Becker muscular dystrophy: case report, review of the literature, and analysis of differentially expressed hub genes.

INTRODUCTION: Becker muscular dystrophy (BMD) is a genetic and progressive neuromuscular disease caused by mutations in the dystrophin gene with no available cure. A case report and comprehensive review of BMD cases aim to provide important clues for early diagnosis and implications for clinical practice. Genes and pathways identified from microarray data of muscle samples from patients with BMD help uncover the potential mechanism and provide novel therapeutic targets for dystrophin-deficient muscular dystrophies. METHODS: We describe a BMD family with a 10-year-old boy as the proband and reviewed BMD cases from PubMed. Datasets from the Gene Expression Omnibus database were downloaded and integrated with the online software. RESULTS: The systematic review revealed the clinical manifestations and mutation points of the dystrophin gene. Gene ontology analysis showed that extracellular matrix organization and extracellular structure organization with enrichment of upregulated genes coexist in three datasets. We present the first report of TUBA1A involvement in the development of BMD/Duchenne muscular dystrophy (DMD). DISCUSSION: This study provides important implications for clinical practice, uncovering the potential mechanism of the progress of BMD/DMD, and provided new therapeutic targets.

A comparison of the five-minute cognitive test with the mini-mental state examination in the elderly for cognitive impairment screening.

The five-minute cognitive test (FCT) is a novel cognitive screening method with the quick and reliable merit for detecting cognitive impairment at an early stage. The diagnostic power of FCT in differentiating subjects with cognitive impairment from people with cognition in a normal range was demonstrated effective as that of the Mini-Mental Status Evaluation (MMSE) in a previous cohort study. Here, we analyzed the effect of sociodemographic and health-related factors on FCT performance and further investigated the consistency of FCT. Then, we compared the correlation of subitem scores of FCT or MMSE with a comprehensive battery of neuropsychological tests that focus on specific domains of cognition. Finally, the association of the total FCT scores with the volumes of brain subregions was investigated. There were 360 subjects aged 60 years or above enrolled in this study, including 226 adults with cognitive abilities in normal range, 107 subjects with mild cognitive impairment (MCI) and 27 mild Alzheimer's disease (AD). The results showed that the total FCT scores was negatively associated with increasing age (ß = -0.146, p < 0.001), and positively associated with education attainment (ß = 0.318, p < 0.001), dwelling condition with family (ß = 0.153, p < 0.001) and the Body Mass Index (ß = 1.519, p < 0.01). The internal consistency of the FCT (Cronbach's α) was 0.644. The sub-scores of FCT showed a significant correlation with other specific neuropsychological tests. Impressively, the total FCT scores showed a significantly positive association with the volumes of hippocampus related subregions (r = 0.523, p < 0.001) and amygdala (r = 0.479, p < 0.001), but not with cerebellum (r = 0.158, p > 0.05) or subcortical subregions (r = 0.070, p > 0.05). Combining with previous data, FCT is a reliable and valid cognitive screening test for detecting cognitive impairment in a community setting.

Oral rehabilitation following successful TMD treatment with condylar position changes: A case report.

BACKGROUND: A 31-year-old woman with crowns, fixed partial prostheses, and dental restorations complained of recurrent pain in the left and right temporomandibular joints during the last 2 years. CLINICAL PRESENTATION: The symptoms of temporomandibular disorder (TMD) resolved successfully after a 3-month-long treatment with a repositioning splint. Pre- and post-operative cone-beam computed tomography revealed slight changes in the condylar position after splint use. Minimally invasive oral rehabilitation guided by digital design was performed to maintain the acquired stable position. The status of the restorations was good, and the TMD symptoms did not relapse during the 3-year follow-up. CONCLUSION: This case report demonstrates the importance of a stable adapted condylar position after extensive prosthodontic treatment.

Metabolic Reprogramming by MYCN Confers Dependence on the Serine-Glycine-One-Carbon Biosynthetic Pathway.

MYCN amplification drives the development of neuronal cancers in children and adults. Given the challenge in therapeutically targeting MYCN directly, we searched for MYCN-activated metabolic pathways as potential drug targets. Here we report that neuroblastoma cells with MYCN amplification show increased transcriptional activation of the serine-glycine-one-carbon (SGOC) biosynthetic pathway and an increased dependence on this pathway for supplying glucose-derived carbon for serine and glycine synthesis. Small molecule inhibitors that block this metabolic pathway exhibit selective cytotoxicity to MYCN-amplified cell lines and xenografts by inducing metabolic stress and autophagy. Transcriptional activation of the SGOC pathway in MYCN-amplified cells requires both MYCN and ATF4, which form a positive feedback loop, with MYCN activation of ATF4 mRNA expression and ATF4 stabilization of MYCN protein by antagonizing FBXW7-mediated MYCN ubiquitination. Collectively, these findings suggest a coupled relationship between metabolic reprogramming and increased sensitivity to metabolic stress, which could be exploited as a strategy for selective cancer therapy. SIGNIFICANCE: This study identifies a MYCN-dependent metabolic vulnerability and suggests a coupled relationship between metabolic reprogramming and increased sensitivity to metabolic stress, which could be exploited for cancer therapy.See related commentary by Rodriguez Garcia and Arsenian-Henriksson, p. 3818.

Maintenance of the Maxillomandibular Position with Digital Workflow in Oral Rehabilitation: A Technical Note.

