IL-7-primed bystander CD8 tumor-infiltrating lymphocytes optimize the antitumor efficacy of T cell engager immunotherapy.

Bispecific T cell engagers (TCEs) show promising clinical efficacy in blood tumors, but their application to solid tumors remains challenging. Here, we show that Fc-fused IL-7 (rhIL-7-hyFc) changes the intratumoral CD8 T cell landscape, enhancing the efficacy of TCE immunotherapy. rhIL-7-hyFc induces a dramatic increase in CD8 tumor-infiltrating lymphocytes (TILs) in various solid tumors, but the majority of these cells are PD-1-negative tumor non-responsive bystander T cells. However, they are non-exhausted and central memory-phenotype CD8 T cells with high T cell receptor (TCR)-recall capacity that can be triggered by tumor antigen-specific TCEs to acquire tumoricidal activity. Single-cell transcriptome analysis reveals that rhIL-7-hyFc-induced bystander CD8 TILs transform into cycling transitional T cells by TCE redirection with decreased memory markers and increased cytotoxic molecules. Notably, TCE treatment has no major effect on tumor-reactive CD8 TILs. Our results suggest that rhIL-7-hyFc treatment promotes the antitumor efficacy of TCE immunotherapy by increasing TCE-sensitive bystander CD8 TILs in solid tumors.

Misdiagnosis of the acute phase of undifferentiated arthritis as pyogenic arthritis: A case report and literature review.

Undifferentiated arthritis is a disease that clinically presents with symptoms and signs of inflammatory arthritis but does not meet the specific diagnostic criteria of rheumatoid arthritis (RA) or spondyloarthropathy. Here, we report our experience with a patient whose diagnosis of RA was delayed due to a lack of evidence for RA. The patient complained of knee joint swelling and pain, but the clinical features did not match those of typical pyogenic arthritis. Because infection could not be completely ruled out, the patient was treated for pyogenic arthritis using arthroscopic synovectomy and antibiotics. However, the pain was not relieved and the rheumatologist suggested a diagnosis of undifferentiated monoarthritis, which is an early stage of RA. The pain eventually spread to other joints, leading to the diagnosis of RA, approximately two months after the initial visit. Considering undifferentiated arthritis and making appropriate differential diagnoses is important to avoid unnecessary treatments such as surgery or prolonged antibiotic use. Clinical relevance: Awareness of the possibility of undifferentiated monoarthritis, an early stage of RA, may be helpful in treating patients with recurrent knee effusion.

Direct posterior endoscopic excision of atypical popliteal cyst: A case report.

Certain types of popliteal cysts do not possess the common pathophysiology of Baker's cysts, such as location or the presence of a one-way valve lesion. The traditional arthroscopic approach and excision of such atypical popliteal cysts are difficult because they do not communicate with the knee joint, especially when located behind the popliteal neurovascular structure. In this case report, we introduce a direct posterior endoscopic technique for the excision of atypical popliteal cysts when accessing them through the traditional arthroscopic approach is unfeasible. In this case, the popliteal cyst was not located between the gastrocnemius medial head and the semimembranosus muscle and did not communicate with the knee joint. Passage of the popliteal artery was observed running on the anteromedial side of the popliteal cyst. Therefore, a direct posterior endoscopic approach was decided for the surgical treatment of the popliteal cyst, and the atypical popliteal cyst was successfully excised without any complications. We also describe the possible advantages and pitfalls of the direct posterior endoscopic approach. Clinical relevance: Direct posterior endoscopic excision using an intra-cystic portal in the prone position is considered a safe and effective treatment method for atypical popliteal cysts.

Comparison of a Cryopneumatic Compression Device and Ice Packs for Cryotherapy Following Anterior Cruciate Ligament Reconstruction.

