Promising immunotherapeutic approaches for primary effusion lymphoma.

Primary effusion lymphoma (PEL) is a large B-cell neoplasm usually presenting as a serious effusion in body cavities without detectable tumor masses. It is an AIDS-related non-Hodgkin's lymphoma (HL) with human herpes virus 8 (HHV8)/Kaposi sarcoma-associated herpes virus (KSHV) infection. A combination antiretroviral therapy (cART) prolongs the lifespan of AIDS and AIDS-related malignant lymphoma patients, but PEL continues to have a dismal prognosis. PEL showed disappointing outcomes with standard chemotherapy such as CHOP or CHOP-like regimens. A PEL status highlights the urgent need for new therapeutic approaches and treatment strategies and improve clinical outcomes. This review discusses the current knowledge and some recent clinical trials for PEL in the platform of immunotherapy as well as promising future immunotherapeutic approaches for PEL.

Liraglutide exhibits potential anti-tumor effects on the progression of intrahepatic cholangiocarcinoma, in vitro and in vivo.

Glucagon-like peptide 1 receptor (GLP-1R) agonist is an emerging anti-diabetic medication whose effects on the risk and progression of cholangiocarcinoma (CCA) are controversial. This study aimed to elucidate the roles of GLP-1R and its agonists on intrahepatic CCA (iCCA) progression. Expressions of GLP-1R in iCCA tissues investigated by immunohistochemistry showed that GLP-1R expressions were significantly associated with poor histological grading (P = 0.027). iCCA cell lines, KKU-055 and KKU-213A, were treated with exendin-4 and liraglutide, GLP-1R agonists, and their effects on proliferation and migration were assessed. Exendin-4 and liraglutide did not affect CCA cell proliferation in vitro, but liraglutide significantly suppressed the migration of CCA cells, partly by inhibiting epithelial-mesenchymal transition. In contrast, liraglutide significantly reduced CCA tumor volumes and weights in xenografted mice (P = 0.046). GLP-1R appeared downregulated when CCA cells were treated with liraglutide in vitro and in vivo. In addition, liraglutide treatment significantly suppressed Akt and STAT3 signaling in CCA cells, by reducing their phosphorylation levels. These results suggested that liraglutide potentially slows down CCA progression, and further clinical investigation would benefit the treatment of CCA with diabetes mellitus.

Cyclic compressive loading induces a mature meniscal cell phenotype in mesenchymal stem cells with an atelocollagen-based scaffold.

Introduction: Biomechanical stimulation is reportedly pivotal in meniscal regeneration, although its effect on mesenchymal stem cell (MSC) meniscal differentiation remains elusive. In this study, we investigated how cyclic compressive loading (CCL) could impact MSCs using three-dimensional cultures in atelocollagen-based meniscal substitute (ACMS). Methods: We extracted MSCs from the meniscus, synovium, and articular cartilage, cultured them in three-dimensional cultures, and exposed them to CCL for 7 days. We then compared the transcriptomes of MSCs treated with and without CCL. Results: Our RNA-seq analysis revealed that CCL induced significant transcriptome changes, significantly affecting chondrocyte-related genes, including SOX9, TGFB1, and PRG4 upregulation. CCL induced transcriptional differentiation of meniscus progenitors toward mature meniscal cells. Conclusion: This study unveils the potential of mechanical stress in promoting MSC meniscal differentiation within ACMS. Our investigations provide new insights for mechanisms underlying meniscal regeneration with ACMS.

Establishment and characterization of TK-ALCL1: a novel NPM-ALK-positive anaplastic large-cell lymphoma cell line.

