A Computational Framework to Identify Biomarkers for Glioma Recurrence and Potential Drugs Targeting Them.

Background: Recurrence is still a major obstacle to the successful treatment of gliomas. Understanding the underlying mechanisms of recurrence may help for developing new drugs to combat gliomas recurrence. This study provides a strategy to discover new drugs for recurrent gliomas based on drug perturbation induced gene expression changes. Methods: The RNA-seq data of 511 low grade gliomas primary tumor samples (LGG-P), 18 low grade gliomas recurrent tumor samples (LGG-R), 155 glioblastoma multiforme primary tumor samples (GBM-P), and 13 glioblastoma multiforme recurrent tumor samples (GBM-R) were downloaded from TCGA database. DESeq2, key driver analysis and weighted gene correlation network analysis (WGCNA) were conducted to identify differentially expressed genes (DEGs), key driver genes and coexpression networks between LGG-P vs LGG-R, GBM-P vs GBM-R pairs. Then, the CREEDS database was used to find potential drugs that could reverse the DEGs and key drivers. Results: We identified 75 upregulated and 130 downregulated genes between LGG-P and LGG-R samples, which were mainly enriched in human papillomavirus (HPV) infection, PI3K-Akt signaling pathway, Wnt signaling pathway, and ECM-receptor interaction. A total of 262 key driver genes were obtained with frizzled class receptor 8 (FZD8), guanine nucleotide-binding protein subunit gamma-12 (GNG12), and G protein subunit ß2 (GNB2) as the top hub genes. By screening the CREEDS database, we got 4 drugs (Paclitaxel, 6-benzyladenine, Erlotinib, Cidofovir) that could downregulate the expression of up-regulated genes and 5 drugs (Fenofibrate, Oxaliplatin, Bilirubin, Nutlins, Valproic acid) that could upregulate the expression of down-regulated genes. These drugs may have a potential in combating recurrence of gliomas. Conclusion: We proposed a time-saving strategy based on drug perturbation induced gene expression changes to find new drugs that may have a potential to treat recurrent gliomas.

Virus-like particle vaccines for poliovirus types 1, 2, and 3 with enhanced thermostability expressed in insect cells.

Poliovirus (PV) is a pathogen that causes poliomyelitis, which may lead to paralysis and fatality. Inactivated PV vaccines (IPVs) and live-attenuated oral PV vaccines (OPVs) are currently used to defend against PV worldwide. Vaccines must be developed in a PV-free environment given the biosafety issues associated with OPV and IPV production and to eradicate PV globally. In this study, PV1, PV2, and PV3 virus-like particles with enhanced thermostability (PV-sVLPs) were produced in large quantities by using a baculovirus expression vector system (BEVS). Mice immunized with PV-sVLPs generated antibodies with strong PV-neutralizing response. In addition, splenocytes collected from immunized mice expressed high levels of IFN-γ, IL-2, GM-CSF, IL-5, and IL-10 upon PV-sVLPs stimulation. These data suggest that PV-sVLPs can serve as vaccines against PV infection.

Automatic Organ Segmentation for CT Scans Based on Super-Pixel and Convolutional Neural Networks.

Accurate segmentation of specific organ from computed tomography (CT) scans is a basic and crucial task for accurate diagnosis and treatment. To avoid time-consuming manual optimization and to help physicians distinguish diseases, an automatic organ segmentation framework is presented. The framework utilized convolution neural networks (CNN) to classify pixels. To reduce the redundant inputs, the simple linear iterative clustering (SLIC) of super-pixels and the support vector machine (SVM) classifier are introduced. To establish the perfect boundary of organs in one-pixel-level, the pixels need to be classified step-by-step. First, the SLIC is used to cut an image into grids and extract respective digital signatures. Next, the signature is classified by the SVM, and the rough edges are acquired. Finally, a precise boundary is obtained by the CNN, which is based on patches around each pixel-point. The framework is applied to abdominal CT scans of livers and high-resolution computed tomography (HRCT) scans of lungs. The experimental CT scans are derived from two public datasets (Sliver 07 and a Chinese local dataset). Experimental results show that the proposed method can precisely and efficiently detect the organs. This method consumes 38 s/slice for liver segmentation. The Dice coefficient of the liver segmentation results reaches to 97.43%. For lung segmentation, the Dice coefficient is 97.93%. This finding demonstrates that the proposed framework is a favorable method for lung segmentation of HRCT scans.

Automatic segmentation of liver tumors from multiphase contrast-enhanced CT images based on FCNs.

This paper presents a novel, fully automatic approach based on a fully convolutional network (FCN) for segmenting liver tumors from CT images. Specifically, we designed a multi-channel fully convolutional network (MC-FCN) to segment liver tumors from multiphase contrast-enhanced CT images. Because each phase of contrast-enhanced data provides distinct information on pathological features, we trained one network for each phase of the CT images and fused their high-layer features together. The proposed approach was validated on CT images taken from two databases: 3Dircadb and JDRD. In the case of 3Dircadb, using the FCN, the mean ratios of the volumetric overlap error (VOE), relative volume difference (RVD), average symmetric surface distance (ASD), root mean square symmetric surface distance (RMSD) and maximum symmetric surface distance (MSSD) were 15.6±4.3%, 5.8±3.5%, 2.0±0.9%, 2.9±1.5mm, 7.1±6.2mm, respectively. For JDRD, using the MC-FCN, the mean ratios of VOE, RVD, ASD, RMSD, and MSSD were 8.1±4.5%, 1.7±1.0%, 1.5±0.7%, 2.0±1.2mm, 5.2±6.4mm, respectively. The test results demonstrate that the MC-FCN model provides greater accuracy and robustness than previous methods.

