Administration of flurbiprofen axetil and dezocine for the postoperative analgesia in patients with non­small cell lung cancer: A randomized, controlled study.

Flurbiprofen axetil or dezocine monotherapy has been applied for analgesia of postoperative non-small cell lung cancer (NSCLC); however, their combination is rarely investigated. Consequently, the present study aimed to explore the effect of flurbiprofen axetil plus dezocine on postoperative pain, surgical outcomes and its safety profile in patients with NSCLC. A total of 150 patients with resectable NSCLC were enrolled and randomized into three groups: i) The flurbiprofen axetil plus dezocine group (n=50), ii) the flurbiprofen axetil group (n=51) and iii) the dezocine group (n=49). A total of 50 mg flurbiprofen axetil, 5 mg of dezocine or their combination were administered intravenously 3 h prior to surgery and subsequently every 12 h until day 3 (D3) following surgery. The postoperative pain was lower in the flurbiprofen axetil plus dezocine group compared with that of the flurbiprofen axetil group at 6 h (P=0.008), 12 h (P=0.003), day 1 (D1) (P=0.013), day 2 (D2) (P=0.036) and D3 (P=0.010); in addition, it was lower in the flurbiprofen axetil plus dezocine group compared with that of the dezocine group at 6 h (P=0.010), 12 h (P=0.012) and D1 (P=0.020). Patient-controlled analgesia consumption was also lower in the flurbiprofen axetil plus dezocine group compared with that of the flurbiprofen axetil (P=0.010) and dezocine (P=0.002) groups. Furthermore, the length of hospital stay was lower in the flurbiprofen axetil plus dezocine group compared with that of the flurbiprofen axetil (P=0.008) and dezocine (P=0.048) groups, while other surgical outcomes and adverse events were similar among these three groups. Moreover, the expression of tumor necrosis factor-α was lower in the flurbiprofen axetil plus dezocine group compared with that of the dezocine group at 12 h (P<0.001), D1 (P<0.001) and D3 (P=0.033). The data indicated that flurbiprofen axetil and dezocine combination was superior to monotherapy for postoperative analgesia in patients with resectable NSCLC.

Swine acute diarrhea syndrome coronavirus Nsp1 suppresses IFN-λ1 production by degrading IRF1 via ubiquitin-proteasome pathway.

Swine acute diarrhea syndrome coronavirus (SADS-CoV) is a novel porcine enteric coronavirus that causes acute watery diarrhea, vomiting, and dehydration in newborn piglets. The type III interferon (IFN-λ) response serves as the primary defense against viruses that replicate in intestinal epithelial cells. However, there is currently no information available on how SADS-CoV modulates the production of IFN-λ. In this study, we utilized IPI-FX cells (a cell line of porcine ileum epithelium) as an in vitro model to investigate the potential immune evasion strategies employed by SADS-CoV against the IFN-λ response. Our results showed that SADS-CoV infection suppressed the production of IFN-λ1 induced by poly(I:C). Through screening SADS-CoV-encoded proteins, nsp1, nsp5, nsp10, nsp12, nsp16, E, S1, and S2 were identified as antagonists of IFN-λ1 production. Specifically, SADS-CoV nsp1 impeded the activation of the IFN-λ1 promoter mediated by MAVS, TBK1, IKKε, and IRF1. Both SADS-CoV and nsp1 obstructed poly(I:C)-induced nuclear translocation of IRF1. Moreover, SADS-CoV nsp1 degraded IRF1 via the ubiquitin-mediated proteasome pathway without interacting with it. Overall, our study provides the first evidence that SADS-CoV inhibits the type III IFN response, shedding light on the molecular mechanisms employed by SADS-CoV to evade the host immune response.

mRNAid, an open-source platform for therapeutic mRNA design and optimization strategies.