TK-ALCL1, a novel anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALK+ ALCL) cell line, was established from the primary tumor site of a 59-year-old Japanese male patient. The immune profile of TK-ALCL1 corresponds to that seen typically in primary ALCL cells, i.e., positive for ALK, CD30, EMA, and CD4, but negative for CD2, CD3, CD5, CD8a, and EBV-related antigens. The rearrangement of the T cell receptor-gamma locus shows that TK-ALCL1 is clonally derived from T-lineage lymphoid cells. FISH and RT-PCR analysis revealed that TK-ALCL1 has the nucleophosmin (NPM)-ALK fusion transcript, which is typical for ALK+ ALCL cell lines. When TK-ALCL1 was subcutaneously inoculated into 6-week-old BALB/c Rag2-/-/Jak3-/- (BRJ) mice, it formed tumor masses within 4-6 weeks. Morphological, immunohistochemical, and molecular genetic investigations confirmed that the xenograft and the original ALCL tumor were identical. The ALK inhibitors Alectinib and Lorlatinib suppressed proliferation in a dose-dependent manner. Thus, TK-ALCL1 provides a useful in vitro and in vivo model for investigation of the biology of ALK+ ALCL and of novel therapeutic approaches targeting ALK.

Identification of unapproved orthopedic regenerative medicine: Usefulness of the Act on Safety of Regenerative Medicine.

In Japan, the Act on Safety of Regenerative Medicine regulates unapproved regenerative medicine. Other nations market regenerative medicine products, bypassing regulatory approval. To identify unapproved orthopedic regenerative medicine, we have used data based on the Act. Platelet-rich plasma was often used. The common target was the knee. Prices averaged $2,490.

Nonunion after medial malleolar osteotomy in total ankle arthroplasties for severe varus deformity: a report of 3 cases.

Of the three ankles after total ankle arthroplasty (TAA) with medial malleolar osteotomy for severe varus deformity (talar varus tilt >10°), two failed in varus migration of the tibial component. In these two cases, tibial osteotomy was performed with varus alignment of 5°and 2°, and with medially shifted placement of tibial component, while one ankle showed no migratoin of prostheses after 5 years, even with nonunion. In this case, tibial osteotomy was performed with a valgus alignment of 4°. Internal fixation after medial malleolar osteotomy should be done for severe varus cases. Medially shifted placement of tibial component should be avoided. Fortunately, the failure did not occur in a case of valgus of the distal tibia. Valgus tibial osteotomy might help to reduce the collision of the talus against the medial malleolus.

Cubitus varus deformity following paediatric supracondylar humeral fracture remodelling predominantly in the sagittal direction: A three-dimensional analysis of eighty-six cases.

PURPOSE: Three-dimensional (3D) capacity for remodelling in cubitus varus deformity (CVD) after paediatric supracondylar humeral fractures (PSHFs) remains unelucidated. This study investigated remodelling patterns after PSHFs by examining 3D deformity distribution over time after injury. METHODS: Computed tomography (CT) data of 86 patients with CVD after PSHFs were analysed. The 3D deformity angles in the sagittal, coronal, and axial directions were assessed and correlated with the duration between the age at injury and CT evaluation. For the subgroup analysis, we performed the same correlation analysis in a younger (< 8 years old) and an older group (≥ 8 years old); we categorized the duration into early (< 2 years), middle (≥ 2 to < 5 years), and late periods (≥ 5 years) and compared the deformity angles of each direction among the three groups. RESULTS: Sagittal deformity showed a moderate correlation with the duration of deformity (r = -0.54; P < 0.001), while coronal and axial deformities showed a negligible correlation. Sagittal deformity showed moderate correlations with the duration in the younger group (r = -0.62; P < 0.001) and weak correlations in the older group (r = -0.37; P = 0.091). In the sagittal direction, the deformity angle in the early period was significantly larger than those in the mid and late periods (P < 0.001). However, there were no significant differences among the three groups in the coronal and axial directions. CONCLUSION: Sagittal deformities in CVDs are capable of remodelling, especially in the early period and at a younger age, whereas coronal and axial deformities are less likely to undergo remodelling.

Assessing the utility of osteoporosis self-assessment tool for Asians in patients undergoing hip surgery.

