tbuckley/cabot-search huggingface dataset:
Nested Neuronal Dynamics Orchestrate a Behavioral Hierarchy across Timescales
Authors: Harris S. Kaplan, Oriana Salazar Thula, Niklas Khoss, Manuel Zimmer
Journal: Neuron (2019)

Classical and modern ethological studies suggest that animal behavior is organized hierarchically across timescales, such that longer-timescale behaviors are composed of specific shorter-timescale actions. Despite progress relating neuronal dynamics to single-timescale behavior, it remains unclear how different timescale dynamics interact to give rise to such higher-order behavioral organization. Here, we show, in the nematode Caenorhabditis elegans, that a behavioral hierarchy spanning three timescales is implemented by nested neuronal dynamics. At the uppermost hierarchical level, slow neuronal population dynamics spanning brain and motor periphery control two faster motor neuron oscillations, toggling them between different activity states and functional roles. At lower hierarchical levels, these faster oscillations are further nested in a manner that enables flexible behavioral control in an otherwise rigid hierarchical framework. Our findings establish nested neuronal activity patterns as a repeated dynamical motif of the C. elegans nervous system, which together implement a controllable hierarchical organization of behavior.
Speak up for health
Authors: Fiona Godlee
Journal: BMJ (2019)

It shouldn’t be news to anyone that air pollution causes disease, disability, and death, but this week we add new causes and costs to the charge sheet. Yaguang Wei and colleagues reviewed data from over 95 million US Medicare claims, harvesting a long list of conditions and huge costs associated with short term exposure to airborne particulates (doi:10.1136/bmj.l6258­­­­). These associations remain even at levels of pollution below the World Health Organization’s guideline. This confirms the view that there is no safe lower limit, say our editorialists (doi:10.1136/bmj.l6609).

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Osteopontin promotes osteosarcoma metastasis to the lung
Authors: Wolf Hassenpflug, Mario Tschan, Bruce Torbett, Brunhilde Felding-Habermann
Journal: Cancer Research (2007)

5381  Osteosarcoma is a highly metastatic bone cancer in adolescents. It primarily metastasizes to lungs and bone. Eighty percent of the patients present with metastatic spreading to the lung, and less than half of them can be cured despite aggressive treatment regimens. Thus, lung metastasis represents the major challenge in osteosarcoma treatment, and we need to identify key mechanisms supporting osteosarcoma colonization of lung tissue in order to develop improved therapies for these patients.  Using SJSA1 human osteosarcoma cells, we developed a novel orthotopic mouse model reproducing key features of human osteosarcoma. After orthotopic injection of SJSA1 osteosarcoma cells into the left tibia of 5 to 7 weeks old male C.B-17 SCID mice, these animals developed primary tumors in the tibia and spontaneous metastases in the lungs. Following reinjection into the venous circulation, cells derived from primary tumors and particularly those from lung lesions were far more efficient in establishing lung metastases than the parental cells.  Previously we showed that this aggressive metastatic behavior of osteosarcoma cells correlates with the activation state of the cell adhesion receptor, integrin avb3, which is expressed primarily in its activated state in the more aggressive tumor cell variants. We now demonstrate that osteopontin, a high-affinity ligand of integrin avb3, is highly overexpressed in the aggressive tumor cell variants. We show that the main function of osteopontin overexpression is to mediate an early survival advantage of the metastatic cells after their arrival in the lung. This effect is demonstrated in experimental metastasis assays in vivo using non-invasive bioluminescent imaging and can be modeled in vitro in cell proliferation assays in a 3D collagen matrix. Both endogenous and exogenous osteopontin promote growth of SJSA1 tumor cells in 3D collagen. This effect is mediated at least in part by integrin avb3 since antibodies against integrin avb3 inhibit tumor cell proliferation. Stable knockdown of osteopontin expression in SJSA1 variants by shRNA reduced osteosarcoma cell survival in 3D collagen, and markedly reduced in vivo lung colonization in our mouse model. We are currently investigating the molecular pathways which drive tumor cell survival through interaction of osteopontin and integrin avb3. Our initial findings suggest that the integrin avb3 and osteopontin axis maybe a potential therapeutic target for treatment of metastatic osteosarcoma.
RETRACTED: METTL14 Suppresses CRC Progression via Regulating N6-Methyladenosine-Dependent Primary miR-375 Processing
Authors: Xiaoxiang Chen, Mu Xu, Xueni Xu, Kaixuan Zeng, Xiangxiang Liu, Li Sun, Bei Pan, Bangshun He, Yuqin Pan, Huiling Sun, Xinyi Xia, Shukui Wang
Journal: Molecular Therapy (2019)

