[Retracted] Proteasome inhibitor sensitizes oral squamous cell carcinoma cells to TRAIL­mediated apoptosis.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that, in Fig. 4 on p. 650, the same ß­actin bands had apparently been used to show the experimental effects of the proteasome inhibitor MG­132 on c­FLIP in HSC­2 cells in Fig. 4A, and the effects of MG­132 on IAPs in HSC­3 cells in Fig. 4B. In addition, for the fourth lane in the gel showing the effects of MG­132 on c­FLIP in HSC­3 cells, this should have been labelled as '+MG­132 / +TRAIL' (not as '­/­'). Upon contacting the authors in relation to this matter, they could only admit that errors had been made in the preparation of the figure; moreover, they no longer had access to the original data owing to the time that has elapsed since the publication of the paper, and it would be impossible for them to now repeat this experiment. After having considered this matter and in conjunction with a request made by the authors, the Editor of Oncology Reports has decided that this paper should be retracted from the publication. Both the Editor and the authors apologize to the readership for any inconvenience caused. [Oncology Reports 25: 645­652, 2011; DOI: 10.3892/or.2010.1127].

PDZD8-deficient mice manifest behavioral abnormalities related to emotion, cognition, and adaptation due to dyslipidemia in the brain.

Although dyslipidemia in the brain has been implicated in neurodegenerative disorders, the molecular mechanisms underlying its pathogenesis have been largely unclear. PDZD8 is a lipid transfer protein and mice deficient in PDZD8 (PDZD8-KO mice) manifest abnormal accumulation of cholesteryl esters (CEs) in the brain due to impaired lipophagy, the degradation system of lipid droplets. Here we show the detailed mechanism of PDZD8-dependent lipophagy. PDZD8 transports cholesterol to lipid droplets (LDs), and eventually promotes fusion of LDs and lysosomes. In addition, PDZD8-KO mice exhibit growth retardation, hyperactivity, reduced anxiety and fear, increased sensorimotor gating, and impaired cued fear conditioned memory and working memory. These results indicate that abnormal CE accumulation in the brain caused by PDZD8 deficiency affects emotion, cognition and adaptive behavior, and that PDZD8 plays an important role in the maintenance of brain function through lipid metabolism.

Laparoscopic Repair Using Self-Fixating Mesh in an Adult Patient with a Sciatic Hernia and Irreducible Small Bowel: A Case Report and Literature Review.

Sciatic hernia is a rare type of pelvic floor hernia. The herniated tissue can include the ureter, small and large bowel, and ovary, among other tissues. Only a few cases of laparoscopic treatment for a sciatic hernia with small-bowel incarceration have been reported. We report our experience using a laparoscopic approach for treatment of sciatic hernia in an 83-year-old woman and review the literature on sciatic hernias. The patient was referred to our hospital complaining of constipation and abdominal bloating. Computed tomography (CT) scanning showed a right sciatic hernia containing the small bowel. Laparoscopic repair of the sciatic hernia was performed using a self-fixating mesh. The patient was discharged after an uneventful postoperative course and has not developed abdominal bloating or constipation postoperatively. In conclusion, a sciatic hernia was successfully repaired using a laparoscopic trans-preperitoneal approach and ProGrip Self-Fixating Mesh.

LOTUS suppresses amyloid ß-induced dendritic spine elimination through the blockade of amyloid ß binding to PirB.

BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide but has no effective treatment. Amyloid beta (Aß) protein, a primary risk factor for AD, accumulates and aggregates in the brain of patients with AD. Paired immunoglobulin-like receptor B (PirB) has been identified as a receptor of Aß and Aß-PirB molecular interactions that cause synapse elimination and synaptic dysfunction. PirB deletion has been shown to suppress Aß-induced synaptic dysfunction and behavioral deficits in AD model mice, implying that PirB mediates Aß-induced AD pathology. Therefore, inhibiting the Aß-PirB molecular interaction could be a successful approach for combating AD pathology. We previously showed that lateral olfactory tract usher substance (LOTUS) is an endogenous antagonist of type1 Nogo receptor and PirB and that LOTUS overexpression promotes neuronal regeneration following damage to the central nervous system, including spinal cord injury and ischemic stroke. Therefore, in this study, we investigated whether LOTUS inhibits Aß-PirB interaction and Aß-induced dendritic spine elimination. METHODS: The inhibitory role of LOTUS against Aß-PirB (or leukocyte immunoglobulin-like receptor subfamily B member 2: LilrB2) binding was assessed using a ligand-receptor binding assay in Cos7 cells overexpressing PirB and/or LOTUS. We assessed whether LOTUS inhibits Aß-induced intracellular alterations and synaptotoxicity using immunoblots and spine imaging in a primary cultured hippocampal neuron. RESULTS: We found that LOTUS inhibits the binding of Aß to PirB overexpressed in Cos7 cells. In addition, we found that Aß-induced dephosphorylation of cofilin and Aß-induced decrease in post-synaptic density-95 expression were suppressed in cultured hippocampal neurons from LOTUS-overexpressing transgenic (LOTUS-tg) mice compared with that in wild-type mice. Moreover, primary cultured hippocampal neurons from LOTUS-tg mice improved the Aß-induced decrease in dendritic spine density. Finally, we studied whether human LOTUS protein inhibits Aß binding to LilrB2, a human homolog of PirB, and found that human LOTUS inhibited the binding of Aß to LilrB2 in a similar manner. CONCLUSIONS: This study implied that LOTUS improved Aß-induced synapse elimination by suppressing Aß-PirB interaction in rodents and inhibited Aß-LilrB2 interaction in humans. Our findings revealed that LOTUS may be a promising therapeutic agent in counteracting Aß-induced AD pathologies.

