Repurposing Anticancer Drugs Targeting the MAPK/ERK Signaling Pathway for the Treatment of Respiratory Virus Infections.

Respiratory virus infections remain a significant challenge to human health and the social economy. The symptoms range from mild rhinitis and nasal congestion to severe lower respiratory tract dysfunction and even mortality. The efficacy of therapeutic drugs targeting respiratory viruses varies, depending upon infection time and the drug resistance engendered by a high frequency of viral genome mutations, necessitating the development of new strategies. The MAPK/ERK pathway that was well delineated in the 1980s represents a classical signaling cascade, essential for cell proliferation, survival, and differentiation. Since this pathway is constitutively activated in many cancers by oncogenes, several drugs inhibiting Raf/MEK/ERK have been developed and currently used in anticancer treatment. Two decades ago, it was reported that viruses such as HIV and influenza viruses could exploit the host cellular MAPK/ERK pathway for their replication. Thus, it would be feasible to repurpose this category of the pathway inhibitors for the treatment of respiratory viral infections. The advantage is that the host genes are not easy to mutate such that the drug resistance rarely occurs during short-period treatment of viruses. Therefore, in this review we will summarize the research progress on the role of the MAPK/ERK pathway in respiratory virus amplification and discuss the potential of the pathway inhibitors (MEK inhibitors) in the treatment of respiratory viral infections.

Sestrin2 in POMC Neurons Modulates Energy Balance and Obesity Related Metabolic Disorders via mTOR Signaling.

Sestrin2 is a highly conserved protein that can be induced under various stress conditions. Researches have revealed that the signaling pathway of the mammalian target of rapamycin (mTOR) is essential in modulating both glucose and lipid metabolism. However, the precise involvement of Sestrin2 in the hypothalamus, particularly in pro-opiomelanocortin (POMC) neurons, in control of energy homeostasis remains uncertain. In this study, we aimed to investigate the functional role of Sestrin2 in hypothalamic POMC neurons in regulation of energy balance, as well as revealing the underlying mechanisms. Therefore, Cre-dependent AAV virus encoding or silencing Sestrin2 was injected into the hypothalamic ARC of Pomc-cre transgenic mice. The results demonstrated that Sestrin2 overexpression in POMC neurons ameliorated high-fat diet (HFD)-induced obesity and increased energy expenditure. Conversely, Sestrin2 deficiency in POMC neurons predisposed mice to HFD induced obesity. Additionally, the thermogenesis of brown adipose tissue and lipolysis of inguinal white adipose tissue were both enhanced by the increased sympathetic nerve innervation in Sestrin2 overexpressed mice. Further exploration revealed that Sestrin2 overexpression inhibited the mTOR signaling pathway in hypothalamic POMC neurons, which may account for the alleviation of systematic metabolic disturbance induced by HFD in these mice. Collectively, our findings demonstrate that Sestrin2 in POMC neurons plays a pivotal role in maintaining energy balance in a context of HFD-induced obesity by inhibiting the mTOR pathway, providing new insights into how hypothalamic neurons respond to nutritional signals to protect against obesity-associated metabolic dysfunction.

Numerical simulation of neural excitation during brain tumor ablation by microsecond pulses.

Replacing monopolar pulse with bipolar pulses of the same energized time can minimize unnecessary neurological side effects during irreversible electroporation (IRE). An improved neural excitation model that considers dynamic conductivity and thermal effects during brain tumor IRE ablation was proposed for the first time in this study. Nerve fiber excitation during IRE ablation by applying a monopolar pulse (100 µs) and a burst of bipolar pulses (energized time of 100 µs with both the sub-pulse length and interphase delay of 1 µs) was investigated. Our results suggest that both thermal effects and dynamic conductivity change the onset time of action potential (AP), and dynamic conductivity also changes the hyperpolarization amplitude. Considering both thermal effects and dynamic conductivity, the hyperpolarization amplitude in nerve fibers located 2 cm from the tumor center was reduced by approximately 23.8 mV and the onset time of AP was delayed by approximately 17.5 µs when a 500 V monopolar pulse was applied. Moreover, bipolar pulses decreased the excitable volume of brain tissue by approximately 68.8 % compared to monopolar pulse. Finally, bipolar pulses cause local excitation with lesser damage to surrounding healthy tissue in complete tumor ablation, demonstrating the potential benefits of bipolar pulses in brain tissue ablation.

