Featured
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| Open AccessIdentification of biomarkers for glycaemic deterioration in type 2 diabetes
There is an urgent need for biomarkers for type 2 diabetes progression that provide a deeper understanding of the disease process. Here, the authors identify biomarkers in three molecular classes, replicate them in other cohorts and explore top protein biomarkers in detail in functional studies.
- Roderick C. Slieker
- , Louise A. Donnelly
- & Guy A. Rutter
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Article
| Open AccessSingle-cell metabolic fingerprints discover a cluster of circulating tumor cells with distinct metastatic potential
Circulating tumor cells (CTCs) are the tumor cells responsible for metastasis. Here, the authors develop a home-built single-cell quantitative mass spectrometric platform and discover a cluster of CTCs with distinct metastatic potential using a molecular typing system based on the single-cell metabolic fingerprints.
- Wenjun Zhang
- , Feifei Xu
- & Yun Chen
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Article
| Open AccessMetabolomic differentiation of benign vs malignant pulmonary nodules with high specificity via high-resolution mass spectrometry analysis of patient sera
Detection of lung adenocarcinoma through serum sampling could be an alternative to CT scanning. Here, the authors use global metabolomics to create a 27 metabolite signature, which showed accuracy in detection in an external validation cohort.
- Yao Yao
- , Xueping Wang
- & Yumin Hu
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Article
| Open AccessAccelerated biological aging and risk of depression and anxiety: evidence from 424,299 UK Biobank participants
Theory indicates that biological aging may contribute to poor mental health in late life. Here, authors show advanced biological aging may represent a potential risk factor for incident depression/anxiety in midlife and older adults and a potential target for risk assessment and intervention.
- Xu Gao
- , Tong Geng
- & Tao Huang
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| Open AccessIdentification of three bacterial species associated with increased appendicular lean mass: the HUNT study
Here, the authors employ data from the population-based Norwegian HUNT cohort (n = 5196, including women and men) to associate the presence of three gut microbial species – Coprococcus comes, Dorea longicatena, and Eubacterium ventriosum – with higher lean mass.
- Louise Grahnemo
- , Maria Nethander
- & Claes Ohlsson
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Article
| Open AccessHistopathology images predict multi-omics aberrations and prognoses in colorectal cancer patients
Histopathological analysis is an essential tool in diagnosing colorectal cancer, but is limited in predicting prognosis and molecular profiles. Here, the authors designed a machine learning-based platform to predict multi-omics profiles and prognosis from pathology images.
- Pei-Chen Tsai
- , Tsung-Hua Lee
- & Kun-Hsing Yu
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Article
| Open AccessPlasma neurodegeneration biomarker concentrations associate with glymphatic and meningeal lymphatic measures in neurological disorders
Plasma neurodegeneration biomarkers are increasingly utilized to predict neurological disease. Here, authors show in different neurological disorders associations between plasma neurodegeneration biomarker concentrations and various measures of glymphatic and meningeal lymphatic functions.
- Per Kristian Eide
- , Aslan Lashkarivand
- & Henrik Zetterberg
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| Open AccessThe Trypanosoma cruzi Antigen and Epitope Atlas: antibody specificities in Chagas disease patients across the Americas
This work reveals the diversity and extent of human antibody specificities in Chagas disease and provides a wealth of well-defined antigenic markers for diagnosis and development of serological applications for this neglected infectious disease.
- Alejandro D. Ricci
- , Leonel Bracco
- & Fernán Agüero
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Article
| Open AccessIMC-Denoise: a content aware denoising pipeline to enhance Imaging Mass Cytometry
Multiplexed imaging technologies can reveal the complex cellular and molecular profiles of tissue. Here, the authors develop and implement a denoising pipeline to significantly enhance imaging mass cytometry quality and improve single-cell analyses.
- Peng Lu
- , Karolyn A. Oetjen
- & Daniel L. J. Thorek
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Article
| Open AccessClinically important alterations in pharmacogene expression in histologically severe nonalcoholic fatty liver disease
This study characterizes expression of pharmacogenes across the histological NAFLD severity spectrum. Here, the authors show the downregulation of CYP2C19 in NAFLD which supports developing personalized medicine approaches for drugs sensitive to metabolism by the CYP2C19 enzyme.
