A Logic of East and West

We propose a logic of east and west (LEW) for points in 1D Euclidean space. It formalises primitive direction relations: east (E), west (W) and indeterminate east/west (Iew). It has a parameter τ ∈ ℕ&gt;1, which is referred to as the level of indeterminacy in directions. For every τ ∈ ℕ&gt;1, we provide a sound and complete axiomatisation of LEW, and prove that its satisfiability problem is NP-complete. In addition, we show that the finite axiomatisability of LEW depends on τ: if τ = 2 or τ = 3, then there exists a finite sound and complete axiomatisation; if τ &gt; 3, then the logic is not finitely axiomatisable. LEW can be easily extended to higher-dimensional Euclidean spaces. Extending LEW to 2D Euclidean space makes it suitable for reasoning about not perfectly aligned representations of the same spatial objects in different datasets, for example, in crowd-sourced digital maps.</p

A radiomics nomogram for predicting cytokeratin 19–positive hepatocellular carcinoma: a two-center study

ObjectivesWe aimed to construct and validate a radiomics-based nomogram model derived from gadoxetic acid–enhanced magnetic resonance (MR) images to predict cytokeratin (CK) 19–positive (+) hepatocellular carcinoma (HCC) and patients’ prognosis.MethodsA two-center and time-independent cohort of 311 patients were retrospectively enrolled (training cohort, n = 168; internal validation cohort, n = 72; external validation cohort, n = 71). A total of 2286 radiomic features were extracted from multisequence MR images with the uAI Research Portal (uRP), and a radiomic feature model was established. A combined model was established by incorporating the clinic-radiological features and the fusion radiomics signature using logistic regression analysis. Receiver operating characteristic curve (ROC) was used to evaluate the predictive efficacy of these models. Kaplan–Meier survival analysis was used to assess 1-year and 2-year progression-free survival (PFS) and overall survival (OS) in the cohort.ResultsBy combining radiomic features extracted in DWI phase, arterial phase, venous and delay phase, the fusion radiomics signature achieved AUCs of 0.865, 0.824, and 0.781 in the training, internal, and external validation cohorts. The final combined clinic-radiological model showed higher AUC values in the three datasets compared with the fusion radiomics model. The nomogram based on the combined model showed satisfactory prediction performance in the training (C-index, 0.914), internal (C-index, 0.855), and external validation (C-index, 0.795) cohort. The 1-year and 2-year PFS and OS of the patients in the CK19+ group were 76% and 73%, and 78% and 68%, respectively. The 1-year and 2-year PFS and OS of the patients in the CK19-negative (−) group were 81% and 77%, and 80% and 74%, respectively. Kaplan–Meier survival analysis showed no significant differences in 1-year PFS and OS between the groups (P = 0.273 and 0.290), but it did show differences in 2-year PFS and OS between the groups (P = 0.032 and 0.040). Both PFS and OS were lower in CK19+ patients.ConclusionThe combined model based on clinic-radiological radiomics features can be used for predicting CK19+ HCC noninvasively to assist in the development of personalized treatment

Prime–boost vaccination with plasmid and adenovirus gene vaccines control HER2/neu(+ )metastatic breast cancer in mice

INTRODUCTION: Once metastasis has occurred, the possibility of completely curing breast cancer is unlikely, particularly for the 30 to 40% of cancers overexpressing the gene for HER2/neu. A vaccine targeting p185, the protein product of the HER2/neu gene, could have therapeutic application by controlling the growth and metastasis of highly aggressive HER2/neu(+ )cells. The purpose of this study was to determine the effectiveness of two gene vaccines targeting HER2/neu in preventive and therapeutic tumor models. METHODS: The mouse breast cancer cell line A2L2, which expresses the gene for rat HER2/neu and hence p185, was injected into the mammary fat pad of mice as a model of solid tumor growth or was injected intravenously as a model of lung metastasis. SINCP-neu, a plasmid containing Sindbis virus genes and the gene for rat HER2/neu, and Adeno-neu, an E1,E2a-deleted adenovirus also containing the gene for rat HER2/neu, were tested as preventive and therapeutic vaccines. RESULTS: Vaccination with SINCP-neu or Adeno-neu before tumor challenge with A2L2 cells significantly inhibited the growth of the cells injected into the mammary fat or intravenously. Vaccination 2 days after tumor challenge with either vaccine was ineffective in both tumor models. However, therapeutic vaccination in a prime–boost protocol with SINCP-neu followed by Adeno-neu significantly prolonged the overall survival rate of mice injected intravenously with the tumor cells. Naive mice vaccinated using the same prime–boost protocol demonstrated a strong serum immunoglobulin G response and p185-specific cellular immunity, as shown by the results of ELISPOT (enzyme-linked immunospot) analysis for IFNγ. CONCLUSION: We report herein that vaccination of mice with a plasmid gene vaccine and an adenovirus gene vaccine, each containing the gene for HER2/neu, prevented growth of a HER2/neu-expressing breast cancer cell line injected into the mammary fat pad or intravenously. Sequential administration of the vaccines in a prime–boost protocol was therapeutically effective when tumor cells were injected intravenously before the vaccination. The vaccines induced high levels of both cellular and humoral immunity as determined by in vitro assessment. These findings indicate that clinical evaluation of these vaccines, particularly when used sequentially in a prime–boost protocol, is justified

