High Fracture Rate of AVANTA Silicone Implant Following Arthroplasty of the Thumb MCP Joint of Rheumatoid Arthritis Patients with Boutonniere Deformities.

We retrospectively investigated the mid-term outcomes of arthroplasty using the AVANTA silicone implant for thumb metacarpophalangeal (MCP) joints with boutonniere deformity in patients with rheumatoid arthritis (RA). This study involved 36 thumbs of 33 RA patients with a mean follow-up period of 5.1 years (range, 2.0-13.3). Postoperatively, the mean extension was significantly increased and the mean flexion was significantly decreased (p<0.001, p<0.001, respectively), resulting in the mean arc of range of motion (ROM) shifting in the direction of extension after surgery. Implant fracture was observed in 10 thumbs (28%), and 4 of these (11%) underwent revision surgery. The survivorship with implant fracture and revision surgery as endpoints were 73.4% and 91.8% at 5 years, respectively. The preoperative arc of ROM and the postoperative flexion range of the implant-fracture group were significantly greater than those in the no-implant-fracture group (p=0.039, 0.034, respectively). These results suggest the importance of patient education and careful rehabilitation to prevent excessive flexion. Overall, the AVANTA silicone implant showed a relatively high rate of implant fracture at our institute.

The histone deacetylase inhibitor OBP-801 has in vitro/in vivo anti-neuroblastoma activity.

BACKGROUND: Patients with high-risk neuroblastoma have a poor prognosis; new therapeutic agents are therefore required. We investigated the antitumor effects of OBP-801, a novel histone deacetylase inhibitor, its underlying mechanism, and its potential as a therapeutic agent for patients with neuroblastoma. METHODS: The study included five human neuroblastoma cell lines: IMR32, GOTO, KP-N-RTBM, SK-N-AS, and SH-SY5Y. We investigated cell proliferation, cell cycle status, protein expression patterns, and apoptosis in neuroblastoma cells after OBP-801 treatment in vitro. Cell survival rate and cell cycle were analyzed using the WST-8 assay and flow cytometry, respectively. Apoptosis was detected using annexin V staining, and the expression of apoptosis-related proteins was investigated by western blotting. The antitumor activity of OBP-801 was examined in an in vivo xenograft mouse model. RESULTS: Dose-effect curve analysis showed that the mean half-maximal inhibitory concentration value was 5.5 ± 5.9 nM for the MYCN-amplified cell lines (IMR32, GOTO, and KP-N-RTBM) and 3.1 ± 0.7 nM for the MYCN-nonamplified cell lines (SK-N-AS and SH-SY5Y). OBP-801 inhibited cell proliferation and growth in all the cell lines. It induced G2/M phase arrest through the p21 (CDKN1A) pathway, increasing histone H3 levels and, subsequently, apoptosis in human neuroblastoma cells. OBP-801 suppressed the growth of neuroblastoma cells in the mouse xenograft model. CONCLUSIONS: Overall, OBP-801 induces M-phase arrest and apoptosis in neuroblastoma cells via mitotic catastrophe. Our results indicate that OBP-801 is a promising therapeutic agent with fewer adverse effects for patients with neuroblastoma.

Subjective and Objective Outcomes of Surgery for Rheumatoid Forefoot Deformities Under the Current Treatment Paradigm.

We investigated the clinical outcomes of surgical procedures for the treatment of forefoot deformities in patients with rheumatoid arthritis. Twenty feet in 16 women (mean age 62.1 years) underwent corrective osteotomy of the first metatarsal bone with shortening oblique osteotomy of the lesser metatarsophalangeal joints (joint-preservation group), while 13 feet in 12 women (mean age 67.4 years) underwent arthrodesis of the first metatarsophalangeal joint with resection arthroplasty of the lesser metatarsophalangeal joints (joint-sacrifice group); mean follow-up for each group was 25.8 and 23.8 months, respectively. The mean total Japanese Society for Surgery of the Foot (JSSF) scale improved significantly from 64.2 to 89.2 in the joint-preservation group (p < .001), and from 54.2 to 74.2 in the joint-sacrifice group (p = .003). In the joint-preservation group, the postoperative range of motion (ROM) of the joint, walking ability, and activities of daily living scores of the JSSF scale were significantly higher than those in the joint-sacrifice group (p = .001, p = .001, and p = .019, respectively). There were no differences in the subscale scores of the self-administered foot evaluation questionnaire between 2 groups either pre- or postoperatively. No differences in the postoperative complications were found between 2 groups. Although the joint-sacrificing procedure resulted in lower objective outcomes than the joint-preserving procedure regarding the ROM of the joint, the walking ability, and the level of activities of daily living, both procedures resulted in similar treatment outcomes when evaluated by the subjective measures.