- Nicholas R. Powell
- , Tiebing Liang
- & Naga Chalasani
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Article
| Open AccessNon-falciparum malaria infection and IgG seroprevalence among children under 15 years in Nigeria, 2018
Nigeria has a high burden of malaria which mostly results from Plasmodium falciparum infection, but other species are also endemic. Here, the authors estimate the prevalence of active infection and previous exposure to P malariae, P ovale, and P vivax in children in Nigeria in 2018 and determine risk factors.
- Camelia Herman
- , Colleen M. Leonard
- & Eric Rogier
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Article
| Open AccessClinical and biomarker analyses of sintilimab plus gemcitabine and cisplatin as first-line treatment for patients with advanced biliary tract cancer
Chemotherapeutic agents and immune checkpoint inhibitors have shown modest efficacy in patients with advanced biliary tract cancers (BTCs). Here the authors report the results of a phase II trial of the anti-PD1 antibody sintilimab plus chemotherapy (gemcitabine and cisplatin) as first-line treatment for patients with advanced BTCs.
- Tian-mei Zeng
- , Guang Yang
- & Zhen-gang Yuan
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Article
| Open AccessMultiplexed analysis of EV reveals specific biomarker composition with diagnostic impact
Multiplexed analyses of near single EVs is currently challenging. Here the authors report the method MASEV, multiplexed analysis of EVs, to interrogate thousands of individual EVs during 5 cycles of multi-channel fluorescence staining for 15 EV biomarkers.
- Joshua D. Spitzberg
- , Scott Ferguson
- & Ralph Weissleder
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Article
| Open AccessTandem mass tag-based quantitative proteomic profiling identifies candidate serum biomarkers of drug-induced liver injury in humans
Diagnosis of rare, unpredictable, drug-induced liver injury (DILI) is a significant challenge for patients, clinicians, and drug development. Here, the authors discover, evaluate, and validate potential blood biomarkers to diagnose DILI and distinguish it from alternative causes of liver injury.
- Kodihalli C. Ravindra
- , Vishal S. Vaidya
- & Shashi K. Ramaiah
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Article
| Open AccessCirculating tumor DNA reveals complex biological features with clinical relevance in metastatic breast cancer
Plasma ctDNA is a promising method to determine patient outcome in multiple cancer types. Here, the authors use shallow WGS to create machine learning signatures to identify tumor phenotypes and predict therapy response in patients with metastatic breast cancer.
- Aleix Prat
- , Fara Brasó-Maristany
- & Ana Vivancos
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| Open AccessGenomic and immune landscape Of metastatic pheochromocytoma and paraganglioma
The molecular mechanisms underlying metastasis in pheochromocytoma/paraganglioma (mPPGL) remain to be explored. Here, the authors perform genomic and immunogenomic profiling of mPPGL tumors and suggest potential biomarkers for risk of metastasis and immunotherapy response.
- Bruna Calsina
- , Elena Piñeiro-Yáñez
- & Mercedes Robledo
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Article
| Open AccessFour-dimensional trapped ion mobility spectrometry lipidomics for high throughput clinical profiling of human blood samples
The circulatory lipidome is a valuable source for disease markers, but reliable marker discovery requires continuous development of lipidomic methods for large-scale clinical profiling. Here, the authors present a 4-dimensional lipidomics solution for confident and reproducible blood lipidome profiling.
- Raissa Lerner
- , Dhanwin Baker
- & Laura Bindila
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Article
| Open AccessForecasting individual progression trajectories in Alzheimer’s disease
Accurate prediction of disease progression in Alzheimer’s disease (AD) is necessary for optimal recruitment of patients to clinical trials. Here, the authors present AD Course Map, a statistical model which helps to predict disease progression in participants, thus decreasing the required sample size for a hypothetical trial.
- Etienne Maheux
- , Igor Koval
- & Stanley Durrleman
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Article
| Open AccessLong-term platinum-based drug accumulation in cancer-associated fibroblasts promotes colorectal cancer progression and resistance to therapy
Standard platinum-based chemotherapy is the basis of treatment of many cancers, however a proportion of patients do not derive benefit. Here the authors show that the platinum-based drug oxaliplatin accumulates in cancer-associated fibroblasts, activating pathways associated with cancer progression and resistance to therapy.
- Jenniffer Linares
- , Anna Sallent-Aragay
- & Alexandre Calon
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| Open AccessAngiotensin-converting enzyme inhibitor promotes angiogenesis through Sp1/Sp3-mediated inhibition of notch signaling in male mice
ACE inhibitors are widely used to treat cardiovascular diseases and promote angiogenesis. Here, the authors show a central role for endothelial USP7-Sp1/Sp3-Notch1 signalling in pathophysiological angiogenesis in response to ACE inhibitor treatment.