Huge esophageal gastrointestinal stromal tumor successfully resected under mediastino-laparoscopic transhiatal esophagectomy: a case report.

BACKGROUND: Esophageal gastrointestinal stromal tumors (E-GISTs) are often diagnosed early due to complaints such as dysphagia and are rarely found to be huge in size. Here, we report the treatment of a case of huge E-GIST successfully resected by minimally invasive surgery after neoadjuvant imatinib therapy. CASE PRESENTATION: An 86-year-old male patient with a 3-month history of dysphagia was referred to our hospital because of a suspected mediastinal tumor on chest X-ray. The chest computed tomography scan revealed a huge solid tumor, of about 100 mm in diameter, protruding into the left thoracic cavity. Histopathological examination results of fine-needle aspiration biopsy under endoscopic ultrasonography revealed a c-kit and CD34-positive esophageal gastrointestinal stromal tumor. The patient received neoadjuvant therapy with imatinib (400 mg/day) to reduce the size of the tumor and prevent rupture during resection. After 28 days of oral administration of imatinib, the tumor size decreased. However, the patient refused to continue treatment with imatinib and therefore underwent mediastino-laparoscopic transhiatal esophagectomy. We successfully resected the tumor completely with mediastino-laparoscopic surgical techniques. Esophageal reconstruction was performed using a gastric tube in the posterior sternal route. After an uneventful postoperative course, the patient was discharged postoperative day 14. Immunohistochemical findings of the resected specimen showed that the tumor cells were positive for c-kit, DOG-1 and CD34 and negative for smooth muscle actin and S100. CONCLUSIONS: Hybrid surgical procedure utilizing mediastino-laparoscopy might be useful for high-risk patient with esophageal tumors.

Long-Term Intraocular Pressure-Lowering Effects and Adverse Events of Ripasudil in Patients with Glaucoma or Ocular Hypertension over 24 Months.

INTRODUCTION: Glaucoma is a leading cause of irreversible blindness and ripasudil was the first Rho kinase inhibitor approved as antiglaucoma medication. Here we present the final analysis of the ROCK-J study, a large-scale post-marketing surveillance study to evaluate the long-term safety and effectiveness of ripasudil in Japanese patients with glaucoma or ocular hypertension in a real-word clinical setting. METHODS: ROCK-J was a 24-month, prospective, open-label, observational study that included ripasudil-naïve patients with glaucoma or ocular hypertension who were initiating treatment with ripasudil according to the Japanese approved indication between June 1, 2015 and April 30, 2017. The primary safety endpoint was the incidence of adverse drug reactions (ADRs) (including blepharitis, plus assessment of its background factors); the primary efficacy endpoint was change in intraocular pressure (IOP) from baseline to 24 months. RESULTS: A total of 3374 Japanese patients with glaucoma or ocular hypertension were evaluated for safety and 3178 for effectiveness of ripasudil over a mean 524.5-day observational period. Overall, 853 (25.3%) patients experienced adverse drug reactions; the most common were blepharitis (8.6%), conjunctival hyperemia (8.5%), and conjunctivitis (6.3%). Multivariate analyses demonstrated that patients were more likely to experience the ADR blepharitis with ripasudil treatment if they were female (hazard ratio [HR] 1.307; p = 0.040), had comorbid or a previous history of blepharitis (HR 2.178; p = 0.001), or had a history of allergy to pollen (HR 1.645; p = 0.003) or medication (HR 2.276; p < 0.001). IOP decreased significantly from baseline with ripasudil; the least-squares mean ± standard error change in IOP from baseline to 24 months was - 2.6 ± 0.1 mmHg (p < 0.001). Significant IOP changes were seen in four types of glaucoma, namely primary open-angle glaucoma, normal-tension glaucoma, primary angle-closure glaucoma, and secondary glaucoma, and ocular hypertension. CONCLUSION: Ripasudil was safe and effective as an antiglaucoma medication with no new safety signals identified and significant reductions in IOP maintained over 24 months of treatment.

