Implementation of dosimetry for molecular radiotherapy; results from a European survey.

Purpose: The use of molecular radiotherapy (MRT) has been rapidly evolving over the last years. The aim of this study was to assess the current implementation of dosimetry for MRTs in Europe.

Methods: A web-based questionnaire was open for treating centres between April and June 2022, and focused on 2020-2022.

Details Matter in Structure-based Drug Design.

Successful structure-based drug design (SBDD) requires the optimization of interactions with the target protein and the minimization of ligand strain. Both factors are often modulated by small changes in the chemical structure which can lead to profound changes in the preferred conformation and interaction preferences of the ligand. We draw from examples of a Roche project targeting phosphodiesterase 10 to highlight that details matter in SBDD.

Factors Influencing Postoperative Complications Following Minimally Invasive Ivor Lewis Esophagectomy: A Retrospective Cohort Study.

Background: Complications arising following minimally invasive Ivor Lewis esophagectomy often result from inadequate enteral nutrition, highlighting the need for proactive measures to prevent such issues. One approach involves identifying high-risk cases prone to complications and implementing percutaneous endoscopic jejunostomy (PEJ) tube placement during esophageal resection to ensure timely enteral nutrition.

Methods: In this single-center, retrospective cohort study, we examined patients who underwent minimally invasive esophagectomy for esophageal cancer at a high-volume center.

Performance evaluation of automated white matter hyperintensity segmentation algorithms in a multicenter cohort on cognitive impairment and dementia.

Background: White matter hyperintensities (WMH), a biomarker of small vessel disease, are often found in Alzheimer's disease (AD) and their advanced detection and quantification can be beneficial for research and clinical applications. To investigate WMH in large-scale multicenter studies on cognitive impairment and AD, appropriate automated WMH segmentation algorithms are required. This study aimed to compare the performance of segmentation tools and provide information on their application in multicenter research.

Hourly marginal electricity mixes and their relevance for assessing the environmental performance of installations with variable load or power.

The ongoing energy transition is causing rapid changes in the electricity system and, in consequence, the environmental impacts associated with electricity generation. In parallel, the daily variability of generation increases with higher shares of renewable energies. This affects the potential environmental impacts or benefits of devices with variable load or power, such as electric vehicles, storage systems or photovoltaic home systems.

Amyloid pathology but not APOE ε4 status is permissive for tau-related hippocampal dysfunction.

We investigated whether the impact of tau-pathology on memory performance and on hippocampal/medial temporal memory function in non-demented individuals depends on the presence of amyloid pathology, irrespective of diagnostic clinical stage. We conducted a cross-sectional analysis of the observational, multicentric DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE). Two hundred and thirty-five participants completed task functional MRI and provided CSF (92 cognitively unimpaired, 100 experiencing subjective cognitive decline and 43 with mild cognitive impairment).

Quality of life and outcome of patients with metastatic pancreatic cancer receiving first-line chemotherapy with nab-paclitaxel and gemcitabine: Real-life results from the prospective QOLIXANE trial of the Platform for Outcome, Quality of Life and Translational Research on Pancreatic Cancer registry.

Few data exist on health-related quality of life (QoL) in patients with metastatic pancreatic cancer (mPC) receiving first-line chemotherapy (Awad L ZE, Mesbah M Boston, MA. Applying survival data methodology to analyze quality of life data, in Mesbah M, Cole BF, Ting Lee M-L (eds): Statistical Methods for Quality of Life Studies: Design, Measurements and Analysis. Kluwer Academic Publishers 2002).

PLCG2 protective variant p.P522R modulates tau pathology and disease progression in patients with mild cognitive impairment.

A rare coding variant (rs72824905, p.P522R) conferring protection against Alzheimer's disease (AD) was identified in the gene encoding the enzyme phospholipase-C-γ2 (PLCG2) that is highly expressed in microglia. To explore the protective nature of this variant, we employed latent process linear mixed models to examine the association of p.

CNDP1 knockout in zebrafish alters the amino acid metabolism, restrains weight gain, but does not protect from diabetic complications.

The gene CNDP1 was associated with the development of diabetic nephropathy. Its enzyme carnosinase 1 (CN1) primarily hydrolyzes the histidine-containing dipeptide carnosine but other organ and metabolic functions are mainly unknown. In our study we generated CNDP1 knockout zebrafish, which showed strongly decreased CN1 activity and increased intracellular carnosine levels.

Real-Time Imaging Reveals Augmentation of Glutamate-Induced Ca Transients by the NO-cGMP Pathway in Cerebellar Granule Neurons.

Dysfunctions of NO-cGMP signaling have been implicated in various neurological disorders. We have studied the potential crosstalk of cGMP and Ca signaling in cerebellar granule neurons (CGNs) by simultaneous real-time imaging of these second messengers in living cells. The NO donor DEA/NO evoked cGMP signals in the granule cell layer of acute cerebellar slices from transgenic mice expressing a cGMP sensor protein.

Nucleus Accumbens Deep Brain Stimulation in Patients with Substance Use Disorders and Delay Discounting.

Deep brain stimulation (DBS) of the nucleus accumbens (NAc) shows first promising results in patients with severe substance use disorder (SUD), a patient group known to have deficits in self-control. One facet of self-control is the ability to forego smaller sooner rewards in favor of larger later rewards (delay discounting, DD). The NAc has been suggested to integrate motivational information to guide behavior while the consequences of NAc-DBS on DD are unknown.

Polymers in Cartilage Defect Repair of the Knee: Current Status and Future Prospects.

Cartilage defects in the knee are often seen in young and active patients. There is a need for effective joint preserving treatments in patients suffering from cartilage defects, as untreated defects often lead to osteoarthritis. Within the last two decades, tissue engineering based techniques using a wide variety of polymers, cell sources, and signaling molecules have been evaluated.

