Introduction Acute lung injury (ALI) is characterized excessive inflammatory signaling and uncontrolled cytokine production. Tristetraprolin (TTP) is a key post-transcriptional regulator of inflammatory cytokines that negatively regulates inflammatory pathways. PP2A emerges as an important player to activate TTP. However, whether pharmacological activation of PP2A can restore TTP activity and thereby attenuate ALI remains unexplored. Material and methods A lipopolysaccharide (LPS)-induced mice model of ALI and LPS-stimulated RAW264.7 macrophages were used to evaluate the effects of FTY720 or siRNA PP2A. Lung injury and inflammation were assessed by histopathology, wet-to-dry weight ratio, bronchoalveolar lavage fluid analysis, and cytokine quantification. PP2A activity, p38 MAPK and TTP phosphorylation, and gene expression were analyzed using phosphatase assays, Western blot, ELISA, and quantitative RT-PCR. Results Pretreatment of FTY720, a well-established PP2A activator, significantly alleviated LPS-induced lung injury, inflammatory cell infiltration, and inflammatory cytokines release in vivo. Treatment with PP2A siRNA blocked the improvement effect induced by FTY720 in LPS-induced lung injury mice. LPS exposure significantly impaired PP2A activity without altering PP2A protein abundance, whereas FTY720 restored PP2A activity in lung tissues. Mechanistically, PP2A activation suppressed p38 MAPK phosphorylation and/or promoted dephosphorylation of TTP in LPS-induced macrophages. Moreover, PP2A activation by FTY720 inhibited p38 MAPK and TTP phosphorylation without affecting TTP transcription, leading to reduced inflammatory cytokine production. Conclusions Our findings demonstrate that PP2A activation blocked inflammatory responses by reprogramming the TTP activity. Pharmacological targeting of PP2A may represent a promising strategy for the treatment of acute lung injury.

OBJECTIVE:To determine whether robotic pancreatoduodenectomy (RPD) is non-inferior to open pancreatoduodenectomy (OPD) in terms of postoperative functional recovery, without compromising safety or oncological quality. DESIGN:Multicentre, single masked, phase 3, non-inferiority randomised controlled trial. SETTING:Seven tertiary high volume pancreatic centres in China, 15 June 2020 to 28 November 2024. PARTICIPANTS:268 adults with resectable pancreatic or periampullary disease. INTERVENTIONS:Participants were randomised to receive standardised RPD (n=142) or OPD (n=126), with enhanced recovery pathways. MAIN OUTCOME MEASURES:The primary outcome was time from surgery to postoperative functional recovery, defined as adequate pain control without parenteral analgesia, ≥50% oral intake without intravenous fluids, independent mobilisation, and absence of active intra-abdominal infection. The restricted mean event time (RMET) within 40 days was a summary for time from surgery to postoperative functional recovery. Secondary outcomes included operative metrics, disease related outcomes, length of stay, postoperative morbidity, including complications of Clavien-Dindo grade II or higher (defined as complications requiring drug treatment or more intensive intervention), and hospital admission costs. RESULTS:Overall, 254 of 268 randomly assigned participants (mean age 62 years; 172 (64.2%) men) underwent surgery, completed follow-up, and were included in the modified intention-to-treat population; 14 did not undergo surgery. In the modified intention-to-treat population, the RMET was 12.1 days (95% confidence interval (CI) 11.2 to 13.1) in the RPD group and 16.0 days (14.5 to 17.5) in the OPD group (difference -3.9 days, 95% CI -5.6 to -2.2; P<0.001). Operative time was longer in the RPD group (300 minutes (interquartile range (IQR) 240-360 minutes) versus 270 (210-300) minutes in the OPD group, P<0.001) but postoperative length of stay was shorter in the RPD group (13 (IQR 11-16) days v 16 (13-20) days, P<0.001). Overall postoperative morbidity was 31.1% (41/132) in the RPD group versus 36.1% (44/122) in the OPD group and incidence of any complications of Clavien-Dindo grade II or higher was 23.5% (31/132) versus 34.4% (42/122), respectively. 90 day mortality was 0.8% (1) in the RPD group and 2.5% (3) in the OPD group. Median total costs of hospital admission (including readmission cost) were higher in the RPD group than in the OPD group (¥130 905 (£14 369; $19 351; €16 628) (IQR ¥114 853-¥152 547) v ¥108 071 (¥92 134-¥128 035), difference ¥22 834 (95% CI ¥16 744 to ¥30 522); P<0.001). CONCLUSIONS:In high volume centres with credentialled surgeons, RPD met the non-inferiority margin for time from surgery to postoperative functional recovery, with comparable disease related outcomes and overall burden from postoperative complications. To generate wider system level efficiency gains, the implementation of RPD should take account of institutional expertise, procedural volume, acquisition of robotic surgical platforms and maintenance costs, and the potential for shorter hospital stay. TRIAL REGISTRATION:ClinicalTrials.gov NCT04400357.

