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Tamibarotene is a synthetic retinoid that inhibits tumor cell proliferation and promotes differentiation. We previously reported on the safety and tolerability of tamibarotene in patients with recurrent or refractory solid tumors. Therefore, in this study, we aimed to evaluate the pharmacokinetic properties of tamibarotene and construct a precise pharmacokinetic model. We also conducted a non-compartmental analysis and population pharmacokinetic (popPK) analysis based on the results of a phase I study. Targeted pediatric and young adult patients with recurrent or refractory solid tumors were administered tamibarotene at doses of 4, 6, 8, 10, and 12 g/m 2 /day. Serum tamibarotene concentrations were evaluated after administration, and a popPK model was constructed for tamibarotene using Phoenix NLME. During model construction, we considered the influence of various parameters (weight, height, body surface area, and age) as covariates. Notably, 22 participants were included in this study, and 109 samples were analyzed. A two-compartment model incorporating lag time was selected as the base model. In the final model, the body surface area was included as a covariate for apparent total body clearance, the central compartment volume of distribution, and the peripheral compartment volume of distribution. Visual prediction checks and bootstrap analysis confirmed the validity and predictive accuracy of the final model as satisfactory.

Background: Cancer has been identified as a risk factor for severe illness and mortality in coronavirus disease (COVID-19), underscoring the importance of recommending COVID-19 vaccinations to patients with cancer. However, few reports have focused on the vaccination status and the incidence of adverse events among patients with cancer. In this study, we aimed to evaluate the vaccination status, incidence of adverse events, concerns, and anxiety related to COVID-19 vaccination among patients with cancer. In addition, we explored the utilization of information sources by these patients and the ease of use., Methods: A survey was conducted among outpatients undergoing chemotherapy who received medication counseling from a pharmacist at Juntendo University Hospital. Responses were gathered from 60 out of the 143 participants. Of the respondents, 96.7% had received two doses of the COVID-19 vaccine., Results: Common adverse events included pain at the injection site, fever, and fatigue, which were experienced by nearly half of the respondents. Approximately 80% expressed some concern regarding vaccination, with predominant concerns about timing in the context of ongoing cancer treatment and surgery. Among the respondents, 41.7% consulted primary care physicians regarding the vaccine, with only one mentioning consultation with hospital pharmacists. Notably, primary care physicians were considered the most approachable and useful healthcare professionals., Conclusions: These results suggest that patients with cancer can safely receive the vaccine, comparable to patients without cancer. However, they still harbor concerns, even when seeking advice from primary care physicians. Few patients consulted pharmacists about vaccination, highlighting an opportunity for pharmacist intervention. Pharmacists fostering trust with patients with cancer is imperative to explore pharmacist intervention methods to promote the continued administration of COVID-19 vaccines and enhance the quality of life for them., (© 2024. The Author(s).)

Antimicrobial resistance (AMR) is a global threat to human health. Education on antibiotics is essential for AMR prevention, and training should be provided for undergraduate pharmacy students. This study evaluated the knowledge regarding antibiotic use and AMR among fourth-year Japanese pharmacy students and the effect of a lecture on treating infectious diseases with antibiotics had on their knowledge. A questionnaire survey was conducted, and the responses were recorded before and after participants attended the lecture. A small subset of the prelecture survey questions was used for the postlecture survey. From a total of 540 participants, 330 and 234 responses were collected before and after the lecture, respectively. In the prelecture survey, 39.4% of the participants incorrectly answered that antibiotics can effectively treat the common cold, 13.3% had taken leftover antibiotics, and 17.3% had taken antibiotics prescribed for their family members or others. Furthermore, the prelecture survey data showed that the mean number (± standard deviation) of correct answers across the eight questions on treatment and diagnosis of infectious diseases and antibiotics was 2.21 ± 1.64. However, in the postsurvey, this figure increased to 5.00 ± 1.82. Although the lecture improved their knowledge to some extent, the results suggested that fourth-year pharmacy students have inaccurate knowledge regarding the appropriate use of antibiotics and AMR. Therefore, it is necessary to improve early-year undergraduate pharmacy education on antibiotics in Japan., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Azechi et al.)

