Enhancing antitumor efficacy of oncolytic virus M1 via albendazole-sustained CD8+ T cell activation.

The immune response plays a crucial role in the functionality of oncolytic viruses. In this study, Albendazole, an antihelminthic drug known to modulate the immune checkpoint PD-L1, was combined with the oncolytic virus M1 (OVM1) to treat mice with either prostate cancer (RM-1) or glioma (GL261) tumors. This combination therapy enhanced anti-tumor effects in immunocompetent mice, but not in immunodeficient ones, without increasing OVM1 replication. Instead, it led to an increase in the number of CD8+ T cells within the tumor, downregulated the expression of PD1 on CD8+ T cells, and upregulated activation markers such as Ki67, CD44, and CD69 and the secretion of cytotoxic factors including interferon (IFN)-γ, granzyme B, and tumor necrosis factor (TNF)-α. Consistently, it enhanced the in vitro tumor-killing activity of lymphocytes from tumor-draining lymph nodes or spleens. The synergistic effect of Albendazole on OVM1 was abolished by depleting CD8+ T cells, suggesting a CD8+ T cell-dependent mechanism. In addition, Albendazole and OVM1 therapy increased CTLA4 expression in the spleen, and the addition of CTLA4 antibodies further enhanced the anti-tumor efficacy in vivo. In summary, Albendazole can act synergistically with oncolytic viruses via CD8+ T cell activation, and the Albendazole/OVM1 combination can overcome resistance to CTLA4-based immune checkpoint blockade therapy.

SBAS-InSAR Based Deformation Monitoring of Tailings Dam: The Case Study of the Dexing Copper Mine No.4 Tailings Dam.

The No.4 tailings pond of the Dexing Copper Mine is the second largest in Asia. The tailing pond is a dangerous source of man-made debris flow with high potential energy. In view of the lack of effective and low-cost global safety monitoring means in this region, in this paper, the time-series InSAR technology is innovatively introduced to monitor the deformation of tailings dam and significant key findings are obtained. First, the surface deformation information of the tailings pond and its surrounding areas was extracted by using SBAS-InSAR technology and Sentinel-1A data. Second, the cause of deformation is explored by analyzing the deformation rate, deformation accumulation, and three typical deformation rate profiles of the representative observation points on the dam body. Finally, the power function model is used to predict the typical deformation observation points. The results of this paper indicated that: (1) the surface deformation of the tailings dam can be categorized into two directions: the upper portion of the dam moving away from the satellite along the Line of Sight (LOS) at a rate of -40 mm/yr, whereas the bottom portion approaching the satellite along the LOS at a rate of 8 mm/yr; (2) the deformation of the dam body is mainly affected by the inventory deposits and the construction materials of the dam body; (3) according to the current trend, deformation of two typical observation points in the LOS direction will reach the cumulative deformation of 80 mm and -360 mm respectively. The research results can provide data support for safety management of No.4 tailings dam in the Dexing Copper Mine, and provide a method reference for monitoring other similar tailings dams.

TUBB2B facilitates progression of hepatocellular carcinoma by regulating cholesterol metabolism through targeting HNF4A/CYP27A1.

Cholesterol metabolism plays a critical role in the progression of hepatocellular carcinoma (HCC), but it is not clear how cholesterol metabolism is regulated. The tubulin beta class I genes (TUBBs) are associated with the prognosis of many different cancers. To confirm the function of TUBBs in HCC, the Kaplan-Meier method and Cox analyses were performed using TCGA and GSE14520 datasets. A higher expression of TUBB2B is an independent prognostic factor for shorter over survival in HCC patients. Deletion of TUBB2B in hepatocytes inhibits proliferation and promotes tumor cell apoptosis, while over-expression of TUBB2B has the opposite function. This result was confirmed in a mouse xenograft tumor model. Mechanistically, TUBB2B induces the expression of CYP27A1, an enzyme responsible for the conversion of cholesterol to 27-hydroxycholesterol, which leads to the up-regulation of cholesterol and the progression of HCC. In addition, TUBB2B regulates CYP27A1 via human hepatocyte nuclear factor 4alpha (HNF4A). These findings indicated that TUBB2B functions as an oncogene in HCC, and plays a role in promoting cell proliferation and anti-apoptosis through targeting HNF4A/CYP27A1/cholesterol.

Differential regulation of H3K9/H3K14 acetylation by small molecules drives neuron-fate-induction of glioma cell.

