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Chr:17q21.31 locus risk haplotype H1 susceptibility to ferroptosis is mediated by endolysosomal pathway
No full textHuman chr:17q21.31 locus is a complex genomic region of high linkage disequilibrium with two main haplotypes, named H1 and H2. The H1 haplotype is genetically associated with a wide spectrum of neurodegenerative diseases (NDs), including tauopathies and synucleinopathies, with the underlying mechanism remaining unknown. We investigated the interplay of environmental and genetic risk factors on neurons derived from iPSCs of both haplotypes under Mild Chronic Oxidative Stress (MCOS) conditions. The observed increased susceptibility of H1 neurons to MCOS leading to an earlier neuronal death, was mediated by ferroptosis. Characterization of the phenotype revealed spatiotemporal propagation and spreading of axonal deterioration and neuronal death in accordance with NDs pathology. Transcriptional profiling pointed to ferroptosis hallmarks and endo-lysosomal vesicles as implicated pathways, while FDA-approved drugs prevented the induced death in H1 neurons. Finally, ROS and lysosomal dynamics during the neuronal maturation shed further light to the differential response of haplotypes to MCOS, which could explain the risk association of the H1 haplotype with NDs
A predictive endocrine resistance index accurately stratifies luminal breast cancer treatment responders and nonresponders
No full textBACKGROUNDEndocrine therapy (ET) with tamoxifen (TAM) or aromatase inhibitors (AI) is highly effective against hormone receptor-positive (HR-positive) early breast cancer (BC), but resistance remains a major challenge. The primary objectives of our study were to understand the underlying mechanisms of primary resistance and to identify potential biomarkers.METHODSWe selected more than 800 patients in 3 subcohorts (Discovery, n = 364, matched pairs; Validation 1, n = 270, Validation 2, n = 176) of the West German Study Group (WSG) ADAPT trial who underwent short-term preoperative TAM or AI treatment. Treatment response was assessed by immunohistochemical labeling of proliferating cells with Ki67 before and after ET. We performed comprehensive molecular profiling, including targeted next-generation sequencing (NGS) and DNA methylation analysis using EPIC arrays, on posttreatment tumor samples.RESULTSTP53 mutations were strongly associated with primary resistance to both TAM and AI. We identified distinct DNA methylation patterns in resistant tumors, suggesting alterations in key signaling pathways and tumor microenvironment composition. Based on these findings and patient age, we developed the Predictive Endocrine ResistanCe Index (PERCI). PERCI accurately stratified responders and nonresponders in both treatment groups in all 3 subcohorts and predicted progression-free survival in an external validation cohort and in the combined subcohorts.CONCLUSIONOur results highlight the potential of PERCI to guide personalized endocrine therapy and improve patient outcomes.TRIAL REGISTRATIONWSG-ADAPT, ClinicalTrials.gov NCT01779206, retrospectively registered 01-25-2013.FUNDINGGerman Cancer Aid (Grant Number 70112954), German Federal Ministry of Education and Research (Grant Number 01ZZ1804C, DIFUTURE)
Association between depression, anxiety and long-term healthcare resource utilization in patients with pulmonary embolism
Get PDFBackground: To date, the utilization of healthcare resources for complications associated with acute pulmonary embolism (PE) have received no attention. This study aimed to explore healthcare utilization and its association with depression and anxiety up to 2 years after in-patient treatment for PE.
Methods: Data from the German 'Lungenembolie Augsburg (LEA)' cohort study was used. Baseline characteristics of the adult patients with PE were collected through an interview during hospital stay and via chart review. Participants completed postal questionnaires 3, 6, 12, and 24 months after their PE event containing questions on healthcare utilization. Depression and anxiety were assessed using the Hospital Anxiety and Depression scale (HADS-D). Negative binomial mixed models were used to investigate the associations between depression and anxiety scores (exposures) and the number of hospitalizations, hospital outpatient clinic visits, general practitioner consultations and medical specialist visits with outcomes adjusted for potential confounders.