Adipose-Derived Extract Suppresses IL-1ß-Induced Inflammatory Signaling Pathways in Human Chondrocytes and Ameliorates the Cartilage Destruction of Experimental Osteoarthritis in Rats.

We investigated the effects of adipose-derived extract (AE) on cultured chondrocytes and in vivo cartilage destruction. AE was prepared from human adipose tissues using a nonenzymatic approach. Cultured human chondrocytes were stimulated with interleukin-1 beta (IL-1ß) with or without different concentrations of AE. The effects of co-treatment with AE on intracellular signaling pathways and their downstream gene and protein expressions were examined using real-time PCR, Western blotting, and immunofluorescence staining. Rat AE prepared from inguinal adipose tissues was intra-articularly delivered to the knee joints of rats with experimental osteoarthritis (OA), and the effect of AE on cartilage destruction was evaluated histologically. In vitro, co-treatment with IL-1ß combined with AE reduced activation of the p38 and ERK mitogen-activated protein kinase (MAPK) pathway and nuclear translocation of the p65 subunit of nuclear factor-kappa B (NF-κB), and subsequently downregulated the expressions of matrix metalloproteinase (MMP)-1, MMP-3, MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4, IL-6, and IL-8, whereas it markedly upregulated the expression of IL-1 receptor type 2 (IL-1R2) in chondrocytes. Intra-articular injection of homologous AE significantly ameliorated cartilage destruction six weeks postoperatively in the rat OA model. These results suggested that AE may exert a chondroprotective effect, at least in part, through modulation of the IL-1ß-induced inflammatory signaling pathway by upregulation of IL-1R2 expression.

RANKL expression in chondrocytes and its promotion by lymphotoxin-α in the course of cartilage destruction during rheumatoid arthritis.

We investigated the expression and localization of the receptor activator nuclear factor κB ligand (RANKL) in cartilage from patients with rheumatoid arthritis (RA) of relevance to cartilage degeneration. We also examined the role of exogenous lymphotoxin (LT)-α on RANKL expression in human chondrocytes and its effect on in vitro osteoclast differentiation. Cartilage and synovial fluid samples were obtained from 45 patients undergoing total joint replacement surgery or joint puncture, including 24 patients with osteoarthritis (OA) and 21 patients with RA. RANKL expression in articular cartilage was examined by immunohistochemistry. LT-α concentrations in synovial fluid were measured using an enzyme-linked immunosorbent assay (ELISA). Normal human chondrocytes were stimulated with LT-α, and the relative mRNA levels of RANKL, osteoprotegerin (OPG), matrix metalloproteinase-9, and vascular endothelial growth factor were examined by real-time polymerase chain reaction. Soluble RANKL protein in culture media was measured using ELISA, and membrane-bound RANKL protein in cells was examined by western blotting. Co-cultures of human chondrocytes with peripheral blood mononuclear cells (PBMCs) were stimulated with macrophage-colony stimulating factor and LT-α, and osteoclast differentiation was evaluated by staining for tartrate-resistant acid phosphatase. LT-α concentrations were higher in RA synovial fluid than in OA samples. The population of RANKL-positive chondrocytes of RA cartilage was higher than that of OA cartilage, and correlated with cartilage degeneration. Stimulation of cultured human chondrocytes by LT-α increased RANKL expression, the RANKL/OPG ratio, and angiogenic factors. Membrane-bound RANKL in chondrocytes was up-regulated after stimulation of LT-α, whereas soluble RANKL in culture medium did not increase. Co-cultures of human chondrocytes and PBMCs demonstrated that LT-α stimulated human chondrocytes to produce RANKL and induced osteoclastic differentiation of PBMCs. RANKL produced by chondrocytes may contribute to cartilage destruction during RA and LT-α could promote the expression of RANKL in human chondrocytes.

