Oxygen Vacancy-Mediated Synthesis of Inter-Atomically Ordered Ultrafine Pt-Alloy Nanoparticles for Enhanced Fuel Cell Performance.

Pt-based intermetallics are expected to be the highly active catalysts for oxygen reduction reaction (ORR) in proton-exchange membrane fuel cells but still face great challenges in controllable synthesis of interatomically ordered and ultrafine intermetallic nanoparticles. Here, we propose an oxygen vacancy-mediated atomic diffusion strategy by mechanical alloying to reduce the energy barrier of the transition from interatomic disordering to ordering, and to resist interparticulate sintering via strong M-O-C bonding. This synthesis results in a nanosized core/shell structure featuring an interatomically ordered PtM core and a Pt shell of two to three atomic layers in thickness and can be extended to the multicomponent PtM (M = Co, FeCo, FeCoNi, FeCoNiGa) systems. The electron enrichment in the Pt outer shell induced by the compressive strain leads to the enhanced antibonding orbital occupation below the Fermi level and accelerated OH* desorption kinetics. The optimized PtCo-O/C-6 catalyst presents excellent ORR activity (mass activity = 1.28 A mgPt-1 at 0.9 ViR-free, peak power densities = 2.38/1.25 W cm-2 in H2-O2/-air) and durability (∼1% activity loss in over 50 h in air condition) in fuel cells at a total Pt loading of 0.1 mgPt cm-2. Furthermore, we establish a systematic correlation to elucidate the formation mechanisms of highly ordered intermetallic catalysts underlying oxygen vacancies. This study provides a general approach for the large-scale production of highly ordered and nanosized Pt-dispersed intermetallic catalysts.

Synergistic Effects of Radical Distributions of Soluble and Insoluble Polymers within Electrospun Nanofibers for an Extending Release of Ferulic Acid.

Polymeric composites for manipulating the sustained release of an encapsulated active ingredient are highly sought after for many practical applications; particularly, water-insoluble polymers and core-shell structures are frequently explored to manipulate the release behaviors of drug molecules over an extended time period. In this study, electrospun core-shell nanostructures were utilized to develop a brand-new strategy to tailor the spatial distributions of both an insoluble polymer (ethylcellulose, EC) and soluble polymer (polyvinylpyrrolidone, PVP) within the nanofibers, thereby manipulating the extended-release behaviors of the loaded active ingredient, ferulic acid (FA). Scanning electron microscopy and transmission electron microscopy assessments revealed that all the prepared nanofibers had a linear morphology without beads or spindles, and those from the coaxial processes had an obvious core-shell structure. X-ray diffraction and attenuated total reflectance Fourier transform infrared spectroscopic tests confirmed that FA had fine compatibility with EC and PVP, and presented in all the nanofibers in an amorphous state. In vitro dissolution tests indicated that the radical distributions of EC (decreasing from shell to core) and PVP (increasing from shell to core) were able to play their important role in manipulating the release behaviors of FA elaborately. On one hand, the core-shell nanofibers F3 had the advantages of homogeneous composite nanofibers F1 with a higher content of EC prepared from the shell solutions to inhibit the initial burst release and provide a longer time period of sustained release. On the other hand, F3 had the advantages of nanofibers F2 with a higher content of PVP prepared from the core solutions to inhibit the negative tailing-off release. The key element was the water permeation rates, controlled by the ratios of soluble and insoluble polymers. The new strategy based on core-shell structure paves a way for developing a wide variety of polymeric composites with heterogeneous distributions for realizing the desired functional performances.

Constructing FeS and ZnS Heterojunction on N,S-Codoped Carbon as Robust Electrocatalyst toward Oxygen Reduction Reaction.

