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Background: Bevacizumab resistance poses barriers to targeted therapy in clear cell renal cell carcinoma (ccRCC). Whether there exist epigenetic targets that modulate bevacizumab sensitivity in ccRCC remains indefinite. The focus of this study is to explore the role of UCHL1 in ccRCC. Methods: Both in vitro and in vivo experiments were utilized to investigate the roles of UCHL1 in ccRCC. In vivo ubiquitination assays were performed to validate the posttranslational modification of KDM4B by UCHL1. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays were utilized to explore KDM4B/VEGFA epigenetic regulations. Results: UCHL1 was increased in ccRCC and associated with unfavorable survival outcomes in patients. UCHL1 was required for ccRCC growth and migration. Mechanistically, the wild-type UCHL1, but not C90A mutant, mediated the deubiquitination of KDM4B and thereby stabilized its proteins. KDM4B was up-regulated in ccRCC and potentiated cell growth. UCHL1 depended on KDM4B to augment ccRCC malignancies. Targeting UCHL1 suppressed tumor growth, colony formation, and migration abilities, which could be rescued by KDM4B. Furthermore, KDM4B was directly bound to the promoter region of VEGFA, abolishing repressive H3K9me3 modifications. KDM4B coordinated with HIF2α to activate VEGFA transcriptional levels. UCHL1-KDM4B axis governs VEGFA levels to sustain the angiogenesis phenotypes. Finally, a specific small-molecule inhibitor (6RK73) targeting UCHL1 remarkably inhibited ccRCC progression and further sensitized ccRCC to bevacizumab treatment. Conclusion: Overall, this study defined an epigenetic mechanism of UCHL1/KDM4B in activating VEGF signaling. The UCHL1-KDM4B axis represents a novel target for treating ccRCC and improving the efficacy of anti-angiogenesis therapy.

Summary: During space travel, microgravity leads to disturbances in cognitive function, while the underlying mechanism is still unclear. Simulated microgravity mice showed neuronal age-like changes in the hippocampus of our study. In the context of microgravity, we discovered m6A modification reshapes in the hippocampal region. When paired with RNA-seq and MeRIP-seq, Shox2 was found to be a powerful regulator in hippocampal neuron that respondes to microgravity. Decreased expression of senescence-associated secretory phenotype factors and improved genes related to synapses led to the restoration of memory function in the hippocampus upon increased expression of Shox2. Moreover, we discovered that IGF2BP2 was required for the m6A modification of the Shox2, and overexpressed IGF2BP2 in the hippocampus protected against both neuronal senescence and learning and memory decline caused by loss of gravity. Accordingly, our research identified the hippocampal IGF2BP2-Shox2 axis as a possible therapeutic approach to maintaining cognitive function during space travel.

Targeting tumor angiogenesis is an important approach in advanced tumor therapy. Here we investigated the effect of the suppressor of variegation 3–9 homolog 1 (SUV39H1) on tumor angiogenesis in oral squamous cell carcinoma (OSCC). The GEPIA database was used to analyze the expression of SUV39H1 in various cancer tissues. The expression of SUV39H1 in OSCC was detected by immunohistochemistry, and the correlation between SUV39H1 and Notch1 and microvascular density (MVD) was analyzed. The effect of SUV39H1 inhibition on OSCC was investigated in vivo by chaetocin treatment. The migration and tube formation of vascular endothelial cells by conditioned culture-medium of different treatments of oral squamous cell cells were measured. The transcriptional level of SUV39H1 is elevated in various cancer tissues. The transcription level of SUV39H1 in head and neck squamous cell carcinoma was significantly higher than that in control. Immunohistochemistry result showed increased SUV39H1 expression in OSCC, which was significantly correlated with T staging. The expression of SUV39H1 was significantly correlated with Notch1 and CD31. In vivo experiment chaetocin treatment significantly inhibit the growth of tumor, and reduce SUV39H1, Notch1, CD31 expression. The decreased expression of SUV39H1 in OSCC cells lead to the decreased expression of Notch1 and VEGF proteins, as well as the decreased migration and tube formation ability of vascular endothelial cells. Inhibition of Notch1 further enhance this effect. Our results suggest inhibition of SUV39H1 may affect angiogenesis by regulating Notch1 expression. This study provides a foundation for SUV39H1 as a potential therapeutic target for OSCC.

