tbuckley/cabot-search huggingface dataset:
The global burden of atopic dermatitis: lessons from the Global Burden of Disease Study 1990–2017*
Authors: M.R. Laughter, M.B.C. Maymone, S. Mashayekhi, B.W.M. Arents, C. Karimkhani, S.M. Langan, R.P. Dellavalle, C. Flohr
Journal: British Journal of Dermatology (2020)

The Global Burden of Disease (GBD) Study provides an annually updated resource to study disease‐related morbidity and mortality worldwide. Here we present the burden estimates for atopic dermatitis (AD), including data from inception of the GBD project in 1990 until 2017. Data on the burden of AD were obtained from the GBD Study. Atopic dermatitis (AD) ranks 15th among all nonfatal diseases and has the highest disease burden among skin diseases as measured by disability‐adjusted life‐years (DALYs). Overall, the global DALY rate for AD in 1990 was 121 [95% uncertainty interval (UI) 65·4–201] and remained similar in 2017 at 123 (95% UI 66·8–205). The three countries with the highest DALY rates of AD were Sweden (327, 95% UI 178–547), the UK (284, 95% UI 155–478) and Iceland (277, 95% UI 149–465), whereas Uzbekistan (85·1, 95% UI 45·2–144), Armenia (85·1, 95% UI 45·8–143) and Tajikistan (85·1, 95% UI 46·1–143) ranked lowest. The global prevalence rate of AD has remained stable from 1990 to 2017. However, the distribution of AD by age groups shows a bimodal curve with the highest peak in early childhood, decreasing in prevalence among young adults, and a second peak in middle‐aged and older populations. We also found a moderate positive correlation between a country's gross domestic product and disease burden. GBD data confirm the substantial worldwide burden of AD, which has remained stable since 1990 but shows significant geographical variation. Lifestyle factors, partially linked to affluence, are likely important disease drivers. However, the GBD methodology needs to be developed further to incorporate environmental risk factors, such as ultraviolet exposure, to understand better the geographical and age‐related variations in disease burden.
Association of Generic Imatinib Availability and Pricing With Trends in Tyrosine Kinase Inhibitor Use in Patients With Chronic Myelogenous Leukemia
Authors: Gary H. Lyman, Henry J. Henk
Journal: JAMA Oncology (2020)

The increasing price of new cancer therapies over the past 3 decades has contributed considerably to increasing health care expenditures.The life expectancy of patients with chronic myelogenous leukemia (CML) treated with imatinib now approaches that of the general population, increasing the prevalence of survivors with CML receiving treatment. 1Beginning in 2006, a series of second-and third-generation tyrosine kinase inhibitors (TKIs) have been approved and gained widespread use based on early results demonstrating deeper molecular responses. 2,3However, subsequent studies have provided no evidence that later-generation TKIs provide superior progression free or overall survival compared with imatinib. 4-6Although a generic imatinib was approved in 2016, high initial prices of brand name and generic imatinib and nextgeneration TKIs have continued to increase, averaging 10% to 20% annually, contributing to financial hardship and possibly poor compliance with effective therapy (https://ascopubs.org/doi/10.1200/JOP.2016.019737).In this article, we provide contemporary data to identify trends in TKI use in patients with CML and the association those treatment choices have with health care costs.
病原性大腸菌における重複グルタミン酸デカルボキシラーゼ遺伝子(gadAおよびgadB)間の最近の遺伝子変換
Authors: M Bergholz Teresa, L Tarr Cheryl, M Christensen Lisa, J Betting David, S Whittam Thomas
Journal: Molecular Biology and Evolution (2007)
Stimuli‐Responsive Biomaterials: Scaffolds for Stem Cell Control
Authors: Amy Gelmi, Carolyn E. Schutt
Journal: Advanced Healthcare Materials (2020)