Objectives: Diagnosis and treatment of osteoporosis are instrumental in obtaining good outcomes of hip surgery. Measuring bone mineral density (BMD) using dual-energy X-ray absorptiometry (DXA) is the gold standard for diagnosing osteoporosis. However, due to limited access to DXA, there is a need for a screening tool to identify patients at a higher risk of osteoporosis. We analyzed the potential utility of the Osteoporosis Self-assessment Tool for Asians (OSTA) as a screening tool for osteoporosis. Methods: A total of 1378 female patients who underwent hip surgery at 8 institutions were analyzed. For each patient, the BMD of the proximal femoral region was measured by DXA (DXA-BMD), and the correlation with OSTA score (as a continuous variable) was assessed. Receiver operating characteristic (ROC) curve analysis was performed to assess the ability of OSTA score to predict osteoporosis. Lastly, the OSTA score was truncated to yield an integer (OSTA index) to clarify the percentage of patients with osteoporosis for each index. Results: DXA-BMD showed a strong correlation with OSTA (r = 0.683; P < 0.001). On ROC curve analysis, the optimal OSTA score cut-off value of -5.4 was associated with 73.8% sensitivity and 80.9% specificity for diagnosis of osteoporosis (area under the curve: 0.842). A decrease in the OSTA index by 1 unit was associated with a 7.3% increase in the probability of osteoporosis. Conclusions: OSTA is a potentially useful tool for screening osteoporosis in patients undergoing hip surgery. Our findings may help identify high-risk patients who require further investigation using DXA.

Tri-specific killer engager: unleashing multi-synergic power against cancer.

Cancer continues to be a global health concern, necessitating innovative solutions for treatment. Tri-specific killer engagers (TriKEs) have emerged as a promising class of immunotherapeutic agents, offering a multifaceted approach to cancer treatment. TriKEs simultaneously engage and activate natural killer (NK) cells while specifically targeting cancer cells, representing an outstanding advancement in immunotherapy. This review explores the generation and mechanisms of TriKEs, highlighting their advantages over other immunotherapies and discussing their potential impact on clinical trials and cancer treatment. TriKEs are composed of three distinct domains, primarily antibody-derived building blocks, linked together by short amino acid sequences. They incorporate critical elements, anti-cluster of differentiation 16 (CD16) and interleukin-15 (IL-15), which activate and enhance NK cell function, together with specific antibody to target each cancer. TriKEs exhibit remarkable potential in preclinical and early clinical studies across various cancer types, making them a versatile tool in cancer immunotherapy. Comparative analyses with other immunotherapies, such as chimeric antigen receptor-T (CAR-T) cell therapy, immune checkpoint inhibitors (ICIs), cytokine therapies, and monoclonal antibodies (mAbs), reveal the unique advantages of TriKEs. They offer a safer pathway for immunotherapy by targeting cancer cells without hyperactivating T cells, reducing off-target effects and complications. The future of TriKEs involves addressing challenges related to dosing, tumor-associated antigen (TAA) expression, and NK cell suppression. Researchers are exploring innovative dosing strategies, enhancing specificity through tumor-specific antigens (TSAs), and combining TriKEs with other therapies for increased efficacy.

A Comparison Between GPT-3.5, GPT-4, and GPT-4V: Can the Large Language Model (ChatGPT) Pass the Japanese Board of Orthopaedic Surgery Examination?

Introduction Recently, large-scale language models, such as ChatGPT (OpenAI, San Francisco, CA), have evolved. These models are designed to think and act like humans and possess a broad range of specialized knowledge. GPT-3.5 was reported to be at a level of passing the United States Medical Licensing Examination. Its capabilities continue to evolve, and in October 2023, GPT-4V became available as a model capable of image recognition. Therefore, it is important to know the current performance of these models because they will be soon incorporated into medical practice. We aimed to evaluate the performance of ChatGPT in the field of orthopedic surgery. Methods We used three years' worth of Japanese Board of Orthopaedic Surgery Examinations (JBOSE) conducted in 2021, 2022, and 2023. Questions and their multiple-choice answers were used in their original Japanese form, as was the official examination rubric. We inputted these questions into three versions of ChatGPT: GPT-3.5, GPT-4, and GPT-4V. For image-based questions, we inputted only textual statements for GPT-3.5 and GPT-4, and both image and textual statements for GPT-4V. As the minimum scoring rate acquired to pass is not officially disclosed, it was calculated using publicly available data. Results The estimated minimum scoring rate acquired to pass was calculated as 50.1% (43.7-53.8%). For GPT-4, even when answering all questions, including the image-based ones, the percentage of correct answers was 59% (55-61%) and GPT-4 was able to achieve the passing line. When excluding image-based questions, the score reached 67% (63-73%). For GPT-3.5, the percentage was limited to 30% (28-32%), and this version could not pass the examination. There was a significant difference in the performance between GPT-4 and GPT-3.5 (p < 0.001). For image-based questions, the percentage of correct answers was 25% in GPT-3.5, 38% in GPT-4, and 38% in GPT-4V. There was no significant difference in the performance for image-based questions between GPT-4 and GPT-4V. Conclusions ChatGPT had enough performance to pass the orthopedic specialist examination. After adding further training data such as images, ChatGPT is expected to be applied to the orthopedics field.

