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| Open AccessProteomic profiling of MIS-C patients indicates heterogeneity relating to interferon gamma dysregulation and vascular endothelial dysfunction
Multi-inflammatory syndrome in children (MIS-C) can be associated with SARS-CoV-2 infection but can also be similar to other inflammatory syndromes. Here the authors characterise the plasma proteome phenotype in MIS-C and compare to other SARS-CoV-2 related syndromes and find disproportionately high IFN-γ responses in MIS-C patients.
- Caroline Diorio
- , Rawan Shraim
- & Edward M. Behrens
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Article
| Open AccessMassive image-based single-cell profiling reveals high levels of circulating platelet aggregates in patients with COVID-19
The authors report the landscape of circulating platelet aggregates in COVID-19 obtained by massive single-cell image-based profiling and temporal monitoring to elucidate the underlying process of COVID-19-assocaited microvascular thrombosis.
- Masako Nishikawa
- , Hiroshi Kanno
- & Keisuke Goda
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Article
| Open AccessA deep learning framework identifies dimensional representations of Alzheimer’s Disease from brain structure
Alzheimer’s disease is heterogeneous in its neuroimaging and clinical phenotypes. Here the authors present a semi-supervised deep learning method, Smile-GAN, to show four neurodegenerative patterns and two progression pathways providing prognostic and clinical information.
- Zhijian Yang
- , Ilya M. Nasrallah
- & Balebail Ashok Raj
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Article
| Open AccessTherapeutic vulnerability to PARP1,2 inhibition in RB1-mutant osteosarcoma
RB1 mutations are seen in 40-60% of sporadic osteosarcoma. Here, the authors demonstrate a selective sensitivity to PARP inhibitors in RB1-mutated osteosarcoma-derived cell lines that is not associated with canonical signatures indicative of a homologous recombination defect.
- Georgia Zoumpoulidou
- , Carlos Alvarez-Mendoza
- & Sibylle Mittnacht
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Article
| Open AccessMapping the serum proteome to neurological diseases using whole genome sequencing
Serum proteins are easily accessible biomarkers and drug targets. Here, the authors use whole genome sequencing data to describe the genetic architecture of neurologically-relevant serum proteins and establish causal protein-neurological disease relationships.
- Grace Png
- , Andrei Barysenka
- & Eleftheria Zeggini
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Article
| Open AccessRisk-stratification of febrile African children at risk of sepsis using sTREM-1 as basis for a rapid triage test
Identification of febrile children at risk of death in low-resource settings can improve survival, but tools for their prompt recognition are lacking. Here, the authors show that sTREM-1 measured at clinical presentation predicts in-hospital mortality in febrile children in Uganda.
- Aleksandra Leligdowicz
- , Andrea L. Conroy
- & Kevin C. Kain
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Article
| Open AccessDynamic recurrence risk and adjuvant chemotherapy benefit prediction by ctDNA in resected NSCLC
ctDNA has been shown to identify minimal residual disease (MRD) and is thus dynamically monitored in different types of tumours. Here, the authors show that serial longitudinal ctDNA analysis can be used as a tool to detect MRD, inform the use of adjuvant therapy, and predict recurrence risk in lung cancer.
- Bin Qiu
- , Wei Guo
- & Jie He
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Article
| Open AccessImmune cell topography predicts response to PD-1 blockade in cutaneous T cell lymphoma
PD-1 blockade is effective for only a subset of patients with cutaneous T cell lymphomas. Here, the authors report a spatial biomarker that uses immune and cancer cell topography to predict response to PD-1 blockade in this disease.
- Darci Phillips
- , Magdalena Matusiak
- & Garry P. Nolan
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Article
| Open AccessSoluble guanylate cyclase signalling mediates etoposide resistance in progressing small cell lung cancer
The emergence of acquired resistance to standard platinum-etoposide chemotherapy in small cell lung cancer (SCLC) is a common event. Here, the authors using paired pre-treatment and post-chemotherapy circulating tumour cell patient-derived explant (CDX) models reveal a mechanism of drug resistance in SCLC mediated by Notch and nitric oxide activation of soluble guanylate cyclase signalling.
- Maximilian W. Schenk
- , Sam Humphrey
- & Kristopher K. Frese
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Article
| Open AccessFocal amplifications are associated with chromothripsis events and diverse prognoses in gastric cardia adenocarcinoma
The role of focal amplifications and extrachromosomal DNA (ecDNA) is unknown in gastric cardia adenocarcinoma (GCA). Here, the authors identify frequent focal amplifications and ecDNAs in Chinese GCA patient samples, as well as the potential associations of these alterations with prognosis and dietary habits.
- Xue-Ke Zhao
- , Pengwei Xing
- & Li-Dong Wang
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Article
| Open AccessGenomic signatures define three subtypes of EGFR-mutant stage II–III non-small-cell lung cancer with distinct adjuvant therapy outcomes
Adjuvant gefitinib improves outcomes in non-small cell lung cancer (NSCLC) patients compared to chemotherapy, but not in all cases. Here, the authors find genomic biomarkers of response to gefitinib in NSCLC patients from the ADJUVANT trial, and propose a score to stratify them by potential benefit from the treatment.
- Si-Yang Liu
- , Hua Bao
- & Yi-Long Wu
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Article
| Open AccessRAB5A expression is a predictive biomarker for trastuzumab emtansine in breast cancer
Antibody Drug Conjugates (ADCs) are emerging in the field of precision cancer medicine. Here, the authors suggest using endocytosis as a predictive biomarker for response
- Olav Engebraaten
- , Christina Yau
- & Anette Weyergang
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Article
| Open AccessNeoadjuvant T-DM1/pertuzumab and paclitaxel/trastuzumab/pertuzumab for HER2+ breast cancer in the adaptively randomized I-SPY2 trial
HER2-targeted therapy improves patient’s outcome in early breast cancer. Here, the authors present the efficacy and biomarker analysis of two HER2-targeted combinations (ado-trastuzumab emtansine plus pertuzumab and paclitaxel, trastuzumab and pertuzumab) in the context of the neoadjuvant I-SPY2 phase 2 adaptive platform trial for early breast cancer at high risk of recurrence.
- Amy S. Clark
- , Christina Yau
- & Angela M. DeMichele
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Article
| Open AccessHigh-coverage metabolomics uncovers microbiota-driven biochemical landscape of interorgan transport and gut-brain communication in mice
The gut microbiota harbours neuroactive potential with links to neurological disorders. Here, the authors apply global metabolomics with an integrated annotation strategy to comparatively profile fecal, blood serum and cerebral cortical brain tissues of eight-week-old germ-free mice vs. age-matched specific-pathogen-free mice, providing a snapshot of the metabolome status linked to the gut-brain axis.
- Yunjia Lai
- , Chih-Wei Liu
- & Kun Lu
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Article
| 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