MicroRNA Involvement in Osteosarcoma

Osteosarcoma (OS) is the most common primary malignant bone tumor, usually arising in the long bones of adolescents and young adults. While our knowledge of the molecular pathogenesis of OS has increased in recent years, we are still far from a comprehensive understanding of the molecular mechanisms of the disease, such as its tumorigenesis, specific mediators of disease progression, occurrence of chemoresistance, and development of metastasis. After the recent discovery of microRNAs (miRNAs), their critical roles in molecular biological processes have been of great interest in the cancer research field, including research on sarcomas. MiRNAs are highly conserved noncoding RNAs which play important roles as oncogenic or suppressive genes to simultaneously regulate multiple targets. Recent genome-wide screening using miRNA expression profiles has identified specific miRNA expression patterns that are associated with the biological and clinical properties of cancers. Additionally, miRNAs and their target genes or proteins can be potential novel biomarkers or therapeutic targets for cancer. However, there are several challenges that must be addressed in order to translate miRNA-based therapeutics to the clinical setting. In this review, we summarize the current understanding of the roles that miRNAs play in OS, and highlight their potential as biomarkers or therapeutic targets

Nature of collective decision-making by simple yes/no decision units Eisuke Hasegawa

The study of collective decision-making spans various fields such as brain and behavioural sciences, economics, management sciences, and artificial intelligence. Despite these interdisciplinary applications, little is known regarding how a group of simple 'yes/no' units, such as neurons in the brain, can select the best option among multiple options. One prerequisite for achieving such correct choices by the brain is correct evaluation of relative option quality, which enables a collective decision maker to efficiently choose the best option. Here, we applied a sensory discrimination mechanism using yes/no units with differential thresholds to a model for making a collective choice among multiple options. The performance corresponding to the correct choice was shown to be affected by various parameters. High performance can be achieved by tuning the threshold distribution with the options' quality distribution. The number of yes/no units allocated to each option and its variability profoundly affects performance. When this variability is large, a quorum decision becomes superior to a majority decision under some conditions. The general features of this collective decision-making by a group of simple yes/no units revealed in this study suggest that this mechanism may be useful in applications across various fields

The yeast Arf-GAP Glo3p is required for the endocytic recycling of cell surface proteins

Small GTP-binding proteins of the Ras superfamily play diverse roles in intracellular trafficking. Among them, the Rab, Arf, and Rho families function in successive steps of vesicle transport, in forming vesicles from donor membranes, directing vesicle trafficking toward target membranes and docking vesicles onto target membranes. These proteins act as molecular switches that are controlled by a cycle of GTP binding and hydrolysis regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). In this study we explored the role of GAPs in the regulation of the endocytic pathway using fluorescently labeled yeast mating pheromone α-factor. Among 25 non-essential GAP mutants, we found that deletion of the GLO3 gene, encoding Arf-GAP protein, caused defective internalization of fluorescently labeled α-factor. Quantitative analysis revealed that glo3Δ cells show defective α-factor binding to the cell surface. Interestingly, Ste2p, the α-factor receptor, was mis-localized from the plasma membrane to the vacuole in glo3Δ cells. Domain deletion mutants of Glo3p revealed that a GAP-independent function, as well as the GAP activity, of Glo3p is important for both α-factor binding and Ste2p localization at the cell surface. Additionally, we found that deletion of the GLO3 gene affects the size and number of Arf1p-residing Golgi compartments and causes a defect in transport from the TGN to the plasma membrane. Furthermore, we demonstrated that glo3Δ cells were defective in the late endosome-to-TGN transport pathway, but not in the early endosome-to-TGN transport pathway. These findings suggest novel roles for Arf-GAP Glo3p in endocytic recycling of cell surface proteins

Polymeric nanoparticle-based delivery of microRNA-199a-3p inhibits proliferation and growth of osteosarcoma cells

Our prior screening of microRNAs (miRs) identified that miR-199a-3p expression is reduced in osteosarcoma cells, one of the most common types of bone tumor. miR-199a-3p exhibited functions of tumor cell growth inhibition, suggesting the potential application of miR-199a-3p as an anticancer agent. In the study reported here, we designed and developed a lipid-modified dextran-based polymeric nanoparticle platform for encapsulation of miRs, and determined the efficiency and efficacy of delivering miR-199a-3p into osteosarcoma cells. In addition, another potent miR, let-7a, which also displayed tumor suppressive ability, was selected as a candidate miR for evaluation. Fluorescence microscopy studies and real-time polymerase chain reaction results showed that dextran nanoparticles could deliver both miR-199a-3p and let-7a into osteosarcoma cell lines (KHOS and U-2OS) successfully. Western blotting analysis and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays demonstrated that dextran nanoparticles loaded with miRs could efficiently downregulate the expression of target proteins and effectively inhibit the growth and proliferation of osteosarcoma cells. These results demonstrate that a lipid-modified dextran-based polymeric nanoparticle platform may be an effective nonviral carrier for potential miR-based anticancer therapeutics

