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| Open AccessIgM N-glycosylation correlates with COVID-19 severity and rate of complement deposition
The role of IgG glycosylation in the immune response has been studied, but less is known about IgM glycosylation. Here the authors characterize glycosylation of SARS-CoV-2 spike specific IgM and show that it correlates with COVID-19 severity and affects complement deposition.
- Benjamin S. Haslund-Gourley
- , Kyra Woloszczuk
- & Mary Ann Comunale
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Article
| Open AccessDistinct mesenchymal cell states mediate prostate cancer progression
The components of the tumour microenvironment contribute to prostate cancer initiation and progression. Here the authors perform single-cell RNA sequencing and spatial transcriptomics analysis of prostate cancer stroma from mouse models at different stages of the disease and develop a gene signature to predict distant metastasis in patients.
- Hubert Pakula
- , Mohamed Omar
- & Massimo Loda
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Article
| Open AccessRadiomic tractometry reveals tract-specific imaging biomarkers in white matter
Diffusion MRI is used for tract-specific microstructural analysis of the white matter. Here, the authors introduce radiomic tractometry (RadTract), enhancing tractometry with radiomics-based imaging biomarkers for improved predictive modelling.
- Peter Neher
- , Dusan Hirjak
- & Klaus Maier-Hein
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| Open AccessThe ALT pathway generates telomere fusions that can be detected in the blood of cancer patients
Telomere fusions are linked to oncogenesis in multiple cancer types, but their patterns are poorly understood. Here, the authors use whole-genome sequencing data to compare fusion events across cancer types, and identify a novel type of telomere fusion pattern associated with the Alternative Lengthening of Telomeres (ALT) pathway that can be used for liquid biopsy analysis.
- Francesc Muyas
- , Manuel José Gómez Rodriguez
- & Ignacio Flores
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Article
| Open AccessSerglycin secreted by late-stage nucleus pulposus cells is a biomarker of intervertebral disc degeneration
Aging-related intervertebral disc degeneration (IVDD) is a leading cause of lower back pain. Here, the authors perform scRNA-seq analysis of intervertebral disc cells from patients, and identify cell populations and mechanisms associated with IVDD.
- Fan Chen
- , Linchuan Lei
- & Jianru Wang
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Article
| Open AccessDistinct gene expression signatures comparing latent tuberculosis infection with different routes of Bacillus Calmette-Guérin vaccination
The ability of BCG vaccination to prevent pulmonary tuberculosis could be improved by targeting mucosal immunity within the lung. Here the authors compare latent Mtb-infected donors with intradermal or oral BCG vaccine recipients to show distinct systemic and pulmonary immune responses are induced by differing routes of natural infection or vaccination.
- Richard F. Silver
- , Mei Xia
- & Daniel F. Hoft
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Article
| Open AccessProteomics-driven noninvasive screening of circulating serum protein panels for the early diagnosis of hepatocellular carcinoma
Hepatocellular carcinoma is often diagnosed at a late stage which limits treatment efficacy. Here, the authors utilise proteomics to identify serum proteomic biomarkers for early diagnosis, and validate using a prospective validation cohort.
- Xiaohua Xing
- , Linsheng Cai
- & Xiaolong Liu
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Article
| Open AccessMapping combinatorial drug effects to DNA damage response kinase inhibitors
DNA damage is a key component of many cancer therapies. Here, the authors utilised a dose-response combination screen of ATR, ATM and DNA-PK inhibitors, and identified combination treatments that achieves high combinatorial efficacy and synergy.
- Hanrui Zhang
- , Julian Kreis
- & Yuanfang Guan
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Article
| Open AccessSphingosine-1-phosphate suppresses GLUT activity through PP2A and counteracts hyperglycemia in diabetic red blood cells
Red blood cells (RBC) carry the majority of sphingosine-1-phosphate (S1P). Here, the authors show that RBC dynamically regulate S1P levels in response to metabolic stress and employ them to regulate glucose uptake, glycolysis and the pentose phosphate pathway as protection against lipid peroxidation.
- Nadine Thomas
- , Nathalie H. Schröder
- & Bodo Levkau
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Article
| Open AccessAmplified fluorogenic immunoassay for early diagnosis and monitoring of Alzheimer’s disease from tear fluid
Accurate diagnosis of Alzheimer’s disease in its earliest stage can prevent the disease and delay the symptoms. Here the authors identify a potential Alzheimer’s biomarker from tear fluid, and develop a nanoparticle-based immunoassay for its detection, demonstrating potential in Alzheimer’s diagnosis.
