Colony stimulating factor 1 (CSF1) receptor (CSF1R) is a receptor protein-tyrosine kinase specifically expressed in monocyte-lineage cells, such as monocytes and macrophages. In this study, we ...characterized the pharmacological properties of an azetidine compound, JTE-952 ((2S)-3-{2-({3-4-(4-cyclopropylbenzyloxy)-3-methoxyphenylazetidine-1-yl}carbonyl)pyridin-4-ylmethoxy}propane-1,2-diol), which is a novel CSF1R tyrosine kinase inhibitor. JTE-952 potently inhibited human CSF1R kinase activity, with a half maximal inhibitory concentration of 11.1 nmol/L, and inhibited the phosphorylation of CSF1R in human macrophages and the CSF1-induced proliferation of human macrophages. It also inhibited human tropomyosin-related kinase A activity, but only at concentrations 200-fold higher than that required to inhibit the activity of CSF1R in inducing the proliferation of human macrophages. JTE-952 displayed no marked inhibitory activity against other kinases. JTE-952 potently inhibited lipopolysaccharide-induced proinflammatory cytokine production by human macrophages and in whole blood. JTE-952 (≥3 mg/kg given orally) also significantly attenuated the CSF1-induced priming of lipopolysaccharide-induced tumor necrosis factor-alpha production in mice and arthritis severity in a mouse model of collagen-induced arthritis. Taken together, these results indicate that JTE-952 is an orally available compound with potent and specific inhibitory activity against CSF1R, both in vitro and in vivo. JTE-952 is a potentially clinically useful agent for various human inflammatory diseases, including rheumatoid arthritis.
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and structural destruction of the joints. Bone damage occurs in an early stage after onset and ...osteoclast activation plays a substantial role in its progression. Colony stimulating factor 1 receptor (CSF1R) is a receptor protein tyrosine kinase specifically expressed in monocytic-lineage cells such as macrophages and osteoclasts. Here, we investigated the effect of JTE-952, a novel CSF1R tyrosine kinase inhibitor, on osteoclast formation in vitro and on bone destruction in a mouse model of collagen-induced arthritis. JTE-952 completely inhibited osteoclast differentiation from human monocytes, with an IC50 of 2.8 nmol/L, and reduced osteoclast formation from the synovial cells of RA patients. Detectable levels of colony stimulating factor 1 (CSF1), a ligand of CSF1R, were observed in the synovial tissues of the arthritis model, similar to those observed in the pathology of human RA. JTE-952 significantly suppressed increases in the bone destruction score, the number of tartrate-resistant-acid-phosphatase-positive cells, and the severity of arthritis in the model mice. We also examined the efficacy of JTE-952 combined with methotrexate. This combination therapy more effectively reduced the severity of bone destruction and arthritis than monotherapy with either agent alone. In summary, JTE-952 potently inhibited human osteoclast formation in vitro and suppressed bone destruction in an experimental arthritis model, especially when combined with methotrexate. These results indicate that JTE-952 should strongly inhibit bone destruction and joint inflammation in RA patients and effectively prevent the progression of the structural destruction of joints.
Abstract Purpose The aim of this study was to investigate root canal configurations in maxillary first and second molars from a Japanese population, as well as the relationship between the root canal ...number and root concavity depth, using micro-computed tomography. Methods Maxillary first (N = 74) and second (N = 70) molars from a Japanese population were used. Virtual horizontal sections were created, and the number of root canals and the degree of root concavity were measured. Mesiobuccal (MB) roots were categorized into Group 1 (with a single root canal) or Group 2 (with two or more root canals). The relationship between the root canal number and root concavity depth was evaluated using the Mann-Whitney U test. Results Approximately 51% and 35% of the MB roots in the three-rooted maxillary first and second molars, respectively, had two or more root canals. The depths of the root concavities in maxillary first molars differed significantly between Groups 1 and 2 at the mesial and distal sides of the MB root, in the section 2 mm apical to the furcation area (p < 0.05). Conclusions A significant relationship between the number of root canals and the depth of root concavity in the MB root of the maxillary first molars was observed. Close clinical monitoring is needed during the removal of calculus and cleaning of the root surfaces of maxillary first molars: specifically, excessive removal of cementum and dentin should be avoided, particularly when the molar has already undergone root canal treatment.
