tbuckley/cabot-search huggingface dataset:
STAT3-mediated upregulation of the AIM2 DNA sensor links innate immunity with cell migration to promote epithelial tumourigenesis
Authors: Ruby E Dawson, Virginie Deswaerte, Alison C West, Ke Tang, Alice J West, Jesse J Balic, Linden J Gearing, Mohamed I Saad, Liang Yu, Yonghui Wu, Prithi S Bhathal, Beena Kumar, Jayati T Chakrabarti, Yana Zavros, Hiroko Oshima, Dennis M Klinman, Masanobu Oshima, Patrick Tan, Brendan J Jenkins
Journal: Gut (2021)

Objective The absent in melanoma 2 (AIM2) cytosolic pattern recognition receptor and DNA sensor promotes the pathogenesis of autoimmune and chronic inflammatory diseases via caspase-1-containing inflammasome complexes. However, the role of AIM2 in cancer is ill-defined. Design The expression of AIM2 and its clinical significance was assessed in human gastric cancer (GC) patient cohorts. Genetic or therapeutic manipulation of AIM2 expression and activity was performed in the genetically engineered gp130 F/F spontaneous GC mouse model, as well as human GC cell line xenografts. The biological role and mechanism of action of AIM2 in gastric tumourigenesis, including its involvement in inflammasome activity and functional interaction with microtubule-associated end-binding protein 1 (EB1), was determined in vitro and in vivo. Results AIM2 expression is upregulated by interleukin-11 cytokine-mediated activation of the oncogenic latent transcription factor STAT3 in the tumour epithelium of GC mouse models and patients with GC. Genetic and therapeutic targeting of AIM2 in gp130 F/F mice suppressed tumourigenesis. Conversely, AIM2 overexpression augmented the tumour load of human GC cell line xenografts. The protumourigenic function of AIM2 was independent of inflammasome activity and inflammation. Rather, in vivo and in vitro AIM2 physically interacted with EB1 to promote epithelial cell migration and tumourigenesis. Furthermore, upregulated expression of AIM2 and EB1 in the tumour epithelium of patients with GC was independently associated with poor patient survival. Conclusion AIM2 can play a driver role in epithelial carcinogenesis by linking cytokine-STAT3 signalling, innate immunity and epithelial cell migration, independent of inflammasome activation.
A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease
Authors: Douglas P. Wightman, Iris E. Jansen, Jeanne E. Savage, Alexey A. Shadrin, Shahram Bahrami, Dominic Holland, Arvid Rongve, Sigrid Børte, Bendik S. Winsvold, Ole Kristian Drange, Amy E. Martinsen, Anne Heidi Skogholt, Cristen Willer, Geir Bråthen, Ingunn Bosnes, Jonas Bille Nielsen, Lars G. Fritsche, Laurent F. Thomas, Linda M. Pedersen, Maiken E. Gabrielsen, Marianne Bakke Johnsen, Tore Wergeland Meisingset, Wei Zhou, Petroula Proitsi, Angela Hodges, Richard Dobson, Latha Velayudhan, Karl Heilbron, Adam Auton, Michelle Agee, Stella Aslibekyan, Elizabeth Babalola, Robert K. Bell, Jessica Bielenberg, Katarzyna Bryc, Emily Bullis, Briana Cameron, Daniella Coker, Gabriel Cuellar Partida, Devika Dhamija, Sayantan Das, Sarah L. Elson, Teresa Filshtein, Kipper Fletez-Brant, Pierre Fontanillas, Will Freyman, Pooja M. Gandhi, Barry Hicks, David A. Hinds, Karen E. Huber, Ethan M. Jewett, Yunxuan Jiang, Aaron Kleinman, Katelyn Kukar, Vanessa Lane, Keng-Han Lin, Maya Lowe, Marie K. Luff, Jey C. McCreight, Matthew H. McIntyre, Kimberly F. McManus, Steven J. Micheletti, Meghan E. Moreno, Joanna L. Mountain, Sahar V. Mozaffari, Priyanka Nandakumar, Elizabeth S. Noblin, Jared O’Connell, Aaron A. Petrakovitz, G. David Poznik, Morgan Schumacher, Anjali J. Shastri, Janie F. Shelton, Jingchunzi Shi, Suyash Shringarpure, Chao Tian, Vinh Tran, Joyce Y. Tung, Xin Wang, Wei Wang, Catherine H. Weldon, Peter Wilton, Julia M. Sealock, Lea K. Davis, Nancy L. Pedersen, Chandra A. Reynolds, Ida K. Karlsson, Sigurdur Magnusson, Hreinn Stefansson, Steinunn Thordardottir, Palmi V. Jonsson, Jon Snaedal, Anna Zettergren, Ingmar Skoog, Silke Kern, Margda Waern, Henrik Zetterberg, Kaj Blennow, Eystein Stordal, Kristian Hveem, John-Anker Zwart, Lavinia Athanasiu, Per Selnes, Ingvild Saltvedt, Sigrid B. Sando, Ingun Ulstein, Srdjan Djurovic, Tormod Fladby, Dag Aarsland, Geir Selbæk, Stephan Ripke, Kari Stefansson, Ole A. Andreassen, Danielle Posthuma
Journal: Nature Genetics (2021)
Controlled release of hydrogen by implantation of magnesium induces P53-mediated tumor cells apoptosis
Authors: Rui Zan, Hao Wang, Weijie Cai, Jiahua Ni, Bérengère J.C. Luthringer-Feyerabend, Wenhui Wang, Hongzhou Peng, Weiping Ji, Jun Yan, Jiazeng Xia, Yang Song, Xiaonong Zhang
Journal: Bioactive Materials (2021)

