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| 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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| 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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| 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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| 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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| 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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| 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
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| Open AccessPrognostic and predictive value of a pathomics signature in gastric cancer
The current tumour-node-metastasis staging system alone cannot provide adequate information for prognosis and adjuvant chemotherapy benefits in patients with gastric cancer. Herein, the authors propose a pathomics signature that was derived from multiple features of haematoxylin and eosin-stained slides.
- Dexin Chen
- , Meiting Fu
- & Jun Yan
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Article
| Open AccessThe prognostic and diagnostic value of intraleukocytic malaria pigment in patients with severe falciparum malaria
Malaria diagnosis by microscopy provides valuable rapid diagnostic and prognostic information, which is critical to clinical management. In this work, authors carry out a meta-analysis on the prognostic and diagnostic value of polymorphonuclear leukocytes and monocytes containing malaria pigment in peripheral blood film counts taken from patients with severe malaria.
- Ketsanee Srinamon
- , James A. Watson
- & Nicholas J. White
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Article
| Open AccessDeep phenotyping and lifetime trajectories reveal limited effects of longevity regulators on the aging process in C57BL/6J mice
Lifespan can be affected by both physiological ageing and specific sets of pathologies associated with old age. Here the authors report a resource of large-scale cross-sectional phenotyping of aging male mice at different time points to analyse a large set of phenotypes and molecular markers, including during genetic and diet interventions affecting lifespan.
- Kan Xie
- , Helmut Fuchs
- & Dan Ehninger
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Article
| Open AccessA click chemistry amplified nanopore assay for ultrasensitive quantification of HIV-1 p24 antigen in clinical samples
Accurate detection of antigen p24 for HIV−1 early diagnosis remains challenging. Here the authors present a click chemistry amplified nanopore (CAN) assay that allows p24 quantification at ultralow concentration range in clinical samples.
- Xiaojun Wei
- , Xiaoqin Wang
- & Chang Liu
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Article
| Open AccessLipidomic signatures align with inflammatory patterns and outcomes in critical illness
Alterations in lipid metabolism and circulating lipid species have been reported in patients with acute critical illness. Here the authors show that selective rise in systemic phosphatidylethanolamine levels is a common feature of critical illness that associates with worse clinical outcomes.
- Junru Wu
- , Anthony Cyr
- & Mieshia Beamon
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Article
| Open AccessFaecal microbiome-based machine learning for multi-class disease diagnosis
Here, using fecal metagenomics data of 2,320 individuals, the authors develop a microbiome-based machine learning approach showing high accuracy for multi-class disease diagnosis, highlighting its potential application in improving noninvasive diagnostics and monitor responses to therapy.
- Qi Su
- , Qin Liu
- & Siew C. Ng
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| Open AccessSevere Neuro-COVID is associated with peripheral immune signatures, autoimmunity and neurodegeneration: a prospective cross-sectional study
Both acute and chronic COVID-19 disease (also known as long-COVID) may affect the central nervous system. Here authors characterize the immunological profile of peripheral blood and cerebrospinal fluid of COVID-19 patients in order to identify the main factors that contribute to neurological impairment and the severity of neurological symptoms in Sars-CoV-2 infection.
- Manina M. Etter
- , Tomás A. Martins
- & Gregor Hutter
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| Open AccessDeep learning-based image analysis predicts PD-L1 status from H&E-stained histopathology images in breast cancer
Programmed death ligand-1 (PD-L1) has been recently adopted for breast cancer as a predictive biomarker for immunotherapies. Here, the authors show that PD-L1 expression can be predicted from H&E-stained images using deep learning.
- Gil Shamai
- , Amir Livne
- & Ron Kimmel
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| Open AccessConnecting multiple microenvironment proteomes uncovers the biology in head and neck cancer
The biological understanding of poor prognosis associated with lymph node metastasis in head and neck cancer (HNC) remains crucial. Here, a proteomic characterisation of 140 multisite samples from a 59-HNC patient cohort and machine learning reveals potential biomarkers and metastasis related signatures.
- Ariane F. Busso-Lopes
- , Leandro X. Neves
- & Adriana F. Paes Leme
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| Open AccessAmyloid-associated increases in soluble tau relate to tau aggregation rates and cognitive decline in early Alzheimer’s disease
The interplay between amyloid and tau pathology in Alzheimer’s disease is still not well understood. Here, the authors show that amyloid-related increased in soluble p-tau is related to subsequent accumulation of tau aggregates and cognitive decline in early stage of the disease.
