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To elucidate molecular pharmacology of Rho-associated coiled-coil containing protein kinase inhibitors (ROCK-i, Ripasudil and Y27632) on their efficiency for aqueous outflow, 2D or 3D cultures of a human trabecular meshwork (HTM) were prepared in the presence of TGFβ2. Those were examined by transendothelial electrical resistance (TEER, 2D), electronic microscopy (EM, 2D and 3D), expression of the extracellular matrix (ECM) including collagen1 (COL1), COL4 and COL6, and fibronectin (FN) by immunolabeling and/or quantitative PCR (3D), and solidity of 3D organoids by a micro-squeezer. TGFβ2 significantly increased the TEER values in 2D cultures, and the ECM expression indicated that the 3D organoids assumed a more densely packed shape. ROCK-i greatly reduced the TGFβ2-induced enhancement of TEER and the immunolabeled ECM expression of the 3D organoids. In contrast, the mRNA expression of COL1 was increased, and those of COL4 and FN were unchanged. EM revealed that TGFβ2 caused the HTM cells to become more compact and abundant ECM deposits within the 3D organoids were observed. These were significantly inhibited by ROCK-i. The dense solids caused by the presence of TGFβ2 were significantly suppressed by ROCK-i. Current study indicates that ROCK-i cause beneficial effects toward the spatial configuration of TGFβ2-induced HTM 3D organoids.

To establish appropriate ex vivo models for a glaucomatous trabecular meshwork (TM), two-dimensional (2D) and three-dimensional (3D) cultures of human trabecular meshwork cells (HTM) were prepared in the presence of 250 nM dexamethasone (DEX) or 5 ng/mL TGFβ2, and characterized by the following analyses; transendothelial electrical resistance (TEER) measurements, FITC dextran permeability, scanning electron microscopy and the expression of the extracellular matrix (ECM) including collagen (COL)1, 4 and 6, and fibronectin (FN), α-smooth muscle actin (α-SMA), tissue inhibitor of metalloproteinase (TIMP)1–4, and matrix metalloproteinase (MMP)2, 9 and 14. DEX and TGFβ2 both caused a significant increase or decrease in the TEER values and FITC dextran permeability. During the 3D spheroid culture, DEX or TGFβ2 induced a mild and significant down-sizing and an increase in stiffness, respectively. TGFβ2 induced a significant up-regulation of COL1 and 4, FN, α-SMA, and MMP 2 and 14 (2D) or COL1 and 6, and TIMP2 and 3 (3D), and DEX induced a significant up-regulation of FN (3D) and TIMP4 (2D and 3D). The findings presented herein indicate that DEX or TGFβ2 resulted in mild and severe down-sized and stiff 3D HTM spheroids, respectively, thus making them viable in vitro HTM models for steroid-induced and primary open angle glaucoma.

A pan-ROCK-inhibitor, ripasudil (Rip), and a ROCK2 inhibitor, KD025, were used To study the effects of Rho-associated coiled-coil containing protein kinase (ROCK)1 and 2 on two-dimensional (2D) and three-dimensional (3D) cultures of a TGFβ2-treated human trabecular meshwork (HTM) cells. In the presence of 5 ng/mL TGFβ2, the effects of these inhibitors were characterized by transendothelial electrical resistance (TEER), FITC-dextran permeability, and the size and stiffness of 3D sphenoids, the expression of extracellular matrix (ECM) including collagen1, 4 and 6, and fibronectin, α-smooth muscle actin, a tissue inhibitor of metalloproteinase (TIMP)1–4, and matrix metalloproteinase (MMP)2, 9 and 14. TGFβ2 caused a significant increase in the TEER values, and decrease in FITC-dextran permeability, as well as a decrease in the sizes and stiffness of the 3D sphenoids. In the presence of ROCK inhibitors, the TGFβ2-induced effects of the TEER and FITC-dextran permeability were inhibited, especially by KD025. Rip induced a significant increase in sizes and a decrease in the stiffness of the TGFβ2-treated 3D sphenoids, although the effects of KD025 were weaker. Gene expressions of most of the ECMs, TIMP2 and MMP9 of 2D and 3D HTM cells were significantly up-regulated by TGFβ2. Those were significantly and differently modulated by Rip or KD025.

The milk fat globule membrane (MFGM) is a structural membrane that covers the globules of triglycerides dispersed in an emulsion of milk. In previous human studies, MFGM ingestion combined with light aerobic exercise training improved agility in elderly individuals. The purpose of this study was to examine whether 4 weeks of daily ingestion of MFGM combined with power training improves instantaneous physical strength - muscle strength, agility, and muscle power compared with placebo (whey protein isolate) in healthy young adults. The study was designed as a randomized, double-blind, and placebo-controlled trial. Ninety-eight healthy young adults aged 20-49 completed the study intervention, and they received either an MFGM powder containing 1.7 g of fat and 160 mg of sphingomyelin or an isocaloric placebo powder daily throughout 4 weeks (3 times/week) of power training. Physical strength tests and body composition measurements were conducted before and after the four-week intervention. An analysis of covariance (ANCOVA) model with baseline values as a covariate was carried out to test differences in post intervention values between groups. Ingestion of MFGM significantly improved peak torque (  = 0.003) and average power (  = 0.019) of isokinetic knee extensors, leg press 1 repetition maximum (RM) (  = 0.004) and sit-ups reps (  = 0.030), but not indicators of agility, compared with placebo after the 4-week intervention. There were no significant changes in lean body mass during the intervention period in either group and no significant differences between groups. We conclude that daily MFGM supplementation combined with power training are effective to improve instantaneous physical strength, such as muscle strength and power, compared with placebo in healthy young adults.

