Showing papers by "University of Texas Health Science Center at San Antonio published in 2018"
Lorenzo Galluzzi1, Lorenzo Galluzzi2, Ilio Vitale3, Stuart A. Aaronson4 +183 more•Institutions (111)
TL;DR: The Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives.
Abstract: Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.
3,301 citations
TL;DR: A diagnostic tool based on a deep-learning framework for the screening of patients with common treatable blinding retinal diseases, which demonstrates performance comparable to that of human experts in classifying age-related macular degeneration and diabetic macular edema.
2,750 citations
TL;DR: It is demonstrated that transplanting relatively small numbers of senescent cells into young mice is sufficient to cause persistent physical dysfunction, as well as to spread cellular senescence to host tissues, and a senolytic can reverse this dysfunction and potently increase lifespan in aged mice.
Abstract: Physical function declines in old age, portending disability, increased health expenditures, and mortality. Cellular senescence, leading to tissue dysfunction, may contribute to these consequences of aging, but whether senescence can directly drive age-related pathology and be therapeutically targeted is still unclear. Here we demonstrate that transplanting relatively small numbers of senescent cells into young mice is sufficient to cause persistent physical dysfunction, as well as to spread cellular senescence to host tissues. Transplanting even fewer senescent cells had the same effect in older recipients and was accompanied by reduced survival, indicating the potency of senescent cells in shortening health- and lifespan. The senolytic cocktail, dasatinib plus quercetin, which causes selective elimination of senescent cells, decreased the number of naturally occurring senescent cells and their secretion of frailty-related proinflammatory cytokines in explants of human adipose tissue. Moreover, intermittent oral administration of senolytics to both senescent cell–transplanted young mice and naturally aged mice alleviated physical dysfunction and increased post-treatment survival by 36% while reducing mortality hazard to 65%. Our study provides proof-of-concept evidence that senescent cells can cause physical dysfunction and decreased survival even in young mice, while senolytics can enhance remaining health- and lifespan in old mice.
1,201 citations
University of Rochester1, University of California, San Francisco2, University of Gothenburg3, University of Birmingham4, University of Bonn5, University of Michigan6, University of Texas Health Science Center at San Antonio7, Columbia University8, Complutense University of Madrid9, University of Hong Kong10
TL;DR: An overview for the new classification of periodontal and peri-implant diseases and conditions is presented, along with a condensed scheme for each of four workgroup sections, but readers are directed to the pertinent consensus reports and review papers for a thorough discussion of the rationale, criteria, and interpretation of the proposed classification.
Abstract: A classification scheme for periodontal and peri-implant diseases and conditions is necessary for clinicians to properly diagnose and treat patients as well as for scientists to investigate etiology, pathogenesis, natural history, and treatment of the diseases and conditions. This paper summarizes the proceedings of the World Workshop on the Classification of Periodontal and Peri-implant Diseases and Conditions. The workshop was co-sponsored by the American Academy of Periodontology (AAP) and the European Federation of Periodontology (EFP) and included expert participants from all over the world. Planning for the conference, which was held in Chicago on November 9 to 11, 2017, began in early 2015. An organizing committee from the AAP and EFP commissioned 19 review papers and four consensus reports covering relevant areas in periodontology and implant dentistry. The authors were charged with updating the 1999 classification of periodontal diseases and conditions and developing a similar scheme for peri-implant diseases and conditions. Reviewers and workgroups were also asked to establish pertinent case definitions and to provide diagnostic criteria to aid clinicians in the use of the new classification. All findings and recommendations of the workshop were agreed to by consensus. This introductory paper presents an overview for the new classification of periodontal and peri-implant diseases and conditions, along with a condensed scheme for each of four workgroup sections, but readers are directed to the pertinent consensus reports and review papers for a thorough discussion of the rationale, criteria, and interpretation of the proposed classification. Changes to the 1999 classification are highlighted and discussed. Although the intent of the workshop was to base classification on the strongest available scientific evidence, lower level evidence and expert opinion were inevitably used whenever sufficient research data were unavailable. The scope of this workshop was to align and update the classification scheme to the current understanding of periodontal and peri-implant diseases and conditions. This introductory overview presents the schematic tables for the new classification of periodontal and peri-implant diseases and conditions and briefly highlights changes made to the 1999 classification. It cannot present the wealth of information included in the reviews, case definition papers, and consensus reports that has guided the development of the new classification, and reference to the consensus and case definition papers is necessary to provide a thorough understanding of its use for either case management or scientific investigation. Therefore, it is strongly recommended that the reader use this overview as an introduction to these subjects. Accessing this publication online will allow the reader to use the links in this overview and the tables to view the source papers (Table 1).
1,066 citations
University of Gothenburg1, University of California, San Francisco2, Universidade Estadual de Maringá3, University of Iowa4, University of California, Los Angeles5, University of Melbourne6, University of Texas Health Science Center at San Antonio7, Complutense University of Madrid8, University of Zurich9, University of Sydney10, Stony Brook University11, Seoul National University12, University of Michigan13, Katholieke Universiteit Leuven14, Kristianstad University College15, University of Bern16, Goethe University Frankfurt17, Columbia University18, University of Basel19
TL;DR: Case definitions in day-to-day clinical practice and in epidemiological or disease-surveillance studies for peri-implant health, peri"-implant mucositis, and peri'simplantitis were introduced.