- Sojeong Lee
- , Eunjung Kim
- & Seungjoo Haam
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Article
| Open AccessChoroidal and retinal thinning in chronic kidney disease independently associate with eGFR decline and are modifiable with treatment
In patients with CKD, there is an unmet need for biomarkers that reliably track kidney injury. Here, in a series of prospective studies, the authors show that retinal OCT metrics reflect kidney injury, are modified by treatments for kidney disease and can predict future decline of kidney function.
- Tariq E. Farrah
- , Dan Pugh
- & Neeraj Dhaun
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Article
| Open AccessBile proteome reveals biliary regeneration during normothermic preservation of human donor livers
Normothermic machine perfusion (NMP) is increasingly used for preserving and evaluating donor livers before transplantation. Here, the authors demonstrate increased regenerative protein profiles in the bile of perfused livers considered suitable for transplantation, providing insight into the mechanisms linked to recovery of the biliary tree following ischemia-reperfusion injury.
- Adam M. Thorne
- , Justina C. Wolters
- & Vincent E. de Meijer
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Article
| Open AccessGenome-wide association analysis of left ventricular imaging-derived phenotypes identifies 72 risk loci and yields genetic insights into hypertrophic cardiomyopathy
Changes of left ventricular structure are used to predict morbidity and mortality in cardiovascular diseases. Here the authors conducted a study using advanced deep learning technology to analyze left ventricular regional wall thickness (LVRWT) in a large population, identifying 72 significant genetic loci linked to LVRWT traits.
- Caibo Ning
- , Linyun Fan
- & Xiaoping Miao
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Article
| Open AccessProteomic characterization of epithelial ovarian cancer delineates molecular signatures and therapeutic targets in distinct histological subtypes
The molecular phenotypic features of epithelial ovarian cancer (EOC) remain elusive. Here, the authors perform mass spectrometry-based proteomic profiling for 269 EOC patients and reveal molecularly distinct features and potential therapeutic targets among the histological subtypes of EOC.
- Ting-Ting Gong
- , Shuang Guo
- & Qi-Jun Wu
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| Open AccessPlasma proteomic profiles predict individual future health risk
The predictive capability of future health risk using plasma proteomic profiles remains largely unexplored. Using 1461 proteins collected from 50k individuals, authors show proteins can derive much better or equivalent performance than established clinical indicators for more than 40 endpoints.
- Jia You
- , Yu Guo
- & Jin-Tai Yu
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Article
| Open AccessDeep topographic proteomics of a human brain tumour
Ultrasensitive, spatially-resolved proteomics techniques allow mapping the organisation of healthy and diseased tissues. Here, the authors develop a workflow for spatially-resolved, quantitative tissue proteomics with spatially aware statistics and clustering, with which they characterise a human atypical teratoid-rhabdoid tumour at different spatial resolutions.
- Simon Davis
- , Connor Scott
- & Roman Fischer
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Article
| Open AccessMultifaceted immune dysregulation characterizes individuals at-risk for rheumatoid arthritis
The presence of antibodies to citrullinated protein antigens (ACPA) in peripheral blood represents a risk a state that is ‘at-risk’ for subsequent development of rheumatoid arthritis (RA). Here authors compare multiple molecular and immunological parameters in individuals who are ACPA positive without inflammatory arthritis, ACPA negative controls and patients diagnosed with ACPA positive early-stage RA to conclude that complex immunopathological processes are present in an ACPA positive state which may be targeted by future preventive approaches for RA.
- Eddie A. James
- , V. Michael Holers
- & Kevin D. Deane
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Article
| Open AccessEarly-to-mid stage idiopathic Parkinson’s disease shows enhanced cytotoxicity and differentiation in CD8 T-cells in females
Men are at a greater risk to develop Parkinson’s disease (PD). However, Hefeng and team revealed enhanced cytotoxicity and terminal differentiation in CD8 T cells of early-to-mid stage idiopathic PD, especially for females, using systems immunology.
- Christophe M. Capelle
- , Séverine Ciré
- & Feng Q. Hefeng
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| Open AccessWireless, battery-free, multifunctional integrated bioelectronics for respiratory pathogens monitoring and severity evaluation
The SARS-CoV-2 pandemic highlighted our need for methods that allow rapid viral surveillance. Here, authors report a wireless, battery-free and wearable self-diagnosis platform that can continuously capture viral particles, diagnose infection status and evaluate symptom severity via breath and blow.