Safety and effectiveness of tofogliflozin in Japanese patients with type 2 diabetes mellitus treated in real-world clinical practice: Results of a 36-month post-marketing surveillance study (J-STEP/LT).

AIMS/INTRODUCTION: Tofogliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that lowers plasma glucose levels by enhancing urinary glucose excretion. After its approval in Japan in 2014 for the treatment of type 2 diabetes mellitus, we carried out a 3-year prospective observational post-marketing surveillance study in Japanese patients (Japanese Study of Tofogliflozin with Type 2 Diabetes Mellitus Patients/Long Term [J-STEP/LT]). MATERIALS AND METHODS: This surveillance was carried out between September 2014 and February 2019, and recorded safety in terms of adverse drug reactions (ADRs) and ADRs of special interest, and effectiveness in terms of changes in glycated hemoglobin and bodyweight from baseline to last observation carried forward. RESULTS: Of 6,897 patients with type 2 diabetes mellitus registered, 6,711 and 6,451 were analyzed for safety and effectiveness, respectively. ADRs were reported in 846 patients (12.61%), with serious ADRs in 101 patients (1.5%). ADRs of special interest included hypoglycemia (62 patients [0.9%]), polyuria/pollakiuria (90 [1.3%]), volume depletion-related disorders (135 [2.0%]), urinary tract infections (91 [1.4%]), genital infections (117 [1.7%]) and skin diseases (53 [0.8%]). One case of diabetic ketoacidosis was reported. The mean ± standard deviation changes from baseline to last observation carried forward in glycated hemoglobin and bodyweight were -0.68 ± 1.34% (n = 6,158, P < 0.0001) and -3.13 ± 4.67 kg (n = 5,213, P < 0.0001), respectively. CONCLUSIONS: J-STEP/LT, a 3-year, prospective, observational, post-marketing study in Japan, found no unprecedented ADRs, and consistent reductions from baseline in glycated hemoglobin and bodyweight over the observation period. The present results provide further evidence regarding the safety and tolerability of tofogliflozin in Japanese patients with type 2 diabetes mellitus.

Changes in maxillary dental arch morphology after implant treatment in the alveolar cleft region.

BACKGROUND: Few reports have examined dental arch morphology (DAM) after dental implant placement in cleft patients and its actual state is unclear. OBJECTIVE: To analyze the presence of changes in DAM and influencing factors in cleft lip and/or palate (CLP) patients who receive implant treatment in the alveolar cleft region. METHODS: Subjects comprised 20 CLP patients in whom maxillary dental arch width (DAW) was evaluated before and after implant treatment based on computed tomography data. First, widths between the canines (W3), between the first premolars (W4), between the second premolars (W5), and between the first molars (W6) were measured before and after surgery. Changes in distance were analyzed using the Wilcoxon signed-rank test, revealing a significant increase in W6. Analysis of Co-Variance was performed with the difference in W6 after implant treatment as the response variable, and the following six items as explanatory variables: sex; cleft type; age at alveolar bone graft; time to implantation after bone grafting; number of implants; and time after completion of the observation period. RESULTS: The reduction in W6 was larger in the order of complete bilateral CLP, complete unilateral CLP, and unilateral cleft lip and alveolus, and the change decreased with an increasing number of implants. CONCLUSIONS: Implant treatment of the alveolar cleft region may result in a slight reduction in width of the dental arch after treatment completion.

Nogo receptor antagonist LOTUS exerts suppression on axonal growth-inhibiting receptor PIR-B.

