Cancer treatment failure, drug resistance, or metastatic recurrence are thought to be caused mainly by the existence of a very small number of cancer stem cells(CSCs). The characteristics of this subgroup of cells inc...Cancer treatment failure, drug resistance, or metastatic recurrence are thought to be caused mainly by the existence of a very small number of cancer stem cells(CSCs). The characteristics of this subgroup of cells include self-renewal, tumorigenesis, multiple differentiation and high invasiveness, metastasis, and drug resistance potential. Many studies have demonstrated that CSCs play important roles in tumor growth, spread and metastatic relapse after treatment, and are closely related to the prognosis of patients.From a therapeutic viewpoint, deep insights into the CSCs biology, development of specific therapeutic strategies for targeting CSCs, and characterization of their microenvironment could be an ideal way to combat cancer.展开更多
Breast cancer,like many other cancers,is believed to be driven by a population of cells that display stem cell properties.Recent studies suggest that cancer stem cells(CSCs)are essential for tumor progression,and tumo...Breast cancer,like many other cancers,is believed to be driven by a population of cells that display stem cell properties.Recent studies suggest that cancer stem cells(CSCs)are essential for tumor progression,and tumor relapse is thought to be caused by the presence of these cells.CSC-targeted therapies have also been proposed to overcome therapeutic resistance in breast cancer after the traditional therapies.Additionally,the metabolic properties of cancer cells differ markedly from those of normal cells.The efficacy of metabolic targeted therapy has been shown to enhance anti-cancer treatment or overcome therapeutic resistance of breast cancer cells.Metabolic targeting of breast CSCs(BCSCs)may be a very effective strategy for anti-cancer treatment of breast cancer cells.Thus,in this review,we focus on discussing the studies involving metabolism and targeted therapy in BCSCs.展开更多
Gastric cancer(GC)is a malignancy with a high incidence and mortality.The tumor immune microenvironment plays an important role in promoting cancer development and supports GC progression.Accumulating evidence shows t...Gastric cancer(GC)is a malignancy with a high incidence and mortality.The tumor immune microenvironment plays an important role in promoting cancer development and supports GC progression.Accumulating evidence shows that GC cells can exert versatile mechanisms to remodel the tumor immune microenvironment and induce immune evasion.In this review,we systematically summarize the intricate crosstalk between GC cells and immune cells,including tumor-associated macrophages,neutrophils,myeloid-derived suppressor cells,natural killer cells,effector T cells,regulatory T cells,and B cells.We focus on how GC cells alter these immune cells to create an immunosuppressive microenvironment that protects GC cells from immune attack.We conclude by compiling the latest progression of immune checkpoint inhibitor-based immunotherapies,both alone and in combination with conventional therapies.Anti-cytotoxic Tlymphocyte-associated protein 4 and anti-programmed cell death protein 1/programmed death-ligand 1 therapy alone does not provide substantial clinical benefit for GC treatment.However,the combination of immune checkpoint inhibitors with chemotherapy or targeted therapy has promising survival advantages in refractory and advanced GC patients.This review provides a comprehensive understanding of the immune evasion mechanisms of GC,and highlights promising immunotherapeutic strategies.展开更多
Background:The advent of immune checkpoint inhibitors(ICIs)has revolutionized the therapeutic options of hepatobiliary malignancies.However,the clinical benefit provided by immunotherapy seems limited to a small subgr...Background:The advent of immune checkpoint inhibitors(ICIs)has revolutionized the therapeutic options of hepatobiliary malignancies.However,the clinical benefit provided by immunotherapy seems limited to a small subgroup of patients with hepatobiliary malignancies.The identification of reliable predictors of the response to immunotherapy is urgently needed.Data sources:Literature search was conducted in Pub Med for relevant articles published up to May 2022.Information of clinical trials was obtained from https://clinicaltrials.gov/.Results:Biomarkers for ICI response of hepatobiliary malignancies remain in the exploration stage and lack compelling evidence.Tumor programmed death-ligand 1(PD-L1)expression is the most widely studied biomarker in hepatocellular carcinoma(HCC)and biliary tract cancers(BTCs),but there are conflicting results on its predictive potential.Tumor mutational burden(TMB)is generally low both in HCC and BTCs,and the clinical trials of TMB are rare in hepatobiliary malignancies.Promisingly,mismatch repair deficiency(dMMR)/high microsatellite instability(MSI-H)may be a predictive biomarker of response to antiPD-1 therapy in BTCs.Furthermore,some emerging biomarkers,such as gut microbiota,show predictive potential in the preliminary studies.Radiomics and liquid-biopsy biomarkers,including circulating tumor cells,circulating tumor DNA(ct DNA)and exosomal PD-L1 provide a quick and non-invasive approach for monitoring the ICI response,showing a new promising direction.Conclusions:Multiple potential biomarkers for predicting ICI response of hepatobiliary malignancies have been explored and tried to apply in clinic.Yet there is no robust evidence to prove their clinical value in predicting immunotherapeutic response for patients with hepatobiliary malignancies.The identification of predictors for response to ICIs is an urgent need and major challenge.Further studies are warranted to validate the role of emerging biomarkers in predicting immunotherapeutic responses.展开更多
Primary liver cancer,mainly hepatocellular carcinoma(HCC),is the sixth most diagnosed cancer and third leading cause of cancer-related death globally.Recently,immunotherapies such as immune checkpoint inhibitors(ICIs)...Primary liver cancer,mainly hepatocellular carcinoma(HCC),is the sixth most diagnosed cancer and third leading cause of cancer-related death globally.Recently,immunotherapies such as immune checkpoint inhibitors(ICIs)have made great progress in the systemic treatment of HCC.However,anti-PD-1 therapy with pembrolizumab or nivolumab as a single agent did not meet their predefined end points of overall survival in the KEYNOTE-240 and Check Mate 459 trials.It is urgent to understand the immunological rationale and explore novel ways to improve the efflcacy of immunotherapy.The combination of ICIs with other therapies,such as tyrosine kinase inhibitors(TKIs),monoclonal antibodies,or local therapy,has been demonstrated to improve overall response rate and survival.In addition,modulating tumor microenvironment is a potential way to overcome the primary and secondary resistance to immunotherapies.In this review,we summarized the latest findings in the immune microenvironment,the mechanisms of their synergistic effects when combined with anti-VEGF agents or TKIs,as well as other kinds of immune treatment.展开更多
