Therapeutic Effect of Colony Stimulating Factor 1 Receptor Kinase Inhibitor, JTE-952, on Methotrexate-Refractory Pathology in a Rat Model of Rheumatoid Arthritis.

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.

Micro-computed tomography analysis of the relationship between root canal number and root concavity in maxillary first and second molars in a Japanese population.

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.

Evaluation of root morphology of maxillary and mandibular second molars lost due to periodontitis.

BACKGROUND AND OBJECTIVE: Little is known about the anatomical characteristics of root morphology in molars lost due to periodontal reason. The aim of this study was to study root morphology in maxillary and mandibular molars lost due to periodontitis by investigating the frequency of root fusion, classifying fusion types, and measuring radicular groove depth by micro-computed tomography. MATERIAL AND METHODS: Ninety-eight posterior teeth were collected from 87 Japanese patients during the study period. Of these, maxillary (N = 36) and mandibular (N = 22) second molars lost most frequently were assessed for root fusion and morphology. RESULTS: The 36 maxillary second molars included nine (25%) teeth with a single root, 14 (39%) with two roots, and 13 (36%) with three roots. Of the 23 maxillary second molars with fused (1 and 2) roots, there were 11 (48%), 2 (9%), 1 (4%), 1 (4%), 3 (13%), and 5 (22%) teeth with root types 1-6, respectively. The 22 mandibular second molars comprised 14 (64%) teeth with a single root, 7 (32%) with two roots, and one (4%) with three roots. Of the 14 mandibular second molars with a fused (1) root, 12 (86%) had a C-shaped root and two (14%) had a non-C-shaped root. CONCLUSION: We observed a higher frequency of root fusion in the present study compared with that reported by previous studies using randomly selected second molars.

JTE-952 Suppresses Bone Destruction in Collagen-Induced Arthritis in Mice by Inhibiting Colony Stimulating Factor 1 Receptor.

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.

Pharmacological Properties of JTE-952, an Orally Available and Selective Colony Stimulating Factor 1 Receptor Kinase Inhibitor.

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-methoxyphenyl]azetidine-1-yl}carbonyl)pyridin-4-yl]methoxy}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.

Discovery of a novel azetidine scaffold for colony stimulating factor-1 receptor (CSF-1R) Type II inhibitors by the use of docking models.

We report the discovery of a novel azetidine scaffold for colony stimulating factor-1 receptor (CSF-1R) Type II inhibitors by using a structure-based drug design (SBDD) based on a docking model. The work leads to the representative compound 4a with high CSF-1R inhibitory activity (IC50 = 9.1 nM). The obtained crystal structure of an azetidine compound with CSF-1R, which matched our predicted docking model, demonstrates that the azetidine compounds bind to the DFG-out conformation of the protein as a Type II inhibitor.

Optimization of an azetidine series as inhibitors of colony stimulating factor-1 receptor (CSF-1R) Type II to lead to the clinical candidate JTE-952.

Optimization of novel azetidine compounds, which we had found as colony stimulating factor-1 receptor (CSF-1R) Type II inhibitors, provided JTE-952 as a clinical candidate with high cellular activity (IC50 = 20 nM) and good pharmacokinetics profile. JTE-952 was also effective against a mouse collagen-induced model of arthritis (mouse CIA-model). Additionally, the X-ray co-crystal structure of JTE-952 with CSF-1R protein was shown to be a Type II inhibitor, and the kinase panel assay indicated that JTE-952 had high kinase selectivity.

Clinical impact of endocapillary proliferation according to the Oxford classification among adults with Henoch-Schönlein purpura nephritis: a multicenter retrospective cohort study.

BACKGROUND: Henoch-Schönlein purpura nephritis (HSPN) is a form of small vessel vasculitis associated with purpura and IgA deposition in the glomeruli. The International Study of Kidney Disease in Children (ISKDC) classification predicts renal prognosis in children with HSPN, but not in adults. Additionally, it is not well known whether the Oxford classification 2016 and/or the Japanese Histologic classification (JHC) are associated with renal outcome. Herein, we investigated the relationship between pathological characteristics and renal outcome among adult patients with HSPN. METHODS: A multicenter retrospective cohort study was conducted in adult patients with HSPN who underwent renal biopsy between 2004 and 2014. Two nephrologists classified each patient according to the Oxford classification 2016, JHC, and the ISKDC classification. Renal outcome was defined by a 30% decline in the eGFR and/or end-stage kidney disease. RESULTS: We enrolled 74 adult patients with HSPN (mean age, 47.8 ± 17.4 years; mean eGFR, 76.4 ± 25.8 ml/min/1.73 m2; median proteinuria, 1.40 [IQR: 0.70-2.38] g/day). During a mean follow-up period of 68.0 ± 33.0 months, fourteen patients (18.9%) reached the renal outcome, and all 14 had received immunosuppressive therapy. The log-rank test revealed that event-free renal survival was significantly shorter in patients with endocapillary proliferation (E1) according to the Oxford classification than in those with E0 (p = 0.0072). However, the JHC, ISKDC classification and other Oxford lesions could not demonstrate a significant difference in event-free renal survival. In a multivariate Cox model adjusted for clinical and pathological factors, age (HR, 1.57; 95% CI, 1.12-2.21) and E lesion (HR, 6.71; 95% CI, 1.06-42.7) were independent risk factors for renal outcome. CONCLUSIONS: Endocapillary proliferation is significantly associated with renal outcome in adult patients with HSPN, including those receiving immunosuppressive therapy. Other Oxford classification lesions, JHC, and ISKDC classification were not associated with renal outcome.