Abstract Background Chronic pancreatitis (CP) is a progressive inflammatory disease characterized by structural damage and chronic pancreatic fibrosis. Frey’s procedure combined both resection and drainage, is a safe and effective procedure for chronic pancreatitis. Methods This study aims to compare the effect of robotic and open Frey’s procedure in our single center. A retrospective study of patients who underwent a Frey’s procedure (robotic and open) due to CP between January 2016 to December 2022 in a hospital in Xi’an Jiaotong University was made. Results In our study, 40 patients met the inclusion criteria, 72.5% of patients were male. The etiology in most cases (47.5%) was idiopathic, and 32.5% of patients were alcoholic. 22.5% patients received extracorporeal shock wave lithotripsy (ESWL) before surgery. 21/40 patients underwent robot assisted Frey’s procedure. The duration of surgery was longer in robotic group (315 min vs. 238 min, p = 0.004). The median length of in-hospital stay and postoperative hospital stay were shorter in the robotic group. There was no significant difference in the postoperative complications and short-term outcomes of pancreatic exocrine and endocrine dysfunction between the two groups. The rate of pain relief was 100%. Although no significant difference was observed in the operation time and postoperative complications between the patient who got pre-operative ESWL or not, patients who received ESWL before surgery were most likely to have easily stones removed. Conclusions Robotic Frey’s procedure is safe and feasible for CP patients. Preoperative ESWL treatment may be helpful for intraoperative pancreatic duct stone removal.

Background Nicotinamide (NAM) metabolism fulfills crucial functions in tumor progression. The present study aims to establish a NAM metabolism-correlated gene (NMRG) signature to assess the immunotherapy response and prognosis of lung adenocarcinoma (LUAD). Methods The training set and validation set (the GSE31210 dataset) were collected The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), respectively. Molecular subtypes of LUAD were classified by consensus clustering. Mutation landscape of the top 20 somatic genes was visualized by maftools package. Subsequently, differential expression analysis was conducted using the limma package, and univariate, multivariate and LASSO regression analyses were performed on the screened genes to construct a risk model for LUAD. Next, the MCP-counter, TIMER and ESTIMATE algorithms were utilized to comprehensively assess the immune microenvironmental profile of LUAD patients in different risk groups. The efficacy of immunotherapy and chemotherapy drugs was evaluated by TIDE score and pRRophetic package. A nomogram was created by integrating RiskScore and clinical features. The mRNA expressions of independent prognostic NMRGs and the migration and invasion of LUAD cells were measured by carrying out cellular assays. Results Two subtypes (C1 and C2) of LUAD were classified, with C1 subtype showing a worse prognosis than C2. The top three genes with a high mutation frequency in C1 and C2 subtypes were TTN (45.25%), FLG (25.25%), and ZNF536 (19.8%). Four independent prognostic NMRGs (GJB3, CPA3, DKK1, KRT6A) were screened and used to construct a RiskScore model, which exhibited a strong predictive performance. High-risk group showed low immune cell infiltration, high TIDE score, and worse prognosis, and the patients in this group exhibited a high drug sensitivity to Cisplatin, Erlotinib, Paclitaxel, Saracatini, and CGP_082996. A nomogram was established with an accurate predictive and diagnostic performance. GJB3, DKK1, CPA3, and KRT6A were all high- expressed in LUAD cells, and silencing GJB3 inhibited the migration and invasion of LUAD cells. Conclusion A novel NMRG signature was developed, contributing to the prognostic evaluation and personalized treatment for LUAD patients.