Reproduction of forearm rotation dynamic using intensity-based biplane 2D-3D registration matching method.

This study aimed to reproduce and analyse the in vivo dynamic rotational motion of the forearm and to clarify forearm motion involvement and the anatomical function of the interosseous membrane (IOM). The dynamic forearm rotational motion of the radius and ulna was analysed in vivo using a novel image-matching method based on fluoroscopic and computed tomography images for intensity-based biplane two-dimensional-three-dimensional registration. Twenty upper limbs from 10 healthy volunteers were included in this study. The mean range of forearm rotation was 150 ± 26° for dominant hands and 151 ± 18° for non-dominant hands, with no significant difference observed between the two. The radius was most proximal to the maximum pronation relative to the ulna, moved distally toward 60% of the rotation range from maximum pronation, and again proximally toward supination. The mean axial translation of the radius relative to the ulna during forearm rotation was 1.8 ± 0.8 and 1.8 ± 0.9 mm for dominant and non-dominant hands, respectively. The lengths of the IOM components, excluding the central band (CB), changed rotation. The transverse CB length was maximal at approximately 50% of the rotation range from maximum pronation. Summarily, this study describes a detailed method for evaluating in vivo dynamic forearm motion and provides valuable insights into forearm kinematics and IOM function.

Recent preclinical and clinical advances in radioimmunotherapy for non-Hodgkin's lymphoma.

Radioimmunotherapy (RIT) is a therapy that combines a radioactive nucleotide with a monoclonal antibody (mAb). RIT enhances the therapeutic effect of mAb and reduces toxicity compared with conventional treatment. The purpose of this review is to summarize the current progress of RIT for treating non-Hodgkin's lymphoma (NHL) based on recent preclinical and clinical studies. The efficacy of RIT targeting the B-lymphocyte antigen cluster of differentiation 20 (CD20) has been demonstrated in clinical trials. Two radioimmunoconjugates targeting CD20, yttrium-90 (90Y)-ibritumomab-tiuxetan (Zevalin) and iodine-131 (131I)-tositumomab (Bexxar), have been approved in the USA Food and Drug Administration (FDA) for treating relapsed/refractory indolent or transformed NHL in 2002 and 2003, respectively. Although these two radioimmunoconjugates are effective and least toxic, they have not achieved popularity due to increasing access to novel therapies and the complexity of their delivery process. RIT is constantly evolving with the identification of novel targets and novel therapeutic strategies using newer radionuclides such as alpha-particle isotopes. Alpha-particles show very short path lengths and high linear energy transfer. These characteristics provide increased tumor cell-killing activities and reduced non-specific bystander responses on normal tissue. This review also discusses reviewed pre-targeted RIT (PRIT) and immuno-positron emission tomography (PET). PRIT potentially increases the dose of radionuclide delivered to tumors while toxicities to normal tissues are limited. Immuno-PET is a molecular imaging tracer that combines the high sensitivity of PET with the specific targeting capability of mAb. Immuno-PET strategies targeting CD20 and other antigens are currently being developed. The theragnostic approach by immuno-PET will be useful in monitoring the treatment response.

Prognostic nutrition index as a predictive factor for overall survival in trabectedin-treated advanced soft tissue sarcoma.