Background: The purpose of the current study was to evaluate and compare the effectiveness of a cryopneumatic compression device with that of standard ice packs following arthroscopic anterior cruciate ligament (ACL) reconstruction, with a primary focus on early postoperative pain. Methods: Participants were divided into two groups: cryopneumatic compression device group (CC group) and standard ice pack group (IP group). Patients in the CC Group (28 patients) received a cryopneumatic compression device (CTC-7, Daesung Maref) treatment, while patients in the IP group (28 patients) received standard ice pack cryotherapy postoperatively. All cryotherapy was applied three times (every 8 hours) per day for 20 minutes until discharge (postoperative day 7). Pain scores were assessed preoperatively and at 4, 7, and 14 days after surgery, and the primary outcome for analysis was pain at postoperative day 4 assessed using a visual analog scale (VAS). Other variables were opioid and rescue medication use, knee and thigh circumferences, postoperative drainage, and joint effusion quantified by a three-dimensional magnetic resonance imaging (MRI) reconstruction model. Results: The mean pain VAS score and difference in VAS relative to the preoperative measurements for postoperative day 4 were significantly lower in the CC group than in the IP group (p = 0.001 and p = 0.007, respectively). The sum of postoperative drainage and effusion quantified by MRI showed a significant reduction of postoperative effusion in the CC group compared to the IP group (p = 0.015). The average total rescue medication consumption was comparable between the two groups. Circumferential measurements at days 7 and 14 postoperatively relative to those at day 4 (index day) demonstrated no significant differences between the groups. Conclusions: Compared to standard ice packs, application of cryopneumatic compression was associated with a significant reduction in VAS pain scores and joint effusion during the early postoperative period following ACL reconstruction.

Evaluation of Appropriateness of the Reimbursement Criteria of Korean Health Insurance Review and Assessment Service for Total Knee Arthroplasty.

Background: We evaluated and compared South Korea's total knee arthroplasty (TKA) reimbursement criteria set by Health Insurance Review and Assessment Service (HIRA) with other TKA appropriateness criteria to find additional criterion to improve its appropriateness by reviewing TKA inappropriate cases. Methods: Two TKA appropriateness criteria and HIRA's reimbursement criteria for TKA were adapted for use on patients undergoing TKA in one institute from December 2017 to April 2020. Preoperative data including 9 validated questionnaires on knee joint-specific parameters, age, and radiography were used. We categorized cases into appropriate, inconclusive, inappropriate groups and analyzed each group. Results: Data on 448 cases that underwent TKA were examined. According to the HIRA's reimbursement criteria, 434 cases (96.9%) were appropriate and 14 cases (3.1%) were inappropriate; superior to other TKA appropriateness criteria. The inappropriate group had Knee Injury and Osteoarthritis Outcome score (KOOS) pain, KOOS symptoms, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score, and Korean Knee score total score with worse symptoms compared to the appropriate group classified by HIRA's reimbursement criteria. Conclusions: In terms of insurance coverage, HIRA's reimbursement criteria was more effective in providing healthcare access to patients who had the most pressing need for TKA compared to other TKA appropriateness criteria. However, we found the lower age limit and patient-reported outcome measures of other criteria as useful tools in improving appropriateness of the current reimbursement criteria.

Acute compartment syndrome after restarting warfarin therapy following polyethylene exchange in unicompartmental knee arthroplasty: case report.

Background: Acute compartment syndrome (ACS) is one of the true emergencies in orthopedics and traumatology. It can lead to permanent damage to skeletal muscles and neurovascular structures if not promptly treated. Although ACS usually occur after major trauma or invasive surgery, it can develop without trauma or after minimally invasive operation in anticoagulated patients. Case report: A 76-year-old woman underwent a polyethylene exchange in unicompartmental knee arthroplasty (UKA). She had had undergone mitral valve replacement and tricuspid valve annuloplasty, and a pacemaker insertion. She was on warfarin therapy at a dose of 3.5 mg daily. For surgical preparation, she discontinued warfarin for 7 days prior to the surgery, and administered enoxaparin sodium at a dose of 120 mg/day. Warfarin was re-administered at a dose of 3.5 mg/day on POD #7, and no postoperative complications were observed until the sutures were removed on POD #14. However, ACS, caused by arterial branch bleeding, occurred on POD #16, 10 days after restarting warfarin therapy. Emergency fasciotomy was performed to decompress the anterior and posterior compartments of left thigh. Finally, she had minimal neurologic deficits, with a left knee ROM of 0°-100° after 6 months. Conclusion: Presented case showed that arterial branch bleeding of the surgical site could occur more than 1 week after restarting warfarin therapy, which in turn may leaded to fatal complications such as ACS. Moreover, in anticoagulated patients, postoperative arterial branch bleeding and compartment syndrome can occur following considerably less invasive surgical procedures, such as polyethylene exchange in UKA. Therefore, surgeons should be aware of the possibility of surgical site bleeding and compartment syndrome for more than a week in patients who restarted warfarin therapy postoperatively, regardless of the invasiveness of surgical procedure.