Highly active and cost-efficient electrocatalysts for oxygen reduction reaction (ORR) are significant for developing renewable energy conversion devices. Herein, a nanocomposite Fe/ZnS-SNC electrocatalyst with an FeS and ZnS heterojunction on N,S-codoped carbon has been fabricated via a facile one-step sulfonating of the pre-designed Zn- and Fe-organic frameworks. Benefitting from the electron transfer from FeS to adjacent ZnS at the heterointerfaces, the optimized Fe/ZnS-SNC900 catalyst exhibits excellent ORR performances, featuring the half-wave potentials of 0.94 V and 0.81 V in alkaline and acidic media, respectively, which is competitive with the commercial 20 wt.% Pt/C (0.87 and 0.76 V). The flexible Zn-air battery equipping Fe/ZnS-SNC900 affords a higher open-circuit voltage (1.45 V) and power density of 30.2 mW cm-2. Fuel cells assembled with Fe/ZnS-SNC900 as cathodic catalysts deliver a higher power output of 388.3 and 242.8 mW cm-2 in H2-O2 and -air conditions. This work proposes advanced heterostructured ORR electrocatalysts that effectively promote renewable energy conversions.

Ginsenoside Rg3 Sensitizes Nasopharyngeal Carcinoma Cells to Radiation by Suppressing Epithelial Mesenchymal Transition.

Radioresistance restrains the therapeutic effect of nasopharyngeal carcinoma (NPC). Ginsenoside Rg3 (Rg3), an active pharmaceutical component extracted from ginseng, shows antitumor effects in various cancers. In this study, we aimed to determine whether Rg3 sensitized NPC cells to radiation and to explore the possible mechanisms. Our results revealed that Rg3 increased radiosensitivity in both HNE1 and CNE2 cell lines. Radiation induced epithelial mesenchymal transition (EMT) in NPC cells and Rg3 blocked this effect. In addition, Rg3 attenuated radiation-induced epidermal growth factor receptor (EGFR) nuclear transport and DNA-dependent protein kinase expression. What's more, Rg3 significantly accelerated the apoptosis rates in irradiated NPC cells. In summary, our data suggested that Rg3 sensitized NPC cells to radiation and suppressed radiation-induced EMT. This effect is mediated through restrained EGFR nuclear translocation and increased cell apoptosis. Thus, Rg3 may be a potential radiation sensitizing agent for NPC.

MicroRNA-363-3p, negatively regulated by long non-coding RNA small nucleolar RNA host gene 5, inhibits tumor progression by targeting Aurora kinase A in colorectal cancer.

MicroRNA-363-3p (miR-363-3p), reportedly, exhibits a tumor-suppressive role in human malignancies. Herein, our research was designed to further explain the functions and molecular mechanisms of miR-363-3p in the progression of colorectal cancer (CRC). With in vitro models, this study found that miR-363-3p was markedly under-expressed in CRC tissues and cells, and its overexpression suppressed the viability, migration, and invasion of CRC cells, and promoted cell apoptosis, whereas inhibiting miR-363-3p expression exhibited an opposite role. Additionally, aurora kinase A (AURKA), capable of counteracting the impacts of miR-363-3p on malignant biological behaviors of CRC cells, was identified as a direct target of miR-363-3p. Besides, miR-363-3p was sponged by long non-coding RNA small nucleolar RNA host gene 5 (SNHG5), which suppressed miR-363-3p expression. This research shows that SNHG5/miR-363-3p/AURKA axis partakes in CRC progression.

Fibrinolytic Serine Proteases, Therapeutic Serpins and Inflammation: Fire Dancers and Firestorms.

The making and breaking of clots orchestrated by the thrombotic and thrombolytic serine protease cascades are critical determinants of morbidity and mortality during infection and with vascular or tissue injury. Both the clot forming (thrombotic) and the clot dissolving (thrombolytic or fibrinolytic) cascades are composed of a highly sensitive and complex relationship of sequentially activated serine proteases and their regulatory inhibitors in the circulating blood. The proteases and inhibitors interact continuously throughout all branches of the cardiovascular system in the human body, representing one of the most abundant groups of proteins in the blood. There is an intricate interaction of the coagulation cascades with endothelial cell surface receptors lining the vascular tree, circulating immune cells, platelets and connective tissue encasing the arterial layers. Beyond their role in control of bleeding and clotting, the thrombotic and thrombolytic cascades initiate immune cell responses, representing a front line, "off-the-shelf" system for inducing inflammatory responses. These hemostatic pathways are one of the first response systems after injury with the fibrinolytic cascade being one of the earliest to evolve in primordial immune responses. An equally important contributor and parallel ancient component of these thrombotic and thrombolytic serine protease cascades are the serine protease inhibitors, termed serpins. Serpins are metastable suicide inhibitors with ubiquitous roles in coagulation and fibrinolysis as well as multiple central regulatory pathways throughout the body. Serpins are now known to also modulate the immune response, either via control of thrombotic and thrombolytic cascades or via direct effects on cellular phenotypes, among many other functions. Here we review the co-evolution of the thrombolytic cascade and the immune response in disease and in treatment. We will focus on the relevance of these recent advances in the context of the ongoing COVID-19 pandemic. SARS-CoV-2 is a "respiratory" coronavirus that causes extensive cardiovascular pathogenesis, with microthrombi throughout the vascular tree, resulting in severe and potentially fatal coagulopathies.

