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Abstract Osteoprotegerin (OPG) is a secreted cytokine that functions as a decoy receptor for receptor activator of nuclear factor kappa-B (RANK) ligand (RANKL). Anti-RANKL treatment for bone metastasis has been widely accepted for solid tumors. However, the mechanism of OPG-RANKL-RANK signaling in systemic colorectal cancer (CRC) metastasis remains unclear. In this study, we investigated the relevance and function of OPG expression in CRC liver metastasis. First, we performed in silico analysis using The Cancer Genome Atlas public database and found that lower OPG expression in CRC was associated with poor overall survival. Immunohistochemistry analyses using resected specimen from patients with CRC in our institute confirmed the result. Patient-matched primary CRC and liver metastases showed a significant downregulation of OPG expression in metastatic lesions. In CRC cell lines, OPG expression did not suppress cell proliferation and migration. However, OPG expression inhibited macrophage migration by suppressing the RANKL-RANK pathway. Moreover, in vivo mouse liver metastasis models showed that OPG expression in CRC cells suppressed liver metastases. In addition, treatment with an anti-RANKL neutralizing antibody also suppressed liver metastases. These results showed that downregulation of OPG expression in CRC cells promotes liver metastasis by activating tumor-associated macrophage, which can become a candidate for targeted therapy with anti-RANKL neutralizing antibody for CRC liver metastasis.

Abstract Background Empirical antibiotic treatment against peritoneal dialysis (PD)-related peritonitis should be immediately initiated before PD effluent culture results are obtained. As culture results guide the choice of antibiotics, culture-negative peritonitis (CNP) is a serious issue. In addition, the identification of the causative organism often indicates a possible source of infection. This study aimed to clarify the predictors of CNP. Methods This single-center, retrospective study was conducted from November 2007–December 2018 in patients undergoing PD with peritonitis at our institution, where 204 peritonitis episodes (57 culture-negative, 147 culture-positive) were investigated based on demographics, and clinical parameters. CNP predictors were investigated using logistic regression. Results CNP rate was significantly higher in female and in patients with higher platelet counts, lower dialysate cell counts at peritonitis diagnosis, and higher serum β2-microglobulin levels. In multivariate logistic regression, female sex (odds ratio [OR] 2.69, 95% confidence interval [CI] 1.31–5.54), dialysate cell count at diagnosis (OR0.99, 95% CI 0.99–0.99), and serum β2-microglobulin level (OR 1.04, 95% CI 1.00–1.07) were significantly associated with CNP. The areas under the receiver operating characteristic curve for female patients, dialysate cell counts at diagnosis of peritonitis, serum β2-microglobulin level, and female patients + dialysate cell counts at diagnosis of peritonitis + serum β2-microglobulin level were 0.604, 0.694, 0.603, and 0.751, respectively. Conclusions Female sex, dialysate cell counts at peritonitis diagnosis, and serum β2-microglobulin levels may be predictors of CNP.

Abstract Background Stenotrophomonas maltophilia (S. maltophilia) is being increasingly recognized as an important cause of nosocomial infections, particularly in immunocompromised patients, such as patients undergoing dialysis. S. maltophilia peritonitis is strongly associated with the loss of peritoneal catheter among patients undergoing peritoneal dialysis (PD) owing to its resistance to different groups of antibiotics. Thus, the aim of this study was to investigate the characteristics of and risk factors for S. maltophilia peritonitis in patients undergoing PD. Methods This single-center, retrospective, case–control study was conducted between April 2013 and October 2022. Patients who were undergoing PD at Kawashima Hospital and were diagnosed with S. maltophilia peritonitis were included in this study. Controls were randomly selected from among patients who were undergoing PD and were diagnosed with peritonitis caused by microorganisms other than S. maltophilia. The demographic data, clinical characteristics, and initial treatment data of the patients were analyzed to determine the risk factors for PD-related S. maltophilia peritonitis. Results Five patients with S. maltophilia peritonitis and 15 controls (three controls to one case) were included in this study. The incidence of S. maltophilia peritonitis was significantly more frequent among patients with diabetes mellitus (80.0% vs. 20.0%; p = 0.031) and among patients with higher white blood cell counts in the dialysate after appropriate antibiotic therapy (2561/µL [349–4654/µL] vs. 20/µL [20–23/µL]; p = 0.0006) than among the control patients. Although all the patients were treated with appropriate antibiotics after the identification of S. maltophilia, they had a significantly higher rate of catheter removal than the controls (80.0% vs. 0.0%; p = 0.001). Conclusions Diabetes mellitus may be an important risk factor for S. maltophilia peritonitis in patients undergoing PD.