Biomechanical comparison of the femoral neck system and the dynamic hip screw in basicervical femoral neck fractures.

The purpose of this study was to compare the fixation stability of proximal fragments and the mechanical characteristics in proximal femur models of basicervical femoral neck fracture fixed by the femoral neck system (FNS) versus the dynamic hip screw. The mean axial stiffness was 234 ± 35 N/mm in the FNS group and 253 ± 42 N/mm in the DHS group, showing no significant difference (p = 0.654). Mean values for x-axis rotation, y-axis rotation, and z-axis rotation after cycle load were 2.2 ± 0.5°, 6.5 ± 1.5°, and 2.5 ± 0.6°, respectively, in the FNS group and 2.5 ± 0.7°, 5.8 ± 2.1°, and 2.2 ± 0.9°, respectively, in the DHS group, showing no significant differences (p = 0.324, p = 0.245, and p = 0.312, respectively). The mean values of cranial and axial migration of screws within the femoral head were 1.5 ± 0.3 and 2.1 ± 0.2 mm, respectively, in the FNS group and 1.2 ± 0.3 and 2.4 ± 0.3 mm, respectively, in the DHS group, showing no significant differences (p = 0.425 and p = 0.625, respectively). The average failure load at vertical load was 1342 ± 201 N in the FNS group and 1450 ± 196 N in the DHS group, showing no significant difference (p = 0.452). FNS fixation might provide biomechanical stability comparable to that of DHS for treating displaced basicervical femoral neck fractures in young adults.

Safety of a single intra-articular injection of LBSA0103 hyaluronic acid in patients with osteoarthritis of the knee: a multicenter, single-arm, prospective, cohort study.

OBJECTIVE: LBSA0103 is a recently developed high-molecular-weight, cross-linked, non-animal hyaluronic acid (HA). The safety of LBSA0103 has been investigated only in a limited number of patients, therefore this prospective study was designed. This study sought to assess the safety including injection-site reactions and adverse drug reactions after a single intra-articular injection of LBSA0103 in patients with osteoarthritis (OA) of the knee joint. METHODS: This study was a multicenter, single-arm, prospective cohort study. After screening, eligible patients with OA of the knee joint (Kellgren-Lawrence grades I-III) were enrolled, received a single intra-articular HA (LBSA0103) injection, and were followed up for two weeks. Any adverse events including injection-site reactions and adverse drug reactions were evaluated by the investigators. RESULTS: A total of 1949 subjects (2976 knee joints) was enrolled, all of whom received a single intra-articular injection of LBSA0103. Injection-site reactions occurred in 5.59% of enrolled subjects (109/1949), and the most frequently reported injection-site reaction was pain (4.87%), followed by swelling (1.03%). Most of the injection-site reactions were transient and resolved within 14 days without additional treatment. The incidence of adverse drug reactions other than injection-site reactions was 0.67% (13/1949). Most adverse events were of mild severity. No serious adverse events related to the study drug were reported. CONCLUSIONS: A single intra-articular injection of LBSA0103 in patients with OA of the knee joint was safe, and no significant safety concerns were observed. As such, LBSA0103 could be safely applied as an intra-articular injection for the management of knee OA. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov (identifier: NCT04369261).

Blocking TNFα attenuates progressive cartilage matrix degradation in inflammatory arthritis.

