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
Reader proteins that bind specific methyllysine are important to biological functions of lysine methylation,but readers of many methyllysine sites are still unknown.Therefore,development of covalent probes is importan...Reader proteins that bind specific methyllysine are important to biological functions of lysine methylation,but readers of many methyllysine sites are still unknown.Therefore,development of covalent probes is important to identify readers from cell samples so as to understand biological roles of lysine methylation.Generally,readers bind methyllysine via aromatic cages that contain tryptophan,tyrosine and phenylalanine,that offer a unique motif for selective crosslinking.We recently reported a site-selective tryptophan crosslinking strategy based on dimethylsulfonium that mimics dimethyllysine to crosslink tryptophan in aromatic cages of readers.Since tyrosine is a key residue for binding affinity to methyllysine,especially some readers that do not contain tryptophan residues in the binding pocket.Here we developed strategies of site-selective crosslinking to tyrosine.Ultraviolet(UV)source was applied to excite tyrosine at neutral pH or phenoxide at basic p H,and subsequent single-electron transfer(SET)from Tyr*to sulfonium inside the binding pocket enables selective crosslinking.In consequence,methyllysine readers with tyrosine-containing aromatic cages could be selectively crosslinked by site-specific sulfonium peptide probes.In addition,we expanded substrates from aromatic cages to tyrosine residues of proximate contact with sulfonium probes.The pair of LgBiT and SmBiT exhibited orthogonal crosslinking in complicated cell samples.As a result,we may expand sulfonium tools to target local tyrosine in future investigations.展开更多
Background:Lung metastases often occur after orthotopic liver transplantation(OLT)for hepatocellular carcinoma(HCC).This study aimed to evaluate the safety and efficacy of combining hypofractionated radiotherapy(HFRT)...Background:Lung metastases often occur after orthotopic liver transplantation(OLT)for hepatocellular carcinoma(HCC).This study aimed to evaluate the safety and efficacy of combining hypofractionated radiotherapy(HFRT)with tyrosine kinase inhibitors(TKIs)in patients with lung metastases from HCC following OLT.Methods:We retrospectively analyzed forty-eight patients with lung metastases post-OLT for HCC,who underwent concurrent HFRT and TKIs between July 2011 and August 2022.The primary endpoint was progression-free survival(PFS),and secondary endpoints included overall survival(OS),local control rate(LCR),in-field objective response rate(ORR),and treatment-related side effects.Results:The median follow-up duration was 42.3 months,with median PFS and OS of 9.9 and 32.7 months,respectively.PFS rates at 1,2,and 3 years were 33.3%,20.8%,and 12.5%,respectively,whereas corresponding OS rates were 91.7%,70.8%,and 33.3%,respectively.Independent adverse factors for PFS included the presence of>3 lung metastases,interval time from OLT to lung metastasis<1 year,and post-HFRT lymphocyte nadir<0.8×10^(9)/L.For OS,independent adverse factors included shorter PFS time,shorter intervals from OLT to lung metastasis,and post-HFRT lymphocyte nadirs<0.8×10^(9)/L.The 1-and 2-year LCRs for lung metastases were 100%and 85.3%,respectively.The best in-field ORR was 95.5%,with no adverse events exceeding grade 2.Radiation pneumonitis occurred in 32 patients(66.7%),with grade 1 in 28 patients(58.3%)and grade 2 in 4 patients(8.3%).Conclusions:The combination of HFRT with TKIs is a feasible,safe,and promising approach for treating lung metastases from HCC post-OLT.展开更多
Receptor tyrosine kinases(RTKs)are biological enzymes expressed on cell membranes that can influence cellular signaling,and their overexpression in tumor cells makes them a key route to assess relevant tumor processes...Receptor tyrosine kinases(RTKs)are biological enzymes expressed on cell membranes that can influence cellular signaling,and their overexpression in tumor cells makes them a key route to assess relevant tumor processes.The development of a delivery system that targets and accumulates in RTKs overexpressing-cells at the on-target site is significant for the monitoring of tumor progression and clinical applications through longer tumor site signaling response under low injection frequency.Here,a host-vip nanoscale fluorescent probe SNI@ZIF-8 based on zeolitic imidazolate framework-8(ZIF-8)and a fluorescent probe SNI constructed from receptor tyrosine kinase inhibitor was proposed and prepared for targeting RTKs and enabling prolonged fluorescence imaging in vivo.The folded conformation of the probe SNI resulted in low background fluorescence,and the unfolding of the SNI conformation upon insertion of the RTKs active pocket showed significant fluorescence enhancement thus enabling real-time detection of RTKs.The host-vip system SNI@ZIF-8 could release vip molecules due to the presence of the enzyme,emphasizing the reporting of stable fluorescent signals over time under low injection frequency.SNI@ZIF-8 could provide a signal response on the cell membrane of RTKs overexpressing cells without interference from other substances,and provided a longer fluorescent signal than SNI at equivalent number of injections in tumor-bearing mice.The host-vip system SNI@ZIF-8,with its obvious tumor site enrichment ability and clear fluorescence imaging ability,could be successfully applied to the detection of RTKs on cell membranes in biological systems,providing a new strategy for determining the process of tumor development in clinical applications.展开更多
