Predictive Value of the Total Bilirubin and CA50 Screened Based on Machine Learning for Recurrence of Bladder Cancer Patients.

Purpose: Recurrence is the main factor for poor prognosis of bladder cancer. Therefore, it is necessary to develop new biomarkers to predict the prognosis of bladder cancer. In this study, we used machine learning (ML) methods based on a variety of clinical variables to screen prognostic biomarkers of bladder cancer. Patients and Methods: A total of 345 bladder cancer patients were participated in this retrospective study and randomly divided into training and testing group. We used five supervised clustering ML algorithms: decision tree (DT), random forest (RF), adaptive boosting (AdaBoost), gradient boosting machine (GBM), and extreme gradient boosting (XGBoost) to obtained prediction information through 34 clinical parameters. Results: By comparing five ML algorithms, we found that total bilirubin (TBIL) and CA50 had the best performance in predicting the recurrence of bladder cancer. In addition, the combined predictive performance of the two is superior to the performance of any single indicator prediction. Conclusion: ML technology can evaluate the recurrence of bladder cancer. This study shows that the combination of TBIL and CA50 can improve the prognosis prediction of bladder cancer recurrence, which can help clinicians make decisions and develop personalized treatment strategies.

Spatiotemporal release of non-nucleotide STING agonist and AKT inhibitor from implantable 3D-printed scaffold for amplified cancer immunotherapy.

Immunotherapy through the activation of the stimulator of interferon genes (STING) signaling pathway is increasingly recognized for its robust anti-tumor efficacy. However, the effectiveness of STING activation is often compromised by inadequate anti-tumor immunity and a scarcity of primed immune cells in the tumor microenvironment. Herein, we design and fabricate a co-axial 3D-printed scaffold integrating a non-nucleotide STING agonist, SR-717, and an AKT inhibitor, MK-2206, in its respective shell and core layers, to synergistically enhance STING activation, thereby suppressing tumor recurrence and growth. SR-717 initiates the STING activation to enhance the phosphorylation of the factors along the STING pathway, while MK-2206 concurrently inhibits the AKT phosphorylation to facilitate the TBK1 phosphorylation of the STING pathway. The sequential and sustained release of SR-717 and MK-2206 from the scaffold results in a synergistic STING activation, demonstrating substantial anti-tumor efficacy across multiple tumor models. Furthermore, the scaffold promotes the recruitment and enrichment of activated dendritic cells and M1 macrophages, subsequently stimulating anti-tumor T cell activity, thereby amplifying the immunotherapeutic effect. This precise and synergistic activation of STING by the scaffold offers promising potential in tumor immunotherapy.

Genetically engineered nanomodulators elicit potent immunity against cancer stem cells by checkpoint blockade and hypoxia relief.

Rapid development of checkpoint inhibitors has provided significant breakthroughs for cancer stem cell (CSC) therapy, while the therapeutic efficacy is restricted by hypoxia-mediated tumor immune evasion, especially hypoxia-induced CD47 overexpression in CSCs. Herein, we developed a genetically engineered CSC membrane-coated hollow manganese dioxide (hMnO2@gCMs) to elicit robust antitumor immunity by blocking CD47 and alleviating hypoxia to ultimately achieve the eradication of CSCs. The hMnO2 core effectively alleviated tumor hypoxia by inducing decomposition of tumor endogenous H2O2, thus suppressing the CSCs and reducing the expression of CD47. Cooperating with hypoxia relief-induced downregulation of CD47, the overexpressed SIRPα on gCM shell efficiently blocked the CD47-SIRPα "don't eat me" pathway, synergistically eliciting robust antitumor-mediated immune responses. In a B16F10-CSC bearing melanoma mouse model, the hMnO2@gCMs showed an enhanced therapeutic effect in eradicating CSCs and inhibiting tumor growth. Our work presents a simple, safe, and robust platform for CSC eradication and cancer immunotherapy.

Lymph node targeting strategy using a hydrogel sustained-release system to load effector memory T cells improves the anti-tumor efficacy of anti-PD-1.

