SEARCH THE INSTITUTIONAL RECORD.

78 of 78 indexed publications

• QM-LIT-0001moderate evidencePrimary research articlepreclinical evidenceOpen access

  Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

  Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. · Lancet (London, England) (2020)

  BackgroundSince December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described.MethodsIn this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and m…

  Disease area

  Cardiovascular disease

  Pathway

  Inflammatory signalling

  Publication type

  peer-reviewed journal article

  Citations

  18,487

  Identifier

  DOI 10.1016/s0140-6736(20)30566-3

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0074preclinical evidencePreclinical studypreclinical evidence

  Ferroptosis: an iron-dependent form of nonapoptotic cell death

  Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, Morrison B, Stockwell BR. · Cell (2012)

  Nonapoptotic forms of cell death may facilitate the selective elimination of some tumor cells or be activated in specific pathological states. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of nonapoptotic cell death that we term ferroptosis. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. We identify the small molecule ferrostatin-1 as a potent inhibitor of ferroptosis in cancer cells and glutamate-induced cell death in organotypic rat brain slices, suggesting similarities between these two processes. Indeed, erastin, like glutamate, inhibits cystine uptake by the cystine/glutamate antiporter (system x(c)(-)), creating a void in the antioxidant defenses of the cell and ultimately leading to iron-dependent, ox…

  Disease area

  Oncology

  Pathway

  Mitochondrial function

  Publication type

  peer-reviewed journal article

  Citations

  15,561

  Identifier

  DOI 10.1016/j.cell.2012.03.042

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0026contextual evidenceNarrative reviewevidence synthesis

  The hallmarks of aging

  López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. · Cell (2013)

  Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. This deterioration is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. Aging research has experienced an unprecedented advance over recent years, particularly with the discovery that the rate of aging is controlled, at least to some extent, by genetic pathways and biochemical processes conserved in evolution. This Review enumerates nine tentative hallmarks that represent common denominators of aging in different organisms, with special emphasis on mammalian aging. These hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell ex…

  Disease area

  Metabolic disease

  Pathway

  Insulin signalling

  Publication type

  peer-reviewed journal article

  Citations

  12,292

  Identifier

  DOI 10.1016/j.cell.2013.05.039

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0075moderate evidencePrimary research articlepreclinical evidence

  The Molecular Signatures Database (MSigDB) hallmark gene set collection

  Liberzon A, Birger C, Thorvaldsdóttir H, Ghandi M, Mesirov JP, Tamayo P. · Cell systems (2015)

  The Molecular Signatures Database (MSigDB) is one of the most widely used and comprehensive databases of gene sets for performing gene set enrichment analysis. Since its creation, MSigDB has grown beyond its roots in metabolic disease and cancer to include >10,000 gene sets. These better represent a wider range of biological processes and diseases, but the utility of the database is reduced by increased redundancy across, and heterogeneity within, gene sets. To address this challenge, here we use a combination of automated approaches and expert curation to develop a collection of "hallmark" gene sets as part of MSigDB. Each hallmark in this collection consists of a "refined" gene set, derived from multiple "founder" sets, that conveys a specific biological state or process and displays coherent expression. The hallmarks effectively summarize most of the relevant information of the ori…

  Disease area

  Oncology

  Pathway

  Mitochondrial function

  Publication type

  peer-reviewed journal article

  Citations

  12,097

  Identifier

  DOI 10.1016/j.cels.2015.12.004

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0016contextual evidenceNarrative reviewevidence synthesis

  The blockade of immune checkpoints in cancer immunotherapy

  Pardoll DM. · Nature reviews. Cancer (2012)

  Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to ac…

  Disease area

  Immunology

  Pathway

  Cell cycle regulation

  Publication type

  peer-reviewed journal article

  Citations

  10,607

  Identifier

  DOI 10.1038/nrc3239

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0017strong evidenceRandomised controlled trialclinical evidence

  Safety, activity, and immune correlates of anti-PD-1 antibody in cancer

  Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M. · The New England journal of medicine (2012)

  BackgroundBlockade of programmed death 1 (PD-1), an inhibitory receptor expressed by T cells, can overcome immune resistance. We assessed the antitumor activity and safety of BMS-936558, an antibody that specifically blocks PD-1.MethodsWe enrolled patients with advanced melanoma, non-small-cell lung cancer, castration-resistant prostate cancer, or renal-cell or colorectal cancer to receive anti-PD-1 antibody at a dose of 0.1 to 10.0 mg per kilogram of body weight every 2 weeks. Response was assessed after each 8-week treatment cycle. Patients received up to 12 cycles until disease progression or a complete response occurred.ResultsA total of 296 patients received treatment through February 24, 2012. Grade 3 or 4 drug-related adverse events occurred in 14% of patients; there were three deaths from pulmonary toxicity. No maximum tolerated dose was defined. Adverse events consistent with…

  Disease area

  Immunology

  Pathway

  Cell cycle regulation

  Publication type

  peer-reviewed journal article

  Citations

  10,126

  Identifier

  DOI 10.1056/nejmoa1200690

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0064moderate evidencePrimary research articlepreclinical evidenceOpen access

  Comprehensive molecular portraits of human breast tumours

  Cancer Genome Atlas Network. · Nature (2012)

  We analysed primary breast cancers by genomic DNA copy number arrays, DNA methylation, exome sequencing, messenger RNA arrays, microRNA sequencing and reverse-phase protein arrays. Our ability to integrate information across platforms provided key insights into previously defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity. Somatic mutations in only three genes (TP53, PIK3CA and GATA3) occurred at >10% incidence across all breast cancers; however, there were numerous subtype-associated and novel gene mutations including the enrichment of specific mutations in GATA3, PIK3CA and MAP3K1 with the luminal A subtype. We identified two novel protein-expression-defined subgroups, possibly produced by stromal/microenvironmental elements, and integrated…

  Disease area

  Oncology

  Pathway

  Cell cycle regulation

  Publication type

  peer-reviewed journal article

  Citations

  10,066

  Identifier

  DOI 10.1038/nature11412

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0036contextual evidenceNarrative reviewevidence synthesis

  The biology, function, and biomedical applications of exosomes

  Kalluri R, LeBleu VS. · Science (New York, N.Y.) (2020)

  The study of extracellular vesicles (EVs) has the potential to identify unknown cellular and molecular mechanisms in intercellular communication and in organ homeostasis and disease. Exosomes, with an average diameter of ~100 nanometers, are a subset of EVs. The biogenesis of exosomes involves their origin in endosomes, and subsequent interactions with other intracellular vesicles and organelles generate the final content of the exosomes. Their diverse constituents include nucleic acids, proteins, lipids, amino acids, and metabolites, which can reflect their cell of origin. In various diseases, exosomes offer a window into altered cellular or tissue states, and their detection in biological fluids potentially offers a multicomponent diagnostic readout. The efficient exchange of cellular components through exosomes can inform their applied use in designing exosome-based therapeutics.

  Disease area

  Metabolic disease

  Pathway

  Mitochondrial function

  Publication type

  peer-reviewed journal article

  Citations

  8,774

  Identifier

  DOI 10.1126/science.aau6977

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0027moderate evidencePrimary research articlepreclinical evidenceOpen access

  World Health Organization 2020 guidelines on physical activity and sedentary behaviour

  Bull FC, Al-Ansari SS, Biddle S, Borodulin K, Buman MP, Cardon G, Carty C, Chaput JP, Chastin S, Chou R, Dempsey PC, DiPietro L, Ekelund U, Firth J, Friedenreich CM, Garcia L, Gichu M, Jago R, Katzmarzyk PT, Lambert E, Leitzmann M, Milton K, Ortega FB, Ranasinghe C, Stamatakis E, Tiedemann A, Troiano RP, van der Ploeg HP, Wari V, Willumsen JF. · British journal of sports medicine (2020)

  ObjectivesTo describe new WHO 2020 guidelines on physical activity and sedentary behaviour.MethodsThe guidelines were developed in accordance with WHO protocols. An expert Guideline Development Group reviewed evidence to assess associations between physical activity and sedentary behaviour for an agreed set of health outcomes and population groups. The assessment used and systematically updated recent relevant systematic reviews; new primary reviews addressed additional health outcomes or subpopulations.ResultsThe new guidelines address children, adolescents, adults, older adults and include new specific recommendations for pregnant and postpartum women and people living with chronic conditions or disability. All adults should undertake 150-300 min of moderate-intensity, or 75-150 min of vigorous-intensity physical activity, or some equivalent combination of moderate-intensity and vig…

  Disease area

  Metabolic disease

  Pathway

  Insulin signalling

  Publication type

  peer-reviewed journal article

  Citations

  7,868

  Identifier

  DOI 10.1136/bjsports-2020-102955

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0002strong evidenceRandomised controlled trialclinical evidence

  Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

  Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, Kastelein JJP, Cornel JH, Pais P, Pella D, Genest J, Cifkova R, Lorenzatti A, Forster T, Kobalava Z, Vida-Simiti L, Flather M, Shimokawa H, Ogawa H, Dellborg M, Rossi PRF, Troquay RPT, Libby P, Glynn RJ, CANTOS Trial Group. · The New England journal of medicine (2017)

  BackgroundExperimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved.MethodsWe conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death.ResultsAt 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that receiv…

  Disease area

  Cardiovascular disease

  Pathway

  Inflammatory signalling

  Publication type

  peer-reviewed journal article

  Citations

  7,783

  Identifier

  DOI 10.1056/nejmoa1707914

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0069moderate evidencePrimary research articlepreclinical evidence

  PD-1 Blockade in Tumors with Mismatch-Repair Deficiency

  Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, Biedrzycki B, Donehower RC, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Duffy SM, Goldberg RM, de la Chapelle A, Koshiji M, Bhaijee F, Huebner T, Hruban RH, Wood LD, Cuka N, Pardoll DM, Papadopoulos N, Kinzler KW, Zhou S, Cornish TC, Taube JM, Anders RA, Eshleman JR, Vogelstein B, Diaz LA. · The New England journal of medicine (2015)

  BackgroundSomatic mutations have the potential to encode "non-self" immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade.MethodsWe conducted a phase 2 study to evaluate the clinical activity of pembrolizumab, an anti-programmed death 1 immune checkpoint inhibitor, in 41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency. Pembrolizumab was administered intravenously at a dose of 10 mg per kilogram of body weight every 14 days in patients with mismatch repair-deficient colorectal cancers, patients with mismatch repair-proficient colorectal cancers, and patients with mismatch repair-deficient cancers that were not colorectal. The coprimary end points were the immune-related objective response rate and the 20-week immune-related progr…

  Disease area

  Oncology

  Pathway

  Inflammatory signalling

  Publication type

  peer-reviewed journal article

  Citations

  7,561

  Identifier

  DOI 10.1056/nejmoa1500596

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0039moderate evidencePrimary research articlepreclinical evidenceOpen access

  Diet rapidly and reproducibly alters the human gut microbiome

  David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, Ling AV, Devlin AS, Varma Y, Fischbach MA, Biddinger SB, Dutton RJ, Turnbaugh PJ. · Nature (2014)

  Long-term dietary intake influences the structure and activity of the trillions of microorganisms residing in the human gut, but it remains unclear how rapidly and reproducibly the human gut microbiome responds to short-term macronutrient change. Here we show that the short-term consumption of diets composed entirely of animal or plant products alters microbial community structure and overwhelms inter-individual differences in microbial gene expression. The animal-based diet increased the abundance of bile-tolerant microorganisms (Alistipes, Bilophila and Bacteroides) and decreased the levels of Firmicutes that metabolize dietary plant polysaccharides (Roseburia, Eubacterium rectale and Ruminococcus bromii). Microbial activity mirrored differences between herbivorous and carnivorous mammals, reflecting trade-offs between carbohydrate and protein fermentation. Foodborne microbes from b…

  Disease area

  Microbiome

  Pathway

  Host–microbe metabolism

  Publication type

  peer-reviewed journal article

  Citations

  7,361

  Identifier

  DOI 10.1038/nature12820

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0031contextual evidenceNarrative reviewevidence synthesis

  mTOR signaling in growth control and disease

  Laplante M, Sabatini DM. · Cell (2012)

  The mechanistic target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate organismal growth and homeostasis. The pathway regulates many major cellular processes and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration. Here, we review recent advances in our understanding of the mTOR pathway and its role in health, disease, and aging. We further discuss pharmacological approaches to treat human pathologies linked to mTOR deregulation.