Food allergy has become a global concern.Spleen tyrosine kinase(SYK)inhibitors are promising therapeutics against allergic disorders.In this study,a total of 300 natural phenolic compounds were firstly subjected to vi...Food allergy has become a global concern.Spleen tyrosine kinase(SYK)inhibitors are promising therapeutics against allergic disorders.In this study,a total of 300 natural phenolic compounds were firstly subjected to virtual screening.Sesamin and its metabolites,sesamin monocatechol(SC-1)and sesamin dicatechol(SC-2),were identified as potential SYK inhibitors,showing high binding affinity and inhibition efficiency towards SYK.Compared with R406(a traditional SYK inhibitor),sesamin,SC-1,and SC-2 had lower binding energy and inhibition constant(Ki)during molecular docking,exhibited higher bioavailability,safety,metabolism/clearance rate,and distribution uniformity ADMET predictions,and showed high stability in occupying the ATP-binding pocket of SYK during molecular dynamics simulations.In anti-dinitrophenyl-immunoglobulin E(Anti-DNP-Ig E)/dinitrophenyl-human serum albumin(DNP-HSA)-stimulated rat basophilic leukemia(RBL-2H3)cells,sesamin in the concentration range of 5-80μmol/L influenced significantly the degranulation and cytokine release,with 54.00%inhibition againstβ-hexosaminidase release and 58.45%decrease in histamine.In BALB/c mice,sesamin could ameliorate Anti-DNP-Ig E/DNP-HSA-induced passive cutaneous anaphylaxis(PCA)and ovalbumin(OVA)-induced active systemic anaphylaxis(ASA)reactions,reduce the levels of allergic mediators(immunoglobulins and pro-inflammatory cytokines),partially correct the imbalance of T helper(Th)cells differentiation in the spleen,and inhibit the phosphorylation of SYK and its downstream signaling proteins,including p38 mitogen-activated protein kinases(p38 MAPK),extracellular signalregulated kinases(ERK),and p65 nuclear factor-κB(p65 NF-κB)in the spleen.Thus,sesamin may be a safe and versatile SYK inhibitor that can alleviate Ig E-mediated food allergies.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
BACKGROUND Centromere protein A(CENPA)exhibits an increased expression level in primary human rectal cancer tissues,but its role has not been investigated.AIM To clarify the specific role and mechanism of CENPA in rec...BACKGROUND Centromere protein A(CENPA)exhibits an increased expression level in primary human rectal cancer tissues,but its role has not been investigated.AIM To clarify the specific role and mechanism of CENPA in rectal cancer progression.METHODS CENPA protein expression in rectal cancer tissues and cell lines were detected.CENPA was overexpressed and knocked down in SW837 and SW480 cells,and proliferation,invasion,apoptosis and epithelial-mesenchymal transition(EMT)marker protein levels were examined.O6-methylguanine DNA methyltransferase(MGMT)promoter methylation was assessed with methylation-specific poly-merase chain reaction.Co-immunoprecipitation assay verified the interaction between MGMT and protein tyrosine phosphatase nonreceptor type 4(PTPN4).SW837 cells with CENPA knockdown were injected subcutaneously into mice,and tumor growth was examined.RESULTS CENPA was upregulated in rectal cancer tissues and cell lines.CENPA overex-pression promoted proliferation,invasion and EMT,and inhibited apoptosis in rectal cancer cells.Whereas CENPA knockdown showed the opposite results.Moreover,CENPA inhibited MGMT expression by promoting DNA methyltrans-ferase 1-mediated MGMT promoter methylation.MGMT knockdown abolished the CENPA knockdown-mediated inhibition of rectal cancer cell progression.MGMT increased PTPN4 protein stability by inhibiting PTPN4 ubiquitination degradation via competing with ubiquitin-conjugating enzyme E2O for interacting with PTPN4.PTPN4 knockdown abolished the inhibitory effects of MGMT overexpression on rectal cancer cell progression.Moreover,CENPA knockdown inhibited xenograft tumor growth in vivo.CONCLUSION CENPA knockdown inhibited rectal cancer cell growth and attenuated xenograft tumor growth through regulating the MGMT/PTPN4 axis.展开更多
Objective:To investigate the mechanism by which advanced glycation end products(AGEs)promote diabetic kidney disease fibrosis by regulating the tyrosine phosphatase SHP1/SHP2 balance and activating the epidermal growt...Objective:To investigate the mechanism by which advanced glycation end products(AGEs)promote diabetic kidney disease fibrosis by regulating the tyrosine phosphatase SHP1/SHP2 balance and activating the epidermal growth factor receptor(EGFR)pathway.Methods:Animal experiments and in vitro cell experiments were conducted using Western blot analysis and tissue cell staining to detect the expression of relevant proteins and cellular morphological changes.Results:AGEs disrupt the SHP1/SHP2 balance,activate the EGFR and TGFβpathways,and promote fibrosis in diabetic nephropathy.Conclusion:AGEs regulate the balance of tyrosine phosphatases SHP1/SHP2,activate the EGFR-mediated signaling pathway,promote the release of inflammatory factors,and ultimately lead to fibrosis in diabetic nephropathy through a novel mechanism.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
The study conducted by Wang et al,focuses on the role of Rho GTPase activating protein 12(ARHGAP12),in hepatocellular carcinoma(HCC).This research reveals that ARHGAP12 expression,markedly elevated in malignant cells ...The study conducted by Wang et al,focuses on the role of Rho GTPase activating protein 12(ARHGAP12),in hepatocellular carcinoma(HCC).This research reveals that ARHGAP12 expression,markedly elevated in malignant cells of HCC,correlates strongly with adverse outcomes for patients.Furthermore,the study illustrates that ARHGAP12 enhances the ability of HCC cells to invade and contributes to their resistance to tyrosine kinase inhibitors(TKIs)through modulation of the focal adhesion pathway.To comprehensively investigate the relationship between ARHGAP12 and TKI resistance,this study integrates single-cell and bulk RNA sequencing methodologies along with data from tumor immune single-cell hub 2,Gene Expression Omnibus,The Cancer Genome Atlas,CellMiner,Genomics of Drug Sensitivity in Cancer 2,as well as immunohisto-chemical staining and proteomic analyses.Statistical analyses,including the Wilcoxon rank-sum test and receiver operating characteristic curve analysis,were employed to evaluate the correlation between ARHGAP12 expression levels and clinical parameters,as well as drug sensitivity.It is evident that a more profound exploration of the molecular dynamics of HCC,especially those related to re-sistance against TKIs,is essential.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
