Nuclear GAPDH in cortical microglia mediates cellular stress-induced cognitive inflexibility.

We report a mechanism that underlies stress-induced cognitive inflexibility at the molecular level. In a mouse model under subacute cellular stress in which deficits in rule shifting tasks were elicited, the nuclear glyceraldehyde dehydrogenase (N-GAPDH) cascade was activated specifically in microglia in the prelimbic cortex. The cognitive deficits were normalized with a pharmacological intervention with a compound (the RR compound) that selectively blocked the initiation of N-GAPDH cascade without affecting glycolytic activity. The normalization was also observed with a microglia-specific genetic intervention targeting the N-GAPDH cascade. At the mechanistic levels, the microglial secretion of High-Mobility Group Box (HMGB), which is known to bind with and regulate the NMDA-type glutamate receptors, was elevated. Consequently, the hyperactivation of the prelimbic layer 5 excitatory neurons, a neural substrate for cognitive inflexibility, was also observed. The upregulation of the microglial HMGB signaling and neuronal hyperactivation were normalized by the pharmacological and microglia-specific genetic interventions. Taken together, we show a pivotal role of cortical microglia and microglia-neuron interaction in stress-induced cognitive inflexibility. We underscore the N-GAPDH cascade in microglia, which causally mediates stress-induced cognitive alteration.

Therapeutic effect of long-acting muscarinic antagonist for treating uncontrolled asthma assessed using impulse oscillometry.

BACKGROUND: In recent years, the incorporation of LAMAs into asthma therapy has been expected to enhance symptom control. However, a significant number of patients with asthma continue to experience poorly managed symptoms. There have been limited investigations on LAMA-induced airway alterations in asthma treatment employing IOS. In this study, we administered a LAMA to patients with poorly controlled asthma, evaluated clinical responses and respiratory function, and investigated airway changes facilitated by LAMA treatments using the IOS. METHODS: Of a total of 1282 consecutive patients with asthma, 118 exhibited uncontrolled symptoms. Among them, 42 switched their treatment to high-dose fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) (ICS/LABA/LAMA). The patients were then assessed using AHQ-33 or LCQ and ACT. Spirometry parameters (such as FEV1 or MMEF) and IOS parameters (such as R20 or AX) were measured and compared before and after exacerbations and the addition of LAMA. RESULTS: Of the 42 patients, 17 who switched to FF/UMEC/VI caused by dyspnea exhibited decreased pulmonary function between period 1 and baseline, followed by an increase in pulmonary function between baseline and period 2. Significant differences were observed in IOS parameters such as R20, R5-R20, Fres, or AX between period 1 and baseline as well as between baseline and period 2. Among the patients who switched to inhaler due to cough, 25 were classified as responders (n = 17) and nonresponders (n = 8) based on treatment outcomes. Among nonresponders, there were no significant differences in spirometry parameters such as FEV1 or PEF and IOS parameters such as R20 or AX between period 1 and baseline. However, among responders, significant differences were observed in all IOS parameters, though not in most spirometry parameters, between period 1 and baseline. Furthermore, significant differences were noted between baseline and period 2 in terms of FEV1, %MMEF, %PEF, and all IOS parameters. CONCLUSION: ICS/LABA/LAMA demonstrates superiority over ICS/LABA in improving symptoms and lung function, which is primarily attributed to the addition of LAMA. Additionally, IOS revealed the effectiveness of LAMA across all airway segments, particularly in the periphery. Hence, LAMA can be effective against various asthma phenotypes characterized by airway inflammation, even in real-world cases.

Usefulness of pituitary high-resolution 3D MRI with deep-learning-based reconstruction for perioperative evaluation of pituitary adenomas.