Uncontrolled inflammatory response is both an intervention target for various diseases, and the design basis for drug delivery strategies. In this work, based on the highly enriched characteristics of M1 type macrophages in local inflammation, we used exosomes derived from bone marrow mesenchymal stem cells (BMSC) as drug carriers, modified with hyaluronic acid (HA) and polyethylene glycol (PEG) to prepare an inflammation targeted and anti-inflammatory treatment nanoplatform (EXs-PH). By targeting M1 macrophages, HA endows EXs-PH with the ability to target inflammation, while PEG reduces the interaction between plasma proteins and exosome membrane proteins, giving the exosomes the ability to circulate within the body for a long time. The results indicate that after HA and PEG (PH) modification, exosomes derived from BMSC (EXs) can effectively enrich in the inflammatory site, achieving precise administration of curcumin (Cur) with anti-inflammatory and repair promoting functions. In vivo experiments on acute and chronic inflammatory models of spinal cord injury (SCI) and rheumatoid arthritis (RA) also showed that PH modified Exs loaded with Cur (Cur@EXs-PH) were more effective in improving the recovery of motor function after lesions. In conclusion, the engineered Cur@EXs-PH we designed, provides a new drug delivery carrier for treating inflammatory diseases.

Long-term spaceflight is known to induce disruptions in circadian rhythms, which are driven by a central pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus, but the underlying molecular mechanisms remain unclear. Here, we developed a rat model that simulated microgravity and isolation environments through tail suspension and isolation (TSI). We found that the TSI environment imposed circadian disruptions to the core body temperature, heart rate, and locomotor-activity rhythms of rats, especially in the amplitude of these rhythms. In TSI model rats’ SCNs, the core circadian gene NR1D1 showed higher protein but not mRNA levels along with decreased BMAL1 levels, which indicated that NR1D1 could be regulated through post-translational regulation. The autophagosome marker LC3 could directly bind to NR1D1 via the LC3-interacting region (LIR) motifs and induce the degradation of NR1D1 in a mitophagy-dependent manner. Defects in mitophagy led to the reversal of NR1D1 degradation, thereby suppressing the expression of BMAL1. Mitophagy deficiency and subsequent mitochondrial dysfunction were observed in the SCN of TSI models. Urolithin A (UA), a mitophagy activator, demonstrated an ability to enhance the amplitude of core body temperature, heart rate, and locomotor-activity rhythms by prompting mitophagy induction to degrade NR1D1. Cumulatively, our results demonstrate that mitophagy exerts circadian control by regulating NR1D1 degradation, revealing mitophagy as a potential target for long-term spaceflight as well as diseases with SCN circadian disruption.

Spinal cord injury (SCI) can cause very serious bodily harm or even paralysis. However, all clinical drugs require long-term use to relieve the disease, causing toxicity and side effects. Zinc tends to activate the self-defense system to repair SCI, but the currently reported zinc supplementation is not efficient to cure SCI due to the poor targeting effects. The zinc delivery system has been employed to improve the targeting efficiency, which also increases the complexity and toxicity of drugs. On the other hand, we envisage that if there is a drug that can accumulate and activate endogenous zinc in the lesions of the spinal cord and stimulate immunotherapy, it can not only reduce long-term drug dependence but also significantly improve the therapeutic effect on SCI. Herein, we found zinc deficiency for SCI mice, but more zinc accumulated in the lesions of the spinal cord after the administration of GSH-AuNCs in SCI mice. Meanwhile, more microglia/macrophages polarize toward M2 from M1 phenotypes after zinc accumulation which enhances immunotherapy effects. Thereafter, the inflammatory response was inhibited, which exerts a neuroprotective effect. As well as this, the current treatment showed memory effects for zinc accumulation even after stopping the drug administration, allowing endogenous zinc to continue its induction of multiple therapeutic effects. Due to the direct and memory curative function, the lesions of SCI mice were well recovered and the motor functions were also significantly improved.

Transportation wastage is inevitable during transportation. With the emergence of container transportation, the transportation wastage generated by most cargo through container transportation has been greatly reduced. However, for products such as grain, oil, and sand transported in bulk, significant transportation wastage still occurs during the process. Under the background of vigorously developing intermodal transportation in the transportation industry, there is still limited research on transportation wastage in bulk intermodal transportation. This study proposes a multi-objective model to determine appropriate transport routes and modes for inland waterway dry bulk transport, minimizing transport time and transport costs considering transport wastage. Using existing machine learning algorithms to predict wastage in multimodal transportation of bulk cargo. The goal is to accurately predict transportation wastage, determine transportation routes and modes. Considering the poor generalization ability of heuristic algorithms, a hyper-heuristic algorithm based on the hypervolume indicator is designed to solve the model, and it is validated through simulation experiments. The analysis results show that the model can effectively reduce the wastage rate during bulk intermodal transportation.