Abstract Background Crescentic immunoglobulin A (IgA) nephropathy, defined as > 50% of the glomeruli with crescents, often has a poor renal prognosis. Because of the high prevalence of pre-eclampsia in the second trimester of pregnancy, we often fail to investigate the new onset of glomerulonephritis and the aggravation of subclinical nephropathies. We report a case of nephrotic syndrome suggestive of crescentic IgA nephropathy possibly triggered by pregnancy. Case presentation A 33-year-old multipara was referred for persistent proteinuria, hematuria, and hypoalbuminemia two months postpartum. The patient was diagnosed with proteinuria for the first time at 36 weeks of gestation. The patient was normotensive during pregnancy. Renal biopsy revealed crescentic IgA nephropathy, with cellular crescents in 80% of the glomeruli and no global sclerosis. After treatment with pulse steroids followed by high-dose oral glucocorticoids and tonsillectomy, a gradual improvement was seen in proteinuria, hematuria, and hypoalbuminemia. Conclusion Although the precise mechanism remains unclear, pregnancy possibly triggered the new onset of crescentic IgA nephropathy or the aggravation of subclinical IgA nephropathy.

This paper demonstrates the in situ sinter bonding of Ag microparticle pastes to a Si substrate via the temporal formation and decomposition of Ag carboxylate on the surface of Ag microparticles. This was proposed via the investigation of Ag sinter bonding using the redox reaction between Ag2O and ethylene glycol, which achieved a bonding strength above 30 MPa even for the bonding temperature at 220 °C. Thermal analysis was used to identify the product of the redox reaction between Ag2O and ethylene glycol and determine the bonding temperature because the final reaction facilitates the interfacial sinter bonding with the substrate. Fourier-transform infrared spectroscopy and nuclear magnetic resonance results indicated the in situ formation of Ag salts of carboxylic acids, such as Ag oxalate on the surface of Ag microparticles. Therefore, the sinter bonding process enabled by the in situ formation and subsequent decomposition of these Ag salts was investigated using Ag microparticles and oxalic acid. Observations of the surface and interfacial morphology of the Ag particles after heating revealed the formation of Ag nanoparticles on the surfaces of the microparticles and the formation of sintering necks between the particles. The bonding experiments demonstrated a significant increase in strength with the addition of oxalic acid to the Ag paste due to the enhanced interfacial sinter bonding with the substrate. The in situ formation and decomposition of Ag salts are promising strategies for improving sintered bonds in electronic devices because they can provide enhanced localized sinter bonding using stable insert materials.

Robotic process automation (RPA) is automating various job processes in many offices. However, most existing RPA systems automate only processes that are performed on computers. It is highly desirable to develop physical RPA systems that incorporate real robots to automate physical job processes. When developing physical RPA systems, handling paper is particularly important because many physical office jobs involve handling paper documents. However, it is not easy for robots to handle paper because paper is fragile. To address this issue, we propose an electroadhesive paper gripper in this study. The use of electroadhesion enables a robot to handle paper in a simple, non-destructive, and quiet manner. We provide (1) a mechanism for lifting a sheet of paper without accurate control of robot hands, (2) a mechanism for a small gripper to hold a large sheet of paper without bending it, and (3) a method for quickly releasing a sheet of paper. Furthermore, we apply the proposed paper gripper to a document-sorting robot. The robot that we have developed automatically arranges a given stack of paper documents in a predetermined order (e.g., alphabetical or numerical). Experimental results show the validity of the paper gripper and the sorting robot.

