Quantitative NMR-Based Lipoprotein Analysis Identifies Elevated HDL-4 and Triglycerides in the Serum of Alzheimer's Disease Patients.

Alzheimer's disease (AD) is the most common form of dementia in the elderly and has been associated with changes in lipoprotein metabolism. We performed quantitative lipoprotein analysis in a local cohort of cognitively impaired elderly and control subjects using standardized nuclear magnetic resonance (NMR) spectroscopy. A commercially available quantitative NMR-based assay covering 112 lipoprotein main and subtype variables was used to investigate blood serum samples from a moderate cohort size of 161 persons (71 female, 90 male), including measures of quality control.

Neurovascular Uncoupling: Multimodal Imaging Delineates the Acute Effects of 3,4-Methylenedioxymethamphetamine.

Psychedelic compounds such as 3,4-methylenedioxymethamphetamine (MDMA) have attracted increasing interest in recent years because of their therapeutic potential in psychiatric disorders. To understand the acute effects of psychedelic drugs in vivo, blood-oxygenation-level-dependent (BOLD) functional MRI (fMRI) has been widely used. In particular, fMRI studies have suggested that MDMA leads to inhibition of brain activity, challenging previous hypotheses indicating mainly excitatory effects based, among others, on increased metabolism shown by F-FDG functional PET (fPET).

Combining CRISPR-Cas9 and brain imaging to study the link from genes to molecules to networks.

Receptors, transporters, and ion channels are important targets for therapy development in neurological diseases, but their mechanistic role in pathogenesis is often poorly understood. Gene editing and in vivo imaging approaches will help to identify the molecular and functional role of these targets and the consequence of their regional dysfunction on the whole-brain level. We combine CRISPR-Cas9 gene editing with in vivo positron emission tomography (PET) and functional MRI (fMRI) to investigate the direct link between genes, molecules, and the brain connectome.

Cerebrovascular G Proteins Protect Against Brain Hypoperfusion and Collateral Failure in Cerebral Ischemia.

Cerebral hypoperfusion and vascular dysfunction are closely related to common risk factors for ischemic stroke such as hypertension, dyslipidemia, diabetes, and smoking. The role of inhibitory G protein-dependent receptor (GPCR) signaling in regulating cerebrovascular functions remains largely elusive. We examined the importance of GPCR signaling in cerebral blood flow (CBF) and its stability after sudden interruption using various in vivo high-resolution magnetic resonance imaging techniques.

A role for artificial intelligence in molecular imaging of infection and inflammation.

The detection of occult infections and low-grade inflammation in clinical practice remains challenging and much depending on readers' expertise. Although molecular imaging, like [F]FDG PET or radiolabeled leukocyte scintigraphy, offers quantitative and reproducible whole body data on inflammatory responses its interpretation is limited to visual analysis. This often leads to delayed diagnosis and treatment, as well as untapped areas of potential application.

The OpenGATE ecosystem for Monte Carlo simulation in medical physics.

This paper reviews the ecosystem of GATE, an open-source Monte Carlo toolkit for medical physics. Based on the shoulders of Geant4, the principal modules (geometry, physics, scorers) are described with brief descriptions of some key concepts (Volume, Actors, Digitizer). The main source code repositories are detailed together with the automated compilation and tests processes (Continuous Integration).

Translational immunoPET imaging using a radiolabeled GD2-specific antibody in neuroblastoma.

Antibodies targeting surface expressed disialoganglioside GD2 are increasingly used in neuroblastoma immunotherapy and might also have potential for use in radioimmunotherapy. As such targeted treatments might benefit from a dedicated theranostic approach, we studied the influence of radiolabeling on the binding characteristics of ch14.18 antibodies produced by Chinese hamster ovary (CHO) cells and evaluated the benefit of GD2-ImmunoPET as a potential tool for therapy planning.

Using micro-synchrotron radiation x-ray fluorescence (µ-SRXRF) for trace metal imaging in the development of MRI contrast agents for prostate cancer imaging.

Background: Contrast agents (CA) are administered in magnetic resonance imaging (MRI) clinical exams to measure tissue perfusion, enhance image contrast between adjacent tissues, or provide additional biochemical information in molecular MRI. The efficacy of a CA is determined by the tissue distribution of the agent and its concentration in the extracellular space of all tissues.

