tbuckley/cabot-search huggingface dataset:
A sobering addition to the literature on COVID-19 and the brain
Authors: Amit Mahajan, Graeme F. Mason
Journal: Journal of Clinical Investigation (2021)

Several coronavirus disease 2019 (COVID-19) studies have focused on neuropathology. In this issue of the JCI, Qin, Wu, and Chen et al. focused specifically on people whose acute infection lacked obvious neurological involvement. Severely infected patients showed abnormal gray matter volumes, white matter diffusion, and cerebral blood flow compared with healthy controls and those with mild infection. The data remain associative rather than mechanistic, but correlations with systemic immune markers suggest effects of inflammation, hypercoagulation, or other aspects of disease severity. Mechanistic research is warranted. Given the lack of obvious neurological symptoms, neurocognitive assessments were not performed, but the findings suggest that such assessments may be warranted in severely affected patients, even without obvious symptoms. Further, studying CNS involvement of other disorders with overlapping pathophysiologies such as inflammation, coagulation, hypoxia, or direct viral infection may reveal the causes for COVID-19-related neuropathology.
Ultrasound-mediated augmented exosome release from astrocytes alleviates amyloid-β-induced neurotoxicity
Authors: Zhiting Deng, Jieqiong Wang, Yang Xiao, Fei Li, Lili Niu, Xin Liu, Long Meng, Hairong Zheng
Journal: Theranostics (2021)

Background: Extracellular vesicles, including exosomes, are secreted by a variety of cell types in the central nervous system. Exosomes play a role in removing intracellular materials from the endosomal system. Alzheimer's disease (AD) is caused by an overproduction or reduced amyloid-beta (Aβ) peptide clearance. Increased Aβ levels in the brain may impair the exosome-mediated Aβ clearance pathway. Therapeutic ultrasound stimulation demonstrated its potential for promoting Aβ degradation efficiency in clinical trials. However, the underlying mechanism of ultrasound stimulation is still unclear. Methods: In this study, astrocytes, the most abundant glial cells in the brain, were used for exosome production. Post insonation, exosomes from ultrasound-stimulated HA cells (US-HA-Exo) were collected, nanoparticle tracking analysis and protein analysis were used to measure and characterize exosomes. Neuroprotective effect of US-HA-Exo in oligomeric Aβ42 toxicated SH-SY5Y cells was tested. Cellular uptake and distribution of exosomes were observed by flow cytometry and confocal laser scanning microscopy. Focused ultrasound (FUS) with microbubbles was employed for blood-brain-barrier opening to achieve brain-targeted exosome delivery. After US-HA-Exo/FUS treatment, amyloid-β plaque in APP/PS1 mice were evaluated by Aβ immunostaining and thioflavin-S staining. Results: We showed that ultrasound resulted in an almost 5-fold increase in the exosome release from human astrocytes. Exosomes were rapidly internalized in SH-SY5Y cells, and colocalized with FITC-Aβ42, causing a decreased uptake of FITC-Aβ42. CCk-8 test results showed that US-HA-Exo could mitigate Aβ toxicity to neurons in vitro. The therapeutic potential of US-HA-Exo/FUS delivery was demonstrated by a decrease in thioflavin-S-positive amyloid plaques and Aβ immuno-staining, a therapeutic target for AD in APP/PS1 transgenic mice. The iTRAQ-based proteomic quantification was performed to gain mechanistic insight into the ultrasound effect on astrocyte-derived exosomes and their ability to alleviate Aβ neurotoxicity. Conclusion: Our results imply that US-HA-Exo have the potential to provide neuroprotective effects to reverse oligomeric amyloid-β-induced cytotoxicity in vitro and, when combined with FUS-induced BBB opening, enable the clearance of amyloid-β plaques in vivo.
P09.56 Real-World Outcomes Among Patients with ROS1-Positive Advanced Non-Small Cell Lung Cancer (NSCLC)
Authors: D. Waterhouse, L. Iadeluca, S. Sura, J. Zhou, K. Wilner, B. Emir, J. Espirito, L. Bartolome
Journal: Journal of Thoracic Oncology (2021)
P76.66 Real-World, First-Line Osimertinib Treatment in Epidermal Growth Factor Receptor Mutation-Positive (EGFRm) Advanced NSCLC
Authors: J. Nieva, F. Griesinger, Y. Kim, A. Cohen, P. Horvat, S. Lu, A. Taylor, N. Yu, W. Sawyer, R. Shenolikar, S. Shaw
Journal: Journal of Thoracic Oncology (2021)
P25.06 Malignant Pleural Mesothelioma: Patient Characteristics, Treatments and Outcomes from a Spanish Center
Authors: Y. Garitaonaindía, M. Martínez, C. Traseira, V. Calvo, A. Collazo, F. Franco, B. Nunez-Garcia, J. Martín, R. Aguado, C. Alfaro, M. Blanco Clemente, A. Morito, G. Visedo, M. Provencio
Journal: Journal of Thoracic Oncology (2021)
Yttrium‐90 Radioembolization for the Treatment of Solitary, Unresectable HCC: The LEGACY Study
Authors: Riad Salem, Guy E. Johnson, Edward Kim, Ahsun Riaz, Vivian Bishay, Eveline Boucher, Kirk Fowers, Robert Lewandowski, Siddharth A. Padia
Journal: Hepatology (2021)