- Alexa Pichet Binette
- , Nicolai Franzmeier
- & Oskar Hansson
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| Open Access2′–5′ oligoadenylate synthetase‑like 1 (OASL1) protects against atherosclerosis by maintaining endothelial nitric oxide synthase mRNA stability
Maintaining optimal eNOS levels is important during cardiovascular events, although little is known regarding the mechanism of eNOS protection. Here, the authors show a regulatory role of endothelial OASL1 in maintaining eNOS mRNA stability and vascular biology under atheroprone conditions.
- Tae Kyeong Kim
- , Sejin Jeon
- & Goo Taeg Oh
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Article
| Open AccessThe contribution of common and rare genetic variants to variation in metabolic traits in 288,137 East Asians
Metabolic traits are heritable intermediate phenotypes widely used in assessing the risk of various diseases. By conducting a genome-wide meta-analysis for metabolic traits in 288,137 East Asians, the authors highlight the interplay of common and rare variants on inherited risk of metabolic traits.
- Young Jin Kim
- , Sanghoon Moon
- & Bong-Jo Kim
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Article
| Open AccessMeasurements of heterogeneity in proteomics analysis of the nanoparticle protein corona across core facilities
Analysis of the protein corona formed around nanoparticles is important for multiple applications in nanomedicine, the methods used at core facilities used for analysis can impact the results. Here, the authors report on a study into the variability of the results obtained from 17 different core facilities and the implications of this.
- Ali Akbar Ashkarran
- , Hassan Gharibi
- & Morteza Mahmoudi
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Article
| Open AccessUnsupervised learning of aging principles from longitudinal data
Biomarkers of age and frailty may aid in understanding the aging process, predicting lifespan or health span and in assessing the effects of anti-aging interventions. Here, the authors show that combining physics-based models and deep learning may enhance understanding of aging from big biomedical data, observe effects of anti-aging interventions in laboratory animals, and discover signatures of longevity.
- Konstantin Avchaciov
- , Marina P. Antoch
- & Peter O. Fedichev
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| Open AccessDeep transfer learning of cancer drug responses by integrating bulk and single-cell RNA-seq data
Single-cell RNA-seq data provide the opportunity to predict drug response in cancer while considering intratumour heterogeneity. Here, the authors develop a deep transfer learning framework - scDEAL - to predict single-cell drug responses in cancer by integrating single-cell and bulk RNA-seq data.
- Junyi Chen
- , Xiaoying Wang
- & Qin Ma
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Article
| Open AccessUltrafast one-minute electronic detection of SARS-CoV-2 infection by 3CLpro enzymatic activity in untreated saliva samples
Methods for the detection of active viral infection are desirable. Here, the authors report an electrochemical approach targeting a SARS-CoV-2 proteolytic enzyme called 3CLpro, as a marker of active infection.
- Ella Borberg
- , Eran Granot
- & Fernando Patolsky
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| Open AccessContinuous biomarker monitoring with single molecule resolution by measuring free particle motion
Various applications would benefit from the ability to continuously measure biomolecules. Here the authors describe a biosensing technology based on the free diffusion of biofunctionalized particles hovering over a sensor surface, which enables monitoring of analytes (pM-µM) over long timespans.
- Alissa D. Buskermolen
- , Yu-Ting Lin
- & Menno W. J. Prins
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Article
| Open AccessStratifin as a novel diagnostic biomarker in serum for diffuse alveolar damage
No reliable serum biomarker for diffuse alveolar damage, a poor prognosis subtype of drug-induced interstitial lung disease, is currently available. Here, the authors show stratifin/14-3-3σ in serum is a promising biomarker for diagnosis of this type of disease.
- Noriaki Arakawa
- , Atsuhito Ushiki
- & Masayuki Hanaoka
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| Open AccessExploiting endogenous and therapy-induced apoptotic vulnerabilities in immunoglobulin light chain amyloidosis with BH3 mimetics
Immunoglobulin light chain amyloidosis is a lethal hematologic disorder driven by clonal plasma cells producing abnormal light chains that damage healthy tissues. Fraser et al. show that BH3 mimetics, which inhibit pro-survival proteins BCL-2 or MCL-1, can effectively eliminate diseased cells.
- Cameron S. Fraser
- , Johan K. E. Spetz
- & Kristopher A. Sarosiek
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| Open AccessAdversarial attacks and adversarial robustness in computational pathology
Artificial Intelligence can support diagnostic workflows in oncology, but they are vulnerable to adversarial attacks. Here, the authors show that convolutional neural networks are highly susceptible to white- and black-box adversarial attacks in clinically relevant classification tasks.
