Bemcentinib and Gilteritinib Inhibit Cell Growth and Impair the Endo-Lysosomal and Autophagy Systems in an AXL-Independent Manner.

AXL, a receptor tyrosine kinase from the TAM (TYRO3 AXL and MER) subfamily, and its ligand growth arrest-specific 6 (GAS6) are implicated in pathogenesis of a wide array of cancers, acquisition of resistance to diverse anticancer therapies and cellular entry of viruses. The continuous development of AXL inhibitors for treatment of patients with cancer and COVID-19 underscores the need to better characterize the cellular effects of AXL targeting.In the present study, we compared the cellular phenotypes of CRISPR-Cas9-induced depletion of AXL and its pharmacological inhibition with bemcentinib, LDC1267 and gilteritinib. Specifically, we evaluated GAS6-AXL signaling, cell viability and invasion, the endo-lysosomal system and autophagy in glioblastoma cells. We showed that depletion of AXL but not of TYRO3 inhibited GAS6-induced phosphorylation of downstream signaling effectors, AKT and ERK1/2, indicating that AXL is a primary receptor for GAS6. AXL was also specifically required for GAS6-dependent increase in cell viability but was dispensable for viability of cells grown without exogenous addition of GAS6. Furthermore, we revealed that LDC1267 is the most potent and specific inhibitor of AXL activation among the tested compounds. Finally, we found that, in contrast to AXL depletion and its inhibition with LDC1267, cell treatment with bemcentinib and gilteritinib impaired the endo-lysosomal and autophagy systems in an AXL-independent manner. IMPLICATIONS: Altogether, our findings are of high clinical importance as we discovered that two clinically advanced AXL inhibitors, bemcentinib and gilteritinib, may display AXL-independent cellular effects and toxicity.

Vitamin D receptor gene polymorphisms in Alzheimer's disease patients.

THE AIM: The aim of this study was to determine whether polymorphisms of the VDR gene may increase the risk of Alzheimer disease (AD) development in Lower Silesian patients in comparison with other populations. MATERIAL AND METHODS: 108 AD patients (aged 73.7±8.6) vs 77 healthy volunteers (aged 64.5±7.8) in the Lower Silesian population were studied. We investigated the frequency of the VDR polymorphisms rs731236 (TaqI), rs7975232 (ApaI), rs10735810 (FokI) and rs1544410 (BsmI) in the AD group vs the healthy group. Afterwards, MEDLINE and ResearchGate were studied to compare our investigation with other populations, due to the relatively small group size in our study. RESULTS: We did not observe any significant differences in frequency of genotypes of rs731236 (TaqI), rs10735810 (FokI) or rs1544410 (BsmI) VDR polymorphisms between the two Lower Silesian groups. Frequency of allele A of ApaI in the control group was significantly higher vs AD patients (p<0.0177) in the Lower Silesian population. Furthermore the difference in the occurrence of allele t in TaqI and allele A in ApaI between AD patients vs the control group was significant (respectively p<0.0056, p<0.0140) in British Europeans. This observation may suggest that allele "a" of the ApaI polymorphism is a risk allele in AD Lower Silesian patients. We compared our results with those obtained for the population of British Europeans. In multivariate stepwise regression, allele "A" of ApaI was associated with 30% lower risk of AD (OR=0.70, p=0.0009) in total treated Polish and British populations. We did not observe similar results in Turkish and Iranian populations. CONCLUSION: Our data suggest that the allele "A" VDR genotype of ApaI reduces AD risk, probably depending on ethnic origin and climatic conditions.

[Selected mice models based on APP, MAPT and presenilin gene mutations in research on the pathogenesis of Alzheimer's disease]. / Wybrane mysie modele oparte na mutacji genów APP, MAPT oraz presenilin wykorzystywane w badaniach nad patogeneza choroby Alzheimera.

The research conducted on animal models of Alzheimer's disease (AD) has provided valuable information about the pathogenesis of this disease and associated behavioral and cognitive deficits as well as the disease-associated anatomical and histopathological lesions of the brain. Transgenic technologies have enabled the creation of animal models based on mutations in APP, MAPT, presenilin genes, tau protein and apoE. Due to economic reasons studies are mainly conducted on mice. Their brain tissue, depending on the mutation, is characterized by histopathological changes, such as the presence of amyloid plaques, tau protein deposits and dystrophic neurites, gliosis, hippocampal atrophy and amyloid accumulation in vessels. Animal cognitive impairment and behavior, which can be demonstrated in behavioral tests, primarily relate to the working and reference memory, alternation and anxiety. Unfortunately, despite the various modifications specific to AD in the genome of animals, scientists have failed to create an animal model characterized by all the pathological changes that can occur in Alzheimer's disease. Nevertheless, the role of transgenic animals is undeniable, both in research on AD neuropathology and for testing new therapies, such as immunotherapy. Despite the occurrence of abundant Alzheimer's disease mice models this article is dedicated to selected models with mutations in the APP, MAPT and presenilin genes and their application for behavioral studies.