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A comprehensive framework for the interpretation of TTN missense variants
No full textBACKGROUND: Missense variants in TTN pose a major challenge in genetic diagnostics due to their high frequency in the general population, the large size of the gene, and the complex multidomain architecture of the titin protein. While the contribution of truncating variants (TTNtv) to titinopathies is well established, the role of rare TTN missense variants remains poorly defined. Advances in computational prediction and functional testing offer new tools to assess their potential pathogenicity, which however are currently not fully utilized for clinical application.METHODS: We analyzed an international cohort of unsolved myopathy cases selected based on the presence of a rare missense variant in trans with a TTNtv. Clinical data were collected from neuromuscular centers worldwide. In silico predictions were generated using AlphaMissense and complemented by minor allele frequency (MAF) and exon usage information. Additional inclusion criteria were based on a MAF < 0.010 and an AlphaMissense score ≥ 0.792 for the missense variants, in accordance with the latest ClinGen guidelines. Selected missense variants were characterized in vitro through protein expression and cell imaging assays to assess their effects on domain solubility and aggregation.RESULTS: Thirty patients with TTNtv/missense combinations were identified, presenting with heterogeneous myopathic phenotypes, ranging from congenital to adult onset. An in-depth analysis on AlphaMissense predictions highlighted those changes most frequently predicted as possibly pathogenic. Functional assays showed that three selected variants with changes to proline, located in β-sheets of Ig domains, led to impaired folding, cytoplasmic aggregation and co-localisation with proteostasis markers. In our cohort, all non-proline mutations occurred at buried sites, while some proline substitutions affected exposed residues. Notably, the variant p.(Gln7023Pro) was identified in 5 unrelated families sharing a conserved haplotype, indicating a common ancestor. This variant and the previously reported p.(Arg25480Pro) now meet ACMG criteria for classification as likely pathogenic.CONCLUSIONS: By integrating clinical, computational, and functional evidence, we propose a framework for interpreting TTN missense variants. Combining multiple lines of evidence is essential for variants' classification and interpretation, especially given TTN complexity. Advancing diagnostic accuracy will require tailored interpretation guidelines and a global effort in data sharing and functional validation.</p
Religious Freedom and Principled Pragmatism:An Augustinian Reading of Finland’s Church-State Settlement
Get PDFThis article offers a theological commentary on religious freedom in Finland through an Augustinian reading of two developments in its contemporary church–state settlement: the Act on the Freedom of Religion (453/2003) and Prosecutor General v. Räsänen (KKO: R2024/57), the so-called Bible-Tweet Case. Together these developments illuminate how a constitutional order understands religion both as a historically embedded institutional reality and as a contested object of civil authority. Responding to the relative absence of sustained theology of law in Finnish church–state scholarship, the article articulates a form of Augustinian pragmatism distilled from Augustine’s mature reflections, especially The City of God and his anti-Donatist letters. This approach foregrounds ordered loves, earthly peace, constrained civil authority, and historical realism as principles for constitutional judgment. Read in this light, the Freedom of Religion Act appears as a constructive instance of such pragmatism, preserving the historically formative role of the Evangelical Lutheran and Orthodox Churches while widening legal recognition and safeguarding freedom of conscience under plural conditions. By contrast, the Bible-Tweet prosecution reveals the strain placed on religious freedom when criminal law is drawn toward adjudicating theological speech. An Augustinian account of limited civil jurisdiction cautions against extending penal authority into the governance of belief while affirming the state’s responsibility to secure civic peace and protect vulnerable groups. The result is not a fixed constitutional template but a disciplined mode of theological reasoning for pluralistic societies
Phase I trial of ADP-A2AFP TCR T-cell therapy in patients with advanced hepatocellular or gastric hepatoid carcinoma