Stem cell fate is closely intertwined with microenvironmental and endogenous cues within the body. Recapitulating this dynamic environment ex vivo can be achieved through engineered biomaterials which can respond to exogenous stimulation (including light, electrical stimulation, ultrasound, and magnetic fields) to deliver temporal and spatial cues to stem cells. These stimuli-responsive biomaterials can be integrated into scaffolds to investigate stem cell response in vitro and in vivo, and offer many pathways of cellular manipulation: biochemical cues, scaffold property changes, drug release, mechanical stress, and electrical signaling. The aim of this review is to assess and discuss the current state of exogenous stimuli-responsive biomaterials, and their application in multipotent stem cell control. Future perspectives in utilizing these biomaterials for personalized tissue engineering and directing organoid models are also discussed.
Regular use of proton pump inhibitors and risk of type 2 diabetes: results from three prospective cohort studies
Authors: Jinqiu Yuan, Qiangsheng He, Long H Nguyen, Martin C S Wong, Junjie Huang, Yuanyuan Yu, Bin Xia, Yan Tang, Yulong He, Changhua Zhang
Journal: Gut (2020)

The association between the regular use of proton pump inhibitors (PPIs) and the risk of type 2 diabetes remains unclear, although a recent randomised controlled trial showed a trend towards increased risk. This study was undertaken to evaluate the regular use of PPIs and risk of type 2 diabetes.This is a prospective analysis of 204 689 participants free of diabetes in the Nurses' Health Study (NHS), NHS II and Health Professionals Follow-up Study (HPFS). Type 2 diabetes was confirmed using American Diabetes Association (ADA) diagnostic criteria. We evaluated hazard ratios (HRs) adjusting for demographic factors, lifestyle habits, the presence of comorbidities, use of other medications and clinical indications.We documented 10 105 incident cases of diabetes over 2 127 471 person-years of follow-up. Regular PPI users had a 24% higher risk of diabetes than non-users (HR 1.24, 95% CI 1.17 to 1.31). The risk of diabetes increased with duration of PPI use. Fully adjusted HRs were 1.05 (95% CI 0.93 to 1.19) for participants who used PPIs for >0-2 years and 1.26 (95% CI 1.18 to 1.35) for participants who used PPIs for >2 years compared with non-users.Regular use of PPIs was associated with a higher risk of type 2 diabetes and the risk increased with longer duration of use. Physicians should therefore exercise caution when prescribing PPIs, particularly for long-term use.
COPA silences STING
Authors: Sophie Rivara, Andrea Ablasser
Journal: The Journal of Experimental Medicine (2020)

Two studies published in this issue of JEM, by Lepelley et al. (https://doi.org/10.1084/jem.20200600) and Deng et al. (https://doi.org/10.1084/jem.20201045), and two additional manuscripts by Mukai et al. (https://doi.org/10.1101/2020.05.20.107664 Preprint v1) and Steiner et al. (https://doi.org/10.1101/2020.07.09.194399 Preprint v1) demonstrate that COPA syndrome–associated high interferon titers are linked to mutations in COPA preventing STING’s retrieval from the Golgi back to the ER and thereby causing chronic immune activation.
Abstract B12: Potential neoantigen release and increased lymphocyte activity is facilitated by matrix metalloproteinase-dependent cleavage of mutant matrisome peptides in cutaneous melanoma
Authors: Saif Zaman, Boris I. Chobrutskiy, Jay S. Patel, Blake M. Callahan, Moody Mihyu, Andrea Diviney, Wei Lue Tong, George Blanck
Journal: Cancer Research (2020)

Abstract Introduction: Proteases in the cancer microenvironment have been studied for decades, with a general conclusion that such proteases facilitate the spread of cancer, although there is some controversy regrading that conclusion in later stages of cancer development. More recently, a very large collection of data regarding mutant amino acids in the potential substrates of the cancer microenvironment has become available. Methods: To better understand the potential impact of these mutant amino acids on protease function and cancer progression, we established a bioinformatics approach to assessing the impact of melanoma mutants, among a previously defined set of ECM structural proteins, on MMP2, a protease extensively associated with melanoma in terms of both protease sensitivity and MHC class I binding using original software. Additionally, T-cell receptor TRα and TRβ recombinations were bioinformatically obtained using whole-exome sequencing data from 479 melanoma tumor samples. Results: Tumor samples with mutant amino acids adjacent to ECM structural protein, MMP2-cleavage sites represented a better survival rate and a larger proportion of mutant peptides with high HLA class I binding affinities, particularly in comparison to melanoma samples lacking a T-cell infiltrate. Furthermore, even better MHC class I binders, as a group, were identified among the sample representing ECM structural proteins mutants not adjacent to MMP2 sensitive sites and evincing a relatively poor survival rate. Conclusion: Overall, this analysis suggested that MMP2 has the capacity of freeing mutant peptides that could facilitate an antitumor response and a better survival rate, and this analysis has the potential of resolving some of the controversy surrounding the role of cancer proteases in cancer progression. Citation Format: Saif Zaman, Boris I. Chobrutskiy, Jay S. Patel, Blake M. Callahan, Moody Mihyu, Andrea Diviney, Wei Lue Tong, George Blanck. Potential neoantigen release and increased lymphocyte activity is facilitated by matrix metalloproteinase-dependent cleavage of mutant matrisome peptides in cutaneous melanoma [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr B12.
Accuracy of New Equation to Calculate Low-Density Lipoprotein Cholesterol
Authors: Seth S. Martin, Mohamed B. Elshazly, Steven R. Jones
Journal: JAMA Cardiology (2020)