In this editorial,the roles of protein tyrosine phosphatase nonreceptor 2(PTPN2)in oncogenic transformation and tumor behavior and its potential as a therapeutic target in the context of gastrointestinal(GI)cancers ar...In this editorial,the roles of protein tyrosine phosphatase nonreceptor 2(PTPN2)in oncogenic transformation and tumor behavior and its potential as a therapeutic target in the context of gastrointestinal(GI)cancers are presented with respect to the article by Li et al published in ninth issue of the World Journal of Gastrointestinal Oncology.PTPN2 is a member of the protein tyrosine phosphatase family of signaling proteins that play crucial roles in the regulation of inflammation and immunity.Accordingly,early findings highlighted the contribution of PTPN2 to the pathogenesis of inflammatory and autoimmune disorders related to its dysfunction.On the other hand,recent studies have indicated that PTPN2 has many different roles in different cancer types,which is associated with the complexity of its regulatory network.PTPN2 dephosphorylates and inactivates EGFR,SRC family kinases,JAK1 and JAK3,and STAT1,STAT3,and STAT5 in cell type-and context-dependent manners,which indicates that PTPN2 can perform either prooncogenic or anti-oncogenic functions depending on the tumor subtype.While PTPN2 has been suggested as a potential therapeutic target in cancer treatment,to the best of ourknowledge,no clear treatment protocol has referred to PTPN2.Although there are only few studies that investigated PTPN2 expression in the GI system cancers,which is a potential limitation,the association of this protein with tumor behavior and the influence of PTPN2 on many therapy-related signaling pathways emphasize that PTPN2 could serve as a new molecular biomarker to predict tumor behavior and as a target for therapeutic intervention against GI cancers.In conclusion,more studies should be performed to better understand the prognostic and therapeutic potential of PTPN2 in GI tumors,especially in tumors resistant to therapy.展开更多
BACKGROUND Chemotherapy,targeted therapy,and immunotherapy have all been shown to achieve some efficacy in treating intrahepatic cholangiocarcinoma(ICC).How-ever,these systemic treatments have not provided optimal res...BACKGROUND Chemotherapy,targeted therapy,and immunotherapy have all been shown to achieve some efficacy in treating intrahepatic cholangiocarcinoma(ICC).How-ever,these systemic treatments have not provided optimal results for some patients.Therefore,the combination of transarterial chemoembolization(TACE)and hepatic artery infusion chemotherapy or other local interventional therapy methods is being considered for the treatment of liver tumors.AIM To evaluate the efficacy and safety of combining chemotherapy,targeted therapy,and immunotherapy,with or without TACE,in patients with ICC.METHODS We recruited 83 patients with unresectable ICC from July 2021 to December 2023 at the Affiliated Hospital of Xuzhou Medical University.Forty-one patients received TACE combined with chemotherapy,tyrosine kinase inhibitors,and pro-grammed death 1(PD-1)/programmed cell death ligand 1(PD-L1)inhibitors(ex-perimental group),whereas 42 patients were treated with chemotherapy,tyrosine kinase inhibitors,and PD-1/PD-L1 inhibitors(control group).Short-term efficacy was assessed using the modified response evaluation criterion,and the objective response rate,disease control rate,progression-free survival,and incidence of adverse events were compared between groups.RESULTS The objective response rate in the experimental group was greater than that in the control group(39.0%vs 19.0%,P<0.05).The disease control rate in the experimental group was significantly greater than that in the control group(75.6%vs 52.4%,P<0.05).The median progression-free survival times were 14.3 months in the experimental group and 12.7 months in the control group(P<0.05).All 41 patients in the experimental group developed postembol-ization syndrome.Among the symptoms,fever and pain were significantly more common in the experimental group than in the control group(85.4%vs 11.9%,P<0.001 and 58.5%vs 9.5%,P<0.001).No grade 4 or 5 treatment-related adverse events were observed in either group.CONCLUSION In patients with unresectable ICC,TACE combined with chemotherapy,tyrosine kinase inhibitors,and PD-1/PD-L1 inhibitors has good efficacy and high safety,indicating potential benefits for these patients.展开更多
Objective： Extracellular signal-regulated kinases （ERKs） can be activated by calcium signals. In this study, we investigated whether calcium-dependent kinases were involved in ERKs cascade activation after global c...Objective： Extracellular signal-regulated kinases （ERKs） can be activated by calcium signals. In this study, we investigated whether calcium-dependent kinases were involved in ERKs cascade activation after global cerebral ischemia. Methods Cerebral ischemia was induced by four-vessel occlusion, and the calcium-dependent proteins were detected by immunoblot. Results Lethal-simulated ischemia significantly resulted in ERKs activation in N-methyl-D-aspartate （NMDA） receptor-dependent manner, accompanying with differential upregulation of Src kinase and Ca^2＋/calmodulin-dependent protein kinase Ⅱ （CaMKⅡ） activities. With the inhibition of Src family tyrosine kinases or CaMKⅡ by administration of PP2 or KN62, the phosphorylation of ERKs was impaired dramatically during post-ischemia recovery. However, ischemic challenge also repressed ERKs activity when Src kinase was excessively activated. Conclusions Src family tyrosine kinases and CaMKⅡ might be involved in the activation of ERKs mediated by NMDA receptor in response to acute ischemic stimuli in vivo, but the intense activation of Src kinase resulted from ischemia may play a reverse role in the ERKs cascade.展开更多
Spleen tyrosine kinase (SYK),a non-receptor tyrosine kinase,is expressed in most hematopoietic cells and non-hematopoietic cells and play a crucial role in both immune and non-immune biological responses.SYK mediate d...Spleen tyrosine kinase (SYK),a non-receptor tyrosine kinase,is expressed in most hematopoietic cells and non-hematopoietic cells and play a crucial role in both immune and non-immune biological responses.SYK mediate diverse cellular responses via an immune-receptor tyrosine-based activation motifs (ITAMs)-dependent signalling pathways,ITAMs-independent and ITAMs-semidependent signalling pathways.In liver,SYK expression has been observed in parenchymal (hepatocytes) and non-parenchymal cells (hepatic stellate cells and Kupffer cells) and found to be positively correlated with the disease severity.The implication of SYK pathway has been reported in different liver diseases including liver fibrosis,viral hepatitis,alcoholic liver disease,non-alcoholic steatohepatitis and hepatocellular carcinoma.Antagonism of SYK pathway using kinase inhibitors have shown to attenuate the progression of liver diseases thereby suggesting SYK as a highly promising therapeutic target.This review summarizes the current understanding of SYK and its therapeutic implication in liver diseases.展开更多