Summary: Patient-derived organoids (PDOs) recapitulate the cellular heterogeneity of the original colorectal tumor tissue. Here, we describe a protocol to generate genetically modified PDOs to investigate cancer stem cells. This protocol uses the CRISPR-Cas9 system to knock-in the IRES-EGFP-P2A-iCaspase9 cassette into the 3′ UTR of the potential cancer stem cell marker gene, which allows us to investigate their potential for self-replication and pluripotency. We describe the procedure for generating mutant PDOs and their application for stem cell research.For complete details on the generation and use of this protocol, please refer to Okamoto et al. Okamoto et al. (2021).

Abstract RAS signaling is a promising target for colorectal cancer (CRC) therapy, and a variety of selective inhibitors have been developed. However, their use has often failed to demonstrate a significant benefit in CRC patients. Here, we used patient-derived organoids (PDOs) derived from a familial adenomatous polyposis (FAP) patient to analyze the response to chemotherapeutic agents targeting EGFR, BRAF and MEK. We found that PDOs carrying KRAS mutations were resistant to MEK inhibition, while those harboring the BRAF class 3 mutation were hypersensitive. We used a systematic approach to examine the phosphorylation of RAS effectors using reverse-phase protein array (RPPA) and found increased phosphorylation of MEK induced by binimetinib. A high basal level of ERK phosphorylation and its rebound activation after MEK inhibition were detected in KRAS-mutant PDOs. Notably, the phosphorylation of EGFR and AKT was more closely correlated with that of MEK than that of ERK. Transcriptome analysis identified MYC-mediated transcription and IFN signaling as significantly correlated gene sets in MEK inhibition. Our experiments demonstrated that RPPA analysis of PDOs, in combination with the genome and transcriptome, is a useful preclinical research platform to understand RAS signaling and provides clues for the development of chemotherapeutic strategies.

Alogliptin is one of the dipeptidyl peptidase-4 inhibitors used to treat patients with type 2 diabetes. Little is known about the nephrotoxicity associated with alogliptin, such as nephrotic syndrome or interstitial nephritis. We report a biopsy-proven rare case of minimal change nephrotic syndrome and interstitial nephritis induced by alogliptin. A 68-year-old man who had been prescribed alogliptin was hospitalized for nephrotic syndrome. On admission, serum creatinine level was elevated with increased urinary β2-microglobulin and N-acetyl-β-d-glucosaminidase excretion. Kidney biopsy revealed minor glomerular abnormalities and interstitial nephritis, and gallium-67 scintigraphy showed uptake in both kidneys. A drug lymphocyte stimulation test for alogliptin was positive. With discontinuation of alogliptin treatment alone, serum creatinine level normalized in parallel with urine β2-microglobulin and N-acetyl-β-d-glucosaminidase levels. In addition, complete remission of nephrotic syndrome was observed. Drug-induced dual pathology has not been previously reported with alogliptin. In summary, clinicians should keep in mind that alogliptin can induce minimal change nephrotic syndrome and interstitial nephritis. Index Words: Alogliptin, minimal change nephrotic syndrome, interstitial nephritis, gallium-67 scintigraphy, drug lymphocyte stimulation test

