A phase I dose-escalation, safety/tolerability, and preliminary efficacy study of the intratumoral administration of GEN0101 in patients with advanced melanoma.

Despite recent advance in immunotherapy agents, safe new therapies that enhance the effects of immune checkpoint inhibitors are still required to develop. We previously demonstrated that hemagglutinating virus of Japan-envelope (HVJ-E) induced not only direct tumor cell death but also antitumor immunity through the activation of T and natural killer (NK) cells, thereafter, developed a manufacturing process of HVJ-E (GEN0101) for clinical use. We here performed a phase Ia clinical trial of intratumoral GEN0101 administration in six patients with stage IIIC or IV malignant melanoma. The primary aim was to evaluate the safety and tolerability of GEN0101, and the secondary aim was to examine the objective tumor response. Patients were separated into two groups (n = 3 each) and received a low dose of 30,000 and high dose of 60,000 mNAU of GEN0101. All patients completed a two-week follow-up evaluation without severe adverse events. The overall response rate was 33% (2 of 6), with 2 partial responses in the high-dose group and 2 with stable disease, and 2 with progressive disease in the low-dose group. Local complete or partial responses were observed in 11 of 18 (61%) target lesions. One patient demonstrated shrinkage of lung metastases after the treatment. The activity of NK cells and interferon-γ levels were increased in the circulation, indicating augmentation of antitumor immunity by GEN0101. This trial showed not only the safety and tolerability but also the significant antitumor effect of GEN0101, suggesting that GEN0101 might be a promising new drug for patients with advanced melanoma.

Differential effects of changes in cardiorespiratory fitness on worst- and best- school subjects.

Accumulating evidence shows a beneficial association between physical fitness and school children's academic performance. However, several other studies have failed to demonstrate such an association. We reanalyzed data of a two-year longitudinal study of the association between changes in cardiorespiratory fitness and academic performance of school children by focusing on intra-individual variability in grade points as a possible source of this discrepancy. We analyzed data from 469 junior high school students to examine if improvements in cardiorespiratory fitness had a differential effect on an individual student's worst and best grade points. Results indicated that improvements in physical fitness were associated with an improvement in the worst grade points. On the contrary, we did not observe a similar longitudinal association with the best grade points. These findings suggest that improving cardiorespiratory fitness improves the worst grade points of an individual, selectively. We suggest that intra-individual variability in grade points might moderate the association between physical fitness and academic performance changes.

Grap2 cyclin D interacting protein negatively regulates CREB­binding protein, inhibiting fibroblast­like synoviocyte growth.

Rheumatoid arthritis (RA) is one of the most critical articular diseases, which is characterized by synovial hyperplasia and impaired quality of life. The clinical features of RA include chronic inflammation of the joints associated with synovial cell overgrowth. However, the mechanism regulating the outgrowth of fibroblast­like synoviocytes (FLS) is not fully understood. The present study reported that grap2 cyclin D interacting protein (GCIP), an inhibitor of DNA binding/differentiation (ID)­like helix­loop­helix protein, interacted with cAMP­response element­binding protein (CREB)­binding protein (CBP). Furthermore, GCIP repressed CREB­ and NF­κB­dependent gene expression by inhibiting CBP binding to RNA polymerase II complexes. GCIP depletion via small interfering RNA enhanced FLS growth, whereas stable GCIP expression suppressed the growth of 293 cells. In addition, GCIP depletion in FLS induced the expression of cyclin D1, a CREB target gene. The present study identified a novel inhibitory mechanism in which an ID protein may functionally target the transcriptional coactivator CBP. These results suggested that GCIP downregulation may be pivotal in FLS outgrowth.

Enhanced expression of synoviolin in peripheral blood from obese/overweight donors.

Obesity is currently a major medical and societal issue. Synoviolin (SYVN1) is an E3 ubiquitin ligase involved in endoplasmic reticulum (ER) stress. Overexpression of Syvn1 has been found in genetically obese mice (ob/ob and db/db), and treatment with a Syvn1 inhibitor suppresses weight gain in some mouse models (C57BL/6J and db/db). However, SYVN1 expression in humans has not yet been elucidated. In the present study, 35 human volunteers were analyzed, and the expression level of SYVN1 mRNA in peripheral blood mononuclear cells (PBMCs) was detected using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis. Expression of SYVN1 mRNA was significantly increased in PBMCs from volunteers with a BMI ≥25.0, compared with volunteers with a BMI <25.0. In addition, PCR array and RT-qPCR of ER stress-responsive genes revealed that the expression of activating transcription factor 6 (ATF6), which plays an important role in the transcriptional activation of SYVN1, was increased in PBMCs from volunteers with a BMI ≥25.0. These results suggest that the ATF6-SYVN1 axis might be an important pathway in the progression of obesity.