Damaged axons in the adult mammalian central nervous system have a restricted regenerative capacity mainly because of Nogo protein, which is a major myelin-associated axonal growth inhibitor with binding to both receptors of Nogo receptor-1 (NgR1) and paired immunoglobulin-like receptor (PIR)-B. Lateral olfactory tract usher substance (LOTUS) exerts complete suppression of NgR1-mediated axonal growth inhibition by antagonizing NgR1. However, the regulation of PIR-B functions in neurons remains unknown. In this study, protein-protein interactions analyses found that LOTUS binds to PIR-B and abolishes Nogo-binding to PIR-B completely. Reverse transcription-polymerase chain reaction and immunocytochemistry revealed that PIR-B is expressed in dorsal root ganglions (DRGs) from wild-type and Ngr1-deficient mice (male and female). In these DRG neurons, Nogo induced growth cone collapse and neurite outgrowth inhibition, but treatment with the soluble form of LOTUS completely suppressed them. Moreover, Nogo-induced growth cone collapse and neurite outgrowth inhibition in Ngr1-deficient DRG neurons were neutralized by PIR-B function-blocking antibodies, indicating that these Nogo-induced phenomena were mediated by PIR-B. Our data show that LOTUS negatively regulates a PIR-B function. LOTUS thus exerts an antagonistic action on both receptors of NgR1 and PIR-B. This may lead to an improvement in the defective regeneration of axons following injury.

Safety and effectiveness of tofogliflozin in Japanese patients with type 2 diabetes mellitus: Results of 24-month interim analysis of a long-term post-marketing study (J-STEP/LT).

AIMS/INTRODUCTION: Tofogliflozin is a potent and highly selective sodium-glucose cotransporter 2 inhibitor, and is currently used to treat patients with type 2 diabetes mellitus. We designed a 3-year study of tofogliflozin in patients with type 2 diabetes mellitus to evaluate the safety and effectiveness in routine clinical practice. The 3- and 12-month interim analysis showed tofogliflozin was well-tolerated, safe and clinically effective. Here, we report the results of the 24-month interim analysis. MATERIALS AND METHODS: This is a 3-year prospective, observational and multicenter post-marketing study (Japanese Study of Tofogliflozin with Type 2 Diabetes Mellitus Patients/Long Term). RESULTS: Of the 6,897 patients enrolled, 6,712 and 6,461 patients were analyzed for the safety and effectiveness of tofogliflozin, respectively. During the 24-month observation period, the incidence rates of adverse drug reactions (ADRs) and serious adverse drug reactions were 11.25 and 1.21%, respectively. As to adverse drug reactions of special interest, the incidence rates of hypoglycemia, polyuria/pollakiuria, volume depletion-related events, urinary tract infections and genital infection were 0.83, 1.28, 1.46, 1.18 and 1.62%, respectively. Renal disorders, and cardiovascular and cerebrovascular disorders occurred in 0.63 and 0.76% of the patients, respectively. Glycated hemoglobin A1c and bodyweight decreased significantly by -0.70% (P < 0.0001) and -2.95 kg (P < 0.0001), respectively, from baseline to week 104 (last observation carried forward). CONCLUSIONS: Significant safety concerns have not been observed, and clinical benefit including a long-term reduction in glycated hemoglobin A1c over a 104-week (24 months) observation period with weight loss was suggested in this 24-month interim analysis of the 3-year Japanese Study of Tofogliflozin with Type 2 Diabetes Mellitus Patients/Long Term in routine clinical practice.

Safety and effectiveness of tofogliflozin in Japanese patients with type 2 diabetes mellitus in real-world practice: Results of 12-month interim analysis of a long-term post-marketing surveillance study (J-STEP/LT).

AIMS/INTRODUCTION: Due to the paucity of tofogliflozin data, we assessed the safety and effectiveness of tofogliflozin among Japanese patients with type 2 diabetes mellitus in the clinical setting, stratifying the patients by age, sex, estimated glomerular filtration (eGFR) rate and body mass index. We report the results of a 12-month interim analysis. MATERIALS AND METHODS: This was a 3-year prospective, observational and multicenter post-marketing study (Japanese Study of tofogliflozin with type 2 diabetes mellitus Patients/Long Term). RESULTS: Out of 6,897 patients enrolled, the safety and effectiveness analysis populations consisted of 6,712 and 6,449 patients, respectively. During 12 months, adverse drug reactions and their incidence were 9.12 and 0.88%, respectively. The incidence of hypoglycemia was 0.67%. Polyuria/pollakiuria occurred more frequently in patients aged ≥65 years than in patients aged <65 years. Women experienced higher rates of urinary tract and genital infection than men. The lowest eGFR subgroup experienced maximum volume depletion-related events. Cardiovascular and cerebrovascular disorders occurred in 0.55% of the patients. Glycated hemoglobin (HbA1c) and bodyweight significantly decreased by -0.76% and -2.73 kg, respectively, from baseline to the last observation carried forward (P < 0.0001). Except for the lowest eGFR subgroup, other eGFR subgroups showed significantly decreased HbA1c values. All eGFR subgroups showed significantly decreased bodyweight, and all body mass index subgroups showed significantly decreased HbA1c and bodyweight. CONCLUSIONS: Our interim 12-month data suggest that tofogliflozin could be used safely and effectively in Japanese patients with type 2 diabetes mellitus, as tofogliflozin was well tolerated with low hypoglycemia risk, and significantly improved HbA1c and bodyweight.