Common vetch is an important leguminous forage for both livestock fodder and green manure and has a tremendous latent capacity in a sustainable agroecosystem. In the present study, a comprehensive transcriptome analysis of the aboveground leaves and underground roots of common vetch under multiple abiotic stress treatments, including NaCl, drought, cold, and cold drought, was performed using hybrid-sequencing technology, i. e. single-molecule real-time sequencing technology (SMRT) and supplemented by next-generation sequencing (NGS) technology. A total of 485,038 reads of insert (ROIs) with a mean length of 2606 bp and 228,261 full-length nonchimeric (FLNC) reads were generated. After deduplication, 39,709 transcripts were generated. Of these transcripts, we identified 1059 alternative splicing (AS) events, 17,227 simple sequence repeats (SSRs), and 1647 putative transcription factors (TFs). Furthermore, 640 candidates long noncoding RNAs (lncRNAs) and 28,256 complete coding sequences (CDSs) were identified. In gene annotation analyses, a total of 38,826 transcripts (97.78%) were annotated in eight public databases. Finally, seven multiple abiotic stress-responsive candidate genes were obtained through gene expression, annotation information, and protein-protein interaction (PPI) networks. Our research not only enriched the structural information of FL transcripts in common vetch, but also provided useful information for exploring the molecular mechanism of multiple abiotic stress tolerance between aboveground and underground tissues in common vetch and related legumes.

To study vibration fatigue damage localization of offshore oil and gas pipelines, aiming at the location error caused by uncertainty of the initial parameters in backpropagation (BP) neural network training, an improved BP neural network based on the genetic algorithm (GA) is proposed to locate pipeline damage. This approach was verified by experiments and simulations. First, a BP neural network for structural damage location was constructed, and a method to optimize the BP neural network parameters based on the GA was established. Then, a finite element model was established based on the measured data from modal tests of a physical pipeline model, and a large number of vibration neural network training samples were obtained using the finite element model. Finally, to show that the improved BP neural network based on the GA had a better damage location accuracy, the location results of the original BP and GA BP methods were compared for cases with no noise and with 5% noise. The results show that the average error of the BP neural network based on the GA was less than 3%, which was 11.6% lower than that of the original BP neural network.

Rainfall interception (I) can considerably influence the transport process of water. The revised sparse Gash model (RSGM) is a tool for determining the I, which assumes that the two climate parameters in the model are equal for all storms. However, few studies have provided additional cases to reexamine the correctness of this assumption and investigated the response of I of single storms to the time-step variability in climatic parameters. Hence, rainfall partitioning was measured during the growing season in 2017 for Pinus tabuliformis, Platycladus orientalis, and Acer truncatum in Northern China, and we ran RSGM on an event basis using different time-step climatic parameters (storm-based, monthly, and fixed) to estimate I. In summary, the modeling accuracy of both cumulative I and individual I was enhanced by increasing the time step of the climatic parameters in this study. These positively support the assumption in the RSGM. These results suggest that it is more appropriate to run the RSGM using fixed climate parameters to estimate I for these tree species during the growing season in northern China. Additionally, the assumption in the RSGM should be appealed to be further confirmed across the widest possible range of species, regions, and time scales. HIGHLIGHTS The reasonableness of an assumption in the revised sparse Gash model (RSGM) was reexamined.; Effects of time-step climatic parameters on the RSGM were compared.; Fixed climatic parameters were more appropriate for the simulation in the studied species.; Simulations of single intercepted events are problematic no matter the time step.; Good model accuracy is from complementation between small and large rainfall events.;

Heterogeneity of kidney cancer poses great challenges in clinical management. Practicians are still in need of an effective way to identify high-risk patients. Here we browsed big data from The Cancer Genome Atlas database with reference to cancer cell stemness and identified genes of interest in clear cell renal cell carcinoma. We further analyzed these genes to uncover their role in cancer promotion and progression and presented an interaction network. The results highlighted the NOTCH signaling pathway and functions related with epithelial cell migration. Finally, we managed to construct a predictive model consisting of a reasonable number of genes that successfully recognized patients at higher risk, rendering these genes suitable as subjects in future research.