Locoregional therapies, including yttrium-90 radioembolization, play an important role in the treatment of unresectable HCC. The aim of the LEGACY (Local radioEmbolization using Glass Microspheres for the Assessment of Tumor Control with Y-90) study was to evaluate objective response rate (ORR) and duration of response (DoR) in patients with solitary unresectable HCC treated with yttrium-90 glass microspheres.LEGACY is a multicenter, single-arm, retrospective study conducted at three sites that included all eligible, consecutive patients with HCC treated with radioembolization between 2014 and 2017. Eligibility criteria included solitary HCC ≤ 8 cm, Child-Pugh A cirrhosis, and Eastern Cooperative Oncology Group performance status 0-1. Primary endpoints were ORR and DoR based on modified Response Evaluation Criteria in Solid Tumors in the treated area (localized), as evaluated by blinded, independent, central review. Radioembolization was performed with intent of ablative-level dosimetry in a selective fashion when possible. Overall survival was evaluated using Kaplan-Meier and multivariate Cox proportional hazards. Among the 162 patients included, 60.5% were Eastern Cooperative Oncology Group 0, and the median tumor size was 2.7 cm (range: 1-8) according to blinded, independent, central review. Radioembolization served as neoadjuvant therapy for transplantation or resection in 21.0% (34 of 162) and 6.8% (11 of 162) of patients, respectively, and as primary treatment for all others. Median follow-up time was 29.9 months by reverse Kaplan-Meier. ORR (best response) was 88.3% (CI: 82.4-92.4), with 62.2% (CI: 54.1-69.8) exhibiting a DoR ≥ 6 months. Three-year overall survival was 86.6% for all patients and 92.8% for those neoadjuvant patients with resected or transplanted liver.In this multicenter study of radioembolization, clinical meaningful response rates and prolonged DoR were observed in the treatment of unresectable, solitary HCC ≤ 8 cm.
Long-term outcomes after endoscopic treatment for Barrett’s neoplasia with radiofrequency ablation ± endoscopic resection: results from the national Dutch database in a 10-year period
Authors: Sanne van Munster, Esther Nieuwenhuis, Bas L A M Weusten, Lorenza Alvarez Herrero, Auke Bogte, Alaa Alkhalaf, B E Schenk, Erik J Schoon, Wouter Curvers, Arjun D Koch, Steffi Elisabeth Maria van de Ven, Pieter Jan Floris de Jonge, Tjon J Tang, Wouter B Nagengast, Frans T M Peters, Jessie Westerhof, Martin H M G Houben, Jacques JGHM Bergman, Roos E Pouw
Journal: Gut (2021)

