Showing papers by "I.M. Sechenov First Moscow State Medical University published in 2019"
Lundbeck1, Aarhus University2, Harvard University3, Broad Institute4, Karolinska Institutet5, Cardiff University6, Statens Serum Institut7, QIMR Berghofer Medical Research Institute8, University of Iceland9, deCODE genetics10, Mental Health Services11, Charité12, University of California, Los Angeles13, Semel Institute for Neuroscience and Human Behavior14, University of Queensland15, Oslo University Hospital16, King's College London17, University of Toronto18, VU University Amsterdam19, Radboud University Nijmegen20, Veterans Health Administration21, Yale University22, Children's Hospital of Philadelphia23, Haukeland University Hospital24, University of Bergen25, University of Pennsylvania26, University of Würzburg27, Maastricht University28, I.M. Sechenov First Moscow State Medical University29, Goethe University Frankfurt30, Universidade Federal do Rio Grande do Sul31, Icahn School of Medicine at Mount Sinai32, University of North Carolina at Chapel Hill33, Emory University34, University of Copenhagen35, Aarhus University Hospital36, State University of New York Upstate Medical University37
TL;DR: A genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls identifies variants surpassing genome- wide significance in 12 independent loci and implicates neurodevelopmental pathways and conserved regions of the genome as being involved in underlying ADHD biology.
Abstract: Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.
1,436 citations
TL;DR: Evidence is presented that the MDS algorithm-predicted hits frequently coincide with those already used as targets of the existing cancer drugs, but several novel candidates can be considered promising for further developments.
Abstract: Despite the significant achievements in chemotherapy, cancer remains one of the leading causes of death. Target therapy revolutionized this field, but efficiencies of target drugs show dramatic variation among individual patients. Personalization of target therapies remains, therefore, a challenge in oncology. Here, we proposed molecular pathway-based algorithm for scoring of target drugs using high throughput mutation data to personalize their clinical efficacies. This algorithm was validated on 3,800 exome mutation profiles from The Cancer Genome Atlas (TCGA) project for 128 target drugs. The output values termed Mutational Drug Scores (MDS) showed positive correlation with the published drug efficiencies in clinical trials. We also used MDS approach to simulate all known protein coding genes as the putative drug targets. The model used was built on the basis of 18,273 mutation profiles from COSMIC database for eight cancer types. We found that the MDS algorithm-predicted hits frequently coincide with those already used as targets of the existing cancer drugs, but several novel candidates can be considered promising for further developments. Our results evidence that the MDS is applicable to ranking of anticancer drugs and can be applied for the identification of novel molecular targets.
503 citations
University of Erlangen-Nuremberg1, University of Bern2, Ludwig Maximilian University of Munich3, Johns Hopkins University School of Medicine4, Danylo Halytsky Lviv National Medical University5, Walter and Eliza Hall Institute of Medical Research6, Jagiellonian University7, Ghent University8, Harvard University9, University of Pittsburgh10, Centro Nacional de Investigaciones Cardiovasculares11, National Institutes of Health12, University of Michigan13, University of Calgary14, Vita-Salute San Raffaele University15, Trinity College, Dublin16, Democritus University of Thrace17, University of Tennessee Health Science Center18, University of California, San Diego19, Radboud University Nijmegen20, I.M. Sechenov First Moscow State Medical University21, University of Antwerp22, Saarland University23, University of Salzburg24, University of Veterinary Medicine Vienna25, University of Münster26
TL;DR: In this paper, the authors present prevailing concepts and state of the science in neutrophil extracellular traps (NET) related research and elaborate on open questions and areas of dispute.
Abstract: Since the discovery and definition of neutrophil extracellular traps (NETs) 14 years ago, numerous characteristics and physiological functions of NETs have been uncovered. Nowadays, the field continues to expand and novel mechanisms that orchestrate formation of NETs, their previously unknown properties, and novel implications in disease continue to emerge. The abundance of available data has also led to some confusion in the NET research community due to contradictory results and divergent scientific concepts, such as pro- and anti-inflammatory roles in pathologic conditions, demarcation from other forms of cell death, or the origin of the DNA that forms the NET scaffold. Here, we present prevailing concepts and state of the science in NET-related research and elaborate on open questions and areas of dispute.
260 citations
TL;DR: Experimental data evidencing the impairment in cellular functions caused by AGE/ALE accumulation under oxidative stress conditions are discussed to demonstrate that the identification of cellular dysfunctions involved in disease initiation and progression can serve as a basis for the discovery of relevant therapeutic agents.