Abstract Background Uncontrollable inflammation and nerve cell apoptosis are the most destructive pathological response after spinal cord injury (SCI). So, inflammation suppression combined with neuroprotection is one of the most promising strategies to treat SCI. Engineered extracellular vesicles with anti-inflammatory and neuroprotective properties are promising candidates for implementing these strategies for the treatment of SCI. Results By combining nerve growth factor (NGF) and curcumin (Cur), we prepared stable engineered extracellular vesicles of approximately 120 nm from primary M2 macrophages with anti-inflammatory and neuroprotective properties (Cur@EVs−cl−NGF). Notably, NGF was coupled with EVs by matrix metalloproteinase 9 (MMP9)-a cleavable linker to release at the injured site accurately. Through targeted experiments, we found that these extracellular vesicles could actively and effectively accumulate at the injured site of SCI mice, which greatly improved the bioavailability of the drugs. Subsequently, Cur@EVs−cl−NGF reached the injured site and could effectively inhibit the uncontrollable inflammatory response to protect the spinal cord from secondary damage; in addition, Cur@EVs−cl−NGF could release NGF into the microenvironment in time to exert a neuroprotective effect against nerve cell damage. Conclusions A series of in vivo and in vitro experiments showed that the engineered extracellular vesicles significantly improved the microenvironment after injury and promoted the recovery of motor function after SCI. We provide a new method for inflammation suppression combined with neuroprotective strategies to treat SCI. Graphical Abstract

Ecological deterioration and water scarcity motivate people to seek a balance between ecological reserves and water consumption in cities located in Semi-humid regions. This study is designed to develop a method for evaluating cooling water-saving characteristics of green space structures. Land surface temperature (TS), vegetation quantity (VQ) and evapotranspiration (ET) of typical green vegetation structures in 50 plots with an average area of 10,000 m2 were studied. Parameters were obtained based on data from three temporal remote sensing images; the surface energy balance algorithm for land (SEBAL) model, single-channel algorithm, and normalized difference vegetation index (NDVI) were utilized in the calculation. The relationships between the TS, VQ, and ET of green land were explored using regression analysis. A comprehensive index (EWI) was proposed to evaluate the cooling and water-saving abilities of different green space structures. Based on assessment results, species were classified into three: good (EWI ≥ 0.795), common (0.795 > EWI ≥ 0.419), and weak (EWI < 0.419). The characteristics of 17 species or species compositions with good cooling and water-saving abilities were summarized as: 1) a mix of the arbor, shrub, and herb, and 2) complete cover of green space by shrub.

Elymus sibiricus L. is a perennial allotetraploid belonging to Triticeae of Poaceae, Elymus L., as the type species of genus Elymus L. The existing geographical distribution pattern and genetic spatial structure of E. sibiricus on Qinghai–Tibetan Plateau (QTP) are not yet clear. In this study, population genetic structure and demography history of 216 individuals from 44 E. sibiricus populations on QTP were studied used specific-locus amplified fragment sequencing (SLAF-seq). The result of genetic diversity showed that there was no single genetic diversity center was observed across all E. sibiricus populations. The results of genetic variation showed that 44 populations were clearly divided into the following three groups: Qinghai Plateau (Group I), South Tibet (Group II), and Hengduan Mountains (Group III). From the three analyses of AMOVA, Mantel test and Treemix, strong genetic differentiation across all populations and low genetic differentiation among populations within three groups. Molecular dating indicated that E. sibiricus diverged at 16.08 Ma (during the early Miocene) can be linked to the Himalayan Motion stage of QTP uplift. It is speculated that the reasons affecting the current phylogeographical pattern are as follows: (1) The environmental changes due to the uplift of the QTP; (2) The geographic distance between the populations (Groups I and III are close in geographic distance, and gene flow are frequent); (3) Geographical barriers (the Tanggula and Bayangela Mountains between Groups I and II). This study provides new evidence and historical perspective to the future exploration of the evolution and geographic distribution pattern of Elymus L.

Abstract Enterovirus A71 (EVA71) infection continues to remain a vital threat to global public health, especially in the Asia–Pacific region. It is one of the most predominant pathogens that cause hand, foot, and mouth disease (HFMD), which occurs mainly in children below 5 years old. Although EVA71 prevalence has decreased sharply in China with the use of vaccines, epidemiological studies still indicate that EVA71 infection involves severe and even fatal HFMD cases. As a result, it remains more fundamental research into the pathogenesis of EVA71 as well as to develop specific anti-viral therapy. Autophagy is a conserved, self-degradation system that is critical for maintaining cellular homeostasis. It involves a variety of biological functions, such as development, cellular differentiation, nutritional starvation, and defense against pathogens. However, accumulating evidence has indicated that EVA71 induces autophagy and hijacks the process of autophagy for their optimal infection during the different stages of life cycle. This review provides a perspective on the emerging evidence that the “positive feedback” between autophagy induction and EVA71 infection, as well as its potential mechanisms. Furthermore, autophagy may be involved in EVA71-induced nervous system impairment through mediating intracranial viral spread and dysregulating host regulator involved self-damage. Autophagy is a promising therapeutic target in EVA71 infection.