PURPOSE: To evaluate the diagnostic value of T1-weighted 3D fast spin-echo sequence (CUBE) with deep learning-based reconstruction (DLR) for depiction of pituitary adenoma and parasellar regions on contrast-enhanced MRI. METHODS: We evaluated 24 patients with pituitary adenoma or residual tumor using CUBE with and without DLR, 1-mm slice thickness 2D T1WI (1-mm 2D T1WI) with DLR, and 3D spoiled gradient echo sequence (SPGR) as contrast-enhanced MRI. Depiction scores of pituitary adenoma and parasellar regions were assigned by two neuroradiologists, and contrast-to-noise ratio (CNR) was calculated. RESULTS: CUBE with DLR showed significantly higher scores for depicting pituitary adenoma or residual tumor compared to CUBE without DLR, 1-mm 2D T1WI with DLR, and SPGR (p < 0.01). The depiction score for delineation of the boundary between adenoma and the cavernous sinus was higher for CUBE with DLR than for 1-mm 2D T1WI with DLR (p = 0.01), but the difference was not significant when compared to SPGR (p = 0.20). CUBE with DLR had better interobserver agreement for evaluating adenomas than 1-mm 2D T1WI with DLR (Kappa values, 0.75 vs. 0.41). The CNR of the adenoma to the brain parenchyma increased to a ratio of 3.6 (obtained by dividing 13.7, CNR of CUBE with DLR, by 3.8, that without DLR, p < 0.01). CUBE with DLR had a significantly higher CNR than SPGR, but not 1-mm 2D T1WI with DLR. CONCLUSION: On the contrast-enhanced MRI, compared to CUBE without DLR, 1-mm 2D T1WI with DLR and SPGR, CUBE with DLR improves the depiction of pituitary adenoma and parasellar regions.

A retrospective study of prognostic factors and prostate-specific antigen dynamics in Japanese patients with metastatic hormone-sensitive prostate cancer who received combined androgen blockade therapy with bicalutamide.

BACKGROUND: This retrospective observational study explored the therapeutic potential of combined androgen blockade (CAB) with bicalutamide (Bic-CAB) as an initial treatment for metastatic hormone-sensitive prostate cancer (mHSPC) in Japan. METHODS: The electronic health records of 159 patients with mHSPC from three Japanese institutions who received initial treatment with Bic-CAB between 2007 and 2017 were analyzed. The time to prostate-specific antigen (PSA) progression, duration of Bic-CAB treatment, and overall survival (OS), with various definitions for PSA progression, were assessed. A multivariate Cox proportional hazards model was constructed using clinical parameters to predict time to the end of Bic-CAB treatment and OS. RESULTS: The median observation period was 46.4 months, and the median age of patients at diagnosis was 71 years. A total of 46.5% patients experienced PSA progression with a median survival duration of 29 months (according to Prostate Cancer Clinical Trials Working Group 3 criteria), and 49.1% patients achieved a PSA nadir < 0.2 ng/mL in a median time of 4.7 months. When stratified by PSA nadir and PSA change, patients at low risk for disease progression with a small PSA change due to low initial PSA had a 5-year OS of 100% and a 10-year OS of 75%. The OS during the observation period was 72.9 months. CONCLUSION: These findings highlight the potential effect of Bic-CAB in patients with mHSPC who were at low risk for disease progression. Initial treatment with Bic-CAB and adjusting treatment early based on PSA dynamics may be a reasonable treatment plan for these patients.

Stimulus effects of extremely low-frequency electric field exposure on calcium oscillations in a human cortical spheroid.