Objective: The expression of B-cell lymphoma 2(Bcl-2) seems to be influenced by the endocrine environment. Numerous reports demonstrate the diverse expression of Bcl-2 family members under sex steroid regulation. With...Objective: The expression of B-cell lymphoma 2(Bcl-2) seems to be influenced by the endocrine environment. Numerous reports demonstrate the diverse expression of Bcl-2 family members under sex steroid regulation. With the exception of estrogen-related tumors, androgen-related tumors have shown their characteristics in Bcl-2 expression. In this study, the status of Bcl-2 expression in male hepatocellular carcinoma(HCC) patients was examined to verify the high incidence of HCC in males.Methods: Tumor tissue microarray was used to examine Bcl-2 expression levels in 374 HCC cases including 306 males and 68 females. Kaplan-Meier method, log-rank test, and Cox proportional hazards model were applied to investigate the predictive value of Bcl-2 in HCC patients.Results: Immunohistochemistry analysis showed that male patients with higher Bcl-2 levels had significantly longer median survival time and recurrence time than those with lower levels. However, no significant differences in outcomes were found between different Bcl-2 levels in female patients. When the male patients were stratified into several age points, the level of Bcl-2expression showed poorer predictive efficiency in the 45–49 and 55–60 age groups in andropause-age patients compared with other age groups. Bcl-2 was an independent prognostic factor for both overall survival(P < 0.0001) and recurrence time(P =0.0001) in male patients. After excluding male patients in the 45–60 age group, the predictive efficiency was enhanced(n = 147,OS, P = 0.0002, TTR, P < 0.0001).Conclusions: Bcl-2 expression is an independent predictor of survival and recurrence in male HCC. Bcl-2 levels may also be regulated by androgens or androgen receptors in male HCC patients. Bcl-2 levels change and exhibit poor predictive efficiency when androgen levels vary dramatically(andropause age).展开更多
Metastasis and metabolism reprogramming are two major hallmarks of cancer.In the initiation and progression of cancer,tumor cells are known to undergo fundamental metabolic changes to sustain their development and pro...Metastasis and metabolism reprogramming are two major hallmarks of cancer.In the initiation and progression of cancer,tumor cells are known to undergo fundamental metabolic changes to sustain their development and progression.In recent years,much more attentions have been drawn to their important roles in facilitating cancer metastasis through regulating the biological properties.In this review,we summarized the recent progresses in the studies of metabolism reprogramming of cancer metastasis,particularly of primary liver cancer,and highlight their potential applications.展开更多
Cancer metastasis is the major cause of cancer-related deaths and accounts for poor therapeutic outcomes.A metastatic cas-cade is a series of complicated biological processes.N6-methyladenosine(m^(6)A)is the most abun...Cancer metastasis is the major cause of cancer-related deaths and accounts for poor therapeutic outcomes.A metastatic cas-cade is a series of complicated biological processes.N6-methyladenosine(m^(6)A)is the most abundant and conserved epi-transcriptomic modification in eukaryotic cells,which has great impacts on RNA production and metabolism,including RNA splicing,processing,degradation and translation.Accumulating evidence demonstrates that m^(6)A plays a critical role in regulating cancer metastasis.However,there is a lack of studies that review the recent advances of m^(6)A in cancer metastasis.Here,we systematically retrieved the functions and mechanisms of how the m^(6)A axis regulates metastasis,and especially summarized the organ-specific liver,lung and brain metastasis mediated by m^(6)A in various cancers.Moreover,we discussed the potential application of m^(6)A modification in cancer diagnosis and therapy,as well as the present limitations and future perspectives of m^(6)A in cancer metastasis.This review provides a comprehensive knowledge on the m^(6)A-mediated regulation of gene expression,which is helpful to extensively understand the complexity of cancer metastasis from a new epitranscriptomic point of view and shed light on the developing novel strategies to anti-metastasis based on m^(6)A alteration.展开更多
Pancreatic cancer,one of the most aggressive malignancies,has no effective treatment due to the lack of targets and drugs related to tumour metastasis.SIRT6 can promote the migration of pancreatic cancer and could be ...Pancreatic cancer,one of the most aggressive malignancies,has no effective treatment due to the lack of targets and drugs related to tumour metastasis.SIRT6 can promote the migration of pancreatic cancer and could be a potential target for antimetastasis of pancreatic cancer.However,highly selective and potency SIRT6 inhibitor that can be used in vivo is yet to be discovered.Here,we developed a noveSIRT6 allosteric inhibitor,compound 11e,with maximal inhibitory potency and an IC_(50) value of 0.98±0.13μmol/L.Moreover,compound 11e exhibited significant selectivity against other histone deacetylases(HADC1-11 and SIRT1-3)at concentrations up to 100μmol/L.The allosteric site and the molecular mechanism of inhibition were extensively elucidated by cocrystal complex structure and dynamic structural analyses.Importantly,we confirmed the antimetastatic function of such inhibitors in four pancreatic cancer cell lines as well as in two mouse models of pancreatic cancer liver metastasis.To our knowledge,this is the first study to reveal the in vivo effects of SIRT6 inhibitors on liver metastatic pancreatic cancer.It not only provides a promising lead compound for subsequent inhibitor developmentargeting SIRT6 but also provides a potential approach to address the challenge of metastasis in pancreatic cancer.展开更多
Intercellular cross-talk plays important roles in cancer progression and metastasis.Yet how these cancer cells interact with each other is still largely unknown.Exosomes released by tumor cells have been proved to be ...Intercellular cross-talk plays important roles in cancer progression and metastasis.Yet how these cancer cells interact with each other is still largely unknown.Exosomes released by tumor cells have been proved to be effective cell-to-cell signal mediators.We explored the functional roles of exosomes in metastasis and the potential prognostic values for hepatocellular carcinoma(HCC).Exosomes were extracted from HCC cells of different metastatic potentials.The metastatic effects of exosomes derived from highly metastatic HCC cells(HMH)were evaluated both in vitro and in vivo.Exosomal proteins were identified with iTRAQ mass spectrum and verified in cell lines,xenograft tumor samples,and functional analyses.Exosomes released by HMH significantly enhanced the in vitro invasion and in vivo metastasis of low metastatic HCC cells(LMH).S100 calcium-binding protein A4(S100A4)was identified as a functional factor in exosomes derived from HMH.S100A4r,ch exosomes significantly promoted tumor metastasis both in vitro and in vivo compared with S100A4^(rich) exosomes or controls.Moreover,exosomal S100A4 could induce expression of osteopontin(OPN),along with other tumor metastasis/stemness-related genes.Exosomal S100A4 activated OPN transcription via STAT3 phosphorylation.HCC patients with high exosomal S100A4 in plasma also had a poorer prognosis.In conclusion,exosomes from HMH could promote the metastatic potential of LMH,and exosomal S100A4 is a key enhancer for HCC metastasis,activating STAT3 phosphorylation and up-regulating OPN expression.This suggested exosomal S100A4 to be a novel prognostic marker and therapeutic target for HCC metastasis.展开更多