  Disease area

  Metabolic disease

  Pathway

  Lipid metabolism

  Publication type

  peer-reviewed journal article

  Citations

  7,018

  Identifier

  DOI 10.1016/j.cell.2012.03.017

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0006moderate evidencePrimary research articlepreclinical evidenceOpen access

  The MR-Base platform supports systematic causal inference across the human phenome

  Hemani G, Zheng J, Elsworth B, Wade KH, Haberland V, Baird D, Laurin C, Burgess S, Bowden J, Langdon R, Tan VY, Yarmolinsky J, Shihab HA, Timpson NJ, Evans DM, Relton C, Martin RM, Davey Smith G, Gaunt TR, Haycock PC. · eLife (2018)

  Results from genome-wide association studies (GWAS) can be used to infer causal relationships between phenotypes, using a strategy known as 2-sample Mendelian randomization (2SMR) and bypassing the need for individual-level data. However, 2SMR methods are evolving rapidly and GWAS results are often insufficiently curated, undermining efficient implementation of the approach. We therefore developed MR-Base (http://www.mrbase.org): a platform that integrates a curated database of complete GWAS results (no restrictions according to statistical significance) with an application programming interface, web app and R packages that automate 2SMR. The software includes several sensitivity analyses for assessing the impact of horizontal pleiotropy and other violations of assumptions. The database currently comprises 11 billion single nucleotide polymorphism-trait associations from 1673 GWAS and…

  Disease area

  Cardiovascular disease

  Pathway

  Lipid metabolism

  Publication type

  peer-reviewed journal article

  Citations

  6,870

  Identifier

  DOI 10.7554/elife.34408

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0018preclinical evidencePreclinical studypreclinical evidence

  Safety and activity of anti-PD-L1 antibody in patients with advanced cancer

  Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM. · The New England journal of medicine (2012)

  BackgroundProgrammed death 1 (PD-1) protein, a T-cell coinhibitory receptor, and one of its ligands, PD-L1, play a pivotal role in the ability of tumor cells to evade the host's immune system. Blockade of interactions between PD-1 and PD-L1 enhances immune function in vitro and mediates antitumor activity in preclinical models.MethodsIn this multicenter phase 1 trial, we administered intravenous anti-PD-L1 antibody (at escalating doses ranging from 0.3 to 10 mg per kilogram of body weight) to patients with selected advanced cancers. Anti-PD-L1 antibody was administered every 14 days in 6-week cycles for up to 16 cycles or until the patient had a complete response or confirmed disease progression.ResultsAs of February 24, 2012, a total of 207 patients--75 with non-small-cell lung cancer, 55 with melanoma, 18 with colorectal cancer, 17 with renal-cell cancer, 17 with ovarian cancer, 14…

  Disease area

  Immunology

  Pathway

  Cell cycle regulation

  Publication type

  peer-reviewed journal article

  Citations

  6,342

  Identifier

  DOI 10.1056/nejmoa1200694

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0070contextual evidenceNarrative reviewevidence synthesis

  Ferroptosis: mechanisms, biology and role in disease

  Jiang X, Jiang X, Stockwell BR, Conrad M. · Nature reviews. Molecular cell biology (2021)

  The research field of ferroptosis has seen exponential growth over the past few years, since the term was coined in 2012. This unique modality of cell death, driven by iron-dependent phospholipid peroxidation, is regulated by multiple cellular metabolic pathways, including redox homeostasis, iron handling, mitochondrial activity and metabolism of amino acids, lipids and sugars, in addition to various signalling pathways relevant to disease. Numerous organ injuries and degenerative pathologies are driven by ferroptosis. Intriguingly, therapy-resistant cancer cells, particularly those in the mesenchymal state and prone to metastasis, are exquisitely vulnerable to ferroptosis. As such, pharmacological modulation of ferroptosis, via both its induction and its inhibition, holds great potential for the treatment of drug-resistant cancers, ischaemic organ injuries and other degenerative dise…

  Disease area

  Oncology

  Pathway

  Inflammatory signalling

  Publication type

  peer-reviewed journal article

  Citations

  6,177

  Identifier

  DOI 10.1038/s41580-020-00324-8

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0007moderate evidencePrimary research articlepreclinical evidenceOpen access

  Global, regional, and national burden of stroke and its risk factors, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019

  GBD 2019 Stroke Collaborators. · The Lancet. Neurology (2021)

  BackgroundRegularly updated data on stroke and its pathological types, including data on their incidence, prevalence, mortality, disability, risk factors, and epidemiological trends, are important for evidence-based stroke care planning and resource allocation. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) aims to provide a standardised and comprehensive measurement of these metrics at global, regional, and national levels.MethodsWe applied GBD 2019 analytical tools to calculate stroke incidence, prevalence, mortality, disability-adjusted life-years (DALYs), and the population attributable fraction (PAF) of DALYs (with corresponding 95% uncertainty intervals [UIs]) associated with 19 risk factors, for 204 countries and territories from 1990 to 2019. These estimates were provided for ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage, and all…

  Disease area

  Cardiovascular disease

  Pathway

  Lipid metabolism

  Publication type

  peer-reviewed journal article

  Citations

  6,063

  Identifier

  DOI 10.1016/s1474-4422(21)00252-0

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0044moderate evidencePrimary research articlepreclinical evidenceOpen access

  Human gut microbiome viewed across age and geography

  Yatsunenko T, Rey FE, Manary MJ, Trehan I, Dominguez-Bello MG, Contreras M, Magris M, Hidalgo G, Baldassano RN, Anokhin AP, Heath AC, Warner B, Reeder J, Kuczynski J, Caporaso JG, Lozupone CA, Lauber C, Clemente JC, Knights D, Knight R, Gordon JI. · Nature (2012)

  Gut microbial communities represent one source of human genetic and metabolic diversity. To examine how gut microbiomes differ among human populations, here we characterize bacterial species in fecal samples from 531 individuals, plus the gene content of 110 of them. The cohort encompassed healthy children and adults from the Amazonas of Venezuela, rural Malawi and US metropolitan areas and included mono- and dizygotic twins. Shared features of the functional maturation of the gut microbiome were identified during the first three years of life in all three populations, including age-associated changes in the genes involved in vitamin biosynthesis and metabolism. Pronounced differences in bacterial assemblages and functional gene repertoires were noted between US residents and those in the other two countries. These distinctive features are evident in early infancy as well as adulthood…

  Disease area

  Microbiome

  Pathway

  Inflammatory signalling

  Publication type

  peer-reviewed journal article

  Citations

  5,851

  Identifier

  DOI 10.1038/nature11053

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0071moderate evidencePrimary research articlepreclinical evidenceOpen access

  PD-1 blockade induces responses by inhibiting adaptive immune resistance

  Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, Chmielowski B, Spasic M, Henry G, Ciobanu V, West AN, Carmona M, Kivork C, Seja E, Cherry G, Gutierrez AJ, Grogan TR, Mateus C, Tomasic G, Glaspy JA, Emerson RO, Robins H, Pierce RH, Elashoff DA, Robert C, Ribas A. · Nature (2014)

  Therapies that target the programmed death-1 (PD-1) receptor have shown unprecedented rates of durable clinical responses in patients with various cancer types. One mechanism by which cancer tissues limit the host immune response is via upregulation of PD-1 ligand (PD-L1) and its ligation to PD-1 on antigen-specific CD8(+) T cells (termed adaptive immune resistance). Here we show that pre-existing CD8(+) T cells distinctly located at the invasive tumour margin are associated with expression of the PD-1/PD-L1 immune inhibitory axis and may predict response to therapy. We analysed samples from 46 patients with metastatic melanoma obtained before and during anti-PD-1 therapy (pembrolizumab) using quantitative immunohistochemistry, quantitative multiplex immunofluorescence, and next-generation sequencing for T-cell antigen receptors (TCRs). In serially sampled tumours, patients responding…

  Disease area

  Oncology

  Pathway

  Inflammatory signalling

  Publication type

  peer-reviewed journal article

  Citations

  5,541

  Identifier

  DOI 10.1038/nature13954

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0003contextual evidenceNarrative reviewevidence synthesisOpen access

  Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018

  Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P, Alnemri ES, Altucci L, Amelio I, Andrews DW, Annicchiarico-Petruzzelli M, Antonov AV, Arama E, Baehrecke EH, Barlev NA, Bazan NG, Bernassola F, Bertrand MJM, Bianchi K, Blagosklonny MV, Blomgren K, Borner C, Boya P, Brenner C, Campanella M, Candi E, Carmona-Gutierrez D, Cecconi F, Chan FK, Chandel NS, Cheng EH, Chipuk JE, Cidlowski · Cell death and differentiation (2018)

  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 discu…

  Disease area

  Cardiovascular disease

  Pathway

  Inflammatory signalling

  Publication type

  peer-reviewed journal article

  Citations

  5,526

  Identifier

  DOI 10.1038/s41418-017-0012-4

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0021contextual evidenceNarrative reviewevidence synthesis

  Hepatocellular carcinoma

  Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, Lencioni R, Koike K, Zucman-Rossi J, Finn RS. · Nature reviews. Disease primers (2021)

  Liver cancer remains a global health challenge, with an estimated incidence of >1 million cases by 2025. Hepatocellular carcinoma (HCC) is the most common form of liver cancer and accounts for ~90% of cases. Infection by hepatitis B virus and hepatitis C virus are the main risk factors for HCC development, although non-alcoholic steatohepatitis associated with metabolic syndrome or diabetes mellitus is becoming a more frequent risk factor in the West. Moreover, non-alcoholic steatohepatitis-associated HCC has a unique molecular pathogenesis. Approximately 25% of all HCCs present with potentially actionable mutations, which are yet to be translated into the clinical practice. Diagnosis based upon non-invasive criteria is currently challenged by the need for molecular information that requires tissue or liquid biopsies. The current major advancements have impacted the management of pati…

  Disease area

  Immunology

  Pathway

  Inflammatory signalling

  Publication type

  peer-reviewed journal article

  Citations

  5,493

  Identifier

  DOI 10.1038/s41572-020-00240-3

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0076contextual evidenceNarrative reviewevidence synthesis

  mTOR Signaling in Growth, Metabolism, and Disease

  Saxton RA, Sabatini DM. · Cell (2017)

  The mechanistic target of rapamycin (mTOR) coordinates eukaryotic cell growth and metabolism with environmental inputs, including nutrients and growth factors. Extensive research over the past two decades has established a central role for mTOR in regulating many fundamental cell processes, from protein synthesis to autophagy, and deregulated mTOR signaling is implicated in the progression of cancer and diabetes, as well as the aging process. Here, we review recent advances in our understanding of mTOR function, regulation, and importance in mammalian physiology. We also highlight how the mTOR signaling network contributes to human disease and discuss the current and future prospects for therapeutically targeting mTOR in the clinic.

