tbuckley/cabot-search huggingface dataset:
Mechanical ventilation promotes lung tumour spread by modulation of cholesterol cell content
Authors: Inés López-Alonso, Cecilia López-Martínez, Paula Martín-Vicente, Laura Amado-Rodríguez, Adrián González-López, Juan Mayordomo-Colunga, Cecilia del Busto, Marina Bernal, Irene Crespo, Aurora Astudillo, Miguel Arias-Guillén, Antonio Fueyo, Isaac Almendros, Jorge Otero, Héctor Sanz-Fraile, Ramón Farré, Guillermo M. Albaiceta
Journal: European Respiratory Journal (2021)

Background Mechanical stretch of cancer cells can alter their invasiveness. During mechanical ventilation, lungs may be exposed to an increased amount of stretch, but the consequences on lung tumours have not been explored. Methods To characterise the influence of mechanical ventilation on the behaviour of lung tumours, invasiveness assays and transcriptomic analyses were performed in cancer cell lines cultured in static conditions or under cyclic stretch. Mice harbouring lung melanoma implants were submitted to mechanical ventilation and metastatic spread was assessed. Additional in vivo experiments were performed to determine the mechanodependent specificity of the response. Incidence of metastases was studied in a cohort of lung cancer patients that received mechanical ventilation compared with a matched group of nonventilated patients. Results Stretch increases invasiveness in melanoma B16F10luc2 and lung adenocarcinoma A549 cells. We identified a mechanosensitive upregulation of pathways involved in cholesterol processing in vitro , leading to an increase in pro-protein convertase subtilisin/kexin type 9 (PCSK9) and LDLR expression, a decrease in intracellular cholesterol and preservation of cell stiffness. A course of mechanical ventilation in mice harbouring melanoma implants increased brain and kidney metastases 2 weeks later. Blockade of PCSK9 using a monoclonal antibody increased cell cholesterol and stiffness and decreased cell invasiveness in vitro and metastasis in vivo . In patients, mechanical ventilation increased PCSK9 abundance in lung tumours and the incidence of metastasis, thus decreasing survival. Conclusions Our results suggest that mechanical stretch promote invasiveness of cancer cells, which may have clinically relevant consequences. Pharmacological manipulation of cholesterol endocytosis could be a novel therapeutic target in this setting.
Glycomaterials to Investigate the Functional Role of Aberrant Glycosylation in Glioblastoma
Authors: Chaitanya Tondepu, Lohitash Karumbaiah
Journal: Advanced Healthcare Materials (2021)

Glioblastoma (GBM) is a stage IV astrocytoma that carries a dismal survival rate of ≈10 months postdiagnosis and treatment. The highly invasive capacity of GBM and its ability to escape therapeutic challenges are key factors contributing to the poor overall survival rate. While current treatments aim to target the cancer cell itself, they fail to consider the significant role that the GBM tumor microenvironment (TME) plays in promoting tumor progression and therapeutic resistance. The GBM tumor glycocalyx and glycan-rich extracellular matrix (ECM), which are important constituents of the TME have received little attention as therapeutic targets. A wide array of aberrantly modified glycans in the GBM TME mediate tumor growth, invasion, therapeutic resistance, and immunosuppression. Here, an overview of the landscape of aberrant glycan modifications in GBM is provided, and the design and utility of 3D glycomaterials are discussed as a tool to evaluate glycan-mediated GBM progression and therapeutic efficacy. The development of alternative strategies to target glycans in the TME can potentially unveil broader mechanisms of restricting tumor growth and enhancing the efficacy of tumor-targeting therapeutics.
Effects of transcranial ultrasound stimulation pulsed at 40 Hz on Aβ plaques and brain rhythms in 5×FAD mice
Authors: Mincheol Park, Gia Minh Hoang, Thien Nguyen, Eunkyung Lee, Hyun Jin Jung, Youngshik Choe, Moon Hwan Lee, Jae Youn Hwang, Jae Gwan Kim, Tae Kim
Journal: Translational Neurodegeneration (2021)

