Background:Resistance to sunitinib represents a major clinical obstacle in the management of clear cell renal cell carcinoma(ccRCC).This investigation aims to identify genes associated with sunitinib resistance and el...Background:Resistance to sunitinib represents a major clinical obstacle in the management of clear cell renal cell carcinoma(ccRCC).This investigation aims to identify genes associated with sunitinib resistance and elucidate potential molecular pathways in ccRCC.Methods:To identify differentially expressed genes(DEGs)in sunitinib-resistant ccRCC cells and their parental cells,bioinformatic analysis was performed on the GSE216494 dataset.Protein-protein interaction(PPI)network and topological analyses pinpointed a hub gene.Sunitinib-resistant A498 and 786-O cell lines were employed for in vitro validation.Sunitinib sensitivity and cell proliferation were evaluated using functional assays,such as colony formation and Cell Counting Kit-8(CCK-8).Protein interactions and signaling pathway activity are investigated using co-immunoprecipitation(Co-IP),dual-luciferase reporter assays,and immunofluorescence.In resistant cells and patient-derived organoids(PDOs),the therapeutic potential of olaparib,either by itself or in conjunction with sunitinib,was assessed.Results:Sunitinib-resistant cells and patient tissues were shown to exhibit consistent upregulation of poly(ADP-ribose)polymerase 9(PARP9).PARP9 knockdown sensitized resistant cells to sunitinib,suppressing proliferation.Conversely,its overexpression induced resistance in parental cells.Additionally,STAT1 and PARP9 interact to promote nuclear translocation and STAT1 phosphorylation.Activation of the STAT1/IRF1 axis further enhanced the expression of ISG15 and IFIT1.Olaparib treatment can increase sunitinib-resistant ccRCC cells.Olaparib can weaken the STAT1/IRF1 signaling pathway and prevent sunitinib-resistant ccRCC cells from proliferating.Importantly,combination treatment with olaparib and sunitinib showed superior antitumor efficacy in ccRCC PDOs.Conclusion:This study demonstrates that PARP9 promotes sunitinib resistance in ccRCC by activating the STAT1/IRF1 pathway and upregulating ISG15/IFIT1.展开更多
Background:Renal cell carcinoma(RCC)is the most common type of kidney cancer in adults,with a poor prognosis in advanced stages.Although histological tumor grading is an established prognostic parameter,it often fails...Background:Renal cell carcinoma(RCC)is the most common type of kidney cancer in adults,with a poor prognosis in advanced stages.Although histological tumor grading is an established prognostic parameter,it often fails to capture the biological heterogeneity of RCC.Therefore,identifying novel biomarkers could enhance early diagnosis and improve predictive accuracy.Here,we aimed to test whether immunophenotypes of specific glutathione peroxidase(GPX)family members may have prognostic value in RCC.Methods:We investigated the relationship between GPX1 and GPX3 immunophenotypes and clinicopathological parameters in 32 surgical specimens of clear cell RCC(ccRCC)with nucleolar grade 1-4(WHO/ISUP grading).We evaluated the GPX1 and GPX3 immunophenotypes and assigned a histological immunoscore for each marker.For analysis,we used Spearman and point-biserial correlation methods.Results:Our findings indicated a significant positive correlation between GPX1 immunoscore and high nucleolar grade(r=0.80,p0.05),nor with capsular infiltration and invasion of the renal pelvis(p>0.05).However,we did find statistically significant positive correlations between GPX1 expression and invasion of the renal vein(p=0.038),perirenal fat(p=0.043),and peripyelic fat(p=0.015).Conclusion:Our data demonstrate that GPX1 and GPX3 immunophenotypes could have a prognostic role for ccRCC,particularly in relation to nucleolar grade.This study has limitations because of the small sample size;however,it underscores the necessity for further research in larger,prospective studies.These studies should more thoroughly examine the associations between GPX1 and GPX3 and clinicopathological parameters,and validate them as potential novel prognostic biomarkers.展开更多
Background:Clear cell sarcoma of the kidney(CCSK)is a rare and highly aggressive pediatric renal malignancy with a marked propensity for metastatic spread.Cases of CCSK associated with inferior vena cava(IVC)tumor thr...Background:Clear cell sarcoma of the kidney(CCSK)is a rare and highly aggressive pediatric renal malignancy with a marked propensity for metastatic spread.Cases of CCSK associated with inferior vena cava(IVC)tumor thrombus(IVCTT)are exceptionally uncommon in the literature.We report a case of CCSK with IVCTT in a 15-month-old male infant.Case Description:We reported a case admitted in May 2020 for a 3-day history of fever and hematuria.Abdominal CT revealed an unevenly enhanced mass and low-density shadows within the IVC.The diagnosis of CCSK was confirmed via needle biopsy.The patient received 4 cycles of adjuvant chemotherapy.The initial surgery lasted 10 h with 600 mL blood loss,and primary closure was achieved.Postoperative management included 6 cycles of radiotherapy and 5 cycles of chemotherapy.In March 2022,CT detected IVCTT recurrence,requiring surgical intervention involving thrombus removal and partial IVC resection.This procedure lasted 8 h with 300 mL blood loss,followed by 5 additional chemotherapy cycles.The patient showed no sign of IVC obstruction,including varicose veins or lower limb edema,and maintained renal function throughout follow-up.However,Intracranial metastases were detected 15 months postoperatively.After the family opted against additional treatment,the patient succumbed to the disease.Conclusions:The management of CCSK associated with IVCTT should include consideration of IVC thrombectomy.In case of recurrent IVCTT with preserved collateral circulation,combined thrombus excision and partial IVC resection may be warranted.展开更多
Acupuncture therapy has demonstrated therapeutic effects on various systemic diseases through the use of specific acupoints along meridians.However,due to the multi-target effect of acupuncture and the complexity of m...Acupuncture therapy has demonstrated therapeutic effects on various systemic diseases through the use of specific acupoints along meridians.However,due to the multi-target effect of acupuncture and the complexity of meridian pathways,the underlying mechanisms of acupuncture have not been well understood.Tissue clearing and three-dimensional(3D)imaging is an emerging medical technology that provides high-resolution 3D molecular information while preserving the structural integrity of tissues.In relevant research articles,tissue-clearing and 3D imaging techniques stood out for their ability to visualize the structural characteristics of meridians and acupoints of intact tissues,in order to reveal their intricate connections by means of topological principles.Specifically,this technology has managed to show that acupuncture points like Guilai(ST29)and Sanyinjiao(SP6),which are commonly used in traditional Chinese medicine for treating gynecological disorders,promote angiogenesis in the ovaries and thus improve follicle numbers in polycystic ovary syndrome-like ovaries.This article summarizes recent progress on tissue-clearing and 3D imaging technologies and anticipates the prospects of utilizing this technology to further explore the effects of acupuncture.展开更多
Clear aligner treatment is a novel technique in current orthodontic practice.Distinct from traditional fixed orthodontic appliances,clear aligners have different material features and biomechanical characteristics and...Clear aligner treatment is a novel technique in current orthodontic practice.Distinct from traditional fixed orthodontic appliances,clear aligners have different material features and biomechanical characteristics and treatment efficiencies,presenting new clinical challenges.Therefore,a comprehensive and systematic description of the key clinical aspects of clear aligner treatment is essential to enhance treatment efficacy and facilitate the advancement and wide adoption of this new technique.This expert consensus discusses case selection and grading of treatment difficulty,principle of clear aligner therapy,clinical procedures and potential complications,which are crucial to the clinical success of clear aligner treatment.展开更多