Hydrogen has been used to suppress tumor growth with considerable efficacy. Inhalation of hydrogen gas and oral ingestion of hydrogen-rich saline are two common systemic routes of hydrogen administration. We have developed a topical delivery method of hydrogen at targeted sites through the degradation of magnesium-based biomaterials. However, the underlying mechanism of hydrogen's role in cancer treatment remains ambiguous. Here, we investigate the mechanism of tumor cell apoptosis triggered by the hydrogen released from magnesium-based biomaterials. We find that the localized release of hydrogen increases the expression level of P53 tumor suppressor proteins, as demonstrated by the in vitro RNA sequencing and protein expression analysis. Then, the P53 proteins disrupt the membrane potential of mitochondria, activate autophagy, suppress the reactive oxygen species in cancer cells, and finally result in tumor suppression. The anti-tumor efficacy of magnesium-based biomaterials is further validated in vivo by inserting magnesium wire into the subcutaneous tumor in a mouse. We also discovered that the minimal hydrogen concentration from magnesium wires to trigger substantial tumor apoptosis is 91.2 μL/mm3 per day, which is much lower than that required for hydrogen inhalation. Taken together, these findings reveal the release of H2 from magnesium-based biomaterial exerts its anti-tumoral activity by activating the P53-mediated lysosome-mitochondria apoptosis signaling pathway, which strengthens the therapeutic potential of this biomaterial as localized anti-tumor treatment.
Regulatory perspectives of combination products
Authors: Jiaxin Tian, Xu Song, Yongqing Wang, Maobo Cheng, Shuang Lu, Wei Xu, Guobiao Gao, Lei Sun, Zhonglan Tang, Minghui Wang, Xingdong Zhang
Journal: Bioactive Materials (2021)

Combination products with a wide range of clinical applications represent a unique class of medical products that are composed of more than a singular medical device or drug/biological product. The product research and development, clinical translation as well as regulatory evaluation of combination products are complex and challenging. This review firstly introduced the origin, definition and designation of combination products. Key areas of systematic regulatory review on the safety and efficacy of device-led/supervised combination products were then presented. Preclinical and clinical evaluation of combination products was discussed. Lastly, the research prospect of regulatory science for combination products was described. New tools of computational modeling and simulation, novel technologies such as artificial intelligence, needs of developing new standards, evidence-based research methods, new approaches including the designation of innovative or breakthrough medical products have been developed and could be used to assess the safety, efficacy, quality and performance of combination products. Taken together, the fast development of combination products with great potentials in healthcare provides new opportunities for the advancement of regulatory review as well as regulatory science.
Author Correction: Direct characterization of cis-regulatory elements and functional dissection of complex genetic associations using HCR–FlowFISH
Authors: Steven K. Reilly, Sager J. Gosai, Alan Gutierrez, Ava Mackay-Smith, Jacob C. Ulirsch, Masahiro Kanai, Kousuke Mouri, Daniel Berenzy, Susan Kales, Gina M. Butler, Adrianne Gladden-Young, Redwan M. Bhuiyan, Michael L. Stitzel, Hilary K. Finucane, Pardis C. Sabeti, Ryan Tewhey
Journal: Nature Genetics (2021)
“Third‐wave” cognitive and behavioral therapies and the emergence of a process‐based approach to intervention in psychiatry
Authors: Steven C. Hayes, Stefan G. Hofmann
Journal: World Psychiatry (2021)