Objective To investigate the role of tyrosine kinase receptor C（TrkC）,the receptor of neurotrophin-3（NT-3）,in neuroplasticity following spinal cord injury（SCI）.Methods Rats with cord transection were allowed to ...Objective To investigate the role of tyrosine kinase receptor C（TrkC）,the receptor of neurotrophin-3（NT-3）,in neuroplasticity following spinal cord injury（SCI）.Methods Rats with cord transection were allowed to survive for 1,3,7 and 14 d post operation（dpo）.TrkC expressions at lower thoracic levels of the spinal cord and in precentral gyrus of cerebral cortex were investigated.Results TrkC protein levels at both the site of injury（T10-T11） and the neighboring segments（T9 and T12） in the spinal cord decreased significantly at 1-7 dpo,followed by a rapid increase at 14 dpo.The temporal changes in TrkC mRNA expression level showed a similar pattern with that of TrkC protein.In addition,the levels of TrkC protein and mRNA at the site of injury（T10-T11） were significantly higher than those at the neighboring spinal segments（T9 and T12）.Besides,the levels of TrkC protein and mRNA were higher at the rostral segment than at the caudal segment.However,in the motor cortex,TrkC protein was not detected and TrkC mRNA was expressed at a very low level.Conclusion These results suggest that TrkC may be involved in neuroplasticity after SCI.展开更多
An organic layer prepared from the seed of Aceriphyllum rossii was studied to identify the active compounds for protein tyrosine phosphatase 1B（PTP1B） inhibition.Bioassay guided fractionation resulted in the isolati...An organic layer prepared from the seed of Aceriphyllum rossii was studied to identify the active compounds for protein tyrosine phosphatase 1B（PTP1B） inhibition.Bioassay guided fractionation resulted in the isolation of PTP1B inhibitory activity of triterpenes（1-4）.These four compounds were identified as aceriphyllic acid C（1）,aceriphyllic acid D（2）,aceriphyllic acid E（3） and aceriphyllic acid F（4）.The isolated 1-4 compounds inhibited PTP1B with IC50 values ranged from（2.1±1.5） μmol/L to（11.2±2.5） μmol/L.Kinetic analysis of PTP1B inhibition by aceriphyllic acid C（1） and aceriphyllic acid D（2） suggested that oleanane-type triterpenes inhibited PTP1B activity in a mixed-type manner.展开更多
The effect of Rg1,a saponin extracted froin Panax ginseng, on the phenotype,receptor and the activity of protein tyrosine kinase (PTK) of lymphocytes isolated from 7 healthy oldpersons were studied. The CD25, CD45RA a...The effect of Rg1,a saponin extracted froin Panax ginseng, on the phenotype,receptor and the activity of protein tyrosine kinase (PTK) of lymphocytes isolated from 7 healthy oldpersons were studied. The CD25, CD45RA and CD45RO phenotypes of lymphocytes were 4eter-mined by indirect immunofluorescence technique. The percentage of CD25, CD45RA and CD45ROpositive lymphocytes was 38.3%±17.3%, 46.0% 15.1%, and 52.6%±14.1% respectively after incu-bation with PHA (5 μ±/ml) for 72 hours. However, there were 58.0%±12.5%, CD25, 64.1% ± 12.4%,CD45RA, and 74.0%±8.0%, CD45RO positive cells in the presence of Rg, ( 1μg/ml) along with PHA(5 μg/ml) over the sanie period of incubation. A significant increase was induced by Rgi (P<0.05).The activities of PTK in the cytoplasm and membrane of lymphocytes were measured by ELISAmcthod after incubation with PHA or PHA+Rg1. The absorbance value of PTK activity in cytoplasmafter 72 hr incubation was 0. 120±0.020 in PHA group, but 0. 1 38±0.015 in PHA+Rg1 group. In thelymphocyte membrane, it was 0.374± 0.060 in PHA group and 0.403 ± 0.008 in PHA+Rg1 group(P<0.001). These results showed that Rgi significantly arid simultaneously increased both the PT Kactivity and the expression of phenotype of lymphocytes.展开更多
A new approach for assembling amperometric mushroom pulp tissue based membrane electrode for determination of L tyrosine analysis is proposed. Ferrocene is used as a mediator of electron transfer between tyrosinase ...A new approach for assembling amperometric mushroom pulp tissue based membrane electrode for determination of L tyrosine analysis is proposed. Ferrocene is used as a mediator of electron transfer between tyrosinase in mushroom tissue and a graphite electrode. The optimal operation conditions are studied. The linear response range of the biosensor is 2 0×10 -4 to 4 5×10 -3 mol·L -1 with response time of less than 5 min and lifetime of at least 30 d. The biosensor can be applied to practical sample analysis.展开更多
Objective: To survey the role of protein tyrosine kinases (PTKs) in the pathogenesis of several hematopoietic malignancies. Methods: By reviewing the published laboratory and clinical studies on PTK-related oncoprotei...Objective: To survey the role of protein tyrosine kinases (PTKs) in the pathogenesis of several hematopoietic malignancies. Methods: By reviewing the published laboratory and clinical studies on PTK-related oncoproteins and their causative role in some leukemias and lymphomas. Results: Protein tyrosine kinases are key participants in signal transduction pathways that regulate cellular growth, activation and differentiations. Aberrant PTK activity resulting from gene mutation (often accompanying chromosome translocation) plays an etiologic role in several clonal hematopoietic malignancies. For example, the PTK product of the BCR-ABL fusion gene resulting from the t (9; 22) translocation exhibits several fold higher tyrosine kinase activity than the product of the ABL gene. Evidence suggests that the BCR-ABL oncoprotein alone is sufficient to case chronic myelogenous leukemia (CML) and other Ph positive acute leukemia. PTK over-activity resulting from chromosomal translocations creating TEL-ABL, TEL-JAK2 and TEL-PDGFRβ fusion proteins plays an important role in the pathogenesis of other types of leukemia. Another example occurs in anaplastic large cell lymphoma (ALCL). Experimental and clinical evidences indicate that translocations involving ALK gene on chromosome 2p23, most commonly resulting in an NPM-ALK fusion oncogene, result in constitutive activation of ALK and cause ALCL. This group of lymphomas is now named ALK positive lymphoma or ALKoma. Conclusion: Genetic lesions creating aberrant fusion proteins that result in excessive PTK activity are increasingly being recognized as central to the pathogenesis of hemotopoietic malignancies. These chimeric PTK molecules represent attractive disease-specific targets against which new classes therapeutic agents are being developed.展开更多
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.