High-intensity, low-frequency (1 Hz to 100 kHz) electric and magnetic fields (EF and MF) cause electrical excitation of the nervous system via an induced EF (iEF) in living tissue. However, the biological properties and thresholds of stimulus effects on synchronized activity in a three-dimensional (3D) neuronal network remain uncertain. In this study, we evaluated changes in neuronal network activity during extremely low-frequency EF (ELF-EF) exposure by measuring intracellular calcium ([Ca2+]i) oscillations, which reflect neuronal network activity. For ELF-EF exposure experiments, we used a human cortical spheroid (hCS), a 3D-cultured neuronal network generated from human induced pluripotent stem cell (hiPSC)-derived cortical neurons. A 50 Hz sinusoidal ELF-EF exposure modulated [Ca2+]i oscillations with dependencies on exposure intensity and duration. Based on the experimental setup and results, the iEF distribution inside the hCS was estimated using high-resolution numerical dosimetry. The numerical estimation revealed threshold values ranging between 255-510 V/m (peak) and 131-261 V/m (average). This indicates that thresholds of neuronal excitation in the hCS were equivalent to those of a thin nerve fiber.

The impact of respiratory reactance in oscillometry on survival in patients with idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a poor prognosis. Pulmonary function tests (PFTs) aid in evaluating the disease status of IPF. The clinical significance of oscillometry measurements in interstitial lung diseases has recently been reported. Our previous study showed that respiratory reactance (Xrs) measured by oscillometry reflected disease severity and predicted subsequent lung capacity decline in patients with IPF. However, the direct impact of Xrs on survival needs to be determined, and there are currently no reference values in oscillometry to predict prognosis. Therefore, this study aimed to investigate the association between oscillometry measurements, particularly Xrs, and survival in patients with IPF and to determine the cutoff values of Xrs that predict 3-year survival. METHODS: We analyzed the relationship between the measured values of PFT and oscillometry derived from 178 patients with IPF. Univariate and multivariate Cox proportional hazards analyses were performed to investigate the relationships between clinical indices at the time of the first oscillometry and survival. We performed the time-dependent receiver operating characteristic (ROC) curve analysis to set the optimized cutoff values of Xrs for 3-year survival prediction. We examined the discriminating power of cutoff values of Xrs on survival using the Kaplan-Meier method and the log-rank test. RESULTS: Xrs components, especially in the inspiratory phase (In), significantly correlated with the PFT values. In the multivariate analyses, Xrs (all of reactance at 5 Hz [X5], resonant frequency [Fres], and low-frequency reactance area [ALX] in the inspiratory phase) had a significant impact on survival (X5, p = 0.003; Fres, p = 0.016; ALX, p = 0.003) independent of age, sex, and other prognostic factors derived from the univariate analysis. The area under the ROC curve was 0.765, 0.759, and 0.766 for X5 In, Fres In, and ALX In, with cutoff values determined at - 0.98, 10.67, and 5.32, respectively. We found significant differences in survival after dividing patients using each of the cutoff values of Xrs. CONCLUSIONS: In patients with IPF, Xrs measured by oscillometry significantly impacted survival. We also determined the cutoff values of Xrs to discriminate patients with poor prognoses.

Real-world epidemiology and treatment patterns of patients with locally advanced or metastatic urothelial carcinoma: Retrospective analysis of Diagnosis Procedure Combination claims data in Japan.

OBJECTIVES: Evaluate real-world epidemiologic trends and treatment patterns in newly diagnosed patients with locally advanced or metastatic urothelial carcinoma (la/mUC) in Japan. METHODS: This retrospective analysis included adults with newly diagnosed la/mUC in Japan (January 2015-December 2019) from a nationwide-linked electronic medical record Diagnostic Procedure Combination claims dataset. Outcomes included epidemiologic trends (incidence and prevalence), baseline demographics, clinical characteristics, and treatment patterns in newly diagnosed patients with la/mUC before (2015-2017) and after (2018-2019) approval of pembrolizumab in Japan. RESULTS: Of 975 patients included, 76.4% were men; 71.6% were aged 70 years or older. Most cases (70.5%) were of the bladder. Between 2015 and 2019, the annual age-adjusted incidence increased from 6.8 to 12.4 per 100 000; the annual age-adjusted period prevalence increased from 13.0 to 25.2 per 100 000; and 307 (31.5%) and 668 (68.5%) patients were diagnosed from 2015 to 2017 and 2018 to 2019, respectively. Overall, 731 (75%) patients received systemic anticancer therapy; all received 1 line and 50.2% received 2 lines of therapy; 78.3% of patients received gemcitabine plus platinum-based therapy and 2.2% received pembrolizumab as first-line treatment. First-line treatment rates increased from 69.4% to 77.5% after pembrolizumab approval. Of 367 patients who received second-line treatment, 22.3% received gemcitabine plus platinum-based therapy; 14.7% received pembrolizumab. CONCLUSIONS: In the Japanese regions considered, incidence and prevalence of newly diagnosed la/mUC increased over time and first-line treatment with pembrolizumab increased after approval.