A salient feature of metastasis is the ability of different tu- mor types to colonize the same or different organ sites. Many genetic and epigenetic events have been identified that con- tributing to the metastatic ca...A salient feature of metastasis is the ability of different tu- mor types to colonize the same or different organ sites. Many genetic and epigenetic events have been identified that con- tributing to the metastatic cascades, including migration, lo- cal invasion, intravasation, survival in the circulation, ex- travasation and colonization, and some key molecules might have dual functions promoting metastasis by providing both local advantage from malignant progression in the primary tu- mor and a distal advantage from infiltration of distant organs. Nevertheless, the metastatic process remains poorly under- stood and the insight into the molecular events that initiate and/or sustain this process remains incomplete.展开更多
Recent evidence has highlighted immune checkpoint inhibitors as among the most promising immunotherapies for various malignancies.However,a significant proportion of HCC patients exhibit poor responses.Lipid metabolic...Recent evidence has highlighted immune checkpoint inhibitors as among the most promising immunotherapies for various malignancies.However,a significant proportion of HCC patients exhibit poor responses.Lipid metabolic heterogeneity is considered a key driver of cancer progression.However,the role of lipid metabolic reprogramming in HCC immunotherapy resistance remains poorly understood.Herein,we aimed to illuminate the potential relationship between lipid metabolic reprogramming and ICI resistance and provide novel strategies to increase the HCC immunotherapy response.Patients who received PD-1/PD-L1 inhibitors were enrolled.The effect of TACC3 on the tumor microenvironment was validated via single-cell RNA sequencing in HCC-bearing mouse models.Targeted metabolomics was performed to analyze the regulatory role of TACC3 in HCC metabolism.To address HCC immunotherapy resistance,we developed a targeted nucleic acid therapeutic utilizing N-acetylgalactosamine(GalNAc)to conjugate siTACC3.Through clinical cohort analysis,we found that TACC3 was overexpressed in HCC patients with poor response to immunotherapy.Furthermore,we demonstrated that silencing tumor-derived TACC3 optimizes the cytotoxicity of infiltrating CD8^(+)T lymphocytes.Both in vitro and in vivo assays suggested that TACC3 maintains ACSL4-mediated polyunsaturated fatty acid(PUFA)metabolism in HCC cells.Additionally,TACC3 accelerates ACSL4 expression by interacting with LARP1 and PABPC1,which stabilize ACSL4 mRNA.The results of preclinical models demonstrated the satisfactory efficacy of GalNAc-conjugated siTACC3 combined with PD-1 inhibitor therapy for HCC.In summary,tumor-derived TACC3 impairs the tumor-killing activity of CD8^(+)T lymphocytes through PUFA metabolism-associated crosstalk.Targeting TACC3 represents a novel and practicable strategy to augment ICI efficacy against HCC.展开更多
Background The efficacy of immune checkpoint inhibitors(ICIs),such as programmed cell death protein-1(PD-1)or its ligand 1(PD-L1)antibody,in hepatocellular carcinoma(HCC)is limited,and it is recommended that they be c...Background The efficacy of immune checkpoint inhibitors(ICIs),such as programmed cell death protein-1(PD-1)or its ligand 1(PD-L1)antibody,in hepatocellular carcinoma(HCC)is limited,and it is recommended that they be combined with other therapies.We evaluated the combination of pegylated interferon-α(Peg-IFNα)with PD-1 blockade in HCC mouse models.Methods We analyzed the effects of Peg-IFNαon tumor-infiltrating immune cells and PD-1 expression in the HCC immune microenvironment and examined the underlying mechanism of its unique effect on the PD-1 pathway.The in vivo efficacy of anti-PD-1 and Peg-IFNαwas evaluated in both subcutaneous and orthotopic mouse models of HCC.Results The combination of Peg-IFNαwith PD-1 blockade dramatically enhanced T-cell infiltration,improved the efficacy of PD-1 antibody and prolonged mouse survival compared with PD-1 antibody monotherapy.Mechanistically,Peg-IFNαcould recruit cytotoxic CD8+T cells to infiltrate the HCC microenvironment by inducing tumor cells to secrete the chemokine CCL4.Nevertheless,the HCC microenvironment quickly overcame the immune responses by upregulating PD-1 expression in CD8+T cells via the IFNα-IFNAR1-JAK1-STAT3 signaling pathway.The combination of PD-1 blockade with Peg-IFNαcould restore the cytotoxic capacity of CD8+T cells and exerted a significant synergistic effect on HCC.Conclusion These results indicate that in addition to initiating the antitumor immune response itself,Peg-IFNαcan also generate a microenvironment favoring PD-1 blockade.Thus,the combination of Peg-IFNαand PD-1 blockade can be a promising strategy for HCC.展开更多
The immunosuppressive microenvironment plays an important role in tumor progression and immunotherapy responses.Golgi membrane protein 1(GOLM1)is correlated to hepatocellular carcinoma(HCC)progression and metastasis.H...The immunosuppressive microenvironment plays an important role in tumor progression and immunotherapy responses.Golgi membrane protein 1(GOLM1)is correlated to hepatocellular carcinoma(HCC)progression and metastasis.However,little is known about the role of GOLM1 in regulating the immunosuppressive environment and its impact on immunotherapeutic efficacy in HCC.In this study,GOLM1 was positively correlated with infiltrating tumor-associated macrophages(TAMs)expressed high levels of programmed death-ligand 1(PD-L1)and CD8^(+)T cell suppression in HCC tissues.Both gain-and loss-of-function studies determined a close correlation between GOLM1 and immunosuppression.In the mechanism,GOLM1 promoted COP9 signalosome 5-mediated PD-L1 deubiquitination in HCC cells and increased the transport of PD-L1 into exosomes via suppression of Rab27b expression.Furthermore,co-culture with exosomes derived from HCC cells upregulated the expression of PD-L1 on macrophages.Zoledronic acid in combination with anti-PD-L1 therapy reduced PD-L1^(+)TAMs infiltration and alleviated CD8^(+)T cell suppression,resulting in tumor growth inhibition in the mouse HCC model.Together,our study unveils a mechanism by which GOLM1 induces CD8^(+)T cells suppression through promoting PD-L1 stabilization and transporting PD-L1 into TAMs with exosome dependent.Targeting PD-L1^(+)TAM could be a novel strategy to enhance the efficacy of anti-PD-L1 therapy in HCC.展开更多
Pancreatic cancer is an increasingly common cause of cancer mortality with a tight correspondence between disease mortality and incidence.Furthermore,it is usually diagnosed at an advanced stage with a very dismal pro...Pancreatic cancer is an increasingly common cause of cancer mortality with a tight correspondence between disease mortality and incidence.Furthermore,it is usually diagnosed at an advanced stage with a very dismal prognosis.Due to the high heterogeneity,metabolic reprogramming,and dense stromal environment associated with pancreatic cancer,patients benefit little from current conventional therapy.Recent insight into the biology and genetics of pancreatic cancer has supported its molecular classification,thus expanding clinical therapeutic options.In this review,we summarize how the biological features of pancreatic cancer and its metabolic reprogramming as well as the tumor microenvironment regulate its development and progression.We further discuss potential biomarkers for pancreatic cancer diagnosis,prediction,and surveillance based on novel liquid biopsies.We also outline recent advances in defining pancreatic cancer subtypes and subtype-specific therapeutic responses and current preclinical therapeutic models.Finally,we discuss prospects and challenges in the clinical development of pancreatic cancer therapeutics.展开更多
