Optimized rAAV8 targeting acinar KLF4 ameliorates fibrosis in chronic pancreatitis via exosomes-enriched let-7s suppressing pancreatic stellate cells activation.

Chronic pancreatitis (CP) is marked by progressive fibrosis and the activation of pancreatic stellate cells (PSC), accompanied by the destruction of pancreatic parenchyma, leading to the loss of acinar cells (ACs). Few researches explored the mechanism by which damaged ACs (DACs) contribute to PSC activation and pancreatic fibrosis. Currently, there are no effective drugs for curing CP or limiting the progression of pancreatic fibrosis. In this research, co-culture with intact acinar cells (IACs) suppressed PSC activation, while co-culture with DACs did the opposite. Krüppel-like factor 4 (KLF4) was significantly upregulated in DACs and was established as the key molecule that switches ACs from PSC-suppressor to PSC-activator. We revealed the exosomes of IACs contributed to the anti-activated function of IACs-CS on PSC. MiRNome profiling showed that let-7 family is significantly enriched in IACs-derived exosomes (>30% miRNome), which partially mediates IACs' suppressive impacts on PSC. Furthermore, it has been observed that the enrichment of let-7 in exosomes was influenced by the expression level of KLF4. Mechanistic studies demonstrated that KLF4 in ACs upregulated Lin28A, thereby decreasing let-7s levels in ACs-derived exosomes, and thus promoting PSC activation. We utilized an adeno-associated virus specifically targeting KLF4 in ACs (shKLF4-pAAV) to suppress PSC activation in CP, resulting in reduced pancreatic fibrosis. IACs-derived exosomes hold potential as potent weapons against PSC activation via let-7s, while activated KLF4/Lin28A signaling in DACs diminished such functions. ShKLF4-pAAV holds promise as a novel therapeutic approach for CP.

The important role of whole-process computed tomography guidance for percutaneous gastrostomy in esophageal cancer patients who are unsuitable for or have had unsuccessful attempts with endoscopic and fluoroscopic gastrostomy.

PURPOSE: To explore the value of clinical application with the whole process computed tomography (CT) guided percutaneous gastrostomy in esophageal tumor patients. MATERIALS AND METHODS: A consecutive series of 32 esophageal tumor patients in whom endoscopic gastrostomy or fluoroscopy guided gastrostomy were considered too dangerous or impossible due to the esophagus complete obstruction, complicate esophageal mediastinal fistula, esophageal trachea fistula or severe heart disease. All of the 32 patients were included in this study from 2 medical center and underwent the gastrostomy under whole process CT guided. RESULTS: All of the gastrostomy procedure was finished successfully under whole process CT guided and the technical success rate was 100%. The average time for each operation was 27 min. No serious complications occurred and the minor complications occurred in 3 patients, including local infection, severe hyperplasia of granulation tissue and tube dislodgment. There were no procedure related deaths. CONCLUSION: The technical success rate of whole process CT guided percutaneous gastrostomy is high and the complication is low. This technique can be used feasible and effectively in some special patients.

Decoupling livestock and poultry pollution emissions from industrial development: A step towards reducing environmental emissions.

China has implemented policies like Leading areas for Agricultural Green Development (LAGD) to mitigate livestock and poultry farming pollution while promoting industry growth. However, it remains uncertain whether LAGDs have successfully balanced emission reduction with stable development. This study examines 165 LAGDs to analyze changes in emissions, assess the decoupling of emission reduction from output value, and identify influencing factors. Findings reveal that emissions from livestock and poultry in LAGDs initially increased and then decreased between 2010 and 2019. Cattle were responsible for over 40% of fecal emissions, and pigs for more than 20%. Additionally, pigs contributed to over 61% of urine emissions. From 2010 to 2014, increases in chemical oxygen demand were mainly due to pigs and cattle. Total nitrogen levels were significantly impacted by cattle, while pigs were affected by total phosphorus. From 2014 to 2019, reductions in emissions were largely attributed to a decrease in pig-related pollutants. The decoupling status shifted from strong to weak and then back to strong between 2014 and 2019. Production efficiency played a crucial role in reducing emissions, while changes in industrial structure moved from supporting to hindering this reduction. Economic development was a primary factor in driving these changes. Standard emissions in Chinese regions showed a rising and then declining trend from 2010 to 2019. The Northeast and Northwest regions of China demonstrated emission trends that were in sync with the growth in rural income. This study offers insights into the successes and challenges of LAGDs in achieving a balance between reduced emissions and development, using quantitative analysis. The findings are instrumental in informing policies for a sustainable livestock and poultry industry. Recommendations include evaluating coordinated approaches to pollution reduction and industrial growth, setting decoupling goals, designing policies based on influential factors, conducting regional assessments of livestock and poultry demand, and implementing region-specific strategies.