A Mouse Model of Acute Liver Injury by Warm, Partial Ischemia-Reperfusion for Testing the Efficacy of Virus-Derived Therapeutics.

Ischemia-reperfusion injury (IRI) drives early and long-term damage to organs as well as compounding damage from acute transplant rejection and surgical trauma. IRI initiates an aggressive and prolonged inflammation leading to tissue injury, organ failure, and death. However, there are few effective therapeutic interventions for IRI. The destructive inflammatory cell activity in IRI is part of an aberrant innate immune response that triggers multiple pathways. Hence, immune-modulating treatments to control pathways triggered by IRI hold great therapeutic potential. Viruses, especially large DNA viruses, have evolved highly effective immune-modulating proteins for the purpose of immune evasion and to protect the virus from the host immune defenses. A number of these immune-modulating proteins have proven therapeutically effective in preclinical models, many with function targeting pathways known to be involved in IRI. The use of virus-derived immune-modulating proteins thus represents a promising source for new treatments to target ischemia-reperfusion injury. Laboratory small animal models of IRI are well established and are able to reproduce many aspects of ischemia-reperfusion injury seen in humans. This chapter will discuss the methods used to perform the IRI procedure in mice, as well as clinically relevant diagnostic tests to evaluate liver injury and approaches for assessing histological damage while testing novel immune modulating protein treatments.

Preclinical Testing of Viral Therapeutic Efficacy in Pristane-Induced Lupus Nephritis and Diffuse Alveolar Hemorrhage Mouse Models.

Systemic lupus erythematosus (SLE) is a multifactorial and heterogeneous autoimmune disease involving multiple organ systems and tissues. Lupus nephritis occurs in approximately 60% of patients with SLE and is the leading cause of morbidity. Diffuse alveolar hemorrhage (DAH) is a rare but very serious complication of SLE with a greater than 50% associated mortality. The etiology of SLE is unclear but has proposed genetic, hormonal, and environmental aspects. Pristane is a saturated terpenoid alkane and has become the most popular laboratory model for inducing lupus in mice. The pristane model of SLE has the capacity to reproduce many components of the human presentation of the disease. Previous studies have demonstrated that virus-derived immune-modulating proteins have the potential to control inflammatory and autoimmune disorders. Serp-1, a 55 kDa secreted and highly glycosylated immune modulator derived from myxoma virus (MYXV), has potent immunomodulatory activity in models of vasculitis, viral sepsis, collagen-induced arthritis, and transplant rejection. This chapter describes the mouse preclinical pristane lupus model as a method to examine virus-derived protein efficacy for treating autoimmune diseases and specifically lupus nephritis and DAH.

Kidney Subcapsular Allograft Transplants as a Model to Test Virus-Derived Chemokine-Modulating Proteins as Therapeutics.

Solid tissue transplant is a growing medical need that is further complicated by a limited donor organ supply. Acute and chronic rejection occurs in nearly all transplants and reduces long-term graft survival, thus increasing the need for repeat transplantation. Viruses have evolved highly adapted responses designed to evade the host's immune defenses. Immunomodulatory proteins derived from viruses represent a novel class of potential therapeutics that are under investigation as biologics to attenuate immune-mediated rejection and damage. These immune-modulating proteins have the potential to reduce the need for traditional posttransplant immune suppressants and improve graft survival. The myxoma virus-derived protein M-T7 is a promising biologic that targets chemokine and glycosaminoglycan pathways central to kidney transplant rejection. Orthotopic transplantations in mice are prohibitively difficult and costly and require a highly trained microsurgeon to successfully perform the procedure. Here we describe a kidney-to-kidney subcapsular transplant model as a practical and simple method for studying transplant rejection, a model that requires fewer mice. One kidney can be used as a donor for transplants into six or more recipient mice. Using this model there is lower morbidity, pain, and mortality for the mice. Subcapsular kidney transplantation provides a first step approach to testing virus-derived proteins as new potential immune-modulating therapeutics to reduce transplant rejection and inflammation.