Alzheimer's disease (AD) is the most common cause of dementia, and is characterized by amyloid-β (Aβ) plaques and tauopathy. Reducing Aβ has been considered a major AD treatment strategy in pharmacological and non-pharmacological approaches. Impairment of gamma oscillations, which play an important role in perception and cognitive function, has been shown in mouse AD models and human patients. Recently, the therapeutic effect of gamma entrainment in AD mouse models has been reported. Given that ultrasound is an emerging neuromodulation modality, we investigated the effect of ultrasound stimulation pulsed at gamma frequency (40 Hz) in an AD mouse model.We implanted electroencephalogram (EEG) electrodes and a piezo-ceramic disc ultrasound transducer on the skull surface of 6-month-old 5×FAD and wild-type control mice (n = 12 and 6, respectively). Six 5×FAD mice were treated with two-hour ultrasound stimulation at 40 Hz daily for two weeks, and the other six mice received sham treatment. Soluble and insoluble Aβ levels in the brain were measured by enzyme-linked immunosorbent assay. Spontaneous EEG gamma power was computed by wavelet analysis, and the brain connectivity was examined with phase-locking value and cross-frequency phase-amplitude coupling.We found that the total Aβ42 levels, especially insoluble Aβ42, in the treatment group decreased in pre- and infra-limbic cortex (PIL) compared to that of the sham treatment group. A reduction in the number of Aβ plaques was also observed in the hippocampus. There was no increase in microbleeding in the transcranial ultrasound stimulation (tUS) group. In addition, the length and number of microglial processes decreased in PIL and hippocampus. Encelphalographic spontaneous gamma power was increased, and cross-frequency coupling was normalized, implying functional improvement after tUS stimulation.These results suggest that the transcranial ultrasound-based gamma-band entrainment technique can be an effective therapy for AD by reducing the Aβ load and improving brain connectivity.
Meet the First Authors
Authors: Xavier Revelo
Journal: Circulation Research (2021)

His laboratory studies the role of the immune system and inflammation in the pathophysiology of cardio-metabolic diseases.Dr Revelo has a broad background in metabolism, physiology and immunology and expertise in metabolic inflammation.He trained in the field of immunometabolism where he studied immune mediators of insulin resistance.Since starting his laboratory in 2018, he leads NIH-funded research investigating the mechanisms by which immune cells promote cardio-metabolic disease.In collaboration with Dr Jop van Berlo, he has uncovered an anti-fibrotic and pro-angiogenic role for cardiac resident macrophages.Dr Revelo is an avid longdistance runner who trains year-round for the marathon distance.He can be found on Twitter @Xavier_Revelo.
CTNI-58. EFFICACY AND SAFETY OF LAROTRECTINIB IN ADULT AND PEDIATRIC PATIENTS WITH TROPOMYOSIN RECEPTOR KINASE (TRK) FUSION-POSITIVE PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS
Authors: François Doz, Cornelis M van Tilburg, Birgit Geoerger, Karsten Nysom, Ingrid Øra, Valentina Boni, Julia Chisholm, Hyun Cheol Chung, Steven G DuBois, Soledad Gallego Melcón, Nicolas U Gerber, Hiroaki Goto, Juneko E Grilley-Olsen, Jordan R Hansford, David S Hong, Antoine Italiano, Hyoung Jin Kang, Michael Capra, Johannes H Schulte, Joanna Stefanowicz, Makoto Tahara, David S Ziegler, Igor T Gavrilovic, Ricarda Norenberg, Laura Dima, Esther De La Cuesta, Theodore W Laetsch, Alexander Drilon, Sébastien Perreault
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND NTRK gene fusions are oncogenic drivers in various CNS and non-CNS tumors. Larotrectinib is a first-in-class, highly selective TRK inhibitor approved for patients with TRK fusion cancer, with a 75% objective response rate (ORR) in 206 evaluable patients with various non-CNS cancers (Hong et al, ASCO 2021). We report data on patients with TRK fusion-positive primary CNS tumors. METHODS Patients with TRK fusion-positive primary CNS tumors in 2 clinical trials (NCT02637687, NCT02576431) were identified. Objective responses were investigator-assessed. RESULTS As of July 2020, 33 patients with TRK fusion-positive primary CNS tumors were identified (19 high-grade gliomas [HGG], 8 low-grade gliomas [LGG], 2 glioneuronal tumors, 2 neuroepithelial tumors, 1 CNS neuroblastoma, 1 small round blue cell tumor). Median age was 8.9 years (range 1.3-79.0). Patients were heavily pre-treated, with 45% having ≥ 2 prior systemic therapies. ORR was 30% (95% CI 16-49): 3 complete responses (all pediatric), 7 partial responses, 20 stable disease, and 3 progressive disease. ORR in patients with HGG and LGG were 26% (95% CI 9-51) and 38% (95% CI 9-76), respectively. Median time to response was 1.9 months. Responses were seen regardless of the number of prior systemic therapies. The 24-week disease control rate was 73% (95% CI 54-87). Median PFS was 18.3 months (95% CI 6.7-not estimable [NE]) and median overall survival (OS) was not reached (95% CI 16.9-NE) at a median follow-up of 16.5 months; 12-month OS rate was 85% (95% CI 71-99). Treatment duration ranged from 1.2 to 31.3+ months. Grade 3-4 treatment-related adverse events (TRAEs) occurred in 3 patients (9%). There were no treatment discontinuations due to TRAEs. CONCLUSIONS In patients with TRK fusion-positive CNS tumors, larotrectinib demonstrated rapid and durable responses, high disease control rate, and favorable safety regardless of age or number of prior systemic therapies.
2D-ultrathin MXene/DOXjade platform for iron chelation chemo-photothermal therapy
Authors: Yunjie Xu, Yingwei Wang, Jusung An, Adam C. Sedgwick, Mingle Li, Jianlei Xie, Weibin Hu, Jianlong Kang, Sajal Sen, Axel Steinbrueck, Bin Zhang, Lijun Qiao, Swelm Wageh, Jonathan F. Arambula, Liping Liu, Han Zhang, Jonathan L. Sessler, Jong Seung Kim
Journal: Bioactive Materials (2021)

