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Malignant peripheral nerve sheath tumors (MPNSTs) are malignant tumors that are derived from Schwann cell lineage around peripheral nerves. As in many other cancer types, cancer stem cells (CSCs) have been identified in MPNSTs, and they are considered the cause of treatment resistance, recurrence, and metastasis. As an element defining the cancer stemness of MPNSTs, we previously reported a molecular mechanism by which exogenous adrenaline activates a core cancer stemness factor, YAP/TAZ, through β2 adrenoceptor (ADRB2). In this study, we found that MPNST cells express catecholamine synthases and that these enzymes are essential for maintaining cancer stemness, such as the ability to self‐renew and maintain an undifferentiated state. Through gene knockdown and inhibition of these enzymes, we confirmed that catecholamines are indeed synthesized in MPNST cells. The results confirmed that catecholamine synthase knockdown in MPNST cells reduces the activity of YAP/TAZ. These data suggest that a mechanism of YAP/TAZ activation by de novo synthesized adrenaline, as well as exogenous adrenaline, may exist in the maintenance of cancer stemness of MPNST cells. This mechanism not only helps to understand the pathology of MPNST, but could also contribute to the development of therapeutic strategies for MPNST. [ABSTRACT FROM AUTHOR]

Cancer stem‐like cells (CSCs) have a unique translation mode, but little is understood about the process of elongation, especially the contribution of tRNA modifications to the maintenance of CSCs properties. Here, it is reported that, contrary to the initial aim, a tRNA‐modifying methylthiotransferase CDKAL1 promotes CSC‐factor SALL2 synthesis by assembling the eIF4F translation initiation complex. CDKAL1 expression is upregulated in patients with worse prognoses and is essential for maintaining CSCs in rhabdomyosarcoma (RMS) and common cancers. Translatome analysis reveals that a group of mRNAs whose translation is CDKAL1‐dependent contains cytosine‐rich sequences in the 5' untranslated region (5'UTR). Mechanistically, CDKAL1 promotes the translation of such mRNAs by organizing the eIF4F translation initiation complex. This complex formation does not require the enzyme activity of CDKAL1 but requires only the NH2‐terminus domain of CDKAL1. Furthermore, sites in CDKAL1 essential for forming the eIF4F complex are identified and discovered candidate inhibitors of CDKAL1‐dependent translation. [ABSTRACT FROM AUTHOR]

Tendons and ligaments are jointed to bones via an enthesis that is essential to the proper function of the muscular and skeletal structures. The aim of the study is to investigate the effect of mechanical stress on the enthesis. We used ex vivo models in organ cultures of rat Achilles tendons with calcaneus including the enthesis. The organ was attached to a mechanical stretching apparatus that can conduct cyclic tensile strain. We made the models of 1‐mm elongation (0.5 Hz, 3% elongation), 2‐mm elongation (0.5 Hz, 5% elongation), and no stress. Histological evaluation by Safranin O staining and Toluidin Blue and Picro Sirius red staining was conducted. Expression of sex‐determining region Y‐box 9 (Sox9), scleraxis (Scx), Runt‐related transcription factor 2 (Runx2), and matrix metalloproteinase 13 (Mmp13) were examined by real‐time polymerase chain reaction and immunocytochemistry. Terminal deoxynucleotidyl transferase‐mediated deoxyuridine triphosphate biotin nick end‐labeling and live/dead staining and was conducted for evaluation of the apoptosis and cell viability. The structure of the enthesis was most maintained in the model of 1‐mm elongation. The electronic microscope showed that the enthesis of the no stress model had ill‐defined borders between fibrocartilage and mineralized fibrocartilage, and that calcification of mineralized fibrocartilage occurred in the model of 2‐mm elongation. Sox9 and Scx was upregulated by 1‐mm elongation, whereas Runx2 and Mmp13 were upregulated by 2‐mm elongation. Apoptosis was inhibited by low stress. The results of this study suggested that 1‐mm elongation can maintain the structure of the enthesis, while 2‐mm elongation promotes degenerative changes. [ABSTRACT FROM AUTHOR]