- Hu Li
- , Huarui Gong
- & Xinge Yu
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Article
| Open AccessPET/CT based cross-modal deep learning signature to predict occult nodal metastasis in lung cancer
Occult node metastasis is a key staging component of non-small cell lung cancer. Here, the authors use deep learning to improve diagnosis of lymph node metastasis from PET and CT radiomics.
- Yifan Zhong
- , Chuang Cai
- & Yunlang She
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Article
| Open AccessCircadian disturbances and frailty risk in older adults
The relationship between circadian function and frailty is not well understood. Here, the authors show that disturbances in circadian rest-activity rhythms were associated with an elevated frailty risk and faster progress of frailty in older adults.
- Ruixue Cai
- , Lei Gao
- & Peng Li
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Article
| Open AccessThe Imageable Genome
The impact of genomic discoveries on global health depends on their efficient translation into clinically applicable testing. Here, the authors present the Imageable Genome - the part of the human genome whose expression can be assessed via molecular imaging - to accelerate translation and to bridge the fields of genomics and molecular imaging.
- Pablo Jané
- , Xiaoying Xu
- & Martin A. Walter
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Article
| Open AccessAutomated temporalis muscle quantification and growth charts for children through adulthood
Temporalis muscle thickness is a promising marker of lean muscle mass but has had limited utility due to its unknown normal growth trajectory and lack of standardized measurement. Here, the authors develop an automated deep learning pipeline to accurately measure temporalis muscle thickness from routine brain magnetic resonance imaging.
- Anna Zapaishchykova
- , Kevin X. Liu
- & Benjamin H. Kann
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Article
| Open AccessA standardized metric to enhance clinical trial design and outcome interpretation in type 1 diabetes
The use of a standardized outcome metric enhances clinical trial interpretation and cross-trial comparison. Here, the authors show the implementation of such a metric using type 1 diabetes trial data, reassess and compare results from these trials, and extend its use to define response to therapy.
- Alyssa Ylescupidez
- , Henry T. Bahnson
- & Carla J. Greenbaum
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| Open AccessValidation of MSIntuit as an AI-based pre-screening tool for MSI detection from colorectal cancer histology slides
Microsatellite instability is a known risk factor for colorectal cancer development and treatment response. Here, the authors utilise deep learning to develop MSIntuit, a pre-screening tool to detect MSI from H&E stained slides.
- Charlie Saillard
- , Rémy Dubois
- & Magali Svrcek
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Article
| Open AccessImmunological and clinicopathological features predict HER2-positive breast cancer prognosis in the neoadjuvant NeoALTTO and CALGB 40601 randomized trials
Neoadjuvant therapies with dual anti-HER2 blockade have proven effective in HER2+ breast cancer treatment. Here, the authors develop a score that integrates antigen receptor repertoire features and clinical parameters to predict prognosis after anti-HER2 neoadjuvant treatments.
- Mattia Rediti
- , Aranzazu Fernandez-Martinez
- & Christos Sotiriou
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| Open AccessDistinct receptor binding domain IgG thresholds predict protective host immunity across SARS-CoV-2 variants and time
Evidence from trials suggests SARS-CoV-2 binding antibody thresholds could serve as surrogate markers of neutralising capacity, but whether this is accurate in the context of variants of concerns, or in the event of prior infection or vaccination remains unclear. Authors explore the performance of receptor binding domain IgG thresholds in predicting a level of neutralising capacity that has demonstrated protection against infection in vaccine trials
- Grace Kenny
- , Sophie O’Reilly
- & Patrick Mallon
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Article
| Open AccessProteomics reveal biomarkers for diagnosis, disease activity and long-term disability outcomes in multiple sclerosis
Precise biomarkers for multiple sclerosis prognosis are vital for treatment decisions. Here, the authors identify specific proteins in cerebrospinal fluid that can predict short-term disease activity and long-term disability outcomes in persons with multiple sclerosis.
- Julia Åkesson
- , Sara Hojjati
- & Mika Gustafsson
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Article
| Open AccessRNA N6-methyladenosine modification-based biomarkers for absorbed ionizing radiation dose estimation
Radiation dosimetry are critical for the medical management of individuals exposed to ionizing radiation (IR). Here, authors show that the RNA m6A levels of Ncoa4, Ate1 and Fgf22 genes in peripheral blood cells could serve as dosimetry of IR exposure.
