Although glioblastoma (GBM) stem-like cells (GSCs), which retain chemo-radio resistance and recurrence, are key prognostic factors in GBM patients, the molecular mechanisms of GSC development are largely unknown. Recently, several studies revealed that extrinsic ribosome incorporation into somatic cells resulted in stem cell properties and served as a key trigger and factor for the cell reprogramming process. In this study, we aimed to investigate the mechanisms underlying GSCs development by focusing on extrinsic ribosome incorporation into GBM cells. Ribosome-induced cancer cell spheroid (RICCS) formation was significantly upregulated by ribosome incorporation. RICCS showed the stem-like cell characters (number of cell spheroid, stem cell markers, and ability for trans differentiation towards adipocytes and osteocytes). In RICCS, the phosphorylation and protein expression of ribosomal protein S6 (RPS6), an intrinsic ribosomal protein, and STAT3 phosphorylation were upregulated, and involved in the regulation of cell spheroid formation. Consistent with those results, glioma-derived extrinsic ribosome also promoted GBM-RICCS formation through intrinsic RPS6 phosphorylation. Moreover, in glioma patients, RPS6 phosphorylation was dominantly observed in high-grade glioma tissues, and predominantly upregulated in GSCs niches, such as the perinecrosis niche and perivascular niche. Those results indicate the potential biological and clinical significance of extrinsic ribosomal proteins in GSC development.

Background Therapeutic drug monitoring for voriconazole is recommended for its optimum pharmacotherapy. Although the feedback of the measurement result of serum voriconazole concentration by outsourcing needs a certain time (days within a 1 week), there was no medical equipment for the measurement available in clinical practice. Recently, a medical equipment based on high performance liquid chromatography, named LM1010, has been developed and authorized for clinical use. In this study, to validate the clinical performance of LM1010, we compared the measured serum voriconazole concentrations by LM1010 with those by outsourcing measurement using liquid chromatography-tandem mass spectrometry. Methods We conducted the observational study approved by the institutional review board of Kumamoto University Hospital (No. 1786). Residual serum samples harvested for therapeutic drug monitoring were separated. Measured concentrations by LM1010 by the standard filter method (needs serum volume of > 400 μL) or the dilute method (needs serum volume of 150 μL) were compared with those by outsourcing, respectively. Acceptable measurement error range of 0.72–1.33 was considered. There were 69 serum samples, where the 35 or 34 samples were employed for evaluation of the standard filter method or the dilute method, respectively. Results The measured concentration using the standard filter method/outsourcing was 2.22/2.10 μg/mL as the median, 1.57–3.40/1.53–3.62 as the interquartile range, < 0.2–10.76/< 0.2–11.46 μg/mL as the range, while those using the dilute method/outsourcing was 2.36/2.29 μg/mL as the median, 1.08–2.94/1.03–3.06 as the interquartile range, 0.24–10.00/< 0.2–10.85 μg/mL as the range. The regression line for the standard filter method or the dilute method were y = 0.935x + 0.154 or y = 0.933x + 0.162, respectively. The standard filter method or the dilute method showed 11.4% samples (4/35, 95%CI 3.2–26.7%) or 8.8% samples (3/34, 95%CI 1.9–23.7%) out of the acceptable measurement error range, respectively. Conclusion Measurement of serum voriconazole concentration by LM1010 can be acceptable in clinical TDM practice.

Nalfura ne is a pharmaceutical agent used in the treatment of cutaneous pruritus. Although its orally disintegrating (OD) lm agent is approved, noninferiority of its disintegration and elution to various OD tablet agents has yet to be demonstrated. This study aimed to evaluate the pharmaceutical characteristics of the nalfura ne OD lm agent. Disintegration and elution performance were tested for 4 different types of nalfura ne OD pharmaceutical agents including 1 lm agent and 3 tablet agents. Visual evaluation was employed for the disintegration test, while measurement of concentration using high performance liquid chromatography with ultraviolet was employed for the elution test. As a result of disintegration evaluation (n = 3), the OD lm agent repeatedly exhibited the same complete disintegration time (60 s), while the other three OD tablet agents showed the time variability (120 s -30 min). After the test start, the OD lm agents began disintegration at 20 s while the OD tablet agents began disintegration immediately. As a result of elution evaluation (n = 6), after the test start, the OD lm agent was eluted 100.6％ in 5 min, while the OD tablet agents were eluted 95.8％, 75.8％ and 80.5％, respectively. In conclusion, this study indicates that the nalfura ne OD lm agent was not inferior to the OD tablet agents in terms of disintegration and elution.

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(1) Background: multiple myeloma patients have benefited from bortezomib therapy, though it has often been discontinued owing to diarrhea. The objective of this study was to verify serum bortezomib concentration in the emergence of diarrhea. (2) Methods: this prospective, observational case-control, and monocentric study was performed with an approval by the Ethics Committee of Kumamoto University Hospital in 2015 (No. 1121) from February 2015 to April 2017. (3) Results: twenty-four patients with bortezomib therapy were recruited; eight patients (33.3%) developed diarrhea at day 3 as median. Median measured trough bortezomib concentration at 24 h after first or second dose for patients with or without diarrhea was 0.87 or 0.48 ng/mL, respectively (p = 0.04, Wilcoxon signed rank test). Receiver operation characteristic (ROC) analysis produced the cut-off concentration of 0.857 ng/mL (area under the ROC curve of 0.797, sensitivity of 0.625, specificity of 0.875). The survival curves between patients with and without diarrhea were similar (p = 0.667); those between patients with higher and lower concentration than median value (0.61 ng/mL) were also similar (p = 0.940). (4) Conclusions: this study indicated the possible involvement of serum bortezomib concentration in the emergence of diarrhea in bortezomib therapy in patients with multiple myeloma.