The Novel Histone Deacetylase Inhibitor, OBP-801, Induces Apoptosis in Rhabdoid Tumors by Releasing the Silencing of NOXA.

Rhabdoid tumor is an aggressive, early childhood tumor. Biallelic inactivation of the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1)/integrase interactor 1 (INI1) gene is the only common genetic feature in rhabdoid tumors. Loss of SMARCB1 function results in downregulation of several tumor suppressor genes including p16, p21, and NOXA The novel histone deacetylase inhibitor, OBP-801, induces p21 and has shown efficacy against various cancers. In our study, OBP-801 strongly inhibited the cell growth of all rhabdoid tumor cell lines in WST-8 assay. However, Western blotting and cell-cycle analysis revealed that OBP-801 did not activate the P21-RB pathway in some cell lines. p21 knockout indicated that p21 did not dominate the OBP-801 antitumor effect in rhabdoid tumor cell lines. We discovered that OBP-801 induced NOXA expression and caspase-dependent apoptosis in rhabdoid tumor cell lines independent of TP53. Chromatin immunoprecipitation assay showed that OBP-801 acetylated histone proteins and recruited RNA polymerase II to the transcription start site (TSS) of the NOXA promotor. Moreover, OBP-801 recruited BRG1 and BAF155, which are members of the SWI/SNF complex, to the TSS of the NOXA promotor. These results suggest that OBP-801 epigenetically releases the silencing of NOXA and induces apoptosis in rhabdoid tumors. OBP-801 strongly inhibited tumor growth in human rhabdoid tumor xenograft mouse models in vivo Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and cleaved caspase-3 were stained in tumors treated with OBP-801. In conclusion, OBP-801 induces apoptosis in rhabdoid tumor cells by epigenetically releasing the silencing of NOXA, which is a key mediator of rhabdoid tumor apoptosis. The epigenetic approach for NOXA silencing with OBP-801 is promising for rhabdoid tumor treatment.

[Erratum] OBP­801, a novel histone deacetylase inhibitor, induces M­phase arrest and apoptosis in rhabdomyosarcoma cells.

Subsequent to the publication of the above article, the authors have realized that errors were introduced into Fig. 4 at the typesetting stage. Essentially, in Fig. 4B, the P­value should have read as "P=0.13" (not as 0.013), and in Fig 4D, the labels for OBP- and OBP+ were set the wrong way around. The correct version of Fig. 4, as originally submitted, is shown opposite. The Editor apologizes to the authors for introducing these errors into their figure, and to the readership for any inconvenience caused. [the original article was published in Oncology Reports 41: 643-649, 2019; DOI: 10.3892/or.2018.6813.

OBP­801, a novel histone deacetylase inhibitor, induces M­phase arrest and apoptosis in rhabdomyosarcoma cells.

Rhabdomyosarcoma (RMS) is an aggressive pediatric cancer of musculoskeletal origin. Despite multidisciplinary approaches, such as surgical resection, irradiation, and intensive chemotherapy, adopted for its treatment, the prognosis of patients with high­risk RMS remains poor. Thus, molecularly targeted therapies are required to improve patient survival and minimize side effects. Histone deacetylases (HDACs) modify transcription by deacetylation of the lysine residues in chromatin histone tails and several non­histone proteins. HDAC inhibitors, classes of compounds targeted to various HDAC proteins, are being studied for their roles in several types of cancers in a rigorous manner. This study aimed to investigate the potential of a novel HDAC inhibitor, OBP­801, as a therapeutic agent for the treatment of RMS. We used 8 RMS cell lines in this study. Protein expression patterns, cell proliferation, cell cycle status, and apoptosis in RMS cells after OBP­801 treatment in vitro were investigated. We also studied the antitumor activity of OBP­801 in an in vivo xenograft mouse model. We observed cell cycle arrest at the M­phase and apoptosis in all RMS cell lines after exposure to pharmacological levels of OBP­801 for 24 h. Immunofluorescence staining revealed that OBP­801 may induce mitotic catastrophe via chromosome misalignment and reduced survivin expression, ultimately leading to apoptosis. Our results demonstrated that the novel HDAC inhibitor OBP­801 was an effective inhibitor of RMS cell line proliferation and may be a potent therapeutic option for RMS.