Tilted Bragg grating in a glycerol-infiltrated specialty optical fiber for temperature and strain measurements.

In this Letter, we propose an in-line tilted fiber Bragg grating sensor for temperature and strain measurements. The grating is inscribed in a specialty optical fiber using tightly focused femtosecond laser pulses and the line-by-line direct writing method. Beside the central core in which the grating is produced, a hollow channel filled with glycerol aqueous solution significantly improves the sensitivity of the fiber cladding modes due to its high thermo-optic coefficient. We show that the temperature sensitivity of the core mode is 9.8 pm/°C, while the one of the cladding modes is strongly altered and can reach -24.3 pm/°C, in the investigated range of 20-40°C. For the strain measurement, sensitivities of the core mode and the cladding modes are similar (∼0.60 pm/µÎµ) between 0 and 2400 µÎµ. The significative difference of temperature sensitivity between the two modes facilitates the discrimination of the dual parameters in simultaneous measurements.

Considering Joule heating in coupled electroporation and electrodeformation modeling of glioblastoma cells.

Cells exposed to a pulsed electric field undergo electroporation(EP) and electrodeformation(ED) under electric field stress, and a coupled model of EP and ED of glioblastoma(GBM) taking into account Joule heating is proposed. The model geometry is extracted from real cell boundaries, and the effects of Joule heating-induced temperature rise on the EP and ED processes are considered. The results show that the temperature rise will increase the cell's local conductivity, leading to a decrease in the transmembrane potential(TMP). The temperature rise also causes a decrease in the dynamic Young's modulus of the cell membrane, making the cell less resistant to deformation. In addition, GBM cells are more susceptible to EP in the middle portion of the cell and ED in the three tentacle portions under pulsed electric fields, and the cells undergo significant positional shifts. The ED of the nucleus is similar to spherical cells, but the degree of ED is smaller.

Early identification of macrophage activation syndrome secondary to systemic lupus erythematosus with machine learning.

OBJECTIVE: The macrophage activation syndrome (MAS) secondary to systemic lupus erythematosus (SLE) is a severe and life-threatening complication. Early diagnosis of MAS is particularly challenging. In this study, machine learning models and diagnostic scoring card were developed to aid in clinical decision-making using clinical characteristics. METHODS: We retrospectively collected clinical data from 188 patients with either SLE or the MAS secondary to SLE. 13 significant clinical predictor variables were filtered out using the Least Absolute Shrinkage and Selection Operator (LASSO). These variables were subsequently utilized as inputs in five machine learning models. The performance of the models was evaluated using the area under the receiver operating characteristic curve (ROC-AUC), F1 score, and F2 score. To enhance clinical usability, we developed a diagnostic scoring card based on logistic regression (LR) analysis and Chi-Square binning, establishing probability thresholds and stratification for the card. Additionally, this study collected data from four other domestic hospitals for external validation. RESULTS: Among all the machine learning models, the LR model demonstrates the highest level of performance in internal validation, achieving a ROC-AUC of 0.998, an F1 score of 0.96, and an F2 score of 0.952. The score card we constructed identifies the probability threshold at a score of 49, achieving a ROC-AUC of 0.994 and an F2 score of 0.936. The score results were categorized into five groups based on diagnostic probability: extremely low (below 5%), low (5-25%), normal (25-75%), high (75-95%), and extremely high (above 95%). During external validation, the performance evaluation revealed that the Support Vector Machine (SVM) model outperformed other models with an AUC value of 0.947, and the scorecard model has an AUC of 0.915. Additionally, we have established an online assessment system for early identification of MAS secondary to SLE. CONCLUSION: Machine learning models can significantly improve the diagnostic accuracy of MAS secondary to SLE, and the diagnostic scorecard model can facilitate personalized probabilistic predictions of disease occurrence in clinical environments.