Recent COVID-19 vaccines unleashed the potential of mRNA-based therapeutics. A common bottleneck across mRNA-based therapeutic approaches is the rapid design of mRNA sequences that are translationally efficient, long-lived and non-immunogenic. Currently, an accessible software tool to aid in the design of such high-quality mRNA is lacking. Here, we present mRNAid, an open-source platform for therapeutic mRNA optimization, design and visualization that offers a variety of optimization strategies for sequence and structural features, allowing one to customize desired properties into their mRNA sequence. We experimentally demonstrate that transcripts optimized by mRNAid have characteristics comparable with commercially available sequences. To encompass additional aspects of mRNA design, we experimentally show that incorporation of certain uridine analogs and untranslated regions can further enhance stability, boost protein output and mitigate undesired immunogenicity effects. Finally, this study provides a roadmap for rational design of therapeutic mRNA transcripts.

Comparative proteomics analysis of kidney in chicken infected by infectious bronchitis virus.

The gamma coronavirus infectious bronchitis virus (IBV) is known to cause an acute and highly contagious infectious disease in poultry. Here, this study aimed to investigate the impact of virulent or avirulent IBV infection on the avian host by conducting proteomics with data-independent acquisition mass spectrometry (DIA-MS) in the kidneys of IBV-infected chickens. The results revealed 267, 489, and 510 differentially expressed proteins (DEPs) in the chicken kidneys at 3, 5, and 7 days postinfection (dpi), respectively, when infected with the GD17/04 strain, which is a highly nephrogenic strain and belongs to the 4/91 genotype. In contrast, the attenuated 4/91 vaccine resulted in the identification of 144, 175, and 258 DEPs at 3, 5, and 7 dpi, respectively. Functional enrichment analyses indicated distinct expression profiles between the 2 IBV strains. Upon GD17/04 infection, metabolic pathways respond initially in the early stage (3 dpi) and immune-related signaling pathways respond in the middle and late stages (5 and 7 dpi). The 4/91 vaccine elicited a completely opposite response compared to the GD17/04 infection. Among all DEPs, 62 immune-related DEPs were focused on and found to be mainly enriched in the type I interferon (IFN-I) signaling pathway and involved in humoral and cellular immunity. Notably, key molecules in the IFN-I signaling pathway including MDA5, LGP2, and TBK1 may serve as regulatory targets of IBV. Overall, this study highlights similarities and discrepancies in the patterns of protein expression at different stages of infection with virulent and avirulent IBV strains, with the IFN-I signaling pathway emerging as a critical response to IBV infection.

Epidemiological investigations and multilocus sequence typing of Mycoplasma gallisepticum collected in China.

Mycoplasma gallisepticum (MG) is one of the important pathogens in poultry industry and has led to major economic losses. Understanding the epidemiology is crucial to improve the control and eradication program of MG. This study collected 1,250 chicken samples, including trachea and lung, from China in 2022 to investigate the epidemiology of MG. Among the collected samples, 938 samples were positive for MG infection, resulting in an average positive rate of 75.04%. Additionally, 570 samples were positive for both MG and Mycoplasma synoviae (MS) coinfection, with an average positive rate of 45.60%. A total of 183 MG infection positive samples in this study were selected for genotyping, and the multilocus sequence typing (MLST) method based on 7 housekeeping genes was used. As a result, 183 samples belonged to 11 sequence types (STs), with ST-78 being the most prevalent. After BURST analysis, all 183 sequences were divided into group 3. Besides, 119 reference sequences from database and 183 sequences of this study were selected to construct the phylogenetic tree using the neighbor-joining method. The results revealed that the sequences from China, total 196 sequences, were classified into 4 branches. The findings suggest that the MG strains in China exhibit diverse genotypes, which may be related to international trade and the use of live vaccines. Furthermore, we detected the drug susceptibility of 10 isolated strains randomly, which may be helpful to guide the clinical use of drugs to control MG infection.

Epidemiological investigations and multilocus sequence typing of Mycoplasma synoviae isolates from chicken farms in China.

