tbuckley/cabot-search huggingface dataset:
Antibody drug conjugates against the receptor for advanced glycation end products (RAGE), a novel therapeutic target in endometrial cancer
Authors: Gareth D. Healey, Belen Pan-Castillo, Jezabel Garcia-Parra, Julia Davies, Shaun Roberts, Eilir Jones, Kalyan Dhar, Sarika Nandanan, Nasima Tofazzal, Luke Piggott, Richard Clarkson, Gillian Seaton, Asa Frostell, Tim Fagge, Colin McKee, Lavinia Margarit, R. Steven Conlan, Deyarina Gonzalez
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> The treatment of endometrial cancer (EC), the most common gynecological cancer, is currently hampered by the toxicity of current cytotoxic agents, meaning novel therapeutic approaches are urgently required. <h3>Methods</h3> A cohort of 161 patients was evaluated for the expression of the receptor for advanced glycation end products (RAGE) in endometrial tissues. The present study also incorporates a variety of in vitro methodologies within multiple cell lines to evaluate RAGE expression and antibody-drug conjugate efficacy, internalisation and intercellular trafficking. Additionally, we undertook in vivo bio-distribution and toxicity evaluation to determine the suitability of our chosen therapeutic approach, together with efficacy studies in a mouse xenograft model of disease. <h3>Results</h3> We have identified an association between over-expression of the receptor for advanced glycation end products (RAGE) and EC (H-score = Healthy: 0.46, SD 0.26; Type I EC: 2.67, SD 1.39; Type II EC: 2.20, SD 1.34; ANOVA, <i>p</i> &lt; 0.0001). Furthermore, increased expression was negatively correlated with patient survival (Spearman's Rank Order Correlation: ρ = − 0.3914, <i>p</i> &lt; 0.05). To exploit this association, we developed novel RAGE-targeting antibody drug conjugates (ADC) and demonstrated the efficacy of this approach. RAGE-targeting ADCs were up to 100-fold more efficacious in EC cells compared to non-malignant cells and up to 200-fold more cytotoxic than drug treatment alone. Additionally, RAGE-targeting ADCs were not toxic in an in vivo pre-clinical mouse model, and significantly reduced tumour growth in a xenograft mouse model of disease. <h3>Conclusions</h3> These data, together with important design considerations implied by the present study, suggest RAGE-ADCs could be translated to novel therapeutics for EC patients.
Temporal and tissue-specific activation of aryl hydrocarbon receptor in discrete mouse models of kidney disease
Authors: Joshua A. Walker, Sean Richards, Mostafa E. Belghasem, Nkiruka Arinze, Sung Bok Yoo, Joseph Y. Tashjian, Stephen A. Whelan, Norman Lee, Vijaya B. Kolachalama, Jean Francis, Katya Ravid, David Sherr, Vipul C. Chitalia
Journal: Kidney International (2019)
Donor Screening for Fecal Microbiota Transplantation
Authors: Zain Kassam, Nancy Dubois, Bharat Ramakrishna, Kelly Ling, Taha Qazi, Mark Smith, Colleen R Kelly, Monika Fischer, Jessica R Allegretti, Shrish Budree, Pratik Panchal, Ciarán P Kelly, Majdi Osman
Journal: New England Journal of Medicine (2019)

Screening Donors for Stool Transplantation Restoration of a healthy stool microbiome has emerged as an approach to treat certain illnesses, including Clostridioides difficile colitis. In this repor...
Open-label randomised pragmatic trial (CONTACT) comparing naproxen and low-dose colchicine for the treatment of gout flares in primary care
Authors: Edward Roddy, Kris Clarkson, Milica Blagojevic-Bucknall, Rajnikant Mehta, Raymond Oppong, Anthony Avery, Elaine M Hay, Carl Heneghan, Liz Hartshorne, Julie Hooper, Gemma Hughes, Sue Jowett, Martyn Lewis, Paul Little, Karen McCartney, Kamal R Mahtani, David Nunan, Miriam Santer, Sam Williams, Christian D Mallen
Journal: Annals of the Rheumatic Diseases (2019)