基金the support from National Natural Science Foundation of China(No.22161132006)Key R&D Program of Zhejiang(No.2024SSYS0036)Westlake University Startup。
文摘Reader proteins that bind specific methyllysine are important to biological functions of lysine methylation,but readers of many methyllysine sites are still unknown.Therefore,development of covalent probes is important to identify readers from cell samples so as to understand biological roles of lysine methylation.Generally,readers bind methyllysine via aromatic cages that contain tryptophan,tyrosine and phenylalanine,that offer a unique motif for selective crosslinking.We recently reported a site-selective tryptophan crosslinking strategy based on dimethylsulfonium that mimics dimethyllysine to crosslink tryptophan in aromatic cages of readers.Since tyrosine is a key residue for binding affinity to methyllysine,especially some readers that do not contain tryptophan residues in the binding pocket.Here we developed strategies of site-selective crosslinking to tyrosine.Ultraviolet(UV)source was applied to excite tyrosine at neutral pH or phenoxide at basic p H,and subsequent single-electron transfer(SET)from Tyr*to sulfonium inside the binding pocket enables selective crosslinking.In consequence,methyllysine readers with tyrosine-containing aromatic cages could be selectively crosslinked by site-specific sulfonium peptide probes.In addition,we expanded substrates from aromatic cages to tyrosine residues of proximate contact with sulfonium probes.The pair of LgBiT and SmBiT exhibited orthogonal crosslinking in complicated cell samples.As a result,we may expand sulfonium tools to target local tyrosine in future investigations.
基金supported by grants from the National Natu-ral Science Foundation of China(82102913 and 82102823)the Special Clinical Research Program of the Health Industry,Shanghai Municipal Health Commission(202340179).
文摘Background:Lung metastases often occur after orthotopic liver transplantation(OLT)for hepatocellular carcinoma(HCC).This study aimed to evaluate the safety and efficacy of combining hypofractionated radiotherapy(HFRT)with tyrosine kinase inhibitors(TKIs)in patients with lung metastases from HCC following OLT.Methods:We retrospectively analyzed forty-eight patients with lung metastases post-OLT for HCC,who underwent concurrent HFRT and TKIs between July 2011 and August 2022.The primary endpoint was progression-free survival(PFS),and secondary endpoints included overall survival(OS),local control rate(LCR),in-field objective response rate(ORR),and treatment-related side effects.Results:The median follow-up duration was 42.3 months,with median PFS and OS of 9.9 and 32.7 months,respectively.PFS rates at 1,2,and 3 years were 33.3%,20.8%,and 12.5%,respectively,whereas corresponding OS rates were 91.7%,70.8%,and 33.3%,respectively.Independent adverse factors for PFS included the presence of>3 lung metastases,interval time from OLT to lung metastasis<1 year,and post-HFRT lymphocyte nadir<0.8×10^(9)/L.For OS,independent adverse factors included shorter PFS time,shorter intervals from OLT to lung metastasis,and post-HFRT lymphocyte nadirs<0.8×10^(9)/L.The 1-and 2-year LCRs for lung metastases were 100%and 85.3%,respectively.The best in-field ORR was 95.5%,with no adverse events exceeding grade 2.Radiation pneumonitis occurred in 32 patients(66.7%),with grade 1 in 28 patients(58.3%)and grade 2 in 4 patients(8.3%).Conclusions:The combination of HFRT with TKIs is a feasible,safe,and promising approach for treating lung metastases from HCC post-OLT.
基金supported by the National Natural Science Foundation of China(Nos.22338005,21977015)。
文摘Receptor tyrosine kinases(RTKs)are biological enzymes expressed on cell membranes that can influence cellular signaling,and their overexpression in tumor cells makes them a key route to assess relevant tumor processes.The development of a delivery system that targets and accumulates in RTKs overexpressing-cells at the on-target site is significant for the monitoring of tumor progression and clinical applications through longer tumor site signaling response under low injection frequency.Here,a host-vip nanoscale fluorescent probe SNI@ZIF-8 based on zeolitic imidazolate framework-8(ZIF-8)and a fluorescent probe SNI constructed from receptor tyrosine kinase inhibitor was proposed and prepared for targeting RTKs and enabling prolonged fluorescence imaging in vivo.The folded conformation of the probe SNI resulted in low background fluorescence,and the unfolding of the SNI conformation upon insertion of the RTKs active pocket showed significant fluorescence enhancement thus enabling real-time detection of RTKs.The host-vip system SNI@ZIF-8 could release vip molecules due to the presence of the enzyme,emphasizing the reporting of stable fluorescent signals over time under low injection frequency.SNI@ZIF-8 could provide a signal response on the cell membrane of RTKs overexpressing cells without interference from other substances,and provided a longer fluorescent signal than SNI at equivalent number of injections in tumor-bearing mice.The host-vip system SNI@ZIF-8,with its obvious tumor site enrichment ability and clear fluorescence imaging ability,could be successfully applied to the detection of RTKs on cell membranes in biological systems,providing a new strategy for determining the process of tumor development in clinical applications.