  Disease area

  Oncology

  Pathway

  Mitochondrial function

  Publication type

  peer-reviewed journal article

  Citations

  5,343

  Identifier

  DOI 10.1016/j.cell.2017.02.004

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0011contextual evidenceNarrative reviewevidence synthesis

  Neuroinflammation in Alzheimer's disease

  Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, Jacobs AH, Wyss-Coray T, Vitorica J, Ransohoff RM, Herrup K, Frautschy SA, Finsen B, Brown GC, Verkhratsky A, Yamanaka K, Koistinaho J, Latz E, Halle A, Petzold GC, Town T, Morgan D, Shinohara ML, Perry VH, Holmes C, Bazan NG, Brooks DJ, Hunot S, Joseph B, Deigendesch N, Garaschuk O, Boddeke E, Dinarello CA, Breitner JC, Co · The Lancet. Neurology (2015)

  Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment, but includes strong interactions with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on microglia and astroglia, and trigger an innate immune response characterised by release of inflammatory mediators, which contribute to disease progression and severity. Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity, are likely to interfere with immunological processes of the brain and further promote disease progression. Modulation of risk factors and targeting of these immune mechanisms could lead to future…

  Disease area

  Cardiovascular disease

  Pathway

  Vascular remodelling

  Publication type

  peer-reviewed journal article

  Citations

  5,130

  Identifier

  DOI 10.1016/s1474-4422(15)70016-5

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0040contextual evidenceNarrative reviewevidence synthesis

  From Dietary Fiber to Host Physiology: Short-Chain Fatty Acids as Key Bacterial Metabolites

  Koh A, De Vadder F, Kovatcheva-Datchary P, Bäckhed F. · Cell (2016)

  A compelling set of links between the composition of the gut microbiota, the host diet, and host physiology has emerged. Do these links reflect cause-and-effect relationships, and what might be their mechanistic basis? A growing body of work implicates microbially produced metabolites as crucial executors of diet-based microbial influence on the host. Here, we will review data supporting the diverse functional roles carried out by a major class of bacterial metabolites, the short-chain fatty acids (SCFAs). SCFAs can directly activate G-coupled-receptors, inhibit histone deacetylases, and serve as energy substrates. They thus affect various physiological processes and may contribute to health and disease.

  Disease area

  Microbiome

  Pathway

  Host–microbe metabolism

  Publication type

  peer-reviewed journal article

  Citations

  4,993

  Identifier

  DOI 10.1016/j.cell.2016.05.041

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0059contextual evidenceNarrative reviewevidence synthesisOpen access

  The amyloid hypothesis of Alzheimer's disease at 25 years

  Selkoe DJ, Hardy J. · EMBO molecular medicine (2016)

  Despite continuing debate about the amyloid β-protein (or Aβ hypothesis, new lines of evidence from laboratories and clinics worldwide support the concept that an imbalance between production and clearance of Aβ42 and related Aβ peptides is a very early, often initiating factor in Alzheimer's disease (AD). Confirmation that presenilin is the catalytic site of γ-secretase has provided a linchpin: all dominant mutations causing early-onset AD occur either in the substrate (amyloid precursor protein, APP) or the protease (presenilin) of the reaction that generates Aβ. Duplication of the wild-type APP gene in Down's syndrome leads to Aβ deposits in the teens, followed by microgliosis, astrocytosis, and neurofibrillary tangles typical of AD Apolipoprotein E4, which predisposes to AD in > 40% of cases, has been found to impair Aβ clearance from the brain. Soluble oligomers of Aβ42 isolated…

  Disease area

  Neurodegeneration

  Pathway

  Proteostasis

  Publication type

  peer-reviewed journal article

  Citations

  4,867

  Identifier

  DOI 10.15252/emmm.201606210

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0019moderate evidencePrimary research articlepreclinical evidenceOpen access

  SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials

  Chan AW, Tetzlaff JM, Gøtzsche PC, Altman DG, Mann H, Berlin JA, Dickersin K, Hróbjartsson A, Schulz KF, Parulekar WR, Krleza-Jeric K, Laupacis A, Moher D. · BMJ (Clinical research ed.) (2013)

  High quality protocols facilitate proper conduct, reporting, and external review of clinical trials. However, the completeness of trial protocols is often inadequate. To help improve the content and quality of protocols, an international group of stakeholders developed the SPIRIT 2013 Statement (Standard Protocol Items: Recommendations for Interventional Trials). The SPIRIT Statement provides guidance in the form of a checklist of recommended items to include in a clinical trial protocol. This SPIRIT 2013 Explanation and Elaboration paper provides important information to promote full understanding of the checklist recommendations. For each checklist item, we provide a rationale and detailed description; a model example from an actual protocol; and relevant references supporting its importance. We strongly recommend that this explanatory paper be used in conjunction with the SPIRIT St…

  Disease area

  Immunology

  Pathway

  Cell cycle regulation

  Publication type

  peer-reviewed journal article

  Citations

  4,784

  Identifier

  DOI 10.1136/bmj.e7586

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0045contextual evidenceNarrative reviewevidence synthesisOpen access

  Biological properties of extracellular vesicles and their physiological functions

  Yáñez-Mó M, Siljander PR, Andreu Z, Zavec AB, Borràs FE, Buzas EI, Buzas K, Casal E, Cappello F, Carvalho J, Colás E, Cordeiro-da Silva A, Fais S, Falcon-Perez JM, Ghobrial IM, Giebel B, Gimona M, Graner M, Gursel I, Gursel M, Heegaard NH, Hendrix A, Kierulf P, Kokubun K, Kosanovic M, Kralj-Iglic V, Krämer-Albers EM, Laitinen S, Lässer C, Lener T, Ligeti E, Linē A, Lipps G, Llorente A, Lötvall J, · Journal of extracellular vesicles (2015)

  In the past decade, extracellular vesicles (EVs) have been recognized as potent vehicles of intercellular communication, both in prokaryotes and eukaryotes. This is due to their capacity to transfer proteins, lipids and nucleic acids, thereby influencing various physiological and pathological functions of both recipient and parent cells. While intensive investigation has targeted the role of EVs in different pathological processes, for example, in cancer and autoimmune diseases, the EV-mediated maintenance of homeostasis and the regulation of physiological functions have remained less explored. Here, we provide a comprehensive overview of the current understanding of the physiological roles of EVs, which has been written by crowd-sourcing, drawing on the unique EV expertise of academia-based scientists, clinicians and industry based in 27 European countries, the United States and Aust…

  Disease area

  Microbiome

  Pathway

  Inflammatory signalling

  Publication type

  peer-reviewed journal article

  Citations

  4,768

  Identifier

  DOI 10.3402/jev.v4.27066

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0049preclinical evidencePreclinical studypreclinical evidence

  A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease

  Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, David E, Baruch K, Lara-Astaiso D, Toth B, Itzkovitz S, Colonna M, Schwartz M, Amit I. · Cell (2017)

  Alzheimer's disease (AD) is a detrimental neurodegenerative disease with no effective treatments. Due to cellular heterogeneity, defining the roles of immune cell subsets in AD onset and progression has been challenging. Using transcriptional single-cell sorting, we comprehensively map all immune populations in wild-type and AD-transgenic (Tg-AD) mouse brains. We describe a novel microglia type associated with neurodegenerative diseases (DAM) and identify markers, spatial localization, and pathways associated with these cells. Immunohistochemical staining of mice and human brain slices shows DAM with intracellular/phagocytic Aβ particles. Single-cell analysis of DAM in Tg-AD and triggering receptor expressed on myeloid cells 2 (Trem2)-/- Tg-AD reveals that the DAM program is activated in a two-step process. Activation is initiated in a Trem2-independent manner that involves downregula…

  Disease area

  Neurodegeneration

  Pathway

  Inflammatory signalling

  Publication type

  peer-reviewed journal article

  Citations

  4,679

  Identifier

  DOI 10.1016/j.cell.2017.05.018

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0008strong evidenceRandomised controlled trialclinical evidence

  Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease

  Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, Sever PS, Pedersen TR, FOURIER Steering Committee and Investigators. · The New England journal of medicine (2017)

  BackgroundEvolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and lowers low-density lipoprotein (LDL) cholesterol levels by approximately 60%. Whether it prevents cardiovascular events is uncertain.MethodsWe conducted a randomized, double-blind, placebo-controlled trial involving 27,564 patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or higher who were receiving statin therapy. Patients were randomly assigned to receive evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or matching placebo as subcutaneous injections. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary efficacy end point was the composite of cardio…

  Disease area

  Cardiovascular disease

  Pathway

  Lipid metabolism

  Publication type

  peer-reviewed journal article

  Citations

  4,551

  Identifier

  DOI 10.1056/nejmoa1615664

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0065contextual evidenceNarrative reviewevidence synthesis

  Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel

  Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, Dombret H, Ebert BL, Fenaux P, Larson RA, Levine RL, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz M, Sierra J, Tallman MS, Tien HF, Wei AH, Löwenberg B, Bloomfield CD. · Blood (2017)

  The first edition of the European LeukemiaNet (ELN) recommendations for diagnosis and management of acute myeloid leukemia (AML) in adults, published in 2010, has found broad acceptance by physicians and investigators caring for patients with AML. Recent advances, for example, in the discovery of the genomic landscape of the disease, in the development of assays for genetic testing and for detecting minimal residual disease (MRD), as well as in the development of novel antileukemic agents, prompted an international panel to provide updated evidence- and expert opinion-based recommendations. The recommendations include a revised version of the ELN genetic categories, a proposal for a response category based on MRD status, and criteria for progressive disease.

  Disease area

  Oncology

  Pathway

  Cell cycle regulation

  Publication type

  peer-reviewed journal article

  Citations

  4,502

  Identifier

  DOI 10.1182/blood-2016-08-733196

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0028moderate evidencePrimary research articlepreclinical evidence

  Heart Disease and Stroke Statistics-2021 Update: A Report From the American Heart Association

  Virani SS, Alonso A, Aparicio HJ, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, Chamberlain AM, Cheng S, Delling FN, Elkind MSV, Evenson KR, Ferguson JF, Gupta DK, Khan SS, Kissela BM, Knutson KL, Lee CD, Lewis TT, Liu J, Loop MS, Lutsey PL, Ma J, Mackey J, Martin SS, Matchar DB, Mussolino ME, Navaneethan SD, Perak AM, Roth GA, Samad Z, Satou GM, Schroeder EB, Shah SH, Shay CM, Stokes A, Va · Circulation (2021)

  BackgroundThe American Heart Association, in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health. The Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, heart failure, valvular disease, venous disease, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs).MethodsThe American Heart Association, through its Statistics Committee, continuously monito…

  Disease area

  Metabolic disease

  Pathway

  Insulin signalling

  Publication type

  peer-reviewed journal article

  Citations

  4,406

  Identifier

  DOI 10.1161/cir.0000000000000950

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0041preclinical evidencePreclinical studypreclinical evidence

  The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis

  Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly-Y M, Glickman JN, Garrett WS. · Science (New York, N.Y.) (2013)

  Regulatory T cells (Tregs) that express the transcription factor Foxp3 are critical for regulating intestinal inflammation. Candidate microbe approaches have identified bacterial species and strain-specific molecules that can affect intestinal immune responses, including species that modulate Treg responses. Because neither all humans nor mice harbor the same bacterial strains, we posited that more prevalent factors exist that regulate the number and function of colonic Tregs. We determined that short-chain fatty acids, gut microbiota-derived bacterial fermentation products, regulate the size and function of the colonic Treg pool and protect against colitis in a Ffar2-dependent manner in mice. Our study reveals that a class of abundant microbial metabolites underlies adaptive immune microbiota coadaptation and promotes colonic homeostasis and health.