The increasing complexity of China’s electricity market creates substantial challenges for settlement automation,data consistency,and operational scalability.Existing provincial settlement systems are fragmented,lack...The increasing complexity of China’s electricity market creates substantial challenges for settlement automation,data consistency,and operational scalability.Existing provincial settlement systems are fragmented,lack a unified data structure,and depend heavily on manual intervention to process high-frequency and retroactive transactions.To address these limitations,a graph-based unified settlement framework is proposed to enhance automation,flexibility,and adaptability in electricity market settlements.A flexible attribute-graph model is employed to represent heterogeneousmulti-market data,enabling standardized integration,rapid querying,and seamless adaptation to evolving business requirements.An extensible operator library is designed to support configurable settlement rules,and a suite of modular tools—including dataset generation,formula configuration,billing templates,and task scheduling—facilitates end-to-end automated settlement processing.A robust refund-clearing mechanism is further incorporated,utilizing sandbox execution,data-version snapshots,dynamic lineage tracing,and real-time changecapture technologies to enable rapid and accurate recalculations under dynamic policy and data revisions.Case studies based on real-world data from regional Chinese markets validate the effectiveness of the proposed approach,demonstrating marked improvements in computational efficiency,system robustness,and automation.Moreover,enhanced settlement accuracy and high temporal granularity improve price-signal fidelity,promote cost-reflective tariffs,and incentivize energy-efficient and demand-responsive behavior among market participants.The method not only supports equitable and transparent market operations but also provides a generalizable,scalable foundation for modern electricity settlement platforms in increasingly complex and dynamic market environments.展开更多
Immune checkpoint inhibitors(ICIs)combined with vascular endothelial growth factor tyrosine kinase inhibitors(VEGF-TKIs)have transformed the treatment landscape of advanced clear cell renal cell carcinoma(ccRCC).Curre...Immune checkpoint inhibitors(ICIs)combined with vascular endothelial growth factor tyrosine kinase inhibitors(VEGF-TKIs)have transformed the treatment landscape of advanced clear cell renal cell carcinoma(ccRCC).Current guidelines favour ICI plus VEGF-TKI(IO+TKI)combinations for favourable-risk disease(International Metastatic RCC Database Consortium[IMDC]score 0)based on improved objective response rates and progression-free survival.However,no IO+TKI combination has demonstrated a statistically significant overall survival(OS)benefit in this subgroup.A pooled analysis of four pivotal phase III trials(n=839 favourable-risk patients)revealed no OS advantage for IO+TKI versus sunitinib monotherapy(hazard ratio[HR]1.24;95%CI 0.86-1.78)despite higher toxicity rates(71-82%Grade≥3 adverse events vs.63-72%with sunitinib)and substantially greater cost.The IMDC favourable-risk category represents approximately 20%of metastatic ccRCC cases and is often characterised by indolent disease biology.Emerging molecular classifications reveal distinct transcriptomic subgroups,including an angiogenic subtype(ccA/CC-e.2/clusters 1-2)enriched in favourable-risk patients,characterised by high hypoxia-inducible factor(HIF)pathway gene expression,frequent PBRM1 mutations,robust VEGF-TKI responsiveness,and comparatively lower benefit from immunotherapy.Current clinical risk stratification fails to capture this molecular heterogeneity,limiting optimal treatment selection.VEGF-TKI monotherapy(median OS 47.6-79.4 months)and active surveillance remain valid,evidence-based alternatives in carefully selected favourable-risk patients,particularly those with asymptomatic,metachronous,or otherwise indolent disease.Uncritical universal use of IO+TKI in this population may therefore represent overtreatment.The development and validation of predictive biomarkers,refinement of molecular risk stratification,and exploration of novel agents with more favourable toxicity profiles(e.g.,HIF-2αinhibitors)are urgently required to personalise therapy and identify candidates for rational treatment de-escalation.展开更多
The construction of spot electricity markets plays a pivotal role in power system reforms,where market clearing systems profoundly influence market efficiency and security.Current clearing systems predominantly adopt ...The construction of spot electricity markets plays a pivotal role in power system reforms,where market clearing systems profoundly influence market efficiency and security.Current clearing systems predominantly adopt a single-system architecture,with research focusing primarily on accelerating solution algorithms through techniques such as high-efficiency parallel solvers and staggered decomposition of mixed-integer programming models.Notably absent are systematic studies evaluating the adaptability of primary-backup clearing systems incontingency scenarios—a critical gap given redundant systems’expanding applications in operational environments.This paper proposes a comprehensive evaluation framework for analyzing dual-system adaptability,demonstrated through an in-depth case study of the Inner Mongolia power market.First,we establish the innovative“Dual-Active Heterogeneous”architecture that enables independent parallelized operation and fault-isolated redundancy.Subsequently,key performance indices are quantitatively evaluated across four critical dimensions:unit commitment decisions,generator output constraints,transmission section congestion patterns,and clearing price formation mechanisms.An integrated fuzzy evaluation methodology incorporating grey relational analysis is employed for objective indicator weighting,enabling systematic quantification of system superiority under specific grid operating states.Empirical results based on actual operational data from 200 generation units demonstrate the framework’s efficacy in guiding optimal system selection,with particularly strong performance observed during peak load periods.The proposed approach shows high generalization potential for other regional markets employing redundant clearing mechanisms—particularly those with increasing renewable penetration and associated uncertainty.展开更多
Background:Clear cell renal carcinoma(ccRCC),the leading histological subtype of RCC,lacks any targeted therapy options.Although some studies have shown that early growth response factor 1(EGR1)has a significant role ...Background:Clear cell renal carcinoma(ccRCC),the leading histological subtype of RCC,lacks any targeted therapy options.Although some studies have shown that early growth response factor 1(EGR1)has a significant role in cancer development and progression,its role and underlying mechanisms in ccRCC remain poorly understood.Methods:The Cancer Genome Atlas(TCGA)database was utilized to examine the expression of EGR1 in ccRCC.The expression of EGR1 in 55 ccRCC tissues was evaluated using immunohistochemistry.The link between EGR1 expression and clinicopathological variables was examined through an analysis.Gain-of-function assays were employed to investigate EGR1’s biological functions in ccRCC cells,involving proliferation,colony formation,invasion assays,and tumorigenesis in nude mice.In order to assess the protein expression of mitogen-activated protein kinase 15(MAPK15),E-cadherin,matrix metalloproteinase-9/-2(MMP-9 and MMP-2),Western blot technique was applied.Results:The results revealed a decrease in EGR1 expression in ccRCC tissues.This decrease was strongly linked to TNM stage,lymphatic metastasis,tumor size,histological grade,and unfavorable prognosis in ccRCC patients.It has been demonstrated that overexpressing EGR1 inhibits the growth of xenograft tumors in vivo and inhibits cell colony formation,motility,and invasion in vitro.Furthermore,EGR1 can prevent the development and movement of ccRCC cells by controlling the expression of MMP-2,MMP-9,E-cadherin,and MAPK15.Conclusions:The EGR1/MAPK15 axis may represent a promising target for drug development,with EGR1 serving as a possible target for ccRCC therapy.展开更多