PurposeTo systematically investigate the characterization of tumor microenvironment (TME) in clear cell renal cell carcinoma (ccRCC), we performed a comprehensive analysis incorporating genomic alterations, cellular interactions, infiltrating immune cells, and risk signature.Patients and MethodsMulti-omics data including RNA-seq, single-nucleotide variant (SNV) data, copy number variation (CNV) data, miRNA, and corresponding prognostic data were obtained from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) database. The CIBERSORT algorithm was utilized to identify prognostic TME subclusters, and TMEscore was further quantified. Moreover, the mutational landscape of TCGA-KIRC was explored. Lastly, TIDE resource was applied to assess the significance of TMEscore in predicting immunotherapeutic benefits.ResultsWe analyzed the TME infiltration patterns from 621 ccRCC patients and identified 5 specific TME subclusters associated with clinical outcomes. Then, we found that TMEcluster5 was significantly related to favorable prognosis and enriched memory B-cell infiltration. Accordingly, we depicted the clustering landscape of TMEclusters, TMEscore levels, tumor mutation burden (TMB), tumor grades, purity, and ploidy in all patients. Lastly, TIDE was used to assess the efficiency of immune checkpoint blockers (ICBs) and found that the TMEscore has superior predictive significance to TMB, making it an essential independent prognostic biomarker and drug indicator for clinical use.ConclusionsOur study depicted the clustering landscape of TMEclusters, TMEscore levels, TMB, tumor grades, purity, and ploidy in total ccRCC patients. The TMEscore was proved to have promising significance for predicting prognosis and ICB responses, in accordance with the goal of developing rationally individualized therapeutic interventions.

An accurate quantitative description of interception is necessary to understand regional water circulation. The revised sparse Gash model (RSGM) is currently used to estimate interception loss. Previous studies have proven that changes in initial plant density, which are caused by thinning, affect the accuracy of RSGM; however, the direct effect of initial density on modeling accuracy remains poorly understood because few studies have collected field data of the same species with various initial densities under similar site conditions. Therefore, six Pinus tabuliformis Carr. plantations with various initial densities were assessed from May to October 2016 in northern China. In summary, RSGM performs better with higher initial densities, and it cannot be suitably applied for plantations with lower initial densities, with the relative error ranging from 18.38 to 53.03%. Sensitivity analysis indicated that the predicted interception is highest sensitive to canopy structure, irrespective of initial density. The influence of climate parameters on simulated results decreased, as initial density increased. These support the notion that amending the representation of the canopy structure in the model and improving the estimation methods for determining the evaporation rate in open canopies can improve accuracy, and that the use of RSGM must first involve the consideration of initial density. HIGHLIGHTS Application of the revised sparse Gash model (RSGM) in six Chinese pine plantations of different initial densities.; RSGM still does not perform well at the sparse initial densities.; Changes in initial plant density can affect the simulation accuracy of RSGM.; Discuss the possibility of perfecting RSGM to improve its accuracy.; Explore the changes in sensitivity of the parameters in RSGM under different initial densities.;

Abstract Background To explore important methylation‐driven genes (MDGs) and risk loci to construct risk model for prognosis of bladder cancer (BCa). Methods We utilized TCGA‐Assembler package to download 450K methylation data and corresponding transcriptome profiles. MethylMix package was used for identifying methylation‐driven genes and functional analysis was mainly performed based on ConsensusPathDB database. Then, Cox regression method was utilized to find prognostic MDGs, and we selected 17 hub genes via stepwise regression and multivariate Cox models. Kruskal‐Wallis test was implemented for comparisons between risk with other clinical variables. Moreover, we constructed the risk model and validated it in GSE13507. Gene set enrichment analysis was performed using the levels of risk score as the phenotype. Additionally, we further screened out the relative methylation sites associated with the 17 hub genes. Cox regression and Survival analysis were conducted to find the specifically prognostic sites. Results Two hundred and twenty‐eight MDGs were chosen by ConsensusPathDB database. Results revealed that most conspicuous pathways were transcriptional mis‐regulation pathways in cancer and EMT. After Cox regression analysis, 17 hub epigenetic MDGs were identified. We calculated the risk score and found satisfactory predictive efficiency by ROC curve (AUC = 0.762). In the validation group from GSE13507, 17 hub genes remained higher predictive value with AUC = 0.723 and patients in high‐risk group. Meanwhile, Kruskal‐Wallis test revealed that higher risk score correlated with a higher level of TNM stage, tumor grade, and advanced pathological stages. Then, identified 38 risk methylated loci that highly associated with prognosis. Last, gene set enrichment analysis revealed that high‐risk level of MDGs may correlate with several important pathways, including MAPK signaling pathway and so on. Conclusion Our study indicated several hub‐MDGs, calculated novel risk score and explored the prognostic value in BCa, which provided a promising approach to BCA prognosis assessment.

