tbuckley/cabot-search huggingface dataset:
Enzyme Prodrug Therapy Engineered into Electrospun Fibers with Embedded Liposomes for Controlled, Localized Synthesis of Therapeutics
Authors: Rona Chandrawati, Morten T. J. Olesen, Thatiane C. C. Marini, Gurpal Bisra, Anne Géraldine Guex, Marcelo G. de Oliveira, Alexander N. Zelikin, Molly M. Stevens
Journal: Advanced Healthcare Materials (2017)

Enzyme prodrug therapy (EPT) enables localized conversion of inert prodrugs to active drugs by enzymes. Performance of EPT necessitates that the enzyme remains active throughout the time frame of the envisioned therapeutic application. β‐glucuronidase is an enzyme with historically validated performance in EPT, however it retains its activity in biomaterials for an insufficiently long period of time, typically not exceeding 7 d. Herein, the encapsulation of β‐glucuronidase in liposomal subcompartments within poly(vinyl alcohol) electrospun fibers is reported, leading to the assembly of biocatalytically active materials with activity of the enzyme sustained over at least seven weeks. It is further shown that liposomes provide the highly beneficial stabilization of the enzyme when incubated in cell culture media. The assembled biocatalytic materials successfully produce antiproliferative drugs (SN‐38) using externally administered prodrugs (SN‐38‐glucuronide) and effectively suppress cell proliferation, with envisioned utility in the design of cardiovascular grafts.
McKenzie Method of Mechanical Diagnosis and Therapy was slightly more effective than placebo for pain, but not for disability, in patients with chronic non-specific low back pain: a randomised placebo controlled trial with short and longer term follow-up
Authors: Alessandra Narciso Garcia, Lucíola da Cunha Menezes Costa, Mark J Hancock, Fabrício Soares de Souza, Geórgia Vieira Freschi de Oliveira Gomes, Matheus Oliveira de Almeida, Leonardo Oliveira Pena Costa
Journal: British Journal of Sports Medicine (2017)

Background The McKenzie Method of Mechanical Diagnosis and Therapy (MDT) is one of the exercise approaches recommended by low back pain (LBP) guidelines. We investigated the efficacy of MDT compared with placebo in patients with chronic LBP. Methods This was a prospectively registered, two-arm randomised placebo controlled trial, with a blinded assessor. A total of 148 patients seeking care for chronic LBP were randomly allocated to either MDT (n=74) or placebo (n=74). Patients from both groups received 10 treatment sessions over 5 weeks. Patients from both groups also received an educational booklet. Clinical outcomes were obtained at the end of treatment (5 weeks) and 3, 6 and 12 months after randomisation. Primary outcomes were pain intensity and disability at the end of treatment (5 weeks). We also conducted a subgroup analysis to identify potential treatment effect modifiers that could predict a better response to MDT treatment. Results The MDT group had greater improvements in pain intensity at the end of treatment (mean difference (MD) −1.00, 95% CI −2.09 to −0.01) but not for disability (MD −0.84, 95% CI −2.62 to 0.93). We did not detect between-group differences for any secondary outcomes, nor were any treatment effect modifiers identified. Patients did not report any adverse events. Conclusion We found a small and likely not clinically relevant difference in pain intensity favouring the MDT method immediately at the end of 5 weeks of treatment but not for disability. No other difference was found for any of the primary or secondary outcomes at any follow-up times. Trial registration number ClinicalTrials.gov ( NCT02123394 )
Synchronous and Metastatic Papillary and Follicular Thyroid Carcinomas with Unique Molecular Signatures
Authors: Vincent Cracolici, Ibro Mujacic, Sabah Kadri, Mir Alikhan, Nifang Niu, Jeremy P. Segal, Lauren E. Rosen, David H. Sarne, Adam Morgan, Samy Desouky, Nicole A. Cipriani
Journal: Endocrine Pathology (2017)
Alendronate may cut hip fracture risk in older patients taking prednisolone
Authors: Jacqui Wise
Journal: BMJ (2017)

Older patients who take the anti-inflammatory steroid prednisolone would benefit from treatment with the osteoporosis drug alendronate because it reduces the risk of hip fracture, a retrospective cohort study published in JAMA has found.1

