Design, Synthesis, and SAR of Covalent KIT and PDGFRA Inhibitors─Exploring Their Potential in Targeting GIST.

Gastrointestinal stromal tumors (GIST), driven by KIT and PDGFRA mutations, are the most common mesenchymal tumors of the gastrointestinal tract. Although tyrosine kinase inhibitors (TKIs) have advanced treatment, resistance mutations and off-target toxicity limit their efficacy. This study develops covalent TKIs targeting drug-resistant GIST through structure-based design, synthesis, and biological evaluation.

KIT ATP-Binding Pocket/Activation Loop Mutations in GI Stromal Tumor: Emerging Mechanisms of Kinase Inhibitor Escape.

Purpose: Imatinib resistance in GI stromal tumors (GISTs) is primarily caused by secondary mutations, and clonal heterogeneity of these secondary mutations represents a major treatment obstacle. KIT inhibitors used after imatinib have clinical activity, albeit with limited benefit. Ripretinib is a potent inhibitor of secondary KIT mutations in the activation loop (AL).

Avapritinib-based SAR studies unveil a binding pocket in KIT and PDGFRA.

Avapritinib is the only potent and selective inhibitor approved for the treatment of D842V-mutant gastrointestinal stromal tumors (GIST), the most common primary mutation of the platelet-derived growth factor receptor α (PDGFRA). The approval was based on the NAVIGATOR trial, which revealed overall response rates of more than 90%. Despite this transformational activity, patients eventually progress, mostly due to acquired resistance mutations or following discontinuation due to neuro-cognitive side effects.

Sensing Liquid- and Gas-Phase Hydrocarbons via Mid-Infrared Broadband Femtosecond Laser Source Spectroscopy.

In this study, we demonstrate the combination of a tunable broadband mid-infrared (MIR) femtosecond laser source separately coupled to a ZnSe crystal horizontal attenuated total reflection (ATR) sensor cell for liquid phase samples and to a substrate-integrated hollow waveguide (iHWG) for gas phase samples. Utilizing this emerging light source technology as an alternative MIR radiation source for Fourier transform infrared (FTIR) spectroscopy opens interesting opportunities for analytical applications. In a first approach, we demonstrate the quantitative analysis of three individual samples, ethanol (liquid), methane (gas), and 2-methyl-1-propene (gas), with limits of detection of 0.

Thin-Film Waveguide Laser Spectroscopy: A Novel Platform for Bacterial Analysis.

Bacterial sensing based on quantum cascade laser spectroscopy coupled with diamond or gallium arsenide thin-film waveguides is a novel analytical tool for gaining high-resolution infrared spectroscopic information of planktonic and sessile bacteria, as shown in the present study for . During observation periods of up to 24 h, diamond and gallium arsenide thin-film waveguide laser spectroscopy was compared to information obtained via conventional Fourier transform infrared spectroscopy. The proliferation behavior of at those surfaces was complementarily investigated using atomic force microscopy and scanning electron microscopy.

Graphene-enhanced quantum cascade laser infrared spectroscopy using diamond thin-film waveguides.

Diamond thin-film waveguides were combined with quantum cascade lasers augmented by drop-casted graphene enabling surface-enhanced infrared absorption spectroscopy. Enhancing the signal provides access to an even more pronounced vibrational signature suitable for analytical scenarios where only a small sample volume and/or low analyte concentration levels are prevalent. To demonstrate the utility of this concept, taurine was investigated as a model analyte.

Espresso Science: Laser-Based Diamond Thin-Film Waveguide Sensors for the Quantification of Caffeine.

Diamond thin-film waveguides with a nanocrystalline diamond layer of approximately 20 μm thickness were used in the mid-infrared regime in combination with quantum cascade lasers to detect the IR signature of caffeine. The diamond thin-film waveguides were fundamentally characterized with respect to their morphological properties via AFM and SEM. Theoretical simulations confirmed the feasibility of using a larger sensing area of approximately 50 mm compared to conventionally used strip waveguides.

Working memory load affects intelligence test performance by reducing the strength of relational item bindings and impairing the filtering of irrelevant information.

There is a broad consensus that individual differences in working memory capacity (WMC) are strongly related to individual differences in intelligence. However, correlational studies do not allow conclusions about the causal nature of the relationship between WMC and fluid intelligence. While research on the cognitive basis of intelligence typically assumes that simpler lower-level cognitive processes contribute to individual differences in higher-order reasoning processes, a reversed causality or a third variable giving rise to two intrinsically uncorrelated variables may exist.

