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| Open AccessPathway signatures derived from on-treatment tumor specimens predict response to anti-PD1 blockade in metastatic melanoma
Gene signatures that predict response to immune checkpoint blockade (ICB) therapies in melanoma have been based on preclinical models and pre-treatment samples. Here the authors develop pathway-based signatures to predict ICB response in melanoma using on-treatment samples, leading to improved performance.
- Kuang Du
- , Shiyou Wei
- & Gao Zhang
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Article
| Open AccessDirect on-swab metabolic profiling of vaginal microbiome host interactions during pregnancy and preterm birth
Here, the authors apply DESI-MS, a sample preparation-free, direct on-swab mass spectrometry analytical tool, to profile the cervicovaginal metabolome of two independent cohorts of pregnant women and, combined with matched metataxonomic and immuno-profiling data, show that DESI-MS predicts vaginal microbiota composition and local inflammatory status associated with preterm birth and clinical interventions used during pregnancy.
- Pamela Pruski
- , Gonçalo D. S. Correia
- & David A. MacIntyre
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Article
| Open AccessFinger sweat analysis enables short interval metabolic biomonitoring in humans
Biomonitoring of sweat from fingertips overcomes current limitations in time-resolved metabolomic profiling of humans and may prove to become a powerful, noninvasive tool for precision medicine. Here, in a feasibility study of short interval sampling of sweat from fingertips, the authors assay individual dynamic metabolic patterns of endogenous and exogenous molecules.
- Julia Brunmair
- , Mathias Gotsmy
- & Christopher Gerner
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Article
| Open AccessHigh-spatial and colourimetric imaging of histone modifications in single senescent cells using plasmonic nanoprobes
The authors demonstrate a colourimetric imaging method using plasmonic nanoparticles for visualisation of heterochromatin histone markers. Based on the distance-dependent coupling effect, resulting in spectral shifts, they observe reorganisation of histone markers caused by oncogene-induced senescence.
- Hyun Ji An
- , Yun Kim
- & Inhee Choi
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Article
| Open AccessSARS-CoV-2 binding and neutralizing antibody levels after Ad26.COV2.S vaccination predict durable protection in rhesus macaques
Several COVID-19 vaccines have received emergency approval, but durability of protection is unclear. Here, the authors describe correlates of protection (CoP) for the Ad26.COV2.S vaccine in rhesus macaques and report that CoP predict the protection observed 6 months post vaccination.
- Ramon Roozendaal
- , Laura Solforosi
- & Roland Zahn
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Article
| Open AccessSARS-CoV-2 antibody seroprevalence and associated risk factors in an urban district in Cameroon
Many African countries have reported relatively low numbers of COVID-19 cases but the true scale of the epidemic is unclear. Here, the authors conduct a population-based survey in a province of Cameroon and estimate 29% seroprevlance, >300 fold higher than the nationwide attack rate implied by case counts.
- Kene Nwosu
- , Joseph Fokam
- & Laura Ciaffi
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Article
| Open AccessMulti-targeted 1H/19F MRI unmasks specific danger patterns for emerging cardiovascular disorders
The prediction of major cardiovascular events is still an unsolved problem. Here, the authors present a multi-color, multi-targeted non-invasive imaging technology that allows reliable in vivo identification of silent but prognostically highly relevant danger patterns prior to myocardial infarction in mice.
- Ulrich Flögel
- , Sebastian Temme
- & Bodo Levkau
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Article
| Open AccessSpatial immunophenotypes predict response to anti-PD1 treatment and capture distinct paths of T cell evasion in triple negative breast cancer
Only a subset of triple negative breast cancer patients respond to immunotherapy. Here, the authors analysed spatial immune contextures, which can be captured by a gene classifier, in relation to genomic alterations, mechanisms of T cell evasion and response to anti-PD1 treatment.
- Dora Hammerl
- , John W. M. Martens
- & Reno Debets
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Article
| Open AccessAnalyses of child cardiometabolic phenotype following assisted reproductive technologies using a pragmatic trial emulation approach
Huang and colleagues used machine-learning estimators to analyse a broad range of parameters in a prospective cohort consisting ART and spontaneously conceived children. Small differences in stature and growth could not be explained by parental or perinatal environment factors, nor differences in fetal DNA methylation. No strong differences in metabolic parameters were seen.
