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
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
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
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
Hepatitis B virus(HBV)reactivation(HBVr)represents a severe and potentially life-threatening condition,and preventive measures are available through blood test screening or prophylactic therapy administration.The asse...Hepatitis B virus(HBV)reactivation(HBVr)represents a severe and potentially life-threatening condition,and preventive measures are available through blood test screening or prophylactic therapy administration.The assessment of HBVr traditionally considers factors such as HBV profile,including hepatitis B surface antigen(HBsAg)and antibody to hepatitis B core antigen,along with type of medication(chemotherapy;immunomodulants).Nevertheless,consideration of possible patient’s underlying tumor and the specific malignancy type(solid or hematologic)plays a crucial role and needs to be assessed for decision-making process.展开更多
Gastric cancer is among the most frequently occurring cancers and a leading cause of cancer-related deaths globally.Because gastric cancer is highly heterogenous and comprised of different subtypes with distinct molec...Gastric cancer is among the most frequently occurring cancers and a leading cause of cancer-related deaths globally.Because gastric cancer is highly heterogenous and comprised of different subtypes with distinct molecular and clinical characteristics,the management of gastric cancer calls for better-defined,biomarker-guided,molecular-based treatment strategies.MET is a receptor tyrosine kinase mediating important physiologic processes,such as embryogenesis,tissue regeneration,and wound healing.However,mounting evidence suggests that aberrant MET pathway activation contributes to tumour proliferation and metastasis in multiple cancer types,including gastric cancer,and is associated with poor patient outcomes.As such,MET-targeting therapies are being actively developed and promising progress has been demonstrated,especially with MET tyrosine kinase inhibitors.This review aims to briefly introduce the role of MET alterations in gastric cancer and summarize in detail the current progress of MET tyrosine kinase inhibitors in this disease area with a focus on savolitinib,tepotinib,capmatinib,and crizotinib.Building on current knowledge,this review further discusses existing challenges in MET alterations testing,possible resistance mechanisms to MET inhibitors,and future directions of MET-targeting therapies.展开更多
BACKGROUND The incidence of primary liver cancer is increasing year by year.In 2022 alone,more than 900000 people were diagnosed with liver cancer worldwide,with hepatocellular carcinoma(HCC)accounting for 75%-85%of c...BACKGROUND The incidence of primary liver cancer is increasing year by year.In 2022 alone,more than 900000 people were diagnosed with liver cancer worldwide,with hepatocellular carcinoma(HCC)accounting for 75%-85%of cases.HCC is the most common primary liver cancer.China has the highest incidence and mortality rate of HCC in the world,and it is one of the malignant tumors that seriously threaten the health of Chinese people.The onset of liver cancer is occult,the early cases lack typical clinical symptoms,and most of the patients are already in the middle and late stage when diagnosed.Therefore,it is very important to find new markers for the early detection and diagnosis of liver cancer,improve the therapeutic effect,and improve the prognosis of patients.Protein tyrosine phosphatase non-receptor 2(PTPN2)has been shown to be associated with colorectal cancer,triple-negative breast cancer,non-small cell lung cancer,and prostate cancer,but its biological role and function in tumors remain to be further studied.AIM To combine the results of relevant data obtained from The Cancer Genome Atlas(TCGA)to provide the first in-depth analysis of the biological role of PTPN2 in HCC.METHODS The expression of PTPN2 in HCC was first analyzed based on the TCGA database,and the findings were then verified by immunohistochemical staining,quantitative real-time polymerase chain reaction(qRT-PCR),and immunoblotting.The value of PTPN2 in predicting the survival of patients with HCC was assessed by analyzing the relationship between PTPN2 expression in HCC tissues and clinicopathological features.Finally,the potential of PTPN2 affecting immune escape of liver cancer was evaluated by tumor immune dysfunction and exclusion and immunohistochemical staining.RESULTS The results of immunohistochemical staining,qRT-PCR,and immunoblotting in combination with TCGA database analysis showed that PTPN2 was highly expressed and associated with a poor prognosis in HCC patients.Kyoto Encyclopedia of Genes and Genomes enrichment analysis showed that PTPN2 was associated with various pathways,including cancer-related pathways,the Notch signaling pathway,and the MAPK signaling pathway.Gene Set Enrichment Analysis showed that PTPN2 was highly expressed in various immune-related pathways,such as the epithelial mesenchymal transition process.A risk model score based on PTPN2 showed that immune escape was significantly enhanced in the high-risk group compared with the low-risk group.CONCLUSION This study investigated PTPN2 from multiple biological perspectives,revealing that PTPN2 can function as a biomarker of poor prognosis and mediate immune evasion in HCC.展开更多