An increased demand for iron is a hallmark of cancer cells and is thought necessary to promote high cell proliferation, tumor progression and metastasis. This makes iron metabolism an attractive therapeutic target. Unfortunately, current iron-based therapeutic strategies often lack effectiveness and can elicit off-target toxicities. We report here a dual-therapeutic prodrug, DOXjade, that allows for iron chelation chemo-photothermal cancer therapy. This prodrug takes advantage of the clinically approved iron chelator deferasirox (ExJade®) and the topoisomerase 2 inhibitor, doxorubicin (DOX). Loading DOXjade onto ultrathin 2D Ti3C2 MXene nanosheets produces a construct, Ti3C2-PVP@DOXjade, that allows the iron chelation and chemotherapeutic functions of DOXjade to be photo-activated at the tumor sites, while potentiating a robust photothermal effect with photothermal conversion efficiencies of up to 40%. Antitumor mechanistic investigations reveal that upon activation, Ti3C2-PVP@DOXjade serves to promote apoptotic cell death and downregulate the iron depletion-induced iron transferrin receptor (TfR). A tumor pH-responsive iron chelation/photothermal/chemotherapy antitumor effect was achieved both in vitro and in vivo. The results of this study highlight what may constitute a promising iron chelation-based phototherapeutic approach to cancer therapy.
An imported case of vaccine-derived poliovirus type 2, Spain in the context of the ongoing polio Public Health Emergency of International Concern, September 2021
Authors: María Dolores Chirlaque López, María Cabrerizo, Bernardo R. Guzmán Herrador, Josefa Masa-Calles, María Ester Alarcón-Linares, Ana Allende, Esteban Aznar Cano, María Isabel Barranco Boada, Elena Cantero Gudino, Sonia Fernández-Balbuena, Ana Fernández Dueñas, María Dolores Fernández-García, Laura García Hernández, Visitación García Ortúzar, Noemí López-Perea, Eduardo Martínez-Salcedo, Antonio Moreno-Docón, María Ordobás Gavín, Inmaculada Rodero Garduño, Maria José Sierra Moros, Fernando Simón Soria, Aurora Limia Sánchez, Berta Suárez Rodríguez
Journal: Eurosurveillance (2021)

The monthly retrospective search for unreported acute flaccid paralysis (AFP) cases conducted as a complementary component of the Spanish AFP surveillance system identified a case of AFP in a child admitted in Spain from Senegal during August 2021. Vaccine-derived poliovirus 2 was identified in the stool in September 2021. We present public health implications and response undertaken within the framework of the National Action Plan for Polio Eradication and the Public Health Emergency of International Concern.
Error in Figure Caption
Journal: JAMA Network Open (2021)