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Cyanine Conjugate‐Based Biomedical Imaging Probes
Authors: Yang Li, Yiming Zhou, Xiuli Yue, Zhifei Dai
Journal: Advanced Healthcare Materials (2020)

Abstract Cyanine is a class of fluorescent dye with meritorious fluorescence properties and has motivated numerous researchers to explore its imaging capabilities by miscellaneous structural modification and functionalization strategies. The covalent conjugation with other functional molecules represents a distinctive design strategy and has shown immense potential in both basic and clinical research. This review article summarizes recent achievements in cyanine conjugate‐based probes for biomedical imaging. Particular attention is paid to the conjugation with targeting warheads and other contrast agents for targeted fluorescence imaging and multimodal imaging, respectively. Additionally, their clinical potential in cancer diagnostics is highlighted and some concurrent impediments for clinical translation are discussed.
Derivation and validation of a predictive model for advanced colorectal neoplasia in asymptomatic adults
Authors: Thomas F Imperiale, Patrick O Monahan, Timothy E Stump, David F Ransohoff
Journal: Gut (2020)

Knowing risk for advanced colorectal neoplasia (AN) could help patients and providers choose among screening tests, improving screening efficiency and uptake. We created a risk prediction model for AN to help decide which test might be preferred, a use not considered for existing models.Average-risk 50-to-80-year olds undergoing first-time screening colonoscopy were recruited from endoscopy units in Indiana. We measured sociodemographic and physical features, medical and family history and lifestyle factors and linked these to the most advanced finding. We derived a risk equation on two-thirds of the sample and assigned points to each variable to create a risk score. Scores with comparable risks were collapsed into risk categories. The model and score were tested on the remaining sample.Among 3025 subjects in the derivation set (mean age 57.3 (6.5) years; 52% women), AN prevalence was 9.4%. The 13-variable model (c-statistic=0.77) produced three risk groups with AN risks of 1.5% (95% CI 0.72% to 2.74%), 7.06% (CI 5.89% to 8.38%) and 27.26% (CI 23.47% to 31.30%) in low-risk, intermediate-risk and high-risk groups (p value <0.001), containing 23%, 59% and 18% of subjects, respectively. In the validation set of 1475 subjects (AN prevalence of 8.4%), model performance was comparable (c-statistic=0.78), with AN risks of 2.73% (CI 1.25% to 5.11%), 5.57% (CI 4.12% to 7.34%) and 25.79% (CI 20.51% to 31.66%) in low-risk, intermediate-risk and high-risk subgroups, respectively (p<0.001), containing proportions of 23%, 59% and 18%.Among average-risk persons, this model estimates AN risk with high discrimination, identifying a lower risk subgroup that may be screened non-invasively and a higher risk subgroup for which colonoscopy may be preferred. The model could help guide patient-provider discussions of screening options, may increase screening adherence and conserve colonoscopy resources.
The influence of the gut microbiota on the bioavailability of oral drugs
Authors: Xintong Zhang, Ying Han, Wei Huang, Mingji Jin, Zhonggao Gao
Journal: Acta Pharmaceutica Sinica B (2020)