BACKGROUND Epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs)significantly improve the survival of patients with Epidermal growth factor receptor(EGFR)sensitive mutations in non-small cell lung can...BACKGROUND Epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs)significantly improve the survival of patients with Epidermal growth factor receptor(EGFR)sensitive mutations in non-small cell lung cancer(NSCLC).CASE SUMMARY A 67-year-old female patient in advanced lung adenocarcinoma suffered from drug resistance after EGFR-TKIs treatment.Secondary pathological tissue biopsy confirmed squamous cell carcinoma(SCC)transformation.Patients inevitably encountered drug resistance issues after receiving EGFR-TKIs treatment for a certain period of time,while EGFR-TKIs can significantly improve the survival of patients with EGFR-sensitive mutations in NSCLC.Notably,EGFR-TKIs resistance includes primary and acquired.Pathological transformation is one of the mechanisms of acquired resistance in EGFR-TKIs,with SCC transformation being relatively rare.Our results provide more detailed results of the patient’s diagnosis and treatment process on SCC transformation after EGFR-TKIs treatment for lung adenocarcinoma.CONCLUSION Squamous cell carcinoma transformation is one of the acquired resistance mechanisms of EGFR-TKIs in advanced lung adenocarcinoma with EGFR mutations.展开更多
In this editorial,we offer a summary of the risk associated with hepatitis B reactivation(HBVr)in the setting of both solid and hematologic malignancies treated with Bruton tyrosine kinase(BTK)inhibitors,with insights...In this editorial,we offer a summary of the risk associated with hepatitis B reactivation(HBVr)in the setting of both solid and hematologic malignancies treated with Bruton tyrosine kinase(BTK)inhibitors,with insights derived from current studies.Furthermore,we emphasize the critical need for a framework regarding robust risk evaluation in patients undergoing such treatments.This framework is essential for identifying those at increased risk of HBVr,enabling healthcare providers to implement proactive measures to prevent reactivation and ensure the safe administration of BTK inhibitor therapy.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)is a major health challenge with high incidence and poor survival rates in China.Systemic therapies,particularly tyrosine kinase inhibitors(TKIs),are the first-line treatment fo...BACKGROUND Hepatocellular carcinoma(HCC)is a major health challenge with high incidence and poor survival rates in China.Systemic therapies,particularly tyrosine kinase inhibitors(TKIs),are the first-line treatment for advanced HCC,but resistance is common.The Rho GTPase family member Rho GTPase activating protein 12(ARHGAP12),which regulates cell adhesion and invasion,is a potential therapeutic target for overcoming TKI resistance in HCC.However,no studies on the expression of ARHGAP12 in HCC and its role in resistance to TKIs have been reported.AIM To unveil the expression of ARHGAP12 in HCC,its role in TKI resistance and its potential associated pathways.METHODS This study used single-cell RNA sequencing(scRNA-seq)to evaluate ARHGAP12 mRNA levels and explored its mechanisms through enrichment analysis.CellChat was used to investigate focal adhesion(FA)pathway regulation.We integrated bulk RNA data(RNA-seq and microarray),immunohistochemistry and proteomics to analyze ARHGAP12 mRNA and protein levels,correlating with clinical outcomes.We assessed ARHGAP12 expression in TKI-resistant HCC,integrated conventional HCC to explore its mechanism,identified intersecting FA pathway genes with scRNA-seq data and evaluated its response to TKI and immunotherapy.RESULTS ARHGAP12 mRNA was found to be highly expressed in malignant hepatocytes and to regulate FA.In malignant hepatocytes in high-score FA groups,MDK-[integrin alpha 6(ITGA6)+integrinβ-1(ITGB1)]showed specificity in ligand-receptor interactions.ARHGAP12 mRNA and protein were upregulated in bulk RNA,immunohistochemistry and proteomics,and higher expression was associated with a worse prognosis.ARHGAP12 was also found to be a TKI resistance gene that regulated the FA pathway.ITGB1 was identified as a crossover gene in the FA pathway in both scRNA-seq and bulk RNA.High expression of ARHGAP12 was associated with adverse reactions to sorafenib,cabozantinib and regorafenib,but not to immunotherapy.CONCLUSION ARHGAP12 expression is elevated in HCC and TKI-resistant HCC,and its regulatory role in FA may underlie the TKI-resistant phenotype.展开更多