Malignant peripheral nerve sheath tumor (MPNST) often does not respond well to chemotherapy and develops against a background of NF1. The purpose of our study was to examine the efficacy of pazopanib against MPNST. Our study was designed as a physician‐initiated phase II clinical trial in patients with advanced MPNST. Patients were registered from 11 large hospitals. The primary endpoint was set to clarify the clinical benefit rate (CBR) at 12 weeks according to response evaluation criteria in solid tumors (RECIST). Progression‐free survival (PFS), overall survival (OS) and the CBR based on modified Choi evaluation at week 12 were set as secondary endpoints along with treatment‐related safety. The study enrolled 12 patients. Median age was 49 years. Seven had Grade 2 and five Grade 3 according to the FNCLCC evaluation. Median follow‐up period was 10.6 months. CBR at 12 weeks was both 50.0% (RECIST and Choi). The median PFS was 5.4 months for both RECIST and Choi, and the median OS was 10.6 months. Of special interest, the median PFS was 2.9 months for patients with FNCLCC Grade 2 and 10.2 months for Grade 3 (both RECIST and Choi). Grade 4 adverse events of neutropenia and lipase elevation were noted in one patient each. The results of this pazopanib therapy were generally better than those of any of the other single molecular targeted therapies reported previously. Although accumulation of more cases remains necessary, we conclude pazopanib treatment for MPNST to be a safe and promising treatment after doxorubicin‐based chemotherapy. What's new? Malignant peripheral nerve sheath tumor (MPNST) is a rare, aggressive soft‐tissue sarcoma (STS). Because STSs are very diverse, little has been learned about how to treat MPNST from STS studies. Here, the authors report results from a phase 2 trial of pazopanib, an orally administered angiogenesis inhibitor, tested in 12 patients with nonresectable advanced MPNST. Pazopanib showed a low response rate, but among responders, provided a 3‐fold increase in progression‐free survival. The safety profile was very manageable, and the drug achieved a better response than other molecular targeted therapies tested previously. [ABSTRACT FROM AUTHOR]

Alveolar soft part sarcoma (ASPS), epithelioid sarcoma (ES), and clear cell sarcoma (CCS) are known to be chemoresistant tumors. The aim of this study was to investigate the effect of pazopanib on these chemoresistant tumors. This study is designed as a single‐arm, multicenter, investigator‐initiated phase II trial. Patient enrollment was undertaken between July 2016 and August 2018 at 10 hospitals participating in the Japanese Musculoskeletal Oncology Group. The primary end‐point is the CBR (CBR, including complete or partial response and stable disease) at 12 weeks after treatment with pazopanib according to RECIST. Eight patients were enrolled within the period. The histological subtypes were 5 ASPS, 2 ES, and 1 CCS. The median follow‐up period was 22.2 (range, 4.9‐24.9) months. All patients initially received pazopanib 800 mg once daily. The CBRs were 87.5% (7 of 8) and 75.0% (6 of 8) according to RECIST and Choi criteria at 12 weeks after pazopanib treatment, respectively. The CBRs at 12 weeks according to RECIST were 80.0%, 100.0%, and 100.0% in ASPS, ES, and CCS, respectively. Partial response was observed in 1 ASPS according to RECIST and 3 ASPS and 1 ES according to Choi criteria at 12 weeks after pazopanib treatment. This study documented antitumor activity of pazopanib, especially in ASPS. These results support the frontline use of pazopanib for ASPS. Prospective data collection is desired using both RECIST and Choi criteria for these rare chemoresistant tumors. [ABSTRACT FROM AUTHOR]

This study was undertaken to clarify the risk factors, including the mutation status of CTNNB1, for the local recurrence after surgery of the rare disease desmoid‐type fibromatosis. It was designed as a multiinstitutional joint research project with 7 major centers in Japan participating. The committee members of 7 major medical centers specializing in bone and soft tissue tumors formed this study group to develop clinical care guidelines. Of 196 cases with specimens and medical records collected from the 7 institutions, 88 surgically treated ones were analyzed regarding clinicopathologic prognostic factors including CTNNB1 mutation status. Excluding R2 cases (n = 3), 5‐year local recurrence‐free survival (LRFS) was 52.9%. No case had received pre‐ or postoperative radiotherapy. Univariate analysis revealed that extremity location (P <.001) and larger size (8 cm or more, P =.036) were significant adverse risk factors for LRFS. Multivariate analysis indicated that extremity location (P <.001) was a significantly adverse factor in addition to recurrent tumor (P =.041), S45F mutation (P =.028), and R1 surgical margin (P =.039). Preoperative drug treatment, including nonsteroidal antiinflammatory drugs, did not reduce the incidence of local recurrence (P =.199). This is the first study to analyze the factors correlating with outcomes of surgical treatment, including CTNNB1 mutation status, in a relatively large number of cases from an Asian country. Tumor location was found to be the most influential prognostic factor for local recurrence, similar to the results from Europe and North America. The development of more sensitive method(s) for determination of CTNNB1 mutation is a priority for future study. [ABSTRACT FROM AUTHOR]