Atomic force and infrared spectroscopic studies on the role of surface charge for the anti-biofouling properties of polydopamine films.

Antibacterial polymer materials have gained interest due to their capability to inhibit or eradicate biofilms with greater efficiency in comparison with their monomeric counterparts. Among the antimicrobial and anti-biofouling polymers, catecholamine-based polymers - and in particular polydopamine - have been studied due to their favorable adhesion properties, which can be tuned by controlling the pH value. In this study, we used atomic force microscopy (AFM)-based spectroscopy to investigate the relation between the adhesion properties and surface charge density and the pH of electrochemically deposited polydopamine films presenting a dissociation constant of polydopamine of 6.

Innovative Substrate-Integrated Hollow Waveguide Coupled Attenuated Total Reflection Sensors for Quantum Cascade Laser Based Infrared Spectroscopy in Harsh Environments.

An innovative mid-infrared spectroscopic sensor system based on quantum cascade lasers has been developed. The system combines the versatility of substrate-integrated hollow waveguides (IHWGs) with the robustness of attenuated total reflection (ATR) crystals employed as internal reflection waveguides for evanescent field sensing. IHWGs are highly reflective metal structures that propagate infrared (IR) radiation and were used as light pipes for coupling radiation into the ATR waveguide.

Genetic factors influencing a neurobiological substrate for psychiatric disorders.

A retrospective meta-analysis of magnetic resonance imaging voxel-based morphometry studies proposed that reduced gray matter volumes in the dorsal anterior cingulate and the left and right anterior insular cortex-areas that constitute hub nodes of the salience network-represent a common substrate for major psychiatric disorders. Here, we investigated the hypothesis that the common substrate serves as an intermediate phenotype to detect genetic risk variants relevant for psychiatric disease. To this end, after a data reduction step, we conducted genome-wide association studies of a combined common substrate measure in four population-based cohorts (n = 2271), followed by meta-analysis and replication in a fifth cohort (n = 865).

White matter hyperintensities are not associated with cognitive decline in early Parkinson's disease - The DeNoPa cohort.

Background: Small vessel disease and white matter hyperintensities (WMH) as its surrogate marker are known to predict cognitive decline in the elderly. However, the influence of vascular lesions on cognitive impairment in Parkinson's disease (PD) has been discussed controversial so far. The Aim of this study was to evaluate the predictive role of volume and location of white matter hyperintensities (WMH) on cognitive decline in de novo PD patients.

Large-scale evidence for an association between low-grade peripheral inflammation and brain structural alterations in major depression in the BiDirect study.

Background: Preliminary research suggests that major depressive disorder (MDD) is associated with structural alterations in the brain; as well as with low-grade peripheral inflammation. However, even though a link between inflammatory processes and altered brain structural integrity has been purported by experimental research, well-powered studies to confirm this hypothesis in patients with MDD have been lacking. We aimed to investigate the potential association between structural brain alterations and low-grade inflammation as interrelated biological correlates of MDD.

Advanced Photonic Sensors Based on Interband Cascade Lasers for Real-Time Mouse Breath Analysis.

A multiparameter gas sensor based on distributed feedback interband cascade lasers emitting at 4.35 μm and ultrafast electro-spun luminescence oxygen sensors has been developed for the quantification and continuous monitoring of CO/CO isotopic ratio changes and oxygen in exhaled mouse breath samples. Mid-infrared absorption spectra for quantitatively monitoring the enrichment of CO levels were recorded in a miniaturized dual-channel substrate-integrated hollow waveguide using balanced ratiometric detection, whereas luminescence quenching was used for synchronously detecting exhaled oxygen levels.

Diagnostic Value of Diffusion Tensor Imaging and Positron Emission Tomography in Early Stages of Frontotemporal Dementia.

Background: Due to suboptimal sensitivity and specificity of structural and molecular neuroimaging tools, the diagnosis of behavioral variant frontotemporal dementia (bvFTD) remains challenging.

Objective: Investigation of the sensitivity of diffusion tensor imaging (DTI) and fluorodeoxyglucose positron emission tomography (FDG-PET) to detect cerebral alterations in early stages of bvFTD despite inconspicuous conventional MRI.

Methods: Thirty patients with early stages of bvFTD underwent a detailed neuropsychological examination, cerebral 3T MRI with DTI analysis, and FDG-PET.

Gray matter correlates of pressure pain thresholds and self-rated pain sensitivity: a voxel-based morphometry study.