In this editorial,we comment on the article(World J Gastrointest Oncol 2024;16:1236-1247),which is a retrospective study of transarterial chemoembolization(TACE)combined with multi-targeted tyrosine kinase inhibitor(T...In this editorial,we comment on the article(World J Gastrointest Oncol 2024;16:1236-1247),which is a retrospective study of transarterial chemoembolization(TACE)combined with multi-targeted tyrosine kinase inhibitor(TKI)and programmed cell death protein-1(PD-1)inhibitor for the treatment of unresectable hepatocellular carcinoma(HCC).Herein,we focus specifically on the mechanisms of this triple therapy,administration sequence and selection of each medication,and implications for future clinical trials.Based on the interaction mechanisms between medications,the triple therapy of TACE+TKI+PD-1 is proposed to complement the deficiency of each monotherapy,and achieve synergistic antitumor effects.Although this triple therapy has been evaluated by several retrospective trials,it is still controversial whether the triple therapy achieves better clinical benefits,due to the flawed study design and heterogeneity in medications.In addition,the administration sequence,which may greatly affect the clinical benefit,needs to be fully considered at clinical decision-making for obtaining better prognosis.We hope that this editorial could contribute to the design and optimization of future trials.展开更多
In this editorial,we comment on the article by Wang et al.This manuscript explores the potential synergistic effects of combining zanubrutinib,a novel oral inhibitor of Bruton’s tyrosine kinase,with high-dose methotr...In this editorial,we comment on the article by Wang et al.This manuscript explores the potential synergistic effects of combining zanubrutinib,a novel oral inhibitor of Bruton’s tyrosine kinase,with high-dose methotrexate(HD-MTX)as a therapeutic intervention for primary central nervous system lymphoma(PCNSL).The study involves a retrospective analysis of 19 PCNSL patients,highlighting clinicopathological characteristics,treatment outcomes,and genomic biomarkers.The results indicate the combination’s good tolerance and strong antitumor activity,with an 84.2%overall response rate.The authors emphasize the potential of zanubrutinib to modulate key genomic features of PCNSL,particularly mutations in myeloid differentiation primary response 88 and cluster of differentiation 79B.Furthermore,the study investigates the role of circulating tumor DNA in cerebrospinal fluid for disease surveillance and treatment response monitoring.In essence,the study provides valuable insights into the potential of combining zanubrutinib with HD-MTX as a frontline therapeutic regimen for PCNSL.The findings underscore the importance of exploring alternative treatment modalities and monitoring genomic and liquid biopsy markers to optimize patient outcomes.While the findings suggest promise,the study’s limitations should be considered,and further research is needed to establish the clinical relevance of this therapeutic approach for PCNSL.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.
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.
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Hepatitis B virus(HBV)reactivation(HBVr)represents a severe and potentially life-threatening condition,and preventive measures are available through blood test screening or prophylactic therapy administration.The assessment of HBVr traditionally considers factors such as HBV profile,including hepatitis B surface antigen(HBsAg)and antibody to hepatitis B core antigen,along with type of medication(chemotherapy;immunomodulants).Nevertheless,consideration of possible patient’s underlying tumor and the specific malignancy type(solid or hematologic)plays a crucial role and needs to be assessed for decision-making process.
基金supported by the National Natural Science Foundation of China(Grant No.81602057)the Beijing Natural Science Foundation(Grant No.Z210015)。
文摘Gastric cancer is among the most frequently occurring cancers and a leading cause of cancer-related deaths globally.Because gastric cancer is highly heterogenous and comprised of different subtypes with distinct molecular and clinical characteristics,the management of gastric cancer calls for better-defined,biomarker-guided,molecular-based treatment strategies.MET is a receptor tyrosine kinase mediating important physiologic processes,such as embryogenesis,tissue regeneration,and wound healing.However,mounting evidence suggests that aberrant MET pathway activation contributes to tumour proliferation and metastasis in multiple cancer types,including gastric cancer,and is associated with poor patient outcomes.As such,MET-targeting therapies are being actively developed and promising progress has been demonstrated,especially with MET tyrosine kinase inhibitors.This review aims to briefly introduce the role of MET alterations in gastric cancer and summarize in detail the current progress of MET tyrosine kinase inhibitors in this disease area with a focus on savolitinib,tepotinib,capmatinib,and crizotinib.Building on current knowledge,this review further discusses existing challenges in MET alterations testing,possible resistance mechanisms to MET inhibitors,and future directions of MET-targeting therapies.
