Editorial Our new column Profiles is a new series that aims to introduce China CDC’s chief experts,major decisionmakers,and key contributors that ensure the high standard of operation of China CDC.These articles are ...Editorial Our new column Profiles is a new series that aims to introduce China CDC’s chief experts,major decisionmakers,and key contributors that ensure the high standard of operation of China CDC.These articles are meant to present high-achieving individuals of China CDC and will describe the background,achievements,and paths to success of the eponymous individuals.展开更多
Crohn’s disease(CD)is caused by immune,environmental,and genetic factors.It can involve the entire gastrointestinal tract,and although its prevalence is rapidly increasing its etiology remains unclear.Emerging biolog...Crohn’s disease(CD)is caused by immune,environmental,and genetic factors.It can involve the entire gastrointestinal tract,and although its prevalence is rapidly increasing its etiology remains unclear.Emerging biological and small-molecule drugs have advanced the treatment of CD;however,a considerable proportion of patients are non-responsive to all known drugs.To achieve a breakthrough in this field,innovations that could guide the further development of effective therapies are of utmost urgency.In this review,we first propose the innovative concept of pan-lymphatic dysfunction for the general distribution of lymphatic dysfunction in various diseases,and suggest that CD is the intestinal manifestation of pan-lymphatic dysfunction based on basic and clinical preliminary data.The supporting evidence is fully summarized,including the existence of lymphatic system dysfunction,recognition of the inside-out model,disorders of immune cells,changes in cell plasticity,partial overlap of the underlying mechanisms,and common gut-derived fatty and bile acid metabolism.Another benefit of this novel concept is that it proposes adopting the zebrafish model for studying intestinal diseases,especially CD,as this model is good at presenting and mimicking lymphatic dysfunction.More importantly,the ensuing focus on improving lymphatic function may lead to novel and promising therapeutic strategies for CD.展开更多
Near-infrared(NIR)transparent inverted all-inorganic perovskite solar cells(PSCs)are excellent top cell candidates in tandem applications.An essential challenge is the replacement of metal contacts with transparent co...Near-infrared(NIR)transparent inverted all-inorganic perovskite solar cells(PSCs)are excellent top cell candidates in tandem applications.An essential challenge is the replacement of metal contacts with transparent conductive oxide(TCO)electrodes,which requires the introduction of a buffer layer to prevent sputtering damage.In this study,we show that the conventional buffers(i.e.,small organic molecules and atomic layer deposited metal oxides)used for organic-inorganic hybrid perovskites are not applicable to all-inorganic perovskites,due to non-uniform coverage of the vulnerable layers underneath,deterioration upon ion bombardment and moisture induced perovskite phase transition,A thin film of metal oxide nanoparticles by the spin-coating method serves as a non-destructive buffer layer for inorganic PSCs.All-inorganic inverted near-infrared-transparent PSCs deliver a PCE of 17.46%and an average transmittance of 73.7%between 780 and 1200 nm.In combination with an 18.56%Cu(In,Ga)Se_(2) bottom cell,we further demonstrate the first all-inorganic perovskite/CIGS 4-T tandem solar cell with a PCE of 24.75%,which exhibits excellent illumination stability by maintaining 86.7%of its initial efficiency after 1400 h.The non-destructive buffer lays the foundation for efficient and stable NIR-transparent inverted inorganic perovskite solar cells and perovskite-based tandems.展开更多
Background Cell metabolism plays a pivotal role in tumor progression,and targeting cancer metabolism might effectively kill cancer cells.We aimed to investigate the role of hexokinases in prostate cancer(PCa)and ident...Background Cell metabolism plays a pivotal role in tumor progression,and targeting cancer metabolism might effectively kill cancer cells.We aimed to investigate the role of hexokinases in prostate cancer(PCa)and identify a crucial target for PCa treatment.Methods The Cancer Genome Atlas(TCGA)database,online tools and clinical samples were used to assess the expression and prognostic role of ADP-dependent glucokinase(ADPGK)in PCa.The effect of ADPGK expression on PCa cell malignant phenotypes was validated in vitro and in vivo.Quantitative proteomics,metabolomics,and extracellular acidification rate(ECAR)and oxygen consumption rate(OCR)tests were performed to evaluate the impact of ADPGK on PCa