Due to its safety, convenience, low cost and good compliance, oral administration attracts lots of attention. However, the efficacy of many oral drugs is limited to their unsatisfactory bioavailability in the gastrointestinal tract. One of the critical and most overlooked factors is the symbiotic gut microbiota that can modulate the bioavailability of oral drugs by participating in the biotransformation of oral drugs, influencing the drug transport process and altering some gastrointestinal properties. In this review, we summarized the existing research investigating the possible relationship between the gut microbiota and the bioavailability of oral drugs, which may provide great ideas and useful instructions for the design of novel drug delivery systems or the achievement of personalized medicine.
Topical antimicrobial peptide omiganan recovers cutaneous dysbiosis but does not improve clinical symptoms in patients with mild to moderate atopic dermatitis in a phase 2 randomized controlled trial
Authors: Tessa Niemeyer–van der Kolk, Thomas P. Buters, Lara Krouwels, Jiry Boltjes, Marieke L. de Kam, Hein van der Wall, Dirk C.J.G. van Alewijk, Ellen H.A. van den Munckhof, Martin J. Becker, Gary Feiss, Edwin F. Florencia, Errol P. Prens, Matthijs Moerland, Jacobus Burggraaf, Robert Rissmann, Martijn B.A. van Doorn
Journal: Journal of the American Academy of Dermatology (2020)
Circulating tumour DNA in metastatic breast cancer to guide clinical trial enrolment and precision oncology: A cohort study
Authors: Andjelija Zivanovic Bujak, Chen-Fang Weng, Maria João Silva, Miriam Yeung, Louisa Lo, Sarah Ftouni, Cassandra Litchfield, Yi-An Ko, Keilly Kuykhoven, Courtney Van Geelen, Sushma Chandrashekar, Mark A. Dawson, Sherene Loi, Stephen Q. Wong, Sarah-Jane Dawson
Journal: PLoS Medicine (2020)

Background Metastatic breast cancer (mBC) is a heterogenous disease with increasing availability of targeted therapies as well as emerging genomic markers of therapeutic resistance, necessitating timely and accurate molecular characterization of disease. As a minimally invasive test, analysis of circulating tumour DNA (ctDNA) is well positioned for real-time genomic profiling to guide treatment decisions. Here, we report the results of a prospective testing program established to assess the feasibility of ctDNA analysis to guide clinical management of mBC patients. Methods and findings Two hundred thirty-four mBC patients (median age 54 years) were enrolled between June 2015 and October 2018 at the Peter MacCallum Cancer Centre, Melbourne, Australia. Median follow-up was 15 months (range 1–46). All patient samples at the time of enrolment were analysed in real time for the presence of somatic mutations. Longitudinal plasma testing during the course of patient management was also undertaken in a subset of patients (n = 67, 28.6%), according to clinician preference, for repeated molecular profiling or disease monitoring. Detection of somatic mutations from patient plasma was performed using a multiplexed droplet digital PCR (ddPCR) approach to identify hotspot mutations in PIK3CA, ESR1, ERBB2, and AKT1. In parallel, subsets of samples were also analysed via next-generation sequencing (targeted panel sequencing and low-coverage whole-genome sequencing [LC-WGS]). The sensitivity of ddPCR and targeted panel sequencing to identify actionable mutations was compared. Results were discussed at a multidisciplinary breast cancer meeting prior to treatment decisions. ddPCR and targeted panel sequencing identified at least 1 actionable mutation at baseline in 80/234 (34.2%) and 62/159 (39.0%) of patients tested, respectively. Combined, both methods detected an actionable alteration in 104/234 patients (44.4%) through baseline or serial ctDNA testing. LC-WGS was performed on 27 patients from the cohort, uncovering several recurrently amplified regions including 11q13.3 encompassing CCND1. Increasing ctDNA levels were associated with inferior overall survival, whether assessed by ddPCR, targeted sequencing, or LC-WGS. Overall, the ctDNA results changed clinical management in 40 patients including the direct recruitment of 20 patients to clinical trials. Limitations of the study were that it was conducted at a single site and that 31.3% of participants were lost to follow-up. Conclusion In this study, we found prospective ctDNA testing to be a practical and feasible approach that can guide clinical trial enrolment and patient management in mBC.
Efficacy of heel lifts versus calf muscle eccentric exercise for mid-portion Achilles tendinopathy (HEALTHY): a randomised trial
Authors: Chantel L Rabusin, Hylton B Menz, Jodie A McClelland, Angela M Evans, Peter Malliaras, Sean I Docking, Karl B Landorf, James M Gerrard, Shannon E Munteanu
Journal: British Journal of Sports Medicine (2020)