Clinically isolated enterovirus A71 subgenogroup C4 strain with lethal pathogenicity in 14-day-old mice and the application as an EV-A71 mouse infection model.

The Enterovirus A71 (EV-A71) subgenogroup C4 is prevalent in China. EV-A71 causes hand, foot and mouth disease (HFMD) in children and may lead to severe neurological diseases. The development of antiviral and protective vaccines against EV-A71 is significantly hindered by the lack of suitable animal models to recapitulate human neurological symptoms. In this study, GZ-CII, a highly virulent EV-A71 subgenogroup C4 strain, was isolated from hospitalized children with HFMD. Intraperitoneal infections of GZ-CII resulted in progressive neurological disease in mice as old as 14 days. Administration of an inactivated EV-A71 vaccine or an anti-EV-A71 immune serum protected the mice against the GZ-CII infection. This demonstrated that a mouse model with EV-A71 GZ-CII could be used to evaluate potential vaccine candidates and therapeutics for subgenogroup C4. Comparing the genome sequence of GZ-CII with that of the avirulent EV-A71 subgenogroup C4 strain revealed unique mutations in GZ-CII. When mutation VP2-K149I was introduced into the nonpathogenic EV-A71 subgenogroup C4 strain, the variant similar to GZ-CII significantly increased viral replication and virulence in mice. These results indicated that the VP2-K149I mutation played an important role in enhancing the virulence of the EV-A71 subgenogroup C4 strain in mice, and that mice infected with the GZ-CII strain are a promising model for evaluating vaccines and therapeutics against the EV-A71 subgenogroup C4.

Human Enterovirus 71 Protein Displayed on the Surface of Saccharomyces cerevisiae as an Oral Vaccine.

Human enterovirus 71 (EV-A71), a major agent of hand, foot, and mouth disease, has become an important public health issue in recent years. No effective antiviral or vaccines against EV-A71 infection are currently available. EV-A71 infection intrudes bodies through the gastric mucosal surface and it is necessary to enhance mucosal immune response to protect children from these pathogens. Recently, the majority of EV-A71 vaccine candidates have been developed for parenteral immunization. However, parenteral vaccine candidates often induce poor mucosal responses. On the other hand, oral vaccines could induce effective mucosal and systemic immunity, and could be easily and safely administered. Thus, proper oral vaccines have attached more interest compared with parenteral vaccine. In this study, the major immunogenic capsid protein of EV-A71 was displayed on the surface of Saccharomyces cerevisiae. Oral immunization of mice with surface-displayed VP1 S. cerevisiae induced systemic humoral and mucosal immune responses, including virus-neutralizing titers, VP1-specific antibody, and the induction of Th1 immune responses in the spleen. Furthermore, oral immunization of mother mice with surface-displayed VP1 S. cerevisiae conferred protection to neonatal mice against the lethal EV-A71 infection. Furthermore, we observed that multiple boost immunization as well as higher immunization dosage could induce higher EV-A71-specific immune response. Our results demonstrated that surface-displayed VP1 S. cerevisiae could be used as potential oral vaccine against EV-A71 infection.

[Treatment of high-energy tibia plateau injury with half-ring external fixation combined with minimum internal fixation].

OBJECTIVE: To evaluate the effect of less invasive surgical treatment for high-energy tibia plateau injury with half-ring external fixation combined with minimum internal fixation. METHODS: From January, 2003 to May,2006, 16 cases of high-energy tibia plateau fracture were treated with half-ring external fixation combined with minimum internal fixation including 10 cases of type V and 6 cases of type VI according to Schatzker's classification. The average age of the patients was 42.4 years (range 25 to 50 years). RESULTS: All patients were followed for an average of 16 months (range 5 to 27 months). All the fractures healed after an average time of 3.5 months. Two patients developed infections of the pin holes. According to the criteria of Rasmussen, excellent results were achieved in 10, good results in 4 cases, moderate in 2, and poor in none. CONCLUSION: Half-ring external fixation combined with minimum internal fixation can be ideal for treatment of complex tibia plateau fracture.

[Treatment of complex bone nonunion with external skeletal fixation].

OBJECTIVES: To summarize the experience in the treatment of 112 cases of complex bone nonunion from 1982 to 1999 in our department and introduce the technique of external skeletal fixation. METHODS: The two fragment ends of all cases were fixed under pressure with half-ring sulcated external skeletal fixator. Those cases complicated by bone defect or limb shortening were operated on with epiphysiotomy to restore the length of the limb in the period of compressive fixation or after the occurrence of bone union according to the condition of complicated infection and the length of the limb shortened. RESULTS: The nonunion of the 112 cases was united eventually. The infection in 34 cases was eradicated. Bone union in cases without infection took 3 approximately 7 months (average 5.2 months) and in cases with infection took 5 approximately 11 months (average 5.5 months). The length of the limb in 11 cases with bone defect was restored in the same period of compressive external fixation and another 8 cases achieved after bone union. The length between the injured and healthy limbs was balanced. CONCLUSIONS: When external skeletal fixation is employed to treat those troublesome cases of bone nonunion, the pins for fixation are inserted in sites far from the lesions and the non-united fragment ends are exposed only in the area without scars. Consequently, there is little interference with the blood circulation and the osteogenic potency of the fragment ends. The sclerotic bone tissue is not excised, the marrow cavity is not chased to be open and the fragment ends are only moderately modified. As a result, the stability of fixation is increased and further shortening of the limb avoided. External skeletal fixation using small pins with cross penetration results in plastic fixation and promotes bone healing. Bone lengthening with epiphysiotomy can restore the balance of the limbs.