BACKGROUND: Trabectedin binds covalently to the DNA minor groove and causes DNA to bend toward the main groove, then trabectedin regulates the transcription of the involved genes in cell proliferation or acts on the mononuclear phagocyte system in tumors, which contributes to its antitumor effects. Several clinical trials confirmed the efficacy of trabectedin for patients with advanced soft tissue sarcoma (STS) although clinically useful biomarkers remained unidentified. This study aimed to identify prognostic factors of trabectedin treatment, especially focusing on the systemic inflammatory, immune response, and nutritional status. METHODS: This study included 44 patients with advanced STS treated with trabectedin from January 2018 to August 2022. We evaluated the associations of clinical factors that influence the efficacy of trabectedin treatment with progression-free survival (PFS) and overall survival (OS), focusing on systemic inflammatory, immune response, and nutritional status represented by the absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic inflammation response index (SIRI), prognostic nutrition index (PNI), and C-reactive protein (CRP) using the Kaplan-Meier method and the log-rank test. RESULTS: ALC, LMR, PNI, NLR, PLR, and SIRI demonstrated no association with PFS. Patients with CRP of ≥0.3 had a significantly shorter PFS than those with CRP of <0.3 (median PFS: 863 vs. 105 days, P = 0.045). PNI of ≥44 (median: 757 days vs. 232 days, P = 0.021) and CRP of <0.3 (median: 877 days vs. 297 days, P = 0.043) were significantly good prognostic factors in terms of OS. CONCLUSIONS: The study results indicate pretreatment PNI and CRP levels as prognostic factors for trabectedin treatment in advanced STS.

Automatic hip osteoarthritis grading with uncertainty estimation from computed tomography using digitally-reconstructed radiographs.

PURPOSE: Progression of hip osteoarthritis (hip OA) leads to pain and disability, likely leading to surgical treatment such as hip arthroplasty at the terminal stage. The severity of hip OA is often classified using the Crowe and Kellgren-Lawrence (KL) classifications. However, as the classification is subjective, we aimed to develop an automated approach to classify the disease severity based on the two grades using digitally-reconstructed radiographs from CT images. METHODS: Automatic grading of the hip OA severity was performed using deep learning-based models. The models were trained to predict the disease grade using two grading schemes, i.e., predicting the Crowe and KL grades separately, and predicting a new ordinal label combining both grades and representing the disease progression of hip OA. The models were trained in classification and regression settings. In addition, the model uncertainty was estimated and validated as a predictor of classification accuracy. The models were trained and validated on a database of 197 hip OA patients, and externally validated on 52 patients. The model accuracy was evaluated using exact class accuracy (ECA), one-neighbor class accuracy (ONCA), and balanced accuracy. RESULTS: The deep learning models produced a comparable accuracy of approximately 0.65 (ECA) and 0.95 (ONCA) in the classification and regression settings. The model uncertainty was significantly larger in cases with large classification errors ( P < 6 e - 3 ). CONCLUSIONS: In this study, an automatic approach for grading hip OA severity from CT images was developed. The models have shown comparable performance with high ONCA, which facilitates automated grading in large-scale CT databases and indicates the potential for further disease progression analysis. Classification accuracy was correlated with the model uncertainty, which would allow for the prediction of classification errors. The code will be made publicly available at https://github.com/NAIST-ICB/HipOA-Grading .

Automated entry of paper-based patient-reported outcomes: Applying deep learning to the Japanese orthopaedic association back pain evaluation questionnaire.

BACKGROUND: Health-related patient-reported outcomes (HR-PROs) are crucial for assessing the quality of life among individuals experiencing low back pain. However, manual data entry from paper forms, while convenient for patients, imposes a considerable tallying burden on collectors. In this study, we developed a deep learning (DL) model capable of automatically reading these paper forms. METHODS: We employed the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire, a globally recognized assessment tool for low back pain. The questionnaire comprised 25 low back pain-related multiple-choice questions and three pain-related visual analog scales (VASs). We collected 1305 forms from an academic medical center as the training set, and 483 forms from a community medical center as the test set. The performance of our DL model for multiple-choice questions was evaluated using accuracy as a categorical classification task. The performance for VASs was evaluated using the correlation coefficient and absolute error as regression tasks. RESULT: In external validation, the mean accuracy of the categorical questions was 0.997. When outputs for categorical questions with low probability (threshold: 0.9996) were excluded, the accuracy reached 1.000 for the remaining 65 % of questions. Regarding the VASs, the average of the correlation coefficients was 0.989, with the mean absolute error being 0.25. CONCLUSION: Our DL model demonstrated remarkable accuracy and correlation coefficients when automatic reading paper-based HR-PROs during external validation.