Abstract: Oxidative stress is a consequence of the use of oxygen in aerobic respiration by living organisms and is denoted as a persistent condition of an imbalance between the generation of reactive oxygen species (ROS) and the ability of the endogenous antioxidant system (AOS) to detoxify them. The oxidative stress theory has been confirmed in many animal studies, which demonstrated that the maintenance of cellular homeostasis and biomolecular stability and integrity is crucial for cellular longevity and successful aging. Mitochondrial dysfunction, impaired protein homeostasis (proteostasis) network, alteration in the activities of transcription factors such as Nrf2 and NF-κB, and disturbances in the protein quality control machinery that includes molecular chaperones, ubiquitin-proteasome system (UPS), and autophagy/lysosome pathway have been observed during aging and age-related chronic diseases. The accumulation of ROS under oxidative stress conditions results in the induction of lipid peroxidation and glycoxidation reactions, which leads to the elevated endogenous production of reactive aldehydes and their derivatives such as glyoxal, methylglyoxal (MG), malonic dialdehyde (MDA), and 4-hydroxy-2-nonenal (HNE) giving rise to advanced lipoxidation and glycation end products (ALEs and AGEs, respectively). Both ALEs and AGEs play key roles in cellular response to oxidative stress stimuli through the regulation of a variety of cell signaling pathways. However, elevated ALE and AGE production leads to protein cross-linking and aggregation resulting in an alteration in cell signaling and functioning which causes cell damage and death. This is implicated in aging and various age-related chronic pathologies such as inflammation, neurodegenerative diseases, atherosclerosis, and vascular complications of diabetes mellitus. In the present review, we discuss experimental data evidencing the impairment in cellular functions caused by AGE/ALE accumulation under oxidative stress conditions. We focused on the implications of ALEs/AGEs in aging and age-related diseases to demonstrate that the identification of cellular dysfunctions involved in disease initiation and progression can serve as a basis for the discovery of relevant therapeutic agents.
250 citations
TL;DR: It is demonstrated that ferrostatin-1 (Fer-1), a specific inhibitor of ferroptosis, decreases the level of pro-ferroptotic hydroperoxy-arachidonoyl-phosphatidylethanolamine, reduces cardiomyocyte cell death and blocks neutrophil recruitment following heart transplantation.
Abstract: Non-apoptotic forms of cell death can trigger sterile inflammation through the release of danger-associated molecular patterns, which are recognized by innate immune receptors. However, despite years of investigation the mechanisms which initiate inflammatory responses after heart transplantation remain elusive. Here, we demonstrate that ferrostatin-1 (Fer-1), a specific inhibitor of ferroptosis, decreases the level of pro-ferroptotic hydroperoxy-arachidonoyl-phosphatidylethanolamine, reduces cardiomyocyte cell death and blocks neutrophil recruitment following heart transplantation. Inhibition of necroptosis had no effect on neutrophil trafficking in cardiac grafts. We extend these observations to a model of coronary artery ligation-induced myocardial ischemia reperfusion injury where inhibition of ferroptosis resulted in reduced infarct size, improved left ventricular systolic function, and reduced left ventricular remodeling. Using intravital imaging of cardiac transplants, we uncover that ferroptosis orchestrates neutrophil recruitment to injured myocardium by promoting adhesion of neutrophils to coronary vascular endothelial cells through a TLR4/TRIF/type I IFN signaling pathway. Thus, we have discovered that inflammatory responses after cardiac transplantation are initiated through ferroptotic cell death and TLR4/Trif-dependent signaling in graft endothelial cells. These findings provide a platform for the development of therapeutic strategies for heart transplant recipients and patients, who are vulnerable to ischemia reperfusion injury following restoration of coronary blood flow.
233 citations
TL;DR: This review summarizes available data on the pathogenesis and clinical features of TBE, plus different vaccine preparations available in Europe and Russia, plus new treatment possibilities, including small molecule drugs and experimental immunotherapies are reviewed.
207 citations
TL;DR: An algorithm is proposed to assess the relevance of the most common bibliometric tools to help the researchers select the fittest journal and know the trends of published submissions by using self-evaluation.
Abstract: Understanding the impact of a publication by using bibliometric indices becomes an essential activity not only for universities and research institutes but also for individual academicians. This paper aims to provide a brief review of the current bibliometric tools used by authors and editors and proposes an algorithm to assess the relevance of the most common bibliometric tools to help the researchers select the fittest journal and know the trends of published submissions by using self-evaluation. We present a narrative review answering at least two related consecutive questions triggered by the topics mentioned above. How prestigious is a journal based on its most recent bibliometrics, so authors may choose it to submit their next manuscript? And, how can they self-evaluate/understand the impact of their whole publishing scientific life? We presented the main relevant definitions of each bibliometrics and grouped them in those oriented to evaluated journals or individuals. Also, we share with our readers our algorithm to assess journals before manuscript submission. Since there is a journal performance market and an article performance market, each one with its patterns, an integrative use of these metrics, rather than just the impact factor alone, might represent the fairest and most legitimate approach to assess the influence and importance of an acceptable research issue, and not only a sound journal in their respective disciplines.
200 citations
TL;DR: The AURA-LV study suggests that the addition of low-dose voclosporin to mycophenolate mofetil and corticosteroids for induction therapy of active LN results in a superior renal response compared to myCophenolatemofetIL and cortICosteroids alone, but higher rates of adverse events including death were observed.
