From evidence to care delivery: Opportunities and risks in health and science policy. A position paper of the Association of the Scientific Medical Societies in Germany (AWMF).

Objective: After over 25 years of developing clinical practice guidelines, the Association of the Scientific Medical Societies in Germany (AWMF) held a symposium to discuss the following topics in order to improve the way evidence is implemented in the delivery of care: expansion of the data pool for guideline development, the regulatory policy framework for this expansion, the transfer of clinical practice guideline statements to medical practice, the associated opportunities and risks resulting from the European legislation.

Methods: The AWMF held its Berlin Forum on 27 April 2022 where experts from scientific medical societies and national institutions in the healthcare sector reported their experiences and perceptions on the topics mentioned. Three writing groups compiled the key statements from these contributions to and discussions made at the Berlin Forum into a position paper.

Mass-Guided Single-Cell MALDI Imaging of Low-Mass Metabolites Reveals Cellular Activation Markers.

Single-cell MALDI mass spectrometry imaging (MSI) of lipids and metabolites >200 Da has recently come to the forefront of biomedical research and chemical biology. However, cell-targeting and metabolome-preserving methods for analysis of low mass, hydrophilic metabolites (<200 Da) in large cell populations are lacking. Here, the PRISM-MS (PRescan Imaging for Small Molecule - Mass Spectrometry) mass-guided MSI workflow is presented, which enables space-efficient single cell lipid and metabolite analysis.

Beyond Huntington's Disease - Late-Onset Chorea Caused by a Homozygous Variant in ERCC4.

Genetic alterations in the ERCC4 gene typically cause Xeroderma pigmentosum and other nucleotide excision repair disorders. Neurologic symptoms are present in some of these patients. In rare cases, ERCC4-mutations can manifest with prominent neurologic symptoms.

M2ara: unraveling metabolomic drug responses in whole-cell MALDI mass spectrometry bioassays.

Summary: Fast computational evaluation and classification of concentration responses for hundreds of metabolites represented by their mass-to-charge (m/z) ratios is indispensable for unraveling complex metabolomic drug actions in label-free, whole-cell Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry (MALDI MS) bioassays. In particular, the identification of novel pharmacodynamic biomarkers to determine target engagement, potency, and potential polypharmacology of drug-like compounds in high-throughput applications requires robust data interpretation pipelines. Given the large number of mass features in cell-based MALDI MS bioassays, reliable identification of true biological response patterns and their differentiation from any measurement artefacts that may be present is critical.

Label-free assessment of complement-dependent cytotoxicity of therapeutic antibodies via a whole-cell MALDI mass spectrometry bioassay.

Potency assessment of monoclonal antibodies or corresponding biosimilars in cell-based assays is an essential prerequisite in biopharmaceutical research and development. However, cellular bioassays are still subject to limitations in sample throughput, speed, and often need costly reagents or labels as they are based on an indirect readout by luminescence or fluorescence. In contrast, whole-cell Matrix-Assisted Laser Desorption/Ionization Time-of-Flight (MALDI-TOF) Mass Spectrometry (MS) has emerged as a direct, fast and label-free technology for functional drug screening being able to unravel the molecular complexity of cellular response to pharmaceutical reagents.

Bottom-up synthetic immunology.

Infectious diseases and cancer evade immune surveillance using similar mechanisms. Targeting immune mechanisms using common strategies thus represents a promising avenue to improve prevention and treatment. Synthetic immunology can provide such strategies by applying engineering principles from synthetic biology to immunology.

optiPRM: A Targeted Immunopeptidomics LC-MS Workflow With Ultra-High Sensitivity for the Detection of Mutation-Derived Tumor Neoepitopes From Limited Input Material.

Personalized cancer immunotherapies such as therapeutic vaccines and adoptive transfer of T cell receptor-transgenic T cells rely on the presentation of tumor-specific peptides by human leukocyte antigen class I molecules to cytotoxic T cells. Such neoepitopes can for example arise from somatic mutations and their identification is crucial for the rational design of new therapeutic interventions. Liquid chromatography mass spectrometry (LC-MS)-based immunopeptidomics is the only method to directly prove actual peptide presentation and we have developed a parameter optimization workflow to tune targeted assays for maximum detection sensitivity on a per peptide basis, termed optiPRM.

Tumoral Interferon Beta Induces an Immune-Stimulatory Phenotype in Tumor-Associated Macrophages in Melanoma Brain Metastases.

Unlabelled: Type I interferons (IFN) are immune-stimulatory cytokines involved in antiviral and antitumor immune responses. They enhance the efficacy of immunogenic anticancer therapies such as radiotherapy by activating both innate and adaptive immune cells. Macrophages are one of the most abundant innate immune cells in the immune microenvironment of melanoma brain metastases (MBM) and can exert potent immune-suppressive functions.

Alzheimer's disease linked Aβ42 exerts product feedback inhibition on γ-secretase impairing downstream cell signaling.

Amyloid β (Aβ) peptides accumulating in the brain are proposed to trigger Alzheimer's disease (AD). However, molecular cascades underlying their toxicity are poorly defined. Here, we explored a novel hypothesis for Aβ42 toxicity that arises from its proven affinity for γ-secretases.

Live imaging of excitable axonal microdomains in ankyrin-G-GFP mice.