PEGylated Serp-1 Markedly Reduces Pristane-Induced Experimental Diffuse Alveolar Hemorrhage, Altering uPAR Distribution, and Macrophage Invasion.

Diffuse alveolar hemorrhage (DAH) is one of the most serious clinical complications of systemic lupus erythematosus (SLE). The prevalence of DAH is reported to range from 1 to 5%, but while DAH is considered a rare complication there is a reported 50-80% mortality. There is at present no proven effective treatment for DAH and the therapeutics that have been tested have significant side effects. There is a clear necessity to discover new drugs to improve outcomes in DAH. Serine protease inhibitors, serpins, regulate thrombotic and thrombolytic protease cascades. We are investigating a Myxomavirus derived immune modulating serpin, Serp-1, as a new class of immune modulating therapeutics for vasculopathy and lung hemorrhage. Serp-1 has proven efficacy in models of herpes virus-induced arterial inflammation (vasculitis) and lung hemorrhage and has also proved safe in a clinical trial in patients with unstable coronary syndromes and stent implant. Here, we examine Serp-1, both as a native secreted protein expressed by CHO cells and as a polyethylene glycol modified (PEGylated) variant (Serp-1m5), for potential therapy in DAH. DAH was induced by intraperitoneal (IP) injection of pristane in C57BL/6J (B6) mice. Mice were treated with 100 ng/g bodyweight of either Serp-1 as native 55 kDa secreted glycoprotein, or as Serp-1m5, or saline controls after inducing DAH. Treatments were repeated daily for 14 days (6 mice/group). Serp-1 partially and Serp-1m5 significantly reduced pristane-induced DAH when compared with saline as assessed by gross pathology and H&E staining (Serp-1, p = 0.2172; Serp-1m5, p = 0.0252). Both Serp-1m5 and Serp-1 treatment reduced perivascular inflammation and reduced M1 macrophage (Serp-1, p = 0.0350; Serp-1m5, p = 0.0053), hemosiderin-laden macrophage (Serp-1, p = 0.0370; Serp-1m5, p = 0.0424) invasion, and complement C5b/9 staining. Extracellular urokinase-type plasminogen activator receptor positive (uPAR+) clusters were significantly reduced (Serp-1, p = 0.0172; Serp-1m5, p = 0.0025). Serp-1m5 also increased intact uPAR+ alveoli in the lung (p = 0.0091). In conclusion, Serp-1m5 significantly reduces lung damage and hemorrhage in a pristane model of SLE DAH, providing a new potential therapeutic approach.

Serine Proteases and Chemokines in Neurotrauma: New Targets for Immune Modulating Therapeutics in Spinal Cord Injury.

Progressive neurological damage after brain or spinal cord trauma causes loss of motor function and treatment is very limited. Clotting and hemorrhage occur early after spinal cord (SCI) and traumatic brain injury (TBI), inducing aggressive immune cell activation and progressive neuronal damage. Thrombotic and thrombolytic proteases have direct effects on neurons and glia, both healing and also damaging bidirectional immune cell interactions. Serine proteases in the thrombolytic cascade, tissue- and urokinase-type plasminogen activators (tPA and uPA), as well as the clotting factor thrombin, have varied effects, increasing neuron and glial cell growth and migration (tPA), or conversely causing apoptosis (thrombin) and activating inflammatory cell responses. tPA and uPA activate plasmin and matrix metalloproteinases (MMPs) that break down connective tissue allowing immune cell invasion, promoting neurite outgrowth. Serine proteases also activate chemokines. Chemokines are small proteins that direct immune cell invasion but also mediate neuron and glial cell communication. We are investigating a new class of therapeutics, virus-derived immune modulators; One that targets coagulation pathway serine proteases and a second that inhibits chemokines. We have demonstrated that local infusion of these biologics after SCI reduces inflammation providing early improved motor function. Serp-1 is a Myxomavirus-derived serine protease inhibitor, a serpin, that inhibits both thrombotic and thrombolytic proteases. M-T7 is a virus-derived chemokine modulator. Here we review the roles of thrombotic and thrombolytic serine proteases and chemoattractant proteins, chemokines, as potential therapeutic targets for SCI. We discuss virus-derived immune modulators as treatments to reduce progressive inflammation and ongoing nerve damage after SCI.

