Machine learning-based on cytotoxic T lymphocyte evasion gene develops a novel signature to predict prognosis and immunotherapy responses for kidney renal clear cell carcinoma patients

BackgroundImmunotherapy resistance has become a difficult point in treating kidney renal clear cell carcinoma (KIRC) patients, mainly because of immune evasion. Currently, there is no effective signature to predict immunotherapy. Therefore, we use machine learning algorithms to construct a signature based on cytotoxic T lymphocyte evasion genes (CTLEGs) to predict the immunotherapy responses of patients, so as to screen patients effective for immunotherapy.MethodsIn public data sets and our in-house cohort, we used 10 machine learning algorithms to screen the optimal model with 89 combinations under the cross-validation framework, and 101 published signatures were collected. The relationship between the CTLEG signature (CTLEGS) and clinical variables was analyzed. We analyzed the role of CTLES in other types of cancer by pan-cancer analysis. The immune cell infiltration and biological characteristics were evaluated. Moreover, the response to immunotherapy and drug sensitivity of different risk groups were investigated. The key gene closely related to the signature was identified by WGCNA. We also conducted cell functional experiments and clinical tissue validation of key gene.ResultsIn public data sets and our in-house cohort, the CTLEGS shows good prediction performance. The CTLEGS can be regard as an independent risk factor for KIRC. Compared with 101 published models, our signature shows considerable superiority. The high-risk group has abundant infiltration of immunosuppressive cells and high expression of T cell depletion markers, which are characterized by immunosuppressive phenotype, minimal benefit from immunotherapy, and resistance to sunitinib and sorafenib. The CTLEGS was also strongly correlated with immunity in pan-cancer. Immunohistochemistry verified that T cell depletion marker LAG3 is highly expressed in high-risk groups in the clinical in-house cohort. The key CTLEG STAT2 can promote the proliferation, migration and invasion of KIRC cell.ConclusionsCTLEGS can accurately predict the prognosis of patients and their response to immunotherapy. It can provide guidance for the precise treatment of KIRC and help clinicians identify patients who may benefit from immunotherapy

Eucalyptus Trees - Ageratina adenophora Complex System: A New Eco-environmental Protection Model

Eucalyptus trees and Ageratina adenophora complex system, a new ecological phenomenon that is worthy of attention, was proposed firstly in this paper, and some scientific problems were summarized from the new phenomenon. Causes of the new phenomenon were analyzed tentatively from the perspective of ecology. It was pointed out that ecological degradation of Eucalyptus plantation and strong invasiveness of A. adenophora are two apparent reasons for formation of Eucalyptus trees and A. adenophora complex system. Basic view of the authors on causes of the new phenomenon was put forward that resistance unbalance between chemical defensive potential of Eucalyptus trees and chemical invasive potential of A. adenophora might be the fundamental reason for formation of Eucalyptus trees and A. adenophora complex system, based on the two apparent reasons respectively connected with allelopathic effects of Eucalyptus trees and A. adenophora as dominant species of the complex system. Some proofs from studies on chemical components and biological activities of Eucalyptus species and A. adenophora have proved the basic view of the authors. It was discussed that formation of the complex system would influence some environmental elements such as soil environment, hydrology environment, and biology environment. It was proposed that three key scientific issues, namely chemical mechanism of formation of the complex system, ecological effects of formation of the complex system, and succession trends and impact factors of the complex system should be mainly studied as special researches to probe ecological relationship of exotic species because of absence study on the complex system and objective requirements of production practice in future. It was emphasized that the proposed researches might be of guidance significance to scientific management and sustainable operation of Eucalyptus plantation under the condition of biological invasion.Eucalyptus trees and Ageratina adenophora complex system, a new ecological phenomenon that is worthy of attention, was proposed firstly in this paper, and some scientific problems were summarized from the new phenomenon. Causes of the new phenomenon were analyzed tentatively from the perspective of ecology. It was pointed out that ecological degradation of Eucalyptus plantation and strong invasiveness of A. adenophora are two apparent reasons for formation of Eucalyptus trees and A. adenophora complex system. Basic view of the authors on causes of the new phenomenon was put forward that resistance unbalance between chemical defensive potential of Eucalyptus trees and chemical invasive potential of A. adenophora might be the fundamental reason for formation of Eucalyptus trees and A. adenophora complex system, based on the two apparent reasons respectively connected with allelopathic effects of Eucalyptus trees and A. adenophora as dominant species of the complex system. Some proofs from studies on chemical components and biological activities of Eucalyptus species and A. adenophora have proved the basic view of the authors. It was discussed that formation of the complex system would influence some environmental elements such as soil environment, hydrology environment, and biology environment. It was proposed that three key scientific issues, namely chemical mechanism of formation of the complex system, ecological effects of formation of the complex system, and succession trends and impact factors of the complex system should be mainly studied as special researches to probe ecological relationship of exotic species because of absence study on the complex system and objective requirements of production practice in future. It was emphasized that the proposed researches might be of guidance significance to scientific management and sustainable operation of Eucalyptus plantation under the condition of biological invasion

