Aberrant activation of Receptor Tyrosine Kinases(RTKs)is a well-established trigger of tumorigenesis,and the over-use of RTK inhibitors often leads to drug resistance and tumor recurrence.While current Drug-Target Int...Aberrant activation of Receptor Tyrosine Kinases(RTKs)is a well-established trigger of tumorigenesis,and the over-use of RTK inhibitors often leads to drug resistance and tumor recurrence.While current Drug-Target Interaction(DTI)prediction methods(including those based on heterogeneous information networks)have shown promise,they remain limited in their ability to fully capture the nature of DTIs and often lack interpretability.To overcome these limitations,this study introduces a novel hybrid optimization model termed MDBO-RF,which integrates a Modified Dung Beetle Optimizer(MDBO)with Random Forest(RF).The key innovation lies in the enhancement of the DBO algorithm through a quaternion-based learning mechanism and the Cauchy mutation strategy,specifically designed to overcome the slow convergence and susceptibility to local optima that plague traditional metaheuristic algorithms used for hyperparameter tuning.The model leverages commonly used molecular descriptors to enhance the prediction of Tyrosine Kinase(TK)inhibitory activity and enable efficient compound screening.Our results demonstrate that MDBO-RF achieves a 3.41%increase in prediction accuracy compared to the standard RF model and outperforms several other contemporary machine learning approaches.The model effectively streamlines the RTK inhibitor screening process by improving prediction accuracy in multi-target competitive binding scenarios and reducing false-positive screening due to off-target effects.This work underscores the value of hybrid optimization strategies in bioinformatics and provides a robust,interpretable tool for accelerating drug discovery.展开更多
The published article titled“MicroRNA-148a Acts as a Tumor Suppressor in Osteosarcoma via Targeting Rho-Associated Coiled-Coil Kinase”has been retracted from Oncology Research,Vol.25,No.8,2017,pp.1231–1243.DOI:10.3...The published article titled“MicroRNA-148a Acts as a Tumor Suppressor in Osteosarcoma via Targeting Rho-Associated Coiled-Coil Kinase”has been retracted from Oncology Research,Vol.25,No.8,2017,pp.1231–1243.DOI:10.3727/096504017X14850134190255 URL:https://www.techscience.com/or/v25n8/56908 Following the publication,concerns have been raised about a number of figures in this article.An unexpected area of similarity was identified in terms of the cellular data,where the results from differently performed experiments were intended to have been shown,although the areas immediately surrounding this area featured comparatively different distributions of cells.In addition,the western blots in this article were presented with atypical,unusually shaped and possibly anomalous protein bands in many cases.展开更多
AIM:To investigate whether vaccinia-related kinase 1(VRK1)mediates transforming growth factor-beta2(TGF-β2)-caused epithelial-mesenchymal transition(EMT)and inflammatory responses in retinal pigment epithelial(RPE)ce...AIM:To investigate whether vaccinia-related kinase 1(VRK1)mediates transforming growth factor-beta2(TGF-β2)-caused epithelial-mesenchymal transition(EMT)and inflammatory responses in retinal pigment epithelial(RPE)cells through regulating snail family transcriptional repressor 1(SNAI1),and to validate its role in a proliferative vitreoretinopathy(PVR)mouse model.METHODS:Human RPE cell line ARPE-19 cells were treated with TGF-β2 to construct an EMT model.Western blot detected VRK1 level.The effects of VRK1 on SNAI1 expression and biological behavior of ARPE-19 cells were detected by immunofluorescence,ELISA,Transwell,and scratch assay,and the interaction between VRK1 and SNAI1 was confirmed through immunoprecipitation.A PVR mouse model was constructed,and the effects of VRK1 or/and SNAI1 on retinal damage were assessed by pathologic staining.Inflammatory factors and EMT-related proteins were assessed with ELISA and Western blot.RESULTS:VRK1 was upregulated in ARPE-19 cells after TGF-β2 treatment.Overexpression of VRK1 increased cell viability,promoted cell migration and EMT,and the levels of inflammatory factors.Silencing of VRK1 reversed the above indexes.There was a direct interaction between VRK1 and SNAI1,and overexpresssion SNAI1 weakened the impacts of silencing of VRK1.In PVR mice,silencing of VRK1 ameliorated retinal structural damage,decreased proinflammatory factor levels,and suppressed SNAI1 and mesenchymal marker expression.SNAI1 overexpression antagonized the protective effects of silencing VRK1 and exacerbated EMT and inflammatory responses.CONCLUSION:VRK1 plays a key role in retinal structural and inflammatory damage in PVR mice by regulating SNAI1 and mediating TGF-β2-caused EMT and inflammatory responses in RPE cells.展开更多
Background:The outcomes of pediatric patients with acute lymphoblastic leukemia(ALL)remain far less than favorable.While apigenin is an anti-cancer agent,studies on the mechanism by which it regulates ALL cell cycle p...Background:The outcomes of pediatric patients with acute lymphoblastic leukemia(ALL)remain far less than favorable.While apigenin is an anti-cancer agent,studies on the mechanism by which it regulates ALL cell cycle progression are inadequate.Ferroptosis and AMP-activated protein kinase(AMPK)signaling are important processes for ALL patients.However,it remains unclear whether apigenin works by affecting AMPK and apoptosis.Materials and Methods:SUP-B15 and T-cell Jurkat ALL cells were treated with apigenin,and cell viability and apoptosis were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)and terminal deoxynucleotidyl transferase dUTP nick end labeling(TUNEL)assays,respectively.The thiobarbituric acid-reactive substances(TBARS)assay was used to evaluate lipid peroxidation.Intracellular Fe2+levels were measured using a commercial kit.Corresponding proteins were detected by western blotting.Results:Results showed that apigenin reduced cell viability and the levels of Ki67 and proliferating cell nuclear antigen(PCNA)expression in a concentration-dependent manner in both types of ALL cells.Apigenin also exerted anti-apoptotic effects on SUP-B15 and Jurkat cells.Apigenin activated AMP-activated protein kinase(AMPK)signaling and induced ferroptosis,and those effects were attenuated by inhibition of AMPK.Eventually,the reduced cell proliferation and increased cell apoptosis caused by apigenin in ALL cells were partly abolished by AMPK inhibition.Conclusion:In summary,apigenin exerted anti-leukemia activity in ALL cells,and that effect was partially achieved by activation of AMPK signaling.Our findings suggest apigenin as a potential drug for treatment of ALL.展开更多
OBJECTIVE:To clarify the effect of Hamayou(Oviductus Ranae) protein hydrolysate(ORPH) on depression and its exact underlying mechanism from a new perspective. METHODS:We used the Chronic Unpredictable Mild Stress(CUMS...OBJECTIVE:To clarify the effect of Hamayou(Oviductus Ranae) protein hydrolysate(ORPH) on depression and its exact underlying mechanism from a new perspective. METHODS:We used the Chronic Unpredictable Mild Stress(CUMS) method to prepare a mouse model of depression and lipopolysaccharide(LPS) to prepare a model of BV2 cellular inflammation to investigate the antidepressant effect and mechanism of action of ORPH. Behavioral changes in mice and cerebral blood flow were detected by behavioral experiments and scatter imaging. Levels of corticosterone(CORT), proinflammatory cytokines and neurotransmitter were detected by enzyme-linked immunosorbent assay. Furthermore, hematoxylin-eosin staining, Tunel staining were used to evaluate the effect of ORPH. The distribution and expression of ionized calcium bindingadaptor molecule-1(Iba-1) in mouse hippocampal tissue and BV2 cells were detected by immunofluorescence. Mitogen-activated protein kinase(MAPK) pathway related protein expression was detected by Western blot. RESULTS:ORPH improved depression-like behavior, ameliorated brain tissue damage and apoptosis, and inhibited microglia activation in brain tissue in mice. In addition, ORPH reduced expression of B-cell lymphoma-2(Bcl-2)-associated X(Bax), cysteinyl aspartate specific proteinase 3(Caspase3), cysteinyl aspartate specific proteinase 9(Caspase9), nuclear factor-kappa B(NF-κB), phosphorylation-p38(p-p38), phosphorylation-Jun Nterminal kinase(p-JNK) proteins, and increased expression of Bcl-2, inhibitory kappa B alpha(IκB-α), phosphorylation-extracellular regulated protein kinases 1/2(p-ERK1/2) proteins. On the other hand, there were fewer Iba-1-positive cells, lower expression of NF-κB, pp38, p-JNK and p-ERK1/2 proteins, and higher expression of IκB-α proteins in BV2 cells in the ORPH group. In addition, ORPH increased 5-hydroxytryptamine, norepinephrine levels and decreased CORT, interleukin-1β(IL-1β), interleukin-6(IL-6), tumor necrosis factor-α(TNF-α) levels. CONCLUSION:ORPH was able to improve depressionlike behaviors and that it took effects by promoting cerebral blood flow, inhibition of hypothalamic-pituitaryadrenal axis overactivation, improving the structural damage of hippocampal tissues, and inhibiting the inflammatory response. ORPH can reduced neuronal damage and inhibiting apoptosis by promoting the MAPK pathway.展开更多
