Featured
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Article
| Open AccessHigh p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer
CDK4/6 inhibitor resistance is common in breast cancer. Here, the authors show that p16 overexpression may be linked to reduced efficacy of CDK4/6 inhibition, and show that the combination with PI3K inhibitors may increase anti-tumour effects.
- Marta Palafox
- , Laia Monserrat
- & Violeta Serra
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Article
| Open AccessDerivation and utility of schizophrenia polygenic risk associated multimodal MRI frontotemporal network
Schizophrenia is highly heritable and characterized by widespread brain abnormalities. Here, the authors identify schizophrenia polygenic risk associated multimodal frontotemporal network that can serve as a transdiagnostic brain signature specific to schizophrenia.
- Shile Qi
- , Jing Sui
- & Vince D. Calhoun
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Article
| Open AccessPredicting response to immunotherapy in gastric cancer via multi-dimensional analyses of the tumour immune microenvironment
Predictive methods for gastric cancer to try and differentiate between potential treatment response are required. Here the authors use a multiplexed immunohistochemistry method to propose the proximity of tumour infiltrating immune cells as an indicator of likely therapeutic response.
- Yang Chen
- , Keren Jia
- & Lin Shen
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Article
| Open AccessIntegrated methylome and phenome study of the circulating proteome reveals markers pertinent to brain health
Characterising associations between the methylome, proteome and phenome may provide insight into biological pathways governing brain health. Here, blood protein markers of brain health are integrated with omics data to reveal DNA methylation differences that associate with these protein markers.
- Danni A. Gadd
- , Robert F. Hillary
- & Riccardo E. Marioni
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Article
| Open AccessMulti-cohort and longitudinal Bayesian clustering study of stage and subtype in Alzheimer’s disease
Different types of atrophy in Alzheimer’s disease may reflect different disease stages or biologically distinct subtypes. Here the authors use longitudinal neuroimaging data to demonstrate five distinct patterns of atrophy with different demographical and cognitive characteristics.
- Konstantinos Poulakis
- , Joana B. Pereira
- & Eric Westman
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Article
| Open AccessDNA methylation-based epigenetic signatures predict somatic genomic alterations in gliomas
No clinical assay currently exists to classify glioma tumours based on gene expression. Here, the authors develop a DNA methylation-based classifier, Unified Diagnostic Pipeline (UniD) that identifies genomic alterations and gene expression subtypes of gliomas.
- Jie Yang
- , Qianghu Wang
- & Erik P. Sulman
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Article
| Open AccessPhagocytosis of Plasmodium falciparum ring-stage parasites predicts protection against malaria
Here the authors show that antibody-dependent phagocytosis of ring-stage P. falciparum parasites is mediated by merozoite antigens and is a strong predictor of protection following challenge in a controlled human malaria infection study in semi-immune Kenyan adults.
- Fauzia K. Musasia
- , Irene N. Nkumama
- & Faith H. A. Osier
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Article
| Open AccessVariance-quantitative trait loci enable systematic discovery of gene-environment interactions for cardiometabolic serum biomarkers
Understanding how our genes interact with the environment is critical to improving health. Using a large-scale discovery pipeline, here the authors investigate synergies between genetic variants and a broad range of environmental factors impacting cardiometabolic health.
- Kenneth E. Westerman
- , Timothy D. Majarian
- & Joanne B. Cole
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Article
| Open AccessBiomarkers of nanomaterials hazard from multi-layer data
Nanomaterials have a range of potential applications, however, toxicity remains a concern, limiting application and requiring extensive testing. Here, the authors report on a predictive framework made using a range of tests linking materials properties with toxicity, allowing the prediction of toxicity from physiochemical and biological properties.
- Vittorio Fortino
- , Pia Anneli Sofia Kinaret
- & Dario Greco
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Article
| Open AccessA proteogenomic signature of age-related macular degeneration in blood
Age related macular degeneration is a common cause of visual impairment in the elderly, but the etiology is not fully understood. Here, the authors use genetic data, serum proteomics, and AMD phenotypic data from a large Icelandic cohort to discover proteins altered in, causally related to AMD or signifying progression of advanced AMD.
