Background: In the clinic, how to stratify renal cell carcinoma (RCC) patients with different risks and to accurately predict their prognostic outcome remains a crucial issue. There is a lack of relevant and reliable biomarkers. In this study, we examined the expression and prognostic value of gankyrin in RCC patients.Methods: The expression of gankyrin in RCC specimens was examined in public database, and validated in specimens in our institution. The clinical practice of gankyrin (or combined with other current clinical parameters) in RCC patients was evaluated in two independent cohorts of RCC patients.Findings: Analyses based on public TCGA, GEO and ONCOMINE databases revealed that gankyrin expression was up-regulated in RCC specimens, which was also confirmed in RCC patients from two independent cohorts. In addition, high gankyrin expression positively associated with disease progression, metastasis and sunitinib-resistance of RCC patients. Kaplan-Meier analysis revealed that patients with higher gankyrin expression presented worse prognosis of RCC patients in the two cohorts. Gankyrin served as an independent prognostic factor for RCC patients even after multivariable adjustment by clinical variables. Furthermore, time-dependent AUC and Harrell's c-index analysis both presented that the incorporation of the gankyrin classifier into the current clinical prognostic parameters such as TNM stage, Furman nuclear grade or SSIGN score achieves a greater accuracy than without it in predicting prognosis of RCC patients. All these results were confirmed in randomized training and validation sets from the above two cohorts of patients.Interpretation: Gankyrin can serve as a reliable biomarker for disease progression and for prognosis of RCC patients. Combining gankyrin with the current clinical parameters may help clinical management for RCC patients.Funding Statement: This work was supported by National Natural Science Foundation of China (No. 81773154, 81772747 and 81301861), Shanghai Natural Science Foundation of China (No. 13ZR1450700), the Shanghai Medical Guidance (Chinese and Western Medicine) Science and Technology Support Project (No. 17411960200) and Outstanding Leaders Training Program of Pudong Health Bureau of Shanghai (No.PWR12016-05).Declaration of Interests: The authors declare no potential conflicts of interest.Ethics Approval Statement: The present study was followed the reporting recommendations for tumor marker prognostic studies (REMARK), and was approved by the institutional ethical review boards from all hospitals, and written informed consent was obtained from all patients.
Ferroptosis is a cell death process discovered in recent years, highly related to cancer, acute kidney injury, and other diseases. In this study, a pan-renal cancer analysis of ferroptosis-associated genes in renal cancer was performed to construct a multigene joint signature for predicting prognosis in renal cancer patients. First, gene expression profiles were downloaded from the TCGA and GTEx databases to search for genes significantly associated with renal cancer prognosis through differential gene expression analysis, weighted gene co-expression network analysis (WGCNA), and survival analysis. Thereafter, the gene-set enrichment analysis (GSEA) was used to identify the biological processes in which ferroptosis-associated genes might be involved. Weighted gene co-expression network analysis resulted in 4,434 differentially expressed genes (DEGs) and 42 co-expression modules, among which ferroptosis-related genes were distributed in 11 gene modules. The survival analysis screening resulted in three DEGs associated with renal cancer prognosis, namely SLC7A11, HMOX1, and MT1G. Specifically, SLC7A11 and HMOX1 were upregulated in renal cancer tissues, while MT1G was downregulated. Receiver operating characteristic (ROC) curves, combined with Kaplan-Meier and Cox regression analysis, revealed that high expression of SLC7A11 was a prognostic risk factor for four different renal cancers, that low expression of HMOX1 was a poor prognostic marker for patients, and that increased expression of MT1G increased the prognostic risk for three additional classes of renal cancer patients, except for renal papillary cell carcinoma. The GSEA results showed that the ferroptosis-related genes from these screens were mainly associated with signaling pathways related to tumor progression and tumor immunity. This study provides potential biological markers for prognosis prediction in renal cancer patients with different subtypes, and these results imply that ferroptosis is highly associated with renal carcinogenesis progression.
