A series of novel indole derivatives were designed and synthesized and their inhibitory activity against B-Raf and HepG2 cell were also described. Among them, compounds 7a and 7b exhibited excellent potency, which sho...A series of novel indole derivatives were designed and synthesized and their inhibitory activity against B-Raf and HepG2 cell were also described. Among them, compounds 7a and 7b exhibited excellent potency, which showed the potential for further research as lead compounds.展开更多
Background: Non-radiographic axial spondyloarthritis is a progressive and disabling inflammatory disease affecting young adults, with limited treatment options. TNFi are more efficacious than JAKi and IL1-7i in nr-ax ...Background: Non-radiographic axial spondyloarthritis is a progressive and disabling inflammatory disease affecting young adults, with limited treatment options. TNFi are more efficacious than JAKi and IL1-7i in nr-ax SPA and it has a well-known safety profile over a longer duration. Recently, many IL-17i and JAKi were approved for the treatment of nr-ax SPA;however, data comparing IL1-7i and JAKi in terms of efficacy and safety is lacking. This systematized review aimed to compare the existing efficacy and safety data of JAKi vs IL-17i in the treatment of patients with nr-ax SPA. Methods: A systematic literature search was performed using relevant keywords in many databases. According to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA, 2020), relevant articles were included and evaluated in this review. Efficacy and safety data were collected, analyzed and compared through week 52. The first check was done by the end of week 14 and week 16 for upadacitinib and IL-17i respectively. Results: Data from four RCTs evaluating upadacitinib, secukinumab, ixekizumab, and bimekizumab comprising 1425 patients were analyzed. Overall, a comparable efficacy and safety profile were observed across different treatment arms through week 52;however, non-significant variations were encountered in some outcome measures. The primary endpoint among these RCTs (ASAS40 response rate) was met and it was higher in patients treated with bimekizumab 160 mg sc Q 4 weeks in TNFi non responders (48%) and lowest in ixekizumab 80 mg sc Q 4 weeks treated patients, (35%) (p Conclusion: The above-mentioned three IL-17i and the only one JAKi demonstrated comparable safety and efficacy profiles with some minor variations. A head-to-head trial comparing the effectiveness and safety characteristics of JAKi vs IL-17i may be needed in patients with active nr-ax SpA.展开更多
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
Refractory thyroid cancer is frequently associated with a poor prognosis,necessitating alternative therapeutic approaches.Tyrosine kinase inhibitors(TKIs)have emerged as a promising treatment option,showing generally ...Refractory thyroid cancer is frequently associated with a poor prognosis,necessitating alternative therapeutic approaches.Tyrosine kinase inhibitors(TKIs)have emerged as a promising treatment option,showing generally favorable clinical outcomes in these challenging cancer subtypes.However,the existing body of research is constrained by small sample sizes and variable findings,limiting the ability to directly compare the efficacy of different TKI agents.This study aimed to bridge that gap through a network meta-analysis,evaluating the relative efficacy and safety of various TKIs in managing refractory thyroid cancer.Utilizing systematic keyword searches in databases such as PubMed,Cochrane Library,Embase,Scopus,Web of Science,and ClinicalTrials.gov,we identified studies that met predefined inclusion criteria.Extracted data were analyzed using Bayesian network meta-analysis methods via R software to ensure a comprehensive assessment.Our findings highlighted specific advantages of certain TKIs for various clinical outcomes.In terms of progression-free survival(PFS),Anlotinib and Apatinib showed notable efficacy.For the objective response rate(ORR),Cabozantinib and Lenvatinib demonstrated superior effectiveness,while for disease control rate(DCR),Apatinib and Lenvatinib were advantageous.Regarding safety profiles,Cabozantinib emerged as the safest option for all-grade adverse events(AEs),with Anlotinib showing a higher risk.For severe AEs(grade 3 or higher),Sorafenib proved to be the safest,while Apatinib carried the highest risk.In summary,Anlotinib,Apatinib,Lenvatinib,and Cabozantinib offered significant benefits for PFS,ORR,and DCR in patients with refractory thyroid cancer.However,Anlotinib and Apatinib were associated with higher AE rates,underlining the importance of balancing efficacy with safety.Cabozantinib and Vandetanib,while exhibiting comparatively safer profiles,showed moderate efficacy.These insights underscored the necessity for tailored treatment decisions that carefully weigh the benefits and risks of each TKI agent.展开更多
BACKGROUND Chemotherapy,targeted therapy,and immunotherapy have all been shown to achieve some efficacy in treating intrahepatic cholangiocarcinoma(ICC).How-ever,these systemic treatments have not provided optimal res...BACKGROUND Chemotherapy,targeted therapy,and immunotherapy have all been shown to achieve some efficacy in treating intrahepatic cholangiocarcinoma(ICC).How-ever,these systemic treatments have not provided optimal results for some patients.Therefore,the combination of transarterial chemoembolization(TACE)and hepatic artery infusion chemotherapy or other local interventional therapy methods is being considered for the treatment of liver tumors.AIM To evaluate the efficacy and safety of combining chemotherapy,targeted therapy,and immunotherapy,with or without TACE,in patients with ICC.METHODS We recruited 83 patients with unresectable ICC from July 2021 to December 2023 at the Affiliated Hospital of Xuzhou Medical University.Forty-one patients received TACE