Get PDFBackground & Aims Patients with advanced hepatocellular carcinoma (HCC) generally experience poor outcomes despite current therapies, necessitating the development of alternative treatments. ADP-A2AFP is an investigational autologous T-cell therapy with an affinity-enhanced T-cell receptor (TCR) targeting alpha-fetoprotein (AFP). Methods We describe a phase I, open-label, first-in-human clinical trial of ADP-A2AFP (NCT03132792) in human leukocyte antigen–eligible participants with AFP-expressing HCC (or other tumor) not amenable to transplant/resection who progressed on, were intolerant to, or refused prior systemic therapy. Participants received lymphodepletion chemotherapy (cyclophosphamide 500 mg/m2/day for 3 days and fludarabine 20 mg/m2/day for 3 days, or cyclophosphamide 600 mg/m2/day for 3 days and fludarabine 30 mg/m2/day for 4 days) followed by ADP-A2AFP intravenous infusion. Safety evaluation was the primary objective; response per RECIST v1.1 was the key secondary endpoint. Results Twenty-one participants, 20 with advanced HCC and one with gastric hepatoid carcinoma received ≥1 ADP-A2AFP infusion. All participants experienced ≥1 grade 3 or higher adverse event; 52.4% experienced ≥1 grade 3 or higher event considered related to ADP-A2AFP treatment. Six participants experienced cytokine release syndrome (grade 1–2: n = 5; grade 4: n = 1). Best overall responses were complete response (n = 1), partial response (n = 1), and stable disease (n = 12); overall response rate was 9.5%. Eight patients had a stable disease duration of ≥16 weeks. Infiltration of ADP-A2AFP TCR and CD8+ T cells was seen in AFP-positive areas of post-treatment tumor samples. A relationship was demonstrated between increased ADP-A2AFP dose and serum AFP reduction in responders. Conclusions Lymphodepletion chemotherapy followed by ADP-A2AFP TCR T-cell therapy showed a manageable safety profile and preliminary indications of antitumor activity in these previously treated patients. Impact and implications Adoptive T-cell therapy could be a much-needed additional treatment strategy for advanced hepatocellular carcinoma. Clinicians and researchers interested in the development of adoptive T-cell therapies for advanced solid tumors will be interested to learn that in this phase I trial, ADP-A2AFP T-cell receptor T-cell therapy was associated with an acceptable benefit-to-risk profile and encouraging antitumor activity, illustrating the treatment potential of adoptive T-cell therapy for advanced hepatocellular carcinoma. Clinicaltrials.gov Number NCT03132792; first posted 2017-04-08.</p
Trade-Offs in the International Legal Regime:The case of the Pandemic Agreement
Get PDFCOVID-19 starkly exposed the systemic frailties of global health governance, particularly concerning the functioning and utility of the International Health Regulations (IHR). Multiple independent reviews declared that the existing framework was designed to constrain rapid global action, and recommended concrete transformational reforms for the global health legal regime.1 Most notably they recommended the negotiation of a new instrument to govern future pandemic prevention, preparedness, and response (PPPR). The appetite for a new instrument was cemented by a statement of support from twenty-six other world leaders and the director-general of World Health Organization (WHO).2 From the start, there was a lack of clear unified vision for what a new treaty ought to achieve. This ideological rift generally fell along the North–South divide, something that continued throughout the negotiations of the treaty. Low- and middle-income countries (LMICs), suffering from the stark inequalities in vaccine access during the COVID-19 pandemic demanded embedding equitable distribution of life-saving health products into legally binding commitments. Meanwhile high-income countries (HICs) sought greater prevention and surveillance activities, determined to prevent spillover events from occurring and spreading in the first place
Location-Dependent Differences in Cardiac and Skeletal Muscle Dysfunction Associated With Truncating Titin (<i>ttn.2</i>) Variants
