Search

In IDH-mutant astrocytoma, IDH2 mutation is quite rare and biological mechanisms underlying tumor progression in IDH2-mutant astrocytoma remain elusive. Here, we report a unique case of IDH2 mutant astrocytoma, CNS WHO grade 3 that developed tumor progression. We performed a comprehensive genomic and epigenomic analysis for primary and recurrent tumors and found that both tumors harbored recurrent IDH2R172K and TP53R248W mutation with CDKN2A/B hemizygous deletion. We also found amplifications of CDK4 and MDM2 with PDGFRA gain in the recurrent tumor and upregulated protein expressions of these genes. We further developed, for the first time, a xenograft mouse model of IDH2R172K and TP53R248W mutant astrocytoma from the recurrent tumor, but not from the primary tumor. Consistent with parent recurrent tumor cells, amplifications of CDK4 and MDM2 and PDGFRA gain were found, while CDKN2A/B was identified as homozygous deletion in the xenografts, qualifying for integrated diagnosis of astrocytoma, IDH2-mutant, CNS WHO grade 4. Cell viability assay found that CDK4/6 inhibitor and PDGFR inhibitor potently decreased cell viability in recurrent tumor cells, as compared to primary tumor cells. These findings suggest that gene alterations that activate retinoblastoma (RB) signaling pathways and PDGFR may drive tumor progression and xenograft formation in IDH2-mutant astrocytoma, which is equivalent to progressive IDH1-mutant astrocytoma. Also, our findings suggest that these genomic alterations may represent therapeutic targets in IDH2-mutant astrocytoma. [ABSTRACT FROM AUTHOR]

Liquid-liquid phase separation (LLPS) has been thought to be the biophysical principle governing the assembly of the multiphase structures of nucleoli, the site of ribosomal biogenesis. Condensates assembled through LLPS increase their sizes to minimize the surface energy as far as their components are available. However, multiple microphases, fibrillar centers (FCs), dispersed in a nucleolus are stable and their sizes do not grow unless the transcription of pre-ribosomal RNA (pre-rRNA) is inhibited. To understand the mechanism of the suppression of the FC growth, we here construct a minimal theoretical model by taking into account nascent pre-rRNAs tethered to FC surfaces by RNA polymerase I. The prediction of this theory was supported by our experiments that quantitatively measure the dependence of the size of FCs on the transcription level. This work sheds light on the role of nascent RNAs in controlling the size of nuclear bodies. Theoretical modeling and experimental tests shed light on the roles of nascent prerRNA, produced by Pol I transcription, in the assembly of the sea-island multi-phase structure in the nucleolus. [ABSTRACT FROM AUTHOR]

Purpose: Bony morphology has been proposed as a potential risk factor for anterior cruciate ligament (ACL) injury. The relationship between bony morphology, knee kinematics, and ACL elongation during high-demand activities remains unclear. The purpose of this study was to determine if bone morphology features that have been associated with ACL injury risk and knee kinematics are also predictive of ACL elongation during fast running and double-legged drop jump. Methods: Nineteen healthy athletes performed fast running and double-legged drop jump within a biplane radiography imaging system. Knee kinematics and ACL elongation were measured bilaterally after using a validated registration process to track bone motion in the radiographs and after identifying ACL attachment sites on magnetic resonance imaging (MRI). Bony morphological features of lateral posterior tibial slope (LPTS), medial tibial plateau (MTP) depth, and lateral femoral condyle anteroposterior width (LCAP)/lateral tibial plateau anteroposterior width (TPAP) were measured on MRI. Relationships between bony morphology and knee kinematics or ACL elongation were identified using multiple linear regression analysis. Results: No associations between bony morphology and knee kinematics or ACL elongation were observed during fast running. During double-legged drop jump, a greater range of tibiofemoral rotation was associated with a steeper LPTS (β = 0.382, p = 0.012) and a deeper MTP depth (β = 0.331, p = 0.028), and a greater range of anterior tibial translation was associated with a shallower MTP depth (β = − 0.352, p = 0.018) and a larger LCAP/ TPAP (β = 0.441, p = 0.005); however, greater ACL elongation was only associated with a deeper MTP depth (β = 0.456, p = 0.006) at toe-off. Conclusion: These findings indicate that observed relationships between bony morphology and kinematics should not be extrapolated to imply a relationship also exists between those bone morphology features and ACL elongation during high-demand activities. These new findings deepen our understanding of the relationship between bony morphology and ACL elongation during high-demand activities. This knowledge can help identify high-risk patients for whom additional procedures during ACL reconstruction are most appropriate. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to investigate the relationship between periprosthetic osteolysis around the talar component and the amount of talar component subsidence after total ankle arthroplasty (TAA). Methods: This study included forty patients who underwent TAA with a mean follow-up of 67.5 ± 17.0 months. The patients were divided into two groups based on the amount of osteolysis around the talar component, as measured by computed tomography at the latest clinic visit: none to 2 mm (N group, n = 20) and greater than or equal to 2 mm (O group, n = 20). The average amount of talar component subsidence, clinical outcomes, and complications were compared between the two groups. In the O group, the correlation between osteolysis and talar component subsidence was evaluated. Results: The average talar component subsidence was significantly different between the N (0.22 ± 0.94 mm) and O groups (2.12 ± 2.28 mm). Five out of 20 ankles in the O group required revision surgery owing to talar component subsidence. The Japanese Society for Surgery of the Foot scores in the N and O groups were significantly different: 93.5 ± 7.7 and 85.3 ± 15.4, respectively. In the O group, we found that osteolysis tended to develop on the lateral side, and the amount of osteolysis was positively correlated with the talar component subsidence (r = 0.59, P =.007). Conclusion: In the O group, a positive correlation between osteolysis and talar component subsidence was found, and five patients required revision surgery. [ABSTRACT FROM AUTHOR]

