DNA-binding affinity and specificity determine the phenotypic diversity in BCL11B-related disorders.

BCL11B is a Cys2-His2 zinc-finger (C2H2-ZnF) domain-containing, DNA-binding, transcription factor with established roles in the development of various organs and tissues, primarily the immune and nervous systems. BCL11B germline variants have been associated with a variety of developmental syndromes. However, genotype-phenotype correlations along with pathophysiologic mechanisms of selected variants mostly remain elusive.

NECTIN-4 PET FOR OPTIMIZING ENFORTUMAB VEDOTIN DOSE-RESPONSE IN UROTHELIAL CARCINOMA.

The optimization of dosing strategies is critical for maximizing efficacy and minimizing toxicity in drug development, particularly for drugs with narrow therapeutic windows such as antibody-drug conjugates (ADCs). This study demonstrates the utility of Nectin-4-targeted positron emission tomography (PET) imaging using [Ga]AJ647 as a non-invasive tool for real-time assessment of target engagement in enfortumab vedotin (EV) therapy for urothelial carcinoma (UC). By leveraging the specificity of [Ga]AJ647 for Nectin-4, we quantified dynamic changes in target engagement across preclinical models and established its correlation with therapeutic outcomes.

Trabecular meshwork ultrastructural changes in primary and secondary glaucoma.

To examine ultrastructural changes in the trabecular meshwork (TM) in patients with primary and secondary glaucoma using scanning electron microscopy (SEM). This was a qualitative descriptive hospital-based study on the ultrastructure of the TM. Pure TM samples were collected after microincisional trabeculectomy from 26 patients with primary or secondary glaucoma and 10 control samples from eye bank donor corneas.

Higher order interaction analysis quantifies coordination in the epigenome revealing novel biological relationships in Kabuki syndrome.

Complex direct and indirect relationships between multiple variables, termed higher order interactions (HOIs), are characteristics of all natural systems. Traditional differential and network analyses fail to account for the omic datasets richness and miss HOIs. We investigated peripheral blood DNA methylation data from Kabuki syndrome type 1 (KS1) and control individuals, identified 2,002 differentially methylated points (DMPs), and inferred 17 differentially methylated regions, which represent only 189 DMPs.

Bi-allelic variants in DAP3 result in reduced assembly of the mitoribosomal small subunit with altered apoptosis and a Perrault-syndrome-spectrum phenotype.

The mitochondrial ribosome (mitoribosome) synthesizes 13 protein subunits of the oxidative phosphorylation system encoded by the mitochondrial genome. The mitoribosome is composed of 12S rRNA, 16S rRNA, and 82 mitoribosomal proteins encoded by nuclear genes. To date, variants in 12 genes encoding mitoribosomal proteins are associated with rare monogenic disorders and frequently show combined oxidative phosphorylation deficiency.

Clinical and genetic characterization of a progressive RBL2-associated neurodevelopmental disorder.

Retinoblastoma (RB) proteins are highly conserved transcriptional regulators that play important roles during development by regulating cell-cycle gene expression. RBL2 dysfunction has been linked to a severe neurodevelopmental disorder. However, to date, clinical features have only been described in six individuals carrying five biallelic predicted loss of function (pLOF) variants.

Patient-reported outcomes and measures are under-utilised in advanced therapy medicinal products trials for orphan conditions.

Objectives: Advanced therapy medicinal products (ATMPs) are medicines based on genes, tissues, or cells and can include gene therapy, somatic-cell therapy, and tissue-engineered medicines. Patient-reported outcomes (PROs) are reports on health and well-being that come directly from the individual without external interpretation. Patient-reported outcome measures (PROMs) are questionnaires aimed at assessing the individual and subjective experience with health and other psychosocial aspects.

Loss of DOT1L function disrupts neuronal transcription, animal behavior, and leads to a novel neurodevelopmental disorder.

Individuals with monoallelic pathogenic variants in the histone lysine methyltransferase DOT1L display global developmental delay and varying congenital anomalies. However, the impact of monoallelic loss of remains unclear. Here, we present a largely female cohort of 11 individuals with variants with developmental delays and dysmorphic facial features.