Influenza Outcomes in Healthy Adults and Children: A Systematic Review and Network Meta-analysis," 1 published August 13, 2021, the hazard ratio data in the caption of Figure 3 should have appeared as 0.67 (0.58-0.77) instead of 0.97 (0.73-1.29).This article has been corrected.
Reconsidering the Utility of Race-Specific Lung Function Prediction Equations
Authors: Aaron D. Baugh, Stephen Shiboski, Nadia N. Hansel, Victor Ortega, Igor Barjaktarevic, R. Graham Barr, Russell Bowler, Alejandro P. Comellas, Christopher B. Cooper, David Couper, Gerard Criner, Jeffrey L. Curtis, Mark Dransfield, Chinedu Ejike, MeiLan K. Han, Eric Hoffman, Jamuna Krishnan, Jerry A. Krishnan, David Mannino, Robert Paine, Trisha Parekh, Stephen Peters, Nirupama Putcha, Stephen Rennard, Neeta Thakur, Prescott G. Woodruff
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

African American individuals have worse outcomes in chronic obstructive pulmonary disease (COPD).
Three Stories About the Value of Advance Care Planning
Authors: J. Randall Curtis
Journal: JAMA (2021)

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β2-spectrin (SPTBN1) as a therapeutic target for diet-induced liver disease and preventing cancer development
Authors: Shuyun Rao, Xiaochun Yang, Kazufumi Ohshiro, Sobia Zaidi, Zhanhuai Wang, Kirti Shetty, Xiyan Xiang, Md. Imtaiyaz Hassan, Taj Mohammad, Patricia S. Latham, Bao-Ngoc Nguyen, Linda Wong, Herbert Yu, Yousef Al-Abed, Bibhuti Mishra, Michele Vacca, Gareth Guenigault, Michael E. D. Allison, Antonio Vidal-Puig, Jihane N. Benhammou, Marcus Alvarez, Päivi Pajukanta, Joseph R. Pisegna, Lopa Mishra
Journal: Science Translational Medicine (2021)

Targeting SBPTN1 with siRNA has the potential to treat NASH and prevent HCC.
Abstract 10508: Variation in Community and Emergency Medical Systems Processes for Out-of-Hospital Cardiac Arrest During the COVID-19 Pandemic: A Systematic Review and Meta-Analysis
Authors: Yoshio Masuda, Seth E Teoh, Darren J Tan, Marcus E Ong, Andrew F Ho, Audrey L Blewer
Journal: Circulation (2021)

Introduction: Bystander cardiopulmonary resuscitation (B-CPR) with early defibrillation and immediate emergency medical services (EMS) care significantly increases a victim's chance of survival from out-of-hospital sudden cardiac arrest (OHCA). Few studies have assessed the overall effect of the COVID-19 pandemic on the prehospital chain of survival. Objectives: We sought to quantify the effect of the COVID-19 pandemic on prehospital processes including B-CPR, bystander defibrillation, community characteristics, and EMS process measures. We hypothesized that B-CPR rates would decrease and OHCA occurring in the home would increase during the pandemic. Methods: We conducted a systematic review and meta-analysis of studies identified through 05/03/2021. We examined 5 bibliographic databases and searched terms including cardiac arrest, OHCA, and COVID-19. Data were abstracted and independently coded. Subgroup analysis and meta-regression analysis were performed. Our primary outcome was B-CPR; our secondary outcomes were community processes and EMS characteristics. Results: The original search yielded 966 articles; 20 articles were included in our analysis. Studies originated from 10 different countries and were retrospective in study design. There was no difference in B-CPR rates during COVID-19 compared to Pre-COVID-19 (OR: 0.94 (0.80-1.11), p=0.46). Patients had a 1.38 (1.11-1.71) higher likelihood of having an OHCA at home during COVID-19 compared to Pre-COVID-19 (p=0.01). Receipt of bystander defibrillation was significantly lower during COVID-19 compared to Pre-COVID-19 (OR: 0.65 (0.48-0.88), p=0.01). There was a significant increase in EMS call to arrival time during COVID-19 compared to Pre-COVID-19 (Mean difference in minutes= 0.27 (0.13-0.40), p&lt;0.01). Statistical heterogeneity was moderate-to-high; findings were robust to sensitivity analyses with no publication bias detected. Conclusion: B-CPR rates remained unchanged during the pandemic, while OHCA in the home increased. Bystander defibrillation decreased, while EMS response time increased during the pandemic. These findings may inform future public programing, particularly to consider interventions to improve the prehospital chain of survival.
CTNI-26. PHASE 2 STUDY OF DIANHYDROGALACTITOL (VAL-083) IN PATIENTS WITH MGMT-UNMETHYLATED, BEVACIZUMAB-NAÏVE GLIOBLASTOMA IN THE RECURRENT AND ADJUVANT SETTING
Authors: Barbara O'Brien, Marta Penas-Prado, Carlos Kamiya-Matsuoka, Shiao-Pei Weathers, W K Alfred Yung, Monica Loghin, Rebecca Harrison, Nazanin Majd, Stephanie Knight, Jeffrey Bacha, Dennis Brown, Gregory Johnson, John Langlands, Richard Schwartz, Sarath Kanekal, Anne Steino, Lorena Lopez, John DeGroot
Journal: Neuro-Oncology (2021)