Objectives To compare the effectiveness and safety of naproxen and low-dose colchicine for treating gout flares in primary care. Methods This was a multicentre open-label randomised trial. Adults with a gout flare recruited from 100 general practices were randomised equally to naproxen 750 mg immediately then 250 mg every 8 hours for 7 days or low-dose colchicine 500 mcg three times per day for 4 days. The primary outcome was change in worst pain intensity in the last 24 hours (0–10 Numeric Rating Scale) from baseline measured daily over the first 7 days: mean change from baseline was compared between groups over days 1–7 by intention to treat. Results Between 29 January 2014 and 31 December 2015, we recruited 399 participants (naproxen n=200, colchicine n=199), of whom 349 (87.5%) completed primary outcome data at day 7. There was no significant between-group difference in average pain-change scores over days 1–7 (colchicine vs naproxen: mean difference −0.18; 95% CI −0.53 to 0.17; p=0.32). During days 1–7, diarrhoea (45.9% vs 20.0%; OR 3.31; 2.01 to 5.44) and headache (20.5% vs 10.7%; 1.92; 1.03 to 3.55) were more common in the colchicine group than the naproxen group but constipation was less common (4.8% vs 19.3%; 0.24; 0.11 to 0.54). Conclusion We found no difference in pain intensity over 7 days between people with a gout flare randomised to either naproxen or low-dose colchicine. Naproxen caused fewer side effects supporting naproxen as first-line treatment for gout flares in primary care in the absence of contraindications. Trial registration number ISRCTN (69836939), clinicaltrials.gov ( NCT01994226 ), EudraCT (2013-001354-95).
JAK3 Mutants Transform Hematopoietic Cells through JAK1 Activation Causing T-Cell Acute Lymphoblastic Leukemia in a Bone Marrow Transplant Mouse Model
Authors: Degryse Sandrine, Charles E de Bock, Carmen Vicente, Luk Cox, Olga Gielen, Nicole Mentens, Kris Jacobs, Ellen Geerdens, Thomas Tousseyn, Jan Cools
Journal: Blood (2014)
pH-responsive perylenediimide nanoparticles for cancer trimodality imaging and photothermal therapy
Authors: Jianhao Li, Chang Liu, Yiseng Hu, Chendong Ji, Shuolin Li, Meizhen Yin
Journal: Theranostics (2019)

Organic chromophores have been well developed for multimodality imaging-guided photothermal therapy (PTT) due to their outstanding optical properties and excellent designability.However, the theranostic efficiencies of most currently available organic chromophores are restricted intrinsically, owing to their poor photostability or complex synthesis procedures.These drawbacks not only increase their cost of synthesis, but also cause side effects in PTT.Method: We presented a facile strategy for constructing a near-infrared (NIR)-absorbing perylenediimide structured with pH-responsive piperazine ring at the bay region.The chromophore was conjugated with carboxyl-end-capped PEG as side chains that can self-assemble into nanoparticles (NPs) in aqueous solution.The NIR optical properties and photothermal conversation ability of PPDI-NPs were investigated.We then studied the imaging-guided PTT of PPDI-NPs under NIR light illumination in 4T1 cells and mice respectively.Results: The excellent photostable PPDI-NPs had near-infrared fluorescence (NIRF) emission and high photothermal conversion efficiency in acidic microenvironment.Importantly, PPDI-NPs can be utilized for the precise detection of tumors by NIRF/photoacoustic/thermal trimodality imaging.Efficient PTT of PPDI-NPs was applied in vitro and in vivo with high biosafety. Conclusion:In summary, we developed pH-responsive perylenediimide nanoparticles as multifunctional phototheranostic agent with high stability and simple synthesis procedures.This study offers a promising organic chromophore for developing phototheranostics in cancer therapy.
Author Correction: Metagenomic analysis of colorectal cancer datasets identifies cross-cohort microbial diagnostic signatures and a link with choline degradation
Authors: Andrew Maltez Thomas, Paolo Manghi, Francesco Asnicar, Edoardo Pasolli, Federica Armanini, Moreno Zolfo, Francesco Beghini, Serena Manara, Nicolai Karcher, Chiara Pozzi, Sara Gandini, Davide Serrano, Sonia Tarallo, Antonio Francavilla, Gaetano Gallo, Mario Trompetto, Giulio Ferrero, Sayaka Mizutani, Hirotsugu Shiroma, Satoshi Shiba, Tatsuhiro Shibata, Shinichi Yachida, Takuji Yamada, Jakob Wirbel, Petra Schrotz-King, Cornelia M. Ulrich, Hermann Brenner, Manimozhiyan Arumugam, Peer Bork, Georg Zeller, Francesca Cordero, Emmanuel Dias-Neto, João Carlos Setubal, Adrian Tett, Barbara Pardini, Maria Rescigno, Levi Waldron, Alessio Naccarati, Nicola Segata
Journal: Nature Medicine (2019)
Incorporation of small extracellular vesicles in sodium alginate hydrogel as a novel therapeutic strategy for myocardial infarction
Authors: Kaiqi Lv, Qingju Li, Ling Zhang, Yingchao Wang, Zhiwei Zhong, Jing Zhao, Xiaoxiao Lin, Jingyi Wang, Keyang Zhu, Changchen Xiao, Changle Ke, Shuhan Zhong, Xianpeng Wu, Jinghai Chen, Hong Yu, Wei Zhu, Xiang Li, Ben Wang, Ruikang Tang, Jian'an Wang, Jinyu Huang, Xinyang Hu
Journal: Theranostics (2019)