Glucocorticoid therapy is widely used to treat inflammatory conditions and is commonly prescribed for patients over 65. However, it can lead to rapid bone loss and …
Neural Circuit-Specialized Astrocytes: Transcriptomic, Proteomic, Morphological, and Functional Evidence
Authors: Hua Chai, Blanca Diaz-Castro, Eiji Shigetomi, Emma Monte, J. Christopher Octeau, Xinzhu Yu, Whitaker Cohn, Pradeep S. Rajendran, Thomas M. Vondriska, Julian P. Whitelegge, Giovanni Coppola, Baljit S. Khakh
Journal: Neuron (2017)

Astrocytes are ubiquitous in the brain and are widely held to be largely identical. However, this view has not been fully tested, and the possibility that astrocytes are neural circuit specialized remains largely unexplored. Here, we used multiple integrated approaches, including RNA sequencing (RNA-seq), mass spectrometry, electrophysiology, immunohistochemistry, serial block-face-scanning electron microscopy, morphological reconstructions, pharmacogenetics, and diffusible dye, calcium, and glutamate imaging, to directly compare adult striatal and hippocampal astrocytes under identical conditions. We found significant differences in electrophysiological properties, Ca2+ signaling, morphology, and astrocyte-synapse proximity between striatal and hippocampal astrocytes. Unbiased evaluation of actively translated RNA and proteomic data confirmed significant astrocyte diversity between hippocampal and striatal circuits. We thus report core astrocyte properties, reveal evidence for specialized astrocytes within neural circuits, and provide new, integrated database resources and approaches to explore astrocyte diversity and function throughout the adult brain.Video AbstracteyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiI0OGY5MjVkMzgwOGU0NTkwZGMzNTRhMjQwZjZkMWM0OCIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjc3ODAzMzg0fQ.MwSBbMAp8Z94bVovEvEtEK9rSaCme1FWQaVStp6O8krax6PBRClksqtYhGWrI6xK8ct9tTpHJOavNya9agX01pfBV5Xv2_BxcAlr-eYdkIlnW6ddiNKQ9_7eEHZulgpmyVbQq2DLjKc1qNoV1ABBLI5qYU4yHQPnu-EI2_RASm5h1NErzRmbGIHeglc9V82L8hZBX8NyvUw74JxMPzvU4cgxuX5JBvnXBUOvw2oTkF0oPeBvpSchW6EKQzen4Skxhu-LXb5aAa3LkCMU3JhcCep28BCCVsKkV1kx3RuXhdJgkWD2ucI-70LBWqUvhtG-49ThFs0TB8dIBr74DrFLKA(mp4, (55.46 MB) Download video
NHS patient data security is to be tightened after cyberattack
Authors: Adrian O’Dowd
Journal: BMJ (2017)

Systems to ensure better protection of patients’ data are to be tightened in England, with extra funding to boost cybersecurity, severer punishments for security lapses, and promises of a new system to allow patients to opt out of their data being shared.

The government has announced a series of steps to improve data handling in the NHS and security of information in the wake of the WannaCry “ransomware” cyberattack in May that paralysed NHS information technology systems across dozens of organisations in England and Scotland.1

Doctors’ leaders have broadly welcomed the new approach but raised concerns over how the planned new opt-out system would affect patients who have already officially instructed GPs not to allow their data to be shared.

The …
Novel Long Non Coding RNA Blackmamba Is Associated to ALK- anaplastic Large Cell Lymphoma
Authors: Valentina Fragliasso, Akanksha Verma, Rohan Bareja, Tayla Heavican, Javeed Iqbal, Wing Chung Chan, Francesco Merli, Alessia Ciarrocchi, Olivier Elemento, Giorgio Inghirami
Journal: Blood (2016)
Deflexifol (a novel formulation of 5FU): Pharmacokinetics in a phase 1 trial in comparison to 5FU.
Authors: Stephen P. Ackland, Madhu Bala Garg, Marie Ranson, Rebecca Jokela, Daniel Brungs, Morteza Aghmesheh, Ali Tafreshi, Richard David Ranson, Suzanne Parker, Paul L. De Souza, Philip R. Clingan
Journal: Journal of Clinical Oncology (2017)

