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
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
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
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
Objective:The purpose of the study was to identify the best sequence of therapy beginning with a tyrosine kinase inhibitor(TKI)as the first-line therapy for patients with metastatic renal cell carcinoma(mRCC)in terms ...Objective:The purpose of the study was to identify the best sequence of therapy beginning with a tyrosine kinase inhibitor(TKI)as the first-line therapy for patients with metastatic renal cell carcinoma(mRCC)in terms of overall survival(OS),progression-free survival(PFS),and rates of discontinuation and adverse effects during the treatment period.Methods:This is a retrospective,nationwide multicenter study of patients with mRCC after diagnosis at 10 different tertiary medical centers in Korea from January 1992 to December 2017.We focused on patients at either“favorable”or“intermediate”risk according to the International mRCC Database Consortium criteria,and they were followed up(median 335 days).Finally,a total of 1409 patients were selected as the study population.We generated a Cox proportional hazard model adjusted for covariates,and the different therapy schemes were statistically tested in terms of OS as well as PFS.In addition,frequencies of discontinuation and adverse events were compared among the therapy schemes.Results:Of the primary patterns of treatment sequences(24 sequences),“sunitinib epazopanib”and“sunitinibeeverolimuseimmunotherapy”showed the most beneficial results in both OS and PFS with significantly lower hazards than“sunitinib”,which is the most commonly treated agent in Korea.Considering that the“TKIeTKI”structure showed relatively higher discontinuation rates with higher adverse effects,the overall beneficial sequence would be“sunitinibeeverolimuseimmunotherapy”.Conclusion:Among several sequential therapy starting with TKIs,“sunitinibeeverolimuse immunotherapy”was found to be the best scheme for mRCC patients with“favorable”or“intermediate”risks.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
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
In this editorial we comment on the article by Ji et al.We focus specifically on the EGFR tyrosine kinase inhibitor(EGFR-TKI)treatment and the development of drug resistance to EGFR-TKIs.
BACKGROUND Radiotherapy stands as a promising therapeutic modality for colorectal cancer(CRC);yet,the formidable challenge posed by radio-resistance significantly undermines its efficacy in achieving CRC remission.AIM...BACKGROUND Radiotherapy stands as a promising therapeutic modality for colorectal cancer(CRC);yet,the formidable challenge posed by radio-resistance significantly undermines its efficacy in achieving CRC remission.AIM To elucidate the role played by microRNA-298(miR-298)in CRC radio-resistance.METHODS To establish a radio-resistant CRC cell line,HT-29 cells underwent exposure to 5 gray ionizing radiation that was followed by a 7-d recovery period.The quantification of miR-298 levels within CRC cells was conducted through quantitative RT-PCR,and protein expression determination was realized through Western blotting.Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and proliferation by clonogenic assay.Radio-induced apoptosis was discerned through flow cytometry analysis.RESULTS We observed a marked upregulation of miR-298 in radio-resistant CRC cells.MiR-298 emerged as a key determinant of cell survival following radiation exposure,as its overexpression led to a notable reduction in radiation-induced apoptosis.Intriguingly,miR-298 expression exhibited a strong correlation with CRC cell viability.Further investigation unveiled human dual-specificity tyrosine(Y)-regulated kinase 1A(DYRK1A)as miR-298’s direct target.CONCLUSION Taken together,our findings underline the role played by miR-298 in bolstering radio-resistance in CRC cells by means of DYRK1A downregulation,thereby positioning miR-298 as a promising candidate for mitigating radioresistance in CRC.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
Dendritic cells (DCs) are immune cells specialized to capture, process and present antigen to T cells in order to initiate an appropriate adaptive immune response. The study of mouse DC has revealed a heterogeneous ...Dendritic cells (DCs) are immune cells specialized to capture, process and present antigen to T cells in order to initiate an appropriate adaptive immune response. The study of mouse DC has revealed a heterogeneous population of cells that differ in their development, surface phenotype and function. The study of human blood and spleen has shown the presence of two subsets of conventional DC including the CDlb/c+ and CD141+CLEC9A+ conventional DC (cDC) and a plasmacytoid DC (pDC) that is CD304+CD123+. Studies on these subpopulations have revealed phenotypic and functional differences that are similar to those described in the mouse. In this study, the three DC subsets have been generated in vitrofrom human CD34+ precursors in the presence of fins-like tyrosine kinase 3 ligand (FIt3L) and thrombopoietin (TPO). The DC subsets so generated, including the CDlb/c+ and CLEC9A+ cDCs and CD123 + pDCs, were largely similar to their blood and spleen counterparts with respect to surface phenotype, toll-like receptor and transcription factor expression, capacity to stimulate T cells, cytokine secretion and cross-presentation of antigens. This system may be utilized to study aspects of DC development and function not possible in vivo.展开更多