Mycoplasma synoviae (M. synoviae) is an important pathogen in poultry industry and has led to major economic losses. Understanding the epidemiology is crucial to improve control and eradication program of M. synoviae. In this study, 487 samples suspected with M. synoviae infection were collected from August 2020 to June 2021 in China. Among 487 samples, 324 samples were MS positive, the positive rate was 66.53%, and 104 strains were isolated from 324 positive samples. The multilocus sequence typing (MLST) method based on seven housekeeping genes was used to conduct genotyping 104 M. synoviae strains isolated, and the 104 isolates belonged to 8 sequence types (STs) after MLST genotyping, and ST-34 had the highest proportion. After BURST analysis, all 104 isolates were divided into group 12 with other 56 strains isolated from China. Phylogenetic tree constructed by neighbor-joining method showed that nearly all of Chinese isolates (160 isolates) clustered together and separated from other reference isolates (217 isolates) in the PubMLST database. In conclusion, this study suggested that the M. synoviae strains in China were highly similar and independent of abroad strains.

Global Dynamics of Porcine Enteric Coronavirus PEDV Epidemiology, Evolution, and Transmission.

With a possible origin from bats, the alphacoronavirus Porcine epidemic diarrhea virus (PEDV) causes significant hazards and widespread epidemics in the swine population. However, the ecology, evolution, and spread of PEDV are still unclear. Here, from 149,869 fecal and intestinal tissue samples of pigs collected in an 11-year survey, we identified PEDV as the most dominant virus in diarrheal animals. Global whole genomic and evolutionary analyses of 672 PEDV strains revealed the fast-evolving PEDV genotype 2 (G2) strains as the main epidemic viruses worldwide, which seems to correlate with the use of G2-targeting vaccines. The evolving pattern of the G2 viruses presents geographic bias as they evolve tachytely in South Korea but undergo the highest recombination in China. Therefore, we clustered six PEDV haplotypes in China, whereas South Korea held five haplotypes, including a unique haplotype G. In addition, an assessment of the spatiotemporal spread route of PEDV indicates Germany and Japan as the primary hubs for PEDV dissemination in Europe and Asia, respectively. Overall, our findings provide novel insights into the epidemiology, evolution, and transmission of PEDV, and thus may lay a foundation for the prevention and control of PEDV and other coronaviruses.

The microbiota regulates hematopoietic stem and progenitor cell development by mediating inflammatory signals in the niche.

The commensal microbiota regulates the self-renewal and differentiation of hematopoietic stem and progenitor cells (HSPCs) in bone marrow. Whether and how the microbiota influences HSPC development during embryogenesis is unclear. Using gnotobiotic zebrafish, we show that the microbiota is necessary for HSPC development and differentiation. Individual bacterial strains differentially affect HSPC formation, independent of their effects on myeloid cells. Early-life dysbiosis in chd8-/- zebrafish impairs HSPC development. Wild-type microbiota promote HSPC development by controlling basal inflammatory cytokine expression in kidney niche, and chd8-/- commensals elicit elevated inflammatory cytokines that reduce HSPCs and enhance myeloid differentiation. We identify an Aeromonas veronii strain with immuno-modulatory activities that fails to induce HSPC development in wild-type fish but selectively inhibits kidney cytokine expression and rebalances HSPC development in chd8-/- zebrafish. Our studies highlight the important roles of a balanced microbiome during early HSPC development that ensure proper establishment of lineal precursor for adult hematopoietic system.

Corrigendum: Plasma exosomal IRAK1 can be a potential biomarker for predicting the treatment response to renin-angiotensin system inhibitors in patients with IgA nephropathy.

[This corrects the article DOI: 10.3389/fimmu.2022.978315.].

Targeted degradation of PCNA outperforms stoichiometric inhibition to result in programed cell death.