  Disease area

  Microbiome

  Pathway

  Host–microbe metabolism

  Publication type

  peer-reviewed journal article

  Citations

  4,399

  Identifier

  DOI 10.1126/science.1241165

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0050contextual evidenceNarrative reviewevidence synthesis

  Alzheimer's disease

  Scheltens P, De Strooper B, Kivipelto M, Holstege H, Chételat G, Teunissen CE, Cummings J, van der Flier WM. · Lancet (London, England) (2021)

  In this Seminar, we highlight the main developments in the field of Alzheimer's disease. The most recent data indicate that, by 2050, the prevalence of dementia will double in Europe and triple worldwide, and that estimate is 3 times higher when based on a biological (rather than clinical) definition of Alzheimer's disease. The earliest phase of Alzheimer's disease (cellular phase) happens in parallel with accumulating amyloid β, inducing the spread of tau pathology. The risk of Alzheimer's disease is 60-80% dependent on heritable factors, with more than 40 Alzheimer's disease-associated genetic risk loci already identified, of which the APOE alleles have the strongest association with the disease. Novel biomarkers include PET scans and plasma assays for amyloid β and phosphorylated tau, which show great promise for clinical and research use. Multidomain lifestyle-based prevention tri…

  Disease area

  Neurodegeneration

  Pathway

  Inflammatory signalling

  Publication type

  peer-reviewed journal article

  Citations

  4,371

  Identifier

  DOI 10.1016/s0140-6736(20)32205-4

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0066moderate evidencePrimary research articlepreclinical evidence

  The somatic genomic landscape of glioblastoma

  Brennan CW, Verhaak RG, McKenna A, Campos B, Noushmehr H, Salama SR, Zheng S, Chakravarty D, Sanborn JZ, Berman SH, Beroukhim R, Bernard B, Wu CJ, Genovese G, Shmulevich I, Barnholtz-Sloan J, Zou L, Vegesna R, Shukla SA, Ciriello G, Yung WK, Zhang W, Sougnez C, Mikkelsen T, Aldape K, Bigner DD, Van Meir EG, Prados M, Sloan A, Black KL, Eschbacher J, Finocchiaro G, Friedman W, Andrews DW, Guha A, I · Cell (2013)

  We describe the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidat…

  Disease area

  Oncology

  Pathway

  Cell cycle regulation

  Publication type

  peer-reviewed journal article

  Citations

  4,198

  Identifier

  DOI 10.1016/j.cell.2013.09.034

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0009contextual evidenceNarrative reviewevidence synthesis

  Heart Disease and Stroke Statistics-2023 Update: A Report From the American Heart Association

  Tsao CW, Aday AW, Almarzooq ZI, Anderson CAM, Arora P, Avery CL, Baker-Smith CM, Beaton AZ, Boehme AK, Buxton AE, Commodore-Mensah Y, Elkind MSV, Evenson KR, Eze-Nliam C, Fugar S, Generoso G, Heard DG, Hiremath S, Ho JE, Kalani R, Kazi DS, Ko D, Levine DA, Liu J, Ma J, Magnani JW, Michos ED, Mussolino ME, Navaneethan SD, Parikh NI, Poudel R, Rezk-Hanna M, Roth GA, Shah NS, St-Onge MP, Thacker EL, · Circulation (2023)

  BackgroundThe American Heart Association, in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health. The Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, heart failure, valvular disease, venous disease, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs).MethodsThe American Heart Association, through its Epidemiology and Prevention Statistics Co…

  Disease area

  Cardiovascular disease

  Pathway

  Lipid metabolism

  Publication type

  peer-reviewed journal article

  Citations

  4,027

  Identifier

  DOI 10.1161/cir.0000000000001123

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0060moderate evidencePrimary research articlepreclinical evidenceOpen access

  Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches

  Welsh JA, Goberdhan DCI, O'Driscoll L, Buzas EI, Blenkiron C, Bussolati B, Cai H, Di Vizio D, Driedonks TAP, Erdbrügger U, Falcon-Perez JM, Fu QL, Hill AF, Lenassi M, Lim SK, Mahoney MG, Mohanty S, Möller A, Nieuwland R, Ochiya T, Sahoo S, Torrecilhas AC, Zheng L, Zijlstra A, Abuelreich S, Bagabas R, Bergese P, Bridges EM, Brucale M, Burger D, Carney RP, Cocucci E, Crescitelli R, Hanser E, Harris · Journal of extracellular vesicles (2024)

  Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies…

  Disease area

  Neurodegeneration

  Pathway

  Proteostasis

  Publication type

  peer-reviewed journal article

  Citations

  3,938

  Identifier

  DOI 10.1002/jev2.12404

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0046preclinical evidencePreclinical studypreclinical evidenceOpen access

  Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation

  Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, deRoos P, Liu H, Cross JR, Pfeffer K, Coffer PJ, Rudensky AY. · Nature (2013)

  Intestinal microbes provide multicellular hosts with nutrients and confer resistance to infection. The delicate balance between pro- and anti-inflammatory mechanisms, essential for gut immune homeostasis, is affected by the composition of the commensal microbial community. Regulatory T cells (Treg cells) expressing transcription factor Foxp3 have a key role in limiting inflammatory responses in the intestine. Although specific members of the commensal microbial community have been found to potentiate the generation of anti-inflammatory Treg or pro-inflammatory T helper 17 (TH17) cells, the molecular cues driving this process remain elusive. Considering the vital metabolic function afforded by commensal microorganisms, we reasoned that their metabolic by-products are sensed by cells of the immune system and affect the balance between pro- and anti-inflammatory cells. We tested this hyp…

  Disease area

  Microbiome

  Pathway

  Inflammatory signalling

  Publication type

  peer-reviewed journal article

  Citations

  3,895

  Identifier

  DOI 10.1038/nature12726

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0061strong evidenceSystematic review or meta-analysisevidence synthesis

  Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease

  Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, DeStafano AL, Bis JC, Beecham GW, Grenier-Boley B, Russo G, Thorton-Wells TA, Jones N, Smith AV, Chouraki V, Thomas C, Ikram MA, Zelenika D, Vardarajan BN, Kamatani Y, Lin CF, Gerrish A, Gerrish A, Schmidt H, Kunkle B, Dunstan ML, Ruiz A, Bihoreau MT, Choi SH, Reitz C, Pasquier F, Cruchaga C, Craig D, Amin N, Berr C, Lopez OL, · Nature genetics (2013)

  Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.

  Disease area

  Neurodegeneration

  Pathway

  Proteostasis

  Publication type

  peer-reviewed journal article

  Citations

  3,816

  Identifier

  DOI 10.1038/ng.2802

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0032moderate evidencePrimary research articlepreclinical evidenceOpen access

  FinnGen provides genetic insights from a well-phenotyped isolated population

  Kurki MI, Karjalainen J, Palta P, Sipilä TP, Kristiansson K, Donner KM, Reeve MP, Laivuori H, Aavikko M, Kaunisto MA, Loukola A, Lahtela E, Mattsson H, Laiho P, Della Briotta Parolo P, Lehisto AA, Kanai M, Mars N, Rämö J, Kiiskinen T, Heyne HO, Veerapen K, Rüeger S, Lemmelä S, Zhou W, Ruotsalainen S, Pärn K, Hiekkalinna T, Koskelainen S, Paajanen T, Llorens V, Gracia-Tabuenca J, Siirtola H, Reis K · Nature (2023)

  Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency 1,2. FinnGen aims to study the genome and national health register data of 500,000 Finnish individuals. Given the relatively high median age of participants (63 years) and the substantial fraction of hospital-based recruitment, FinnGen is enriched for disease end points. Here we analyse data from 224,737 participants from FinnGen and study 15 diseases that have previously been investigated in large genome-wide association studies (GWASs). We also include meta-analyses of biobank data from Estonia and the United Kingdom. We identified 30 new associations, primarily low-frequency variants, enriched in the Finnish population. A GWAS of 1,932 diseases also identified 2,733 genome-wide significant…

  Disease area

  Metabolic disease

  Pathway

  Lipid metabolism

  Publication type

  peer-reviewed journal article

  Citations

  3,777

  Identifier

  DOI 10.1038/s41586-022-05473-8

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0054contextual evidenceNarrative reviewevidence synthesis

  AMPK: guardian of metabolism and mitochondrial homeostasis

  Herzig S, Shaw RJ. · Nature reviews. Molecular cell biology (2018)

  Cells constantly adapt their metabolism to meet their energy needs and respond to nutrient availability. Eukaryotes have evolved a very sophisticated system to sense low cellular ATP levels via the serine/threonine kinase AMP-activated protein kinase (AMPK) complex. Under conditions of low energy, AMPK phosphorylates specific enzymes and growth control nodes to increase ATP generation and decrease ATP consumption. In the past decade, the discovery of numerous new AMPK substrates has led to a more complete understanding of the minimal number of steps required to reprogramme cellular metabolism from anabolism to catabolism. This energy switch controls cell growth and several other cellular processes, including lipid and glucose metabolism and autophagy. Recent studies have revealed that one ancestral function of AMPK is to promote mitochondrial health, and multiple newly discovered targ…

  Disease area

  Neurodegeneration

  Pathway

  Mitochondrial function

  Publication type

  peer-reviewed journal article

  Citations

  3,470

  Identifier

  DOI 10.1038/nrm.2017.95

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0051preclinical evidencePreclinical studypreclinical evidence

  Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson's Disease

  Sampson TR, Debelius JW, Thron T, Janssen S, Shastri GG, Ilhan ZE, Challis C, Schretter CE, Rocha S, Gradinaru V, Chesselet MF, Keshavarzian A, Shannon KM, Krajmalnik-Brown R, Wittung-Stafshede P, Knight R, Mazmanian SK. · Cell (2016)

  The intestinal microbiota influence neurodevelopment, modulate behavior, and contribute to neurological disorders. However, a functional link between gut bacteria and neurodegenerative diseases remains unexplored. Synucleinopathies are characterized by aggregation of the protein α-synuclein (αSyn), often resulting in motor dysfunction as exemplified by Parkinson's disease (PD). Using mice that overexpress αSyn, we report herein that gut microbiota are required for motor deficits, microglia activation, and αSyn pathology. Antibiotic treatment ameliorates, while microbial re-colonization promotes, pathophysiology in adult animals, suggesting that postnatal signaling between the gut and the brain modulates disease. Indeed, oral administration of specific microbial metabolites to germ-free mice promotes neuroinflammation and motor symptoms. Remarkably, colonization of αSyn-overexpressing…

  Disease area

  Neurodegeneration

  Pathway

  Inflammatory signalling

  Publication type

  peer-reviewed journal article

  Citations

  2,872

  Identifier

  DOI 10.1016/j.cell.2016.11.018

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0037strong evidenceSystematic review or meta-analysisevidence synthesis

  Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing

  Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Damotte V, Naj AC, Boland A, Vronskaya M, van der Lee SJ, Amlie-Wolf A, Bellenguez C, Frizatti A, Chouraki V, Martin ER, Sleegers K, Badarinarayan N, Jakobsdottir J, Hamilton-Nelson KL, Moreno-Grau S, Olaso R, Raybould R, Chen Y, Kuzma AB, Hiltunen M, Morgan T, Ahmad S, Vardarajan BN, Epelbaum J, Hoffmann P, Boada M, Beecham GW, Garnier JG, Harold D, Fit · Nature genetics (2019)

  Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal domi…

  Disease area

  Metabolic disease

  Pathway

  Mitochondrial function

  Publication type

  peer-reviewed journal article

  Citations

  2,793

  Identifier

  DOI 10.1038/s41588-019-0358-2

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0052strong evidenceSystematic review or meta-analysisevidence synthesis

  TREM2 variants in Alzheimer's disease

  Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, Cruchaga C, Sassi C, Kauwe JS, Younkin S, Hazrati L, Collinge J, Pocock J, Lashley T, Williams J, Lambert JC, Amouyel P, Goate A, Rademakers R, Morgan K, Powell J, St George-Hyslop P, Singleton A, Hardy J, Alzheimer Genetic Analysis Group. · The New England journal of medicine (2013)

  BackgroundHomozygous loss-of-function mutations in TREM2, encoding the triggering receptor expressed on myeloid cells 2 protein, have previously been associated with an autosomal recessive form of early-onset dementia.MethodsWe used genome, exome, and Sanger sequencing to analyze the genetic variability in TREM2 in a series of 1092 patients with Alzheimer's disease and 1107 controls (the discovery set). We then performed a meta-analysis on imputed data for the TREM2 variant rs75932628 (predicted to cause a R47H substitution) from three genomewide association studies of Alzheimer's disease and tested for the association of the variant with disease. We genotyped the R47H variant in an additional 1887 cases and 4061 controls. We then assayed the expression of TREM2 across different regions of the human brain and identified genes that are differentially expressed in a mouse model of Alzhe…

  Disease area

  Neurodegeneration

  Pathway

  Inflammatory signalling

  Publication type

  peer-reviewed journal article

  Citations

  2,538

  Identifier

  DOI 10.1056/nejmoa1211851

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0062moderate evidencePrimary research articlepreclinical evidenceOpen access