文摘BACKGROUND The incidence of primary liver cancer is increasing year by year.In 2022 alone,more than 900000 people were diagnosed with liver cancer worldwide,with hepatocellular carcinoma(HCC)accounting for 75%-85%of cases.HCC is the most common primary liver cancer.China has the highest incidence and mortality rate of HCC in the world,and it is one of the malignant tumors that seriously threaten the health of Chinese people.The onset of liver cancer is occult,the early cases lack typical clinical symptoms,and most of the patients are already in the middle and late stage when diagnosed.Therefore,it is very important to find new markers for the early detection and diagnosis of liver cancer,improve the therapeutic effect,and improve the prognosis of patients.Protein tyrosine phosphatase non-receptor 2(PTPN2)has been shown to be associated with colorectal cancer,triple-negative breast cancer,non-small cell lung cancer,and prostate cancer,but its biological role and function in tumors remain to be further studied.AIM To combine the results of relevant data obtained from The Cancer Genome Atlas(TCGA)to provide the first in-depth analysis of the biological role of PTPN2 in HCC.METHODS The expression of PTPN2 in HCC was first analyzed based on the TCGA database,and the findings were then verified by immunohistochemical staining,quantitative real-time polymerase chain reaction(qRT-PCR),and immunoblotting.The value of PTPN2 in predicting the survival of patients with HCC was assessed by analyzing the relationship between PTPN2 expression in HCC tissues and clinicopathological features.Finally,the potential of PTPN2 affecting immune escape of liver cancer was evaluated by tumor immune dysfunction and exclusion and immunohistochemical staining.RESULTS The results of immunohistochemical staining,qRT-PCR,and immunoblotting in combination with TCGA database analysis showed that PTPN2 was highly expressed and associated with a poor prognosis in HCC patients.Kyoto Encyclopedia of Genes and Genomes enrichment analysis showed that PTPN2 was associated with various pathways,including cancer-related pathways,the Notch signaling pathway,and the MAPK signaling pathway.Gene Set Enrichment Analysis showed that PTPN2 was highly expressed in various immune-related pathways,such as the epithelial mesenchymal transition process.A risk model score based on PTPN2 showed that immune escape was significantly enhanced in the high-risk group compared with the low-risk group.CONCLUSION This study investigated PTPN2 from multiple biological perspectives,revealing that PTPN2 can function as a biomarker of poor prognosis and mediate immune evasion in HCC.
文摘BACKGROUND Epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs)significantly improve the survival of patients with Epidermal growth factor receptor(EGFR)sensitive mutations in non-small cell lung cancer(NSCLC).CASE SUMMARY A 67-year-old female patient in advanced lung adenocarcinoma suffered from drug resistance after EGFR-TKIs treatment.Secondary pathological tissue biopsy confirmed squamous cell carcinoma(SCC)transformation.Patients inevitably encountered drug resistance issues after receiving EGFR-TKIs treatment for a certain period of time,while EGFR-TKIs can significantly improve the survival of patients with EGFR-sensitive mutations in NSCLC.Notably,EGFR-TKIs resistance includes primary and acquired.Pathological transformation is one of the mechanisms of acquired resistance in EGFR-TKIs,with SCC transformation being relatively rare.Our results provide more detailed results of the patient’s diagnosis and treatment process on SCC transformation after EGFR-TKIs treatment for lung adenocarcinoma.CONCLUSION Squamous cell carcinoma transformation is one of the acquired resistance mechanisms of EGFR-TKIs in advanced lung adenocarcinoma with EGFR mutations.
文摘In this editorial,we offer a summary of the risk associated with hepatitis B reactivation(HBVr)in the setting of both solid and hematologic malignancies treated with Bruton tyrosine kinase(BTK)inhibitors,with insights derived from current studies.Furthermore,we emphasize the critical need for a framework regarding robust risk evaluation in patients undergoing such treatments.This framework is essential for identifying those at increased risk of HBVr,enabling healthcare providers to implement proactive measures to prevent reactivation and ensure the safe administration of BTK inhibitor therapy.
基金Supported by National Natural Science Foundation of China,No.82260581Guangxi Zhuang Autonomous Region Health Committee Scientific Research Project,No.Z20201147+3 种基金Guangxi Medical University Education and Teaching Reform Project,No.2021XJGA02Undergraduate Teaching Reform Project of Guangxi Higher Education,No.2023JGB163Guangxi Medical University Teacher Teaching Ability Development Project,No.2202JFA20China Undergraduate Innovation and Entrepreneurship Training Program,No.S202310598170.