Get PDFBACKGROUND: Truncating variants in the TTN gene (TTNtv), encoding the giant sarcomeric protein titin, cause a range of human cardiac and skeletal muscle disorders of varying penetrance and severity. The effects of variant location on clinical manifestations are incompletely understood. METHODS: We generated 6 zebrafish lines carrying truncating ttn.2 variants in the Z-disk, I-band, A-band, and M-band titin regions. Expression of titin transcripts and protein levels was evaluated using quantitative polymerase chain reaction and proteomics. Phenotype analysis was performed during embryonic development and in adult hearts. RESULTS: Homozygous embryos from all lines except the C-terminal line, e232, showed a significant reduction of Z-disk and I-band ttn.2 transcripts, but A-band and M-band transcript levels were reduced only in lines with truncations distal to the cronos promoter. These homozygous embryos uniformly died by 7 to 10 days postfertilization with marked impairment of cardiac morphology and function. Skeletal muscle motility and sarcomere organization were more disrupted in mutants with truncations distal to the cronos promoter compared with those proximal. In contrast, homozygous e232 embryos, which lacked only the titin kinase and M-band regions, had relatively preserved cardiac function with incorporation of truncated Ttn.2/Cronos protein and normal sarcomere assembly, but selective degradation of fast skeletal muscle sarcomeres. All heterozygous embryos were phenotypically indistinguishable from wild type. High-frequency echocardiography in adult heterozygous fish showed reduced ventricular contraction under resting conditions in A-band mutants. Heterozygous Z-disk and I-band mutants had no significant baseline impairment but were unable to augment ventricular contraction in response to acute adrenaline exposure, indicating a lack of cardiac reserve. CONCLUSIONS: Our data suggest that cardiac and skeletal muscle dysfunction associated with truncating ttn.2 variants is influenced by age, variant location, and the amount of functional titin protein. The distinctive phenotype associated with distal C-terminal truncations may reflect different requirements for C-terminal titin for maintenance of fast, slow, and cardiac muscle sarcomeres.</p
Legal Mobilisation in EU Foreign Policy vis-à-vis Occupation:A Comparison of Israel/Palestine and Morocco/Western Sahara
Get PDFHow does the use of law by non-state actors (NSAs) influence EU foreign policy? A comparative analysis of the cases of Israel/Palestine and Morocco/Western Sahara demonstrates that legal mobilisation by non-state actors has had divergent impacts on EU foreign policy. On the one hand, legal mobilisation led to long-term effects in the case of EU foreign policy towards Israel/Palestine: through lobbying based on legal framing, NSAs contributed to the reframing of EU-Israel relations, leading to the exclusion of the occupied Palestinian territories from the scope of EU-Israel agreements. On the other hand, litigation in the case of Morocco/Western Sahara had a short-term impact by annulling EU-Morocco agreements due to their extension to Western Sahara without the consent of the Sahrawi people. However, this did not result in a change in the overall understanding of EU-Morocco relations, as reflected in renewed attempts to include Western Sahara under EU-Morocco agreements and in the increasing number of member states recognising Morocco’s Autonomy Plan for – and in some cases sovereignty over – Western Sahara as the most viable option. This comparison shows that mobilising law can be a powerful tool for NSAs to influence EU foreign policy, but this requires skilful entrepreneurs able to apply legal principles to concrete facts, as well as a favourable context, to ensure that when legal inconsistencies are highlighted, the EU is capable of engaging in a reframing process to correct them
A Jagged1-regulated hybrid-EMT state identifies pancreatic cancer stem cells
Get PDFPancreatic ductal adenocarcinoma (PDAC) shows great cellular heterogeneity, with pronounced epithelial and mesenchymal cancer cell populations. We previously identified a PDAC subpopulation, marked by the tetraspanin CD9, which is capable of initiating PDAC and giving rise to PDAC heterogeneity. Here, we characterize a subset of CD9-high (CD9hi) tumor-initiating cells (TICs) with hybrid epithelial-mesenchymal transition (EMT) features, which show increased cancer stem cell properties, as evidenced by increased capacity to form organoids and generate epithelial and mesenchymal tumor cell progeny. Depletion of hybrid-EMT CD9hi cells leads to a gradual collapse of organoid formation and tumorigenic capability, suggesting that CD9hi TICs are required for long-term organoid formation and tumorigenicity. Hybrid- EMT CD9hi TICs upregulate the Notch ligand Jagged1, and Jag1 depletion or Notch inhibition impairs TIC self-renewal and PDAC cell differentiation. Conversely, Jag1 overexpression augments TIC self- renewal. Thus, Jagged1-mediated Notch signaling controls a hybrid-EMT state that is a defining feature of TICs in PDAC