Biodegraders are targeted protein degradation constructs composed of mini-proteins/peptides linked to E3 ligase receptors. We gained deeper insights into their utility by studying Con1-SPOP, a biodegrader against proliferating cell nuclear antigen (PCNA), an oncology target. Con1-SPOP proved pharmacologically superior to its stoichiometric (non-degrading) inhibitor equivalent (Con1-SPOPmut) as it had more potent anti-proliferative effects and uniquely induced DNA damage, cell apoptosis, and necrosis. Proteomics showed that PCNA degradation gave impaired mitotic division and mitochondria dysfunction, effects not seen with the stoichiometric inhibitor. We further showed that doxycycline-induced Con1-SPOP achieved complete tumor growth inhibition in vivo. Intracellular delivery of mRNA encoding Con1-SPOP via lipid nanoparticles (LNPs) depleted endogenous PCNA within hours of application with nanomolar potency. Our results demonstrate the utility of biodegraders as biological tools and highlight target degradation as a more efficacious approach versus stoichiometric inhibition. Once in vivo delivery is optimized, biodegraders may be leveraged as an exciting therapeutic modality.

Kidney-Targeted Nanoparticles Loaded with the Natural Antioxidant Rosmarinic Acid for Acute Kidney Injury Treatment.

Acute kidney injury (AKI) is a common clinical disease with high morbidity and mortality, and with a lack of effective drugs for treatment. Oxidative stress is very important in the occurrence and progression of AKI, and antioxidants use is one of the promising treatments. Rosmarinic acid (RA) is a ubiquitous natural polyphenol with powerful antioxidant and anti-inflammatory activities. Due to its inherent characteristic with poor water solubility and inferior bioavailability, its clinical application is impeded. Hence, the authors design a nanoparticle for effectively delivering RA, which is a chemical complex of RA and fourth-generation poly-amidoamine-based amphiphilic polymer (G4-PAMAM). The nanoparticle is modified with l-serine due to the specific interaction between kidney injury molecule-1 (Kim-1) and serine, which eventually generates a promising AKI kidney-targeting nanoparticle (S-G-R). The S-G-R is rapidly cumulated and long-term retained in ischemia-reperfusion-induced AKI kidneys, especially in the damaged renal tubular cells. The S-G-R exhibits more excellent antioxidative and antiapoptotic effects in vitro and has a more outstanding ability to improve the renal function, repair damaged renal tissue, and decrease oxidative stress, inflammatory response and apoptosis of tubular cells in vivo. Overall, this study might develop a safe and effective targeting strategy for the therapy of AKI.

Plasma exosomal IRAK1 can be a potential biomarker for predicting the treatment response to renin-angiotensin system inhibitors in patients with IgA nephropathy.

Background: Renin-angiotensin system inhibitors (RASi) are the first choice and basic therapy for the treatment of IgA nephropathy (IgAN) with proteinuria. However, approximately 40% of patients have no response to RASi treatment. The aim of this study was to screen potential biomarkers for predicting the treatment response of RASi in patients with IgAN. Methods: We included IgAN patients who were treatment-naive. They received supportive treatment, including a maximum tolerant dose of RASi for 3 months. According to the degree of decrease in proteinuria after 3 months of follow-up, these patients were divided into a sensitive group and a resistant group. The plasma of the two groups of patients was collected, and the exosomes were extracted for high-throughput sequencing. The screening of hub genes was performed using a weighted gene co-expression network (WGCNA) and filtering differentially expressed genes (DEGs). We randomly selected 20 patients in the sensitive group and 20 patients in the resistant group for hub gene validation by real-time quantitative polymerase chain reaction (qRT-PCR). A receiver operating characteristic (ROC) curve was used to evaluate hub genes that predicted the efficacy of the RASi response among the 40 validation patients. Results: After screening 370 IgAN patients according to the inclusion and exclusion criteria and the RASi treatment response evaluation, there were 38 patients in the sensitive group and 32 patients in the resistant group. IRAK1, ABCD1 and PLXNB3 were identified as hub genes by analyzing the high-throughput sequencing of the plasma exosomes of the two groups through WGCNA and DEGs screening. The sequencing data were consistent with the validation data showing that these three hub genes were upregulated in the resistant group compared with the sensitive group. The ROC curve indicated that IRAK1 was a good biomarker to predict the therapeutic response of RASi in patients with IgAN. Conclusions: Plasma exosomal IRAK1 can be a potential biomarker for predicting the treatment response of RASi in patients with IgAN.