Prosthodontic oral rehabilitation procedures are time consuming and require efforts to maintain the confirmed maxillomandibular relationship. Several occlusal registrations and impressions are needed, and cross-mounting is performed to transfer the diagnostic wax-up to master working casts. The introduction of a digital workflow protocol reduces steps in the required process, and occlusal registrations with less deformation are used. The outcome is a maintained maxillomandibular position that is accurately and conveniently transferred.

Treatment-Related Death during Concurrent Chemoradiotherapy for Locally Advanced Non-Small Cell Lung Cancer: A Meta-Analysis of Randomized Studies.

Treatment related death (TRD) is the worst adverse event in chemotherapy and radiotherapy for patients with cancer, the reports for TRDs were sporadically. We aimed to study TRDs in non-small cell lung cancer (NSCLC) patients treated with concurrent chemoradiotherapy (CCRT), and determine whether high radiation dose and newer chemotherapy regimens were associated with the risk of TRD. Data from randomized clinical trials for locally advanced/unresectable NSCLC patients were analyzed. Eligible studies had to have at least one arm with CCRT. The primary endpoint was TRD. Pooled odds ratios (ORs) for TRDs were calculated. In this study, a total of fifty-three trials (8940 patients) were eligible. The pooled TRD rate (accounting for heterogeneity) was 1.44% for all patients. In 20 trials in which comparison of TRDs between CCRT and non-CCRT was possible, the OR (95% CI) of TRDs was 1.08 (0.70-1.66) (P = 0.71). Patients treated with third-generation chemotherapy and concurrent radiotherapy had an increase of TRDs compared to those with other regimens in CCRT (2.70% vs. 1.37%, OR = 1.50, 95% CI: 1.09-2.07, P = 0.008). No significant difference was found in TRDs between high (≥ 66 Gy) and low (< 66 Gy) radiation dose during CCRT (P = 0.605). Neither consolidation (P = 0.476) nor induction chemotherapy (P = 0.175) had significant effects with increased TRDs in this study. We concluded that CCRT is not significantly associated with the risk of TRD compared to non-CCRT. The third-generation chemotherapy regimens may be a risk factor with higher TRDs in CCRT, while high dose radiation is not significantly associated with more TRDs. This observation deserves further study.

KDM4C and ATF4 Cooperate in Transcriptional Control of Amino Acid Metabolism.

The histone lysine demethylase KDM4C is often overexpressed in cancers primarily through gene amplification. The molecular mechanisms of KDM4C action in tumorigenesis are not well defined. Here, we report that KDM4C transcriptionally activates amino acid biosynthesis and transport, leading to a significant increase in intracellular amino acid levels. Examination of the serine-glycine synthesis pathway reveals that KDM4C epigenetically activates the pathway genes under steady-state and serine deprivation conditions by removing the repressive histone modification H3 lysine 9 (H3K9) trimethylation. This action of KDM4C requires ATF4, a transcriptional master regulator of amino acid metabolism and stress responses. KDM4C activates ATF4 transcription and interacts with ATF4 to target serine pathway genes for transcriptional activation. We further present evidence for KDM4C in transcriptional coordination of amino acid metabolism and cell proliferation. These findings suggest a molecular mechanism linking KDM4C-mediated H3K9 demethylation and ATF4-mediated transactivation in reprogramming amino acid metabolism for cancer cell proliferation.

Transcriptional Profiling Reveals a Common Metabolic Program in High-Risk Human Neuroblastoma and Mouse Neuroblastoma Sphere-Forming Cells.

High-risk neuroblastoma remains one of the deadliest childhood cancers. Identification of metabolic pathways that drive or maintain high-risk neuroblastoma may open new avenues of therapeutic interventions. Here, we report the isolation and propagation of neuroblastoma sphere-forming cells with self-renewal and differentiation potential from tumors of the TH-MYCN mouse, an animal model of high-risk neuroblastoma with MYCN amplification. Transcriptional profiling reveals that mouse neuroblastoma sphere-forming cells acquire a metabolic program characterized by transcriptional activation of the cholesterol and serine-glycine synthesis pathways, primarily as a result of increased expression of sterol regulatory element binding factors and Atf4, respectively. This metabolic reprogramming is recapitulated in high-risk human neuroblastomas and is prognostic for poor clinical outcome. Genetic and pharmacological inhibition of the metabolic program markedly decreases the growth and tumorigenicity of both mouse neuroblastoma sphere-forming cells and human neuroblastoma cell lines. These findings suggest a therapeutic strategy for targeting the metabolic program of high-risk neuroblastoma.

[Application of low intensity ultrasound in the extraction of totally impacted mandibular third molars].

PURPOSE: To observe the clinical effects of low intensity ultrasound in extraction of totally impacted third molars. METHODS: 40 patients with totally impacted third molars on both sides of the mandible verified by X-ray were selected. After extraction of the teeth, the socket on one side was treated with low intensity ultrasound while the other side underwent no treatment. Statistical analysis was performed with SPSS 10.0 on all patients in form of pain, swelling, dry socket and bone healing. RESULTS: In the experimental group, 4 patients complained of severe pain while 16 patients in the control group (P < 0.05). Moderate or severe swelling were not uncommon in both experimental and control groups (P > 0.05); No patients suffered from dry socket in the experimental group and 4 patients suffered from dry socket in the control group (P < 0.05); There were 35 patients with complete bone healing in the experimental group while 21 patients with complete bone healing in the control group (P < 0.01). CONCLUSIONS: The use of low intensity ultrasound in extraction of totally impacted mandibular third molars reduced the severity of post-operative pain and the incidence dry socket, and it also stimulated bone healing, but it showed no effect on relieving post-operative swelling.