Infigratinib, a selective FGFR1-3 tyrosine kinase inhibitor, alters dentoalveolar development at high doses.

BACKGROUND: Fibroblast growth factor receptor-3 (FGFR3) gain-of-function mutations are linked to achondroplasia. Infigratinib, a FGFR1-3 tyrosine kinase inhibitor, improves skeletal growth in an achondroplasia mouse model. FGFs and their receptors have critical roles in developing teeth, yet effects of infigratinib on tooth development have not been assessed. Dentoalveolar and craniofacial phenotype of Wistar rats dosed with low (0.1 mg/kg) and high (1.0 mg/kg) dose infigratinib were evaluated using micro-computed tomography, histology, and immunohistochemistry. RESULTS: Mandibular third molars were reduced in size and exhibited aberrant crown and root morphology in 100% of female rats and 80% of male rats at high doses. FGFR3 and FGF18 immunolocalization and extracellular matrix protein expression were unaffected, but cathepsin K (CTSK) was altered by infigratinib. Cranial vault bones exhibited alterations in dimension, volume, and density that were more pronounced in females. In both sexes, interfrontal sutures were significantly more patent with high dose vs vehicle. CONCLUSIONS: High dose infigratinib administered to rats during early stages affects dental and craniofacial development. Changes in CTSK from infigratinib in female rats suggest FGFR roles in bone homeostasis. While dental and craniofacial disruptions are not expected at therapeutic doses, our findings confirm the importance of dental monitoring in clinical studies.

Differential Activity of APOBEC3F, APOBEC3G, and APOBEC3H in the Restriction of HIV-2.

Human immunodeficiency virus (HIV) mutagenesis is driven by a variety of internal and external sources, including the host APOBEC3 (apolipoprotein B mRNA editing enzyme catalytic polypetide-like 3; A3) family of mutagenesis factors, which catalyze G-to-A transition mutations during virus replication. HIV-2 replication is characterized by a relative lack of G-to-A mutations, suggesting infrequent mutagenesis by A3 proteins. To date, the activity of the A3 repertoire against HIV-2 has remained largely uncharacterized, and the mutagenic activity of these proteins against HIV-2 remains to be elucidated. In this study, we provide the first comprehensive characterization of the restrictive capacity of A3 proteins against HIV-2 in cell culture using a dual fluorescent reporter HIV-2 vector virus. We found that A3F, A3G, and A3H restricted HIV-2 infectivity in the absence of Vif and were associated with significant increases in the frequency of viral mutants. These proteins increased the frequency of G-to-A mutations within the proviruses of infected cells as well. A3G and A3H also reduced HIV-2 infectivity via inhibition of reverse transcription and the accumulation of DNA products during replication. In contrast, A3D did not exhibit any restrictive activity against HIV-2, even at higher expression levels. Taken together, these results provide evidence that A3F, A3G, and A3H, but not A3D, are capable of HIV-2 restriction. Differences in A3-mediated restriction of HIV-1 and HIV-2 may serve to provide new insights in the observed mutation profiles of these viruses.

Early pathways to research at the NIH.

This article, written by current student trainees within various intramural programs at the National Institutes of Health (NIH), describes how the NIH experience weaves world-class interdisciplinary research into the education of future oral healthcare professionals. This article highlights 4 programs and provides perspectives from current NIH student trainees on the significance of their programs to their career growth in an effort to increase program awareness for faculty and students, thus escalating participation of predental and dental students in programs at the NIH. Although the number of individuals pursuing careers in oral health research has been alarmingly few, dentistry is in a unique position to drastically expand its collaborative scientific workforce. Research must be integrated into the training of increased numbers of future dental professionals. This article describes how NIH programs address specific needs of the dental profession, including reducing disparities, advancing evidence-based personalized medicine, and solving multidisciplinary health challenges.