Multi-omics analyses of early-onset familial Alzheimer's disease and Sanfilippo syndrome zebrafish models reveal commonalities in disease mechanisms.

Sanfilippo syndrome (mucopolysaccharidosis type III, MPSIII) causes childhood dementia, while Alzheimer's disease is the most common type of adult-onset dementia. There is no cure for either of these diseases, and therapeutic options are extremely limited. Increasing evidence suggests commonalities in the pathogenesis of these diseases.

Exploring Top-Down Mass Spectrometric Approaches To Probe Forest Cobra () Venom Proteoforms.

Snake venoms are comprised of bioactive proteins and peptides that facilitate severe snakebite envenomation symptoms. A comprehensive understanding of venom compositions and the subtle heterogeneity therein is important. While bottom-up proteomics has been the well-established approach to catalogue venom compositions, top-down proteomics has emerged as a complementary strategy to characterize venom heterogeneity at the intact protein level.

Evaluation of neuroretina following i.v. or intra-CSF AAV9 gene replacement in mice with MPS IIIA, a childhood dementia.

Background: Sanfilippo syndrome (mucopolysaccharidosis type IIIA; MPS IIIA) is a childhood dementia caused by inherited mutations in the sulfamidase gene. At present, there is no treatment and children with classical disease generally die in their late teens. Intravenous or intra-cerebrospinal fluid (CSF) injection of AAV9-gene replacement is being examined in human clinical trials; evaluation of the impact on brain disease is an intense focus; however, MPS IIIA patients also experience profound, progressive photoreceptor loss, leading to night blindness.

Photobiomodulation in the infrared spectrum reverses the expansion of circulating natural killer cells and brain microglial activation in Sanfilippo mice.

Sanfilippo syndrome results from inherited mutations in genes encoding lysosomal enzymes that catabolise heparan sulfate (HS), leading to early childhood-onset neurodegeneration. This study explores the therapeutic potential of photobiomodulation (PBM), which is neuroprotective and anti-inflammatory in several neurodegenerative diseases; it is also safe and PBM devices are readily available. We investigated the effects of 10-14 days transcranial PBM at 670 nm (2 or 4 J/cm/day) or 904 nm (4 J/cm/day) in young (3 weeks) and older (15 weeks) Sanfilippo or mucopolysaccharidosis type IIIA (MPS IIIA) mice.

Compromised transcription-mRNA export factor THOC2 causes R-loop accumulation, DNA damage and adverse neurodevelopment.

We implicated the X-chromosome THOC2 gene, which encodes the largest subunit of the highly-conserved TREX (Transcription-Export) complex, in a clinically complex neurodevelopmental disorder with intellectual disability as the core phenotype. To study the molecular pathology of this essential eukaryotic gene, we generated a mouse model based on a hypomorphic Thoc2 exon 37-38 deletion variant of a patient with ID, speech delay, hypotonia, and microcephaly. The Thoc2 exon 37-38 deletion male (Thoc2) mice recapitulate the core phenotypes of THOC2 syndrome including smaller size and weight, and significant deficits in spatial learning, working memory and sensorimotor functions.

Spatial MS multiomics on clinical prostate cancer tissues.

Mass spectrometry (MS) and MS imaging (MSI) are used extensively for both the spatial and bulk characterization of samples in lipidomics and proteomics workflows. These datasets are typically generated independently due to different requirements for sample preparation. However, modern omics technologies now provide higher sample throughput and deeper molecular coverage, which, in combination with more sophisticated bioinformatic and statistical pipelines, make generating multiomics data from a single sample a reality.

Drosophila melanogaster models of MPS IIIC (Hgsnat-deficiency) highlight the role of glia in disease presentation.

Sanfilippo syndrome (Mucopolysaccharidosis type III or MPS III) is a recessively inherited neurodegenerative lysosomal storage disorder. Mutations in genes encoding enzymes in the heparan sulphate degradation pathway lead to the accumulation of partially degraded heparan sulphate, resulting ultimately in the development of neurological deficits. Mutations in the gene encoding the membrane protein heparan-α-glucosaminide N-acetyltransferase (HGSNAT; EC2.

Characterisation of the forest cobra (Naja melanoleuca) venom using a multifaceted mass spectrometric-based approach.

Snake venoms consist of highly biologically active proteins and peptides that are responsible for the lethal physiological effects of snakebite envenomation. In order to guide the development of targeted antivenom strategies, comprehensive understanding of venom compositions and in-depth characterisation of various proteoforms, often not captured by traditional bottom-up proteomic workflows, is necessary. Here, we employ an integrated 'omics' and intact mass spectrometry (MS)-based approach to profile the heterogeneity within the venom of the forest cobra (Naja melanoleuca), adopting different analytical strategies to accommodate for the dynamic molecular mass range of venom proteins present.

