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| Open AccessImmune-related adverse events and the balancing act of immunotherapy
The benefit from immune checkpoint inhibitors is tempered by immunologic toxicities, which involve diverse organs, have varying biology, onset time, and severity. Herein, we identify important areas of controversy and open research questions in the field of immune-related toxicity.
- Michael Conroy
- & Jarushka Naidoo
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Article
| Open AccessAge influences on the molecular presentation of tumours
Ageing is a known risk factor in the development of cancers, but its association with molecular alterations is not fully explored. Here, the authors analyse pan-cancer age-associated molecular alterations in datasets from the TCGA, PCAWG and AACR-GENIE projects and identify prognostic biomarkers.
- Constance H. Li
- , Syed Haider
- & Paul C. Boutros
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Article
| Open AccessmolBV reveals immune landscape of bacterial vaginosis and predicts human papillomavirus infection natural history
Here, Burk et al. develop an algorithm to diagnose bacterial vaginosis (BV) using the 16S rRNA gene, called molBV, which they use to profile the inflammatory landscape of BV and predict progression of human papillomavirus infection to cervical pre-cancer.
- Mykhaylo Usyk
- , Nicolas F. Schlecht
- & Robert D. Burk
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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 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 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 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 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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Matters Arising
| Open AccessInconsistent prediction capability of ImmuneCells.Sig across different RNA-seq datasets
- Xu Xiao
- , Canqiang Xu
- & Rongshan Yu
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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 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 AccessCirculating mucosal-associated invariant T cells identify patients responding to anti-PD-1 therapy
Immune checkpoint inhibition (ICI) shows potential for cancer therapies, but response rates vary. Here, the authors use single-cell analyses to show that, in a 28 patient cohort, patients stratified by mucosal-associated invariant T (MAIT) percentages show different response rates, and ICI responders have more MAIT cells expressing CXCR4 and granzyme B.
- Sara De Biasi
- , Lara Gibellini
- & Andrea Cossarizza
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Article
| Open AccessIntegrated cytokine and metabolite analysis reveals immunometabolic reprogramming in COVID-19 patients with therapeutic implications
Metabolism changes can modulate immune responses in many contexts, and vice versa. Here the authors associate metabolomic, as well as cytokine and chemokine, data from stratified COVID-19 patients to find that arginine, tryptophan and purine metabolic pathways correlate with hyperproliferation, thus hinting at potential therapeutic targets for severe COVID-19 patients.
- Nan Xiao
- , Meng Nie
- & Zeping Hu
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Article
| Open AccessBiological and therapeutic implications of a unique subtype of NPM1 mutated AML
Molecular heterogeneity of acute myeloid leukaemia (AML) across patients is a major challenge for prognosis and therapy. Here, the authors show that NPM1 mutated AML is a heterogeneous class, consisting of two subtypes which exhibit distinct molecular characteristics, differentiation state, patient survival and drug response.
- Arvind Singh Mer
- , Emily M. Heath
- & Benjamin Haibe-Kains
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Article
| Open AccessGenome-wide association study identifies risk loci for progressive chronic lymphocytic leukemia
The clinical course of chronic lymphocytic leukaemia (CLL) is variable and difficult to predict. Here, the authors conduct a genome wide association study meta-analysis for time to first treatment in CLL patients and report two loci associating with progressive disease.
- Wei-Yu Lin
- , Sarah E. Fordham
- & James M. Allan
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Article
| Open AccessThe transcriptome of circulating sexually committed Plasmodium falciparum ring stage parasites forecasts malaria transmission potential
Malaria gametocytes are sexual-stage parasites transmitted from mammalian host’s blood back to their insect vector. Here, Prajapati et al. identify gametocyte-committed ring-stage biomarkers allowing to forecast malaria transmission potential.
- Surendra K. Prajapati
- , Ruth Ayanful-Torgby
- & Kim C. Williamson
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Article
| Open AccessSARS-CoV-2 viral load is associated with increased disease severity and mortality
In this study, Massachusetts Consortium for Pathogen Readiness (MassCPR) investigators assess the relationship between SARS-CoV-2 viral load and COVID-19 disease severity and report that the levels of detectable viral RNA, especially in plasma, correlates with severity of respiratory disease, inflammatory markers and predicted risk of death.
- Jesse Fajnzylber
- , James Regan
- & Alex Zhu
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Article
| Open AccessMachine learning based early warning system enables accurate mortality risk prediction for COVID-19
Methods to stratify patients according to mortality risk are essential to allocate limited heath resources during the COVID-19 crisis. Here, using machine learning methods, the authors present a mortality risk prediction model for COVID-19 that uses patients’ clinical data on admission to stratify patients by mortality risk.