Fabry disease is a rare X-linked lysosomal storage disorder caused by mutations in the alpha-galactosidase A (GLA) gene that results in deficiency of the enzyme GLA and leads to the accumulation of ...globotriaosylceramide (GL-3) in cells. The accumulation of GL-3 may lead to life-threatening complications. Significant advances in genetic sequencing technology have led to a better understanding of genotype-phenotype interactions in Fabry disease. Fabry disease with an R112H mutation is known as the non-classic type. However, the long-term clinical course of the disease remains unknown. We herein report a patient with a 30-year natural history of non-classic Fabry disease with an R112H mutation.
A higher body mass index (BMI) has been associated with better survival among chronic kidney disease patients in some reports. However, more research is required to determine the associations between ...BMI and mortality in incident hemodialysis patients. Therefore, this study aimed to investigate the association between mortality and BMI measured at the first hemodialysis session and 2 weeks after hemodialysis initiation in Japanese patients with incident hemodialysis. We retrospectively enrolled 266 adult patients with incident hemodialysis who were treated at our hospital between May 2013 and June 2019. The data on BMI was obtained at the first hemodialysis session and 2 weeks after hemodialysis initiation. Patients were divided into tertiles based on BMI <18.5 (low), 18.5-23.9 (normal), and greater than or equal to24 (high) kg/m.sup.2 . The normal group was used as the reference group. The primary outcome was all-cause mortality. The mean age of patient was 68.9 ± 12.0 years, and the BMI was 23.3 ± 4.24 kg/m.sup.2 at the first hemodialysis session. The body mass index was 22.0 ± 3.80 kg/m.sup.2 at 2 weeks after hemodialysis initiation. During a mean follow-up of 3.89 ± 2.12 years, 80 (30.1%) deaths occurred. In multivariate analyses, low BMI at the first hemodialysis session was significantly associated with worse all-cause mortality (hazard ratio, 2.39; 95% confidence interval, 1.13-5.03). At 2 weeks after hemodialysis initiation, high BMI was significantly associated with better all-cause mortality (hazard ratio, 0.38; 95% confidence interval, 0.18-0.81). At 2 weeks after HD initiation, high BMI was associated with lower mortality in Japanese patients with incident hemodialysis.
Myoglobin is a well-known cause of acute kidney injury (AKI) due to rhabdomyolysis. However, whether or not removing serum myoglobin by on-line hemodiafiltration (OHDF) improves the kidney function ...remains unclear. We herein report a patient with a history of methamphetamine abuse who developed AKI due to rhabdomyolysis. A urinalysis and blood collection results obtained before and after OHDF demonstrated that OHDF improved the kidney function by removing a large amount of serum myoglobin rather than via urinary excretion. In conclusion, OHDF may prevent AKI progression effectively when the urine volume is insufficient.
Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation and the destruction of bone and cartilage in affected joints. One of the unmet medical needs in the treatment of RA is ...to effectively prevent the structural destruction of joints, especially bone, which progresses because of resistance to conventional drugs that mainly have anti-inflammatory effects, and directly leads to a decline in the QOL of patients. We previously developed a novel and orally available type II kinase inhibitor of colony-stimulating factor-1 receptor (CSF1R), JTE-952. CSF1R is specifically expressed by monocytic-lineage cells, including bone-resorbing osteoclasts, and is important for promoting the differentiation and proliferation of osteoclasts. In the present study, we investigated the therapeutic effect of JTE-952 on methotrexate (MTX)-refractory joint destruction in a clinically established adjuvant-induced arthritis rat model. JTE-952 did not suppress paw swelling under inflammatory conditions, but it inhibited the destruction of joint structural components including bone and cartilage in the inflamed joints. In addition, decreased range of joint motion and mechanical hyperalgesia after disease onset were suppressed by JTE-952. These results suggest that JTE-952 is expected to prevent the progression of the structural destruction of joints and its associated effects on joint motion and pain by inhibiting CSF1/CSF1R signaling in RA pathology, which is resistant to conventional disease-modifying anti-rheumatic drugs such as MTX.