Abstract: A classification for peri-implant diseases and conditions was presented. Focused questions on the characteristics of peri-implant health, peri-implant mucositis, peri-implantitis, and soft- and hard-tissue deficiencies were addressed. Peri-implant health is characterized by the absence of erythema, bleeding on probing, swelling, and suppuration. It is not possible to define a range of probing depths compatible with health; Peri-implant health can exist around implants with reduced bone support. The main clinical characteristic of peri-implant mucositis is bleeding on gentle probing. Erythema, swelling, and/or suppuration may also be present. An increase in probing depth is often observed in the presence of peri-implant mucositis due to swelling or decrease in probing resistance. There is strong evidence from animal and human experimental studies that plaque is the etiological factor for peri-implant mucositis. Peri-implantitis is a plaque-associated pathological condition occurring in tissues around dental implants, characterized by inflammation in the peri-implant mucosa and subsequent progressive loss of supporting bone. Peri-implantitis sites exhibit clinical signs of inflammation, bleeding on probing, and/or suppuration, increased probing depths and/or recession of the mucosal margin in addition to radiographic bone loss. The evidence is equivocal regarding the effect of keratinized mucosa on the long-term health of the peri-implant tissue. It appears, however, that keratinized mucosa may have advantages regarding patient comfort and ease of plaque removal. Case definitions in day-to-day clinical practice and in epidemiological or disease-surveillance studies for peri-implant health, peri-implant mucositis, and peri-implantitis were introduced. The proposed case definitions should be viewed within the context that there is no generic implant and that there are numerous implant designs with different surface characteristics, surgical and loading protocols. It is recommended that the clinician obtain baseline radiographic and probing measurements following the completion of the implant-supported prosthesis.
767 citations
TL;DR: Current data on the structural and functional properties of CD44, the known roles for CD44 in tumorigencity, the regulation ofCD44 expression, and the potential for targeting CD44 for cancer therapy are reviewed.
Abstract: CD44, a non-kinase transmembrane glycoprotein, is overexpressed in several cell types including cancer stem cells and frequently shows alternative spliced variants that are thought to play a role in cancer development and progression. Hyaluronan, the main ligand for CD44, binds to and activates CD44 resulting in activation of cell signaling pathways that induces cell proliferation, increases cell survival, modulates cytoskeletal changes, and enhances cellular motility. The different functional roles of CD44 standard (CD44s) and specific CD44 variant (CD44v) isoforms are not fully understood. CD44v contain additional peptide motifs that can interact with and sequester growth factors and cytokines at the cell surface thereby functioning as coreceptors to facilitate cell signaling. Moreover, CD44v were expressed in metastasized tumors, whereas switching between CD44v and CD44s may play a role in regulating epithelial to mesenchymal transition (EMT) and in the adaptive plasticity of cancer cells. Here, we review current data on the structural and functional properties of CD44, the known roles for CD44 in tumorigencity, the regulation of CD44 expression, and the potential for targeting CD44 for cancer therapy.
707 citations
TL;DR: With mental illness a growing concern within graduate education, data from a new survey should prompt both academia and policy makers to consider intervention strategies.
Abstract: With mental illness a growing concern within graduate education, data from a new survey should prompt both academia and policy makers to consider intervention strategies.
659 citations
University of Birmingham1, University of Texas Health Science Center at San Antonio2, The Forsyth Institute3, University of Adelaide4, Charité5, Goethe University Frankfurt6, University of Alabama at Birmingham7, University at Buffalo8, University of Toronto9, Hadassah Medical Center10, Tufts University11, University of Copenhagen12, University of Iowa13, University of California, San Francisco14, University of Bern15, University of Giessen16, Osaka University17, Texas A&M University18, University of São Paulo19, Ohio State University20, Katholieke Universiteit Leuven21, University of Ferrara22, University of Basel23, University of Graz24, Niigata University25
TL;DR: While gingival health and gingivitis have many clinical features, case definitions are primarily predicated on presence or absence of bleeding on probing, which creates differences in the way in which a "case" of gedival health or gingIVitis is defined for clinical practice as opposed to epidemiologically in population prevalence surveys.
Abstract: Periodontal health is defined by absence of clinically detectable inflammation. There is a biological level of immune surveillance that is consistent with clinical gingival health and homeostasis. Clinical gingival health may be found in a periodontium that is intact, i.e. without clinical attachment loss or bone loss, and on a reduced periodontium in either a non-periodontitis patient (e.g. in patients with some form of gingival recession or following crown lengthening surgery) or in a patient with a history of periodontitis who is currently periodontally stable. Clinical gingival health can be restored following treatment of gingivitis and periodontitis. However, the treated and stable periodontitis patient with current gingival health remains at increased risk of recurrent periodontitis, and accordingly, must be closely monitored. Two broad categories of gingival diseases include non-dental plaque biofilm-induced gingival diseases and dental plaque-induced gingivitis. Non-dental plaque biofilm-induced gingival diseases include a variety of conditions that are not caused by plaque and usually do not resolve following plaque removal. Such lesions may be manifestations of a systemic condition or may be localized to the oral cavity. Dental plaque-induced gingivitis has a variety of clinical signs and symptoms, and both local predisposing factors and systemic modifying factors can affect its extent, severity, and progression. Dental plaque-induced gingivitis may arise on an intact periodontium or on a reduced periodontium in either a non-periodontitis patient or in a currently stable "periodontitis patient" i.e. successfully treated, in whom clinical inflammation has been eliminated (or substantially reduced). A periodontitis patient with gingival inflammation remains a periodontitis patient (Figure 1), and comprehensive risk assessment and management are imperative to ensure early prevention and/or treatment of recurrent/progressive periodontitis. Precision dental medicine defines a patient-centered approach to care, and therefore, creates differences in the way in which a "case" of gingival health or gingivitis is defined for clinical practice as opposed to epidemiologically in population prevalence surveys. Thus, case definitions of gingival health and gingivitis are presented for both purposes. While gingival health and gingivitis have many clinical features, case definitions are primarily predicated on presence or absence of bleeding on probing. Here we classify gingival health and gingival diseases/conditions, along with a summary table of diagnostic features for defining health and gingivitis in various clinical situations.