Image-guided core needle biopsy for musculoskeletal lesions

Background: Image-guided percutaneous core needle biopsy (CNB) has been an important diagnostic procedure for musculoskeletal lesions. Here we surveyed the variety of diagnostic strategies available and assessed the clinical usefulness and limitations of image-guided CNB carried out by a multidisciplinary team comprising specialists in various fields. Methods: We conducted a retrospective study of 284 image-guided CNBs among 1899 consecutive biopsy procedures carried out at our institution for musculoskeletal tumorous conditions, focusing on their effectiveness including diagnostic accuracy and utility for classification of specimens according to malignant potential and histological subtype as well as their correlation with biopsy routes. Results: Among the 284 studied biopsies, 252 (88.7%) were considered clinically “effective”. The sensitivity for detection of malignancy was 94.0% (110/117) and the specificity was 95.3% (41/43). The diagnostic accuracy for detection of malignancy was 94.4% (151/160) and that for histological subtype was 92.3% (48/52). The clinical effectiveness of the procedure was correlated with the complexity of the biopsy route (P = 0.015); the trans-pedicular, trans-retroperitoneal and trans-sciatic foramen approaches tended to yield ineffective results. Repeat biopsy did not have a significant impact on the effectiveness of image-guided CNB (P = 0.536). Conclusions: The diagnostic accuracy rates of image-guided CNB performed at multidisciplinary sarcoma units were usable even for patients who have variety of diagnostic biopsy procedures. It is important to establish and implement diagnostic strategies based on an understanding that complicated routes, especially for spine and pelvic lesions, may be associated with ineffectiveness and/or complications

Metastatic Patterns of Myxoid/Round Cell Liposarcoma: A Review of a 25-Year Experience

Myxoid/round cell liposarcoma (MRCL), unlike other soft tissue sarcomas, has been associated with unusual pattern of metastasis to extrapulmonary sites. In an attempt to elucidate the clinical features of MRCL with metastatic lesions, 58 cases, from the medical database of Keio University Hospital were used for the evaluation. 47 patients (81%) had no metastases, whereas 11 patients (11%) had metastases during their clinical course. Among the 11 patients with metastatic lesions, 8 patients (73%) had extrapulmonary metastases and 3 patients (27%) had pulmonary metastases. Patients were further divided into three groups; without metastasis, with extrapulmonary metastasis, and with pulmonary metastasis. When the metastatic patterns were stratified according to tumor size, there was statistical significance between the three groups (P = 0.028). The 8 cases with extrapulmonary metastases were all larger than 10 cm. Similarly, histological grading had a significant impact on metastatic patterns (P = 0.027). 3 cases with pulmonary metastatic lesions were all diagnosed as high grade. In conclusion, large size and low histological grade were significantly associated with extrapulmonary metastasis

The Pavlik harness in the treatment of developmentally dislocated hips: results of Japanese multicenter studies in 1994 and 2008

AbstractBackgroundIt has already been more than 50years since the Pavlik harness was introduced in Japan, and today the Pavlik harness is widely recognized as the standard initial treatment modality for developmental dysplasia of the hip. We performed a multicenter nationwide questionnaire study concerning the results of Pavlik harness treatment twice in 1994 and 2008.MethodsIn 1994 and in 2008, we sent questionnaires to 12 institutes in Japan specializing mainly in pediatric orthopedics. We compare the results of these two studies and discuss differences in reduction rates, incidence of avascular necrosis in the femoral epiphysis and the percentage of joints with acceptable morphology (Severin grade I+II/total) at skeletal maturity. We statistically assessed these results to see whether there were changes in the treatment outcomes over this 14-year period.ResultsReduction of the dislocated hips was obtained by the Pavlik harness in 80.2% (1990/2481 hips; 1994) and 81.9% (1248/1523 hips; 2008). The incidences of avascular necrosis of the proximal femoral epiphysis in the dysplastic hips were 14.3% (119/835 hips; 1994) and 11.5% (76/663 hips; 2008). The type of avascular necrosis in hips from the 2008 study was determined according to the classification of Kalamchi and MacEwen: 24/69 hips (34.8%) were classified as group I; 20/69 hips (29.0%) as group II; 11/69 hips (15.9%) as group Ill; 14/69 hips (20.3%) as group IV. The percentages of hips with acceptable outcomes at skeletal maturity discerned from Severin X-ray changes (grade I+II/total) were 72.3% (604/835 hips; 1994) and 77.7% (488/628 hips; 2008).ConclusionReduction rates and the incidence of avascular necrosis in 2008 were statistically similar to the results in 1994. The rate of acceptable outcome (Severin grade I+II/total) in 2008 was statistically higher than that of 1994