Multi-omics and tumor immune microenvironment characterization of a prognostic model based on aging-related genes in melanoma.

Melanoma is a common and fatal cutaneous malignancy with strong invasiveness and high mortality rate. Clinically, elderly melanoma patients tend to exhibit stronger invasion ability and poorer prognosis. Given the heterogeneity of tumors, we analyzed the prognosis and risk assessment of melanoma through aging-related genes rather than age stratification. FOXM1 and CCL4 were identified to be closely associated with melanoma prognosis. Single-cell transcriptome analysis showed that FOXM1 was significantly up-regulated in tumor cells, while CCL4 was markedly elevated in immune cells. A melanoma prognostic model was constructed based on the two independent prognostic factors. This model showed a high accuracy in predicting the mortality of melanoma patients over several years. The patients in low-risk group appeared to have more immune cell infiltration and better immune therapy efficacy. Cellular experiments showed that CCL4 could promote apoptosis of melanoma cells through immune cells, and apoptosis could regulate the expression of FOXM1. In addition, the results of the spatial transcriptome and immunohistochemistry suggested that CCL4 was highly expressed in macrophages and the expression of FOXM1 in melanoma cell was negatively correlated with immune cell infiltration, especially macrophages. Here, we established a novel prognostic model for melanoma, which showed promising predictive performance and may serve as a biomarker for the efficacy of immune checkpoint inhibition therapy in melanoma patients. In addition, we explored the function of two genes in the model in melanoma.

Upregulation of CYR61 by TGF-ß and YAP signaling exerts a counter-suppression of hepatocellular carcinoma.

Transforming growth factor-ß (TGF-ß) and Hippo signaling are two critical pathways engaged in cancer progression by regulating both oncogenes and tumor suppressors, yet how the two pathways coordinately exert their functions in the development of hepatocellular carcinoma (HCC) remains elusive. In this study, we firstly conducted an integrated analysis of public liver cancer databases and our experimental TGF-ß target genes, identifying CYR61 as a pivotal candidate gene relating to HCC development. The expression of CYR61 is downregulated in clinical HCC tissues and cell lines than that in the normal counterparts. Evidence revealed that CYR61 is a direct target gene of TGF-ß in liver cancer cells. In addition, TGF-ß-stimulated Smad2/3 and the Hippo pathway downstream effectors YAP and TEAD4 can form a protein complex on the promoter of CYR61, thereby activating the promoter activity and stimulating CYR61 gene transcription in a collaborative manner. Functionally, depletion of CYR61 enhanced TGF-ß- or YAP-mediated growth and migration of liver cancer cells. Consistently, ectopic expression of CYR61 was capable of impeding TGF-ß- or YAP-induced malignant transformation of HCC cells in vitro and attenuating HCC xenograft growth in nude mice. Finally, transcriptomic analysis indicates that CYR61 can elicit an antitumor program in liver cancer cells. Together, these results add new evidence for the crosstalk between TGF-ß and Hippo signaling and unveil an important tumor suppressor function of CYR61 in liver cancer.

Identification of immune-related genes and integrated analysis of immune-cell infiltration in melanoma.