Here we present the first report of solitary primary peripheral nerve onset cytotoxic molecule (CM)‐positive peripheral T‐cell lymphoma (PTCL) diagnosed after nerve biopsy. An 84‐year‐old female with rheumatoid arthritis (RA) complained of asymmetric severe tenderness in her upper limbs. The biopsy pathology revealed a direct invasion of CM‐positive PTCL. When RA patients complain of numbness, tenderness, or weakness, lymphomatic peripheral nerve invasion should be considered. [ABSTRACT FROM AUTHOR]

ABSTRACT: This study aimed to evaluate the relationship between preoperative lateral meniscal extrusion (LME) and arthroscopic findings of lateral meniscus posterior root tear (LMPRT) in knees with anterior cruciate ligament (ACL) tear. Thirty‐five knees that had LMPRTs with concomitant ACL tears on arthroscopy were evaluated. Patients were divided into two groups, partial and complete root tears, via arthroscopic findings at the time of ACL reconstruction. For comparison, we added two groups, using the same database; 20 normal knees (normal group) and 20 ACL‐injured knees without LM injury (intact LM group). We retrospectively measured preoperative LMEs using magnetic resonance imaging (MRI). Twenty‐three knees had partial LMPRTs. Complete LMPRTs were observed in 12 knees. The average LME was −0.1 ± 0.4 mm in the normal group, 0.2 ± 0.5 mm in the intact LM group, 0.4 ± 0.8 mm in the partial LMPRT group, and 2.0 ± 0.6 mm in the complete LMPRT group. A significant difference in preoperative LMEs was observed between the complete LMPRT group and the other groups (p < 0.001). The receiver operating curve analysis, which distinguishes a partial tear from a complete tear, identified an optimal cut‐off point of 1.1 mm for preoperative LME. This LME cut‐off had a sensitivity of 100% and specificity of 83% for complete LMPRT. We found that preoperative LMEs were larger in complete LMPRTs associated with ACL injuries than in partial LMPRTs. Our results suggest that preoperative MRI‐detected LME may be a useful indicator for estimating LMPRT severity in ACL‐injured knees. Level of evidence: Retrospective comparative study level IV. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1894–1900, 2018. [ABSTRACT FROM AUTHOR]

Osteosarcoma is an aggressive malignant bone tumor that causes bone destruction. Although tumor-specific replicating oncolytic adenovirus OBP-301 induces an antitumor effect in an osteosarcoma tumor, it cannot prevent bone destruction. Zoledronic acid ( ZOL) is a clinically available agent that inhibits bone destruction. In this study, we investigated the potential of combination therapy with OBP-301 and ZOL against osteosarcomas with bone destruction. The antitumor activity of OBP-301 and ZOL in monotherapy or combination therapy was assessed using three human osteosarcoma cell lines (143B, MNNG/ HOS, Sa OS-2). The cytotoxic effect of OBP-301 and/or ZOL was measured by assay of cell apoptosis. The effect of OBP-301 and ZOL on osteoclast activation was investigated. The potential of combination therapy against tumor growth and bone destruction was analyzed using an orthotopic 143B osteosarcoma xenograft tumor model. OBP-301 and ZOL decreased the viability of human osteosarcoma cells. Combination therapy with OBP-301 and ZOL displayed a synergistic antitumor effect, in which OBP-301 promoted apoptosis through suppression of anti-apoptotic myeloid cell leukemia 1 ( MCL1). Combination therapy significantly inhibited tumor-mediated osteoclast activation, tumor growth and bone destruction compared to monotherapy. These results suggest that combination therapy of OBP-301 and ZOL suppresses osteosarcoma progression via suppression of MCL1 and osteoclast activation. [ABSTRACT FROM AUTHOR]