Communication between tumors and lymph nodes carries substantial significance for antitumor immunotherapy. Remodeling the immune microenvironment of tumor-draining lymph nodes (TdLN) plays a key role in enhancing the anti-tumor ability of immunotherapy. In this study, we constructed a biomimetic artificial lymph node structure composed of F127 hydrogel loading effector memory T (TEM) cells and PD-1 inhibitors (aPD-1). The biomimetic lymph nodes facilitate the delivery of TEM cells and aPD-1 to the TdLN and the tumor immune microenvironment, thus realizing effective and sustained anti-tumor immunotherapy. Exploiting their unique gel-forming and degradation properties, the cold tumors were speedily transformed into hot tumors via TEM cell supplementation. Meanwhile, the efficacy of aPD-1 was markedly elevated compared with conventional drug delivery methods. Our finding suggested that the development of F127@TEM@aPD-1 holds promising potential as a future novel clinical drug delivery technique. STATEMENT OF SIGNIFICANCE: F127@TEM@aPD-1 show unique advantages in cancer treatment. When injected subcutaneously, F127@TEM@aPD-1 can continuously supplement TEM cells and aPD-1 to tumor draining lymph nodes (TdLN) and the tumor microenvironment, not only improving the efficacy of ICB therapy through slow release, but also exhibiting dual regulatory effects on the tumor and TdLN.

Reliable prognostic definition and immunotherapy response prediction in bladder cancer, based on a novel aging-associated 5-gene signature model.

Background: Bladder cancer (BC) is a urological tumor which can be associated with a poor prognosis. Aging is a crucial factor in cancer development, but the role and prognostic value of aging-related genes (ARGs) in BC are unclear. Methods: In this study, with reference to The Cancer Genome Atlas (TCGA) database, a 5-gene signature model was constructed for the analysis of BC prognosis, immune microenvironment, and immunotherapy response. Least absolute shrinkage and selection operator (LASSO) and univariate Cox regression analyses were applied. Results: There was significant heterogeneity in the genetic variation and expression profiles of ARGs in BC. Striking variations were revealed in survival outcomes between high- and low-risk groups by Kaplan-Meier curves. The majority of samples of cases in the high-risk group belonged to the middle and late stage of the tumor and had a higher abundance of immune infiltration and immune checkpoint expression, and better immunotherapeutic effects. Conclusions: The risk score model of ARGs achieved more satisfactory results in the prediction of prognosis, clinical characteristics, immune infiltration, tumor mutational load, and immunotherapy in BC patients with good stability and reproducibility, offering innovative approaches and orientations for the diagnosis and treatment of patients with BC in the future.

A comprehensive analysis of the prognostic and immunological role of ANK3 in pan-cancer.

Background: Cancer is a common cause of death around the world. Immunotherapy plays a significant role in cancer treatment but still has limitations. The ankyrin-3 (ANK3) gene has been shown to have a variety of biological roles and has also been shown to be closely linked to individual cancers. Methods: We systematically investigated the role of ANK3 in pan-cancer, particularly in relation to immunity. We collected data from a number of databases, including the The University of ALabama at Birmingham CANcer data analysis Portal (UALCAN), tumor-immune system interactions (TISIDB), cBioPortal, Tumor Immune Estimation Resource (TIMER), Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), BioGRID, and SangerBox databases. R (version 3.6.3) was used for the statistical analysis and data visualization. The expression of ANK3 in tumors and its effects on patient prognosis, immune infiltration, neoantigens, the microenvironment, immune checkpoints (ICs), the tumor mutation burden, microsatellite instability (MSI), methylation, mismatch repair (MMR) genes, and cancer-associated fibroblasts were investigated. A gene set enrichment analysis (GSEA) was also conducted. Results: The ANK3 gene was differentially expressed at the messenger RNA (mRNA) and protein levels in various human tumors. The prognosis of patients with different types of malignancies was correlated with the level of ANK3 expression. The immunological microenvironment was also linked to ANK3 expression, especially in colon adenocarcinoma (COAD), kidney renal clear cell carcinoma (KIRC), and liver hepatocellular carcinoma (LIHC). ANK3 was also associated with ICs, immune neoantigens, MSI, the tumor mutation load, MMR genes, and DNA methylation. Finally, we found the key pathway related to the ANK3 gene through the enrichment analysis. Conclusions: ANK3 could serve as a new biomarker specific to prognosis and immunotherapy in various cancers. Our findings could contribute to the development of novel strategies for treating malignancies.

LNC000152 Mediates Aluminum-Induced Proliferation of Reactive Astrocytes.