Deriving Immune-Modulating Peptides from Viral Serine Protease Inhibitors (Serpins).

Viruses have devised highly effective approaches that modulate the host immune response, blocking immune responses that are designed to eradicate viral infections. Over millions of years of evolution, virus-derived immune-modulating proteins have become extraordinarily potent, in some cases working at picomolar concentrations when expressed into surrounding tissues and effectively blocking host defenses against viral invasion and replication. The marked efficiency of these immune-modulating proteins is postulated to be due to viral engineering of host immune modulators as well as design and development of new strategies (i.e., some derived from host proteins and some entirely unique). Two key characteristics of viral immune modulators confer both adaptive advantages and desirable functions for therapeutic translation. First, many virus-derived immune modulators have evolved structures that are not readily recognized or regulated by mammalian immune pathways, ensuring little to no neutralizing antibody responses or proteasome-mediated degradation. Second, these immune modulators tend to target early steps in central immune responses, producing a powerful downstream inhibitory "domino effect" which may alter cell activation and gene expression.We have proposed that peptide metabolites of these immune-modulating proteins can enhance and extend protein function. Active immunomodulating peptides have been derived from both mammalian and viral proteins. We previously demonstrated that peptides derived from computationally predicted cleavage sites in the reactive center loop (RCL) of a viral serine proteinase inhibitor (serpin ) from myxoma virus, Serp-1 , can modify immune response activation. We have also demonstrated modulation of host gut microbiota produced by Serp-1 and RCL-derived peptide , S7, in a vascular inflammation model. Of interest, generation of derived peptides that maintain therapeutic function from a serpin can act by a different mechanism. Whereas Serp-1 has canonical serpin-like function to inhibit serine proteases, S7 instead targets mammalian serpins. Here we describe the derivation of active Serp- RCL peptides and their testing in inflammatory vasculitis models.

Topical Application of Virus-Derived Immunomodulating Proteins and Peptides to Promote Wound Healing in Mouse Models.

Immune modulators play critical roles in the progression of wounds to normal or conversely delayed healing, through the regulation of normal tissue regrowth, scarring, inflammation, and growth factor expression. Many immune modulator recombinants are under active preclinical study or in clinical trial to promote improved acute or chronic wound healing and to reduce scarring. Viruses have evolved highly efficient immune modulators for the evasion of host-defensive immune responses that target and kill invasive viruses. Recent studies have proven that some of these virus-derived immune modulators can be used to promote wound healing with significantly improved speed and reduced scarring in rodent models. Mouse full-thickness excisional wound model is one of the most commonly used animal models used to study wound healing for its similarity to humans in the healing phases and associated cellular and molecular mechanisms. This chapter introduces this mouse dermal wound healing model in detail for application in studying viral immune modulators as new treatments to promote wound healing. Details of hydrogel, protein construction, and topical application methods for these therapeutic proteins are provided in this chapter.

Recombinant Myxoma Virus-Derived Immune Modulator M-T7 Accelerates Cutaneous Wound Healing and Improves Tissue Remodeling.