Bone marrow mesenchymal stem cell (MSC)-derived small extracellular vesicles (sEVs) have been widely used for treating myocardial infarction (MI). However, low retention and short-lived therapeutic effects are still significant challenges. This study aimed to determine whether incorporation of MSC-derived sEVs in alginate hydrogel increases their retention in the heart thereby improving therapeutic effects. Methods: The optimal sodium alginate hydrogel incorporating sEVs system was determined by its release ability of sEVs and rheology of hydrogel. Ex vivo fluorescence imaging was utilized to evaluate the retention of sEVs in the heart. Immunoregulation and effects of sEVs on angiogenesis were analyzed by immunofluorescence staining. Echocardiography and Masson's trichrome staining were used to estimate cardiac function and infarct size. Results: The delivery of sEVs incorporated in alginate hydrogel (sEVs-Gel) enhanced their retention in the heart. Compared with sEVs only treatment (sEVs), sEVs-Gel treatment significantly decreased cardiac cell apoptosis and promoted the polarization of macrophages at day 3 after MI. sEVs-Gel treatment also increased scar thickness and angiogenesis at four weeks post-infarction. Measurement of cardiac function and infarct size were significantly better in the sEVs-Gel group than in the group treated with sEVs only. Conclusion: Delivery of sEVs incorporated in alginate hydrogel provides a novel approach of cell-free therapy and optimizes the therapeutic effect of sEVs for MI.
STING activation in cancer immunotherapy
Authors: Ting Su, Yu Zhang, Kristoffer Valerie, Xiang-Yang Wang, Shuibin Lin, Guizhi Zhu
Journal: Theranostics (2019)