The technology of plastic film mulching is widely applied in Xinjiang, but it also brings about serious issues of residual film pollution. Currently, the 1MSF-2.0 residual film recovery machine can effectively address the problem. However, it faces challenges such as high overall machine weight and noticeable frame vibrations, which affect the stability of the entire machine operation. The frame, as the installation foundation, needs to bear loads and impact. Therefore, the reliability of the frame is crucial for the stability of the entire machine. Improving the frame’s vibration is of great importance. In response to the significant vibration issues during the operation of the 1MSF-2.0 residual film recovery machine, this paper utilized Workbench 2020 R2 to establish a finite element model of the machine frame and conducted static analysis to obtain strength information, thereby initially understanding the optimization space of the frame. Building upon this, Mechanical was employed to solve the first 14 natural frequencies and mode shapes of the frame, and the accuracy of the theoretical analysis was verified through modal testing. After analyzing the frequency characteristics of external excitation forces, it was found that the fourth-order natural frequency of the frame fell within the frequency range of the excitation force of the shaft of the straw grinder, causing resonance in the frame and necessitating structural optimization. The optimal results indicated that the optimized frame increased in mass by 4.41%, reduced the maximum stress value by 2.56 MPa, and increased the fourth-order natural frequency to 22.7 Hz, avoiding the frequency range of the excitation force of the shaft of the straw grinder, thus improving the resonance issue. This paper provides a reference for optimizing the design of the frame of the residual film recovery machine.
Optical coherence tomography angiography (Angio-OCT), mainly based on the temporal dynamics of OCT scattering signals, has found a range of potential applications in clinical and scientific research. Based on the model of random phasor sums, temporal statistics of the complex-valued OCT signals are mathematically described. Statistical distributions of the amplitude differential and complex differential Angio-OCT signals are derived. The theories are validated through the flow phantom and live animal experiments. Using the model developed, the origin of the motion contrast in Angio-OCT is mathematically explained, and the implications in the improvement of motion contrast are further discussed, including threshold determination and its residual classification error, averaging method, and scanning protocol. The proposed mathematical model of Angio-OCT signals can aid in the optimal design of the system and associated algorithms.
Post-ripening fruits need to be ripened to reach edible conditions, as they are not yet mature enough when picked. Ripening technology is based mainly on temperature control and gas regulation, with the proportion of ethylene being one of the key gas regulation parameters. A sensor's time domain response characteristic curve was obtained through the ethylene monitoring system. The first experiment showed that the sensor has good response speed (maximum of first derivative: 2.01714; minimum of first derivative: -2.01714), stability (xg: 2.42%; trec: 2.05%; Dres: 3.28%), and repeatability (xg: 20.6; trec: 52.4; Dres: 2.31). The second experiment showed that optimal ripening parameters include color, hardness (Change Ⅰ: 88.53%, Change Ⅱ: 75.28%), adhesiveness (Change Ⅰ: 95.29%, Change Ⅱ: 74.72%), and chewiness (Change Ⅰ: 95.18%, Change Ⅱ: 74.25%), verifying the response characteristics of the sensor. This paper proves that the sensor was able to accurately monitor changes in concentration which reflect changes in fruit ripeness, and that the optimal parameters were the ethylene response parameter (Change Ⅰ: 27.78%, Change Ⅱ: 32.53%) and the first derivative parameter (Change Ⅰ: 202.38%, Change Ⅱ: -293.28%). Developing a gas-sensing technology suitable for fruit ripening is of great significance.
