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,the roles of protein tyrosine phosphatase nonreceptor 2(PTPN2)in oncogenic transformation and tumor behavior and its potential as a therapeutic target in the context of gastrointestinal(GI)cancers ar...In this editorial,the roles of protein tyrosine phosphatase nonreceptor 2(PTPN2)in oncogenic transformation and tumor behavior and its potential as a therapeutic target in the context of gastrointestinal(GI)cancers are presented with respect to the article by Li et al published in ninth issue of the World Journal of Gastrointestinal Oncology.PTPN2 is a member of the protein tyrosine phosphatase family of signaling proteins that play crucial roles in the regulation of inflammation and immunity.Accordingly,early findings highlighted the contribution of PTPN2 to the pathogenesis of inflammatory and autoimmune disorders related to its dysfunction.On the other hand,recent studies have indicated that PTPN2 has many different roles in different cancer types,which is associated with the complexity of its regulatory network.PTPN2 dephosphorylates and inactivates EGFR,SRC family kinases,JAK1 and JAK3,and STAT1,STAT3,and STAT5 in cell type-and context-dependent manners,which indicates that PTPN2 can perform either prooncogenic or anti-oncogenic functions depending on the tumor subtype.While PTPN2 has been suggested as a potential therapeutic target in cancer treatment,to the best of ourknowledge,no clear treatment protocol has referred to PTPN2.Although there are only few studies that investigated PTPN2 expression in the GI system cancers,which is a potential limitation,the association of this protein with tumor behavior and the influence of PTPN2 on many therapy-related signaling pathways emphasize that PTPN2 could serve as a new molecular biomarker to predict tumor behavior and as a target for therapeutic intervention against GI cancers.In conclusion,more studies should be performed to better understand the prognostic and therapeutic potential of PTPN2 in GI tumors,especially in tumors resistant to therapy.展开更多
Objective To approach the associated mechanism by which α-synuclein (α-Syn) might regulate the metabolism of dopamine. Methods A DNA fragment, located at --495 to +25 of the human tyrosine hydroxylase (TH) gene...Objective To approach the associated mechanism by which α-synuclein (α-Syn) might regulate the metabolism of dopamine. Methods A DNA fragment, located at --495 to +25 of the human tyrosine hydroxylase (TH) gene, was amplified by PCR and inserted into the pGL3-Basic luciferase reporter vector. The recombinant plasmid pGL3-THprom was transfected into a dopammergic cell line MES23.5 or a α-Syn over-expressed MES23.5 (named MES23.5/hα-Syn^+). The promoter activity was detected by the Dual Luciferase Assay System. Results The luciferase activities in the MES23.5 cells transfected with pGl.,3-Basic, pGL3-THprom, and pGL3-Control vectors were 5.60±0.67, 26.80±4.11, and 32.90±4.75, respectively. On the other hand, the luciferase activity of pGL3-THprom in the MES23.5 (26.80±4.11) was significantly higher than that in the MES23.5/hα-Syn^+(14.40±0.61) (P〈0.01). Conclusion These results indicate that the -495 to +25 region in the TH gene possesses promoter activity for controlling the gene expression, and that α-Syn may negatively regulate the metabolism of dopamine by affecting the function of TH promoter as a trans-acting factor.展开更多
Tyrosine hydroxylase is a key enzyme in dopamine biosynthesis. Change in tyrosine hydroxylase expression in the nigrostriatal system is closely related to the occurrence and development of Parkinson's disease. Verbas...Tyrosine hydroxylase is a key enzyme in dopamine biosynthesis. Change in tyrosine hydroxylase expression in the nigrostriatal system is closely related to the occurrence and development of Parkinson's disease. Verbascoside, an extract from Radix Rehmanniae Praeparata has been shown to be clinically effective in treating Parkinson's disease. However, the underlying mechanisms remain unclear. It is hypothesized that the effects of verbascoside on Parkinson's disease are related to tyrosine hydroxylase expression change in the nigrostriatal system. Rat models of Parkinson's disease were established and verbascoside(60 mg/kg) was administered intraperitoneally once a day. After 6 weeks of verbascoside treatment, rat rotational behavior was alleviated; tyrosine hydroxylase m RNA and protein expression and the number of tyrosine hydroxylase-immunoreactive neurons in the rat right substantia nigra were significantly higher than the Parkinson's model group. These findings suggest that the mechanism by which verbascoside treats Parkinson's disease is related to the regeneration of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra.展开更多
The present study examined changes in retinal tyrosine hydroxylase (TH) expression in rats having undergone optic nerve transection and housed under a normal day/night cycle or in the dark. The aim was to investigat...The present study examined changes in retinal tyrosine hydroxylase (TH) expression in rats having undergone optic nerve transection and housed under a normal day/night cycle or in the dark. The aim was to investigate the effects of amacrine cells on axonal regeneration in retinal ganglion cells and on the synapses that transmit visual signals. The results revealed that retinal TH expression gradually decreased following optic nerve transection in rats housed under a normal day/night cycle reaching a minimum at 5 days. In contrast, retinal TH expression decreased to a minimum at 1 day following optic nerve transection in dark reared rats, gradually increasing afterward and reaching a normal level at 5 7 days. The number of TH-positive synaptic particles correlated with the TH levels indicating that dark rearing can help maintain TH expression during the synaptic degeneration stage (5 7 days after optic nerve injury) in retinal amacrine cells.展开更多
