Uncemented hip arthroplasty and denosumab: increased postoperative dipeptide concentrations and identification of potential new bone turnover biomarkers.

Denosumab is a potent antagonist of RANKL and is widely used to treat severe postmenopausal osteoporosis. Using high-resolution mass spectrometry (HRMS), we aimed to identify molecular mediators associated with the rapid reactivation of osteoclasts following discontinuation of denosumab. In a previously reported randomized controlled trial, 64 patients undergoing uncemented total hip arthroplasty were randomized to receive 2 doses of 60 mg denosumab or placebo, administered 1-3 d and 6 mo postoperatively.

The overlooked trio: sleep duration, sampling time and physical exercise alter levels of olink-assessed blood biomarkers of cardiovascular risk.

Biomarker profiling from biofluids such as blood are widely measured in clinical research, using for example Olink proteomics panels. One such research focus area is cardiovascular disease (CVD), for which chronic sleep restriction (SR) is a risk factor. However, it remains unclear whether blood levels of commonly measured CVD biomarkers are sensitive to acute dynamic factors such as SR, physical exercise (PEx), and time of day.

Conformal prediction enables disease course prediction and allows individualized diagnostic uncertainty in multiple sclerosis.

Accurate assessment of progression and disease course in multiple sclerosis (MS) is vital for timely and appropriate clinical intervention. The gradual transition from relapsing-remitting MS (RRMS) to secondary progressive MS (SPMS) is often diagnosed retrospectively with a typical delay of three years. To address this diagnostic delay, we developed a predictive model that uses electronic health records to distinguish between RRMS and SPMS at each individual visit.

Associations of PFAS and OH-PCBs with risk of multiple sclerosis onset and disability worsening.

Exposure to per- and polyfluorinated substances (PFAS) and hydroxylated polychlorinated biphenyls (OH-PCBs) is associated with adverse human health effects, including immunosuppression. It is unknown if these substances can affect the course of autoimmune diseases. This study was based on 907 individuals with multiple sclerosis (MS) and 907 matched controls, where the MS cases were followed longitudinally using the Swedish MS register.

Fibromyalgia patients have altered lipid concentrations associated with disease symptom severity and anti-satellite glial cell IgG antibodies.

Autoimmunity and immunoglobulin G (IgG) autoantibodies may contribute to pain in a subset of fibromyalgia (FM) patients. Previously, IgG from FM patients was found to induce pain-like behavior in mice and bind to satellite glial cells (anti-SGC IgG). The anti-SGC IgG levels were also associated with more severe symptomatology.

Autologous hematopoietic stem cell transplantation significantly alters circulating ceramides in peripheral blood of relapsing-remitting multiple sclerosis patients.

Background: The common inflammatory disease multiple sclerosis (MS) is a disease of the central nervous system. For more than 25 years autologous hematopoietic stem cell transplantation (AHSCT) has been used to treat MS. It has been shown to be highly effective in suppressing inflammatory activity in relapsing-remitting MS (RRMS) patients.

Disease phenotype prediction in multiple sclerosis.

Progressive multiple sclerosis (PMS) is currently diagnosed retrospectively. Here, we work toward a set of biomarkers that could assist in early diagnosis of PMS. A selection of cerebrospinal fluid metabolites (n = 15) was shown to differentiate between PMS and its preceding phenotype in an independent cohort (AUC = 0.

Integration of small RNAs from plasma and cerebrospinal fluid for classification of multiple sclerosis.

Multiple Sclerosis (MS) is an autoimmune, neurological disease, commonly presenting with a relapsing-remitting form, that later converts to a secondary progressive stage, referred to as RRMS and SPMS, respectively. Early treatment slows disease progression, hence, accurate and early diagnosis is crucial. Recent advances in large-scale data processing and analysis have progressed molecular biomarker development.

GenErode: a bioinformatics pipeline to investigate genome erosion in endangered and extinct species.

Background: Many wild species have suffered drastic population size declines over the past centuries, which have led to 'genomic erosion' processes characterized by reduced genetic diversity, increased inbreeding, and accumulation of harmful mutations. Yet, genomic erosion estimates of modern-day populations often lack concordance with dwindling population sizes and conservation status of threatened species. One way to directly quantify the genomic consequences of population declines is to compare genome-wide data from pre-decline museum samples and modern samples.

Evaluation of polarity switching for untargeted lipidomics using liquid chromatography coupled to high resolution mass spectrometry.

