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Longitudinal effects of dimethyl fumarate on patient-reported outcome measures in multiple sclerosis: treatment satisfaction, quality of life, depressive symptoms, sleep, and work productivity
No full textBACKGROUND: Oral therapies for relapsing-remitting multiple sclerosis (RRMS) may enhance treatment satisfaction and quality of life. Patient-reported outcome measures (PROMs) provide structured insight into treatment effectiveness and disease impact beyond clinician-reported scales. OBJECTIVE: To assess treatment satisfaction and other PROMs in RRMS patients initiating dimethyl fumarate (DMF), either treatment-naïve or switching from injectable therapies. METHODS: PROFIT was a 12-month, multicenter, phase 4, open-label, single-arm observational study conducted in Iran. Patients received DMF with a slow-dose titration regimen to mitigate gastrointestinal adverse effects. The primary endpoint was the change in treatment satisfaction, assessed by the Treatment Satisfaction Questionnaire for Medication (TSQM-14), from baseline to month 12 among previously treated patients. Key secondary endpoints included changes in additional PROMs, including health-related quality of life (HRQoL), depressive symptoms, sleep quality, and work productivity. Patient-reported outcomes were assessed using the EuroQol-5D-3L (EQ-5D-3L), Beck Depression Inventory-Fast Screen (BDI-7), Pittsburgh Sleep Quality Index (PSQI), and Work Productivity and Activity Impairment-Multiple Sclerosis (WPAI-MS) at baseline, 6 months, and 12 months. Adverse events were monitored monthly, with safety evaluated as a secondary outcome. RESULTS: Of 645 patients (72.3 % female; mean age 34.0 years), 473 (73.3 %) completed the 12-month follow-up, while 172 (26.7 %) discontinued treatment. The primary endpoint, change in treatment satisfaction (TSQM-14) among previously treated patients, showed significant improvement across all domains: effectiveness (+13.01), side effects (+7.76), convenience (+35.21), and global satisfaction (+15.75) (all p < 0.001). Secondary endpoints also demonstrated favorable changes, including EQ-5D-3L utility (+0.07), EQ-5D Visual Analogue Scale (VAS) (+3.86), PSQI (-1.62), WPAI absenteeism (-7.55 %), and BDI-7 (-0.11) (all p < 0.001). Treatment discontinuations (26.7 %) were primarily due to gastrointestinal adverse events (n = 45, 26.0 %), followed by physician decision (n = 34, 20.0 %), disease progression (n = 26, 15.0 %), patient preference (n = 19, 11.0 %), pregnancy (n = 14, 8.0 %), elevated liver enzymes (n = 13, 7.0 %), and other causes (n = 21, 12.0 %). Adverse events declined over time, confirming a favorable and manageable safety profile. CONCLUSION: DMF was associated with improvements in treatment satisfaction, quality of life, sleep quality, work productivity, and depressive symptoms in both treatment-naïve and previously treated RRMS patients, with high adherence and manageable side effects. These findings provide real-world evidence from an Iranian RRMS cohort, supporting DMF as a well-tolerated, patient-centered option with multidimensional benefits observed under routine clinical conditions
DNA-protein cross-links promote cGAS-STING–driven premature aging and embryonic lethality
No full textDNA-protein cross-links (DPCs) are highly toxic DNA lesions that block replication and transcription, but their impact on organismal physiology is unclear. We identified a role for the metalloprotease SPRTN in preventing DPC-driven immunity and its pathological consequences. Loss of SPRTN activity during replication and mitosis lead to unresolved DNA damage, chromosome segregation errors, micronuclei formation, and cytosolic DNA release that activates the cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway. In a Sprtn knock-in mouse model of Ruijs-Aalfs progeria syndrome, chronic cGas-Sting signaling caused embryonic lethality through inflammation and innate immune responses. Surviving mice displayed aging phenotypes beginning in embryogenesis, which persisted into adulthood. Genetic or pharmacological inhibition of cGas-Sting rescued embryonic lethality and alleviated progeroid phenotypes
Immunofluorescence imaging-guided laser microdissection for ultralow input spatial tissue proteomics
No full textLaser microdissection (LMD) enables the precise isolation of specific cells or regions of interest from tissue sections, guiding downstream molecular analyses with high spatial resolution. In this protocol, we describe an optimized protocol combining whole-slide immunofluorescence imaging, LMD, and low-input liquid chromatography (LC) mass spectrometry (MS)-based proteomics of FFPE tissue sections
Multi-omics insight into cardiac myofibril remodeling in post-prandial burmese pythons