The axon initial segment (AIS) constitutes not only the site of action potential initiation, but also a hub for activity-dependent modulation of output generation. Recent studies shedding light on AIS function used predominantly post-hoc approaches since no robust murine live reporters exist. Here, we introduce a reporter line in which the AIS is intrinsically labeled by an ankyrin-G-GFP fusion protein activated by Cre recombinase, tagging the native gene.

Integrative Single-Plaque Analysis Reveals Signature Aβ and Lipid Profiles in the Alzheimer's Brain.

Cerebral accumulation of amyloid-β (Aβ) initiates molecular and cellular cascades that lead to Alzheimer's disease (AD). However, amyloid deposition does not invariably lead to dementia. Amyloid-positive but cognitively unaffected (AP-CU) individuals present widespread amyloid pathology, suggesting that molecular signatures more complex than the total amyloid burden are required to better differentiate AD from AP-CU cases.

Cell-cell contacts prevent t-BuOOH-triggered ferroptosis and cellular damage in vitro by regulation of intracellular calcium.

Tert-butyl hydroperoxide (t-BuOOH) is an organic hydroperoxide widely used as a model compound to induce oxidative stress. It leads to a plethora of cellular damage, including lipid peroxidation, DNA double-strand breaks (DNA DSBs), and breakdown of the mitochondrial membrane potential (MMP). We could show in several cell lines that t-BuOOH induces ferroptosis, triggered by iron-dependent lipid peroxidation.

Patients' perspective on the chronic pain classification in the 11th revision of the International Classification of Diseases (ICD-11): results from an international web-based survey.

The 11th revision of the International Classification of Diseases and Related Health Problems (ICD-11) aims at improving the lives of persons with the lived experience of chronic pain by providing clearly defined and clinically useful diagnoses that can reduce stigma, facilitate communication, and improve access to pain management, among others. The aim of this study was to assess the perspective of people with chronic pain on these diagnoses. An international web-based survey was distributed among persons with the lived experience of chronic pain.

Skin Innervation.

All layers and appendages of the skin are densely innervated by afferent and efferent neurons providing sensory information and controlling skin perfusion and sweating. In mice, neuronal functions have been comprehensively linked to unique single-cell expression patterns and to characteristic arborization of nerve endings in skin and dorsal horn, whereas for humans, specific molecular markers for functional classes of afferent neurons are still lacking. Moreover, bidirectional communication between sensory neurons and local skin cells has become of particular interest, resulting in a broader physiological understanding of sensory function but also of trophic functions and immunomodulation in disease states.

PerSurge (NOA-30) phase II trial of perampanel treatment around surgery in patients with progressive glioblastoma.

Background: Glioblastoma is the most frequent and a particularly malignant primary brain tumor with no efficacy-proven standard therapy for recurrence. It has recently been discovered that excitatory synapses of the AMPA-receptor subtype form between non-malignant brain neurons and tumor cells. This neuron-tumor network connectivity contributed to glioma progression and could be efficiently targeted with the EMA/FDA approved antiepileptic AMPA receptor inhibitor perampanel in preclinical studies.

High-Throughput Miniaturized Synthesis of PROTAC-Like Molecules.

The development of miniaturized high-throughput in situ screening platforms capable of handling the entire process of drug synthesis to final screening is essential for advancing drug discovery in the future. In this study, an approach based on combinatorial solid-phase synthesis, enabling the efficient synthesis of libraries of proteolysis targeting chimeras (PROTACs) in an array format is presented. This on-chip platform allows direct biological screening without the need for transfer steps.

APP substrate ectodomain defines amyloid-β peptide length by restraining γ-secretase processivity and facilitating product release.

Sequential proteolysis of the amyloid precursor protein (APP) by γ-secretases generates amyloid-β (Aβ) peptides and defines the proportion of short-to-long Aβ peptides, which is tightly connected to Alzheimer's disease (AD) pathogenesis. Here, we study the mechanism that controls substrate processing by γ-secretases and Aβ peptide length. We found that polar interactions established by the APP ectodomain (ECD), involving but not limited to its juxtamembrane region, restrain both the extent and degree of γ-secretases processive cleavage by destabilizing enzyme-substrate interactions.

Alzheimer's disease linked Aβ42 exerts product feedback inhibition on γ-secretase impairing downstream cell signaling.

Amyloid β (Aβ) peptides accumulating in the brain are proposed to trigger Alzheimer's disease (AD). However, molecular cascades underlying their toxicity are poorly defined. Here, we explored a novel hypothesis for Aβ42 toxicity that arises from its proven affinity for γ-secretases.

Clinical Features and Voxel-Based-Symptom-Lesion Mapping of Silent Aspiration in Acute Infratentorial Stroke.

Post-stroke dysphagia (PSD) is a severe and common complication after ischemic stroke. The role of silent aspiration as an important contributing factor in the development of a dysphagia-associated complications, in particular aspiration-associated pneumonia has been insufficiently understood. The aim of this study was to investigate the characteristics and risk factors of silent aspiration in patients with acute infratentorial stroke by FEES and to identify culprit lesions in stroke patient with a high risk of silent aspiration via voxel-based-symptom-lesion mapping (VBS/ML).

Impact of cryopreservation on viability, gene expression and function of enteric nervous system derived neurospheres.

Impairment of both the central and peripheral nervous system is a major cause of mortality and disability. It varies from an affection of the brain to various types of enteric dysganglionosis. Congenital enteric dysganglionosis is characterized by the local absence of intrinsic innervation due to deficits in either migration, proliferation or differentiation of neural stem cells.