Longitudinal relationship of favorable weight change to academic performance in children.

Although there is a growing consensus about the positive relationship between prevention of overweight/obesity and academic performance in children, relevant studies targeting the relationship between underweight and academic performance are scarce. This study aimed to examine the longitudinal relationship of favorable weight change to academic performance in schoolchildren. We analyzed 2-year longitudinal data derived from 197 seventh-grade children aged 12-13 years. Academic performance was assessed using the total grade points of five academic subjects. Body mass index (BMI) was calculated as body weight (kg)/height (m2). A significant interaction effect of baseline BMI and BMI changes over 2 years (B = -0.10, SE B = 0.03, ß = -0.40, t = -3.37, p < 0.001) was noted after controlling for confounders such as socioeconomic status, afterschool learning duration, screen time, exercise habits, and cardiorespiratory fitness. When the centered baseline BMI was outside the interval [-2.49, 3.21], the slope of the change in BMI was significant (p < 0.05). Simple slope analyses revealed a positive relationship of weight gain when baseline BMI = mean - 1 SD (B = 0.40, SE B = 0.18, ß = 0.31, t = 2.20, p = 0.03) and weight loss when baseline BMI = mean + 1 SD (B = -0.26, SE B = 0.13, ß = -0.20, t = -1.97, p = 0.05) to total grade points of five school subjects. A split-group validation was performed and robust results of original analyses were detected (i.e., significant interaction effect of baseline BMI and BMI changes over 2 years (group A: B = -0.11, SE B = 0.05, ß = -0.47, t = -2.39, p = 0.02; group B: B = -0.14, SE B = 0.05, ß = -0.47, t = -2.78, p = 0.007). Favorable changes in weight status, i.e., weight loss in children with overweight/obesity and weight gain in children with mild underweight/underweight, have a positive influence on academic performance in children independent of socioeconomic factors, learning habits, screen time, exercise habits, and cardiorespiratory fitness.

Relationship of participation in specific sports to academic performance in adolescents: A 2-year longitudinal study.

Physical activity is considered a promising behavior to improve cognitive function and academic performance in adolescents. As evidence on the relationship of specific sports activity is not conclusive, this study aimed to determine the longitudinal relationships of different sports to academic performance in adolescents and evaluate the cardiorespiratory fitness mediation effect of these sports. We focused on the demands of complex motor skills and the differences between individual sports vs team sports. Four hundred and sixty-three 7th-grade students (227 girls and 236 boys) were followed up over 2 years. Data regarding participation in sports activities, types of sports activities, academic performance, and cardiorespiratory fitness were obtained at baseline and after a 2-year follow-up. Structural equation modeling revealed that participation in all sports activity was positively associated with improvement of academic performance from baseline to follow-up, and that these associations were mediated by cardiorespiratory fitness gains. Participation in sports activities that require more complex motor skills and individual sports activity was directly associated with an improvement of academic performance from baseline to follow-up. Furthermore, quitting sports activities was negatively associated with academic performance via a reversal in cardiorespiratory fitness gains. These findings indicate that participation in specific sports may have significant benefits for academic performance in adolescents. Although these relationships are presumably mediated by cardiorespiratory fitness, sports activities that require more complex motor skills and individual sports participation may be directly related to academic performance. Considering that quitting sports activities reversed these benefits, sustained participation in sports is important for academic success.

Music Intervention Reduces Persistent Fibromyalgia Pain and Alters Functional Connectivity Between the Insula and Default Mode Network.