- Hanlin Lu
- , Peidong Yuan
- & Wencheng Zhang
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| Open AccessEstablishment and validation of a plasma oncofetal chondroitin sulfated proteoglycan for pan-cancer detection
Developing multi-cancer early detection (MCED) tests based on cfDNA or protein markers holds great promise for effective cancer screening. Here, the authors show a sensitive, non-invasive pan-cancer detection method that concurrently detects the oncofetal chondroitin sulfate (ofCS) glycans and its protein backbone in plasma.
- Pei-Fen Zhang
- , Zi-Yi Wu
- & Wei-Hua Jia
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Article
| Open AccessAtlas of plasma NMR biomarkers for health and disease in 118,461 individuals from the UK Biobank
The authors report a systematic analyses of blood biomarkers for metabolism against the whole spectrum of diseases in 100,000 individuals and reveals a prominent role of numerous metabolic biomarkers as risk markers beyond heart disease and diabetes.
- Heli Julkunen
- , Anna Cichońska
- & Peter Würtz
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| Open AccessQuantifying PON1 on HDL with nanoparticle-gated electrokinetic membrane sensor for accurate cardiovascular risk assessment
Measuring proteomic subfractions of HDL can help during cardiovascular risk assessment. Here, the authors show, using a Nanoparticle-Gated Electrokinetic Membrane Sensor, the efficacy of Paroxonase 1 on HDL in its ability to diagnose cardiovascular disease compared to other commonly used methods.
- Sonu Kumar
- , Nalin Maniya
- & Hsueh-Chia Chang
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Article
| Open AccessNext-Generation Morphometry for pathomics-data mining in histopathology
Pathology diagnostics still rely on tissue morphology assessment by trained experts. Here, the authors perform deep-learning-based segmentation followed by large-scale feature extraction of histological images, i.e., next-generation morphometry, to enable outcome-relevant and disease-specific pathomics analysis of non-tumor kidney pathology.
- David L. Hölscher
- , Nassim Bouteldja
- & Peter Boor
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| Open AccessEstimation and implications of the genetic architecture of fasting and non-fasting blood glucose
Most genetic studies of glucose levels have been done on fasting samples, which can be difficult to obtain. Here, the authors identify 156 genetic loci controlling the physiological variation of glucose levels in healthy non-fasting individuals, demonstrating that the results non-fasting samples can be used to predict fasting glucose levels.
- Zhen Qiao
- , Julia Sidorenko
- & Loic Yengo
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Article
| Open AccessDNA methylation analysis explores the molecular basis of plasma cell-free DNA fragmentation
Cell free DNA is produced through a non-random process. Here, the authors use orientation-aware fragmentation analysis to identify DNA methylation as a regulator of nuclease function.
- Yunyun An
- , Xin Zhao
- & Kun Sun
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Article
| Open AccessHigh-throughput telomere length measurement at nucleotide resolution using the PacBio high fidelity sequencing platform
There exist challenges in quantifying the length of individual telomeres at single nucleotide resolution. Here the authors report a method to capture telomeres and accurately analyse their length in human cell lines and patient peripheral blood leukocyte samples using single-molecule real-time sequencing.
- Cheng-Yong Tham
- , LaiFong Poon
- & Shang Li
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Article
| Open AccessGut microbiome dysbiosis drives metabolic dysfunction in Familial dysautonomia
Familial dysautonomia is a rare genetic disease caused in part by neurodegeneration. Here, the authors show that the gut-metabolism axis is altered in both patients and transgenic mice and that disease pathology is ameliorated by controlling microbiome divergence.
- Alexandra M. Cheney
- , Stephanann M. Costello
- & Seth T. Walk
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Article
| Open AccessEarly response evaluation by single cell signaling profiling in acute myeloid leukemia
The molecular mechanisms underlying response to chemotherapy in Acute myeloid leukemia (AML) remain to be explored. Here, the authors perform 36-dimensional mass cytometry in 32 AML patients during intensive chemotherapy and suggest functional signalling analysis for prognosis prediction early after treatment in AML.
- Benedicte Sjo Tislevoll
- , Monica Hellesøy
- & Bjørn Tore Gjertsen
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Article
| Open AccessSystematic review and individual-patient-data meta-analysis of non-invasive fibrosis markers for chronic hepatitis B in Africa
Authors carry out a systematic review and meta-analysis to evaluate the performance of fibrosis biomarkers for the diagnosis of fibrosis and cirrhosis in patients with chronic hepatitis B virus infection living in sub-Saharan Africa.