Radiosynthesis and in vitro validation of (3)H-NS14492 as a novel high affinity alpha7 nicotinic receptor radioligand.

The neuronal α7 nicotinic acetylcholine receptor is a homo-pentameric ligand-gated ion channel that is a promising drug target for cognitive deficits in Alzheimer׳s disease and schizophrenia. We have previously described (11)C-NS14492 as a suitable agonist radioligand for in vivo positron emission tomography (PET) occupancy studies of the α7 nicotinic receptor in the pig brain. In order to investigate the utility of the same compound for in vitro studies, (3)H-NS14492 was synthesized and its binding properties were characterized using in vitro autoradiography and homogenate binding assays in pig frontal cortex.

Memory concerns, memory performance and risk of dementia in patients with mild cognitive impairment.

Background: Concerns about worsening memory ("memory concerns"; MC) and impairment in memory performance are both predictors of Alzheimer's dementia (AD). The relationship of both in dementia prediction at the pre-dementia disease stage, however, is not well explored. Refined understanding of the contribution of both MC and memory performance in dementia prediction is crucial for defining at-risk populations.

Can we discover pharmacological promiscuity early in the drug discovery process?

The term 'pharmacological promiscuity' describes the activity of a single compound against multiple targets. When undesired, promiscuity is a major safety concern that needs to be detected as early as possible in the drug discovery process. The analysis of large datasets reveals that the majority of promiscuous compounds are characterized by recognizable molecular properties and structural motifs, the most important one being a basic center with a pK(a)(B)>6.

Discovery of potent, balanced and orally active dual NK1/NK3 receptor ligands.

During a program directed at selective NK(1) receptor antagonists, we serendipitously discovered an NK(1) receptor ligand with additional affinity for the NK(3) receptor. Recognising an opportunity for a drug discovery program aiming for dual NK(1)/NK(3) receptor antagonists, we prepared a series of analogues from a novel, versatile building block. From this series emerged compounds with high and balanced affinities for the NK(1) and the NK(3) receptors.

MR-guided liver tumor ablation employing open high-field 1.0T MRI for image-guided brachytherapy.

Objective: To determine the feasibility and safety of image-guided brachytherapy employing a modified open high-field MR system.

Methods: This is a follow-up study of a development project enabling technologies for interventional use of 1.0T open MRI.

Pharmacological promiscuity: dependence on compound properties and target specificity in a set of recent Roche compounds.

The term "pharmacological promiscuity" describes a compound's pharmacological activity at multiple targets. Pharmacological promiscuity is undesired in typical drug discovery projects, which focus on the "one drug-one target" paradigm. Off-target activity can lead to adverse drug reactions, or can obscure pharmacodynamic effects in animal models.

Cyclic guanidines as dual 5-HT5A/5-HT7 receptor ligands: optimising brain penetration.

The optimisation of molecular properties within a series of 2-amino dihydroquinazoline 5-HT5A/5-HT7 receptor ligands resulted in a significantly improved brain-to-plasma ratio, enhancing the pharmacological utility of these compounds. By modulating the lipophilicity and pKa, a 20-fold increase in brain-to-plasma ratio could be achieved, leading to micromolar brain concentrations after oral administration. The enantiomers of one representative of this series of improved compounds were separated, and the configuration of the eutomer was determined by X-ray crystallography.

Cyclic guanidines as dual 5-HT5A/5-HT7 receptor ligands: structure-activity relationship elucidation.

The optimisation of affinity and selectivity in a novel series of dual 5-HT5A/5-HT7 receptor ligands is described. Brain penetrant 2-aminodihydroquinazolines with low nanomolar affinities were identified.

Novel orally active, dibenzazepinone-based gamma-secretase inhibitors.

Structural modifications of the gamma-secretase inhibitor, LY411575, led to a malonamide analogue (S),(S)-1 with potent inhibitory activity in vitro, but disappointing activity in a mouse model of Alzheimer's disease. Identification and replacement of a metabolically labile position provided an improved compound (R/S),(S)-13 with high in vitro activity (IC(50)=1.7 nM), and in vivo activity after oral administration (MED=3 mg/kg).

11 Years of cyanopyrrolidines as DPP-IV inhibitors.

Cyanopyrrolidines (cyanopyrrolidides, pyrrolidine-2-nitriles, prolinenitriles) as inhibitors of the serine protease dipeptidyl peptidase IV (DPP-IV, DP IV, CD26, EC 3.4.14.

Amyloid beta peptide ratio 42/40 but not A beta 42 correlates with phospho-Tau in patients with low- and high-CSF A beta 40 load.

Neurochemical dementia diagnostics (NDD) can significantly improve the clinically based categorization of patients with early dementia disorders, and the cerebrospinal fluid (CSF) concentrations of amyloid beta peptides ending at the amino acid position of 42 (A beta x-42 and A beta 1-42) are widely accepted biomarkers of Alzheimer's disease (AD). However, in subjects with constitutively high- or low-CSF concentrations of total A beta peptides (tA beta), the NDD interpretation might lead to erroneous conclusions as these biomarkers seem to correlate better with the total A beta load than with the pathological status of a given patient in such cases. In this multicenter study, we found significantly increased CSF concentrations of phosphorylated Tau (pTau181) and total Tau in the group of subjects with high CSF A beta x-40 concentrations and decreased A beta x-42/x-40 concentration ratio compared with the group of subjects with low CSF A beta x-40 and normal A beta ratio (p<0.

Pharmacological management of renal fibrotic disease.

Chronic kidney diseases frequently advance to end-stage renal failure, and the number of patients affected is steadily increasing worldwide. At the molecular level, progression of renal insufficiency correlates closely with ongoing pathological matrix protein expansion (i.e.