基金Incubation Program of Youth Innovation in Shandong ProvinceKey Research and Development Program of Shandong Province(2021TZXD007)。
文摘Food allergy has become a global concern.Spleen tyrosine kinase(SYK)inhibitors are promising therapeutics against allergic disorders.In this study,a total of 300 natural phenolic compounds were firstly subjected to virtual screening.Sesamin and its metabolites,sesamin monocatechol(SC-1)and sesamin dicatechol(SC-2),were identified as potential SYK inhibitors,showing high binding affinity and inhibition efficiency towards SYK.Compared with R406(a traditional SYK inhibitor),sesamin,SC-1,and SC-2 had lower binding energy and inhibition constant(Ki)during molecular docking,exhibited higher bioavailability,safety,metabolism/clearance rate,and distribution uniformity ADMET predictions,and showed high stability in occupying the ATP-binding pocket of SYK during molecular dynamics simulations.In anti-dinitrophenyl-immunoglobulin E(Anti-DNP-Ig E)/dinitrophenyl-human serum albumin(DNP-HSA)-stimulated rat basophilic leukemia(RBL-2H3)cells,sesamin in the concentration range of 5-80μmol/L influenced significantly the degranulation and cytokine release,with 54.00%inhibition againstβ-hexosaminidase release and 58.45%decrease in histamine.In BALB/c mice,sesamin could ameliorate Anti-DNP-Ig E/DNP-HSA-induced passive cutaneous anaphylaxis(PCA)and ovalbumin(OVA)-induced active systemic anaphylaxis(ASA)reactions,reduce the levels of allergic mediators(immunoglobulins and pro-inflammatory cytokines),partially correct the imbalance of T helper(Th)cells differentiation in the spleen,and inhibit the phosphorylation of SYK and its downstream signaling proteins,including p38 mitogen-activated protein kinases(p38 MAPK),extracellular signalregulated kinases(ERK),and p65 nuclear factor-κB(p65 NF-κB)in the spleen.Thus,sesamin may be a safe and versatile SYK inhibitor that can alleviate Ig E-mediated food allergies.
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.
基金This study was reviewed and approved by the Ethic Committee of Medical College of Henan Vocational University of Science and Technology(Approval No.HVUYL414101416920231017001)all participants signed a written informed consent.
文摘BACKGROUND Centromere protein A(CENPA)exhibits an increased expression level in primary human rectal cancer tissues,but its role has not been investigated.AIM To clarify the specific role and mechanism of CENPA in rectal cancer progression.METHODS CENPA protein expression in rectal cancer tissues and cell lines were detected.CENPA was overexpressed and knocked down in SW837 and SW480 cells,and proliferation,invasion,apoptosis and epithelial-mesenchymal transition(EMT)marker protein levels were examined.O6-methylguanine DNA methyltransferase(MGMT)promoter methylation was assessed with methylation-specific poly-merase chain reaction.Co-immunoprecipitation assay verified the interaction between MGMT and protein tyrosine phosphatase nonreceptor type 4(PTPN4).SW837 cells with CENPA knockdown were injected subcutaneously into mice,and tumor growth was examined.RESULTS CENPA was upregulated in rectal cancer tissues and cell lines.CENPA overex-pression promoted proliferation,invasion and EMT,and inhibited apoptosis in rectal cancer cells.Whereas CENPA knockdown showed the opposite results.Moreover,CENPA inhibited MGMT expression by promoting DNA methyltrans-ferase 1-mediated MGMT promoter methylation.MGMT knockdown abolished the CENPA knockdown-mediated inhibition of rectal cancer cell progression.MGMT increased PTPN4 protein stability by inhibiting PTPN4 ubiquitination degradation via competing with ubiquitin-conjugating enzyme E2O for interacting with PTPN4.PTPN4 knockdown abolished the inhibitory effects of MGMT overexpression on rectal cancer cell progression.Moreover,CENPA knockdown inhibited xenograft tumor growth in vivo.CONCLUSION CENPA knockdown inhibited rectal cancer cell growth and attenuated xenograft tumor growth through regulating the MGMT/PTPN4 axis.
基金Baoding Municipal Science and Technology Plan Project(Project No.:2441ZF089)。
文摘Objective:To investigate the mechanism by which advanced glycation end products(AGEs)promote diabetic kidney disease fibrosis by regulating the tyrosine phosphatase SHP1/SHP2 balance and activating the epidermal growth factor receptor(EGFR)pathway.Methods:Animal experiments and in vitro cell experiments were conducted using Western blot analysis and tissue cell staining to detect the expression of relevant proteins and cellular morphological changes.Results:AGEs disrupt the SHP1/SHP2 balance,activate the EGFR and TGFβpathways,and promote fibrosis in diabetic nephropathy.Conclusion:AGEs regulate the balance of tyrosine phosphatases SHP1/SHP2,activate the EGFR-mediated signaling pathway,promote the release of inflammatory factors,and ultimately lead to fibrosis in diabetic nephropathy through a novel mechanism.
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 The National Health Commission's Key Laboratory of Gastrointestinal Tumor Diagnosis and Treatment for the Year 2022,National Health Commission's Master's and Doctoral/Postdoctoral Fund Project,No.NHCDP2022001Gansu Provincial People's Hospital Doctoral Supervisor Training Project,No.22GSSYA-3.
文摘The study conducted by Wang et al,focuses on the role of Rho GTPase activating protein 12(ARHGAP12),in hepatocellular carcinoma(HCC).This research reveals that ARHGAP12 expression,markedly elevated in malignant cells of HCC,correlates strongly with adverse outcomes for patients.Furthermore,the study illustrates that ARHGAP12 enhances the ability of HCC cells to invade and contributes to their resistance to tyrosine kinase inhibitors(TKIs)through modulation of the focal adhesion pathway.To comprehensively investigate the relationship between ARHGAP12 and TKI resistance,this study integrates single-cell and bulk RNA sequencing methodologies along with data from tumor immune single-cell hub 2,Gene Expression Omnibus,The Cancer Genome Atlas,CellMiner,Genomics of Drug Sensitivity in Cancer 2,as well as immunohisto-chemical staining and proteomic analyses.Statistical analyses,including the Wilcoxon rank-sum test and receiver operating characteristic curve analysis,were employed to evaluate the correlation between ARHGAP12 expression levels and clinical parameters,as well as drug sensitivity.It is evident that a more profound exploration of the molecular dynamics of HCC,especially those related to re-sistance against TKIs,is essential.
