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We have identified WISPER , a cardiac fibroblast-specific lncRNA overexpressed in human cardiovascular diseases, including hypertrophic cardiomyopathy (HCM), and shown to promote transcriptional activation of the myofibroblast cell-state, resulting in pathological fibrosis in preclinical models. High WISPER expression driving excessive interstitial fibrosis is thought to highly contribute to the underlying pathophysiology of HCM, especially in non-obstructive HCM (nHCM). In turn, interstitial and replacement fibrosis are known to lead to worse outcomes, including diastolic dysfunction, arrythmias, heart failure and death. HTX-001 is a synthetic antisense oligonucleotide (ASO) which was developed to suppress WISPER RNA expression, produce a reduction in myocardial fibrosis, reverse existing cardiac interstitial fibrosis, and bring an effective and targeted anti-fibrotic therapy to patients with HCM. Prior work in heart failure with preserved ejection fraction demonstrates that small reductions in myocardial fibrosis are associated with reductions in natriuretic peptide levels, indicating decreased wall stress and the expanded interstitial space, which can result in improved outcomes. WISPER expression was validated in patient datasets. In vivo efficacy studies using ASOs targeting Wisper were performed in mouse myocardial infarction (MI) and transaortic constriction models (references in Figure) and in the Göttingen minipig post-MI model (data to be presented). Study readouts included histology, echocardiography and transcriptomics analysis. We show that HTX-001 treatment in preclinical animal models of pathological cardiac remodelling reduces cardiac fibrosis and improves heart function. Multi-omics analysis demonstrates WISPER -mediated control of extracellular matrix levels, pro-fibrotic and pro-inflammatory gene expression, resulting in a switch in cardiac tissue metabolism from healthy fatty acid metabolism to glycolytic metabolism. Pharmacokinetic and pharmacodynamic analyses indicate suitable drug-like characteristics of HTX-001, including target engagement in cardiac tissue that is also measurable using WISPER mechanism of action-related biomarkers in plasma or serum. Overall, preclinical data suggest that HTX-001 is expected to be efficacious as a single agent with a unique mechanism of action that is non-overlapping with other currently available or investigational agents for HCM. We intend to develop HTX-001 for nHCM as the first indication given the burden of disease and lack of suitable and effective therapies. Clinical trials are expected to commence in 2025. [ABSTRACT FROM AUTHOR]

Sexual violence represents a widespread social problem associated with serious lifelong consequences. In many cases, an outcome of sexual violence is the victim's unwanted pregnancy, usually ended in an abortion. The objective of this paper is to report five rape cases, including rapes of a minor and young woman, two incest cases and a case of human trafficking for sexual exploitation, where every case resulted in the victim's pregnancy. In each case, pregnancy was terminated in the first trimester or at the beginning of the second trimester in the relevant medical center or clinic. Fresh fetal blood or aborted tissue samples were delivered to our laboratory in order to perform paternity testing for the purpose of proving the crime. DNA extraction using Qiagen Dneasy™ Tissue Kit was optimized according to the sample type. Amplification of autosomal STR (Short Tandem Repeat) markers was performed using the PowerPlex®16 System. In two cases, mixtures of maternal and fetal DNA in the aborted fetal material were found. Using the LRmix Studio v.2.1.5 Software for interpreting DNA mixtures based on a probabilistic model, the likelihoods of maternal contribution and presence of fetal allelic variants inherited from the alleged father/suspect were calculated. Based on these results, we confirmed the presence of assumed fetal fractions (determined before software analysis) in the mixtures. In all cases, positive paternity proved the crime (probabilities of paternity >99.9999%). This cases report once again pointed out the importance of DNA analysis in the process of clarifying and solving forensic cases and demonstrated that the LRmix Studio v.2.1.5 Software can deal with complex cases such as sexual assaults. • We report on five forensic cases of sexual assault resulting in the victim's pregnancy followed by an abortion. • Mixtures of maternal and fetal DNAs in fetal material required special statistical analysis and interpretation of results. • STR (Short Tandem Repeat) typing successfully resolved all cases of sexual assault. • LRmix Studio v.2.1.5 Software can deal with complex forensic cases. [ABSTRACT FROM AUTHOR]