Betaine-homocysteine methyltransferase(BHMT)regulates protein methylation and is correlated with tumorigenesis;however,the effects and regulation of BHMT in hepatocarcinogenesis remain largely unexplored.Here,we deter...Betaine-homocysteine methyltransferase(BHMT)regulates protein methylation and is correlated with tumorigenesis;however,the effects and regulation of BHMT in hepatocarcinogenesis remain largely unexplored.Here,we determined the clinical significance of BHMT in the occurrence and progression of hepatocellular carcinoma(HCC)using tissue samples from 198 patients.BHMT was to be frequently found(86.6%)expressed at relatively low levels in HCC tissues and was positively correlated with the overall survival of patients with HCC.Bhmt overexpression effectively suppressed several malignant phenotypes in hepatoma cells in vitro and in vivo,whereas complete knockout of Bhmt(Bhmt^(−/−))produced the opposite effect.We combined proteomics,metabolomics,and molecular biological strategies and detected that Bhmt^(−/−)promoted hepatocarcinogenesis and tumor progression by enhancing the activity of glucose-6-phosphate dehydrogenase(G6PD)and PPP metabolism in DEN-induced HCC mouse and subcutaneous tumor-bearing models.In contrast,restoration of Bhmt with an AAV8-Bhmt injection or pharmacological inhibition of G6PD attenuated hepatocarcinogenesis.Additionally,coimmunoprecipitation identified monomethylated modifications of the G6PD,and BHMT regulated the methylation of G6PD.Protein sequence analysis,generation and application of specific antibodies,and site-directed mutagenesis indicated G6PD methylation at the arginine residue 246.Furthermore,we established bidirectionally regulated BHMT cellular models combined with methylation-deficient G6PD mutants to demonstrate that BHMT potentiated arginine methylation of G6PD,thereby inhibiting G6PD activity,which in turn suppressed hepatocarcinogenesis.Taken together,this study reveals a new methylation-regulatory mechanism in hepatocarcinogenesis owing to BHMT deficiency,suggesting a potential therapeutic strategy for HCC treatment.展开更多
Currently,there is no effective drugs for treating clinically COVID-19 except dexamethasone.We previously revealed that human identical sequences of SARS-CoV-2 promote the COVID-19 progression by upregulating hyaluron...Currently,there is no effective drugs for treating clinically COVID-19 except dexamethasone.We previously revealed that human identical sequences of SARS-CoV-2 promote the COVID-19 progression by upregulating hyaluronic acid(HA).As the inhibitor of HA synthesis,hymecromone is an approved prescription drug used for treating biliary spasm.Here,we aimed to investigate the relation between HA and COVID-19,and evaluate the therapeutic effects of hymecromone on COVID-19.Firstly,HA was closely relevant to clinical parameters,including lymphocytes(n=158;r=−0.50;P<0.0001),C-reactive protein(n=156;r=0.55;P<0.0001),D-dimer(n=154;r=0.38;P<0.0001),and fibrinogen(n=152;r=0.37;P<0.0001),as well as the mass(n=78;r=0.43;P<0.0001)and volume(n=78;r=0.41;P=0.0002)of ground-glass opacity,the mass(n=78;r=0.48;P<0.0001)and volume(n=78;r=0.47;P<0.0001)of consolidation in patient with low level of hyaluronan(HA<48.43 ng/mL).Furthermore,hyaluronan could directly cause mouse pulmonary lesions.Besides,hymecromone remarkably reduced HA via downregulating HAS2/HAS3 expression.Moreover,89%patients with hymecromone treatment had pulmonary lesion absorption while only 42%patients in control group had pulmonary lesion absorption(P<0.0001).In addition,lymphocytes recovered more quickly in hymecromone-treated patients(n=8)than control group(n=5)(P<0.05).These findings suggest that hymecromone is a promising drug for COVID-19 and deserves our further efforts to determine its effect in a larger cohort.展开更多
The global coronavirus disease 2019(COVID-19)pandemic has caused more than 6.1 million deaths until March 24,2022,as reported by the World Health Organization(WHO).Recently,breakthrough infections have appeared in ind...The global coronavirus disease 2019(COVID-19)pandemic has caused more than 6.1 million deaths until March 24,2022,as reported by the World Health Organization(WHO).Recently,breakthrough infections have appeared in individuals fully vaccinated against SARS-Co V-2^(1),which could be attributed to the rapid mutation of the RNA virus2.Currently,following the Delta variant,the Omicron variant of SARS-Co V-2 is increasingly becoming the dominant epidemic strain in the world.展开更多
Cabozantinib,mainly targeting cMet and vascular endothelial growth factor receptor 2,is the second-line treatment for patients with advanced hepatocellular carcinoma(HCC).However,the lower response rate and resistance...Cabozantinib,mainly targeting cMet and vascular endothelial growth factor receptor 2,is the second-line treatment for patients with advanced hepatocellular carcinoma(HCC).However,the lower response rate and resistance limit its enduring clinical benefit.In this study,we found that cMet-low HCC cells showed primary resistance to cMet inhibitors,and the combination of cabozantinib and mammalian target of rapamycin(mTOR)inhibitor,rapamycin,exhibited a synergistic inhibitory effect on the in vitro cell proliferation and in vivo tumor growth of these cells.Mechanically,the combination of rapamycin with cabozantinib resulted in the remarkable inhibition of AKT,extracellular signal-regulated protein kinases,mTOR,and common downstream signal molecules of receptor tyrosine kinases;decreased cyclin D1 expression;and induced cell cycle arrest.Meanwhile,rapamycin enhanced the inhibitory effects of cabozantinib on the migration and tubule formation of human umbilical vascular endothelial cells and human growth factor-induced invasion of cMet inhibitor-resistant HCC cells under hypoxia condition.These effects were further validated in xenograft models.In conclusion,our findings uncover a potential combination therapy of cabozantinib and rapamycin to combat cabozantinib-resistant HCC.展开更多
基金supported by the grants from the National Key Basic Research Program of China (Grant No. 2013CB910500)China National Key Projects for Infectious Disease (Grant No. 2012ZX10002-012)National Natural Science Foundation of China (Grant No. 81372647)
文摘Cancer treatment failure, drug resistance, or metastatic recurrence are thought to be caused mainly by the existence of a very small number of cancer stem cells(CSCs). The characteristics of this subgroup of cells include self-renewal, tumorigenesis, multiple differentiation and high invasiveness, metastasis, and drug resistance potential. Many studies have demonstrated that CSCs play important roles in tumor growth, spread and metastatic relapse after treatment, and are closely related to the prognosis of patients.From a therapeutic viewpoint, deep insights into the CSCs biology, development of specific therapeutic strategies for targeting CSCs, and characterization of their microenvironment could be an ideal way to combat cancer.