Objective To identify pyroptosis,apoptosis,and necroptosis(PANoptosis)-related genes(PRGs)in clear cell renal cell carcinoma(ccRCC)for patient stratification and prognosis prediction.Methods We used differential expre...Objective To identify pyroptosis,apoptosis,and necroptosis(PANoptosis)-related genes(PRGs)in clear cell renal cell carcinoma(ccRCC)for patient stratification and prognosis prediction.Methods We used differential expression analysis and weighted gene co-expression network analysis(WGCNA)to identify ccRCC-specific PRGs.A prognostic model,the PANoptosis-index(PANI),was constructed using least absolute shrinkage and selection operator(LASSO)and Cox regression.The PANI model,comprising PRGs,was validated through single-cell RNA-sequencing(scRNA-seq),immunohistochemistry,and reverse transcription-quantitative polymerase chain reaction(RT-qPCR).Patient cohorts were categorized into high-and low-PANI groups,and the model’s performance was appraised using various metrics.External validation was performed with the E-MTAB-1980 dataset.Functional and gene set enrichment analyses distinguished biological differences between groups.Mutational landscapes and tumor immune microenvironments were compared.Sensitivity to immunotherapy and antineoplastic drugs was also predicted using PANI.The effects of Z-DNA-binding protein 1(ZBP1)on cell proliferation and migration were assessed by cell counting kit-8(CCK-8)and Transwell assays.Results We identified five PRGs(ZBP1,tumor necrosis factor superfamily protein 14(TNFSF14),cyclin-dependent kinase inhibitor 3(CDKN3),parathyroid hormone-like hormone(PTHLH),and heme-oxygenase 1(HMOX1))constituting PANI,independently associated with ccRCC patient prognosis.The PANI-based nomogram,integrated with clinical factors,demonstrated high predictive accuracy for prognosis.High-PANI patients exhibited distinct co-mutation patterns in ccRCC driver genes and lower survival probabilities,with an enriched immune-related functional profile,indicating an activated immune environment.These patients also showed increased sensitivity to immunotherapy and antineoplastic drugs.The knockdown of ZBP1,a key PRG in the PANI,significantly reduced ccRCC cell proliferation and migration.Conclusions PANI provides precise prognosis and immunotherapy response predictions for ccRCC patients,facilitating individualized treatment strategies.展开更多
Combining transparent embedding with sectioning is likely to be the future direction for tissue clearing and 3-dimensional(3D)imaging.A newly published transparent embedding system,TESOS(Transparent Embedding Solvent ...Combining transparent embedding with sectioning is likely to be the future direction for tissue clearing and 3-dimensional(3D)imaging.A newly published transparent embedding system,TESOS(Transparent Embedding Solvent System),ensures consistent submicron resolution imaging throughout the entire sample,and can be compatible with different microscopy systems.This method shows great potential in connectome mapping,and might be an optimal option for future 3D multiplex immunofluorescence and RNA in situ hybridization imaging.Additional efforts would be needed to innovate labeling,imaging,and data processing strategies to fully utilize the potential of transparent embedding systems in highresolution imaging of large-scale samples.展开更多
Glycerophosphodiester phosphodiesterase 1(GDPD1)plays an important function in the abiotic stress responses and participates in the accumulation of sn-glycerol-3-phosphate(G3P)in plants,which is key to plant systemic ...Glycerophosphodiester phosphodiesterase 1(GDPD1)plays an important function in the abiotic stress responses and participates in the accumulation of sn-glycerol-3-phosphate(G3P)in plants,which is key to plant systemic acquired resistance(SAR).However,the role of GDPD1 in plant responses to biotic stress remains poorly understood.This study characterized the antivirus function of the GDPD1 gene(designated as ClGDPD1)from Eureka lemon.ClGDPD1 is located in the membrane and endoplasmic reticulum,where it interacts with the citrus yellow vein clearing virus(CYVCV)coat protein(CP).Compared to individually expressed ClGDPD1 or coexpressed ClGDPD1+CP140-326,transiently coexpressed ClGDPD1+CP or ClGDPD1+CP1-139 significantly upregulated the key substance contents and genes expression involved in glycerophospholipid metabolism.Over-expression of ClGDPD1 significantly facilitated the accumulation of G3P,upregulated the expression of SAR-related genes,and increased the resistance of transgenic Eureka lemon to CYVCV infection.Furthermore,exogenous glycerol treatment and over-expression of ClGPDH increased the G3P content and reduced CYVCV titers in plants or hairy roots.These results indicated that the enhanced resistance of ClGDPD1 transgenic Eureka lemon to CYVCV may be due to facilitating G3P accumulation through the interaction of ClGDPD1 with CP.Our findings provide novel insights into the role of ClGDPD1 as an important regulatory center in mediating the citrus defense response to viral infections.展开更多
Background:Clear cell renal cell carcinoma(ccRCC)is an aggressive malignancy associated with limited treatment options and poor prognosis.Emerging studies suggest that the actin-regulating protein actin-related protei...Background:Clear cell renal cell carcinoma(ccRCC)is an aggressive malignancy associated with limited treatment options and poor prognosis.Emerging studies suggest that the actin-regulating protein actin-related protein 2/3 complex subunit 1B(ARPC1B),a key regulatory protein within the actin cytoskeleton,could play a pivotal role in ccRCC progression.The current study aimed to uncover the biological functions of ARPC1B and the molecular mechanisms driving its effects in ccRCC.Methods:ARPC1B expression and prognostic implications were analyzed using data sourced from the Gene Expression Profiling Interactive Analysis(GEPIA)platform,immunohistochemical(IHC)staining on 150 tumor samples along with 30 corresponding normal tissues,and Western blotting(WB)analyses across multiple ccRCC-derived cell lines.Functional assays assessing cell proliferation,colony formation capability,migration,invasion,and in vivo tumorigenicity were conducted following either ARPC1B suppression or upregulation.Additionally,WB analysis was utilized to evaluate proteins linked to epithelial-to-mesenchymal transition(EMT)and the Wnt/β-catenin pathway.Results:The findings revealed a substantial elevation of ARPC1B in ccRCC tissues and cell lines,significantly associated with advanced TNM stages,higher Fuhrman grades,and reduced overall survival(OS)(p<0.001).Multivariate statistical analysis identified ARPC1B as a standalone prognostic factor.Silencing ARPC1B notably impaired ccRCC cellular activities,and tumorigenesis in animalmodels,whereas augmented ARPC1B expression enhanced these malignant phenotypes.Mechanistically,downregulation of ARPC1B suppressed Wnt/β-catenin signaling and disrupted EMT,indicated by reducedβ-catenin,c-Myc,cyclin D1,and ZEB-1 levels,and concurrently increased E-cadherin expression.Additionally,reactivation of theWnt/β-catenin pathway partly reversed the inhibitory effects of ARPC1B depletion on tumor growth and invasiveness.Conclusions:ARPC1B emerges as an essential oncogenic factor in ccRCC by stimulating EMT and activating the Wnt/β-catenin pathway,ultimately enhancing tumor aggressiveness and metastatic potential.Thus,targeting ARPC1B represents a promising therapeutic strategy,warranting further exploration in ccRCC management.展开更多
Purpose–As an important part of the management of railway passenger transport,the rationality and effectiveness of the clearing method of railway passenger transport are directly related to the operating efficiency a...Purpose–As an important part of the management of railway passenger transport,the rationality and effectiveness of the clearing method of railway passenger transport are directly related to the operating efficiency and service quality of railway passenger transport enterprises.This paper aims to comprehensively and deeply discuss the evolution and development process of China’s railway passenger transport clearing method,analyze its characteristics and influences in each stage,identify the main factors affecting its evolution and development and then put forward thoughts on improving the future development of the clearing method.Design/methodology/approach–Through a detailed review of the railway passenger transport clearing methods from the planned economy period to the reform and opening up period and into the new century,the basis,mode,subject and object of clearing in different development stages are systematically compared.Findings–It comprehensively reveals the evolution of the clearing method,sorted out the characteristics and changes of the clearing method at each stage and the adaptability to the development of railway passenger transport at that time.The characteristics of the development of clearing measures for railway passenger transport in different stages and their far-reaching influence on railway passenger transport business are deeply analyzed.Originality/value–This paper summarized the factors influencing the development of China’s railway passenger transportation clearing approach evolution,including the simplified rules of clearing,enhanced the market adaptability,establishing and perfecting the incentive mechanism,strengthening the construction of informatization,etc.This paper puts forward the ways to improve the railway passenger transportation clearing future development thinking.展开更多