Because damage to hyaline cartilage is irreversible, relieving progressive cartilage destruction is an important therapeutic approach for inflammatory arthritis. In the present study, human hyaline chondrocytes were isolated from total knee replacements of 15 patients with osteoarthritis (OA) and three with rheumatoid arthritis (RA). Synovial fluid of OA (n=25) and RA (n=34) were collected to measure tumor necrosis factor α (TNFα) using ELISA. Consistent with previous studies, the synovial fluid exhibited high TNFα levels and hyaline cartilage was severely destroyed in patients with RA. TNFα-treated chondrocytes were used as model for inflammatory arthritis. TNFα did not influence proliferation or extracellular matrix expression in chondrocytes, but induced matrix metalloproteinase (MMP)1, 3 and 13 expression levels in chondrocytes, which was accompanied by activation of nuclear factor-κB signaling. During chondrogenic differentiation, TNFα attenuated mRNA expression levels of anabolic factors (collagen type 2 and aggrecan) and enhanced mRNA expression of catabolic factors (MMP1, MMP3 and MMP13) in chondrocytes. Moreover, anti-TNFα agents (Golimumab) inhibited the TNFα-induced metabolic shift in chondrocytes and chondrogenic differentiation. The present study revealed a mechanism by which TNFα may induce metabolic shift in chondrocytes, leading to progressive chondrocyte destruction.

Increased external rotation of the osteoarthritic knee joint according to the genu varum deformity.

PURPOSE: To evaluate the rotational profile of the lower extremity using computed tomography (CT) in accordance with the degree of varus deformity in medial condyle-affected knee joint osteoarthritis (OA). METHODS: This retrospective study included 1036 patients (872 lower extremities) with end-stage knee OA. The coronal alignment of the lower extremity was measured using standing anteroposterior radiography. The CT parameters of femoral anteversion and tibial torsion were assessed in relation to the knee joint. The axes were the femoral neck axis; the distal femoral axis, which was composed of the anterior trochlear axis, the clinical transepicondylar axis, and the posterior condylar axis; the axis of the proximal tibial condyles; and the bimalleolar axis. RESULTS: There was a tendency for increased external rotation of the knee joint parameters in relation to the hip and ankle joints as varus deformity of the lower extremity increased. The relative external rotational deformity of the knee joint in relation to the hip joint had a positive value with a good correlation. The relative external rotational deformity of the knee joint in relation to the ankle joint also demonstrated a positive value with a good correlation. CONCLUSION: The distal femur and proximal tibia (knee joint) tended to rotate externally in relation to the hip and ankle joint, respectively, as the degree of varus deformity increased. This study identified the relationship between lower extremity varus deformity and rotational deformity of knee joints with OA. LEVEL OF EVIDENCE: III.

RNA interference-mediated suppression of TNF-α converting enzyme as an alternative anti-TNF-α therapy for rheumatoid arthritis.

Excessive tumor necrosis factor-α (TNF-α) is associated with the pathogenesis of rheumatoid arthritis (RA). Approximately 90% of patients with RA, who have inadequate response to methotrexate, follow anti-TNF-α therapy as the first-line immuno-treatment. However, ineffective long-term anti-TNF-α antibody cycling for 40% of non-responders to anti-TNF-α antibodies is costly and associated with various side effects, which needs alternative mechanism of action therapies. In the present study, a novel strategy to down-regulate TNF-α level was developed by using an alternative method of suppressing TNF-α converting enzyme (TACE), a transmembrane enzyme involved in cleaving and releasing bioactive soluble TNF-α. TACE suppression can be an effective remedy to block the production of soluble TNF-α, leading to an increased sensitivity to anti-TNF-α non-responders. A disease site-targeted RNA interference system was developed by forming non-viral complex between shRNA against TACE (shTACE) and bone resorption site-specific peptide carrier composed of aspartate repeating and arginine repeating sequences. The shTACE/peptide carrier complex alleviated arthritic symptoms in collagen induced arthritis (CIA) models by demonstrating enhanced anti-inflammatory and anti-osteoclastogenic effects. Similar results were obtained with human primary synovial cells and osteoclast precursor isolated from tissues and synovial fluids of RA patients. Taken together, the shTACE/targeting peptide complex provides a strong potential as an alternative anti-TNF-α therapeutic for RA treatment.

Comparative Analysis of Diaphyseal versus Metaphyseal tracker Placement in Imageless Navigation Systems for Total Knee Arthroplasty.