- Jonathan Yinhao Huang
- , Shirong Cai
- & Shiao-Yng Chan
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Article
| Open AccessIdentification of the factor XII contact activation site enables sensitive coagulation diagnostics
Blood coagulation is started by contact to surfaces and this is the principle for a commonly used diagnostic clotting test, aPTT. Here, the authors identify the structure in coagulation factor XII that initiates surface-driven coagulation and use the information to develop improved aPTT assays.
- Marco Heestermans
- , Clément Naudin
- & Thomas Renné
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Article
| Open AccessProfiling the inhibitory receptors LAG-3, TIM-3, and TIGIT in renal cell carcinoma reveals malignancy
Targeting the inhibitory receptors (IRs) LAG-3, TIM-3 and TIGIT is a promising immune-oncology approach and the identification of biomarkers of response is crucial. Here, the authors apply automated single-cell count for these IRs in human renal cell carcinoma and investigate the immunogenomic landscape of the disease.
- Kimiharu Takamatsu
- , Nobuyuki Tanaka
- & Mototsugu Oya
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Article
| Open AccessTherapeutic targeting of the PLK1-PRC1-axis triggers cell death in genomically silent childhood cancer
In this study, the authors show that that oncogenic hijacking of PRC1 sensitizes genomically stable Ewing sarcoma cells for PLK1 inhibition alone or in synergy with a microtubule-destabilizing drug via induction of cytokinesis defects, rendering PRC1 a promising, broadly applicable predictive biomarker
- Jing Li
- , Shunya Ohmura
- & Thomas G. P. Grünewald
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Article
| Open AccessTranslating polygenic risk scores for clinical use by estimating the confidence bounds of risk prediction
The application of polygenic risk scores to individual-level disease susceptibility is challenging, as risk is evaluated at a group-level. Here, the authors describe a machine learning method, Mondrian Cross-Conformal Prediction, that reports disease status conditional probability value at the individual level.
- Jiangming Sun
- , Yunpeng Wang
- & Kasper Lage
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Article
| Open AccessPredicting post-operative right ventricular failure using video-based deep learning
The echocardiogram allows for a comprehensive assessment of the cardiac musculature and valves, but its rich temporally resolved data remain underutilized. Here, the authors develop a video AI system trained to predict post-operative right ventricular failure.
- Rohan Shad
- , Nicolas Quach
- & William Hiesinger
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Article
| Open AccessA comprehensive risk score for effective risk stratification and screening of nasopharyngeal carcinoma
Epstein-Barr virus (EBV) is associated with high risk for nasopharyngeal carcinoma (NPC). Here, the authors develop a comprehensive risk score that combines risk effects of EBV and human genetics for NPC risk stratification.
- Xiang Zhou
- , Su-Mei Cao
- & Miao Xu
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Article
| Open AccessCopy number signatures predict chromothripsis and clinical outcomes in newly diagnosed multiple myeloma
Chromothripsis is associated with unfavourable outcomes in multiple myeloma (MM), but its detection usually requires whole genome sequencing. Here the authors develop an approach to detect chromothripsis in MM based on copy-number signatures that also works with whole exome sequencing data.
- Kylee H. Maclachlan
- , Even H. Rustad
- & Francesco Maura
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Article
| Open AccessCas9-derived peptides presented by MHC Class II that elicit proliferation of CD4+ T-cells
There have been reports of immune responses against Cas9 which may impair clinical use. Here the authors scan a cohort comparable to the North American population vis-à-vis distribution of MHC-II variants to identify Cas9 peptides presented by MHC-II proteins and can stimulate CD4 + T-cells.
- Vijaya L. Simhadri
- , Louis Hopkins
- & Zuben E. Sauna
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Article
| Open AccessAn N-Cadherin 2 expressing epithelial cell subpopulation predicts response to surgery, chemotherapy and immunotherapy in bladder cancer
The identification of response biomarkers for surgery, chemotherapy and immune checkpoint therapy in bladder cancer is crucial. Here, single nuclei RNA sequencing and spatial profiling identify a cancer cell population expressing Neural Type Cadherin 2 that associates with distinct treatment outcomes.
- Kenneth H. Gouin III
- , Nathan Ing
- & Dan Theodorescu
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Article
| Open AccessLoss of Smad4 promotes aggressive lung cancer metastasis by de-repression of PAK3 via miRNA regulation
The underlying mechanisms by which Smad4 loss-of-function accelerates lung cancer metastasis is unclear. Here, the authors show PAK3 as a downstream effector of Smad4 promoting metastatic signalling and suggest Smad4-PAK3 regulation as a point of potential therapy in metastatic lung cancer.