573 citations
University of Düsseldorf1, Florida International University2, University of Texas Health Science Center at San Antonio3, King's College London4, Karolinska Institutet5, University of Nottingham6, University of Texas at Austin7, University of Warwick8, MedStar National Rehabilitation Hospital9, University of Colorado Boulder10
TL;DR: Specific guidelines and a checklist are provided that will hopefully improve the transparency, traceability, replicability and reporting of meta‐analytical results of neuroimaging data.
481 citations
University of Miami1, Mayo Clinic2, University of North Carolina at Chapel Hill3, University of Texas Health Science Center at San Antonio4, University of Michigan5, University of Minnesota6, Department of Urology, University of Virginia7, University of Chicago8, Ohio State University9, Vanderbilt University Medical Center10, Loyola University Medical Center11, University of Washington12, Harvard University13, Brigham and Women's Hospital14, University of Oklahoma15, University of California, Irvine16, Stanford University17
TL;DR: In patients with bladder cancer, robotic Cystectomy was non-inferior to open cystectomy for 2-year progression-free survival and increased adoption of robotic surgery in clinical practice should lead to future randomised trials to assess the true value of this surgical approach in patients with other cancer types.
479 citations
Baylor College of Medicine1, Harvard University2, Kaiser Permanente3, Emory University4, Ochsner Medical Center5, Icahn School of Medicine at Mount Sinai6, University of California, Los Angeles7, Cedars-Sinai Medical Center8, University of Tennessee Health Science Center9, University of Texas Health Science Center at San Antonio10, American Association of Clinical Endocrinologists11, Tulane University12, University of Alabama at Birmingham13, University of Washington14, University of Miami15, Washington University in St. Louis16, Mount Sinai Hospital17, University of California, Irvine18, Grady Memorial Hospital19
TL;DR: The objective of the trial was to establish whether or not the initial treatment strategy improved the patient’s quality of life and/or lowered the risk of adverse events.
TL;DR: In this paper, the authors combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci associated with general cognitive function.
Abstract: General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10-8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.
TL;DR: The pathophysiological roles of fundamental cellular and molecular mechanisms of aging, including oxidative stress, mitochondrial dysfunction, impaired resistance to molecular stressors, chronic low-grade inflammation, genomic instability, cellular senescence, epigenetic alterations, loss of protein homeostasis, deregulated nutrient sensing, and stem cell dysfunction in the vascular system are considered.
Abstract: Aging of the vasculature plays a central role in morbidity and mortality of older people. To develop novel treatments for amelioration of unsuccessful vascular aging and prevention of age-related vascular pathologies, it is essential to understand the cellular and functional changes that occur in the vasculature during aging. In this review, the pathophysiological roles of fundamental cellular and molecular mechanisms of aging, including oxidative stress, mitochondrial dysfunction, impaired resistance to molecular stressors, chronic low-grade inflammation, genomic instability, cellular senescence, epigenetic alterations, loss of protein homeostasis, deregulated nutrient sensing, and stem cell dysfunction in the vascular system are considered in terms of their contribution to the pathogenesis of both microvascular and macrovascular diseases associated with old age. The importance of progeronic and antigeronic circulating factors in relation to development of vascular aging phenotypes are discussed. Finally, future directions and opportunities to develop novel interventions to prevent/delay age-related vascular pathologies by targeting fundamental cellular and molecular aging processes are presented.
Stanford University1, University of Calgary2, Centers for Disease Control and Prevention3, George Washington University4, Cleveland Clinic5, Johns Hopkins University School of Medicine6, University of California, Los Angeles7, University of Florida Health Science Center8, Kaiser Permanente9, Emory University10, Icahn School of Medicine at Mount Sinai11, Princeton University12, University of Texas Health Science Center at San Antonio13, Harvard University14, Loma Linda University15, Cincinnati Children's Hospital Medical Center16, University of Washington17, St. Louis Children's Hospital18, University of Utah19, Children's Hospital of Philadelphia20, University of North Carolina at Chapel Hill21, John H. Stroger, Jr. Hospital of Cook County22, Vanderbilt University23, University of Pittsburgh24, Nationwide Children's Hospital25, The Ohio State University Wexner Medical Center26, Boston Children's Hospital27, University of Miami28, University of California, San Diego29, American Academy of Neurology30, University of Kansas31, University of Virginia32, Penn State Milton S. Hershey Medical Center33
TL;DR: This guideline identifies the best practices for mTBI based on the current evidence and creates user-friendly guideline implementation materials that are concise and actionable.