Although the etiology of inflammatory bowel disease (IBD) remains unclear,compromised epithelial barrier integrity is believed to promote susceptibility toIBD and be associated with disease severity, suggesting that i...Although the etiology of inflammatory bowel disease (IBD) remains unclear,compromised epithelial barrier integrity is believed to promote susceptibility toIBD and be associated with disease severity, suggesting that improving gut barrierintegrity may palliate or treat IBD. Such a notion gets support from the clinicalfindings that mucosal healing in IBD patients is associated with improvedprognosis, and reduced risk of relapse or colitis-associated cancer. It thereforebecomes critical to understand the intracellular signals that regulate mucosalhealing and gut barrier integrity. Focal adhesion kinase (FAK) is a non-receptortyrosine kinase that critically modulates epithelial cell growth and mobility andhas been associated with carcinogenesis. However, studies also suggest that FAKactivation may promote mucosal healing under conditions of colitis, which shouldreduce the risk of colitis-associated cancer. These findings highlight a potentiallytransformative role for FAK in the context of IBD. Understanding the molecularmechanisms by which FAK influences gut barrier repair and mucosal integritycould offer novel therapeutic avenues for treating IBD and preventing its longtermcomplications. This review focuses on the potential role of FAK in promotingcolitis-associated mucosal healing and the underlying molecular mechanismsdriving these processes, offering critical insights into IBD pathogenesis and therapy.展开更多
Background:Lung cancer is one of the deadliest cancers worldwide,creating a pressing need to develop novel drugs that inhibit oncogenic signaling pathways.Numerous studies have shown that berberine(BBR)has anti–lung ...Background:Lung cancer is one of the deadliest cancers worldwide,creating a pressing need to develop novel drugs that inhibit oncogenic signaling pathways.Numerous studies have shown that berberine(BBR)has anti–lung cancer potential.We aimed to explore the anti–lung cancer effect of BBR and related mechanisms by targeting the glycogen synthase kinase 3β(GSK3β)/β-catenin pathway.Methods:Lung adenocarcinoma(LUAD)cells A549 and NCI-H1975 were treated with BBR.Results:Our results showed that BBR inhibited cell proliferation by decreasing c-Myc levels and induced cel cycle arrest in the G0/G1 phase by lowering cyclin D1 levels.BBR induced apoptosis by upregulating cleaved caspase 3 levels.BBR inhibited cell migration and invasion by decreasing N-cadherin levels.Furthermore,BBR upregulated the expression of GSK3βprotein and phospho-β-catenin proteins in the cytoplasm,while decreasing the expression ofβ-catenin protein.Next,LUAD cel s were exposed to CHIR-99021(a GSK3βinhibitor).This treatment led to an increase in c-Myc,cyclin D1,andβ-catenin levels at specific concentrations.BBR partially reversed the effects of CHIR-99021.Finally,LUAD cells were treated with CHIR-99021(4μmoL/L)combined with BBR(30 and 60μmoL/L)for 24 h.The expression of programmed death ligand 1(PD-L1)was assessed by Western blot analysis.Jurkat T cells and A549 cel s were cocultured for 24 h to examine the lactate dehydrogenase release rate.Results suggested that BBR suppressed the expression of PD-L1 and heightened the immune lethality of T cells.Conclusions:BBR suppressed the proliferative activity of LUAD cell lines A549 and NCI-H1975 in vitro,induced cell cycle arrest and cancer cel apoptosis in the G0/G1 stage,and repressed the migration and invasion of cancer cells.BBR reduced the PD-L1 protein expression and enhanced T-cell–mediated cytotoxicity.These effects appear to be related to BBR's regulation of the GSK3β/β-catenin pathway.展开更多
BACKGROUND Regulator of G protein signaling(RGS)proteins participate in tumor formation and metastasis by acting on theα-subunit of heterotrimeric G proteins.The speci-fic effect of RGS,particularly RGS4,on the progr...BACKGROUND Regulator of G protein signaling(RGS)proteins participate in tumor formation and metastasis by acting on theα-subunit of heterotrimeric G proteins.The speci-fic effect of RGS,particularly RGS4,on the progression of gastric cancer(GC)is not yet clear.AIM To explore the role and underlying mechanisms of action of RGS4 in GC develop-ment.METHODS The prognostic significance of RGS4 in GC was analyzed using bioinformatics based public databases and verified by immunohistochemistry and quantitative polymerase chain reaction in 90 patients with GC.Function assays were employed to assess the carcinogenic impact of RGS4,and the mechanism of its possible influence was detected by western blot analysis.A nude mouse xenograft model was established to study the effects of RGS4 on GC growth in vitro.RESULTS RGS4 was highly expressed in GC tissues compared with matched adjacent normal tissues.Elevated RGS4 expression was correlated with increased tumor-node-metastasis stage,increased tumor grade as well as poorer overall survival in patients with GC.Cell experiments demonstrated that RGS4 knockdown suppressed GC cell proliferation,migration and invasion.Similarly,xenograft experiments confirmed that RGS4 silencing significantly inhibited tumor growth.Moreover,RGS4 knockdown resulted in reduced phosphorylation levels of focal adhesion kinase,phosphatidyl-inositol-3-kinase,and protein kinase B,decreased vimentin and N-cadherin,and elevated E-cadherin.CONCLUSION High RGS4 expression in GC indicates a worse prognosis and RGS4 is a prognostic marker.RGS4 influences tumor progression via the focal adhesion kinase/phosphatidyl-inositol-3-kinase/protein kinase B pathway and epithelial-mesenchymal transition.展开更多
The interaction between the gut microbiota and cyclic adenosine monophosphate(cAMP)-protein kinase A(PKA)signaling pathway in the host's central nervous system plays a crucial role in neurological diseases and enh...The interaction between the gut microbiota and cyclic adenosine monophosphate(cAMP)-protein kinase A(PKA)signaling pathway in the host's central nervous system plays a crucial role in neurological diseases and enhances communication along the gut–brain axis.The gut microbiota influences the cAMP-PKA signaling pathway through its metabolites,which activates the vagus nerve and modulates the immune and neuroendocrine systems.Conversely,alterations in the cAMP-PKA signaling pathway can affect the composition of the gut microbiota,creating a dynamic network of microbial-host interactions.This reciprocal regulation affects neurodevelopment,neurotransmitter control,and behavioral traits,thus playing a role in the modulation of neurological diseases.The coordinated activity of the gut microbiota and the cAMP-PKA signaling pathway regulates processes such as amyloid-β protein aggregation,mitochondrial dysfunction,abnormal energy metabolism,microglial activation,oxidative stress,and neurotransmitter release,which collectively influence the onset and progression of neurological diseases.This study explores the complex interplay between the gut microbiota and cAMP-PKA signaling pathway,along with its implications for potential therapeutic interventions in neurological diseases.Recent pharmacological research has shown that restoring the balance between gut flora and cAMP-PKA signaling pathway may improve outcomes in neurodegenerative diseases and emotional disorders.This can be achieved through various methods such as dietary modifications,probiotic supplements,Chinese herbal extracts,combinations of Chinese herbs,and innovative dosage forms.These findings suggest that regulating the gut microbiota and cAMP-PKA signaling pathway may provide valuable evidence for developing novel therapeutic approaches for neurodegenerative diseases.展开更多
BACKGROUND The classification of uterine sarcomas is based on distinctive morphological and immunophenotypic characteristics,increasingly supported by molecular genetic diagnostics.Data on neurotrophic tyrosine recept...BACKGROUND The classification of uterine sarcomas is based on distinctive morphological and immunophenotypic characteristics,increasingly supported by molecular genetic diagnostics.Data on neurotrophic tyrosine receptor kinase(NTRK)gene fusionpositive uterine sarcoma,potentially aggressive and morphologically similar to fibrosarcoma,are limited due to its recent recognition.Pan-TRK immunohistochemistry(IHC)analysis serves as an effective screening tool with high sensitivity and specificity for NTRK-fusion malignancies.CASE SUMMARY We report a case of a malignant mesenchymal tumor originating from the uterine cervix,which was pan-TRK IHC-positive but lacked NTRK gene fusions,accompanied by a brief literature review.A 55-year-old woman presented to the emergency department with abdominal pain and distension,exhibiting significant ascites and multiple solid pelvic masses.Pelvic examination revealed a tumor encompassing the uterine cervix,extending to the vagina and uterine corpus.A punch biopsy of the cervix indicated NTRK sarcoma with positive immunochemical pan-TRK stain.However,subsequent next generation sequencing revealed no NTRK gene fusion,leading to a diagnosis of poorly differentiated,advanced-stage sarcoma.CONCLUSION The clinical significance of NTRK gene fusion lies in potential treatment with TRK inhibitors for positive sarcomas.Identifying such rare tumors is crucial due to the potential applicability of tropomyosin receptor kinase inhibitor treatment.展开更多