Complex dermal wounds represent major medical and financial burdens, especially in the context of comorbidities such as diabetes, infection and advanced age. New approaches to accelerate and improve, or "fine tune" the healing process, so as to improve the quality of cutaneous wound healing and management, are the focus of intense investigation. Here, we investigate the topical application of a recombinant immune modulating protein which inhibits the interactions of chemokines with glycosaminoglycans, reducing damaging or excess inflammation responses in a splinted full-thickness excisional wound model in mice. M-T7 is a 37 kDa-secreted, virus-derived glycoprotein that has demonstrated therapeutic efficacy in numerous animal models of inflammatory immunopathology. Topical treatment with recombinant M-T7 significantly accelerated wound healing when compared to saline treatment alone. Healed wounds exhibited properties of improved tissue remodeling, as determined by collagen maturation. M-T7 treatment accelerated the rate of peri-wound angiogenesis in the healing wounds with increased levels of TNF, VEGF and CD31. The immune cell response after M-T7 treatment was associated with a retention of CCL2 levels, and increased abundances of arginase-1-expressing M2 macrophages and CD4 T cells. Thus, topical treatment with recombinant M-T7 promotes a pro-resolution environment in healing wounds, and has potential as a novel treatment approach for cutaneous tissue repair.

Deriving Immune Modulating Drugs from Viruses-A New Class of Biologics.

Viruses are widely used as a platform for the production of therapeutics. Vaccines containing live, dead and components of viruses, gene therapy vectors and oncolytic viruses are key examples of clinically-approved therapeutic uses for viruses. Despite this, the use of virus-derived proteins as natural sources for immune modulators remains in the early stages of development. Viruses have evolved complex, highly effective approaches for immune evasion. Originally developed for protection against host immune responses, viral immune-modulating proteins are extraordinarily potent, often functioning at picomolar concentrations. These complex viral intracellular parasites have "performed the R&D", developing highly effective immune evasive strategies over millions of years. These proteins provide a new and natural source for immune-modulating therapeutics, similar in many ways to penicillin being developed from mold or streptokinase from bacteria. Virus-derived serine proteinase inhibitors (serpins), chemokine modulating proteins, complement control, inflammasome inhibition, growth factors (e.g., viral vascular endothelial growth factor) and cytokine mimics (e.g., viral interleukin 10) and/or inhibitors (e.g., tumor necrosis factor) have now been identified that target central immunological response pathways. We review here current development of virus-derived immune-modulating biologics with efficacy demonstrated in pre-clinical or clinical studies, focusing on pox and herpesviruses-derived immune-modulating therapeutics.

Leader Inclusiveness and Taking Charge: The Role of Thriving at Work and Regulatory Focus.

Based on self-determination theory, this study developed and tested a moderated mediation model to explore the effect of leader inclusiveness on employee taking charge behavior in addition to the mediating role of thriving at work and the moderating role of regulatory focus in this relationship. We tested the model with a sample of 206 employees from a large state-owned firm in China. Structural equation modeling revealed that leader inclusiveness was positively related to thriving at work, which in turn influenced taking charge. Promotion focus significantly moderated the relationship between leader inclusiveness and thriving at work and the mediating effect of thriving at work. As a result, the relationship and its mediating mechanism became stronger when the promotion focus of employees was high.

NAMPT: A potential prognostic and therapeutic biomarker in patients with glioblastoma.

Glioblastoma (GBM) is the most common primary intracranial malignancy. GBM still exhibits high recurrence and mortality rates even following combined treatment with surgery, radiotherapy and chemotherapy, Therefore, the identification of novel therapeutic targets is urgent. Previous research has shown that nicotinamide phosphoribosyltransferase (NAMPT) plays a key role in cell metabolism and is closely related to the occurrence and development of many tumor types; yet, little is known concerning its relationship with GBM. Oncomine database analysis showed that the expression of NAMPT in GBM was higher than that in normal tissues; this finding was further confirmed by immunohistochemical staining of a tissue microarray. Data analysis with the R2 platform showed that patients with higher expression of NAMPT had worse prognoses than those with lower NAMPT expression. Using the GBM data in TCGA, four pathways enriched in the high NAMPT expression group were identified by gene set enrichment analysis (GSEA). NAMPT expression was knocked down in U87 and U251 GBM cells by lentiviral vectors carrying a small hairpin RNA (shRNA) targeting NAMPT. CCK­8, colony formation, wound healing, Transwell and apoptosis assays were carried out. The results showed that NAMPT knockdown decreased cell proliferation, migration, and invasion and promoted apoptosis. U87 GBM cells were used in a model of subcutaneous tumorigenesis in nude mice. The results showed that NAMPT knockdown slowed the growth of tumors in vivo. Therefore, we speculate that NAMPT may be a potential prognostic and therapeutic biomarker for glioblastoma.

