Artificial intelligence in drug repurposing for rare diseases: a mini-review.

Drug repurposing, the process of identifying new uses for existing drugs beyond their original indications, offers significant advantages in terms of reduced development time and costs, particularly in addressing unmet medical needs in rare diseases. Artificial intelligence (AI) has emerged as a transformative force in healthcare, and by leveraging AI technologies, researchers aim to overcome some of the challenges associated with rare diseases. This review presents concrete case studies, as well as pre-existing platforms, initiatives, and companies that demonstrate the application of AI for drug repurposing in rare diseases. Despite representing a modest part of the literature compared to other diseases such as COVID-19 or cancer, the growing interest, and investment in AI for drug repurposing in rare diseases underscore its potential to accelerate treatment availability for patients with unmet medical needs.

"Ways in which the neonatal Fc-receptor is involved in autoimmunity".

Since the neonatal IgG Fc receptor (FcRn) was discovered, its role has evolved from immunoglobulin recycling and biodistribution to antigen presentation and immune complex routing, bringing it to the center of both humoral and cellular immune responses. FcRn is thus involved in the pathophysiology of immune-related diseases such as cancer, infection, and autoimmune disorders. This review focuses on the role of FcRn in autoimmunity, based on the available data from both animal models and human studies. The knowledge concerning ways in which FcRn is involved in autoimmune response has led to the development of inhibitors for the treatment of autoimmune diseases, also described here. Up to date, the literature remains scarce, shedding light on the need for further studies to fully understand the various pathophysiological roles of this unique receptor.

An Accessible and Unique Insight into Metastasis Mutational Content Through Whole-exome Sequencing of Circulating Tumor Cells in Metastatic Prostate Cancer.

BACKGROUND: Genomic analysis of circulating tumor cells (CTCs) could provide a unique and accessible representation of tumor diversity but remains hindered by technical challenges associated with CTC rarity and heterogeneity. OBJECTIVE: To evaluate CTCs as surrogate samples for genomic analyses in metastatic castration-resistant prostate cancer (mCRPC). DESIGN, SETTING, AND PARTICIPANTS: Three isolation strategies (filter laser-capture microdissection, self-seeding microwell chips, and fluorescence-activated cell sorting) were developed to capture CTCs with various epithelial and mesenchymal phenotypes and isolate them at the single-cell level. Whole-genome amplification (WGA) and WGA quality control were performed on 179 CTC samples, matched metastasis biopsies, and negative controls from 11 patients. All patients but one were pretreated with enzalutamide or abiraterone. Whole-exome sequencing (WES) of 34 CTC samples, metastasis biopsies, and negative controls were performed for seven patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: WES of CTCs was rigorously qualified in terms of percentage coverage at 10× depth, allelic dropout, and uncovered regions. Shared somatic mutations between CTCs and matched metastasis biopsies were identified. A customized approach based on determination of mutation rates for CTC samples was developed for identification of CTC-exclusive mutations. RESULTS AND LIMITATIONS: Shared mutations were mostly detected in epithelial CTCs and were recurrent. For two patients for whom a deeper analysis was performed, a few CTCs were sufficient to represent half to one-third of the mutations in the matched metastasis biopsy. CTC-exclusive mutations were identified in both epithelial and nonepithelial CTCs and affected cytoskeleton, invasion, DNA repair, and cancer-driver genes. Some 41% of CTC-exclusive mutations had a predicted deleterious impact on protein function. Phylogenic relationships between CTCs with distinct phenotypes were evidenced. CONCLUSIONS: CTCs can provide unique insight into metastasis mutational diversity and reveal undiagnosed genomic aberrations in matched metastasis biopsies. PATIENT SUMMARY: Our results demonstrate the clinical potential of circulating tumor cells to provide insight into metastatic events that could be critical to target using precision medicine.

Morphofunctional interactions between galanin and GnRH-containing neurones in the diencephalon of the ewe. The effect of oestradiol.

In rodents, the neuropeptide galanin (Gal) is involved in controlling the release of gonadotrophin-releasing hormone (GnRH). In the female, this peptide is colocalized in a subpopulation of GnRH neurones and its expression is stimulated by oestradiol. In the ewe, the morphofunctional relationship between these two neuronal peptides is poorly understood. The morphological interaction between Gal and GnRH was studied in ewes treated with oestradiol or with colchicine and in control animals. Five ewes were treated for 6h with oestradiol implants, a treatment known to induce a preovulatory surge of GnRH, and compared with five control animals. In addition, four animals received an intracerebroventricular injection of colchicine known to increase the intracellular level of galanin immunoreactivity. The morphological relationship between the two peptides was investigated by immunofluorescence using specific antibodies on the same sections, and the results were analysed using confocal microscopy. In colchicine-treated ewes, numerous Gal-immunoreactive neurones were found in the preoptic area in the vicinity of GnRH-immunoreactive neurones, but the two peptides were never observed in the same neurone. In all animals, Gal-ir fibres were observed to be in apposition to GnRH-containing perikarya in the preoptic area and these appositions were more numerous in oestradiol-treated ewes than in control animals. In contrast with rodents, galanin was not colocalized with GnRH in the neurones of the preoptic area of ewes, but this peptide could control GnRH neuronal secretion through axosomatic interactions. However, the presence of synaptic contacts between galanin terminals and GnRH perikarya needs to be confirmed by electron microscopy. As in rodents and primates, galanin could mediate the positive feedback of oestradiol on GnRH neurones during the preovulatory surge in ewes.

Fetal exposure to teratogens: evidence of genes involved in autism.

Environmental challenges during the prenatal period can result in behavioral abnormalities and cognitive deficits that appear later in life such as autism. Prenatal exposure to valproic acid, ethanol, thalidomide and misoprostol has been shown to be associated with an increased incidence of autism. In addition, rodents exposed in utero to some of these drugs show autism-like abnormalities, including brain changes and lifelong behavior dysfunction. Our aim is to summarize current understanding of the relationship between in utero exposure to these drugs and autism in humans and in autism-like animal model phenotypes. It also highlights the importance of these models to understanding the neurobiology of autism, particularly in the identification of susceptibility genes. These drugs are able to modulate the expression of many genes involved in processes such as proliferation, apoptosis, neuronal differentiation and migration, synaptogenesis and synaptic activity. It seems essential to focus research on genes expressed during early neurodevelopment which may be the target of mutations or affected by drugs such as those included in this review.