Purpose: Gastrointestinal stromal tumor (GIST) has been considered radiation-resistant and data on the radiotherapy for GIST in previous studies are lacking. The purpose of this article is to accumulate more experienc...Purpose: Gastrointestinal stromal tumor (GIST) has been considered radiation-resistant and data on the radiotherapy for GIST in previous studies are lacking. The purpose of this article is to accumulate more experience in the application of radiotherapy for GISTs. Materials and methods: Review our own case material and the relevant English literature. Results: A huge pelvic GIST after resistance to tyrosine kinase inhibitors (TKIs) has been well controlled by simultaneous-integrated boost intensity-modulated radiation therapy (SIB-IMRT). The time from the initial shrinkage of the mass and subsequent stabilization to now was more than 18 months. The patient was palliated from the series of symptoms caused by tumor compression and well tolerated to the adverse reactions by radiotherapy. And the previous studies have shown that GISTs had a certain sensitivity to radiotherapy. Conclusion: SIB-IMRT may provide a new means of achieving objective response and prolonging survival in selected GIST patients.展开更多
Background: Non-radiographic axial spondyloarthritis is a progressive and disabling inflammatory disease affecting young adults, with limited treatment options. TNFi are more efficacious than JAKi and IL1-7i in nr-ax ...Background: Non-radiographic axial spondyloarthritis is a progressive and disabling inflammatory disease affecting young adults, with limited treatment options. TNFi are more efficacious than JAKi and IL1-7i in nr-ax SPA and it has a well-known safety profile over a longer duration. Recently, many IL-17i and JAKi were approved for the treatment of nr-ax SPA;however, data comparing IL1-7i and JAKi in terms of efficacy and safety is lacking. This systematized review aimed to compare the existing efficacy and safety data of JAKi vs IL-17i in the treatment of patients with nr-ax SPA. Methods: A systematic literature search was performed using relevant keywords in many databases. According to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA, 2020), relevant articles were included and evaluated in this review. Efficacy and safety data were collected, analyzed and compared through week 52. The first check was done by the end of week 14 and week 16 for upadacitinib and IL-17i respectively. Results: Data from four RCTs evaluating upadacitinib, secukinumab, ixekizumab, and bimekizumab comprising 1425 patients were analyzed. Overall, a comparable efficacy and safety profile were observed across different treatment arms through week 52;however, non-significant variations were encountered in some outcome measures. The primary endpoint among these RCTs (ASAS40 response rate) was met and it was higher in patients treated with bimekizumab 160 mg sc Q 4 weeks in TNFi non responders (48%) and lowest in ixekizumab 80 mg sc Q 4 weeks treated patients, (35%) (p Conclusion: The above-mentioned three IL-17i and the only one JAKi demonstrated comparable safety and efficacy profiles with some minor variations. A head-to-head trial comparing the effectiveness and safety characteristics of JAKi vs IL-17i may be needed in patients with active nr-ax SpA.展开更多
Modern medicine faces the formidable challenge of cancer because of its ability to evade immune surveillance and cultivate resistance to conventional therapies. Cancer cells, when overexpressed with CD47, send a “don...Modern medicine faces the formidable challenge of cancer because of its ability to evade immune surveillance and cultivate resistance to conventional therapies. Cancer cells, when overexpressed with CD47, send a “don’t eat me” signal to macrophages, successfully shielding them from immune destruction. Similarly, tyrosine kinase inhibitors (TKIs) have revolutionized cancer treatment by targeting oncogenic pathways, but their effectiveness is often compromised by resistance and minimal residual disease. This review explores a novel combination of CD47-SIRP-blockade and TKIs, addressing the limitations of monotherapies in cancer treatment. Disrupting the CD47-SIRPα interaction stimulates macrophage-mediated phagocytosis and revives exhausted T cells, while TKIs simultaneously target tumor growth drivers. Confirmation from preclinical studies indicates that this combination is capable of enhancing anti-tumor immunity and remodeling tumor microenvironments for enhanced therapeutic outcomes. However, hematotoxicity and tumor heterogeneity present challenges in the path to clinical translation. This review presents current findings, identifies key research areas, and proposes future directions to enhance this combinatorial approach. In the midst of a new era in cancer treatment, immune modulation combined with targeted therapies promises to offer more effective, less toxic, and personalized treatment options. This combination approach has the potential to significantly improve cancer treatment strategies by overcoming current therapeutic limitations.展开更多
Chen et al demonstrated that regulator of G protein signaling(RGS)4 promotes gastric cancer(GC)progression by activating the focal adhesion kinase/phospha-tidyl-inositol-3-kinase/protein kinase B pathway and inducing ...Chen et al demonstrated that regulator of G protein signaling(RGS)4 promotes gastric cancer(GC)progression by activating the focal adhesion kinase/phospha-tidyl-inositol-3-kinase/protein kinase B pathway and inducing epithelial-mesen-chymal transition.Although their multilevel approach integrating clinical data,functional assays,and xenograft models demonstrated a key role for RGS4 in GC pathogenesis,several limitations should be considered.The mechanism of the RGS4-focal adhesion kinase interaction remains unclear,specifically whether it involves direct binding or intermediaries.The clinical analysis of 90 patients lacks stratification by GC subtypes or immune features,potentially limiting generaliz-ability.Furthermore,fully validating RGS4’s oncogenic role requires additional studies,including functional assays in chemotherapy-resistant and metastatic cell lines,metastasis models including orthotopic implantation and tail vein injection,and comparison with other RGS family members.Addressing these via targeted mechanistic studies and expanded clinical validation could strengthen RGS4’s po-tential as a therapeutic target in GC.展开更多
As an important shellfish group,the oyster can induce severe allergic reactions.We aimed to identify and characterize the major allergen in Crassostrea gigas,and elucidate the molecular basis of its allergenicity and ...As an important shellfish group,the oyster can induce severe allergic reactions.We aimed to identify and characterize the major allergen in Crassostrea gigas,and elucidate the molecular basis of its allergenicity and cross-reactivity.The native and recombinant C.gigas-arginine kinase(AK)displayed significant immunoglobulin(Ig)G-and Ig E-binding activity.The Ig E-binding activity of C.gigas-AK could be reduced by thermal treatment and strong acidic and alkaline conditions.Besides,cross-reactivity of AK was demonstrated between shellfish species.Among seven epitope peptides identified here,P2 is responsible for the specificity of C.gigas-AK,while P3 is responsible for cross-reactions between mollusks and crustaceans.Furthermore,Glu98 and His31 in the light chain,Arg101,and Lys57 in the heavy chain are identified as key Ig E residues in recognizing epitopes.These findings provide new insights into the prevention and treatment of shellfish allergy and the development of hypoallergenic shellfish products.展开更多