For decades, cognitive and behavioral therapies (CBTs) have been tested in randomized controlled trials for specific psychiatric syndromes that were assumed to represent expressions of latent diseases. Although these protocols were more effective as compared to psychological control conditions, placebo treatments, and even active pharmacotherapies, further advancement in efficacy and dissemination has been inhibited by a failure to focus on processes of change. This picture appears now to be evolving, due both to a collapse of the idea that mental disorders can be classified into distinct, discrete categories, and to the more central attention given to processes of change in newer, so‐called “third‐wave” CBTs. Here we review the context for this historic progress and evaluate the impact of these newer methods and models, not as protocols for treating syndromes, but as ways of targeting an expanded range of processes of change. Five key features of “third‐wave” therapies are underlined: a focus on context and function; the view that new models and methods should build on other strands of CBT; a focus on broad and flexible repertoires vs. an approach to signs and symptoms; applying processes to the clinician, not just the client; and expanding into more complex issues historically more characteristic of humanistic, existential, analytic, or system‐oriented approaches. We argue that these newer methods can be considered in the context of an idiographic approach to process‐based functional analysis. Psychological processes of change can be organized into six dimensions: cognition, affect, attention, self, motivation and overt behavior. Several important processes of change combine two or more of these dimensions. Tailoring intervention strategies to target the appropriate processes in a given individual would be a major advance in psychiatry and an important step toward precision mental health care.
Justin Amery: GP, palliative care doctor, and writer
Authors: John Illman
Journal: BMJ (2021)

Credit: Damian Halliwell

Justin Amery was an innovative GP, a palliative care pioneer, mentor, educator, poet, and the author of 12 books. He was also, colleagues say, a maverick. Learning that nine doses of covid-19 vaccine could be drawn from an eight dose Pfizer phial, he insisted: “There is no way I’m going to throw away vaccine. Just do it.” This practice had yet to be officially sanctioned.

Wearing a bright yellow piece of tinsel around his head for the first covid clinic, he declared that it was the best day of his career. His colleague Laura Watson said, “He was fizzing with excitement. He regarded it as a great opportunity to save lives.” He even went on to the street and into local shops to ensure every available dose found an arm. His enthusiasm was infectious.

Amery was among the first GPs to recognise the potential of the additional roles reimbursement scheme. His Oxford practice, Hedena Health, one of the first in the region to become a limited company, includes 10 nurses, three paramedics, and three pharmacists.

Hedena was also an early advocate of telephone consultations and is renowned for creating career changing opportunities for staff. The practice manager became the chief executive …
NICE approves new cholesterol lowering drug after NHS strikes deal with manufacturer
Authors: Jacqui Wise
Journal: BMJ (2021)

A novel anti-cholesterol drug, to be given in primary care as a twice yearly injection, has been recommended for people with primary hypercholesterolaemia or mixed dyslipidaemia who have had a previous cardiovascular event.1

The National Institute for Health and Care Excellence (NICE) made the decision to recommend inclisiran after a “population level” commercial deal between NHS England and NHS Improvement and the drug’s manufacturer, Novartis. The manufacturer’s list price is £1987.36 (€2317; $2735) for a 284 mg dose pack, but the size of the NHS discount is confidential.