The cholinergic system serves as a central regulatory network for neurotransmission and behavioral control, and its complex signaling architecture renders it highly vulnerable to mixed environmental pollutants. In real-world scenarios, pollutants typically exist as complex mixtures whose synergistic or antagonistic interactions increase toxicity uncertainty, thereby challenging the traditional single-pollutant, single-target paradigm in mixture risk prediction. Integrating evidence across pollutant categories to uncover shared mechanistic principles is therefore essential for building a predictive assessment framework. Through quantitative interactome analysis of twenty pollutant categories, we identify two unifying principles of cholinergic disruption: mechanistic convergence and target heterogeneity. Pollutant effects converge on a limited set of shared pathways, primarily acetylcholinesterase (AChE) inhibition and acetylcholine receptor (AChR) modulation, while molecular targets differ in sensitivity, forming an AChE and nicotinic AChRs (nAChRs) core attack module. We further propose a dual-axis model of damage facilitation and regulatory remodeling, delineating the transition from acute target-specific perturbations to chronic regulatory dysfunction. The model establishes chemical structure as a key determinant through a three-tier cascade encompassing molecular initiating events, distributional behavior, and metabolic fate. This framework supports a tiered risk-assessment strategy that integrates qualitative, quantitative, and computational approaches. By linking molecular perturbations to ecological outcomes, we establish an exposure-target-outcome paradigm that captures multilayered pollutant impacts. Finally, we identify key bottlenecks in predictive modeling, cross-species extrapolation, and regulatory translation, and propose a translational roadmap integrating multi-omics biomarkers, advanced in vitro models, and artificial intelligence to advance environmental neurotoxicology toward a mechanism-driven predictive science.

Objective:Insulinoma is a rare pancreatic neuroendocrine neoplasm caused by pancreatic beta cell tumor or beta cell proliferation resulting in excessive insulin secretion. Due to its rarity, surgical analysis and summary studies on patients with insulinoma are few and the sample size is limited. Methods:In this study, we retrospective the cumulative experiences including demographics, clinical characteristics, detailed surgical reports and postoperative outcome of 76 patients diagnosed with insulinoma from 2010 to 2020 at the First Affiliated Hospital of Xi'an Jiaotong University. Results:Our cohort consisted of 48 females and 28 males with an average diagnosis age of 52 years. Loss of consciousness (68 %), sweating (59 %), vertigo (56 %) are three most shown symptoms. The average time from symptom onset to diagnosis of insulinoma was 33.4 month. When CT combined with MRI was used, the diagnostic rate was as high as 96.87 %. Of the 76 patients, 48.68 % of preoperative tumors were in the head/neck, and the remaining 51.32 % were in the body/tail. Most of the patients received surgery for enucleation (65.79 %). The duration of surgery was 216 ± 105 min. The incidence of postoperative pancreatic fistula was 53.95 %. Postoperative pancreatic hemorrhage occurred in 6 patients (7.89 %), all of whom were pancreatic head/neck surgery patients. The incidence of pancreatic fistula, bleeding and major complications after the operation of pancreatic head/neck insulinoma was higher than that of pancreatic body/tail insulinoma. Conclusion:CT combined with MRI can localize insulinoma in most patients. As a parenchyma-sparing pancreatectomy, enucleation is the procedure of choice if possible. The incidence of postoperative hemorrhage should be more vigilant after the surgery of pancreatic head/neck insulinoma. The intraoperative suture of high-risk vessels prone to bleeding should be performed if necessary.

