Danger-associated molecular patterns (DAMPs) derived from damaged or dying cells elicit inflammation and potentiate antitumor immune responses. We found that treatment of cancer cells with the antitumor agent topotecan (TPT), an inhibitor of topoisomerase I (TOP1), induces DAMP secretion that triggers dendritic cell activation and cytokine production. TPT administration inhibits tumor growth in tumor-bearing mice, which is accompanied by infiltration of activated DCs and CD8⁺ T cells. These effects are abrogated in mice lacking stimulator of interferon genes (STING), an essential molecule in cytosolic DNA-mediated innate immune responses. Furthermore, we identified ribosomal protein L15 (RPL15), a 60S ribosomal protein, as a novel TPT target and showed that TPT inhibited pre-ribosomal subunit formation via its binding to RPL15, resulting in the induction of DAMP-mediated antitumor immune activation independent of TOP1. RPL15 knockdown induced DAMP secretion and increased the cytotoxic T lymphocyte (CTL) population but decreased the T-regulatory cell (Treg) population in a B16-F10 murine melanoma model, which sensitized B16-F10 tumors against programmed death receptor-1(PD-1) blockade. Our study identified a novel TPT target protein and showed that ribosomal stress is a trigger of DAMP secretion, which contributes to antitumor immunotherapy.

Bicyclic depsipeptide natural products containing an intramolecular disulfide bond are potent histone deacetylase (HDAC) inhibitors. Among them, FK228 (romidepsin) is approved for treating cutaneous T-cell lymphoma and peripheral T-cell lymphoma. This study focused on developing a new synthesis method for producing this class of natural products for use as HDAC inhibitors with high efficacy and low toxicity. In this paper, the total syntheses of FK228 as well as spiruchostatins A and B are described. The synthesis routes include a convergent way to assemble seco-acids via the amide condensation of amine segments with carboxylic acid segments. The syntheses of C4- and C7-modified FK228 analogs (FK-A1 to FK-A8) are also described. The evaluation of HDAC and cell growth inhibitory activities of the synthesized analogs revealed novel aspects of their structure-activity relationship. Potent and highly isoform-selective HDAC1 inhibitors were identified. Furthermore, the analogs showed phosphatidylinositol 3-kinase (PI3K) inhibitory activity. Structural optimization of the analogs as HDAC/PI3K dual inhibitors led to the identification of FK-A11 as the most potent analog.

In order to provide sustainable medical care in a super-aging society, pharmacists are required to play a role in integrated community care systems in cooperation with multiple professionals, in addition to prescription-based dispensing. We propose the necessity of building an interprofessional information sharing system, lifelong training for pharmacists, and the establishment of a professional certification system.

The corona virus disease 2019 (COVID-19) pandemic has revealed an urgent need for a sustainable healthcare system, especially human resource development. Nurses play a front-line role in the prevention of infection and countermeasures for people with health problems in health, medical, and welfare systems, and society demands that their role be further expanded. The education and training programs for nursing professionals are diverse. This study focuses on under-graduate nursing education and post-graduate education, and outlines the development of human resources in nursing for resilient leadership in times of crisis. Under-graduate nursing education is developing and expanding based on the Model Core Curriculum for Nursing Education and the reference standards for quality assurance in nursing education, while assuring the quality. For the advancement of health care and society in times of crisis, it is essential to develop nursing human resources who can respond to crises of life, livelihood, and survival across multiple dimensions. To achieve this, it is necessary for educational institutions, medical institutions, and governmental agencies to strengthen cooperation and collaboration, and to promote the development of human resources who can build a sustainable, equitable, and resilient society.