Background:This research aims to investigate potential gene targets and mechanisms through which the traditional Chinese medicine(TCM)Bupleuri Radix(Chaihu)may impact on clear cell renal cell carcinoma(ccRCC)treatment...Background:This research aims to investigate potential gene targets and mechanisms through which the traditional Chinese medicine(TCM)Bupleuri Radix(Chaihu)may impact on clear cell renal cell carcinoma(ccRCC)treatment.Methods:Public databases were employed to identify Cedrenol,an active component of Bupleuri Radix,and its associated gene targets.Among these,the gene RORC(also known as RORγ)was selected for detailed analysis due to its high expression correlation.Expression levels of RORC across various cancers were assessed using the TCGA pan-cancer dataset.Further analyses,including differential expression,prognostic relevance,immune infiltration,single-gene,and functional enrichment analyses,were conducted using the TCGA ccRCC dataset.Additionally,potential drug sensitivities and molecular docking interactions with RORC were explored using the GSCALite and CellMiner databases.The effects of RORC on ccRCC were also validated through cellular experiments.Results:RORC exhibited elevated expression in clear cell renal carcinoma tissue in contrast to normal tissues,and lower RORC expression was related to better prognosis.Immune cell infiltration analysis suggested that RORC may influence the penetration of cells that inhibit immune responses,such as regulatory T cells,thereby affecting ccRCC progression.Furthermore,molecular docking studies revealed that several drugs,including Axitinib,Docetaxel,Methotrexate,and Temsirolimus,have a high affinity for RORC and exhibit strong molecular binding.In cellular experiment experiments confirmed that RORC knockdown led to reduced proliferation,metastasis,and ccRCC cell invasion.Conclusion:The study implies that RORC may be a potential gene target for Bupleuri Radix in the management of ccRCC.展开更多
Objective:Wallerian degeneration is a pathological process closely related to peripheral nerve regeneration following injury,and includes the disintegration and phagocytosis of peripheral nervous system cells.Traditio...Objective:Wallerian degeneration is a pathological process closely related to peripheral nerve regeneration following injury,and includes the disintegration and phagocytosis of peripheral nervous system cells.Traditionally,morphological changes are observed by performing immunofluorescence staining after sectioning,which results in the loss of some histological information.The purpose of this study was to explore a new,nondestmetive,and systematic method for observing axonal histological changes during Wallerian degeneration.Methods:Thirty male Thy1-YFP-16 mice(SPF grade,6 weeks old,20±5 g)were randomly selected and divided into clear,unobstructed brain imaging cocktails and computational analysis(CUBIC)optical clearing(n=15)and traditional method groups(n=15).Five mice in each group were sacrificed at 1st,3rd,and 5th day following a crush operation.The histological axon changes were observed by CUBIC light optical clearing treatment,direct tissue section imaging,and HE staining.Results:The results revealed that,compared with traditional imaging methods,there was no physical damage to the samples,which allowed for three-dimensional and deep-seated tissue imaging through CUBIC.Local image information could be nicely obtained by direct fluorescence imaging and HE staining,but it was difficult to obtain image information of the entire sample.At the same time,the image information obtained by fluorescence imaging and HE staining was partially lost.Conclusion:The combining of CUBIC and Thy1-YFP transgenic mice allowed for a clear and comprehensive observation of histological changes of axons in Wallerian degeneration.展开更多
Objective:Clear cell renal cell carcinoma(ccRCC)is the most common subtype of renal cell carcinoma(RCC)and is characterized by biallelic inactivation of the von Hippel-Lindau(VHL)tumor suppressor gene.One effect of VH...Objective:Clear cell renal cell carcinoma(ccRCC)is the most common subtype of renal cell carcinoma(RCC)and is characterized by biallelic inactivation of the von Hippel-Lindau(VHL)tumor suppressor gene.One effect of VHL inactivation is hypoxia inducible factor alpha(HIFa)-independent constitutive activation of nuclear factor kappa B(NF-κB)and c-jun N-terminal kinase(JNK).Both NF-κB and JNK drive ccRCC growth and epithelial to mesenchymal transition(EMT).The purpose of this study was to determine the biochemical effects of pomegranate juice extracts(PE)on RCC cell lines.Methods:The pre-clinical effects of PE on NF-κB,JNK,and the EMT phenotype were assayed,including its effect on proliferation,anchorage-independent growth,and invasion of pVHLdeficient RCCs.Results:PE inhibits the NF-κB and JNK pathways and consequently inhibits the EMT phenotype of pVHL-deficient ccRCCs.The effects of PE are concentration-dependent and affect not only biochemical markers of EMT(i.e.,cadherin expression)but also functional manifestations of EMT,such as invasion.These effects are manifested within days of exposure to PE when diluted 2000-fold.Highly dilute concentrations of PE(106 dilution),which do not impact these pathways in the short term,were found to have NF-κB and JNK inhibitory effects and ability to reverse the EMT phenotype following prolonged exposure.Conclusion:These findings suggest that PE may mediate inhibition growth of pVHL-deficient ccRCCs and raises the possibility of its use as a dietary adjunct to managing patients with active surveillance for small,localized,incidentally identified renal tumors so as to avoid more invasive procedures such as nephrectomy.展开更多
Tissue optical clearing by use of optical clearing agents(OCAs)has been proven to have potential to reduce the highly scattering effect of biological tissues in optical techniques.However,the difference in tissue samp...Tissue optical clearing by use of optical clearing agents(OCAs)has been proven to have potential to reduce the highly scattering effect of biological tissues in optical techniques.However,the difference in tissue samples could lead to unreliable results,making it difficult to quantitatively control the dose of OCAs during the course of tissue optical clearing.In this work,in order to study the effects of optical clearing,we customized tissue-like phantoms with optical properties of some biological tissue.Diffuse reflectance and total transmittance of tissue-like phantoms with different OCAs(DMSO or glycerol)and porcine skin tissues were measured.Then optical property parameters were calculated by inverse adding-doubling(IAD)algorithm.Results showed that OCAs could lead to a reduction in scattering of tissue-like phantoms as it did to porcine skin tissue in vitro.Furthermore,a series of relational expressions could be fit to quantitatively describe the relationship between the doses of OCAs and the reduction of scattering effects.Therefore,proper tissue-like phantom could facilitate optical clearing to be used in quantitative control of tissue optical properties,and further promote the application potential of optical clearing to light-based noninvasive diagnostic and therapeutic techniques.展开更多
Clear-cell sarcoma is a rare, malignant soft tissue tumor that displays melanocytic differentiation with a distinct molecular profile. It is rarely localized in the gastrointestinal tract. Herein we reported a case of...Clear-cell sarcoma is a rare, malignant soft tissue tumor that displays melanocytic differentiation with a distinct molecular profile. It is rarely localized in the gastrointestinal tract. Herein we reported a case of multiple synchronous clear-cell sarcomas of the gastrointestinal tract with parotid gland metastasis. A 51-year-old male patient presented with a growing painless mass under the right ear. A preoperative positron emission tomography/computed tomography showed multiple intestinal masses and a mass in the right parotid with increased glucose uptake, and he underwent operative treatment with resection of three tumors in the jejunum and ileum and then received a right parotidectomy. Postoperative pathological examination showed that cells in the intestinal tumor were consistent with clear-cell sarcoma of the gastrointestinal tract, and the malignant cells in the parotid gland were similar to the intestinal tumor. Immunohistochemical studies revealed positive expression of HMB-45, Melan-A, and S-100. EWSR1 gene fusion transcripts were undetectable by fluorescence in situ hybridization.展开更多
基金funded by the Special Fund for Clinical Research of Wu Jieping Medical Foundation(320.6750.2025-02-7)the Horizontal Research Project of the Affiliated Hospital of Qingdao University and Yunnan Yunke Biotechnology Institution(5212).