Effects of driving style on the fuel consumption of city buses under different road conditions and vehicle masses

The variance in fuel consumption caused by driving style (DS) difference exceeds 10% and reaches a maximum of 20% under different road conditions, even for experienced bus drivers. To study the influence of DS on fuel consumption, a method for summarizing DS characteristic parameters on the basis of vehicle-engine combined model is proposed. With this method, the author proposes 26 DS characteristic parameters related to fuel consumption in the accelerating, normal running, and decelerating processes of vehicles. The influence of DS characteristic parameters on fuel consumption under different road conditions and vehicle masses is quantitatively analyzed on the basis of real driving data over 100,000 km. Analysis results show that the influence of DS characteristic parameters on fuel consumption changes with road condition and vehicle mass, with road condition serving a more important function. However, the DS characteristics in the accelerating process of vehicles are decisive for fuel consumption under different conditions. This study also calculates the minimum sample size necessary for analyzing the effect of DS characteristics on fuel consumption. The statistical analysis based on the real driving data over 2500 km can determine the influence of DS on fuel consumption under a given power-train configuration and road condition. The analysis results can be employed to evaluate the fuel consumption of drivers, as well as to guide the design of Driver Advisory System for Eco-driving directly

RNA-Binding Proteins in Bladder Cancer

RNA-binding proteins (RBPs) are key regulators of transcription and translation, with highly dynamic spatio-temporal regulation. They are usually involved in the regulation of RNA splicing, polyadenylation, and mRNA stability and mediate processes such as mRNA localization and translation, thereby affecting the RNA life cycle and causing the production of abnormal protein phenotypes that lead to tumorigenesis and development. Accumulating evidence supports that RBPs play critical roles in vital life processes, such as bladder cancer initiation, progression, metastasis, and drug resistance. Uncovering the regulatory mechanisms of RBPs in bladder cancer is aimed at addressing the occurrence and progression of bladder cancer and finding new therapies for cancer treatment. This article reviews the effects and mechanisms of several RBPs on bladder cancer and summarizes the different types of RBPs involved in the progression of bladder cancer and the potential molecular mechanisms by which they are regulated, with a view to providing information for basic and clinical researchers

Effects of the major formaldehyde catalyzer ADH5 on phenotypes of fanconi anemia zebrafish model

[Background] Fanconi anemia (FA) is a devastating hereditary disorder for which we desperately need a novel therapeutic strategy. It is caused by mutations in one of at least 22 genes in the FA pathway and is characterized by developmental abnormalities, bone marrow failure, and cancer predisposition. The FA pathway is required for the efficient repair of damaged DNA, including interstrand cross-links (ICL). Recent studies indicate formaldehyde as an ultimate endogenous cause of DNA damage in FA pathophysiology. Formaldehyde can form DNA adducts as well as ICLs by inducing covalent linkages between opposite strands of double-stranded DNA. [Methods and results] In this study, we generated a disease model of FA in zebrafish by disrupting the ube₂t or fancd₂ gene, which resulted in a striking phenotype of female-to-male sex reversal. Since formaldehyde is detoxified from the body by alcohol dehydrogenase₅ (ADH₅), we generated fancd₂⁻/⁻/adh₅⁻/⁻ zebrafish. We observed a body size reduction and a lower number of mature spermatozoa than wild-type or single knockout zebrafish. To evaluate if increased activity in ADH₅ can affect the FA phenotype, we overexpressed human ADH₅ in fancd₂⁻/⁻zebrafish. The progress of spermatogenesis seemed to be partially recovered due to ADH₅ overexpression. [Conclusions] Our results suggest potential utility of an ADH₅ enzyme activator as a therapeutic measure for the clearance of formaldehyde and treatment of FA

CircSorbs1 regulates myocardial regeneration and reduces cancer therapy-related cardiovascular toxicity through the Mir-99/GATA4 pathway

Abstract Due to the cancer therapy-related cardiovascular toxicity, heart failure following cancer therapy has a significant mortality rate. Gene-targeted therapy promotes the re-entry of existing cardiomyocytes into the cell cycle to achieve myocardial regeneration, which is a promising strategy for preventing and treating heart failure after myocardial infarction. Circular RNAs (circRNAs) are considered as potential targets for myocardial regeneration due to their strong stability, resistance to degradation, and potential role in heart development and cardiovascular diseases. By comparing the myocardial tissue of mice in the sham operation group and the Doxorubicin therapy group (DOX), we observed a significant decrease in Cirsorbs expression in the DOX group. Cirsorbs was predominantly localized in cardiomyocytes and exhibited high conservation. Subsequent investigations revealed that Cirsorbs could promote myocardial proliferation and inhibit myocardial apoptosis. Mechanistic studies further demonstrated that Cirsorbs could bind to miR99 and reduce its expression level. Meanwhile, miR99 was found to bind to GATA4 mRNA and decrease its expression level. The binding of Cirsorbs to miR99 alleviated the repression of miR99, thereby enhancing GATA4 expression and the transcription of downstream cyclin A2 and cyclin E1. This, in turn, increased cardiomyocyte proliferation and reduced apoptosis. In conclusion, Cirsorbs holds promise as an effective target for myocardial regeneration in reducing cancer therapy-related cardiovascular toxicity