175 citations
Roy Burstein1, Nathaniel J Henry1, Michael Collison1, Laurie B. Marczak1 +663 more•Institutions (290)
TL;DR: A high-resolution, global atlas of mortality of children under five years of age between 2000 and 2017 highlights subnational geographical inequalities in the distribution, rates and absolute counts of child deaths by age.
Abstract: Since 2000, many countries have achieved considerable success in improving child survival, but localized progress remains unclear. To inform efforts towards United Nations Sustainable Development Goal 3.2—to end preventable child deaths by 2030—we need consistently estimated data at the subnational level regarding child mortality rates and trends. Here we quantified, for the period 2000–2017, the subnational variation in mortality rates and number of deaths of neonates, infants and children under 5 years of age within 99 low- and middle-income countries using a geostatistical survival model. We estimated that 32% of children under 5 in these countries lived in districts that had attained rates of 25 or fewer child deaths per 1,000 live births by 2017, and that 58% of child deaths between 2000 and 2017 in these countries could have been averted in the absence of geographical inequality. This study enables the identification of high-mortality clusters, patterns of progress and geographical inequalities to inform appropriate investments and implementations that will help to improve the health of all populations.
159 citations
TL;DR: Among patients undergoing elective CABG, anesthesia with a volatile agent did not result in significantly fewer deaths at 1 year than total intravenous anesthesia, and the trial was stopped for futility.
Abstract: Background Volatile (inhaled) anesthetic agents have cardioprotective effects, which might improve clinical outcomes in patients undergoing coronary-artery bypass grafting (CABG). Methods ...
143 citations
Paris Descartes University1, Ghent University Hospital2, University of Florence3, Rambam Health Care Campus4, University of Bari5, I.M. Sechenov First Moscow State Medical University6, Seconda Università degli Studi di Napoli7, Katholieke Universiteit Leuven8, university of lille9, Dresden University of Technology10, Russian Academy11, Hospital General Universitario Gregorio Marañón12, University of Erlangen-Nuremberg13, University of Cologne14, Sapienza University of Rome15, Rutgers University16, Carol Davila University of Medicine and Pharmacy17, Nippon Medical School18, Tulane University19, Lund University20, University of Verona21
TL;DR: Rituximab use was associated with a good safety profile in this large SSc-cohort and significant change was observed on skin fibrosis, but not on lung, but the limitation is the observational design.
Abstract: Objective To assess the safety and efficacy of rituximab in systemic sclerosis (SSc) in clinical practice. Methods We performed a prospective study including patients with SSc from the European Scleroderma Trials and Research (EUSTAR) network treated with rituximab and matched with untreated patients with SSc. The main outcomes measures were adverse events, skin fibrosis improvement, lung fibrosis worsening and steroids use among propensity score-matched patients treated or not with rituximab. Results 254 patients were treated with rituximab, in 58% for lung and in 32% for skin involvement. After a median follow-up of 2 years, about 70% of the patients had no side effect. Comparison of treated patients with 9575 propensity-score matched patients showed that patients treated with rituximab were more likely to have skin fibrosis improvement (22.7 vs 14.03 events per 100 person-years; OR: 2.79 [1.47–5.32]; p=0.002). Treated patients did not have significantly different rates of decrease in forced vital capacity (FVC)>10% (OR: 1.03 [0.55–1.94]; p=0.93) nor in carbon monoxide diffusing capacity (DLCO) decrease. Patients having received rituximab were more prone to stop or decrease steroids (OR: 2.34 [1.56–3.53], p Conclusion Rituximab use was associated with a good safety profile in this large SSc-cohort. Significant change was observed on skin fibrosis, but not on lung. However, the limitation is the observational design. The potential stabilisation of lung fibrosis by rituximab has to be addressed by a randomised trial.
TL;DR: It is demonstrated that, in mice, longitudinal bone growth during fetal and neonatal periods relies on the gradual consumption of chondroprogenitors, whereas in adults, a stem cell niche is formed allowing renewing ofChondro Progenitors and leading to formation of large, stable monoclonal columns of chONDrocytes.
Abstract: Longitudinal bone growth in children is sustained by growth plates, narrow discs of cartilage that provide a continuous supply of chondrocytes for endochondral ossification1. However, it remains unknown how this supply is maintained throughout childhood growth. Chondroprogenitors in the resting zone are thought to be gradually consumed as they supply cells for longitudinal growth1,2, but this model has never been proved. Here, using clonal genetic tracing with multicolour reporters and functional perturbations, we demonstrate that longitudinal growth during the fetal and neonatal periods involves depletion of chondroprogenitors, whereas later in life, coinciding with the formation of the secondary ossification centre, chondroprogenitors acquire the capacity for self-renewal, resulting in the formation of large, stable monoclonal columns of chondrocytes. Simultaneously, chondroprogenitors begin to express stem cell markers and undergo symmetric cell division. Regulation of the pool of self-renewing progenitors involves the hedgehog and mammalian target of rapamycin complex 1 (mTORC1) signalling pathways. Our findings indicate that a stem cell niche develops postnatally in the epiphyseal growth plate, which provides a continuous supply of chondrocytes over a prolonged period. Clonal genetic tracing is used to demonstrate that, in mice, longitudinal bone growth during fetal and neonatal periods relies on the gradual consumption of chondroprogenitors, whereas in adults, a stem cell niche is formed allowing renewing of chondroprogenitors and leading to formation of large, stable monoclonal columns of chondrocytes.