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In this editorial,the roles of protein tyrosine phosphatase nonreceptor 2(PTPN2)in oncogenic transformation and tumor behavior and its potential as a therapeutic target in the context of gastrointestinal(GI)cancers are presented with respect to the article by Li et al published in ninth issue of the World Journal of Gastrointestinal Oncology.PTPN2 is a member of the protein tyrosine phosphatase family of signaling proteins that play crucial roles in the regulation of inflammation and immunity.Accordingly,early findings highlighted the contribution of PTPN2 to the pathogenesis of inflammatory and autoimmune disorders related to its dysfunction.On the other hand,recent studies have indicated that PTPN2 has many different roles in different cancer types,which is associated with the complexity of its regulatory network.PTPN2 dephosphorylates and inactivates EGFR,SRC family kinases,JAK1 and JAK3,and STAT1,STAT3,and STAT5 in cell type-and context-dependent manners,which indicates that PTPN2 can perform either prooncogenic or anti-oncogenic functions depending on the tumor subtype.While PTPN2 has been suggested as a potential therapeutic target in cancer treatment,to the best of ourknowledge,no clear treatment protocol has referred to PTPN2.Although there are only few studies that investigated PTPN2 expression in the GI system cancers,which is a potential limitation,the association of this protein with tumor behavior and the influence of PTPN2 on many therapy-related signaling pathways emphasize that PTPN2 could serve as a new molecular biomarker to predict tumor behavior and as a target for therapeutic intervention against GI cancers.In conclusion,more studies should be performed to better understand the prognostic and therapeutic potential of PTPN2 in GI tumors,especially in tumors resistant to therapy.
文摘BACKGROUND Chemotherapy,targeted therapy,and immunotherapy have all been shown to achieve some efficacy in treating intrahepatic cholangiocarcinoma(ICC).How-ever,these systemic treatments have not provided optimal results for some patients.Therefore,the combination of transarterial chemoembolization(TACE)and hepatic artery infusion chemotherapy or other local interventional therapy methods is being considered for the treatment of liver tumors.AIM To evaluate the efficacy and safety of combining chemotherapy,targeted therapy,and immunotherapy,with or without TACE,in patients with ICC.METHODS We recruited 83 patients with unresectable ICC from July 2021 to December 2023 at the Affiliated Hospital of Xuzhou Medical University.Forty-one patients received TACE combined with chemotherapy,tyrosine kinase inhibitors,and pro-grammed death 1(PD-1)/programmed cell death ligand 1(PD-L1)inhibitors(ex-perimental group),whereas 42 patients were treated with chemotherapy,tyrosine kinase inhibitors,and PD-1/PD-L1 inhibitors(control group).Short-term efficacy was assessed using the modified response evaluation criterion,and the objective response rate,disease control rate,progression-free survival,and incidence of adverse events were compared between groups.RESULTS The objective response rate in the experimental group was greater than that in the control group(39.0%vs 19.0%,P<0.05).The disease control rate in the experimental group was significantly greater than that in the control group(75.6%vs 52.4%,P<0.05).The median progression-free survival times were 14.3 months in the experimental group and 12.7 months in the control group(P<0.05).All 41 patients in the experimental group developed postembol-ization syndrome.Among the symptoms,fever and pain were significantly more common in the experimental group than in the control group(85.4%vs 11.9%,P<0.001 and 58.5%vs 9.5%,P<0.001).No grade 4 or 5 treatment-related adverse events were observed in either group.CONCLUSION In patients with unresectable ICC,TACE combined with chemotherapy,tyrosine kinase inhibitors,and PD-1/PD-L1 inhibitors has good efficacy and high safety,indicating potential benefits for these patients.
基金Acknowledgements： This work was supported by the Natural Science Foundation of Jiangsu Province, China （No. 04KJB310082） and the Science and Technology Development Foundation of Nanjing Medical University （No. 06NMUZ002）.
文摘Objective： Extracellular signal-regulated kinases （ERKs） can be activated by calcium signals. In this study, we investigated whether calcium-dependent kinases were involved in ERKs cascade activation after global cerebral ischemia. Methods Cerebral ischemia was induced by four-vessel occlusion, and the calcium-dependent proteins were detected by immunoblot. Results Lethal-simulated ischemia significantly resulted in ERKs activation in N-methyl-D-aspartate （NMDA） receptor-dependent manner, accompanying with differential upregulation of Src kinase and Ca^2＋/calmodulin-dependent protein kinase Ⅱ （CaMKⅡ） activities. With the inhibition of Src family tyrosine kinases or CaMKⅡ by administration of PP2 or KN62, the phosphorylation of ERKs was impaired dramatically during post-ischemia recovery. However, ischemic challenge also repressed ERKs activity when Src kinase was excessively activated. Conclusions Src family tyrosine kinases and CaMKⅡ might be involved in the activation of ERKs mediated by NMDA receptor in response to acute ischemic stimuli in vivo, but the intense activation of Src kinase resulted from ischemia may play a reverse role in the ERKs cascade.
基金Supported by the Endowment Fund for the Education Republic of Indonesia(Lembaga Pengelola Dana Pendidikan/LPDP RI)No.44/LPDP/2015
文摘Spleen tyrosine kinase (SYK),a non-receptor tyrosine kinase,is expressed in most hematopoietic cells and non-hematopoietic cells and play a crucial role in both immune and non-immune biological responses.SYK mediate diverse cellular responses via an immune-receptor tyrosine-based activation motifs (ITAMs)-dependent signalling pathways,ITAMs-independent and ITAMs-semidependent signalling pathways.In liver,SYK expression has been observed in parenchymal (hepatocytes) and non-parenchymal cells (hepatic stellate cells and Kupffer cells) and found to be positively correlated with the disease severity.The implication of SYK pathway has been reported in different liver diseases including liver fibrosis,viral hepatitis,alcoholic liver disease,non-alcoholic steatohepatitis and hepatocellular carcinoma.Antagonism of SYK pathway using kinase inhibitors have shown to attenuate the progression of liver diseases thereby suggesting SYK as a highly promising therapeutic target.This review summarizes the current understanding of SYK and its therapeutic implication in liver diseases.