OBJECTIVE: The aims of the present study were to examine the effects of short-term music interventions among patients with fibromyalgia (FM) and to clarify the alterations in functional connectivity and persistent pain. DESIGN: Pilot study. SETTING: All participants were evaluated at Juntendo University from November 2017 to January 2019. SUBJECTS: We enrolled female patients who had been clinically diagnosed with FM (N = 23). METHODS: All participants listened to Mozart's Duo for Violin and Viola No. 1, K. 423, in a quiet room for 17 minutes. We compared the degree of pain using resting-state functional magnetic resonance imaging and the numeric rating scale before and after listening to music. RESULTS: Pain scores were significantly reduced after listening to music. Further, we observed there was a significant difference in connectivity between the right insular cortex (IC) and posterior cingulate cortex (PCC)/precuneus (PCu) before and after listening to music. We also found that the difference between the right IC-PCu connectivity and the difference in pain scores were significantly correlated. CONCLUSIONS: We found that a short period of music intervention reduced chronic pain and altered functional IC-default mode network connectivity. Furthermore, music potentially normalized the neural network via IC-default mode network connectivity, yielding temporary pain relief in patients with FM. Further longitudinal studies with larger sample sizes are required to confirm these results.

Intratumoral and s.c. injection of inactivated hemagglutinating virus of Japan envelope (GEN0101) in metastatic castration-resistant prostate cancer.

Inactivated hemagglutinating virus of Japan envelope (HVJ-E) has an antitumor effect and tumor immunity. We undertook an open-label, phase I, dose-escalation study in patients with castration-resistant prostate cancer (CRPC) to determine the safety and efficacy of intratumoral and s.c. injection of HVJ-E (GEN0101). Patients with CRPC, who were resistant to or unable to receive standard of care, were included. GEN0101 was injected directly into the prostate and s.c. in two 28-day treatment cycles. The primary end-points were to evaluate the safety and tolerability of GEN0101 and determine its recommended dose. The secondary end-points were to analyze the antitumor effect and tumor immunity. Three patients received 30 000 mNAU GEN0101 and 6 received 60 000 mNAU. There was no dose-limiting toxicity, and the recommended dose of GEN0101 was defined as 60 000 mNAU. Radiographically, 1 patient had stable disease and 2 had progressive disease in the low-dose group, whereas 5 patients had stable disease and 1 had progressive disease in the high-dose group. Three patients in the high-dose group showed reduction in lymph node metastasis. Prostate-specific antigen increase rates in the high-dose group were suppressed more than those in the low-dose group. Natural killer cell activity was enhanced in 2 patients of the low-dose group and in 5 patients in the high-dose group. In conclusion, intratumoral and s.c. injections of GEN0101 were well-tolerated and feasible to use. The study is registered with the UMIN Clinical Trials Registry (no. UMIN000017092).

Intratumoral injection of hemagglutinating virus of Japan-envelope vector yielded an antitumor effect for advanced melanoma: a phase I/IIa clinical study.

Hemagglutinating virus of Japan (HVJ; Sendai virus) is an RNA virus that has cell fusion activity. HVJ-envelope (HVJ-E) is a UV-irradiated HVJ particle that loses viral replication and protein synthesis activity but retains cell fusion activity. We recently reported that HVJ-E has antitumor effects on several types of tumors. Here, we describe the results of a first-in-human phase I/IIa study in patients with advanced melanoma, receiving intratumoral administration of HVJ-E. The primary aim was to evaluate the safety and tolerability of HVJ-E, and the secondary aim was to examine the objective tumor response and antitumor immunity. Six patients with stage IIIC or IV progressive malignant melanoma with skin or lymph metastasis were enrolled. Patients were separated into two groups (n = 3 each) and received low and high doses of HVJ-E. Five of the six patients completed 4 weeks of follow-up evaluation; one patient discontinued treatment owing to progressive disease. Complete or partial responses were observed in 3 of 6 (50%) injected target lesions, 7 of 15 (47%) noninjected target lesions, and 10 of 21 (48%) target lesions. Induction of antitumor immunity was observed: activation of natural killer cells, a marked increase in interferon-γ levels in the peripheral blood, and infiltration of cytotoxic T cells into both injected and noninjected tumor lesions. Thus, intratumoral injection of HVJ-E in advanced melanoma patients showed safety and tolerability with local regression of the tumor mediated by antitumor immunity. The results suggest that HVJ-E might be a new treatment approach in patients with advanced melanoma.

Absence of Relatives Impairs the Approach of Nurses to Cardiopulmonary Resuscitation in Non-Cancer Elderly Patients without a Do-Not-Attempt-Resuscitation Order: A Vignette-Based Questionnaire Study.