Methods: In this work, micro-synchrotron radiation x-ray fluorescence (µ-SRXRF) was used to examine and characterize a gadolinium-based zinc-sensitive agent (GdL) currently under development for detection of prostate cancer (PCa) by MRI.

Practical considerations for navigating the regulatory landscape of non-clinical studies for clinical translation of radiopharmaceuticals.

Background: The development of radiopharmaceuticals requires extensive evaluation before they can be applied in a diagnostic or therapeutic setting in Nuclear Medicine. Chemical, radiochemical, and pharmaceutical parameters must be established and verified to ensure the quality of these novel products.

Main Body: To provide supportive evidence for the expected human in vivo behaviour, particularly related to safety and efficacy, additional tests, often referred to as "non-clinical" or "preclinical" are mandatory.

Novel adapter CAR-T cell technology for precisely controllable multiplex cancer targeting.

Chimeric antigen receptor (CAR)-T therapy holds great promise to sustainably improve cancer treatment. However, currently, a broad applicability of CAR-T cell therapies is hampered by limited CAR-T cell versatility and tractability and the lack of exclusive target antigens to discriminate cancerous from healthy tissues. To achieve temporal and qualitative control on CAR-T function, we engineered the Adapter CAR (AdCAR) system.

CD147 a direct target of miR-146a supports energy metabolism and promotes tumor growth in ALK+ ALCL.

We recently reported that miR-146a is differentially expressed in ALK+ and ALK- anaplastic large cell lymphoma (ALCL). In this study, the downstream targets of miR-146a in ALK+ ALCL were investigated by transcriptome analysis, identifying CD147 as potential target gene. Because CD147 is differentially expressed in ALK+ ALCL versus ALK- ALCL and normal T cells, this gene emerged as a strong candidate for the pathogenesis of this tumor.

Mesaconate is synthesized from itaconate and exerts immunomodulatory effects in macrophages.

Since its discovery in inflammatory macrophages, itaconate has attracted much attention due to its antimicrobial and immunomodulatory activity. However, instead of investigating itaconate itself, most studies used derivatized forms of itaconate and thus the role of non-derivatized itaconate needs to be scrutinized. Mesaconate, a metabolite structurally very close to itaconate, has never been implicated in mammalian cells.

Intratumoral in vivo staging of breast cancer by multi-tracer PET and advanced analysis.

The staging and local management of breast cancer involves the evaluation of the extent and completeness of excision of both the invasive carcinoma component and also the intraductal component or ductal carcinoma in situ. When both invasive ductal carcinoma and coincident ductal carcinoma in situ are present, assessment of the extent and localization of both components is required for optimal therapeutic planning. We have used a mouse model of breast cancer to evaluate the feasibility of applying molecular imaging to assess the local status of cancers in vivo.

Quantitative Metabolomics of Tissue, Perfusate, and Bile from Rat Livers Subjected to Normothermic Machine Perfusion.

Machine perfusion (MP) allows the maintenance of liver cells in a metabolically active state ex vivo and can potentially revert metabolic perturbations caused by donor warm ischemia, procurement, and static cold storage (SCS). The present preclinical research investigated the metabolic outcome of the MP procedure by analyzing rat liver tissue, bile, and perfusate samples by means of high-field (600 MHz) nuclear magnetic resonance (NMR) spectroscopy. An established rat model of normothermic MP (NMP) was used.

Identification of neurodegeneration indicators and disease progression in metachromatic leukodystrophy using quantitative NMR-based urinary metabolomics.

Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by a deficiency of the arylsulfatase A (ARSA). ARSA deficiency leads to an accumulation of sulfatides primarily in the nervous system ultimately causing demyelination. With evolving therapeutic options, there is an increasing need for indicators to evaluate disease progression.

NEMA NU 4-2008 performance evaluation and MR compatibility tests of an APD-based small animal PET-insert for simultaneous PET/MR imaging.

An avalanche photodiode (APD)-based small animal positron emission tomography (PET)-insert was fully evaluated for its PET performance, as well as potential influences on magnetic resonance imaging (MRI) performance. This PET-insert has an extended axial field of view (FOV) compared with the previous design to increase system sensitivity, as well as an updated cooling and temperature regulation to enable stable and reproducible PET acquisitions. The PET performance was evaluated according to the National Electrical Manufacturers Association NU4-2008 protocol.