combined with chemotherapy,tyrosine kinase inhibitors,and pro-grammed death 1(PD-1)/programmed cell death ligand 1(PD-L1)inhibitors(ex-perimental group),whereas 42 patients were treated with chemotherapy,tyrosine kinase inhibitors,and PD-1/PD-L1 inhibitors(control group).Short-term efficacy was assessed using the modified response evaluation criterion,and the objective response rate,disease control rate,progression-free survival,and incidence of adverse events were compared between groups.RESULTS The objective response rate in the experimental group was greater than that in the control group(39.0%vs 19.0%,P<0.05).The disease control rate in the experimental group was significantly greater than that in the control group(75.6%vs 52.4%,P<0.05).The median progression-free survival times were 14.3 months in the experimental group and 12.7 months in the control group(P<0.05).All 41 patients in the experimental group developed postembol-ization syndrome.Among the symptoms,fever and pain were significantly more common in the experimental group than in the control group(85.4%vs 11.9%,P<0.001 and 58.5%vs 9.5%,P<0.001).No grade 4 or 5 treatment-related adverse events were observed in either group.CONCLUSION In patients with unresectable ICC,TACE combined with chemotherapy,tyrosine kinase inhibitors,and PD-1/PD-L1 inhibitors has good efficacy and high safety,indicating potential benefits for these patients.展开更多
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
Ulcerative colitis(UC)is a chronic inflammatory bowel disease having high morbidity and a significant negative influence on patients’quality of life.Traditional medicinal strategies available,including amino salicyla...Ulcerative colitis(UC)is a chronic inflammatory bowel disease having high morbidity and a significant negative influence on patients’quality of life.Traditional medicinal strategies available,including amino salicylates,corticosteroids,and biologics,offer limited efficacy,safety,and durability of response.The advancement in small-molecule Janus kinase(JAK)inhibitors has introduced a novel,oral therapeutic option that targets intracellular signaling pathways implicated in UC pathogenesis.Tofacitinib is the first approved JAK inhibitor for the treatment of moderate-to-severe UC.This drug,despite offering promising efficacy,has various safety concerns,especially the occurrence of thromboembolic events.These adverse effects have stressed the devel-opment of more selective agents such as upadacitinib and filgotinib.This mini-review explores the current perspectives of JAK inhibitors in UC,particularly focusing on their mechanisms of action,safety profiles,clinical trial outcomes,and emerging strategies to enhance their use.This review also highlights future directions,including the potential of selective JAK1 inhibition and the role of personalized medicine in refining therapeutic decisions.Understanding the emerging place of JAK inhibitors within the UC treatment strategies offers excellent opportunities to increase patient care and long-term disease management.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
Non-infectious uveitis(NIU),although a highly blinding but preventable cause of blindness around the world,has few approved pharmaceuticals for its treatment.Lack of access to effective treatment is likely a major cau...Non-infectious uveitis(NIU),although a highly blinding but preventable cause of blindness around the world,has few approved pharmaceuticals for its treatment.Lack of access to effective treatment is likely a major cause of poor visual outcomes in NIU.However,despite a revolution in rheumatologic disease treatment with the advent of multiple biologic therapeutics selectively targeting the immune response,there remains a gap in the long-term management of NIU.Adalimumab remains the only systemic medication approved for the treatment of NIU by the Food and Drug Administration(FDA).All other systemic treatments,including older anti-metabolites such as methotrexate and mycophenolate,are used offlabel for NIU,posing significant treatment challenges.Given the nature and rarity of the disease,there are few well designed,large,clinical trials evaluating the efficacy of novel therapeutic agents within this field.We therefore read with great interest Srivastava et al.’s randomized clinical trial on the efficacy of filgotinib,a Janus kinase inhibitor(JAKi),in active NIU(1).The early termination of the trial due to business considerations highlights the industry difficulty in FDA medication approval for NIU.展开更多
Background:KIT proto-oncogene,receptor tyrosine kinase(KIT,CD117)and platelet-derived growth factor-alpha(PDGFRA)are key drivers of gastrointestinal stromal tumors(GIST),but resistance to targeted therapy often arises...Background:KIT proto-oncogene,receptor tyrosine kinase(KIT,CD117)and platelet-derived growth factor-alpha(PDGFRA)are key drivers of gastrointestinal stromal tumors(GIST),but resistance to targeted therapy often arises from tumor protein p53(p53)alterations and loss of cell cycle control.However,the role of p53 status in GIST therapeutic potential has rarely been studied,so this study aimed to employ both wild-type andmutant p53 GIST models to investigate how p53 dysfunction influences the efficacy of p53 pathway-targeted therapies.Methods:The efficacy of the mouse double minute 2 homolog(MDM2)inhibitor(HDM201)and the Wee1 G2 checkpoint kinase(Wee1)inhibitor(adavosertib)was confirmed in both p53 wild-type(p53 WT)and p53 mutant(p53 MT)GIST cells.The anti-proliferative effects were assessed using the Cell Counting Kit-8(CCK-8)assay.Flow cytometry(FACS)and immunoblotting were employed to evaluate apoptosis and the expression of proteins related to drug efficacy.These findings were further validated in a xenograft model.Results:HDM201 selectively inhibited growth and triggered apoptosis in p53WT GIST cells,while adavosertib was effective mainly in p53 MT cells.Western blot analysis revealed thatHDM201 increased p53 and p21 levels in p53WT cells,and adavosertib affectedWee1 and phospho-cdc2 expression in both p53WT and p53 MT cells.In a xenograft mouse model,HDM201 significantly reduced the tumor volume and weight in p53WTGIST cells,whereas p53MT tumors showed only a moderate size reduction with adavosertib,without significant changes.Conclusions:Our results highlight the importance of p53 status in guiding GIST treatment.p53 WT tumors respond toMDM2 inhibitors,while p53 MTtumors show greater sensitivity toWee1 inhibitors,supporting p53 pathway targeting as a promising strategy for GIST patients.展开更多