Results: Out of 569 patients (55 % male, mean age 63.0 ± 14.5 years), 18.3 % had at least mild symptoms of depression and 21.3 % had at least mild symptoms of anxiety at the initial hospitalization. During the first 3 months after hospital discharge, 28.1 % of the patients had at least one hospital readmission. Higher HADS-D depression scores were significantly associated with more hospitalizations (p = 0.0063), hospital outpatient clinic visits (p = 0.0009) and visits to general practitioners (p = 0.0434). Higher HADS-D anxiety scores were significantly associated with more hospitalizations (p = 0.0413) and visits to medical experts (p = 0.0268).
Conclusions: Depression and anxiety were significantly associated with increased healthcare utilization in patients with PE
Association Between Habitual Dietary Intake and Urinary Metabolites in Adults—Results of a Population-Based Study
Get PDFBackground: Chronic non-communicable diseases (NCDs) are a major global health challenge, with unhealthy diets contributing significantly to their burden. Metabolomics data offer new possibilities for identifying nutritional biomarkers, as demonstrated in short-term intervention studies. This study investigated associations between habitual dietary intake and urinary metabolites, a not well-studied area.
Methods: Data were available from 496 participants of the population-based MEIA study. Linear and median regression models examined associations between habitual dietary intake and metabolites, adjusted for possible confounders. K-means clustering identified urinary metabolite clusters, and multinomial regression models were applied to analyze associations between food intake and metabolite clusters.
Results: Using linear regression models, previously reported associations could be replicated, including citrus intake with proline betaine, protein intake with urea, and fiber intake with hippurate. Novel findings include positive associations of poultry intake with taurine, indoxyl sulfate, 1-methylnicotinamide, and trimethylamine-N-oxide. Milk substitutes were positively associated with urinary uracil, pseudouridine, 4-hydroxyhippurate, and 3-hydroxyhippurate, and inversely associated with quinic acid. Dietary fiber intake showed a positive association with 3-(3-hydroxyphenyl)-3-hydroxypropionic acid and a negative association with indoxyl sulfate. We identified sucrose and taurine as key metabolites differentiating metabolite clusters. Multinomial regression analysis confirmed significantly different dietary associations across clusters, particularly for fruits, processed meat, poultry, and alcoholic beverages.
Conclusions: This study highlights established and novel food-metabolite associations, demonstrating the potential of urinary metabolomics for use as nutritional biomarkers in individuals from the general population
Imagery rescripting of interpersonal transgressions: Forgiveness, revenge, and commitment in the victim-transgressor relationship
Get PDFImagery Rescripting (ImRs) is a well-established psychotherapeutic intervention for treating aversive memories, such as those related to interpersonal transgressions. However, questions remain regarding the optimal implementation of ImRs, particularly concerning which components are most effective. In this experimental study (N = 271), we examined whether guiding participants to imagine forgiving versus taking revenge on a transgressor would differentially affect key emotional and cognitive outcomes. Additionally, we investigated the moderating role of the initial victim-transgressor commitment. Participants were instructed to imagine being the victims in a fictional interpersonal transgression. The imagined transgressor was a person with whom they had either a weak or strong commitment. Participants then engaged in an audio-guided ImRs session oriented toward either forgiveness or revenge, before indicating their aggressive inclinations, positive and negative affect, justice-related satisfaction, and feelings of empowerment. Results indicated that forgiveness-oriented ImRs led to lower aggressive inclinations and negative affect, as well as higher justice-related satisfaction, compared to revenge-oriented ImRs. No differences emerged between conditions in positive affect and feelings of empowerment. Moreover, the effectiveness of both ImRs approaches was independent of the victim-transgressor commitment. These findings suggest that forgiveness-oriented ImRs may offer a promising approach to reduce the emotional consequences of transgressions, with a reduced risk of increasing aggressive inclinations among victims. This highlights the potential value of incorporating forgiveness into ImRs protocols. However, given the fictional nature of the transgression and the standardized, non-clinical setting, further research is needed to evaluate the clinical applicability of these findings
Explaining Seeking, Scanning, and Avoidance of Information About the Mammography-Screening: Results of a Two-Wave Online Survey with a Stratified Sample of Women