Unraveling the importance of functionally extreme tadpole types to functional diversity: a case study in temperate montane streams.

BACKGROUND: Functional diversity is important to maintain ecosystem functioning. Species with different ecomorphological traits may display distinct functional roles in ecosystems. Accordingly, functionally extreme species are more important as they can exhibit specific strategies. However, little is known about the distribution patterns of functionally extreme species at a local scale and whether the prior extinction of extreme species can cause significant effects on functional diversity. In addition, no empirical studies have been conducted on the microhabitat determinants of extreme species to maintain the functional diversity. RESULTS: This study collected 1470 tadpoles belonging to 6 families and 20 anuran species. These species were subsequently divided into 65 functional entities based on their developmental stages to incorporate intraspecific traits variability. As a result, we detected seven extreme functional entities, accounting for 10.7% of the total number of entities. Moreover, the prior extinction of extreme entities can lead to a significant decrease in functional diversity compared with the random extinction of entities. Microhabitat variables such as conductivity, water depth, and current velocity determined the distribution of extreme entities. CONCLUSION: Although the functionally extreme entities only represented a small proportion of the total number of tadpoles, they played irreplaceable roles in maintaining functional diversity. Their extinction may induce high functional vulnerability in tadpole communities. Therefore, anuran species with extreme tadpole traits need to be projected for amphibian conservation.

Eco-friendly triboelectric nanogenerator based on degradable rape straw powder for monitoring human movement.

Green energy from the surrounding environment has great potential for reducing environmental pollution and sustainable development. Triboelectric nanogenerators (TENGs) are of great interest as they can easily harvest mechanical energy from the environment. Here, we present a triboelectric nanogenerator (RS-TENG) based on rape straw (RS), which was developed from a film composed of waste RS and polyvinyl alcohol (PVA). Due to the high content of carbonyl, hydroxyl and amino acid functional groups in RS, the ability of RS/PVA to lose electrons is increased. The proposed RS-TENG device with a size of 6.25 cm2exhibits open circuit voltage (78 V), short circuit current (5.3µA) performance under uniform external stress at a frequency of 3.5 Hz and 10 N in the cylinder motor. 104.5µW was obtained with a load resistance of 25 MΩ. Results obtained from degradability tests revealed that the RS/PVA film was able to degrade over a period of 30 d (In PBS solution). The RS-TENG produces a significantly high current signal under conditions of finger bending, elbow movements, and foot tapping. Practical tests of the RS-TENG have shown that it is a promising sensing device that will be widely used in the future.

Overcoming resistance to oncolytic virus M1 by targeting PI3K-γ in tumor-associated myeloid cells.

Oncolytic viruses (OVs) have become a category of promising anticancer immunotherapeutic agents over the last decade. However, the fact that many individuals fail to respond to OVs highlights the importance of defining the barely known immunosuppressive mechanisms that lead to treatment resistance. Here we found that the immunosuppression mediated by tumor-associated myeloid cells (TAMCs) directly quenches the antitumor effect of oncolytic virus M1 (OVM). OVM induces myeloid cells to migrate into tumors and strengthens their immunosuppressive phenotypes. Mechanically, tumor cells treated with OVM secrete interleukin-6 (IL-6) to activate the phosphatidylinositol 3-kinase (PI3K)-γ/Akt axis in TAMCs, promoting infiltration of TAMCs and aggravating their inhibition on cytotoxic CD8+ T lymphocytes. Pharmacologically targeting PI3K-γ relieves TAMC-mediated immunosuppression and enhances the efficacy of OVM. Additional treatment with immune checkpoint antibodies eradicates multiple refractory solid tumors and induces potent long-term antitumor immune memory. Our findings indicate that OVM functions as a double-edged sword in antitumor immunity and provide insights into the rationale for liberating T cell-mediated antitumor activity by abolishing TAMC-mediated immunosuppression.

Partial Substitution of Fish Meal with Soy Protein Concentrate on Growth, Liver Health, Intestinal Morphology, and Microbiota in Juvenile Large Yellow Croaker (Larimichthys crocea).