AIM To study the molecular mechanisms ofretinoic acid(RA)on proliferation andexpression of cyclin-dependent kinase inhibitors(CKI),i.e.p16,p21 and p27 in cultured rathepatic stellate cells(HSC)stimulated withtransform...AIM To study the molecular mechanisms ofretinoic acid(RA)on proliferation andexpression of cyclin-dependent kinase inhibitors(CKI),i.e.p16,p21 and p27 in cultured rathepatic stellate cells(HSC)stimulated withtransforming growth factor beta 1(TGF-β1).METHODS HSC were isolated from healthy ratlivers and cultured.After stimulated with1 mg/L TGF-β1,subcultured HSC were treatedwith or without 1 nmol/L RA.MTT assay,immunocytochemistry(ICC)for p16,p21,p27and α-smooth muscle actin(α-SMA)protein,insitu hybridization(ISH)for retinoic acidreceptor beta 2(RAR-β2)and p16,p21 and p27mRNA and quantitative image analysis(partially)were performed.RESULTS RA inhibited HSC proliferation(41.50%,P【0.05),decreased the protein levelof α-SMA(55.09%,P【0.05),and induced HSCto express RAR-β2 mRNA.In addition,RAincreased the protein level of p16(218.75%,P【0.05)and induced p21 protein expression;meanwhile,p27 was undetectable by ICC in bothcontrol and RA-treated HSC.However,RA hadno influence on the mRNA levels of p16,p21 orp27 as determined by ISH.CONCLISION Up-regulation of p16 and p21 on post-transcriptional level may contribule, in part to RA inhibition of TGF-β1-initiated rat HSC activation in vitro.展开更多
Dysregulation of kinases has been proven to be one of the main causes of abnormal growth and survival of cancer cells.Selective modulations of kinase activities have become the focus of many research programs for the ...Dysregulation of kinases has been proven to be one of the main causes of abnormal growth and survival of cancer cells.Selective modulations of kinase activities have become the focus of many research programs for the development of safe and effective chemotherapy for cancers.So far,fifteen kinase inhibitors have received FDA approval for the treatment of various forms of cancers.Among them,the allosteric kinase inhibitors have been shown to have superior clinical profile in terms of safety and efficacy.In this review,we summarize the allosteric conformations of kinases,their corresponding inhibitors and the modes of their interactions.展开更多
BACKGROUND Mixed lineage kinase domain-like protein(MLKL)serves as a critical mediator in necroptosis,a form of regulated cell death linked to various liver diseases.This study aims to specifically investigate the rol...BACKGROUND Mixed lineage kinase domain-like protein(MLKL)serves as a critical mediator in necroptosis,a form of regulated cell death linked to various liver diseases.This study aims to specifically investigate the role of MLKL’s adenosine triphosphate(ATP)-binding pocket in facilitating necroptosis-independent pathways that may contribute to liver disease progression.By focusing on this mechanism,we seek to identify potential therapeutic targets that can modulate MLKL activity,offering new strategies for the prevention and treatment of liver-related pathologies.AIM To investigate the possibility of using the ATP-binding pocket-associated,necro-ptosis-independent MLKL pathway as a target for liver diseases.METHODS Cell death following necroptosis stimuli was evaluated using cell proliferation assays,flow cytometry,and electron microscopy in various cells.The human liver organoid system was used to evaluate whether the MLKL ATP pocket-binding inhibitor could attenuate inflammation.Additionally,alcoholic and non-alcoholic fatty liver diseases animal models were used to determine whether MLKL ATP pocket inhibitors could attenuate liver injury.RESULTS While an MLKL ATP pocket-binding inhibitor did not prevent necroptosis-induced cell death in RAW 264.7 cells,it did reduce the necroptosis-led expression of CXCL2,ICAM,and VCAM.Notably,MLKL ATP pocket inhibitor diminishes the expression of CXCL2,ICAM,and VCAM by inhibiting the IκB kinase and nuclear factor kappa-B pathways without inducing necroptosis-induced cell death in two-dimensional cell culture as well as the human-derived liver organoid system.Although MLKL ATP-binding inhibitor was ineffective in non-alcoholic fatty liver disease animal models,MLKL ATP-binding inhibitor attenuated hepatic inflammation in the alcoholic liver disease model.CONCLUSION MLKL ATP pocket-binding inhibitor exerted anti-inflammatory effects through the necroptosis-independent MLKL pathway in an animal model of alcoholic liver disease.展开更多
Medicinal chemistry strategies have contributed to the development, experimental study of and clinical trials assessment of the first type of protein kinase small molecule inhibitor to target the Janus kinase/Signal T...Medicinal chemistry strategies have contributed to the development, experimental study of and clinical trials assessment of the first type of protein kinase small molecule inhibitor to target the Janus kinase/Signal Transducers and Activators of Transcription(JAK/STAT) signaling pathway. The orally administered small molecule inhibitor, tofacitinib, is the first drug to target the JAK/STAT pathway for entry into the armamentarium of the medical therapy of rheumatoid arthritis. The introduction of tofacitinib into general rheumatologic practice coupled with increasing understanding that additional cellular signal transduction pathways including the mitogen-activated protein kinase and phosphatidylinositide-3-kinase/Akt/mammalian target of rapa-mycin pathways as well as spleen tyrosine kinase also contribute to immune-mediated inflammatory in rheumatoid arthritis makes it likely that further development of orally administered protein kinase small molecule inhibitors for rheumatoid arthritis will occur in the near future.展开更多