Safety and effectiveness of tofogliflozin in elderly Japanese patients with type 2 diabetes mellitus: A subanalysis of a post-marketing study (J-STEP/EL Study).

AIMS/INTRODUCTION: This subanalysis aimed to assess the safety and effectiveness of tofogliflozin by using data from the Japanese Study of Tofogliflozin with Type 2 Diabetes Mellitus Patients in an Observational Study of the Elderly to categorize elderly Japanese patients with type 2 diabetes mellitus by the number of concomitant oral antidiabetic drugs (OADs) and insulin use at baseline. MATERIALS AND METHODS: Japanese Study of Tofogliflozin with Type 2 Diabetes Mellitus Patients in an Observational Study of the Elderly is a 1-year prospective, observational and multicenter post-marketing study that enrolled all patients with type 2 diabetes mellitus aged ≥65 years who started tofogliflozin during the first 3 months after its launch in May 2014 in Japan. RESULTS: The safety and effectiveness analysis sets included 1,497 and 1,422 patients, respectively. Overall, 18.10 and 2.20% of the patients experienced adverse drug reactions (ADRs) and serious ADRs, respectively. ADRs of special interest in the total, 0 OAD, one OAD, two OADs, three or more OADs and insulin groups occurred in 12.22, 10.04, 12.35, 13.32, 11.27 and 14.91% of patients, respectively. Volume depletion-related events were the most frequently observed ADRs of special interest. Hypoglycemia occurred in 1.07% of patients. Overall, glycated hemoglobin and bodyweight were significantly decreased, but the estimated glomerular filtration rate was not significantly changed. CONCLUSIONS: Our finding suggests that tofogliflozin could be safely and effectively used in elderly Japanese patients with type 2 diabetes mellitus, irrespective of the number of OADs and the use of insulin.

Axonal regeneration and functional recovery driven by endogenous Nogo receptor antagonist LOTUS in a rat model of unilateral pyramidotomy.

The adult mammalian central nervous system (CNS) rarely recovers from injury. Myelin fragments contain axonal growth inhibitors that limit axonal regeneration, thus playing a major role in determining neural recovery. Nogo receptor-1 (NgR1) and its ligands are among the inhibitors that limit axonal regeneration. It has been previously shown that the endogenous protein, lateral olfactory tract usher substance (LOTUS), antagonizes NgR1-mediated signaling and accelerates neuronal plasticity after spinal cord injury and cerebral ischemia in mice. However, it remained unclear whether LOTUS-mediated reorganization of descending motor pathways in the adult brain is physiologically functional and contributes to functional recovery. Here, we generated LOTUS-overexpressing transgenic (LOTUS-Tg) rats to investigate the role of LOTUS in neuronal function after damage. After unilateral pyramidotomy, motor function in LOTUS-Tg rats recovered significantly compared to that in wild-type animals. In a retrograde tracing study, labeled axons spanning from the impaired side of the cervical spinal cord to the unlesioned hemisphere of the red nucleus and sensorimotor cortex were increased in LOTUS-Tg rats. Anterograde tracing from the unlesioned cortex also revealed enhanced ipsilateral connectivity to the impaired side of the cervical spinal cord in LOTUS-Tg rats. Moreover, electrophysiological analysis showed that contralesional cortex stimulation significantly increased ipsilateral forelimb movement in LOTUS-Tg rats, which was consistent with the histological findings. According to these data, LOTUS overexpression accelerates ipsilateral projection from the unlesioned cortex and promotes functional recovery after unilateral pyramidotomy. LOTUS could be a future therapeutic option for CNS injury.

CAD/CAM splint and surgical navigation allows accurate maxillary segment positioning in Le Fort I osteotomy.