Rutin is a valuable traditional Chinese medicine known for its anti-inflammatory and anticancer effects. It has been shown to be effective in treating various inflammation-associated diseases. Here, we investigated the influence of rutin on acute pancreatitis and tumorigenesis. Using C57BL/6J mice and Kras mutant transgenic mice, we induced pancreatitis and acinar regeneration models. Pancreatic malondialdehyde (MDA), superoxide dismutase (SOD) activity and reduced glutathione (GSH) contents were measured for oxidative stress. Histological staining and a pancreatic acinar 3D culture model were used to clarify the influence of rutin on ADM in vivo and in vitro. Western blotting was adopted to detect ADM markers amylase and CK19. We found that rutin ameliorated inflammatory injury to the pancreas in both caerulein- and arginine-induced AP. Then, we revealed that the anti-damage effect of rutin may be due to its inhibition of oxidative stress. In addition, an acinar 3D culture model showed that rutin inhibited the formation of ADM by activating AMPK in acinar cells. Finally, the activation of AMPK is believed to be a potential mechanism by which rutin exerts inhibitory effects on Kras-driven tumorigenesis. Rutin inhibited AP-induced pancreatic injury and oncogenic Kras-driven tumorigenesis by inhibiting ADM.

A middle-aged male patient was hospitalized for 6 months of upper abdominal pain. The patient had experienced 3 episodes of acute pancreatitis in the past 6 years. All the examination pointed to chronic pancreatitis and tumor, which, however, covering up the truth that the patient was in infection with Clonorchis sinensis in his pancreas. As the condition met the surgical indications, we performed pancreaticoduodenectomy and found the infection of Clonorchis sinensis in the postoperative pathological report. The patient maintains healthy during subsequent follow-up. Pancreatic mass with Clonorchis sinensis infected were rarely seen clinically, here we report the case which indicates that further study on parasite and pancreatic lesion should be implemented. This case report is in accordance with Strengthening the Reporting of Clinical Case Report and the Helsinki Declaration.

Dysfunction of respiratory epithelial cells is acknowledged as an important pathogenesis of asthma. Tumor necrosis factor-α induced protein 8 like-2 (TNFAIP8L2 or TIPE2) is a famous suppressor of hyperinflammation, which has been involved in regulating asthma progression, however, its role in pyroptosis and oxidative stress of bronchial epithelial cells is still unclear. 1 μg/mL LPS and 50 ng/mL IL-13 was used to induce dysfunction of human bronchial epithelial cells BEAS-2B, and TIPE2 expression was detected at different time points after incubation. Next, TIPE2 expression vector (pcDNA-TIPE2) was transfected into BEAS-2B cells to investigate its involvement in LPS/IL-13-induced pyroptosis and oxidative stress. Then, bioinformatics analysis and co-immunoprecipitation(co-IP) assay were used to verify the binding protein of TIPE2, and rescue experiments were performed to validate the molecular mechanism through which TIPE2 regulated pyroptosis and oxidative stress of BEAS-2B cells. Finally, ovalbumin (OVA) was used to establish an asthmatic animal model in Balb/c female mice, adenovirus-mediated overexpression vector of TIPE2 (Ad-TIPE2) was applied to administrate the asthmatic mice, and the effect of TIPE2 on the progression of asthma was investigated. LPS/IL-13 treatment induced cell death (PI+ cells) and TIPE2 downregulation in a time-dependent manner. LPS/IL-13 treatment promoted NLRP3-mediated pyroptosis, secretion of pro-inflammatory cytokines, and oxidative stress in BEAS-2B cells, while overexpression of TIPE2 was able to largely reverse the effect of LPS/IL-13. TIPE2 directly interacted with the E3 ubiquitin ligase β-Transducin Repeat-containing protein (FBW1A) and positively regulated its expression. Rescue experiments with recombinant ubiquitin protein (Ub) and the ubiquitination inhibitor MG132 demonstrated that F-box and WD repeat protein 1A (FBW1A)-mediated ubiquitination of NLRP3 and C1qbp is required in TIPE2 deficiency-induced pyroptosis, mitochondrial damage and oxidative stress. Overexpression of TIPE2 suppressed NLRP3-mediated pyroptosis and C1qbp-mediated oxidative stress and improved respiratory function and pulmonary tissue damage in vivo. TIPE2 protects asthmatic bronchial epithelial cells from NLRP3-induced pyroptosis and C1qbp-induced oxidative stress by interacting with the E3 ubiquitin ligase FBW1A in vitro and in vivo.