Background: Because cisplatin (CDDP) decreases upon light exposure, it is necessary to prevent such exposure during administration. However, the shielding conditions employed are not uniform. Therefore, in this study, we examined the shielding effects of four shading covers, which are commonly used to ensure the stability of CDDP in clinical settings., Methods: Four shielding conditions, along with a control, were tested under a 1000-Lux white fluorescent lamp at room temperature: aluminum foil (Al), brown shading cover (BSC), yellow shading cover (YSC), milky-white anti-exposure cover (MAC), and no shading cover (NSC). Under each shielding condition, the relationship between the wavelength and transmittance was monitored in the range of 200-800 nm. CDDP was diluted to three concentration levels: 50, 100, and 250 μg/mL. Furthermore, the amount of remaining CDDP and the pH in the solutions were measured for 120 h., Results: We found that BSC, YSC, and MAC conditions allowed various levels of transmittance; however, Al could not completely transmit light at all wavelengths. Moreover, we showed that the CDDP decreased under MAC and NSC conditions in a time-dependent manner, whereas this decrease was prevented under Al, BSC, and YSC conditions till 120 h. We also demonstrated increases in pH under MAC and NSC conditions in a time-dependent manner, which was prevented under Al, BSC, and YSC conditions till 120 h. Similar results were observed for all three CDDP concentration levels. The results also indicated the approximate relationship between the amount of remaining CDDP and the pH increase., Conclusions: Considering the opacity of each cover, our results suggest that BSC and YSC are useful and effective for minimizing CDDP degradation in clinical settings. Our results also indicate the alternatives for preparing, storing, and administering CDDP in clinical facilities, making the treatment schedule more flexible. Cumulatively, these findings indicate that the use of the appropriate shading covers, such as BSC or YSC, prevents the decrease in CDDP under fluorescent lighting, potentially contributing to achieving its full therapeutic effect., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Attention deficit is commonly observed in several psychiatric conditions. In particular, patients with attention deficit hyperactivity disorder exhibit not only attention deficit, but also intra-individual variability in response times (IIV-RT) during the performance of cognitive tasks related to attention span and sustained attention. Although obsessive compulsive disorder (OCD) is commonly observed across childhood, little is known about abnormalities in IIV-RT during the auditory odd-ball task, and how these changes relate to event-related potentials (ERPs) components. In the present study, we compared the ERPs of 15 adolescent and pediatric patients with OCD with 15 healthy age, sex, and IQ-matched controls. We found that tau of IIV-TR was not significantly different between the OCD group and controls, whereas the OCD group exhibited lower mu and sigma compared to controls. Furthermore, we revealed that P300 amplitude was significantly attenuated in the OCD group at Fz, C3, and C4, compared with controls. The present study thereby provided the first evidence that individuals with pediatric or adolescent OCD exhibit lower variability in reaction time in IIV-RT during an auditory odd-ball task than controls. These results suggest that there are no impairments in attention span and sustained attention in pediatric and adolescent patients with OCD., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Vancomycin-intermediately resistant Staphylococcus aureus (VISA) and heterogeneous VISA (hVISA) are associated with treatment failure. hVISA contains only a subpopulation of cells with increased minimal inhibitory concentrations, and its detection is problematic because it is classified as vancomycin-susceptible by standard susceptibility testing and the gold-standard method for its detection is impractical in clinical microbiology laboratories. Recently, a research group developed a machine-learning classifier to distinguish VISA and hVISA from vancomycin-susceptible S. aureus (VSSA) according to matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) data. Nonetheless, the sensitivity of hVISA classification was found to be 76%, and the program was not completely automated with a graphical user interface. Here, we developed a more accurate machine-learning classifier for discrimination of hVISA from VSSA and VISA among MRSA isolates in Japanese hospitals by means of MALDI-TOF MS data. The classifier showed 99% sensitivity of hVISA classification. Furthermore, we clarified the procedures for preparing samples and obtaining MALDI-TOF MS data and developed all-in-one software, hVISA Classifier, with a graphical user interface that automates the classification and is easy for medical workers to use; it is publicly available at https://github.com/bioprojects/hVISAclassifier. This system is useful and practical for screening MRSA isolates for the hVISA phenotype in clinical microbiology laboratories and thus should improve treatment of MRSA infections.

