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| Open AccessA crowdsourced analysis to identify ab initio molecular signatures predictive of susceptibility to viral infection
The response to respiratory virus exposure can currently not be predicted by pre- or early post-exposure molecular signatures. Here, the authors conduct a community-based analysis of blood gene expression from healthy individuals exposed to respiratory viruses and provide predictive models and biological insight into the physiological response.
- Slim Fourati
- , Aarthi Talla
- & Solveig K. Sieberts
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Article
| Open AccessAnalysis of extracellular mRNA in human urine reveals splice variant biomarkers of muscular dystrophies
Patients with myotonic dystrophy need to undergo invasive muscle biopsies to monitor disease progression and response to therapy. Here, the authors show that extracellular RNAs in human urine can be used as biomarkers to differentiate patients from unaffected controls, and to monitor exon skipping in patients with Duchenne muscular dystrophy taking the drug eteplirsen.
- Layal Antoury
- , Ningyan Hu
- & Thurman M. Wheeler
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Article
| Open AccessCerebello-thalamo-cortical hyperconnectivity as a state-independent functional neural signature for psychosis prediction and characterization
Brain function alterations in schizophrenia and other psychotic disorders remain poorly understood. Here, the authors discover that increased neural connectivity in the cerebello-thalamo-cortical circuitry predicts psychosis in those at high risk, and is present in people with schizophrenia.
- Hengyi Cao
- , Oliver Y. Chén
- & Tyrone D. Cannon
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Article
| Open AccessBrain and psychological determinants of placebo pill response in chronic pain patients
People vary in the extent to which they feel better after taking an inert, placebo, treatment, but the basis for individual placebo response is unclear. Here, the authors show how brain structural and functional variables, as well as personality traits, predict placebo response in those with chronic back pain.
- Etienne Vachon-Presseau
- , Sara E. Berger
- & A. Vania Apkarian
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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 AccessA study paradigm integrating prospective epidemiologic cohorts and electronic health records to identify disease biomarkers
Biomarker identification requires prohibitively large cohorts with gene expression and phenotype data. The approach introduced here learns polygenic predictors of expression from genetic and expression data, used to infer biomarker levels in patients with genetic and disease information.
- Jonathan D. Mosley
- , QiPing Feng
- & Dan M. Roden
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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 AccessThe germline genetic component of drug sensitivity in cancer cell lines
Little is known about the contribution of germline genetic variants to cancer drug sensitivity. Here, the authors devise an approach for joint analysis of germline variants and somatic mutations, identifying substantial germline contributions to variation in drug sensitivity.
- Michael P. Menden
- , Francesco Paolo Casale
- & Oliver Stegle
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Article
| Open AccessPredicting treatment benefit in multiple myeloma through simulation of alternative treatment effects
Selection of the right cancer treatment is still a challenge. Here, the authors introduce a framework to analyze treatment benefits, using the idea that patients with similar genetic tumor profiles receiving different treatments can be used to model their responses to the alternative treatment.
- Joske Ubels
- , Pieter Sonneveld
- & Jeroen de Ridder
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Article
| Open AccessMulti-omics monitoring of drug response in rheumatoid arthritis in pursuit of molecular remission
Little information is available on molecular changes in response to treatment of rheumatoid arthritis (RA). Here the authors report a multi-omics study collecting patients' transcriptome, proteome, and immunophenotype data to help understand the impact of drug treatments on RA molecular phenotypes.
- Shinya Tasaki
- , Katsuya Suzuki
- & Tsutomu Takeuchi
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Article
| Open AccessHarnessing synthetic lethality to predict the response to cancer treatment
Synthetic lethality (SL) offers a new precision oncology approach, which is based on targeting cancer-specific vulnerabilities across the whole genome, going beyond cancer drivers. The authors develop an approach termed ISLE to identify clinically relevant SL interactions and use them for patient stratification and novel target identification.
- Joo Sang Lee
- , Avinash Das
- & Eytan Ruppin
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Article
| Open AccessPreDicta chip-based high resolution diagnosis of rhinovirus-induced wheeze
Rhinovirus (RV) infections can trigger acute exacerbations of respiratory diseases. Here, Niespodziana et al. develop a PreDicta chip that identifies the culprit RV strain from small blood samples and show that RV-A and RV-C strains are associated with most severe symptoms.