BackgroundLung adenocarcinoma (LUAD), the most common histological subtype of lung cancer, demonstrates significant intertumoral heterogeneity. While dendritic cells (DCs) are essential mediators of antitumor immunity, their transcriptional diversity and prognostic value in LUAD remain underexplored.MethodsWe constructed a cellular atlas by integrating single-cell RNA sequencing (scRNA-seq) data from LUAD and normal tissues, emphasizing dendritic cells. High-dimensional weighted gene co-expression network analysis (hdWGCNA) and pseudotime analysis were utilized to identify functional modules and lineage trajectories. A dendritic cell-related signature (DCRS) was constructed using multiple machine learning algorithms (Lasso-Cox, RSF, CoxBoost, Stepwise-Cox), and its prognostic performance was validated in seven external cohorts. Immune landscape, genomic instability, drug sensitivity, and immunotherapy response were further analyzed. The functional role of PLEK2, a DCRS hub gene, was validated in clinical samples and LUAD cell lines.ResultsWe identified six DC clusters with distinct developmental states and transcriptional programs. The M2 module was enriched in prognostically relevant clusters and used to derive the DCRS. Patients in the high-DCRS group exhibited worse prognosis, lower immune infiltration, higher chromosomal instability and tumor mutation burden, and reduced responsiveness to immunotherapy. Drug sensitivity analysis revealed that the low-DCRS group was more responsive to multiple chemotherapeutic agents. Functional validation confirmed that PLEK2 was overexpressed in LUAD tissues and promoted tumor cell proliferation, migration, and colony formation.ConclusionWe established a novel DCRS with robust prognostic and predictive value in LUAD. This work highlights the pivotal role of dendritic cell programs in shaping the tumor microenvironment and provides potential targets for improving precision immunotherapy.

This study aimed to identify new pyroptosis-associated tumor antigens for use in mRNA vaccines and the screening of sensitive LUAD populations suitable for vaccination. The association between tumor immune infiltrating cell abundance and potential tumor antigens was investigated and visualized using the analysis modules of gene expression, clinical outcomes, and somatic copy number variation. In addition, the pyroptosis-related genes (PRGs) were clustered, the relative pyroptosis subtypes (PSs) and gene modules were identified, and the prognostic value of the PSs was examined. The expression of key PRGs in two lung adenocarcinoma cell lines was verified by RT-qPCR. Four tumor pyroptosis-associated antigens, CARD8, NAIP, NLRP1, and NLRP3, were screened as potential candidates for LUAD mRNA vaccine development. In the construction of consensus clusters for PRGs, two PSs, PS1 and PS2, were classified, in which patients with PS1 LUAD had a better prognosis. In contrast, patients with PS2 LUAD may have better responsiveness to mRNA vaccine treatment. The key PRGs can be regarded as biomarkers to predict the LUAD prognosis and identify patients suitable for mRNA vaccines. The RT-qPCR results showed that the expression levels of CSMD3, LRP1B, MUC16 and TTN were significantly increased in the two lung adenocarcinoma cell lines, while the expression levels of CARD8, TP53 and ZFHX4 were significantly reduced. The antigens CARD8, NAIP, NLRP1, and NLRP3, which are associated with tumor pyroptosis, could be candidate molecules for LUAD mRNA vaccine development. Patients with PS2 LUAD may be suitable candidates for mRNA vaccine treatment.

Fucoxanthin (Fx), a xanthophyll carotenoid abundant in brown algae, possesses several biological functions, such as antioxidant, anti-inflammatory, and cardiac-protective activities. However, the role of Fx in myocardial ischemia/reperfusion (MI/R) is still unclear. Thus, the aim of this study was to investigate the effect of Fx on MI/R-induced injury and explore the underlying mechanisms. Our results showed that in vitro, Fx treatment significantly suppressed inflammatory response, oxidative stress, and apoptosis in rat cardiomyocytes exposed to hypoxia/reoxygenation (H/R). In addition, Fx led to increased phosphorylation of AMPK, AKT, and GSK-3β, and enhanced activation of Nrf2 in cardiomyocytes under H/R conditions. Notably, pretreatment with Compound C (AMPK inhibitor), partially reduced the beneficial effects of Fx in cardiomyocytes exposed to H/R. In vivo, Fx ameliorated myocardial damage, inhibited inflammatory response, oxidative stress, and apoptosis, and activated the AMPK/GSK-3β/Nrf2 signaling in myocardial tissues in MI/R rat model. Taken together, these findings indicated that Fx attenuates MI/R-induced injury by inhibiting oxidative stress, inflammatory response, and apoptosis. The AMPK/GSK-3β/Nrf2 pathway is involved in the cardioprotective effect of Fx in MI/R injury. Thus, Fx may be a promising drug for the treatment of MI/R.