To compare the efficacy of in-shoe heel lifts to calf muscle eccentric exercise in reducing pain and improving function in mid-portion Achilles tendinopathy.This was a parallel-group randomised superiority trial at a single centre (La Trobe University Health Sciences Clinic, Discipline of Podiatry, Melbourne, Victoria, Australia). One hundred participants (52 women and 48 men, mean age 45.9, SD 9.4 years) with clinically diagnosed and ultrasonographically confirmed mid-portion Achilles tendinopathy were randomly allocated to either a (1) heel lifts (n=50) or (2) eccentric exercise (n=50) group. The primary outcome measure was the Victorian Institute of Sport Assessment-Achilles (VISA-A) questionnaire at 12 weeks. Differences between groups were analysed using intention to treat with analysis of covariance.There was 80% follow-up of participants (n=40 per group) at 12 weeks. The mean VISA-A score improved by 26.0 points (95% CI 19.6 to 32.4) in the heel lifts group and by 17.4 points (95% CI 9.5 to 25.3) in the eccentric exercise group. On average, there was a between-group difference in favour of the heel lifts for the VISA-A (adjusted mean difference 9.6, 95% CI 1.8 to 17.4, p=0.016), which approximated, but did not meet our predetermined minimum important difference of 10 points.In adults with mid-portion Achilles tendinopathy, heel lifts were more effective than calf muscle eccentric exercise in reducing pain and improving function at 12 weeks. However, there is uncertainty in the estimate of effect for this outcome and patients may not experience a clinically worthwhile difference between interventions.ACTRN12617001225303.
Angiotensin‐converting enzyme inhibitor/angiotensin <scp>II</scp> receptor blocker treatment and haemodynamic factors are associated with increased cardiac <scp>mRNA</scp> expression of angiotensin‐converting enzyme <scp>2</scp> in patients with cardiovascular disease
Authors: Simon Lebek, Maria Tafelmeier, Rebecca Messmann, Zdenek Provaznik, Christof Schmid, Lars S. Maier, Christoph Birner, Michael Arzt, Stefan Wagner
Journal: European Journal of Heart Failure (2020)

Abstract Aims Coronavirus disease 2019 (COVID‐19) is a widespread pandemic with an increased morbidity and mortality, especially for patients with cardiovascular diseases. Angiotensin‐converting enzyme 2 (ACE2) has been identified as necessary cell entry point for SARS‐CoV‐2. Previous animal studies have demonstrated an increased ACE2 expression following treatment with either angiotensin‐converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB) that have led to a massive precariousness regarding the optimal cardiovascular therapy during this pandemic. Methods and results We have measured ACE2 mRNA expression using real‐time quantitative polymerase chain reaction in atrial biopsies of 81 patients undergoing coronary artery bypass grafting and we compared 62 patients that received ACEi/ARB vs. 19 patients that were not ACEi/ARB‐treated. We found atrial ACE2 mRNA expression to be significantly increased in patients treated with an ACEi or an ARB, independent of potential confounding comorbidities. Interestingly, the cardiac ACE2 mRNA expression correlated significantly with the expression in white blood cells of 22 patients encouraging further evaluation if the latter may be used as a surrogate for the former. Similarly, analysis of 18 ventricular biopsies revealed a significant and independent increase in ACE2 mRNA expression in patients with end‐stage heart failure that were treated with ACEi/ARB. On the other hand, cardiac unloading with a left ventricular assist device significantly reduced ventricular ACE2 mRNA expression. Conclusion Treatment with ACEi/ARB is independently associated with an increased myocardial ACE2 mRNA expression in patients with coronary artery disease and in patients with end‐stage heart failure. Further trials are needed to test whether this association is deleterious for patients with COVID‐19, or possibly protective. Nevertheless, haemodynamic factors seem to be equally important for regulation of cardiac ACE2 mRNA expression.