- Narmin Ghaffari Laleh
- , Daniel Truhn
- & Jakob Nikolas Kather
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| Open AccessCost-effective methylome sequencing of cell-free DNA for accurately detecting and locating cancer
Early cancer detection by cell-free DNA (cfDNA) is challenged by the low amount of tumour DNA in cfDNA, tumour heterogeneity and the small patient cohorts. Here, the authors develop a method, cfMethyl-Seq, for cost-effective methylome profiling of cfDNA and for detecting and locating cancer.
- Mary L. Stackpole
- , Weihua Zeng
- & Xianghong Jasmine Zhou
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Article
| Open AccessTP53 mutations and RNA-binding protein MUSASHI-2 drive resistance to PRMT5-targeted therapy in B-cell lymphoma
Inhibition of the protein arginine methyltransferase PRMT5 has been suggested as a promising therapy for lymphoma. Here, the authors show that TP53 loss of function and MUSASHI-2 (MSI2) expression are biomarkers of resistance to PRMT5-targeted therapy in B-cell lymphoma. Moreover, combining PRMT5 inhibition with MSI2 or BCL-2 inhibitors blocks the translation of key drivers of lymphoma, c-MYC and BCL-2, inhibiting cell growth.
- Tatiana Erazo
- , Chiara M. Evans
- & Michael G. Kharas
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| Open AccessIntegrated stem cell signature and cytomolecular risk determination in pediatric acute myeloid leukemia
Relapsed pediatric acute myeloid leukemia is associated with poor prognosis. Here, the authors use RNA-seq data from 1503 primary samples to create a combined transcriptional and cytomolecular signature to improve relapse risk prediction.
- Benjamin J. Huang
- , Jenny L. Smith
- & Soheil Meshinchi
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Article
| Open AccessSpatio-temporal analysis of prostate tumors in situ suggests pre-existence of treatment-resistant clones
Spatial heterogeneity in prostate cancer can contribute to its resistance to androgen deprivation therapy (ADT). Here, the authors analyse prostate cancer samples before and after ADT using Spatial Transcriptomics, and find heterogeneous pre-treatment tumour cell populations and stromal cells that are associated with resistance.
- Maja Marklund
- , Niklas Schultz
- & Joakim Lundeberg
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Article
| Open AccessThe complement C3-complement factor D-C3a receptor signalling axis regulates cardiac remodelling in right ventricular failure
Right ventricular (RV) failure is clinically crucial, but there is no specific therapy. Here, the authors show that the complement alternative pathway is activated in RV failure and that blockade of the pathway ameliorates RV failure in mice.
- Shogo Ito
- , Hisayuki Hashimoto
- & Shinsuke Yuasa
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| Open AccessIdentifying interpretable gene-biomarker associations with functionally informed kernel-based tests in 190,000 exomes
Genetic association studies for rare variants suffer from lack of power and thus there is a need for methods to improve rare variant discovery. Here, the authors present functionally informed association tests with increased statistical power to aid discovery and interpretation of rare variants.
- Remo Monti
- , Pia Rautenstrauch
- & Christoph Lippert
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| Open AccessTargeted immunotherapy against distinct cancer-associated fibroblasts overcomes treatment resistance in refractory HER2+ breast tumors
A substantial proportion of HER2+ breast cancer patients do not benefit from HER2-targeted therapy. Here, the authors identify a population of cancer-associated fibroblasts involved in the suppression of trastuzumab-induced ADCC that can be pharmacologically targeted to raise treatment effectiveness in unresponsive tumors.
- Elisa I. Rivas
- , Jenniffer Linares
- & Alexandre Calon
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| Open AccessCAR-T cell therapy-related cytokine release syndrome and therapeutic response is modulated by the gut microbiome in hematologic malignancies
The success rate of chimeric antigen receptor T cell therapy is high in blood cancers, yet individual patient characteristics might reduce therapeutic benefit. Here authors show that therapeutic response in multiple myeloma, acute lymphoblastic leukemia and non-Hodgkin lymphoma, and occurrence of severe cytokine release syndrome in multiple myeloma are associated with specific gut microbiome alterations.
- Yongxian Hu
- , Jingjing Li
- & He Huang
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| Open AccessPharmacogenomics polygenic risk score for drug response prediction using PRS-PGx methods
To try to predict an individual’s drug response using genetic data, most studies have used traditional polygenic risk score (PRS) methods. Here, the authors develop a pharmacogenomics-specific PRS method, which can improve drug response prediction and patient stratification in pharmacogenomics studies.
- Song Zhai
- , Hong Zhang
- & Judong Shen
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Article
| Open AccessBiomarker correlates with response to NY-ESO-1 TCR T cells in patients with synovial sarcoma
Biomarkers predictive of response to T cell therapy remain to be better defined. This study identifies potential predictive and pharmacodynamic markers of response to NY-ESO-1 T-cell therapy in a solid tumor that may inform lymphodepletion, cell dose, and strategies to enhance anticancer efficacy.