Upregulation of LncRNA UCA1 promotes cardiomyocyte proliferation by inhibiting the miR-128/SUZ12/P27 pathway

Enhancing cardiomyocyte proliferation is essential to reverse or slow down the heart failure progression in many cardiovascular diseases such as myocardial infarction (MI). Long non-coding RNAs (lncRNAs) have been reported to regulate cardiomyocyte proliferation. In particular, lncRNA urothelial carcinoma-associated 1 (lncUCA1) played multiple roles in regulating cell cycle progression and cardiovascular diseases, making lncUCA1 a potential target for promoting cardiomyocyte proliferation. However, the role of lncUCA1 in cardiomyocyte proliferation remains unknown. This study aimed at exploring the function and underlying molecular mechanism of lncUCA1 in cardiomyocyte proliferation. Quantitative RT-PCR showed that lncUCA1 expression decreased in postnatal hearts. Gain-and-loss-of-function experiments showed that lncUCA1 positively regulated cardiomyocyte proliferation in vitro and in vivo. The bioinformatics program identified miR-128 as a potential target of lncUCA1, and loss of miR-128 was reported to promote cardiomyocyte proliferation by inhibiting the SUZ12/P27 pathway. Luciferase reporter assay, qRT-PCR, western blotting, and immunostaining experiments further revealed that lncUCA1 acted as a ceRNA of miR-128 to upregulate its target SUZ12 and downregulate P27, thereby increasing cyclin B1, cyclin E, CDK1 and CDK2 expression to promote cardiomyocyte proliferation. In conclusion, upregulation of lncRNA UCA1 promoted cardiomyocyte proliferation by inhibiting the miR-128/SUZ12/P27 pathway. Our results indicated that lncUCA1 might be a new therapeutic target for stimulating cardiomyocyte proliferation

Scabertopin Derived from Elephantopus scaber L. Mediates Necroptosis by Inducing Reactive Oxygen Species Production in Bladder Cancer In Vitro

Bladder cancer remains one of the most common malignant tumors that threatens human health worldwide. It imposes a heavy burden on patients and society due to the high medical costs associated with its easy metastasis and recurrence. Although several treatment options for bladder cancer are available, their clinical efficacy remains unsatisfactory. Therefore, actively exploring new drugs and their mechanisms of action for the clinical treatment of bladder cancer is very important. Scabertopin is one of the major sesquiterpene lactones found in Elephantopus scaber L. Sesquiterpene lactones are thought to have fairly strong anti-cancer efficacy. However, the anticancer effect of sesquiterpenoid scabertopin on bladder cancer and its mechanism are still unclear. The aim of this study is to evaluate the antitumor activity of scabertopin in bladder cancer and its potential molecular mechanism in vitro. Our results suggest that scabertopin can induce RIP1/RIP3-dependent necroptosis in bladder cancer cells by promoting the production of mitochondrial reactive oxygen species (ROS), inhibit the expression of MMP-9 by inhibiting the FAK/PI3K/Akt signaling pathway, and ultimately inhibit the migration and invasion ability of bladder cancer cells. At the same time, we also demonstrated that the half-inhibition concentration (IC50) of scabertopin on various bladder cancer cell lines (J82, T24, RT4 and 5637) is much lower than that on human ureteral epithelial immortalized cells (SV-HUC-1). The above observations indicate that scabertopin is a potential therapeutic agent for bladder cancer that acts by inducing necroptosis and inhibiting metastasis

Genome-Wide Screening Identifies Gene AKR1C1 Critical for Resistance to Pirarubicin in Bladder Cancer

Non-muscle-invasive bladder cancer (NMIBC) is a common tumor of the urinary system. Given its high rates of recurrence, progression, and drug resistance, NMIBC seriously affects the quality of life and limits the survival time of patients. Pirarubicin (THP) is a bladder infusion chemotherapy drug recommended by the guidelines for NMIBC. Although the widespread use of THP reduces the recurrence rate of NMIBC, 10–50% of patients still suffer from tumor recurrence, which is closely related to tumor resistance to chemotherapy drugs. This study was performed to screen the critical genes causing THP resistance in bladder cancer cell lines by using the CRISPR/dCas9-SAM system. Thus, AKR1C1 was screened. Results showed that the high expression of AKR1C1 could enhance the drug resistance of bladder cancer to THP both in vivo and in vitro. This gene could reduce the levels of 4-hydroxynonenal and reactive oxygen species (ROS) and resist THP-induced apoptosis. However, AKR1C1 did not affect the proliferation, invasion, or migration of the bladder cancer cells. Aspirin, which is an AKR1C1 inhibitor, could help reduce the drug resistance caused by AKR1C1. After receiving THP treatment, the bladder cancer cell lines could upregulate the expression of the AKR1C1 gene through the ROS/KEAP1/NRF2 pathway, leading to resistance to THP treatment. Using tempol, which is an inhibitor of ROS, could prevent the upregulation of AKR1C1 expression