- Asgeir Johannessen
- , Alexander J. Stockdale
- & Maud Lemoine
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| Open AccessMulti-organ imaging demonstrates the heart-brain-liver axis in UK Biobank participants
While heart disease, dementia and liver disease often co-occur, multi-organ imaging is needed for deeper elucidation of these cross-organ links. Here, the authors use image-derived phenotypes to describe underlying associations between heart, brain and liver health in a large population cohort.
- Celeste McCracken
- , Zahra Raisi-Estabragh
- & Stefan Neubauer
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| Open AccessA comparison of the genes and genesets identified by GWAS and EWAS of fifteen complex traits
Genome-wide and epigenome-wide association studies both link genomic regions to human traits, but here the authors demonstrate that these study types are capturing different genes and biological aspects of complex traits.
- Thomas Battram
- , Tom R. Gaunt
- & Gibran Hemani
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| Open AccessMulti-omics identify falling LRRC15 as a COVID-19 severity marker and persistent pro-thrombotic signals in convalescence
End-stage kidney disease confers a high risk for severe COVID-19 infection. Using an at-risk group (end-stage kidney disease patients with COVID-19), authors using RNA-sequencing of immune cells and plasma proteomic profiling to investigate the host response to viral infection.
- Jack S. Gisby
- , Norzawani B. Buang
- & James E. Peters
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Article
| Open AccessLocally organised and activated Fth1hi neutrophils aggravate inflammation of acute lung injury in an IL-10-dependent manner
Acute respiratory distress syndrome (ARDS) is an acute pulmonary disease involving neutrophils. Here the authors characterise lung neutrophil infiltration during ARDS and show that there are neutrophils with different function and transcriptional profile which are regulated by IL-10.
- Kun Wang
- , Muyun Wang
- & Wei Gao
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Article
| Open AccessTumor fractions deciphered from circulating cell-free DNA methylation for cancer early diagnosis
‘Circulating cell-free DNA can be used to predict cancer, but it is more challenging to assess in early stage cancer. Here, the authors created a diagnostic model using tumor fractions deciphered from circulating cfDNA methylation signatures, which exhibited an 86% sensitivity in detecting early-stage cancer.
- Xiao Zhou
- , Zhen Cheng
- & Weibin Cheng
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Article
| Open AccessMolecular models of multiple sclerosis severity identify heterogeneity of pathogenic mechanisms
Multiple sclerosis (MS) changes the composition of the CSF. Here the authors use patient samples and aggregate CSF biomarkers into models that predict disability across all MS phenotypes, and identify potentially causal mechanisms and molecular disease heterogeneity.
- Peter Kosa
- , Christopher Barbour
- & Bibiana Bielekova
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Article
| Open AccessCausal inference in medical records and complementary systems pharmacology for metformin drug repurposing towards dementia
Previous observational studies of the diabetes drugs metformin vs. sulfonylureas have yielded mixed results about whether metformin reduces the risk of dementia, relative to the sulfonylureas. Here, the authors apply a novel competing risks approach to emulate dementia-related target trials in electronic health records of diabetic patients and a complementary systems pharmacology evaluation on human neural cells.
- Marie-Laure Charpignon
- , Bella Vakulenko-Lagun
- & Mark W. Albers
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| Open AccessAn umbrella review of the evidence linking oral health and systemic noncommunicable diseases
Previous studies have supported a potential bidirectional association between oral diseases and systemic noncommunicable diseases (NCDs) Here the authors perform an umbrella review of meta-analyses for the association between oral health and NCDs, and report that 27 NCDs were associated with oral disease, however, the overall strength of evidence was found to be unfavorable and with methodological inconsistencies.
- João Botelho
- , Paulo Mascarenhas
- & Vanessa Machado
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Article
| Open AccessWhole genome sequencing identifies structural variants contributing to hematologic traits in the NHLBI TOPMed program
Most genetic association studies have been done on single nucleotide polymorphisms and small indels, while other types of variants have been less studied. Here, the authors use whole genome sequencing in a diverse population to identify and provide experimental evidence for associations between structural variants and blood-cell traits.