AIM:To evaluate whether a novel tyrosine kinase inhibitor nintedanib could inhibit basic fibroblast growth factor(bFGF)and vascular endothelial growth factor(VEGF)simultaneously for retinal vascular disease in vivo.ME...AIM:To evaluate whether a novel tyrosine kinase inhibitor nintedanib could inhibit basic fibroblast growth factor(bFGF)and vascular endothelial growth factor(VEGF)simultaneously for retinal vascular disease in vivo.METHODS:After a laser induced rabbit retinal vein occlusion(RVO)model was made,0.5 mg of nintedanib was injected intravitreally in the left eye on the third day while the right eye was as a control.Intracameral samples were taken on the day before laser treatment and days 1,3,7,14,21,and 28 after treatment.Enzyme-linked immunosorbent assay(ELISA)was used to test the bFGF and VEGF-A concentrations in the aqueous humor.RESULTS:Both bFGF and VEGF-A rose significantly on the third day after laser treatment in both eyes.In the control eye the bFGF concentration peaked on the 14th day while the VEGF-A concentration dropped rapidly soon after the third day.After nintadanib injection in the study eye,both bFGF and VEGF-A showed a significant reduction on the 4th day(7th day after laser treatment)when compared to the control eye,and kept on low level in the following several weeks.CONCLUSION:Intravitreal injection of nintedanib can inhibit the expression of bFGF and VEGF in the process of RVO model to a certain extent,which is expected to become a new method for the treatment of retinal vascular diseases or fibrotic diseases.展开更多
The body of evidence investigating human epidermal growth factor receptor-2(HER2)directed therapy in patients with breast cancer(BC)has been growing within the last decade.Recently,the use of tyrosine kinase inhibitor...The body of evidence investigating human epidermal growth factor receptor-2(HER2)directed therapy in patients with breast cancer(BC)has been growing within the last decade.Recently,the use of tyrosine kinase inhibitors(TKIs)has been of particular interest in the treatment of human malignancies.This literature commentary is intended to highlight the most recent findings associated with the widely-studied TKI agents and their clinical significance in improving the outcomes of HER2 positive BC.展开更多
BACKGROUND Diffuse large B-cell lymphoma(DLBCL)is a common aggressive non-Hodgkin's lymphoma(NHL),accounting for 30%-40%of adult NHLs.This report aims to explore the efficacy and safety of rituximab combined with ...BACKGROUND Diffuse large B-cell lymphoma(DLBCL)is a common aggressive non-Hodgkin's lymphoma(NHL),accounting for 30%-40%of adult NHLs.This report aims to explore the efficacy and safety of rituximab combined with Bruton tyrosine kinase inhibitors(BTKis)in the treatment of elderly patients with DLBCL.CASE SUMMARY The clinical data of two elderly patients with DLBCL who received rituximab combined with BTKi in our hospital were retrospectively analyzed,and the literature was reviewed.The patients were treated with chemotherapy using the R-miniCHOP regimen for two courses.Then,they received rituximab in combination with BTKi.CONCLUSION The treatment experience in these cases demonstrates the potential efficacy of rituximab combined with BTKi to treat elderly DLBCL patients,thus providing a new treatment strategy.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
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
Hepatitis B virus(HBV) reactivation is a well-recognized complication in patients with chronic HBV infection receiving cytotoxic or immunosuppressive chemotherapy.Imatinib mesylate and nilotinib are selective Bcr/Abl ...Hepatitis B virus(HBV) reactivation is a well-recognized complication in patients with chronic HBV infection receiving cytotoxic or immunosuppressive chemotherapy.Imatinib mesylate and nilotinib are selective Bcr/Abl tyrosine kinase inhibitors,which are now widely used in the treatment of patients with chronic myeloid leukemia.Although HBV reactivation induced by imatinib mesylate has been reported,nilotinib-related HBV reactivation has not been reported in the English literature.We report here 2 cases of HBV reactivation in chronic myeloid leukemia patients receiving imatinib mesylate and a novel case of nilotinib related HBV reactivation.展开更多
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.