Efficacy of On-line Hemodiafiltration for Rhabdomyolysis Presenting with Acute Kidney Injury Due to Unexpected Drug Abuse.

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.

Vascular access interventional therapy of early arteriovenous fistula occlusion leading to long-term patency: A case report.

Arteriovenous fistulas (AVFs) are frequently used for hemodialysis access, but approximately 15%-20% of AVFs fail to mature within 3 months of their creation. Vascular access interventional therapy (VAIVT) is typically performed for treating an immature AVF. However, it should be performed 4-6 weeks or later after AVF creation. Here, we present a case in which VAIVT effectively addressed AVF occlusion that occurred only 9 days after its creation. The patient was an 82-year-old woman with chronic kidney disease who underwent surgery to create a left radiocephalic AVF for hemodialysis. Nine days postoperatively, disappearance of the AVF sound prompted an angiography, revealing thrombosis near the AVF anastomosis. VAIVT successfully restored blood flow, resulting in AVF maturation, and with no thrombosis or flow dysfunction at 21 months after VAIVT. To the best of our knowledge, this case presents the earliest successful intervention for an occluded AVF.

Gingival enlargement improvement following medication change from amlodipine to benidipine and periodontal therapy.

The use of calcium channel blockers (CCBs) is associated with gingival enlargement, which adversely affects oral function, hygiene and aesthetics. Although CCB-induced gingival enlargement is a known adverse effect, it is rarely or never caused by some CCBs. In this paper, we report the case of a late 80's female patient with hypertension who experienced amlodipine-induced gingival enlargement. The patient's antihypertensive medication was changed from amlodipine to another CCB of the same class, benidipine, which has not been reported to cause gingival enlargement. The patient also received periodontal therapy. A significant improvement in gingival enlargement was noted, and blood pressure control was maintained. This case indicates that it might be beneficial for patients with hypertension presenting CCB-induced gingival enlargement to switch from the CCB that caused gingival enlargement to another CCB with little to no risk.

The association between body mass index and all-cause mortality in Japanese patients with incident hemodialysis.

BACKGROUND: 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. METHODS: 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 ≥24 (high) kg/m2]. The normal group was used as the reference group. The primary outcome was all-cause mortality. RESULTS: The mean age of patient was 68.9 ± 12.0 years, and the BMI was 23.3 ± 4.24 kg/m2 at the first hemodialysis session. The body mass index was 22.0 ± 3.80 kg/m2 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). CONCLUSION: At 2 weeks after HD initiation, high BMI was associated with lower mortality in Japanese patients with incident hemodialysis.

The 30-year Natural History of Non-classic Fabry Disease with an R112H Mutation.

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.

Multiple assessment of molars with hypercementosis lost due to periodontitis using X-ray micro-computed tomography, electron microprobe analysis, and histological sections.

This article aimed to achieve a better understanding of cementum hyperplasia in the maxillary second molars lost due to periodontitis. Six maxillary second molars with hypercementosis were measured for the mineral concentration using micro-computed tomography and calcium element distributions using electron microprobe analysis. Calcium was distributed throughout the cementum, although the mineral concentration differed based on the cementum depth. The hyperplastic cementum was of the extrinsic fiber-rich cellular mixed stratified type. These results have implications for future studies aiming to diagnose hypercementosis. Further studies are needed to investigate the composition of the cementum matrix.

An autopsy case of ovarian mucinous cystic tumor complicated by ovarian abscess and a review of the English literature.

Ovarian tumors are rarely associated with abscesses. Herein, an autopsy case of an ovarian mucinous cystic tumor complicated by an abscess, along with a review of previous cases, suggests the necessity of considering ovarian abscess as a cause of inflammation in patients with the ovarian tumors.

Smoking Status and Risk Awareness of Heated Tobacco Product Use among General Dental Practitioners Belonging to the Aichi Dental Association, Japan.