- Yue Gao
- , Guang-Yao Cai
- & Qing-Lei Gao
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Article
| Open AccessComprehensive molecular comparison of BRCA1 hypermethylated and BRCA1 mutated triple negative breast cancers
BRCA-deficient breast cancer is characterised by homologous recombination deficiency. Here, the authors show that hypermethylated BRCA1 phenotypically copies mutated BRCA1 in triple negative breast cancers.
- Dominik Glodzik
- , Ana Bosch
- & Johan Staaf
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Article
| Open AccessITLN1 modulates invasive potential and metabolic reprogramming of ovarian cancer cells in omental microenvironment
Advanced ovarian cancer usually spreads to the omentum. Here, the authors show that circulating intelectin-1 (ITLN1) has prognostic significance in patients with advanced ovarian cancer, and that mesothelial cell-derived ITLN1 in the omental tumor microenvironment suppresses ovarian cancer progression.
- Chi-Lam Au-Yeung
- , Tsz-Lun Yeung
- & Samuel C. Mok
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Article
| Open AccessPancreatic circulating tumor cell profiling identifies LIN28B as a metastasis driver and drug target
Metastatic dissemination contributes to the lethality in pancreatic ductal adenocarcinoma (PDAC). Here, the authors perform RNA-sequencing on patient derived circulating tumor cells (CTCs) and identify three major CTC subgroups, and show the therapeutic potential of targeting LIN28B/let-7 pathway to halt cancer metastasis.
- Joseph W. Franses
- , Julia Philipp
- & David T. Ting
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Article
| Open AccessMethCORR modelling of methylomes from formalin-fixed paraffin-embedded tissue enables characterization and prognostication of colorectal cancer
Molecular analysis of archival formalin-fixed clinical tissues can be difficult. Here, researchers have developed MethCORR, an approach that infers gene expression from DNA methylation data and use the approach for molecular characterization and prognostication of colorectal cancer using archival samples.
- Trine B. Mattesen
- , Mads H. Rasmussen
- & Jesper B. Bramsen
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Article
| Open AccessPrimary tumors release ITGBL1-rich extracellular vesicles to promote distal metastatic tumor growth through fibroblast-niche formation
Mechanisms regulating the formation of pre-metastatic niches remain poorly understood. Here, the authors show that ITGBL1-containing extracellular vesicles derived from primary colorectal cancer cells activate the production of inflammatory cytokines by resident fibroblasts in distant organs, promoting metastatic cancer growth.
- Qing Ji
- , Lihong Zhou
- & Qi Li
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Article
| Open AccessWhite blood cell and cell-free DNA analyses for detection of residual disease in gastric cancer
Identifying patients that will respond to a particular therapy remains a key challenge in precision oncology. Here, in gastric cancer, the authors show that circulating tumour DNA can predict recurrence, provided that the signal from white blood cells is filtered out.
- Alessandro Leal
- , Nicole C. T. van Grieken
- & Victor E. Velculescu
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Article
| Open AccessA robust and efficient method for Mendelian randomization with hundreds of genetic variants
Mendelian randomization (MR) is a method for inferring causal relationships between risk factors and outcomes via associated genetic variants. Here, Burgess et al. develop the contamination mixture method which yields robust MR results in the presence of invalid instrumental variables and groups variants by their effect estimates.
- Stephen Burgess
- , Christopher N Foley
- & Joanna M. M. Howson
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Article
| Open AccessPain-free resting-state functional brain connectivity predicts individual pain sensitivity
An fMRI-based brain signature to predict an individual’s pain sensitivity could be useful clinically. Here the authors identify a network in the resting brain which can be used to predict responses to noxious stimuli in healthy subjects.
- Tamas Spisak
- , Balint Kincses
- & Ulrike Bingel
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Article
| Open AccessAn open source automated tumor infiltrating lymphocyte algorithm for prognosis in melanoma
Histology data exists for many cancer samples and the ability to automatically image this data may provide prognostic information. Here, the authors generated an algorithm to measure tumour infiltrating lymphocytes in melanoma histology specimens and show that the ratio of these immune cells to tumour cells has prognostic value.
- Balazs Acs
- , Fahad Shabbir Ahmed
- & David L. Rimm
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Article
| Open AccessHigh-fat diet fuels prostate cancer progression by rewiring the metabolome and amplifying the MYC program
Prostate cancer progression may be enhanced by a high-fat diet. Here the authors show that a diet high in saturated fats enhance the MYC-driven transcriptional program, a feature that independently predicts prostate cancer progression and death.