Hepatocellular carcinoma （HCC） is one of the most common human cancers, and its incidence is still increasing in many countries. The prognosis of HCC patients remains poor, and identification of useful molecular pro...Hepatocellular carcinoma （HCC） is one of the most common human cancers, and its incidence is still increasing in many countries. The prognosis of HCC patients remains poor, and identification of useful molecular prognostic markers is required. Many recent studies have shown that functional alterations of cellcycle regulators can be observed in HCC. Among the various types of cell-cycle regulators, p16 and p27 are frequently inactivated in HCC and are considered to be potent tumor suppressors, p16, a G1-specific cell-cycle inhibitor that prevents the association of cyclindependent kinase （CDK） 4 and CDK6 with cyclin DI, is frequently inactivated in HCC via CpG methylation of its promoter region, p16 may be involved in the early steps of hepatocarcinogenesis, since p16 gene methylation has been detected in subsets of pre-neoplastic liver cirrhosis patients, p27, a negative regulator of the G1-S phase transition through inhibition of the kinase activities of Cdk2/cyclin A and Cdk2/cyclin E complexes, is now considered to be an adverse prognostic factor in HCC. In some cases of HCC with increased cell proliferation, p27 is overexpressed but inactivated by sequestration into cyclin D1-CDK4-containing complexes. Since loss of p16 is closely related to functional inactivation of p27 in HCC, investigating both p16 and p27 may be useful for precise prognostic predictions in individuals with HCC.展开更多
First-generation epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs), including gefitinib and erlotinib, have proven to be highly effective agents for advanced non-small cell lung cancer(NSCLC) in p...First-generation epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs), including gefitinib and erlotinib, have proven to be highly effective agents for advanced non-small cell lung cancer(NSCLC) in patients harboring an activating EGFR mutation such as the exon 19 deletion mutation and L858 R. Although those reversible small molecular targeted agents provide a significant response and survival benefit, all responders eventually acquire resistance. Secondgeneration EGFR-targeting agents, such as irreversible EGFR/HER2 tyrosine kinase inhibitors and pan-HER TKIs, may improve survival further and be useful for patients who acquired resistance to first-generation EGFR-TKIs. This review discusses novel therapeutic strategies for EGFR-mutated advanced NSCLC using first- and second-generation EGFR-TKIs.展开更多
Oral tyrosine kinase inhibitors(TKIs) against epidermal growth factor receptor(EGFR) family have been introduced into the clinic to treat human malignancies for decades. Despite superior properties of EGFR-TKIs as sma...Oral tyrosine kinase inhibitors(TKIs) against epidermal growth factor receptor(EGFR) family have been introduced into the clinic to treat human malignancies for decades. Despite superior properties of EGFR-TKIs as small molecule targeted drugs, their applications are still restricted due to their low solubility, capricious oral bioavailability, large requirement of daily dose, high binding tendency to plasma albumin and initial/acquired drug resistance. Nanotechnology is a promising tool to improve efficacy of these drugs. Through non-oral routes. Various nanotechnology-based delivery approaches have been developed for providing efficient delivery of EGFR-TKIs with a better pharmacokinetic profile and tissue-targeting ability. This review aims to indicate the advantage of nanocarriers for EGFR-TKIs delivery.展开更多
The synthesis and biological evaluation of two series of salicylanilide derivatives on the EGFR and ErbB-2 tyrosine kinases inhibitory activities were conducted.Of the tested compounds those having an additional aryl ...The synthesis and biological evaluation of two series of salicylanilide derivatives on the EGFR and ErbB-2 tyrosine kinases inhibitory activities were conducted.Of the tested compounds those having an additional aryl group substituted on the anilino ring were active on the EGFR tyrosine kinase inhibition（7a-c and 13a,13c,13d,13f）.The inhibitory activities were all in the low micromolar or submicromolar range.In addition,compound 13a was found to have dual inhibitory activities both on EGFR and ErbB-2 tyrosine kinases（1.654±1.280 and 7.134±1.265μmol/L）.展开更多