摘要Background:Resistance to sunitinib represents a major clinical obstacle in the management of clear cell renal cell carcinoma(ccRCC).This investigation aims to identify genes associated with sunitinib resistance and elucidate potential molecular pathways in ccRCC.Methods:To identify differentially expressed genes(DEGs)in sunitinib-resistant ccRCC cells and their parental cells,bioinformatic analysis was performed on the GSE216494 dataset.Protein-protein interaction(PPI)network and topological analyses pinpointed a hub gene.Sunitinib-resistant A498 and 786-O cell lines were employed for in vitro validation.Sunitinib sensitivity and cell proliferation were evaluated using functional assays,such as colony formation and Cell Counting Kit-8(CCK-8).Protein interactions and signaling pathway activity are investigated using co-immunoprecipitation(Co-IP),dual-luciferase reporter assays,and immunofluorescence.In resistant cells and patient-derived organoids(PDOs),the therapeutic potential of olaparib,either by itself or in conjunction with sunitinib,was assessed.Results:Sunitinib-resistant cells and patient tissues were shown to exhibit consistent upregulation of poly(ADP-ribose)polymerase 9(PARP9).PARP9 knockdown sensitized resistant cells to sunitinib,suppressing proliferation.Conversely,its overexpression induced resistance in parental cells.Additionally,STAT1 and PARP9 interact to promote nuclear translocation and STAT1 phosphorylation.Activation of the STAT1/IRF1 axis further enhanced the expression of ISG15 and IFIT1.Olaparib treatment can increase sunitinib-resistant ccRCC cells.Olaparib can weaken the STAT1/IRF1 signaling pathway and prevent sunitinib-resistant ccRCC cells from proliferating.Importantly,combination treatment with olaparib and sunitinib showed superior antitumor efficacy in ccRCC PDOs.Conclusion:This study demonstrates that PARP9 promotes sunitinib resistance in ccRCC by activating the STAT1/IRF1 pathway and upregulating ISG15/IFIT1.
摘要Background:Renal cell carcinoma(RCC)is the most common type of kidney cancer in adults,with a poor prognosis in advanced stages.Although histological tumor grading is an established prognostic parameter,it often fails to capture the biological heterogeneity of RCC.Therefore,identifying novel biomarkers could enhance early diagnosis and improve predictive accuracy.Here,we aimed to test whether immunophenotypes of specific glutathione peroxidase(GPX)family members may have prognostic value in RCC.Methods:We investigated the relationship between GPX1 and GPX3 immunophenotypes and clinicopathological parameters in 32 surgical specimens of clear cell RCC(ccRCC)with nucleolar grade 1-4(WHO/ISUP grading).We evaluated the GPX1 and GPX3 immunophenotypes and assigned a histological immunoscore for each marker.For analysis,we used Spearman and point-biserial correlation methods.Results:Our findings indicated a significant positive correlation between GPX1 immunoscore and high nucleolar grade(r=0.80,p0.05),nor with capsular infiltration and invasion of the renal pelvis(p>0.05).However,we did find statistically significant positive correlations between GPX1 expression and invasion of the renal vein(p=0.038),perirenal fat(p=0.043),and peripyelic fat(p=0.015).Conclusion:Our data demonstrate that GPX1 and GPX3 immunophenotypes could have a prognostic role for ccRCC,particularly in relation to nucleolar grade.This study has limitations because of the small sample size;however,it underscores the necessity for further research in larger,prospective studies.These studies should more thoroughly examine the associations between GPX1 and GPX3 and clinicopathological parameters,and validate them as potential novel prognostic biomarkers.
基金Research Project of Hunan Health Commission in 2023(D202304058618)Innovation Project of Hunan Science and Technology Department(2018SK504)National Nature Science Foundation of China(No.82203414).
摘要Background:Clear cell sarcoma of the kidney(CCSK)is a rare and highly aggressive pediatric renal malignancy with a marked propensity for metastatic spread.Cases of CCSK associated with inferior vena cava(IVC)tumor thrombus(IVCTT)are exceptionally uncommon in the literature.We report a case of CCSK with IVCTT in a 15-month-old male infant.Case Description:We reported a case admitted in May 2020 for a 3-day history of fever and hematuria.Abdominal CT revealed an unevenly enhanced mass and low-density shadows within the IVC.The diagnosis of CCSK was confirmed via needle biopsy.The patient received 4 cycles of adjuvant chemotherapy.The initial surgery lasted 10 h with 600 mL blood loss,and primary closure was achieved.Postoperative management included 6 cycles of radiotherapy and 5 cycles of chemotherapy.In March 2022,CT detected IVCTT recurrence,requiring surgical intervention involving thrombus removal and partial IVC resection.This procedure lasted 8 h with 300 mL blood loss,followed by 5 additional chemotherapy cycles.The patient showed no sign of IVC obstruction,including varicose veins or lower limb edema,and maintained renal function throughout follow-up.However,Intracranial metastases were detected 15 months postoperatively.After the family opted against additional treatment,the patient succumbed to the disease.Conclusions:The management of CCSK associated with IVCTT should include consideration of IVC thrombectomy.In case of recurrent IVCTT with preserved collateral circulation,combined thrombus excision and partial IVC resection may be warranted.
基金supported by the National Natural Science Foundation of China(Nos.82174497,82305386 and 81973945)Innovative Research Team of High-level Local Universities in Shanghai+1 种基金Shanghai Key Laboratory for Acupuncture Mechanism and Acupoint Function(No.21DZ2271800)Shanghai Municipal Science and Technology Major Project(No.2018SHZDZX01)。
摘要Acupuncture therapy has demonstrated therapeutic effects on various systemic diseases through the use of specific acupoints along meridians.However,due to the multi-target effect of acupuncture and the complexity of meridian pathways,the underlying mechanisms of acupuncture have not been well understood.Tissue clearing and three-dimensional(3D)imaging is an emerging medical technology that provides high-resolution 3D molecular information while preserving the structural integrity of tissues.In relevant research articles,tissue-clearing and 3D imaging techniques stood out for their ability to visualize the structural characteristics of meridians and acupoints of intact tissues,in order to reveal their intricate connections by means of topological principles.Specifically,this technology has managed to show that acupuncture points like Guilai(ST29)and Sanyinjiao(SP6),which are commonly used in traditional Chinese medicine for treating gynecological disorders,promote angiogenesis in the ovaries and thus improve follicle numbers in polycystic ovary syndrome-like ovaries.This article summarizes recent progress on tissue-clearing and 3D imaging technologies and anticipates the prospects of utilizing this technology to further explore the effects of acupuncture.
摘要Clear aligner treatment is a novel technique in current orthodontic practice.Distinct from traditional fixed orthodontic appliances,clear aligners have different material features and biomechanical characteristics and treatment efficiencies,presenting new clinical challenges.Therefore,a comprehensive and systematic description of the key clinical aspects of clear aligner treatment is essential to enhance treatment efficacy and facilitate the advancement and wide adoption of this new technique.This expert consensus discusses case selection and grading of treatment difficulty,principle of clear aligner therapy,clinical procedures and potential complications,which are crucial to the clinical success of clear aligner treatment.