We previously reported a novel phenotype of vancomycin-intermediate Staphylococcus aureus (VISA), i.e., "slow VISA," whose colonies appear only after 72 h of incubation. Slow-VISA strains can be difficult to detect because prolonged incubation is required and the phenotype is unstable. To develop a method for detection of slow-VISA isolates, we studied 23 slow-VISA isolates derived from the heterogeneous VISA (hVISA) clinical strain Mu3. We identified single nucleotide polymorphisms (SNPs) in genes involved in various pathways which have been implicated in the stringent response, such as purine/pyrimidine synthesis, cell metabolism, and cell wall peptidoglycan synthesis. We found that mupirocin, which also induces the stringent response, caused stable expression of vancomycin resistance. On the basis of these results, we developed a method for detection of slow-VISA strains by use of 0.032 μg/ml mupirocin (Yuki Katayama, 7 March 2017, patent application PCT/JP2017/008975). Using this method, we detected 53 (15.6%) slow-VISA isolates among clinical methicillin-resistant S. aureus (MRSA) isolates. In contrast, the VISA phenotype was detected in fewer than 1% of isolates. Deep-sequencing analysis showed that slow-VISA clones are present in small numbers among hVISA isolates and proliferate in the presence of vancomycin. This slow-VISA subpopulation may account in part for the recurrence and persistence of MRSA infection., (Copyright © 2017 Katayama et al.)

Vascular calcification increases the risk of cardiovascular mortality. We previously reported that expression of elastin decreases with progression of inorganic phosphorus (Pi)-induced vascular smooth muscle cell (VSMC) calcification. However, the regulatory mechanisms of elastin mRNA expression during vascular calcification remain unclear. MicroRNA-29 family members (miR-29a, b and c) are reported to mediate elastin mRNA expression. Therefore, we aimed to determine the effect of miR-29 on elastin expression and Pi-induced vascular calcification. Calcification of human VSMCs was induced by Pi and evaluated measuring calcium deposition. Pi stimulation promoted Ca deposition and suppressed elastin expression in VSMCs. Knockdown of elastin expression by shRNA also promoted Pi-induced VSMC calcification. Elastin pre-mRNA measurements indicated that Pi stimulation suppressed elastin expression without changing transcriptional activity. Conversely, Pi stimulation increased miR-29a and miR-29b expression. Inhibition of miR-29 recovered elastin expression and suppressed calcification in Pi-treated VSMCs. Furthermore, over-expression of miR-29b promoted Pi-induced VSMC calcification. RT-qPCR analysis showed knockdown of elastin expression in VSMCs induced expression of osteoblast-related genes, similar to Pi stimulation, and recovery of elastin expression by miR-29 inhibition reduced their expression. Our study shows that miR-29-mediated suppression of elastin expression in VSMCs plays a pivotal role in osteoblastic differentiation leading to vascular calcification., (© 2015 The Molecular Biology Society of Japan and Wiley Publishing Asia Pty Ltd.)

