Recently,genetically targeted cancer therapies have been a topic of great interest.Synthetic lethality provides a new approach for the treatment of mutated genes that were previously considered unable to be targeted i...Recently,genetically targeted cancer therapies have been a topic of great interest.Synthetic lethality provides a new approach for the treatment of mutated genes that were previously considered unable to be targeted in traditional genotype-targeted treatments.The increasing researches and applications in the clinical setting made synthetic lethality a promising anticancer treatment option.However,the current understandings on different conditions of synthetic lethality have not been systematically assessed and the application of synthetic lethality in clinical practice still faces many challenges.Here,we propose a novel and systematic classification of synthetic lethality divided into gene level,pathway level,organelle level,and conditional synthetic lethality,according to the degree of specificity into its biological mechanism.Multiple preclinical findings of synthetic lethality in recent years will be reviewed and classified under these different categories.Moreover,synthetic lethality targeted drugs in clinical practice will be briefly discussed.Finally,we will explore the essential implications of this classification as well as its prospects in eliminating existing challenges and the future directions of synthetic lethality.展开更多
Minimally invasive surgery is a trend in hepatobiliary surgery.A 56-year-old female patient was admitted to our institution for intrahepatic lithiasis.The CT scan showed multiple calculi in the left liver,dilation of ...Minimally invasive surgery is a trend in hepatobiliary surgery.A 56-year-old female patient was admitted to our institution for intrahepatic lithiasis.The CT scan showed multiple calculi in the left liver,dilation of the left intrahepatic bile duct and liver atrophy of the left lobe.Robotic single-incision left hemihepatectomy by the single-site systemwas successfully applied.With the idea of enhanced recovery after surgery,the patient was discharged on the third day after the operation without any morbidity.Robotic single-incision surgery is more frequent in gynecologic and urological surgery.As far as we know,this is the first robotic single-incision left hemihepatectomy report in the world.展开更多
The treatment of hepatocellular carcinoma(HCC)has been dominated by multikinase inhibitors for more than a decade.However,drug resistance can severely restrict the efficacy of these drugs.Using CRISPR/CAS9 genome libr...The treatment of hepatocellular carcinoma(HCC)has been dominated by multikinase inhibitors for more than a decade.However,drug resistance can severely restrict the efficacy of these drugs.Using CRISPR/CAS9 genome library screening,we evaluated Kelch-like ECH-associated protein 1(KEAP1)as a key regulator of sorafenib’s susceptibility in HCC.We also investigated whether KEAP1’s knockdown can stabilize nuclear factor(erythroid-derived 2)-like 2(NRF2)protein levels that led to sorafenib’s resistance,including an NRF2 inhibitor that can synergize with sorafenib to abolish HCC’s growth in vitro and in vivo.Furthermore,we clarified that fibroblast growth factor 21(FGF21)is an important downstream regulator of NRF2 in HCC.Intriguingly,we observed that FGF21 bound to NRF2 through the C-terminus of FGF21,thereby stabilizing NRF2 by reducing its ubiquitination and generating a positive feedback loop in sorafenib-resistant HCC.These findings,therefore,propose that targeting FGF21 is a promising strategy to combat HCC sorafenib’s resistance.展开更多
The treatment for hepatocellular carcinoma(HCC)is promising in recent years,but still facing critical challenges.The first targeted therapy,sorafenib,prolonged the overall survival by months.However,resistance often o...The treatment for hepatocellular carcinoma(HCC)is promising in recent years,but still facing critical challenges.The first targeted therapy,sorafenib,prolonged the overall survival by months.However,resistance often occurs,largely limits its efficacy.Sorafenib was found to target the electron transport chain complexes,which results in the generation of reactive oxygen species(ROS).To maintain sorafenib resistance and further facilitate tumor progression,cancer cells develop strategies to overcome excessive ROS production and obtain resistance to oxidative stress-induced cell death.In the present study,we investigated the roles of ROS in sorafenib resistance,and found suppressed ROS levels and reductive redox states in sorafenib-resistant HCC cells.Mitochondria in sorafenib-resistant cells maintained greater functional and morphological integrity under the treatment of sorafenib.However,cellular oxygen consumption rate and mitochondria DNA content analyses revealed fewer numbers of mitochondria in sorafenib-resistant cells.Further investigation attributed this finding to decreased mitochondrial biogenesis,likely caused by the accelerated degradation of peroxisome proliferator-activated receptor y coactivator ip(PGC1P).Mechanistic dissection showed that upregulated UBQLN1 induced PGCip degradation in a ubiquitination-independent manner to attenuate mitochondrial biogenesis and ROS production in sorafenib-resistant cells under sorafenib treatment.Furthermore,clinical investigations further indicated that the patients with higher UBQLN1 levels experienced worse recurrence-free survival.In conclusion,we propose a novel mechanism involving mitochondrial biogenesis and ROS homeostasis in sorafenib resistance,which may offer new therapeutic targets and strategies for HCC patients.展开更多
基金supported by the Opening Fund of Engineering Research Center of Cognitive Healthcare of Zhejiang Province(No.2018KFJJ09)Scientific Research Fund of Zhejiang Provincial Education Department(Y201941406)+2 种基金National Natural Science Foundation of China(Nos.81827804 and 81800540)Zhejiang Clinical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases(No.2018E50003)Science and Technology Innovative Activity Plan and New Seedling Talent Plan for College Students in Zhejiang Province(No.2020R401217)。
文摘Recently,genetically targeted cancer therapies have been a topic of great interest.Synthetic lethality provides a new approach for the treatment of mutated genes that were previously considered unable to be targeted in traditional genotype-targeted treatments.The increasing researches and applications in the clinical setting made synthetic lethality a promising anticancer treatment option.However,the current understandings on different conditions of synthetic lethality have not been systematically assessed and the application of synthetic lethality in clinical practice still faces many challenges.Here,we propose a novel and systematic classification of synthetic lethality divided into gene level,pathway level,organelle level,and conditional synthetic lethality,according to the degree of specificity into its biological mechanism.Multiple preclinical findings of synthetic lethality in recent years will be reviewed and classified under these different categories.Moreover,synthetic lethality targeted drugs in clinical practice will be briefly discussed.Finally,we will explore the essential implications of this classification as well as its prospects in eliminating existing challenges and the future directions of synthetic lethality.