文摘BACKGROUND Hepatocellular carcinoma(HCC)is a major health challenge with high incidence and poor survival rates in China.Systemic therapies,particularly tyrosine kinase inhibitors(TKIs),are the first-line treatment for advanced HCC,but resistance is common.The Rho GTPase family member Rho GTPase activating protein 12(ARHGAP12),which regulates cell adhesion and invasion,is a potential therapeutic target for overcoming TKI resistance in HCC.However,no studies on the expression of ARHGAP12 in HCC and its role in resistance to TKIs have been reported.AIM To unveil the expression of ARHGAP12 in HCC,its role in TKI resistance and its potential associated pathways.METHODS This study used single-cell RNA sequencing(scRNA-seq)to evaluate ARHGAP12 mRNA levels and explored its mechanisms through enrichment analysis.CellChat was used to investigate focal adhesion(FA)pathway regulation.We integrated bulk RNA data(RNA-seq and microarray),immunohistochemistry and proteomics to analyze ARHGAP12 mRNA and protein levels,correlating with clinical outcomes.We assessed ARHGAP12 expression in TKI-resistant HCC,integrated conventional HCC to explore its mechanism,identified intersecting FA pathway genes with scRNA-seq data and evaluated its response to TKI and immunotherapy.RESULTS ARHGAP12 mRNA was found to be highly expressed in malignant hepatocytes and to regulate FA.In malignant hepatocytes in high-score FA groups,MDK-[integrin alpha 6(ITGA6)+integrinβ-1(ITGB1)]showed specificity in ligand-receptor interactions.ARHGAP12 mRNA and protein were upregulated in bulk RNA,immunohistochemistry and proteomics,and higher expression was associated with a worse prognosis.ARHGAP12 was also found to be a TKI resistance gene that regulated the FA pathway.ITGB1 was identified as a crossover gene in the FA pathway in both scRNA-seq and bulk RNA.High expression of ARHGAP12 was associated with adverse reactions to sorafenib,cabozantinib and regorafenib,but not to immunotherapy.CONCLUSION ARHGAP12 expression is elevated in HCC and TKI-resistant HCC,and its regulatory role in FA may underlie the TKI-resistant phenotype.
基金The National Natural Science Foundation of China,No.82104525The Natural Science Foundation of the Jiangsu Higher Education Institutions of China,No.21KJB360009.
文摘In this editorial,we comment on the article(World J Gastrointest Oncol 2024;16:1236-1247),which is a retrospective study of transarterial chemoembolization(TACE)combined with multi-targeted tyrosine kinase inhibitor(TKI)and programmed cell death protein-1(PD-1)inhibitor for the treatment of unresectable hepatocellular carcinoma(HCC).Herein,we focus specifically on the mechanisms of this triple therapy,administration sequence and selection of each medication,and implications for future clinical trials.Based on the interaction mechanisms between medications,the triple therapy of TACE+TKI+PD-1 is proposed to complement the deficiency of each monotherapy,and achieve synergistic antitumor effects.Although this triple therapy has been evaluated by several retrospective trials,it is still controversial whether the triple therapy achieves better clinical benefits,due to the flawed study design and heterogeneity in medications.In addition,the administration sequence,which may greatly affect the clinical benefit,needs to be fully considered at clinical decision-making for obtaining better prognosis.We hope that this editorial could contribute to the design and optimization of future trials.
文摘In this editorial,we comment on the article by Wang et al.This manuscript explores the potential synergistic effects of combining zanubrutinib,a novel oral inhibitor of Bruton’s tyrosine kinase,with high-dose methotrexate(HD-MTX)as a therapeutic intervention for primary central nervous system lymphoma(PCNSL).The study involves a retrospective analysis of 19 PCNSL patients,highlighting clinicopathological characteristics,treatment outcomes,and genomic biomarkers.The results indicate the combination’s good tolerance and strong antitumor activity,with an 84.2%overall response rate.The authors emphasize the potential of zanubrutinib to modulate key genomic features of PCNSL,particularly mutations in myeloid differentiation primary response 88 and cluster of differentiation 79B.Furthermore,the study investigates the role of circulating tumor DNA in cerebrospinal fluid for disease surveillance and treatment response monitoring.In essence,the study provides valuable insights into the potential of combining zanubrutinib with HD-MTX as a frontline therapeutic regimen for PCNSL.The findings underscore the importance of exploring alternative treatment modalities and monitoring genomic and liquid biopsy markers to optimize patient outcomes.While the findings suggest promise,the study’s limitations should be considered,and further research is needed to establish the clinical relevance of this therapeutic approach for PCNSL.