PURPOSE: To evaluate the accuracy of the maxillary segment positioning method using a splint fabricated by computer-aided design/computer-aided manufacturing (CAD/CAM) and surgical navigation in patients who required two-jaw surgery. METHODS: Subjects were 35 patients requiring two-jaw surgery. A 3-dimensional (3D) skull model was prepared using cone-beam computed tomography (CBCT) data and dentition model scan data. Two-jaw surgery was simulated using this model, and a splint for maxillary positioning was fabricated by CAD/CAM. Using coordinate transformation software, the coordinate axis of surgical simulation data was merged with the navigation system, and data were imported to the navigation system. The maxillary segment was placed using the CAD/CAM splint, and consistency of the maxillary segment position with that planned by simulation was confirmed using the navigation system. CBCT taken at 4 weeks postoperatively and the prediction image fabricated using surgical simulation were superimposed. Predicted movement distances (PMD) at 6 arbitrary measurement points and actual movement distance (AMD) in surgery were measured. Differences of 3D measurements between the surgical simulation and postoperative results were evaluated. RESULTS: No significant differences were seen between PMD and AMD at most measurement points on the X and Y axes. Although significant differences between PMD and AMD were seen on the Z axis, no difference was evident between linear distance on the estimated image and postoperative CBCT image at most measurement points in 3D space. Mean error at measurement points between the PMD and AMD ranged from 0.57 mm to 0.78 mm on the X axis, 0.64 mm-1.03 mm on the Y axis, and 0.84 mm-0.90 mm in the Z axis. CONCLUSION: Position of the maxillary segment moved by the CAD/CAM splint in Le Fort I osteotomy was almost consistent with the position established by simulation using the navigation system, confirming clinical accuracy.

Long-term safety and efficacy of the sodium-glucose cotransporter 2 inhibitor, tofogliflozin, added on glucagon-like peptide-1 receptor agonist in Japanese patients with type 2 diabetes mellitus: A 52-week open-label, multicenter, post-marketing clinical study.

AIMS/INTRODUCTION: Tofogliflozin is a potent and highly selective sodium-glucose cotransporter 2 inhibitor that is currently used to treat patients with type 2 diabetes mellitus. The aim of the present study was to evaluate the safety and efficacy of tofogliflozin add-on to glucagon-like peptide-1 (GLP-1) receptor agonist monotherapy. MATERIALS AND METHODS: In this 52-week, prospective, multicenter, single arm, post-marketing clinical study, Japanese patients who had already been receiving GLP-1 receptor agonist monotherapy for ≥8 weeks, glycated hemoglobin ≥7.0 and <10.5%, and body mass index ≥18.5 and <35.0 kg/m2 were enrolled. Tofogliflozin 20 mg was orally administered once daily for 52 weeks with GLP-1 receptor agonist. Primary end-points were safety and change in glycated hemoglobin from baseline to week 52. Safety was assessed on the basis of the adverse events. Changes from baseline in fasting plasma glucose, bodyweight, blood pressure, uric acid and lipid parameters were assessed as secondary efficacy end-points. RESULTS: Of the 67 patients enrolled, 63 patients completed the study. Overall, 26 adverse drug reactions occurred in 17 patients (25.4%). Adverse drug reactions with a frequency of two or more patients (3.0%) were constipation, thirst, dehydration and pollakiuria. Hypoglycemia (n = 1) was limited. With the addition of tofogliflozin to GLP-1 receptor agonist, the subsequent mean (standard deviation) reduction in glycated hemoglobin was -0.6% (1.0%; P < 0.0001). Fasting plasma glucose, bodyweight and blood pressure were significantly improved. CONCLUSIONS: Tofogliflozin add-on to GLP-1 receptor agonist monotherapy is an effective treatment option with an acceptable safety profile.

Long-Term Follow-Up after Conservative Surgical Treatment of Odontogenic Myxoma: A Case Report and Literature Review.

Odontogenic myxoma (OM) is a relatively rare, benign odontogenic tumor with locally aggressive behavior, but it is a nonmetastasizing neoplasm of the jaw bones. Although radical resection with an appropriate surgical margin is recommended, emerging evidence has suggested that a more conservative approach will result in acceptable recurrence rates with less morbidity if careful long-term follow-up is provided. A 56-year-old Japanese man with odontogenic myxoma of the left mandible was conservatively treated by surgical enucleation and curettage because he desired functional and cosmetic preservation. During a follow-up period of 100 months, the patient has remained clinically and radiologically free of recurrence. As far as we can ascertain, 20 reports published after 1990 described 37 patients with mandibular OM that had been treated by conservative surgery. Tumors recurred during a mean follow-up of 49.2 ± 42.8 months in 7 (18.9%) patients, and only one of five patients who were followed up for over 100 months developed recurrence. The rate of recurrence decreased from 24.0% to 8.3% when follow-up exceeded 60 months. Although enucleation and curettage have proven effective, the risk of recurrence remains considerable and long-term follow-up is indispensable. More evidence of long-term outcomes after conservative surgery for OM is needed.

