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Associations of the adaptive immune system and age-related macular degeneration
No full textIn recent years, the adaptive immune system has gained a significant amount of attention due to its potential role in age-related macular degeneration (AMD). Orthologous approaches including cellular and animal models as well as pilot clinical trials have paved the way to understand the occurrence, alterations, and interactions of T cell populations in the retina. Interestingly, the notions of the involvement of the adaptive immune system in AMD have also gained support through recent findings in various neurodegenerative and chronic low-grade diseases, including multiple sclerosis, Parkinson's disease, or arteriosclerosis. In this group of pathologies, cells of the adaptive immune system bypass immune barriers and fuel inflammatory processes at immune-privileged sites. These findings have pointed at immunosenescence as a critical pro-inflammatory process involving T cell biology. Using a murine model relevant to the pathophysiology of geographic atrophy, we have demonstrated that specific populations of memory T cells are recruited to the retina prior to neurodegeneration. The investigation of these retinas at later degenerative stages revealed the presence of activated cytotoxic T cells at the injury site. These compelling results support the participation of the adaptive immune system in retina degeneration and highlight the potential of T cell populations as an early therapeutic target to slow the progression of AMD
Vitamin B12 levels association with functional and structural biomarkers of central nervous system injury in older adults
Get PDFOBJECTIVE: Vitamin B12 (B12) plays a critical role in fatty- and amino-acid metabolism and nucleotide synthesis. While the association between B12 deficiency and neurological dysfunction is well-known, the exact threshold for adequacy remains undefined in terms of functional impairment and evidence of injury. The objective was to assess whether B12 levels within the current normal range in a cohort of healthy older adults may be associated with measurable evidence of neurological injury or dysfunction. METHODS: We enrolled 231 healthy elderly volunteers (median age 71.2 years old) with a median B12 blood concentration of 414.8 pmol/L (as measured by automated chemiluminescence assay). We performed multifocal visual evoked potential testing, processing speed testing, and magnetic resonance imaging to assess neurological status. Moreover, we measured serum biomarkers of neuroaxonal injury, astrocyte involvement, and amyloid pathology. RESULTS: Low (log-transformed) B12, especially decreased holo-transcobalamin, was associated with visual evoked potential latency delay (estimate = -0.04; p = 0.023), processing speed impairment (in an age-dependent manner; standardized β = -2.39; p = 0.006), and larger volumes of white matter hyperintensities on MRI (β = -0.21; p = 0.039). Remarkably, high levels of holo-haptocorrin (biologically inactive fraction of B12) correlated with serum levels of Tau, a biomarker of neurodegeneration (β = 0.22, p = 0.015). INTERPRETATION: Healthy older subjects exhibit neurological changes at both ends of the measurable "normal" B12 spectrum. These findings challenge our current understanding of optimal serum B12 levels and suggest revisiting how we establish appropriate nutritional recommendations. ANN NEUROL 2025
Sex-specific association of myocardial fibrosis with mortality in patients with aortic stenosis
No full textIMPORTANCE: Myocardial fibrosis in aortic stenosis (AS) may exhibit sex differences. However, its prognostic significance in women with AS remains unclear. OBJECTIVE: To investigate sex differences in myocardial fibrosis assessed by cardiovascular magnetic resonance (CMR) and evaluate its prognostic value in women and men with AS. DESIGN, SETTING, AND PARTICIPANTS: Patients with severe AS who underwent CMR before aortic valve replacement (AVR) were prospectively enrolled from 13 international sites between March 2011 and September 2021. Myocardial fibrosis was evaluated using extracellular volume fraction (ECV%) and late gadolinium enhancement (LGE). The main analysis was conducted on patients without obstructive coronary artery disease (CAD), defined as those with no history of myocardial infarction and no concomitant coronary artery bypass grafting. Data were analyzed from December 2023 to February 2024. EXPOSURES: Surgical or transcatheter AVR. MAIN OUTCOMES AND MEASURES: The primary outcome was post–AVR all-cause mortality and the secondary outcome was cardiovascular mortality. RESULTS: Of 822 patients, 670 were without obstructive CAD (368 men [55%] and 302 women [45%]). Among these, women and men had a similar age (median, 72 years vs 71 years, respectively), comorbidities, and AS severity. ECV% was similar between sexes; however, women had less LGE (both infarct and noninfarct LGE). After a