EFHD1 promotes osteosarcoma proliferation and drug resistance by inhibiting the opening of the mitochondrial membrane permeability transition pore (mPTP) by binding to ANT3.

Chemoresistance is the main obstacle in the clinical treatment of osteosarcoma (OS). In this study, we investigated the role of EF-hand domain-containing protein 1 (EFHD1) in OS chemotherapy resistance. We found that the expression of EFHD1 was highly correlated with the clinical outcome after chemotherapy. We overexpressed EFHD1 in 143B cells and found that it increased their resistance to cell death after drug treatment. Conversely, knockdown of EFHD1 in 143BR cells (a cisplatin-less-sensitive OS cell line derived from 143B cells) increased their sensitivity to treatment. Mechanistically, EFHD1 bound to adenine nucleotide translocase-3 (ANT3) and inhibited its conformational change, thereby inhibiting the opening of the mitochondrial membrane permeability transition pore (mPTP). This effect could maintain mitochondrial function, thereby favoring OS cell survival. The ANT3 conformational inhibitor carboxyatractyloside (CATR), which can promote mPTP opening, enhanced the chemosensitivity of EFHD1-overexpressing cells when combined with cisplatin. The ANT3 conformational inhibitor bongkrekic acid (BKA), which can inhibit mPTP opening, restored the resistance of EFHD1 knockdown cells. In conclusion, our results suggest that EFHD1-ANT3-mPTP might be a promising target for OS therapy in the future.

Comparative evaluation of image registration methods with different interest regions in lung cancer radiotherapy.

BACKGROUND: Lung cancer is a leading cause of morbidity and mortality worldwide. Radiotherapy for lung cancer is beneficial in both the radical and palliative settings, and technologic advances in recent years now afford an opportunity for this treatment to be more targeted than ever before. Although the delivery of more accurate forms of radiotherapy has minimized the risks of side-effects, how to utilize this treatment to optimize outcomes remains questionable. This study aimed to evaluate the accuracy of cone beam computed tomography (CBCT) image registration used in image-guided radiotherapy, providing reasonable guidance for clinic application of CBCT in lung cancer. METHODS: A total of 53 patients with lung carcinoma including 34 central and 19 peripheral lesions were collected in this study. Varian-IX linear accelerator on-board imaging (OBI) system was used to acquire CBCT scans in three-dimensional (3D) conformal radiotherapy before delivery. Different regions (whole lung/target/vertebrae/ipsilateral structure) were manually registered, and the position deviation and the registration time were analyzed. RESULTS: It was suggested that 34 cases belonged to central type and 19 cases belonged to peripheral type. The volume of left lung and right lung was 1242.98 ± 452.46 cc, 1689.69 ± 574.31 cc, respectively. Tumor size was 6.65 ± 3.87 cm in diameter, and 129.67 ± 136.48 cc in volume. The percentage of left lung and right lung was 6.17 ± 1.24%, 4.74 ± 0.38%, respectively. The position deviation value and absolute value of image registration methods of X, Y and Z axis were not significant (P > 0.05). However, registration time (s) between whole lung registration group, tumor registration group, vertebral body registration group, affected lung registration group, and artificial registration group, was 3.651 ± 0.867 s, 1.144 ± 0.129 s, 1.226 ± 0.126 s, 2.081 ± 0.427 s, 179.491 ± 71.975 s, respectively. The differences were significant (P < 0.05). The registration differences between small tumor group and large tumor group were not statistically significant (P > 0.05). CONCLUSION: The automatic image matching of OBI is accuracy and high reliability in recognition of offset error. Registering body or ipsilateral structure is recommended to be used in CBCT for lung cancer.

Comparison of different registration methods and landmarks for image-guided radiation therapy of pulmonary tumors.

BACKGROUND: To compare the accuracy, advantages and disadvantages of automatic registration methods at different anatomical-sites for thoracic image-guided radiation therapy (IGRT). METHODS: The Varian-IX IGRT system was used to perform a manual registration of the images collected on the first fraction of 60 patients with lung cancer (42 cases central location and 18 cases of peripheral). The registered images were used as reference images. Offline registration was performed for computed tomography-CBCT images using four methods: whole image registration, ipsilateral registration, soft tissue tumor registration, and vertebral body registration. Time taken to complete and deviation value were analyzed between the different methods. RESULTS: There were significant differences in absolute deviation value of all the three directions (P < 0.001) and the time consumption (P < 0.001) between 4 methods. The Z direction had significant differences in deviation value of 4 methods (0.023 ± 0.128 mm, - 0.030 ± 0.175 mm, - 0.010 ± 0.238 mm, - 0.075 ± 0.137 mm, P = 0.011). The difference was significant in the X direction of the ipsilateral registration method between central and peripheral lung cancer (0.033 ± 0.053 mm vs. 0.067 ± 0.067 mm, P = 0.045). CONCLUSIONS: The whole lung or affected side registration methods could be recommended to be used in the automatic registration function of the Varian-IX's On-Board Imaging (OBI) system.