Objective Radiofrequency ablation (RFA)±endoscopic resection (ER) is the preferred treatment for early neoplasia in Barrett’s oesophagus (BE). We aimed to report short-term and long-term outcomes for all 1384 patients treated in the Netherlands (NL) from 2008 to 2018, with uniform treatment and follow-up (FU) in a centralised setting. Design Endoscopic therapy for early BE neoplasia in NL is centralised in nine expert centres with specifically trained endoscopists and pathologists that adhere to a joint protocol. Prospectively collected data are registered in a uniform database. Patients with low/high-grade dysplasia or low-risk cancer, were treated by ER of visible lesions followed by trimonthly RFA sessions of any residual BE until complete eradication of BE (CE-BE). Patients with ER alone were not included. Results After ER (62% of cases; 43% low-risk cancers) and median 1 circumferential and 2 focal RFA (p25-p75 0–1; 1–2) per patient, CE-BE was achieved in 94% (1270/1348). Adverse events occurred in 21% (268/1386), most commonly oesophageal stenosis (15%), all were managed endoscopically. A total of 1154 patients with CE-BE were analysed for long-term outcomes. During median 43 months (22–69) and 4 endoscopies (1–5), 38 patients developed dysplastic recurrence (3%, annual recurrence risk 1%), all were detected as endoscopically visible abnormalities. Random biopsies from a normal appearing cardia showed intestinal metaplasia (IM) in 14% and neoplasia in 0%. A finding of IM in the cardia was reproduced during further FU in only 33%, none progressed to neoplasia. Frequent FU visits in the first year of FU were not associated with recurrence risk. Conclusion In a setting of centralised care, RFA±ER is effective for eradication of Barrett’s related neoplasia and has remarkably low rates of dysplastic recurrence. Our data support more lenient FU intervals, with emphasis on careful endoscopic inspection. Random biopsies from neosquamous epithelium and cardia are of questionable value. Netherlands trial register number NL7039.
Charge-switchable zwitterionic polycarboxybetaine particle as an intestinal permeation enhancer for efficient oral insulin delivery
Authors: Yan Li, Weihong Ji, Huan Peng, Ruichen Zhao, Tianlu Zhang, Zhiguo Lu, Jun Yang, Ruiyuan Liu, Xin Zhang
Journal: Theranostics (2021)

Insulin, a peptide hormone, is one of the most common and effective antidiabetic drugs. Although oral administration is considered to be the most convenient and safe choice for patients, the oral bioavailability of insulin is very low due to the poor oral absorption into blood circulation. Intestinal epithelium is a major barrier for the oral absorption of insulin. Therefore, it is vital to develop intestinal permeation enhancer to increase the antidiabetic efficacy of insulin after oral administration. Methods: Charge-switchable zwitterionic polycarboxybetaine (PCB) was used to load insulin to form PCB/insulin (PCB/INS) particles through the electrostatic interaction between positively charged PCB in pH 5.0 and negatively charged insulin in 0.01 M NaOH. The opening effect of PCB/INS particles on intestinal epithelium was evaluated by detecting the changes of claudin-4 (CLDN4) protein and transepithelial electrical resistance (TEER) after incubation or removal. The mechanism was further elucidated based on the results of Western blot and fluorescence images. The PCB/INS particles were then used for type 1 diabetes mellitus therapy after oral administration. Results: PCB could load insulin with the loading efficiency above 86% at weight ratio of 8:1. PCB/INS particles achieved sustained release of insulin at pH 7.4 due to their charge-switchable ability. Surprisingly, PCB/INS particles induced the open of the tight junctions of intestinal epithelium in endocytosis-mediated lysosomal degradation pathway, which resulted in increased intestinal permeability of insulin. Additionally, the opening effect of PCB/INS particles was reversible, and the decreased expression of CLDN4 protein and TEER values were gradually recovered after particles removal. In streptozotocin-induced type 1 diabetic rats, oral administration of PCB/INS particles with diameter sub-200 nm, especially in capsules, significantly enhanced the bioavailability of insulin and achieved longer duration of hypoglycemic effect than the subcutaneously injected insulin. Importantly, there was no endotoxin and pathological change during treatment, indicating that PCB/INS particles were safe enough for in vivo application. Conclusion: These findings indicate that this system can provide a platform for oral insulin and other protein drugs delivery.
Targeted regulation of lymphocytic ER stress response with an overall immunosuppression to alleviate allograft rejection
Authors: Yingying Shi, Yichao Lu, Chunqi Zhu, Zhenyu Luo, Xiang Li, Yu Liu, Mengshi Jiang, Xu Liu, Lihua Luo, Yongzhong Du, Jian You
Journal: Biomaterials (2021)
Abstract 16468: Low Dose Amiodarone is Safe and Effective in Control of Atrial Fibrillation
Authors: Frank A McGrew, Sandy Charlton, Brian Dragutsky
Journal: Circulation (2020)