Therapeutic Potential of Bromodomain and Extra-Terminal Domain Inhibitors for Synovial Sarcoma Cells.

Synovial sarcoma (SS), a rare subtype of soft-tissue sarcoma distinguished by expression of the fusion gene SS18-SSX, predominantly affects the extremities of young patients. Existing anticancer drugs have limited efficacy against this malignancy, necessitating the development of innovative therapeutic approaches. Given the established role of SS18-SSX in epigenetic regulation, we focused on bromodomain and extra-terminal domain protein (BET) inhibitors and epigenetic agents. Our investigation of the BET inhibitor ABBV-075 revealed its pronounced antitumor effects, inducing G1-phase cell-cycle arrest and apoptosis, in four SS cell lines. Notably, BET inhibitors exhibited regulatory control over crucial cell-cycle regulators, such as MYC, p21, CDK4, and CDK6. Additionally, RNA sequencing findings across the four cell lines revealed the significance of fluctuating BCL2 family protein expression during apoptotic induction. Notably, variations in the expression ratio of the anti-apoptotic factor BCLxL and the pro-apoptotic factor BIM may underlie susceptibility to ABBV-075. Additionally, knockdown of SS18-SSX, which upregulates BCL2, reduced the sensitivity to ABBV-075. These findings suggest the potential utility of BET inhibitors targeting the SS18-SSX-regulated intrinsic apoptotic pathway as a promising therapeutic strategy for SS.

Novel Midkine Inhibitor Induces Cell Cycle Arrest and Apoptosis in Multiple Myeloma.

BACKGROUND/AIM: Multiple myeloma (MM), the second most common hematological malignancy, is characterized by the accumulation of malignant plasma cells within the bone marrow. Despite various drug classes for MM treatment, it remains incurable, necessitating novel and efficacious agents. This study aims to explore the anti-cancer activity of a midkine inhibitor, iMDK (C21H13FN2O2S), in myeloma cell lines. MATERIALS AND METHODS: This study assessed the antiproliferative activity using the MTT assay. Cell cycle and apoptosis were evaluated using flow cytometry. To further investigate the inhibitory mechanism, western blotting was used to detect cell cycle-related proteins, pro-apoptotic proteins, and anti-apoptotic proteins. RESULTS: iMDK inhibits MM cell proliferation in a dose- and time-dependent manner, inducing cell cycle arrest and apoptosis. The reduction in Cdc20 expression by iMDK treatment leads to G2/M phase cell cycle arrest. Furthermore, iMDK down-regulates anti-apoptotic proteins (Bcl-2, Bcl-xL, Mcl-1, and c-FLIP), thereby activating both intrinsic and extrinsic apoptosis pathways. CONCLUSION: iMDK could be a potential candidate for MM treatment.

Acceptable range of forearm deformity derived from relation to three-dimensional analysis and clinical impairments.

This study aimed to investigate deformity patterns that cause clinical impairments and determine the acceptable range of deformity in the treatment of forearm diaphyseal fractures. A three-dimensional (3D) deformity analysis based on computed bone models was performed on 39 patients with malunited diaphyseal both-bone forearm fractures to investigate the 3D deformity patterns of the radius and ulna at the fracture location and the relationship between 3D deformity and clinical impairments. Clinical impairments were evaluated using forearm motion deficit. Cutoff values of forearm deformities were calculated by performing receiver operating characteristic analysis using the deformity angle and the limited forearm rotation range of motion (less than 50° of pronation or supination) resulting in activities of daily living (ADL) impairment as variables. The extension, varus, and pronation deformities most commonly occurred in the radius, whereas the extension deformity was commonly observed in the ulna. A positive correlation was observed between pronation deficit and extension deformity of the radius (R = 0.41) and between supination deficit and pronation deformity of the ulna (R = 0.44). In contrast, a negative correlation was observed between pronation deficit and pronation deformity of the radius (R = -0.44) and between pronation deficit and pronation deformity of the ulna (R = -0.51). To minimize ADL impairment, radial extension deformity should be <18.4°, radial rotation deformity <12.8°, and ulnar rotation deformity <16.6°. The deformities in the sagittal and axial planes of the radius and in the axial plane of the ulna were responsible for the limited forearm rotation.