Periodontal regenerative therapy using recombinant human fibroblast growth factor (rhFGF)-2 in combination with carbonate apatite granules or rhFGF-2 alone: 12-month randomized controlled trial.

OBJECTIVES: This randomized controlled trial compared the outcomes of recombinant human fibroblast growth factor (rhFGF)-2 plus carbonate apatite (CO3Ap) granules with rhFGF-2 alone in the treatment of intrabony periodontal defects. MATERIALS AND METHODS: Patients with Stage III Grade B/C periodontitis who had completed initial periodontal therapy and had intrabony defects with a depth of ≥ 3 mm were included. Defects were treated solely with rhFGF-2 (control) or rhFGF-2 plus CO3Ap (test). Periodontal parameters and a patient-reported outcome measure (PROM) were assessed at baseline, at 6, 9 and 12 months postoperatively. The primary outcome was the change in clinical attachment level (CAL) from baseline to 12 months postoperatively. Using the Friedman test with Dunn's post-test, intragroup data were compared over time, and Mann-Whitney U test was used to assess intergroup data at each time point. RESULTS: Forty-eight sites in 38 patients were subjected to analysis. At 12 months postoperatively, CAL in both groups showed a significant improvement from baseline (p < 0.001). CAL gain was 3.4 ± 1.3 mm in the test group and 3.2 ± 1.2 mm in the control group, with no significant intergroup difference (p = 0.567). Radiographic bone fill in the test group (67.2%) was significantly greater than in the control group (32.4%) (p < 0.001). PROM scores showed no difference between groups. CONCLUSIONS: At 12 months, the outcomes including CAL gain and PROM showed no significant differences between groups, although the combination treatment enhanced radiographic bone fill. CLINICAL RELEVANCE: The use of rhFGF-2 (with/without CO3Ap) could lead to significant improvement in clinical parameters in the treatment of intrabony periodontal defects. The benefit of adding CO3Ap to rhFGF-2 therapy needs further evaluation. CLINICAL TRIAL REGISTRATION NUMBER: The University Hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR) : UMIN000040783.

Evaluation of cholesterol crystals in carotid plaque by dual energy computed tomography.

Cholesterol crystals (CCs) in carotid plaques might be an indicator of vulnerability, although they have not been fully investigated and non-invasive methods of assessment have not been established. This study examines the validity of assessing CCs using dual-energy computed tomography (DECT) that uses X-rays with different tube voltages for imaging, allowing material discrimination. We retrospectively evaluated patients who had undergone preoperative cervical computed tomography angiography and carotid endarterectomy between December 2019 and July 2020. We developed CC-based material decomposition images (MDIs) by scanning CCs crystallized in the laboratory using DECT. We compared the percentage of CCs in stained slides defined by cholesterol clefts with the percentage of CCs displayed by CC-based MDIs. Thirty-seven pathological sections were obtained from 12 patients. Thirty-two sections had CCs; of these, 30 had CCs on CC-based MDIs. CC-based MDIs and pathological specimens showed a strong correlation. Thus, DECT allows the evaluation of CCs in carotid artery plaques.

Formation of internal carotid artery aneurysms following gamma knife radiosurgery for pituitary adenomas: a case series and literature review.