Cancer immunotherapy modulates and leverages the host immune system to treat cancer. The past decade has witnessed historical advancement of cancer immunotherapy. A myriad of approaches have been explored to elicit or augment anticancer innate immunity and/or adaptive immunity. Recently, activation of stimulator of interferon (IFN) genes (STING), an intracellular receptor residing in the endoplasmic reticulum, has shown great potential to enhance antitumor immunity through the induction of a variety of pro-inflammatory cytokines and chemokines, including type I IFNs. A number of natural and synthetic STING agonists have been discovered or developed, and tested in preclinical models and in the clinic for the immunotherapy of diseases such as cancer and infectious diseases. Cyclic dinucleotides (CDNs), such as cyclic dimeric guanosine monophosphate (c-di-GMP), cyclic dimeric adenosine monophosphate (c-di-AMP), and cyclic GMP-AMP (cGAMP), are a class of STING agonists that can elicit immune responses. However, natural CDNs are hydrophilic small molecules with negative charges and are susceptible to enzymatic degradation, leading to low bioavailability in target tissues yet unwanted toxicities and narrow therapeutic windows. Drug delivery systems, coupled with nucleic acid chemistry, have been exploited to address these challenges. Here, we will discuss the underlying immunological mechanisms and approaches to STING activation, with a focus on the delivery of STING agonists, for cancer immunotherapy.
Investigation of galactose-alpha-1,3-galactose epitope and immunoproteomic characterisation of thermally processed beef proteins
Authors: Thi Anh Thu Tran, Danijela Apostolović, Carl Hamsten, Maria Starkhammar, Katarina Smiljanić, N. Bigdeli, Tanja Ćirković-Veličković, Marianne van Hage
Journal: Allergy (2014)
Tobacco Use in Top-Grossing Movies — United States, 2010–2018
Authors: Michael A. Tynan, Jonathan R. Polansky, Danielle Driscoll, Claire Garcia, Stanton A. Glantz
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

The Surgeon General has concluded that there is a causal relationship between depictions of smoking in movies and initiation of smoking among young persons (1). Youths heavily exposed to onscreen smoking imagery are more likely to begin smoking than are those with minimal exposure (1,2). To assess tobacco-use imagery in top-grossing youth-rated movies (General Audiences [G], Parental Guidance [PG], and Parents Strongly Cautioned [PG-13]),* 2010-2018 data from the Breathe California Sacramento Region and University of California-San Francisco's Onscreen Tobacco Database were analyzed.† The percentage of all top-grossing movies with tobacco incidents remained stable from 2010 (45%) to 2018 (46%), including youth-rated movies (31% both years). However, total tobacco incidents increased 57% from 2010 to 2018, with a 120% increase in PG-13 movies. Tobacco incidents in PG-13 fictional movies declined 57% from 511 in 2010 to an all-time low of 221 in 2018. Although the number of PG-13 fictional movies with tobacco incidents declined 40% during 2010-2018, the number of PG-13 biographical dramas with tobacco incidents increased 233%. In 2018, biographical dramas accounted for most tobacco incidents, including 82% of incidents in PG-13 movies; 73% of characters who used tobacco in these biographical dramas were fictional. Continued efforts could help reduce tobacco incidents in top-grossing movies, particularly in PG-13 biographical dramas, to help prevent youth smoking initiation.
Association of Cord Plasma Biomarkers of In Utero Acetaminophen Exposure With Risk of Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder in Childhood
Authors: Yuelong Ji, Romuladus E. Azuine, Yan Zhang, Wenpin Hou, Xiumei Hong, Guoying Wang, Anne Riley, Colleen Pearson, Barry Zuckerman, Xiaobin Wang
Journal: JAMA Psychiatry (2019)