Difference between the Right and Left Phrenic Nerve Conduction Times, Latency, and Amplitude.

We studied phrenic nerve conduction times in 90 phrenic nerves of 45 normal subjects. The phrenic nerve was stimulated at the posterior border of the sternomastoid muscle in the supraclavicular fossa, just above the clavicle, with bipolar surface electrodes. For recording, positive and negative electrodes were placed on the xiphoid process and at the eighth intercostal bone-cartilage transition, respectively. We studied both the right and left sides to determine whether there was any difference between the two sides. The mean onset latency (± SD) of the right compound muscle action potentials (CMAPs) (5.99±0.39 msec) was significantly shorter than that of the left CMAPs (6.45±0.50 msec). The mean peak latency was significantly shorter in the right CMAPs (10.22±1.33 msec) than the left CMAPs (12.48±2.02 msec). The mean (± SD) amplitude was significantly lower in the left CMAPs (0.42±0.11 mV) than the right CMAPs (0.49±0.10 mV). The difference between the length of the nerve on the right and left sides might have affected the difference in latency between the two sides.

A 5-Year Follow-Up of Triple-Seronegative Myasthenia Gravis Successfully Treated with Tacrolimus Therapy.

Seronegative myasthenia gravis (MG) is a generalized form of MG that is diagnosed on the basis of clinical symptoms, electrophysiological testing, and pharmacological responses, in the absence of a seropositive status for anti-acetylcholine receptor (AChR) antibodies. Generalized MG that is seronegative for anti-AChR, anti-muscle-specific kinase (MuSK), and anti-low density lipoprotein receptor related protein 4 (Lrp4) antibodies is known as triple-seronegative MG. We here describe a case of triple-seronegative MG in an 8-year-old boy. His first symptom was dysphagia, at 3 years of age, and he subsequently developed ptosis, rhinolalia, and a waddling gait. A genetic analysis was conducted to exclude the possibility of congenital myasthenia syndrome due to the patient's resistance to steroid therapy. His condition was successfully managed with tacrolimus therapy over a 5-year follow-up period. Recently, several studies have reported the therapeutic utility of tacrolimus in juvenile seropositive MG; in contrast, a few reports have described tacrolimus treatment in cases of seronegative MG. Our findings suggest that tacrolimus therapy is a safe and effective option for the treatment of juvenile seronegative MG.

Inhibitory effect of JAK inhibitor on mechanical stress-induced protease expression by human articular chondrocytes.

OBJECTIVE: To investigate whether janus kinase (JAK) inhibitor exhibits a chondro-protective effect against mechanical stress-induced expression of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) and matrix metalloproteinase (MMPs) in human chondrocytes. MATERIALS AND METHODS: Normal human articular chondrocytes were seeded onto stretch chambers and incubated with or without tofacitinib (1000 nM) for 12 h before mechanical stimulation or cytokine stimulation. Uni-axial cyclic tensile strain (CTS) (0.5 Hz, 10% elongation, 30 min) was applied and the gene expression levels of type II collagen α1 chain (COL2A1), aggrecan (ACAN), ADAMTS4, ADAMTS5, MMP13, and runt-related transcription factor 2 (RUNX-2) were examined by real-time polymerase chain reaction. Nuclear translocation of RUNX-2 and nuclear factor-κB (NF-κB) was examined by immunocytochemistry, and phosphorylation of mitogen-activated protein kinase (MAPK) and signaling transducer and activator of transcription (STAT) 3 was examined by western blotting. The concentration of interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α in the supernatant was examined by enzyme-linked immunosorbent assay. RESULTS: COL2A1 and ACAN gene expression levels were decreased by CTS, but these catabolic effects were canceled by tofacitinib. Tofacitinib significantly down-regulated CTS-induced expression of ADAMTS4, ADAMTS5, MMP13, and RUNX2, and the release of IL-6 in supernatant by chondrocytes. Tofacitinib also reduced CTS-induced nuclear translocation of RUNX-2 and NF-κB, and phosphorylation of MAPK and STAT3. CONCLUSION: Tofacitinib suppressed mechanical stress-induced expression of ADAMTS4, ADAMTS5, and MMP13 by human chondrocytes through inhibition of the JAK/STAT and MAPK cascades.