The present study investigated the growth performance, feed utilization, intestinal morphology, and microbiota communities of juvenile large yellow croaker (Larimichthys crocea) fed diets containing different proportions of soy protein concentrate (SPC) (0, 15%, 30%, and 45%, namely FM, SPC15, SPC30, and SPC45) as a substitute for fish meal (FM) for 8 weeks. The weight gain (WG) and specific growth rate (SGR) in fish fed SPC45 were significantly lower than those fed FM and SPC15 but not differ with these fed SPC30. The feed efficiency (FE) and protein efficiency ratio (PER) decreased sharply when the dietary SPC inclusion level was higher than 15%. The activity of alanine aminotransferase (ALT) and expression of alt and aspartate aminotransferase (ast) were significantly higher in fish fed SPC45 than those fed FM. The activity and mRNA expression of acid phosphatase were opposite. The villi height (VH) in distal intestine (DI) showed a significant quadratic response to increasing dietary SPC inclusion levels and was highest in SPC15. The VH in proximal intestine, middle intestine decreased significantly with increasing dietary SPC levels. The 16S rRNA sequences in intestine revealed that fish fed SPC15 had higher bacterial diversity and abundance of Phylum Firmicutes such as order Lactobacillales and order Rhizobiaceae than those fed other diets. Genus vibrio, family Vibrionaceae and order Vibrionales within phylum Proteobacteria were enriched in fish fed FM and SPC30 diets. Tyzzerella and Shewanella that belongs to phylum Firmicutes and Proteobacteria, respectively, were enriched in fish fed SPC45 diet. Our results indicated that SPC replacing more than 30% FM could lead to lower quality diet, retard growth performance, ill health, disordered intestine structure, and microbiota communities. Tyzzerella could be the bacteria indicator of intestinal in large yellow croaker fed low quality diet due to high SPC content. Based on the quadratic regression analysis of WG, the best growth performance could be observed when the replacement of FM with SPC was 9.75%.

Effects of Dietary Fish Meal Replaced by Fish Steak Meal on Growth Performance, Antioxidant Capacity, Intestinal Health and Microflora, Inflammatory Response, and Protein Metabolism of Large Yellow Croaker Larimichthys crocea.

Although fish steak meal (FSM) is a potentially available protein source, its efficiency as a fish meal (FM) substitute remains unclear to date. To this end, this study was carried out to determine the effects of dietary FM replaced by FSM on growth performance, antioxidant capacity, intestinal health and microflora, inflammatory response, and protein metabolism of large yellow croaker. Five isolipidic and isonitrogenous diets were formulated by substituting FM with FSM at levels of 0% (FSM0, control diet), 25% (FSM25), 50% (FSM50), 75% (FSM75), and 100% (FSM100), and were fed to juvenile large yellow croaker for 8 weeks. Compared with the control diet, the replacement of 25% dietary FM with FSM did not markedly alter the weight gain (WG) and specific growth rate (SGR). When the FM substitution level was over 25%, WG and SGR markedly reduced. The intestinal structure observation found that the FSM75 and FSM100 diets markedly decreased villus height, villus width, and muscle thickness of the anterior intestine. The FSM75 and FSM100 diets significantly decreased enzyme activities of amylase (AMS), lipase (LPS), trypsin, catalase (CAT), and total superoxide dismutase (T-SOD) and the total antioxidant capacity (T-AOC), and increased the malondialdehyde (MDA) content in the liver of large yellow croaker. The mRNA expression levels of intestinal barrier and inflammatory response-related genes suggested that the FSM50, FSM75, and FSM100 diets significantly decreased the mRNA abundances of intestinal barrier-related genes and anti-inflammatory response-related genes, and increased the mRNA abundances of proinflammatory gene il-6 in the anterior intestine. The compositions of intestinal microflora displayed that the FSM50, FSM75, and FSM100 diets decreased relative abundances of Firmicutes phylum and increased relative abundances of Proteobacteria phylum. In addition, the results of protein expression levels showed that the phosphorylation level of mammalian target of rapamycin (mTOR) and 4E-binding protein 1 (4E-BP1) in FSM75 and FSM100 groups were markedly reduced. In conclusion, FSM can replace up to 25% dietary FM without compromising the growth performance, intestinal health, and protein metabolism of the large yellow croaker.

[Palliative Care for End-Stage Renal Disease:A Case Report and Literature Review].