ABSTRACT The anterior root of the lateral meniscus provides functional stability to the meniscus. In this study, we evaluated the relationship between the position of the tibial tunnel and extrusion of the lateral meniscus after anterior cruciate ligament reconstruction, where extrusion provides a proxy measure of injury to the anterior root. The relationship between extrusion and tibial tunnel location was retrospectively evaluated from computed tomography and magnetic resonance images of 26 reconstructed knees, contributed by 25 patients aged 17-31 years. A measurement grid was used to localize the position of the tibial tunnel based on anatomical landmarks identified from the three-dimensional reconstruction of axial computed tomography images of the tibial plateaus. The reference point-to-tibial tunnel distance (mm) was defined as the distance from the midpoint of the lateral edge of the grid to the posterolateral aspect of the tunnel aperture. The optimal cutoff of this distance to minimize post-operative extrusion was identified using receiver operating curve analysis. Extrusion of the lateral meniscus was positively correlated to the reference point-to-tibial tunnel distance ( r2 = 0.64; p < 0.001), with a cutoff distance of 5 mm having a sensitivity to extrusion of 83% and specificity of 93%. The mean extrusion for a distance >5 mm was 0.40 ± 0.43 mm, compared to 1.40 ± 0.51 mm for a distance ≤5 mm ( p < 0.001). Therefore, a posterolateral location of the tibial tunnel aperture within the footprint of the anterior cruciate ligament decreases the reference point-to-tibial tunnel distance and increases extrusion of the lateral meniscus post-reconstruction. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1625-1633, 2017. [ABSTRACT FROM AUTHOR]

Background: In this era of individualized cancer treatment, data that could be applied to predicting the survival of patients with osteosarcoma are still limited because of the rarity of the disease and the difficulty in accumulating a sufficient number of patients. Therefore, a multi-institutional collaboration was implemented to develop and externally validate nomograms that would predict metastasis-free survival (MFS) and overall survival (OAS) for patients with nonmetastatic osteosarcoma.Methods: This study retrospectively examined 1070 patients treated with neoadjuvant chemotherapy and surgery for nonmetastatic osteosarcoma. Data from Japanese patients (n = 557) were used to develop multivariate nomograms based on Cox regression. Six clinical and pathologic variables were built into nomograms estimating the probability of MFS and OAS 3 and 5 years after diagnosis. The model was internally validated for discrimination and calibration with bootstrap resampling and was externally validated with an independent patient cohort from Korea (n = 513).Results: A patient's age, tumor site, and histologic response were found to have a stronger influence on MFS and OAS in the model than sex, tumor size, or pathologic fracture. The nomograms and calibration plots based on these results well predicted the probability of MFS (concordance index, 0.631) and OAS (concordance index, 0.679). The concordance indices for external validation were 0.682 for MFS and 0.665 for OAS.Conclusions: The nomograms were externally validated and verified to be useful for the prediction of MFS and OAS and for the assessment of the postoperative prognosis. They can be used for counseling patients and for establishing appropriate surveillance strategies after surgery. [ABSTRACT FROM AUTHOR]

ABSTRACT We previously reported that mechanical stretch regulates Sry-type HMG box (SOX) 9-dependent α1(II) collagen ( COL2A1) expression in inner meniscus cells. This study examined the role of the small Rho guanosine 5' triphosphatase Rac1 and Rho-associated kinase (ROCK) in the regulation of stretch-induced SOX9 gene expression in cultured human inner meniscus cells. COL2A1 and SOX9 gene expression was assessed by real-time PCR after application of uni-axial cyclic tensile strain (CTS) in the presence or absence of ROCK and Rac1 inhibitors. The subcellular localization of SOX9 and the Rac1 effector cyclic AMP response element-binding protein (CREB), the phosphorylation state of SOX9, Rac1 activation, and the binding of CREB to the SOX9 promoter were assessed. CTS increased the expression of COL2A1 and SOX9, which was suppressed by inhibition of Rac1. ROCK inhibition enhanced COL2A1 and SOX9 gene expression in the absence of CTS. CTS stimulated the nuclear translocation and phosphorylation of SOX9, and increased Rac1 activation. CTS also increased the binding of CREB to the SOX9 promoter. The results suggest that mechanical stretch-dependent upregulation of SOX9 by CREB in inner meniscus cells depends on the antagonistic activities of ROCK and Rac1. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:1479-1486, 2014. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are small non-coding RNAs capable of inhibiting gene expression post-transcriptionally and expression profiling can provide therapeutic targets and tools for cancer diagnosis. Chondrosarcoma is a mesenchymal tumor with unknown cause and differentiation status. Here, we profiled miRNA expression of chondrosarcoma, namely clinical samples from human conventional chondrosarcoma tissue, established chondrosarcoma cell lines, and primary non-tumorous adult articular chondrocytes, by miRNA array and quantitative real-time PCR. A wide variety of miRNAs were differently downregulated in chondrosarcoma compared to non-tumorous articular chondrocytes; 27 miRNAs: miR-10b, 23b, 24-1*, 27b, 100, 134, 136, 136*, 138, 181d, 186, 193b, 221*, 222, 335, 337-5p, 376a, 376a*, 376b, 376c, 377, 454, 495, 497, 505, 574-3p, and 660, were significantly downregulated in chondrosarcoma and only 2: miR-96 and 183, were upregulated. We further validated the expression levels of miRNAs by quantitative real-time PCR for miR-181a, let-7a, 100, 222, 136, 376a, and 335 in extended number of chondrosarcoma clinical samples. Among them, all except miR-181a were found to be significantly downregulated in chondrosarcoma derived samples. The findings provide potential diagnostic value and new molecular understanding of chondrosarcoma. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31:1992-1998, 2013 [ABSTRACT FROM AUTHOR]