2530 Background: Simultaneous administration of 5-fluorouracil (5FU) and leucovorin (LV) is generally not feasible as 5FU and LV are chemically incompatible (CaPO4 crystals), so the maximum possible interaction for benefit is not achieved. Deflexifol, an all in one formulation of 5FU/LV with cyclodextrin (HP-β-CD 100mg/ml, 5-FU 15mg/ml &amp; LV 1mg/ml) at pH 7, was developed to overcome this problem. Methods: Limited sampling PK was done with dose 1 and 6 in a standard 3+3 phase I trial of Deflexifol given in two schedules (46-h infusion Q2W or bolus weekly x6) with no intrapatient dose escalation, at doses shown in Table. Sample times were infusion: 0, 2, 46h; bolus: 0, 0.2, 0.4, 1, 24h. 5FU and dihydroFU were measured as per Ackland et al, Anal Biochem 1997. 5FU AUC, clearance (CLR) and t1/2 were estimated for each patient to assess PK variability and adequacy of dosing compared to previous reports. Results: 40 patients were treated (21 infusion, 19 bolus, median age 67, 19 M, 21 F). The MTD(bolus) was 575 mg/m 2 , with no DLT in infusion schedule to 3600 mg/m 2 . PK showed substantial inter-patient variability – CLR(bolus) 21-900 L/h, t1/2 0.11-0.52 h, with intra-patient dose 6 CLR = 54-117% of dose 1, and a trend to increased AUC (mg/L.h) with dose (Table). Infusion CLR and AUC estimates were highly variable (CLR range 2-1200), with many cases with insufficient data. Compared to historical data with 5FU alone, AUC was likely subtherapeutic until 475mg/m 2 bolus and for many patients with infusion &lt;3000mg/m 2 . Conclusions: 5FU PK with Deflexifol is similar to 5FU alone. No evidence of saturation of kinetics over this dose range was seen, or induction of metabolism with repeated dosing. In each schedule AUC data supports the clinical impression of reduced toxicity at the same dose of 5FU. Accurate estimation of infusion PK requires more than 2 timepoints. PK in a phase II study is planned. Clinical trial information: 044867. [Table: see text]
A Novel Regulatory Mechanism of Smooth Muscle α-Actin Expression by NRG-1/circACTA2/miR-548f-5p Axis
Authors: Yan Sun, Zhan Yang, Bin Zheng, Xin-hua Zhang, Man-li Zhang, Xue-shan Zhao, Hong-ye Zhao, Toru Suzuki, Jin-kun Wen
Journal: Circulation Research (2017)