This study showed that abnormal behavioral changes were greatly improved in rats displaying Parkinson's disease-like symptoms after intragastric administration of Xifeng Dingchan decoction at 15, 7.5, 3.75 g/kg per d...This study showed that abnormal behavioral changes were greatly improved in rats displaying Parkinson's disease-like symptoms after intragastric administration of Xifeng Dingchan decoction at 15, 7.5, 3.75 g/kg per day. In addition, tyrosine hydroxylase mRNA expression in the substantia nigra of the midbrain was up-regulated, and tyrosine hydroxylase content in the midbrain ventral tegmentum and substantia nigra pars compacta was also increased. The effect of administration of Xifeng Dingchan decoction at 7.5 g/kg per day was similar to that of Madopar at 67.5 mg/kg per day. These results indicate that the therapeutic effect of Xifeng Dingchan decoction on Parkinson's disease is associated with the up-regulated protein and mRNA expression of tyrosine hydroxylase in the midbrain.展开更多
Objective To study the effects of deltamethrin on tyrosine hydroxylase in nigrostriatum of male rats. Methods Sprague-Dawley rats were daily treated with deltamethrin at 6.25 or 12.5 mg/kg body weight by gavage for 10...Objective To study the effects of deltamethrin on tyrosine hydroxylase in nigrostriatum of male rats. Methods Sprague-Dawley rats were daily treated with deltamethrin at 6.25 or 12.5 mg/kg body weight by gavage for 10 days. Then HPLC-fluorescence detection was used to analyze the contents of dopamine (DA), 3,4-dihydmxyphenylacetic acid (DOPAC) and homoranillic acid (HVA) in substantial nigra and striatum. The activities of tyrosine hydroxylase (TH) were also detected by HPLC-fluorescence detection. TH mRNA or TH protein levels were measured by RT-PCR and immunohistochemistry method. Results The content of DA in stfiatum was significantly decreased by the treatments, suggesting an inhibition of DA synthesis by deltamethrin. The contents of DA metabolites DOPAC and HVA increased, indicating increased dopamine turnover. Furthermore, deltamethrin significantly decreased the activity, as well as the mRNA and protein levels of TH. Conclusions These findings reveal a novel aspect of deltamethfin neurotoxicity and suggest tyrosine hydroxylase as a molecular target of deltamethin on dopamine metabolism in the nigrostriatal pathway.展开更多
BACKGROUND: Electromagnetic radiation can influence dopamine (DA) synthesis in brain tissues or ceils, but electromagnetic frequencies, intensities, and radiation time can produce different effects. In addition, th...BACKGROUND: Electromagnetic radiation can influence dopamine (DA) synthesis in brain tissues or ceils, but electromagnetic frequencies, intensities, and radiation time can produce different effects. In addition, the signal pathway by which electromagnetic radiation influences DA synthesis remains controversial. OBJECTIVE: To determine tyrosine hydroxylase (TH) expression in PC12 cells and DA levels in cell culture media after different periods of low-frequency pulsed electric field (LF-PEF) stimulation, and to determine how LF-PEF signaling stimulates TH synthesis using inhibitors. DESIGN, TIME AND SETTING: A parallel, controlled, cell experiment was performed at the Laboratory of Cell Biology, School of Life Science, East China Normal University, between January and October 2006. MATERIALS: PC12 cells were purchased from the Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, China. Nerve growth factor was purchased from PeproTech, USA. The protein kinase A inhibitor, H-89, and mitogen-activated protein kinase kinase inhibitor, U0126, were purchased from Sigma, USA. METHODS: (1) Following routine culture in Dulbecco's modified eagle medium, primary PC12 cells were stimulated under LF-PEF (pulse frequency 50.Hz, pulse width 20 μs, peak field strength 1 V/m) for 5, 10, 15, 20, and 30 minutes. (2) Inhibitors (H-89 or U0126, 1 μmol/L) were added 30 minutes before LF-PEF stimulation for 10 minutes. MAIN OUTCOME MEASURES: (1) TH expression was determined by Western blot in PC12 cells at 0.5, 1,2, 3, and 4 days after LF-PEF stimulation. Similarly, DA was measured by high-performance liquid chromatography in media at 2, 3, 4, or 5 days after LF-PEE (2) TH expression was detected 1 day after H-89 or U0126 treatment and LF-PEE RESULTS: (1) Short-term LF-PEF stimulation (5 and 10 minutes) increased TH expression and media DA levels after short-term culture (2 days) (P 〈 0.01), but both parameters decreased with longer culture (3 4 days) (P 〈 0.01). Long-term LF-PEF stimulation (15, 20, or 30 minutes) decreased TH and DA synthesis, followed by a rapid increase (P 〈 0.01). (2) H89 could completely inhibit TH expression in PC12 cells stimulated by LF-PEF for 10 minutes, while the inhibition rate of U0126 was 53.2%. CONCLUSION: Short-term LF-PEF first promotes then inhibits, while long-term LF-PEF first inhibits then promotes, TH and DA synthesis. LF-PEF stimulation regulates TH expression primarily by activating protein kinase A to regulate DA synthesis.展开更多