Aluminum is a metal element with significant neurotoxicity, and there is a substantial correlation between aluminum exposure and cognitive dysfunction. Glial fibrillary acidic protein (GFAP) is widely used as a marker of reactive astrocyte proliferation in response to pathological injury of the central nervous system. Studies of various neurodegenerative diseases have confirmed that the expression changes in GFAP are associated with nerve injury. We investigated the role of LNC000152 in the aluminum-induced reactive proliferation of astrocytes. By establishing two aluminum-exposed cell models of rat primary astrocytes and CTX-TNA2 cell lines, we examined the expression of LNC000152 and GFAP and detected cell proliferation with EdU and cell cycle changes with flow cytometry. The role of aluminum in promoting glial cell proliferation was verified; the expression levels of LNC000152 and GFAP increased with the concentration of aluminum exposure. Intervention of LNC000152 expression by siRNA technology revealed that LNC000152 affected glial cell responsive proliferation by influencing GFAP expression. These results suggest that LNC000152 plays a role in the reactive proliferation of astrocytes induced by aluminum.

Microwave-responsive gadolinium metal-organic frameworks nanosystem for MRI-guided cancer thermotherapy and synergistic immunotherapy.

The clinical application of cancer immunotherapy is unsatisfied due to low response rates and systemic immune-related adverse events. Microwave hyperthermia can be used as a synergistic immunotherapy to amplify the antitumor effect. Herein, we designed a Gd-based metal-organic framework (Gd-MOF) nanosystem for MRI-guided thermotherapy and synergistic immunotherapy, which featured high performance in drug loading and tumor tissue penetration. The PD-1 inhibitor (aPD-1) was initially loaded in the porous Gd-MOF (Gd/M) nanosystem. Then, the phase change material (PCM) and the cancer cell membrane were further sequentially modified on the surface of Gd/MP to obtain Gd-MOF@aPD-1@CM (Gd/MPC). When entering the tumor microenvironment (TME), Gd/MPC induces immunogenic death of tumor cells through microwave thermal responsiveness, improves tumor suppressive immune microenvironment and further enhances anti-tumor ability of T cells by releasing aPD-1. Meanwhile, Gd/MPC can be used for contrast-enhanced MRI. Transcriptomics data revealed that the downregulation of MSK2 in cancer cells leads to the downregulation of c-fos and c-jun, and ultimately leads to the apoptosis of cancer cells after treatment. In general, Gd/MPC nanosystem not only solves the problem of system side effect, but also achieves the controlled drug release via PCM, providing a promising theranostic nanoplatform for development of cancer combination immunotherapy.

Retrospective study of single-use digital flexible ureteroscopic lithotripsy versus miniaturized percutaneous nephrolithotomy for 1.5-2.5cm lower pole renal stones.

PURPOSE: Retrospective analysis was performed on the clinical information of patients with 1.5-2.5 cm lower pole renal stones treated by single-use digital flexible ureteroscopic lithotripsy (fURS) and miniaturized percutaneous nephrolithotomy (MPCNL) in affiliated hospital of the Nantong University from January 2020 to December 2022. To compare the safety and efficacy of single-use fURS and MPCNL in the treatment from 1.5cm to 2.5cm lower pole renal stones. METHODS: Clinical information of 141 patients were collected and divided into single-use fURS group and MPCNL group according to their treatment methods, including 83 patients in the single-use fURS group and 58 patients in the MPCNL group. Baseline data, data on the clinical characteristics of stones, laboratory examination data, operation time, and postoperative data of the two groups were collected. Statistical analysis was made on the collected data to analyze the differences and causes between the two groups of patients. RESULTS: There was no significant difference in the baseline data and preoperative clinical features of 141 patients between the two groups (P > 0.05). In comparison of postoperative serum indexes, the drop values of hemoglobin and creatinine in single-use fURS group were lower than those in MPCNL group, and the difference was statistically significant (P < 0.05). The stone free rate was higher in the MPCNL group than in the single-use fURS group on the first day after surgery. At the 1st month after surgery, the two groups were similar. At 3rd month after surgery, the single-use fURS group was slightly higher than the MPCNL group, with no statistical significance (P > 0.05). The total complication rate in single-use fURS group was slightly lower than that in MPCNL group, but there was no statistical significance (P > 0.05). CONCLUSIONS: Single-use fURS has similar safety and efficacy to MPCNL in the treatment of 1.5-2.5cm lower pole renal stones. Single-use fURS may be a new option for the treatment of these stones.

Role of the RIP3-PGAM5-Drp1 pathway in aluminum-induced PC12 cells necroptosis.