文摘Breast cancer,like many other cancers,is believed to be driven by a population of cells that display stem cell properties.Recent studies suggest that cancer stem cells(CSCs)are essential for tumor progression,and tumor relapse is thought to be caused by the presence of these cells.CSC-targeted therapies have also been proposed to overcome therapeutic resistance in breast cancer after the traditional therapies.Additionally,the metabolic properties of cancer cells differ markedly from those of normal cells.The efficacy of metabolic targeted therapy has been shown to enhance anti-cancer treatment or overcome therapeutic resistance of breast cancer cells.Metabolic targeting of breast CSCs(BCSCs)may be a very effective strategy for anti-cancer treatment of breast cancer cells.Thus,in this review,we focus on discussing the studies involving metabolism and targeted therapy in BCSCs.
基金The Natural Science Foundation of China,No.81672378,No.81201521,No.81873874 and No.81773089the Clinical Research Plan of SHDC,No.SHDC2020CR2021B。
文摘Gastric cancer(GC)is a malignancy with a high incidence and mortality.The tumor immune microenvironment plays an important role in promoting cancer development and supports GC progression.Accumulating evidence shows that GC cells can exert versatile mechanisms to remodel the tumor immune microenvironment and induce immune evasion.In this review,we systematically summarize the intricate crosstalk between GC cells and immune cells,including tumor-associated macrophages,neutrophils,myeloid-derived suppressor cells,natural killer cells,effector T cells,regulatory T cells,and B cells.We focus on how GC cells alter these immune cells to create an immunosuppressive microenvironment that protects GC cells from immune attack.We conclude by compiling the latest progression of immune checkpoint inhibitor-based immunotherapies,both alone and in combination with conventional therapies.Anti-cytotoxic Tlymphocyte-associated protein 4 and anti-programmed cell death protein 1/programmed death-ligand 1 therapy alone does not provide substantial clinical benefit for GC treatment.However,the combination of immune checkpoint inhibitors with chemotherapy or targeted therapy has promising survival advantages in refractory and advanced GC patients.This review provides a comprehensive understanding of the immune evasion mechanisms of GC,and highlights promising immunotherapeutic strategies.
文摘Background:The advent of immune checkpoint inhibitors(ICIs)has revolutionized the therapeutic options of hepatobiliary malignancies.However,the clinical benefit provided by immunotherapy seems limited to a small subgroup of patients with hepatobiliary malignancies.The identification of reliable predictors of the response to immunotherapy is urgently needed.Data sources:Literature search was conducted in Pub Med for relevant articles published up to May 2022.Information of clinical trials was obtained from https://clinicaltrials.gov/.Results:Biomarkers for ICI response of hepatobiliary malignancies remain in the exploration stage and lack compelling evidence.Tumor programmed death-ligand 1(PD-L1)expression is the most widely studied biomarker in hepatocellular carcinoma(HCC)and biliary tract cancers(BTCs),but there are conflicting results on its predictive potential.Tumor mutational burden(TMB)is generally low both in HCC and BTCs,and the clinical trials of TMB are rare in hepatobiliary malignancies.Promisingly,mismatch repair deficiency(dMMR)/high microsatellite instability(MSI-H)may be a predictive biomarker of response to antiPD-1 therapy in BTCs.Furthermore,some emerging biomarkers,such as gut microbiota,show predictive potential in the preliminary studies.Radiomics and liquid-biopsy biomarkers,including circulating tumor cells,circulating tumor DNA(ct DNA)and exosomal PD-L1 provide a quick and non-invasive approach for monitoring the ICI response,showing a new promising direction.Conclusions:Multiple potential biomarkers for predicting ICI response of hepatobiliary malignancies have been explored and tried to apply in clinic.Yet there is no robust evidence to prove their clinical value in predicting immunotherapeutic response for patients with hepatobiliary malignancies.The identification of predictors for response to ICIs is an urgent need and major challenge.Further studies are warranted to validate the role of emerging biomarkers in predicting immunotherapeutic responses.
基金supported by grants from the National Natural Science Foundation of China(81902390)the Major Program of National Natural Science Foundation of China(91959203)the Key Program of the National Natural Science Foundation of China(81930074)。
文摘Primary liver cancer,mainly hepatocellular carcinoma(HCC),is the sixth most diagnosed cancer and third leading cause of cancer-related death globally.Recently,immunotherapies such as immune checkpoint inhibitors(ICIs)have made great progress in the systemic treatment of HCC.However,anti-PD-1 therapy with pembrolizumab or nivolumab as a single agent did not meet their predefined end points of overall survival in the KEYNOTE-240 and Check Mate 459 trials.It is urgent to understand the immunological rationale and explore novel ways to improve the efflcacy of immunotherapy.The combination of ICIs with other therapies,such as tyrosine kinase inhibitors(TKIs),monoclonal antibodies,or local therapy,has been demonstrated to improve overall response rate and survival.In addition,modulating tumor microenvironment is a potential way to overcome the primary and secondary resistance to immunotherapies.In this review,we summarized the latest findings in the immune microenvironment,the mechanisms of their synergistic effects when combined with anti-VEGF agents or TKIs,as well as other kinds of immune treatment.