Abstract: Importance Mild traumatic brain injury (mTBI), or concussion, in children is a rapidly growing public health concern because epidemiologic data indicate a marked increase in the number of emergency department visits for mTBI over the past decade. However, no evidence-based clinical guidelines have been developed to date for diagnosing and managing pediatric mTBI in the United States. Objective To provide a guideline based on a previous systematic review of the literature to obtain and assess evidence toward developing clinical recommendations for health care professionals related to the diagnosis, prognosis, and management/treatment of pediatric mTBI. Evidence Review The Centers for Disease Control and Prevention (CDC) National Center for Injury Prevention and Control Board of Scientific Counselors, a federal advisory committee, established the Pediatric Mild Traumatic Brain Injury Guideline Workgroup. The workgroup drafted recommendations based on the evidence that was obtained and assessed within the systematic review, as well as related evidence, scientific principles, and expert inference. This information includes selected studies published since the evidence review was conducted that were deemed by the workgroup to be relevant to the recommendations. The dates of the initial literature search were January 1, 1990, to November 30, 2012, and the dates of the updated literature search were December 1, 2012, to July 31, 2015. Findings The CDC guideline includes 19 sets of recommendations on the diagnosis, prognosis, and management/treatment of pediatric mTBI that were assigned a level of obligation (ie, must, should, or may) based on confidence in the evidence. Recommendations address imaging, symptom scales, cognitive testing, and standardized assessment for diagnosis; history and risk factor assessment, monitoring, and counseling for prognosis; and patient/family education, rest, support, return to school, and symptom management for treatment. Conclusions and Relevance This guideline identifies the best practices for mTBI based on the current evidence; updates should be made as the body of evidence grows. In addition to the development of the guideline, CDC has created user-friendly guideline implementation materials that are concise and actionable. Evaluation of the guideline and implementation materials is crucial in understanding the influence of the recommendations.
Mayo Clinic1, University of Florence2, University of Insubria3, Cornell University4, Icahn School of Medicine at Mount Sinai5, University of Texas MD Anderson Cancer Center6, University of Texas Health Science Center at San Antonio7, University of Paris8, Heidelberg University9, University of Barcelona10, Guy's and St Thomas' NHS Foundation Trust11, Queen's University Belfast12, RWTH Aachen University13, Catholic University of the Sacred Heart14, University of Hamburg15, Leibniz University of Hanover16, Uppsala University17
TL;DR: This document updates the recommendations on the management of Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-neg MPNs), and both recombinant interferon alpha and the JAK1/JAK2 inhibitor ruxolitinib are recommended as second-line therapies for PV patients who are intolerant or have inadequate response to hydroxyurea.
Abstract: This document updates the recommendations on the management of Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-neg MPNs) published in 2011 by the European LeukemiaNet (ELN) consortium. Recommendations were produced by multiple-step formalized procedures of group discussion. A critical appraisal of evidence by using Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methodology was performed in the areas where at least one randomized clinical trial was published. Seven randomized controlled trials provided the evidence base; earlier phase trials also informed recommendation development. Key differences from the 2011 diagnostic recommendations included: lower threshold values for hemoglobin and hematocrit and bone marrow examination for diagnosis of polycythemia vera (PV), according to the revised WHO criteria; the search for complementary clonal markers, such as ASXL1, EZH2, IDH1/IDH2, and SRSF2 for the diagnosis of myelofibrosis (MF) in patients who test negative for JAK2V617, CALR or MPL driver mutations. Regarding key differences of therapy recommendations, both recombinant interferon alpha and the JAK1/JAK2 inhibitor ruxolitinib are recommended as second-line therapies for PV patients who are intolerant or have inadequate response to hydroxyurea. Ruxolitinib is recommended as first-line approach for MF-associated splenomegaly in patients with intermediate-2 or high-risk disease; in case of intermediate-1 disease, ruxolitinib is recommended in highly symptomatic splenomegaly. Allogeneic stem cell transplantation is recommended for transplant-eligible MF patients with high or intermediate-2 risk score. Allogeneic stem cell transplantation is also recommended for transplant-eligible MF patients with intermediate-1 risk score who present with either refractory, transfusion-dependent anemia, blasts in peripheral blood > 2%, adverse cytogenetics, or high-risk mutations. In these situations, the transplant procedure should be performed in a controlled setting.
University of California, Los Angeles1, King's College London2, University of Florida3, Washington University in St. Louis4, Abbott Northwestern Hospital5, University of Michigan6, University of Kansas7, Columbia University Medical Center8, Indiana University9, Overlook Medical Center10, University of Rochester Medical Center11, Rush University Medical Center12, Rutgers University13, University of Cincinnati14, Hackensack University Medical Center15, University of California, Irvine16, Winthrop-University Hospital17, Rhode Island Hospital18, University of Colorado Hospital19, Henry Ford Health System20, University of Texas Health Science Center at San Antonio21, University of Pennsylvania22, University of North Carolina at Chapel Hill23, City of Hope National Medical Center24, Thomas Jefferson University25, St. Joseph Hospital26, Vanderbilt University27, Beth Israel Deaconess Medical Center28, Baylor University Medical Center29, Medical University of South Carolina30, Mount Sinai Hospital31, Dresden University of Technology32, Tufts University33, Stony Brook University34, Université de Sherbrooke35, University of California, San Diego36, Houston Methodist Hospital37, Geisinger Health System38, Kaiser Permanente39, University of Kentucky40, Montreal Neurological Institute and Hospital41, Hofstra University42, University of Washington43, Northwest Biotherapeutics44
TL;DR: Addition of DCVax-L to standard therapy is feasible and safe in glioblastoma patients, and may extend survival, and overall adverse events withDCVax were comparable to standard Therapy alone.