This work was designed to compare the intraoperative parameters and clinical and radiologic outcomes of total knee arthroplasty (TKA) during a minimum follow-up period of 2 years and to discuss the pros and cons of two different tracker placement (diaphyseal and metaphyseal) navigation systems. The null hypothesis was that there would be no clinical or radiologic difference between the two different systems. Primary TKA was performed in a total of 100 knees using the two different image-free navigation systems (group 1: diaphyseal tracker placement and group 2: metaphyseal tracker placement) with the strict gap balancing technique. Symptom severity was assessed at preoperative and at 3, 6, 12, and 24 months after surgery using the Knee Society Score (KSS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score. Possible adverse issues (major and minor) associated with TKA procedure were observed. Careful assessments were also made of the screw insertion site for infection, stress fractures, and any other related adverse effects. The follow-up periods for groups 1 and 2 were 38 ± 8 months and 38 ± 7 months, respectively. The minimum follow-up period was 24 months. The mechanical alignment improved to 0.1 (valgus) ± 2.2 (group 1) and 0.2 (valgus) ± 2.1 (group 2). There were no radiologic differences between the groups (p > 0.05). In both groups, the KSS and WOMAC improved from before surgery to 24 months after surgery (p < 0.0001). However, the total operation time was 50 ± 5 minutes for group 1, compared to 65 ± 13 minutes for group 2 (p < 0.0001). The metaphyseal tracker navigation system resulted in increased operation time.

TGFß1 Suppressed Matrix Mineralization of Osteoblasts Differentiation by Regulating SMURF1-C/EBPß-DKK1 Axis.

Transforming growth factor ß1 (TGFß1) is a major mediator in the modulation of osteoblast differentiation. However, the underlying molecular mechanism is still not fully understood. Here, we show that TGFß1 has a dual stage-dependent role in osteoblast differentiation; TGFß1 induced matrix maturation but inhibited matrix mineralization. We discovered the underlying mechanism of the TGFß1 inhibitory role in mineralization using human osteoprogenitors. In particular, the matrix mineralization-related genes of osteoblasts such as osteocalcin (OCN), Dickkopf 1 (DKK1), and CCAAT/enhancer-binding protein beta (C/EBPß) were dramatically suppressed by TGFß1 treatment. The suppressive effects of TGFß1 were reversed with anti-TGFß1 treatment. Mechanically, TGFß1 decreased protein levels of C/EBPß without changing mRNA levels and reduced both mRNA and protein levels of DKK1. The degradation of the C/EBPß protein by TGFß1 was dependent on the ubiquitin-proteasome pathway. TGFß1 degraded the C/EBPß protein by inducing the expression of the E3 ubiquitin ligase Smad ubiquitin regulatory factor 1 (SMURF1) at the transcript level, thereby reducing the C/EBPß-DKK1 regulatory mechanism. Collectively, our findings suggest that TGFß1 suppressed the matrix mineralization of osteoblast differentiation by regulating the SMURF1-C/EBPß-DKK1 axis.

Tumor suppressive function of Matrin 3 in the basal-like breast cancer.

BACKGROUND: Basal-like breast cancer (BLBC) or triple-negative breast cancer (TNBC) is an aggressive and highly metastatic subtype of human breast cancer. The present study aimed to elucidate the potential tumor-suppressive function of MATR3, an abundant nuclear protein, in BLBC/TNBC, whose cancer-relevance has not been characterized. METHODS: We analyzed in vitro tumorigenecity by cell proliferation and soft agar colony formation assays, apoptotic cell death by flow cytometry and Poly (ADP-ribose) polymerase (PARP) cleavage, epithelial-mesenchymal transition (EMT) by checking specific EMT markers with real-time quantitative PCR and in vitro migration and invasion by Boyden Chamber assays. To elucidate the underlying mechanism by which MATR3 functions as a tumor suppressor, we performed Tandem affinity purification followed by mass spectrometry (TAP-MS) and pathway analysis. We also scrutinized MATR3 expression levels in the different subtypes of human breast cancer and the correlation between MATR3 expression and patient survival by bioinformatic analyses of publicly available transcriptome datasets. RESULTS: MATR3 suppressed in vitro tumorigenecity, promoted apoptotic cell death and inhibited EMT, migration, and invasion in BLBC/TNBC cells. Various proteins regulating apoptosis were identified as MATR3-binding proteins, and YAP/TAZ pathway was suppressed by MATR3. MATR3 expression was inversely correlated with the aggressive and metastatic nature of breast cancer. Moreover, high expression levels of MATR3 were associated with a good prognosis of breast cancer patients. CONCLUSIONS: Our data demonstrate that MATR3 functions as a putative tumor suppressor in BLBC/TNBC cells. Also, MATR3 potentially plays a role as a biomarker in predicting chemotherapy-sensitivity and patient survival in breast cancer patients.