The awareness of healthcare practitioners concerning heated tobacco product (HTP) use risks has been evaluated; however, few studies have investigated general dental practitioners' awareness regarding HTP-use risks. In this cross-sectional study, we investigated dentists' awareness of the risks of smoking, particularly HTP use. A self-administered questionnaire, including eight questions on conventional cigarette and HTP smoking/using status and both knowledge and awareness of HTP-use risks, was posted to 3883 dentists belonging to the Aichi Dental Association, Japan, in August 2019. Statistical analysis was performed using the Statistical Package for Social Sciences; statistical significance was set at p < 0.05. We analyzed the data of 1317 dentists (participation rate, 41.6%). The study group included cigarette smokers (11.5%) and HTP users (8.5%), among whom 41.1% were dual users. HTP users were more likely than never smokers/users to correctly perceive HTP-use risks (p < 0.05). This study indicates that in Japan, the proportion of HTP users is higher than that of the general population. It is important to educate not only smokers/users but also never smokers/users on the risks of smoking and using HTPs. Smoking cessation, including ceasing HTP use, and aiming to quit smoking and HTP use among dentists would contribute to appropriate smoking cessation among patients.

Social nicotine dependence in Australian dental undergraduate students.

OBJECTIVES: This study aimed to investigate dental undergraduate students' tobacco usage and social nicotine dependence in Australia. A special interest was to identify the role of factors such as age, gender, year of dental education and cohabitants' smoking status for social nicotine dependence. MATERIALS AND METHODS: A sample of 252, first-to-fifth year undergraduate students in an Australian dental school was used. Each completed a self-administered questionnaire. RESULTS: The smoking rate was 4.8%. Current smokers displayed higher social nicotine dependence than those that had never smoked (t=3.1, df=244, P=0.002). Dental undergraduate students that showed higher social nicotine dependence (P=0.001, OR=1.3, 95% CI: 1.1-1.6), or that had smoking cohabitants (P=0.016, OR=4.8, 95% CI: 1.3-17.0), were more likely to smoke. Students' social nicotine dependence increased with year of dental study (P=0.043, ß=0.4, t=2.0). Social nicotine dependence enhanced tobacco usage among Year-1-to-4 students (P=0.005, OR=1.4, 95% CI: 1.1-1.7) but not Year-5 undergraduates (P=0.432). CONCLUSIONS: Social nicotine dependence has become a developing issue in dental education. Tobacco control should be highlighted in the dental curriculum. Future investigations into the effects of dental education on social nocotine dependence and tobacco usage are indicated.

Nephrotic syndrome with focal segmental glomerular lesions unclassified by Columbia classification; Pathology and clinical implication.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Japanese adult patients with nephrotic syndrome showing unclassified segmental lesions as Columbia classification may be equivalent clinical impact as Columbia classification of FSGS.

A large-scale observational study to investigate the current status of diabetic complications and their prevention in Japan (JDCP study 6): baseline dental and oral findings.

Japan Diabetes Complication and Prevention prospective (JDCP) study was conducted to examine the association between glycemic control and oral conditions in a large database of Japanese patients with diabetes. It included a total of 6099 patients with diabetes (range, 40-75 years) who had been treated as outpatients between 2007 and 2009. The mean number of present teeth at baseline was 19.8 and women with type 2 diabetes had fewer teeth than men with type 2 diabetes. Within the previous year, 17% of all patients had lost teeth. At baseline, 32% had experienced gingival swelling, 69% had brushed more than twice a day, 37% had used interdental cleaning aids, and 43% had undergone regular dental checkups. Multiple logistic regression analysis indicated that type 1 patients with HbA1c ≥ 7.0% were at higher risk of having fewer than 20 teeth (odds ratio [OR] 2.38; 95% confidence interval [CI] 1.25-4.78), and type 2 patients with HbA1c ≥ 8.0% also were at high risk of having fewer than 20 teeth (OR 1.16; 95% CI 1.00-1.34), after adjustment for nine possible confounding factors. In conclusion, patients with diabetes were found to be at high risk of tooth loss, and the poorer the glycemic control, the higher the risk of tooth loss in these patients.

Ectopic Relapse of Anti-neutrophil Cytoplasmic Antibody-associated Pituitary Vasculitis with No Elevation of Anti-neutrophil Cytoplasmic Antibodies after Renal Remission.

The relationship between anti-neutrophil cytoplasmic antibody (ANCA) titer levels and relapse risk in patients with ANCA-associated vasculitis (AAV) following clinical remission remains controversial. We herein report a case showing ectopic relapse of AAV in the pituitary with no ANCA elevation after renal remission. Magnetic resonance imaging revealed an enlarged pituitary gland. A pituitary biopsy showed geographic necrosis with multinucleated giant cells. We diagnosed this case as relapse of AAV in the pituitary. One month after rituximab therapy, the pituitary gland volume had decreased. The intensification of therapy due to the possibility of vasculitis relapse may facilitate better control of AAV.