Since end-stage renal disease leads to a variety of problems such as disability,reduced quality of life,and mental and psychological disorders,it has become a serious public health problem around the globe.Renal palliative care integrates palliative care philosophy in the care for patients with end-stage renal disease.As a planned,comprehensive,patient-centered care,renal palliative care focuses on the patient's symptoms and needs,aiming to reduce the suffering throughout the course of the disease,including but not limited to end-of-life care.This study reports the palliative care practice for a patient on maintenance dialysis in the Blood Purification Center of Peking Union Medical College Hospital and reviews the present situation of palliative care in end-stage renal disease.

Dual MOF-Derived MoS2 /CdS Photocatalysts with Rich Sulfur Vacancies for Efficient Hydrogen Evolution Reaction.

Cocatalyst plays an important role in efficient charge transfer and separation for photocatalysis. Herein, a MoS2 /CdS photocatalyst with MoS2 as cocatalyst was designed by using Mo-MOF and Cd-MOF as precursors. Due to the existence of rich sulfur vacancies and 1T phase, MoS2 shows strong charge capture and transport ability. The photo-generated electrons on conduction band (CB) can be bound by the sulfur vacancy of CdS and effectively transported to MoS2 through the compact interface between the CdS nanoparticles and 2D large-scale MoS2 . The optimal photocatalyst 1 %MoS2 /CdS exhibited dramatically improved photocatalytic hydrogen production activity, which is 28 times that of pristine CdS and even about 2 times that of 1 %Pt/CdS with same loading amount of noble metal Pt. This work highlights the role of Mo-MOF derived MoS2 with 1T-2H phases as a sustainable and prospective candidate of cocatalyst for improving charge separation and photocatalytic stability of MoS2 /CdS composites.

A chromosome-level genome assembly of Paracymoriza distinctalis (Lepidoptera: Crambidae: Acentropinae).

Paracymoriza distinctalis is a semiaquatic lepidopteran insect, which is of great value for studying the differentiation of the Pyraloidea superfamily. However, the understanding of heredity, evolution, and functional genomics of P. distinctalis are limited by few genome-wide resources. Here, we applied PacBio sequencing and the chromosome capture technique to assemble the first P. distinctalis genome from a single female individual. The genome size is 1.2 Gb with 32 chromosomes and the N50 is 38.91 Mb. Approximately 576.37 Mb, accounting for 48.93% of the genome, was identified as repeats. The genome comprises 39,003 protein-coding genes, 66.56% of which were functionally annotated. Comparative genomics analysis suggested that the common ancestor of P. distinctalis and Chilo suppressalis lived ~83.5 million years ago. This chromosome-level genome assembly work is not only conducive to the understanding of P. distinctalis, but also may promote the study of the genomes of other lepidopteran species.

A Novel Efficient Convolutional Neural Algorithm for Multi-Category Aliasing Hardware Recognition.

When performing robotic automatic sorting and assembly operations of multi-category hardware, there are some problems with the existing convolutional neural network visual recognition algorithms, such as large computing power consumption, low recognition efficiency, and a high rate of missed detection and false detection. A novel efficient convolutional neural algorithm for multi-category aliasing hardware recognition is proposed in this paper. On the basis of SSD, the novel algorithm uses Resnet-50 instead of VGG16 as the backbone feature extraction network, and it integrates ECA-Net and Improved Spatial Attention Block (ISAB): two attention mechanisms to improve the ability of learning and extract target features. Then, we pass the weighted features to extra feature layers to build an improved SSD algorithm. At last, in order to compare the performance difference between the novel algorithm and the existing algorithms, three kinds of hardware with different sizes are chosen to constitute an aliasing scene that can simulate an industrial site, and some comparative experiments have been completed finally. The experimental results show that the novel algorithm has an mAP of 98.20% and FPS of 78, which are better than Faster R-CNN, YOLOv4, YOLOXs, EfficientDet-D1, and original SSD in terms of comprehensive performance. The novel algorithm proposed in this paper can improve the efficiency of robotic sorting and assembly of multi-category hardware.

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.

A Reference chart for clinical biochemical tests of hemolyzed serum samples.