A Do-Not-Attempt-Resuscitation (DNAR) order solely precludes performing cardiopulmonary resuscitation (CPR) following cardiopulmonary arrest. A patient's personal status is known to influence a range of clinical practices, not only CPR, when a DNAR order is given. We assessed whether the absence of supporting relatives or a diagnosis of dementia can influence nurses' perceptions of clinical practices for elderly patients with non-malignant and chronic diseases. A vignette-based questionnaire was used to evaluate nurses' beliefs both before and after issuance of a DNAR order. Three vignettes were developed: the control vignette described an 85-year-old woman with repeated heart failure, the second and third incorporated a lack of relatives and a dementia diagnosis, respectively. The survey assessed the approach of nurses to 10 routine medical procedures, including CPR, clinical laboratory testing and nursing care, using a 5-base Likert-scale, for six vignette scenarios. A questionnaire was completed by 186 nurses (64% response). The pre-DNAR non-relative vignette showed significantly lower scores for CPR, indicating a deterioration in willingness to perform CPR, compared to the pre-DNAR control (median [interquartile]; 3 [2-4] and 4 [3-4] in the non-relative and control vignettes, respectively, p < 0.001). No significant differences were observed between the dementia and control vignettes. Absence of contactable relatives and resultant lack of communication can diminish the perception of nurses regarding the provision of CPR, even when a DNAR does not exist. This result suggests a necessity for comprehensive training all medical staff about issuance of DNAR orders and what care should be provided thereafter.

SPACIA1/SAAL1 Deletion Results in a Moderate Delay in Collagen-Induced Arthritis Activity, along with mRNA Decay of Cyclin-dependent Kinase 6 Gene.

This study was performed to elucidate the molecular function of the synoviocyte proliferation-associated in collagen-induced arthritis (CIA) 1/serum amyloid A-like 1 (SPACIA1/SAAL1) in mice CIA, an animal model of rheumatoid arthritis (RA), and human RA-synovial fibroblasts (RASFs). SPACIA1/SAAL1-deficient mice were generated and used to create mouse models of CIA in mild or severe disease conditions. Cell cycle-related genes, whose expression levels were affected by SPACIA1/SAAL1 small interfering RNA (siRNA), were screened. Transcriptional and post-transcriptional effects of SPACIA1/SAAL1 siRNA on cyclin-dependent kinase (cdk) 6 gene expression were investigated in human RASFs. SPACIA1/SAAL1-deficient mice showed later onset and slower progression of CIA than wild-type mice in severe disease conditions, but not in mild conditions. Expression levels of cdk6, but not cdk4, which are D-type cyclin partners, were downregulated by SPACIA1/SAAL1 siRNA at the post-transcriptional level. The exacerbation of CIA depends on SPACIA1/SAAL1 expression, although CIA also progresses slowly in the absence of SPACIA1/SAAL1. The CDK6, expression of which is up-regulated by the SPACIA1/SAAL1 expression, might be a critical factor in the exacerbation of CIA.

Identification of the inhibitory activity of walnut extract on the E3 ligase Syvn1.

Synoviolin (Syvn1), an E3 ubiquitin ligase in endoplasmic reticulum­associated protein degradation, is involved in rheumatoid arthritis, fibrosis, liver cirrhosis and obesity. We previously demonstrated that Syvn1 negatively regulates the function of peroxisome proliferator­activated receptor gamma coactivator­1ß (PGC­1ß). In addition, treatment with a Syvn1 inhibitor suppressed weight gain in a mouse model of obesity by activating PGC­1ß via Syvn1 inhibition. It has been suggested that the Syvn1 inhibitors may have therapeutic benefits in obese patients. The present study tested the inhibitory activity of walnut extract, a natural product, on Syvn1 activity. Walnut extract inhibited the effect of Syvn1 on the cell proliferation of rheumatoid synovial cells and repressed the interaction between PGC­1ß and Syvn1 in an in vitro binding assay. Polyubiquitination of PGC­1ß by Syvn1 was suppressed by walnut extract in a concentration­dependent manner, but walnut extract did not have an inhibitory effect on the autoubiquitination of Syvn1. Treatment with walnut extract in mouse embryonic fibroblasts increased the number of mitochondria, suggesting that exposure to the extract recovered PGC­1ß function. These results demonstrated that constituents of walnut extract may serve as lead compounds in drug development efforts aiming to produce drugs to treat patients with obesity and obesity­associated metabolic diseases.

The NRF2­PGC­1ß pathway activates kynurenine aminotransferase 4 via attenuation of an E3 ubiquitin ligase, synoviolin, in a cecal ligation/perforation­induced septic mouse model.

