Xiang Wang, Matthias Niklasch, Tiantian Liu, Yang Wang, Bisheng Shi, Wenjie Yuan, Thomas F. Baumert, Zhenghong Yuan, Shuping Tong, Michael Nassal, Yu-Mei Wen
Journal: Journal of Hepatology (2019)
Workshops of the seventh international brain-computer interface meeting: not getting lost in translation
Authors: Jane E. Huggins, Christoph Guger, Erik Aarnoutse, Brendan Allison, Charles W. Anderson, Steven Bedrick, Walter Besio, Ricardo Chavarriaga, Jennifer L. Collinger, An H. Do, Christian Herff, Matthias Hohmann, Michelle Kinsella, Kyuhwa Lee, Fabien Lotte, Gernot Müller-Putz, Anton Nijholt, Elmar Pels, Betts Peters, Felix Putze, Rüdiger Rupp, Gerwin Schalk, Stephanie Scott, Michael Tangermann, Paul Tubig, Thorsten Zander
Journal: Brain-Computer Interfaces (2019)

The Seventh International Brain-Computer Interface (BCI) Meeting was held May 21-25th, 2018 at the Asilomar Conference Grounds, Pacific Grove, California, United States. The interactive nature of this conference was embodied by 25 workshops covering topics in BCI (also called brain-machine interface) research. Workshops covered foundational topics such as hardware development and signal analysis algorithms, new and imaginative topics such as BCI for virtual reality and multi-brain BCIs, and translational topics such as clinical applications and ethical assumptions of BCI development. BCI research is expanding in the diversity of applications and populations for whom those applications are being developed. BCI applications are moving toward clinical readiness as researchers struggle with the practical considerations to make sure that BCI translational efforts will be successful. This paper summarizes each workshop, providing an overview of the topic of discussion, references for additional information, and identifying future issues for research and development that resulted from the interactions and discussion at the workshop.
Predicting 6-Month Mortality for Older Adults Hospitalized With Acute Myocardial Infarction
Authors: John A. Dodson, Alexandra M. Hajduk, Mary Geda, Harlan M. Krumholz, Terrence E. Murphy, Sui Tsang, Mary E. Tinetti, Michael G. Nanna, Richard McNamara, Thomas M. Gill, Sarwat I. Chaudhry
Journal: Annals of Internal Medicine (2019)

Background: Older adults with acute myocardial infarction (AMI) have higher prevalence of functional impairments, including deficits in cognition, strength, and sensory domains, than their younger counterparts. Objective: To develop and evaluate the prognostic utility of a risk model for 6-month post-AMI mortality in older adults that incorporates information about functional impairments. Design: Prospective cohort study. (ClinicalTrials.gov: NCT01755052). Setting: 94 hospitals throughout the United States. Participants: 3006 persons aged 75 years or older who were hospitalized with AMI and discharged alive. Measurements: Functional impairments were assessed during hospitalization via direct measurement (cognition, mobility, muscle strength) or self-report (vision, hearing). Clinical variables associated with mortality in prior risk models were ascertained by chart review. Seventy-two candidate variables were selected for inclusion, and backward selection and Bayesian model averaging were used to derive (n = 2004 participants) and validate (n = 1002 participants) a model for 6-month mortality. Results: Participants' mean age was 81.5 years, 44.4% were women, and 10.5% were nonwhite. There were 266 deaths (8.8%) within 6 months. The final risk model included 15 variables, 4 of which were not included in prior risk models: hearing impairment, mobility impairment, weight loss, and lower patient-reported health status. The model was well calibrated (Hosmer–Lemeshow P > 0.05) and showed good discrimination (area under the curve for the validation cohort = 0.84). Adding functional impairments significantly improved model performance, as evidenced by category-free net reclassification improvement indices of 0.21 (P = 0.008) for hearing impairment and 0.26 (P < 0.001) for mobility impairment. Limitation: The model was not externally validated. Conclusion: A newly developed model for 6-month post-AMI mortality in older adults was well calibrated and had good discriminatory ability. This model may be useful in decision making at hospital discharge. Primary Funding Source: National Heart, Lung, and Blood Institute of the National Institutes of Health.
Young Enough to Undergo Allogeneic Transplantation for Myelodysplastic Syndromes?
Authors: Georg-Nikolaus Franke, Anne Sophie Kubasch, Uwe Platzbecker
Journal: JAMA Oncology (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Treatment of Hyperglycemia in Patients With Acute Stroke—Reply
Authors: Askiel Bruno, Karen C. Johnston, Valerie L. Durkalski-Mauldin
Journal: JAMA (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
126TiP a Phase I Study of NBTXR3 Activated by Radiotherapy for Patients with Advanced Cancers Treated with an Anti-PD-1 Therapy
Authors: C. Shen, K. Jameson, J. Weiss, T. Hackman, D. Corum, J.A. Akulian, R. Dixon, A. Pearson, J. Frakes, P. Said, H. Miraoui, E. Baskin-Bey, T. Seiwert
Journal: Annals of Oncology (2019)
Dupilumab as a novel steroid-sparing treatment for IgG4-related disease
Authors: Rachel S Simpson, Stephanie Ka Ching Lau, Jason Kihyuk Lee
Journal: Annals of the Rheumatic Diseases (2019)