Results of Total Elbow Arthroplasty with Cementless Implantation of an Alumina Ceramic Elbow Prosthesis for Patients with Rheumatoid Arthritis.

We investigated the long-term clinical results of total elbow arthroplasty (TEA) by cementless fixation of alumina ceramic unlinked elbow prostheses (J-alumina ceramic elbows: JACE) for the reconstruction of elbow joints with rheumatoid arthritis (RA). Seventeen elbows in 17 patients (aged 44-72 years, average 54.8) replaced by JACE TEA without bone cement were investigated. The average follow-up period was 10.7 (range, 1.0-19.3) years. Clinical conditions of each elbow before and after surgery were assessed according to the Mayo Elbow Performance Index (MEPI). Radiographic loosening was defined as a progressive radiolucent line of more than 1 mm that was completely circumferential around the intramedullary stem. The average MEPI significantly improved from 46.8 points preoperatively to 66.8 points at final follow-up (p=0.0226). However, aseptic loosening was noted in 10 of 17 elbows (58.8%) and revision surgery was required in 7 (41.2%). Most loosening was observed on the humeral side. With radiographic loosening and revision surgery defined as the end points, the likelihoods of prosthesis survival were 41.2% and 51.8%, respectively, up to 15 years by Kaplan-Meier analysis. The clinical results of JACE implantation without bone cement were disappointing, with high revision and loosening rates of the humeral component.

Swyer-James Syndrome in a 7-Year-Old Female.

Swyer-James syndrome is a rare syndrome that occurs as a result of repeated bronchiolitis and pneumonitis in childhood. Most cases are asymptomatic, and subsequent diagnosis may not occur until adulthood. We present the case of a 7-year-old female with Swyer-James syndrome, which was initially diagnosed and treated as asthma. The patient developed respiratory distress and atelectasis which were treated with biphasic cuirass ventilation. This case suggests that Swyer-James syndrome should be a concern in patients with chronic cough and wheezing, and highlights the importance of taking a careful history and appropriate radiological investigations for diagnosis. Once Swyer-James syndrome is diagnosed, prophylaxis and appropriate management of respiratory infections becomes important.

Identification of a homozygous JAK3 V674A mutation caused by acquired uniparental disomy in a relapsed early T-cell precursor ALL patient.

Investigation of genetic alterations associated with relapse in acute lymphoblastic leukemia (ALL) may help to identify druggable targets for specific therapies. Early T-cell precursor ALL (ETP-ALL) is a subtype of T-ALL with poor prognosis. Although the genetic landscape of ETP-ALL has been determined, genetic alterations related to the relapse of ETP-ALL have not been fully investigated. Here, we report the first patient with relapsed pediatric ETP-ALL to exhibit a homozygous JAK3 activating mutation, V674A, caused by acquired uniparental disomy (UPD). Single nucleotide polymorphism array analysis revealed acquired UPD (aUPD) at the 19p13.3-p12 locus only in leukemic cells at relapse. Sanger sequence of the JAK3 gene, which was located at 19p13.1 and frequently mutated in ETP-ALL, was performed in paired leukemic samples to determine homozygous JAK3 V674A mutation only in relapsed leukemic cells. In contrast, leukemic cells at initial diagnosis harbored hemizygous JAK3 V674A mutation. Further, whole-exome sequencing revealed mutations in 18 genes only in relapsed samples, although none of these was recurrent in T-ALL. These findings suggest that aUPD at 19p13.1 is partly associated with relapse in this patient. Pharmacological inhibition of JAK3 may be therapeutic in such cases.