Untargeted lipidomics using liquid chromatography high-resolution mass spectrometry (LC-HRMS) was performed using polarity switching, and in positive and negative polarity separately on the same set of serum samples, and the performances of the methods were evaluated. Polarity switching causes an increase in the cycle time of the HRMS measurements (1.18 s/cycle vs 0.

Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation.

Rationale: Asthma phenotyping requires novel biomarker discovery.

Objectives: To identify plasma biomarkers associated with asthma phenotypes by application of a new proteomic panel to samples from two well-characterised cohorts of severe (SA) and mild-to-moderate (MMA) asthmatics, COPD subjects and healthy controls (HCs).

Methods: An antibody-based array targeting 177 proteins predominantly involved in pathways relevant to inflammation, lipid metabolism, signal transduction and extracellular matrix was applied to plasma from 525 asthmatics and HCs in the U-BIOPRED cohort, and 142 subjects with asthma and COPD from the validation cohort BIOAIR.

Metabolic drift in the aging nervous system is reflected in human cerebrospinal fluid.

Chronic diseases affecting the central nervous system (CNS) like Alzheimer's or Parkinson's disease typically develop with advanced chronological age. Yet, aging at the metabolic level has been explored only sporadically in humans using biofluids in close proximity to the CNS such as the cerebrospinal fluid (CSF). We have used an untargeted liquid chromatography high-resolution mass spectrometry (LC-HRMS) based metabolomics approach to measure the levels of metabolites in the CSF of non-neurological control subjects in the age of 20 up to 74.

A plasma lipid signature predicts incident coronary artery disease.

Background: Dyslipidemia is a hallmark of cardiovascular disease but is characterized by crude measurements of triglycerides, HDL- and LDL cholesterol. Lipidomics enables more detailed measurements of plasma lipids, which may help improve risk stratification and understand the pathophysiology of cardiovascular disease.

Methods: Lipidomics was used to measure 184 lipids in plasma samples from the Malmö Diet and Cancer - Cardiovascular Cohort (N = 3865), taken at baseline examination.

Sex-dependent role of microglia in disulfide high mobility group box 1 protein-mediated mechanical hypersensitivity.

High mobility group box 1 protein (HMGB1) is increasingly regarded as an important player in the spinal regulation of chronic pain. Although it has been reported that HMGB1 induces spinal glial activation in a Toll-like receptor (TLR)4-dependent fashion, the aspect of sexual dimorphisms has not been thoroughly addressed. Here, we examined whether the action of TLR4-activating, partially reduced disulfide HMGB1 on microglia induces nociceptive behaviors in a sex-dependent manner.

Increased CSF Levels of Apolipoproteins and Complement Factors in Trigeminal Neuralgia Patients-In Depth Proteomic Analysis Using Mass Spectrometry.

The main cause of trigeminal neuralgia (TN) is compression of a blood vessel at the root entry zone of the trigeminal nerve. However, a neurovascular conflict does not seem to be the only etiology and other mechanisms are implicated in the development of the disease. We hypothesized that TN patients may have distinct protein expression in the CSF.

Targeted metabolomics of CSF in healthy individuals and patients with secondary progressive multiple sclerosis using high-resolution mass spectrometry.

Introduction: Standardized commercial kits enable targeted metabolomics analysis and may thus provide an attractive complement to the more explorative approaches. The kits are typically developed for triple quadrupole mass spectrometers using serum and plasma.

Objectives: Here we measure the concentrations of preselected metabolites in cerebrospinal fluid (CSF) using a kit developed for high-resolution mass spectrometry (HRMS).

Inhibition of mPGES-1 or COX-2 Results in Different Proteomic and Lipidomic Profiles in A549 Lung Cancer Cells.

Pharmacological inhibition of microsomal prostaglandin E synthase (mPGES)-1 for selective reduction in prostaglandin E (PGE) biosynthesis is protective in experimental models of cancer and inflammation. Targeting mPGES-1 is envisioned as a safer alternative to traditional non-steroidal anti-inflammatory drugs (NSAIDs). Herein, we compared the effects of mPGES-1 inhibitor Compound III (CIII) with the cyclooxygenase (COX)-2 inhibitor NS-398 on protein and lipid profiles in interleukin (IL)-1β-induced A549 lung cancer cells using mass spectrometry.