Safety and efficacy of tofogliflozin in Japanese patients with type 2 diabetes mellitus in real-world clinical practice: Results of 3-month interim analysis of a long-term post-marketing surveillance study (J-STEP/LT).

AIMS/INTRODUCTION: The present study analysis was carried out to evaluate the safety and efficacy of tofogliflozin, a sodium-glucose cotransporter 2 inhibitor, in Japanese patients with type 2 diabetes mellitus in real-world clinical practice. MATERIALS AND METHODS: This was a 3-year non-interventional observational study of patients with type 2 diabetes mellitus newly administered tofogliflozin who were uncontrolled on current therapy. We carried out a 12-week interim analysis of tofogliflozin as part of 3-year post-marketing surveillance study. The incidence of adverse drug reactions was evaluated as a safety end-point. As efficacy end-points, glycated hemoglobin and bodyweight were evaluated. RESULTS: A total of 6,897 patients were enrolled. Tofogliflozin significantly reduced mean changes from baseline glycated hemoglobin (-0.63%, P < 0.0001) and bodyweight (-2.02 kg, P < 0.0001). The change in glycated hemoglobin and bodyweight reductions in response to tofogliflozin was consistently observed in all body mass index subgroups. Adverse drug reactions occurred in 345 of 6,712 patients (5.14%). There was a low incidence of adverse drug reactions known to be associated with sodium-glucose cotransporter 2 inhibitors, and they were reported as non-serious. The incidences of polyuria/pollakiuria were higher in patients aged ≥65 years than <65 years, and were significantly different among estimated glomerular filtration rate subgroups. Urinary tract and genital infections occurred more frequently in women than in men. CONCLUSIONS: Tofogliflozin was well tolerated, and no emerging new safety concerns were observed. Tofogliflozin significantly improved glycemic control with no impact on bodyweight gain. The short-term administration of tofogliflozin is considered to have a favorable benefit-risk profile in Japanese patients with type 2 diabetes mellitus.

The soluble form of LOTUS inhibits Nogo receptor type 1-mediated signaling induced by B lymphocyte stimulator and chondroitin sulfate proteoglycans.

There are global efforts in developing therapeutic strategies for central nervous system (CNS) injuries using multimodal approaches. Nogo receptor type 1 (NgR1) has been known as a primary molecule limiting neuronal regeneration in the adult CNS. We identified lateral olfactory tract usher substance (LOTUS) as an endogenous NgR1 antagonist. Membrane-bound LOTUS interacts with NgR1 and inhibits its function by blocking its ligand binding. Five molecules including Nogo, myelin-associated glycoprotein (MAG), oligodendrocyte myelin glycoprotein (OMgp), B lymphocyte stimulator (BLyS) and chondroitin sulfate proteoglycans (CSPGs) have been identified as NgR1 ligands. These ligands bind to NgR1 and activate NgR1 signaling, leading to axon growth inhibition such as growth cone collapse and neurite outgrowth inhibition. We have recently reported that the soluble form of LOTUS (s-LOTUS) also suppressed NgR1-mediated signaling induced by myelin axonal inhibitors (MAIs) including Nogo, MAG and OMgp by binding with both NgR1 and its co-receptor p75 neurotrophin receptor (p75NTR). Though s-LOTUS has been reported to suppress MAIs, whether s-LOTUS also suppresses NgR1 signaling induced by BLyS and CSPGs remains to be elucidated. Here, we show that s-LOTUS inhibits NgR1-mediated signaling induced by BLyS and CSPGs. Although treatment with s-LOTUS did not suppress BLyS-NgR1 interaction, s-LOTUS inhibited growth cone collapse and neurite outgrowth inhibition induced by BLyS and CSPGs in chick dorsal root ganglion (DRG) neurons. Furthermore, s-LOTUS compensated for the suppressive function of endogenous LOTUS in NgR1-mediated signaling in olfactory bulb neurons of lotus-knockout mice. These findings suggest that s-LOTUS is a potent therapeutic agent for neuronal regeneration in the CNS injuries.

The Soluble Form of LOTUS inhibits Nogo Receptor-Mediated Signaling by Interfering with the Interaction Between Nogo Receptor Type 1 and p75 Neurotrophin Receptor.