The Ministry of Health, Labour and Welfare's “Study Group on the Training and Qualification Improvement of Pharmacists” met 10 times from July 2000 to June 2021, and its “Summary” was published on June 30, 2021. The purpose of this study group was to examine the future of pharmacists in Japan, based on the results of a survey on the supply and demand of pharmacists, in the face of the declining birth rate, aging population, and regional differences in population. The study group also assessed changes in the roles and duties of pharmacists, such as the promotion of family pharmacists and pharmacies, the promotion of team medicine in medical institutions, and the response of pharmacists to the regional comprehensive care system. The purpose of this symposium was to discuss how to train and improve the quality of pharmacists in the future, while taking into account the results of the survey on the estimated supply and demand of pharmacists. In this symposium, we would like to introduce what was actively discussed in the study group and what was compiled based on the discussion.

The anticipation of Japan's decreased birthrate and a shift to an aged society has led to the field of medical care to review the country's social security system. The review calls for a reform of the medical insurance system under the universal health coverage system to fit the changing demographic. The target year of 2025 has the government advocating for an “integrated community care system”, with the ‘baby-boom generation’ turning 75. This is a sustainable regional system that can cope with the aging society and the declining birthrate simultaneously. Within this new system, I would like to discuss The Strategic Plan of the Japan Pharmaceutical Association, released with the aim of realizing pharmacists and pharmacy services that can immediately respond to the expectations of society; from the perspective of the theme of this symposium, “Communicating the image of pharmacists in a community-based society”.

In order to provide safe and effective pharmaceutical care to patients and their family members in clinical practice, pharmacists should receive appropriate clinical training after obtaining their license, as is standard in other medical professions. At present, there is no national framework in Japan for the early clinical training of pharmacists after licensure. However, pharmacy residency programs have been autonomously developed and implemented at some university hospitals and other medical institutions. This article describes the current status of clinical training of pharmacists after licensure in Japan. Furthermore, the standards for pharmacy residency programs, the outline of a core program for clinical training, and the career paths of hospital pharmacists after training are discussed.

In Japan, each society has developed its own certification system for the pharmacy specialists in a specific area of pharmaceutical care. Since 2020, we have conducted research activities supported by a Grant-in-Aid for Scientific Research from the Ministry of Health, Labour and Welfare to assure the quality of pharmacy specialists similar as other medical professionals. We proposed three reform plans. First, we defined a pharmacist career path after obtaining a license by redefining the name of a qualified pharmacist: Step 1, Training-Certified Pharmacist; Step 2, Board-Certified Pharmacist; and Step 3, Pharmacy Specialist. Second, we proposed common external standards for the Pharmacy Specialist. Third, we proposed the need for third-party certification for pharmacy specialists. New reforms for the pharmacy specialists are required under the autonomy of pharmacists.

Studies on the isolation and molecular mechanisms of phytochemicals with anti-tumor or anti-inflammatory properties are important to developing new drugs for cancer and neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. In the course of a study to screen bioactive isoflavones from Erythrina poeppigiana (Leguminosae), we isolated an isoflavone with potent apoptosis-inducing activity against human leukemia HL-60 cells. It was designated erypoegin K. The studies demonstrated an enantiomer, (S)-erypoegin K, displayed selective cytotoxic activity, was a novel inhibitor of topoisomerase II, and possessed anti-tumor activity both in vitro and in vivo. We identified other apoptosis-inducing isoflavones with the ability to inhibit glyoxalase I. Dimeric acridone alkaloids, carbazole alkaloids, and coumarin and quinoline derivatives—all obtained mainly from plants in the family Rutaceae—induced apoptosis of HL-60 cells via the production of reactive oxygen species and mitochondrial dysfunction. We also identified terpenoid coumarins, carbazole quinones, rotenoid derivatives, and quinolone alkaloids with anti-inflammatory activities. These compounds reduced nitric oxide (NO) production from RAW264.7 macrophage cells stimulated with lipopolysaccharides and interferon-γ. Some of the compounds displayed neuroprotective activity by reducing NO production. This review primarily describes our recent studies on erypoegin K, and other compounds with apoptosis-inducing and anti-inflammatory activities.