The AS/AGU rat has a recessive single point mutation in the gene coding for the gamma isoform of protein kinase C (PKC-γ) resulting in a failure to release dopamine in the striatum and impaired movement including a s...The AS/AGU rat has a recessive single point mutation in the gene coding for the gamma isoform of protein kinase C (PKC-γ) resulting in a failure to release dopamine in the striatum and impaired movement including a staggering gait, difficulty in initiating movement and a slight whole body tremor. This study examined the levels tyrosine hydroxylase, ubiquitin and parkin in individual SNC cell bodies, there was no evidence of a reduction in tyrosine hydroxylase levels although levels of ubiquitin and parkin were elevated in the cytoplasm. The findings support the hypothesis that the initial bar to dopamine availability in the striatum is reduced release, with substantia nigra cell death being a later phenomenon.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
The use of gene therapy has been intensively studied as a potential method to treat Parkinson’s disease (PD) and other degenerative brain diseases. However, the effects of experimental measures and approaches on the ...The use of gene therapy has been intensively studied as a potential method to treat Parkinson’s disease (PD) and other degenerative brain diseases. However, the effects of experimental measures and approaches on the outcome of gene delivery or on the physiological state of target tissues have not been analyzed as much and systematically. Therefore, we have infused adenovirus vectors expressing either a therapeutic tyrosine hydroxylase (TH) gene or a lacZ reporter gene into striatum in a rat model of PD. The experimental procedures were tested using the Ad lacZ vector in order to optimize concentrations, volumes, infusion speeds and transfection times. The expression of Ad lacZ vector was lower and declined earlier in the lesioned than unlesioned striatum suggesting that the lesion affects on the transfection efficiency and outcome of gene transfection. The effect of three different approaches of Ad TH vector transfection was compared: 1) the delivery of Ad TH gene vector alone into one single site of striatum, 2) the delivery of Ad TH gene vector alone into multiple sites of striatum, and 3) the delivery of Ad TH gene vector into one site of striatum followed by a continuous infusion of tetrahydrobiopterin (BH4) cofactor with a mini pump. There was a small and transient unsignificant decrease in the turning behavior when the Ad TH vector was delivered into one site of the striatum. Simultaneous infusion into several sites or together with BH4 cofactor did not improve more the effect of gene delivery. Thus, although the effects were unsignificant, the Ad TH transfection seemed to decrease the turning behavior in the rat model of PD and the optimal effect was seen at some specific doses and time points. Furthermore, the outcome of gene therapy could depend in addition to the amount and efficacy of gene vectors also on the physiological state and experimental strategies.展开更多
BACKGROUND The incidence of primary liver cancer is increasing year by year.In 2022 alone,more than 900000 people were diagnosed with liver cancer worldwide,with hepatocellular carcinoma(HCC)accounting for 75%-85%of c...BACKGROUND The incidence of primary liver cancer is increasing year by year.In 2022 alone,more than 900000 people were diagnosed with liver cancer worldwide,with hepatocellular carcinoma(HCC)accounting for 75%-85%of cases.HCC is the most common primary liver cancer.China has the highest incidence and mortality rate of HCC in the world,and it is one of the malignant tumors that seriously threaten the health of Chinese people.The onset of liver cancer is occult,the early cases lack typical clinical symptoms,and most of the patients are already in the middle and late stage when diagnosed.Therefore,it is very important to find new markers for the early detection and diagnosis of liver cancer,improve the therapeutic effect,and improve the prognosis of patients.Protein tyrosine phosphatase non-receptor 2(PTPN2)has been shown to be associated with colorectal cancer,triple-negative breast cancer,non-small cell lung cancer,and prostate cancer,but its biological role and function in tumors remain to be further studied.AIM To combine the results of relevant data obtained from The Cancer Genome Atlas(TCGA)to provide the first in-depth analysis of the biological role of PTPN2 in HCC.METHODS The expression of PTPN2 in HCC was first analyzed based on the TCGA database,and the findings were then verified by immunohistochemical staining,quantitative real-time polymerase chain reaction(qRT-PCR),and immunoblotting.The value of PTPN2 in predicting the survival of patients with HCC was assessed by analyzing the relationship between PTPN2 expression in HCC tissues and clinicopathological features.Finally,the potential of PTPN2 affecting immune escape of liver cancer was evaluated by tumor immune dysfunction and exclusion and immunohistochemical staining.RESULTS The results of immunohistochemical staining,qRT-PCR,and immunoblotting in combination with TCGA database analysis showed that PTPN2 was highly expressed and associated with a poor prognosis in HCC patients.Kyoto Encyclopedia of Genes and Genomes enrichment analysis showed that PTPN2 was associated with various pathways,including cancer-related pathways,the Notch signaling pathway,and the MAPK signaling pathway.Gene Set Enrichment Analysis showed that PTPN2 was highly expressed in various immune-related pathways,such as the epithelial mesenchymal transition process.A risk model score based on PTPN2 showed that immune escape was significantly enhanced in the high-risk group compared with the low-risk group.CONCLUSION This study investigated PTPN2 from multiple biological perspectives,revealing that PTPN2 can function as a biomarker of poor prognosis and mediate immune evasion in HCC.展开更多