Epigenetic alterations contributed to human carcinogenesis immensely. N6-methyladenosine (m6A) is one of the most preventive and abundant modifications on RNA molecules present in eukaryotes. However, the biological function of m6A methylation in colorectal cancer (CRC) remains largely unclear. Here, we found that METTL14 was downregulated in CRC tissues and cell lines, and closely correlated with overall survival (OS). METTL14 knockdown significantly reduced m6A levels in total RNAs and promoted CRC cell growth and metastasis, whereas METTL14 overexpression markedly increased m6A levels in total RNA and inhibited CRC cell growth and metastasis. Furthermore, we demonstrated that miR-375 was a downstream target of METTL14. We also verified that METTL14 suppressed CRC cell growth via the miR-375/Yes-associated protein 1 (YAP1) pathway, as well as inhibited CRC cell migration and invasion through the miR-375/SP1 pathway. Taken together, our studies showed an important role for METTL14 in CRC progression and provided novel insight into m6A modification in CRC progression. Epigenetic alterations contributed to human carcinogenesis immensely. N6-methyladenosine (m6A) is one of the most preventive and abundant modifications on RNA molecules present in eukaryotes. However, the biological function of m6A methylation in colorectal cancer (CRC) remains largely unclear. Here, we found that METTL14 was downregulated in CRC tissues and cell lines, and closely correlated with overall survival (OS). METTL14 knockdown significantly reduced m6A levels in total RNAs and promoted CRC cell growth and metastasis, whereas METTL14 overexpression markedly increased m6A levels in total RNA and inhibited CRC cell growth and metastasis. Furthermore, we demonstrated that miR-375 was a downstream target of METTL14. We also verified that METTL14 suppressed CRC cell growth via the miR-375/Yes-associated protein 1 (YAP1) pathway, as well as inhibited CRC cell migration and invasion through the miR-375/SP1 pathway. Taken together, our studies showed an important role for METTL14 in CRC progression and provided novel insight into m6A modification in CRC progression.
Impaired Coronary Tissue Plasminogen Activator Release Is Associated With Coronary Atherosclerosis and Cigarette Smoking
Authors: David E. Newby, Andrew L. McLeod, Neal G. Uren, Laura Flint, Christopher A. Ludlam, David J. Webb, Keith A. A. Fox, Nicholas A. Boon
Journal: Circulation (2001)