Introduction: Amiodarone is the most effective drug for the treatment of atrial fibrillation (AF), but long-term administration of standard doses can have prohibitive side effects. Little data is available for use of lower doses. We sought to determine the lowest effective dose for rhythm control in a single physician practice. Methods: Consecutive AF patients treated with Amiodarone using a down-titration schema were prospectively followed. The goal was the lowest dose providing effective rhythm control defined as less than 1% AF burden in patients with devices (42% of patients) or no symptoms or no AF on ECG at last office visit in non-device patients. Results: 170 patents (89M, 81F) were followed for a mean period of 63 months (range 12-177). 79 of 170 (46%) had devices (6 ILR, 29 PM, 27 ICD, 17 CRT). 5 patients had drug-related transient side effects, including 1 transient hyperthyroidism. No patient had pulmonary fibrosis or death. 130 of 170 patients (76%) had successful control of AF. Table 1 shows the number of patents effectively controlled at each weekly dose level. 51% had success at less than or equal to 400mg per week. Renal disease, systolic heart failure with reduced ejection fraction, and advanced age were common comorbidities. Conclusions: Low-dose Amiodarone is safe and effective for control of AF in most patients if carefully used in a down-titration protocol. Device diagnostics aid in patient management.
Inhaled JAK inhibitor GDC-0214 reduces exhaled nitric oxide in patients with mild asthma: A randomized, controlled, proof-of-activity trial
Authors: Irene E Braithwaite, Fang Cai, Jennifer A Tom, Joshua M Galanter, Ryan P Owen, Rui Zhu, Mathew Williams, Anna G McGregor, Avi Eliahu, Matthew R Durk, Hart S Dengler, Mark Zak, Jane R Kenny, Maria E Wilson, Richard Beasley, Hubert Chen
Journal: Journal of Allergy and Clinical Immunology (2021)