The Wnt/β‐catenin signaling pathway plays a key role in development and carcinogenesis. Although some target genes of this signaling have been identified in various tissues and neoplasms, the comprehensive understanding of the target genes and their roles in the development of human cancer, including hepatoma and colorectal cancer remain to be fully elucidated. In this study, we searched for genes regulated by the Wnt signaling in liver cancer using HuH‐7 hepatoma cells. A comparison of the expression profiles between cells expressing an active form of mutant β‐catenin and cells expressing enhanced green fluorescent protein (EGFP) identified seven genes upregulated by the mutant β‐catenin gene (CTNNB1). Among the seven genes, we focused in this study on ODAM, odontogenic, ameloblast associated, as a novel target gene. Interestingly, its expression was frequently upregulated in hepatocellular carcinoma, colorectal adenocarcinoma, and hepatoblastoma. We additionally identified a distant enhancer region that was associated with the β‐catenin/TCF7L2 complex. Further analyses revealed that ODAM plays an important role in the regulation of the cell cycle, DNA synthesis, and cell proliferation. These data may be useful for clarification of the main molecular mechanism(s) underlying these cancers. We have identified odontogenic ameloblast associated (ODAM) as a novel target gene of the Wnt/ß‐catenin signaling. Its expression is augmented in the majority of hepatoblastoma cells, and some hepatocellular and colorectal carcinoma cells. Elevated ODAM expression is associated with the proliferation of tumor cells.

Objectives To evaluate whether visual assessment of T2-weighted imaging (T2WI) or an apparent diffusion coefficient (ADC) could predict lymphovascular invasion (LVI) status in cases with clinically node-negative invasive breast cancer. Materials and methods One hundred and thirty-six patients with 136 lesions underwent MRI. Visual assessment of T2WI, tumour-ADC, peritumoral maximum-ADC and the peritumour-tumour ADC ratio (the ratio between them) were compared with LVI status of surgical specimens. Results No significant relationship was found between LVI and T2WI. Tumour-ADC was significantly lower in the LVI-positive ( n  = 77, 896 ± 148 × 10 −6  mm 2 /s) than the LVI-negative group ( n  = 59, 1002 ± 163 × 10 −6  mm 2 /s; p  < 0.0001). Peritumoral maximum-ADC was significantly higher in the LVI-positive (1805 ± 355 × 10 −6  mm 2 /s) than the LVI-negative group (1625 ± 346 × 10 −6  mm 2 /s; p  = 0.0003). Peritumour-tumour ADC ratio was significantly higher in the LVI-positive (2.05 ± 0.46) than the LVI-negative group (1.65 ± 0.40; p  < 0.0001). Receiver operating characteristic curve analysis revealed that the area under the curve (AUC) of the peritumour-tumour ADC ratio was the highest (0.81). The most effective threshold for the peritumour-tumour ADC ratio was 1.84, and the sensitivity, specificity, positive predictive value and negative predictive value were 77 % (59/77), 76 % (45/59), 81 % (59/73) and 71 % (45/63), respectively. Conclusions We suggest that the peritumour-tumour ADC ratio can assist in predicting LVI status on preoperative imaging. Key points • Tumour ADC was significantly lower in LVI-positive than LVI-negative breast cancer. • Peritumoral maximum-ADC was significantly higher in LVI-positive than LVI-negative breast cancer. • Peritumour-tumour ADC ratio was significantly higher in LVI-positive breast cancer. • Diagnostic performance of the peritumour-tumour ADC ratio was highest for positive LVI. • Peritumour-tumour ADC ratio showed higher diagnostic ability in postmenopausal than premenopausal patients.

The spread of coronavirus disease (COVID-19) has limited the implementation of face-to-face non-pharmacological treatment for the prevention of dementia. As a result, online non-pharmacological treatment has become increasingly important. In this study, we used an online conferencing system to implement an online version of a physical exercise program with music, and examined its effect on cognitive function. The participants were 114 healthy older adults [63 men and 51 women; mean age of 70.7 years (standard deviation = 4.6)]. Seventy-five participants were allocated to the physical exercise with music group (60 min, once a week, total 20 sessions), while the remaining 39 participants were assigned to the control group, and only underwent the examinations. In the physical exercise with music group, we performed neuropsychological examinations and brain tests both before and after the exercise program. Neuropsychological tests included the Mini-Mental State Examination, Raven's Colored Progressive Matrices (RCPM), the Rivermead Behavioral Memory Test, graphic imitation, word fluency (WF) (animal names and initial sounds), and the Trail Making Test-A/B. As an assessment of brain function, we developed an online examination of subtle cognitive decline, including tests of number and word memory, spatial grasp, the N-back task, and change inference. In the N-back task, the physical exercise with music group improved significantly relative to the control group ( = 0.008). The present findings suggest that the online version of the physical exercise with music program improved working memory, which mainly involves the frontal lobe.