Gefitinib,erlotinib,afatinib and osimertinib have been recommended as the first-line treatment for epidermal growth factor receptor(EGFR)-mutated advanced non-small cell lung cancer(NSCLC),whereas no studies have comp...Gefitinib,erlotinib,afatinib and osimertinib have been recommended as the first-line treatment for epidermal growth factor receptor(EGFR)-mutated advanced non-small cell lung cancer(NSCLC),whereas no studies have compared the cost-effectiveness of these four tyrosine kinase inhibitors(TKIs)simultaneously in China.In the present study,we aimed to estimate the cost-effectiveness of erlotinib,gefitinib,afatinib and osimertinib for untreated EGFR-mutated advanced NSCLC.A Markov model was constructed to compare the 10-year impact of four TKIs for patients with treatment-naive EGFR-mutated advanced NSCLC from the perspective of the Chinese medical system.Clinical data and utility values were derived from published literature,and costs were obtained from Chinese official websites.The primary output indicator was the incremental cost-effectiveness ratio(ICER).Sensitivity analyses were performed to test the robustness of the model.We found that afatinib was estimated to spend the lowest cost with minimum life-years(LYs),while osimertinib was the most expensive regimen with maximum LYs.The ICER of gefitinib versus afatinib was$732/quality-adjusted life-year(QALY),which was less than the willingness-to-pay(WTP)of$29382/QALY.Compared with gefitinib,erlotinib yielded a higher cost and a shorter lifetime,hence it was identified as a dominated strategy.Then,osimertinib was compared to gefitinib,which produced an ICER of$71330/QALY,exceeding the WTP.It suggested that gefitinib was the most cost-effective regimen as the first-line treatment for EGFR-mutated advanced NSCLC.Decreasing the osimertinib price or increasing the WTP threshold to$68558/QALY might enhance the favorability of the outcome,by which osimertinib might become more cost-effective.One-way sensitivity analysis manifested that the model was robust.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
基金financially supported by the Natural Science Foundation of Jiangsu Province(No.BK2009303)the National Natural Science Foundation of China(No.30973609)+1 种基金Fundamental Research Funds for the Central Universities(No.JKZ2011004)Specialized Research Fund for the Doctoral Program of Higher Education(No.20100096110007)
文摘A series of novel indole derivatives were designed and synthesized and their inhibitory activity against B-Raf and HepG2 cell were also described. Among them, compounds 7a and 7b exhibited excellent potency, which showed the potential for further research as lead compounds.
文摘Background: Non-radiographic axial spondyloarthritis is a progressive and disabling inflammatory disease affecting young adults, with limited treatment options. TNFi are more efficacious than JAKi and IL1-7i in nr-ax SPA and it has a well-known safety profile over a longer duration. Recently, many IL-17i and JAKi were approved for the treatment of nr-ax SPA;however, data comparing IL1-7i and JAKi in terms of efficacy and safety is lacking. This systematized review aimed to compare the existing efficacy and safety data of JAKi vs IL-17i in the treatment of patients with nr-ax SPA. Methods: A systematic literature search was performed using relevant keywords in many databases. According to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA, 2020), relevant articles were included and evaluated in this review. Efficacy and safety data were collected, analyzed and compared through week 52. The first check was done by the end of week 14 and week 16 for upadacitinib and IL-17i respectively. Results: Data from four RCTs evaluating upadacitinib, secukinumab, ixekizumab, and bimekizumab comprising 1425 patients were analyzed. Overall, a comparable efficacy and safety profile were observed across different treatment arms through week 52;however, non-significant variations were encountered in some outcome measures. The primary endpoint among these RCTs (ASAS40 response rate) was met and it was higher in patients treated with bimekizumab 160 mg sc Q 4 weeks in TNFi non responders (48%) and lowest in ixekizumab 80 mg sc Q 4 weeks treated patients, (35%) (p Conclusion: The above-mentioned three IL-17i and the only one JAKi demonstrated comparable safety and efficacy profiles with some minor variations. A head-to-head trial comparing the effectiveness and safety characteristics of JAKi vs IL-17i may be needed in patients with active nr-ax SpA.
文摘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BACKGROUND Chemotherapy,targeted therapy,and immunotherapy have all been shown to achieve some efficacy in treating intrahepatic cholangiocarcinoma(ICC).How-ever,these systemic treatments have not provided optimal results for some patients.Therefore,the combination of transarterial chemoembolization(TACE)and hepatic artery infusion chemotherapy or other local interventional therapy methods is being considered for the treatment of liver tumors.AIM To evaluate the efficacy and safety of combining chemotherapy,targeted therapy,and immunotherapy,with or without TACE,in patients with ICC.METHODS We recruited 83 patients with unresectable ICC from July 2021 to December 2023 at the Affiliated Hospital of Xuzhou Medical University.Forty-one patients received TACE combined with chemotherapy,tyrosine kinase inhibitors,and pro-grammed death 1(PD-1)/programmed cell death ligand 1(PD-L1)inhibitors(ex-perimental group),whereas 42 patients were treated with chemotherapy,tyrosine kinase inhibitors,and PD-1/PD-L1 inhibitors(control group).Short-term efficacy was assessed using the modified response evaluation criterion,and the objective response rate,disease control rate,progression-free survival,and incidence of adverse events were compared between groups.RESULTS The objective response rate in the experimental group was greater than that in the control group(39.0%vs 19.0%,P<0.05).The disease control rate in the experimental group was significantly greater than that in the control group(75.6%vs 52.4%,P<0.05).The median progression-free survival times were 14.3 months in the experimental group and 12.7 months in the control group(P<0.05).All 41 patients in the experimental group developed postembol-ization syndrome.Among the symptoms,fever and pain were significantly more common in the experimental group than in the control group(85.4%vs 11.9%,P<0.001 and 58.5%vs 9.5%,P<0.001).No grade 4 or 5 treatment-related adverse events were observed in either group.CONCLUSION In patients with unresectable ICC,TACE combined with chemotherapy,tyrosine kinase inhibitors,and PD-1/PD-L1 inhibitors has good efficacy and high safety,indicating potential benefits for these patients.