In the present study we have found that proto-oncogene c-fos protein can expressin the noradrenergic neurons of rat hindbrain following peripheral electrical stimulation. Ratswere given peripheral electrical stimulati...In the present study we have found that proto-oncogene c-fos protein can expressin the noradrenergic neurons of rat hindbrain following peripheral electrical stimulation. Ratswere given peripheral electrical stimulation via thin stainless steel pins inserted into the pointsnear knee joint (S36) and ankle joint (Sp6) which mimic the manipulation of electroacupuncture(EA) performed in humans. Animals were perfused for double staining immunohistochemistry 2hafter the termination of EA. In rats subjected to EA stimulation Fos-like protein was found in thetyrosine hydroxylase (TH)-like immunoreactive neurons in rat hindbrain. The Fos and TH coex-isting neurons were distributed in the locus coeruleus, solitary tract nucleus, ventrolateral medul-la, periaqeductal gray, as well as superior colliculus. The percentage of the coexisting neuronscompared with the total number of neurons containing Fos-like protein in these nuclei rangedfrom 6% to 32%. The results suggest that the noradrenergic neurons in these regions may be ac-tivted by acupuncture stimulation.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
Buoyed by the discovery of small-molecule tyrosine kinase inhibitors(smTKIs),significant impact has been made in cancer chemotherapeutics.However,some of these agents still encounter off-target toxicities and suboptim...Buoyed by the discovery of small-molecule tyrosine kinase inhibitors(smTKIs),significant impact has been made in cancer chemotherapeutics.However,some of these agents still encounter off-target toxicities and suboptimal efficacies due to their inferior biopharmaceutical and/or pharmacokinetic properties.Almost all of these molecules exhibit significant inter-and intra-patient variations in plasma concentration-time profiles.Thus,therapeutic drug monitoring,dose adjustments and precision medicine are being contemplated by clinicians.Complex formulations or nanoformulation-based drug delivery systems offer promising approaches to provide drug encapsulation or spatiotemporal control over the release,overcoming the biopharmaceutical and pharmacokinetic limitations and improving the therapeutic outcomes.In this context,the present review comprehensively tabulates and critically analyzes all the relevant properties(T1/2,solubility,pKa,therapeutic index,IC50,metabolism etc.)of the approved smTKIs.A detailed appraisal is conducted on the advancements made in complex formulations of smTKIs,with a focus on strategies to enhance their pharmacokinetic profile,tumor targeting ability,and therapeutic efficacy.Various nanocarrier platforms,have been discussed,highlighting their unique features and potential applications in cancer therapy.Nanoformulations have been shown to improve bioavailability and reduce dosing frequency for several smTKIs in animal models.It is inferred that extensive efforts will be made in developing complex formulations of smTKIs in near future.The review concludes with key recommendations for the developing of smTKIs to facilitate early clinical translation.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
Objectives:EGFR tyrosine kinase inhibitor(EGFR-TKI)therapies such as erlotinib and gefitinib are approved for the treatment of non-small cell lung cancer(NSCLC).However,the high incidence of acquired resistance to the...Objectives:EGFR tyrosine kinase inhibitor(EGFR-TKI)therapies such as erlotinib and gefitinib are approved for the treatment of non-small cell lung cancer(NSCLC).However,the high incidence of acquired resistance to these EGFR-TKIs may preclude their effectiveness.Piperlongumine(PPL),an extract from the long pepper fruit(Piper longum),has been shown to possess anticancer properties.The purpose of the study was to investigate piperlongumine as an anticancer agent and to study a combination treatment approach with EGFR-TKIs against lung cancer cells.Methods:Anticancer efficacy of PPL,erlotinib(ERL),gefitinib(GEF),and cisplatin(CIS)were investigated in H1299 and H1975 cell lines.Cells were treated with PPL,ERL,GEF,and CIS alone,and in combination,cell viability was determined after 72 h.The mechanism of PPL-induced cytotoxicity was investigated via reactive oxygen species(ROS)induction,and apoptosis induction using acridine orange/ethidium bromide staining and flow cytometry.The effect of treatment on EGFR-mediated oncogenic signaling was investigated by immunoblotting for mitogenic and apoptotic markers.Results:PPL exhibited a potent cytotoxic effect in H1299 and H1975 cells compared to ERL,GEF,and CIS.Combination treatments of PPL with GEF and ERL showed significant reductions in cancer cells compared to control in both cell lines,which were associated with apoptotic induction,but without significant ROS induction.Compared to control,PPL with GEF significantly increased apoptotic cell death in H1975as confirmed with flow cytometry.Treatment with PPL alone and in combination induced anti-mitogenic and apoptotic responses at the molecular level.Conclusion:PPL sensitized lung cancer cells to EGFR-TKI and induced potent cytotoxic effects at low concentrations.展开更多
基金Supported by Grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute,funded by the Ministry of Health&Welfare,Republic of Korea,No.RS-2022-KH129889.