Get PDFWhether individuals engage with or avoid health information and which sources are used is crucial for informed decision-making about mammography. Therefore, we aim to develop a typology of mammography-related information behaviors and explore their determinants, which were derived from the Theory of Motivated Information Management (TMIM). Based on a two-wave online survey of a sample of German women aged 40 to 69 years (N = 1,138), a cluster analysis resulted in five person-centric types of information behavior that cover respondents’ variety of engagement with mammography-related information: The seekers, the scanners, the avoiders, the involved, and the inactive. The types indicated that most individuals possess a high preference for one strategy of information behavior. Looking at the determinants of belonging to a particular type of information behavior, it becomes apparent that the factors of the TMIM have only limited explanatory power. The most relevant factors in distinguishing the types of information behaviors are benefit perceptions, worry, interest, avoidance efficacy, seeking, and avoidance-related outcome expectancies. Scanners and seekers had higher benefit perceptions. Seekers were further motivated by greater worries, while involved ones felt more interested and held stronger expectancies. Avoiders were more anxious and had a higher avoidance efficacy. The study suggests that inactive individuals and avoiders are highly prevalent and relevant target groups for health interventions that support informed decision-making. To facilitate informed decision-making, women should be encouraged to weigh benefits and harms of their options and to address negative emotions, such as anxiety, that may exist or arise during decision-making
Feasibility and potential diagnostic value of [18F]PI-2620 PET in patients with down syndrome and Alzheimer’s disease
Get PDFPurpose of the report: Adults with Down Syndrome (DS) have a substantially increased risk for Alzheimer’s disease (AD) due to the triplicated amyloid-precursor-protein gene on chromosome 21, resulting in amyloid and tau accumulation. However, tau PET assessments are not sufficiently implemented in DS-AD research or clinical work-up, and second-generation tau tracers such as [18F]PI-2620 have not been thoroughly characterized in adults with DS. We aim at illustrating feasibility and potential diagnostic value of tau PET imaging with [18F]PI-2620 for the diagnosis of DS-AD.
Materials and methods: Five adults with DS (40% female, aged 43–62) and cognitive decline underwent clinical assessments, neuropsychological testing, lumbar puncture and multimodal neuroimaging. All underwent [18F]PI-2620 tau PET. Visual read of tau PET scans was performed by three blinded raters, assessing increased tracer uptake in brain areas corresponding to the six Braak stage regions and basal ganglia.
Results: Visual read of tau burden revealed three tau-positive individuals which corresponded to their clinical decline while two cognitively stable individuals were rated as negative. Rating showed high inter-rater reliability for all Braak stages.
Conclusion: Tau PET imaging is a feasible and important biomarker assessment in the differential diagnosis of cognitive decline in adults with DS at risk of developing AD
A bipolar disorder-associated missense variant alters adenylyl cyclase 2 activity and promotes mania-like behavior
Get PDFThe single nucleotide polymorphism rs13166360, causing a substitution of valine (Val) 147 to leucine (Leu) in the adenylyl cyclase 2 (ADCY2), has previously been associated with bipolar disorder (BD). Here we show that the disease-associated ADCY2 missense mutation diminishes the enzyme´s capacity to generate the second messenger 3’,5’-cylic adenosine monophosphate (cAMP) by altering its subcellular localization. We established mice specifically carrying the Val to Leu substitution using CRISPR/Cas9-based gene editing. Mice homozygous for the Leu variant display symptoms of a mania-like state accompanied by cognitive impairments. Mutant animals show additional characteristic signs of rodent mania models, i.e., they are hypersensitive to amphetamine, the observed mania-like behaviors are responsive to lithium treatment and the Val to Leu substitution results in a shifted excitatory/inhibitory synaptic balance towards more excitation. Exposure to chronic social defeat stress switches homozygous Leu variant carriers from a mania- to a depressive-like state, a transition which is reminiscent of the alternations characterizing the symptomatology in BD patients. Single-cell RNA-seq (scRNA-seq) revealed widespread Adcy2 mRNA expression in numerous hippocampal cell types. Differentially expressed genes particularly identified from glutamatergic CA1 neurons point towards ADCY2 variant-dependent alterations in multiple biological processes including cAMP-related signaling pathways. These results validate ADCY2 as a BD risk gene, provide insights into underlying disease mechanisms, and potentially open novel avenues for therapeutic intervention strategies