Background: The poor prognosis of clear cell renal cell carcinoma (ccRCC) patients is due to progression and targeted drug resistance, the molecular mechanisms of which should be further elucidated. This study examined the biological function and related mechanisms of gankyrin in ccRCC based on our previous study.Methods:In vitro functional experiments, in vivo models of subcutaneous tumor formation, lung metastasis, and orthotopic ccRCC, cytokine antibody arrays, protein spectrometry, co-IP, ChIP, etc. were used to examine the biological role and molecular mechanisms of gankyrin in ccRCC. A total of 256 ccRCC patients were employed and randomly divided into the training cohort and the validation cohort to examine the prognostic value of gankyrin and CCL24 by IHC and statistical analyses.Findings: The ccRCC cell lines 786-O and 769-P overexpressing gankyrin exhibited increased proliferation, invasion, migration, tumorigenicity, and pazopanib resistance and decreased apoptosis. Gankyrin knockdown achieved the opposite results. Mechanistically, gankyrin recruited STAT3 upon direct binding, and STAT3 bound to the CCL24 promoter to trigger its expression and transcription. Reciprocally, the increased autocrine CCL24 enhanced the expression of gankyrin and STAT3 activation via CCR3 in ccRCC, forming a positive autocrine regulatory loop. Furthermore, blocking the positive loop by knockdown of gankyrin or treatment with the CCR3 inhibitor SB328437 reversed the pazopanib resistance and inhibited lung metastasis of ccRCC in vivo. Moreover, a positive correlation between gankyrin and CCL24 expression in ccRCC specimens was revealed, and improved prognostic accuracy was accomplished by combining gankyrin and CCL24 with existing clinical prognostic indicators TNM stage and SSIGN score in predicting ccRCC patients' prognosis.Interpretation: Targeting the autocrine regulatory loop gankyrin/STAT3/CCL24/CCR3 might serve as a remedy for patients with advanced ccRCC. Combining gankyrin and CCL24 with the current clinical indicators better predicts prognosis of ccRCC patients.Funding Statement: The Top-level Clinical Discipline Project of Shanghai Pudong (PWYgf2018-03), National Natural Science Foundation of China (No. 81773154, 81772747, 81974391), the Program of Shanghai Academic/Technology Research Leader (No. 19XD1405100), the Shanghai "Rising Stars of Medical Talent" Youth Development Program: Outstanding Youth Medical Talents (Xin-gang Cui), Meng Chao Talent Training Program--Cultivation of Leading Talents Reserve (Xin-gang Cui), and the Shanghai Medical Guidance (Chinese and Western Medicine) Science and Technology Support Project (No. 17411960200).Declaration of Interests: The authors declare that they have no potential conflicts of interest to disclose.Ethics Approval Statement: All experiments were approved by the institutional ethical review board from the hospital, and written informed consent was obtained from all patients. All experimental animal procedures were approved by the Animal Care and Use Committee of Gongli Hospital (Shanghai, China).
Abstract The poor prognosis of clear-cell renal cell carcinoma (ccRCC) patients is due to progression and targeted drug resistance, but the underlying molecular mechanisms need further elucidation. This study examined the biological function and related mechanisms of gankyrin in ccRCC based on the results of our previous study. To this end, in vitro functional experiments; in vivo models of subcutaneous tumor formation, lung metastasis, and orthotopic ccRCC; and antibody chip detection, co-IP, ChIP assays were performed to examine the biological role and molecular mechanisms of gankyrin in ccRCC. Two hundred fifty-six ccRCC patients were randomly divided into training and validation cohorts to examine the prognostic value of gankyrin and other markers through IHC and statistical analyses. We observed that the gankyrin-overexpressing ccRCC cell lines 786-O and 769-P exhibited increased proliferation, invasion, migration, tumorigenicity, and pazopanib resistance and decreased apoptosis, while gankyrin knockdown achieved the opposite results. Mechanistically, gankyrin recruited STAT3 via direct binding, and STAT3 binding to the CCL24 promoter promoted its expression. Reciprocally, an increase in autocrine CCL24 enhanced the expression of gankyrin and STAT3 activation via CCR3 in ccRCC, forming a positive autocrine-regulatory loop. Furthermore, in vivo experimental results revealed that blocking the positive loop through gankyrin knockdown or treatment with the CCR3 inhibitor SB328437 reversed the resistance to pazopanib and inhibited lung metastasis in ccRCC. Moreover, a positive correlation between gankyrin and STAT3 or CCL24 expression in ccRCC specimens was observed, and improved accuracy for ccRCC patient prognosis was achieved by combining gankyrin and STAT3 or CCL24 expression with existing clinical prognostic indicators, including the TNM stage and SSIGN score. In summary, targeting the gankyrin/STAT3/CCL24/CCR3 autocrine-regulatory loop may serve as a remedy for patients with advanced ccRCC, and combining gankyrin and STAT3 or CCL24 expression with the current clinical indicators better predicts ccRCC patient prognosis.