Abstract: Following publication of the original article [1], the authors reported an error in the spelling of one of the author names. In this Correction the incorrect and correct author names are indicated and the author name has been updated in the original publication. The authors also reported an error in the Methods section of the original article. In this Correction the incorrect and correct versions of the affected sentence are indicated. The original article has not been updated with regards to the error in the Methods section.
TL;DR: These transcriptome datasets provide an information-rich resource for studies of SSCs, male meiosis, testicular cancer, male infertility, or contraceptive development, as well as a gene expression roadmap to be emulated in efforts to achieve spermatogenesis in vitro.
TL;DR: It is suggested that lipid peroxidation drives GSDMD-mediated pyroptosis and hence constitutes a potential therapeutic target for lethal infection.
TL;DR: Although these conditions are rare, a proportion of patients with interstitial lung diseases (ILDs) may develop a progressive-fibrosing phenotype, and identification of these patients is crucial, and requires a multidisciplinary approach, to ensure optimal diagnosis and management.
Abstract: Although these conditions are rare, a proportion of patients with interstitial lung diseases (ILDs) may develop a progressive-fibrosing phenotype. Progressive fibrosis is associated with worsening respiratory symptoms, lung function decline, limited response to immunomodulatory therapies, decreased quality of life and, potentially, early death. Idiopathic pulmonary fibrosis may be regarded as a model for other progressive-fibrosing ILDs. Here we focus on other ILDs that may present a progressive-fibrosing phenotype, namely idiopathic nonspecific interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, connective tissue disease-associated ILDs (e.g. rheumatoid arthritis-related ILD), fibrotic chronic hypersensitivity pneumonitis, fibrotic chronic sarcoidosis and ILDs related to other occupational exposures. Differential diagnosis of these ILDs can be challenging, and requires detailed consideration of clinical, radiological and histopathological features. Accurate and early diagnosis is crucial to ensure that patients are treated optimally.
TL;DR: Using four AD transgenic mouse models, it is found that NFTs, but not Aβ plaques, display a senescence‐like phenotype, which contributes to neurodegeneration.
Abstract: Tau protein accumulation is the most common pathology among degenerative brain diseases, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), traumatic brain injury (TBI), and over twenty others. Tau-containing neurofibrillary tangle (NFT) accumulation is the closest correlate with cognitive decline and cell loss (Arriagada, Growdon, Hedley-Whyte, & Hyman, ), yet mechanisms mediating tau toxicity are poorly understood. NFT formation does not induce apoptosis (de Calignon, Spires-Jones, Pitstick, Carlson, & Hyman, 2009), which suggests that secondary mechanisms are driving toxicity. Transcriptomic analyses of NFT-containing neurons microdissected from postmortem AD brain revealed an expression profile consistent with cellular senescence. This complex stress response induces aberrant cell cycle activity, adaptations to maintain survival, cellular remodeling, and metabolic dysfunction. Using four AD transgenic mouse models, we found that NFTs, but not Aβ plaques, display a senescence-like phenotype. Cdkn2a transcript level, a hallmark measure of senescence, directly correlated with brain atrophy and NFT burden in mice. This relationship extended to postmortem brain tissue from humans with PSP to indicate a phenomenon common to tau toxicity. Tau transgenic mice with late-stage pathology were treated with senolytics to remove senescent cells. Despite the advanced age and disease progression, MRI brain imaging and histopathological analyses indicated a reduction in total NFT density, neuron loss, and ventricular enlargement. Collectively, these findings indicate a strong association between the presence of NFTs and cellular senescence in the brain, which contributes to neurodegeneration. Given the prevalence of tau protein deposition among neurodegenerative diseases, these findings have broad implications for understanding, and potentially treating, dozens of brain diseases.
University of Bonn1, University of Rochester2, Temple University3, Case Western Reserve University4, Paris Diderot University5, Istanbul University6, Vita-Salute San Raffaele University7, University of Alabama at Birmingham8, King's College London9, University of Hong Kong10, The Forsyth Institute11, Columbia University12, National and Kapodistrian University of Athens13, Dalhousie University14, University of Texas Health Science Center at San Antonio15, Newcastle University16, University of Maryland, Baltimore17, University of Bern18, Georgia Regents University19, University of Bristol20, Niigata University21
TL;DR: In this paper, the authors reviewed and updated the 1999 classification with regard to these diseases and conditions, and developed case definitions and diagnostic considerations, which is based on the results of these reviews and on expert opinion of the participants.