Background —The aim of the study was to establish the influence of proximal coronary artery atheroma and smoking habit on the stimulated release of tissue plasminogen activator (tPA) from the heart. Methods and Results —After diagnostic coronary angiography in 25 patients, the left anterior descending coronary artery (LAD) was instrumented, and the proximal LAD plaque volume was determined by use of intravascular ultrasound (IVUS). Blood flow and fibrinolytic responses to selective LAD infusion of saline, substance P (10 to 40 pmol/min; endothelium-dependent), and sodium nitroprusside (5 to 20 μg/min; endothelium-independent) were measured by intracoronary IVUS and Doppler, combined with arterial and coronary sinus blood sampling. Mean plaque burden was 5.5±0.8 mm 3 /mm vessel (range 0.6 to 13.7 mm 3 /mm vessel). LAD blood flow increased with both substance P and sodium nitroprusside ( P &lt;0.001), although coronary sinus plasma tPA antigen and activity concentrations increased only during substance P infusion ( P &lt;0.006 for both). There was a strong inverse correlation between the LAD plaque burden and release of active tPA ( r =−0.61, P =0.003). Cigarette smoking was associated with impaired coronary release of active tPA (current smokers, 31±23 IU/min; ex-smokers, 50±33 IU/min; nonsmokers 202±73 IU/min; P &lt;0.05). Conclusions —We found that both the coronary atheromatous plaque burden and smoking habit are associated with a reduced acute local fibrinolytic capacity of the heart. These important findings provide evidence of a direct link between endogenous fibrinolysis, endothelial dysfunction, and atherothrombosis in the coronary circulation and may explain the greater efficacy of thrombolytic therapy for myocardial infarction in cigarette smokers.
Dose-Intensification in Early Unfavorable Hodgkin Lymphoma: Long-Term Follow up of the German Hodgkin Study Group (GHSG) HD14 Trial
Authors: Sarah Gillessen, Annette Plütschow, Michael Fuchs, Jana Markova, Richard Greil, Max S. Topp, Julia Meissner, Josée M Zijlstra, Dennis A. Eichenauer, Volker Diehl, Peter Borchmann, Andreas Engert, Bastian von Tresckow
Journal: Blood (2019)
Common DNA sequence variation influences 3-dimensional conformation of the human genome
Authors: David U. Gorkin, Yunjiang Qiu, Ming Hu, Kipper Fletez-Brant, Tristin Liu, Anthony D. Schmitt, Amina Noor, Joshua Chiou, Kyle J. Gaulton, Jonathan Sebat, Yun Li, Kasper D. Hansen, Bing Ren
Journal: Genome biology (2019)

Abstract Background The 3-dimensional (3D) conformation of chromatin inside the nucleus is integral to a variety of nuclear processes including transcriptional regulation, DNA replication, and DNA damage repair. Aberrations in 3D chromatin conformation have been implicated in developmental abnormalities and cancer. Despite the importance of 3D chromatin conformation to cellular function and human health, little is known about how 3D chromatin conformation varies in the human population, or whether DNA sequence variation between individuals influences 3D chromatin conformation. Results To address these questions, we perform Hi-C on lymphoblastoid cell lines from 20 individuals. We identify thousands of regions across the genome where 3D chromatin conformation varies between individuals and find that this variation is often accompanied by variation in gene expression, histone modifications, and transcription factor binding. Moreover, we find that DNA sequence variation influences several features of 3D chromatin conformation including loop strength, contact insulation, contact directionality, and density of local cis contacts. We map hundreds of quantitative trait loci associated with 3D chromatin features and find evidence that some of these same variants are associated at modest levels with other molecular phenotypes as well as complex disease risk. Conclusion Our results demonstrate that common DNA sequence variants can influence 3D chromatin conformation, pointing to a more pervasive role for 3D chromatin conformation in human phenotypic variation than previously recognized.
An RNA-Binding Protein Secreted by a Bacterial Pathogen Modulates RIG-I Signaling
Authors: Alessandro Pagliuso, To Nam Tham, Eric Allemand, Stevens Robertin, Bruno Dupuy, Quentin Bertrand, Christophe Bécavin, Mikael Koutero, Valérie Najburg, Marie-Anne Nahori, Frédéric Tangy, Fabrizia Stavru, Sergey Bessonov, Andréa Dessen, Christian Muchardt, Alice Lebreton, Anastassia V. Komarova, Pascale Cossart
Journal: Cell Host & Microbe (2019)

RNA-binding proteins (RBPs) perform key cellular activities by controlling the function of bound RNAs. The widely held assumption that RBPs are strictly intracellular has been challenged by the discovery of secreted RBPs. However, extracellular RBPs have been described in eukaryotes, while secreted bacterial RBPs have not been reported. Here, we show that the bacterial pathogen Listeria monocytogenes secretes a small RBP that we named Zea. We show that Zea binds a subset of L. monocytogenes RNAs, causing their accumulation in the extracellular medium. Furthermore, during L. monocytogenes infection, Zea binds RIG-I, the non-self-RNA innate immunity sensor, potentiating interferon-β production. Mouse infection studies reveal that Zea affects L. monocytogenes virulence. Together, our results unveil that bacterial RNAs can be present extracellularly in association with RBPs, acting as "social RNAs" to trigger a host response during infection.
Professionalism and the Review of Systems—Reply
Authors: Marissa A. Hendrickson, Genevieve B. Melton, Michael B. Pitt
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
Oncology practice changes during a multistep Oncology Care Model practice transformation project.
Authors: Debra Wujcik, Susan T. Owenby, Moh'd M. Khushman, Daniel Cameron, Thomas Wayne Butler, Cathy Tinnea, Austin Cadden, Jennifer Young Pierce, Sachin Gopalkrishn Pai
Journal: Journal of Clinical Oncology (2019)