Sepsis­associated encephalopathy (SAE) is a systemic inflammatory response syndrome of which the precise associated mechanisms remain unclear. Synoviolin (Syvn1) is an E3 ubiquitin ligase involved in conditions associated with chronic inflammation, including rheumatoid arthritis, obesity, fibrosis and liver cirrhosis. However, the role of Syvn1 in acute inflammation is not clear. The aim of the present study was to investigate the role of Syvn1 in a septic mouse model induced by cecal ligation/perforation (CLP). Metabolome analysis revealed that kynurenine (KYN), a key factor for the development of neuroinflammation, was increased in CLP­induced septic mice. Notably, KYN was not detected in CLP­induced septic Syvn1­deficient mice. KYN is converted to kynurenic acid (KYNA) by kynurenine aminotransferases (KATs), which has a neuroprotective effect. The expression of KAT4 was significantly increased in Syvn1­deficient mice compared to that in wild­type mice. Promoter analysis demonstrated that Syvn1 knockdown induced the KAT4 promoter activity, as assessed by luciferase reporter activity, whereas Syvn1 overexpression repressed this activity in a dose­dependent manner. Furthermore, the KAT4 promoter was significantly activated by the transcriptional factors, NF­E2­related factor 2 and peroxisome proliferator­activated receptor coactivator 1ß, which are targets of Syvn1­induced degradation. In conclusion, the results of the current study demonstrates that the repression of Syvn1 expression induces the conversion of neurotoxic KYN to neuroprotective KYNA in a CLP­induced mouse model of sepsis, and that Syvn1 is a potential novel target for the treatment of SAE.

An E3 Ubiquitin Ligase, Synoviolin, Is Involved in the Degradation of Homocysteine-Inducible Endoplasmic Reticulum Protein.

Homocysteine-inducible endoplasmic reticulum (ER) protein (Herp) is an ER stress-inducible membrane protein involved in ER-associated degradation. Herp expression is maintained at low levels through a strict regulatory mechanism, but the details of this mechanism and the reasons why Herp expression is restricted in this manner remain unclear. Here, we show that Herp degradation involves synoviolin, an ER-resident E3 ubiquitin ligase. Herp protein levels were found to be markedly elevated in synoviolin-null cells, and Herp expression decreased when synoviolin was overexpressed. However, the lysine residues of Herp, which are ubiquitinated by E3 ubiquitin ligase, were not sufficient for regulation of Herp degradation. These results suggest that Herp degradation is mediated via synoviolin and that Herp ubiquitination involves amino acids other than lysine.

Retraction: Murine hypothalamic destruction with vascular cell apoptosis subsequent to combined administration of human papilloma virus vaccine and pertussis toxin.

This corrects the article DOI: 10.1038/srep36943.

Modeling relationships of achievement motivation and physical fitness with academic performance in Japanese schoolchildren: Moderation by gender.

The aim of this study was to determine, using structural equation modeling, the comprehensive relationships of achievement motivation (self-fulfillment achievement motivation [SFAM] and competitive achievement motivation [CAM]), daily behaviors (exercise habits, screen time, and learning duration), body mass index [BMI], and cardiorespiratory fitness [CRF]) with academic performance among schoolchildren. Three hundred twenty-five schoolchildren (172 males and 153 females; 12-13 years old) were recruited. Academic performance was assessed using the total grade points in 8 academic subjects (GP8); CRF using the 20-m shuttle run; and achievement motivation, daily behaviors, and socioeconomic status using questionnaires. Socioeconomic status was included as a control variable. In males, two cascade associations of achievement motivation to GP8 were detected: (1) SFAM → screen time/learning duration → GP8, and (2) CAM → exercise habit → CRF → GP8 (χ2 = 8.72, p = .19, AGFI = .92). In females, two cascade associations were also detected: (1) SFAM → screen time/learning habit → GP8, and (2) exercise habit → BMI2 → GP8 (χ2 = 6.17, p = .41, AGFI = .93). Our results suggest that greater achievement motivation is associated with academic success via various physiological/behavioral factors, and that these associations differ by gender.

Abatacept in combination with methotrexate in Japanese biologic-naive patients with active rheumatoid arthritis: a randomised placebo-controlled phase IV study.