Bermudagrass (Cynodon dactylon Pers.) is a wild Poaceae turfgrass with various genotypes and phenotypes. In this study, 16 wild bermudagrass germplasms were collected from 16 different sites along latitudinal gradients, and different temperature treatments were compiled and used for physiological and transcriptome analysis. To explore the correlation between the key differentially expressed genes and physiological indicators, a total of 14,654 DEGs were integrated from the comparison of different temperature treatments and used for weighted gene co-expression network analysis. Through comparative transcriptome analysis and gene annotation, the results showed that differential gene expression profiles in networks are associated with the plant growth, photosystem, redox system, and transcriptional regulation to cold stress in bermudagrass. In particular, genes encoding HSP70/90 and HsfA3/A8 are not only regulated by temperature stress, but also directly or indirectly interplay with the processes of peroxide scavenging and chlorophyll synthesis under cold stress. Besides, through a weight evaluation analysis of various physiological indexes, we identified an accession of wild bermudagrass with relatively strong cold resistance. These results provide important clues and resources to further study the responses to low-temperature stress in bermudagrass.

ObjectiveThe aim of this study is to investigate the biological functions and the underlying mechanisms of DNA polymerase epsilon subunit 2 (POLE2) in renal cell carcinoma (RCC).MethodsThe datasets of POLE2 expression in The Cancer Genome Atlas Kidney Clear Cell Carcinoma (TCGA-KIRC) and International Cancer Genome Consortium (ICGC) databases was selected and the correlation between POLE2 and various clinicopathological parameters was analyzed. The POLE2 expression in RCC tissues was examined by immunohistochemistry. The POLE2 knockdown cell lines were constructed. In vitro and in vivo experiments were carried out to investigate the function of POLE2 on cellular biology of RCC, including cell viability assay, clone formation assay, flow cytometry, wound-healing assay, Transwell assay, qRT-PCR, Western blot, etc. Besides, microarray, co-immunoprecipitation, rescue experiment, and Western blot were used to investigate the molecular mechanisms underlying the functions of POLE2.ResultsPOLE2 was overexpressed in RCC tissues, and high expression of POLE2 was correlated with poor prognosis of RCC. Furthermore, knockdown of POLE2 significantly inhibited cell proliferation, migration, and facilitated apoptosis in vitro. In vivo experiments revealed that POLE2 attenuated RCC tumorigenesis and tumor growth. we also illuminated that stanniocalcin 1 (STC1) was a downstream gene of POLE2, which promoted the occurrence and development of RCC. Besides, knockdown of POLE2 significantly upregulated the expression levels of Bad and p21 while the expression levels of HSP70, IGF-I, IGF-II, survivin, and sTNF-R1 were significantly downregulated. Western blot analysis also showed that knockdown of POLE2 inhibited the expression levels of Cancer-related pathway proteins including p-Akt, CCND1, MAPK9, and PIK3CA.ConclusionKnockdown of POLE2 attenuates RCC cells proliferation and migration by regulating STC1, suggesting that POLE2-STC1 may become a potential target for RCC therapy.

PurposeThis study aimed to evaluate the clinical utility of 18F-PSMA-1007 positron emission tomography (PSMA PET)/magnetic resonance imaging (MRI) imaging in patients with suspected or defined prostate cancer.MethodsIn the pilot study, we retrospectively investigated 62 patients who underwent PSMA-PET/MRI for suspected or defined PCa between June 2019 and June 2020. Patients were grouped into three subgroups: (1) suspected PCa without histological evidence, (2) primary PCa, (3) biochemical recurrent prostate cancer (BRPCa). Two nuclear physicians independently interpreted the results of PSMA-PET/MRI. Management strategies before PSMA-PET/MRI were retrospectively reported, and the management strategy was re-evaluated for each patient considering the PSMA-PET/MRI result. The changes in strategies were recorded. Besides, the correlation between prostate specific antigen (PSA) level and management changes was also accessed by Fisher exact test, and two-side p < 0.05 was assumed as statistical significance.ResultsThere were 28 patients in the suspected PCa group (group 1), 12 in the primary PCa group (group 2), and 22 in the BRPCa group (group 3). Overall, the intended decisions were changed in 26 (41.9%) of 62 patients after PSMA-PET/MRI, including 11/28 (39.3%) in suspected PCa group, 1/12 (8.4%) in primary PCa group, and 14/24 (63.6%) in BCR group. In group 1, the main impact on subsequent management included decreased active surveillance (from 20 to 9) and increased prostate biopsy (from 8 to 19). PSA levels were not significantly associated with management changes in suspected PCa patients (p = 0.865). In group 2, the main impact on subsequent management included decreased radical surgery (from 8 to 7), and multimodal therapy appearance (n = 1). Only in the category of PSA levels of ≥20 ng/ml, the management of primary PCa was changed. In group 3, the main impact on subsequent management included decreased salvage radiotherapy (from 5 to 2), increased systemic therapy (from 6 to 7), and increased multimodal therapy (from 11 to 13). The highest proportion of management changes occurred in BCR patients with 0.5≤PSA