Rationale: Neuregulin-1 (NRG-1) includes an extracellular epidermal growth factor–like domain and an intracellular domain (NRG-1-ICD). In response to transforming growth factor-β1, its cleavage by proteolytic enzymes releases a bioactive fragment, which suppresses the vascular smooth muscle cell (VSMC) proliferation by activating ErbB (erythroblastic leukemia viral oncogene homolog) receptor. However, NRG-1-ICD function in VSMCs remains unknown. Objective: Here, we characterize the function of NRG-1-ICD and underlying mechanisms in VSMCs. Methods and Results: Immunofluorescence staining, Western blotting, and quantitative real-time polymerase chain reaction showed that NRG-1 was expressed in rat, mouse, and human VSMCs and was upregulated and cleaved in response to transforming growth factor-β1. In the cytoplasm of HASMCs (human aortic smooth muscle cells), the NRG-1-ICD participated in filamentous actin formation by interacting with α-SMA (smooth muscle α-actin). In the nucleus, the Nrg-1-ICD induced circular ACTA2 (alpha-actin-2; circACTA2) formation by recruitment of the zinc-finger transcription factor IKZF1 (IKAROS family zinc finger 1) to the first intron of α-SMA gene. We further confirmed that circACTA2, acting as a sponge binding microRNA (miR)-548f-5p, interacted with miR-548f-5p targeting 3′ untranslated region of α-SMA mRNA, which in turn relieves miR-548f-5p repression of the α-SMA expression and thus upregulates α-SMA expression, thereby facilitating stress fiber formation and cell contraction in HASMCs. Accordingly, in vivo studies demonstrated that the localization of the interaction of circACTA2 with miR-548f-5p is significantly decreased in human intimal hyperplastic arteries compared with normal arteries, implicating that dysregulation of circACTA2 and miR-548f-5p expression is involved in intimal hyperplasia. Conclusions: These results suggest that circACTA2 mediates NRG-1-ICD regulation of α-SMA expression in HASMCs via the NRG-1-ICD/circACTA2/miR-548f-5p axis. Our data provide a molecular basis for fine-tuning α-SMA expression and VSMC contraction by transcription factor, circular RNA, and microRNA.
Delayed Alveolar Epithelialization: A Distinct Pathology in Diffuse Acute Lung Injury
Authors: Martin S. Taylor, Raghu R. Chivukula, Laura C. Myers, William R. Jeck, Purushothama R. Tata, Walter J. O’Donnell, Carol F. Farver, B. Taylor Thompson, Jayaraj Rajagopal, Richard L. Kradin
Journal: American Journal of Respiratory and Critical Care Medicine (2017)
Blocking TGF-β and β-Catenin Epithelial Crosstalk Exacerbates CKD
Authors: Stellor Nlandu-Khodo, Surekha Neelisetty, Melanie Phillips, Marika Manolopoulou, Gautam Bhave, Lauren May, Peter E. Clark, Haichun Yang, Agnes B. Fogo, Raymond C. Harris, M. Mark Taketo, Ethan Lee, Leslie S. Gewin
Journal: Journal of the American Society of Nephrology (2017)

The TGF- β and Wnt/ β -catenin pathways have important roles in modulating CKD, but how these growth factors affect the epithelial response to CKD is not well studied. TGF- β has strong profibrotic effects, but this pleiotropic factor has many different cellular effects depending on the target cell type. To investigate how TGF- β signaling in the proximal tubule, a key target and mediator of CKD, alters the response to CKD, we injured mice lacking the TGF- β type 2 receptor specifically in this epithelial segment. Compared with littermate controls, mice lacking the proximal tubular TGF- β receptor had significantly increased tubular injury and tubulointerstitial fibrosis in two different models of CKD. RNA sequencing indicated that deleting the TGF- β receptor in proximal tubule cells modulated many growth factor pathways, but Wnt/ β -catenin signaling was the pathway most affected. We validated that deleting the proximal tubular TGF- β receptor impaired β -catenin activity in vitro and in vivo . Genetically restoring β -catenin activity in proximal tubules lacking the TGF- β receptor dramatically improved the tubular response to CKD in mice. Deleting the TGF- β receptor alters many growth factors, and therefore, this ameliorated response may be a direct effect of β -catenin activity or an indirect effect of β -catenin interacting with other growth factors. In conclusion, blocking TGF- β and β -catenin crosstalk in proximal tubules exacerbates tubular injury in two models of CKD.
Ataluren in patients with nonsense mutation Duchenne muscular dystrophy (ACT DMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial
Authors: Craig M McDonald, Craig Campbell, Ricardo Erazo Torricelli, Richard S Finkel, Kevin M Flanigan, Nathalie Goemans, Peter Heydemann, Anna Kaminska, Janbernd Kirschner, Francesco Muntoni, Andrés Nascimento Osorio, Ulrike Schara, Thomas Sejersen, Perry B Shieh, H Lee Sweeney, Haluk Topaloglu, Már Tulinius, Juan J Vilchez, Thomas Voit, Brenda Wong, Gary Elfring, Hans Kroger, Xiaohui Luo, Joseph McIntosh, Tuyen Ong, Peter Riebling, Marcio Souza, Robert J Spiegel, Stuart W Peltz, Eugenio Mercuri, Lindsay N Alfano, Michelle Eagle, Meredith K James, Linda Lowes, Anna Mayhew, Elena S Mazzone, Leslie Nelson, Kristy J Rose, Hoda Z Abdel-Hamid, Susan D Apkon, Richard J Barohn, Enrico Bertini, Clemens Bloetzer, Lausanne Canton de Vaud, Russell J Butterfield, Brigitte Chabrol, Jong-Hee Chae, Daehak-ro Jongno-gu, Giacomi Pietro Comi, Basil T Darras, Jahannaz Dastgir, Isabelle Desguerre, Raul G Escobar, Erika Finanger, Michela Guglieri, Imelda Hughes, Susan T Iannaccone, Kristi J Jones, Peter Karachunski, Martin Kudr, Timothy Lotze, Jean K Mah, Katherine Mathews, Yoram Nevo, Julie Parsons, Yann Péréon, Alexandra Prufer de Queiroz Campos Araujo, J Ben Renfroe, Maria Bernadete Dutra de Resende, Monique Ryan, Kathryn Selby, Gihan Tennekoon, Giuseppe Vita
Journal: The Lancet (2017)
miR-196a Enhances Neuronal Morphology through Suppressing RANBP10 to Provide Neuroprotection in Huntington's Disease
Authors: Lu-Shiun Her, Su-Han Mao, Chih-Yi Chang, Pei-Hsun Cheng, Yu-Fan Chang, Han-In Yang, Chuan-Mu Chen, Shang-Hsun Yang
Journal: Theranostics (2017)