Long-term functional outcomes of BIFOLD osteosynthesis in distal femoral fractures with metaphyseal comminution: A retrospective analysis.

Background: This retrospective study aimed to evaluate the long-term functional outcomes of BIFOLD osteosynthesis, employing retrograde nailing and distal femoral locked plating, in patients with distal femoral fractures and metaphyseal comminution.

Methods: A retrospective analysis was conducted on patients treated for distal femur fractures with metaphyseal comminution between 2012 and 2022, with a minimum follow-up of 2 years. Inclusion criteria encompassed distal femur fractures with metaphyseal comminution, excluding specific conditions.

Ultrastructural polymicrobial interactions and antimicrobial resistance in cornea model.

To investigate antagonistic interactions among pathogens, in donor corneas infected with monomicrobial or polymicrobial combinations of antibiotic susceptible and resistant clinical isolates of (MSSA, MRSA) and (S-PA, MDR-PA). Scanning electron microscopy and antimicrobial susceptibility testing (AST, broth microdilution for minimum inhibitory and bactericidal concentrations [MIC/MBC]) pre-and post-polymicrobial interactions, in infected donor corneas. MSSA lost viability with S-PA/MDR-PA, while MRSA formed larger cells, biofilm and lower MIC (teicoplanin) with S-PA, but lost viability with MDR-PA.

Comparative evaluation between guided endodontics and conventional techniques for calcific metamorphosis - A systematic review and meta-analysis.

The aim of the study was to review and determine whether guided endodontic treatment or conventional technique is a better treatment alternative for patients with calcific metamorphosis. The review was done according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement (PRISMA) guidelines. Databases were searched from 2000 to December 2022 for studies reporting the treatment of calcific metamorphosis through guided endodontic treatment or conventional technique.

Biallelic variants in result in reduced assembly of the mitoribosomal small subunit with altered intrinsic and extrinsic apoptosis and a Perrault syndrome-spectrum phenotype.

The mitoribosome synthesizes 13 protein subunits of the oxidative phosphorylation system encoded by the mitochondrial genome. The mitoribosome is composed of 12S rRNA, 16S rRNA and 82 mitoribosomal proteins encoded by nuclear genes. To date, variants in 12 genes encoding mitoribosomal proteins are associated with rare monogenic disorders, and frequently show combined oxidative phosphorylation deficiency.

Platelet-Rich Fibrin: A Self-Derived Biomaterial for Surgical Treatment of a Periapical Lesion.

This case report explores the application of platelet-rich fibrin (PRF) as an autologous biomaterial in the surgical management of a periapical cyst in an 18-year-old female patient. The patient presented with pain, discoloration, and swelling in the maxillary left central incisor region, indicative of an asymptomatic periapical lesion associated with a history of trauma. Despite initial endodontic treatment with calcium hydroxide, the lesion persisted, necessitating surgical intervention.

Radiosynthesis of [F]brequinar for PET imaging of hDHODH for potential studies of acute myeloid leukemia and cancers.

Dihydroorotate dehydrogenase (DHODH), an enzyme that plays a critical role in the pyrimidine biosynthesis, has been recognized as a promising target for the treatment of diseases that involve cellular proliferation, such as autoimmune diseases and cancers. Pharmacological inhibition of human DHODH (hDHODH) that offers a potential therapeutic strategy for the treatment in adult subjects with acute myeloid leukemia (AML) has recently been supported by phase I/II clinical trials for the treatment of patients with relapsed/refractory AML. To facilitate the development of optimized hDHODH inhibitors, the presence of an imaging probe that is able to demonstrate target engagement is critical and desirable.

Discovery of DNA methylation signature in the peripheral blood of individuals with history of antenatal exposure to valproic acid.

Purpose: Valproic acid or valproate is an effective antiepileptic drug; however, embryonic exposure to valproate can result in a teratogenic disorder referred to as fetal valproate syndrome (OMIM #609442). Currently there are no diagnostic biomarkers for the condition. This study aims to define an episignature biomarker for teratogenic antenatal exposure to valproate.