- Katarzyna Niespodziana
- , Katarina Stenberg-Hammar
- & Rudolf Valenta
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Article
| Open AccessRecurrent rearrangements of FOS and FOSB define osteoblastoma
FOS has been linked to bone tumour pathogenesis, and viral homologue v-fos causes osteosarcoma in mice. Here, the authors report rearrangement of FOS and its paralogue FOSB in osteoblastoma and osteoid osteoma, revealing human bone tumours that are defined by mutations of FOS and FOSB.
- Matthew W. Fittall
- , William Mifsud
- & Sam Behjati
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Article
| Open AccessVariability in the location of high frequency oscillations during prolonged intracranial EEG recordings
High frequency oscillations (HFO) are a promising biomarker for identifying epileptogenic zones without the need to monitor spontaneous seizure episodes. Here the authors report that there is much variability in the location of HFOs offering a note of caution toward using HFO locations from short recordings as a guide for surgery.
- Stephen V. Gliske
- , Zachary T. Irwin
- & William C. Stacey
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Article
| Open AccessEnhanced pupillary light reflex in infancy is associated with autism diagnosis in toddlerhood
Previous studies showed that children with autism spectrum disorder (ASD) have atypicalities in the pupillary light reflex (PLR). This study uses longitudinal monitoring of infants at risk for ASD to show that PLR magnitude at 10 months of age is associated with later ASD diagnosis and symptom severity.
- Pär Nyström
- , Teodora Gliga
- & Terje Falck-Ytter
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Article
| Open AccessNon-invasive detection of human cardiomyocyte death using methylation patterns of circulating DNA
The detection of cardiomyocyte death is a critical aspect in the diagnosis and monitoring of heart diseases. Here the authors show that cardiomyocyte-specific methylation patterns of circulating cell-free DNA may serve as a biomarker of cardiac cell death in infarcted and septic patients.
- Hai Zemmour
- , David Planer
- & Yuval Dor
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Review Article
| Open AccessPrediction complements explanation in understanding the developing brain
This review summarizes how predictive modeling, a method that uses brain features to predict individual differences in behavior, is used to understand developmental periods. Rosenberg et al focus specifically on adolescence and examples of characteristic adolescent behaviors such as risk-taking.
- Monica D. Rosenberg
- , B. J. Casey
- & Avram J. Holmes
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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 AccessDynamic network biomarker indicates pulmonary metastasis at the tipping point of hepatocellular carcinoma
Biomarkers of the tipping point before metastasis in hepatocellular carcinoma (HCC) could help stratify patient treatment. Here, the authors study dynamic network biomarkers to identify CALM3 as a potential suppressor of metastasis, the level of which can predict overall survival and relapse-free survival in postoperative HCC.
- Biwei Yang
- , Meiyi Li
- & Jinglin Xia
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Article
| Open AccessUnravelling the immune signature of Plasmodium falciparum transmission-reducing immunity
Naturally acquired antibodies may inhibit Plasmodium survival in mosquitoes, alter malaria transmission dynamics, and form the basis for transmission-blocking vaccines. Here, using sera from malaria-exposed individuals, Stone et al. reveal novel antibody correlates of transmission-reducing activity.
- Will J. R. Stone
- , Joseph J. Campo
- & Matthijs M. Jore
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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 AccessMultiplex glycan bead array for high throughput and high content analyses of glycan binding proteins
The low throughput or content of current methods for the analysis of glycans-glycan binding proteins (GBPs) interactions hampers their clinical applications. Here, the authors conjugate synthesized glycans to Luminex beads to detect GBPs and apply it for the discovery of ovarian cancer biomarkers.
- Sharad Purohit
- , Tiehai Li
- & Jin-Xiong She
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Article
| Open AccessNovel peptide probes to assess the tensional state of fibronectin fibers in cancer
The extracellular matrix is under variable strain, but we lack the tools to detect differences in strain. Here the authors develop a probe based on a bacterial fibronectin-binding peptide that binds to relaxed fibronectin fibrils and detects relaxed matrix in cell culture, tissue slices and in vivo.
- Simon Arnoldini
- , Alessandra Moscaroli
- & Viola Vogel
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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 AccessWhole blood stabilization for the microfluidic isolation and molecular characterization of circulating tumor cells
The current FDA-approved whole blood stabilization method for circulating tumor cell (CTC) isolation suffers from RNA degradation. Here the authors combine hypothermic preservation and antiplatelet strategies to stabilize whole blood up to 72 h without compromising CTC yield and RNA integrity.
- Keith H. K. Wong
- , Shannon N. Tessier
- & Mehmet Toner
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Article
| Open AccessDetermining therapeutic susceptibility in multiple myeloma by single-cell mass accumulation
Multiple myeloma is characterized by high rates of drug resistance and relapse. Here the authors utilize a functional assay to assess the ex vivo drug sensitivity of single multiple myeloma cells based on measuring the mass accumulation rate of individual cells.