MicroRNAs (miRNAs) play important roles in several neurobiological processes, including the development and progression of diseases.Previously, we identified that one specific miRNA, miR-196a, provides neuroprotective effects on Huntington's disease (HD), although the detailed mechanism is still unclear.Based on our bioinformatic analyses, we hypothesize miR-196a might offer neuroprotective functions through improving cytoskeletons of brain cells.Here, we show that miR-196a could enhance neuronal morphology, further ameliorating intracellular transport, synaptic plasticity, neuronal activity, and learning and memory abilities.Additionally, we found that miR-196a could suppress the expression of RAN binding protein 10 (RANBP10) through binding to its 3' untranslated region, and higher expression of RANBP10 exacerbates neuronal morphology and intracellular transport.Furthermore, miR-196a enhances neuronal morphology through suppressing RANBP10 and increasing the ability of β-tubulin polymerization.Most importantly, we observed higher expression of RANBP10 in the brains of HD transgenic mice, and higher expression of RANBP10 might exacerbate the pathological aggregates in HD.Taken together, we provide evidence that enhancement of neuronal morphology through RANBP10 is one of the neuroprotective mechanisms for miR-196a.Since miR-196a has also been reported in other neuronal diseases, this study might offer insights with regard to the therapeutic use of miR-196a in other neuronal diseases.
Safety and Preliminary Efficacy of "Ready to Administer" Cytomegalovirus (CMV)-Specific T Cells for the Treatment of Patients with Refractory CMV Infection
Authors: Ifigeneia Tzannou, Kathryn S. Leung, Caridad Martinez, Swati Naik, Stephen Gottschalk, Adrian P. Gee, Bambi Grilley, Ayumi Watanabe, Ann M. Leen, Sunitha Kakarla, Bilal Omer
Journal: Blood (2016)
Abstract 17098: Cardiac overexpression of GTP cyclohydrolase 1 attenuates cardiac remodeling after myocardial infarction by a neuronal nitric oxide synthase-mediated mechanism
Authors: Zhi-Dong Ge, Yanan Liu, Shelley L Baumgardt, Juan Fang, Yang Shi, Jeannette Vasquez-Vivar, Zeljko J Bosnjak
Journal: Circulation (2016)