Identifying DUSP-1 and FOSB as hub genes in immunoglobulin A nephropathy by WGCNA and DEG screening and validation.

Background: The mechanism of immunoglobulin A nephropathy (IgAN) is still unknown. A bioinformatics analysis is a powerful method to identify the biomarkers and possible therapeutic targets of a certain disease from related datasets. Methods: The GSE93973 dataset, obtained from the Gene Expression Omnibus (GEO) database, was used to construct a weighted gene co-expression network (WGCNA) and filter differentially expressed genes (DEGs). The biological process (BP) enrichment among all the genes in the key modules was analyzed through a Gene Ontology (GO) enrichment analysis. We selected the overlap of hub genes in the WGCNA and Protein-Protein Interaction (PPI) network as the final hub genes in IgAN. We verified the final hub genes in two other datasets and in clinical kidney tissue specimens. A receiver operating characteristic (ROC) curve was used to evaluate the diagnostic efficacy of hub genes for IgAN. Results: The turquoise module, which contained 1,806 genes, was the module with the highest correlation coefficient with IgAN in the GSE93973 dataset. The GO enrichment analysis showed that these 1,806 genes were mainly enriched in inflammation and immune responses. There were five hub genes identified by WGCNA and 34 hub genes identified in a DEG analysis in the GSE93973 dataset. DUSP1 and FOSB were identified as the final hub genes in IgAN. The validation results of the final hub genes in two other databases and clinical kidney tissue specimens validated the result that, compared to the control group, FOSB and DUSP1 were expressed at lower levels in the glomerulus of IgAN patients. The ROC curve indicated that DUSP1 and FOSB were good diagnostic indicators for IgAN. Conclusions: Our analysis identified two hub genes that might be potential targets for the intervention and treatment of IgAN.

Semaglutide Protects against 6-OHDA Toxicity by Enhancing Autophagy and Inhibiting Oxidative Stress.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder for which no effective treatment is available. Studies have demonstrated that improving insulin resistance in type 2 diabetes mellitus (T2DM) can benefit patients with PD. In addition, a neuroprotective effect of glucagon-like peptide-1 (GLP-1) receptor agonists was demonstrated in experimental models of PD. In addition, there are some clinical trials to study the neuroprotective effect of GLP-1 analog on PD patients. Semaglutide is a long-acting, once-a-week injection treatment and the only available oral form of GLP-1 analog. In the present study, we treated the human neuroblastoma SH-SY5Y cell line with 6-hydroxydopamine (6-OHDA) as a PD in vitro model to explore the neuroprotective effects and potential mechanisms of semaglutide to protect against PD. Moreover, we compared the effect of semaglutide with liraglutide given at the same dose. We demonstrated that both semaglutide and liraglutide protect against 6-OHDA cytotoxicity by increasing autophagy flux and decreasing oxidative stress as well as mitochondrial dysfunction in SH-SY5Y cells. Moreover, by comparing the neuroprotective effects of semaglutide and liraglutide on PD cell models at the same dose, we found that semaglutide was superior to liraglutide for most parameters measured. Our results indicate that semaglutide, the new long-acting and only oral GLP-1 analog, may be represent a promising treatment for PD.

Case Report: Recurrent Deposition in Renal Allografts: A Rare Case of Fibronectin Glomerulopathy Overlooked in Native Kidneys.

Fibronectin glomerulopathy (FNG) is a rare inherited kidney disease characterized by extensive deposition of fibronectin in the glomeruli, especially in the mesangial and subendothelial regions. The disease progresses slowly and eventually leads to kidney failure in 15-20 years. Here, we report an interesting case. The patient presented with proteinuria and was diagnosed with immune complex-mediated glomerulonephritis, and lupus nephritis was suspected. This patient progressed to end-stage renal disease after 18 years and received an allogeneic kidney transplant. However, proteinuria recurred 27 months after kidney transplantation. The renal biopsy found extensive deposition in glomeruli, and the patient was diagnosed with FNG using mass spectrometry analysis and confirmed by immunohistochemistry in both the native and transplanted kidneys. Gene sequencing revealed that a missense mutation in the fibronectin 1 (FN1) gene caused reduced binding to heparin, endothelial cells, and podocytes and impaired stress fiber formation. The patient had stable renal function but persistent nephrotic proteinuria after 6 months of follow-up. Given the persistence of abnormal circulating fibronectin levels, FNG can relapse following renal transplantation. The circulating fibronectin deposits on grafts, and renal function progressively deteriorates after recurrence. Therefore, whether renal transplantation is an acceptable treatment for FNG is still debatable.