Refractory thyroid cancer is frequently associated with a poor prognosis,necessitating alternative therapeutic approaches.Tyrosine kinase inhibitors(TKIs)have emerged as a promising treatment option,showing generally ...Refractory thyroid cancer is frequently associated with a poor prognosis,necessitating alternative therapeutic approaches.Tyrosine kinase inhibitors(TKIs)have emerged as a promising treatment option,showing generally favorable clinical outcomes in these challenging cancer subtypes.However,the existing body of research is constrained by small sample sizes and variable findings,limiting the ability to directly compare the efficacy of different TKI agents.This study aimed to bridge that gap through a network meta-analysis,evaluating the relative efficacy and safety of various TKIs in managing refractory thyroid cancer.Utilizing systematic keyword searches in databases such as PubMed,Cochrane Library,Embase,Scopus,Web of Science,and ClinicalTrials.gov,we identified studies that met predefined inclusion criteria.Extracted data were analyzed using Bayesian network meta-analysis methods via R software to ensure a comprehensive assessment.Our findings highlighted specific advantages of certain TKIs for various clinical outcomes.In terms of progression-free survival(PFS),Anlotinib and Apatinib showed notable efficacy.For the objective response rate(ORR),Cabozantinib and Lenvatinib demonstrated superior effectiveness,while for disease control rate(DCR),Apatinib and Lenvatinib were advantageous.Regarding safety profiles,Cabozantinib emerged as the safest option for all-grade adverse events(AEs),with Anlotinib showing a higher risk.For severe AEs(grade 3 or higher),Sorafenib proved to be the safest,while Apatinib carried the highest risk.In summary,Anlotinib,Apatinib,Lenvatinib,and Cabozantinib offered significant benefits for PFS,ORR,and DCR in patients with refractory thyroid cancer.However,Anlotinib and Apatinib were associated with higher AE rates,underlining the importance of balancing efficacy with safety.Cabozantinib and Vandetanib,while exhibiting comparatively safer profiles,showed moderate efficacy.These insights underscored the necessity for tailored treatment decisions that carefully weigh the benefits and risks of each TKI agent.展开更多
BACKGROUND Colorectal cancer(CRC)is a prevalent malignant tumor characterized by a high mortality rate,with significant challenges persisting in the identification and management of its metastatic stage.The role of ch...BACKGROUND Colorectal cancer(CRC)is a prevalent malignant tumor characterized by a high mortality rate,with significant challenges persisting in the identification and management of its metastatic stage.The role of checkpoint kinase 1(CHEK1),a cell cycle checkpoint kinase,in CRC has not been fully clarified.We hypothesize that the upregulation of CHEK1 may enhance the proliferation of CRC cells,indicating its potential as a novel therapeutic target for CRC therapy.AIM To investigate the expression and function of CHEK1 in CRC,this study utilizes single-cell RNA sequencing and tissue microarray data.METHODS Single-cell RNA sequencing technology was employed to analyze CRC cells from the GSE144735 dataset,and immunohistochemistry was conducted to confirm the expression of CHEK1 in CRC and adjacent tissues.We also integrated mRNA expression data from multiple public databases to assess global CHEK1 expre-ssion in CRC.Molecular docking experiments were performed to explore the in-teraction between CHEK1 and the potential drug nitidine chloride(NC),as well as to investigate the influence of CHEK1 on CRC cell proliferation.RESULTS We found comparatively elevated CHEK1 expression in the malignant epithelial cells of CRC,with marked upregulation of its mRNA levels in CRC tissues.Immunohistochemical analysis further confirmed the high expression of CHEK1 in CRC tissues,and the receiver operating characteristic curve demonstrated high accuracy(area under the curve=0.964)for CHEK1 as a biomarker.Analysis of global datasets indicated a statistically significant overexpression of CHEK1 in CRC(standard mean difference=1.81,P<0.01),with summary receiver operating characteristic analysis yielding sensitivity and specificity values of 0.83 and 0.88,respectively.Molecular docking studies indicated that NC specifically targeted CHEK1,while clustered regularly interspaced short palindromic repeats knockout experiments demonstrated that CHEK1 promoted CRC cell proliferation.CONCLUSION Upregulation of CHEK1 promotes CRC cell proliferation.However,the dataset's diversity is limited,requiring further investigation into its specific mechanisms.展开更多
BACKGROUND High levels of acetaminophen(APAP)consumption can result in significant liver toxicity.Mogroside V(MV)is a bioactive,plant-derived triterpenoid known for its various pharmacological activities.However,the i...BACKGROUND High levels of acetaminophen(APAP)consumption can result in significant liver toxicity.Mogroside V(MV)is a bioactive,plant-derived triterpenoid known for its various pharmacological activities.However,the impact of MV on acute liver injury(ALI)is unknown.AIM To investigate the hepatoprotective potential of MV against liver damage caused by APAP and to examine the underlying mechanisms.METHODS Mice were divided into three groups:Saline,APAP and APAP+MV.MV(10 mg/kg)was given intraperitoneally one hour before APAP(300 mg/kg)administration.Twenty-four hours after APAP exposure,serum transaminase levels,liver necrotic area,inflammatory responses,nitrotyrosine accumulation,and c-jun-N-terminal kinase(JNK)activation were assessed.Additionally,we analyzed reactive oxygen species(ROS)levels,JNK activation,and cell death in alpha mouse liver 12(AML12)cells.RESULTS MV pre-treatment in vivo led to a reduction in the rise of aspartate transaminase and alanine transaminase levels,mitigated liver damage,decreased nitrotyrosine accumulation,and blocked JNK phosphorylation resulting from APAP exposure,without affecting glutathione production.Similarly,MV diminished the APAP-induced increase in ROS,JNK phosphorylation,and cell death in vitro.CONCLUSION Our study suggests that MV treatment alleviates APAP-induced ALI by reducing ROS and JNK activation.展开更多
Cancer is characterized by abnormal cell proliferation.Cyclins and cyclin-dependent kinases(CDKs)have been recognized as essential regulators of the intricate cell cycle,orchestrating DNA replication and transcription...Cancer is characterized by abnormal cell proliferation.Cyclins and cyclin-dependent kinases(CDKs)have been recognized as essential regulators of the intricate cell cycle,orchestrating DNA replication and transcription,RNA splicing,and protein synthesis.Dysregulation of the CDK pathway is prevalent in the development and progression of human cancers,rendering cyclins and CDKs attractive therapeutic targets.Several CDK4/6 inhibitors have demonstrated promising anti-cancer efficacy and have been successfully translated into clinical use,fueling the development of CDK-targeted therapies.With this enthusiasm for finding novel CDK-targeting anti-cancer agents,there have also been exciting advances in the field of targeted protein degradation through innovative strategies,such as using proteolysis-targeting chimera,heat shock protein 90(HSP90)-mediated targeting chimera,hydrophobic tag-based protein degradation,and molecular glue.With a focus on the translational potential of cyclin-and CDK-targeting strategies in cancer,this review presents the fundamental roles of cyclins and CDKs in cancer.Furthermore,it summarizes current strategies for the proteasome-dependent targeted degradation of cyclins and CDKs,detailing the underlying mechanisms of action for each approach.A comprehensive overview of the structure and activity of existing CDK degraders is also provided.By examining the structure‒activity relationships,target profiles,and biological effects of reported cyclin/CDK degraders,this review provides a valuable reference for both CDK pathway-targeted biomedical research and cancer therapeutics.展开更多
Casein kinase 1(CK1)is an important member of the serine/threonine protein kinase family,playing a crucial role in various cellular processes,including cell cycle regulation,signal transduction,DNA repair,and circadia...Casein kinase 1(CK1)is an important member of the serine/threonine protein kinase family,playing a crucial role in various cellular processes,including cell cycle regulation,signal transduction,DNA repair,and circadian rhythm control.CK1 is also essential in the nervous system,where it regulates neuronal growth,differentiation,and synaptic plasticity.Studies have shown that CK1δ phosphorylates neuron-specific proteins to regulate axonal growth and synaptogenesis.Primary cilia are non-motile microtubule structures present on the surface of most mammalian cells.Recent studies have revealed their multiple roles in cellular physiology and development,and dysfunction of cilia can impact the development and function of the nervous system.CK1 has an important role in the formation and function of primary cilia.By regulating various signaling pathways and the phosphorylation status of proteins,CK1 affects the generation,maintenance,and signaling transduction of cilia.In this review,the relationship between CK1,primary cilia,and the nervous system was explored,focusing on how CK1 influences cilia to regulate the structure and function of the nervous system.展开更多
基金National Key Research and Development Program of China(No.2022YFD1802104).