Epidemiological studies from diverse global regions suggest a correlation between the accumulation of aluminum in the brain and the onset of various neurodegenerative diseases, including Alzheimer's disease, of which, neuronal cells death happen. Our previous research has found the potential of aluminum to induce neuronal cell death. A comprehensive exploration of the regulatory pathways influenced by aluminum in neuronal cell death could contribute to the development of strategies aimed at preventing the detrimental impact of aluminum on neuronal cells. This study is dedicated to exploring the impact of aluminum on mitochondrial homeostasis through the RIP3-PGAM5-Drp1 pathway, with a specific focus on its potential role in necroptosis. We observed that the inhibition of RIP3 function and the reduction in PGAM5 protein expression both mitigate aluminum-induced necroptosis in PC12 cells and enhance mitochondrial function. However, the inhibition of PGAM5 protein expression does not exert an impact on the expression of RIP3 and MLKL proteins. In summary, our study posits that aluminum can induce necroptosis in PC12 cells through the RIP3-PGAM5-Drp1 pathway.

Inhibition of urethral stricture by a catheter loaded with nanoparticle/ pirfenidone complexes.

Background: Urethral strictures are common injurious conditions of the urinary system. Reducing and preventing urethral strictures has become a hot and challenging topic for urological surgeons and related researchers. In this study, we developed a catheter loaded with nanoparticle/pirfenidone (NP/PFD) complexes and evaluated its effectiveness at inhibiting urethral stricture in rabbits, providing more references for the clinical prevention and reduction of urethral stenosis. Methods: Twelve adult male New Zealand rabbits were selected and divided into the following four groups in a ratio of 1:1:1:1 using the random number table method: Group A, sham; Group B, urethral stricture (US); Group C, US + unmodified catheter; and Group D, US + NP/PFD catheter. On the 30th day after modelling, retrograde urethrography was performed to evaluate urethral stricture formation, and histopathological examination was performed on the tissues of the corresponding surgical site. Meanwhile, changes in the expression level of Transforming growth factor ß1 (TGF-ß1) in the tissues were detected by immunohistochemistry. Results: The NP/PFD complexes adhered uniformly to the catheter surface. They remained on the surface of the catheter after insertion into the urethra. In addition, the NP/PFD complexes spread into the urethral epithelium 2 weeks after surgery. Ultimately, urethral strictures were significantly reduced with the placement of the NP/PFD complex catheter. Conclusion: Our catheter loaded with NP/PFD complexes effectively delivered PFD to the urethral epithelium through continuous local delivery, thereby reducing fibrosis and stricture after urethral injury, which may be associated with the inhibition of TGF-ß1 expression.

A comprehensive analysis of MYO6 as a promising biomarker for diagnosis, prognosis, and immunity in clear cell renal cell carcinoma.

Background: Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cell carcinoma. The myosin 6 (MYO6) plays an important role in tumorigenesis and progression. However, its prognostic and immunological effects in ccRCC have not been comprehensively and systematically studied. Therefore, this study aimed to investigate the prognostic value and immune-related role of MYO6 in ccRCC. Methods: The expression of MYO6 mRNA and protein in normal and tumor tissues using The Cancer Genome Atlas (TCGA) and other public databases were analyzed. In order to further improve the accuracy of the results, immunohistochemistry (IHC) was performed to verify the results. R software, an integrated repository portal for tumor-immune system interactions (TISIDB) and other online analysis tools were used to investigate the relationship between MYO6 expression and clinicopathological features, diagnostic and prognostic value, and the level of immune infiltration in patients with ccRCC. MYO6 genomic alterations were then investigated using the cBio Cancer Genomics Portal (cBioPortal) database. Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and Gene Set Enrichment Analysis (GSEA) enrichment analysis were used to elucidate the biological processes and signaling pathways. Finally, a protein interaction network was constructed using Biological Universal Repository for Interactive Datasets (BioGRID) and some online analysis tools to investigate the correlation between MYO6 and its co-expressed genes in ccRCC patients. Results: In the present study, MYO6 expression was significantly reduced in ccRCC tumors compared with normal tissues.This was consistent with the results of immunohistochemistry. Lower MYO6 expression levels were significantly associated with higher cancer grade and later TNM stage in ccRCC. Compared with the MYO6 high expression group, ccRCC patients with low MYO6 expression had a poor prognosis of overall survival (OS). MYO6 expression has diagnostic and prognostic potential in ccRCC. MYO6 expression is associated with different tumor-infiltrating immune cells, especially macrophages. Conclusions: The findings suggest that reduced MYO6 expression levels are associated with disease progression, poor prognosis, and immune cell infiltration, and can be considered as a promising prognostic biomarker for ccRCC.