OBJECTIVE: This study was conducted to screen out immune-related genes in connection with the prognosis of melanoma, construct a prognosis model and explore the relevant mechanisms. METHODS AND MATERIALS: 1973 genes associated with immune system were derived from the Immport database, and RNA-seq data of melanoma and information of patients were searched from the Xena database. Cox univariate analysis, Lasso analysis and Cox multivariate analysis were used to screen out six genes to construct the model. Then the risk scores were estimated for patients based on our constructed prognosis model. Estimate was used to affirm that the model was about immune infiltration, and CIBERSORT was used to screen out immune cells associated with prognosis. TIDE was applied to predict the efficacy of immunotherapy. Finally, GSE65904 and GSE19234 were used to confirm the effectiveness of the model. RESULTS: ADCYAP1R1, GPI, NTS might cause poor prognosis while IFITM1, KIR2DL4, LIF were more likely conductive to prognosis of melanoma patients and a model of prognosis was constructed on the basis of these six genes. The effectiveness of the model has been proven by the ROC curve, and the miRNAs targeting the screened genes were found out, suggesting that the immune system might impact on the prognosis of melanoma by T cell CD8+, T cell CD4+ memory and NK cells. CONCLUSIONS: In this study, the screened six genes were associated with the prognosis of melanoma, which was conductive to clinical prognostic prediction and individualized treatment strategy.

Macrophages regulate healing-associated fibroblasts in diabetic wound.

BACKGROUND: Recovery from a foot ulcer is compromised in a diabetic status, due to the impaired tissue microenvironment that consists of altered inflammation, angiogenesis and fibrosis. Phenotypic alterations in both macrophages and fibroblasts have been detected in the diabetic wound. Recently, a fibroblast subpopulation that expresses high matrix metalloproteinase 1 (MMP1), MMP3, MMP11 and Chitinase-3-Like Protein 1 (CHI3L1) was associated with a successful diabetic wound healing. However, it is not known whether these healing-associated fibroblasts are regulated by macrophages. METHODS AND RESULTS: We used bioinformatic tools to analyze selected public databases on normal and diabetic skin from patients, and identified genes significantly altered in diabetes. In a mouse model for diabetic wound healing, we detected not only a loss of the spatiotemporal changes in interleukin 1ß (IL1ß), IL6, IL10 and vascular endothelial growth factor A (VEGF-A) in wound macrophages, but also a compromised expression of MMP1, MMP3, MMP11, CHI3L1 and VEGF-A in healing-associated wound fibroblasts in a diabetic status. Co-culture with diabetic macrophages significantly reduced the expression of MMP1, MMP3, MMP11, CHI3L1 and VEGF-A in fibroblasts from non-diabetic wound. Co-culture with non-diabetic macrophages or diabetic macrophages supplied with IL6 significantly increased the expression of MMP1, MMP3, MMP11, CHI3L1 and VEGF-A in fibroblasts from diabetic wound. Moreover, macrophage-specific expression of IL6 significantly improved wound healing and angiogenesis in diabetic mice. CONCLUSIONS: Macrophages may induce the activation of wound-healing-associated fibroblasts, while the defective macrophages in diabetes may be corrected with IL6 treatment as a promising therapy for diabetic foot disease.

Metformin Suppresses Stemness of Non-Small-Cell Lung Cancer Induced by Paclitaxel through FOXO3a.

Cancer stem cells (CSCs) play a pivotal role in drug resistance and metastasis. Among the key players, Forkhead box O3a (FOXO3a) acts as a tumor suppressor. This study aimed to unravel the role of FOXO3a in mediating the inhibitory effect of metformin on cancer stemness derived from paclitaxel (PTX)-resistant non-small-cell lung cancer (NSCLC) cells. We showed that CSC-like features were acquired by the chronic induction of resistance to PTX, concurrently with inactivation of FOXO3a. In line with this, knockdown of FOXO3a in PTX-sensitive cells led to changes toward stemness, while overexpression of FOXO3a in PTX-resistant cells mitigated stemness in vitro and remarkably curbed the tumorigenesis of NSCLC/PTX cells in vivo. Furthermore, metformin suppressed the self-renewal ability of PTX-resistant cells, reduced the expression of stemness-related markers (c-MYC, Oct4, Nanog and Notch), and upregulated FOXO3a, events concomitant with the activation of AMP-activated protein kinase (AMPK). All these changes were recapitulated by silencing FOXO3a in PTX-sensitive cells. Intriguingly, the introduction of the AMPK dominant negative mutant offset the inhibitory effect of metformin on the stemness of PTX-resistant cells. In addition, FOXO3a levels were elevated by the treatment of PTX-resistant cells with MK2206 (an Akt inhibitor) and U0126 (a MEK inhibitor). Collectively, our findings indicate that metformin exerts its effect on FOXO3a through the activation of AMPK and the inhibition of protein kinase B (Akt) and MAPK/extracellular signal-regulated kinase (MEK), culminating in the suppression of stemness in paclitaxel-resistant NSCLC cells.