- Alexandra Gyurdieva
- , Stefan Zajic
- & Ioanna Eleftheriadou
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Article
| Open AccessDerivation and validation of an epigenetic frailty risk score in population-based cohorts of older adults
Frailty is associated with an increased risk for negative health outcomes in older populations, and being able to predict frailty could facilitate prevention measures. By performing an epigenome-wide screen, the authors derived a DNA methylation based measure for frailty which can predict both prevalence and longer-term incidence of frailty.
- Xiangwei Li
- , Thomas Delerue
- & Hermann Brenner
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Article
| Open AccessHigh p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer
CDK4/6 inhibitor resistance is common in breast cancer. Here, the authors show that p16 overexpression may be linked to reduced efficacy of CDK4/6 inhibition, and show that the combination with PI3K inhibitors may increase anti-tumour effects.
- Marta Palafox
- , Laia Monserrat
- & Violeta Serra
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Article
| Open AccessReversal of the renal hyperglycemic memory in diabetic kidney disease by targeting sustained tubular p21 expression
Persistent diabetic complications despite controlled blood glucose levels, known as hyperglycemic memory, remain a poorly understood phenomenon in diabetic kidney disease. Here the authors identify senescence-associated gene p21 as a regulator of hyperglycemic memory, the suppression of which improves hyperglycemic memory and renal function.
- Moh’d Mohanad Al-Dabet
- , Khurrum Shahzad
- & Berend Isermann
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Article
| Open AccessGenome-wide mutational signatures in low-coverage whole genome sequencing of cell-free DNA
Detection of mutational signatures in cell-free DNA (cfDNA) is challenging due to low sequence coverage and low mutant allele fractions. Here, the authors identify mutational signatures in plasma whole genome sequencing of cancer patients and use machine learning to distinguish them from healthy individuals.
- Jonathan C. M. Wan
- , Dennis Stephens
- & Luis A. Diaz Jr.
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Article
| Open AccessDerivation and utility of schizophrenia polygenic risk associated multimodal MRI frontotemporal network
Schizophrenia is highly heritable and characterized by widespread brain abnormalities. Here, the authors identify schizophrenia polygenic risk associated multimodal frontotemporal network that can serve as a transdiagnostic brain signature specific to schizophrenia.
- Shile Qi
- , Jing Sui
- & Vince D. Calhoun
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Article
| Open AccessHuman acute inflammatory recovery is defined by co-regulatory dynamics of white blood cell and platelet populations
Inflammation is a protective response of the body. Here, authors show that healthy inflammation induces remarkably consistent changes in white cell and platelet populations, regardless of the underlying cause, including heart attack, infection and trauma.
- Brody H. Foy
- , Thoralf M. Sundt
- & John M. Higgins
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Article
| Open AccessPredicting response to immunotherapy in gastric cancer via multi-dimensional analyses of the tumour immune microenvironment
Predictive methods for gastric cancer to try and differentiate between potential treatment response are required. Here the authors use a multiplexed immunohistochemistry method to propose the proximity of tumour infiltrating immune cells as an indicator of likely therapeutic response.
- Yang Chen
- , Keren Jia
- & Lin Shen
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Article
| Open AccessCross-tissue analysis of blood and brain epigenome-wide association studies in Alzheimer’s disease
DNA methylation differences in Alzheimer’s disease have been previously reported, although the interpretation of the differences is unclear. Here, the authors performed epigenome-wide meta-analyses of DNA methylation in blood and brain, and developed a methylation-based risk prediction model for AD.
- Tiago C. Silva
- , Juan I. Young
- & Lily Wang
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Article
| Open AccessIntegrated methylome and phenome study of the circulating proteome reveals markers pertinent to brain health
Characterising associations between the methylome, proteome and phenome may provide insight into biological pathways governing brain health. Here, blood protein markers of brain health are integrated with omics data to reveal DNA methylation differences that associate with these protein markers.
- Danni A. Gadd
- , Robert F. Hillary
- & Riccardo E. Marioni
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| Open AccessMulti-cohort and longitudinal Bayesian clustering study of stage and subtype in Alzheimer’s disease
Different types of atrophy in Alzheimer’s disease may reflect different disease stages or biologically distinct subtypes. Here the authors use longitudinal neuroimaging data to demonstrate five distinct patterns of atrophy with different demographical and cognitive characteristics.
- Konstantinos Poulakis
- , Joana B. Pereira
- & Eric Westman