A novel and efficient simulation technique for the purpose of optimization of vacuum-carburizing process was proposed. This method consists of three steps: calculation of gas convection and ...diffusion, calculation of only gas diffusion, and calculation of carbon diffusion in steel. The first step provides the gas convection velocity that is employed in the second step. Adsorption rate of carbon on the steel surface is obtained in the second step, and carbon concentration in the steel is calculated in the third step based on the adsorption rate of carbon.Experiments were conducted to verify the proposed method in both laboratory- and industrial-scale reactors. Comparison of the computational predictions to the experimental data revealed that the proposed simulation technique enabled accurate prediction of the adsorption rate of carbon on the steel surface at various temperature conditions, the amount of carburized carbon at each operating time, and the profile of carbon concentration in the steel that is, in other words, the carburized depth. In addition, the calculation of the industrial-scale reactor, whose simulation model consisted of approximately seven million computational meshes, was completed within about two days. Therefore, the proposed simulation technique could be used to control and optimize the process in industrial vacuum-carburizing reactors.
The Columbia classification is widely used for diagnosis of focal segmental glomerulosclerosis (FSGS). In practice, we occasionally encounter segmental glomerular lesions unclassified as Columbia ...classification. We analyzed the clinical implication of unclassified segmental lesions comparing with Columbia-classified FSGS.
A retrospective cohort study from 13 local hospitals in Japan. From 172 biopsy cases diagnosed with FSGS or minimal change disease (MCD)/FSGS spectrum with unclassified segmental lesions, adult patients with nephrotic syndrome who received immunosuppressive therapies were included. The cases are classified by pathology, i.e., typical FSGS lesions sufficiently classified into subgroups of Columbia classification: collapsing (COL), tip (TIP), cellular (CEL), perihilar (PH), and not otherwise specified (NOS), and unclassified by the Columbia classification into three subgroups: "endothelial damage,"; "simple attachment,"; and "minor cellular lesion,". The response to immunosuppressive treatment and 30% decline of eGFR were compared.
Among 48 eligible cases, all were Japanese, 34 were typical FSGS; 13 TIP, 15 CEL, 6 NOS, and no COL or PH cases. Fourteen were unclassified cases: endothelial damage (n = 6), simple attachment (n = 5), and minor cellular lesion (n = 3). The median age of overall patients was 60 years old and the median of eGFR and urinary protein creatinine ratio was 51.5 mL/min/1.73m2 and 7.35, respectively. They received similar therapeutic regimen. Kaplan-Meier analysis revealed no significant difference in treatment response between typical FSGS and unclassified cases. Evaluating among the subgroups, endothelial damage, simple attachment and minor cellular lesion showed similar treatment response to TIP or CEL. No significant difference was also observed in the 30% decline of eGFR.
Japanese adult patients with nephrotic syndrome showing unclassified segmental lesions as Columbia classification may be equivalent clinical impact as Columbia classification of FSGS.
MicroRNA (miRNA) is an emerging subclass of small non-coding RNAs that regulates gene expression and has a pivotal role for many physiological processes including cancer development. Recent reports ...revealed the role of miRNAs as ideal biomarkers and therapeutic targets due to their tissue- or disease-specific nature. Head and neck cancer (HNC) is a major cause of cancer-related mortality and morbidity, and laryngeal cancer has the highest incidence in it. However, the molecular mechanisms involved in laryngeal cancer development remain to be known and highly sensitive biomarkers and novel promising therapy is necessary.
To explore laryngeal cancer-specific miRNAs, RNA from 5 laryngeal surgical specimens including cancer and non-cancer tissues were hybridized to microarray carrying 723 human miRNAs. The resultant differentially expressed miRNAs were further tested by using quantitative real time PCR (qRT-PCR) on 43 laryngeal tissue samples including cancers, noncancerous counterparts, benign diseases and precancerous dysplasias. Significant expressional differences between matched pairs were reproduced in miR-133b, miR-455-5p, and miR-196a, among which miR-196a being the most promising cancer biomarker as validated by qRT-PCR analyses on additional 84 tissue samples. Deep sequencing analysis revealed both quantitative and qualitative deviation of miR-196a isomiR expression in laryngeal cancer. In situ hybridization confirmed laryngeal cancer-specific expression of miR-196a in both cancer and cancer stroma cells. Finally, inhibition of miR-196a counteracted cancer cell proliferation in both laryngeal cancer-derived cells and mouse xenograft model.
Our study provided the possibilities that miR-196a might be very useful in diagnosing and treating laryngeal cancer.
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