Filipin complex-reactive brain lesions: a cautionary tale.

Objective: Filipin complex is an autooxidation-prone fluorescent histochemical stain used in the diagnosis of Niemann-Pick Disease Type C (NP-C), a neurodegenerative lysosomal storage disorder. It is also widely used by researchers examining the distribution and accumulation of unesterified cholesterol in cell and animal models of neurodegenerative diseases including NP-C and Sanfilippo syndrome (mucopolysaccharidosis IIIA; MPS IIIA). Recently, it has been suggested to be useful in studying Alzheimer's and Huntington's disease.

Repetitive, non-invasive imaging of neurodegeneration, and prevention of it with gene replacement, in mice with Sanfilippo syndrome.

Hampering assessment of treatment outcomes in gene therapy and other clinical trials in patients with childhood dementia is the lack of an objective, non-invasive measure of neurodegeneration. Optical coherence tomography (OCT) is a widely available, rapid, non-invasive, and quantitative method for examining the integrity of the neuroretina. Profound brain and retinal dysfunction occur in patients and animal models of childhood dementia, including Sanfilippo syndrome and we recently revealed a correlation between the age of onset and rate of progression of retinal and brain degeneration in sulfamidase-deficient Sanfilippo mice.

Long-term safety and effectiveness of alirocumab and evolocumab in familial hypercholesterolemia (FH) in Belgium.

In 2019, the European Atherosclerosis Society (EAS) published updated guidelines, recommending even lower blood cholesterol targets than previously. In patients with familial hypercholesterolaemia (FH), who have very elevated blood cholesterol levels and are at ('Very') 'High risk' of atherosclerotic cardiovascular disease (ASCVD), this represents a real challenge. Anti-Proprotein convertase subtilisin/kexin type 9 monoclonal antibody (anti-PCSK9 mAb) has been commercially available for FH in Belgium since 2015.

A clinically applicable molecular classification of oncocytic cell thyroid nodules.

Whole chromosome instability with near-whole genome haploidization (GH) and subsequent endoreduplication is considered a main genomic driver in the tumorigenesis of oncocytic cell thyroid neoplasms (OCN). These copy number alterations (CNA) occur less frequently in oncocytic thyroid adenoma (OA) than in oncocytic carcinoma (OCA), suggesting a continuous process. The current study described the CNA patterns in a cohort of 30 benign and malignant OCN, observed using a next-generation sequencing (NGS) panel that assesses genome-wide loss of heterozygosity (LOH) and chromosomal imbalances using 1500 single-nucleotide polymorphisms (SNPs) across all autosomes and the X chromosome in DNA derived from cytological and histological samples.

Biomarkers for predicting disease course in Sanfilippo syndrome: An urgent unmet need in childhood-onset dementia.

Sanfilippo syndrome (MPS III) is an autosomal recessive inherited disorder causing dementia in children, following an essentially normal early developmental period. First symptoms typically include delayed language development, hyperactivity and/or insomnia from 2 years of age, followed by unremitting and overt loss of previously acquired skills. There are no approved treatments, and the median age of death is 18 years.

Colchicine exerts anti-atherosclerotic and -plaque-stabilizing effects targeting foam cell formation.

Colchicine is a broad-acting anti-inflammatory agent that has attracted interest for repurposing in atherosclerotic cardiovascular disease. Here, we studied its ability at a human equivalent dose of 0.5 mg/day to modify plaque formation and composition in murine atherosclerosis and investigated its actions on macrophage responses to atherogenic stimuli in vitro.

Health-related quality of life following FDG-PET/CT for cytological indeterminate thyroid nodules.

Objective: This study assessed the health-related quality of life (HRQoL) in patients undergoing 2-[18F]fluoro-2-deoxy-D-glucose (FDG)-PET/CT for an indeterminate (Bethesda III/IV) thyroid nodule. FDG-PET/CT accurately rules out malignancy and prevents 40% of futile diagnostic surgeries in these nodules.

Design: Secondary analyses of HRQoL data from a randomised controlled multicentre trial (NCT02208544) in 126 patients from 15 hospitals in the Netherlands were done.

Unravelling Prostate Cancer Heterogeneity Using Spatial Approaches to Lipidomics and Transcriptomics.

Due to advances in the detection and management of prostate cancer over the past 20 years, most cases of localised disease are now potentially curable by surgery or radiotherapy, or amenable to active surveillance without treatment. However, this has given rise to a new dilemma for disease management; the inability to distinguish indolent from lethal, aggressive forms of prostate cancer, leading to substantial overtreatment of some patients and delayed intervention for others. Driving this uncertainty is the critical deficit of novel targets for systemic therapy and of validated biomarkers that can inform treatment decision-making and to select and monitor therapy.

