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Structural, functional and biochemical characterisation of apolipoprotein(a)-containing low-density lipoproteins
No full textAtherosclerosis is the leading cause of cardiovascular diseases and remains a global health challenge. Low-density lipoproteins are crucial in atherogenesis, with plasma levels as significant independent predictors of the condition. Lipoprotein(a), Lp(a), is an LDL variant considered a stand-alone atherosclerosis predictor. Although structurally similar in composition to LDL, Lp(a) contains an additional protein, apolipoprotein(a), covalently linked to apolipoprotein-B100 via a disulfide bond. This distinguishing protein is believed to confer Lp(a) its distinctive properties, including marked heterogeneity. While many studies have structurally characterised LDL particles, Lp(a) remains understudied. In this study, we isolated LDL particles from serum of normolipidemic, healthy individuals with either low or high Lp(a) levels. Our study provides biochemical, structural and functional characterisation of low and high Lp(a)-total LDL fractions. Fourier transform infrared spectroscopy (FTIR) revealed that high Lp(a) LDL exhibited a reduced ability to remove lipids from model membranes compared to low Lp(a) LDL. However, this functional difference could not be sufficiently associated with structural differences in total LDL fractions, as determined by small-angle X-ray scattering (SAXS), except for a significant difference in the particles' core-to-shell scattering mass (SM) ratio. Western blot analysis further revealed a higher abundance of Lp(a) in a small-dense subfraction, LDL6, leading us to hypothesise that structural differences might be more evident in these subfractions than in total fractions. Supporting this hypothesis, SAXS measurements on LDL6 subfractions from two subjects, with low and high Lp(a), revealed an increased protein shell thickness in high Lp(a) LDL6, a feature not directly observed in total fractions. Our data thus suggests a key role of LDL6 in LDL dysfunction
Low tumour burden is associated with observation after surgery in patients with grade 2 astrocytoma and oligodendroglioma: results from the prospective multicentre LoG-Glio registry
No full textPurposeRecent evidence-based guidelines recommend adjuvant therapy following surgery for most patients with WHO grade 2 and 3 gliomas. However, deviations from these recommendations are frequently observed in clinical practice. This study aimed to evaluate patterns of postoperative management across Germany, using multicentre registry data from certified neuro-oncology centres.MethodsWe analysed data from the ongoing multicentre registry study, which prospectively collects adult patients with IDH-mutant WHO grade 2 and 3 diffuse gliomas. Patients treated at 14 certified neuro-oncology centres were included. Multivariate logistic regression was used to identify factors associated with observation, chemotherapy, or radiotherapy. We assessed concordance between guideline recommendations and actual treatment during the first year after surgery.ResultsA total of 217 patients with astrocytoma or oligodendroglioma were included, of whom 169 (78%) had WHO grade 2 tumours. Observation alone was selected in 90 (53%) patients with grade 2 tumours. Gross total resection was independently associated with observation (OR 0.10; 95% CI, 0.04–0.22; p ConclusionThe presence of residual tumour after surgery was the principal determinant of postoperative management in patients with WHO grade 2 gliomas. Age ≥ 40 years did not independently influence clinical decision-making. These findings highlight a gap between guidelines and real-world practice and underscore the need for more flexible, individualised treatment frameworks
13th Tuscany Retreat on Cancer Research and Apoptosis: genetic profiling, resistance mechanisms and novel treatment concepts in cancer and neurodegeneration
No full textCompound heterozygous NFKB1 missense variants in cis associated with immunodeficiency
No full textHeterozygous pathogenic NFKB1 variants are one of the most frequent monogenic causes of disease in patients with inborn errors of immunity (IEI) and mainly compromise protein expression. NFKB1 encodes the precursor protein p105, which is processed into p50, the key transcription factor of canonical NF-κB1 signaling. Insufficiency of p105/p50 presents with immunodeficiency and autoinflammation.Here, we evaluated two NFKB1 missense variants, identified in compound heterozygosity in cis (c.[150A>C;156A>C]; p.[Gln50His;Lys52Asn]) in a patient with immunodeficiency. While the isomorphic Q50H variant enhanced the rather marginal defect of K52N, the combination of both caused a pathogenic protein damage in p50. Our findings highlight an inherent challenge when analyzing single variants ‘isolated’ from their genetic context. Particularly when filtering out additional variants, e.g. based on allele frequencies, pathogenic effects originating from compound heterozygosity may be overlooked
Spatial transcriptomics expression prediction from histopathology based on cross-modal mask reconstruction and contrastive learning
No full textLocalized ionomer degradation analysis of sulfonated poly(phenylene sulfones) in fuel cell applications using confocal Raman microscopy
No full textHeterogeneity of eGFR slopes according to etiology, eGFR and UACR in a large cohort of CKD patients
No full textIntroductionThe rate of decline in estimated glomerular filtration rate (GFR, eGFR) is increasingly recognized as a quantitative marker of chronic kidney disease (CKD) progression. However, data on eGFR slopes have mainly been reported in cohorts enriched for fast progression and the heterogeneity of eGFR slopes across the spectrum of CKD remains poorly defined.MethodsIn 5214 participants of the German CKD (GCKD) study, we modeled eGFR slopes using per-protocol and clinical measurements. We used linear-mixed effects models, with eGFR slope as the outcome and baseline demographics as independent variables to (i) describe eGFR slope heterogeneity; (ii) assess differences by CKD etiology, eGFR and urinary albumin-to-creatinine ratio (UACR) categories, sex, and age; and (iii) determine associations of slopes with estimated eGFR decline (30%, 40%, and 57%) and observed end points (kidney failure with replacement therapy, mortality).ResultsOn average, 9 eGFR values per participant (interquartile range: 7–12) over 6.5 years were used for slope calculation. The adjusted mean annual eGFR slope was −1.43 ml/min per 1.73 m2. Slopes were similar across eGFR categories, but steeper with higher UACR. Faster eGFR decline was observed in participants of younger age and in those with polycystic kidney disease or diabetic kidney disease (DKD). Although eGFR slopes did not consistently differ by sex, women with diabetes as the leading cause of CKD had lower slopes than their male counterparts. A rapid annual decline (> 5 ml/min per 1.73 m2) occurred in 4.3%, with variation in frequency by CKD cause and UACR.ConclusionIn conclusion, though the average eGFR slope was low, it varied considerably, depending on CKD etiology and UACR. This data may help to put slope estimates in individual patients and defined subpopulations into perspective
Personalised and standardised wafer-based open-label placebos reduce perceived stress among university students: A three-arm randomised controlled trial
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