Full text linkBurmese pythons exhibit rapid cardiac remodeling in response to a dramatic increase in metabolic rate during digestion. Here, we performed single-myofibril mechanics measurements and myosin heavy chain metabolic assays to evaluate the impact of feeding on the cardiomyocyte sarcomere, the fundamental molecular unit of muscle contraction, using two experimental paradigms: normal feeding (one meal per month) and frequent feeding (eight meals per month). Myofibril tension and rate of relaxation increased during digestion in both paradigms, while frequent feeding was further associated with slower myofibril activation kinetics and faster myosin heavy chain ATP turnover. To identify molecular changes at the sarcomere and gain potential mechanistic insight, we performed multi-omics analyses. RNA sequencing identified increased expression of some sarcomere genes during digestion; however, proteomics analysis suggested a delay in sarcomere protein synthesis at the peak of remodeling, as expression of many sarcomere proteins decreased. Analysis of post-translational modifications (ubiquitinomics, phospho-proteomics, acetylomics) identified hundreds of significantly regulated sites on sarcomere proteins during digestion, including many on the tension-regulating titin and myosin heavy chain proteins. Our results detail the molecular underpinnings of cardiac remodeling in digesting Burmese pythons and suggest that the solution in nature for rapidly increasing cardiac contractility is a post-translational sarcomere tuning program
Subjective cognition trajectories, Alzheimer biomarkers, and incident mild cognitive impairment
No full textBackground: Subjective cognitive decline (SCD) is common in older adults and may precede mild cognitive impairment (MCI). Whether longitudinal changes in self- or study partner (SP)-reported SCD improve early identification of individuals at risk for clinical progression, particularly along the Alzheimer’s disease (AD) biological continuum, remains unclear. Methods: We pooled data from two longitudinal observational cohorts (DELCODE and ADNI). Cognitively unimpaired (CU) participants were recruited through public advertisement or memory clinics and included if baseline amyloid status, ≥ 2 SCD assessments, and clinical follow-up were available. SCD was assessed using the Everyday Cognition questionnaire (self- and SP-report). Linear mixed-effects models examined longitudinal associations between SCD trajectories, baseline AD biomarkers, and progression to incident MCI. Multivariable Cox proportional hazards models tested whether one-year changes in SCD predicted subsequent progression. Findings: Among 770 participants (median age 69·9years [IQR 66·0–74·6]; 52·6% women; median follow-up 5·0years [4·0-7·0]), amyloid-positive individuals and those who progressed to MCI showed steeper longitudinal increases in both SCD reports. In amyloid-positive participants, only increases in SP-reported SCD differentiated progressors from non-progressors. One-year increases in SP-reported SCD predicted a higher risk of subsequent MCI compared with unchanged scores (hazard ratio 3·24 [95%CI 1·73-6·07]), with effects confined to amyloidpositive participants. Interpretation: Longitudinal increases in SP-reported cognitive difficulties, particularly over short intervals, are associated with near-term progression to MCI in amyloid-positive CU older adults. SP-based longitudinal monitoring may represent a low-burden approach to support earlier clinical surveillance in aging populations. Funding: German Center for Neurodegenerative Diseases, US National Institutes of Health
Improving cardiovascular risk stratification through the derivation and validation of an elevated triglyceride-glucose index
Full text linkBACKGROUND AND AIMS: Triglyceride-glucose (TyG) index, is an emerging prognostic biomarker in atherosclerotic cardiovascular disease (ASCVD). Validation of its clinical value and of clinically relevant prognostic cut-off, remains an unmet need to integrate TyG into primary prevention protocols. METHODS: To assess the clinical applicability of TyG, a composite of cardiovascular mortality, myocardial infarction, coronary revascularization or stroke was used as the primary endpoint in a general population cohort (ATTICA cohort, n = 1677, derivation cohort). Next, we derived an optimal prognostic TyG cut-off and externally validated it in a primary prevention cohort (n = 1237). To assess the clinical value of TyG, we analysed 1170 consecutively recruited patients from an ongoing registry aiming to stratify ASCVD risk (Athens Cardiometabolic Cohort) and assessed indices of subclinical arterial injury and progression of atherosclerosis. The TyG index was calculated by the formula: ln[fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]. RESULTS: TyG index was independently associated with increased CVD events in the derivation cohort (HR = 1.33, p = 0.020). The incremental value of a derived optimal cut-off of 8.46 over SCORE2 was confirmed in both derivation and validation cohorts [net reclassification index (NRI) = 0.668 and 0.469 respectively, Delta Harrell's C index = 0.054 and 0.044 respectively, p < 0.05 for all]. Elevated TyG index was associated with more diseased vascular beds (OR = 2.00, 95% CI 1.24-3.24), progression of subclinical carotid atherosclerosis (OR = 2.99, 95% CI 1.10-8.17) at follow-up and established ASCVD (p < 0.05 for all). CONCLUSIONS: TyG is associated with increased prevalence and progression of subclinical and clinically overt ASCVD. In individuals assessed for primary prevention a TyG≥8.46 may serve as a risk enhancer
Reconstructing the three-dimensional architecture of extrachromosomal DNA with ec3D