French Institute of Health and Medical Research1, University College London2, University of Paris-Sud3, I.M. Sechenov First Moscow State Medical University4, University of Erlangen-Nuremberg5, Salford Royal NHS Foundation Trust6, Turku University Hospital7, Charles University in Prague8, University of Zurich9, University of Porto10, Universidade Nova de Lisboa11, University of Würzburg12, University of Turin13
TL;DR: A comprehensive systematic literature review of all original articles on Enzyme Replacement Therapy (ERT) in the treatment of Fabry disease published up until January 2017 is presented in adult male patients.
Abstract: Background Enzyme replacement therapy (ERT) with recombinant human α-galactosidase has been available for the treatment of Fabry disease since 2001 in Europe and 2003 in the USA. Treatment outcomes with ERT are dependent on baseline patient characteristics, and published data are derived from heterogeneous study populations. Methods We conducted a comprehensive systematic literature review of all original articles on ERT in the treatment of Fabry disease published up until January 2017. This article presents the findings in adult male patients. Results Clinical evidence for the efficacy of ERT in adult male patients was available from 166 publications including 36 clinical trial publications. ERT significantly decreases globotriaosylceramide levels in plasma, urine, and in different kidney, heart, and skin cell types, slows the decline in estimated glomerular filtration rate, and reduces/stabilizes left ventricular mass and cardiac wall thickness. ERT also improves nervous system, gastrointestinal, pain, and quality of life outcomes. Conclusions ERT is a disease-specific treatment for patients with Fabry disease that may provide clinical benefits on several outcomes and organ systems. Better outcomes may be observed when treatment is started at an early age prior to the development of organ damage such as chronic kidney disease or cardiac fibrosis. Consolidated evidence suggests a dose effect. Data described in male patients, together with female and paediatric data, informs clinical practice and therapeutic goals for individualized treatment.
TL;DR: This in vitro study assesses the accuracy of 5 different IOSs in the impressions of single and multiple implants, and finds a significant difference in trueness was found between the contexts.
Abstract: Until now, a few studies have addressed the accuracy of intraoral scanners (IOSs) in implantology. Hence, the aim of this in vitro study was to assess the accuracy of 5 different IOSs in the impressions of single and multiple implants, and to compare them. Plaster models were prepared, representative of a partially edentulous maxilla (PEM) to be restored with a single crown (SC) and a partial prosthesis (PP), and a totally edentulous maxilla (TEM) to be restored with a full-arch (FA). These models were scanned with a desktop scanner, to capture reference models (RMs), and with 5 IOSs (CS 3600®, Trios3®, Omnicam®, DWIO®, Emerald®); 10 scans were taken for each model, using each IOS. All IOS datasets were loaded into a reverse-engineering software where they were superimposed on the corresponding RMs, to evaluate trueness, and superimposed on each other within groups, to determine precision. A statistical analysis was performed. In the SC, CS 3600® had the best trueness (15.2 ± 0.8 μm), followed by Trios3® (22.3 ± 0.5 μm), DWIO® (27.8 ± 3.2 μm), Omnicam® (28.4 ± 4.5 μm), Emerald® (43.1 ± 11.5 μm). In the PP, CS 3600® had the best trueness (23 ± 1.1 μm), followed by Trios3® (28.5 ± 0.5 μm), Omnicam® (38.1 ± 8.8 μm), Emerald® (49.3 ± 5.5 μm), DWIO® (49.8 ± 5 μm). In the FA, CS 3600® had the best trueness (44.9 ± 8.9 μm), followed by Trios3® (46.3 ± 4.9 μm), Emerald® (66.3 ± 5.6 μm), Omnicam® (70.4 ± 11.9 μm), DWIO® (92.1 ± 24.1 μm). Significant differences were found between the IOSs; a significant difference in trueness was found between the contexts (SC vs. PP vs. FA). In the SC, CS 3600® had the best precision (11.3 ± 1.1 μm), followed by Trios3® (15.2 ± 0.8 μm), DWIO® (27.1 ± 10.7 μm), Omnicam® (30.6 ± 3.3 μm), Emerald® (32.8 ± 10.7 μm). In the PP, CS 3600® had the best precision (17 ± 2.3 μm), followed by Trios3® (21 ± 1.9 μm), Emerald® (29.9 ± 8.9 μm), DWIO® (34.8 ± 10.8 μm), Omnicam® (43.2 ± 9.4 μm). In the FA, Trios3® had the best precision (35.6 ± 3.4 μm), followed by CS 3600® (35.7 ± 4.3 μm), Emerald® (61.5 ± 18.1 μm), Omnicam® (89.3 ± 14 μm), DWIO® (111 ± 24.8 μm). Significant differences were found between the IOSs; a significant difference in precision was found between the contexts (SC vs. PP vs. FA). The IOSs showed significant differences between them, both in trueness and in precision. The mathematical error increased in the transition from SC to PP up to FA, both in trueness than in precision.