metabolism.The underlying mechanisms were explored through ADPGK overexpression and knockdown,co-immunoprecipitation(Co-IP),ECAR analysis and cell counting kit-8(CCK-8)assays.Results ADPGK was the only glucokinase that was both upregulated and predicted worse overall survival(OS)in prostate adenocarcinoma(PRAD).Clinical sample analysis demonstrated that ADPGK was markedly upregulated in PCa tissues vs.non-PCa tissues.High ADPGK expression indicates worse survival outcomes,and ADPGK serves as an independent factor of biochemical recurrence.In vitro and in vivo experiments showed that ADPGK overexpression promoted PCa cell proliferation and migration,and ADPGK inhibition suppressed malignant phenotypes.Metabolomics,proteomics,and ECAR and OCR tests revealed that ADPGK significantly accelerated glycolysis in PCa.Mechanistically,ADPGK binds aldolase C(ALDOC)to promote glycolysis via AMP-activated protein kinase(AMPK)phosphorylation.ALDOC was positively correlated with ADPGK,and high ALDOC expression was associated with worse survival outcomes in PCa.Conclusions In summary,ADPGK is a driving factor in PCa progression,and its high expression contributes to a poor prognosis in PCa patients.ADPGK accelerates PCa glycolysis and progression by activating ALDOC-AMPK signaling,suggesting that ADPGK might be an effective target and marker for PCa treatment and prognosis evaluation.展开更多
Objective:Triple-negative breast cancer(TNBC)is a heterogeneous and aggressive cancer.Although our previous study classified primary TNBC into four subtypes,comprehensive longitudinal investigations are lacking.Method...Objective:Triple-negative breast cancer(TNBC)is a heterogeneous and aggressive cancer.Although our previous study classified primary TNBC into four subtypes,comprehensive longitudinal investigations are lacking.Methods:We assembled a large-scale,real-world cohort comprised of 880 TNBC patients[465 early-stage TNBC(eTNBC)and 415 metastatic TNBC(mTNBC)patients]who were treated at Fudan University Shanghai Cancer Center.The longitudinal dynamics of TNBC subtypes during disease progression were elucidated in this patient cohort.Comprehensive analysis was performed to compare primary and metastatic lesions within specific TNBC subtypes.Results:The recurrence and metastasis rates within 3 years after initial diagnosis in the eTNBC cohort were 10.1%(47/465).The median overall survival(OS)in the mTNBC cohort was 27.2 months[95%confidence interval(CI),24.4–30.2 months],which indicated a poor prognosis.The prognostic significance of the original molecular subtypes in both eTNBC and mTNBC patients was confirmed.Consistent molecular subtypes were maintained in 77.5%of the patients throughout disease progression with the mesenchymal-like(MES)subtype demonstrating a tendency for subtype transition and brain metastasis.Additionally,a precision treatment strategy based on the metastatic MES subtype of target lesions resulted in improved progression-free survival in the FUTURE trial.Conclusions:Our longitudinal study comprehensively revealed the clinical characteristics and survival of patients with the original TNBC subtypes and validated the consistency of most molecular subtypes throughout disease progression.However,we emphasize the major importance of repeat pathologic confirmation of the MES subtype.展开更多
Objective:Mammographic calcifications are a common feature of breast cancer,but their molecular characteristics and treatment implications in hormone receptor-positive(HR+)/human epidermal growth factor receptor 2-neg...Objective:Mammographic calcifications are a common feature of breast cancer,but their molecular characteristics and treatment implications in hormone receptor-positive(HR+)/human epidermal growth factor receptor 2-negative(HER2−)breast cancer remain unclear.Methods:We retrospectively collected mammography records of an HR+/HER2−breast cancer cohort(n=316)with matched clinicopathological,genomic,transcriptomic,and metabolomic data.On the basis of mammographic images,we grouped tumors by calcification status into calcification-negative tumors,tumors with probably benign calcifications,tumors with calcification of lowmoderate suspicion for maligancy and tumors with calcification of high suspicion for maligancy.We then explored the molecular characteristics associated with each calcification status across multiple dimensions.Results:Among the different statuses,tumors with probably benign calcifications exhibited elevated hormone receptor immunohistochemical staining scores,estrogen receptor(ER)pathway activation,lipid metabolism,and sensitivity to endocrine therapy.Tumors with calcifications of high suspicion for malignancy had relatively larger tumor sizes,elevated lymph node metastasis incidence,Ki-67 staining scores,genomic instability,cell cycle pathway activation,and may benefit from cyclin-dependent kinase 4 and 6(CDK4/6)inhibitors.Conclusions:Our research established links between tumor calcifications and molecular features,thus proposing potential precision treatment strategies for HR+/HER2−breast cancer.展开更多