- Xiaohong Tan
- , Lu Tong
- & Xiaotao Li
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Article
| Open AccessDownregulation of exhausted cytotoxic T cells in gene expression networks of multisystem inflammatory syndrome in children
Multisystem inflammatory syndrome in children (MIS-C) onsets in COVID-19 patients with manifestations similar to Kawasaki disease (KD). Here the author probe the peripheral blood transcriptome of MIS-C patients to find signatures related to natural killer (NK) cell activation and CD8+ T cell exhaustion that are shared with KD patients.
- Noam D. Beckmann
- , Phillip H. Comella
- & Alexander W. Charney
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Article
| Open AccessA microRNA panel compared to environmental and polygenic scores for colorectal cancer risk prediction
Appropriate risk models could facilitate risk stratification for colorectal cancer (CRC) screening. Here, the authors propose a blood-based microRNA signature observed to have altered expression in pre-diagnostic samples, which might be useful to identify high-risk populations for colorectal cancer screening.
- Janhavi R. Raut
- , Ben Schöttker
- & Hermann Brenner
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Article
| Open AccessAutomatic detection of 39 fundus diseases and conditions in retinal photographs using deep neural networks
Systems for automatic detection of a single disease may miss other important conditions. Here, the authors show a deep learning platform can detect 39 common retinal diseases and conditions.
- Ling-Ping Cen
- , Jie Ji
- & Mingzhi Zhang
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Article
| Open AccessEnhanced NF-κB signaling in type-2 dendritic cells at baseline predicts non-response to adalimumab in psoriasis
Biomarkers to indicate potential response to biologic therapeutics are needed for patients with psoriasis. Here the authors show that phosphorylation of NFκBp65 in cDC2 before therapy is an indication of non-response to the anti-TNF therapy adalimumab in patients with psoriasis.
- Rosa Andres-Ejarque
- , Hira Bahadur Ale
- & Deborah Stocken
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Article
| Open AccessCirculating trophoblast cell clusters for early detection of placenta accreta spectrum disorders
Placenta accreta spectrum (PAS) is a high-risk obstetrical complication associated with significant morbidity and mortality. Here the authors discover a uniquely high prevalence of circulating trophoblasts clusters in PAS and explore their diagnostic potential to augment current diagnostic modalities for the early detection of PAS.
- Yalda Afshar
- , Jiantong Dong
- & Yazhen Zhu
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Article
| Open AccessThe impact of site-specific digital histology signatures on deep learning model accuracy and bias
Deep learning models have been trained on The Cancer Genome Atlas to predict numerous features directly from histology, including survival, gene expression patterns, and driver mutations. Here, the authors demonstrate that site-specific histologic signatures can lead to biased estimates of accuracy for such models, and propose a method to minimize such bias.
- Frederick M. Howard
- , James Dolezal
- & Alexander T. Pearson
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Article
| Open AccessPhosphorylated tau181 in plasma as a potential biomarker for Alzheimer’s disease in adults with Down syndrome
Plasma tau phosphorylated at threonine 181 (p-tau181) predicts Alzheimer’s disease (AD) pathology. Here, the authors investigated whether plasma ptau181 could be a potential biomarker of AD in individuals with Down syndrome (DS) and find plasma p-tau181 can detect AD in DS adults.
- Alberto Lleó
- , Henrik Zetterberg
- & Juan Fortea
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Matters Arising
| Open AccessInconsistent prediction capability of ImmuneCells.Sig across different RNA-seq datasets
- Xu Xiao
- , Canqiang Xu
- & Rongshan Yu
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Matters Arising
| Open AccessReply to: “Inconsistent prediction capability of ImmuneCells.Sig across different RNA-seq datasets”
- Donghai Xiong
- , Yian Wang
- & Ming You
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Article
| Open AccessThe T cell receptor repertoire of tumor infiltrating T cells is predictive and prognostic for cancer survival
Precision medicine needs prognostic markers to select the patients that will benefit more from targeted therapy. Authors show here that high level of baseline T cell receptor diversity is an indicator of favourable prognosis in multiple cancer types, and monoclonal expansion of T-cells correlates with good response to immune checkpoint blockade therapy in metastatic melanoma patients.
- Sara Valpione
- , Piyushkumar A. Mundra
- & Richard Marais
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Article
| Open AccessHigher CSF sTNFR1-related proteins associate with better prognosis in very early Alzheimer’s disease
Neuroinflammation is observed in Alzheimer’s disease. Here the authors show that 15 proteins related to inflammation found in CSF can potentially be used as a prognostic biomarker.