A systematic comparison of anti-angiogenesis efficacy and cardiotoxicity of receptor tyrosine kinase inhibitors in zebrafish model.

Pathological angiogenesis is fundamental to progression of cancerous tumors and blinding eye diseases. Anti-angiogenic receptor tyrosine kinase inhibitors (TKIs) are in broad use for the treatment of these diseases. With more and more TKIs available, it is a challenge to make an optimal choice. It remains unclear whether TKIs demonstrate similar anti-angiogenesis activities in different tissues. Many TKIs have shown varying degrees of toxic effects that should also be considered in clinical use. This study investigates the anti-angiogenic effects of 13 FDA-approved TKIs on the intersegmental vessels (ISVs), subintestinal vessels (SIVs) and retinal vasculature in zebrafish embryos. The results show that vascular endothelial growth factor receptor TKIs (VEGFR-TKIs) exhibit anti-angiogenic abilities similarly on ISVs and SIVs, and their efficacy is consistent with their IC50 values against VEGFR2. In addition, VEGFR-TKIs selectively induces the apoptosis of endothelial cells in immature vessels. Among all TKIs tested, axitinib demonstrates a strong inhibition on retinal neovascularization at a low dose that do not strongly affect ISVs and SIVs, supporting its potential application for retinal diseases. Zebrafish embryos demonstrate cardiotoxicity after VEGFR-TKIs treatment, and ponatinib and sorafenib show a narrow therapeutic window, suggesting that these two drugs may need to be dosed more carefully in patients. We propose that zebrafish is an ideal model for studying in vivo antiangiogenic efficacy and cardiotoxicity of TKIs.

Identification and Pathogenicity Analysis of the Pathogen Causing Spotted Spleen in Muscovy Duck.

Since September 2020, the clinical symptoms of Muscovy duck spleen spots have appeared in Guangdong, Guangxi, Jiangxi, Hunan, Hubei, and other provinces, resulting in a large number of Muscovy duck deaths and great economic losses. The absence of the typical clinical symptoms caused by pathogenic microorganisms makes the cause of the spotted spleen a mystery. High-throughput sequencing results suggested that Riemerella anatipestifer (R. anatipestifer) may be the pathogen. Then, R. anatipestifer was regarded as the research target for isolation, identification, and pathogenicity assessment. After biochemical test, PCR amplification, and serotype determination, it was confirmed that the isolated strain CZG-1 was serotype 15 R. anatipestifer. Typical spotted spleen symptoms were observed after CZG-1 infection. Furthermore, drug sensitivity assays showed the similar drug-resistant spectrum of R. anatipestifer serotype 15 to other serotypes; for example, all test strains were resistant to polymyxin, gentamicin, and neomycin. The CZG-1 strain has high pathogenicity, and its lethal dose of 50% (LD50) is 35.122 CFU/ml. Virulence gene determination showed that the CZG-1 strain had at least five virulence genes, bioF, TSS9-1, TSS9-2, PncA, and 0373Right. Above all, this study identified and proved that the pathogen of spotted spleen in ducks was R. anatipestifer serotype 15, which caused death of ducks without the typical symptoms of bacterial infection. The results of this study enriched the knowledge of symptom after R. anatipestifer infection, provided a reference to the identification of the pathogen of spotted spleen, and provided theoretical basis for prevention and control of spotted spleen.