Differentiation therapy using small molecules is a promising strategy for improving the prognosis of glioblastoma (GBM). Histone acetylation plays an important role in cell fate determination. Nevertheless, whether histone acetylation in specific sites determines GBM cells fate remains to be explored. Through screening from a 349 small molecule-library, we identified that histone deacetylase inhibitor (HDACi) MS-275 synergized with 8-CPT-cAMP was able to transdifferentiate U87MG GBM cells into neuron-like cells, which were characterized by cell cycle arrest, rich neuron biomarkers, and typical neuron electrophysiology. Intriguingly, acetylation tags of histone 3 at lysine 9 (H3K9ac) were decreased in the promoter of multiple oncogenes and cell cycle genes, while ones of H3K9ac and histone 3 at lysine 14 (H3K14ac) were increased in the promoter of neuron-specific genes. We then compiled a list of genes controlled by H3K9ac and H3K14ac, and proved that it is a good predictive power for pathologic grading and survival prediction. Moreover, cAMP agonist combined with HDACi also induced glioma stem cells (GSCs) to differentiate into neuron-like cells through the regulation of H3K9ac/K14ac, indicating that combined induction has the potential for recurrence-preventive application. Furthermore, the combination of cAMP activator plus HDACi significantly repressed the tumor growth in a subcutaneous GSC-derived tumor model, and temozolomide cooperated with the differentiation-inducing combination to prolong the survival in an orthotopic GSC-derived tumor model. These findings highlight epigenetic reprogramming through H3K9ac and H3K14ac as a novel approach for driving neuron-fate-induction of GBM cells.

Translation and psychometric evaluation of a scale to measure the fear of activity in Chinese patients with coronary artery disease.

AIM: To translate and test the psychometric properties of a Chinese version scale to measure the Fear of Activity in patients with Coronary Artery Disease. DESIGN: A cross-sectional design. METHODS: The translation of the scale to measure Fear of Activity in Patients with Coronary Artery Disease included three steps, forward-back translation, expert discussion and pilot survey. The internal consistency and test-retest reliability were used to assess the reliability of the Chinese version scale of the Fear of Activity. Content, construct, criterion, and known-group validity of the scale were also evaluated. DATA SOURCES: A total of 275 patients with Coronary Artery Disease were recruited from a university-affiliated hospital in Guangzhou, southern China. RESULTS: The overall content validity index of the Chinese version scale of the Fear of Activity in Patients with Coronary Artery Disease was 0.90. Principal component analyses extracted four factors with a cumulative variance contribution of 57.5%. There is a strong correlation (r = 0.83) between this scale and Tampa Scale for Kinesiophobia Heart. The total scores of the Chinese version scale of the Fear of Activity in female patients were higher than those in male patients with Coronary Artery Disease, indicating that the scale was able to distinguish the differences between low and high score groups. The Internal consistency and test-retest reliability coefficients of the scale were 0.74 and 0.82, respectively. CONCLUSION: The Chinese version scale of the Fear of Activity in Patients with Coronary Artery Disease, which consists of 21 items with four dimensions, is a reliable and valid instrument to evaluate the fear of activity in patients with Coronary Artery Disease. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: The Chinese version scale of the Fear of Activity in Patients with Coronary Artery Disease can be used to assess the levels of fear of activity in patients with Coronary Artery Disease and explores the factors that influence fear of activity in the population. IMPACT: This study translates and confirms the psychometric properties of the Chinese version scale of the Fear of Activity in Patients with Coronary Artery Disease in China. It is useful in both research and clinical fields to explore the fear of activity and its associated factors in patients with Coronary Artery Disease. REPORTING METHOD: The study design followed the guideline of Strengthening the Reporting of Observational Studies in Epidemiology statement. PATIENT OR PUBLIC CONTRIBUTION: Patients in a university-affiliated hospital participated in this study and contributed to data collection.

Disruption of ß-catenin-mediated negative feedback reinforces cAMP-induced neuronal differentiation in glioma stem cells.

Accumulating evidence supports the existence of glioma stem cells (GSCs) and their critical role in the resistance to conventional treatments for glioblastoma multiforme (GBM). Differentiation therapy represents a promising alternative strategy against GBM by forcing GSCs to exit the cell cycle and reach terminal differentiation. In this study, we demonstrated that cAMP triggered neuronal differentiation and compromised the self-renewal capacity in GSCs. In addition, cAMP induced negative feedback to antagonize the differentiation process by activating ß-catenin pathway. Suppression of ß-catenin signaling synergized with cAMP activators to eliminate GSCs in vitro and extended the survival of animals in vivo. The cAMP/PKA pathway stabilized ß-catenin through direct phosphorylation of the molecule and inhibition of GSK-3ß. The activated ß-catenin translocated into the nucleus and promoted the transcription of APELA and CARD16, which were found to be responsible for the repression of cAMP-induced differentiation in GSCs. Overall, our findings identified a negative feedback mechanism for cAMP-induced differentiation in GSCs and provided potential targets for the reinforcement of differentiation therapy for GBM.

Identification of the receptor of oncolytic virus M1 as a therapeutic predictor for multiple solid tumors.