  New insights into the genetic etiology of Alzheimer's disease and related dementias

  Bellenguez C, Küçükali F, Jansen IE, Kleineidam L, Moreno-Grau S, Amin N, Naj AC, Campos-Martin R, Grenier-Boley B, Andrade V, Holmans PA, Boland A, Damotte V, van der Lee SJ, Costa MR, Kuulasmaa T, Yang Q, de Rojas I, Bis JC, Yaqub A, Prokic I, Chapuis J, Ahmad S, Giedraitis V, Aarsland D, Garcia-Gonzalez P, Abdelnour C, Alarcón-Martín E, Alcolea D, Alegret M, Alvarez I, Álvarez V, Armstrong NJ, · Nature genetics (2022)

  Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The imp…

  Disease area

  Neurodegeneration

  Pathway

  Proteostasis

  Publication type

  peer-reviewed journal article

  Citations

  2,531

  Identifier

  DOI 10.1038/s41588-022-01024-z

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0022moderate evidencePrimary research articlepreclinical evidence

  International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data

  Arber DA, Orazi A, Hasserjian RP, Borowitz MJ, Calvo KR, Kvasnicka HM, Wang SA, Bagg A, Barbui T, Branford S, Bueso-Ramos CE, Cortes JE, Dal Cin P, DiNardo CD, Dombret H, Duncavage EJ, Ebert BL, Estey EH, Facchetti F, Foucar K, Gangat N, Gianelli U, Godley LA, Gökbuget N, Gotlib J, Hellström-Lindberg E, Hobbs GS, Hoffman R, Jabbour EJ, Kiladjian JJ, Larson RA, Le Beau MM, Loh ML, Löwenberg B, Maci · Blood (2022)

  The classification of myeloid neoplasms and acute leukemias was last updated in 2016 within a collaboration between the World Health Organization (WHO), the Society for Hematopathology, and the European Association for Haematopathology. This collaboration was primarily based on input from a clinical advisory committees (CACs) composed of pathologists, hematologists, oncologists, geneticists, and bioinformaticians from around the world. The recent advances in our understanding of the biology of hematologic malignancies, the experience with the use of the 2016 WHO classification in clinical practice, and the results of clinical trials have indicated the need for further revising and updating the classification. As a continuation of this CAC-based process, the authors, a group with expertise in the clinical, pathologic, and genetic aspects of these disorders, developed the International…

  Disease area

  Immunology

  Pathway

  Inflammatory signalling

  Publication type

  peer-reviewed journal article

  Citations

  2,436

  Identifier

  DOI 10.1182/blood.2022015850

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0004preclinical evidencePreclinical studypreclinical evidence

  A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases

  Coll RC, Robertson AA, Chae JJ, Higgins SC, Muñoz-Planillo R, Inserra MC, Vetter I, Dungan LS, Monks BG, Stutz A, Croker DE, Butler MS, Haneklaus M, Sutton CE, Núñez G, Latz E, Kastner DL, Mills KH, Masters SL, Schroder K, Cooper MA, O'Neill LA. · Nature medicine (2015)

  The NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome is a component of the inflammatory process, and its aberrant activation is pathogenic in inherited disorders such as cryopyrin-associated periodic syndrome (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease and atherosclerosis. We describe the development of MCC950, a potent, selective, small-molecule inhibitor of NLRP3. MCC950 blocked canonical and noncanonical NLRP3 activation at nanomolar concentrations. MCC950 specifically inhibited activation of NLRP3 but not the AIM2, NLRC4 or NLRP1 inflammasomes. MCC950 reduced interleukin-1β (IL-1β) production in vivo and attenuated the severity of experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis. Furthermore, MCC950 treatment rescued neonatal lethality in a mouse model of CA…

  Disease area

  Cardiovascular disease

  Pathway

  Inflammatory signalling

  Publication type

  peer-reviewed journal article

  Citations

  2,417

  Identifier

  DOI 10.1038/nm.3806

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0012preclinical evidencePreclinical studypreclinical evidenceOpen access

  Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan

  Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ, Zhong J, Saltness RA, Jeganathan KB, Verzosa GC, Pezeshki A, Khazaie K, Miller JD, van Deursen JM. · Nature (2016)

  Cellular senescence, a stress-induced irreversible growth arrest often characterized by expression of p16(Ink4a) (encoded by the Ink4a/Arf locus, also known as Cdkn2a) and a distinctive secretory phenotype, prevents the proliferation of preneoplastic cells and has beneficial roles in tissue remodelling during embryogenesis and wound healing. Senescent cells accumulate in various tissues and organs over time, and have been speculated to have a role in ageing. To explore the physiological relevance and consequences of naturally occurring senescent cells, here we use a previously established transgene, INK-ATTAC, to induce apoptosis in p16(Ink4a)-expressing cells of wild-type mice by injection of AP20187 twice a week starting at one year of age. We show that compared to vehicle alone, AP20187 treatment extended median lifespan in both male and female mice of two distinct genetic backgrou…

  Disease area

  Cardiovascular disease

  Pathway

  Vascular remodelling

  Publication type

  peer-reviewed journal article

  Citations

  2,370

  Identifier

  DOI 10.1038/nature16932

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0020strong evidenceSystematic review or meta-analysisevidence synthesis

  Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations

  Liu JZ, van Sommeren S, Huang H, Ng SC, Alberts R, Takahashi A, Ripke S, Lee JC, Jostins L, Shah T, Abedian S, Cheon JH, Cho J, Dayani NE, Franke L, Fuyuno Y, Hart A, Juyal RC, Juyal G, Kim WH, Morris AP, Poustchi H, Newman WG, Midha V, Orchard TR, Vahedi H, Sood A, Sung JY, Malekzadeh R, Westra HJ, Yamazaki K, Yang SK, International Multiple Sclerosis Genetics Consortium, International IBD Geneti · Nature genetics (2015)

  Ulcerative colitis and Crohn's disease are the two main forms of inflammatory bowel disease (IBD). Here we report the first trans-ancestry association study of IBD, with genome-wide or Immunochip genotype data from an extended cohort of 86,640 European individuals and Immunochip data from 9,846 individuals of East Asian, Indian or Iranian descent. We implicate 38 loci in IBD risk for the first time. For the majority of the IBD risk loci, the direction and magnitude of effect are consistent in European and non-European cohorts. Nevertheless, we observe genetic heterogeneity between divergent populations at several established risk loci driven by differences in allele frequency (NOD2) or effect size (TNFSF15 and ATG16L1) or a combination of these factors (IL23R and IRGM). Our results provide biological insights into the pathogenesis of IBD and demonstrate the usefulness of trans-ancestr…

  Disease area

  Immunology

  Pathway

  Cell cycle regulation

  Publication type

  peer-reviewed journal article

  Citations

  2,228

  Identifier

  DOI 10.1038/ng.3359

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0067strong evidenceRandomised controlled trialclinical evidence

  Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer

  Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA, DESTINY-Breast04 Trial Investigators. · The New England journal of medicine (2022)

  BackgroundAmong breast cancers without human epidermal growth factor receptor 2 (HER2) amplification, overexpression, or both, a large proportion express low levels of HER2 that may be targetable. Currently available HER2-directed therapies have been ineffective in patients with these "HER2-low" cancers.MethodsWe conducted a phase 3 trial involving patients with HER2-low metastatic breast cancer who had received one or two previous lines of chemotherapy. (Low expression of HER2 was defined as a score of 1+ on immunohistochemical [IHC] analysis or as an IHC score of 2+ and negative results on in situ hybridization.) Patients were randomly assigned in a 2:1 ratio to receive trastuzumab deruxtecan or the physician's choice of chemotherapy. The primary end point was progression-free survival in the hormone receptor-positive cohort. The key secondary end points were progression-free surviv…

  Disease area

  Oncology

  Pathway

  Cell cycle regulation

  Publication type

  peer-reviewed journal article

  Citations

  2,210

  Identifier

  DOI 10.1056/nejmoa2203690

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0010strong evidenceSystematic review or meta-analysisevidence synthesisOpen access

  A comprehensive 1,000 Genomes-based genome-wide association meta-analysis of coronary artery disease

  Nikpay M, Goel A, Won HH, Hall LM, Willenborg C, Kanoni S, Saleheen D, Kyriakou T, Nelson CP, Hopewell JC, Webb TR, Zeng L, Dehghan A, Alver M, Armasu SM, Auro K, Bjonnes A, Chasman DI, Chen S, Ford I, Franceschini N, Gieger C, Grace C, Gustafsson S, Huang J, Hwang SJ, Kim YK, Kleber ME, Lau KW, Lu X, Lu Y, Lyytikäinen LP, Mihailov E, Morrison AC, Pervjakova N, Qu L, Rose LM, Salfati E, Saxena R, · Nature genetics (2015)

  Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of ∼185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genet…

  Disease area

  Cardiovascular disease

  Pathway

  Lipid metabolism

  Publication type

  peer-reviewed journal article

  Citations

  2,186

  Identifier

  DOI 10.1038/ng.3396

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0033moderate evidencePrimary research articlepreclinical evidence

  2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines

  Joglar JA, Chung MK, Armbruster AL, Benjamin EJ, Chyou JY, Cronin EM, Deswal A, Eckhardt LL, Goldberger ZD, Gopinathannair R, Gorenek B, Hess PL, Hlatky M, Hogan G, Ibeh C, Indik JH, Kido K, Kusumoto F, Link MS, Linta KT, Marcus GM, McCarthy PM, Patel N, Patton KK, Perez MV, Piccini JP, Russo AM, Sanders P, Streur MM, Thomas KL, Times S, Tisdale JE, Valente AM, Van Wagoner DR, Peer Review Committe · Circulation (2024)

  AimThe "2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation" provides recommendations to guide clinicians in the treatment of patients with atrial fibrillation.MethodsA comprehensive literature search was conducted from May 12, 2022, to November 3, 2022, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. Additional relevant studies, published through November 2022, during the guideline writing process, were also considered by the writing committee and added to the evidence tables, where appropriate.StructureAtrial fibrillation is the most sustained common arrhythmia, and its incidence and prevalence are increasing in the United States and globally…

  Disease area

  Metabolic disease

  Pathway

  Lipid metabolism

  Publication type

  peer-reviewed journal article

  Citations

  1,982

  Identifier

  DOI 10.1161/cir.0000000000001193

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0077strong evidenceSystematic review or meta-analysisevidence synthesisOpen access

  Combination therapy in combating cancer

  Bayat Mokhtari R, Homayouni TS, Baluch N, Morgatskaya E, Kumar S, Das B, Yeger H. · Oncotarget (2017)

  Combination therapy, a treatment modality that combines two or more therapeutic agents, is a cornerstone of cancer therapy. The amalgamation of anti-cancer drugs enhances efficacy compared to the mono-therapy approach because it targets key pathways in a characteristically synergistic or an additive manner. This approach potentially reduces drug resistance, while simultaneously providing therapeutic anti-cancer benefits, such as reducing tumour growth and metastatic potential, arresting mitotically active cells, reducing cancer stem cell populations, and inducing apoptosis. The 5-year survival rates for most metastatic cancers are still quite low, and the process of developing a new anti-cancer drug is costly and extremely time-consuming. Therefore, new strategies that target the survival pathways that provide efficient and effective results at an affordable cost are being considered.…

  Disease area

  Oncology

  Pathway

  Mitochondrial function

  Publication type

  peer-reviewed journal article

  Citations

  1,795

  Identifier

  DOI 10.18632/oncotarget.16723

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0023moderate evidencePrimary research articlepreclinical evidenceOpen access

  British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults

  Lamb CA, Kennedy NA, Raine T, Hendy PA, Smith PJ, Limdi JK, Hayee B, Lomer MCE, Parkes GC, Selinger C, Barrett KJ, Davies RJ, Bennett C, Gittens S, Dunlop MG, Faiz O, Fraser A, Garrick V, Johnston PD, Parkes M, Sanderson J, Terry H, IBD guidelines eDelphi consensus group, Gaya DR, Iqbal TH, Taylor SA, Smith M, Brookes M, Hansen R, Hawthorne AB. · Gut (2019)

