An Evaluation of Rare Cancer Policies in Europe: A Survey Among Healthcare Providers.

Rare cancers, defined as those with an annual incidence of fewer than six cases per 100,000 individuals, are associated with significant health inequalities. This study aimed to assess the knowledge, attitudes, and perceptions of healthcare providers with expertise in rare cancers regarding the effectiveness of enacted or planned rare cancer policies across Europe. Between 25 March 2023 and 5 March 2024, we conducted an online survey targeting 738 healthcare providers affiliated with the European Reference Networks and the Organization of European Cancer Institutes, yielding 92 complete responses from 28 European countries (response rate: 12.

Mosaicism and intronic variants in RB1 gene revealed by next generation sequencing in a cohort of Spanish retinoblastoma patients.

Constitutional variants in the RB1 gene predispose individuals to the development of Retinoblastoma (RB) and the occurrence of second tumors in adulthood. Detection of causal RB1 gene variants is essential to establish the genetic diagnosis and to performing familial studies and counseling. In our cohort of 579 Spanish RB patients, 15% of cases suspected to have a genetic origin remained negative after traditional Sanger sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA) of RB1 gene, likely due to the possibility of mosaicism or non-coding variants.

Gene editing without ex vivo culture evades genotoxicity in human hematopoietic stem cells.

Gene editing the BCL11A erythroid enhancer is a validated approach to fetal hemoglobin (HbF) induction for β-hemoglobinopathy therapy, though heterogeneity in edit allele distribution and HbF response may impact its safety and efficacy. Here, we compare combined CRISPR-Cas9 editing of the BCL11A +58 and +55 enhancers with leading gene modification approaches under clinical investigation. Dual targeting of the BCL11A +58 and +55 enhancers with 3xNLS-SpCas9 and two single guide RNAs (sgRNAs) resulted in superior HbF induction, including in sickle cell disease (SCD) patient xenografts, attributable to simultaneous disruption of core half E-box/GATA motifs at both enhancers.

BCL11A +58/+55 enhancer-editing facilitates HSPC engraftment and HbF induction in rhesus macaques conditioned with a CD45 antibody-drug conjugate.

Editing the +58 region of the BCL11A erythroid enhancer has shown promise in treating β-globin disorders. To address variations in fetal hemoglobin (HbF) response, we investigated editing both +58 and +55 enhancers. Rhesus macaques transplanted with edited hematopoietic stem/progenitor cells (HSPCs) following busulfan conditioning exhibited durable, high-level (∼90%) editing frequencies post transplantation with sustained HbF reactivation over 4 years, without hematological perturbations.

piRNA Defense Against Endogenous Retroviruses.

Infection by retroviruses and the mobilization of transposable elements cause DNA damage that can be catastrophic for a cell. If the cell survives, the mutations generated by retrotransposition may confer a selective advantage, although, more commonly, the effect of new integrants is neutral or detrimental. If retrotransposition occurs in gametes or in the early embryo, it introduces genetic modifications that can be transmitted to the progeny and may become fixed in the germline of that species.

as a Model for Human Disease: Insights into Rare and Ultra-Rare Diseases.

Rare and ultra-rare diseases constitute a significant medical challenge due to their low prevalence and the limited understanding of their origin and underlying mechanisms. These disorders often exhibit phenotypic diversity and molecular complexity that represent a challenge to biomedical research. There are more than 6000 different rare diseases that affect nearly 300 million people worldwide.

Rational Design of Enhanced Nme2Cas9 and Nme2Cas9 Nucleases and Base Editors.

CRISPR-Cas genome editing tools enable precise, RNA-guided modification of genomes within living cells. The most clinically advanced genome editors are Cas9 nucleases, but many nuclease technologies provide only limited control over genome editing outcomes. Adenine base editors (ABEs) and cytosine base editors (CBEs) enable precise and efficient nucleotide conversions of A:T-to-G:C and C:G-to-T:A base pairs, respectively.

Biallelic PIGM Coding Variant Causes Intractable Epilepsy and Intellectual Disability Without Thrombotic Events.

During the past two decades, an emerging group of genes coding for proteins involved in glycosylphosphatidylinositol (GPI) anchor biosynthesis are being implicated in early-infantile epileptic encephalopathy. Amongst these, a hypomorphic promoter mutation in the mannosyltransferase-encoding PIGM gene was described in seven patients to date, exhibiting intractable absence epilepsy, portal and cerebral vein thrombosis and intellectual disability (ID). We describe here three siblings exhibiting intractable epilepsy and ID, found to harbor a homozygous c.

Sensors in Bone: Technologies, Applications, and Future Directions.

Osteoporosis, a prevalent ailment worldwide, compromises bone strength and resilience, particularly afflicting the elderly population. This condition significantly heightens susceptibility to fractures even from trivial incidents, such as minor falls or impacts. A major challenge in diagnosing osteoporosis is the absence of discernible symptoms, allowing osteoporosis to remain undetected until the occurrence of a fracture event.

The G4 resolvase Dhx36 modulates cardiomyocyte differentiation and ventricular conduction system development.