Individual differences in sensitivity to pain are large and have clinical and scientific importance. Although heavily influenced by situational factors, they also relate to genetic factors and psychological traits, and are reflected by differences in functional activation in pain-related brain regions. Here, we used voxel-based morphometry to investigate if individual pain sensitivity is related to local gray matter volumes.

Sample heterogeneity in unipolar depression as assessed by functional connectivity analyses is dominated by general disease effects.

Objectives: Combinations of resting-state fMRI and machine-learning techniques are increasingly employed to develop diagnostic models for mental disorders. However, little is known about the neurobiological heterogeneity of depression and diagnostic machine learning has mainly been tested in homogeneous samples. Our main objective was to explore the inherent structure of a diverse unipolar depression sample.

Effects of Different Exercise Strategies and Intensities on Memory Performance and Neurogenesis.

It is well established that physical exercise affects both hippocampal neurogenesis and memory functions. Until now, distinctive effects of controlled and voluntary training (VT) on behavior and neurogenesis as well as interactions between exercise intensity, neurogenesis and memory performance are still elusive. The present study tested the impact of moderate controlled and VT on memory formation and hippocampal neurogenesis and evaluated interactions between exercise performance, learning efficiency and proliferation of progenitor cells in the hippocampus.

Prefrontal gray matter volume mediates genetic risks for obesity.

Genetic and neuroimaging research has identified neurobiological correlates of obesity. However, evidence for an integrated model of genetic risk and brain structural alterations in the pathophysiology of obesity is still absent. Here we investigated the relationship between polygenic risk for obesity, gray matter structure and body mass index (BMI) by the use of univariate and multivariate analyses in two large, independent cohorts (n=330 and n=347).

The Association of Lesion Location and Sleep Related Breathing Disorder in Patients with Acute Ischemic Stroke.

Background And Aims: Sleep related breathing disorders (SRBD) are common in patients with ischemic stroke and are associated with poor outcome. SRBD after stroke were assumed to be a direct consequence of injury of specific central nervous system structures. However, whether specific locations of ischemic infarcts cause SRBD is yet unknown.

Diagnostic classification of unipolar depression based on resting-state functional connectivity MRI: effects of generalization to a diverse sample.

In small, selected samples, an approach combining resting-state functional connectivity MRI and multivariate pattern analysis has been able to successfully classify patients diagnosed with unipolar depression. Purposes of this investigation were to assess the generalizability of this approach to a large clinically more realistic sample and secondarily to assess the replicability of previously reported methodological feasibility in a more homogeneous subgroup with pronounced depressive symptoms. Two independent subsets were drawn from the depression and control cohorts of the BiDirect study, each with 180 patients with and 180 controls without depression.

Computed tomography-based quantification of lesion water uptake identifies patients within 4.5 hours of stroke onset: A multicenter observational study.

Objective: Many patients with stroke cannot receive intravenous thrombolysis because the time of symptom onset is unknown. We tested whether computed tomography (CT)-based quantification of water uptake in the ischemic tissue can identify patients with stroke onset within 4.5 hours, the time window of thrombolysis.

Outcome After Thrombectomy and Intravenous Thrombolysis in Patients With Acute Ischemic Stroke: A Prospective Observational Study.

Background And Purpose: In patients with ischemic stroke, randomized trials showed a better functional outcome after endovascular therapy with new-generation thrombectomy devices compared with medical treatment, including intravenous thrombolysis. However, effects on mortality and the generalizability of results to routine clinical practice are uncertain.

Methods: In a prospective observational register-based study patients with ischemic stroke treated either with thrombectomy, intravenous thrombolysis, or their combination were included.

MR imaging of the brain in large cohort studies: feasibility report of the population- and patient-based BiDirect study.

Objectives: To describe the implementation and protocol of cerebral magnetic resonance imaging (MRI) in the longitudinal BiDirect study and to report rates of study participation as well as management of incidental findings.

Methods: Data came from the BiDirect study that investigates the relationship between depression and arteriosclerosis and comprises 2258 participants in three cohorts: 999 patients with depression, 347 patients with manifest cardiovascular disease (CVD) and 912 population-based controls. The study program includes MRI of the brain.

Volume transition analysis: a new approach to resolve reclassification of brain tissue in repeated MRI scans.

Background: Variability in brain tissue volumes derived from magnetic resonance images is attributable to various sources. In quantitative comparisons it is therefore crucial to distinguish between biologically and methodically conditioned variance and to take spatial accordance into account.

New Method: We introduce volume transition analysis as a method that not only provides details on numerical and spatial accordance of tissue volumes in repeated scans but also on voxel shifts between tissue types.