Alterations in the tyrosine and phenylalanine pathways revealed by biochemical profiling in cerebrospinal fluid of Huntington's disease subjects.

Huntington's disease (HD) is a severe neurological disease leading to psychiatric symptoms, motor impairment and cognitive decline. The disease is caused by a CAG expansion in the huntingtin (HTT) gene, but how this translates into the clinical phenotype of HD remains elusive. Using liquid chromatography mass spectrometry, we analyzed the metabolome of cerebrospinal fluid (CSF) from premanifest and manifest HD subjects as well as control subjects.

Interoperable and scalable data analysis with microservices: applications in metabolomics.

Motivation: Developing a robust and performant data analysis workflow that integrates all necessary components whilst still being able to scale over multiple compute nodes is a challenging task. We introduce a generic method based on the microservice architecture, where software tools are encapsulated as Docker containers that can be connected into scientific workflows and executed using the Kubernetes container orchestrator.

Results: We developed a Virtual Research Environment (VRE) which facilitates rapid integration of new tools and developing scalable and interoperable workflows for performing metabolomics data analysis.

Improved Differential Diagnosis of Alzheimer's Disease by Integrating ELISA and Mass Spectrometry-Based Cerebrospinal Fluid Biomarkers.

Background: Alzheimer's disease (AD) is diagnosed based on a clinical evaluation as well as analyses of classical biomarkers: Aβ42, total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF). Although the sensitivities and specificities of the classical biomarkers are fairly good for detection of AD, there is still a need to develop novel biochemical markers for early detection of AD.

Objective: We explored if integration of novel proteins with classical biomarkers in CSF can better discriminate AD from non-AD subjects.

Integration of magnetic resonance imaging and protein and metabolite CSF measurements to enable early diagnosis of secondary progressive multiple sclerosis.

Molecular networks in neurological diseases are complex. Despite this fact, contemporary biomarkers are in most cases interpreted in isolation, leading to a significant loss of information and power. We present an analytical approach to scrutinize and combine information from biomarkers originating from multiple sources with the aim of discovering a condensed set of biomarkers that in combination could distinguish the progressive degenerative phenotype of multiple sclerosis (SPMS) from the relapsing-remitting phenotype (RRMS).

Container-based bioinformatics with Pachyderm.

Motivation: Computational biologists face many challenges related to data size, and they need to manage complicated analyses often including multiple stages and multiple tools, all of which must be deployed to modern infrastructures. To address these challenges and maintain reproducibility of results, researchers need (i) a reliable way to run processing stages in any computational environment, (ii) a well-defined way to orchestrate those processing stages and (iii) a data management layer that tracks data as it moves through the processing pipeline.

Results: Pachyderm is an open-source workflow system and data management framework that fulfils these needs by creating a data pipelining and data versioning layer on top of projects from the container ecosystem, having Kubernetes as the backbone for container orchestration.

The human CSF pain proteome.

Chronic pain represents one of the major medical challenges in the 21st century, affecting >1.5 billion of the world population. Overlapping and heterogenous symptoms of various chronic pain conditions complicate their diagnosis, emphasizing the need for more specific biomarkers to improve the diagnosis and understand the disease mechanisms.

Spinal injection of newly identified cerebellin-1 and cerebellin-2 peptides induce mechanical hypersensitivity in mice.

By screening for neuropeptides in the mouse spinal cord using mass spectrometry (MS), we have previously demonstrated that one of the 78 peptides that is expressed predominantly (> 6-fold) in the dorsal horn compared to the ventral spinal cord is the atypical peptide desCER [des-Ser1]-cerebellin, which originates from the precursor protein cerebellin 1 (CBLN1). Furthermore, we found that intrathecal injection of desCER induces mechanical hypersensitivity in a dose dependent manner. The current study was designed to further investigate the relative expression of other CBLN derived peptides in the spinal cord and to examine whether they share similar nociceptive properties.

Systematic analysis of the cerebrospinal fluid proteome of fibromyalgia patients.

Fibromyalgia (FM) is a syndrome characterized by widespread muscular pain, fatigue and functional symptoms, which is known to be difficult to diagnose as the various symptoms overlap with many other conditions. Currently, there are no biomarkers for FM, and the diagnosis is made subjectively by the clinicians. We have performed shotgun proteomics on cerebrospinal fluid (CSF) from FM patients and non-pain controls to find potential biomarker candidates for this syndrome.