median follow-up of 3.7 (IQR, 2.1-4.7) years, there were 76 deaths (11.3%), including 29 adjudicated cardiovascular deaths, in patients without obstructive CAD. Increasing ECV% and LGE were associated with higher all-cause and cardiovascular mortality in both sexes. Cox analyses demonstrated that both ECV% and LGE were associated with higher all-cause mortality without significant interaction by sex (women: adjusted hazard ratio [HR], 1.08 per 1% ECV% increase; 95% CI, 1.04-1.12; P < .001; men: adjusted HR, 1.01; 95% CI, 0.96-1.06; P = .66; P for interaction by sex = .09 and women: adjusted HR, 2.49 for the presence of LGE; 95% CI, 1.07-5.80; P = .03; men: adjusted HR, 1.82; 95% CI, 1.00-3.32; P = .04; P for interaction by sex = .68). In the entire population (n = 822), both noninfarct and infarct-related LGE were associated with increased mortality without significant interaction by sex. CONCLUSIONS AND RELEVANCE: In this study, patients with severe AS who underwent AVR exhibited similar ECV% between sexes, while women had lower LGE. Increased myocardial fibrosis provided important prognostic value for both sexes
Teclistamab in relapsed systemic sclerosis after autologous haematopoietic stem cell transplantation
No full textAn interdisciplinary approach is necessary in the treatment of cognitive decline in MS: no
No full textPreclinical in vitro and in vivo evidence for targeting CD74 as an effective treatment strategy for cutaneous T-cell lymphomas
Get PDFBACKGROUND: Prognosis and quality of life in patients with advanced cutaneous T-cell lymphoma (CTCL), particularly in those with Sézary syndrome (SS) or advanced-stage mycosis fungoides (MF), are poor. Monoclonal antibodies or antibody–drug conjugates (ADCs) have been added into CTCL treatment algorithms, but the spectrum of antibody-targetable cell surface antigens in T-cell non-Hodgkin lymphomas (T-NHLs) is limited. OBJECTIVES: To evaluate the expression of the major histocompatibility complex class II chaperone CD74 in common subtypes of CTCL by various methods, and to explore the efficacy of targeting CD74 in CTCL cells with an anti-CD74 ADC in vitro and in vivo. METHODS: We comprehensively investigated the expression of CD74 in well-defined CTCL cell lines by polymerase chain reaction, immunoblotting and flow cytometry. More than 140 primary CTCL samples of all common subtypes were analysed by immunohistochemistry, flow cytometry, immunofluorescence and ‘co-detection by indexing’ (CODEX) multiplexed tissue imaging, as well as by single-cell RNA sequencing (scRNAseq) analyses. DNA methylation of CTCL cell lines was interrogated by the generation of genome-wide methylation profiling. The effect of a maytansinoid-conjugated humanized ADC against CD74 was investigated in CTCL cell lines in vitro, alone or in combination with gemcitabine, and in vivo after xenotransplantation of CTCL cell lines in NOD-scid Il2rg(null) mice. RESULTS: We demonstrated that CD74 is widely and robustly expressed in CTCL cells. In addition, CD74 expression in SS and MF was confirmed by scRNAseq data analysis and was correlated in CTCL cell lines with CD74 DNA hypomethylation. CD74 was rapidly internalized in CTCL cells and CD74 targeting by the ADC STRO-001 efficiently killed CTCL-derived cell lines. Finally, targeting of CD74 synergized with conventional chemotherapy in vitro and eradicated murine xenotransplants of CTCL cell lines in vivo. CONCLUSIONS: CD74 is expressed in common CTCL subtypes. Targeting CD74 efficiently killed CTCL cells in vitro and in vivo. We therefore suggest the targeting of CD74 to be a highly promising treatment strategy for CTCL
Assessing reliability and comparability of 4D flow CMR whole heart measurements using retrospective valve tracking: a single-vendor study in the Berlin Research Network
No full textINTRODUCTION: This study investigated intracardiac flow dynamics and assessed the comparability and reliability of 4D flow CMR measurements across multiple sites within the Berlin Research Network for Cardiovascular Magnetic Resonance (BER-CMR) using 3D cine phase-contrast imaging with three-directional velocity encoding in a healthy traveling cohort. METHODS: In a prospective multi-site cohort study, 20 healthy volunteers underwent CMR at different sites. Quantitative assessment of Forward flow Volume (FFV), Peak (PV) and Mean Velocity (MV) across the heart's valves were conducted using retrospective valve tracking. FFV of the aortic and pulmonary valves, measured via 4D flow CMR, was compared to each other and to Stroke Volume (SV) from cine imaging. Reliability was assessed using scan-rescan tolerance ranges from a single site, with equivalency assumed if other sites' confidence intervals fell within these ranges. Intra- and interobserver analyses evaluated measurement consistency. RESULTS: The final analysis included 19 healthy volunteers. Intersite comparability analysis across all four heart valves revealed a strong reliability for FFV, PV and MV, except for FFV at the mitral valve at two sites and PV at the tricuspid valve at one site. Correlation analysis of SV and FFV of the corresponding ventriculoarterial valves demonstrated good agreement (aortic valve: r = 0.89, P 0.90, p < 0.001). CONCLUSION: 4D flow CMR whole-heart measurements in healthy volunteers were consistent across sites, showing strong agreement despite physiological and technical variability. These findings support future multicenter studies