Abstract Aberrant epigenetic reprogramming represents a hallmark of renal cell carcinoma (RCC) tumorigenesis and progression. Whether there existed other epigenetic vulnerabilities that could serve as therapeutic targets remained unclear and promising. Here, we combined the clustered regularly interspaced short palindromic repeats functional screening results and multiple RCC datasets to identify JMJD6 as the potent target in RCC. JMJD6 expression correlated with poor survival outcomes of RCC patients and promoted RCC progression in vitro and in vivo. Mechanistically, aberrant p300 led to high JMJD6 expression, which activated a series of oncogenic crosstalk. Particularly, high‐throughput sequencing data revealed that JMJD6 could assemble super‐enhancers to drive a list of identity genes in kidney cancer, including VEGFA, β‐catenin, and SRC. Moreover, this JMJD6‐mediated oncogenic effect could be suppressed by a novel JMJD6 inhibitor (SKLB325), which was further demonstrated in RCC cells, patient‐derived organoid models, and in vivo. Given the probable overlapped crosstalk between JMJD6 signature and tyrosine kinase inhibitors downstream targets, targeting JMJD6 sensitized RCC to sunitinib and was synergistic when they were combined together. Collectively, this study indicated that targeting JMJD6 was an effective approach to treat RCC patients.

Alfalfa polysaccharides (AP) receive wide attention in the field of medicine, because of their anti-inflammatory property. However, AP has high molecular weight and poor water solubility, resulting in low biological activity. We wanted to obtain highly bioactive alfalfa polysaccharides for further research. Herein, we successfully synthesized highly substituted sulfated alfalfa polysaccharides (SAP) via the chlorosulfonic acid (CSA)-pyridine (Pyr) method, which was optimized using response surface methodology (RSM). Under the best reaction conditions, that is, the reaction temperature, time, and ratio of CSA to Pyr being 55 °C, 2.25 h, and 1.5:1, respectively, the maximum degree of substitution of SAP can reach up to 0.724. Fourier transform infrared spectroscopy also confirmed the existence of sulfonic acid groups on SAP. Despite the increased average molecular weight of SAP, its water solubility is improved, which is beneficial for its biological activity. Further in vitro results showed that SAP exhibited better antioxidant activity and antibacterial ability than AP. Besides, the former can efficiently enhance the viability of oxidatively stressed intestinal epithelial cells compared with the latter. Furthermore, SAP has the potential to inhibit obesity. It is concluded that sulfation modification could improve the antioxidant, antibacterial, bovine intestinal epithelial cells’ proliferation-promoting, and the obesity inhibition abilities of AP. The improvement of AP biological activity may provide references for the utilization of plant extracts that have weaker biological activity.

Objective To evaluate the impact of an enhanced recovery after surgery (ERAS) pathway on patients undergoing minimally invasive radical prostatectomy at a single institute. Methods In this retrospective study, 301 patients who underwent laparoscopic or robot-assisted laparoscopic radical prostatectomy from May 2014 to September 2018 were consecutively recruited. Before April 2017, the patients were treated with conventional care; all patients were treated with the ERAS pathway thereafter. The primary outcome was the postoperative length of hospital stay (LOS). The secondary outcomes were hospitalization costs and postoperative complications. Results In total, 138 patients were treated with the ERAS pathway, and the remaining patients underwent conventional care. The postoperative LOS was significantly shorter in the ERAS group than in the conventional group (median, 6 vs. 8 days). The hospitalization costs were also significantly lower in the ERAS group ($4086 vs. $5530). Ten (6.1%) patients in the ERAS group and 17 (12.3%) patients in the conventional group developed postoperative complications. The multivariable analysis showed that ERAS care was a significant independent predictive factor for a shortened LOS and reduced hospitalization costs. Conclusions The ERAS pathway was associated with a shortened LOS and reduced hospitalization costs for patients undergoing minimally invasive radical prostatectomy.