Objective To investigate the expression and function of Mohawk (MKX) in human adult anterior cruciate ligament (ACL) tissue and ligament cells from normal and osteoarthritis (OA)-affected knees. Methods Knee joints were obtained at autopsy (within 24-48 hours postmortem) from 13 donors with normal knees (mean ± SD age 36.9 ± 11.0 years), 16 donors with knee OA (age 79.7 ± 11.4 years), and 8 aging donors without knee OA (age 76.9 ± 12.9 years). All cartilage surfaces were graded macroscopically. MKX expression was analyzed by immunohistochemistry and quantitative polymerase chain reaction. ACL-derived cells were used to study regulation of MKX expression by interleukin-1β (IL-1β). MKX was knocked down with small interfering RNA (siRNA) to analyze the function of MKX in extracellular matrix (ECM) production and differentiation in ACL-derived cells. Results The expression of MKX was significantly decreased in ACL-derived cells from OA knees compared with normal knees. Consistent with this finding, immunohistochemistry analysis showed that MKX-positive cells were significantly reduced in ACL tissue from OA donors, in particular in cells located in disorientated fibers. In ACL-derived cells, IL-1β strongly suppressed MKX expression and reduced expression of the ligament ECM genes COL1A1 and TNXB. In contrast, SOX9, a chondrocyte master transcription factor, was up-regulated by IL-1β treatment. Importantly, knockdown of MKX expression with siRNA up-regulated SOX9 expression in ACL-derived cells, whereas the expression of COL1A1 and TNXB was reduced. Conclusion Reduced expression of MKX is a feature of degenerated ACL in OA-affected joints, and this may be mediated in part by IL-1β. MKX appears necessary to maintain the tissue-specific cellular differentiation status and ECM production in adult human tendons and ligaments. [ABSTRACT FROM AUTHOR]

The meniscus is a fibrocartilaginous tissue that plays an important role in controlling complex biomechanics of the knee. A perimeniscal capillary plexus supplies the outer meniscus, whereas the inner meniscus is composed of avascular tissue. Anti-angiogenic molecules, such as chondromodulin-I (ChM-I) and endostatin, have pivotal roles in preserving the avascularity of cartilage. However, the anti-angiogenic role of ChM-I is unclear in the meniscus. We hypothesized that the inner meniscus might maintain its avascular feature by expressing ChM-I. Immunohistochemical analyses revealed that ChM-I was mainly detected in the inner and superficial zones of the meniscus. On the other hand, endostatin distribution was similar between the inner and outer meniscus. In Western blot, ChM-I was detected only in the inner meniscus, whereas endostatin was equally observed in both inner and outer menisci. In addition, ChM-I concentration of the inner meniscus-derived conditioned medium was higher than that of the outer meniscus-derived medium. ChM-I removal from the inner meniscus-derived medium and functional blocking of ChM-I significantly increased endothelial cell proliferation. In this study, we demonstrated that the inner meniscus contained larger amounts of ChM-I, and that the inner meniscus-derived ChM-I inhibited endothelial cell proliferation. Our results suggest that ChM-I may be a key anti-angiogenic factor for maintaining the avascularity of the inner meniscus. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 538-543, 2013 [ABSTRACT FROM AUTHOR]