Only two aneurysm formations in the internal carotid artery after gamma knife radiosurgery (GKRS) for pituitary adenomas are reported so far. Here, out of the 482 patients who underwent GKRS for pituitary adenomas at our institute, at least five developed aneurysms within the area of high single-dose irradiation. Three patients presented with epistaxis due to aneurysmal rupture and one presented with abducens paralysis due to nerve compression, while one was asymptomatic. The interval between irradiation and aneurysmal detection ranged from 14 to 21 years. Aneurysm formation in those conditions may be higher than previously thought.

[Cost-Effectiveness Analysis and Budget Impact Analysis of Enzalutamide for the Treatment of Metastatic Hormone-Sensitive Prostate Cancer].

We conducted cost-effectiveness analysis and budget impact analysis for androgen deprivation therapy (ADT) plus enzalutamide (ENZ) on patients with metastatic hormone-sensitive prostate cancer (mHSPC) from the publicly-funded healthcare system perspective. Using a partitioned survival model, lifetime costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) of ADT＋ENZ were estimated against ADT alone, ADT plus abiraterone (ADT＋ABI), and ADT plus apalutamide (ADT＋APA). Total healthcare cost differences with and without ENZ in mHSPC therapy were estimated for the period from 2022 to 2026. Based on cost-effectiveness analysis, the ICER of ADT＋ENZ versus ADT alone was estimated as ￥7.18 million/QALY gained. ADT＋ABI and ADT＋APA were dominated options (extended dominance). Budget impact analysis showed that incorporation of ENZ had a net budget impact of ￥57.19 billion, an 8.4% increase, over these 5 years. This amounted to a budgetary impact of ￥16,000 per patient per month at year 5. However, the number of patients with disease progressed to metastatic castration-resistant prostate cancer (mCRPC) would be reduced from 79,000 (without ENZ) to 65,000 (with ENZ), resulting in a 17% cost reduction within the mCRPC phase. In conclusion, ADT＋ENZ would be a cost-effective option, at the willingness to pay threshold of ￥7.5 million/QALY gained. Introduction of ENZ in the mHSPC treatment would result in a marginal increase in the total budget. However, ENZ is also expected to provide clinical benefits in reducing the number of patients with disease that would otherwise progress to mCRPC during these 5 years, resulting in cost savings in this phase.

Treatment of Gingival Recession in Multiple Teeth Using Coronally Advanced Flap with Connective Tissue Graft: A Case Report.

This report describes a case of gingival recession in multiple teeth with severe dentin hypersensitivity (DH) in which treatment included periodontal plastic surgery. The patient was a 34-year-old woman presenting with the chief complaint of DH at gingivalrecession sites. The patient had undergone orthodontic treatment when she was 30 years old. An initial examination revealed that none of the sites showed a probing depth of ≥4 mm and 21% of sites bleeding on probing. The clinical diagnosis was plaque-induced gingivitis. Teeth #14, 16, 23, 25, 26, 34, 35, 45, and 46 showed gingival recession ranging from 1 to 4 mm. Gingival recession at #45 extended to the muco-gingival junction. No association with alveolar bone loss was observed in any of the interdental areas. Therefore, the sites presenting with gingival recession were classified as Miller Class I, except #45, which was classified as Class II. The periodontal phenotype was 'thin'. Based on the results of clinical examination and diagnosis, initial periodontal therapy (IP) consisting of oral hygiene instruction, supra-gingival scaling, application of a desensitizing agent, and composite resin restoration was performed. The Visual Analog Scale (VAS) score, which was used to assess degree of DH, showed only a minimal decrease, however, at post-IP. Subsequently, a modified coronally advanced tunnel (a modified technique for achieving a coronally advanced flap) using a connective tissue graft was performed in #14, 16, 23, 25, 26, 45, and 46. After re-evaluation, the patient was placed on maintenance care. The series of interventions resulted in a considerable improvement in the VAS and oral health-related quality of life scores. Furthermore, a change in the periodontal phenotype, from 'thin' to 'thick', was observed, which may contribute to the prevention of further gingival recession and DH. The present case suggests that periodontal plastic surgery is an effective treatment modality for the resolution of DH.