- William T. Hu
- , Tugba Ozturk
- & Gloria Chiang
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Article
| Open AccessPredicting disease course in ulcerative colitis using stool proteins identified through an aptamer-based screen
Stool biomarkers hold promise for monitoring disease activity and predicting clinical course in inflammatory bowel disease (IBD) as they originate from the inflamed tissue. Here the authors report an aptamer-based proteomic screen, and discover several stool proteins that predict remission at four weeks.
- Sanam Soomro
- , Suresh Venkateswaran
- & Chandra Mohan
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Article
| Open AccessEnhanced specificity of clinical high-sensitivity tumor mutation profiling in cell-free DNA via paired normal sequencing using MSK-ACCESS
Liquid biopsies allow the non-invasive detection of somatic mutations from tumours. Here, the authors develop and test MSK-ACCESS, an NGS-based clinical assay for identifying low frequency mutations in 129 genes and describe how it benefits patients in the clinic.
- A. Rose Brannon
- , Gowtham Jayakumaran
- & Ryma Benayed
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Article
| Open AccessPolθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance
Polθ has been recently identified as a therapeutic target in cancer but specific inhibitors are currently unavailable. Here, the authors identify small molecule inhibitors of Polθ’s polymerase activity which elicit BRCA1/2 synthetic lethality, enhance the effect of PARP inhibitors and target PARP inhibitor resistance caused by 53BP1/Shieldin pathway defects.
- Diana Zatreanu
- , Helen M. R. Robinson
- & Christopher J. Lord
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Article
| Open AccessMultianalyte serology in home-sampled blood enables an unbiased assessment of the immune response against SARS-CoV-2
Here, Roxhed et al. develop a multiplexed approach to screen IgG and IgM levels against several SARS-CoV-2 proteins in home-sampled dried blood spots and estimate seroprevalence of 12.5% in Stockholm in spring of 2020.
- Niclas Roxhed
- , Annika Bendes
- & Jochen M. Schwenk
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Article
| Open AccessComprehensive micro-scaled proteome and phosphoproteome characterization of archived retrospective cancer repositories
Formalin-fixed, paraffin-embedded (FFPE) specimens are an attractive resource for retrospective clinical proteomics studies. Here, the authors benchmark and optimize proteomics workflows for FFPE sample analysis and provide guidelines on which methods to use for different samples and applications.
- Corinna Friedrich
- , Simon Schallenberg
- & Philipp Mertins
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Article
| Open AccessPlasma biomarkers of Alzheimer’s disease improve prediction of cognitive decline in cognitively unimpaired elderly populations
Plasma biomarkers of amyloid, tau and neurodegeneration (ATN) need to be characterized in cognitively unimpaired (CU) elderly individuals. Here, the authors show plasma ATN biomarkers predict clinical deterioration and cognitive decline and show in a simulated clinical trial combining all three biomarkers reduced the required sample size.
- Nicholas C. Cullen
- , Antoine Leuzy
- & Oskar Hansson
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Article
| Open AccessAberrant dynamics of cognitive control and motor circuits predict distinct restricted and repetitive behaviors in children with autism
Restricted and repetitive behaviors (RRBs) are a core clinical feature of autism, yet the brain basis of RRBs is unknown. Here, the authors demonstrate that aberrant cognitive control and motor circuit dynamics differentially predict three distinct symptom clusters that define RRBs.
- Kaustubh Supekar
- , Srikanth Ryali
- & Vinod Menon
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Article
| Open AccessMOGONET integrates multi-omics data using graph convolutional networks allowing patient classification and biomarker identification
Our understanding of human disease can be improved by integrating the abundance of high throughput biomedical data. Here, the authors use deep learning methods successfully used on images to integrate various types of omics data to improve patient classification and identify disease biomarkers.
- Tongxin Wang
- , Wei Shao
- & Kun Huang
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Article
| Open AccessA multicentre validation study of the diagnostic value of plasma neurofilament light
Cerebrospinal fluid neurofilament light (NfL) is a biomarker for neurodegeneration that can also be assessed in blood. Here the authors show in a validation study the potential for plasma NfL as a biomarker for several neurodegenerative diseases.