Case Report: Diagnosis and Treatment of Two Clinical Cases of Visceral Leishmaniasis-Related Hemophagocytic Lymphohistiocytosis.

Visceral leishmaniasis-related hemophagocytic lymphohistiocytosis (VL-HLH) is a potentially life-threatening secondary hemophagocytic lymphocytic syndrome caused by protozoan parasites of the Leishmania species and transmitted by infected sandflies. Therefore, it is important to be highly vigilant of the infection, particularly the visceral subtype, to share information with the public health system, and to improve the early diagnosis rate so that appropriate treatment can be initiated promptly. We report two isolated cases of VL-HLH. The main clinical manifestations were fever, pancytopenia, splenomegaly, hypofibrinogenemia, and hyperferremia, which meet the HLH-2004 diagnostic criteria. In our experience, anti-HLH treatment was not very effective for either case. No Leishmania organism was found in the first bone marrow smear of either patient. The first patient was diagnosed after identification of Leishmania amastigotes via sternal bone marrow biopsy, rK39 immunochromatography test, and metagenomic next-generation sequencing. The other patient was diagnosed by rK39-rapid diagnostic test and polymerase chain reaction. However, because of the delayed diagnosis in both cases, their conditions continued to deteriorate and both patients eventually died of the disease. Leishmaniasis is a parasitic disease with regional specificity and a low incidence. The occurrence of secondary HLH has a great impact on prognosis. When encountering secondary HLH in clinical practice, leishmaniasis should remain on the list of differential causes. Because of a high mortality rate if diagnosed late, it is crucial to be vigilant of VL-HLH in practice so that early detection, diagnosis, and treatment of the disease can be achieved to reduce adverse patient outcomes.

Photoactivatable Sequential Destruction of Multiorganelles for Cancer Therapy.

Organelle-targeted therapy guided by fluorescence imaging is promising for precise cancer treatment. However, most current organelle-targeted therapeutics can only destruct single organelles, which suffer from limited therapeutic efficacy. To address this challenge, a photoactivatable probe was developed for sequential photodynamic destruction of multiorganelles in cancer cells, including lysosomes, lipid droplets, and mitochondria. This photoactivatable probe not only exhibits efficient cancer cell eradication in vitro but also can suppress tumor growth in vivo. Simultaneously, the photoactivatable probe enables sequential destruction of multiple organelles in cancer cells, which can be observed in situ through the conversion of green-to-red fluorescence facilitated by a photooxidative dehydrogenation reaction. We believe this photoactivatable probe for sequential destruction of multiple organelles associated with fluorescence color conversion provides a new strategy for cancer treatment with greatly improved efficacy.

Multifunctional 3D-printed scaffolds eradiate orthotopic osteosarcoma and promote osteogenesis via microwave thermo-chemotherapy combined with immunotherapy.

Tumor recurrence and a lack of bone-tissue integration are two critical concerns in the surgical treatment of osteosarcoma. Thus, an advanced multifunctional therapeutic platform capable of simultaneously eliminating residual tumor cells and promoting bone regeneration is urgently needed for efficient osteosarcoma treatment. Herein, to thoroughly eliminate tumors and simultaneously promote bone regeneration, an intelligent multifunctional therapeutic scaffold has been engineered by integrating microwave-responsive zeolitic imidazolate framework 8 (ZIF-8) nanomaterials loaded with a chemotherapeutic drug and an immune checkpoint inhibitor onto 3D-printed titanium scaffolds. The constructed scaffold features distinct microwave-thermal sensitization and tumor microenvironment-responsive characteristics, which can induce tumor immunogenic death by microwave hyperthermia and chemotherapy. Orthotopic implantation of the nanocomposite scaffold results in an enhanced immune response against osteosarcoma that may effectively inhibit tumor recurrence through synergistic immunotherapy. During long-term implantation, the zinc ions released from the degradation of ZIF-8 can induce the osteogenic differentiation of stem cells. The porous structure and mechanical properties of the 3D-printed titanium scaffolds provide a structural microenvironment for bone regeneration. This study provides a paradigm for the design of multifunctional microwave-responsive composite scaffolds for use as a therapy for osteosarcoma, which could lead to improved strategies for the treatment of the disease.