Meindert Boysen, NICE deputy chief executive and director of its Centre for Health Technology Evaluation, called inclisiran “a potential game changer in preventing thousands of people from dying prematurely …
Annals Graphic Medicine - Wanted: All COVID-19 Variants
Authors: Oscar Li
Journal: Annals of Internal Medicine (2021)

Web Exclusives31 August 2021Annals Graphic Medicine - Wanted: All COVID-19 VariantsFREEOscar Li, BSOscar Li, BSJohns Hopkins University School of Medicine, Baltimore, Maryland (O.L.)Author, Article, and Disclosure Informationhttps://doi.org/10.7326/G21-0048 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Download figure Download PowerPoint Author, Article, and Disclosure InformationAuthors: Oscar Li, BSAffiliations: Johns Hopkins University School of Medicine, Baltimore, Maryland (O.L.)Disclosures: The author has reported no disclosures of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G21-0048.Author/Illustrator Information: Oscar Li, BS, is a medical student at the Johns Hopkins University School of Medicine. In his free time, he enjoys drawing and animating short films (e-mail, onlioscarli@gmail.com; website, www.onlyoscarli.com).This article was published at Annals.org on 31 August 2021. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics September 2021Volume 174, Issue 9Page: W90-W91 ePublished: 31 August 2021 Issue Published: September 2021 Copyright & PermissionsCopyright © 2021 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Safety, pharmacodynamics, and exposure-response modeling results from a first-in-human phase 1 study of nedosiran (PHYOX1) in primary hyperoxaluria
Authors: Bernd Hoppe, Annelize Koch, Pierre Cochat, Sander F. Garrelfs, Michelle A. Baum, Jaap W. Groothoff, Graham Lipkin, Martin Coenen, Gesa Schalk, Aniruddha Amrite, David McDougall, Kelly Barrios, Craig B. Langman
Journal: Kidney International (2021)

Primary hyperoxaluria (PH) is a family of ultra-rare autosomal recessive inherited disorders of hepatic glyoxylate metabolism characterized by oxalate overproduction. Nedosiran is an RNA interference agent that inhibits hepatic lactate dehydrogenase, the enzyme responsible for the common, final step of oxalate production in all three genetic subtypes of PH. Here, we assessed in a two-part, randomized, single-ascending-dose, phase 1 study (PHYOX1) the safety, pharmacokinetics, pharmacodynamics, and exposure-response of subcutaneous nedosiran in 25 healthy participants (Group A) and 18 patients with PH1 or PH2 (Group B). Group A received nedosiran (0.3, 1.5, 3.0, 6.0, then 12.0 mg/kg) or placebo, and Group B received open-label nedosiran (1.5, 3.0, or 6.0 mg/kg). No significant safety concerns were identified. Injection site reactions (four or more hours post dose) occurred in 13.3% of participants in Group A and 27.8% of participants in Group B. Mean maximum reduction in 24-hour urinary oxalate excretion from baseline to day 57 (end of study) across Group B dose cohorts was 55% (range: 22%-100%) after single-dose nedosiran, with 33% participants reaching normal 24-hour urinary oxalate excretion. Based on the available modeling and simulation data, a fixed monthly dose of nedosiran 160 mg (free acid; equivalent to 170 mg sodium salt) in adults was associated with the highest proportion of simulated individuals achieving normal or near-normal 24-hour urinary oxalate excretion and fewest fluctuations in urinary oxalate response. Thus, single-dose nedosiran demonstrated acceptable safety and evidence of a pharmacodynamic effect in both PH1 and PH2 subpopulations consistent with its mechanism of action.
Optimizing channel selection using multi-objective FODPSO for BCI applications
Authors: Poonam Sheoran, J.S. Saini
Journal: Brain-Computer Interfaces (2021)

Brain-computer interfacing (BCI) requires multichannel electroencephalogram (EEG) or electrocorticogram (ECoG) signal acquisition for better performance. The selection of optimum channels that provides the best accuracy is itself a problem to solve because noisy/irrelevant channels can complexify the system and degrade its performance. This paper presents a novel automated model for optimum channel selection for BCI applications using the Fractional Order Darwinian Particle Swarm Optimization (FODPSO). To assess the information content of selected channels, a Support Vector Machine (SVM) classifier is used. The weighted sum of the number of channels and the classification accuracy on validation samples is taken as the fitness value for the FODPSO based binary optimization method (where all the variables are binary). The FODPSO and SVM based algorithm is evaluated on the electrocorticography (ECoG) recordings that have been used in BCI competition III. Dual tree complex wavelet transform (DTCWT) is used for preprocessing of the data and sample entropy is calculated for obtaining the most informative features from the preprocessed data. Eight channels are selected using this algorithm, yielding a classification accuracy of 0.81±0.02 for the testing dataset (classifying the ECoG signals of imagined movement of little finger and tongue) that compares favorably with the already reported methods. Experimental results successfully demonstrate that this channel selection algorithm works better both in terms of classification accuracy and in the reduction of the number of required channels.
Accounting for Age in the Definition of Chronic Kidney Disease
Authors: Ping Liu, Rob R. Quinn, Ngan N. Lam, Meghan J. Elliott, Yuan Xu, Matthew T. James, Braden Manns, Pietro Ravani
Journal: JAMA Internal Medicine (2021)