Background: Partly due to the limited effect of chemotherapy or other therapeutic strategies, which may be due to the insufficient knowledge of the tumor promotion markers and targets, pancreatic cancer (PC) holds the position of one of the most malignant tumors. This study aims to find a diagnosis/therapeutic molecule that can predict the prognosis of PC with different gene background. Methods: The Cancer Genome Atlas (TCGA) pancreatic duct adenocarcinoma (PAAD)–based single nucleotide polymorphisms and gene expression data were used to find the differentially expressed genes (DEGs) between KRAS/TP53 mutant samples and no gene mutation samples. Gene Set Enrichment Analysis (GSEA)-based Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and R-based gene oncology (GO) or immune cell invasion assay were used to explore the above DEGs involved pathways. The single-center PC cohort accompanied with next-generation sequence testing was used to verify the TCGA PAAD–based bioinformatic results. Results: First, we found PC patients who harbored KRAS and/or TP53 gene mutation have poor overall survival. Besides, the enrichment analysis showed that mutant KRAS/TP53 was correlated with PC tumor-promotion–related pathways and immune microenvironment. Next, we detected that prostate stem cell antigen (PSCA) was one of the most differential genes in KRAS/TP53 mutant PC tissues. Indeed, the bioinformatic analysis and our clinical data showed that PSCA was a biomarker of poor prognosis in PC. Conclusion: PSCA is a critical biomarker for predicting the prognosis of KRAS/TP53 mutant PC patients.

Pancreatic cancer (PC) is highly malignancy with poor survival. Ferroptosis offers a novel therapeutic target for cancer treatment and glutathione peroxidase 4 (GPX4) shields tumor cells from ferroptosis damage. Although Sterol regulatory element-binding protein 1 (SREBP1) has been implicated in the development of pancreatic cancer, its underlying mechanisms remain unclear. This research aims to explore the role of SREBP1 in ferroptosis by using its inhibitor Fatostatin. In this study, Fatostatin was found to inhibit the proliferation and clonogenicity of pancreatic cancer cell lines. This was accompanied by a reduction in intracellular lipid synthesis, increased iron accumulation, elevated levels of reactive oxygen species (ROS), and accumulation of malondialdehyde (MDA). The JASPAR database shows that there is a binding site of the SREBP1 on the promoter region of GPX4. What's more, it was verified that SREBP1 can transcriptionally regulate GPX4 by CHIP. In vivo experiments further revealed that Fatostatin could suppress the growth of subcutaneous tumors in nude mice. In conclusion, our study suggests that Fatostatin may inhibit pancreatic cancer cell proliferation by inducing ferroptosis through the SREBP1/GPX4 pathway. These findings shed light on the therapeutic potential of Fatostatin and lay the groundwork for future investigations into its mechanism of action in pancreatic cancer.

In this study, we employed bioinformatics techniques to investigate the radiosensitization mechanisms of graphene oxide (GO) and silver-platinum (AgPt) nanocomposites (NCs) on microRNAs (miRNAs) in non-small cell lung cancer (NSCLC). The GO@AgPt nanocomposites were synthesized through a hydrothermal method involving graphene oxide. Characterization and structural analysis were performed using transmission electron microscopy (TEM), atomic force microscopy (AFM), X-ray photoelectron spectroscopy (XPS), and Fourier transform infrared spectroscopy (FTIR). Our experimental model was A549 cells, categorized into three groups: the blank group, control group, and GO@AgPt group. The blank group remained untreated, while the control group was exposed to 4Gy X-ray irradiation. The GO@AgPt group received 15 μg/mL GO@AgPt for 4 hours before exposure to 4Gy X-ray irradiation. Cellular RNA was extracted from each group, and a transcriptome sequencing library was constructed. Subsequent analysis identified differential genes, followed by gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway assessments. Our results revealed the uniform attachment of AgPt spherical nanoparticles (NPs) with an approximate diameter of 10 nm to the GO surface. The GO@AgPt nanocomposites comprised four single-layer GO sheets, each approximately 4 nm in thickness, with the Ag peak area being about six times that of the Pt peak area. A total of 197 miRNAs exhibited differential expression between the GO@AgPt and control groups, with 94 up-regulated and 103 down-regulatedmiRNAs. These miRNAs were associated with biological processes such as positive regulation of gene expression, cell surface interactions, and growth factor binding. Furthermore, they were implicated in various pathways, including microRNAs in cancer, fatty acid metabolism, human T-cell leukemia virus 1 infection, FoxO signaling, and alcoholic liver disease. Our findings demonstrate that GO@AgPt nanocomposites enhance the radio-sensitization effect in NSCLC, with 197 differentialmiRNAs participating in the process.