FAST-IT: ind imple est - n IA (transient ischaemic attack): a prospective cohort study to develop a multivariable prediction model for diagnosis of TIA through proteomic discovery and candidate lipid mass spectrometry, neuroimaging and machine learning-study protocol.

Introduction: Transient ischaemic attack (TIA) may be a warning sign of stroke and difficult to differentiate from minor stroke and TIA-mimics. Urgent evaluation and diagnosis is important as treating TIA early can prevent subsequent strokes. Recent improvements in mass spectrometer technology allow quantification of hundreds of plasma proteins and lipids, yielding large datasets that would benefit from different approaches including machine learning.

Equivalent Carbon Number and Interclass Retention Time Conversion Enhance Lipid Identification in Untargeted Clinical Lipidomics.

Chromatography is often used as a method for reducing sample complexity prior to analysis by mass spectrometry, and the use of retention time (RT) is becoming increasingly popular to add valuable supporting information in lipid identification. The RT of lipids with the same headgroup in reversed-phase separation can be predicted using the equivalent carbon number (ECN) model. This model describes the effects of acyl chain length and degree of saturation on lipid RT.

[F]FDG-PET/CT to prevent futile surgery in indeterminate thyroid nodules: a blinded, randomised controlled multicentre trial.

Purpose: To assess the impact of an [F]FDG-PET/CT-driven diagnostic workup to rule out malignancy, avoid futile diagnostic surgeries, and improve patient outcomes in thyroid nodules with indeterminate cytology.

Methods: In this double-blinded, randomised controlled multicentre trial, 132 adult euthyroid patients with scheduled diagnostic surgery for a Bethesda III or IV thyroid nodule underwent [F]FDG-PET/CT and were randomised to an [F]FDG-PET/CT-driven or diagnostic surgery group. In the [F]FDG-PET/CT-driven group, management was based on the [F]FDG-PET/CT result: when the index nodule was visually [F]FDG-positive, diagnostic surgery was advised; when [F]FDG-negative, active surveillance was recommended.

Yield and costs of molecular diagnostics on thyroid cytology slides in the Netherlands, adapting the Bethesda classification.

Objective: To evaluate our institutional experience with molecular diagnostics (MD) on thyroid cytology smears, evaluate the costs and describe MD guided clinical management of indeterminate Bethesda III/V thyroid nodules.

Methods: We performed a retrospective review of 164 Bethesda III or V thyroid cytopathology reports subjected to MD from 2013 to 2020, that altered Bethesda classification or management. MD consisted of mutation and gene fusion analysis by next-generation sequencing (NGS) of morphologically analysed and selected cytological slides.

MUCOPOLYSACCHARIDOSIS II (MPS II) IN A FREE-LIVING KAKA (NESTOR MERIDIONALIS) IN NEW ZEALAND.

A lysosomal storage disease, identified as a mucopolysaccharidosis (MPS), was diagnosed in a free-living Kaka (Nestor meridionalis), an endemic New Zealand parrot, which exhibited weakness, incoordination, and seizures. Histopathology showed typical colloid-like cytoplasmic inclusions in Purkinje cells and many other neurons throughout the brain. Electron microscopy revealed that storage bodies contained a variety of linear, curved, or circular membranous profiles and electron-dense bodies.

Lipidomic Profiling of Clinical Prostate Cancer Reveals Targetable Alterations in Membrane Lipid Composition.

Dysregulated lipid metabolism is a prominent feature of prostate cancer that is driven by androgen receptor (AR) signaling. Here we used quantitative mass spectrometry to define the "lipidome" in prostate tumors with matched benign tissues ( = 21), independent unmatched tissues ( = 47), and primary prostate explants cultured with the clinical AR antagonist enzalutamide ( = 43). Significant differences in lipid composition were detected and spatially visualized in tumors compared with matched benign samples.

To Make or Take: Bacterial Lipid Homeostasis during Infection.

Bacterial fatty acids are critical components of the cellular membrane. A shift in environmental conditions or in the bacterium's lifestyle may result in the requirement for a distinct pool of fatty acids with unique biophysical properties. This can be achieved by the modification of existing fatty acids or via synthesis.

Chronic Nonbacterial Osteomyelitis of the Sternocostoclavicular Region in Adults: A Single-Center Dutch Cohort Study.

Sternocostoclavicular hyperostosis (SCCH) is a rare autoinflammatory bone disorder caused by chronic nonbacterial osteomyelitis (CNO), which is associated with sclerosis and hyperostosis primarily affecting the sternum, the medial end of the clavicles, and the first ribs. Other areas of the axial skeleton may also be affected. The more severe synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome is additionally associated with dermatoses and joint manifestations.