Poly(A)-Binding Protein Cytoplasmic 1 Inhibits Porcine Epidemic Diarrhea Virus Replication by Interacting with Nucleocapsid Protein.

Porcine epidemic diarrhea virus (PEDV) is the etiological agent of porcine epidemic diarrhea (PED) characterized by vomit, watery diarrhea, dehydration and high mortality. Outbreaks of highly pathogenic variant strains of PEDV have resulted in extreme economic losses to the swine industry all over the world. The study of host-virus interaction can help to better understand the viral pathogenicity. Many studies have shown that poly(A)-binding proteins are involved in the replication process of various viruses. Here, we found that the infection of PEDV downregulated the expression of poly(A)-binding protein cytoplasmic 1 (PABPC1) at the later infection stage in Vero cells. The overexpression of PABPC1 inhibited the proliferation of PEDV at transcription and translation level, and siRNA-mediated depletion of PABPC1 promoted the replication of PEDV. Furthermore, mass spectrometry analysis and immunoprecipitation assay confirmed that PABPC1 interacted with the nucleocapsid (N) protein of PEDV. Confocal microscopy revealed the co-localizations of PABPC1 with N protein in the cytoplasm. Taken together, these results demonstrate the antiviral effect of PABPC1 against PEDV replication by interacting with N protein, which increases understanding of the interaction between PEDV and host.

Zebrafish Xenograft Model for Studying Pancreatic Cancer-Instructed Innate Immune Microenvironment.

Pancreatic ductal adenocarcinoma (PDAC) has up to half the tumor mass of tumor-associated myeloid cells. Myeloid innate immune cells play important roles in regulating cancer cell recognition and tumor growth. PDAC cells often mold myeloid cells into pro-tumoral state to fuel cancer growth and induce immune suppression. However, how tumor cells educate the innate immune responses remains largely unknown. In this study, we used four different human PDAC cell lines (PANC1, BxPC3, AsPC1, and CFPAC1) to establish the zebrafish xenograft model and investigated the interaction between pancreatic cancer and innate immune cells. The primary tumor-derived cancer cells PANC1 and BxPC3 activated innate immune anti-tumoral responses efficiently, while cancer cells from metastatic tissues AsPC1 and CFPAC1 induced an innate immune suppression and educated innate immune cells towards pro-tumoral state. Chemical conversion of innate immune cells to anti-tumoral state inhibited tumor growth for AsPC1 and CFPAC1. Moreover, genetic and pharmacological inhibition of macrophages also significantly reduced tumor growth, supporting the important roles of macrophages in innate immune suppression. REG4 expression is high in AsPC1 and CFPAC1. Knockdown of REG4 induced innate immune activation and reduced tumor growth in the xenografts, indicating that REG4 is a beneficial target for PDAC therapy. Our study provides a fast in-vivo model to study PDAC-innate immune interaction and their plasticity that could be used to study the related mechanism as well as identify new drugs to enhance immunotherapy.

PLK2 targets GSK3ß to protect against cisplatin-induced acute kidney injury.

Cisplatin-induced acute kidney injury (AKI), which is accompanied by a rapid decline in renal function and a high risk of death, is a complex critical illness with no effective or specific treatment. Polo-like kinase 2 (PLK2), a serine/threonine kinase, is involved in the progression of multiple diseases, including cancers, cardiac fibrosis, diabetic nephropathy, etc. Here, by integrating two Gene Expression Omnibus (GEO) datasets of cisplatin-induced AKI animal models, we identified PLK2 as a significantly up-regulated gene in AKI renal tissues, which was then verified in different AKI animal models and cell models. Suppressing PLK2 using siRNAs or inhibitors could enhance cisplatin-induced AKI by inducing severe apoptosis and oxidative stress damage, while enforced PLK2 expression could prevent renal dysfunction induced by cisplatin. We further discovered that PLK2 might phosphorylate glycogen synthase kinase 3ß (GSK3ß) in the pathogenesis of AKI. In conclusion, our results show that PLK2 play a protective role in cisplatin-induced AKI and may be a new protective target of cisplatin nephrotoxicity.