文摘Aberrant activation of Receptor Tyrosine Kinases(RTKs)is a well-established trigger of tumorigenesis,and the over-use of RTK inhibitors often leads to drug resistance and tumor recurrence.While current Drug-Target Interaction(DTI)prediction methods(including those based on heterogeneous information networks)have shown promise,they remain limited in their ability to fully capture the nature of DTIs and often lack interpretability.To overcome these limitations,this study introduces a novel hybrid optimization model termed MDBO-RF,which integrates a Modified Dung Beetle Optimizer(MDBO)with Random Forest(RF).The key innovation lies in the enhancement of the DBO algorithm through a quaternion-based learning mechanism and the Cauchy mutation strategy,specifically designed to overcome the slow convergence and susceptibility to local optima that plague traditional metaheuristic algorithms used for hyperparameter tuning.The model leverages commonly used molecular descriptors to enhance the prediction of Tyrosine Kinase(TK)inhibitory activity and enable efficient compound screening.Our results demonstrate that MDBO-RF achieves a 3.41%increase in prediction accuracy compared to the standard RF model and outperforms several other contemporary machine learning approaches.The model effectively streamlines the RTK inhibitor screening process by improving prediction accuracy in multi-target competitive binding scenarios and reducing false-positive screening due to off-target effects.This work underscores the value of hybrid optimization strategies in bioinformatics and provides a robust,interpretable tool for accelerating drug discovery.
文摘The published article titled“MicroRNA-148a Acts as a Tumor Suppressor in Osteosarcoma via Targeting Rho-Associated Coiled-Coil Kinase”has been retracted from Oncology Research,Vol.25,No.8,2017,pp.1231–1243.DOI:10.3727/096504017X14850134190255 URL:https://www.techscience.com/or/v25n8/56908 Following the publication,concerns have been raised about a number of figures in this article.An unexpected area of similarity was identified in terms of the cellular data,where the results from differently performed experiments were intended to have been shown,although the areas immediately surrounding this area featured comparatively different distributions of cells.In addition,the western blots in this article were presented with atypical,unusually shaped and possibly anomalous protein bands in many cases.
文摘AIM:To investigate whether vaccinia-related kinase 1(VRK1)mediates transforming growth factor-beta2(TGF-β2)-caused epithelial-mesenchymal transition(EMT)and inflammatory responses in retinal pigment epithelial(RPE)cells through regulating snail family transcriptional repressor 1(SNAI1),and to validate its role in a proliferative vitreoretinopathy(PVR)mouse model.METHODS:Human RPE cell line ARPE-19 cells were treated with TGF-β2 to construct an EMT model.Western blot detected VRK1 level.The effects of VRK1 on SNAI1 expression and biological behavior of ARPE-19 cells were detected by immunofluorescence,ELISA,Transwell,and scratch assay,and the interaction between VRK1 and SNAI1 was confirmed through immunoprecipitation.A PVR mouse model was constructed,and the effects of VRK1 or/and SNAI1 on retinal damage were assessed by pathologic staining.Inflammatory factors and EMT-related proteins were assessed with ELISA and Western blot.RESULTS:VRK1 was upregulated in ARPE-19 cells after TGF-β2 treatment.Overexpression of VRK1 increased cell viability,promoted cell migration and EMT,and the levels of inflammatory factors.Silencing of VRK1 reversed the above indexes.There was a direct interaction between VRK1 and SNAI1,and overexpresssion SNAI1 weakened the impacts of silencing of VRK1.In PVR mice,silencing of VRK1 ameliorated retinal structural damage,decreased proinflammatory factor levels,and suppressed SNAI1 and mesenchymal marker expression.SNAI1 overexpression antagonized the protective effects of silencing VRK1 and exacerbated EMT and inflammatory responses.CONCLUSION:VRK1 plays a key role in retinal structural and inflammatory damage in PVR mice by regulating SNAI1 and mediating TGF-β2-caused EMT and inflammatory responses in RPE cells.
基金supported by The National Natural Science Foundation of China(No.31902283)Research Foundation for Master students at the Affiliated Hospital of Zunyi Medical College(No.22-2018).
文摘Background:The outcomes of pediatric patients with acute lymphoblastic leukemia(ALL)remain far less than favorable.While apigenin is an anti-cancer agent,studies on the mechanism by which it regulates ALL cell cycle progression are inadequate.Ferroptosis and AMP-activated protein kinase(AMPK)signaling are important processes for ALL patients.However,it remains unclear whether apigenin works by affecting AMPK and apoptosis.Materials and Methods:SUP-B15 and T-cell Jurkat ALL cells were treated with apigenin,and cell viability and apoptosis were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)and terminal deoxynucleotidyl transferase dUTP nick end labeling(TUNEL)assays,respectively.The thiobarbituric acid-reactive substances(TBARS)assay was used to evaluate lipid peroxidation.Intracellular Fe2+levels were measured using a commercial kit.Corresponding proteins were detected by western blotting.Results:Results showed that apigenin reduced cell viability and the levels of Ki67 and proliferating cell nuclear antigen(PCNA)expression in a concentration-dependent manner in both types of ALL cells.Apigenin also exerted anti-apoptotic effects on SUP-B15 and Jurkat cells.Apigenin activated AMP-activated protein kinase(AMPK)signaling and induced ferroptosis,and those effects were attenuated by inhibition of AMPK.Eventually,the reduced cell proliferation and increased cell apoptosis caused by apigenin in ALL cells were partly abolished by AMPK inhibition.Conclusion:In summary,apigenin exerted anti-leukemia activity in ALL cells,and that effect was partially achieved by activation of AMPK signaling.Our findings suggest apigenin as a potential drug for treatment of ALL.
基金Science and Technology Development Project of Jilin Province:Preparation and Evaluation of an Animal Model of Liverdepression Type Depression (20220505038ZP)Exploring the Material Basis and Action Pathway of the Antipyretic Effect of Baihu Tang based on Histologic Techniques (20240602036RC)。
文摘OBJECTIVE:To clarify the effect of Hamayou(Oviductus Ranae) protein hydrolysate(ORPH) on depression and its exact underlying mechanism from a new perspective. METHODS:We used the Chronic Unpredictable Mild Stress(CUMS) method to prepare a mouse model of depression and lipopolysaccharide(LPS) to prepare a model of BV2 cellular inflammation to investigate the antidepressant effect and mechanism of action of ORPH. Behavioral changes in mice and cerebral blood flow were detected by behavioral experiments and scatter imaging. Levels of corticosterone(CORT), proinflammatory cytokines and neurotransmitter were detected by enzyme-linked immunosorbent assay. Furthermore, hematoxylin-eosin staining, Tunel staining were used to evaluate the effect of ORPH. The distribution and expression of ionized calcium bindingadaptor molecule-1(Iba-1) in mouse hippocampal tissue and BV2 cells were detected by immunofluorescence. Mitogen-activated protein kinase(MAPK) pathway related protein expression was detected by Western blot. RESULTS:ORPH improved depression-like behavior, ameliorated brain tissue damage and apoptosis, and inhibited microglia activation in brain tissue in mice. In addition, ORPH reduced expression of B-cell lymphoma-2(Bcl-2)-associated X(Bax), cysteinyl aspartate specific proteinase 3(Caspase3), cysteinyl aspartate specific proteinase 9(Caspase9), nuclear factor-kappa B(NF-κB), phosphorylation-p38(p-p38), phosphorylation-Jun Nterminal kinase(p-JNK) proteins, and increased expression of Bcl-2, inhibitory kappa B alpha(IκB-α), phosphorylation-extracellular regulated protein kinases 1/2(p-ERK1/2) proteins. On the other hand, there were fewer Iba-1-positive cells, lower expression of NF-κB, pp38, p-JNK and p-ERK1/2 proteins, and higher expression of IκB-α proteins in BV2 cells in the ORPH group. In addition, ORPH increased 5-hydroxytryptamine, norepinephrine levels and decreased CORT, interleukin-1β(IL-1β), interleukin-6(IL-6), tumor necrosis factor-α(TNF-α) levels. CONCLUSION:ORPH was able to improve depressionlike behaviors and that it took effects by promoting cerebral blood flow, inhibition of hypothalamic-pituitaryadrenal axis overactivation, improving the structural damage of hippocampal tissues, and inhibiting the inflammatory response. ORPH can reduced neuronal damage and inhibiting apoptosis by promoting the MAPK pathway.