Although the interaction between tumors and tumor-associated macrophages (TAMs) has been reported to facilitate the targeted drug resistance and progression of clear cell renal cell carcinoma (ccRCC), the related mechanisms remain unknown. Here, we report that SOX17 serves as a novel tumor suppressor in ccRCC and a positive regulatory loop, SOX17low/YAP/TEAD1/CCL5/CCR5/STAT3, facilitates the ccRCC-TAM interaction. SOX17 expression was commonly downregulated and negatively correlated with TAM infiltration in ccRCC specimens, and the integration of SOX17 and TAMs with the existing clinical indicators TNM stage or SSIGN score achieved better accuracy for predicting the prognosis of ccRCC patients. Mechanistically, SOX17 knockdown activated YAP signaling by promoting the transcription and nuclear distribution of YAP, which recruited TEAD1 to trigger CCL5 transcription. Then, CCL5 educated macrophages toward TAMs, which reciprocally enhanced ccRCC progression through CCL5/CCR5 and activated STAT3/SOX17low/YAP. However, SOX17 overexpression in ccRCC achieved the opposite effect. Thus, a positive regulatory loop, SOX17low/YAP/TEAD1/CCL5/CCR5/STAT3, was identified in the ccRCC-TAM interaction. Furthermore, targeting tumor-TAM interactions by blocking this positive regulatory network impaired the metastasis and targeted drug resistance of ccRCC in in vivo mouse models of lung metastasis and orthotopic ccRCC. These findings provide a new mechanism underlying the tumor-TAM interplay in ccRCC progression and present a potential target for inhibiting targeted drug resistance and metastasis in advanced ccRCC.
Background: Interaction between tumors and tumor-infiltrating immune cells (TIICs) has been reported to facilitate the progression of clear cell renal cell carcinoma (ccRCC), but whether combining intra-tumoral markers and TIICs better predicts patients' prognosis remains unknown. This study mainly determined the prognostic value of a novel tumor-suppressor UBR5 in ccRCC patients by combining with tumor-associated macrophages (TAMs).Methods: Immunohistochemistry (IHC) and statistical analyses were performed to examine the prognostic value of UBR5 and TIICs in two independent cohorts of ccRCC patients. In vitro functional assays, in vivo tumor xenograft experiments, and a co-culture system were used to examine the biological role of UBR5 and its interaction with TAMs in ccRCC.Findings: UBR5 was commonly down-regulated in human ccRCC and negatively associated with disease progression and poor prognosis of ccRCC patients. In addition, UBR5 expression was inversely correlated with infiltration of TAMs in ccRCC, and combining expressions of UBR5 and TAMs better predicted ccRCC patients' prognosis. Even after multivariable adjustment, UBR5 and TAMs appeared to be independent risk factors respectively. By time-dependent c-index analysis, the incorporation of both UBR5 and TAMs into the clinical indicators TNM stage or SSIGN score exhibited higher c-index value than anyone of them alone. Furthermore, above results were confirmed in the randomized training, validation, and combined cohorts. Moreover, UBR5 inhibited proliferation, induced apoptosis, suppressed invasion, migration and in vivo tumor growth of ccRCC cells. In addition, intra-tumoral UBR5 inhibited the recruitment and activation of TAMs, which alleviated the increased malignant characteristics of ccRCC cells induced by TAMs.Interpretation: UBR5 serves as a tumor-suppressor in ccRCC and inhibits ccRCC-TAMs interaction. Moreover, integrating intra-tumoral UBR5 expression and TAMs with the current clinical parameters achieves better prognostic accuracy.Funding Statement: This work was supported by The Top-level Clinical Discipline Project of Shanghai Pudong (PWYgf2018-03), National Natural Science Foundation of China (No. 81772747, 81773154, 81974391), the Program of Shanghai Academic/Technology Research Leader (No. 19XD1405100), the Shanghai "Rising Stars of Medical Talent" Youth Development Program: Outstanding Youth Medical Talents (Xin-gang Cui), Meng Chao Talent Training Program--Cultivation of Leading Talents Reserve (Xin-gang Cui), and the Shanghai Medical Guidance (Chinese and Western Medicine) Science and Technology Support Project (No. 17411960200).Declaration of Interests: The authors declare no potential conflicts of interest.Ethics Approval Statement: All experiments were approved by the institutional ethical review boards from all hospitals, and all written informed consents were obtained from the ccRCC patients.
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