Non-small cell lung cancer (NSCLC) is the main histological subtype of lung cancer with a high incidence and mortality. Circular RNAs (circRNAs) exert vital functions in various cancers by acting as a sponge of miRNAs to abolish their inhibitory effect on target genes. This study aims to explore the biological function of circRNA NEDD4 binding protein 2 like 2 (circ-N4BP2L2) in NSCLC. We found that circ-N4BP2L2 was upregulated in NSCLC tissues and cells by using RT-qPCR. A549 cells were transfected with pcDNA-circN4BP2L2 or sh-circN4BP2L2 to obtain circN4BP2L2-overexpressed or -silenced cells, and then cell proliferation, invasion and apoptosis were determined. The results showed that knockdown of circ-N4BP2L2 repressed cell proliferation, invasion as well as mitochondrial function, and promoted cell apoptosis; while overexpression of circ-N4BP2L2 resulted in the opposite results. Mechanistically, the targeting correlations between miR-135a-5p and circ-N4BP2L2 or ADP-ribosylation factorlike 5B (ARL5B) were confirmed by using dual luciferase reporter, RNA pull-down and RNA immunoprecipitation assays. In addition, we found that circ-N4BP2L2 could promote the expression of ARL5B by serving as a sponge of miR-135a-5p. Moreover, rescue assays revealed that silencing miR-135a-5p or overexpressing ARL5B was able to abate the effects of circ-N4BP2L2 knockdown on malignant phenotypes and mitochondrial function of A549 cells. Finally, tumorigenicity assay demonstrated that circ-N4BP2L2 facilitated NSCLC tumor growth in vivo. Taken together, circ-N4BP2L2 enhanced NSCLC progression via the miR-135a-5p/ARL5B axis, which may provide a novel therapeutic target of NSCLC.

Glucagonoma is an extremely rare neuroendocrine tumor that arises from pancreatic islet alpha cells. Although glucagonoma is usually accompanied by a variety of characteristic clinical symptoms, early diagnosis is still difficult due to the scarcity of the disease. In this study, we present the cumulative experiences, clinical characteristics and treatments of seven patients diagnosed with glucagonoma during the past 10 years at the First Affiliated Hospital of Xi’an Jiaotong University. The seven patients in our cohort consisted of six females and one male with an average diagnosis age of 40.1 years (range 23–51). The average time from onset of symptoms to diagnosis of glucagonoma was 14 months (range 2–36 months). All the patients visited dermatology first for necrolytic migratory erythema (NME) 7/7 (100%), and other presenting symptoms included diabetes mellitus (DM) 4/7 (57%), stomatitis 2/7 (28%), weight loss 4/7 (57%), anemia 4/7 (57%), diarrhea 1/7 (14%), and DVT1/7 (14%). Plasma glucagon levels were increased in all patients (range 216.92–3155 pg/mL) and declined after surgery. Imaging studies revealed that four of seven patients had liver metastasis. Six of seven patients received surgical resection, and all of them received somatostatin analog therapy. Symptoms improved significantly in 6 out of 7 patients. Three of seven patients died of this disease by the time of follow-up. Our data suggest that if persistent NME is associated with DM and high glucagon levels, timely abdominal imaging should be performed to confirm glucagonoma. Once diagnosed, surgery and somatostatin analogs are effective for symptom relief and tumor control.