Abstract: Background A variety of systemic diseases and conditions can affect the course of periodontitis or have a negative impact on the periodontal attachment apparatus. Gingival recessions are highly prevalent and often associated with hypersensitivity, the development of caries and non-carious cervical lesions on the exposed root surface and impaired esthetics. Occlusal forces can result in injury of teeth and periodontal attachment apparatus. Several developmental or acquired conditions associated with teeth or prostheses may predispose to diseases of the periodontium. The aim of this working group was to review and update the 1999 classification with regard to these diseases and conditions, and to develop case definitions and diagnostic considerations. Methods Discussions were informed by four reviews on 1) periodontal manifestions of systemic diseases and conditions; 2) mucogingival conditions around natural teeth; 3) traumatic occlusal forces and occlusal trauma; and 4) dental prostheses and tooth related factors. This consensus report is based on the results of these reviews and on expert opinion of the participants. Results Key findings included the following: 1) there are mainly rare systemic conditions (such as Papillon-Lefevre Syndrome, leucocyte adhesion deficiency, and others) with a major effect on the course of periodontitis and more common conditions (such as diabetes mellitus) with variable effects, as well as conditions affecting the periodontal apparatus independently of dental plaque biofilm-induced inflammation (such as neoplastic diseases); 2) diabetes-associated periodontitis should not be regarded as a distinct diagnosis, but diabetes should be recognized as an important modifying factor and included in a clinical diagnosis of periodontitis as a descriptor; 3) likewise, tobacco smoking - now considered a dependence to nicotine and a chronic relapsing medical disorder with major adverse effects on the periodontal supporting tissues - is an important modifier to be included in a clinical diagnosis of periodontitis as a descriptor; 4) the importance of the gingival phenotype, encompassing gingival thickness and width in the context of mucogingival conditions, is recognized and a novel classification for gingival recessions is introduced; 5) there is no evidence that traumatic occlusal forces lead to periodontal attachment loss, non-carious cervical lesions, or gingival recessions; 6) traumatic occlusal forces lead to adaptive mobility in teeth with normal support, whereas they lead to progressive mobility in teeth with reduced support, usually requiring splinting; 7) the term biologic width is replaced by supracrestal tissue attachment consisting of junctional epithelium and supracrestal connective tissue; 8) infringement of restorative margins within the supracrestal connective tissue attachment is associated with inflammation and/or loss of periodontal supporting tissue. However, it is not evident whether the negative effects on the periodontium are caused by dental plaque biofilm, trauma, toxicity of dental materials or a combination of these factors; 9) tooth anatomical factors are related to dental plaque biofilm-induced gingival inflammation and loss of periodontal supporting tissues. Conclusion An updated classification of the periodontal manifestations and conditions affecting the course of periodontitis and the periodontal attachment apparatus, as well as of developmental and acquired conditions, is introduced. Case definitions and diagnostic considerations are also presented.
University of Bonn1, University of Rochester2, Temple University3, Case Western Reserve University4, Paris Diderot University5, Istanbul University6, University of Alabama at Birmingham7, King's College London8, University of Hong Kong9, The Forsyth Institute10, Columbia University11, National and Kapodistrian University of Athens12, Dalhousie University13, University of Texas Health Science Center at San Antonio14, Newcastle University15, University of Maryland, Baltimore16, University of Bern17, Georgia Regents University18, University of Bristol19, Niigata University20
TL;DR: An updated classification of theperiodontal manifestations and conditions affecting the course of periodontitis and the periodontal attachment apparatus, as well as of developmental and acquired conditions, is introduced.
TL;DR: It is suggested that melatonin improves lipid metabolism in high‐fat diet‐fed mice, and the potential mechanisms may be associated with reprogramming gut microbiota, especially, Bacteroides and Alistipes‐mediated acetic acid production.
Abstract: Melatonin has been shown to improve lipid metabolism and gut microbiota communities in animals and humans; however, it remains to know whether melatonin prevents obesity through gut microbiota. Here, we found that high-fat diet promoted the lipid accumulation and intestinal microbiota dysbiosis in mice, while oral melatonin supplementation alleviated the lipid accumulation and reversed gut microbiota dysbiosis, including the diversity of intestinal microbiota, relative abundances of Bacteroides and Alistipes, and functional profiling of microbial communities, such as energy metabolism, lipid metabolism, and carbohydrate metabolism. Interestingly, melatonin failed to alleviate the high-fat-induced lipid accumulation in antibiotic-treated mice; however, microbiota transplantation from melatonin-treated mice alleviated high-fat diet-induced lipid metabolic disorders. Notably, short-chain fatty acids were decreased in high-fat diet-fed mice, while melatonin treatment improved the production of acetic acid. Correlation analysis found a marked correlation between production of acetic acid and relative abundances of Bacteroides and Alistipes. Importantly, sodium acetate treatment also alleviated high-fat diet-induced lipid metabolic disorders. Taken together, our results suggest that melatonin improves lipid metabolism in high-fat diet-fed mice, and the potential mechanisms may be associated with reprogramming gut microbiota, especially, Bacteroides and Alistipes-mediated acetic acid production. Future studies are needed for patients with metabolic syndrome to fully understand melatonin's effects on body weight and lipid profiles and the potential mechanism of gut microbiota.
TL;DR: Gene editing of a single gene in the brain of an adult mouse model of fragile X syndrome, achieved via the intracranial injection of a nonviral Cas9 delivery vehicle, rescues mice from the exaggerated repetitive behaviours caused by the disease.
Abstract: Technologies that can safely edit genes in the brains of adult animals may revolutionize the treatment of neurological diseases and the understanding of brain function. Here, we demonstrate that intracranial injection of CRISPR–Gold, a nonviral delivery vehicle for the CRISPR–Cas9 ribonucleoprotein, can edit genes in the brains of adult mice in multiple mouse models. CRISPR–Gold can deliver both Cas9 and Cpf1 ribonucleoproteins, and can edit all of the major cell types in the brain, including neurons, astrocytes and microglia, with undetectable levels of toxicity at the doses used. We also show that CRISPR–Gold designed to target the metabotropic glutamate receptor 5 (mGluR5) gene can efficiently reduce local mGluR5 levels in the striatum after an intracranial injection. The effect can also rescue mice from the exaggerated repetitive behaviours caused by fragile X syndrome, a common single-gene form of autism spectrum disorders. CRISPR–Gold may significantly accelerate the development of brain-targeted therapeutics and enable the rapid development of focal brain-knockout animal models.