Periodontal Regenerative Therapy with Recombinant Human Fibroblast Growth Factor (rhFGF) -2 for Stage III Grade C Periodontitis: A Case Report with 6-month Follow-up.

This report describes a case of generalized chronic periodontitis requiring periodontal regenerative therapy. The patient was a 56-year-old woman visiting the Tokyo Dental College Suidobashi Hospital with the chief complaint of swelling in the maxillary right gingiva. An initial examination revealed 34.0% of sites with a probing depth (PD) of ≥4 mm. The prevalence of sites with bleeding on probing was 32.7%. The plaque control record (PCR) score was 65.7%. Radiographic examination revealed angular bone resorption at #18 and 48. Horizontal absorption was also observed in other areas. The percent bone loss/age at #48 was 1.07. A clinical diagnosis of generalized chronic periodontitis (Stage III, Grade C) was made. Based on the clinical diagnosis of severe chronic periodontitis, initial periodontal therapy was performed. An improvement was observed in periodontal conditions at re-evaluation. The PCR score was 16.7%. Periodontal surgery was performed for teeth with a residual PD of ≥4 mm. Periodontal regenerative therapy using rhFGF-2 were performed on intrabony defects in #18 and 48. Open flap debridement was performed on #16, 26, and 27. Following evaluation, oral function was restored using all-ceramic crowns (#46). At 6 months postoperatively, the patient was transitioned to supportive periodontal therapy (SPT). During the 6-month SPT, stable periodontal conditions that facilitated a favourable level of plaque control were maintained.

A Case Report of Periodontal Regenerative Therapy Using Recombinant Human Fibroblast Growth Factor 2 and Deproteinized Bovine Bone Mineral with Non-incised Papillae Surgical Approach (NIPSA) for Angular Bone Defect in Patient with Stage III Grade C Periodontitis.

This report describes a case of Stage III Grade C periodontitis requiring periodontal regenerative therapy. The patient was a 19-year-old woman who presented with the chief complaint of gingival recession in the incisor region. An initial examination revealed that 45.3% of sites had a probing depth of ≥4 mm and 45.8% bleeding on probing. Radiographic examination showed angular bone resorption in #25, 26, 31, 36, and 46 and horizontal resorption in other regions. Initial periodontal therapy was implemented based on a clinical diagnosis of Stage III Grade C periodontitis (generalized aggressive periodontitis). Occlusal adjustment was also performed at sites showing premature contact (#26 and 36) after suppression of inflammation. Periodontal regenerative therapy using recombinant human fibroblast growth factor (rhFGF) -2 was performed on #25, 26, and 46. Combination therapy with rhFGF-2 and deproteinized bovine bone mineral (DBBM) was performed on #31 and 36. A non-incised papillae surgical approach (NIPSA) was used on #31. Periodontal conditions were then re-evaluated and the patient placed on supportive periodontal therapy. Regenerative therapy using rhFGF-2 and DBBM with NIPSA yielded an improvement in clinical parameters and bone resorption. This improvement has been adequately maintained over a 12-month period. Continued care is needed to maintain stable periodontal conditions.

Treatment of Stage III Grade C Periodontitis with Periodontal Regenerative Therapy including Guided Tissue Regeneration (GTR) and Recombinant Human Fibroblast Growth Factor (rhFGF)-2: A Case Report.