Abstract Current standard-of-care for glioblastoma (GBM) includes surgery followed by concurrent therapy with radiation and temozolomide (TMZ) followed by adjuvant TMZ. Almost all GBM patients experience recurrent/progressive disease despite upfront standard-of-care treatment, with a median survival of 3-9 months after recurrence. Unmethylated promoter for O6-methylguanine-DNA-methyltransferase (MGMT) is a validated biomarker for TMZ-resistance and is correlated with poor patient prognosis. VAL-083 is a bi-functional DNA-targeting agent which rapidly induces interstrand DNA cross-links at N7-guanine inducing double-strand breaks causing cell death and acts independently of MGMT DNA repair. This trial is an open-label two-arm biomarker-driven phase 2 clinical trial in MGMT-unmethylated, bevacizumab-naïve GBM patients with either recurrent (Group 1) or newly diagnosed GBM requiring adjuvant therapy after chemo-irradiation with temozolomide (Group 2). Patients receive VAL-083 IV at 30 or 40 mg/m2/d on days 1, 2, and 3 of a 21-day cycle. The primary objective of this study is to determine the effect of VAL-083 on median overall survival (mOS) in MGMT-unmethylated recurrent GBM patients (Group 1); and progression-free survival (PFS) in newly diagnosed GBM patients requiring adjuvant therapy after chemo-irradiation with temozolomide (Group 2), compared to historical controls in both groups. Tumor response is assessed by MRI every 42 days, using RANO criteria. The initial starting dose in this study was 40 mg/m2/d on days 1, 2, and 3 of a 21-day cycle, which was subsequently reduced to 30 mg/m2/d to improve tolerance due to myelosuppression. As of May 2021, Group 1 (Recurrent GBM) is fully enrolled: 35 evaluable patients have received 40 mg/m2/d and 48 evaluable patients have received 30 mg/m2/d VAL-083. In the adjuvant setting (Group 2), 35 evaluable patients have been enrolled (30 mg/m2/day). Enrollment, safety data and efficacy updates will be presented at the meeting. Clinicaltrials.gov identifier: NCT02717962.
TAZ-induced Cybb contributes to liver tumor formation in non-alcoholic steatohepatitis
Authors: Xiaobo Wang, Sharon Zeldin, Hongxue Shi, Changyu Zhu, Yoshinobu Saito, Kathleen E. Corey, Stephanie A. Osganian, Helen E. Remotti, Elizabeth C. Verna, Utpal B. Pajvani, Robert F. Schwabe, Ira Tabas
Journal: Journal of Hepatology (2021)
1. Improving Care and Promoting Health in Populations: <i>Standards of Medical Care in Diabetes—2022</i>
Journal: Diabetes Care (2021)

The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc22-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc22-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.
Is there a place for cell therapies in patients with severe psoriasis?
Journal: British Journal of Dermatology (2021)

There have been major developments in the treatment of psoriasis, an immune‐mediated skin disease, in recent years, most notably with ‘biologic’ therapies that target components of the immune system. However, these agents do not cure the disease and there are a few patients with severe psoriasis who fail to respond to any treatments currently available. Cell therapy has been used successfully in other immune‐mediated conditions such as multiple sclerosis, Crohn disease and arthritis. It involves isolating and preparing cells from the patient (autologous) or a donor (allogeneic) and injecting them into the patient.