Vascular calcification is known to reduce the elasticity of aorta. Several studies have suggested that autophagy-lysosomal pathway (ALP) in vascular smooth muscle cells (VSMCs) is associated with vascular calcification. A major component of oxidized low-density lipoproteins, 7-ketocholesterol (7-KC), has been reported to promote inorganic phosphorus (Pi)-induced vascular calcification and induce ALP. The aim of this study was to unravel the relationship between ALP and the progression of calcification by 7-KC. Calcification of human VSMCs was induced by Pi stimulation in the presence or absence of 7-KC. FACS analysis showed that 7-KC-induced apoptosis at a high concentration (30 μM), but not at a low concentration (15 μM). Interestingly, 7-KC promoted calcification in VSMCs regardless of apoptosis. Immunoblotting and immunostaining showed that 7-KC inhibits not only the fusion of autophagosomes and lysosomes but also causes a swell of lysosomes with the reduction of cathepsin B and D. Moreover, lysosomal protease inhibitors exacerbated the apoptosis-independent calcification by 7-KC although inhibition of autophagosome formation by Atg5 siRNA did not. Finally, the 7-KC-induced progression of calcification was alleviated by the treatment with antioxidant. Taken together, our data showed that 7-KC promotes VSMC calcification through lysosomal-dysfunction-dependent oxidative stress., (© 2015 The Molecular Biology Society of Japan and Wiley Publishing Asia Pty Ltd.)

Aim: Vascular calcification, an independent risk factor for cardiovascular disease in patients with chronic kidney disease(CKD), refers to the mineralization of vascular smooth muscle cells(VSMCs) caused by phenotypic changes toward osteoblast-like cells. DNA methylation, mediated by DNA methyltransferases(DNMTs), plays an important role in the differentiation of osteoblasts. We herein assessed the effects of a DNMT inhibitor on phenotypic changes in VSMCs and the development of vascular calcification., Methods: The effects of 5-aza-2'-deoxycytidine(5-aza-dC), a DNMT inhibitor, on human aortic smooth muscle cells(HASMCs) were evaluated. The expression and DNA methylation status of osteogenic genes were determined using RT-qPCR and bisulfite sequencing, respectively. Mineralization of HASMCs was induced by high concentrations of inorganic phosphate(Pi), as confirmed by quantitation of the calcium levels and von Kossa staining. Moreover, we examined the effects of the suppression of DNMT1 and/or alkaline phosphatase(ALP) on the mineralization of HASMCs., Results: 5-aza-dC increased the expression and activity of ALP and reduced the DNA methylation levels of the ALP promoter region in the HASMCs. In addition, both treatment with 5-aza-dC and downregulation of the DNMT1 expression promoted the Pi-induced mineralization of HASMCs. Moreover, both treatment with phosphonoformic acid(PFA), a sodium-dependent phosphate transporter inhibitor, and suppression of the ALP expression inhibited the 5-aza-dC-promoted mineralization of HASMCs., Conclusions: The present study showed that DNMT inhibitors facilitate the Pi-induced development of vascular calcification via the upregulation of the ALP expression along with a reduction in the DNA methylation level of the ALP promoter region.

Aim: Vascular calcification, a major complication of chronic kidney disease (CKD), refers to the mineralization of vascular smooth muscle cells (VSMCs), resulting from a phenotypic change towards osteoblast-like cells. Histone deacetylase inhibitors (HDIs), potential therapeutic agents for CKD, are known to promote the differentiation and mineralization of osteoblasts. In this study, we aimed to determine the effects of an HDI on the phenotypic change of VSMCs and the development of vascular calcification., Methods: The effect of trichostatin A (TSA), an HDI, on human aortic smooth muscle cells (HASMCs) was determined. The mineralization of HASMCs was induced by inorganic phosphorus (Pi), and was confirmed by quantitation of Ca levels and by von Kossa staining. Furthermore, we examined the effect of alkaline phosphatase (ALP) suppression using siRNA on Pi-induced vascular calcification in the presence or absence of TSA., Results: TSA increased the expression and activity of ALP in HASMCs at a concentration which showed an inhibitory effect of histone deacetylase (HDAC) activity but not on cell viability. Moreover, TSA promoted the Pi-induced mineralization of HASMCs. In addition, both phosphonoformic acid (PFA), which is a sodium-dependent phosphate transporter inhibitor, and suppression of ALP expression by siRNA markedly inhibited the TSA-promoted mineralization of HASMCs., Conclusion: These data show that inhibition of HDAC activity promotes Pi-induced vascular calcification via the up-regulation of ALP expression. Taken together, HDIs may increase the risk of vascular calcification in CKD patients.