TL;DR: It is found that the pre-established IFN status of the cell, instead of LPS-induced IFN, is critical for the early initiation of necroptosis in macrophages, providing a link between pathological IFN and tissue damage during autoimmunity.
Abstract: Interferons (IFNs) are critical determinants in immune-competence and autoimmunity, and are endogenously regulated by a low-level constitutive feedback loop. However, little is known about the functions and origins of constitutive IFN. Recently, lipopolysaccharide (LPS)-induced IFN was implicated as a driver of necroptosis, a necrotic form of cell death downstream of receptor-interacting protein (RIP) kinase activation and executed by mixed lineage kinase like-domain (MLKL) protein. We found that the pre-established IFN status of the cell, instead of LPS-induced IFN, is critical for the early initiation of necroptosis in macrophages. This pre-established IFN signature stems from cytosolic DNA sensing via cGAS/STING, and maintains the expression of MLKL and one or more unknown effectors above a critical threshold to allow for MLKL oligomerization and cell death. Finally, we found that elevated IFN-signaling in systemic lupus erythematosus (SLE) augments necroptosis, providing a link between pathological IFN and tissue damage during autoimmunity.
TL;DR: The present review focuses on major physiological gastro-intestinal tract challenges involved in altering the pharmacokinetics of delivery systems, pathophysiology of MH and fibrosis, reported drug-polysaccharide cargos and focusing on conventional to advanced disease responsive delivery strategies, highlighting their limitations and future perspectives in intestinal inflammation therapy.
Radboud University Nijmegen1, Medical University of Vienna2, Harvard University3, University of Amsterdam4, Charité5, University of Manchester6, University of Birmingham7, University Hospitals Birmingham NHS Foundation Trust8, University of Aberdeen9, Autonomous University of Barcelona10, Queen Mary University of London11, University of Barcelona12, I.M. Sechenov First Moscow State Medical University13, Erasmus University Rotterdam14, Paris Descartes University15, Huntsman Cancer Institute16, National and Kapodistrian University of Athens17, University of British Columbia18, Memorial Sloan Kettering Cancer Center19, University of Grenoble20, Erasmus University Medical Center21, Institut Gustave Roussy22, Università telematica San Raffaele23, University of Regensburg24, Humanitas University25, University of Paris26, University of Southampton27, University Hospital of Lausanne28, Utrecht University29, Ghent University Hospital30, Aberdeen Royal Infirmary31, University of Bologna32, Monash University, Clayton campus33, The Royal Marsden NHS Foundation Trust34, University of California, San Diego35, University of Erlangen-Nuremberg36, University of Western Australia37, University of Leeds38, University of Milan39, University of Glasgow40, University of Texas MD Anderson Cancer Center41, University of Oxford42, University Medical Center Groningen43, Copenhagen University Hospital44, University of Zurich45, Université Paris-Saclay46, Royal Surrey County Hospital47, University of Tübingen48, Akershus University Hospital49, Leiden University Medical Center50, University of Minho51, University of Sydney52, Technische Universität München53, Brighton and Sussex Medical School54, University of Hamburg55, Ruhr University Bochum56, Cornell University57, University of Lyon58, Monash University59, Umeå University60, University of Bern61, Cliniques Universitaires Saint-Luc62, Katholieke Universiteit Leuven63, University of Medicine, Pharmacy, Science and Technology of Târgu Mureș64, Metropolitan University65, Mount Sinai Health System66, Auckland City Hospital67, University of Graz68, Institute of Cancer Research69
TL;DR: A steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey as mentioned in this paper, and 22 of 27 (81%) statements achieved consensus.
TL;DR: Compared to standard approaches where curves are fitted to protein solubility data acquired at different temperatures and drug concentrations, Proteome Integral Solubility Alteration (PISA) assay increases the analysis throughput by one to two orders of magnitude for unlimited number of factor variation points in such a scheme.
Abstract: Various agents, including drugs as well as nonmolecular stimuli, induce alterations in the physicochemical properties of proteins in cell lysates, living cells, and organisms. These alterations can be probed by applying a stability- and solubility-modifying factor, such as elevated temperature, to a varying degree. As a second dimension of variation, drug concentration or agent intensity/concentration can be used. Compared to standard approaches where curves are fitted to protein solubility data acquired at different temperatures and drug concentrations, Proteome Integral Solubility Alteration (PISA) assay increases the analysis throughput by 1 to 2 orders of magnitude for an unlimited number of factor variation points in such a scheme. The consumption of the compound and biological material decreases in PISA by the same factor. We envision widespread use of the PISA approach in chemical biology and drug development.