BackgroundThe Janus kinase (JAK) pathway mediates the activity of many asthma-relevant cytokines, including IL-4 and IL-13. GDC-0214 is a potent, inhaled, small-molecule JAK inhibitor being developed for the treatment of asthma.ObjectiveWe sought to determine whether GDC-0214 reduces fractional exhaled nitric oxide (Feno), a JAK1-dependent biomarker of airway inflammation, in patients with mild asthma.MethodsWe conducted a double-blind, randomized, placebo-controlled, phase 1 proof-of-activity study in adults with mild asthma and Feno higher than 40 parts per billion (ppb). Subjects were randomized 2:1 (GDC-0214:placebo) into 4 sequential ascending-dose cohorts (1 mg once daily [QD], 4 mg QD, 15 mg QD, or 15 mg twice daily). All subjects received 4 days of blinded placebo, then 10 days of either active drug or placebo. The primary outcome was placebo-corrected percent reduction in Feno from baseline to day 14. Baseline was defined as the average Feno during the blinded placebo period. Pharmacokinetics, safety, and tolerability were also assessed.ResultsThirty-six subjects (mean age, 28 years; 54% females) were enrolled. Mean Feno at baseline across all subjects was 93 ± 43 ppb. At day 14, placebo-corrected difference in Feno was −23% (95% CI, −37.3 to −9) for 15 mg QD and −42% (95% CI, −57 to −27.4) for 15 mg twice daily. Higher plasma exposure was associated with greater Feno reduction. No dose-limiting adverse events, serious adverse events, or treatment discontinuations occurred. There were no major imbalances in adverse events or laboratory findings, or evidence of systemic JAK inhibition.ConclusionsGDC-0214, an inhaled JAK inhibitor, caused dose-dependent reductions in Feno in mild asthma and was well tolerated without evidence of systemic toxicity.
Balancing the stability and drug activation in adaptive nanoparticles potentiates chemotherapy in multidrug-resistant cancer
Authors: Jianqin Wan, Lingling Huang, Jiangting Cheng, Huangfu Qi, Jiahui Jin, Hangxiang Wang
Journal: Theranostics (2021)

Rationale: Prodrug strategies that render the drug temporarily inactive through a cleavable linkage are able to modulate the physicochemical properties of drugs for adaptive nanoparticle (NP) formulation. Here we used cabazitaxel as a model compound to test the validity of our "balancing NP stability and specific drug activation" strategy. Methods: Cabazitaxel is conjugated to hydrophobic polylactide fragments with varying chain lengths via a self-immolation linkage, yielding polymeric prodrugs that can be reactivated by reductive agents in cells. Following a nanoprecipitation protocol, cabazitaxel prodrugs can be stably entrapped in amphiphilic polyethylene-block-polylactide matrices to form core-shell nanotherapies with augmented colloidal stability. Results: Upon cellular uptake followed by intracellular reduction, the NPs spontaneously release chemically unmodified cabazitaxel and exert high cytotoxicity. Studies with near-infrared dye-labeled NPs demonstrate that the nanodelivery of the prodrugs extends their systemic circulation, accompanied with increased drug concentrations at target tumor sites. In preclinical mouse xenograft models, including two paclitaxel-resistant xenograft models, the nanotherapy shows a remarkably higher efficacy in tumor suppression and an improved safety profile than free cabazitaxel. Conclusion: Collectively, our approach enables more effective and less toxic delivery of the cabazitaxel drug, which could be a new generalizable strategy for re-engineering other toxic and water-insoluble therapeutics.
Guideline-directed management of COVID-19: Do's and Don'ts
Authors: Martin Kolb, Anh Tuan Dinh-Xuan, Laurent Brochard
Journal: European Respiratory Journal (2021)

The coronavirus disease 2019 (COVID-19) pandemic continues to dominate our daily lives. The "second wave" has slowed down in most regions around the globe, just to give way to the third wave of infections. Hospitalisations and death are again on the rise despite public health measures and vaccination programmes. Unfortunately, we have to expect that COVID-19 will persist as a major challenge for the delivery of medical care for a long while to go. Despite all efforts, a significant number of patients, in particular the elderly and those with risk factors, will get ill from this disease and some will eventually require hospitalisation. This editorial summarises the highlights of the European Respiratory Society COVID-19 treatment guideline <https://bit.ly/3tClBRe>
Abstract 11928: Cardiovascular Effectiveness of Empagliflozin Compared to DPP4 Inhibitors and to GLP1 Receptor Agonists: Interim Analysis From the Empagliflozin Comparative Effectiveness and Safety (EMPRISE) Study
Authors: Elisabetta Patorno, Ajinkya Pawar, Jessica Franklin, Mehdi Najafzadeh, Deborah Wexler, Anouk Déruaz-Luyet, Kimberly Brodovicz, Lily Bessette, Sebastian Schneeweiss
Journal: Circulation (2019)