文摘Although the etiology of inflammatory bowel disease (IBD) remains unclear,compromised epithelial barrier integrity is believed to promote susceptibility toIBD and be associated with disease severity, suggesting that improving gut barrierintegrity may palliate or treat IBD. Such a notion gets support from the clinicalfindings that mucosal healing in IBD patients is associated with improvedprognosis, and reduced risk of relapse or colitis-associated cancer. It thereforebecomes critical to understand the intracellular signals that regulate mucosalhealing and gut barrier integrity. Focal adhesion kinase (FAK) is a non-receptortyrosine kinase that critically modulates epithelial cell growth and mobility andhas been associated with carcinogenesis. However, studies also suggest that FAKactivation may promote mucosal healing under conditions of colitis, which shouldreduce the risk of colitis-associated cancer. These findings highlight a potentiallytransformative role for FAK in the context of IBD. Understanding the molecularmechanisms by which FAK influences gut barrier repair and mucosal integritycould offer novel therapeutic avenues for treating IBD and preventing its longtermcomplications. This review focuses on the potential role of FAK in promotingcolitis-associated mucosal healing and the underlying molecular mechanismsdriving these processes, offering critical insights into IBD pathogenesis and therapy.
基金Supported by a grant from the National Natural Science Foundation of China(no.82174457)。
文摘Background:Lung cancer is one of the deadliest cancers worldwide,creating a pressing need to develop novel drugs that inhibit oncogenic signaling pathways.Numerous studies have shown that berberine(BBR)has anti–lung cancer potential.We aimed to explore the anti–lung cancer effect of BBR and related mechanisms by targeting the glycogen synthase kinase 3β(GSK3β)/β-catenin pathway.Methods:Lung adenocarcinoma(LUAD)cells A549 and NCI-H1975 were treated with BBR.Results:Our results showed that BBR inhibited cell proliferation by decreasing c-Myc levels and induced cel cycle arrest in the G0/G1 phase by lowering cyclin D1 levels.BBR induced apoptosis by upregulating cleaved caspase 3 levels.BBR inhibited cell migration and invasion by decreasing N-cadherin levels.Furthermore,BBR upregulated the expression of GSK3βprotein and phospho-β-catenin proteins in the cytoplasm,while decreasing the expression ofβ-catenin protein.Next,LUAD cel s were exposed to CHIR-99021(a GSK3βinhibitor).This treatment led to an increase in c-Myc,cyclin D1,andβ-catenin levels at specific concentrations.BBR partially reversed the effects of CHIR-99021.Finally,LUAD cells were treated with CHIR-99021(4μmoL/L)combined with BBR(30 and 60μmoL/L)for 24 h.The expression of programmed death ligand 1(PD-L1)was assessed by Western blot analysis.Jurkat T cells and A549 cel s were cocultured for 24 h to examine the lactate dehydrogenase release rate.Results suggested that BBR suppressed the expression of PD-L1 and heightened the immune lethality of T cells.Conclusions:BBR suppressed the proliferative activity of LUAD cell lines A549 and NCI-H1975 in vitro,induced cell cycle arrest and cancer cel apoptosis in the G0/G1 stage,and repressed the migration and invasion of cancer cells.BBR reduced the PD-L1 protein expression and enhanced T-cell–mediated cytotoxicity.These effects appear to be related to BBR's regulation of the GSK3β/β-catenin pathway.
基金Supported by the Fundamental Research Program of Shanxi Province,No.202203021222418Research Program of Shanxi Provincial Health Commission,No.2023061+2 种基金Fundamental Research Cooperation Program of Beijing-Tianjin-Hebei Region of Natural Science Foundation of Tianjin,No.22JCZXJC00140Tianjin Major Science and Technology Project,No.21ZXJBSY00110Tianjin Health and Science and Technology Project,No.TJWJ2024ZK001.
文摘BACKGROUND Regulator of G protein signaling(RGS)proteins participate in tumor formation and metastasis by acting on theα-subunit of heterotrimeric G proteins.The speci-fic effect of RGS,particularly RGS4,on the progression of gastric cancer(GC)is not yet clear.AIM To explore the role and underlying mechanisms of action of RGS4 in GC develop-ment.METHODS The prognostic significance of RGS4 in GC was analyzed using bioinformatics based public databases and verified by immunohistochemistry and quantitative polymerase chain reaction in 90 patients with GC.Function assays were employed to assess the carcinogenic impact of RGS4,and the mechanism of its possible influence was detected by western blot analysis.A nude mouse xenograft model was established to study the effects of RGS4 on GC growth in vitro.RESULTS RGS4 was highly expressed in GC tissues compared with matched adjacent normal tissues.Elevated RGS4 expression was correlated with increased tumor-node-metastasis stage,increased tumor grade as well as poorer overall survival in patients with GC.Cell experiments demonstrated that RGS4 knockdown suppressed GC cell proliferation,migration and invasion.Similarly,xenograft experiments confirmed that RGS4 silencing significantly inhibited tumor growth.Moreover,RGS4 knockdown resulted in reduced phosphorylation levels of focal adhesion kinase,phosphatidyl-inositol-3-kinase,and protein kinase B,decreased vimentin and N-cadherin,and elevated E-cadherin.CONCLUSION High RGS4 expression in GC indicates a worse prognosis and RGS4 is a prognostic marker.RGS4 influences tumor progression via the focal adhesion kinase/phosphatidyl-inositol-3-kinase/protein kinase B pathway and epithelial-mesenchymal transition.
基金supported by the National Natural Science Foundation of China,No.82003965the Science and Technology Research Project of Sichuan Provincial Administration of Traditional Chinese Medicine,No.2024MS167(to LH)+2 种基金the Xinglin Scholar Program of Chengdu University of Traditional Chinese Medicine,No.QJRC2022033(to LH)the Improvement Plan for the'Xinglin Scholar'Scientific Research Talent Program at Chengdu University of Traditional Chinese Medicine,No.XKTD2023002(to LH)the 2023 National Project of the College Students'Innovation and Entrepreneurship Training Program at Chengdu University of Traditional Chinese Medicine,No.202310633028(to FD)。
文摘The interaction between the gut microbiota and cyclic adenosine monophosphate(cAMP)-protein kinase A(PKA)signaling pathway in the host's central nervous system plays a crucial role in neurological diseases and enhances communication along the gut–brain axis.The gut microbiota influences the cAMP-PKA signaling pathway through its metabolites,which activates the vagus nerve and modulates the immune and neuroendocrine systems.Conversely,alterations in the cAMP-PKA signaling pathway can affect the composition of the gut microbiota,creating a dynamic network of microbial-host interactions.This reciprocal regulation affects neurodevelopment,neurotransmitter control,and behavioral traits,thus playing a role in the modulation of neurological diseases.The coordinated activity of the gut microbiota and the cAMP-PKA signaling pathway regulates processes such as amyloid-β protein aggregation,mitochondrial dysfunction,abnormal energy metabolism,microglial activation,oxidative stress,and neurotransmitter release,which collectively influence the onset and progression of neurological diseases.This study explores the complex interplay between the gut microbiota and cAMP-PKA signaling pathway,along with its implications for potential therapeutic interventions in neurological diseases.Recent pharmacological research has shown that restoring the balance between gut flora and cAMP-PKA signaling pathway may improve outcomes in neurodegenerative diseases and emotional disorders.This can be achieved through various methods such as dietary modifications,probiotic supplements,Chinese herbal extracts,combinations of Chinese herbs,and innovative dosage forms.These findings suggest that regulating the gut microbiota and cAMP-PKA signaling pathway may provide valuable evidence for developing novel therapeutic approaches for neurodegenerative diseases.