IgG4-related disease (IgG4-RD) is a rare fibroinflammatory, multisystemic condition with a relapsing-remitting progression.1 The level of serum IgG4 correlates with inflammatory activity and organ involvement.1 Glucocorticoids are first line for IgG4-RD, but there are numerous adverse effects with chronic use.2 Dupilumab is a monoclonal antibody that acts on the interleukin 4 (IL-4) receptor alpha, shared by the IL-4 and IL-13 receptors.1 IL-4 causes isotype switching from IgM to IgG4 and IL-13 is implicated in fibrosis.3 Thus, it was postulated by the authors to investigate dupilumab as a novel steroid-sparing treatment for IgG4-RD.

A 67-year-old man with no known allergies and a history of sensory neural hearing loss, recurrent bronchitis, spinal stenosis, moderate positional obstructive sleep apnoea, asthma, atopic dermatitis (which caused swelling around his eyes) and allergic rhinoconjunctivitis underwent extensive investigations over the past 2 years due to suspected IgG4-RD.

The patient’s initial complaint was pruritic erythematous lesions on the legs, arms, chest and palms. …
Multiple KRAS mutations detected by cancer related DNA in patients with resected pancreas adenocarcinoma during treatment with TG01/GM-CSF and gemcitabine (CT TG01-01)
Authors: D. Palmer, A.-S. Møller, B. Greenhalf, Y.T. Ma, J.W. Valle, T.J. Gjertsen, L. Kuryk
Journal: Annals of Oncology (2019)
Air Pollution (Particulate Matter) Exposure and Associations with Depression, Anxiety, Bipolar, Psychosis and Suicide Risk: A Systematic Review and Meta-Analysis
Authors: Isobel Braithwaite, Shuo Zhang, James B. Kirkbride, David P. J. Osborn, Joseph F. Hayes
Journal: Environmental Health Perspectives (2019)

Background: Particulate air pollution’s physical health effects are well known, but associations between particulate matter (PM) exposure and mental illness have not yet been established. However, there is increasing interest in emerging evidence supporting a possible etiological link. Objectives: This systematic review aims to provide a comprehensive overview and synthesis of the epidemiological literature to date by investigating quantitative associations between PM and multiple adverse mental health outcomes (depression, anxiety, bipolar disorder, psychosis, or suicide). Methods: We undertook a systematic review and meta-analysis. We searched Medline, PsycINFO, and EMBASE from January 1974 to September 2017 for English-language human observational studies reporting quantitative associations between exposure to PM &lt;1.0μm in aerodynamic diameter (ultrafine particles) and PM &lt;2.5 and &lt;10μm in aerodynamic diameter (PM2.5 and PM10, respectively) and the above psychiatric outcomes. We extracted data, appraised study quality using a published quality assessment tool, summarized methodological approaches, and conducted meta-analyses where appropriate. Results: Of 1,826 citations identified, 22 met our overall inclusion criteria, and we included 9 in our primary meta-analyses. In our meta-analysis of associations between long-term (&gt;6 months) PM2.5 exposure and depression (n=5 studies), the pooled odds ratio was 1.102 per 10-μg/m3 PM2.5 increase (95% CI: 1.023, 1.189; I2=0.00%). Two of the included studies investigating associations between long-term PM2.5 exposure and anxiety also reported statistically significant positive associations, and we found a statistically significant association between short-term PM10 exposure and suicide in meta-analysis at a 0-2 d cumulative exposure lag. Discussion: Our findings support the hypothesis of an association between long-term PM2.5 exposure and depression, as well as supporting hypotheses of possible associations between long-term PM2.5 exposure and anxiety and between short-term PM10 exposure and suicide. The limited literature and methodological challenges in this field, including heterogeneous outcome definitions, exposure assessment, and residual confounding, suggest further high-quality studies are warranted to investigate potentially causal associations between air pollution and poor mental health. https://doi.org/10.1289/EHP4595