- Valur Emilsson
- , Elias F. Gudmundsson
- & Tony E. Walshe
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| Open AccessThe potential of polygenic scores to improve cost and efficiency of clinical trials
Polygenic scores can identify individuals with high disease risk based on inborn DNA variation. We explore their potential to enrich clinical trials by identifying individuals based on higher risk of disease (‘prognostic enrichment’), or increased probability of benefit (‘predictive enrichment’).
- Akl C. Fahed
- , Anthony A. Philippakis
- & Amit V. Khera
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Article
| Open AccessNoninvasive urinary protein signatures associated with colorectal cancer diagnosis and metastasis
More sensitive and specific non-invasive biomarkers are desired for early detection of cancer. Here, the authors show a protein signature in the urine that increases sensitivity for colorectal cancer detection when combined with fecal immunochemical tests and corrects diagnosis in some fecal immunochemical tests-negative patients.
- Yulin Sun
- , Zhengguang Guo
- & Xiaohang Zhao
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Article
| Open AccessPoly(GR) and poly(GA) in cerebrospinal fluid as potential biomarkers for C9ORF72-ALS/FTD
The GGGGCC repeat expansion in C9ORF72-ALS/FTD can be translated into five dipeptide repeat (DPR) proteins, including poly(GR) and poly(GA). Here, the authors develop assays to detect the levels of these DPR proteins in the CSF of individuals with ALS/FTD.
- Gopinath Krishnan
- , Denitza Raitcheva
- & Fen-Biao Gao
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Article
| Open AccessCDK12 promotes tumorigenesis but induces vulnerability to therapies inhibiting folate one-carbon metabolism in breast cancer
Finding biomarkers for targeted therapy is a promising approach to treat cancer. Here, the authors show that in breast cancer preclinical models and patients, CDK12 promotes tumourigenesis but induces selective vulnerability to therapies that target folate one-carbon metabolism.
- M. G. Filippone
- , D. Gaglio
- & S. Pece
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Article
| Open AccessGeneration of human islet cell type-specific identity genesets
Cell therapy to replace β-cells is a potential therapeutic avenue to treat diabetes, but the production of insulin-secreting replacement cells requires reliable tools to assess islet cellular identity. Here the authors use single-cell transcriptomics meta-analysis to construct gene sets that describe the identity of human α-, β-, γ- and δ-cells.
- Léon van Gurp
- , Leon Fodoulian
- & Pedro L. Herrera
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Article
| Open AccessUsing deep learning to predict abdominal age from liver and pancreas magnetic resonance images
Approaches to both determine abdominal age and identify risk factors for accelerated abdominal age will help delay the onset of several diseases. Here, the authors build an abdominal age predictor by training convolutional neural networks to predict abdominal age from liver and pancreas MRIs.
- Alan Le Goallec
- , Samuel Diai
- & Chirag J. Patel
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Article
| Open AccessA polygenic risk score for nasopharyngeal carcinoma shows potential for risk stratification and personalized screening
Polygenic Risk Scores (PRS) show promise for facilitating cancer risk stratification. Here, the authors performed a large genome-wide association study and develop a PRS for nasopharyngeal carcinoma, which could improve risk stratification and personalized screening.
- Yong-Qiao He
- , Tong-Min Wang
- & Wei-Hua Jia
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Article
| Open AccessPredictive biomarkers for survival benefit with ramucirumab in urothelial cancer in the RANGE trial
Identification of biomarkers to stratify patients who might benefit from treatment is needed to optimize targeted therapies. Here, based on an analysis of the RANGE trial (NCT02426125), the authors report potentially predictive biomarkers for survival benefit in patients with platinum-refractory advanced urothelial carcinoma treated with the anti-VEGFR2 monoclonal antibody ramucirumab.