文摘Objective: The expression of B-cell lymphoma 2(Bcl-2) seems to be influenced by the endocrine environment. Numerous reports demonstrate the diverse expression of Bcl-2 family members under sex steroid regulation. With the exception of estrogen-related tumors, androgen-related tumors have shown their characteristics in Bcl-2 expression. In this study, the status of Bcl-2 expression in male hepatocellular carcinoma(HCC) patients was examined to verify the high incidence of HCC in males.Methods: Tumor tissue microarray was used to examine Bcl-2 expression levels in 374 HCC cases including 306 males and 68 females. Kaplan-Meier method, log-rank test, and Cox proportional hazards model were applied to investigate the predictive value of Bcl-2 in HCC patients.Results: Immunohistochemistry analysis showed that male patients with higher Bcl-2 levels had significantly longer median survival time and recurrence time than those with lower levels. However, no significant differences in outcomes were found between different Bcl-2 levels in female patients. When the male patients were stratified into several age points, the level of Bcl-2expression showed poorer predictive efficiency in the 45–49 and 55–60 age groups in andropause-age patients compared with other age groups. Bcl-2 was an independent prognostic factor for both overall survival(P < 0.0001) and recurrence time(P =0.0001) in male patients. After excluding male patients in the 45–60 age group, the predictive efficiency was enhanced(n = 147,OS, P = 0.0002, TTR, P < 0.0001).Conclusions: Bcl-2 expression is an independent predictor of survival and recurrence in male HCC. Bcl-2 levels may also be regulated by androgens or androgen receptors in male HCC patients. Bcl-2 levels change and exhibit poor predictive efficiency when androgen levels vary dramatically(andropause age).
基金This study was supported by National Major Science and Technology Projects of China(No.2017ZX10203207)National Natural Science Foundation of China(No.81472677).
文摘Metastasis and metabolism reprogramming are two major hallmarks of cancer.In the initiation and progression of cancer,tumor cells are known to undergo fundamental metabolic changes to sustain their development and progression.In recent years,much more attentions have been drawn to their important roles in facilitating cancer metastasis through regulating the biological properties.In this review,we summarized the recent progresses in the studies of metabolism reprogramming of cancer metastasis,particularly of primary liver cancer,and highlight their potential applications.
基金supported by the Key Program of the National Natural Science Foundation of China(81930074,2020-2024)the Major Program of National Natural Science Foundation of China(91959203,2020-2023)the Natural Science Foundation of China(81672820,2017-2020,81672378,2017-2020,82173093)。
文摘Cancer metastasis is the major cause of cancer-related deaths and accounts for poor therapeutic outcomes.A metastatic cas-cade is a series of complicated biological processes.N6-methyladenosine(m^(6)A)is the most abundant and conserved epi-transcriptomic modification in eukaryotic cells,which has great impacts on RNA production and metabolism,including RNA splicing,processing,degradation and translation.Accumulating evidence demonstrates that m^(6)A plays a critical role in regulating cancer metastasis.However,there is a lack of studies that review the recent advances of m^(6)A in cancer metastasis.Here,we systematically retrieved the functions and mechanisms of how the m^(6)A axis regulates metastasis,and especially summarized the organ-specific liver,lung and brain metastasis mediated by m^(6)A in various cancers.Moreover,we discussed the potential application of m^(6)A modification in cancer diagnosis and therapy,as well as the present limitations and future perspectives of m^(6)A in cancer metastasis.This review provides a comprehensive knowledge on the m^(6)A-mediated regulation of gene expression,which is helpful to extensively understand the complexity of cancer metastasis from a new epitranscriptomic point of view and shed light on the developing novel strategies to anti-metastasis based on m^(6)A alteration.
基金supported by the National Key R&D Program of China(grant no.2022YFF1203005)the National Natural Science Foundation of China(22237005,81903458,82273425)+1 种基金Innovative research team of high-level local universities in Shanghai(SHSMU-ZDCX20212700,China)China Postdoctoral Science Foundation(2019M660090)。
文摘Pancreatic cancer,one of the most aggressive malignancies,has no effective treatment due to the lack of targets and drugs related to tumour metastasis.SIRT6 can promote the migration of pancreatic cancer and could be a potential target for antimetastasis of pancreatic cancer.However,highly selective and potency SIRT6 inhibitor that can be used in vivo is yet to be discovered.Here,we developed a noveSIRT6 allosteric inhibitor,compound 11e,with maximal inhibitory potency and an IC_(50) value of 0.98±0.13μmol/L.Moreover,compound 11e exhibited significant selectivity against other histone deacetylases(HADC1-11 and SIRT1-3)at concentrations up to 100μmol/L.The allosteric site and the molecular mechanism of inhibition were extensively elucidated by cocrystal complex structure and dynamic structural analyses.Importantly,we confirmed the antimetastatic function of such inhibitors in four pancreatic cancer cell lines as well as in two mouse models of pancreatic cancer liver metastasis.To our knowledge,this is the first study to reveal the in vivo effects of SIRT6 inhibitors on liver metastatic pancreatic cancer.It not only provides a promising lead compound for subsequent inhibitor developmentargeting SIRT6 but also provides a potential approach to address the challenge of metastasis in pancreatic cancer.
基金supported by the Program of Shanghai Academic Research Leader(20XD1400900)the National Key Research and Development Program of China(2017YFC1308604)the National Natural Science Foundation of China(81702857,81672820,81930074,91959203 and 81372647).
文摘Intercellular cross-talk plays important roles in cancer progression and metastasis.Yet how these cancer cells interact with each other is still largely unknown.Exosomes released by tumor cells have been proved to be effective cell-to-cell signal mediators.We explored the functional roles of exosomes in metastasis and the potential prognostic values for hepatocellular carcinoma(HCC).Exosomes were extracted from HCC cells of different metastatic potentials.The metastatic effects of exosomes derived from highly metastatic HCC cells(HMH)were evaluated both in vitro and in vivo.Exosomal proteins were identified with iTRAQ mass spectrum and verified in cell lines,xenograft tumor samples,and functional analyses.Exosomes released by HMH significantly enhanced the in vitro invasion and in vivo metastasis of low metastatic HCC cells(LMH).S100 calcium-binding protein A4(S100A4)was identified as a functional factor in exosomes derived from HMH.S100A4r,ch exosomes significantly promoted tumor metastasis both in vitro and in vivo compared with S100A4^(rich) exosomes or controls.Moreover,exosomal S100A4 could induce expression of osteopontin(OPN),along with other tumor metastasis/stemness-related genes.Exosomal S100A4 activated OPN transcription via STAT3 phosphorylation.HCC patients with high exosomal S100A4 in plasma also had a poorer prognosis.In conclusion,exosomes from HMH could promote the metastatic potential of LMH,and exosomal S100A4 is a key enhancer for HCC metastasis,activating STAT3 phosphorylation and up-regulating OPN expression.This suggested exosomal S100A4 to be a novel prognostic marker and therapeutic target for HCC metastasis.