Oral microbiome studies have mainly focussed on bacteria, with the relationship between viruses and oral cancers remaining poorly understood. Oral cancers can develop even in the absence of any history of daily smoking or drinking. Oral cancer patients frequently have multiple primary cancers in the oral cavity and other organs, such as the upper gastrointestinal tract. Merkel cell polyomavirus (MCPyV) is a novel oncovirus identified from a subtype of skin cancer in 2008. In this study, we investigated the potential involvement of MCPyV in the pathogenesis of oral squamous cell carcinoma (OSCC). Participants comprised 115 Japanese patients with OSCC (single primary: 109 tumours in 109 patients; multiple primaries: 16 tumours in 6 patients) treated in our department between 2014 and 2017. DNA was extracted from formalin-fixed paraffin-embedded specimens of primary lesions. MCPyV DNA copy counts were analysed by quantitative real-time polymerase chain reaction. Twenty-four of the 115 patients (20.9%) were positive for MCPyV DNA. No association was found between presence or absence of MCPyV DNA and clinical characteristics other than number of primary lesions. The MCPyV DNA-positive rate was significantly higher for multiple primary OSCCs (62.5%, 10/16 tumours) than for single primary OSCCs (16.5%, 18/109 tumours; P < 0.001). Furthermore, MCPyV DNA load was significantly higher for patients with multiple primaries (P < 0.05). MCPyV was observed more frequently and DNA load was significantly higher with multiple primary OSCCs than with single primary OSCC. MCPyV may play some role as an oncovirus for multiple primary OSCCs. [ABSTRACT FROM AUTHOR]

Background: In the past, different stress generation studies have used self-report measures comprising different items to assess each category of negative events. Moreover, the validity of these scales has not been adequately investigated. Therefore, we developed a self-report measure dedicated to assessing experiences of negative interpersonal dependent events, negative non-interpersonal dependent events, and negative independent events in university students, which was named the Negative Independent/Dependent Events Scale. Methods: Japanese undergraduate students (N = 247; mean age = 19.18 years, SD = 3.08) responded to the Negative Independent/Dependent Events Scale, which had items selected for adequate content validity. They also responded to self-report measures of depressive symptoms, reassurance-seeking behaviors, inattention, and lack of perseverance. Results: All the negative events subscales had moderate positive correlations with depressive symptoms. In addition, the negative interpersonal dependent events subscale showed a moderate positive correlation with reassurance-seeking behaviors, and the negative non-interpersonal dependent events subscale showed a strong positive correlation with inattention. Furthermore, the negative non-interpersonal dependent events subscale was more strongly correlated with inattention than the other two negative events subscales. In contrast, the negative interpersonal dependent events subscale was more strongly correlated with reassurance-seeking behaviors than with the negative independent events subscale but not more strongly than with the negative non-interpersonal dependent events subscale. Conclusions: These findings indicated the acceptable construct validity of the Negative Independent/Dependent Events Scale. However, further research is necessary to establish the discriminant validity of the negative interpersonal dependent events subscale and the negative non-interpersonal dependent events subscale. [ABSTRACT FROM AUTHOR]