BACKGROUND: Although the effect of hemolysis has been extensively evaluated on clinical biochemical tests, a practical guidance for laboratory staff to rapidly determine whether a hemolyzed blood sample is acceptable and how to interpret the results is lacking. Here, we introduce a chart as a convenient reference for dealing with such samples. METHODS: Serum samples with 0.1%, 0.3%, 1%, 3%, and 10% hemolysis were prepared from sonicated endogenous red blood cells and received 35 wet and 22 dry clinical biochemical tests, respectively. The contributing part in the biochemical test result at each hemolysis condition was derived by subtracting the original test result of this sample with no hemolysis. The net results were used for analyses and preparation of the reference chart. RESULTS: The reference chart displayed the analytically calculated hemolysis interference and related statistical analyses. The chart also provided the color appearance of serum samples at each hemolysis condition for clinical staffs to determine whether a hemolyzed sample could be accepted. CONCLUSION: In clinical laboratories, preparation of such a reference chart is extremely useful in dealing with hemolyzed blood samples for clinical biochemical tests.

Multiple Receptive Field Network (MRF-Net) for Autonomous Underwater Vehicle Fishing Net Detection Using Forward-Looking Sonar Images.

Underwater fishing nets represent a danger faced by autonomous underwater vehicles (AUVs). To avoid irreparable damage to the AUV caused by fishing nets, the AUV needs to be able to identify and locate them autonomously and avoid them in advance. Whether the AUV can avoid fishing nets successfully depends on the accuracy and efficiency of detection. In this paper, we propose an object detection multiple receptive field network (MRF-Net), which is used to recognize and locate fishing nets using forward-looking sonar (FLS) images. The proposed architecture is a center-point-based detector, which uses a novel encoder-decoder structure to extract features and predict the center points and bounding box size. In addition, to reduce the interference of reverberation and speckle noises in the FLS image, we used a series of preprocessing operations to reduce the noises. We trained and tested the network with data collected in the sea using a Gemini 720i multi-beam forward-looking sonar and compared it with state-of-the-art networks for object detection. In order to further prove that our detector can be applied to the actual detection task, we also carried out the experiment of detecting and avoiding fishing nets in real-time in the sea with the embedded single board computer (SBC) module and the NVIDIA Jetson AGX Xavier embedded system of the AUV platform in our lab. The experimental results show that in terms of computational complexity, inference time, and prediction accuracy, MRF-Net is better than state-of-the-art networks. In addition, our fishing net avoidance experiment results indicate that the detection results of MRF-Net can support the accurate operation of the later obstacle avoidance algorithm.

Lonidamine potentiates the oncolytic efficiency of M1 virus independent of hexokinase 2 but via inhibition of antiviral immunity.

BACKGROUND: Viruses are obligate parasites that depend on host cells to provide the energy and molecular precursors necessary for successful infection. The main component of virus-induced metabolic reprogramming is the activation of glycolysis, which provides biomolecular resources for viral replication. However, little is known about the crosstalk between oncolytic viruses and host glycolytic processes. METHODS: A MTT assay was used to detect M1 virus-induced cell killing. Flow cytometry was used to monitor infection of M1 virus expressing the GFP reporter gene. qPCR and western blotting were used to detect gene expression. RNA sequencing was performed to evaluate gene expression under different drug treatments. Scanning electron microscopy was performed to visualize the endoplasmic reticulum (ER). Caspase activity was detected. Last, a mouse xenograft model was established to evaluate the antitumor effect in vivo. Most data were analyzed with a two-tailed Student's t test or one-way ANOVA with Dunnett's test for pairwise comparisons. Tumor volumes were analyzed by repeated measures of ANOVA. The Wilcoxon signed-rank test was used to compare nonnormally distributed data. RESULTS: Here, we showed that the glucose analog 2-deoxy-D-glucose (2-DG) inhibited infection by M1 virus, which we identified as a novel type of oncolytic virus, and decreased its oncolytic effect, indicating the dependence of M1 replication on glycolysis. In contrast, lonidamine, a reported hexokinase 2 (HK2) inhibitor, enhanced the infection and oncolytic effect of M1 virus independent of HK2. Further transcriptomic analysis revealed that downregulation of the antiviral immune response contributes to the lonidamine-mediated potentiation of the infection and oncolytic effect of M1 virus, and that MYC is the key factor in the pool of antiviral immune response factors inhibited by lonidamine. Moreover, lonidamine potentiated the irreversible ER stress-mediated apoptosis induced by M1 virus. Enhancement of M1's oncolytic effect by lonidamine was also identified in vivo. CONCLUSIONS: This research demonstrated the dependence of M1 virus on glycolysis and identified a candidate synergist for M1 virotherapy.

Differential regulatory network-based quantification and prioritization of key genes underlying cancer drug resistance based on time-course RNA-seq data.