Prior studies have raised concern about maternal acetaminophen use during pregnancy and increased risk of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in their children; however, most studies have relied on maternal self-report.To examine the prospective associations between cord plasma acetaminophen metabolites and physician-diagnosed ADHD, ASD, both ADHD and ASD, and developmental disabilities (DDs) in childhood.This prospective cohort study analyzed 996 mother-infant dyads, a subset of the Boston Birth Cohort, who were enrolled at birth and followed up prospectively at the Boston Medical Center from October 1, 1998, to June 30, 2018.Three cord acetaminophen metabolites (unchanged acetaminophen, acetaminophen glucuronide, and 3-[N-acetyl-l-cystein-S-yl]-acetaminophen) were measured in archived cord plasma samples collected at birth.Physician-diagnosed ADHD, ASD, and other DDs as documented in the child's medical records.Of 996 participants (mean [SD] age, 9.8 [3.9] years; 548 [55.0%] male), the final sample included 257 children (25.8%) with ADHD only, 66 (6.6%) with ASD only, 42 (4.2%) with both ADHD and ASD, 304 (30.5%) with other DDs, and 327 (32.8%) who were neurotypical. Unchanged acetaminophen levels were detectable in all cord plasma samples. Compared with being in the first tertile, being in the second and third tertiles of cord acetaminophen burden was associated with higher odds of ADHD diagnosis (odds ratio [OR] for second tertile, 2.26; 95% CI, 1.40-3.69; OR for third tertile, 2.86; 95% CI, 1.77-4.67) and ASD diagnosis (OR for second tertile, 2.14; 95% CI, 0.93-5.13; OR for third tertile, 3.62; 95% CI, 1.62-8.60). Sensitivity analyses and subgroup analyses found consistent associations between acetaminophen buden and ADHD and acetaminophen burden and ASD across strata of potential confounders, including maternal indication, substance use, preterm birth, and child age and sex, for which point estimates for the ORs vary from 2.3 to 3.5 for ADHD and 1.6 to 4.1 for ASD.Cord biomarkers of fetal exposure to acetaminophen were associated with significantly increased risk of childhood ADHD and ASD in a dose-response fashion. Our findings support previous studies regarding the association between prenatal and perinatal acetaminophen exposure and childhood neurodevelopmental risk and warrant additional investigations.
Economic and Clinical Burden of Nonalcoholic Steatohepatitis in Patients With Type 2 Diabetes in the U.S.
Authors: Zobair M. Younossi, Radhika P. Tampi, Andrei Racila, Ying Qiu, Leah Burns, Issah Younossi, Fatema Nader
Journal: Diabetes Care (2019)

OBJECTIVE Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD) and is strongly associated with type 2 diabetes mellitus (T2DM). Patients with both T2DM and NASH have increased risk for adverse clinical outcomes, leading to higher risk for mortality and morbidity. We built a Markov model with 1-year cycles and 20-year horizon to estimate the economic burden of NASH with T2DM in the U.S. RESEARCH DESIGN AND METHODS Cohort size was determined by population size, prevalence of T2DM, and prevalence and incidence of NASH in 2017. The model includes 10 health states—NAFL, NASH fibrosis stages F0 through F3, compensated and decompensated cirrhosis, hepatocellular carcinoma, 1 year post–liver transplant, and post–liver transplant—as well as liver-related, cardiovascular, and background mortality. Transition probabilities were calculated from meta-analyses and literature. Annual costs for NASH and T2DM were taken from literature and billing codes. RESULTS We estimated that there were 18.2 million people in the U.S. living with T2DM and NAFLD, of which 6.4 million had NASH. Twenty-year costs for NAFLD in these patients were $55.8 billion. Over the next 20 years, NASH with T2DM will account for 65,000 transplants, 1.37 million cardiovascular-related deaths, and 812,000 liver-related deaths. CONCLUSIONS This model predicts significant clinical and economic burden due to NASH with T2DM over the next 20 years. In fact, this burden may be greater since we assumed conservative inputs for our model and did not increase costs or the incidence of T2DM over time. It is highly likely that interventions reducing morbidity and mortality in NASH patients with T2DM could potentially reduce this projected clinical and economic burden.
Prunin suppresses viral IRES activity and is a potential candidate for treating enterovirus A71 infection
Authors: Saravanan Gunaseelan, Kai Zhi Wong, Nyo Min, Jialei Sun, Nur Khairiah Binte Mohd Ismail, Yee Joo Tan, Regina Ching Hua Lee, Justin Jang Hann Chu
Journal: Science Translational Medicine (2019)

Prunin suppresses HEVA71 translation in vitro and in vivo by impeding activity of the HEVA71 internal ribosome entry site.
Very Low-Energy Diets—Opportunity for Greater Weight Loss, but Risk of Bone Loss
Authors: Marinka Steur
Journal: JAMA Network Open (2019)