This report describes a case of periodontitis treated with periodontal surgery including guided tissue regeneration (GTR) and recombinant human fibroblast growth factor (rhFGF)-2. The patient was a 54-year-old woman who visited the Tokyo Dental College Suidobashi Hospital with the chief complaint of swelling in the maxillary right gingiva. An initial examination revealed 30.4% of sites with a probing depth (PD) of ≥4 mm. The prevalence of sites with bleeding on probing was 57.7%. The plaque control record (PCR) score was 66.1%. Radiographic examination revealed vertical bone defects in the molar region. Based on these findings, the clinical diagnosis was generalized chronic periodontitis (Stage III, Grade C). Initial periodontal therapy yielded an improvement in periodontal conditions, with the PCR score reducing to 13.8%. Periodontal surgery was performed for teeth with a residual PD ≥4 mm. Guided tissue regeneration was performed on #37 and 47. A series of periodontal regenerative treatments comprising application of rhFGF-2 was performed on angular bone defects in #14, 15, 25, and 27. Open flap debridement was performed on #16, 17, 26, 36, and 46. Following evaluation, oral function was restored by placing all-ceramic crowns on #21 and 26. The patient was then placed on supportive periodontal therapy. In the present case of generalized chronic periodontitis, periodontal regenerative therapy with GTR and rhFGF-2 yielded stable periodontal conditions.

N-glycosylation regulates MET processing and signaling.

MET, the receptor for the hepatocyte growth factor (HGF), is strongly associated with resistance to tyrosine kinase inhibitors, key drugs that are used in the therapy of non-small cell lung cancer. MET contains 11 potential N-glycosylation sites, but the site-specific roles of these N-glycans have not been elucidated. We report herein that these N-glycans regulate the proteolytic processing of MET and HGF-induced MET signaling, and that this regulation is site specific. Inhibitors of N-glycosylation were found to suppress the processing and trafficking of endogenous MET in H1975 and EBC-1 lung cancer cells and exogenous MET in CHO-K1 cells. We purified the recombinant extracellular domain of human MET and determined the site-specific N-glycan structures and occupancy using mass spectrometry. The results indicated that most sites were fully glycosylated and that the dominant population was the complex type. To examine the effects of the deletion of N-glycans of MET, we prepared endogenous MET knockout Flp-In CHO cells and transfected them with a series of N-glycan-deletion mutants of MET. The results showed that several N-glycans are implicated in the processing of MET. The findings also suggested that the N-glycans of the SEMA domain of MET positively regulate HGF signaling, and the N-glycans of the region other than the SEMA domain negatively regulate HGF signaling. Processing, cell surface expression, and signaling were significantly suppressed in the case of the all-N-glycan-deletion mutant. The overall findings suggest that N-glycans of MET affect the status and the function of the receptor in a site-specific manner.

Impact of Nuclear Envelope Stress on Physiological and Pathological Processes in Central Nervous System.

The nuclear envelope (NE) separates genomic DNA from the cytoplasm and provides the molecular platforms for nucleocytoplasmic transport, higher-order chromatin organization, and physical links between the nucleus and cytoskeleton. Recent studies have shown that the NE is often damaged by various stresses termed "NE stress", leading to critical cellular dysfunction. Accumulating evidence has revealed the crucial roles of NE stress in the pathology of a broad spectrum of diseases. In the central nervous system (CNS), NE dysfunction impairs neural development and is associated with several neurological disorders, such as Alzheimer's disease and autosomal dominant leukodystrophy. In this review, the structure and functions of the NE are summarized, and the concepts of NE stress and NE stress responses are introduced. Additionally, the significant roles of the NE in the development of CNS and the mechanistic connections between NE stress and neurological disorders are described.

Chondrocyte proliferation regulated by secreted luminal domain of ER stress transducer BBF2H7/CREB3L2.