Over the last decade, oncolytic virus (OV) therapy has shown its promising potential in tumor treatment. The fact that not every patient can benefit from it highlights the importance for defining biomarkers that help predict patients' responses. As particular self-amplifying biotherapeutics, the anti-tumor effects of OVs are highly dependent on the host factors for viral infection and replication. By using weighted gene co-expression network analysis (WGCNA), we found matrix remodeling associated 8 (MXRA8) is positively correlated with the oncolysis induced by oncolytic virus M1 (OVM). Consistently, MXRA8 promotes the oncolytic efficacy of OVM in vitro and in vivo. Moreover, the interaction of MXRA8 and OVM studied by single-particle cryo-electron microscopy (cryo-EM) showed that MXRA8 directly binds to this virus. Therefore, MXRA8 acts as the entry receptor of OVM. Pan-cancer analysis showed that MXRA8 is abundant in most solid tumors and is highly expressed in tumor tissues compared with adjacent normal ones. Further study in cancer cell lines and patient-derived tumor tissues revealed that the tumor selectivity of OVM is predominantly determined by a combinational effect of the cell membrane receptor MXRA8 and the intracellular factor, zinc-finger antiviral protein (ZAP). Taken together, our study may provide a novel dual-biomarker for precision medicine in OVM therapy.

Cytotoxic T lymphocyte-associated protein 4 antibody aggrandizes antitumor immune response of oncolytic virus M1 via targeting regulatory T cells.

Oncolytic virotherapies are perceived as remarkable immunotherapies coming into view and represent highly promising cancer treatments, yet to figure out its specific immune responses and underlying barriers remains critical. Albeit recent studies have demonstrated that oncolytic viruses (OVs) could fine tune tumor microenvironment (TME) to elicit tumor suppression mainly due to effective T-cell responses, the interaction between suppressive T cells and OVs is barely undetermined. Herein, we found that regulatory T cells (Treg cells) were increased in the TME following systemic administration of oncolytic virus M1 along with the higher expression of relative cytokines and chemokines in both mouse RM-1 prostatic carcinoma model and mouse B16F10 melanoma model. Besides, Treg cells expressed high levels of CD25 post-M1 treatment, and its suppressive effect on CD8+ T cells was also elevated. Depletion of Treg cells in M1-treated groups significantly reinforced antitumor effect of M1. Specific targeting of Treg cells using cytotoxic T lymphocyte-associated protein 4 (CTLA-4) antibody (Ab) in combination with M1 treatment elicited a more profound tumor suppression and longer overall survival time than M1 alone in both tumor models. Moreover, CTLA-4 Ab further aggrandized antitumor immune response elicited by M1, including increased infiltration of CD45+ immune cells and CD8+ or CD4+ T lymphocytes, decreased ratio of Treg cells to CD4+ T lymphocytes, the intensified lymphocytotoxicity and elevated secretion of cytotoxic cytokines like interferon-γ, granzyme B and perforin. Therefore, our findings constituted a suggestive evidence that targeting Treg cells in M1-based oncolytic virotherapy may achieve a highly response in clinical cancer research.

Effects of Differentiation and Antisenescence from BMSCs to Hepatocy-Like Cells of the PAAm-IGF-1/TNF-α Biomaterial.

Aiming at the cells' differentiation phenomenon and senescence problem in liver tissue engineering, this work is designed to synthesize three different chargeable polymers (polypropylene acid (PAAc), polyethylene glycol (PEG), and polypropylene amine (PAAm)) coimmobilized by the insulin-like growth factor 1 (IGF-1) and tumor necrosis factor-α (TNF-α). We explore the hepatocyte differentiation effect and the antisenecence effect of PSt-PAAm-IGF-1/TNF-α biomaterial which was selected from the three different chargeable polymers in bone marrow mesenchymal stem cells (BMSCs). Our work will establish a model for studying the biochemical molecular regulation mechanism and signal transduction pathway of cell senescence in liver tissue engineering, which provide a molecular basis for developing biomaterials for liver tissue engineering.

An extended patch-dynamic framework for food chains in fragmented landscapes.

Habitat destruction, a key determinant of species loss, can be characterized by two components, patch loss and patch fragmentation, where the former refers to the reduction in patch availability, and the latter to the division of the remaining patches. Classical metacommunity models have recently explored how food web dynamics respond to patch loss, but the effects of patch fragmentation have largely been overlooked. Here we develop an extended patch-dynamic model that tracks the patch occupancy of the various trophic links subject to colonization-extinction-predation dynamics by incorporating species dispersal with patch connectivity. We found that, in a simple food chain, species at higher trophic level become extinct sooner with increasing patch loss and fragmentation due to the constraint in resource availability, confirming the trophic rank hypothesis. Yet, effects of fragmentation on species occupancy are largely determined by patch loss, with maximal fragmentation effects occurring at intermediate patch loss. Compared to the spatially explicit simulations that we also performed, the current model with pair approximation generates similar community patterns especially in spatially clustered landscapes. Overall, our extended framework can be applied to model more complex food webs in fragmented landscapes, broadening the scope of existing metacommunity theory.