- Hongxia Chen
- , Xi Zhao
- & Gangqiao Zhou
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Article
| Open AccessGut microbiota impacts bone via Bacteroides vulgatus-valeric acid-related pathways
Gut microbiota has been reported to influence osteoporosis risk, but the individual species, and underlying mechanisms, remain largely unknown. Here, the authors identify Bacteroides vulgatus and serum valeric acid as potential targets for osteoporosis prevention/treatment.
- Xu Lin
- , Hong-Mei Xiao
- & Hong-Wen Deng
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Article
| Open AccessThe α-synuclein PET tracer [18F] ACI-12589 distinguishes multiple system atrophy from other neurodegenerative diseases
A PET tracer for α-synuclein would help diagnosis and treatment of α-syn-related diseases. Here the authors show that ACI-12589 shows an uptake in the cerebellar white matter in patients with multiple-system atrophy.
- Ruben Smith
- , Francesca Capotosti
- & Oskar Hansson
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Article
| Open AccessUncertainty-inspired open set learning for retinal anomaly identification
Failure to recognize samples from unseen classes is a major limitation of AI recognition and classification of retinal anomalies. Here, the authors present the Uncertainty-inspired Open Set learning model that categorises fundus images into pre-trained categories, and provides an uncertainty score that alerts the need for manual inspection when dealing with out-of-distribution images.
- Meng Wang
- , Tian Lin
- & Huazhu Fu
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Article
| Open AccessNivolumab and ipilimumab in recurrent or refractory cancer of unknown primary: a phase II trial
Standard of care for unfavorable-risk cancer of unknown primary (CUP) comprises platinum-based chemotherapy as first-line treatment, however therapeutic options remain limited. Here the authors report the results of a phase II trial of combined nivolumab (anti-PD1) and ipilimumab (anti-CTLA4) in patients with unfavorable CUP.
- Maria Pouyiourou
- , Bianca N. Kraft
- & Alwin Krämer
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Article
| Open AccessPlasma biomarkers predict Alzheimer’s disease before clinical onset in Chinese cohorts
Performance of plasma biomarkers of amyloid (A), tau (T) and neurodegeneration (N) for Alzheimer’s disease (AD) in Chinese cohorts is unknown. Here, the authors report that plasma ATN biomarkers can predict AD 8–10 years before symptoms in Chinese cohorts.
- Huimin Cai
- , Yana Pang
- & Longfei Jia
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Article
| Open AccessIntegrated radiogenomics models predict response to neoadjuvant chemotherapy in high grade serous ovarian cancer
Response to treatment in high grade serous ovarian carcinoma (HGSOC) is highly variable. Here, the authors leverage a radiogenomic model to predict neoadjuvant chemotherapy response in HGSOC, including clinical data, medical imaging, and blood-based biomarkers such as CA-125 and ctDNA features.
- Mireia Crispin-Ortuzar
- , Ramona Woitek
- & James D. Brenton
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Article
| Open AccessClinical utility of polygenic scores for cardiometabolic disease in Arabs
Arabs account for 5% of the world population and have a high burden of cardiometabolic disease. Here, the authors optimize polygenic scores for 10 cardiometabolic traits in 5399 Arabs, achieving a performance on par with that among European-ancestry individuals.
- Injeong Shim
- , Hiroyuki Kuwahara
- & Akl C. Fahed
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Article
| Open AccessMetabolic fingerprinting on retinal pigment epithelium thickness for individualized risk stratification of type 2 diabetes mellitus
The retina’s role in type 2 diabetes is not well understood. Here, the authors show that retinal pigment epithelium thickness, with its metabolic fingerprints, might offer improved predictability and clinical utility beyond traditional indicators.
- Shaopeng Yang
- , Zhuoting Zhu
- & Wei Wang
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Article
| Open AccessA human lung alveolus-on-a-chip model of acute radiation-induced lung injury
Acute exposure to radiation can lead to acute pneumonitis, fibrosis or death. Here the authors develop an alveolus-on chip model to study the molecular characteristics of radiation induced lung injury, better understand radiation induced lung disease and facilitate drug screening.
- Queeny Dasgupta
- , Amanda Jiang
- & Donald E. Ingber
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Article
| Open AccessRevealing invisible cell phenotypes with conditional generative modeling
Biological research relies on observing cell phenotypes, often obscured by natural variability. Here, the authors use generative modelling to unveil hidden changes triggered by infections, mutations, or drugs, allowing for accessible discovery of biomarkers.