基金funded by the Science and Technology Project of State Grid Corporation of China(5108-202355437A-3-2-ZN).
摘要The increasing complexity of China’s electricity market creates substantial challenges for settlement automation,data consistency,and operational scalability.Existing provincial settlement systems are fragmented,lack a unified data structure,and depend heavily on manual intervention to process high-frequency and retroactive transactions.To address these limitations,a graph-based unified settlement framework is proposed to enhance automation,flexibility,and adaptability in electricity market settlements.A flexible attribute-graph model is employed to represent heterogeneousmulti-market data,enabling standardized integration,rapid querying,and seamless adaptation to evolving business requirements.An extensible operator library is designed to support configurable settlement rules,and a suite of modular tools—including dataset generation,formula configuration,billing templates,and task scheduling—facilitates end-to-end automated settlement processing.A robust refund-clearing mechanism is further incorporated,utilizing sandbox execution,data-version snapshots,dynamic lineage tracing,and real-time changecapture technologies to enable rapid and accurate recalculations under dynamic policy and data revisions.Case studies based on real-world data from regional Chinese markets validate the effectiveness of the proposed approach,demonstrating marked improvements in computational efficiency,system robustness,and automation.Moreover,enhanced settlement accuracy and high temporal granularity improve price-signal fidelity,promote cost-reflective tariffs,and incentivize energy-efficient and demand-responsive behavior among market participants.The method not only supports equitable and transparent market operations but also provides a generalizable,scalable foundation for modern electricity settlement platforms in increasingly complex and dynamic market environments.
摘要Immune checkpoint inhibitors(ICIs)combined with vascular endothelial growth factor tyrosine kinase inhibitors(VEGF-TKIs)have transformed the treatment landscape of advanced clear cell renal cell carcinoma(ccRCC).Current guidelines favour ICI plus VEGF-TKI(IO+TKI)combinations for favourable-risk disease(International Metastatic RCC Database Consortium[IMDC]score 0)based on improved objective response rates and progression-free survival.However,no IO+TKI combination has demonstrated a statistically significant overall survival(OS)benefit in this subgroup.A pooled analysis of four pivotal phase III trials(n=839 favourable-risk patients)revealed no OS advantage for IO+TKI versus sunitinib monotherapy(hazard ratio[HR]1.24;95%CI 0.86-1.78)despite higher toxicity rates(71-82%Grade≥3 adverse events vs.63-72%with sunitinib)and substantially greater cost.The IMDC favourable-risk category represents approximately 20%of metastatic ccRCC cases and is often characterised by indolent disease biology.Emerging molecular classifications reveal distinct transcriptomic subgroups,including an angiogenic subtype(ccA/CC-e.2/clusters 1-2)enriched in favourable-risk patients,characterised by high hypoxia-inducible factor(HIF)pathway gene expression,frequent PBRM1 mutations,robust VEGF-TKI responsiveness,and comparatively lower benefit from immunotherapy.Current clinical risk stratification fails to capture this molecular heterogeneity,limiting optimal treatment selection.VEGF-TKI monotherapy(median OS 47.6-79.4 months)and active surveillance remain valid,evidence-based alternatives in carefully selected favourable-risk patients,particularly those with asymptomatic,metachronous,or otherwise indolent disease.Uncritical universal use of IO+TKI in this population may therefore represent overtreatment.The development and validation of predictive biomarkers,refinement of molecular risk stratification,and exploration of novel agents with more favourable toxicity profiles(e.g.,HIF-2αinhibitors)are urgently required to personalise therapy and identify candidates for rational treatment de-escalation.
基金supported by NARI Relays Electric Co.,Ltd.under the Project“Research on Evaluation of Clearing Results and Switching Criteria for Primary-Backup Systems in Electricity SpotMarkets”(Project No.CGSQ240800443).
摘要The construction of spot electricity markets plays a pivotal role in power system reforms,where market clearing systems profoundly influence market efficiency and security.Current clearing systems predominantly adopt a single-system architecture,with research focusing primarily on accelerating solution algorithms through techniques such as high-efficiency parallel solvers and staggered decomposition of mixed-integer programming models.Notably absent are systematic studies evaluating the adaptability of primary-backup clearing systems incontingency scenarios—a critical gap given redundant systems’expanding applications in operational environments.This paper proposes a comprehensive evaluation framework for analyzing dual-system adaptability,demonstrated through an in-depth case study of the Inner Mongolia power market.First,we establish the innovative“Dual-Active Heterogeneous”architecture that enables independent parallelized operation and fault-isolated redundancy.Subsequently,key performance indices are quantitatively evaluated across four critical dimensions:unit commitment decisions,generator output constraints,transmission section congestion patterns,and clearing price formation mechanisms.An integrated fuzzy evaluation methodology incorporating grey relational analysis is employed for objective indicator weighting,enabling systematic quantification of system superiority under specific grid operating states.Empirical results based on actual operational data from 200 generation units demonstrate the framework’s efficacy in guiding optimal system selection,with particularly strong performance observed during peak load periods.The proposed approach shows high generalization potential for other regional markets employing redundant clearing mechanisms—particularly those with increasing renewable penetration and associated uncertainty.
基金supported by grants from the Shenzhen Basic Research Project(JCYJ20210324125803008)the Shenzhen Longhua District Science and Innovation Bureau Fund for Medical Institutions(2022143).
摘要Background:Clear cell renal carcinoma(ccRCC),the leading histological subtype of RCC,lacks any targeted therapy options.Although some studies have shown that early growth response factor 1(EGR1)has a significant role in cancer development and progression,its role and underlying mechanisms in ccRCC remain poorly understood.Methods:The Cancer Genome Atlas(TCGA)database was utilized to examine the expression of EGR1 in ccRCC.The expression of EGR1 in 55 ccRCC tissues was evaluated using immunohistochemistry.The link between EGR1 expression and clinicopathological variables was examined through an analysis.Gain-of-function assays were employed to investigate EGR1’s biological functions in ccRCC cells,involving proliferation,colony formation,invasion assays,and tumorigenesis in nude mice.In order to assess the protein expression of mitogen-activated protein kinase 15(MAPK15),E-cadherin,matrix metalloproteinase-9/-2(MMP-9 and MMP-2),Western blot technique was applied.Results:The results revealed a decrease in EGR1 expression in ccRCC tissues.This decrease was strongly linked to TNM stage,lymphatic metastasis,tumor size,histological grade,and unfavorable prognosis in ccRCC patients.It has been demonstrated that overexpressing EGR1 inhibits the growth of xenograft tumors in vivo and inhibits cell colony formation,motility,and invasion in vitro.Furthermore,EGR1 can prevent the development and movement of ccRCC cells by controlling the expression of MMP-2,MMP-9,E-cadherin,and MAPK15.Conclusions:The EGR1/MAPK15 axis may represent a promising target for drug development,with EGR1 serving as a possible target for ccRCC therapy.
基金supported by the Zhejiang Provincial Natural Science Foundation of China(No.LZ22H160008)the Zhejiang Medical Science and Technology Project(Nos.2022RC059 and 2023KY931),China.