Full text linkExtrachromosomal DNAs (ecDNAs) are circular DNA molecules prevalent in human cancers that drive tumor evolution and drug resistance. Their circular topology, which disrupts topological domains and rewires regulatory circuits, has typically been studied via pairwise interactions. Here we develop ec3D, a computational method for reconstructing three-dimensional ecDNA structures from Hi-C data. Given a candidate ecDNA sequence and whole-genome Hi-C data, ec3D reconstructs spatial structures by maximizing the Poisson likelihood of observed interactions. We validate ec3D using simulated structures, previously characterized cancer cell lines, and microscopy imaging. Our reconstructions reveal that ecDNAs occupy spherical configurations and mediate unique long-range regulatory interactions involved in gene regulation. Through algorithmic innovations, ec3D can resolve complex structures with duplicated segments, identify multi-way interactions, and identify potential intermolecular (trans) interactions. Our findings provide insights into how ecDNA’s spatial organization bypasses normal chromosomal constraints and contributes to increased oncogene expression
Strong constitutive NF-κB signaling in B cells drives SLL/CLL-like lymphomagenesis and overcomes microenvironmental dependencies
Full text linkAberrant activation of NF-κB transcription factors is a hallmark of human lymphomas. Most lymphoma-intrinsic as well as microenvironment-induced NF-κB activation occurs upstream of the key kinase IKK2, therefore affecting additional pathways. Here, we show that canonical NF-κB signaling in mouse B cells, induced through the expression of one or two copies of a constitutively active IKK2 variant, dose-dependently drives lymphomagenesis. The observed phenotype and stereotypic B cell receptor clonality resemble human small lymphocytic lymphoma (SLL) and chronic lymphocytic leukemia (CLL). Stronger IKK2 signaling drives early B1a cell expansion and uniform SLL/CLL-like lymphomagenesis, while intermediate signals cause more heterogeneous malignancies. Mechanistically, constitutive IKK2 signals provide a profound cell-intrinsic competitive advantage to B1a cells and dose-dependently synergize with TCL1 overexpression in driving aggressive CLL. Further, strong constitutive NF-κB activation overcomes critical microenvironmental dependencies of TCL1-driven lymphomas. Our findings establish canonical NF-κB as an oncogenic driver in lymphoma and reveal reduced microenvironment dependency as a key NF-κB-mediated mechanism, thus highlighting its therapeutic relevance
Potenzial der Bildgebung im klinischen Alltag: Fokus auf die kardiovaskuläre MRT [Potential of imaging in the clinical routine: focus on cardiovascular MRI]
No full textCardiac magnetic resonance imaging (CMR) provides decisive advantages, particularly in coronary heart disease, myocarditis and cardiomyopathy. It accurately detects ischemia, scarring, edema and microvascular disorders, enables reliable risk stratification and supports treatment decisions such as revascularization or medication adjustments. Modern quantitative perfusion methods and artificial intelligence (AI)-based analyses further increase the diagnostic accuracy. In inflammatory myocardial and pericardial diseases, CMR using mapping techniques and late gadolinium enhancement (LGE) forms the basis for differentiated diagnostics and estimation of the prognosis. It also enables a precise etiological classification and provides prognostically relevant parameters in cases of hypertrophic, dilated, arrhythmogenic and restrictive cardiomyopathies. In the diagnostics of valvular diseases and the planning of interventional procedures and cardiac tumors, CMR provides essential additional information and demonstrates a high sensitivity and specificity. New techniques such as quantitative 4‑dimensional (4D) flow measurements, high-resolution 3D imaging and electrocardiograph (ECG)-independent scans will further increase its value. Due to the increasing number of CMR examinations, standardized procedures, qualified personnel and structured training programs are essential to ensure a high quality of care in the long term
Aberrant SUMOylation restricts the targetable cancer immunopeptidome
Full text linkA balanced SUMOylation equilibrium safeguards the functional anti-tumor immune response. Oncogene activation drives SUMOylation, rendering aberrant SUMOylation a hallmark of cancer. To delineate the impact of activated SUMOylation on the tumor-immune synapse, we applied HLA class-I-targeted ligandomics and identified a function of activated SUMOylation in restricting the immunopeptidome landscape. Importantly, aberrant SUMOylation suppressed a unique HLA-I peptide and oncoprotein-derived neoepitope repertoire, enabling cancer cells to evade T cell immune surveillance. Mechanistically, SUMOylation impaired the immunoproteasome constitution and proteolytic activity, thus limiting the diversity of the peptide landscape. Further, SUMOylation altered TAP1 transporter binding preferences, thereby mimicking viral immune evasion strategies. As an actionable application, pharmacological inhibition of SUMOylation unmasked the targetable immunopeptidome, enhanced the tumor cell susceptibility to T cell killing and substantially reshaped the immune cell landscape. These findings highlight SUMOylation as a critical regulator of the adaptive anti-tumor immune response. We propose SUMOylation inhibition as a strategy to enhance immunogenic peptide presentation, thereby improving the efficacy of cancer immunotherapies