- Arif E. Cetin
- , Mark M. Stevens
- & Scott R. Manalis
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Article
| Open AccessTranscriptional signature of human pro-inflammatory TH17 cells identifies reduced IL10 gene expression in multiple sclerosis
CD4+ T cells secreting interleukin-17 (TH17) have diverse functions in modulating autoimmune diseases. Here the authors show via transcriptome analyses that a subset of human TH 17 co-expressing interferon-γ (TH1/17) has a molecular signature similar to “pathogenic” mouse TH 17 but distinct from “non-pathogenic” mouse TH 17.
- Dan Hu
- , Samuele Notarbartolo
- & Howard L. Weiner
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Article
| Open AccessEarliest accumulation of β-amyloid occurs within the default-mode network and concurrently affects brain connectivity
Abnormal levels of Aβ42 in the cerebrospinal fluid occur prior to a positive amyloid PET scan in the brain of individuals with Alzheimer’s disease and here the authors use this temporal pattern to identify individuals with very early stage AD. They show that Aβ fibrils start to accumulate in some of the regions of the default mode network and affect brain connectivity before neurodegeneration occurs.
- Sebastian Palmqvist
- , Michael Schöll
- & Oskar Hansson
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Article
| Open AccessNon-invasive assessment of hepatic mitochondrial metabolism by positional isotopomer NMR tracer analysis (PINTA)
Liver mitochondrial metabolism plays an important role for glucose and lipid homeostasis and its alterations contribute to metabolic disorders, including fatty liver and diabetes. Here Perry et al. develop a method for the measurement of hepatic fluxes by using lactate and glucose tracers in combination with NMR spectroscopy.
- Rachel J. Perry
- , Liang Peng
- & Gerald I. Shulman
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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 AccessCaloric restriction delays age-related methylation drift
Caloric restriction has been shown to increase lifespan in mammals. Here, the authors provide evidence that age-related methylation drift correlates with lifespan and that caloric restriction in mice and rhesus monkeys results in attenuation of age-related methylation drift.
- Shinji Maegawa
- , Yue Lu
- & Jean-Pierre J. Issa
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Article
| Open AccessIn vivo quantitative imaging of tumor pH by nanosonophore assisted multispectral photoacoustic imaging
Background optical absorption of several biomolecules impedes an effective in vivo pH imaging in tumors. Here, the authors developed a visible light-based in vivo pH mapping method by coupling photoacoustic imaging and pH-responsive modified nanoparticles that selectively target tumor cells.
- Janggun Jo
- , Chang H. Lee
- & Xueding Wang
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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 AccessBiochemical phosphates observed using hyperpolarized 31P in physiological aqueous solutions
Real-time monitoring of phosphate metabolism and distribution in the live body without ionizing radiation is highly desirable. Here, the authors show dissolution-dynamic nuclear polarization technology can enable nuclear magnetic resonance detection of hyperpolarized 31P of important biological phosphates in aqueous solutions.
- Atara Nardi-Schreiber
- , Ayelet Gamliel
- & Rachel Katz-Brull
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Article
| Open AccessDiagnosing peri-implant disease using the tongue as a 24/7 detector
Early detection of gum inflammation caused by dental implants helps prevent tissue damage. Here, the authors present a peptide sensor that generates a bitter taste when cleaved by proteases present in peri-implant disease, embed it in a chewing gum, and compare the probe to existing sensors using patient saliva.
- J. Ritzer
- , T. Lühmann
- & L. Meinel
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Article
| Open AccessPlasmonic silver nanoshells for drug and metabolite detection
Preparation of samples for diagnosis can affect the detection of biomarkers and metabolites. Here, the authors use a silver nanoparticle plasmonics approach for the detection of biomarkers in patients as well as investigate the distribution of drugs in serum and cerebral spinal fluid.
- Lin Huang
- , Jingjing Wan
- & Kun Qian
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Article
| Open AccessLarge meta-analysis of genome-wide association studies identifies five loci for lean body mass
Lean body mass is a highly heritable trait and is associated with various health conditions. Here, Kiel and colleagues perform a meta-analysis of genome-wide association studies for whole body lean body mass and find five novel genetic loci to be significantly associated.