文摘BACKGROUND The classification of uterine sarcomas is based on distinctive morphological and immunophenotypic characteristics,increasingly supported by molecular genetic diagnostics.Data on neurotrophic tyrosine receptor kinase(NTRK)gene fusionpositive uterine sarcoma,potentially aggressive and morphologically similar to fibrosarcoma,are limited due to its recent recognition.Pan-TRK immunohistochemistry(IHC)analysis serves as an effective screening tool with high sensitivity and specificity for NTRK-fusion malignancies.CASE SUMMARY We report a case of a malignant mesenchymal tumor originating from the uterine cervix,which was pan-TRK IHC-positive but lacked NTRK gene fusions,accompanied by a brief literature review.A 55-year-old woman presented to the emergency department with abdominal pain and distension,exhibiting significant ascites and multiple solid pelvic masses.Pelvic examination revealed a tumor encompassing the uterine cervix,extending to the vagina and uterine corpus.A punch biopsy of the cervix indicated NTRK sarcoma with positive immunochemical pan-TRK stain.However,subsequent next generation sequencing revealed no NTRK gene fusion,leading to a diagnosis of poorly differentiated,advanced-stage sarcoma.CONCLUSION The clinical significance of NTRK gene fusion lies in potential treatment with TRK inhibitors for positive sarcomas.Identifying such rare tumors is crucial due to the potential applicability of tropomyosin receptor kinase inhibitor treatment.
文摘In this editorial,the roles of protein tyrosine phosphatase nonreceptor 2(PTPN2)in oncogenic transformation and tumor behavior and its potential as a therapeutic target in the context of gastrointestinal(GI)cancers are presented with respect to the article by Li et al published in ninth issue of the World Journal of Gastrointestinal Oncology.PTPN2 is a member of the protein tyrosine phosphatase family of signaling proteins that play crucial roles in the regulation of inflammation and immunity.Accordingly,early findings highlighted the contribution of PTPN2 to the pathogenesis of inflammatory and autoimmune disorders related to its dysfunction.On the other hand,recent studies have indicated that PTPN2 has many different roles in different cancer types,which is associated with the complexity of its regulatory network.PTPN2 dephosphorylates and inactivates EGFR,SRC family kinases,JAK1 and JAK3,and STAT1,STAT3,and STAT5 in cell type-and context-dependent manners,which indicates that PTPN2 can perform either prooncogenic or anti-oncogenic functions depending on the tumor subtype.While PTPN2 has been suggested as a potential therapeutic target in cancer treatment,to the best of ourknowledge,no clear treatment protocol has referred to PTPN2.Although there are only few studies that investigated PTPN2 expression in the GI system cancers,which is a potential limitation,the association of this protein with tumor behavior and the influence of PTPN2 on many therapy-related signaling pathways emphasize that PTPN2 could serve as a new molecular biomarker to predict tumor behavior and as a target for therapeutic intervention against GI cancers.In conclusion,more studies should be performed to better understand the prognostic and therapeutic potential of PTPN2 in GI tumors,especially in tumors resistant to therapy.
基金This work was supported by the Key Project of National Natural Science Foundation of China (No. 30430280)the National Natural Science Foundation of China (No. 30271437, No.30270482)the Natural Science Foundation of Beijing Municipality (No. 7022011 ).
文摘Objective To approach the associated mechanism by which α-synuclein (α-Syn) might regulate the metabolism of dopamine. Methods A DNA fragment, located at --495 to +25 of the human tyrosine hydroxylase (TH) gene, was amplified by PCR and inserted into the pGL3-Basic luciferase reporter vector. The recombinant plasmid pGL3-THprom was transfected into a dopammergic cell line MES23.5 or a α-Syn over-expressed MES23.5 (named MES23.5/hα-Syn^+). The promoter activity was detected by the Dual Luciferase Assay System. Results The luciferase activities in the MES23.5 cells transfected with pGl.,3-Basic, pGL3-THprom, and pGL3-Control vectors were 5.60±0.67, 26.80±4.11, and 32.90±4.75, respectively. On the other hand, the luciferase activity of pGL3-THprom in the MES23.5 (26.80±4.11) was significantly higher than that in the MES23.5/hα-Syn^+(14.40±0.61) (P〈0.01). Conclusion These results indicate that the -495 to +25 region in the TH gene possesses promoter activity for controlling the gene expression, and that α-Syn may negatively regulate the metabolism of dopamine by affecting the function of TH promoter as a trans-acting factor.