基金Supported by Grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute,funded by the Ministry of Health&Welfare,Republic of Korea,No.RS-2022-KH129889.
文摘BACKGROUND The classification of uterine sarcomas is based on distinctive morphological and immunophenotypic characteristics,increasingly supported by molecular genetic diagnostics.Data on neurotrophic tyrosine receptor kinase(NTRK)gene fusionpositive uterine sarcoma,potentially aggressive and morphologically similar to fibrosarcoma,are limited due to its recent recognition.Pan-TRK immunohistochemistry(IHC)analysis serves as an effective screening tool with high sensitivity and specificity for NTRK-fusion malignancies.CASE SUMMARY We report a case of a malignant mesenchymal tumor originating from the uterine cervix,which was pan-TRK IHC-positive but lacked NTRK gene fusions,accompanied by a brief literature review.A 55-year-old woman presented to the emergency department with abdominal pain and distension,exhibiting significant ascites and multiple solid pelvic masses.Pelvic examination revealed a tumor encompassing the uterine cervix,extending to the vagina and uterine corpus.A punch biopsy of the cervix indicated NTRK sarcoma with positive immunochemical pan-TRK stain.However,subsequent next generation sequencing revealed no NTRK gene fusion,leading to a diagnosis of poorly differentiated,advanced-stage sarcoma.CONCLUSION The clinical significance of NTRK gene fusion lies in potential treatment with TRK inhibitors for positive sarcomas.Identifying such rare tumors is crucial due to the potential applicability of tropomyosin receptor kinase inhibitor treatment.
文摘Purpose: Gastrointestinal stromal tumor (GIST) has been considered radiation-resistant and data on the radiotherapy for GIST in previous studies are lacking. The purpose of this article is to accumulate more experience in the application of radiotherapy for GISTs. Materials and methods: Review our own case material and the relevant English literature. Results: A huge pelvic GIST after resistance to tyrosine kinase inhibitors (TKIs) has been well controlled by simultaneous-integrated boost intensity-modulated radiation therapy (SIB-IMRT). The time from the initial shrinkage of the mass and subsequent stabilization to now was more than 18 months. The patient was palliated from the series of symptoms caused by tumor compression and well tolerated to the adverse reactions by radiotherapy. And the previous studies have shown that GISTs had a certain sensitivity to radiotherapy. Conclusion: SIB-IMRT may provide a new means of achieving objective response and prolonging survival in selected GIST patients.
文摘Background: Non-radiographic axial spondyloarthritis is a progressive and disabling inflammatory disease affecting young adults, with limited treatment options. TNFi are more efficacious than JAKi and IL1-7i in nr-ax SPA and it has a well-known safety profile over a longer duration. Recently, many IL-17i and JAKi were approved for the treatment of nr-ax SPA;however, data comparing IL1-7i and JAKi in terms of efficacy and safety is lacking. This systematized review aimed to compare the existing efficacy and safety data of JAKi vs IL-17i in the treatment of patients with nr-ax SPA. Methods: A systematic literature search was performed using relevant keywords in many databases. According to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA, 2020), relevant articles were included and evaluated in this review. Efficacy and safety data were collected, analyzed and compared through week 52. The first check was done by the end of week 14 and week 16 for upadacitinib and IL-17i respectively. Results: Data from four RCTs evaluating upadacitinib, secukinumab, ixekizumab, and bimekizumab comprising 1425 patients were analyzed. Overall, a comparable efficacy and safety profile were observed across different treatment arms through week 52;however, non-significant variations were encountered in some outcome measures. The primary endpoint among these RCTs (ASAS40 response rate) was met and it was higher in patients treated with bimekizumab 160 mg sc Q 4 weeks in TNFi non responders (48%) and lowest in ixekizumab 80 mg sc Q 4 weeks treated patients, (35%) (p Conclusion: The above-mentioned three IL-17i and the only one JAKi demonstrated comparable safety and efficacy profiles with some minor variations. A head-to-head trial comparing the effectiveness and safety characteristics of JAKi vs IL-17i may be needed in patients with active nr-ax SpA.
文摘Modern medicine faces the formidable challenge of cancer because of its ability to evade immune surveillance and cultivate resistance to conventional therapies. Cancer cells, when overexpressed with CD47, send a “don’t eat me” signal to macrophages, successfully shielding them from immune destruction. Similarly, tyrosine kinase inhibitors (TKIs) have revolutionized cancer treatment by targeting oncogenic pathways, but their effectiveness is often compromised by resistance and minimal residual disease. This review explores a novel combination of CD47-SIRP-blockade and TKIs, addressing the limitations of monotherapies in cancer treatment. Disrupting the CD47-SIRPα interaction stimulates macrophage-mediated phagocytosis and revives exhausted T cells, while TKIs simultaneously target tumor growth drivers. Confirmation from preclinical studies indicates that this combination is capable of enhancing anti-tumor immunity and remodeling tumor microenvironments for enhanced therapeutic outcomes. However, hematotoxicity and tumor heterogeneity present challenges in the path to clinical translation. This review presents current findings, identifies key research areas, and proposes future directions to enhance this combinatorial approach. In the midst of a new era in cancer treatment, immune modulation combined with targeted therapies promises to offer more effective, less toxic, and personalized treatment options. This combination approach has the potential to significantly improve cancer treatment strategies by overcoming current therapeutic limitations.
文摘Chen et al demonstrated that regulator of G protein signaling(RGS)4 promotes gastric cancer(GC)progression by activating the focal adhesion kinase/phospha-tidyl-inositol-3-kinase/protein kinase B pathway and inducing epithelial-mesen-chymal transition.Although their multilevel approach integrating clinical data,functional assays,and xenograft models demonstrated a key role for RGS4 in GC pathogenesis,several limitations should be considered.The mechanism of the RGS4-focal adhesion kinase interaction remains unclear,specifically whether it involves direct binding or intermediaries.The clinical analysis of 90 patients lacks stratification by GC subtypes or immune features,potentially limiting generaliz-ability.Furthermore,fully validating RGS4’s oncogenic role requires additional studies,including functional assays in chemotherapy-resistant and metastatic cell lines,metastasis models including orthotopic implantation and tail vein injection,and comparison with other RGS family members.Addressing these via targeted mechanistic studies and expanded clinical validation could strengthen RGS4’s po-tential as a therapeutic target in GC.
基金financially supported by the State key research and development plan(2019YFC1605000)the National Natural Science Foundation of China(31871735)。
文摘As an important shellfish group,the oyster can induce severe allergic reactions.We aimed to identify and characterize the major allergen in Crassostrea gigas,and elucidate the molecular basis of its allergenicity and cross-reactivity.The native and recombinant C.gigas-arginine kinase(AK)displayed significant immunoglobulin(Ig)G-and Ig E-binding activity.The Ig E-binding activity of C.gigas-AK could be reduced by thermal treatment and strong acidic and alkaline conditions.Besides,cross-reactivity of AK was demonstrated between shellfish species.Among seven epitope peptides identified here,P2 is responsible for the specificity of C.gigas-AK,while P3 is responsible for cross-reactions between mollusks and crustaceans.Furthermore,Glu98 and His31 in the light chain,Arg101,and Lys57 in the heavy chain are identified as key Ig E residues in recognizing epitopes.These findings provide new insights into the prevention and treatment of shellfish allergy and the development of hypoallergenic shellfish products.
基金The Natural Science Foundation of Fujian,China(Grant No.2021J01397)Fujian Provincial Health Technology Project(Grant No.2022GGA010)Fujian Provincial Joint Funding Project of Scientific and Technological Innovation(Grant No.2023Y9347).