Biomechanical function of the anterolateral ligament of the knee: a systematic review.

BACKGROUND: It has been suggested that the anterolateral ligament (ALL) is an important anterolateral stabilizer of the knee joint which functions to prevent anterolateral subluxation and anterior subluxation at certain flexion angles in the knee. PURPOSE: To analyze and systematically interpret the biomechanical function of the ALL. METHODS: An online search was conducted for human cadaveric biomechanical studies that tested function of the ALL in resisting anterolateral subluxation and anterior subluxation of the knee. Two reviewers independently searched Medline, Embase, and the Cochrane Database of Systematic Reviews for studies up to 25 September 2018. Biomechanical studies not reporting the magnitude of anterior tibial translation or tibial internal rotation in relation to the function of the ALL were excluded. RESULTS: Twelve biomechanical studies using human cadavers evaluating parameters including anterior tibial translation and/or internal tibial rotation in anterior cruciate ligament (ACL)-sectioned and ALL-sectioned knees were included in the review. Five studies reported a minor increase or no significant increase in anterior tibial translation and internal tibial rotation with further sectioning of the ALL in ACL-deficient knees. Five studies reported a significant increase in knee laxity in tibial internal rotation or pivot shift with addition of sectioning the ALL in ACL-deficient knees. Two studies reported a significant increase in both anterior tibial translation and internal tibial rotation during application of the anterior-drawer and pivot-shift tests after ALL sectioning. CONCLUSION: There was inconsistency in the biomechanical characteristics of the ALL of the knee in resisting anterolateral and anterior subluxation of the tibia.

Transforaminal epidural steroid injections in cervical spinal disease with moderate to severe disability: Comparative study in patients with or without surgery.

Despite many clinical trials on cervical epidural steroid injections, the indications for and long-standing outcomes of this treatment remain controversial. We evaluated the outcomes and indications for transforaminal cervical epidural steroid injection (TCESI) in patients with moderate to severe disability.We prospectively gathered data from patients with 1 or 2-level cervical degenerative disease (herniated disc, foraminal stenosis) with moderate to severe disability (3.5 < initial visual analog scale < 6.5, 15 < Neck Disability Index < 35) and greater than 12 weeks of pain, despite conservative treatment. Patients with persistent disability and those who desired surgical intervention underwent decompression surgery. The clinical and demographic characteristics were compared between groups.Of the 309 patients who underwent TCESI, 221 (72%) did not receive surgical treatment during the 1-year follow-up period. The remaining 88 patients (28%) underwent surgery at a mean of 4.1 months after initial TCESI. Patients who underwent injection alone showed a significant decrease in disability and pain that persisted until the 1-year follow-up visit (P < .05). In patients who underwent surgery, the mean disability and pain scores after injection did not decrease for several months, although the scores significantly decreased up to 1 year after surgery (P < .05).The TCESI significantly decreased pain and disability in the moderate to severe disability group up to 1 year after injection. We recommend cervical TCESI as an initial treatment with moderate to severe disability patients.

Acetabular cup migration after primary cementless total hip arthroplasty in rheumatoid arthritis and its influencing factors: a comparative study with osteoarthritic hip.