CEA: Combination-based gene set functional enrichment analysis.

Functional enrichment analysis is a fundamental and challenging task in bioinformatics. Most of the current enrichment analysis approaches individually evaluate functional terms and often output a list of enriched terms with high similarity and redundancy, which makes it difficult for downstream studies to extract the underlying biological interpretation. In this paper, we proposed a novel framework to assess the performance of combination-based enrichment analysis. Using this framework, we formulated the enrichment analysis as a multi-objective combinatorial optimization problem and developed the CEA (Combination-based Enrichment Analysis) method. CEA provides the whole landscape of term combinations; therefore, it is a good benchmark for evaluating the current state-of-the-art combination-based functional enrichment methods in a comprehensive manner. We tested the effectiveness of CEA on four published microarray datasets. Enriched functional terms identified by CEA not only involve crucial biological processes of related diseases, but also have much less redundancy and can serve as a preferable representation for the enriched terms found by traditional single-term-based methods. CEA has been implemented in the R package CopTea and is available at http://github.com/wulingyun/CopTea/.

NetGen: a novel network-based probabilistic generative model for gene set functional enrichment analysis.

BACKGROUND: High-throughput experimental techniques have been dramatically improved and widely applied in the past decades. However, biological interpretation of the high-throughput experimental results, such as differential expression gene sets derived from microarray or RNA-seq experiments, is still a challenging task. Gene Ontology (GO) is commonly used in the functional enrichment studies. The GO terms identified via current functional enrichment analysis tools often contain direct parent or descendant terms in the GO hierarchical structure. Highly redundant terms make users difficult to analyze the underlying biological processes. RESULTS: In this paper, a novel network-based probabilistic generative model, NetGen, was proposed to perform the functional enrichment analysis. An additional protein-protein interaction (PPI) network was explicitly used to assist the identification of significantly enriched GO terms. NetGen achieved a superior performance than the existing methods in the simulation studies. The effectiveness of NetGen was explored further on four real datasets. Notably, several GO terms which were not directly linked with the active gene list for each disease were identified. These terms were closely related to the corresponding diseases when accessed to the curated literatures. NetGen has been implemented in the R package CopTea publicly available at GitHub ( http://github.com/wulingyun/CopTea/ ). CONCLUSION: Our procedure leads to a more reasonable and interpretable result of the functional enrichment analysis. As a novel term combination-based functional enrichment analysis method, NetGen is complementary to current individual term-based methods, and can help to explore the underlying pathogenesis of complex diseases.

Investigation of the immature stage of the cord blood banks and their regulation in China.

Cord blood banks (CBBs) collect umbilical cord blood and isolate therefrom the stem cells which may be transplanted into patients serving treatment of many kinds of serious diseases. As one kind of health resource, CBBs need regulation to guarantee its fair development and safe application. During the past decade, several CBBs have been established in China and related measures have been administered to regulate their establishment and manipulation. How about the actual situation of CBBs in China, including, how are they regulated and what are the problems with the CBBs in practice? Upon introduction to cord blood and the CBBs, this paper investigates the practical situation of the CBBs in China and their regulation, and explores the corresponding problems which need to be dealt with. It is held that the CBB system in China is still at an initial stage, not only for its establishment and operation, but for its regulation as well; and, therefore, justification of a more sustainable CBB system for a better development is needed in China.

Regulation of GMOs in China.

Genetically modified organisms (GMOs) are created by biotechnology to serve people with much benefit while may impose risks to ecological environment and human health and therefore need careful regulation. During the past two decades, GMOs have been well developed in China and so has their corresponding regulation. This paper reviews and comments the multiple aspects of mainly the agricultural GMOs, including their safety assessment, control measures, trade activities, import, labels, and GM food, which have been prescribed by the corresponding laws, regulations and administrative measures. It is held that till present a framework for regulation of agricultural GMOs and GM food has been established basically in China, while a more comprehensive system for regulation of all kinds of GMOs and all kinds of related activities is still needed at present and in the future.