Third-trimester NT-proBNP for pre-eclampsia risk prediction: a comparison with sFlt-1/PlGF in a population-based cohort
Get PDFBACKGROUND: The association between lower first-trimester N-terminal pro B-type natriuretic peptide (NT-proBNP) levels and increased pre-eclampsia risk remains poorly understood, contrasting with the elevated NT-proBNP levels observed at the time of pre-eclampsia diagnosis. OBJECTIVES: The aim of this study was to assess the utility of third-trimester NT-proBNP for assessing pre-eclampsia risk before onset. METHODS: NT-proBNP and the soluble Fms-like tyrosine kinase 1 to placental growth factor ratio (sFlt-1/PlGF) were measured in 1,476 pregnant individuals from the Odense Child Cohort at a median gestational age of 29 weeks (Q1-Q3: 28.4-29.4). Pre-eclampsia cases were categorized by timing: 11 individuals (0.7%) developed pre-eclampsia within 4 weeks, while 110 (7.5%) developed pre-eclampsia more than 4 weeks after sampling. RESULTS: Higher NT-proBNP levels were significantly associated with increased risk of pre-eclampsia within 4 weeks but reduced risk beyond 4 weeks. After adjusting for age, body mass index, nulliparity, systolic blood pressure, and the sFlt-1/PlGF ratio, the adjusted OR was 2.18 (95% CI: 0.88-5.42, P = 0.09) for onset within 4 weeks and 0.72 (95% CI: 0.55-0.93, P = 0.012) for onset beyond 4 weeks. However, combining NT-proBNP with the sFlt-1/PlGF ratio did not improve the predictive accuracy for short- or long-term pre-eclampsia risk compared to the sFlt-1/PlGF ratio alone. CONCLUSIONS: Unselected NT-proBNP screening in the early third trimester has limited clinical value for predicting short- or long-term pre-eclampsia risk when compared to angiogenic biomarkers
Structural determinants of mucins in influenza virus inhibition: the role of sialylated glycans and molecular size
Get PDFMucins are heavily glycosylated proteins that play a crucial role in protecting mucosal surfaces against pathogens, including influenza viruses. This study investigates the antiviral properties of bovine submaxillary mucins (BSM) as a model for oral mucins against the influenza virus (A/H3N2 subtype), focusing on glycan composition and mucin size. BSM was purified, and characterized by proteomic and glycomic analysis and its antiviral efficacy was assessed after selective removal of sialic acids, N-glycans, or all glycans via enzymatic and chemical treatments. We employed virus binding and inhibition assays, including microscale thermophoresis (MST) and hemagglutination inhibition (HAI), to characterize processed mucins for structure activity correlations. Removal of sialic acids reduced BSM's antiviral activity by over 10-fold, while complete glycan removal abolished it entirely, highlighting sialylated O-glycans as critical for viral inhibition. N-glycan removal had minimal impact on antiviral efficacy. A size-dependent antiviral effect was observed: smaller mucin fragments (∼50 and 330 kDa), which retained comparable O-glycosylation patterns, showed significantly reduced inhibition and viral binding affinity several orders of magnitude below intact BSM. These findings underscore the importance of mucin size and sialylated O-glycans in antiviral defense mechanisms against influenza
State of the art and perspectives of gene therapy in heart failure. A scientific statement of the Heart Failure Association of the ESC, the ESC Council on Cardiovascular Genomics and the ESC Working Group on Myocardial & Pericardial Diseases
Get PDFGene therapy has recently become a reality in the treatment of cardiovascular diseases. Strategies to modulate gene expression using antisense oligonucleotides or small interfering RNA are proving to be safe and effective in the clinic. Adeno-associated viral vector-based gene delivery and CRISPR-Cas9-based genome editing have emerged as efficient strategies for gene delivery and repair in humans. Overall, gene therapy holds the promise not only of expanding current treatment options, but also of intervening in previously untackled causal disease mechanisms with little side effects. This scientific statement provides a comprehensive overview of the various modalities of gene therapy used to treat heart failure and some of its risk factors, and their application in the clinical setting. It discusses specifically the possibilities of gene therapy for hereditary heart diseases and (non)-genetic heart failure. Furthermore, it addresses safety and clinical trial design issues and challenges for future regulatory strategies