Inhibition of PI3K/AKT Signaling Pathway Radiosensitizes Pancreatic Cancer Cells with ARID1A Deficiency in Vitro.

Pancreatic cancer is among the most aggressive human cancers, and is resistant to regular chemotherapy and radiotherapy. The AT-rich interactive domain containing protein 1A (ARID1A) gene, a crucial chromatin remodeling gene, mutates frequently in a broad spectrum of cancers, including pancreatic cancer. Recent evidence suggests that ARID1A acts as tumor suppressor and plays an important role in DNA damage repair (DDR). However, the effect of ARID1A on the radiosensitivity of pancreatic cancer remains unclear. Herein, we investigated the involvement of ARID1A depletion in the radioresistance of pancreatic cancer cells, and explored the underlying mechanisms. The results reveal that knockdown of ARID1A enhances the radioresistance of pancreatic cancer cells through suppressing apoptosis, impairing G2-M checkpoint arrest, strengthening DDR, and accompanying activation of PI3K/AKT signaling pathway. Moreover, upon inhibition of PI3K/AKT pathway by PI3K-inhibitor LY294002 or AKT-inhibitor mk2206, the radiosensitivity of ARID1A-deficient pancreatic cancer cells is improved in vitro via increased apoptosis and weakened DDR. Taken together, these data suggest that loss of ARID1A expression enhances radioresistance of pancreatic cancer through activation of PI3K/AKT pathway, which maybe a promising target for radiosensitization of ARID1A-deficient pancreatic cancer.

HAT1 induces lung cancer cell apoptosis via up regulating Fas.

The dysfunction of apoptosis is one of the factors contributing to lung cancer (LC) growth. Histone acetyltransferase HAT1 can up regulate cell apoptosis. This study aims to investigate the mechanism by which HAT1 induces LC cell (LCC) apoptosis via up regulating the expression of Fas. In this study, the surgically removed human LC tissues were collected. LCCs were isolated from the LC tissues and analyzed for the expression of HAT1 and Fas by RT-qPCR and Western blotting. We observed that the expression of Fas was negatively correlated with PAR2 in LCCs. Activation of PAR2 suppressed the expression of Fas in normal lung epithelial cells. The expression of HAT1 was lower and positively correlated with Fas expression and negatively correlated with PAR2 expression in LCCs. Activation of PAR2 suppressed Fas expression in lung epithelial cells via inhibiting HAT1. Restoration of HAT1 expression restored Fas expression in LCCs and induced LCC apoptosis. In conclusion, less expression of HAT1 in LCCs was associated with the pathogenesis of LC. Up regulation of HAT1 expression in LCCs can induce LCCs apoptosis, which may be a potential novel therapy for the treatment of LC.

Notch1 ablation radiosensitizes glioblastoma cells.

Broad specific Notch1 inhibitors suppress glioblastoma multiforme (GBM) growth but have significant gastrointestinal toxicities. Here, we examined Notch1 expression in GBM tissue specimens and its correlation with the overall survival (OS) of GBM patients. Furthermore, using the CRISPR/Cas9 system, we investigated the effects of Notch1 downregulation on clonogenic growth and angiogenesis of GBM cells and xenografts. Immunohistochemistry showed positive Notch1 expression in 71% (49/69) of GBM tissues. Our multivariate Cox regression analysis further revealed that Notch1 expression was an independent adverse prognostic factor for OS. Notch1 downregulation suppressed the growth of GBM cells U87MG and U251. The mean duration to reach 6 x the starting volume was 18.3 days for xenografts with Notch1 downregulation and 13.4 days for the control xenografts. Immunofluorescent staining further disclosed that Notch1 downregulation markedly increased the number of γH2AX foci and radiosensitized GBM cells. Notch1 downregulation also impaired angiogenesis and attenuated VEGF and hypoxic response to irradiation in xenografts. In conclusion, Notch1 ablation inhibited GBM cell proliferation and neovascularization and radiosensitized GBM cells and xenografts, suggesting a pivotal role of Notch1 in tumor growth, angiogenesis, and radioresistance in GBM.