AIM To investigate the role of the miR-133a-UCP2 pathway in the pathogenesis of inflammatory bowel disease (IBD) and to explore the potential downstream mechanisms with respect to inflammation, oxidative stress and en...AIM To investigate the role of the miR-133a-UCP2 pathway in the pathogenesis of inflammatory bowel disease (IBD) and to explore the potential downstream mechanisms with respect to inflammation, oxidative stress and energy metabolism. METHODS C57BL/6 mice were fed dextran sulfate sodium (DSS) liquid for 7 consecutive days, followed by the administration of saline to the DSS group, UCP2 siRNA to the UCP2 group and a miR-133a mimic to the miR-133a group on days 8 and 11. Body weight, stool consistency and rectal bleeding were recorded daily, and these composed the disease activity index (DAI) score for the assessment of disease severity. After cervical dislocation was performed on day 14, the length of the colon in each mouse was measured, and colonic tissue was collected for further study, which included the following: haematoxylin and eosin staining, UCP2 and miR-133a detection by immunohistochemical staining, western blot and quantitative real-time PCR, measurement of apoptosis by TUNEL assay, and the assessment of inflammation (TNF-alpha, IL-1 beta, IL-6 and MCP1), oxidative stress (H2O2 and MDA) and metabolic parameters (ATP) by ELISA and colorimetric methods. RESULTS An animal model of IBD was successfully established, as shown by an increased DAI score, shortened colon length and specific pathologic changes, along with significantly increased UCP2 and decreased miR-133a levels. Compared with the DSS group, the severity of IBD was alleviated in the UCP2 and the miR-133a groups after successful UCP2 knockdown and miR-133a overexpression. The extent of apoptosis, as well as the levels of TNF-alpha, IL-1 beta, MDA and ATP, were significantly increased in both the UCP2 and miR-133a groups compared with the DSS group. CONCLUSION The miR-133a-UCP2 pathway participates in IBD by altering downstream inflammation, oxidative stress and markers of energy metabolism, which provides novel clues and potential therapeutic targets for IBD.展开更多
The Shanxi Formation(Shan 1 and Shan 2 Members)shales show good prospects in shale gas development in the Yan'an area of Ordos Basin.Based on the simulation experiment of hydrocarbon generation of low maturity sha...The Shanxi Formation(Shan 1 and Shan 2 Members)shales show good prospects in shale gas development in the Yan'an area of Ordos Basin.Based on the simulation experiment of hydrocarbon generation of low maturity shale samples,the hydrocarbon generation characteristics of shale samples was studied systematically.Then,combined with the geochemical analysis of shale and gas generation simulation,shale gas potential was evaluated.The results reveal that Shan 1 and Shan 2 shale samples are favorable for shale gas enrichment by and large,with C_(1)-C_(5) maximum yields of 146.96-160.83 mg/g TOC and 148.48-148.67 mg/g TOC respectively at a heat rate of 20℃/h and 2℃/h.The Shan 1 and Shan 2 shales are basically the same in terms of organic carbon production potential of each unit.The carbon isotopic composition of alkane gas reveals that heteroatomic compounds(NSOs)cracking is an important mechanism for shale gas generation of Shanxi Formation shales,and conducive to gas generation at highto over-mature stages.Given thermal history and kinetic parameters of hydrocarbon generation,the shales of Shanxi Formation reached the maximum gas production potential in the Late Cretaceous,with a maximum yield of 160.3 mg/g TOC under present geological conditions.During geological history,the Shanxi Formation shales went through high-to over-maturity evolution,mainly producing dry gas,and their gas generation capacity was controlled by the organic matter abundance and cracking capacity.The gas generation potential of Shan 2 shale is higher than that of Shan 1,due to its higher TOC.展开更多