- Alexis Lamiable
- , Tiphaine Champetier
- & Auguste Genovesio
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Article
| Open AccessTripartite motif containing 26 prevents steatohepatitis progression by suppressing C/EBPδ signalling activation
Nonalcoholic steatohepatitis (NASH) is a heterogeneous disease with complicated pathogenesis. Here the authors identify that the E3 ligase TRIM26 confers protection against NASH development via suppression of CCAAT/enhancer binding protein delta (C/EBPδ).
- Minxuan Xu
- , Jun Tan
- & Lianyi Han
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Article
| Open AccessProteomics of CKD progression in the chronic renal insufficiency cohort
Progression of chronic kidney disease may lead to kidney failure and cardiovascular, metabolic and bone disease complications. Here, the authors conduct a large-scale proteomic study in patients with chronic kidney disease, identify numerous proteins that predict kidney failure, some of which are likely causal mediators and hence potential therapeutic targets.
- Ruth F. Dubin
- , Rajat Deo
- & Peter Ganz
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Article
| Open AccessMetabolic phenotyping of BMI to characterize cardiometabolic risk: evidence from large population-based cohorts
A substantial proportion of patients with cardiometabolic conditions appear to have normal BMI. Conversely, not all obese individuals exhibit these disorders. Here, we show that a metabolic BMI score derived from lipidomic models, allows quantify metabolic dysregulation in obesity independently of BMI.
- Habtamu B. Beyene
- , Corey Giles
- & Peter J. Meikle
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Article
| Open AccessCombining Asian and European genome-wide association studies of colorectal cancer improves risk prediction across racial and ethnic populations
Most genetic studies have been done on European cohorts, which affects the efficacy of polygenic risk scores in non-European populations. Here, the authors demonstrate that a colorectal cancer PRS including Asian and European ancestries has improved performance over the European-centric PRS across racial and ethnic groups.
- Minta Thomas
- , Yu-Ru Su
- & Li Hsu
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Article
| Open AccessMultimodal analysis of cell-free DNA whole-methylome sequencing for cancer detection and localization
cfDNA is a promising tool to detect early cancer, however, it has been limited by detection limits and technological ability. Here, the authors develop a method for simultaneous cfDNA methylation, fragmentation and copy number alteration sequencing and apply to a cohort of healthy and cancer patients.
- Fenglong Bie
- , Zhijie Wang
- & Shugeng Gao
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Article
| Open AccessSocial and psychological adversity are associated with distinct mother and infant gut microbiome variations
Here, in a cohort of mother-child dyads, the authors show that maternal prenatal social disadvantage and psychosocial stressors associate with distinct gut microbiome taxonomic and functional diversity in both the mothers and their four-month children.
- Barbara B. Warner
- , Bruce A. Rosa
- & Makedonka Mitreva
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Article
| Open AccessPlasma metabolomic profiles associated with mortality and longevity in a prospective analysis of 13,512 individuals
The metabolic alterations underpinning aging processes and mortality in humans are not well understood. Here, the authors show that differences in levels of nucleosides, amino acids, and several lipid subclasses can predict mortality and longevity.
- Fenglei Wang
- , Anne-Julie Tessier
- & Marta Guasch-Ferré
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| Open AccessDetection of diagnostic and prognostic methylation-based signatures in liquid biopsy specimens from patients with meningiomas
Recurrence of meningiomas is unpredictable by current methods based on surgically removed specimens, and identification of patients likely to recur could inform treatment strategy. Here, the authors analysed DNA methylation in liquid biopsy specimens from meningioma patients to help classify recurrence risk noninvasively even before surgery.
- Grayson A. Herrgott
- , James M. Snyder
- & Houtan Noushmehr
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Article
| Open AccessCSF proteome profiling reveals biomarkers to discriminate dementia with Lewy bodies from Alzheimer´s disease
This study characterizes the CSF proteome changes underlying Dementia with Lewy Bodies (DLB) and identifies pathophysiological and diagnostic leads associated to this cause of dementia. Findings have been translated into a biomarker panel that could identify DLB patients with high accuracy across different cohorts.
- Marta del Campo
- , Lisa Vermunt
- & Charlotte E. Teunissen
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| Open AccessQuantifying the causal impact of biological risk factors on healthcare costs
Understanding the causal impact that risk factors have on healthcare cost is critical to evaluate healthcare interventions. Here, authors show that waist circumference, body mass index, and blood pressure have robust causal impact on healthcare cost.
- Jiwoo Lee
- , Sakari Jukarainen
- & Andrea Ganna