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Background: The management of ulnar collateral ligament (UCL) injuries widely varies among surgeons. Although various treatment options have been proposed including surgical and conservative treatments, no golden standard treatment strategy has been established of yet. The American survey reported an overall experienced and well-trained cohort of surgeons often reached consensus opinions on how to approach UCL injury. However, the consensus among Japanese surgeons on the treatment of UCL injuries remains unclear. The purpose of this study was to survey current trends among Japanese orthopaedic surgeons in the treatment of UCL injuries in baseball players., Methods: An online survey was distributed to the active members of the Japanese doctor's network for baseball injury prevention, which was formed by partial members of the medical committee in the Japan Baseball Council. The survey was composed of three sections: demographics of the surveyees, preferred operative and nonoperative management of UCL injuries, and five fictional clinical case scenarios of baseball players with a UCL injury., Results: The 131 e-mailed invitations to society members yielded 78 completed online surveys with a participation rate of 60%. Sixty-four respondents (82%) reported >15 years of clinical experience. Sixty-five respondents (83%) performed ≤5 UCL reconstructions per year. As nonsurgical management of UCL injuries, seventy-four surgeons (95%) preferred physiotherapy followed by intraarticular injection (46%). For surgical management, seventy-three surgeons (93%) preferred UCL reconstruction. Of the five case scenarios, a consensus was reached in three cases: to perform surgery on the patient with full-thickness UCL tear. When operative management was the preferred option, a consensus was reached to perform UCL reconstruction., Conclusion: Japanese doctors involved in the treatment of baseball injuries reached a consensus to indicate high-level athletes with a full-thickness UCL tear for surgery. When operative management was the preferred option, a consensus was reached to perform UCL reconstruction. These results may contribute to the decision-making for managing UCL injuries., Competing Interests: Declaration of competing interest The authors declare there are no conflicts of interest., (Copyright © 2024 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Background: The long-term prognostic impact of IVUS findings following Absorb BVS implantation remains uncertain. This study aimed to identify the IVUS predictors of long-term clinical outcomes following ABSORB bioresorbable vascular scaffold (BVS) implantation from the pooled IVUS substudy cohorts of the ABSORB III and Japan trials., Methods: A total of 298 lesions in 286 patients were enrolled with 2:1 randomization to ABSORB BVS vs. cobalt-chromium everolimus-eluting stents. This sub-analysis included 168 lesions of 160 patients in the Absorb arm whose post-procedural quantitative IVUS were available. The primary endpoint of this analysis was device-oriented composite endpoint (DOCE) of target lesion failure, including cardiac death, target vessel-related myocardial infarction, or ischemia-driven target lesion revascularization. The median follow-up duration was 4.9 [3.1-5.0] years., Results: During follow-up, DOCE occurred in 10.1% of lesions treated with Absorb BVS. Among several post-procedural IVUS indices associated with DOCE, non-uniform device expansion (defined as uniformity index = minimum / maximum device area) (hazard ratio 0.47 per 0.1 increase [95%CI 0.28 to 0.77]; p = 0.003) and residual reference plaque burden (hazard ratio 4.01 per 10% increase [95%CI 1.50 to 10.77]; p = 0.006) were identified as independent predictors of DOCE by Cox multivariable analysis., Conclusions: Nonuniform device expansion and substantial untreated residual plaque in reference segments were associated with long-term adverse events following BVS implantation. Baseline imaging to identify the appropriate device landing zone and procedural imaging to achieve uniform device expansion if possible (e.g. through post-dilatation) may improve clinical outcomes of BVS implantation., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01751906 (ABSORB III); NCT01844284 (ABSORB Japan)., (Copyright © 2021. Published by Elsevier Ltd.)