- David P. Labbé
- , Giorgia Zadra
- & Myles Brown
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Article
| Open AccessTherapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis associates with ROS pathway in monocytes
Dimethyl fumarate (DMF) is an established treatment for relapsing multiple sclerosis with unclear mechanism of action. Here the authors distinguish DMF responders by monocyte counts and redox gene signature in a prospective longitudinal cohort at 3 month of therapy, and associate NOX3 genetic variants with outcome.
- Karl E. Carlström
- , Ewoud Ewing
- & Fredrik Piehl
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Article
| Open AccessJNK1/2 represses Lkb1-deficiency-induced lung squamous cell carcinoma progression
LKB1 is frequently mutated in lung squamous cell carcinomas. Here, the authors show that sole LKB1 depletion is sufficient to drive the development of this cancer, where downstream defective MKK7-JNK1/2 signalling activates the ∆Np63/p63 pathway to induce subsequent epithelial cells transformation and tumour progression.
- Jian Liu
- , Tianyuan Wang
- & Francesco J. DeMayo
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Article
| Open AccessA gut microbiome signature for cirrhosis due to nonalcoholic fatty liver disease
Development of cirrhosis in individuals with non-alcoholic fatty liver disease can predict mortality. Here the authors used a unique twin and family cohort to identify a gut microbiome-derived 16sRNA signature that can detect cirrhosis in individuals with non-alcoholic fatty liver disease.
- Cyrielle Caussy
- , Anupriya Tripathi
- & Rohit Loomba
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Article
| Open AccessClinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanisms
FLT3 is commonly mutated in acute myeloid leukaemia and treatment with FLT3 inhibitors often ends with relapse. Here, the authors perform exome sequencing of samples from patients treated with the FLT3 inhibitor, crenolanib, to show that resistance occurs due to diverse molecular mechanisms, not primarily due to secondary FLT3 mutations.
- Haijiao Zhang
- , Samantha Savage
- & Jeffrey W. Tyner
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Article
| Open AccessTranscriptome 3′end organization by PCF11 links alternative polyadenylation to formation and neuronal differentiation of neuroblastoma
In gene regulation, diversification at the transcriptome 3′end is linked to differentiation and dedifferentiation. Here, the authors discover extensive transcriptome 3′end-alterations in neuroblastoma, regulated by PCF11, and provide an interactive data repository of transcriptome-wide alternative polyadenylation.
- Anton Ogorodnikov
- , Michal Levin
- & Sven Danckwardt
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Article
| Open AccessSCFFBW7-mediated degradation of Brg1 suppresses gastric cancer metastasis
Upstream pathways regulating Brg1 stability and their role in carcinogenesis are unknown. Here they show Brg1 to be phosphorylated by CK1δ to promote its ubiquitination by SCFFBW7 (FBW7), Brg1 stabilization to promote gastric cancer metastasis, and suggest targeting Brg1 in FBW7 compromised gastric cancer.
- Li-Yu Huang
- , Junjie Zhao
- & Wenyi Wei
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Article
| Open AccessIn vivo phosphoproteomics reveals kinase activity profiles that predict treatment outcome in triple-negative breast cancer
Triple-negative breast cancer (TNBC) lacks prognostic and predictive markers. Here, the authors use phosphoproteomics to define kinases with distinct activity profiles in TNBC, demonstrating their prognostic value as well as their utility for simplifying TNBC classification and designing drug regimens.
- Ivana Zagorac
- , Sara Fernandez-Gaitero
- & Miguel Quintela-Fandino
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Article
| Open AccessA community approach to mortality prediction in sepsis via gene expression analysis
Sepsis is characterized by deregulated host response to infection. Efficient therapies are still needed but a limitation for sepsis treatment is the heterogeneity in patients. Here Sweeney et al. generate prognostic models based on gene expression to improve risk stratification classification and prediction for 30-day mortality of patients.
- Timothy E. Sweeney
- , Thanneer M. Perumal
- & Raymond J. Langley
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Article
| Open AccessCharacterizing steroid hormone receptor chromatin binding landscapes in male and female breast cancer
Male breast cancer (MBC) is rare and largely hormonally driven. Here, the authors examine the action of steroid hormone receptors in male and female breast cancers and find gender selective hormone receptor action that associates with the survival of MBC patients.
- Tesa M. Severson
- , Yongsoo Kim
- & Wilbert Zwart
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Article
| Open AccessNSD1- and NSD2-damaging mutations define a subset of laryngeal tumors with favorable prognosis
The authors use an integrative clustering approach to identify two laryngeal cancer clusters with distinct prognosis and show that mutations damaging the NSD1 and NSD2 methyltransferases segregate to the cluster with favorable prognosis, and independently predict longer survival in patients with laryngeal, but not other head and neck cancers.