基金supported by a grant from Science and Technology Support Traditional Chinese Drug Research and Development Project of Shanghai of China,No.12401900302Traditional Chinese Medicine Research Foundation of Shanghai Municipal Health Bureau of China,No.2012J009A+2 种基金a grant from Annual Research Budget of Shanghai University of Traditional Chinese Medicine of China in 2013,No.2013JW25the National Natural Science Foundation of China,No.3067268430973722
文摘Tyrosine hydroxylase is a key enzyme in dopamine biosynthesis. Change in tyrosine hydroxylase expression in the nigrostriatal system is closely related to the occurrence and development of Parkinson's disease. Verbascoside, an extract from Radix Rehmanniae Praeparata has been shown to be clinically effective in treating Parkinson's disease. However, the underlying mechanisms remain unclear. It is hypothesized that the effects of verbascoside on Parkinson's disease are related to tyrosine hydroxylase expression change in the nigrostriatal system. Rat models of Parkinson's disease were established and verbascoside(60 mg/kg) was administered intraperitoneally once a day. After 6 weeks of verbascoside treatment, rat rotational behavior was alleviated; tyrosine hydroxylase m RNA and protein expression and the number of tyrosine hydroxylase-immunoreactive neurons in the rat right substantia nigra were significantly higher than the Parkinson's model group. These findings suggest that the mechanism by which verbascoside treats Parkinson's disease is related to the regeneration of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra.
基金supported by the National Natural Science Foundation of China (Influence of visual deprivation on bipolar cell synaptic formation and degeneration following opticnerve transection), No. 30671100
文摘The present study examined changes in retinal tyrosine hydroxylase (TH) expression in rats having undergone optic nerve transection and housed under a normal day/night cycle or in the dark. The aim was to investigate the effects of amacrine cells on axonal regeneration in retinal ganglion cells and on the synapses that transmit visual signals. The results revealed that retinal TH expression gradually decreased following optic nerve transection in rats housed under a normal day/night cycle reaching a minimum at 5 days. In contrast, retinal TH expression decreased to a minimum at 1 day following optic nerve transection in dark reared rats, gradually increasing afterward and reaching a normal level at 5 7 days. The number of TH-positive synaptic particles correlated with the TH levels indicating that dark rearing can help maintain TH expression during the synaptic degeneration stage (5 7 days after optic nerve injury) in retinal amacrine cells.
基金Projects of Heilongjiang Province Administration of Traditional Chinese Medicine,No.ZH04Z74Second-Class Award of Scientific Advancement of Heilongjiang Province Administration of Traditional Chinese Medicine in 2007
文摘This study showed that abnormal behavioral changes were greatly improved in rats displaying Parkinson's disease-like symptoms after intragastric administration of Xifeng Dingchan decoction at 15, 7.5, 3.75 g/kg per day. In addition, tyrosine hydroxylase mRNA expression in the substantia nigra of the midbrain was up-regulated, and tyrosine hydroxylase content in the midbrain ventral tegmentum and substantia nigra pars compacta was also increased. The effect of administration of Xifeng Dingchan decoction at 7.5 g/kg per day was similar to that of Madopar at 67.5 mg/kg per day. These results indicate that the therapeutic effect of Xifeng Dingchan decoction on Parkinson's disease is associated with the up-regulated protein and mRNA expression of tyrosine hydroxylase in the midbrain.
基金This work was supported by National Natural Science Foundation of China (No: 30371225).
文摘Objective To study the effects of deltamethrin on tyrosine hydroxylase in nigrostriatum of male rats. Methods Sprague-Dawley rats were daily treated with deltamethrin at 6.25 or 12.5 mg/kg body weight by gavage for 10 days. Then HPLC-fluorescence detection was used to analyze the contents of dopamine (DA), 3,4-dihydmxyphenylacetic acid (DOPAC) and homoranillic acid (HVA) in substantial nigra and striatum. The activities of tyrosine hydroxylase (TH) were also detected by HPLC-fluorescence detection. TH mRNA or TH protein levels were measured by RT-PCR and immunohistochemistry method. Results The content of DA in stfiatum was significantly decreased by the treatments, suggesting an inhibition of DA synthesis by deltamethrin. The contents of DA metabolites DOPAC and HVA increased, indicating increased dopamine turnover. Furthermore, deltamethrin significantly decreased the activity, as well as the mRNA and protein levels of TH. Conclusions These findings reveal a novel aspect of deltamethfin neurotoxicity and suggest tyrosine hydroxylase as a molecular target of deltamethin on dopamine metabolism in the nigrostriatal pathway.