Extensive genetic studies have elucidated cardiomyocyte differentiation and associated gene networks using single-cell RNA-seq, yet the intricate transcriptional mechanisms governing cardiac conduction system (CCS) development and working cardiomyocyte differentiation remain largely unexplored. Here we show that mice deleted for Dhx36 (encoding the Dhx36 helicase) in the embryonic or neonatal heart develop overt dilated cardiomyopathy, surface ECG alterations related to cardiac impulse propagation, and (in the embryonic heart) a lack of a ventricular conduction system (VCS). Heart snRNA-seq and snATAC-seq reveal the role of Dhx36 in CCS development and in the differentiation of working cardiomyocytes.

The importance of genetic counselling for turner syndrome transition.

The healthcare transition (HCT) is the process of planning, monitoring, and adjusting the clinical management from children's care to adult specialists. Although this practice is common for all children, it is especially crucial (and challenging) for those with chronic disorders and genetic conditions that also involve mental health issues, requiring a multidisciplinary approach. In this review, we aim to assess the current status of transition for girls and young women with Turner syndrome (TS) as a model as it is one of the most common sexual chromosomal aneuploidies.

Loss-of-function in RBBP5 results in a syndromic neurodevelopmental disorder associated with microcephaly.

Purpose: Epigenetic dysregulation has been associated with many inherited disorders. RBBP5 (HGNC:9888) encodes a core member of the protein complex that methylates histone 3 lysine-4 and has not been implicated in human disease.

Methods: We identify 5 unrelated individuals with de novo heterozygous variants in RBBP5.

PRC1.6 localizes on chromatin with the human silencing hub (HUSH) complex for promoter-specific silencing.

An obligate step in the life cycle of HIV-1 and other retroviruses is the establishment of the provirus in target cell chromosomes. Transcriptional regulation of proviruses is complex, and understanding the mechanisms underlying this regulation has ramifications for fundamental biology, human health, and gene therapy implementation. The three core components of the Human Silencing Hub (HUSH) complex, TASOR, MPHOSPH8 (MPP8), and PPHLN1 (Periphilin 1), were identified in forward genetic screens for host genes that repress provirus expression.

Engineering a targeted and safe bone anabolic gene therapy to treat osteoporosis in alveolar bone loss.

Alveolar bone loss in elderly populations is highly prevalent and increases the risk of tooth loss, gum disease susceptibility, and facial deformity. Unfortunately, there are very limited treatment options available. Here, we developed a bone-targeted gene therapy that reverses alveolar bone loss in patients with osteoporosis by targeting the adaptor protein Schnurri-3 (SHN3).

Nucleic acid aptamers protect against lead (Pb(II)) toxicity.

Lead (Pb(II)) is a pervasive heavy metal toxin with many well-established negative effects on human health. Lead toxicity arises from cumulative, repeated environmental exposures. Thus, prophylactic strategies to protect against the bioaccumulation of lead could reduce lead-associated human pathologies.

Family Planning and Preconception Care Service Management: The Key Role of Bulgarian GPs.

Assisting women in attaining their reproductive goals is crucial for improving the well-being of families and children. As the first point of contact for healthcare, general practitioners (GPs) are ideal for family planning (FP) and preconception care (PCC). However, primary care interventions' efficacy is unclear.

AAV9-Mediated Intrastriatal Delivery of Reduces Hyperlocomotion in Heterozygous R209H Mutant Mice.

Mutations in the gene, which encodes the abundant brain G-protein G , result in neurologic disorders characterized by developmental delay, epilepsy, and movement abnormalities. There are over 50 mutant alleles associated with disorders; the R209H mutation results in dystonia, choreoathetosis, and developmental delay without seizures. Mice heterozygous for the human mutant allele ( ) exhibit hyperactivity in open field tests but no seizures.

AAV5 Delivery of CRISPR/Cas9 Mediates Genome Editing in the Lungs of Young Rhesus Monkeys.

Genome editing has the potential to treat genetic diseases in a variety of tissues, including the lung. We have previously developed and validated a dual adeno-associated virus (AAV) CRISPR platform that supports effective editing in the airways of mice. To validate this delivery vehicle in a large animal model, we have shown that intratracheal instillation of CRISPR/Cas9 in AAV5 can edit a housekeeping gene or a disease-related gene in the lungs of young rhesus monkeys.

Getting your DUCs in a row - standardising the representation of Digital Use Conditions.

Improving patient care and advancing scientific discovery requires responsible sharing of research data, healthcare records, biosamples, and biomedical resources that must also respect applicable use conditions. Defining a standard to structure and manage these use conditions is a complex and challenging task. This is exemplified by a near unlimited range of asset types, a high variability of applicable conditions, and differing applications at the individual or collective level.

Common conditions of use elements. Atomic concepts for consistent and effective information governance.

Myriad policy, ethical and legal considerations underpin the sharing of biological resources, implying the need for standardised and yet flexible ways to digitally represent diverse 'use conditions'. We report a core lexicon of terms that are atomic, non-directional 'concepts of use', called Common Conditions of use Elements. This work engaged biobanks and registries relevant to the European Joint Programme for Rare Diseases and aimed to produce a lexicon that would have generalised utility.