Nogo receptor type 1 (NgR1) is known to inhibit neuronal regeneration in the CNS. Previously, we have shown that lateral olfactory tract usher substance (LOTUS) interacts with NgR1 and inhibits its function by blocking its ligand binding. Therefore, LOTUS is expected to have therapeutic potential for the promotion of neuronal regeneration. However, it remains unknown whether the soluble form of LOTUS (s-LOTUS) also has an inhibitory action on NgR1 function as a candidate for therapeutic agents. Here, we show that s-LOTUS inhibits NgR1-mediated signaling by inhibiting the molecular interaction between NgR1 and its coreceptor, p75 neurotrophin receptor (p75NTR). In contrast to the membrane-bound form of LOTUS, s-LOTUS did not block ligand binding to NgR1. However, we identified p75NTR as a novel LOTUS binding partner and found that s-LOTUS suppressed the interaction between p75NTR and NgR1. s-LOTUS inhibited myelin-associated inhibitor (MAI)-induced RhoA activation in murine cortical neurons. Functional analyses revealed that s-LOTUS inhibited MAI-induced growth cone collapse and neurite outgrowth inhibition in chick DRG neurons. In addition, whereas olfactory bulb neurons of lotus-KO mice are sensitive to MAI due to a lack of LOTUS expression, treatment with s-LOTUS inhibited MAI-induced growth cone collapse in these neurons. Finally, we observed that s-LOTUS promoted axonal regeneration in optic nerve crush injury of mice (either sex). These findings suggest that s-LOTUS inhibits NgR1-mediated signaling, possibly by interfering with the interaction between NgR1 and p75NTR Therefore, s-LOTUS may have potential as a therapeutic agent for neuronal regeneration in the damaged CNS.SIGNIFICANCE STATEMENT Nogo receptor type 1 (NgR1) is a receptor well known to inhibit neuronal regeneration in the CNS. Because the membrane-bound form of lateral olfactory tract usher substance (LOTUS) antagonizes NgR1 through a cis-type molecular interaction between LOTUS and NgR1, the soluble form of LOTUS (s-LOTUS) is expected to be a therapeutic agent for neuronal regeneration. In our present study, we show that s-LOTUS inhibits the interaction between NgR1 and p75NTR, NgR1 ligand-induced RhoA activation, growth cone collapse, and neurite outgrowth inhibition and promotes axonal regeneration. Our results indicate that s-LOTUS inhibits NgR1-mediated signaling through a trans-type molecular interaction between LOTUS and NgR1 and, therefore, s-LOTUS may have therapeutic potential for neuronal regeneration.

Cerebrospinal fluid level of Nogo receptor 1 antagonist lateral olfactory tract usher substance (LOTUS) correlates inversely with the extent of neuroinflammation.

BACKGROUND: Although inflammation in the central nervous system is responsible for multiple neurological diseases, the lack of appropriate biomarkers makes it difficult to evaluate inflammatory activities in these diseases. Therefore, a new biomarker reflecting neuroinflammation is required for accurate diagnosis, appropriate therapy, and comprehension of pathogenesis of these neurological disorders. We previously reported that the cerebrospinal fluid (CSF) concentration of lateral olfactory tract usher substance (LOTUS), which promotes axonal growth as a Nogo receptor 1 antagonist, negatively correlates with disease activity in multiple sclerosis, suggesting that variation in LOTUS reflects the inflammatory activities and is a useful biomarker to evaluate the disease activity. To extend this observation, we analyzed the variation of LOTUS in the CSF of patients with bacterial and viral meningitis, which are the most common neuroinflammatory diseases. METHODS: CSF samples were retrospectively obtained from patients with meningitis (n = 40), who were followed up by CSF study at least twice, and from healthy controls (n = 27). Patients were divided into bacterial (n = 14) and viral meningitis (n = 18) after exclusion of eight patients according to the criteria of this study. LOTUS concentrations, total protein levels, and CSF cell counts in the acute and recovery phases were analyzed chronologically. We also used lipopolysaccharide-injected mice as a model of neuroinflammation to evaluate LOTUS mRNA and protein expression in the brain. RESULTS: Regardless of whether meningitis was viral or bacterial, LOTUS concentrations in the CSF of patients in acute phase were lower than those of healthy controls. As the patients recovered from meningitis, LOTUS levels in the CSF returned to the normal range. Lipopolysaccharide-injected mice also exhibited reduced LOTUS mRNA and protein expression in the brain. CONCLUSIONS: CSF levels of LOTUS correlated inversely with disease activity in both bacterial and viral meningitis, as well as in multiple sclerosis, because neuroinflammation downregulated LOTUS expression. Our data strongly suggest that variation of CSF LOTUS is associated with neuroinflammation and is useful as a biomarker for a broader range of neuroinflammatory diseases.