Cellulose-degrading bacteria improve conversion efficiency in the co-digestion of dairy and chicken manure by black soldier fly larvae.

Black soldier fly larvae (BSFL) have potential utility in converting livestock manure into larval biomass as a protein source for livestock feed. However, BSFL have limited ability to convert dairy manure (DM) rich in lignocellulose. Our previous research demonstrated that feeding BSFL with mixtures of 40% dairy manure and 60% chicken manure (DM40) provides a novel strategy for significantly improving their efficiency in converting DM. However, the mechanisms underlying the efficient conversion of DM40 by BSFL are unclear. In this study, we conducted a holistic study on the taxonomic stucture and potential functions of microbiota in the larval gut and manure during the DM and DM40 conversion by BSFL, as well as the effects of BSFL on cellulosic biodegradation and biomass production. Results showed that BSFL can consume cellulose and other nutrients more effectively and harvest more biomass in a shorter conversion cycle in the DM40 system. The larval gut in the DM40 system yielded a higher microbiota complexity. Bacillus and Amphibacillus in the BSFL gut were strongly correlated with the larval cellulose degradation capacity. Furthermore, in vitro screening results for culturable cellulolytic microbes from the larval guts showed that the DM40 system isolated more cellulolytic microbes. A key bacterial strain (DM40L-LB110; Bacillus subtilis) with high cellulase activity from the larval gut of DM40 was validated for potential industrial applications. Therefore, mixing an appropriate proportion of chicken manure into DM increased the abundance of intestinal bacteria (Bacillus and Amphibacillus) producing cellulase and improved the digestion ability (particularly cellulose degradation) of BSFL to cellulose-rich manure through changes in microbial communities composition in intestine. This study reveals the microecological mechanisms underlying the high-efficiency conversion of cellulose-rich manure by BSFL and provide potential applications for the large-scale cellulose-rich wastes conversion by intestinal microbes combined with BSFL.

Immunoglobulin G inhibits glucocorticoid-induced osteoporosis through occupation of FcγRI.

Glucocorticoid-induced osteoporosis (GIOP) is a severe and common complication of long-term usage of glucocorticoids (GCs) and lacks of efficient therapy. Here, we investigated the mechanism of anti-inflammation effect and osteoclastogenesis side effect of GCs and immunoglobulin G (IgG) treatment against GIOP. GCs inhibited SLE IgG-induced inflammation, while IgG inhibited GCs-induced osteoclastogenesis. FcγRI and glucocorticoid receptor (GR) were found directly interacted with each other. GCs and IgG could reduce the expression of FcγRI on macrophages. The deficiency of FcγRI affected osteoclastogenesis by GCs and systemic lupus erythematosus (SLE) IgG-induced inflammation. Also, IgG efficiently reduced GIOP in mice. These data showed that GCs could induce osteoporosis and inhibit IgG-induced inflammation through FcγRI while IgG efficiently suppressed osteoporosis induced by GCs through FcγRI. Hence, our findings may help in developing a feasible therapeutic strategy against osteoporosis, such as GIOP.

Simultaneous synthesis and integration of nanoscale silicon by three-photon laser direct writing.