Introduction:  Cardiac remodeling after myocardial infarction is associated with dysregulation of nitric oxide synthase and sarcoplasmic reticulum Ca 2+  handling proteins. Emerging evidence suggests that GTP cyclohydrolase 1 (GCH1) regulates the function and expression of nitric oxide synthase and sarcoplasmic reticulum Ca 2+  handling proteins.   Hypothesis:  We hypothesized that cardiac overexpression of GCH1 will benefit postinfarct cardiac remodeling.   Methods:  Myocardial infarction was produced in transgenic mice with cardiomyocyte-specific overexpression of human GCH1 and in control C57BL/6 mice by ligating the left coronary artery. Sham control mice underwent the same procedures except coronary artery ligation. The left ventricular geometry and function were measured with echocardiography, in Masson’s trichrome-stained heart sections, or in isolated Langendorff-perfused hearts. The expression of GCH1, dimeric and monomeric nitric oxide synthases, sarcoplasmic reticulum Ca 2+  handling proteins were determined by Western blot analyses.   Results:  Compared with sham-operated mice, C57BL/6 mice undergoing coronary artery ligation showed significant decreases in cardiac GCH1 proteins (GCH1/GAPDH: 0.14±0.04 in infarction vs 0.50±0.08 in sham, n=6 mice/group, P 2+  ATPase/GAPDH; and significant increases in infarct size, left ventricular internal diameters, and interstitial fibrosis 4 weeks after surgery. These adverse changes in the left ventricle were significantly attenuated in GCH1 overexpressing mice. Treatment of GCH1 overexpressing mice with 7-nitroindazole (an inhibitor for neuronal nitric oxide synthase) for 4 weeks blocked the beneficial effects of GCH1 overexpression on the heart after myocardial infarction.   Conclusions:  Cardiac overexpression of GCH1 ameliorates postinfarct cardiac remodeling by elevating the dimerization of neuronal nitric oxide synthase and expression of sarcoplasmic reticulum Ca 2+  handling proteins.
Effect of initiating use of an insulin pump in adults with type 1 diabetes using multiple daily insulin injections and continuous glucose monitoring (DIAMOND): a multicentre, randomised controlled trial
Authors: Roy W Beck, Tonya D Riddlesworth, Katrina J Ruedy, Craig Kollman, Andrew J Ahmann, Richard M Bergenstal, Anuj Bhargava, Bruce W Bode, Stacie Haller, Davida F Kruger, Janet B McGill, William Polonsky, David Price, Elena Toschi, Elena Toschi, Howard Wolpert, Astrid Atakov-Castillo, Edvina Markovic, Stephen Aronoff, Satanya Brooks, Gloria Martinez, Angela Mendez, Theresa Dunnam, Anuj Bhargava, Kathy Fitzgerald, Diana Wright, Teck Khoo, Pierre Theuma, Tara Herrold, Debra Thomsen, Richard Bergenstal, Kathleen McCann, Arlene Monk, Char Ashanti, David Liljenquist, Heather Judge, Jean Halford, Davida Kruger, Shiri Levy, Arti Bhan, Terra Cushman, Lameka Dawson, Heather Remtema, Fawn Wolf, James Neifing, Jennifer Murdoch, Susan Staat, Tamara Mayfield, Andrew Ahmann, Bethany Klopfenstein, Farahnaz Joarder, Kathy Hanavan, Jessica Castle, Diana Aby-Daniel, Victoria Morimoto, Donald DeFrang, Bethany Wollam, Janet McGill, Olivia Jordan, Carol Recklein, Mark Kipnes, Stacie Haller, Terri Ryan, Bruce Bode, Jennifer Boyd, Nitin Rastogi, Katherine Lindmark, William Biggs, Lorena Sandoval, Robin Eifert, Becky Cota, Quang Nguyen, Alejandra Martinez, Cathy Duran, Scott Segel, David Sutton, Miguel Roura, Rebecca Rosenwasser, Jennifer McElveen, Emily Knisely, Anne Johnson, A. Ola Odugbesan, Karla Wardell, Carolyn Paulus, Jack Wahlen, Jon Winkfield, Hilary Wahlen, Emily Hepworth, David Winkfield, Sue Owens, Steven Leichter, Emily Evans, Sarah Konigsberg, Jennifer Rahman, Linda Gaudiani, Natalie Woods, Jesse Cardozo, Kate Wheeler, Jennifer Kane, Terri Eubanks, Katrina Ruedy, Roy W. Beck, Craig Kollman, Tonya Riddlesworth, Thomas Mouse, David Price, Eileen Casal, Claudia Graham, William Polonsky
Journal: The Lancet Diabetes & Endocrinology (2017)