基金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.
文摘Ulcerative colitis(UC)is a chronic inflammatory bowel disease having high morbidity and a significant negative influence on patients’quality of life.Traditional medicinal strategies available,including amino salicylates,corticosteroids,and biologics,offer limited efficacy,safety,and durability of response.The advancement in small-molecule Janus kinase(JAK)inhibitors has introduced a novel,oral therapeutic option that targets intracellular signaling pathways implicated in UC pathogenesis.Tofacitinib is the first approved JAK inhibitor for the treatment of moderate-to-severe UC.This drug,despite offering promising efficacy,has various safety concerns,especially the occurrence of thromboembolic events.These adverse effects have stressed the devel-opment of more selective agents such as upadacitinib and filgotinib.This mini-review explores the current perspectives of JAK inhibitors in UC,particularly focusing on their mechanisms of action,safety profiles,clinical trial outcomes,and emerging strategies to enhance their use.This review also highlights future directions,including the potential of selective JAK1 inhibition and the role of personalized medicine in refining therapeutic decisions.Understanding the emerging place of JAK inhibitors within the UC treatment strategies offers excellent opportunities to increase patient care and long-term disease management.
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.
基金Unrestricted departmental grant from Research to Prevent Blindness.T.M.J.receives funding from the National Institutes of Health(K12TR005104).
文摘Non-infectious uveitis(NIU),although a highly blinding but preventable cause of blindness around the world,has few approved pharmaceuticals for its treatment.Lack of access to effective treatment is likely a major cause of poor visual outcomes in NIU.However,despite a revolution in rheumatologic disease treatment with the advent of multiple biologic therapeutics selectively targeting the immune response,there remains a gap in the long-term management of NIU.Adalimumab remains the only systemic medication approved for the treatment of NIU by the Food and Drug Administration(FDA).All other systemic treatments,including older anti-metabolites such as methotrexate and mycophenolate,are used offlabel for NIU,posing significant treatment challenges.Given the nature and rarity of the disease,there are few well designed,large,clinical trials evaluating the efficacy of novel therapeutic agents within this field.We therefore read with great interest Srivastava et al.’s randomized clinical trial on the efficacy of filgotinib,a Janus kinase inhibitor(JAKi),in active NIU(1).The early termination of the trial due to business considerations highlights the industry difficulty in FDA medication approval for NIU.
基金financially supported by grants from the Chang-Gung Memorial Hospital(CMRPG3J0971~3,CMRPVVP0111,and CMRPVVQ0041 to CEWCMRPG3P0101 to HJS)the National Science and Technology Council(113-2628-B-182-001-MY3 and 113-2811-B-182-024 to CEW).
文摘Background:KIT proto-oncogene,receptor tyrosine kinase(KIT,CD117)and platelet-derived growth factor-alpha(PDGFRA)are key drivers of gastrointestinal stromal tumors(GIST),but resistance to targeted therapy often arises from tumor protein p53(p53)alterations and loss of cell cycle control.However,the role of p53 status in GIST therapeutic potential has rarely been studied,so this study aimed to employ both wild-type andmutant p53 GIST models to investigate how p53 dysfunction influences the efficacy of p53 pathway-targeted therapies.Methods:The efficacy of the mouse double minute 2 homolog(MDM2)inhibitor(HDM201)and the Wee1 G2 checkpoint kinase(Wee1)inhibitor(adavosertib)was confirmed in both p53 wild-type(p53 WT)and p53 mutant(p53 MT)GIST cells.The anti-proliferative effects were assessed using the Cell Counting Kit-8(CCK-8)assay.Flow cytometry(FACS)and immunoblotting were employed to evaluate apoptosis and the expression of proteins related to drug efficacy.These findings were further validated in a xenograft model.Results:HDM201 selectively inhibited growth and triggered apoptosis in p53WT GIST cells,while adavosertib was effective mainly in p53 MT cells.Western blot analysis revealed thatHDM201 increased p53 and p21 levels in p53WT cells,and adavosertib affectedWee1 and phospho-cdc2 expression in both p53WT and p53 MT cells.In a xenograft mouse model,HDM201 significantly reduced the tumor volume and weight in p53WTGIST cells,whereas p53MT tumors showed only a moderate size reduction with adavosertib,without significant changes.Conclusions:Our results highlight the importance of p53 status in guiding GIST treatment.p53 WT tumors respond toMDM2 inhibitors,while p53 MTtumors show greater sensitivity toWee1 inhibitors,supporting p53 pathway targeting as a promising strategy for GIST patients.