Typical fabrication processes of compact silicon quantum dot (Si QD) devices or components entail several synthesis, processing and stabilization steps, leading to manufacture and cost inefficiency. Here we report a single step strategy through which nanoscale architectures based on Si QDs can be simultaneously synthesized and integrated in designated positions by using a femtosecond laser (532 nm wavelength and 200 fs pulse duration) direct writing technique. The extreme environments of a femtosecond laser focal spot can result in millisecond synthesis and integration of Si architectures stacked by Si QDs with a unique crystal structure (central hexagonal). This approach involves a three-photon absorption process that can obtain nanoscale Si architecture units with a narrow line width of 450 nm. These Si architectures exhibited bright luminescence peaked at 712 nm. Our strategy can fabricate Si micro/nano-architectures to tightly attach to a designated position in one step, which demonstrates great potential for fabricating active layers of integrated circuit components or other compact devices based on Si QDs.

Direct Laser Writing of Functional QD-Polymer Structure with High Resolution.

Promising direct laser writing (DLW) technology has been introduced to process functional quantum dot (QD)-polymer nanocomposites. The results reveal that after surface modification, the QDs are compatible with the SR399 monomer, and the homogeneous incorporation of QDs is accordingly obtained owing to the copolymerization and resultant cross-linking of QDs into SR399 resin under DLW processing with a laser wavelength (λ) of 532 nm. Moreover, compared with other scholars, we have proved that the surface modified QDs incorporated into the nanocomposites that can be successfully processed via DLW can reach a concentration of up to 150 mg/mL. Owing to the threshold behavior and nonlinear nature of the DLW process, it is feasible to modify the attendant exposure kinetics and design lines of any small size by selecting an appropriate laser power (P) and scan speed (v). The superfine feature size of 65 nm (λ/8) of the red QD-polymer suspended line can be tailored by applying the optimized P of 15 mW and v of 700 µm/s, and the finest green QD-polymer suspended line also reaches 65 nm (λ/8) with the optimized P of 14 mW and v of 250 µm/s used. Moreover, DLW processed QD-polymer structures present strong and homogeneous photoluminescence emission, which shows great potential for application in high-resolution displays, anti-counterfeit technology, and optical encryption. Additionally, the two types of long pass QD-polymer absorptive filters prepared by DLW exhibit superior optical performance with a considerably high transmittance of more than 90% for red QD-polymer block filter, and over 70% for green QD-polymer block filter in the transmittance region, which means that different filters with specific performance can be easily customized to meet the demand of various microdevices. Therefore, the DLW process can be applied to produce geometrically complex micro- and nanoscale functional structures, which will contribute to the development of advanced optoelectronic devices.

Tea domain transcription factor TEAD4 mitigates TGF-ß signaling and hepatocellular carcinoma progression independently of YAP.

Tea domain transcription factor 4 (TEAD4) plays a pivotal role in tissue development and homeostasis by interacting with Yes-associated protein (YAP) in response to Hippo signaling inactivation. TEAD4 and YAP can also cooperate with transforming growth factor-ß (TGF-ß)-activated Smad proteins to regulate gene transcription. Yet, it remains unclear whether TEAD4 plays a YAP-independent role in TGF-ß signaling. Here, we unveil a novel tumor suppressive function of TEAD4 in liver cancer via mitigating TGF-ß signaling. Ectopic TEAD4 inhibited TGF-ß-induced signal transduction, Smad transcriptional activity, and target gene transcription, consequently suppressing hepatocellular carcinoma cell proliferation and migration in vitro and xenograft tumor growth in mice. Consistently, depletion of endogenous TEAD4 by siRNAs enhanced TGF-ß signaling in cancer cells. Mechanistically, TEAD4 associates with receptor-regulated Smads (Smad2/3) and Smad4 in the nucleus, thereby impairing the binding of Smad2/3 to the histone acetyltransferase p300. Intriguingly, these negative effects of TEAD4 on TGF-ß/Smad signaling are independent of YAP, as impairing the TEAD4-YAP interaction through point mutagenesis or depletion of YAP and/or its paralog TAZ has little effect. Together, these results unravel a novel function of TEAD4 in fine tuning TGF-ß signaling and liver cancer progression in a YAP-independent manner.

Three-Dimensional Nanolithography with Visible Continuous Wave Laser through Triplet Up-Conversion.