- Michiel S. van der Heijden
- , Thomas Powles
- & Alexandra Drakaki
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Article
| Open AccessSerum proteomics links suppression of tumor immunity to ancestry and lethal prostate cancer
Ancestry-related differences in immunobiology may explain the health disparities observed in prostate cancer patients, with men of African origin bearing the highest prostate cancer burden. By measuring immune-related proteins in serum samples, here the authors report that systemic cytokines linked to suppression of tumor immunity are upregulated in men of African ancestry and associated with reduced survival.
- Tsion Zewdu Minas
- , Julián Candia
- & Stefan Ambs
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Article
| Open AccessA hydrogen sulphide-responsive and depleting nanoplatform for cancer photodynamic therapy
Abnormal levels of intracellular hydrogen sulphide (H2S) have been associated with different pathological conditions, including cancer. Here the authors report the design of a H2S-responsive and -depleting nanoplatform that, combined with NIR-II photodynamic properties, can be used for H2S imaging and cancer therapy.
- Yuqi Zhang
- , Jing Fang
- & Haibin Shi
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Article
| Open AccessAutoantibodies targeting GPCRs and RAS-related molecules associate with COVID-19 severity
COVID-19, similarly to systemic autoimmune diseases, is characterised by the presence of autoantibodies. Authors show here that the abundance and network signature of autoantibodies targeting G protein-coupled receptors and RAS-related proteins are altered in COVID-19 patients, and the level of disruption marks clinical severity.
- Otavio Cabral-Marques
- , Gilad Halpert
- & Yehuda Shoenfeld
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Article
| Open AccessQuantifying arousal and awareness in altered states of consciousness using interpretable deep learning
The authors propose an explainable consciousness indicator using deep learning to quantify arousal and awareness under sleep, anesthesia, and in patients with disorders of consciousness.
- Minji Lee
- , Leandro R. D. Sanz
- & Seong-Whan Lee
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Article
| Open AccessMicrobial-driven preterm labour involves crosstalk between the innate and adaptive immune response
Gaining mechanistic insight into the microbiological and immunological factors that are associated with spontaneous preterm birth is important for the development of prevention strategies. Here authors show that the complement system in conjunction with specific vaginal microbial and associated immunological changes are contributing to this condition.
- Denise Chan
- , Phillip R. Bennett
- & Lynne Sykes
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Article
| Open AccessDihydroceramide- and ceramide-profiling provides insights into human cardiometabolic disease etiology
Among lipid classes, ceramides are linked to impaired cardiometabolic health. Here the authors report the association of specific ceramides and dihydroceramides on the risk of developing type 2 diabetes and or cardiovascular disease in a prospective population cohort.
- C. Wittenbecher
- , R. Cuadrat
- & M. B. Schulze
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Article
| Open AccessStratification of hospitalized COVID-19 patients into clinical severity progression groups by immuno-phenotyping and machine learning
Developing predictive methods to identify patients with high risk of severe COVID-19 disease is of crucial importance. Authors show here that by measuring anti-SARS-CoV-2 antibody and cytokine levels at the time of hospital admission and integrating the data by unsupervised hierarchical clustering/machine learning, it is possible to predict unfavourable outcome.
- Yvonne M. Mueller
- , Thijs J. Schrama
- & Peter D. Katsikis
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Article
| Open AccessImmunoglobulin signature predicts risk of post-acute COVID-19 syndrome
Studying a prospective cohort, the authors develop and validate a predictive score for post-acute COVID-19 syndrome, also known as long-COVID. This score relies on an immunoglobulin signature and is independent of timepoint of blood sampling.
- Carlo Cervia
- , Yves Zurbuchen
- & Onur Boyman
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Article
| Open AccessDNA methylation aging and transcriptomic studies in horses
Methylation levels of specific sites in the genome is correlated with aging. Here the authors develop a human-horse clock which could assist in translating anti-aging interventions from humans to horses and vice versa.
- Steve Horvath
- , Amin Haghani
- & Carrie J. Finno
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Article
| 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 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 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 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 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 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 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 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 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 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 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