Tibial morphology of symptomatic osteoarthritic knees varies according to location: a retrospective observational study in Japanese patients.

This study analyzed 31 patients with symptomatic osteoarthritic knees scheduled to undergo knee arthroplasty or high tibial osteotomy and demonstrated shape variations in their proximal tibia using an average three-dimensional (3D) bone model. Preoperative computed tomography of the affected knees was reconstructed as 3D bone models using a triangle mesh of surface layers. The initial case was defined as the template, and the other models were reconstructed into homologous models with the same number of mesh vertices as that in the template. The corresponding mesh vertices of the other models were averaged to evaluate the spatial position on the particular mesh vertex of the template. This was applied to all the mesh vertices of the template to generate the average 3D model. To quantify the variation in surface geometry, average minimum distance from the average bone model to 31 models was recorded. The medial proximal tibial cortex (1.63 mm) revealed lesser variation compared to the tibial tuberosity (2.50 mm) and lateral cortex (2.38 mm), (p = 0.004 and p = 0.020, respectively). The medial tibial plateau (1.46 mm) revealed larger variation compared to the lateral tibial plateau (1.16 mm) (p = 0.044). Understanding 3D geometry could help in development of implants for arthroplasty and knee osteotomy.

Iguratimod suppresses sclerostin and receptor activator of NF-κB ligand production via the extracellular signal-regulated kinase/early growth response protein 1/tumor necrosis factor alpha pathway in osteocytes and ameliorates disuse osteoporosis in mice.

Disuse osteoporosis is a prevalent complication among patients afflicted with rheumatoid arthritis (RA). Although reports have shown that the antirheumatic drug iguratimod (IGU) ameliorates osteoporosis in RA patients, details regarding its effects on osteocytes remain unclear. The current study examined the effects of IGU on osteocytes using a mouse model of disuse-induced osteoporosis, the pathology of which crucially involves osteocytes. A reduction in distal femur bone mass was achieved after 3 weeks of hindlimb unloading in mice, which was subsequently reversed by intraperitoneal IGU treatment (30 mg/kg; five times per week). Histology revealed that hindlimb-unloaded (HLU) mice had significantly increased osteoclast number and sclerostin-positive osteocyte rates, which were suppressed by IGU treatment. Moreover, HLU mice exhibited a significant decrease in osteocalcin-positive cells, which was attenuated by IGU treatment. In vitro, IGU suppressed the gene expression of receptor activator of NF-κB ligand (RANKL) and sclerostin in MLO-Y4 and Saos-2 cells, which inhibited osteoclast differentiation of mouse bone marrow cells in cocultures. Although IGU did not affect the nuclear translocation or transcriptional activity of NF-κB, RNA sequencing revealed that IGU downregulated the expression of early growth response protein 1 (EGR1) in osteocytes. HLU mice showed significantly increased EGR1- and tumor necrosis factor alpha (TNFα)-positive osteocyte rates, which were decreased by IGU treatment. EGR1 overexpression enhanced the gene expression of TNFα, RANKL, and sclerostin in osteocytes, which was suppressed by IGU. Contrarily, small interfering RNA-mediated suppression of EGR1 downregulated RANKL and sclerostin gene expression. These findings indicate that IGU inhibits the expression of EGR1, which may downregulate TNFα and consequently RANKL and sclerostin in osteocytes. These mechanisms suggest that IGU could potentially be used as a treatment option for disuse osteoporosis by targeting osteocytes.