TL;DR: Melatonin is optimally positioned to scavenge the radicals and reduce the degree of oxidative damage, and in light of the “free radical theory of aging”, high melatonin levels in mitochondria would be expected to protect against age-related organismal decline.
Abstract: Melatonin, along with its metabolites, have long been known to significantly reduce the oxidative stress burden of aging cells or cells exposed to toxins. Oxidative damage is a result of free radicals produced in cells, especially in mitochondria. When measured, melatonin, a potent antioxidant, was found to be in higher concentrations in mitochondria than in other organelles or subcellular locations. Recent evidence indicates that mitochondrial membranes possess transporters that aid in the rapid uptake of melatonin by these organelles against a gradient. Moreover, we predicted several years ago that, because of their origin from melatonin-producing bacteria, mitochondria likely also synthesize melatonin. Data accumulated within the last year supports this prediction. A high content of melatonin in mitochondria would be fortuitous, since these organelles produce an abundance of free radicals. Thus, melatonin is optimally positioned to scavenge the radicals and reduce the degree of oxidative damage. In light of the “free radical theory of aging”, including all of its iterations, high melatonin levels in mitochondria would be expected to protect against age-related organismal decline. Also, there are many age-associated diseases that have, as a contributing factor, free radical damage. These multiple diseases may likely be deferred in their onset or progression if mitochondrial levels of melatonin can be maintained into advanced age.
University of Pennsylvania1, VA Palo Alto Healthcare System2, Southern Methodist University3, Carl R. Darnall Army Medical Center4, University of Texas Health Science Center at San Antonio5, University of Texas at Austin6, Boston University7, VA Boston Healthcare System8, Harvard University9, University of Texas at San Antonio10
TL;DR: Among active duty military personnel with PTSD, massed therapy (10 sessions over 2 weeks) reduced PTSD symptom severity more than MCC at 2-week follow-up and was noninferior to spaced therapy ( 10 sessions over 8 weeks), and there was no significant difference between spaced therapy and PCT.
Abstract: Importance Effective and efficient treatment is needed for posttraumatic stress disorder (PTSD) in active duty military personnel Objective To examine the effects of massed prolonged exposure therapy (massed therapy), spaced prolonged exposure therapy (spaced therapy), present-centered therapy (PCT), and a minimal-contact control (MCC) on PTSD severity Design, Setting, and Participants Randomized clinical trial conducted at Fort Hood, Texas, from January 2011 through July 2016 and enrolling 370 military personnel with PTSD who had returned from Iraq, Afghanistan, or both Final follow-up was July 11, 2016 Interventions Prolonged exposure therapy, cognitive behavioral therapy involving exposure to trauma memories/reminders, administered as massed therapy (n = 110; 10 sessions over 2 weeks) or spaced therapy (n = 109; 10 sessions over 8 weeks); PCT, a non–trauma-focused therapy involving identifying/discussing daily stressors (n = 107; 10 sessions over 8 weeks); or MCC, telephone calls from therapists (n = 40; once weekly for 4 weeks) Main Outcomes and Measures Outcomes were assessed before and after treatment and at 2-week, 12-week, and 6-month follow-up Primary outcome was interviewer-assessed PTSD symptom severity, measured by the PTSD Symptom Scale–Interview (PSS-I; range, 0-51; higher scores indicate greater PTSD severity; MCID, 318), used to assess efficacy of massed therapy at 2 weeks posttreatment vs MCC at week 4; noninferiority of massed therapy vs spaced therapy at 2 weeks and 12 weeks posttreatment (noninferiority margin, 50% [23 points on PSS-I, with 1-sided α = 05]);and efficacy of spaced therapy vs PCT at posttreatment Results Among 370 randomized participants, data were analyzed for 366 (mean age, 327 [SD, 73] years; 44 women [120%]; mean baseline PSS-I score, 2549 [636]), and 216 (590%) completed the study At 2 weeks posttreatment, mean PSS-I score was 1762 (mean decrease from baseline, 713) for massed therapy and 2141 (mean decrease, 343) for MCC (difference in decrease, 370 [95% CI,072 to 668];P = 02) At 2 weeks posttreatment, mean PSS-I score was 1803 for spaced therapy (decrease, 729; difference in means vs massed therapy, 079 [1-sided 95% CI, −∞ to 229;P = 049 for noninferiority]) and at 12 weeks posttreatment was 1888 for massed therapy (decrease, 632) and 1834 for spaced therapy (decrease, 697; difference, 055 [1-sided 95% CI, −∞ to 205;P = 03 for noninferiority]) At posttreatment, PSS-I scores for PCT were 1865 (decrease, 731; difference in decrease vs spaced therapy, 010 [95% CI, −248 to 227];P = 93) Conclusions and Relevance Among active duty military personnel with PTSD, massed therapy (10 sessions over 2 weeks) reduced PTSD symptom severity more than MCC at 2-week follow-up and was noninferior to spaced therapy (10 sessions over 8 weeks), and there was no significant difference between spaced therapy and PCT The reductions in PTSD symptom severity with all treatments were relatively modest, suggesting that further research is needed to determine the clinical importance of these findings Trial Registration clinicaltrialsgov Identifier:NCT01049516
TL;DR: A previously undefined role for m6A in cancer is unveiled and it is shown that the collaboration among writers-erasers-readers sets up the m 6A threshold to ensure the stability of progrowth/proliferation-specific genes, and protumorigenic stimulus, such as hypoxia.