The intrinsic zone-specific properties of the menisci are determined by biomechanical environments. In this study, we examined mechanical stretch-dependent expression of multifunctional growth factor CYR61/CTGF/NOV (CCN) 2, and investigated the role of CCN2 in meniscus cells. Uni-axial cyclic tensile strain (CTS) was applied using a STB-140 system. CTS-induced expression of CCN2 and α1(I) collagen (COL1A1) was assessed by quantitative real-time PCR analysis. The distribution of CCN2 and Smad2/3 in stretched cells was investigated by immunohistochemical analysis. Smad2/3-dependent CCN2 transactivation was measured by luciferase reporter assay. The relationship between Smad2/3 and CTS-induced CCN2 transcription was investigated by chromatin immunoprecipitation. CTS stimulated gene expression of CCN2 and COL1A1 in inner meniscus cells, but not in outer meniscus cells. Recombinant CCN2 increased COL1A1 expression only in inner meniscus cells. CCN2 synthesis and nuclear translocalization of phosphorylated Smad2/3 in inner meniscus cells were stimulated by CTS. The CCN2 promoter activity was synergistically enhanced by overexpressed Smad3 in stretched inner meniscus cells, but was not by Smad2. Chromatin immunoprecipitation revealed that CTS increased the association between Smad3 and the Smad-binding element on the CCN2 proximal promoter in inner meniscus cells. Our results suggest that stretch-induced CCN2 may have a crucial role in regulating COL1A1 expression in the inner meniscus. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 30:1738-1745, 2012 [ABSTRACT FROM AUTHOR]

The meniscus plays an important role in controlling the biomechanics of the knee. However, the mechanical stress-related response in meniscus cells remains unclear. We investigated mechanical stretch-regulated gene expression in human meniscus cells. Human inner and outer meniscus cells were prepared from the inner and outer halves of the lateral meniscus. The gene expressions of Sry-type HMG box (SOX) 9 and α1(II) collagen (COL2A1) were assessed by real-time PCR analyses after cyclic tensile strain (CTS) treatment (0.5 Hz, 5% stretch). The localization and phosphorylation of SOX9 were evaluated by immunohistochemical and Western blot (WB) analyses. Chromatin immunoprecipitation (IP) analysis was performed to assess the stretch-related protein-DNA complex formation between SOX9 and the COL2A1 enhancer on chromatin. Type II collagen deposition and SOX9 production were detected only in inner menisci. CTS treatments increased expression of the COL2A1 and SOX9 genes in inner meniscus cells, but not in outer meniscus cells. In addition, CTS treatments stimulated nuclear translocalization and phosphorylation of SOX9 in inner meniscus cells. Chromatin IP analyses revealed that CTS increased the association between SOX9 and its DNA-binding site, included in the COL2A1 enhancer, on chromatin. Our results indicate that inner and outer meniscus cells have different properties in mechanical stretch-induced COL2A1 expression. In inner meniscus cells, mechanical stretch may have an essential role in the epigenetic regulation of COL2A1 expression. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 30:468-474, 2012 [ABSTRACT FROM AUTHOR]

Previous studies showed that the insertion of the intramuscular tendons of the deltoid muscle formed three discrete lines. The purpose of the present study was to establish a new dividing method of the deltoid muscle into various anatomical segments based on the distribution of the intramuscular tendons with their insertions (anatomical study). We further hoped to clarify the relationship between the anatomical segments and their activity pattern assessed by positron emission tomography with [F]-2-fluoro-deoxyglucose (FDG-PET; PET study). Sixty cadaveric shoulders were investigated in the anatomical study. Three tendinous insertions of the deltoid muscle to the humerus were identified. Then, the intramuscular tendons were traced from their humeral insertions to the proximal muscular origins. The extent of each anatomical segment of the muscle including its origin and insertion was determined through careful dissection. Six healthy volunteers were examined using FDG-PET for the PET study. PET images were obtained after exercise of elevation in the scapular plane. On the PET images, margins of each anatomical segment of the deltoid muscle were determined using magnetic resonance images. Then, the standardized uptake value in each segment was calculated to quantify its activity. The anatomical study demonstrated that the deltoid muscle was divided into seven segments based on the distribution of its intramuscular tendons. The PET study revealed that the intake of FDG was not uniform in the deltoid muscle. The area with high FDG intake corresponded well to the individual muscular segments separated by the intramuscular tendons. We conclude that the deltoid muscle has seven anatomical segments, which seem to represent the functional units of this muscle. [ABSTRACT FROM AUTHOR]