- M. Carola Zillikens
- , Serkalem Demissie
- & Douglas P. Kiel
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Article
| Open AccessA transcriptomics data-driven gene space accurately predicts liver cytopathology and drug-induced liver injury
Predicting the hepatotoxic effects of new drugs is still a challenge. Using toxicogenomics data, the authors here define a predictive toxicogenomic space (PTGS), the component gene space capturing dose-dependent cytotoxicity, and demonstrate that it can be used to accurately predict drug-induced liver pathology, including human drug-induced liver injury fromin vitrodata.
- Pekka Kohonen
- , Juuso A. Parkkinen
- & Roland C. Grafström
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Article
| Open AccessCharacterizing sleep spindles in 11,630 individuals from the National Sleep Research Resource
Sleep patterns vary and are associated with health and disease. Here Purcellet alcharacterize sleep spindle activity in 11,630 individuals and describe age-related changes, genetic influences, and possible confounding effects, serving as a resource for further understanding the physiology of sleep.
- S. M. Purcell
- , D. S. Manoach
- & R. Stickgold
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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 AccessA molecular portrait of microsatellite instability across multiple cancers
Some cancers with DNA mismatch repair deficiency display microsatellite instability. Here the authors analyse twenty three cancer types at the exome and whole-genome level, and identify loci with recurrent microsatellite instability that could be used to identify patients who would benefit from immunotherapy.
- Isidro Cortes-Ciriano
- , Sejoon Lee
- & Peter J. Park
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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 AccessInhibiting the system xC−/glutathione axis selectively targets cancers with mutant-p53 accumulation
Efficient therapeutic strategies to target mutant-p53 cancers are needed. Here, the authors demonstrate the molecular mechanism through which mutant-p53 tumours are susceptible to oxidative damage and propose a potential strategy for targeting such cancers by inhibiting the SLC7A11-glutathione axis.
- David S. Liu
- , Cuong P. Duong
- & Nicholas J. Clemons
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Article
| Open AccessDNA methylation signatures in peripheral blood strongly predict all-cause mortality
DNA methylation is modulated by environmental factors and has a role in many complex diseases. Here, the authors find that methylation at specific DNA sites is associated with all-cause mortality, and a methylation-based risk score may be informative for risk assessment and stratification.
- Yan Zhang
- , Rory Wilson
- & Hermann Brenner
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Article
| Open AccessBlunted ventral striatal responses to anticipated rewards foreshadow problematic drug use in novelty-seeking adolescents
Some adolescents seek novelty, but it is unknown whether the brain circuits underlying this behaviour can be used to predict later, problematic behaviour. Here, authors show that diminished ventral striatal and prefrontal activity in response to anticipated rewards at age 14 in these individuals predicts problematic drug use at age 16.
- Christian Büchel
- , Jan Peters
- & Veronika Ziesch
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Article
| Open AccessQuantifying cerebral contributions to pain beyond nociception
Pain is affected by cerebral processes in addition to afferent nociceptive input. Here the authors develop an fMRI-based signature that predicts pain independent of the intensity of nociceptive signals and mediates the pain-modulating effects of several cognitive interventions.
- Choong-Wan Woo
- , Liane Schmidt
- & Tor D. Wager
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Article
| Open AccessMolecular dissection of colorectal cancer in pre-clinical models identifies biomarkers predicting sensitivity to EGFR inhibitors
The heterogeneity of colorectal cancer has important clinical and therapeutic implications. Here the authors analysed the responses of a large biobank of organoids and xenografts derived from colorectal patients to a panel of clinically relevant therapeutic agents to identify genes signatures associated with drug response.
- Moritz Schütte
- , Thomas Risch
- & Marie-Laure Yaspo
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Article
| Open AccessReconciled rat and human metabolic networks for comparative toxicogenomics and biomarker predictions
The rat is a widely-used model for human biology, but we must be aware of metabolic differences. Here, the authors reconstruct the genome-scale metabolic network of the rat, and after reconciling it with an improved human metabolic model, demonstrate the power of the models to integrate toxicogenomics data, providing species-specific biomarker predictions in response to a panel of drugs.
- Edik M. Blais
- , Kristopher D. Rawls
- & Jason A. Papin
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Article
| Open AccessMEK inhibitors block growth of lung tumours with mutations in ataxia–telangiectasia mutated
ATM is a tumor suppressor often mutated in lung adenocarcinoma. In this study, the authors starting from a synthetic lethal screen, demonstrate that tumor cells with mutations in ATM exhibit increased sensitivity to MEK1/2 inhibition through the modulation of the AKT/mTOR pathway.
- Michal Smida
- , Ferran Fece de la Cruz
- & Sebastian M. B. Nijman