Distigmine sometimes causes severe adverse events, and the serum butyrylcholinesterase (BChE) level is reduced by distigmine. However, limited data are available on the association between serum BChE level and the risk of distigmine-induced adverse events. To clarify the association between the risk of distigmine-induced adverse events and serum BChE level, we retrospectively reviewed 371 patients with 2199 measurements of serum BChE levels at three hospitals, of whom 24 (6.5%) had adverse events. Multivariate logistic regression analysis was performed to identify risk factors associated with adverse events of distigmine. The risk of adverse events was associated with distigmine dose>0.15 mg/kg/d [odds ratio (OR) 3.55, 95% confidence interval (CI) 1.07-11.70, p=0.04], serum BChE level 80-112 U/L (OR 3.13, 95% CI 1.03-9.52, p=0.04), and serum BChE level <80 U/L (OR 13.70, 95% CI 5.14-36.50, p<0.01). Serum BChE might be a useful biomarker for estimating the risk of distigmine-induced adverse events. The risk of adverse events might be decreased by closely monitoring serum BChE and assessing distigmine dose in patients with high risk factors.

Copper is one of the essential trace elements in humans, and its deficiency causes various diseases. Zinc acetate dihydrate is administered to treat hypozincemia in preterm infants; however, zinc inhibits the gastrointestinal absorption of copper, which may cause copper deficiency. To safely treat hypozincemia in preterm infants, we retrospectively analyzed the factors reducing serum copper concentrations when zinc is administered to preterm infants with hypozincemia. Seventy preterm infants were included in the present study. Serum zinc and copper concentrations, doses, and other clinical characteristics were retrieved from electronic medical records. The administration of zinc acetate dihydrate decreased serum copper concentrations in 21 out of 70 patients. In comparisons between the two groups with and without a decrease in serum copper concentrations, significant differences were observed in postmenstrual age (34.9 and 35.9 weeks, respectively) and serum zinc concentrations (62.0 and 58.0 μg/dL, respectively) at the start of the zinc acetate dihydrate treatment. A logistic regression analysis identified postmenstrual age as a significant factor decreasing serum copper concentrations. In the ROC curve, the cut-off value for postmenstrual age for a decrease in serum copper concentrations was 34.143 weeks. The present results suggest that when zinc acetate dihydrate is administered to preterm infants with a low postmenstrual age who are at higher risk of decreased serum copper concentrations, particularly to those with a postmenstrual age <34 weeks, it is important to consider copper deficiency and periodically measure serum copper concentrations.

Olive weevils, Pimelocerus (Dyscerus) perforatus Roelofs, utilize olive trees as a host plant. The adult female uses an elongated snout to puncture the trunk and lay one egg a day, resulting in dozens of eggs over its lifetime. The hatched larvae grow by eating the olive trunk. When olive trees die due to feeding damage, olive productivity is seriously impaired. Since there is no effective pesticide for olive weevils so far, the authors aimed to develop a repellent for adult olive weevils from the viewpoint of integrated pest management. We prepared a measurable apparatus for the repellent action against olive weevils and screened chemical substances by using the apparatus. When the repellent activity was measured using vanillin and its derivatives, a clear repellent effect could be confirmed for two types of vanillin derivatives, such as o-vanillin, and 2-hydroxy-4-methoxybenzaldehyde. In addition, when the repellent activity against olive weevils was measured using monoterpenes, four types of acyclic monoterpenes, geraniol, β-citronellol, citral, and linalool, and three types of monocyclic monoterpenes, (−)-limonene, (+)-limonene, and (−)-menthol, and a bicyclic monoterpene, (1R)-(+)-α-pinene, were found to have dose-dependent repellent activity with statistical significance. In the future, it is expected that the formulation for applying the repellent substances to olive trees and the study of their practicality in olive fields will progress.