基金the National Natural Science Foundation of China,No.50677022
文摘BACKGROUND: Electromagnetic radiation can influence dopamine (DA) synthesis in brain tissues or ceils, but electromagnetic frequencies, intensities, and radiation time can produce different effects. In addition, the signal pathway by which electromagnetic radiation influences DA synthesis remains controversial. OBJECTIVE: To determine tyrosine hydroxylase (TH) expression in PC12 cells and DA levels in cell culture media after different periods of low-frequency pulsed electric field (LF-PEF) stimulation, and to determine how LF-PEF signaling stimulates TH synthesis using inhibitors. DESIGN, TIME AND SETTING: A parallel, controlled, cell experiment was performed at the Laboratory of Cell Biology, School of Life Science, East China Normal University, between January and October 2006. MATERIALS: PC12 cells were purchased from the Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, China. Nerve growth factor was purchased from PeproTech, USA. The protein kinase A inhibitor, H-89, and mitogen-activated protein kinase kinase inhibitor, U0126, were purchased from Sigma, USA. METHODS: (1) Following routine culture in Dulbecco's modified eagle medium, primary PC12 cells were stimulated under LF-PEF (pulse frequency 50.Hz, pulse width 20 μs, peak field strength 1 V/m) for 5, 10, 15, 20, and 30 minutes. (2) Inhibitors (H-89 or U0126, 1 μmol/L) were added 30 minutes before LF-PEF stimulation for 10 minutes. MAIN OUTCOME MEASURES: (1) TH expression was determined by Western blot in PC12 cells at 0.5, 1,2, 3, and 4 days after LF-PEF stimulation. Similarly, DA was measured by high-performance liquid chromatography in media at 2, 3, 4, or 5 days after LF-PEE (2) TH expression was detected 1 day after H-89 or U0126 treatment and LF-PEE RESULTS: (1) Short-term LF-PEF stimulation (5 and 10 minutes) increased TH expression and media DA levels after short-term culture (2 days) (P 〈 0.01), but both parameters decreased with longer culture (3 4 days) (P 〈 0.01). Long-term LF-PEF stimulation (15, 20, or 30 minutes) decreased TH and DA synthesis, followed by a rapid increase (P 〈 0.01). (2) H89 could completely inhibit TH expression in PC12 cells stimulated by LF-PEF for 10 minutes, while the inhibition rate of U0126 was 53.2%. CONCLUSION: Short-term LF-PEF first promotes then inhibits, while long-term LF-PEF first inhibits then promotes, TH and DA synthesis. LF-PEF stimulation regulates TH expression primarily by activating protein kinase A to regulate DA synthesis.
文摘The AS/AGU rat has a recessive single point mutation in the gene coding for the gamma isoform of protein kinase C (PKC-γ) resulting in a failure to release dopamine in the striatum and impaired movement including a staggering gait, difficulty in initiating movement and a slight whole body tremor. This study examined the levels tyrosine hydroxylase, ubiquitin and parkin in individual SNC cell bodies, there was no evidence of a reduction in tyrosine hydroxylase levels although levels of ubiquitin and parkin were elevated in the cytoplasm. The findings support the hypothesis that the initial bar to dopamine availability in the striatum is reduced release, with substantia nigra cell death being a later phenomenon.
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.
文摘The use of gene therapy has been intensively studied as a potential method to treat Parkinson’s disease (PD) and other degenerative brain diseases. However, the effects of experimental measures and approaches on the outcome of gene delivery or on the physiological state of target tissues have not been analyzed as much and systematically. Therefore, we have infused adenovirus vectors expressing either a therapeutic tyrosine hydroxylase (TH) gene or a lacZ reporter gene into striatum in a rat model of PD. The experimental procedures were tested using the Ad lacZ vector in order to optimize concentrations, volumes, infusion speeds and transfection times. The expression of Ad lacZ vector was lower and declined earlier in the lesioned than unlesioned striatum suggesting that the lesion affects on the transfection efficiency and outcome of gene transfection. The effect of three different approaches of Ad TH vector transfection was compared: 1) the delivery of Ad TH gene vector alone into one single site of striatum, 2) the delivery of Ad TH gene vector alone into multiple sites of striatum, and 3) the delivery of Ad TH gene vector into one site of striatum followed by a continuous infusion of tetrahydrobiopterin (BH4) cofactor with a mini pump. There was a small and transient unsignificant decrease in the turning behavior when the Ad TH vector was delivered into one site of the striatum. Simultaneous infusion into several sites or together with BH4 cofactor did not improve more the effect of gene delivery. Thus, although the effects were unsignificant, the Ad TH transfection seemed to decrease the turning behavior in the rat model of PD and the optimal effect was seen at some specific doses and time points. Furthermore, the outcome of gene therapy could depend in addition to the amount and efficacy of gene vectors also on the physiological state and experimental strategies.
文摘BACKGROUND The incidence of primary liver cancer is increasing year by year.In 2022 alone,more than 900000 people were diagnosed with liver cancer worldwide,with hepatocellular carcinoma(HCC)accounting for 75%-85%of cases.HCC is the most common primary liver cancer.China has the highest incidence and mortality rate of HCC in the world,and it is one of the malignant tumors that seriously threaten the health of Chinese people.The onset of liver cancer is occult,the early cases lack typical clinical symptoms,and most of the patients are already in the middle and late stage when diagnosed.Therefore,it is very important to find new markers for the early detection and diagnosis of liver cancer,improve the therapeutic effect,and improve the prognosis of patients.Protein tyrosine phosphatase non-receptor 2(PTPN2)has been shown to be associated with colorectal cancer,triple-negative breast cancer,non-small cell lung cancer,and prostate cancer,but its biological role and function in tumors remain to be further studied.AIM To combine the results of relevant data obtained from The Cancer Genome Atlas(TCGA)to provide the first in-depth analysis of the biological role of PTPN2 in HCC.METHODS The expression of PTPN2 in HCC was first analyzed based on the TCGA database,and the findings were then verified by immunohistochemical staining,quantitative real-time polymerase chain reaction(qRT-PCR),and immunoblotting.The value of PTPN2 in predicting the survival of patients with HCC was assessed by analyzing the relationship between PTPN2 expression in HCC tissues and clinicopathological features.Finally,the potential of PTPN2 affecting immune escape of liver cancer was evaluated by tumor immune dysfunction and exclusion and immunohistochemical staining.RESULTS The results of immunohistochemical staining,qRT-PCR,and immunoblotting in combination with TCGA database analysis showed that PTPN2 was highly expressed and associated with a poor prognosis in HCC patients.Kyoto Encyclopedia of Genes and Genomes enrichment analysis showed that PTPN2 was associated with various pathways,including cancer-related pathways,the Notch signaling pathway,and the MAPK signaling pathway.Gene Set Enrichment Analysis showed that PTPN2 was highly expressed in various immune-related pathways,such as the epithelial mesenchymal transition process.A risk model score based on PTPN2 showed that immune escape was significantly enhanced in the high-risk group compared with the low-risk group.CONCLUSION This study investigated PTPN2 from multiple biological perspectives,revealing that PTPN2 can function as a biomarker of poor prognosis and mediate immune evasion in HCC.