基金supported by grants from the National Natural Science Foundation of China(No.82072625)Key Research and Development Project of Zhejiang Province(No.2021C03127)+3 种基金National Natural Science Foundation of China(No.81827804)National Natural Science Foundation of China(No.81772546)Zhejiang Clinical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases(No.2018E50003)Key Research and Development Project of Zhejiang Province(No.2018C03083).
文摘Minimally invasive surgery is a trend in hepatobiliary surgery.A 56-year-old female patient was admitted to our institution for intrahepatic lithiasis.The CT scan showed multiple calculi in the left liver,dilation of the left intrahepatic bile duct and liver atrophy of the left lobe.Robotic single-incision left hemihepatectomy by the single-site systemwas successfully applied.With the idea of enhanced recovery after surgery,the patient was discharged on the third day after the operation without any morbidity.Robotic single-incision surgery is more frequent in gynecologic and urological surgery.As far as we know,this is the first robotic single-incision left hemihepatectomy report in the world.
基金supported by the National Natural Science Foundation of China(81702981,81827804,81902367,81772546and LQ18H160010)Zhejiang Provincial Natural Science Foundation of China(LY20H160021 and Y15H160052)+1 种基金China Postdoctoral Science Foundation(2020T130584 and 2020M671755)Health Innovation Talent Support Project of Zhejiang Medical and Health Science and Technology Plan(2021447581)。
文摘The treatment of hepatocellular carcinoma(HCC)has been dominated by multikinase inhibitors for more than a decade.However,drug resistance can severely restrict the efficacy of these drugs.Using CRISPR/CAS9 genome library screening,we evaluated Kelch-like ECH-associated protein 1(KEAP1)as a key regulator of sorafenib’s susceptibility in HCC.We also investigated whether KEAP1’s knockdown can stabilize nuclear factor(erythroid-derived 2)-like 2(NRF2)protein levels that led to sorafenib’s resistance,including an NRF2 inhibitor that can synergize with sorafenib to abolish HCC’s growth in vitro and in vivo.Furthermore,we clarified that fibroblast growth factor 21(FGF21)is an important downstream regulator of NRF2 in HCC.Intriguingly,we observed that FGF21 bound to NRF2 through the C-terminus of FGF21,thereby stabilizing NRF2 by reducing its ubiquitination and generating a positive feedback loop in sorafenib-resistant HCC.These findings,therefore,propose that targeting FGF21 is a promising strategy to combat HCC sorafenib’s resistance.
基金supported by the National Natural Science Foundation of China under No.81827804(to C.X.),Grant No.81772546(to C.X.),No.81902367(to XJ.),and No.82072625(to L.X.)China Postdoctoral Science Foundation under Grant No.2020M671755(to X.J.)+3 种基金Natural Science Foundation of Zhejiang Province under Grant No.LY15H160014(to C.L.)Zhejiang Clinical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases under Grant No.2018E50003(to C.X.)Key Research and Development Project of Zhejiang Province under Grant No.2018C03083(to C.X.),and 2020C03122(to W.Y.)Health innovation Talent Support Project of Zhejiang Medical and Health Science and Technology Plan under Grant No.2021447581(to XJ.).
文摘The treatment for hepatocellular carcinoma(HCC)is promising in recent years,but still facing critical challenges.The first targeted therapy,sorafenib,prolonged the overall survival by months.However,resistance often occurs,largely limits its efficacy.Sorafenib was found to target the electron transport chain complexes,which results in the generation of reactive oxygen species(ROS).To maintain sorafenib resistance and further facilitate tumor progression,cancer cells develop strategies to overcome excessive ROS production and obtain resistance to oxidative stress-induced cell death.In the present study,we investigated the roles of ROS in sorafenib resistance,and found suppressed ROS levels and reductive redox states in sorafenib-resistant HCC cells.Mitochondria in sorafenib-resistant cells maintained greater functional and morphological integrity under the treatment of sorafenib.However,cellular oxygen consumption rate and mitochondria DNA content analyses revealed fewer numbers of mitochondria in sorafenib-resistant cells.Further investigation attributed this finding to decreased mitochondrial biogenesis,likely caused by the accelerated degradation of peroxisome proliferator-activated receptor y coactivator ip(PGC1P).Mechanistic dissection showed that upregulated UBQLN1 induced PGCip degradation in a ubiquitination-independent manner to attenuate mitochondrial biogenesis and ROS production in sorafenib-resistant cells under sorafenib treatment.Furthermore,clinical investigations further indicated that the patients with higher UBQLN1 levels experienced worse recurrence-free survival.In conclusion,we propose a novel mechanism involving mitochondrial biogenesis and ROS homeostasis in sorafenib resistance,which may offer new therapeutic targets and strategies for HCC patients.