We previously designed the formulation containing minoxidil (MXD) nanoparticles (MXD-NPs), and found that the MXD-NPs can mainly deliver MXD into hair bulbs via hair follicles pathway, and that the therapeutic efficiency for hair growth is higher in comparison with the formulation containing dissolved MXD. In this study, we investigated whether the skin environmental changes by the treatment of steam towel, ethanol, l-menthol and commercially available (CA) carpronium affect the drug behavior in the MXD-NPs-applied mice. The steam towel, ethanol, l-menthol and CA-carpronium were pre-treated 3 min before MXD-NPs application, and the MXD content in the hair bulge, bulb, skin tissue and blood of mice were measured 4 h after MXD-NPs application. No significant difference of MXD levels in the blood was observed by the pre-treatment of steam towel, ethanol, l-menthol and CA-carpronium. On the other hand, the pre-treatment of steam towel and l-menthol enhanced the MXD levels in hair bulge and/or bulb. Although, the MXD levels in hair bulge and bulb were not changed by the pre-treatment of ethanol, the MXD levels in skin tissue was higher than that of saline-pre-treated group (control). The MXD levels in hair bulge, bulb and skin tissue of mice pre-treated with CA-carpronium were remarkably higher in comparison with control. In conclusion, we showed that the changes in skin environment by the steam towel, ethanol, l-menthol and CA-carpronium affected the absorption of MXD-NPs, and these increased MXD levels in the hair bulb and blood by the combination may enhance the therapeutic efficiency without side effects.

Prognostic factors for patients with relapse and unresectable biliary tract cancer, treated with Tegafur Gimeracil Oteracil Potassium (S-1) after failure of gemcitabine (GEM), are unclear. We searched for prognostic factors in patients with relapse and unresectable biliary tract cancer treated with S-1 after failure of GEM, and investigated the relationship between prognostic factors, and the therapeutic effect of S-1. We retrospectively analyzed data of 33 patients with relapse and unresectable biliary tract cancer treated with S-1 after failure of GEM treatment. Statistically significant prognostic factors were extracted using Cox's proportional hazard model. Data was also collected on prognostic factors prior to the first dose of S-1, final prescription of S-1, and end of treatment. Changes in prognostic factors before the first dose of S-1, at final prescription of S-1, and at the end of treatment were evaluated using the Friedman test. Multivariate analysis identified neutrophil-lymphocyte ratio (NLR) [hazard ratio (HR)=4.599, p=0.004] and prognostic nutritional index (PNI) (HR=4.985, p=0.004) as independent poor prognostic factors for overall survival. Regarding the relationship between the therapeutic effect and prognostic factors, a significant change was observed in the change in PNI value from first administration of S-1 to the end of treatment (p=0.002). NLR and PNI are suggested to be prognostic factors in patients with relapse and unresectable biliary tract cancer, treated with S-1 after failure of GEM. Changes in PNI from the start of administration of S-1 may be related to therapeutic efficacy.

Lacosamide is a novel antiepileptic drug. Although many antiepileptic drugs reportedly pose a risk to fetuses, patients with epilepsy are advised to continue their medications during pregnancy. There have been few reports on lacosamide use during pregnancy, and its effects on the fetus remain unclear. Here, we report a case of lacosamide use during pregnancy. The 33-year-old patient was treated with oral lacosamide (400 mg/d) for symptomatic partial epilepsy. She was concomitantly treated with folic acid (5 mg/d) beginning 4 days before her last menstrual cycle. She was also concomitantly treated with oral perampanel (2 mg/d) at 5-7 weeks' gestation for seizure control but discontinued perampanel after the pregnancy was discovered. She progressed through her pregnancy with only mild seizures. Fetal growth was normal and ultrasonography revealed no external malformations. The patient had an elective cesarean section at 37 weeks and 2 days owing to a previous post-cesarean pregnancy. Her baby boy weighed 3025 g; his Apgar score was 8 and 9, 1 and 5 min, respectively, and his umbilical artery blood pH was 7.348. He had no congenital anomalies and no neonatal drug withdrawal symptoms. This suggests that lacosamide may have a low risk of teratogenicity and fetal toxicity. Thus, this case is valuable for clinicians who are considering the administration of antiepileptic drugs during pregnancy. In the future, more reports on the use of lacosamide during pregnancy should be collected.