  Ulcerative colitis and Crohn's disease are the principal forms of inflammatory bowel disease. Both represent chronic inflammation of the gastrointestinal tract, which displays heterogeneity in inflammatory and symptomatic burden between patients and within individuals over time. Optimal management relies on understanding and tailoring evidence-based interventions by clinicians in partnership with patients. This guideline for management of inflammatory bowel disease in adults over 16 years of age was developed by Stakeholders representing UK physicians (British Society of Gastroenterology), surgeons (Association of Coloproctology of Great Britain and Ireland), specialist nurses (Royal College of Nursing), paediatricians (British Society of Paediatric Gastroenterology, Hepatology and Nutrition), dietitians (British Dietetic Association), radiologists (British Society of Gastrointestinal…

  Disease area

  Immunology

  Pathway

  Inflammatory signalling

  Publication type

  peer-reviewed journal article

  Citations

  1,785

  Identifier

  DOI 10.1136/gutjnl-2019-318484

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0034strong evidenceRandomised controlled trialclinical evidence

  Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial

  Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, Chalasani N, Dasarathy S, Diehl AM, Hameed B, Kowdley KV, McCullough A, Terrault N, Clark JM, Tonascia J, Brunt EM, Kleiner DE, Doo E, NASH Clinical Research Network. · Lancet (London, England) (2015)

  BackgroundThe bile acid derivative 6-ethylchenodeoxycholic acid (obeticholic acid) is a potent activator of the farnesoid X nuclear receptor that reduces liver fat and fibrosis in animal models of fatty liver disease. We assessed the efficacy of obeticholic acid in adult patients with non-alcoholic steatohepatitis.MethodsWe did a multicentre, double-blind, placebo-controlled, parallel group, randomised clinical trial at medical centres in the USA in patients with non-cirrhotic, non-alcoholic steatohepatitis to assess treatment with obeticholic acid given orally (25 mg daily) or placebo for 72 weeks. Patients were randomly assigned 1:1 using a computer-generated, centrally administered procedure, stratified by clinical centre and diabetes status. The primary outcome measure was improvement in centrally scored liver histology defined as a decrease in non-alcoholic fatty liver disease ac…

  Disease area

  Metabolic disease

  Pathway

  Lipid metabolism

  Publication type

  peer-reviewed journal article

  Citations

  1,760

  Identifier

  DOI 10.1016/s0140-6736(14)61933-4

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0042strong evidenceRandomised controlled trialclinical evidence

  Gut bacteria selectively promoted by dietary fibers alleviate type 2 diabetes

  Zhao L, Zhang F, Ding X, Wu G, Lam YY, Wang X, Fu H, Xue X, Lu C, Ma J, Yu L, Xu C, Ren Z, Xu Y, Xu S, Shen H, Zhu X, Shi Y, Shen Q, Dong W, Liu R, Ling Y, Zeng Y, Wang X, Zhang Q, Wang J, Wang L, Wu Y, Zeng B, Wei H, Zhang M, Peng Y, Zhang C. · Science (New York, N.Y.) (2018)

  The gut microbiota benefits humans via short-chain fatty acid (SCFA) production from carbohydrate fermentation, and deficiency in SCFA production is associated with type 2 diabetes mellitus (T2DM). We conducted a randomized clinical study of specifically designed isoenergetic diets, together with fecal shotgun metagenomics, to show that a select group of SCFA-producing strains was promoted by dietary fibers and that most other potential producers were either diminished or unchanged in patients with T2DM. When the fiber-promoted SCFA producers were present in greater diversity and abundance, participants had better improvement in hemoglobin A1c levels, partly via increased glucagon-like peptide-1 production. Promotion of these positive responders diminished producers of metabolically detrimental compounds such as indole and hydrogen sulfide. Targeted restoration of these SCFA producers…

  Disease area

  Microbiome

  Pathway

  Host–microbe metabolism

  Publication type

  peer-reviewed journal article

  Citations

  1,738

  Identifier

  DOI 10.1126/science.aao5774

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0047strong evidenceRandomised controlled trialclinical evidence

  A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice

  Plovier H, Everard A, Druart C, Depommier C, Van Hul M, Geurts L, Chilloux J, Ottman N, Duparc T, Lichtenstein L, Myridakis A, Delzenne NM, Klievink J, Bhattacharjee A, van der Ark KC, Aalvink S, Martinez LO, Dumas ME, Maiter D, Loumaye A, Hermans MP, Thissen JP, Belzer C, de Vos WM, Cani PD. · Nature medicine (2017)

  Obesity and type 2 diabetes are associated with low-grade inflammation and specific changes in gut microbiota composition. We previously demonstrated that administration of Akkermansia muciniphila to mice prevents the development of obesity and associated complications. However, the underlying mechanisms of this protective effect remain unclear. Moreover, the sensitivity of A. muciniphila to oxygen and the presence of animal-derived compounds in its growth medium currently limit the development of translational approaches for human medicine. We have addressed these issues here by showing that A. muciniphila retains its efficacy when grown on a synthetic medium compatible with human administration. Unexpectedly, we discovered that pasteurization of A. muciniphila enhanced its capacity to reduce fat mass development, insulin resistance and dyslipidemia in mice. These improvements were n…

  Disease area

  Microbiome

  Pathway

  Inflammatory signalling

  Publication type

  peer-reviewed journal article

  Citations

  1,673

  Identifier

  DOI 10.1038/nm.4236

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0013preclinical evidencePreclinical studypreclinical evidenceOpen access

  Cellular senescence mediates fibrotic pulmonary disease

  Schafer MJ, White TA, Iijima K, Haak AJ, Ligresti G, Atkinson EJ, Oberg AL, Birch J, Salmonowicz H, Zhu Y, Mazula DL, Brooks RW, Fuhrmann-Stroissnigg H, Pirtskhalava T, Prakash YS, Tchkonia T, Robbins PD, Aubry MC, Passos JF, Kirkland JL, Tschumperlin DJ, Kita H, LeBrasseur NK. · Nature communications (2017)

  Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by interstitial remodelling, leading to compromised lung function. Cellular senescence markers are detectable within IPF lung tissue and senescent cell deletion rejuvenates pulmonary health in aged mice. Whether and how senescent cells regulate IPF or if their removal may be an efficacious intervention strategy is unknown. Here we demonstrate elevated abundance of senescence biomarkers in IPF lung, with p16 expression increasing with disease severity. We show that the secretome of senescent fibroblasts, which are selectively killed by a senolytic cocktail, dasatinib plus quercetin (DQ), is fibrogenic. Leveraging the bleomycin-injury IPF model, we demonstrate that early-intervention suicide-gene-mediated senescent cell ablation improves pulmonary function and physical health, although lung fibrosis is visibly unaltere…

  Disease area

  Cardiovascular disease

  Pathway

  Vascular remodelling

  Publication type

  peer-reviewed journal article

  Citations

  1,414

  Identifier

  DOI 10.1038/ncomms14532

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0029strong evidenceSystematic review or meta-analysisevidence synthesisOpen access

  New genetic loci link adipose and insulin biology to body fat distribution

  Shungin D, Winkler TW, Croteau-Chonka DC, Ferreira T, Locke AE, Mägi R, Strawbridge RJ, Pers TH, Fischer K, Justice AE, Workalemahu T, Wu JMW, Buchkovich ML, Heard-Costa NL, Roman TS, Drong AW, Song C, Gustafsson S, Day FR, Esko T, Fall T, Kutalik Z, Luan J, Randall JC, Scherag A, Vedantam S, Wood AR, Chen J, Fehrmann R, Karjalainen J, Kahali B, Liu CT, Schmidt EM, Absher D, Amin N, Anderson D, Be · Nature (2015)

  Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway anal…

  Disease area

  Metabolic disease

  Pathway

  Insulin signalling

  Publication type

  peer-reviewed journal article

  Citations

  1,369

  Identifier

  DOI 10.1038/nature14132

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0043strong evidenceSystematic review or meta-analysisevidence synthesisOpen access

  Role of gut microbiota in type 2 diabetes pathophysiology

  Gurung M, Li Z, You H, Rodrigues R, Jump DB, Morgun A, Shulzhenko N. · EBioMedicine (2020)

  A substantial body of literature has provided evidence for the role of gut microbiota in metabolic diseases including type 2 diabetes. However, reports vary regarding the association of particular taxonomic groups with disease. In this systematic review, we focused on the potential role of different bacterial taxa affecting diabetes. We have summarized evidence from 42 human studies reporting microbial associations with disease, and have identified supporting preclinical studies or clinical trials using treatments with probiotics. Among the commonly reported findings, the genera of Bifidobacterium, Bacteroides, Faecalibacterium, Akkermansia and Roseburia were negatively associated with T2D, while the genera of Ruminococcus, Fusobacterium, and Blautia were positively associated with T2D. We also discussed potential molecular mechanisms of microbiota effects in the onset and progression…

  Disease area

  Microbiome

  Pathway

  Host–microbe metabolism

  Publication type

  peer-reviewed journal article

  Citations

  1,259

  Identifier

  DOI 10.1016/j.ebiom.2019.11.051

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0072strong evidenceRandomised controlled trialclinical evidence

  Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial

  Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O'Day SJ, Ascierto PA, Salama AK, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang · The Lancet. Oncology (2015)

  BackgroundPatients with melanoma that progresses on ipilimumab and, if BRAF(V600) mutant-positive, a BRAF or MEK inhibitor or both, have few treatment options. We assessed the efficacy and safety of two pembrolizumab doses versus investigator-choice chemotherapy in patients with ipilimumab-refractory melanoma.MethodsWe carried out a randomised phase 2 trial of patients aged 18 years or older from 73 hospitals, clinics, and academic medical centres in 12 countries who had confirmed progressive disease within 24 weeks after two or more ipilimumab doses and, if BRAF(V600) mutant-positive, previous treatment with a BRAF or MEK inhibitor or both. Patients had to have resolution of all ipilimumab-related adverse events to grade 0-1 and prednisone 10 mg/day or less for at least 2 weeks, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and at least one measurable les…

  Disease area

  Oncology

  Pathway

  Inflammatory signalling

  Publication type

  peer-reviewed journal article

  Citations

  1,245

  Identifier

  DOI 10.1016/s1470-2045(15)00083-2

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0014strong evidenceSystematic review or meta-analysisevidence synthesis

  Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits

  Evangelou E, Warren HR, Mosen-Ansorena D, Mifsud B, Pazoki R, Gao H, Ntritsos G, Dimou N, Cabrera CP, Karaman I, Ng FL, Evangelou M, Witkowska K, Tzanis E, Hellwege JN, Giri A, Velez Edwards DR, Sun YV, Cho K, Gaziano JM, Wilson PWF, Tsao PS, Kovesdy CP, Esko T, Mägi R, Milani L, Almgren P, Boutin T, Debette S, Ding J, Giulianini F, Holliday EG, Jackson AU, Li-Gao R, Lin WY, Luan J, Mangino M, Old · Nature genetics (2018)

  High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.