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Objective:The purpose of the study was to identify the best sequence of therapy beginning with a tyrosine kinase inhibitor(TKI)as the first-line therapy for patients with metastatic renal cell carcinoma(mRCC)in terms of overall survival(OS),progression-free survival(PFS),and rates of discontinuation and adverse effects during the treatment period.Methods:This is a retrospective,nationwide multicenter study of patients with mRCC after diagnosis at 10 different tertiary medical centers in Korea from January 1992 to December 2017.We focused on patients at either“favorable”or“intermediate”risk according to the International mRCC Database Consortium criteria,and they were followed up(median 335 days).Finally,a total of 1409 patients were selected as the study population.We generated a Cox proportional hazard model adjusted for covariates,and the different therapy schemes were statistically tested in terms of OS as well as PFS.In addition,frequencies of discontinuation and adverse events were compared among the therapy schemes.Results:Of the primary patterns of treatment sequences(24 sequences),“sunitinib epazopanib”and“sunitinibeeverolimuseimmunotherapy”showed the most beneficial results in both OS and PFS with significantly lower hazards than“sunitinib”,which is the most commonly treated agent in Korea.Considering that the“TKIeTKI”structure showed relatively higher discontinuation rates with higher adverse effects,the overall beneficial sequence would be“sunitinibeeverolimuseimmunotherapy”.Conclusion:Among several sequential therapy starting with TKIs,“sunitinibeeverolimuse immunotherapy”was found to be the best scheme for mRCC patients with“favorable”or“intermediate”risks.
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Supported by Grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute,funded by the Ministry of Health&Welfare,Republic of Korea,No.RS-2022-KH129889.
文摘BACKGROUND The classification of uterine sarcomas is based on distinctive morphological and immunophenotypic characteristics,increasingly supported by molecular genetic diagnostics.Data on neurotrophic tyrosine receptor kinase(NTRK)gene fusionpositive uterine sarcoma,potentially aggressive and morphologically similar to fibrosarcoma,are limited due to its recent recognition.Pan-TRK immunohistochemistry(IHC)analysis serves as an effective screening tool with high sensitivity and specificity for NTRK-fusion malignancies.CASE SUMMARY We report a case of a malignant mesenchymal tumor originating from the uterine cervix,which was pan-TRK IHC-positive but lacked NTRK gene fusions,accompanied by a brief literature review.A 55-year-old woman presented to the emergency department with abdominal pain and distension,exhibiting significant ascites and multiple solid pelvic masses.Pelvic examination revealed a tumor encompassing the uterine cervix,extending to the vagina and uterine corpus.A punch biopsy of the cervix indicated NTRK sarcoma with positive immunochemical pan-TRK stain.However,subsequent next generation sequencing revealed no NTRK gene fusion,leading to a diagnosis of poorly differentiated,advanced-stage sarcoma.CONCLUSION The clinical significance of NTRK gene fusion lies in potential treatment with TRK inhibitors for positive sarcomas.Identifying such rare tumors is crucial due to the potential applicability of tropomyosin receptor kinase inhibitor treatment.
文摘In this editorial we comment on the article by Ji et al.We focus specifically on the EGFR tyrosine kinase inhibitor(EGFR-TKI)treatment and the development of drug resistance to EGFR-TKIs.
基金This study was reviewed and approved by the Experimental Animal Ethics Committee of the First Affiliated Hospital of Guangxi Medical University(Approval No.2023-E386-01).
文摘BACKGROUND Radiotherapy stands as a promising therapeutic modality for colorectal cancer(CRC);yet,the formidable challenge posed by radio-resistance significantly undermines its efficacy in achieving CRC remission.AIM To elucidate the role played by microRNA-298(miR-298)in CRC radio-resistance.METHODS To establish a radio-resistant CRC cell line,HT-29 cells underwent exposure to 5 gray ionizing radiation that was followed by a 7-d recovery period.The quantification of miR-298 levels within CRC cells was conducted through quantitative RT-PCR,and protein expression determination was realized through Western blotting.Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and proliferation by clonogenic assay.Radio-induced apoptosis was discerned through flow cytometry analysis.RESULTS We observed a marked upregulation of miR-298 in radio-resistant CRC cells.MiR-298 emerged as a key determinant of cell survival following radiation exposure,as its overexpression led to a notable reduction in radiation-induced apoptosis.Intriguingly,miR-298 expression exhibited a strong correlation with CRC cell viability.Further investigation unveiled human dual-specificity tyrosine(Y)-regulated kinase 1A(DYRK1A)as miR-298’s direct target.CONCLUSION Taken together,our findings underline the role played by miR-298 in bolstering radio-resistance in CRC cells by means of DYRK1A downregulation,thereby positioning miR-298 as a promising candidate for mitigating radioresistance in CRC.