摘要Objective To identify pyroptosis,apoptosis,and necroptosis(PANoptosis)-related genes(PRGs)in clear cell renal cell carcinoma(ccRCC)for patient stratification and prognosis prediction.Methods We used differential expression analysis and weighted gene co-expression network analysis(WGCNA)to identify ccRCC-specific PRGs.A prognostic model,the PANoptosis-index(PANI),was constructed using least absolute shrinkage and selection operator(LASSO)and Cox regression.The PANI model,comprising PRGs,was validated through single-cell RNA-sequencing(scRNA-seq),immunohistochemistry,and reverse transcription-quantitative polymerase chain reaction(RT-qPCR).Patient cohorts were categorized into high-and low-PANI groups,and the model’s performance was appraised using various metrics.External validation was performed with the E-MTAB-1980 dataset.Functional and gene set enrichment analyses distinguished biological differences between groups.Mutational landscapes and tumor immune microenvironments were compared.Sensitivity to immunotherapy and antineoplastic drugs was also predicted using PANI.The effects of Z-DNA-binding protein 1(ZBP1)on cell proliferation and migration were assessed by cell counting kit-8(CCK-8)and Transwell assays.Results We identified five PRGs(ZBP1,tumor necrosis factor superfamily protein 14(TNFSF14),cyclin-dependent kinase inhibitor 3(CDKN3),parathyroid hormone-like hormone(PTHLH),and heme-oxygenase 1(HMOX1))constituting PANI,independently associated with ccRCC patient prognosis.The PANI-based nomogram,integrated with clinical factors,demonstrated high predictive accuracy for prognosis.High-PANI patients exhibited distinct co-mutation patterns in ccRCC driver genes and lower survival probabilities,with an enriched immune-related functional profile,indicating an activated immune environment.These patients also showed increased sensitivity to immunotherapy and antineoplastic drugs.The knockdown of ZBP1,a key PRG in the PANI,significantly reduced ccRCC cell proliferation and migration.Conclusions PANI provides precise prognosis and immunotherapy response predictions for ccRCC patients,facilitating individualized treatment strategies.
基金supported by a startup fund from the Chinese Institute for Brain Research,National Natural Science Foundation of China(82101059)research funding from West China School/Hospital of Stomatology Sichuan University(RCDWJS2022-11).
摘要Combining transparent embedding with sectioning is likely to be the future direction for tissue clearing and 3-dimensional(3D)imaging.A newly published transparent embedding system,TESOS(Transparent Embedding Solvent System),ensures consistent submicron resolution imaging throughout the entire sample,and can be compatible with different microscopy systems.This method shows great potential in connectome mapping,and might be an optimal option for future 3D multiplex immunofluorescence and RNA in situ hybridization imaging.Additional efforts would be needed to innovate labeling,imaging,and data processing strategies to fully utilize the potential of transparent embedding systems in highresolution imaging of large-scale samples.
基金partially supported by China Agriculture Research System of MOF and MARA(CARS-26-05B)Overseas Expertise Introduction Project for Discipline Innovation,Ministry of Education of the People's Republic of China(CN)(B18044).
摘要Glycerophosphodiester phosphodiesterase 1(GDPD1)plays an important function in the abiotic stress responses and participates in the accumulation of sn-glycerol-3-phosphate(G3P)in plants,which is key to plant systemic acquired resistance(SAR).However,the role of GDPD1 in plant responses to biotic stress remains poorly understood.This study characterized the antivirus function of the GDPD1 gene(designated as ClGDPD1)from Eureka lemon.ClGDPD1 is located in the membrane and endoplasmic reticulum,where it interacts with the citrus yellow vein clearing virus(CYVCV)coat protein(CP).Compared to individually expressed ClGDPD1 or coexpressed ClGDPD1+CP140-326,transiently coexpressed ClGDPD1+CP or ClGDPD1+CP1-139 significantly upregulated the key substance contents and genes expression involved in glycerophospholipid metabolism.Over-expression of ClGDPD1 significantly facilitated the accumulation of G3P,upregulated the expression of SAR-related genes,and increased the resistance of transgenic Eureka lemon to CYVCV infection.Furthermore,exogenous glycerol treatment and over-expression of ClGPDH increased the G3P content and reduced CYVCV titers in plants or hairy roots.These results indicated that the enhanced resistance of ClGDPD1 transgenic Eureka lemon to CYVCV may be due to facilitating G3P accumulation through the interaction of ClGDPD1 with CP.Our findings provide novel insights into the role of ClGDPD1 as an important regulatory center in mediating the citrus defense response to viral infections.
摘要Background:Clear cell renal cell carcinoma(ccRCC)is an aggressive malignancy associated with limited treatment options and poor prognosis.Emerging studies suggest that the actin-regulating protein actin-related protein 2/3 complex subunit 1B(ARPC1B),a key regulatory protein within the actin cytoskeleton,could play a pivotal role in ccRCC progression.The current study aimed to uncover the biological functions of ARPC1B and the molecular mechanisms driving its effects in ccRCC.Methods:ARPC1B expression and prognostic implications were analyzed using data sourced from the Gene Expression Profiling Interactive Analysis(GEPIA)platform,immunohistochemical(IHC)staining on 150 tumor samples along with 30 corresponding normal tissues,and Western blotting(WB)analyses across multiple ccRCC-derived cell lines.Functional assays assessing cell proliferation,colony formation capability,migration,invasion,and in vivo tumorigenicity were conducted following either ARPC1B suppression or upregulation.Additionally,WB analysis was utilized to evaluate proteins linked to epithelial-to-mesenchymal transition(EMT)and the Wnt/β-catenin pathway.Results:The findings revealed a substantial elevation of ARPC1B in ccRCC tissues and cell lines,significantly associated with advanced TNM stages,higher Fuhrman grades,and reduced overall survival(OS)(p<0.001).Multivariate statistical analysis identified ARPC1B as a standalone prognostic factor.Silencing ARPC1B notably impaired ccRCC cellular activities,and tumorigenesis in animalmodels,whereas augmented ARPC1B expression enhanced these malignant phenotypes.Mechanistically,downregulation of ARPC1B suppressed Wnt/β-catenin signaling and disrupted EMT,indicated by reducedβ-catenin,c-Myc,cyclin D1,and ZEB-1 levels,and concurrently increased E-cadherin expression.Additionally,reactivation of theWnt/β-catenin pathway partly reversed the inhibitory effects of ARPC1B depletion on tumor growth and invasiveness.Conclusions:ARPC1B emerges as an essential oncogenic factor in ccRCC by stimulating EMT and activating the Wnt/β-catenin pathway,ultimately enhancing tumor aggressiveness and metastatic potential.Thus,targeting ARPC1B represents a promising therapeutic strategy,warranting further exploration in ccRCC management.
基金supported by the Research and Development Plan Project of China State Railway Group Co.,Ltd.(Project No.P2023X029).
摘要Purpose–As an important part of the management of railway passenger transport,the rationality and effectiveness of the clearing method of railway passenger transport are directly related to the operating efficiency and service quality of railway passenger transport enterprises.This paper aims to comprehensively and deeply discuss the evolution and development process of China’s railway passenger transport clearing method,analyze its characteristics and influences in each stage,identify the main factors affecting its evolution and development and then put forward thoughts on improving the future development of the clearing method.Design/methodology/approach–Through a detailed review of the railway passenger transport clearing methods from the planned economy period to the reform and opening up period and into the new century,the basis,mode,subject and object of clearing in different development stages are systematically compared.Findings–It comprehensively reveals the evolution of the clearing method,sorted out the characteristics and changes of the clearing method at each stage and the adaptability to the development of railway passenger transport at that time.The characteristics of the development of clearing measures for railway passenger transport in different stages and their far-reaching influence on railway passenger transport business are deeply analyzed.Originality/value–This paper summarized the factors influencing the development of China’s railway passenger transportation clearing approach evolution,including the simplified rules of clearing,enhanced the market adaptability,establishing and perfecting the incentive mechanism,strengthening the construction of informatization,etc.This paper puts forward the ways to improve the railway passenger transportation clearing future development thinking.