基金supported by the grants from National Natural Science Foundation of China (No. U0632008)the Key Project of Science and Technology Research Foundation of Guangdong Province,China (No. 2008A030201019,2007-05/06-7005206)+1 种基金the Key Project of Science and Technology Research Foundation of Guangzhou municipality,China (No. 09B52120112,2008A1-E4011-6)the Foundation for Medical and Scientific Technology Research of Guangdong Province,China (No. A2009293)
文摘Objective To investigate the role of tyrosine kinase receptor C（TrkC）,the receptor of neurotrophin-3（NT-3）,in neuroplasticity following spinal cord injury（SCI）.Methods Rats with cord transection were allowed to survive for 1,3,7 and 14 d post operation（dpo）.TrkC expressions at lower thoracic levels of the spinal cord and in precentral gyrus of cerebral cortex were investigated.Results TrkC protein levels at both the site of injury（T10-T11） and the neighboring segments（T9 and T12） in the spinal cord decreased significantly at 1-7 dpo,followed by a rapid increase at 14 dpo.The temporal changes in TrkC mRNA expression level showed a similar pattern with that of TrkC protein.In addition,the levels of TrkC protein and mRNA at the site of injury（T10-T11） were significantly higher than those at the neighboring spinal segments（T9 and T12）.Besides,the levels of TrkC protein and mRNA were higher at the rostral segment than at the caudal segment.However,in the motor cortex,TrkC protein was not detected and TrkC mRNA was expressed at a very low level.Conclusion These results suggest that TrkC may be involved in neuroplasticity after SCI.
基金The Scientific Research Foundation for the Returned Overseas Chinese Scholars(Grant No.20091590)State Education Ministry and Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules(Yanbian University),Ministry of Education,China(Grant No.201003)
文摘An organic layer prepared from the seed of Aceriphyllum rossii was studied to identify the active compounds for protein tyrosine phosphatase 1B（PTP1B） inhibition.Bioassay guided fractionation resulted in the isolation of PTP1B inhibitory activity of triterpenes（1-4）.These four compounds were identified as aceriphyllic acid C（1）,aceriphyllic acid D（2）,aceriphyllic acid E（3） and aceriphyllic acid F（4）.The isolated 1-4 compounds inhibited PTP1B with IC50 values ranged from（2.1±1.5） μmol/L to（11.2±2.5） μmol/L.Kinetic analysis of PTP1B inhibition by aceriphyllic acid C（1） and aceriphyllic acid D（2） suggested that oleanane-type triterpenes inhibited PTP1B activity in a mixed-type manner.
文摘The effect of Rg1,a saponin extracted froin Panax ginseng, on the phenotype,receptor and the activity of protein tyrosine kinase (PTK) of lymphocytes isolated from 7 healthy oldpersons were studied. The CD25, CD45RA and CD45RO phenotypes of lymphocytes were 4eter-mined by indirect immunofluorescence technique. The percentage of CD25, CD45RA and CD45ROpositive lymphocytes was 38.3%±17.3%, 46.0% 15.1%, and 52.6%±14.1% respectively after incu-bation with PHA (5 μ±/ml) for 72 hours. However, there were 58.0%±12.5%, CD25, 64.1% ± 12.4%,CD45RA, and 74.0%±8.0%, CD45RO positive cells in the presence of Rg, ( 1μg/ml) along with PHA(5 μg/ml) over the sanie period of incubation. A significant increase was induced by Rgi (P<0.05).The activities of PTK in the cytoplasm and membrane of lymphocytes were measured by ELISAmcthod after incubation with PHA or PHA+Rg1. The absorbance value of PTK activity in cytoplasmafter 72 hr incubation was 0. 120±0.020 in PHA group, but 0. 1 38±0.015 in PHA+Rg1 group. In thelymphocyte membrane, it was 0.374± 0.060 in PHA group and 0.403 ± 0.008 in PHA+Rg1 group(P<0.001). These results showed that Rgi significantly arid simultaneously increased both the PT Kactivity and the expression of phenotype of lymphocytes.
文摘A new approach for assembling amperometric mushroom pulp tissue based membrane electrode for determination of L tyrosine analysis is proposed. Ferrocene is used as a mediator of electron transfer between tyrosinase in mushroom tissue and a graphite electrode. The optimal operation conditions are studied. The linear response range of the biosensor is 2 0×10 -4 to 4 5×10 -3 mol·L -1 with response time of less than 5 min and lifetime of at least 30 d. The biosensor can be applied to practical sample analysis.
基金This work was partially supported by a grant from World Health Organization Fellowship (XS) (WPRO AWARD No. 0008/99).
文摘Objective: To survey the role of protein tyrosine kinases (PTKs) in the pathogenesis of several hematopoietic malignancies. Methods: By reviewing the published laboratory and clinical studies on PTK-related oncoproteins and their causative role in some leukemias and lymphomas. Results: Protein tyrosine kinases are key participants in signal transduction pathways that regulate cellular growth, activation and differentiations. Aberrant PTK activity resulting from gene mutation (often accompanying chromosome translocation) plays an etiologic role in several clonal hematopoietic malignancies. For example, the PTK product of the BCR-ABL fusion gene resulting from the t (9; 22) translocation exhibits several fold higher tyrosine kinase activity than the product of the ABL gene. Evidence suggests that the BCR-ABL oncoprotein alone is sufficient to case chronic myelogenous leukemia (CML) and other Ph positive acute leukemia. PTK over-activity resulting from chromosomal translocations creating TEL-ABL, TEL-JAK2 and TEL-PDGFRβ fusion proteins plays an important role in the pathogenesis of other types of leukemia. Another example occurs in anaplastic large cell lymphoma (ALCL). Experimental and clinical evidences indicate that translocations involving ALK gene on chromosome 2p23, most commonly resulting in an NPM-ALK fusion oncogene, result in constitutive activation of ALK and cause ALCL. This group of lymphomas is now named ALK positive lymphoma or ALKoma. Conclusion: Genetic lesions creating aberrant fusion proteins that result in excessive PTK activity are increasingly being recognized as central to the pathogenesis of hemotopoietic malignancies. These chimeric PTK molecules represent attractive disease-specific targets against which new classes therapeutic agents are being developed.