PURPOSE: To compare the radiographic migration profiles of primary cementless total hip arthroplasty (THA) between patients with rheumatoid arthritis (RA) and those with osteoarthritis (OA). METHODS: A total of 197 patients (215 hips) who underwent cementless THA for RA or OA between January 2001 and January 2013 and followed up for a minimum of 5.5 years were included. Ninety-four RA patients (109 hips) were compared with 103 OA patients (106 hips). Radiological evaluation was performed for acetabular cup loosening, and cup migration was measured using Einzel-Bild-Röntgen-Analyse (EBRA) software. Multiple variables were assessed to identify influencing factors for cup migration. RESULTS: Early cup migration was observed in 13 hips (11.9%) in the RA group and four hips (3.8%) in the OA group, showing a significant difference (p = 0.041). Acetabular cup loosening occurred in three cups (2.8%) in the RA group and in one cup (0.9%) in the OA group, showing no significant difference (p = 0.321). Total cup migration was higher in the RA group (2.62 mm) than in the OA group (1.44 mm, p = 0.005). Total cup migration was significantly higher in patients aged < 50 years than in those aged > 50 years (p = 0.005). Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibody influenced total cup migration. Patients with seropositive RA showed significantly higher total cup migration and early cup migration incidence than those with seronegative RA (p = 0.005, p = 0.038, respectively). CONCLUSIONS: Acetabular cups in primary cementless THAs of RA patients were less stable in terms of cup migration compared with that of OA patients.

DKK1 Induced by 1,25D3 Is Required for the Mineralization of Osteoblasts.

1α,25-dihydroxyvitamin D3 (1,25D3), the most popular drug for osteoporosis treatment, drives osteoblast differentiation and bone mineralization. Wnt/ß-catenin signaling is involved in commitment and differentiation of osteoblasts, but the role of the Dickkopf-related protein 1 (DKK1), a Wnt antagonist, in osteoblasts remains unknown. Here, we demonstrate the molecular mechanism of DKK1 induction by 1,25D3 and its physiological role during osteoblast differentiation. 1,25D3 markedly promoted the expression of both CCAAT/enhancer binding protein beta (C/EBPß) and DKK1 at day 7 during osteoblast differentiation. Interestingly, mRNA and protein levels of C/EBPß and DKK1 in osteoblasts were elevated by 1,25D3. We also found that C/EBPß, in response to 1,25D3, directly binds to the human DKK1 promoter. Knockdown of C/EBPß downregulated the expression of DKK1 in osteoblasts, which was partially reversed by 1,25D3. In contrast, overexpression of C/EBPß upregulated DKK1 expression in osteoblasts, which was enhanced by 1,25D3. Furthermore, 1,25D3 treatment in osteoblasts stimulated secretion of DKK1 protein within the endoplasmic reticulum to extracellular. Intriguingly, blocking DKK1 attenuated calcified nodule formation in mineralized osteoblasts, but not ALP activity or collagen synthesis. Taken together, these observations suggest that 1,25D3 promotes the mineralization of osteoblasts through activation of DKK1 followed by an increase of C/EBPß.

Tumor suppressive function of Matrin 3 in the basal-like breast cancer

BACKGROUND: Basal-like breast cancer (BLBC) or triple-negative breast cancer (TNBC) is an aggressive and highly metastatic subtype of human breast cancer. The present study aimed to elucidate the potential tumor-suppressive function of MATR3, an abundant nuclear protein, in BLBC/TNBC, whose cancer-relevance has not been characterized. METHODS: We analyzed in vitro tumorigenecity by cell proliferation and soft agar colony formation assays, apoptotic cell death by flow cytometry and Poly (ADP-ribose) polymerase (PARP) cleavage, epithelial-mesenchymal transition (EMT) by checking specific EMT markers with real-time quantitative PCR and in vitro migration and invasion by Boyden Chamber assays. To elucidate the underlying mechanism by which MATR3 functions as a tumor suppressor, we performed Tandem affinity purification followed by mass spectrometry (TAP-MS) and pathway analysis. We also scrutinized MATR3 expression levels in the different subtypes of human breast cancer and the correlation between MATR3 expression and patient survival by bioinformatic analyses of publicly available transcriptome datasets. RESULTS: MATR3 suppressed in vitro tumorigenecity, promoted apoptotic cell death and inhibited EMT, migration, and invasion in BLBC/TNBC cells. Various proteins regulating apoptosis were identified as MATR3-binding proteins, and YAP/TAZ pathway was suppressed by MATR3. MATR3 expression was inversely correlated with the aggressive and metastatic nature of breast cancer. Moreover, high expression levels of MATR3 were associated with a good prognosis of breast cancer patients. CONCLUSIONS: Our data demonstrate that MATR3 functions as a putative tumor suppressor in BLBC/TNBC cells. Also, MATR3 potentially plays a role as a biomarker in predicting chemotherapy-sensitivity and patient survival in breast cancer patients.