Objectives To evaluate whether apparent diffusion coefficient (ADC) parameters could identify invasive components in cases with ductal carcinoma in situ (DCIS) diagnosed by biopsy. Methods This retrospective study was approved by the institutional review board and the requirement to obtain informed consent was waived. Sixty-nine consecutive women with 70 lesions diagnosed with DCIS by biopsy underwent breast magnetic resonance (MR) imaging. Multiple regions of interest were placed (as many as possible) within the lesion on ADC maps. The minimum ADC values and the ADC difference values obtained as the difference between minimum and maximum ADCs were evaluated. Results Surgical specimens revealed 51 lesions with pure DCIS and the remaining 19 lesions with DCIS with invasive components (DCIS-IC). The minimum ADC value for DCIS-IC (0.99 ± 0.04 × 10 −3  mm 2 /s) was significantly lower than that of pure DCIS (1.15 ± 0.03 × 10 −3  mm 2 /s) ( P   =  0.0037). The ADC difference value for DCIS-IC (0.38 ± 0.05 × 10 −3  mm 2 /s) was significantly higher than that of pure DCIS (0.17 ± 0.03 × 10 −3  mm 2 /s). ROC curve analysis for differentiating DCIS-IC from pure DCIS revealed that the area under the curve was 0.71 for minimum ADC value and 0.77 for ADC difference value. Conclusions The minimum ADC values and ADC difference values could suggest the presence of invasive components. Key Points • Identification of invasive components in DCIS before treatment is clinically important. • Diffusion-weighted MR imaging can help lesion assessment in breast cancer. • The minimum ADC value may suggest the presence of an invasive component in DCIS. • The ADC difference value also suggests the presence of an invasive component in DCIS. • Preoperative evaluation of diffusion-weighted MR imaging may help surgical planning for DCIS.

Introduction Recent advances in artificial intelligence (AI) have been substantial. We investigated the effectiveness of an online meeting in which normal older adults (otokai) used a music‐generative AI that transforms text to music (Music Trinity Generative Algorithm‐Human Refined [MusicTGA‐HR]). Methods One hundred eighteen community‐dwelling, cognitively normal older adults were recruited through the internet (64 men, 54 women; mean age: 69.4 ± 4.4 years). Using MusicTGA‐HR, the participants chose music that they thought was the most suitable to a given theme. We established 11 classes of 7–10 members and one instructor each. Each class held an online meeting once a week, and each participant presented the music they chose. The other participants and the instructor then commented on the music. Neuropsychological assessments were performed before and after the intervention for 6 months, and the results before and after the intervention were statistically analyzed. Results The category and letter word fluencies (WFs) were significantly improved (category WF: p = .003; letter WF: p = .036), and the time of the Trail‐Making Test‐B was also significantly shortened (p = .039). The Brain Assessment, an online cognitive test we developed, showed significant improvement in the memory of numbers (p < .001). Conclusion The online meeting of the otokai, which used music‐generative AI, improved the frontal lobe function and memory of independent normal older adults. We investigated the effectiveness of an online meeting in which normal older adults (otokai) used a music‐generative artificial intelligence (AI) that transforms text to music (Music Trinity Generative Algorithm‐Human Refined [MusicTGA‐HR]). Using MusicTGA‐HR, the participants chose music that they thought was the most suitable to a given theme. Each class held an online meeting once a week for 6 months, and each participant presented the music they selected. As a result, the frontal lobe function and memory were improved.

Ribavirin, a nucleoside analog, is used to treat chronic hepatitis C (HCV) infections. Therapeutic drug monitoring for ribavirin is useful for predicting the effect of treatment. In this study, the selective extraction of ribavirin from serum samples and the HPLC-UV detection method were investigated using a monolithic silica disk-packed spin column with phenylboronate moieties. In this study, 0.6% ammonia and 1% formic acid solutions were used as the conditioning and elution solutions, respectively, and recoveries of >90% were obtained. Ribavirin was separated on an InertSustain AQ-C18 column by isocratic elution. The mobile phase consisted of a mixture of 7 mM Na2SO4 and 60 mM H3PO4 in H2O. Linear regression curves were observed for calibrations over a concentration range of 0.25–25 µg/mL. The lower limit of detection was 0.05 µg/mL, and the lower limit of quantification was 0.1 µg/mL. The intra- and inter-day precisions were below 3.2 and 3.1%, respectively. This method can be applied to quantify ribavirin levels in human serum and may be useful for pharmacokinetic studies.