The endoplasmic reticulum (ER) stress transducer BBF2H7/CREB3L2 is an ER-resident transmembrane transcription factor. In response to physiological ER stress, it is processed at the transmembrane region to generate a cytoplasmic N terminus, which contains a basic leucine zipper (bZIP) domain, and luminal C terminus. The BBF2H7 N terminus functions as a transcription factor to promote the expression of ER-Golgi trafficking-related genes and plays crucial roles in chondrocyte differentiation. Here, we found that the BBF2H7 C terminus is secreted into the extracellular space as a signaling molecule for cell-to-cell communication. The secreted BBF2H7 C terminus directly binds to both Indian hedgehog and its receptor Patched-1, followed by activation of Hedgehog signaling, resulting in promoting the proliferation of neighboring chondrocytes. The dual N- and C-terminal functions of BBF2H7 triggered by physiological ER stress may allow chondrocytes to simultaneously regulate distinct cellular events for differentiation and proliferation in developing cartilage.

Real-world use of enzalutamide in men with nonmetastatic castration-resistant prostate cancer in Japan.

BACKGROUND: The purpose of the study is to evaluate real-world effectiveness and safety of enzalutamide in men with nonmetastatic castration-resistant prostate cancer (nmCRPC) in Japan. METHODS: This was a retrospective evaluation of medical records from men in Japan who started enzalutamide treatment from November 1, 2014, to March 31, 2018, and received androgen deprivation therapy throughout. The primary endpoint was time to prostate-specific antigen (PSA) progression. Secondary endpoints included PSA response rate, time to first use of new antineoplastic therapy, time to first use of cytotoxic chemotherapy, and enzalutamide treatment duration. An exploratory analysis of metastasis-free survival (MFS) was also performed. Adverse events (AEs) were analyzed to assess safety. RESULTS: Based on data from medical records of 205 men in Japan, median time to PSA progression was 27 months (95% confidence interval [CI] 19-not reached [NR]), with 82.5% and 52.0% of men achieving PSA response rates of ≥ 50% and ≥ 90%, respectively. Median time to first use of new antineoplastic therapy was 36 months (95% CI 27-NR) and median enzalutamide treatment duration was 13 months (interquartile range: 7-24). Median time to first use of cytotoxic chemotherapy was NR (95% CI 41-NR). Median MFS was 29 months (95% CI 23-35). In total, 51.7% of men experienced AEs, with malaise (18.5%), decreased appetite (10.7%), and nausea (4.9%) the most frequently reported. CONCLUSIONS: This is the first study to demonstrate the real-world effectiveness and safety of enzalutamide in men with nmCRPC in Japan, further informing healthcare providers about available treatment options for this patient population.

Health-related quality of life with enzalutamide versus flutamide in castration-resistant prostate cancer from the AFTERCAB study.

BACKGROUND: Patient-reported outcome (PRO) measures can provide valuable information in evaluating patients' health-related quality of life (HRQoL). Post hoc analysis of the AFTERCAB study was conducted to evaluate the HRQoL benefit of enzalutamide plus androgen deprivation therapy (ADT) compared to flutamide plus ADT for the treatment of patients with castration-resistant prostate cancer (CRPC) in Japan. METHODS: The open-label AFTERCAB study was conducted from November 2016 to March 2020 in Japanese men aged ≥ 20 years with asymptomatic or mildly symptomatic CRPC. Patients received enzalutamide plus ADT or flutamide plus ADT, respectively, as first-line alternative androgen therapy (AAT). HRQoL was analyzed through the Functional Assessment of Cancer Therapy-Prostate, EuroQoL 5-Dimension 5-Level instruments, Brief Pain Inventory-Short Form, and Brief Fatigue Inventory. The longitudinal changes in HRQoL, HRQoL deterioration based on minimally important difference (MID), and time to HRQoL deterioration were evaluated for first-line AAT. RESULTS: Overall, HRQoL between the enzalutamide and flutamide groups was similar during first-line treatment. No statistically significant HRQoL difference in change from baseline to week 61 (least square mean difference; p value) was observed. Furthermore, proportions of pain progression, symptom worsening, and HRQoL deterioration based on MID, were not significantly different between groups. CONCLUSIONS: The results were similar in all subscales of each PRO, demonstrating similar HRQoL deterioration based on MID criteria between the enzalutamide and flutamide groups.