Objectives: The aim of this study was to investigate the vascular responses and fates of the scaffold after bioresorbable vascular scaffold (BVS) implantation using multimodality imaging., Background: Serial comprehensive image assessments after BVS implantation in the context of a randomized trial have not yet been reported., Methods: In the ABSORB Japan trial, 400 patients were randomized to a BVS (n = 266) or a cobalt-chromium everolimus-eluting stent (n = 134). Through 3 years, patients underwent serial angiography and intravascular ultrasound or optical coherence tomography (OCT)., Results: Luminal dimension at 3 years was consistently smaller with the BVS than with the cobalt-chromium everolimus-eluting stent (mean angiographic minimal luminal diameter 2.04 ± 0.63 mm vs. 2.40 ± 0.56 mm, mean difference -0.37 mm [95% confidence interval: -0.50 to -0.24 mm]; p < 0.001), mainly because of smaller device area (6.13 ± 2.03 mm 2 vs. 7.15 ± 2.16 mm 2 , mean difference -1.04 mm 2 [95% confidence interval: -1.66 to -0.42 mm 2 ]; p < 0.001), and larger neointimal area (2.10 ± 0.61 mm 2 vs. 1.86 ± 0.64 mm 2 , mean difference 0.24 mm 2 [95% confidence interval: 0.06 to 0.43 mm 2 ]; p = 0.01) by OCT. BVS-treated vessels did not show previously reported favorable vessel responses, such as positive vessel remodeling, late luminal enlargement, and restoration of vasomotion, although the OCT-based healing score was on average zero (interquartile range: 0.00 to 0.00). At 3 years, intraluminal scaffold dismantling (ISD) was observed in 14% of BVS. On serial OCT, ISD was observed in 6 lesions at 2 years, where the struts had been fully apposed at post-procedure, while ISD was observed in 12 lesions at 3 years, where 8 lesions were free from ISD on 2-year OCT. In 5 cases of very late scaffold thrombosis, strut discontinuities were detected in all 4 cases with available OCT immediately before reintervention., Conclusions: In this multimodality serial imaging study, luminal dimension at 3 years was smaller with the BVS than with the cobalt-chromium everolimus-eluting stent. ISD, suspected to be one of the mechanisms of very late BVS thrombosis, was observed in a substantial proportion of cases at 3 years, which developed between post-procedure and 2 years and even beyond 2 years. (AVJ-301 Clinical Trial: A Clinical Evaluation of AVJ-301 [Absorb™ BVS] in Japanese Population [ABSORB JAPAN]; NCT01844284)., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to characterize post-procedural intravascular ultrasound (IVUS) findings in the ABSORB Japan trial, specifically stratified by the size of target coronary arteries., Background: Despite overall noninferiority confirmed in recent randomized trials comparing bioresorbable vascular scaffolds (BVS) (Absorb BVS) and cobalt-chromium everolimus-eluting metallic stents (CoCr-EES), higher event rates of Absorb BVS have been reported with suboptimal deployment, especially in small coronary arteries., Methods: In the ABSORB Japan trial, 150 patients (2:1 randomization) were scheduled in the IVUS cohort. Small vessel was defined as mean reference lumen diameter <2.75 mm. Tapered-vessel lesions were defined as tapering index (proximal/distal reference lumen diameter) ≥1.2., Results: Overall, IVUS revealed that the Absorb BVS arm had smaller device expansion than the CoCr-EES arm did, which was particularly prominent in small- and tapered-vessel lesions. Higher tapering index was also associated with higher rates of incomplete strut apposition in Absorb BVS, but not in CoCr-EES. With respect to procedural techniques, small-vessel lesions were treated more frequently with noncompliant balloons at post-dilatation but using significantly lower pressure in the Absorb BVS arm. In contrast, tapered-vessel lesions were post-dilated at equivalent pressure but with significantly smaller balloon catheters in the Absorb BVS arm, compared with the CoCr-EES arm., Conclusions: The significantly smaller device expansion especially in small vessels may account for the poorer outcomes of Absorb BVS in this lesion type. Appropriate optimization strategy, possibly different between polymeric and metallic devices, needs to be established for bioresorbable scaffold technology. (AVJ-301 Clinical Trial: A Clinical Evaluation of AVJ-301 Absorb™ BVS) in Japanese Population [ABSORB JAPAN]; NCT01844284)., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Thiol-based redox control is among the most important mechanisms for maintaining cellular redox homeostasis, with essential participation of cysteine thiols of oxidoreductases. To explore cellular redox regulatory networks, direct interactions among active cysteine thiols of oxidoreductases and their targets must be clarified. We applied a recently described thiol-ene crosslinking-based strategy, named divinyl sulfone (DVSF) method, enabling identification of new potential redox relay partners of the cytosolic oxidoreductases thioredoxin (TXN) and thioredoxin domain containing 17 (TXNDC17). Applying multiple methods, including classical substrate-trapping techniques, will increase understanding of redox regulatory mechanisms in cells., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Molecular organization of the eukaryote chaperonin known as CCT/TRiC complex was recently clarified. Eight distinct subunits are uniquely organized, providing a favorable folding cavity for specific client proteins such as tubulin and actin. Because of its heterogeneous subunit composition, CCT complex has polarized inner faces, which may underlie an essential part of its chaperonin function. In this study, we structurally characterized the closed and open states of CCT complex, using molecular dynamics analyses. Our results showed that the inter-subunit interaction energies were asymmetrically distributed and were remodeled during conformational changes of CCT complex. In addition, exploration of redox related characteristics indicated changes in inner surface properties, including electrostatic potential, pK a and exposure of inner cysteine thiol groups, between the closed and open states. Cysteine activation events were experimentally verified by interaction analyses, using tubulin as a model