The kinetics, activation energy, and mechanism of esterification of cotton by mixed polycarboxylic acids, namely, 1,2,3,4-butanetetracarboxylic acid (BTCA) and citric acid (CA), were studied during the curing process of cotton fibers in comparison with the esterification by BTCA alone. The reaction rates of these two polycarboxylic acid finishing systems under different temperatures and the dependency of their reaction rate constants on temperature were studied. Consequently, in the temperature range from 120°C to 180°C, the activation energy of the mixed polycarboxylic acids (BTCA+CA) was obtained as Ea=40.7 kJ/mol, which was slightly lower than that for the BTCA finishing system. The reaction occurring between the carboxylic acid group of BTCA and the hydroxyl group of CA was proposed. To confirm and prove the speculation, experiments were conducted to investigate the changes in wrinkle recovery angle and tensile strength retention by changing the concentration of both the single polycarboxylic acid and mixed polycarboxylic acids. The results show that, besides esterification of cotton fibers, citric acid probably functioned as an extender in the curing process, when it was combined with BTCA.

Ecological restoration (ER) programs play an important role in local and global climate change and carbon management policy interventions. Water resource is a key criterion for assessing the sustainability of ERs. Herein, we explored the spatiotemporal patterns of rainfall interception (RI, an important component of ecosystem water budgets), and its drivers after ER implementation in China. Further, we assessed whether ERs are sustainable by analyzing the trends of RI and water supply. As expected, we found that ERs caused an increase in RI in China from 2001 to 2018 (0.64 mm yr ^−1 , p < 0.01). Changes in the normalized difference vegetation index and leaf area index contributed to a higher change in RI compared with other drivers. The decrease in RI was mainly recorded in the Qinghai–Tibet Plateau in Southwest, northern North, and southern Central and Southern China. Conversely, an increasing trend of RI was recorded in the Loess Plateau in Northwest, Northeast, and East China. Moreover, ERs are not always unsustainable in China, especially in Northeast, East, Central and Southern, and high-latitude regions of northern North China. Even in the Loess Plateau, which was criticized by previous studies, the unsustainability occurred only in the semi-humid region. Future ERs should be prioritized in southern parts of Eastern, Central, and Southern China, and must be appropriately considered in the Northeast and high-latitude regions in North China. It should be alert to the pressures of ERs on water supply, and its demand remains vigilant in the Qinghai–Tibet Plateau and semihumid areas of the Loess Plateau. This study provides new ideas for accurately evaluating the impact of ERs on water security and the sustainability of ERs.

The compound 2-phosphonobutane-1,2,4-tricarboxylic acid (PBTCA) is an eco-friendly water treatment agent possessing flame-retardant phosphorus element and multi-carboxylic acid groups in its molecular structure. In the present work, PBTCA is employed as a finishing agent to improve the flame retardancy of the wool fabrics by the pad-dry-cure technique. The treated wool (10.2% weight gain) by 100 g/L of PBTCA showed an increased flame retardancy with a limiting oxygen index value (LOI) of 44% with a minimum char length of 40 mm. Importantly, the treated wool can self-extinguish after 30 washing cycles. The PBTCA-treated wool exhibited better stability with obviously increased char residue of 39.7% and 28.7% at 600 °C, while only 25.9% and 13.2% were measured for the control wool in nitrogen and air atmosphere, respectively. In addition, the high thermal stability of the treated wool with astonishing char-forming ability is confirmed by the SEM images of the wool after the isothermal heating treatment at different temperatures. Finally, a two-stage flame-retarding mechanism of enhanced crosslinking and char formability of PBTCA-treated wool is proposed and analyzed by infrared spectroscopy (TG-FTIR) and thermal (DSC and TGA) results of the pyrolytic volatiles of the treated wool.

Abstract Background To assess the safety and efficacy of laparoscopic retroperitoneal resection for retroperitoneal lymphatic cysts. Methods A retrospective analysis was conducted based on clinical data from eight patients with hydronephrosis caused by retroperitoneal lymphatic cysts. All patients underwent laparoscopic retroperitoneal lymphatic cyst resection and received postoperative follow-up. A follow-up ultrasound was performed postoperatively every 6–12 months to evaluate the recovery of the hydronephrosis. Results All operations were successful, and their postoperative pathological results revealed lymphatic cyst walls. The operation time ranged from 43 to 88 min (mean: 62 min), with a blood loss of 20 to 130 mL (mean: 76 mL), and the length of hospital stay was 3 to 6 days (mean: 4.5 days). Within the follow-up of 12 to 36 months (mean: 28.5 months), great relief was detected in all eight cases, and no recurrence was found. Moreover, complications such as renal pedicle or renal pelvis injury were not observed. Conclusions Laparoscopic retroperitoneal lymphatic cyst resection is an effective treatment for retroperitoneal lymphatic cysts and has the advantages of being minimally invasive, producing less intraoperative blood loss and leading to a quick recovery. This treatment thus deserves further studies.