Adenovirus with DNA Packaging Gene Mutations Increased Virus Release

Adenoviruses (Ads) have been extensively manipulated for the development of cancer selective replication, leading to cancer cell death or oncolysis. Clinical studies using E1-modified oncolytic Ads have shown that this therapeutic platform was safe, but with limited efficacy, indicating the necessity of targeting other viral genes for manipulation. To improve the therapeutic efficacy of oncolytic Ads, we treated the entire Ad genome repeatedly with UV-light and have isolated AdUV which efficiently lyses cancer cells as reported previously (Wechman, S. L. et al. Development of an Oncolytic Adenovirus with Enhanced Spread Ability through Repeated UV Irradiation and Cancer Selection. Viruses 2016, 8, 6). In this report, we show that no mutations were observed in the early genes (E1 or E4) of AdUV while several mutations were observed within the Ad late genes which have structural or viral DNA packaging functions. This study also reported the increased release of AdUV from cancer cells. In this study, we found that AdUV inhibits tumor growth following intratumoral injection. These results indicate the potentially significant role of the viral late genes, in particular the DNA packaging genes, to enhance Ad oncolysis

Molecular basis for viral selective replication in cancer cells: activation of CDK2 by adenovirus-induced cyclin E.

Adenoviruses (Ads) with deletion of E1b55K preferentially replicate in cancer cells and have been used in cancer therapies. We have previously shown that Ad E1B55K protein is involved in induction of cyclin E for Ad replication, but this E1B55K function is not required in cancer cells in which deregulation of cyclin E is frequently observed. In this study, we investigated the interaction of cyclin E and CDK2 in Ad-infected cells. Ad infection significantly increased the large form of cyclin E (cyclin EL), promoted cyclin E/CDK2 complex formation and increased CDK2 phosphorylation at the T160 site. Activated CDK2 caused pRb phosphorylation at the S612 site. Repression of CDK2 activity with the chemical inhibitor roscovitine or with specific small interfering RNAs significantly decreased pRb phosphorylation, with concomitant repression of viral replication. Our results suggest that Ad-induced cyclin E activates CDK2 that targets the transcriptional repressor pRb to generate a cellular environment for viral productive replication. This study reveals a new molecular basis for oncolytic replication of E1b-deleted Ads and will aid in the development of new strategies for Ad oncolytic virotherapies

Oncolytic Replication of E1b-Deleted Adenoviruses

Various viruses have been studied and developed for oncolytic virotherapies. In virotherapy, a relatively small amount of viruses used in an intratumoral injection preferentially replicate in and lyse cancer cells, leading to the release of amplified viral particles that spread the infection to the surrounding tumor cells and reduce the tumor mass. Adenoviruses (Ads) are most commonly used for oncolytic virotherapy due to their infection efficacy, high titer production, safety, easy genetic modification, and well-studied replication characteristics. Ads with deletion of E1b55K preferentially replicate in and destroy cancer cells and have been used in multiple clinical trials. H101, one of the E1b55K-deleted Ads, has been used for the treatment of late-stage cancers as the first approved virotherapy agent. However, the mechanism of selective replication of E1b-deleted Ads in cancer cells is still not well characterized. This review will focus on three potential molecular mechanisms of oncolytic replication of E1b55K-deleted Ads. These mechanisms are based upon the functions of the viral E1B55K protein that are associated with p53 inhibition, late viralmRNAexport, and cell cycle disruption

Spontaneous Activity Associated with Delusions of Schizophrenia in the Left Medial Superior Frontal Gyrus: A Resting-State fMRI Study.

Delusions of schizophrenia have been found to be associated with alterations of some brain regions in structure and task-induced activation. However, the relationship between spontaneously occurring symptoms and spontaneous brain activity remains unclear. In the current study, 14 schizophrenic patients with delusions and 14 healthy controls underwent a resting-state functional magnetic resonance imaging (RS-fMRI) scan. Patients with delusions of schizophrenia patients were rated with Positive and Negative Syndrome Scale (PANSS) and Characteristics of Delusional Rating Scale (CDRS). Regional homogeneity (ReHo) was calculated to measure the local synchronization of the spontaneous activity in a voxel-wise way. A two-sample t-test showed that ReHo of the right anterior cingulate gyrus and left medial superior frontal gyrus were higher in patients, and ReHo of the left superior occipital gyrus was lower, compared to healthy controls. Further, among patients, correlation analysis showed a significant difference between delusion scores of CRDS and ReHo of brain regions. ReHo of the left medial superior frontal gyrus was negatively correlated with patients' CDRS scores but not with delusional PANSS scores. These results suggested that altered local synchronization of spontaneous brain activity may be related to the pathophysiology of delusion in schizophrenia

Effects of CDK2-specific siRNA on Ad replication in A549 human lung cancer cells.

<p>(A) A549 cells were transfected with 200 nM siRNA duplexes targeting different coding regions of CDK2. “Mix” represents the mixture of three pairs of siRNA duplexes (#1, #2 and #3). Cells were harvested at 48 h after transfection. Cell lysates were immunoblotted for CDK2, CDK4, and actin. (B) At 48 h after transfection with CDK2 siRNA duplex or a duplex of non-specific control siRNA, cells were infected with Adwt or Adhz63 at an MOI of 5. CPE was photographed at 48 h p.i. All microscopy is originally at a magnification of x100. (C) The viral titers were determined at 48 h p.i. with the infection unit method. The values are means ± S.D. of independent triplicate. * P<0.05 compared with the control group, Student's <i>t</i>-test. (D) The infected cells were harvested at 24 h after infection. Cell lysates were immunoblotted for CDK2, pCDK2 T160, pRb, p-pRb S612, cyclin E, cyclin EL, and actin. Actin was used as a loading control.</p