Using the same level of estimated glomerular filtration rate (eGFR) to define chronic kidney disease (CKD) regardless of patient age may classify many elderly people with a normal physiological age-related eGFR decline as having a disease.To compare the outcomes associated with CKD as defined by a fixed vs an age-adapted eGFR threshold.This population-based cohort study was conducted in Alberta, Canada and used linked administrative and laboratory data from adults with incident CKD from April 1, 2009, to March 31, 2017, defined by a sustained reduction in eGFR for longer than 3 months below a fixed or an age-adapted eGFR threshold. Non-CKD controls were defined as being 65 years or older with a sustained eGFR of 60 to 89 mL/min/1.73 m2 for longer than 3 months and normal/mild albuminuria. The follow-up ended on March 31, 2019. The data were analyzed from February to April 2020.A fixed eGFR threshold of 60 vs thresholds of 75, 60, and 45 mL/min/1.73 m2 for age younger than 40, 40 to 64, and 65 years or older, respectively.Competing risks of kidney failure (kidney replacement initiation or sustained eGFR <15 mL/min/1.73 m2 for >3 months) and death without kidney failure.The fixed and age-adapted CKD cohorts included 127 132 (69 546 women [54.7%], 57 586 men [45.3%]) and 81 209 adults (44 582 women [54.9%], 36 627 men [45.1%]), respectively (537 vs 343 new cases per 100 000 person-years). The fixed-threshold cohort had lower risks of kidney failure (1.7% vs 3.0% at 5 years) and death (21.9% vs 25.4%) than the age-adapted cohort. A total of 53 906 adults were included in both cohorts. Of the individuals included in the fixed-threshold cohort only (n = 72 703), 54 342 (75%) were 65 years or older and had baseline eGFR of 45 to 59 mL/min/1.73 m2 with normal/mild albuminuria. The 5-year risks of kidney failure and death among these elderly people were similar to those of non-CKD controls, with a risk of kidney failure of 0.12% or less in both groups across all age categories and a risk of death at 69, 122, 279, and 935 times higher than the risk of kidney failure for 65 to 69, 70 to 74, 75 to 79, and 80 years or older, respectively.This cohort study of adults with CKD suggests that the current criteria for CKD that use the same eGFR threshold for all ages may result in overestimation of the CKD burden in an aging population, overdiagnosis, and unnecessary interventions in many elderly people who have age-related loss of eGFR.
High-performance renal imaging with a radiolabeled, non-excretable chimeric fusion protein
Authors: Dawei Jiang, Muhsin H Younis, Xiaoli Lan, Weibo Cai
Journal: Theranostics (2021)

Ideal nuclear imaging tracers should exhibit high target uptake and low background signal. Traditional renal scintigraphy and SPECT scans examine kidney function via static or dynamic tracing of radioactive probes in the kidneys. The lack of tracer affinity to specific biological processes and high background uptake from urinary excretion have added many difficulties to precision renal diagnosis. In this issue of Theranostics, Jin and colleagues innovatively devised a recombinant probe for preferential kidney imaging through targeting of tubular neonatal Fc receptor and proximal tubular basement membrane for sustained tubular reabsorption and accumulation. This work has broad implications regarding how an in depth understanding of physiology and pathology may be of service for tracer development, renal diagnosis, and disease theranostics.
Age at Diabetes Onset and Subsequent Risk of Dementia—Reply
Authors: Claudio Barbiellini Amidei, Aurore Fayosse, Archana Singh-Manoux
Journal: JAMA (2021)

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