  Disease area

  Cardiovascular disease

  Pathway

  Vascular remodelling

  Publication type

  peer-reviewed journal article

  Citations

  1,209

  Identifier

  DOI 10.1038/s41588-018-0205-x

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0055preclinical evidencePreclinical studypreclinical evidenceOpen access

  Parkin and PINK1 mitigate STING-induced inflammation

  Sliter DA, Martinez J, Hao L, Chen X, Sun N, Fischer TD, Burman JL, Li Y, Zhang Z, Narendra DP, Cai H, Borsche M, Klein C, Youle RJ. · Nature (2018)

  Although serum from patients with Parkinson's disease contains elevated levels of numerous pro-inflammatory cytokines including IL-6, TNF, IL-1β, and IFNγ, whether inflammation contributes to or is a consequence of neuronal loss remains unknown1. Mutations in parkin, an E3 ubiquitin ligase, and PINK1, a ubiquitin kinase, cause early onset Parkinson's disease2,3. Both PINK1 and parkin function within the same biochemical pathway and remove damaged mitochondria from cells in culture and in animal models via mitophagy, a selective form of autophagy4. The in vivo role of mitophagy, however, is unclear, partly because mice that lack either PINK1 or parkin have no substantial Parkinson's-disease-relevant phenotypes5-7. Mitochondrial stress can lead to the release of damage-associated molecular patterns (DAMPs) that can activate innate immunity8-12, suggesting that mitophagy may mitigate inf…

  Disease area

  Neurodegeneration

  Pathway

  Mitochondrial function

  Publication type

  peer-reviewed journal article

  Citations

  1,150

  Identifier

  DOI 10.1038/s41586-018-0448-9

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0048strong evidenceSystematic review or meta-analysisevidence synthesisOpen access

  How informative is the mouse for human gut microbiota research?

  Nguyen TL, Vieira-Silva S, Liston A, Raes J. · Disease models & mechanisms (2015)

  The microbiota of the human gut is gaining broad attention owing to its association with a wide range of diseases, ranging from metabolic disorders (e.g. obesity and type 2 diabetes) to autoimmune diseases (such as inflammatory bowel disease and type 1 diabetes), cancer and even neurodevelopmental disorders (e.g. autism). Having been increasingly used in biomedical research, mice have become the model of choice for most studies in this emerging field. Mouse models allow perturbations in gut microbiota to be studied in a controlled experimental setup, and thus help in assessing causality of the complex host-microbiota interactions and in developing mechanistic hypotheses. However, pitfalls should be considered when translating gut microbiome research results from mouse models to humans. In this Special Article, we discuss the intrinsic similarities and differences that exist between th…

  Disease area

  Microbiome

  Pathway

  Inflammatory signalling

  Publication type

  peer-reviewed journal article

  Citations

  1,079

  Identifier

  DOI 10.1242/dmm.017400

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0056moderate evidencePrimary research articlepreclinical evidence

  NF-κB Restricts Inflammasome Activation via Elimination of Damaged Mitochondria

  Zhong Z, Umemura A, Sanchez-Lopez E, Liang S, Shalapour S, Wong J, He F, Boassa D, Perkins G, Ali SR, McGeough MD, Ellisman MH, Seki E, Gustafsson AB, Hoffman HM, Diaz-Meco MT, Moscat J, Karin M. · Cell (2016)

  Nuclear factor κB (NF-κB), a key activator of inflammation, primes the NLRP3-inflammasome for activation by inducing pro-IL-1β and NLRP3 expression. NF-κB, however, also prevents excessive inflammation and restrains NLRP3-inflammasome activation through a poorly defined mechanism. We now show that NF-κB exerts its anti-inflammatory activity by inducing delayed accumulation of the autophagy receptor p62/SQSTM1. External NLRP3-activating stimuli trigger a form of mitochondrial (mt) damage that is caspase-1- and NLRP3-independent and causes release of direct NLRP3-inflammasome activators, including mtDNA and mtROS. Damaged mitochondria undergo Parkin-dependent ubiquitin conjugation and are specifically recognized by p62, which induces their mitophagic clearance. Macrophage-specific p62 ablation causes pronounced accumulation of damaged mitochondria and excessive IL-1β-dependent inflammat…

  Disease area

  Neurodegeneration

  Pathway

  Mitochondrial function

  Publication type

  peer-reviewed journal article

  Citations

  1,045

  Identifier

  DOI 10.1016/j.cell.2015.12.057

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0005strong evidenceSystematic review or meta-analysisevidence synthesisOpen access

  The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis

  Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium, Swerdlow DI, Holmes MV, Kuchenbaecker KB, Engmann JE, Shah T, Sofat R, Sofat R, Guo Y, Chung C, Peasey A, Pfister R, Mooijaart SP, Ireland HA, Leusink M, Langenberg C, Li KW, Palmen J, Howard P, Cooper JA, Drenos F, Hardy J, Nalls MA, Li YR, Lowe G, Stewart M, Bielinski SJ, Peto J, Timpson NJ, Gallacher J, Dunlop M, Houl · Lancet (London, England) (2012)

  BackgroundA high circulating concentration of interleukin 6 is associated with increased risk of coronary heart disease. Blockade of the interleukin-6 receptor (IL6R) with a monoclonal antibody (tocilizumab) licensed for treatment of rheumatoid arthritis reduces systemic and articular inflammation. However, whether IL6R blockade also reduces risk of coronary heart disease is unknown.MethodsApplying the mendelian randomisation principle, we used single nucleotide polymorphisms (SNPs) in the gene IL6R to evaluate the likely efficacy and safety of IL6R inhibition for primary prevention of coronary heart disease. We compared genetic findings with the effects of tocilizumab reported in randomised trials in patients with rheumatoid arthritis.FindingsIn 40 studies including up to 133,449 individuals, an IL6R SNP (rs7529229) marking a non-synonymous IL6R variant (rs8192284; p.Asp358Ala) was a…

  Disease area

  Cardiovascular disease

  Pathway

  Inflammatory signalling

  Publication type

  peer-reviewed journal article

  Citations

  938

  Identifier

  DOI 10.1016/s0140-6736(12)60110-x

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0035strong evidenceSystematic review or meta-analysisevidence synthesisOpen access

  The relationship between different dimensions of alcohol use and the burden of disease-an update

  Rehm J, Gmel GE, Gmel G, Hasan OSM, Imtiaz S, Popova S, Probst C, Roerecke M, Room R, Samokhvalov AV, Shield KD, Shuper PA. · Addiction (Abingdon, England) (2017)

  Background and aimsAlcohol use is a major contributor to injuries, mortality and the burden of disease. This review updates knowledge on risk relations between dimensions of alcohol use and health outcomes to be used in global and national Comparative Risk Assessments (CRAs).MethodsSystematic review of reviews and meta-analyses on alcohol consumption and health outcomes attributable to alcohol use. For dimensions of exposure: volume of alcohol use, blood alcohol concentration and patterns of drinking, in particular heavy drinking occasions were studied. For liver cirrhosis, quality of alcohol was additionally considered. For all outcomes (mortality and/or morbidity): cause of death and disease/injury categories based on International Classification of Diseases (ICD) codes used in global CRAs; harm to others.ResultsIn total, 255 reviews and meta-analyses were identified. Alcohol use wa…

  Disease area

  Metabolic disease

  Pathway

  Lipid metabolism

  Publication type

  peer-reviewed journal article

  Citations

  870

  Identifier

  DOI 10.1111/add.13757

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0024strong evidenceSystematic review or meta-analysisevidence synthesisOpen access

  Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity

  Tsoi LC, Spain SL, Knight J, Ellinghaus E, Stuart PE, Capon F, Ding J, Li Y, Tejasvi T, Gudjonsson JE, Kang HM, Allen MH, McManus R, Novelli G, Samuelsson L, Schalkwijk J, Ståhle M, Burden AD, Smith CH, Cork MJ, Estivill X, Bowcock AM, Krueger GG, Weger W, Worthington J, Tazi-Ahnini R, Nestle FO, Hayday A, Hoffmann P, Winkelmann J, Wijmenga C, Langford C, Edkins S, Andrews R, Blackburn H, Strange · Nature genetics (2012)

  To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of 3 genome-wide association studies (GWAS) and 2 independent data sets genotyped on the Immunochip, including 10,588 cases and 22,806 controls. We identified 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals. We also identified, using conditional analyses, five independent signals within previously known loci. The newly identified loci shared with other autoimmune diseases include candidate genes with roles in regulating T-cell function (such as RUNX3, TAGAP and STAT3). Notably, they included candidate genes whose products are involved in innate host defense, including interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C) and nuclear factor (NF)-κB signaling (CARD14 and CARM1). These results portend a bette…

  Disease area

  Immunology

  Pathway

  Inflammatory signalling

  Publication type

  peer-reviewed journal article

  Citations

  837

  Identifier

  DOI 10.1038/ng.2467

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0068strong evidenceSystematic review or meta-analysisevidence synthesisOpen access

  Targeting p53 pathways: mechanisms, structures, and advances in therapy

  Wang H, Guo M, Wei H, Chen Y. · Signal transduction and targeted therapy (2023)

  The TP53 tumor suppressor is the most frequently altered gene in human cancers, and has been a major focus of oncology research. The p53 protein is a transcription factor that can activate the expression of multiple target genes and plays critical roles in regulating cell cycle, apoptosis, and genomic stability, and is widely regarded as the "guardian of the genome". Accumulating evidence has shown that p53 also regulates cell metabolism, ferroptosis, tumor microenvironment, autophagy and so on, all of which contribute to tumor suppression. Mutations in TP53 not only impair its tumor suppressor function, but also confer oncogenic properties to p53 mutants. Since p53 is mutated and inactivated in most malignant tumors, it has been a very attractive target for developing new anti-cancer drugs. However, until recently, p53 was considered an "undruggable" target and little progress has be…

  Disease area

  Oncology

  Pathway

  Cell cycle regulation

  Publication type

  peer-reviewed journal article

  Citations

  828

  Identifier

  DOI 10.1038/s41392-023-01347-1

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0057strong evidenceSystematic review or meta-analysisevidence synthesisOpen access

  The SH-SY5Y cell line in Parkinson's disease research: a systematic review

  Xicoy H, Xicoy H, Wieringa B, Martens GJ. · Molecular neurodegeneration (2017)

  Parkinson's disease (PD) is a devastating and highly prevalent neurodegenerative disease for which only symptomatic treatment is available. In order to develop a truly effective disease-modifying therapy, improvement of our current understanding of the molecular and cellular mechanisms underlying PD pathogenesis and progression is crucial. For this purpose, standardization of research protocols and disease models is necessary. As human dopaminergic neurons, the cells mainly affected in PD, are difficult to obtain and maintain as primary cells, current PD research is mostly performed with permanently established neuronal cell models, in particular the neuroblastoma SH-SY5Y lineage. This cell line is frequently chosen because of its human origin, catecholaminergic (though not strictly dopaminergic) neuronal properties, and ease of maintenance. However, there is no consensus on many fund…

  Disease area

  Neurodegeneration

  Pathway

  Mitochondrial function

  Publication type

  peer-reviewed journal article

  Citations

  788

  Identifier

  DOI 10.1186/s13024-017-0149-0

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0030strong evidenceRandomised controlled trialclinical evidenceOpen access

  Mediterranean diet intervention alters the gut microbiome in older people reducing frailty and improving health status: the NU-AGE 1-year dietary intervention across five European countries

  Ghosh TS, Rampelli S, Jeffery IB, Santoro A, Neto M, Capri M, Giampieri E, Jennings A, Candela M, Turroni S, Zoetendal EG, Hermes GDA, Elodie C, Meunier N, Brugere CM, Pujos-Guillot E, Berendsen AM, De Groot LCPGM, Feskins EJM, Kaluza J, Pietruszka B, Bielak MJ, Comte B, Maijo-Ferre M, Nicoletti C, De Vos WM, Fairweather-Tait S, Cassidy A, Brigidi P, Franceschi C, O'Toole PW. · Gut (2020)

  ObjectiveAgeing is accompanied by deterioration of multiple bodily functions and inflammation, which collectively contribute to frailty. We and others have shown that frailty co-varies with alterations in the gut microbiota in a manner accelerated by consumption of a restricted diversity diet. The Mediterranean diet (MedDiet) is associated with health. In the NU-AGE project, we investigated if a 1-year MedDiet intervention could alter the gut microbiota and reduce frailty.DesignWe profiled the gut microbiota in 612 non-frail or pre-frail subjects across five European countries (UK, France, Netherlands, Italy and Poland) before and after the administration of a 12-month long MedDiet intervention tailored to elderly subjects (NU-AGE diet).ResultsAdherence to the diet was associated with specific microbiome alterations. Taxa enriched by adherence to the diet were positively associated wi…