基金the National Natural Science Foundation of China,No.39670287the Scientific Research Foundation for Doctorate Education,State Education Commission.No.96026530
文摘AIM To study the molecular mechanisms ofretinoic acid(RA)on proliferation andexpression of cyclin-dependent kinase inhibitors(CKI),i.e.p16,p21 and p27 in cultured rathepatic stellate cells(HSC)stimulated withtransforming growth factor beta 1(TGF-β1).METHODS HSC were isolated from healthy ratlivers and cultured.After stimulated with1 mg/L TGF-β1,subcultured HSC were treatedwith or without 1 nmol/L RA.MTT assay,immunocytochemistry(ICC)for p16,p21,p27and α-smooth muscle actin(α-SMA)protein,insitu hybridization(ISH)for retinoic acidreceptor beta 2(RAR-β2)and p16,p21 and p27mRNA and quantitative image analysis(partially)were performed.RESULTS RA inhibited HSC proliferation(41.50%,P【0.05),decreased the protein levelof α-SMA(55.09%,P【0.05),and induced HSCto express RAR-β2 mRNA.In addition,RAincreased the protein level of p16(218.75%,P【0.05)and induced p21 protein expression;meanwhile,p27 was undetectable by ICC in bothcontrol and RA-treated HSC.However,RA hadno influence on the mRNA levels of p16,p21 orp27 as determined by ISH.CONCLISION Up-regulation of p16 and p21 on post-transcriptional level may contribule, in part to RA inhibition of TGF-β1-initiated rat HSC activation in vitro.
文摘Dysregulation of kinases has been proven to be one of the main causes of abnormal growth and survival of cancer cells.Selective modulations of kinase activities have become the focus of many research programs for the development of safe and effective chemotherapy for cancers.So far,fifteen kinase inhibitors have received FDA approval for the treatment of various forms of cancers.Among them,the allosteric kinase inhibitors have been shown to have superior clinical profile in terms of safety and efficacy.In this review,we summarize the allosteric conformations of kinases,their corresponding inhibitors and the modes of their interactions.
基金Supported by the National Research Foundation of Korea Grant Funded by the Korea Government,No.RS-2024-00440477the Korea Institute of Science and Technology Institutional Program,No.2E33111-24-042.
文摘BACKGROUND Mixed lineage kinase domain-like protein(MLKL)serves as a critical mediator in necroptosis,a form of regulated cell death linked to various liver diseases.This study aims to specifically investigate the role of MLKL’s adenosine triphosphate(ATP)-binding pocket in facilitating necroptosis-independent pathways that may contribute to liver disease progression.By focusing on this mechanism,we seek to identify potential therapeutic targets that can modulate MLKL activity,offering new strategies for the prevention and treatment of liver-related pathologies.AIM To investigate the possibility of using the ATP-binding pocket-associated,necro-ptosis-independent MLKL pathway as a target for liver diseases.METHODS Cell death following necroptosis stimuli was evaluated using cell proliferation assays,flow cytometry,and electron microscopy in various cells.The human liver organoid system was used to evaluate whether the MLKL ATP pocket-binding inhibitor could attenuate inflammation.Additionally,alcoholic and non-alcoholic fatty liver diseases animal models were used to determine whether MLKL ATP pocket inhibitors could attenuate liver injury.RESULTS While an MLKL ATP pocket-binding inhibitor did not prevent necroptosis-induced cell death in RAW 264.7 cells,it did reduce the necroptosis-led expression of CXCL2,ICAM,and VCAM.Notably,MLKL ATP pocket inhibitor diminishes the expression of CXCL2,ICAM,and VCAM by inhibiting the IκB kinase and nuclear factor kappa-B pathways without inducing necroptosis-induced cell death in two-dimensional cell culture as well as the human-derived liver organoid system.Although MLKL ATP-binding inhibitor was ineffective in non-alcoholic fatty liver disease animal models,MLKL ATP-binding inhibitor attenuated hepatic inflammation in the alcoholic liver disease model.CONCLUSION MLKL ATP pocket-binding inhibitor exerted anti-inflammatory effects through the necroptosis-independent MLKL pathway in an animal model of alcoholic liver disease.
基金Supported by A contract from Genentech/Roche Group and the Case Western Reserve University School of Medicine Visual Sciences Research Core,No.P30 EY-011373
文摘Medicinal chemistry strategies have contributed to the development, experimental study of and clinical trials assessment of the first type of protein kinase small molecule inhibitor to target the Janus kinase/Signal Transducers and Activators of Transcription(JAK/STAT) signaling pathway. The orally administered small molecule inhibitor, tofacitinib, is the first drug to target the JAK/STAT pathway for entry into the armamentarium of the medical therapy of rheumatoid arthritis. The introduction of tofacitinib into general rheumatologic practice coupled with increasing understanding that additional cellular signal transduction pathways including the mitogen-activated protein kinase and phosphatidylinositide-3-kinase/Akt/mammalian target of rapa-mycin pathways as well as spleen tyrosine kinase also contribute to immune-mediated inflammatory in rheumatoid arthritis makes it likely that further development of orally administered protein kinase small molecule inhibitors for rheumatoid arthritis will occur in the near future.