基金supported by Hubei Provincial Department of Science and Technology,Innovation and Development Joint Fund(No.2022CFD145)Young Talents Project of Hubei Provincial Administration of Traditional Chinese Medicine(No.ZY2023Q002).
摘要Background:This research aims to investigate potential gene targets and mechanisms through which the traditional Chinese medicine(TCM)Bupleuri Radix(Chaihu)may impact on clear cell renal cell carcinoma(ccRCC)treatment.Methods:Public databases were employed to identify Cedrenol,an active component of Bupleuri Radix,and its associated gene targets.Among these,the gene RORC(also known as RORγ)was selected for detailed analysis due to its high expression correlation.Expression levels of RORC across various cancers were assessed using the TCGA pan-cancer dataset.Further analyses,including differential expression,prognostic relevance,immune infiltration,single-gene,and functional enrichment analyses,were conducted using the TCGA ccRCC dataset.Additionally,potential drug sensitivities and molecular docking interactions with RORC were explored using the GSCALite and CellMiner databases.The effects of RORC on ccRCC were also validated through cellular experiments.Results:RORC exhibited elevated expression in clear cell renal carcinoma tissue in contrast to normal tissues,and lower RORC expression was related to better prognosis.Immune cell infiltration analysis suggested that RORC may influence the penetration of cells that inhibit immune responses,such as regulatory T cells,thereby affecting ccRCC progression.Furthermore,molecular docking studies revealed that several drugs,including Axitinib,Docetaxel,Methotrexate,and Temsirolimus,have a high affinity for RORC and exhibit strong molecular binding.In cellular experiment experiments confirmed that RORC knockdown led to reduced proliferation,metastasis,and ccRCC cell invasion.Conclusion:The study implies that RORC may be a potential gene target for Bupleuri Radix in the management of ccRCC.
基金supported by grants from the National Key Research and Development Program of China(No.2016YFC1101604)the Fundamental Research Funds for the Central Universities+2 种基金Clinical Medicine Plus X-Young Scholars Project of Peking University China(No.PKU2020LCXQ020)Guangdong Basic and Applied Basic Research Foundation(No.2019A1515110983,No.2021A1515012586)Bethune Charitable Foundation and CSPC Osteoporosis Research Foundation Project(No.G-X-2020-1107-21).
摘要Objective:Wallerian degeneration is a pathological process closely related to peripheral nerve regeneration following injury,and includes the disintegration and phagocytosis of peripheral nervous system cells.Traditionally,morphological changes are observed by performing immunofluorescence staining after sectioning,which results in the loss of some histological information.The purpose of this study was to explore a new,nondestmetive,and systematic method for observing axonal histological changes during Wallerian degeneration.Methods:Thirty male Thy1-YFP-16 mice(SPF grade,6 weeks old,20±5 g)were randomly selected and divided into clear,unobstructed brain imaging cocktails and computational analysis(CUBIC)optical clearing(n=15)and traditional method groups(n=15).Five mice in each group were sacrificed at 1st,3rd,and 5th day following a crush operation.The histological axon changes were observed by CUBIC light optical clearing treatment,direct tissue section imaging,and HE staining.Results:The results revealed that,compared with traditional imaging methods,there was no physical damage to the samples,which allowed for three-dimensional and deep-seated tissue imaging through CUBIC.Local image information could be nicely obtained by direct fluorescence imaging and HE staining,but it was difficult to obtain image information of the entire sample.At the same time,the image information obtained by fluorescence imaging and HE staining was partially lost.Conclusion:The combining of CUBIC and Thy1-YFP transgenic mice allowed for a clear and comprehensive observation of histological changes of axons in Wallerian degeneration.
摘要Objective:Clear cell renal cell carcinoma(ccRCC)is the most common subtype of renal cell carcinoma(RCC)and is characterized by biallelic inactivation of the von Hippel-Lindau(VHL)tumor suppressor gene.One effect of VHL inactivation is hypoxia inducible factor alpha(HIFa)-independent constitutive activation of nuclear factor kappa B(NF-κB)and c-jun N-terminal kinase(JNK).Both NF-κB and JNK drive ccRCC growth and epithelial to mesenchymal transition(EMT).The purpose of this study was to determine the biochemical effects of pomegranate juice extracts(PE)on RCC cell lines.Methods:The pre-clinical effects of PE on NF-κB,JNK,and the EMT phenotype were assayed,including its effect on proliferation,anchorage-independent growth,and invasion of pVHLdeficient RCCs.Results:PE inhibits the NF-κB and JNK pathways and consequently inhibits the EMT phenotype of pVHL-deficient ccRCCs.The effects of PE are concentration-dependent and affect not only biochemical markers of EMT(i.e.,cadherin expression)but also functional manifestations of EMT,such as invasion.These effects are manifested within days of exposure to PE when diluted 2000-fold.Highly dilute concentrations of PE(106 dilution),which do not impact these pathways in the short term,were found to have NF-κB and JNK inhibitory effects and ability to reverse the EMT phenotype following prolonged exposure.Conclusion:These findings suggest that PE may mediate inhibition growth of pVHL-deficient ccRCCs and raises the possibility of its use as a dietary adjunct to managing patients with active surveillance for small,localized,incidentally identified renal tumors so as to avoid more invasive procedures such as nephrectomy.
基金supported by the National Natural Science Foundation of China(NSFC,Nos.30600126,30700168 and 30900275).
摘要Tissue optical clearing by use of optical clearing agents(OCAs)has been proven to have potential to reduce the highly scattering effect of biological tissues in optical techniques.However,the difference in tissue samples could lead to unreliable results,making it difficult to quantitatively control the dose of OCAs during the course of tissue optical clearing.In this work,in order to study the effects of optical clearing,we customized tissue-like phantoms with optical properties of some biological tissue.Diffuse reflectance and total transmittance of tissue-like phantoms with different OCAs(DMSO or glycerol)and porcine skin tissues were measured.Then optical property parameters were calculated by inverse adding-doubling(IAD)algorithm.Results showed that OCAs could lead to a reduction in scattering of tissue-like phantoms as it did to porcine skin tissue in vitro.Furthermore,a series of relational expressions could be fit to quantitatively describe the relationship between the doses of OCAs and the reduction of scattering effects.Therefore,proper tissue-like phantom could facilitate optical clearing to be used in quantitative control of tissue optical properties,and further promote the application potential of optical clearing to light-based noninvasive diagnostic and therapeutic techniques.
基金Supported by Basic Scientific Research Business of Chinese Academy of Medical Sciences,No.2016ZX310020
摘要Clear-cell sarcoma is a rare, malignant soft tissue tumor that displays melanocytic differentiation with a distinct molecular profile. It is rarely localized in the gastrointestinal tract. Herein we reported a case of multiple synchronous clear-cell sarcomas of the gastrointestinal tract with parotid gland metastasis. A 51-year-old male patient presented with a growing painless mass under the right ear. A preoperative positron emission tomography/computed tomography showed multiple intestinal masses and a mass in the right parotid with increased glucose uptake, and he underwent operative treatment with resection of three tumors in the jejunum and ileum and then received a right parotidectomy. Postoperative pathological examination showed that cells in the intestinal tumor were consistent with clear-cell sarcoma of the gastrointestinal tract, and the malignant cells in the parotid gland were similar to the intestinal tumor. Immunohistochemical studies revealed positive expression of HMB-45, Melan-A, and S-100. EWSR1 gene fusion transcripts were undetectable by fluorescence in situ hybridization.