substrate. Our data highlighted the importance of dynamics-based structural profiling of asymmetrically oriented chaperonin function., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Immunotherapy including interferon-alpha (IFN-α) is one of the treatment options for metastatic renal cell carcinoma (mRCC) patients. Despite clinical benefits for the selected patients, IFN-α therapy has some problems, such as poor tolerability and dose-limiting adverse effects. In addition, the frequent injections reduce a patient's quality of life and compliance. Recently, an injectable and biodegradable hydrogel system to prolong drug release is reported. In this study, we investigated the anticancer effect of IFN-α (Sumiferon®)-incorporated hyaluronic acid-tyramine (HA-Tyr) hydrogels in human RCC-xenografted in nude mice. We also evaluated the synergistic efficacy of IFN-α-incorporated HA-Tyr hydrogels+sorafenib in this model. IFN-α-incorporated HA-Tyr hydrogels+sorafenib most effectively inhibited tumor growth on human RCC cells xenografted in nude mice. In addition, IFN-α-incorporated HA-Tyr hydrogels+sorafenib inhibited the proliferation of tumor in nude mice by inducing apoptosis and the suppression of angiogenesis. Our results suggest a possibility that HA-Tyr hydrogel drug delivery system prolongs the biological half-life of natural human IFN-α and enhances its anticancer effects on human RCC cells., Statement of Significance: The scope of this study is to provide an alternative approach to improve the anticancer efficacy in renal cell carcinoma (RCC) treatment by using hyaluronic acid-tyramine (HA-Tyr) hydrogel drug delivery system. We investigated the anticancer effect of natural interferon-α (IFN-α)-incorporated HA-Tyr hydrogels in RCC cells. We also evaluated the synergistic efficacy of natural human IFN-α-incorporated HA-Tyr hydrogels+sorafenib. We demonstrated that HA-Tyr hydrogel system is able to release natural human IFN-α in sustained manner and enhances its anticancer effects on human RCC cells. In addition, we suggested that IFN-α-incorporated HA-Tyr hydrogels+sorafenib exhibited most effectively anticancer effects. Hence, we believe that this approach could be applied to treatment with RCC in the future., (Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Aims: In this study, we investigated the involvement of apoptosis signal-regulating kinase 1 (ASK1) in oxidative stress and osmotic stress-induced hepatocyte death., Main Methods: Activation of ASK1-JNK/p38 cascade and resulting cell death induced by oxidative and osmotic stress was investigated by Western immunoblot analysis and cell toxicity assay using human hepatoma cell lines, Huh7 expressing high level of ASK1 and HepG2 cells expressing low level of ASK1. Gene knock-down of ASK1 using shRNA against ASK1 was conducted using mouse hepatocyte cell line, AML12., Key Findings: Activation of ASK1-JNK/p38 cascade and cell death in Huh7 expressing high level of ASK1 was markedly induced by the oxidative stress. HepG2 expressing low level of ASK1 was resistant to oxidative stress while cell death induced by osmotic stress was comparable between Huh7 and HepG2 cells. Although the phosphorylation of ASK1 was not observed by osmotic stress, the phosphorylation of p38 and JNK and resulting cell death was induced in both cell lines. The phosphorylation of ASK1 and p38/JNK in the mouse primary hepatocyte were also increased by oxidative stress. Knock-down of ASK1 mRNA in AML12 in vitro significantly reduced oxidative stress-induced cell death, however, knock-down of ASK1 in cells did not affect the osmotic stress-induced cell death., Significance: This study revealed that ASK1 regulates oxidative stress- but not osmotic stress-induced hepatocyte death, suggesting ASK1 plays a critical role in oxidative-stress induced hepatocyte death. These results raise the possibility that an ASK1 may be a promising therapeutic target for liver diseases caused by oxidative stress.

Background: In a previous clinicopathological study, we observed mesangial factor V expression accompanied by the intact form of cross-linked fibrin deposition in the active type of IgA nephropathy. The conversion of prothrombin to thrombin by factor Xa is potently accelerated more than 104-fold by the presence of factor V, which is a membrane-bound cofactor. Another membrane-bound cofactor, tissue factor, is known to play an initiating role in the coagulation cascade and to be synthesized in mesangial cells (MCs) by the stimulation of tumor necrosis factor-alpha (TNF-alpha). However, the synthesis of factor V, which plays on the terminating stage of prothrombin activation, has not been reported previously in MCs by in vitro study. Our current study tested the coagulation process via expression of factor V by the stimulation of proinflammatory cytokine, TNF-alpha, in cultured human MCs., Methods: To evaluate factor V protein expression, immunoperoxidase staining with densitometric evaluation and Western blot analysis were conducted after stimulation of TNF-alpha. To test factor V activity, stimulated MCs were incubated in combination with factor Xa, prothrombin, fibrinogen and factor XIII, and fibrin production on MCs was assessed after immunoperoxidase staining on the cell surface. In a blocking test using an antibody against factor V, suppression of fibrin production was evaluated to clarify the role of factor V activity. For the evaluation of factor V mRNA expression in cultured human MCs, in situ hybridization and Northern blot analysis were performed., Results: Factor V protein expression in MCs after TNF-alpha stimulation increased both time- and dose-dependently. As a marker of factor V activity with exogenous factor Xa, fibrin production on TNF-alpha-stimulated MCs was increased in a time-dependent manner and was inhibited by the addition of anti-factor V antibody. Factor V mRNA was identified in MCs by in situ hybridization and showed an increase after stimulation with TNF-alpha on Northern blot analysis., Conclusions: Our data suggest that the coagulation process proceeds on MCs as the result of increased expression of endogenous factor V activity on its cell surface in cooperation with exogenous factor Xa.