Roux-En-Y Gastric Bypass (RYGB) Surgery during High Liquid Sucrose Diet Leads to Gut Microbiota-Related Systematic Alterations.

Roux-en-Y gastric bypass (RYGB) surgery has been proven successful in weight loss and improvement of co-morbidities associated with obesity. Chronic complications such as malabsorption of micronutrients in up to 50% of patients underline the need for additional therapeutic approaches. We investigated systemic RYGB surgery effects in a liquid sucrose diet-induced rat obesity model.

LXRα activation and Raf inhibition trigger lethal lipotoxicity in liver cancer.

The success of molecular therapies targeting specific metabolic pathways in cancer is often limited by the plasticity and adaptability of metabolic networks. Here we show that pharmacologically induced lipotoxicity represents a promising therapeutic strategy for the treatment of hepatocellular carcinoma (HCC). LXRα-induced liponeogenesis and Raf-1 inhibition are synthetic lethal in HCC owing to a toxic accumulation of saturated fatty acids.

Foudroyant cerebral venous (sinus) thrombosis triggered through CLEC-2 and GPIIb/IIIa dependent platelet activation.

Cerebral venous (sinus) thrombosis (CVT) is an unusual manifestation of venous thrombosis causing severe neurological impairment and seizures. Molecular mechanisms underlying CVT, potentially involving pathological platelet activation, are unknown. Here we show that antibody-(INU1-fab)-induced cooperative signaling of two platelet receptors, C-type lectin-like receptor-2 (CLEC-2) and GPIIb/IIIa, triggers within minutes a CVT-like thrombotic syndrome in mice, characterized by tonic-myoclonic seizures, platelet consumption and death.

Patient-individual phenotypes of glioblastoma stem cells are conserved in culture and associate with radioresistance, brain infiltration and patient prognosis.

Identification of prognostic or predictive molecular markers in glioblastoma resection specimens may lead to strategies for therapy stratification and personalized treatment planning. Here, we analyzed in primary glioblastoma stem cell (pGSC) cultures the mRNA abundances of seven stem cell (MSI1, Notch1, nestin, Sox2, Oct4, FABP7 and ALDH1A3), and three radioresistance or invasion markers (CXCR4, IK and BK ). From these abundances, an mRNA signature was deduced which describes the mesenchymal-to-proneural expression profile of an individual GSC culture.

Imaging the Rewired Metabolism in Lung Cancer in Relation to Immune Therapy.

Metabolic reprogramming is recognized as one of the hallmarks of cancer. Alterations in the micro-environmental metabolic characteristics are recognized as important tools for cancer cells to interact with the resident and infiltrating T-cells within this tumor microenvironment. Cancer-induced metabolic changes in the micro-environment also affect treatment outcomes.

Single-Domain Antibodies for Targeting, Detection, and Imaging of Human CD4 Cells.

The advancement of new immunotherapies necessitates appropriate probes to monitor the presence and distribution of distinct immune cell populations. Considering the key role of CD4 cells in regulating immunological processes, we generated novel single-domain antibodies [nanobodies (Nbs)] that specifically recognize human CD4. After in-depth analysis of their binding properties, recognized epitopes, and effects on T-cell proliferation, activation, and cytokine release, we selected CD4-specific Nbs that did not interfere with crucial T-cell processes and converted them into immune tracers for noninvasive molecular imaging.

Tissue metabolites in diffuse glioma and their modulations by IDH1 mutation, histology, and treatment.

The discovery of the oncometabolite 2-hydroxyglutarate in isocitrate dehydrogenase 1-mutated (IDH1-mutated) tumor entities affirmed the role of metabolism in cancer. However, large databases with tissue metabolites that are modulated by IDH1 mutation remain an area of development. Here, we present an unprecedented and valuable resource for tissue metabolites in diffuse glioma and their modulations by IDH1 mutation, histology, and tumor treatments in 101 tissue samples from 73 diffuse glioma patients (24 astrocytoma, 17 oligodendroglioma, 32 glioblastoma), investigated by NMR-based metabolomics and supported by RNA-Seq.