Direct laser writing (DLW) technology usually fabricates micronanostructures based on the principle of two-photon polymerization. However, two-photon polymerization requires high laser intensity which can be achieved by expensive femtosecond lasers. To address the issue, a direct laser writing method has been proposed in this work; it is based on triplet up-conversion which is characterized by its low cost, high precision, multidimensional property, and rapid processing. The feasibility of this method is jointly verified by applying both dynamic modeling and experiments. Based on the obtained results, the low laser intensity fabrication of multidimensional nanostructures is achieved. The minimum line width (∼50 nm) of micronanostructures is reached when the laser intensity is set at 2.5 × 105 W/cm2 along with a processing speed of 150 µm/s. As a result, the direct laser writing method, based on triplet up-conversion, offers a new route to achieve low-intensity and high-precision micronanostructure fabrication.

Phosphorylation of enteroviral 2Apro at Ser/Thr125 benefits its proteolytic activity and viral pathogenesis.

Enteroviral 2A proteinase (2Apro ), a well-established and important viral functional protein, plays a key role in shutting down cellular cap-dependent translation, mainly via its proteolytic activity, and creating optimal conditions for Enterovirus survival. Accumulated data show that viruses take advantage of various signaling cascades for their life cycle; studies performed by us and others have demonstrated that the extracellular signal-regulated kinase (ERK) pathway is essential for enterovirus A71 (EV-A71) and other viruses replication. We recently showed that ERK1/2 is required for the proteolytic activity of viral 2Apro ; however, the mechanism underlying the regulation of 2Apro remains unknown. Here, we demonstrated that the 125th residue Ser125 of EV-A71 2Apro or Thr125 of coxsackievirus B3 2Apro , which is highly conserved in the Enterovirus, was phosphorylated by ERK1/2. Importantly, 2Apro with phosphor-Ser/Thr125 had much stronger proteolytic activity toward eukaryotic initiation factor 4GI and rendered the virus more efficient for multiplication and pathogenesis in hSCARB2 knock-in mice than that in nonphospho-Ser/Thr125A (S/T125A) mutants. Notably, phosphorylation-mimic mutations caused deleterious changes in 2Apro catalytic function (S/T125D/E) and in viral propagation (S125D). Crystal structure simulation analysis showed that Ser125 phosphorylation in EV-A71 2Apro enabled catalytic Cys to adopt an optimal conformation in the catalytic triad His-Asp-Cys, which enhances 2Apro proteolysis. Therefore, we are the first to report Ser/Thr125 phosphorylation of 2Apro increases enteroviral adaptation to the host to ensure enteroviral multiplication, causing pathogenicity. Additionally, weakened viruses containing a S/T125A mutation could be a general strategy to develop attenuated Enterovirus vaccines.

Oncolytic Adenovirus, a New Treatment Strategy for Prostate Cancer.

Prostate cancer is the most common cancer and one of the leading causes of cancer mortality in males. Androgen-deprivation therapy (ADT) is an effective strategy to inhibit tumour growth at early stages. However, 10~50% of cases are estimated to progress to metastatic castration-resistant prostate cancer (mCRPC) which currently lacks effective treatments. Clinically, salvage treatment measures, such as endocrine therapy and chemotherapy, are mostly used for advanced prostate cancer, but their clinical outcomes are not ideal. When the existing clinical therapeutic methods can no longer inhibit the development of advanced prostate cancer, human adenovirus (HAdV)-based gene therapy and viral therapy present promising effects. Pre-clinical studies have shown its powerful oncolytic effect, and clinical studies are ongoing to further verify its effect and safety in prostate cancer treatment. Targeting the prostate by HAdV alone or in combination with radiotherapy and chemotherapy sheds light on patients with castration-resistant and advanced prostate cancer. This review summarizes the advantages of oncolytic virus-mediated cancer therapy, strategies of HAdV modification, and existing preclinical and clinical investigations of HAdV-mediated gene therapy to further evaluate the potential of oncolytic adenovirus in prostate cancer treatment.