Drug resistance is a major cause for the failure of cancer chemotherapy or targeted therapy. However, the molecular regulatory mechanisms controlling the dynamic evolvement of drug resistance remain poorly understood. Thus, it is important to develop methods for identifying key gene regulatory mechanisms of the resistance to specific drugs. In this study, we developed a data-driven computational framework, DryNetMC, using a differential regulatory network-based modeling and characterization strategy to quantify and prioritize key genes underlying cancer drug resistance. The DryNetMC does not only infer gene regulatory networks (GRNs) via an integrated approach, but also characterizes and quantifies dynamical network properties for measuring node importance. We used time-course RNA-seq data from glioma cells treated with dbcAMP (a cAMP activator) as a realistic case to reconstruct the GRNs for sensitive and resistant cells. Based on a novel node importance index that comprehensively quantifies network topology, network entropy and expression dynamics, the top ranked genes were verified to be predictive of the drug sensitivities of different glioma cell lines, in comparison with other existing methods. The proposed method provides a quantitative approach to gain insights into the dynamic adaptation and regulatory mechanisms of cancer drug resistance and sheds light on the design of novel biomarkers or targets for predicting or overcoming drug resistance.

The role of human cytomegalovirus in atherosclerosis: a systematic review.

Atherosclerosis is a progressive vascular disease with increasing morbidity and mortality year by year in modern society. Human cytomegalovirus (HCMV) infection is closely associated with the development of atherosclerosis. HCMV infection may accelerate graft atherosclerosis and the development of transplant vasculopathy in organ transplantation. However, our current understanding of HCMV-associated atherosclerosis remains limited and is mainly based on clinical observations. The underlying mechanism of the involvement of HCMV infection in atherogenesis remains unclear. Here, we summarized current knowledge regarding the multiple influences of HCMV on a diverse range of infected cells, including vascular endothelial cells, vascular smooth muscle cells, monocytes, macrophages, and T cells. In addition, we described potential HCMV-induced molecular mechanisms, such as oxidative stress, endoplasmic reticulum stress, autophagy, lipid metabolism, and miRNA regulation, which are involved in the development of HCMV-associated atherogenesis. Gaining an improved understanding of these mechanisms will facilitate the development of novel and effective therapeutic strategies for the treatment of HCMV-related cardiovascular disease.

Deficiency of the IRE1α-Autophagy Axis Enhances the Antitumor Effects of the Oncolytic Virus M1.

Oncolytic virotherapy is an emerging treatment modality that uses replication-competent viruses to destroy cancer cells. M1 is a naturally occurring alphavirus (Togaviridae) which shows potent oncolytic activities against many cancers. Accumulation of unfolded proteins during virus replication leads to a transcriptional/translational response known as the unfolded protein response (UPR), which might counteract the antitumor effect of the oncolytic virus. In this report, we show that either pharmacological or biological inhibition of IRE1α or PERK, but not ATF6, substantially increases the oncolytic effects of the M1 virus. Moreover, inhibition of IRE1α blocks M1 virus-induced autophagy, which restricts the antitumor effects of the M1 virus through degradation of viral protein, in glioma cells. In addition, IRE1α suppression significantly increases the oncolytic effect of M1 virus in an orthotopic glioma model. From a molecular pathology study, we found that IRE1α is expressed at lower levels in higher-grade gliomas, suggesting greater antitumor efficacy of the oncolytic virus M1. Taken together, these findings illustrate a defensive mechanism of glioma cells against the oncolytic virus M1 and identify possible approaches to enhance the oncolytic viral protein accumulation and the subsequent lysis of tumor cells.IMPORTANCE Although oncolytic virotherapy is showing great promise in clinical applications, not all patients are benefiting. Identifying inhibitory signals in refractory cancer cells for each oncolytic virus would provide a good chance to increase the therapeutic effect. Here we describe that infection with the oncolytic virus M1 triggers the unfolded protein response (UPR) and subsequent autophagy, while blocking the UPR-autophagy axis significantly potentiates the antitumor efficacy of M1 in vitro and in vivo A survey of cancer tissue banks revealed that IRE1α, a key element in the UPR pathway, is commonly downregulated in higher-grade human gliomas, suggesting favorable prospects for the application of M1. Our work provides a potential predictor and target for enhancement of the therapeutic effectiveness of the M1 virus. We predict that the mechanism-based combination therapy will promote cancer virotherapy in the future.