The EMPA-REG OUTCOME trial showed a reduction of 35% for heart failure hospitalization (HHF) and similar incidence of myocardial infarction (MI) and Stroke in patients with Type 2 diabetes (T2D) at...
MA13.07 Structural Classification of Atypical EGFR Mutations Identifies 4 Major Subgroups with Distinct Patterns of Drug Sensitivity
Authors: J. Robichaux, X. Le, R.s.k. Vijayan, K. Hicks, Y. Elamin, H. Tran, S. Varghese, J. He, F. Zhang, L. Hu, A. Poteete, W. Rinsurongkawong, X. Zhang, M. Nilsson, X. Liu, L. Diao, J. Zhang, R. Madison, A. Schrock, J. Saam, B. Fang, J. Wang, J. Cross, J. Gray, J. Heymach
Journal: Journal of Thoracic Oncology (2021)
FP13.03 IMpower110: Updated OS Analysis of Atezolizumab vs Platinum-Based Chemotherapy as First-Line Treatment in PD-L1–Selected NSCLC
Authors: R. Herbst, F. De Marinis, G. Giaccone, A. Vergnenegre, C. Barrios, M. Morise, E. Felip, C. Oprean, Y. Kim, Z. Andric, S. Mocci, I. Enquist, K. Komatsubara, M. Mccleland, Y. Deng, H. Kuriki, M. Villalobos, S. Phan, D. Spigel, J. Jassem
Journal: Journal of Thoracic Oncology (2021)
The Role of Acute Myeloid Leukemia Minimal Residual Disease in Regulatory Decision-making
Authors: Donna Przepiorka, R. Angelo de Claro, Richard Pazdur
Journal: JAMA Oncology (2021)

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P46.03 DNA Methylation Analysis in Smokers and Non-Smokers (Passive and ex-Smokers)
Authors: D.M. Aguilar-Beltrán, A.G. Alcázar-Ramos, A.L. Vega-Rodríguez, D.G. García-Gutiérrez, A.D. Bertadillo-Jilote, A. Rodríguez-Torres, B. Ugalde-Villanueva, M.D.P. Figueroa-Corona, M.A. Meraz-Ríos, K.I. Lira-De León
Journal: Journal of Thoracic Oncology (2021)
Plasma cells promote osteoclastogenesis and periarticular bone loss in autoimmune arthritis
Authors: Noriko Komatsu, Stephanie Win, Minglu Yan, Nam Cong-Nhat Huynh, Shinichiro Sawa, Masayuki Tsukasaki, Asuka Terashima, Warunee Pluemsakunthai, George Kollias, Tomoki Nakashima, Hiroshi Takayanagi
Journal: Journal of Clinical Investigation (2021)

In rheumatoid arthritis (RA), osteoclastic bone resorption causes structural joint damage as well as periarticular and systemic bone loss. Periarticular bone loss is one of the earliest indices of RA, often preceding the onset of clinical symptoms via largely unknown mechanisms. Excessive osteoclastogenesis induced by receptor activator of NF-κB ligand (RANKL) expressed by synovial fibroblasts causes joint erosion, whereas the role of RANKL expressed by lymphocytes in various types of bone damage has yet to be elucidated. In the bone marrow of arthritic mice, we found an increase in the number of RANKL-expressing plasma cells, which displayed an ability to induce osteoclastogenesis in vitro. Genetic ablation of RANKL in B-lineage cells resulted in amelioration of periarticular bone loss, but not of articular erosion or systemic bone loss, in autoimmune arthritis. We also show conclusive evidence for the critical contribution of synovial fibroblast RANKL to joint erosion in collagen-induced arthritis on the arthritogenic DBA/1J background. This study highlights the importance of plasma-cell RANKL in periarticular bone loss in arthritis and provides mechanistic insight into the early manifestation of bone lesion induced by autoimmunity.