Biomimetic manganese-based theranostic nanoplatform for cancer multimodal imaging and twofold immunotherapy.

The limited clinical response and serious side effect have been challenging in cancer immunotherapy resulting from immunosuppressive tumor microenvironment (TME) and inferior drug targeting. Herein, an active targeting TME nanoplatform capable of revising the immunosuppressive TME microenvironment is designed. Briefly, gold nanorods (GNRs) are covered with silica dioxide (SiO2) and then coated manganese dioxide (MnO2) to obtain GNRs@SiO2@MnO2 (GSM). Myeloid-derived suppressor cells (MDSCs) membrane is further camouflaged on the surface of GSM to obtain GNRs@SiO2@MnO2@MDSCs (GSMM). In this system, GSMM inherits active targeting TME capacity of MDSCs. The localized surface plasmon resonance of GNRs is developed in near-infrared II window by MnO2 layer coating, realizing NIR-II window photothermal imaging and photoacoustic imaging of GSMM. Based on the release of Mn2+ in acidic TME, GSMM can be also used for magnetic resonance imaging. In cancer cells, Mn2+ catalyzes H2O2 into ·OH for (chemodynamic therapy) CDT leading to activate cGAS-STING, but also directly acts on STING inducing secretion of type I interferons, pro-inflammatory cytokines and chemokines. Additionally, photothermal therapy and CDT-mediated immunogenic cell death of tumor cells can further enhance anti-tumor immunity via exposure of CRT, HMGB1 and ATP. In summary, our nanoplatform realizes multimodal cancer imaging and dual immunotherapy.

Highly Expressed LINC00958 Modulates the Growth and Epithelial-Mesenchymal Transition of Bladder Cancer Cells Through SAPK/JNK Signaling Pathway.

Objective: To determine the expression of LINC00958 (BLACAT2) in bladder cancer (BC), the most common malignancy in the urinary system, and to determine its exact mechanism of action, so as to provide novel references for future clinical diagnosis and treatment of BC and lay a foundation for the follow-up research on LINC00958. Materials and Methods: Human bladder transitional cell carcinoma cells (T24 and J82) and human normal urothelial cells (SV-HUC-1) were purchased to detect the expression of LINC00958 and SAPK/JNK signaling pathway-related proteins. sh-LINC00958 targeting to silence LINC00958 expression and corresponding negative blank (sh-Control) were transfected into T24 and J82. Additionally, BC cells cultured with SP600125 (SP600125 group), a specific inhibitor of SAPK/JNK signaling pathway, and those cultured with the same amount of normal saline (Blank group) were also constructed. Cell growth capacity, cell invasiveness, and expression of epithelial-mesenchymal transition (EMT)-associated proteins were determined using CCK-8 & clone formation assays, Transwell assay, and Western blot, respectively. Results: The online databases Gene Expression Profiling Interactive Analysis, European Bioinformatics Institute, and StarBase revealed elevated LINC00958 expression in BC, and a potential association between LINC00958 and patient prognosis and survival. PCR results showed that LINC00958 was increased in T24 and J82 compared with the sh-Control group (p < 0.05). The results of biological behavior test revealed that the proliferation and invasiveness capacity of the sh-LINC00958 group decreased, while that of the SP600125 group increased compared with the Blank group (both p < 0.05). In the rescue experiment, the influence of sh-LINC00958 on BC cells was completely reversed by SP600125 (p > 0.05); In addition, the expression of E-cadherin, an EMT marker protein, was lower compared with the SH-LINC0958 group, while the Vimentin expression was higher (p < 0.05). Similarly, the wound-healing assay determined reduced cell healing rate in the sh-LINC00958 group (p < 0.05), and there was no difference between the sh-LINC00958+SP600125 group and the sh-Control group (p > 0.05). Conclusion: LINC00958 shows elevated expression in BC and promotes the growth and EMT of BC cell via inhibiting the SAPK/JNK signaling pathway, which has important potential as a new clinical diagnostic marker and therapeutic target for BC.

Identifying unusual human exposures to pesticides: Qilu Lake Basin as an overlooked source.