  Disease area

  Metabolic disease

  Pathway

  Insulin signalling

  Publication type

  peer-reviewed journal article

  Citations

  712

  Identifier

  DOI 10.1136/gutjnl-2019-319654

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0063strong evidenceRandomised controlled trialclinical evidenceOpen access

  A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer's disease with lecanemab, an anti-Aβ protofibril antibody

  Swanson CJ, Zhang Y, Dhadda S, Wang J, Kaplow J, Lai RYK, Lannfelt L, Bradley H, Rabe M, Koyama A, Reyderman L, Berry DA, Berry S, Gordon R, Kramer LD, Cummings JL. · Alzheimer's research & therapy (2021)

  BackgroundLecanemab (BAN2401), an IgG1 monoclonal antibody, preferentially targets soluble aggregated amyloid beta (Aβ), with activity across oligomers, protofibrils, and insoluble fibrils. BAN2401-G000-201, a randomized double-blind clinical trial, utilized a Bayesian design with response-adaptive randomization to assess 3 doses across 2 regimens of lecanemab versus placebo in early Alzheimer's disease, mild cognitive impairment due to Alzheimer's disease (AD) and mild AD dementia.MethodsBAN2401-G000-201 aimed to establish the effective dose 90% (ED90), defined as the simplest dose that achieves ≥90% of the maximum treatment effect. The primary endpoint was Bayesian analysis of 12-month clinical change on the Alzheimer's Disease Composite Score (ADCOMS) for the ED90 dose, which required an 80% probability of ≥25% clinical reduction in decline versus placebo. Key secondary endpoints i…

  Disease area

  Neurodegeneration

  Pathway

  Proteostasis

  Publication type

  peer-reviewed journal article

  Citations

  706

  Identifier

  DOI 10.1186/s13195-021-00813-8

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0038strong evidenceRandomised controlled trialclinical evidence

  Effect of Caloric Restriction or Aerobic Exercise Training on Peak Oxygen Consumption and Quality of Life in Obese Older Patients With Heart Failure With Preserved Ejection Fraction: A Randomized Clinical Trial

  Kitzman DW, Brubaker P, Morgan T, Haykowsky M, Hundley G, Kraus WE, Eggebeen J, Nicklas BJ. · JAMA (2016)

  ImportanceMore than 80% of patients with heart failure with preserved ejection fraction (HFPEF), the most common form of heart failure among older persons, are overweight or obese. Exercise intolerance is the primary symptom of chronic HFPEF and a major determinant of reduced quality of life (QOL).ObjectiveTo determine whether caloric restriction (diet) or aerobic exercise training (exercise) improves exercise capacity and QOL in obese older patients with HFPEF.Design, setting, and participantsRandomized, attention-controlled, 2 × 2 factorial trial conducted from February 2009 through November 2014 in an urban academic medical center. Of 577 initially screened participants, 100 older obese participants (mean [SD]: age, 67 years [5]; body mass index, 39.3 [5.6]) with chronic, stable HFPEF were enrolled (366 excluded by inclusion and exclusion criteria, 31 for other reasons, and 80 decl…

  Disease area

  Metabolic disease

  Pathway

  Mitochondrial function

  Publication type

  peer-reviewed journal article

  Citations

  699

  Identifier

  DOI 10.1001/jama.2015.17346

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0025strong evidenceRandomised controlled trialclinical evidenceOpen access

  Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial

  Marconi VC, Ramanan AV, de Bono S, Kartman CE, Krishnan V, Liao R, Piruzeli MLB, Goldman JD, Alatorre-Alexander J, de Cassia Pellegrini R, Estrada V, Som M, Cardoso A, Chakladar S, Crowe B, Reis P, Zhang X, Adams DH, Ely EW, COV-BARRIER Study Group. · The Lancet. Respiratory medicine (2021)

  BackgroundBaricitinib is an oral selective Janus kinase 1/2 inhibitor with known anti-inflammatory properties. This study evaluates the efficacy and safety of baricitinib in combination with standard of care for the treatment of hospitalised adults with COVID-19.MethodsIn this phase 3, double-blind, randomised, placebo-controlled trial, participants were enrolled from 101 centres across 12 countries in Asia, Europe, North America, and South America. Hospitalised adults with COVID-19 receiving standard of care were randomly assigned (1:1) to receive once-daily baricitinib (4 mg) or matched placebo for up to 14 days. Standard of care included systemic corticosteroids, such as dexamethasone, and antivirals, including remdesivir. The composite primary endpoint was the proportion who progressed to high-flow oxygen, non-invasive ventilation, invasive mechanical ventilation, or death by day…

  Disease area

  Immunology

  Pathway

  Inflammatory signalling

  Publication type

  peer-reviewed journal article

  Citations

  570

  Identifier

  DOI 10.1016/s2213-2600(21)00331-3

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0073strong evidenceSystematic review or meta-analysisevidence synthesisOpen access

  Neutrophil to lymphocyte ratio and cancer prognosis: an umbrella review of systematic reviews and meta-analyses of observational studies

  Cupp MA, Cariolou M, Tzoulaki I, Aune D, Evangelou E, Berlanga-Taylor AJ. · BMC medicine (2020)

  BackgroundAlthough neutrophils have been linked to the progression of cancer, uncertainty exists around their association with cancer outcomes, depending on the site, outcome and treatments considered. We aimed to evaluate the strength and validity of evidence on the association between either the neutrophil to lymphocyte ratio (NLR) or tumour-associated neutrophils (TAN) and cancer prognosis.MethodsWe searched MEDLINE, Embase and Cochrane Database of Systematic Reviews from inception to 29 May 2020 for systematic reviews and meta-analyses of observational studies on neutrophil counts (here NLR or TAN) and specific cancer outcomes related to disease progression or survival. The available evidence was graded as strong, highly suggestive, suggestive, weak or uncertain through the application of pre-set GRADE criteria.ResultsA total of 204 meta-analyses from 86 studies investigating the…

  Disease area

  Oncology

  Pathway

  Inflammatory signalling

  Publication type

  peer-reviewed journal article

  Citations

  554

  Identifier

  DOI 10.1186/s12916-020-01817-1

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0053strong evidenceRandomised controlled trialclinical evidenceOpen access

  Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer's disease

  Moussa C, Hebron M, Huang X, Ahn J, Rissman RA, Aisen PS, Turner RS. · Journal of neuroinflammation (2017)

  BackgroundTreatment of mild-moderate Alzheimer's disease (AD) subjects (N = 119) for 52 weeks with the SIRT1 activator resveratrol (up to 1 g by mouth twice daily) attenuates progressive declines in CSF Aβ40 levels and activities of daily living (ADL) scores.MethodsFor this retrospective study, we examined banked CSF and plasma samples from a subset of AD subjects with CSF Aβ42 ResultsCompared to the placebo-treated group, at 52 weeks, resveratrol markedly reduced CSF MMP9 and increased macrophage-derived chemokine (MDC), interleukin (IL)-4, and fibroblast growth factor (FGF)-2. Compared to baseline, resveratrol increased plasma MMP10 and decreased IL-12P40, IL12P70, and RANTES. In this subset analysis, resveratrol treatment attenuated declines in mini-mental status examination (MMSE) scores, change in ADL (ADCS-ADL) scores, and CSF Aβ42 levels during the 52-week trial, but did not al…

  Disease area

  Neurodegeneration

  Pathway

  Inflammatory signalling

  Publication type

  peer-reviewed journal article

  Citations

  522

  Identifier

  DOI 10.1186/s12974-016-0779-0

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0078strong evidenceRandomised controlled trialclinical evidenceOpen access

  High-dose resveratrol supplementation in obese men: an investigator-initiated, randomized, placebo-controlled clinical trial of substrate metabolism, insulin sensitivity, and body composition

  Poulsen MM, Vestergaard PF, Clasen BF, Radko Y, Christensen LP, Stødkilde-Jørgensen H, Møller N, Jessen N, Pedersen SB, Jørgensen JO. · Diabetes (2013)

  Obesity, diabetes, hypertension, and hyperlipidemia constitute risk factors for morbidity and premature mortality. Based on animal and in vitro studies, resveratrol reverts these risk factors via stimulation of silent mating type information regulation 2 homolog 1 (SIRT1), but data in human subjects are scarce. The objective of this study was to examine the metabolic effects of high-dose resveratrol in obese human subjects. In a randomized, placebo-controlled, double-blinded, and parallel-group design, 24 obese but otherwise healthy men were randomly assigned to 4 weeks of resveratrol or placebo treatment. Extensive metabolic examinations including assessment of glucose turnover and insulin sensitivity (hyperinsulinemic euglycemic clamp) were performed before and after the treatment. Insulin sensitivity, the primary outcome measure, deteriorated insignificantly in both groups. Endogen…

  Disease area

  Oncology

  Pathway

  Mitochondrial function

  Publication type

  peer-reviewed journal article

  Citations

  370

  Identifier

  DOI 10.2337/db12-0975

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0015strong evidenceRandomised controlled trialclinical evidenceOpen access

  Exercise training improves peak oxygen consumption and haemodynamics in patients with severe pulmonary arterial hypertension and inoperable chronic thrombo-embolic pulmonary hypertension: a prospective, randomized, controlled trial

  Ehlken N, Lichtblau M, Klose H, Weidenhammer J, Fischer C, Nechwatal R, Uiker S, Halank M, Olsson K, Seeger W, Gall H, Rosenkranz S, Wilkens H, Mertens D, Seyfarth HJ, Opitz C, Ulrich S, Egenlauf B, Grünig E. · European heart journal (2016)

  AimsThe impact of exercise training on the right heart and pulmonary circulation has not yet been invasively assessed in patients with pulmonary hypertension (PH) and right heart failure. This prospective randomized controlled study investigates the effects of exercise training on peak VO2/kg, haemodynamics, and further clinically relevant parameters in PH patients.Methods and resultsEighty-seven patients with pulmonary arterial hypertension and inoperable chronic thrombo-embolic PH (54% female, 56 ± 15 years, 84% World Health Organization functional class III/IV, 53% combination therapy) on stable disease-targeted medication were randomly assigned to a control and training group. Medication remained unchanged during the study period. Non-invasive assessments and right heart catheterization at rest and during exercise were performed at baseline and after 15 weeks. Primary endpoint was…

  Disease area

  Cardiovascular disease

  Pathway

  Vascular remodelling

  Publication type

  peer-reviewed journal article

  Citations

  168

  Identifier

  DOI 10.1093/eurheartj/ehv337

  Source

  Europe PMC / PubMed

  Read the source publication
• QM-LIT-0058strong evidenceRandomised controlled trialclinical evidence

  Integrated analysis of methylome and transcriptome responses to exercise training in children with overweight/obesity

  Plaza-Florido A, Anguita-Ruiz A, Esteban FJ, Aguilera CM, Labayen I, Reitzner SM, Sundberg CJ, Radom-Aizik S, Ortega FB, Altmäe S. · Physiological genomics (2025)

  We examined the effects of a 20-wk exercise intervention on whole blood genome-wide DNA methylation signature and its association with the exercise-induced changes in gene expression profiles in boys and girls with overweight/obesity (OW/OB). Twenty-three children (10.05 ± 1.39 yr, 56% girls) with OW/OB were randomized to either a 20-wk exercise intervention [exercise group (EG); n = 10; 4 boys/6 girls] or to usual lifestyle [control group (CG); n = 13; 6 boys/7 girls]. Whole blood genome-wide methylome (CpG sites) analysis using Infinium Methylation EPIC array and transcriptome analysis using RNA-seq (STRT2 protocol) were performed. Exercise-induced modifications in DNA methylation at 485 and 386 CpGs sites in boys and girls, respectively. These CpG sites are mapped to loci enriched in distinct gene pathways related to metabolic diseases, fatty acid metabolism, and immune function. I…

  Disease area

  Neurodegeneration

  Pathway

  Mitochondrial function

  Publication type

  peer-reviewed journal article

  Citations

  6

  Identifier

  DOI 10.1152/physiolgenomics.00059.2024

  Source

  Europe PMC / PubMed

  Read the source publication