88 Background: Treatment of lung cancer has seen a paradigm shift in recent years. While the availability of newer treatment options such as targeted therapy and immunotherapy have provided new hope for better outcomes, this has added to the cost of care. Participation in the Center for Medicare Services’ Oncology Care Model (OCM) provides opportunities for oncology practices to identify practice transformation (PT) change strategies that result in improved quality of care (QOL) and cost savings. Methods: A lung cancer PT team convened to facilitate changes that improve patient outcomes and decrease costs at an OCM organization. The year-long project included clinical treatment updates, quantitative and qualitative assessments, and data sharing. Practice changes focused on biomarker driven treatment selection, nurse navigation to better manage symptoms and decrease emergency department (ED) visits and hospitalizations, and earlier advanced care planning (ACP) discussions. Surveys were completed by oncology physicians and nurse practitioners at baseline (n = 9) and end of the project (n = 7). Results: After education, there were more correct responses in 3 of 6 knowledge questions and providers noted less concern about performance status or co-morbidities when prescribing immunotherapy. Providers noted fewer barriers with biomarker documentation; self-reported confidence in 4 questions of biomarker selection was unchanged. Providers reported increased participation of nurse navigators to impact ED visits and hospitalizations over time. Documentation of ACP discussions increased, 42% (8/19) to 56% (13/23), but did not reach statistical significance due to sample size. Although providers reported changes toward earlier ACP discussions, 1 in 3 still wait until performance status declines to initiate discussion. Conclusions: Systematic PT can improve quality of patients care and measures used in value-based care reimbursement models. Providers need ongoing education, practice feedback, and organizational support to effect positive practice changes. In addition, new strategies to increase provider ability to initiate end of life discussions need to be explored.
Pre-Clinical Efficacy of the Novel Kinase Inhibitor Nintedanib on PAX5 Fusion Genes in Pediatric Ph-like B-Cell Precursor Acute Lymphoblastic Leukemia
Authors: Grazia Fazio, Silvia Bresolin, Claudia Saitta, Daniela Silvestri, Elena Vendramini, Chiara Palmi, Silvia Rigamonti, Marta Galbiati, Manuel Quadri, Stefano Mecca, Angela Maria Savino, Michela Bardini, Andrea Grioni, Maria Grazia Valsecchi, Geertruy te Kronnie, Andrea Biondi, Giovanni Cazzaniga
Journal: Blood (2019)
Nasal epithelial barrier dysfunction increases sensitization and mast cell degranulation in the absence of allergic inflammation
Authors: Inge Kortekaas Krohn, Sven F. Seys, Gitte Lund, Anne‐Charlotte Jonckheere, Isabelle Dierckx de Casterlé, Jan L. Ceuppens, Brecht Steelant, Peter W. Hellings
Journal: Allergy (2019)