Although common exposure pathways of pesticides (e.g., crop consumption) have been intensively studied, we noticed that some unusual occupational exposures to pesticides were overlooked and could lead to unacceptable health risks. In this study, we presented information on the occurrence of 5 triazine pesticides (TRIs) and 3 neonicotine pesticides (NEOs) detected in water samples of Qilu Lake Basin in China. We identified the unusual occupational exposure scenarios as (i) adult females washing the harvested vegetables, and (ii) adult males catching fish in Qilu Lake; next, the health risk assessment was conducted using collected data. The results showed that the mean Σ5 TRI concentrations ranged from 505.87 ng/L in spring to 864.04 ng/L in summer, and the river water samples around Qilu Lake had the highest concentrations. The mean concentrations of Σ3 NEOs ranged from 885.86 ng/L in winter to 2593.04 ng/L in summer. Occupational exposed populations were bearing one to two orders of magnitude higher exposure doses than local adults. Although the carcinogenic risks caused by atrazine in water were at acceptable levels for local residents, all the occupational exposed males were at moderate risks, and 15.78 %-43.50 % of occupational exposed females in different seasons were even at high risks. The non-carcinogenic risks caused by pesticides in water were all at negligible levels, but the occupational exposed population were facing up to two orders of magnitude higher risks than local residents. This study established a sound basis for further decision-making to take necessary action on protection of sensitive population groups.

Activation of the Akt/FoxO3 signaling pathway enhances oxidative stress-induced autophagy and alleviates brain damage in a rat model of ischemic stroke.

Autophagy has been implicated in stroke. Our previous study showed that the FoxO3 transcription factor promotes autophagy after transient cerebral ischemia/reperfusion (I/R). However, whether the Akt/FoxO3 signaling pathway plays a regulatory role in autophagy in cerebral I/R-induced oxidative stress injury is still unclear. The present study aims to investigate the effects of the Akt/FoxO3 signaling pathway on autophagy activation and neuronal injury in vitro and in vivo. By employing LY294002 or insulin to regulate the Akt/FoxO3 signaling pathway, we found that insulin pretreatment increased cell viability, decreased reactive oxygen species production, and enhanced the expression of antiapoptotic and autophagy-related proteins following H2O2 injury in HT22 cells. In addition, insulin significantly decreased neurological deficit scores and infarct volume and increased the expression of antiapoptotic and autophagy-related proteins following I/R injury in rats. However, LY294002 showed the opposite effects under these conditions. Altogether, these results indicate that Akt/FoxO3 signaling pathway activation inhibited oxidative stress-mediated cell death through activation of autophagy. Our study supports a critical role for the Akt/FoxO3 signaling pathway in autophagy activation in stroke.

Comprehensive Pan-Cancer Analysis of GINS2 for Human Tumour Prognosis and as an Immunological Biomarker.

Background: In recent years, more and more reports have shown that GINS complex subunit 2 (GINS2) plays an important role in the occurrence and progression of tumours. However, there is a lack of comprehensive and systematic research on its prognostic and immune effects in pan-cancer. Therefore, this study is aimed at investigating the prognostic value and immune-related role of GINS2 in human tumours and providing a comprehensive understanding of its carcinogenic mechanism in pan-cancer. Methods: We investigated different databases, including TIMER, TCGA, GTEX, CPTAC, GEPIA, and SangerBox. The study was carried out on the expression and prognosis of GINS2 in human tumours, immune infiltration and microenvironment, immune checkpoints, neoantigens, tumour mutational burden, microsatellite instability, mismatch repair (MMR) genes, methylation, cancer-associated fibroblasts (CAFs), and enrichment analysis of gene set. Results: GINS2 plays a potential carcinogenic role in various human tumours through mRNA and protein levels. It is highly expressed in most cancers, and its expression is significantly correlated with tumour prognosis. In addition, the expression of GINS2 is associated with immune microenvironment and immune infiltration, especially in brain lower-grade glioma, lung squamous cell carcinoma, TGCT, breast invasive carcinoma, and glioblastoma multiforme. At the same time, GINS2 is related to immune neoantigens and the expression profiles of immune checkpoint genes in pan-cancer. It also affects the expression of DNA MMR genes and methyltransferase in pan-cancer. Finally, the correlation between GINS2 and CAF abundance in most tumours was studied, and an enrichment analysis of GINS2 and its related proteins was also carried out. Conclusion: This is the first study on GINS2 as a prognostic and immune mechanism in pan-cancer. GINS2 may be a valuable prognostic immunological biomarker of pan-cancer. This paper provides a relatively comprehensive understanding on the correlation of GINS2 with pan-cancer.