Abstract: The importance of RNA methylation in biological processes is an emerging focus of investigation. We report that altering m6A levels by silencing either N6-adenosine methyltransferase METTL14 (methyltransferase-like 14) or demethylase ALKBH5 (ALKB homolog 5) inhibits cancer growth and invasion. METTL14/ALKBH5 mediate their protumorigenic function by regulating m6A levels of key epithelial-mesenchymal transition and angiogenesis-associated transcripts, including transforming growth factor–β signaling pathway genes. Using MeRIP-seq (methylated RNA immunoprecipitation sequencing) analysis and functional studies, we find that these target genes are particularly sensitive to changes in m6A modifications, as altered m6A status leads to aberrant expression of these genes, resulting in inappropriate cell cycle progression and evasion of apoptosis. Our results reveal that METTL14 and ALKBH5 determine the m6A status of target genes by controlling each other’s expression and by inhibiting m6A reader YTHDF3 (YTH N6-methyladenosine RNA binding protein 3), which blocks RNA demethylase activity. Furthermore, we show that ALKBH5/METTL14 constitute a positive feedback loop with RNA stability factor HuR to regulate the stability of target transcripts. We discover that hypoxia alters the level/activity of writers, erasers, and readers, leading to decreased m6A and consequently increased expression of target transcripts in cancer cells. This study unveils a previously undefined role for m6A in cancer and shows that the collaboration among writers-erasers-readers sets up the m6A threshold to ensure the stability of progrowth/proliferation-specific genes, and protumorigenic stimulus, such as hypoxia, perturbs that m6A threshold, leading to uncontrolled expression/activity of those genes, resulting in tumor growth, angiogenesis, and progression.
National University of Singapore1, Keio University2, Yokohama City University3, National Institute of Genetics4, University of California, San Diego5, University of Texas Health Science Center at San Antonio6, University of Regensburg7, Baker IDI Heart and Diabetes Institute8, Åbo Akademi University9, Max Planck Society10, Babraham Institute11, Karolinska Institutet12
TL;DR: A community-led process to elaborate and define a set of generally accepted guidelines for quantitative MS-based lipidomics of blood plasma or serum, with harmonization of data acquired on different instrumentation platforms across independent laboratories as an ultimate goal is initiated.
TL;DR: Melatonin's family is rather exceptional, offering versatile and collective antioxidant protection against OS, and it certainly seems that melatonin is one of nature's defenses against oxidative damage.
Abstract: Oxidative stress (OS) represents a threat to the chemical integrity of biomolecules including lipids, proteins, and DNA. The associated molecular damage frequently results in serious health issues, which justifies our concern about this phenomenon. In addition to enzymatic defense mechanisms, there are compounds (usually referred to as antioxidants) that offer chemical protection against oxidative events. Among them, melatonin and its metabolites constitute a particularly efficient chemical family. They offer protection against OS as individual chemical entities through a wide variety of mechanisms including electron transfer, hydrogen transfer, radical adduct formation, and metal chelation, and by repairing biological targets. In fact, many of them including melatonin can be classified as multipurpose antioxidants. However, what seems to be unique to the melatonin's family is their collective effects. Because the members of this family are metabolically related, most of them are expected to be present in living organisms wherever melatonin is produced. Therefore, the protection exerted by melatonin against OS may be viewed as a result of the combined antioxidant effects of the parent molecule and its metabolites. Melatonin's family is rather exceptional in this regard, offering versatile and collective antioxidant protection against OS. It certainly seems that melatonin is one of the best nature's defenses against oxidative damage.
TL;DR: The findings improve the current understanding of EWSR1 function, elucidate the mechanistic basis of the sensitivity of Ewing sarcoma to chemotherapy (including PARP1 inhibitors) and highlight a class of BRCA-deficient-like tumours.
Abstract: Ewing sarcoma is an aggressive paediatric cancer of the bone and soft tissue. It results from a chromosomal translocation, predominantly t(11;22)(q24:q12), that fuses the N-terminal transactivation domain of the constitutively expressed EWSR1 protein with the C-terminal DNA binding domain of the rarely expressed FLI1 protein. Ewing sarcoma is highly sensitive to genotoxic agents such as etoposide, but the underlying molecular basis of this sensitivity is unclear. Here we show that Ewing sarcoma cells display alterations in regulation of damage-induced transcription, accumulation of R-loops and increased replication stress. In addition, homologous recombination is impaired in Ewing sarcoma owing to an enriched interaction between BRCA1 and the elongating transcription machinery. Finally, we uncover a role for EWSR1 in the transcriptional response to damage, suppressing R-loops and promoting homologous recombination. Our findings improve the current understanding of EWSR1 function, elucidate the mechanistic basis of the sensitivity of Ewing sarcoma to chemotherapy (including PARP1 inhibitors) and highlight a class of BRCA-deficient-like tumours.