基金supported by the National Natural Science Foundation of China(81472677)
文摘A salient feature of metastasis is the ability of different tu- mor types to colonize the same or different organ sites. Many genetic and epigenetic events have been identified that con- tributing to the metastatic cascades, including migration, lo- cal invasion, intravasation, survival in the circulation, ex- travasation and colonization, and some key molecules might have dual functions promoting metastasis by providing both local advantage from malignant progression in the primary tu- mor and a distal advantage from infiltration of distant organs. Nevertheless, the metastatic process remains poorly under- stood and the insight into the molecular events that initiate and/or sustain this process remains incomplete.
基金supported by the National Natural Science Foundation of China(82430089,82202974)the China Postdoctoral Science Foundation(2024M750533)the Shanghai Anti-Cancer Association(SACA-CY22C10).
文摘Recent evidence has highlighted immune checkpoint inhibitors as among the most promising immunotherapies for various malignancies.However,a significant proportion of HCC patients exhibit poor responses.Lipid metabolic heterogeneity is considered a key driver of cancer progression.However,the role of lipid metabolic reprogramming in HCC immunotherapy resistance remains poorly understood.Herein,we aimed to illuminate the potential relationship between lipid metabolic reprogramming and ICI resistance and provide novel strategies to increase the HCC immunotherapy response.Patients who received PD-1/PD-L1 inhibitors were enrolled.The effect of TACC3 on the tumor microenvironment was validated via single-cell RNA sequencing in HCC-bearing mouse models.Targeted metabolomics was performed to analyze the regulatory role of TACC3 in HCC metabolism.To address HCC immunotherapy resistance,we developed a targeted nucleic acid therapeutic utilizing N-acetylgalactosamine(GalNAc)to conjugate siTACC3.Through clinical cohort analysis,we found that TACC3 was overexpressed in HCC patients with poor response to immunotherapy.Furthermore,we demonstrated that silencing tumor-derived TACC3 optimizes the cytotoxicity of infiltrating CD8^(+)T lymphocytes.Both in vitro and in vivo assays suggested that TACC3 maintains ACSL4-mediated polyunsaturated fatty acid(PUFA)metabolism in HCC cells.Additionally,TACC3 accelerates ACSL4 expression by interacting with LARP1 and PABPC1,which stabilize ACSL4 mRNA.The results of preclinical models demonstrated the satisfactory efficacy of GalNAc-conjugated siTACC3 combined with PD-1 inhibitor therapy for HCC.In summary,tumor-derived TACC3 impairs the tumor-killing activity of CD8^(+)T lymphocytes through PUFA metabolism-associated crosstalk.Targeting TACC3 represents a novel and practicable strategy to augment ICI efficacy against HCC.
基金This work was supported by the National Natural Science Foundation of China(81902390 and 81902952)the National Key Research and Development Program of China(2017YFC1308604).
文摘Background The efficacy of immune checkpoint inhibitors(ICIs),such as programmed cell death protein-1(PD-1)or its ligand 1(PD-L1)antibody,in hepatocellular carcinoma(HCC)is limited,and it is recommended that they be combined with other therapies.We evaluated the combination of pegylated interferon-α(Peg-IFNα)with PD-1 blockade in HCC mouse models.Methods We analyzed the effects of Peg-IFNαon tumor-infiltrating immune cells and PD-1 expression in the HCC immune microenvironment and examined the underlying mechanism of its unique effect on the PD-1 pathway.The in vivo efficacy of anti-PD-1 and Peg-IFNαwas evaluated in both subcutaneous and orthotopic mouse models of HCC.Results The combination of Peg-IFNαwith PD-1 blockade dramatically enhanced T-cell infiltration,improved the efficacy of PD-1 antibody and prolonged mouse survival compared with PD-1 antibody monotherapy.Mechanistically,Peg-IFNαcould recruit cytotoxic CD8+T cells to infiltrate the HCC microenvironment by inducing tumor cells to secrete the chemokine CCL4.Nevertheless,the HCC microenvironment quickly overcame the immune responses by upregulating PD-1 expression in CD8+T cells via the IFNα-IFNAR1-JAK1-STAT3 signaling pathway.The combination of PD-1 blockade with Peg-IFNαcould restore the cytotoxic capacity of CD8+T cells and exerted a significant synergistic effect on HCC.Conclusion These results indicate that in addition to initiating the antitumor immune response itself,Peg-IFNαcan also generate a microenvironment favoring PD-1 blockade.Thus,the combination of Peg-IFNαand PD-1 blockade can be a promising strategy for HCC.
基金This work was supported by grants from the National Key Project for Infectious Diseases of China(2017ZX10203207)the National Natural Science Foundation of China(81672848,81972703,82072696).
文摘The immunosuppressive microenvironment plays an important role in tumor progression and immunotherapy responses.Golgi membrane protein 1(GOLM1)is correlated to hepatocellular carcinoma(HCC)progression and metastasis.However,little is known about the role of GOLM1 in regulating the immunosuppressive environment and its impact on immunotherapeutic efficacy in HCC.In this study,GOLM1 was positively correlated with infiltrating tumor-associated macrophages(TAMs)expressed high levels of programmed death-ligand 1(PD-L1)and CD8^(+)T cell suppression in HCC tissues.Both gain-and loss-of-function studies determined a close correlation between GOLM1 and immunosuppression.In the mechanism,GOLM1 promoted COP9 signalosome 5-mediated PD-L1 deubiquitination in HCC cells and increased the transport of PD-L1 into exosomes via suppression of Rab27b expression.Furthermore,co-culture with exosomes derived from HCC cells upregulated the expression of PD-L1 on macrophages.Zoledronic acid in combination with anti-PD-L1 therapy reduced PD-L1^(+)TAMs infiltration and alleviated CD8^(+)T cell suppression,resulting in tumor growth inhibition in the mouse HCC model.Together,our study unveils a mechanism by which GOLM1 induces CD8^(+)T cells suppression through promoting PD-L1 stabilization and transporting PD-L1 into TAMs with exosome dependent.Targeting PD-L1^(+)TAM could be a novel strategy to enhance the efficacy of anti-PD-L1 therapy in HCC.
基金This work was supported by the following:the National Key Research and Development Program of China(No.2017YFC1308604)National Natural Science Foundation of China(Nos.81802903,81672820,81940074,and 81872356)+1 种基金the Program of Shanghai Academic Research Leader(No.20XD1400900)the Shanghai International Science and Technology Collaboration Program.