- Suraj Peri
- , Evgeny Izumchenko
- & Erica A. Golemis
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Article
| Open AccessMitochondrial mutations drive prostate cancer aggression
In prostate cancer, the role of mutations in the maternally-inherited mitochondrial genome are not well known. Here, the authors demonstrate frequent, age-dependent mitochondrial mutation in prostate cancer. Strong links between mitochondrial and nuclear mutational profiles are associated with clinical aggressivity.
- Julia F. Hopkins
- , Veronica Y. Sabelnykova
- & Paul C. Boutros
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Article
| Open AccessAPOBEC3A is an oral cancer prognostic biomarker in Taiwanese carriers of an APOBEC deletion polymorphism
Oral squamous cell carcinoma is a prevalent malignancy in Taiwan. Here, the authors show that OSCC in Taiwanese show a frequent deletion polymorphism in the cytidine deaminases gene cluster APOBEC3 resulting in increased expression of A3A, which is shown to be of clinical prognostic relevance.
- Ting-Wen Chen
- , Chi-Ching Lee
- & Yu-Sun Chang
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Article
| Open AccessLong noncoding RNA LncHIFCAR/MIR31HG is a HIF-1α co-activator driving oral cancer progression
Cancer cells adapt to the changing microenvironment by activating different pathways through multiple mechanisms. Here the authors identify long noncoding RNAMIR31HGas a HIF-1α co-activator required for the induction of the hypoxic response and show its oncogenic role in oral carcinogenesis.
- Jing-Wen Shih
- , Wei-Fan Chiang
- & Hsing-Jien Kung
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Article
| Open AccessMicroRNAs 146a/b-5 and 425-3p and 24-3p are markers of antidepressant response and regulate MAPK/Wnt-system genes
Antidepressant drugs are the most common treatment for depressive episodes but only a fraction of patients experience adequate response. Here the authors find dysregulation of miRNAs in peripheral blood samples from depressed patients after antidepressant treatment, and show that the miRNAs are regulators of psychiatrically relevant signalling pathways.
- Juan Pablo Lopez
- , Laura M. Fiori
- & Gustavo Turecki
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Article
| Open AccessLeukaemia cell of origin identified by chromatin landscape of bulk tumour cells
A tumour’s cell of origin may influence tumour progression and response to therapy. Here, the authors demonstrate that the cell of origin determines the aggressiveness of AML in a mouse model and identify unique biomarkers of the specific leukaemia cell of origin by profiling open chromatin regions of AML samples.
- Joshy George
- , Asli Uyar
- & Jennifer J. Trowbridge
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Article
| Open AccessFrequent alterations in cytoskeleton remodelling genes in primary and metastatic lung adenocarcinomas
Despite lung adenocarcinoma having a high global mortality, the genetic mutations present in Asian patients are uncharacterized. Here the authors use genomic and transcriptomic analysis to identify thirteen significantly affected genes, including RHPN2, GLI3, MRC2, TP53 and IQGAP3.
- Kui Wu
- , Xin Zhang
- & Jianxing He
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Article
| Open AccessEZH2-mediated loss of miR-622 determines CXCR4 activation in hepatocellular carcinoma
Chemokines and their receptors have key roles in tumorigenesis. Here, the authors demonstrate that CXRC4 is overexpressed in hepatocellular carcinoma and is associated with poor prognosis and, mechanistically CXCR4 is increased in expression via EZH2 repression of microRNA-622.
- Haiou Liu
- , Yidong Liu
- & Jiejie Xu
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Article
| Open AccessSTAT3 regulated ARF expression suppresses prostate cancer metastasis
IL6-STAT3 signaling is activated in prostate cancer, however inhibiting this pathway has not lead to a survival advantage in patients. Here, Pencik et al.show that loss of the IL6-STAT3 axis in mice and humans leads to metastasis due to loss of ARF, unravelling STAT3 and ARF as potential prognostic markers in prostate cancer.
- Jan Pencik
- , Michaela Schlederer
- & Lukas Kenner
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Article
| Open AccessUCHL1 provides diagnostic and antimetastatic strategies due to its deubiquitinating effect on HIF-1α
When stabilized, HIF-1 can activate adaptation to hypoxia and metastasis. Here the authors show that upregulation of Ubiquitin C-terminal hydrolase-L1 in human cancers promotes metastasis and correlates with poor prognosis because of its role in opposing ubiquitin-mediated degradation of HIF-1.
- Yoko Goto
- , Lihua Zeng
- & Hiroshi Harada
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Article
| Open AccessIdentification of high-quality cancer prognostic markers and metastasis network modules
There has been great interest in attempting to identify gene expression signatures that predict cancer survival. In this study a new algorithm is developed to analyse gene expression datasets that accurately classify both ER+ and ER− breast cancers into low- and high-risk groups.
- Jie Li
- , Anne E.G. Lenferink
- & Edwin Wang