The implication of chaperonin containing T-complex protein-1 subunit 3 (CCT3) in carcinogenesis has been observed in a diverse malignancies. However, the relevance of CCT3 in non-small cell lung cancer (NSCLC) has not been well addressed. This research is dedicated to investigating the expression pattern and functional role of CCT3 in NSCLC. An elevation in CCT3 levels was observed in NSCLC tissue, which was linked to a reduced overall survival rate. The inhibition of CCT3 by shRNA-mediated gene silencing induced suppressive effects on the transformative phenotypes of NSCLC cells, including the inhibition of cell proliferation and invasion, and the induction of cell cycle arrest and apoptosis. Further investigation revealed that the silencing of CCT3 led to the suppression of Yes-associated protein 1 (YAP1), and decreased the expression of YAP1 target genes in NSCLC cells. The activation of YAP1 via forced expression of constitutively active YAP1 mutant reversed CCT3-restraint-evoked antitumor effects in NSCLC cells. Crucially, NSCLC cells with CCT3 silencing also exhibited weakened oncogenicity in nude mice associated with the down-regulation of YAP1 activation in xenografts. To sum up, these observations of our work show that the inhibition of CCT3 produces antitumor effects in NSCLC via the suppression of YAP1. This study unveils a possible role CCT3/YAP1 axis in NSCLC and suggests CCT3 as a candidate anticancer target.

The epidermal growth factor receptor (EGFR) signaling is frequently activated in lung cancer. In our previous study, a new class of compounds containing pyrido[3,4-d]pyrimidine scaffold with an acrylamide moiety was designed as irreversible EGFR-tyrosine kinase inhibitors to overcome acquired EGFR-T790M resistance. In this study, we selected the most promising compound Z25h to further investigate its effects and the underlying mechanism against non-small cell lung adenocarcinoma cells in vitro. Four different non-small cell lung adenocarcinoma cell lines were selected to test the antiviability profile of Z25h, and Hcc827 was the most sensitive to the drug treatment. Z25h caused cell cycle arrest at G0-G1 phase, and triggered strong early apoptosis in Hcc827 cells at 0.1 μM and late apoptosis in A549, H1975 and H1299 cells at 10 μM by 48 h treatment. Z25h inhibited the activation of EGFR and its downstream PI3K/AKT/mTOR pathway in the four tested cell lines, leading to the inhibition of cellular biosynthetic and metabolic processes and the promotion of apoptotic process. However, the effect of Z25h on mitogen-activated protein kinase pathway varies from cell lines. In addition, Z25h sensitized H1975 cells to X-ray radiation, and it also enhanced the radiation effect on A549 cells, while no obvious effect of Z25h was observed on the cell viability inhibition of H1299 cells induced by radiation. Hereby, Z25h might be considered as a potential therapeutic drug candidate for non-small cell lung adenocarcinoma treatment.

Kidney cancer is the third most common malignancy of the urinary system, of which, kidney renal clear cell carcinoma (KIRC) accounts for the vast majority. Runt-related transcription factors (RUNX) are involved in multiple cellular functions. However, the diverse expression patterns and prognostic values of RUNX genes in kidney cancer remained to be elucidated. In our study, we mined the DNA methylation, transcriptional and survival data of RUNX genes in patients with different kinds of kidney cancer through Oncomine, Gene Expression Profiling Interactive Analysis, UALCAN, Kaplan–Meier Plotter, cBioPortal and LinkedOmics. We found that RUNX1 and RUNX3 were upregulated in KIRC tissues compared with those in normal tissues. The survival analysis results indicated a high transcription level of RUNX1 was associated with poor overall survival (OS) in KIRC patients. Furthermore, KIRC tumor tissues had significantly lower levels of RUNX1 promoter methylation than that in paracancerous tissues, with decreased DNA methylation of RUNX1 notably associated with poor OS in KIRC. In conclusion, our results revealed that RUNX1 may be a potential therapeutic target for treating KIRC, and RUNX1 promoter methylation level shows promise as a novel diagnostic and prognostic biomarker, which laid a foundation for further study.