文摘Hepatocellular carcinoma （HCC） is one of the most common human cancers, and its incidence is still increasing in many countries. The prognosis of HCC patients remains poor, and identification of useful molecular prognostic markers is required. Many recent studies have shown that functional alterations of cellcycle regulators can be observed in HCC. Among the various types of cell-cycle regulators, p16 and p27 are frequently inactivated in HCC and are considered to be potent tumor suppressors, p16, a G1-specific cell-cycle inhibitor that prevents the association of cyclindependent kinase （CDK） 4 and CDK6 with cyclin DI, is frequently inactivated in HCC via CpG methylation of its promoter region, p16 may be involved in the early steps of hepatocarcinogenesis, since p16 gene methylation has been detected in subsets of pre-neoplastic liver cirrhosis patients, p27, a negative regulator of the G1-S phase transition through inhibition of the kinase activities of Cdk2/cyclin A and Cdk2/cyclin E complexes, is now considered to be an adverse prognostic factor in HCC. In some cases of HCC with increased cell proliferation, p27 is overexpressed but inactivated by sequestration into cyclin D1-CDK4-containing complexes. Since loss of p16 is closely related to functional inactivation of p27 in HCC, investigating both p16 and p27 may be useful for precise prognostic predictions in individuals with HCC.
文摘First-generation epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs), including gefitinib and erlotinib, have proven to be highly effective agents for advanced non-small cell lung cancer(NSCLC) in patients harboring an activating EGFR mutation such as the exon 19 deletion mutation and L858 R. Although those reversible small molecular targeted agents provide a significant response and survival benefit, all responders eventually acquire resistance. Secondgeneration EGFR-targeting agents, such as irreversible EGFR/HER2 tyrosine kinase inhibitors and pan-HER TKIs, may improve survival further and be useful for patients who acquired resistance to first-generation EGFR-TKIs. This review discusses novel therapeutic strategies for EGFR-mutated advanced NSCLC using first- and second-generation EGFR-TKIs.
基金financially supported by the National Natural Science Foundation (31525009 and 31771096)The National Key Research and Development Program of China (2017YFC1103502)+2 种基金Sichuan Innovative Research Team Program for Young Scientists (2016TD0004)Distinguished Young Scholars of Sichuan University (2011SCU04B18)1·3·5 project for disciplines of excellence, West China Hospital, Sichuan University.
文摘Oral tyrosine kinase inhibitors(TKIs) against epidermal growth factor receptor(EGFR) family have been introduced into the clinic to treat human malignancies for decades. Despite superior properties of EGFR-TKIs as small molecule targeted drugs, their applications are still restricted due to their low solubility, capricious oral bioavailability, large requirement of daily dose, high binding tendency to plasma albumin and initial/acquired drug resistance. Nanotechnology is a promising tool to improve efficacy of these drugs. Through non-oral routes. Various nanotechnology-based delivery approaches have been developed for providing efficient delivery of EGFR-TKIs with a better pharmacokinetic profile and tissue-targeting ability. This review aims to indicate the advantage of nanocarriers for EGFR-TKIs delivery.
基金supported by the Research Fund for the Doctoral Program of Higher Education of China(No 20100071120051)the Fundamental Research Funds for the Central Universities(No10FX061)
文摘The synthesis and biological evaluation of two series of salicylanilide derivatives on the EGFR and ErbB-2 tyrosine kinases inhibitory activities were conducted.Of the tested compounds those having an additional aryl group substituted on the anilino ring were active on the EGFR tyrosine kinase inhibition（7a-c and 13a,13c,13d,13f）.The inhibitory activities were all in the low micromolar or submicromolar range.In addition,compound 13a was found to have dual inhibitory activities both on EGFR and ErbB-2 tyrosine kinases（1.654±1.280 and 7.134±1.265μmol/L）.
文摘Gefitinib,erlotinib,afatinib and osimertinib have been recommended as the first-line treatment for epidermal growth factor receptor(EGFR)-mutated advanced non-small cell lung cancer(NSCLC),whereas no studies have compared the cost-effectiveness of these four tyrosine kinase inhibitors(TKIs)simultaneously in China.In the present study,we aimed to estimate the cost-effectiveness of erlotinib,gefitinib,afatinib and osimertinib for untreated EGFR-mutated advanced NSCLC.A Markov model was constructed to compare the 10-year impact of four TKIs for patients with treatment-naive EGFR-mutated advanced NSCLC from the perspective of the Chinese medical system.Clinical data and utility values were derived from published literature,and costs were obtained from Chinese official websites.The primary output indicator was the incremental cost-effectiveness ratio(ICER).Sensitivity analyses were performed to test the robustness of the model.We found that afatinib was estimated to spend the lowest cost with minimum life-years(LYs),while osimertinib was the most expensive regimen with maximum LYs.The ICER of gefitinib versus afatinib was$732/quality-adjusted life-year(QALY),which was less than the willingness-to-pay(WTP)of$29382/QALY.Compared with gefitinib,erlotinib yielded a higher cost and a shorter lifetime,hence it was identified as a dominated strategy.Then,osimertinib was compared to gefitinib,which produced an ICER of$71330/QALY,exceeding the WTP.It suggested that gefitinib was the most cost-effective regimen as the first-line treatment for EGFR-mutated advanced NSCLC.Decreasing the osimertinib price or increasing the WTP threshold to$68558/QALY might enhance the favorability of the outcome,by which osimertinib might become more cost-effective.One-way sensitivity analysis manifested that the model was robust.
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.
