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Royal jelly (RJ) produced by honey bees is known to contain three major nutrients including amino acids, vitamins and minerals.1) Additionally, RJ has various biological activities such as a hypotensive effect, insulin-like action and antitumor activity.2-4) Therefore, it is possible that RJ may have some effects on insulin resistance, which is considered to be a cause of various lifestyle-related diseases. Many clinical studies have shown a possible relationship between hypertension and insulin resistance, since patients with type 2 (noninsulin dependent) diabetes mellitus frequently have insulin resistance associated with hypertension. 5-7)Chronic administration of fructose to rats has been reported to cause insulin resistance, which is characterized by increased serum insulin and euglycemia.8) Especially, a hyperinsulinemic state associated with hypertension was more prominently induced by fructose drinking than by fructose feeding.9) Previously, we reported that rats with chronic hyperinsulinemia, which was induced by giving a 15% fructose solution in drinking water for 10 weeks (fructose-drinking rats, FDR), showed deficient neuronal regulation of vascular tone, and this leads to hypertension. 10,11) Recently, we demonstrated that chronic administration of RJ prevented development of insulin resistance in Ohtsuka Long-Evanse Fatty (OLETF) rats, which is a spontaneous type 2 diabetic model. 12)Thus, in the present study, we investigated the effects of RJ on the insulin resistance in FDR. We also examined whether RJ prevents hypertension and altered vascular responsiveness induced by insulin resistance using isolated mesenteric vascular beds of rats. MATERIALS AND METHODS AnimalsSix week-old male Wistar rats were used in this study. They were given 15% fructose solution as drinking water ad libitum for 8 weeks. The control group was given tap water instead of 15% fructose solution. Three rats were housed in each cage (W 220ϫL 320ϫH 135 mm; Natsume Seisakusho, Tokyo, Japan), and given normal rat chow (Oriental Yeast, Tokyo, Japan). They were housed in the Animal Research Center of Okayama University at a controlled ambient temperature of 22Ϯ2°C with 50Ϯ10% relative humidity and with a 12-h light/12-h dark cycle (lights on at 8:00 a.m.). This study was carried out in accordance with the Guidelines for Animal Experiments at Okayama University Advanced Science Research Center, Japanese Government Animal Protection and Management Law (No. 105) and the Japanese Government Notification on Feeding and Safekeeping of Animals (No. 6). Every effort was made to minimize the number of animals used and their suffering.Long-Term Administration of RJ RJ, which was enzymatically treated and supplied by Yamada Apiculture Center, Inc. (Okayama, Japan) (Lot No. 020605), was used in this study. RJ was diluted by adding distilled water and orally administered at doses of 100 mg/kg/d and 300 mg/kg/d for 8 weeks from 6 to 14 weeks of age. Each animal was lightly anesthetized with ether and orally administrated RJ solution at a volum...

Immune checkpoint inhibitors (ICIs) elicit antitumour effects by activating the host immunity and cause immune-related adverse events (irAes). ici-related interstitial lung disease (ici-iLD) is a fatal irAE that is difficult to treat; moreover, its incidence is relatively higher in patients with lung cancer. therefore, early ici-iLD detection and intervention are important for patient safety. However, a risk assessment method for ici-iLD has not been established and the prediction of ici-iLD occurrence is difficult. The aim of our study was to identify the risk factors associated with ICI-ILD. To this end, we retrospectively analysed 102 patients with lung cancer who first received ICI and completed the treatment between April 2016 and December 2019 at Tokushima University Hospital. Nineteen patients had all grades of ICI-ILD and 10 had grade ≥ 3 ICI-ILD. The 30-day mortality rate of patients with grade ≥ 3 ICI-ILD was the highest among all patients (P < 0.01). The multivariate logistic analysis indicated that the performance status ≥ 2 alone and both performance status ≥ 2 and ≥ 50 pack-year were independent risk factors of ICI-ILD of grade ≥ 3 and all grades, respectively. Overall, our study provides insights to predict ici-iLD occurrence. Immune checkpoint inhibitors (ICIs) are antibodies that inhibit programmed death-1 (PD-1), PD ligand-1 (PD-L1), and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), which are called immune checkpoint molecules. These molecules negatively regulate the host immunity; thus, the inhibition of these molecules activates the host immunity and exerts cross-organ antitumour effects 1. In the treatment of lung cancer, some clinical trials have revealed that the administration of ICI alone and in combination with cytotoxic anticancer agents resulted in better clinical outcomes than previous standard treatments; thus, the use of ICI significantly improved lung cancer treatment 2-4. However, the activation of the host immunity by ICI leads to characteristic adverse events, known as immune-related adverse events (irAEs), which exhibit profiles different from those caused by cytotoxic anticancer agents 5,6. Therefore, the management of irAEs is essential for an effective ICI treatment. These irAEs affect various organs, such as the skin, endocrine glands, gastrointestinal tract, and liver, but only a few events are fatal because the majority of them can be controlled by adequate treatment 5,7. Specifically, ICI-related interstitial lung disease (ICI-ILD) has a low incidence (1-5%) and a high severity or mortality rate, according to clinical trials (50-60%) 8,9. Patients with lung cancer are known to have relatively higher ICI-ILD rates than those with other cancers 10. A prospective study of patients with lung cancer reported that the incidence of ICI-ILD was 14.5%, which is higher than that in clinical trials 11. ICI-ILD has also been reported to affect the prognosis of patients with lung cancer 11,12 .

The aim of this study was to investigate age-related changes in the density of calcitonin gene-

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