Radhika V. Seimon, PhD; Anthony L. Wild-Taylor, BSc (Hons); Shelley E. Keating, PhD; Sally McClintock, MSc; Claudia Harper, BSc (Hons); Alice A. Gibson, PhD; Nathan A. Johnson, PhD; Hamish A. Fernando, PhD; Tania P. Markovic, MD; Jacqueline R. Center, MD; Janet Franklin, PhD; Peter Y. Liu, MD; Stuart M. Grieve, MD; Jim Lagopoulos, PhD; Ian D. Caterson, MD; Nuala M. Byrne, PhD; Amanda Sainsbury, PhD
Coniferaldehyde attenuates Alzheimer's pathology <i>via</i> activation of Nrf2 and its targets
Authors: Yaqiong Dong, Tessandra Stewart, Lidan Bai, Xue Li, Ting Xu, Jeffrey Iliff, Min Shi, Danfeng Zheng, Lan Yuan, Taotao Wei, Xiaoda Yang, Jing Zhang
Journal: Theranostics (2019)

Background: Alzheimer's disease (AD) currently lacks a cure. Because substantial neuronal damage usually occurs before AD is advanced enough for diagnosis, the best hope for disease-modifying AD therapies likely relies on early intervention or even prevention, and targeting multiple pathways implicated in early AD pathogenesis rather than focusing exclusively on excessive production of β-amyloid (Aβ) species. Methods: Coniferaldehyde (CFA), a food flavoring and agonist of NF-E2-related factor 2 (Nrf2), was selected by multimodal in vitro screening, followed by investigation of several downstream effects potentially involved. Furthermore, in the APP/PS1 AD mouse model, the therapeutic effects of CFA (0.2 mmol kg-1d-1) were tested beginning at 3 months of age. Behavioral phenotypes related to learning and memory capacity, brain pathology and biochemistry, including Aβ transport, were assessed at different time intervals. Results: CFA promoted neuron viability and showed potent neuroprotective effects, especially on mitochondrial structure and functions. In addition, CFA greatly enhanced the brain clearance of Aβ in both free and extracellular vesicle (EV)-contained Aβ forms. In the APP/PS1 mouse model, CFA effectively abolished brain Aβ deposits and reduced the level of toxic soluble Aβ peptides, thus eliminating AD-like pathological changes in the hippocampus and cerebral cortex and preserving learning and memory capacity of the mice. Conclusion: The experimental evidence overall indicated that Nrf2 activation may contribute to the potent anti-AD effects of CFA. With an excellent safety profile, further clinical investigation of coniferaldehyde might bring hope for AD prevention/therapy.
Advances in asthma and allergic disease genetics: Is bigger always better?
Authors: Nathan Schoettler, Elke Rodríguez, Stephan Weidinger, Carole Ober
Journal: Journal of Allergy and Clinical Immunology (2019)

This review focuses on genome-wide association studies (GWASs) of asthma and allergic diseases published between January 1, 2018, and June 30, 2019. During this time period, there were 38 GWASs reported in 19 articles, including the largest performed to date for many of these conditions. Overall, we learned that childhood-onset asthma is associated with the most independent loci compared with other defined groups of asthma and allergic disease cases; adult-onset asthma and moderate-to-severe asthma are associated with fewer genes, which are largely a subset of those associated with childhood-onset asthma. There is significant genetic overlap between asthma and allergic diseases, particularly with respect to childhood-onset asthma, which involves genes that reflect the importance of barrier function biology, and to HLA region genes, which are the most frequently associated genes overall in both groups of diseases. Although the largest GWASs in African American and Latino/Hispanic populations were reported during this period, they are still significantly underpowered compared with studies reported in populations of European ancestry, highlighting the need for larger studies, particularly in patients with childhood-onset asthma and allergic diseases, in these important populations that carry the greatest burden of disease.
Rammya Mathew: We must build capacity and infrastructure for effective quality improvement
Authors: Rammya Mathew
Journal: BMJ (2019)

I’ve recently been considering whether quality improvement is as accessible as it’s often made out to be. There’s a pervading sense that anyone can attend a course and then have a go. But people actively involved in healthcare improvement will know that, if it’s to be done well, it requires the understanding and application of improvement models, data science, and behavioural psychology. And, above all, quality improvement needs to be underpinned by strong clinical leadership.

By downplaying the technical and relational aspects of quality improvement, and by encouraging people to take on quality improvement …