Ohio State University1, Beth Israel Deaconess Medical Center2, I.M. Sechenov First Moscow State Medical University3, Medical University of Vienna4, University of Milan5, University of Belgrade6, Cardiff University7, Cleveland Clinic8, Ottawa Hospital Research Institute9, Paris Descartes University10
TL;DR: This work presents a meta-analyses of Hematology and Hemostasis and Thrombosis at the cellular and molecular level, which shows clear trends in prognosis and in particular in the cases of high-risk patients with known blood clotting disorders.
TL;DR: From this study, the current field of use of Digital Smile Design techniques in the various branches of medicine and dentistry have emerged, as well as information about its reliability.
Abstract: Breakthroughs in technology have not been possible without influencing the medical sciences. Dentistry and dental materials have been fully involved in the technological and information technology evolution, so much so that they have revolutionized dental techniques. In this study, we want to create the first collection of articles on the use of digital techniques and software, such as Digital Smile Design. The aim is to collect all of the results regarding the use of this software, and to highlight the fields of use. Twenty-four articles have been included in the review, and the latter describes the use of Digital Smile Design and, in particular, the field of use. The study intends to be present which dental fields use “digitization”. Progress in this field is constant, and will be of increasing interest to dentistry by proposing a speed of treatment planning and a reliability of results. The digital workflow allows for rehabilitations that are reliable both from an aesthetic and functional point of view, as demonstrated in the review. From this study, the current field of use of Digital Smile Design techniques in the various branches of medicine and dentistry have emerged, as well as information about its reliability.
Peking Union Medical College1, Xiamen University2, China Medical University (Taiwan)3, Fujian Medical University4, Sungkyunkwan University5, I.M. Sechenov First Moscow State Medical University6, Central University of Venezuela7, Shandong University8, Henan University9, İnönü University10, Korea University11, Queen Alexandra Hospital12, Taipei Medical University Hospital13, Osaka Medical College14, Tata Memorial Hospital15, Cairo University16, Zhengzhou University17, Jilin University18, Nagoya University19, Harbin Medical University20, Fudan University21, Central South University22, Binzhou Medical College23, Zhejiang University24, Kyung Hee University25, Tongji University26
TL;DR: After three rounds of discussion by all members of the International Alliance of NOSES, the consensus is finally completed and it is urgent and necessary to reach a consensus as an industry guideline to standardize the implementation of NosES in colorectal surgery.
Abstract: In recent years, natural orifice specimen extraction surgery (NOSES) in the treatment of colorectal cancer has attracted widespread attention. The potential benefits of NOSES including reduction in postoperative pain and wound complications, less use of postoperative analgesic, faster recovery of bowel function, shorter length of hospital stay, better cosmetic and psychological effect have been described in colorectal surgery. Despite significant decrease in surgical trauma of NOSES have been observed, the potential pitfalls of this technique have been demonstrated. Particularly, several issues including bacteriological concerns, oncological outcomes and patient selection are raised with this new technique. Therefore, it is urgent and necessary to reach a consensus as an industry guideline to standardize the implementation of NOSES in colorectal surgery. After three rounds of discussion by all members of the International Alliance of NOSES, the consensus is finally completed, which is also of great significance to the long-term progress of NOSES worldwide.
TL;DR: This review focuses on the role of multiple epigenetic factors in the pathogenesis and progression of the disease, not only in synovial fibroblasts, immune cells, but also in the peripheral blood of patients with RA, which clearly shows their high diagnostic potential and promising targets for therapy in the future.
Abstract: Rheumatoid arthritis (RA) is a systemic autoimmune disease that affects about 1% of the world's population. The etiology of RA remains unknown. It is considered to occur in the presence of genetic and environmental factors. An increasing body of evidence pinpoints that epigenetic modifications play an important role in the regulation of RA pathogenesis. Epigenetics causes heritable phenotype changes that are not determined by changes in the DNA sequence. The major epigenetic mechanisms include DNA methylation, histone proteins modifications and changes in gene expression caused by microRNAs and other non-coding RNAs. These modifications are reversible and could be modulated by diet, drugs, and other environmental factors. Specific changes in DNA methylation, histone modifications and abnormal expression of non-coding RNAs associated with RA have already been identified. This review focuses on the role of these multiple epigenetic factors in the pathogenesis and progression of the disease, not only in synovial fibroblasts, immune cells, but also in the peripheral blood of patients with RA, which clearly shows their high diagnostic potential and promising targets for therapy in the future.
TL;DR: Aβ has now been established as anti-microbial peptide capable of inducing pore formation, thus justifying their infection-mediated accumulation, and a proper combination of anti-inflammatory, anti-viral, and antibiotic therapeutics might potentially prevent the progression of AD.