OBJECTIVES: To evaluate efficacy and safety of abatacept+methotrexate (MTX) in biologic-naive, anticitrullinated protein antibody (ACPA)-positive Japanese patients with active rheumatoid arthritis (RA) and early erosion versus placebo+MTX. METHODS: In this phase IV, multicentre, double-blind study (NCT01758198), patients were randomised (1:1) to receive intravenous abatacept (~10 mg/kg) or placebo, plus MTX (≥6 mg/week). Primary efficacy objectives were to compare American College of Rheumatology 20 (ACR20) response rates at week 16 and mean change from baseline in van der Heijde-modified total Sharp score (vdH-mTSS) at week 24 between abatacept+MTX and placebo+MTX groups. RESULTS: Overall, 203 and 202 patients received abatacept+MTX and placebo+MTX, respectively. At week 16, ACR20 response rates were higher in the abatacept (75.4%) versus placebo group (27.7%; p<0.001). Mean change from baseline in vdH-mTSS at week 24 was 0.84 in the abatacept and 1.26 in the placebo group (p=0.017). Radiographic non-progression rates (change in vdH-mTSS≤smallest detectable change (2.4)) were 88.1% and 75.4% in abatacept and placebo groups, respectively. Adjusted mean change from baseline in Disease Activity Score 28 (C-reactive protein) (DAS28 (CRP)) at week 16 demonstrated a numerically greater reduction in the abatacept versus placebo group. Proportions of patients with DAS28 (CRP), Simplified Disease Activity Index and Clinical Disease Activity Index remission up to week 52 were higher in the abatacept versus placebo group. The abatacept safety profile was consistent with previous observations. CONCLUSIONS: Compared with MTX alone, abatacept+MTX improved clinical symptoms and inhibited structural damage progression in ACPA-positive, Japanese patients with RA, early erosion and inadequate response to MTX.

Direct and indirect relationships of physical fitness, weight status, and learning duration to academic performance in Japanese schoolchildren.

The purpose of this study was to determine, using structural equation modelling (SEM), the direct and indirect influence of daily behaviours (i.e. exercise/learning durations), weight status, and physical fitness on academic performance among seventh-grade schoolchildren, after controlling for socioeconomic status. We analysed cross-sectional data from 274 schoolchildren (159 males and 115 females; 12-13 years old). Academic performance was assessed using the total grade points in eight academic subjects. Physical fitness was evaluated using the total score of eight physical fitness tests and weight status using body mass index. The daily behaviours and socioeconomic status were assessed by the questionnaire. The SEM showed an adequate fit to the data (χ2 = 0.684, p = .710, RMSEA = .000). Physical fitness and learning durations had direct effects on academic performance (ß = .301, p < .001; ß = .132, p = .037, respectively) after controlling for confounders. Healthy weight status and exercise habits positively indirectly influenced academic performance via physical fitness. These findings suggest that, independent of socioeconomic status and learning durations, exercise habits and maintaining healthy weight status may indirectly contribute to academic success via better physical fitness in children.

Inhibitory effects of ubiquitination of synoviolin by PADI4.

Rheumatoid arthritis (RA) is a chronic inflammatory articular disease that is characterized by synovial hyperplasia. A number of signaling pathways are associated with the development and induced symptoms of RA. Notably, patients with RA have increased protein citrullination and generation of auto­antibodies against citrullinated proteins. Genome wide association studies have revealed that peptidyl­arginine deiminase 4 (PADI4) is an enzyme implicated in citrullination in the RA synovium. Autoantibodies targeting citrullinated proteins are used as diagnostic markers in patients with RA. The functions associated with citrullinated proteins are thought to induce autoimmunity, however, the regulatory mechanisms of citrullination via PADI4 are unclear. The group has previously cloned an E3 ubiquitin ligase, synoviolin (SYVN1), from the RA synovium, demonstrating that SYVN1 serves critical roles in synovial hyperplasia. The data indicated that the endoplasmic reticulum (ER) associated degradation system, which involves SYVN1, may have important roles in the proliferation of synoviocytes. In addition, ubiquitination by SYVN1 is associated with fibrosis, inflammation and cytokine production via the regulation of ER stress signals and quality control of proteins. The present study investigated the crosstalk between the representative post­translational signaling processes, citrullination and ubiquitination. The results revealed that PADI4 interacted with SYVN1 directly and that overexpression of PADI4 suppressed the ubiquitination of proteins. Thus, a reduction in ER stress induced by PADI4 may abrogate the initiation of chronic RA by suppressing the proliferative signals of RA synoviocytes.