Abstract Background Increased epithelial permeability has been reported in allergic rhinitis, with histamine and type‐2 inflammation being responsible for tight junction dysfunction. The impact of an epithelial barrier defect on allergic sensitization and mast cell (MC) degranulation remains speculative. Methods Transepithelial passage of allergens was evaluated on primary human nasal epithelial cell cultures. Active sensitization was attempted by repeated intranasal ovalbumin (OVA) applications in Naïve mice. In a passive sensitization model, mice were injected with IgE to Dermatophagoides pteronyssinus (r Der p )2 and then exposed intranasally to the allergen. Chitosan was used to disrupt nasal epithelial integrity in vitro and in vivo . Results Chitosan strongly reduced transepithelial electrical resistance and facilitated transepithelial allergen passage in cultured primary nasal epithelial cells. In vivo , intranasal chitosan affected occludin expression and facilitated allergen passage. After epithelial barrier disruption, intranasal OVA application induced higher OVA‐specific IgG1 and total IgE in serum, and increased eosinophilia and interleukin‐5 in bronchoalveolar lavage (BAL) compared to sham‐OVA mice. Chitosan exposure, prior to r Der p 2 allergen challenge in passively sensitized mice, resulted in increased β‐hexosaminidase levels in serum and BAL compared to sham‐r Der p 2 mice. Intranasal treatment with the synthetic glucocorticoid fluticasone propionate prevented chitosan‐induced barrier dysfunction, allergic sensitization, and MC degranulation. Conclusion Epithelial barrier dysfunction facilitates transepithelial allergen passage, allergic sensitization, and allergen‐induced MC degranulation even in the absence of inflammatory environment. These results emphasize the crucial role of an intact epithelial barrier in prevention of allergy.
BTLA blockade enhances Cancer therapy by inhibiting IL-6/IL-10-induced CD19high B lymphocytes
Authors: Yu-Li Chen, Han-Wei Lin, Chung-Liang Chien, Yen-Ling Lai, Wei-Zen Sun, Chi-An Chen, Wen-Fang Cheng
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> The standard treatment for epithelial ovarian carcinoma (EOC) is surgery followed by platinum/paclitaxel-based chemotherapy, but the overall survival rate is poor. The purpose of this study was to investigate the therapeutic potential of chemotherapy combined with inhibition of B and T lymphocyte attenuator (BTLA) for clinical use to treat EOC. <h3>Methods</h3> Initially, we evaluated the potential application of chemotherapy combined with anti-BTLA antibody in an animal model. We then analyzed the distribution and regulation of BTLA expression on immunocytes in vitro. Finally, we examined the correlation between BTLA expression levels in cancerous tissues and prognosis in 254 EOC cases. <h3>Results</h3> The combination of chemotherapy and anti-BTLA antibody for inhibiting BTLA significantly reduced peritoneal tumor volume and extended survival in tumor-bearing mice. In addition, BTLA could be identified mostly on B lymphocytes, especially on CD19<sup>hi</sup> B cells, rather than on T lymphocytes and natural killer cells. Under regulation of interleukins 6 and 10, more BTLA<sup>+</sup>CD19<sup>hi</sup> B lymphocytes could be induced through AKT and STAT3 signaling pathways. Detectable BTLA expression in ovarian cancerous tissues was associated with worse disease-free and overall survivals of EOC patients. <h3>Conclusions</h3> BTLA detected in cancerous tissues can predict poor outcome of EOC patients. Inhibition of BTLA combined with chemotherapy can elevate immune activation and generate potent anti-tumor effects. Thus, the combination of chemotherapy and anti-BTLA antibody may hold potential clinical application for the treatment of EOC patients. <h3>Trial registration</h3> The Trial Registration Number was NCT00854399.
Effects of the Therapeutic Armamentarium on Survival and Time to Next Treatment in CMML Subtypes: An International Analysis of 950 Cases Coordinated By the AGMT Study Group
Authors: Lisa Pleyer, Michael Leisch, Alexandra Kourakli, Eric Padron, Jaroslaw P. Maciejewski, Blanca Xicoy, Jennifer Kaivers, Johanna Ungerstedt, Sonja Heibl, Peristera Patiou, Anthony M. Hunter, Elvira Mora, Klaus Geissler, Maria Dimou, María-José Jimenez, David Kiesl, Nora-Athina Viniou, Bhumika J. Patel, Montserrat Arnan Sangerman, Peter Valent, Christoforos Roubakis, Teresa Bernal del Castillo, Athanasios Galanopoulos, Marisa Calabuig, Nicolas Bonadies, Antonio Medina de Almeida, Jaroslav Cermak, Andres Jerez, Julia Montoro, Albert Cortés, Alejandro Avendaño Pita, Bernardo López Andrade, Eva Hellstrom Lindberg, Ulrich Germing, Mikkael A. Sekeres, Alan F. List, Argiris Symeonidis, Guillermo F. Sanz, Richard Greil
Journal: Blood (2019)