- Marsha M. Wheeler
- , Adrienne M. Stilp
- & Alex P. Reiner
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Article
| Open AccessPhosphoproteomic analysis of neoadjuvant breast cancer suggests that increased sensitivity to paclitaxel is driven by CDK4 and filamin A
Phosphoproteomics is a promising tool for identifying biomarkers of treatment response in cancer. Here, the authors analyse proteomics profiling of HER2-negative female breast cancer patients and identify potential predictors of paclitaxel response.
- S. Mouron
- , M. J. Bueno
- & M. Quintela-Fandino
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Article
| Open AccessLY6D marks pre-existing resistant basosquamous tumor subpopulations
The identification of distinct cell populations with cellular plasticity in skin basal cell carcinoma is important for understanding treatment resistance mechanisms. Here, the authors identify the resistant LY6D+ basosquamous population that correlates with poor clinical outcomes.
- Daniel Haensel
- , Sadhana Gaddam
- & Anthony E. Oro
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Article
| Open AccessA framework for clinical cancer subtyping from nucleosome profiling of cell-free DNA
Nucleosome profiling from cell-free DNA (cfDNA) represents a potential approach for cancer detection and classification. Here, the authors develop Griffin, a computational framework for tumour subtype classification based on cfDNA nucleosome profiling that can work with ultra-low pass sequencing data.
- Anna-Lisa Doebley
- , Minjeong Ko
- & Gavin Ha
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Article
| Open AccessGraph-based autoencoder integrates spatial transcriptomics with chromatin images and identifies joint biomarkers for Alzheimer’s disease
Methods for jointly analysing the different spatial data modalities in 3D are lacking. Here the authors report the computational framework STACI (Spatial Transcriptomic data using over-parameterized graph-based Autoencoders with Chromatin Imaging data) which they apply to an Alzheimer’s disease mouse model.
- Xinyi Zhang
- , Xiao Wang
- & Caroline Uhler
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Article
| Open AccessNasal DNA methylation at three CpG sites predicts childhood allergic disease
Accurate prediction of the onset of childhood allergy is important to clarify the difference between various respiratory diseases. Here the authors propose that the methylation status of three sites in nasal DNA predicts the onset of childhood allergy which may aid diagnosis and monitoring.
- Merlijn van Breugel
- , Cancan Qi
- & Cheng-Jian Xu
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Article
| Open AccessA self-powered ingestible wireless biosensing system for real-time in situ monitoring of gastrointestinal tract metabolites
Metabolic dynamics within the small intestine are difficult to study due to the lack of in situ access. Here, the authors report an ingestible, self-powered, and wireless biosensing system, demonstrating proof-of-principle real-time glucose monitoring in the small intestines of pigs.
- Ernesto De la Paz
- , Nikhil Harsha Maganti
- & Patrick P. Mercier
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Article
| Open AccessExperimental evidence for temporal uncoupling of brain Aβ deposition and neurodegenerative sequelae
The poor correlation between brain Aβ deposition and clinical symptoms in Alzheimer´s disease remains puzzling. Here, the authors show a temporal dissociation of Aβ deposition and neurodegeneration.
- Christine Rother
- , Ruth E. Uhlmann
- & Mathias Jucker
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Article
| Open AccessA single-cell analysis reveals tumor heterogeneity and immune environment of acral melanoma
Studying the cell composition of acral melanoma at the single-cell level could provide some clues about its poor response to immunotherapy. Here, the authors analyse acral and cutaneous melanoma patient samples using single-cell RNA-sequencing, and reveal a severe immunosuppressive state in acral melanomas
- Chao Zhang
- , Hongru Shen
- & Jilong Yang
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Article
| Open AccessCXCL13 is a predictive biomarker in idiopathic multicentric Castleman disease
Idiopathic multicentric Castleman disease (iMCD) is a life-threatening inflammatory disease requiring immediate intervention, for which the recommended first-line therapy is the Interleukin-6 pathway inhibitor siltuximab. Authors here show that the change in levels of the chemokine CXCL13 shortly following the start of siltuximab treatment is predictive of response.
- Sheila K. Pierson
- , Laura Katz
- & David C. Fajgenbaum
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Article
| Open AccessMulti-omics signatures of the human early life exposome
Environmental exposures in early life can have lasting health effects, but the molecular mechanisms are not well understood. Here, the authors discover >1000 associations between exposure factors and child multi-omics profiles, revealing signatures for diet, toxic chemical compounds, essential trace elements, and weather conditions.
- Léa Maitre
- , Mariona Bustamante
- & Martine Vrijheid