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.
文摘Dendritic cells (DCs) are immune cells specialized to capture, process and present antigen to T cells in order to initiate an appropriate adaptive immune response. The study of mouse DC has revealed a heterogeneous population of cells that differ in their development, surface phenotype and function. The study of human blood and spleen has shown the presence of two subsets of conventional DC including the CDlb/c+ and CD141+CLEC9A+ conventional DC (cDC) and a plasmacytoid DC (pDC) that is CD304+CD123+. Studies on these subpopulations have revealed phenotypic and functional differences that are similar to those described in the mouse. In this study, the three DC subsets have been generated in vitrofrom human CD34+ precursors in the presence of fins-like tyrosine kinase 3 ligand (FIt3L) and thrombopoietin (TPO). The DC subsets so generated, including the CDlb/c+ and CLEC9A+ cDCs and CD123 + pDCs, were largely similar to their blood and spleen counterparts with respect to surface phenotype, toll-like receptor and transcription factor expression, capacity to stimulate T cells, cytokine secretion and cross-presentation of antigens. This system may be utilized to study aspects of DC development and function not possible in vivo.
基金Supported by Medical Health Science and Technology Project of Zhejiang Province(No.2020KY654).
文摘AIM:To evaluate whether a novel tyrosine kinase inhibitor nintedanib could inhibit basic fibroblast growth factor(bFGF)and vascular endothelial growth factor(VEGF)simultaneously for retinal vascular disease in vivo.METHODS:After a laser induced rabbit retinal vein occlusion(RVO)model was made,0.5 mg of nintedanib was injected intravitreally in the left eye on the third day while the right eye was as a control.Intracameral samples were taken on the day before laser treatment and days 1,3,7,14,21,and 28 after treatment.Enzyme-linked immunosorbent assay(ELISA)was used to test the bFGF and VEGF-A concentrations in the aqueous humor.RESULTS:Both bFGF and VEGF-A rose significantly on the third day after laser treatment in both eyes.In the control eye the bFGF concentration peaked on the 14th day while the VEGF-A concentration dropped rapidly soon after the third day.After nintadanib injection in the study eye,both bFGF and VEGF-A showed a significant reduction on the 4th day(7th day after laser treatment)when compared to the control eye,and kept on low level in the following several weeks.CONCLUSION:Intravitreal injection of nintedanib can inhibit the expression of bFGF and VEGF in the process of RVO model to a certain extent,which is expected to become a new method for the treatment of retinal vascular diseases or fibrotic diseases.
基金Supported by the Elsa U.Pardee Foundation Grant,No.671432(to Sahu RP)NIH R21 Grant,No.ES033806(to Sahu RP).
文摘The body of evidence investigating human epidermal growth factor receptor-2(HER2)directed therapy in patients with breast cancer(BC)has been growing within the last decade.Recently,the use of tyrosine kinase inhibitors(TKIs)has been of particular interest in the treatment of human malignancies.This literature commentary is intended to highlight the most recent findings associated with the widely-studied TKI agents and their clinical significance in improving the outcomes of HER2 positive BC.
文摘BACKGROUND Diffuse large B-cell lymphoma(DLBCL)is a common aggressive non-Hodgkin's lymphoma(NHL),accounting for 30%-40%of adult NHLs.This report aims to explore the efficacy and safety of rituximab combined with Bruton tyrosine kinase inhibitors(BTKis)in the treatment of elderly patients with DLBCL.CASE SUMMARY The clinical data of two elderly patients with DLBCL who received rituximab combined with BTKi in our hospital were retrospectively analyzed,and the literature was reviewed.The patients were treated with chemotherapy using the R-miniCHOP regimen for two courses.Then,they received rituximab in combination with BTKi.CONCLUSION The treatment experience in these cases demonstrates the potential efficacy of rituximab combined with BTKi to treat elderly DLBCL patients,thus providing a new treatment strategy.
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.
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Hepatitis B virus(HBV) reactivation is a well-recognized complication in patients with chronic HBV infection receiving cytotoxic or immunosuppressive chemotherapy.Imatinib mesylate and nilotinib are selective Bcr/Abl tyrosine kinase inhibitors,which are now widely used in the treatment of patients with chronic myeloid leukemia.Although HBV reactivation induced by imatinib mesylate has been reported,nilotinib-related HBV reactivation has not been reported in the English literature.We report here 2 cases of HBV reactivation in chronic myeloid leukemia patients receiving imatinib mesylate and a novel case of nilotinib related HBV reactivation.