基金Chinese postdoctoral foundationa grand from the National Institute of Drug Abuse, USA (DA 03983)
文摘In the present study we have found that proto-oncogene c-fos protein can expressin the noradrenergic neurons of rat hindbrain following peripheral electrical stimulation. Ratswere given peripheral electrical stimulation via thin stainless steel pins inserted into the pointsnear knee joint (S36) and ankle joint (Sp6) which mimic the manipulation of electroacupuncture(EA) performed in humans. Animals were perfused for double staining immunohistochemistry 2hafter the termination of EA. In rats subjected to EA stimulation Fos-like protein was found in thetyrosine hydroxylase (TH)-like immunoreactive neurons in rat hindbrain. The Fos and TH coex-isting neurons were distributed in the locus coeruleus, solitary tract nucleus, ventrolateral medul-la, periaqeductal gray, as well as superior colliculus. The percentage of the coexisting neuronscompared with the total number of neurons containing Fos-like protein in these nuclei rangedfrom 6% to 32%. The results suggest that the noradrenergic neurons in these regions may be ac-tivted by acupuncture stimulation.
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.
文摘Buoyed by the discovery of small-molecule tyrosine kinase inhibitors(smTKIs),significant impact has been made in cancer chemotherapeutics.However,some of these agents still encounter off-target toxicities and suboptimal efficacies due to their inferior biopharmaceutical and/or pharmacokinetic properties.Almost all of these molecules exhibit significant inter-and intra-patient variations in plasma concentration-time profiles.Thus,therapeutic drug monitoring,dose adjustments and precision medicine are being contemplated by clinicians.Complex formulations or nanoformulation-based drug delivery systems offer promising approaches to provide drug encapsulation or spatiotemporal control over the release,overcoming the biopharmaceutical and pharmacokinetic limitations and improving the therapeutic outcomes.In this context,the present review comprehensively tabulates and critically analyzes all the relevant properties(T1/2,solubility,pKa,therapeutic index,IC50,metabolism etc.)of the approved smTKIs.A detailed appraisal is conducted on the advancements made in complex formulations of smTKIs,with a focus on strategies to enhance their pharmacokinetic profile,tumor targeting ability,and therapeutic efficacy.Various nanocarrier platforms,have been discussed,highlighting their unique features and potential applications in cancer therapy.Nanoformulations have been shown to improve bioavailability and reduce dosing frequency for several smTKIs in animal models.It is inferred that extensive efforts will be made in developing complex formulations of smTKIs in near future.The review concludes with key recommendations for the developing of smTKIs to facilitate early clinical translation.
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.
文摘Objectives:EGFR tyrosine kinase inhibitor(EGFR-TKI)therapies such as erlotinib and gefitinib are approved for the treatment of non-small cell lung cancer(NSCLC).However,the high incidence of acquired resistance to these EGFR-TKIs may preclude their effectiveness.Piperlongumine(PPL),an extract from the long pepper fruit(Piper longum),has been shown to possess anticancer properties.The purpose of the study was to investigate piperlongumine as an anticancer agent and to study a combination treatment approach with EGFR-TKIs against lung cancer cells.Methods:Anticancer efficacy of PPL,erlotinib(ERL),gefitinib(GEF),and cisplatin(CIS)were investigated in H1299 and H1975 cell lines.Cells were treated with PPL,ERL,GEF,and CIS alone,and in combination,cell viability was determined after 72 h.The mechanism of PPL-induced cytotoxicity was investigated via reactive oxygen species(ROS)induction,and apoptosis induction using acridine orange/ethidium bromide staining and flow cytometry.The effect of treatment on EGFR-mediated oncogenic signaling was investigated by immunoblotting for mitogenic and apoptotic markers.Results:PPL exhibited a potent cytotoxic effect in H1299 and H1975 cells compared to ERL,GEF,and CIS.Combination treatments of PPL with GEF and ERL showed significant reductions in cancer cells compared to control in both cell lines,which were associated with apoptotic induction,but without significant ROS induction.Compared to control,PPL with GEF significantly increased apoptotic cell death in H1975as confirmed with flow cytometry.Treatment with PPL alone and in combination induced anti-mitogenic and apoptotic responses at the molecular level.Conclusion:PPL sensitized lung cancer cells to EGFR-TKI and induced potent cytotoxic effects at low concentrations.