文摘Refractory thyroid cancer is frequently associated with a poor prognosis,necessitating alternative therapeutic approaches.Tyrosine kinase inhibitors(TKIs)have emerged as a promising treatment option,showing generally favorable clinical outcomes in these challenging cancer subtypes.However,the existing body of research is constrained by small sample sizes and variable findings,limiting the ability to directly compare the efficacy of different TKI agents.This study aimed to bridge that gap through a network meta-analysis,evaluating the relative efficacy and safety of various TKIs in managing refractory thyroid cancer.Utilizing systematic keyword searches in databases such as PubMed,Cochrane Library,Embase,Scopus,Web of Science,and ClinicalTrials.gov,we identified studies that met predefined inclusion criteria.Extracted data were analyzed using Bayesian network meta-analysis methods via R software to ensure a comprehensive assessment.Our findings highlighted specific advantages of certain TKIs for various clinical outcomes.In terms of progression-free survival(PFS),Anlotinib and Apatinib showed notable efficacy.For the objective response rate(ORR),Cabozantinib and Lenvatinib demonstrated superior effectiveness,while for disease control rate(DCR),Apatinib and Lenvatinib were advantageous.Regarding safety profiles,Cabozantinib emerged as the safest option for all-grade adverse events(AEs),with Anlotinib showing a higher risk.For severe AEs(grade 3 or higher),Sorafenib proved to be the safest,while Apatinib carried the highest risk.In summary,Anlotinib,Apatinib,Lenvatinib,and Cabozantinib offered significant benefits for PFS,ORR,and DCR in patients with refractory thyroid cancer.However,Anlotinib and Apatinib were associated with higher AE rates,underlining the importance of balancing efficacy with safety.Cabozantinib and Vandetanib,while exhibiting comparatively safer profiles,showed moderate efficacy.These insights underscored the necessity for tailored treatment decisions that carefully weigh the benefits and risks of each TKI agent.
基金Supported by Innovation Project of Guangxi Graduate Education,No.YCBZ2023096Guangxi Zhuang Autonomous Region Health Commission Scientific Research Project,No.Z20210442+1 种基金China Undergraduate Innovation and Entrepreneurship Training Program,No.S202410598185Future Academic Star of Guangxi Medical University,No.WLXSZX24101.
文摘BACKGROUND Colorectal cancer(CRC)is a prevalent malignant tumor characterized by a high mortality rate,with significant challenges persisting in the identification and management of its metastatic stage.The role of checkpoint kinase 1(CHEK1),a cell cycle checkpoint kinase,in CRC has not been fully clarified.We hypothesize that the upregulation of CHEK1 may enhance the proliferation of CRC cells,indicating its potential as a novel therapeutic target for CRC therapy.AIM To investigate the expression and function of CHEK1 in CRC,this study utilizes single-cell RNA sequencing and tissue microarray data.METHODS Single-cell RNA sequencing technology was employed to analyze CRC cells from the GSE144735 dataset,and immunohistochemistry was conducted to confirm the expression of CHEK1 in CRC and adjacent tissues.We also integrated mRNA expression data from multiple public databases to assess global CHEK1 expre-ssion in CRC.Molecular docking experiments were performed to explore the in-teraction between CHEK1 and the potential drug nitidine chloride(NC),as well as to investigate the influence of CHEK1 on CRC cell proliferation.RESULTS We found comparatively elevated CHEK1 expression in the malignant epithelial cells of CRC,with marked upregulation of its mRNA levels in CRC tissues.Immunohistochemical analysis further confirmed the high expression of CHEK1 in CRC tissues,and the receiver operating characteristic curve demonstrated high accuracy(area under the curve=0.964)for CHEK1 as a biomarker.Analysis of global datasets indicated a statistically significant overexpression of CHEK1 in CRC(standard mean difference=1.81,P<0.01),with summary receiver operating characteristic analysis yielding sensitivity and specificity values of 0.83 and 0.88,respectively.Molecular docking studies indicated that NC specifically targeted CHEK1,while clustered regularly interspaced short palindromic repeats knockout experiments demonstrated that CHEK1 promoted CRC cell proliferation.CONCLUSION Upregulation of CHEK1 promotes CRC cell proliferation.However,the dataset's diversity is limited,requiring further investigation into its specific mechanisms.
基金Supported by Guangxi Natural Science Foundation of China,No.2024GXNSFAA010040Special Fund of the Central Government Guiding Local Scientific and Technological Development by Guangxi Science and Technology Department,No.GuikeZY21195024National Natural Science Foundation of China,No.82260499 and No.82460463.
文摘BACKGROUND High levels of acetaminophen(APAP)consumption can result in significant liver toxicity.Mogroside V(MV)is a bioactive,plant-derived triterpenoid known for its various pharmacological activities.However,the impact of MV on acute liver injury(ALI)is unknown.AIM To investigate the hepatoprotective potential of MV against liver damage caused by APAP and to examine the underlying mechanisms.METHODS Mice were divided into three groups:Saline,APAP and APAP+MV.MV(10 mg/kg)was given intraperitoneally one hour before APAP(300 mg/kg)administration.Twenty-four hours after APAP exposure,serum transaminase levels,liver necrotic area,inflammatory responses,nitrotyrosine accumulation,and c-jun-N-terminal kinase(JNK)activation were assessed.Additionally,we analyzed reactive oxygen species(ROS)levels,JNK activation,and cell death in alpha mouse liver 12(AML12)cells.RESULTS MV pre-treatment in vivo led to a reduction in the rise of aspartate transaminase and alanine transaminase levels,mitigated liver damage,decreased nitrotyrosine accumulation,and blocked JNK phosphorylation resulting from APAP exposure,without affecting glutathione production.Similarly,MV diminished the APAP-induced increase in ROS,JNK phosphorylation,and cell death in vitro.CONCLUSION Our study suggests that MV treatment alleviates APAP-induced ALI by reducing ROS and JNK activation.
基金supported by the Zhejiang Provincial Nat ural Science Foundation of China(Nos.LZ23C060002 and LZ24H160004)the National Natural Science Foundation of China(Nos.32270746,82203247,82203415,82272637,82204429,and 82073332)+2 种基金the National Key Research and Development Program of China(No.2022YFE0107800)the Medical Interdisciplinary Innovation Program 2024,Zhejiang University School of Medicine,and the Fundamental Research Funds for the Central Universities(No.K20220228)It is add-itionally supported by the National Institute of Health(No.R01-CA200992-03).
文摘Cancer is characterized by abnormal cell proliferation.Cyclins and cyclin-dependent kinases(CDKs)have been recognized as essential regulators of the intricate cell cycle,orchestrating DNA replication and transcription,RNA splicing,and protein synthesis.Dysregulation of the CDK pathway is prevalent in the development and progression of human cancers,rendering cyclins and CDKs attractive therapeutic targets.Several CDK4/6 inhibitors have demonstrated promising anti-cancer efficacy and have been successfully translated into clinical use,fueling the development of CDK-targeted therapies.With this enthusiasm for finding novel CDK-targeting anti-cancer agents,there have also been exciting advances in the field of targeted protein degradation through innovative strategies,such as using proteolysis-targeting chimera,heat shock protein 90(HSP90)-mediated targeting chimera,hydrophobic tag-based protein degradation,and molecular glue.With a focus on the translational potential of cyclin-and CDK-targeting strategies in cancer,this review presents the fundamental roles of cyclins and CDKs in cancer.Furthermore,it summarizes current strategies for the proteasome-dependent targeted degradation of cyclins and CDKs,detailing the underlying mechanisms of action for each approach.A comprehensive overview of the structure and activity of existing CDK degraders is also provided.By examining the structure‒activity relationships,target profiles,and biological effects of reported cyclin/CDK degraders,this review provides a valuable reference for both CDK pathway-targeted biomedical research and cancer therapeutics.
文摘Casein kinase 1(CK1)is an important member of the serine/threonine protein kinase family,playing a crucial role in various cellular processes,including cell cycle regulation,signal transduction,DNA repair,and circadian rhythm control.CK1 is also essential in the nervous system,where it regulates neuronal growth,differentiation,and synaptic plasticity.Studies have shown that CK1δ phosphorylates neuron-specific proteins to regulate axonal growth and synaptogenesis.Primary cilia are non-motile microtubule structures present on the surface of most mammalian cells.Recent studies have revealed their multiple roles in cellular physiology and development,and dysfunction of cilia can impact the development and function of the nervous system.CK1 has an important role in the formation and function of primary cilia.By regulating various signaling pathways and the phosphorylation status of proteins,CK1 affects the generation,maintenance,and signaling transduction of cilia.In this review,the relationship between CK1,primary cilia,and the nervous system was explored,focusing on how CK1 influences cilia to regulate the structure and function of the nervous system.