Abstract: Over the past three decades, there has been constant postulation regarding the infectious etiology of Alzheimer disease (AD), which in turn suggests the vital role of various infectious agents in AD-associated inflammatory pathways. Recent findings indicate anti-microbial properties of Aβ, and suggest that Aβ production and deposition in AD might be induced by infectious agents. Several types of spirochetes have been associated to dementia, cortical atrophy, and pathological and biological hallmarks of AD. A significant association between AD spirochetes and other pathogens like HSV-1 and Chlamydia pneumonia has now become well established. In neurons infected by HSV-1 showed Aβ and hyperphosphorylated Tau accumulation. The expression of pro-inflammatory molecules have been found to be enhanced by specific bacterial ligands, and viral and bacterial DNA and RNA, thus activating the immune system. Aβ has now been established as anti-microbial peptide capable of inducing pore formation, thus justifying their infection-mediated accumulation. Thus, a proper combination of anti-inflammatory, anti-viral, and antibiotic therapeutics might potentially prevent the progression of AD. Here, we discussed the potential role of bacterial, fungi, and viral infections in AD causation and progression, and the potential-associated therapies to counter the AD condition.
TL;DR: The different compositions in terms of macronutrient and micronutrients of milk from different mammalian species are reviewed, including special milk formulas indicated for cow’s milk allergy, and of plant-based milk alternatives.
Abstract: Cow’s milk and dairy are commonly consumed foods in the human diet and contribute to maintaining a healthy nutritional state, providing unique sources of energy, calcium, protein, and vitamins, especially during early childhood. Milk formula is usually made from cow’s milk and represents the first food introduced into an infant’s diet when breastfeeding is either not possible or insufficient to cover nutritional needs. Very recently, increased awareness of cow’s milk protein allergy and intolerance, and higher preference to vegan dietary habits have influenced parents towards frequently choosing cows’ milk substitutes for children, comprising other mammalian milk types and plant-based milk beverages. However, many of these milk alternatives do not necessarily address the nutritional requirements of infants and children. There is a strong need to promote awareness about qualitative and quantitative nutritional compositions of different milk formulas, in order to guide parents and medical providers selecting the best option for children. In this article, we sought to review the different compositions in terms of macronutrients and micronutrients of milk from different mammalian species, including special milk formulas indicated for cow’s milk allergy, and of plant-based milk alternatives.
TL;DR: The role of Cathepsin B in the oncogenic process and perspective the use of Cat hepsins B for diagnostic and therapeutic applications are discussed.
TL;DR: Procoagulant activity of MSCs/EVs associated with the presence of phosphatidylserine and tissue factor is revealed, which requires further analysis to avoid adverse effects of M SC therapy in patients with a risk of thrombosis.
Abstract: Mesenchymal stem cells (MSCs) have emerged as a potent therapeutic tool for the treatment of a number of pathologies, including immune pathologies. However, unwelcome effects of MSCs on blood coagulation have been reported, motivating us to explore the thrombotic properties of human MSCs from the umbilical cord. We revealed strong procoagulant effects of MSCs on human blood and platelet-free plasma using rotational thromboelastometry and thrombodynamic tests. A similar potentiation of clotting was demonstrated for MSC-derived extracellular vesicles (EVs). To offer approaches to avoid unwanted effects, we studied the impact of a heparin supplement on MSC procoagulative properties. However, MSCs still retained procoagulant activity toward blood from children receiving a therapeutic dose of unfractionated heparin. An analysis of the mechanisms responsible for the procoagulant effect of MSCs/EVs revealed the presence of tissue factor and other proteins involved in coagulation-associated pathways. Also, we found that some MSCs and EVs were positive for annexin V, which implies the presence of phosphatidylserine on their surfaces, which can potentiate clot formation. Thus, we revealed procoagulant activity of MSCs/EVs associated with the presence of phosphatidylserine and tissue factor, which requires further analysis to avoid adverse effects of MSC therapy in patients with a risk of thrombosis.
TL;DR: In this article, the authors reported the experimental observation of a near-field curved light generated at the output of a dielectric cuboid, featuring a broken symmetry and dimensions comparable to the electromagnetic (EM) wavelength.
Abstract: In this letter, we reported the experimental observation of a photonic hook (PH)—a type of near-field curved light generated at the output of a dielectric cuboid, featuring a broken symmetry and dimensions comparable to the electromagnetic (EM) wavelength. Given that the specific value of the wavelength is not critical once the mesoscale conditions for the particle are met, we verified these predictions experimentally using a 0.25 THz continuous-wave source. The radius of curvature associated with the PH-generated is smaller than the wavelength, while its minimum beam-waist is about 0.44λ. This represents the smallest radius of curvature ever recorded for any EM beam. The observed phenomenon is of potential interest in optics and photonics, particularly, in super-resolution microscopy, manipulation of particles and liquids, photolithography, and material processing. Finally, it has a universal character and should be inherent to acoustic and surface waves, electrons, neutrons, protons, and other beams interacting with asymmetric mesoscale obstacles.
TL;DR: It is shown that palmitoylation of 5-HT1AR by thePalmitoyltransferase enzyme ZDHHC21 contributes to depression-like behaviour in rodents and might be implicated in major depressive disorder.