- Nicholas J. Ashton
- , Shorena Janelidze
- & Oskar Hansson
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Article
| Open AccessSARS-CoV-2 RNAemia and proteomic trajectories inform prognostication in COVID-19 patients admitted to intensive care
Here the authors use RT-qPCR and mass spectrometry to analyze longitudinal blood samples from intensive care unit (ICU) COVID-19 patients and controls. They find that viral RNA and pentraxin-3 predict 28-day ICU mortality and that galectin-3-binding protein is an interaction partner of SARS-CoV-2 spike glycoprotein with antiviral properties.
- Clemens Gutmann
- , Kaloyan Takov
- & Manuel Mayr
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Article
| Open AccessOPG/TRAIL ratio as a predictive biomarker of mortality in patients with type A acute aortic dissection
Despite many therapeutic improvements, mortality risk in patients with type A acute aortic dissection remains high. Here the authors construct a biomarker-guided risk stratification tool to predict death, which could potentially contribute to treatment decision-making and improvement of the prognosis.
- Jie Lu
- , Ping Li
- & Yulin Li
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Article
| Open AccessImaging-based spectrometer-less optofluidic biosensors based on dielectric metasurfaces for detecting extracellular vesicles
The authors engineer a type of bound states in the continuum in diatomic dielectric metasurfaces, allowing for high-quality resonances with accessible enhanced fields. Metasurface microarrays are integrated with microfluidics on an imaging platform for real-time detection of biosamples, based on reconstructing spectral shift information.
- Yasaman Jahani
- , Eduardo R. Arvelo
- & Hatice Altug
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Article
| Open AccessMultimodal analysis of cell-free DNA whole-genome sequencing for pediatric cancers with low mutational burden
Liquid biopsies enable minimally invasive applications for diagnosis and treatment monitoring. Here the authors analyse fragmentation patterns of circulating tumour DNA on multiple levels and develop a bioinformatic tool, LIQUORICE, to accurately detect and classify paediatric cancers with low mutational burden.
- Peter Peneder
- , Adrian M. Stütz
- & Eleni M. Tomazou
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Article
| Open AccessIdentification of microbial markers across populations in early detection of colorectal cancer
The gut microbiome plays an important role in colorectal carcinogenesis and predictive microbiome signatures have been proposed for colorectal cancer (CRC) diagnosis. Here the authors perform a meta-analysis of 16S rRNA-based profiles to identify microbial markers able to discriminate patients with adenoma from control and CRC, building a model that can be applied for the early detection of CRC.
- Yuanqi Wu
- , Na Jiao
- & Lixin Zhu
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Article
| Open AccessDeep learning predicts cardiovascular disease risks from lung cancer screening low dose computed tomography
Low dose computed tomography (LDCT) for lung cancer screening offers an opportunity for simultaneous CVD risk estimation in at-risk patients. Here, the authors develop a deep learning model to perform this task, showing human-level performance.
- Hanqing Chao
- , Hongming Shan
- & Pingkun Yan
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Article
| Open AccessGene-level metagenomic architectures across diseases yield high-resolution microbiome diagnostic indicators
Here, combing the massive gene-universe of the gut microbiome to identify strain-specific, cross-disease, associations across seven human diseases, the authors introduce the concept of microbiome architecture, defined as the complete set of positive and negative associations between microbial genes and human host disease, highlighting microbiome architectures as potential diagnostic indicators.
- Braden T. Tierney
- , Yingxuan Tan
- & Chirag J. Patel
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Article
| Open AccessA machine learning model for identifying patients at risk for wild-type transthyretin amyloid cardiomyopathy
Transthyretin amyloid cardiomyopathy is a treatable but often unrecognized cause of heart failure. We derived and validated a machine learning model based on medical diagnostic codes that identifies heart failure patients at risk for wild-type transthyretin amyloid cardiomyopathy.
- Ahsan Huda
- , Adam Castaño
- & Sanjiv J. Shah
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Article
| Open AccessTaxonomic signatures of cause-specific mortality risk in human gut microbiome
Gut microbiome composition has a role in health and disease. Here the authors show that microbiome signatures related to the Enterobacteriaceae family are associated with cause-specific mortality risk in a well phenotyped Finish population over a 15-year follow-up.
- Aaro Salosensaari
- , Ville Laitinen
- & Teemu Niiranen
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Article
| Open AccessComprehensive cell type decomposition of circulating cell-free DNA with CelFiE
Tissue damage and turnover lead to the release of DNA in the blood and can be used to monitor changes in tissue state. Here, the authors developed a tool to accurately estimate the proportion of cell types contributing to cell-free DNA in the blood, with an application to pregnant women and ALS patients.
- Christa Caggiano
- , Barbara Celona
- & Noah Zaitlen