Cellular activities responding to growth factors are important in ligament healing. The anterior cruciate ligament (ACL) has poor healing potential compared to the medial collateral ligament (MCL). To assess the differences, we investigated the proliferation, migration, adhesion, and matrix synthesis responding to growth factors in rabbit ACL and MCL fibroblasts. ACL cell proliferation to basic fibroblast growth factor (bFGF), bone morphogenetic protein-2, growth and differentiation factor (GDF)-5, and GDF-7 treatment was similar to that of MCL cells. GDF-5 enhanced Col1a1 expression in ACL and MCL fibroblasts up to 4.7- and 17-fold levels of control, respectively. MCL fibroblasts showed stronger migration activities in response to bFGF and GDF-5 than ACL cells. GDF-5/7 and bFGF also changed the stress fiber formation and cellular adhesion by modulating the distribution of integrin α2. Functional blocking analyses using anti-integrin α2 antibodies revealed that cellular migration responding to growth factors depended on the integrin α2-mediated adhesion on type I collagen. The expression of integrin α2 was also increased by growth factors in both cells. Our results demonstrate that GDF-5/7 and bFGF stimulate cellular migration by modulating integrin α2 expression and integrin α2-dependent adhesion, especially in MCL fibroblasts. These findings suggest that the different healing potential between ACL and MCL may be caused by different cellular behavior in the integrin α2-mediated cellular migration in response to growth factors. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:225-231, 2010 [ABSTRACT FROM AUTHOR]

ABSTRACT Background Methods Results Conclusions Clear cell sarcoma (CCS) and alveolar soft part sarcoma (ASPS) are rare, and standard systemic therapy is not established except for sunitinib in ASPS. It is known that CCS and ASPS have a common biological feature of melanoma and Xp11.2/TFE3 translocation renal cell carcinoma, and immune‐checkpoint inhibitors (ICIs) are effective in these tumors. The authors conducted a phase 2 trial to evaluate the efficacy and safety of nivolumab for CCS and ASPS.The number of patients expected to be enrolled was 15–25 and was determined based on the Bayesian design. The primary end point was the confirmed objective response rate (ORR) according to the central review and the secondary end points included ORR, progression‐free survival (PFS), overall survival (OS), and safety.A total of 26 patients (CCS, 12; ASPS, 14) were enrolled. Efficacy and safety were analyzed on 25 and 26 patients, respectively. The minimum number of responses required for a positive conclusion regarding the efficacy was four. However, only one patient (4.0%) with ASPS had a partial response. Complete response, stable disease, progression disease, and not evaluable were 0%, 60%, 32%, and 4.0%, respectively. Adverse events of grade 3 or 4 occurred in 57.7% (15 of 26). The median PFS was 4.9 months (95% confidence interval [CI], 3.7–8.6 months) and the median OS was 15.8 months (95% CI, 8.2–not reached).The primary end point of the ORR was not met for CCS and ASPS on the central review. Further studies are needed to evaluate ICIs in patients with ASPS. [ABSTRACT FROM AUTHOR]

Menisci are a pair of crescent-shaped fibrocartilages, particularly of which their inner region of meniscus is an avascular tissue. It has characteristics similar to those of articular cartilage, and hence is inferior in healing. We previously reported that low-intensity pulsed ultrasound (LIPUS) treatment stimulates the production of CCN2/CTGF, a protein involved in repairing articular cartilage, and the gene expression of major cartilage matrices such as type II collagen and aggrecan in cultured chondrocytes. Therefore, in this present study, we investigated whether LIPUS has also favorable effect on meniscus cells and tissues. LIPUS applied with a 60 mW/cm 2 intensity for 20 min stimulated the gene expression and protein production of CCN2 via ERK and p38 signaling pathways, as well as gene expression of SOX9, aggrecan, and collagen type II in human inner meniscus cells in culture, and slightly stimulated the gene expression of CCN2 and promoted the migration in human outer meniscus cells in culture. LIPUS also induced the expression of Ccn2, Sox9, Col2a1, and Vegf in rat intact meniscus. Furthermore, histological evaluations showed that LIPUS treatment for 1 to 4 weeks promoted healing of rat injured lateral meniscus, as evidenced by better and earlier angiogenesis and extracellular matrix synthesis. The data presented indicate that LIPUS treatment might prevent meniscus from degenerative change and exert a reparative effect on injured meniscus via up-regulation of repairing factors such as CCN2 and that it might thus be useful for treatment of an injured meniscus as a non-invasive therapy.