In smart manufacturing, human-cyber-physical systems host digital twins and IoT-based networks. The networks weave manufacturing enablers such as CNC machine tools, robots, CAD/CAM systems, process planning systems, enterprise resource planning systems, and human resources. The twins work as the brains of the enablers; that is, the twins supply the required knowledge and help enablers solve problems autonomously in real-time. Since surface roughness is a major concern of all manufacturing processes, twins to solve surface roughness-relevant problems are needed. The twins must machine-learn the required knowledge from the relevant datasets available in big data. Therefore, preparing surface roughness-relevant datasets to be included in the human-cyber-physical system-friendly big data is a critical issue. However, preparing such datasets is a challenge due to the lack of a steadfast procedure. This study sheds some light on this issue. A state-of-the-art method is proposed to prepare the said datasets for surface roughness, wherein each dataset consists of four segments: semantic annotation, roughness model, simulation algorithm, and simulation system. These segments provide input information for digital twins’ input, modeling, simulation, and validation modules. The semantic annotation segment boils down to a concept map. A human- and machine-readable concept map is thus developed where the information of other segments (roughness model, simulation algorithm, and simulation system) is integrated. The delay map of surface roughness profile heights plays a pivotal role in the proposed dataset preparation method. The successful preparation of datasets of surface roughness underlying milling, turning, grinding, electric discharge machining, and polishing shows the efficacy of the proposed method. The method will be extended to the manufacturing processes in the next phase of this study.

Background: We aimed to determine a cut-off value for physical activity (PA), measured using an accelerometer, between patients with knee osteoarthritis (OA) who decided to undergo total knee arthroplasty (TKA) and those who continued conservative treatment. Methods: Forty-two participants were assigned to either a TKA group or a non-TKA group (21 per group). They were instructed to wear an accelerometer throughout the day. Average daily steps (steps/day), average daily time of light PA (LPA) (min/day), and average daily time of moderate-to-vigorous PA (MVPA) (min/day) were measured for seven days. Variables between the two groups were compared using univariate analyses, and then a stepwise logistic regression was conducted to determine which variables best correlated with undergoing TKA. The PA cut-offs were analysed using the receiver operating characteristic curve. Results: Pain severity (p = 0.002), KL grade (p = 0.001), and MVPA (p = 0.012) differed significantly between the groups. The most useful cut-off value was 5.84 (min/day) for MVPA (AUC = 0.773), although only pain severity and KL grade were found to be significant contributors to undergoing TKA. Conclusions: Our results revealed there was a significant decrease in PA levels (MVPA cut-off, 5–6 min/day) in the TKA group compared with the non-TKA group.

Introduction : During laparoscopic abdominoperineal resection (APR) for low rectal cancer, it is difficult to resect the levator muscles and remove a cylindrical specimen without venturing close to the rectal wall to ensure negative circumferential resection margins (CRM). To solve this problem, we developed a needle-guided, laparoscopic, abdominoperineal resection (LAPR) technique. Aim: To present the safety and superiority of our technique, “needle-guided LAPR”. Material and methods: In 2015, we performed needle-guided LAPR in 5 patients. In brief, the procedure is performed as follows. After total mesorectum excision to the level of the levator muscles, a needle is inserted through the perineum from the dorsal side of the internal aspect of the anus toward the sacral tip. The levator muscles and fat tissue are resected laparoscopically by following the needle. After the levator muscles have been resected, the needle is followed in a similar manner to resect the specimen from the perineum, enabling easy access to the intra-abdominal space and removal of the specimen. No position change is required during the perineal operation or pelvic floor reconstruction. Results : Mean age was 68 years and 3 patients were male. There were no intraoperative complications or conversions to open surgery. The mean operation time and intraoperative blood loss were 319 min and 131 ml, respectively. All specimens were cylindrical in shape and had negative CRM. There were no postoperative complications. Conclusions : Needle-guided LAPR was easily and safely performed to achieve accurate resection of the levator muscles. This technique could contribute to standardization of LAPR.

There is increasing interest in the development of noble metal separation/recovery processes, especially for applications to “urban mining”. Common separation/recovery processes for noble metals use a solvent (liquid-liquid) extraction technique in hydrometallurgy. However, these processes are time-consuming and not environmentally friendly, because they use organic solvents for sequential metal ion extractions. Electrowinning is an alternative approach for selective metal precipitation that involves controlling the redox potentials of electrodes but requires specialized equipment and generates hydrogen as a byproduct at the cathode surface under dilute conditions. In the present study, we investigated selective gold recovery from a homogenous aqueous solution containing a mixture of dilute HAuCl4 and H2PtCl6 (5.0 × 10−5 M each) and aromatic amino acid-containing peptides (2.0 × 10−4 M each). Gold selectivity was determined by analyzing the compositions of the solids and supernatants obtained from the reaction mixtures. A much higher gold selectivity (gold/platinum (Au/Pt) atomic ratio = 7.5) was obtained using an anthracene-containing peptide compared to peptides containing one or two naphthalene ring(s). Our proposed approach is applicable to the sequential separation of several noble metal ions, such as Au, palladium (Pd), Pt, iridium (Ir) and rhodium (Rh), and simply requires developing aromatics suitable for each noble metal of interest.