Abstract: The serotonergic system and in particular serotonin 1A receptor (5-HT1AR) are implicated in major depressive disorder (MDD). Here we demonstrated that 5-HT1AR is palmitoylated in human and rodent brains, and identified ZDHHC21 as a major palmitoyl acyltransferase, whose depletion reduced palmitoylation and consequently signaling functions of 5-HT1AR. Two rodent models for depression-like behavior show reduced brain ZDHHC21 expression and attenuated 5-HT1AR palmitoylation. Moreover, selective knock-down of ZDHHC21 in the murine forebrain induced depression-like behavior. We also identified the microRNA miR-30e as a negative regulator of Zdhhc21 expression. Through analysis of the post-mortem brain samples in individuals with MDD that died by suicide we find that miR-30e expression is increased, while ZDHHC21 expression, as well as palmitoylation of 5-HT1AR, are reduced within the prefrontal cortex. Our study suggests that downregulation of 5-HT1AR palmitoylation is a mechanism involved in depression, making the restoration of 5-HT1AR palmitoylation a promising clinical strategy for the treatment of MDD. Palmitoylation is a post translational modification that regulates GPCR activity. Here the authors show that palmitoylation of 5-HT1AR by the palmitoyltransferase enzyme ZDHHC21 contributes to depression-like behaviour in rodents and might be implicated in major depressive disorder.
TL;DR: To evaluate the safety and efficacy of belimumab as adjunctive therapy to maintain remission in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV).
Abstract: Objective To evaluate the safety and efficacy of belimumab as adjunctive therapy to maintain remission in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Methods In this multicenter, double-blind, placebo-controlled study, patients with AAV (ages ≥18 years) were randomized 1:1 to receive azathioprine (2 mg/kg/day), low-dose oral glucocorticoids (≤10 mg/day), and either intravenous belimumab (10 mg/kg) or placebo, following remission induction with rituximab or cyclophosphamide along with glucocorticoids. The primary end point was time to first protocol-specified event (PSE), with first PSE defined as a Birmingham Vasculitis Activity Score (BVAS) of ≥6, presence of ≥1 major BVAS item, or receipt of prohibited medications for any reason, resulting in treatment failure (adjusted for ANCA type [proteinase 3 (PR3) or myeloperoxidase (MPO)], disease stage at induction, and induction regimen). Vasculitis relapse was defined as the PSE of either a BVAS activity score of ≥6 or receipt of prohibited medications for vasculitis. Changes in treatment practice led to truncation of the study population from ~300 patients to ~100 patients. Results The intent-to-treat population totaled 105 patients with AAV, of whom 52 (40 with PR3-ANCAs, 12 with MPO-ANCAs) received placebo and 53 (41 with PR3-ANCAs, 12 with MPO-ANCAs) received belimumab; 27 of the patients were in rituximab-induced disease remission, while 78 were in cyclophosphamide-induced disease remission at baseline. Compared with placebo, treatment with belimumab did not reduce the risk of a PSE (adjusted hazard ratio [HR] 1.07, 95% confidence interval [95% CI] 0.44-2.59; P = 0.884) or vasculitis relapse (adjusted HR 0.88, 95% CI 0.29-2.65; P = 0.821). The overall rate of PSEs was low (11 [21.2%] of 52 patients receiving placebo, 10 [18.9%] of 53 patients receiving belimumab). Vasculitis relapse in the placebo group (n = 8) occurred independent of the induction regimen, disease stage, or ANCA type. All vasculitis relapses in the belimumab group (n = 6) occurred in patients who had PR3-ANCA-associated vasculitis with cyclophosphamide-induced disease remission. Adverse events occurred in 49 (92.5%) of 53 patients receiving belimumab and 43 (82.7%) of 52 patients receiving placebo, with no new safety concerns. Conclusion Belimumab plus azathioprine and glucocorticoids for the maintenance of remission in AAV did not reduce the risk of relapse.
TL;DR: The role of E-cadherin and the non-coding RNAs-mediated mechanisms of its expressional control in the EMT during stomach carcinogenesis are focused on.
Abstract: The epithelial–mesenchymal transition (EMT) is thought to be at the root of invasive and metastatic cancer cell spreading. E-cadherin is an important player in this process, which forms the structures that establish and maintain cell–cell interactions. A partial or complete loss of E-cadherin expression in the EMT is presumably mediated by mechanisms that block the expression of E-cadherin regulators and involve the E-cadherin-associated transcription factors. The protein is involved in several oncogenic signaling pathways, such as the Wnt/β-catenin, Rho GTPase, and EGF/EGFR, whereby it plays a role in many tumors, including gastric cancer. Such noncoding transcripts as microRNAs and long noncoding RNAs—critical components of epigenetic control of gene expression in carcinogenesis—contribute to regulation of the E-cadherin function by acting directly or through numerous factors controlling transcription of its gene, and thus affecting not only cancer cell proliferation and metastasis, but also the EMT. This review focuses on the role of E-cadherin and the non-coding RNAs-mediated mechanisms of its expressional control in the EMT during stomach carcinogenesis.