Integrated mechanical and structural characterisation of 24 commercial hyaluronic acid fillers: A multi-parametric framework for comparative analysis
No full textThe clinical performance of hyaluronic acid (HA) dermal fillers depends on their mechanical and structural characteristics, as well as their susceptibility to enzyme degradation (hyaluronidase), yet current evaluations often rely on single-point measures. This study examined twenty-four commercial HA fillers under injection-relevant conditions, combining oscillatory shear rheology, enzymatic degradation assays, and uniaxial tensile testing to develop an integrated assessment framework. Their structure at the nanoscale was also examined with small-angle X-ray scattering. The findings indicate that nonlinear rheological metrics, combined with tensile and enzymatic degradation profiles, provide a more comprehensive understanding of filler behaviour than conventional oscillatory shear moduli alone. This multi-parametric approach may support evidence-based product selection, enabling better matching of filler properties to anatomical site requirements, mobility demands, reabsorbability and biodegradability needs in clinical practice.</p
Prevention and treatment of thrombosis in patients with decompensated cirrhosis
No full textPatients with decompensated cirrhosis commonly have indications for anticoagulation, including stroke prevention in atrial fibrillation and the prevention and treatment of venous thromboembolism, particularly portal vein thrombosis. While the rates of anticoagulation in those with indications for therapy have improved over time, the concern for bleeding due to altered hepatic elimination of anticoagulants and exclusion of patients with cirrhosis from pivotal randomized trials of direct oral anticoagulants and warfarin continue to create challenges in defining best practices for anticoagulation in patients with cirrhosis, especially in decompensated disease. In this review, we present 3 commonly encountered clinical scenarios in patients with decompensated cirrhosis requiring consideration of anticoagulation: a patient with atrial fibrillation and elevated baseline international normalized ratio, a patient with atrial fibrillation and recurrent bleeding while on anticoagulation, and a patient with portal vein thrombosis and thrombocytopenia. For each scenario, we discuss the available literature and propose a management approach.</p
Gender-specific economic interventions for women’s mental health and well-being in South Asia:a systematic review
Get PDFBackgroundThe prevalence of common mental disorders (CMDs) in South Asia is higher among women than men. Reasons include lower socioeconomic status and greater exposure to social, economic and environmental disadvantage. Economic determinants are important, modifiable risk factors for CMDs.AimsThis systematic review aimed to evaluate the evidence for impacts of economic interventions on women’s well-being and CMD outcomes in South Asia.MethodWe searched for peer-reviewed quantitative research studies in eight databases (3ie, EconLit, Embase Classic, Embase, Global Health, J-PAL, Medline, APA PsychInfo, Scopus) and studies included in relevant systematic reviews of economic interventions which measured CMDs and well-beingamong female participants in South Asia. We assessed the risk of bias of included studies using the Joanna Briggs Institute checklist. Following data extraction, we synthesised our findings through narrative synthesis.ResultsWe identified eight eligible studies evaluating five types of economic intervention: microfinance, employment, conditional cash transfers, self-help groups (SHGs) and economic empowerment programmes. Studies were conducted in Afghanistan (n = 1), Bangladesh (n = 2) and India (n = 5). Approximately 60% of studies reported statistically significant associations between receipt of economic interventions and improved CMD symptoms or well-being among female participants. Risk of bias was moderate and study designs were heterogeneous. Attention to gendered risks of economic interventions in countries with strong patriarchal norms was limited.ConclusionThe limited published evidence suggests that economic interventions can have positive impacts on CMDs and well-being among women in South Asia. However, methodological limitations and lack of geographical representation mean that further research is needed to evaluate the risks and benefits of economic interventions for diverse women in South Asia