Treatment-related damage in elderly-onset ANCA-associated vasculitis: safety outcome analysis of two nationwide prospective cohort studies

Background It is not elucidated that there is treatment-related damage in elderly patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV). Methods Elderly (≥ 75 years of age) patients were enrolled from two nationwide prospective inception cohort studies. The primary outcome was 12-month treatment-related Vasculitis Damage Index (VDI) score. Secondary outcomes included serious infections within 6 months, total VDI score, remission, and relapse. Patient characteristics and outcomes were compared across three different initial glucocorticoid (GC) dose groups: high-dose, prednisolone (PSL) ≥ 0.8 mg/kg/day; medium-dose, 0.6 ≤ PSL  Results Of the 179 eligible patients, the mean age was 80.0 years; 111 (62%) were female. The mean Birmingham Vasculitis Activity Score was 16.1. Myeloperoxidase-ANCA findings were positive in 168 (94%) patients, while proteinase 3-ANCA findings were positive in 11 (6%). The low-dose group was older and had higher serum creatinine levels than the other groups. There were no statistically significant intergroup differences in remission or relapse, whereas serious infection developed more frequently in the high-dose (29 patients [43%]) than the low-dose (13 patients [22%]) or medium-dose (10 patients [19%]) groups (p = 0.0007). Frequent VDI items at 12 months included hypertension (19%), diabetes (13%), atrophy and weakness (13%), osteoporosis (8%), and cataracts (8%). Logistic regression analysis revealed that GC dose at 12 months (odds ratio, 1.14; 95% confidence interval, 1.00–1.35) was a predictor for diabetes. Conclusion A reduced initial GC dose with rapid reduction might be required to ensure the safe treatment of elderly AAV patients

New therizinosaurid dinosaur from the marine Osoushinai Formation (Upper Cretaceous, Japan) provides insight for function and evolution of therizinosaur claws

The record of therizinosaurs is rich in Asian countries such as Mongolia and China. Fragmentary therizinosaur specimens have been reported from the Lower and Upper Cretaceous deposits in Japan. One of these specimens, from the lower Campanian Osoushinai Formation in Nakagawa Town of Hokkaido Prefecture, was previously identified as a maniraptoran theropod dinosaur, possibly therizinosaur, but its taxonomic status remained unresolved. This study re-examines the specimen and provides a more detailed description and attempts to resolve its taxonomic status. Our study demonstrates that it is a new taxon, Paralitherizinosaurus japonicus gen. et sp. nov., because it shows a unique combination of characters in the metacarpal I and unguals. Our phylogenetic analysis places this new taxon within an unresolved clade of Therizinosauridae in the strict consensus tree. The 50% majority-rule consensus tree shows better resolution within Therizinosauridae, showing an unresolved monophyletic clade of Paralitherizinosaurus, Therizinosaurus, Suzhousaurus, and the Bissekty form. Geometric morphometric analysis suggests that Paralitherizinosaurus unguals most closely resemble Therizinosaurus unguals in being slender and has weak flexor tubercles. This study also shows an evolutionary trend in ungual shape, which associates a decrease in mechanical advantage, development of flexor tubercle, and hypothesized output (product of mechanical advantage and development of flexor tubercle) in derived therizinosaurs, supporting the hook-and-pull function of claws to bring vegetation to its mouth. Paralitherizinosaurus is the youngest therizinosaur from Japan and the first recovered from the marine deposits in Asia. This suggests a long temporal existence of therizinosaurs at the eastern edge of the Asian continent and adaptation of therizinosaurs to coastal environments

A genome-wide screen for FTY720-sensitive mutants reveals genes required for ROS homeostasis

Fingolimod hydrochloride (FTY720), a sphingosine-1-phosphate (S1P) analogue, is an approved immune modulator for the treatment of multiple sclerosis (MS). Notably, in addition to its well-known mode of action as an S1P modulator, accumulating evidence suggests that FTY720 induces apoptosis in various cancer cells via reactive oxygen species (ROS) generation. Although the involvement of multiple signaling molecules, such as JNK (Jun N-terminal kinase), Akt (alpha serine/threonine-protein kinase) and Sphk has been reported, the exact mechanisms how FTY720 induces cell growth inhibition and the functional relationship between FTY720 and these signaling pathways remain elusive. Our previous reports using the fission yeast Schizosaccharomyces pombe as a model system to elucidate FTY720-mediated signaling pathways revealed that FTY720 induces an increase in intracellular Ca2+ concentrations and ROS generation, which resulted in the activation of the transcriptional responses downstream of Ca2+/calcineurin signaling and stress-activated MAPK signaling, respectively. Here, we performed a genome-wide screening for genes whose deletion induces FTY720-sensitive growth in S. pombe and identified 49 genes. These gene products are related to the biological processes involved in metabolic processes, transport, transcription, translation, chromatin organization, cytoskeleton organization and intracellular signal transduction. Notably, most of the FTY720-sensitive deletion cells exhibited NAC-remedial FTY720 sensitivities and dysregulated ROS homeostasis. Our results revealed a novel gene network involving ROS homeostasis and the possible mechanisms of the FTY720 toxicity