In the present study, we investigated the neuroprotective effects of Kangen-karyu (KGK) in a repeated cerebral ischemia model (2 × 10 min, 1-h interval). A 21-day pre- and postischemic treatment with KGK (10 – 300 mg/kg) and aspirin (5 mg/kg) improved the spatial memory impairment and neuronal death in the hippocampal CA1 region induced by repeated cerebral ischemia. However, a 7-day post-ischemic treatment with KGK did not attenuate the spatial memory impairment and neuronal death in this model. To determine the mechanism of action of KGK, we investigated the effects of a 14-day pre-ischemic treatment with KGK on cerebral blood flow in the hippocampal area of the repeated cerebral ischemia model using laser Doppler flowmetry. The 14-day pre-ischemic treatment with KGK increased the cerebral blood flow during reperfusion. These results suggest that a 21-day pre- and post-ischemic treatment with KGK can protect against brain damage caused by cerebral ischemia by increasing the cerebral blood flow in the hippocampal area. Keywords:: Kangen-karyu, repeated cerebral ischemia, cerebral blood flow, neuronal death

Background. Although retinol-binding protein 4 (RBP4) associates with insulin resistance and remnant-like particles triglyceride (RLP-TG) elevated in the insulin resistant state, few data exist regarding the relationship between RBP4 and RLP-TG. Subjects and Methods. The study included 92 Japanese type 2 diabetic mellitus (T2DM) male patients (age years, body mass index (BMI) kg/m2, waist circumference (WC) cm, and HbA1c (NGSP) %). Patients on medications affecting insulin sensitivity, including fibrates, biguanides, and thiazolidinedione, were excluded. Visceral fat area (VFA) and subcutaneous fat area (SFA) were measured by computed tomography. Results. RBP4 levels showed a significant positive correlation with RLP-TG ( and ), TG ( and ), RLP-TG/TG ( and ), and age ( and ), although there was no significant correlation with VFA, SFA, adiponectin levels, or homeostasis model of assessment insulin resistance (HOMA-R). Multiple regression analysis revealed that RBP4 was an independent determinant of RLP-TG () but was not a determinant of TG. Conclusions. RBP4 correlates positively with serum RLP-TG independent of fat accumulation in T2DM. RBP4 may regulate remnant metabolism independent of glycemic control in T2DM.

X-linked Alport syndrome is a hereditary progressive renal disease resulting from the disruption of collagen a 3a 4a 5 (IV) heterotrimerization caused by pathogenic variants in the COL4A5 gene. This study aimed to report a male case of X-linked Alport syndrome with a mild phenotype accompanied by an atypical expression pattern of type IV collagen a 5 [a5 (IV)] chain in glomerulus. A 38-year-old male presented with proteinuria (2.3 g/day) and hematuria. He has been detected urinary protein and occult blood since childhood. A renal biopsy was performed at the age of 29 years; however, a diagnosis of Alport syndrome was not considered. A renal biopsy 9 years later revealed diffuse thinning and lamellation of the glomerular basement membrane. A staining for a5 (IV) revealed a normal expression pattern in the glomerular basement membrane and a complete negative expression in Bowman's capsule and distal tubular basement membrane. Using next-generation sequencing, we detected a COL4A5 missense variant within exon 35 (NM_000495.5: c.3088G>A, p. G1030S). The possibility of X-linked Alport syndrome should be considered when negative expression of a 5 (IV) staining on Bowman's capsule was observed. [ABSTRACT FROM AUTHOR]