Gifu Pharmaceutical University

Cyclin-dependent kinase 8 (CDK8) is a transcription-related CDK family member implicated in the regulation of bone homeostasis, and we recently demonstrated that our internally developed CDK8 inhibitor KY-065 can prevent postmenopausal osteoporosis in a mouse model. Achondroplasia (ACH), the most common form of genetic dwarfism in humans, is caused by a gain-of-function mutation in fibroblast growth factor receptor 3 (FGFR3), a receptor tyrosine kinase that activates downstream mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription (STAT) signaling pathways. The first precision drug approved for the treatment of ACH in children, the C-type natriuretic peptide analog vosoritide, antagonizes the MAPK pathway, while there are currently no effective and safe medications targeting the STAT1 pathway. Here, we demonstrate that KY-065 rescues impaired chondrogenesis and stunted long bone growth in the Fgfr3^Ach mouse model of ACH. KY-065 inhibited CDK8 with high affinity in vitro by competing with ATP. The CDK8 expression and STAT1^Ser727 phosphorylation were upregulated in chondrocytes isolated from ACH model mice, and KY-065 repressed its phosphorylation and restored normal chondrogenic differentiation without affecting MAPK activation. Moreover, daily administration of 10 mg/kg KY-065 to Fgfr3^Ach mice (yielding a peak concentration of 22.0 ± 1.47 μM in plasma) resulted in significant elongation of long bone and improved growth plate cytoarchitecture. Collectively, these findings identify the CDK8 in chondrocytes as a potential therapeutic target for ACH and KY-065 as a promising candidate drug treatment for this debilitating skeletal disease.

Amyotrophic lateral sclerosis (ALS) is characterized by the mislocalization and abnormal deposition of TAR DNA-binding protein 43 (TDP-43). This protein plays important roles in RNA metabolism and transport in motor neurons and glial cells. In addition, abnormal iron accumulation and oxidative stress are observed in the brain and spinal cord of patients with ALS exhibiting TDP-43 pathology and in animal models of ALS. We have previously demonstrated that TDP-43 downregulation significantly affects the expression of ferritin heavy chain (Fth1) mRNA in the axonal regions of neurons. Nevertheless, the mechanisms by which TDP-43 contributes to oxidative stress and iron accumulation in the central nervous system remain elusive. In this study, we aimed to investigate whether Fth1 mRNA is a target transported to the axon by TDP-43 using biophysical and biochemical analyses. Our results revealed Fth1 mRNA as a target mRNA transported to axons by TDP-43. Moreover, we demonstrated that TDP-43 regulates iron homeostasis and oxidative stress in neurons via Fth1 mRNA transport to the axons, possibly followed by a local translation of the ferritin heavy chain in the axons. This study suggests that TDP-43 plays an important role in preventing iron-mediated oxidative stress in neurons, with its loss contributing to ALS pathogenesis.

There are no reports on the side effects of chemotherapy on the quality of life (QOL) of patients with malignant lymphoma or on the intensity of anxiety affecting these side effects. We conducted a prospective observational study to evaluate the association between anxiety, chemotherapy side effects, and QOL in patients with malignant lymphoma undergoing their first cancer chemotherapy treatment.

We studied anxiety intensity, side effects, and QOL changes in 60 patients with malignant lymphoma who received their first course of initial chemotherapy at Gifu Municipal Hospital (Japan) between January 2021 and December 2022. Questionnaires were administered before and after the first chemotherapy course. The questionnaires included patient information and the STAI-JYZ, EQ-5D-5L, and EORTC QLQ-C30. EQ-5D-5L utility values and EORTC QLQ-C30 item scores were compared before and after the first chemotherapy course. The proportion of patients with issues with the five EORTC QLQ-C30 items was compared before and after the first chemotherapy. QOL was compared based on side effects and severity. QOL based on anxiety intensity was also compared.

The number of patients reporting problems with their usual activities significantly increased after the first chemotherapy course. Emotional functioning on the EORTC QLQ-C30 significantly increased after the first chemotherapy course. Patients' anxiety, depression, and pain decreased after the first course of chemotherapy. Patients with anorexia had lower utility values and EORTC QLQ-C30 Global health status. The utility values of the anxiety group increased significantly after chemotherapy.

Chemotherapy reduced activity but improved mental and psychological status. Anorexia negatively affects QOL and improves the QOL of patients with anxiety undergoing chemotherapy. This study clarified the relationship between anxiety, side effects, and QOL associated with cancer chemotherapy in patients with malignant lymphoma.