文摘Pancreatic cancer is an increasingly common cause of cancer mortality with a tight correspondence between disease mortality and incidence.Furthermore,it is usually diagnosed at an advanced stage with a very dismal prognosis.Due to the high heterogeneity,metabolic reprogramming,and dense stromal environment associated with pancreatic cancer,patients benefit little from current conventional therapy.Recent insight into the biology and genetics of pancreatic cancer has supported its molecular classification,thus expanding clinical therapeutic options.In this review,we summarize how the biological features of pancreatic cancer and its metabolic reprogramming as well as the tumor microenvironment regulate its development and progression.We further discuss potential biomarkers for pancreatic cancer diagnosis,prediction,and surveillance based on novel liquid biopsies.We also outline recent advances in defining pancreatic cancer subtypes and subtype-specific therapeutic responses and current preclinical therapeutic models.Finally,we discuss prospects and challenges in the clinical development of pancreatic cancer therapeutics.
基金supported by the National Natural Science Foundation of China(82103282)Higher Education Disciplinary Innovation Program(D20036)+2 种基金Henan Province Medical Science and Technology Research Plan(SBGJ202103061,LHGJ20190135)“Science and Technology to create Central Plains”Young Talent Lifting Project(2023HYTP041)Henan Charity General Federation of Hepatobiliary Care Fund(GDXZ2023002).
文摘Betaine-homocysteine methyltransferase(BHMT)regulates protein methylation and is correlated with tumorigenesis;however,the effects and regulation of BHMT in hepatocarcinogenesis remain largely unexplored.Here,we determined the clinical significance of BHMT in the occurrence and progression of hepatocellular carcinoma(HCC)using tissue samples from 198 patients.BHMT was to be frequently found(86.6%)expressed at relatively low levels in HCC tissues and was positively correlated with the overall survival of patients with HCC.Bhmt overexpression effectively suppressed several malignant phenotypes in hepatoma cells in vitro and in vivo,whereas complete knockout of Bhmt(Bhmt^(−/−))produced the opposite effect.We combined proteomics,metabolomics,and molecular biological strategies and detected that Bhmt^(−/−)promoted hepatocarcinogenesis and tumor progression by enhancing the activity of glucose-6-phosphate dehydrogenase(G6PD)and PPP metabolism in DEN-induced HCC mouse and subcutaneous tumor-bearing models.In contrast,restoration of Bhmt with an AAV8-Bhmt injection or pharmacological inhibition of G6PD attenuated hepatocarcinogenesis.Additionally,coimmunoprecipitation identified monomethylated modifications of the G6PD,and BHMT regulated the methylation of G6PD.Protein sequence analysis,generation and application of specific antibodies,and site-directed mutagenesis indicated G6PD methylation at the arginine residue 246.Furthermore,we established bidirectionally regulated BHMT cellular models combined with methylation-deficient G6PD mutants to demonstrate that BHMT potentiated arginine methylation of G6PD,thereby inhibiting G6PD activity,which in turn suppressed hepatocarcinogenesis.Taken together,this study reveals a new methylation-regulatory mechanism in hepatocarcinogenesis owing to BHMT deficiency,suggesting a potential therapeutic strategy for HCC treatment.
基金the National Key R&D Program of China(2018YFC1005004)Major Special Projects of Basic Research of Shanghai Science and Technology Commission(18JC1411101)+1 种基金National Natural Science Foundation of China(31872814,32000505)Shanghai Science and Technology Innovation Action Plan,Medical Innovation Research Special Project(20Z11900900).
文摘Currently,there is no effective drugs for treating clinically COVID-19 except dexamethasone.We previously revealed that human identical sequences of SARS-CoV-2 promote the COVID-19 progression by upregulating hyaluronic acid(HA).As the inhibitor of HA synthesis,hymecromone is an approved prescription drug used for treating biliary spasm.Here,we aimed to investigate the relation between HA and COVID-19,and evaluate the therapeutic effects of hymecromone on COVID-19.Firstly,HA was closely relevant to clinical parameters,including lymphocytes(n=158;r=−0.50;P<0.0001),C-reactive protein(n=156;r=0.55;P<0.0001),D-dimer(n=154;r=0.38;P<0.0001),and fibrinogen(n=152;r=0.37;P<0.0001),as well as the mass(n=78;r=0.43;P<0.0001)and volume(n=78;r=0.41;P=0.0002)of ground-glass opacity,the mass(n=78;r=0.48;P<0.0001)and volume(n=78;r=0.47;P<0.0001)of consolidation in patient with low level of hyaluronan(HA<48.43 ng/mL).Furthermore,hyaluronan could directly cause mouse pulmonary lesions.Besides,hymecromone remarkably reduced HA via downregulating HAS2/HAS3 expression.Moreover,89%patients with hymecromone treatment had pulmonary lesion absorption while only 42%patients in control group had pulmonary lesion absorption(P<0.0001).In addition,lymphocytes recovered more quickly in hymecromone-treated patients(n=8)than control group(n=5)(P<0.05).These findings suggest that hymecromone is a promising drug for COVID-19 and deserves our further efforts to determine its effect in a larger cohort.
文摘The global coronavirus disease 2019(COVID-19)pandemic has caused more than 6.1 million deaths until March 24,2022,as reported by the World Health Organization(WHO).Recently,breakthrough infections have appeared in individuals fully vaccinated against SARS-Co V-2^(1),which could be attributed to the rapid mutation of the RNA virus2.Currently,following the Delta variant,the Omicron variant of SARS-Co V-2 is increasingly becoming the dominant epidemic strain in the world.
基金supported by grants from the National Key Project for Infectious Disease of China(No.2017ZX 10203207)and the National Natural Science Foundation of China(Nos.81972737.81930074,91959203,and 81872356).
文摘Cabozantinib,mainly targeting cMet and vascular endothelial growth factor receptor 2,is the second-line treatment for patients with advanced hepatocellular carcinoma(HCC).However,the lower response rate and resistance limit its enduring clinical benefit.In this study,we found that cMet-low HCC cells showed primary resistance to cMet inhibitors,and the combination of cabozantinib and mammalian target of rapamycin(mTOR)inhibitor,rapamycin,exhibited a synergistic inhibitory effect on the in vitro cell proliferation and in vivo tumor growth of these cells.Mechanically,the combination of rapamycin with cabozantinib resulted in the remarkable inhibition of AKT,extracellular signal-regulated protein kinases,mTOR,and common downstream signal molecules of receptor tyrosine kinases;decreased cyclin D1 expression;and induced cell cycle arrest.Meanwhile,rapamycin enhanced the inhibitory effects of cabozantinib on the migration and tubule formation of human umbilical vascular endothelial cells and human growth factor-induced invasion of cMet inhibitor-resistant HCC cells under hypoxia condition.These effects were further validated in xenograft models.In conclusion,our findings uncover a potential combination therapy of cabozantinib and rapamycin to combat cabozantinib-resistant HCC.