Fos-related antigen 1(Fra-1)is a nuclear transcription factor that regulates cell growth,differentiation,and apoptosis.It is involved in the proliferation,invasion,apoptosis and epithelial mesenchymal transformation o...Fos-related antigen 1(Fra-1)is a nuclear transcription factor that regulates cell growth,differentiation,and apoptosis.It is involved in the proliferation,invasion,apoptosis and epithelial mesenchymal transformation of malignant tumor cells.Fra-1 is highly expressed in gastric cancer(GC),affects the cycle distribution and apoptosis of GC cells,and participates in GC occurrence and development.However,the detailed mechanism of Fra-1 in GC is unclear,such as the identification of Fra-1-interacting proteins and their role in GC pathogenesis.In this study,we identified tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein eta(YWHAH)as a Fra-1-interacting protein in GC cells using co-immunoprecipitation combined with liquid chromatography-tandem mass spectrometry.Experiments showed that YWHAH positively regulated Fra-1 mRNA and protein expression,and affected GC cell proliferation.Whole proteome analysis showed that Fra-1 affected the activity of the high mobility group AT-hook 1(HMGA1)/phosphatidylinositol-4,5-bisphosphate 3-kinase(PI3K)/protein kinase B(AKT)/mechanistic target of rapamycin(mTOR)signaling pathway in GC cells.Western blotting and flow cytometry confirmed that YWHAH activated HMGA1/PI3K/AKT/mTOR signaling pathway by positively regulating Fra-1 to affect GC cell proliferation.These results will help to discover new molecular targets for the early diagnosis,treatment,and prognosis prediction of GC.展开更多
BACKGROUND Obesity plays a vital role in the occurrence and development of non-alcoholic steatohepatitis(NASH).However,the underlining mechanism is still unclear,where adipose tissue(AT)derived exosomes may actively p...BACKGROUND Obesity plays a vital role in the occurrence and development of non-alcoholic steatohepatitis(NASH).However,the underlining mechanism is still unclear,where adipose tissue(AT)derived exosomes may actively participate.MicroRNAs(miRNAs)are commonly secreted from exosomes for cell communication.Though the regulation of miR-103 on insulin sensitivity has been reported,the specific role of AT-derived exosomes miR-103 in NASH is still vague and further investigation may provide novel therapeutic choices.AIM To determine the specific role of AT-derived exosomes miR-103 in developing NASH through various methods.METHODS The expression levels of miR-103 in the AT-derived exosomes and livers were detected and compared between NASH mice and control.The effect of miR-103 on NASH progression was also explored by antagonizing miR-103,including steatosis and inflammation degree changes.The interaction between miR-103 and the autophagy-related gene phosphatase and tensin homolog(PTEN)was confirmed by dual-luciferase reporter assay.The role of the interaction between miR-103 and PTEN on autophagy was verified in NASH-like cells.Finally,the effects of miR-103 from adipose-derived exosomes on NASH and autophagy were analyzed through animal experiments.RESULTS The expression of miR-103 was increased in NASH mice,compared to the control,and inhibition of miR-103 could alleviate NASH.The results of the dual-luciferase reporter assay showed miR-103 could interact with PTEN.MiR-103-anta decreased p-AMPKa,p-mammalian target of rapamycin(mTOR),and p62 but increased the protein levels of PTEN and LC3-II/I and the number of autophagosomes in NASH mice.Similar results were also observed in NASH-like cells,and further experiments showed PTEN silencing inhibited the effect of miR-103-anta.AT derivedexosome miR-103 aggravated NASH and increased the expressions of p-AMPKa,p-mTOR,and p62 but decreased the protein levels of PTEN and LC3-II/I and the number of autophagosomes in mice.CONCLUSION AT derived-exosome increased the levels of miR-103 in the liver,and miR-103 aggravated NASH.Mechanically,miR-103 could interact with PTEN and inhibit autophagy.展开更多
目的探讨绿茶多酚(GTP)对2,4,6-三硝基苯磺酸(TNBS)诱导的结肠炎小鼠的治疗作用及可能机制。方法建立TNBS结肠炎模型,将造模成功的小鼠随机分为模型组和GTP处理组,每组10只。GTP处理组小鼠每日给予0.2 mL GTP灌胃(100 mg/kg),模型组每...目的探讨绿茶多酚(GTP)对2,4,6-三硝基苯磺酸(TNBS)诱导的结肠炎小鼠的治疗作用及可能机制。方法建立TNBS结肠炎模型,将造模成功的小鼠随机分为模型组和GTP处理组,每组10只。GTP处理组小鼠每日给予0.2 mL GTP灌胃(100 mg/kg),模型组每日给予0.2 mL生理盐水灌胃。处理4周后处死小鼠,采用HE染色评估疾病活动度,采用ELISA检测小鼠结肠黏膜组织匀浆白细胞介素10(IL-10)、IL-6、肿瘤坏死因子α(TNF-α),免疫荧光染色检测肠黏膜屏障紧密连接蛋白1(ZO-1)及密封蛋白1(claudin-1)的表达,Western blot法检测肠黏膜ZO-1、claudin-1、磷酸化的Janus激酶2(p-JAK2)、磷酸化的信号转导子与转录激活子3(p-STAT3)的蛋白水平。结果在GTP处理的第3周及第4周,小鼠疾病活动指数均显著低于模型组小鼠。GTP处理组小鼠的结肠炎症评分及肠黏膜IL-6、TNF-α水平显著低于TNBS组,而IL-10显著高于TNBS组。与TNBS组小鼠相比,GTP处理显著提高小鼠claudin-1、ZO-1的表达水平,且小鼠肠黏膜p-JAK2及p-STAT3表达水平显著降低。结论GTP通过抑制肠道JAK2/STAT3信号通路发挥抗炎及肠黏膜屏障结构保护作用。展开更多
文摘Editorial Our new column Profiles is a new series that aims to introduce China CDC’s chief experts,major decisionmakers,and key contributors that ensure the high standard of operation of China CDC.These articles are meant to present high-achieving individuals of China CDC and will describe the background,achievements,and paths to success of the eponymous individuals.
文摘Crohn’s disease(CD)is caused by immune,environmental,and genetic factors.It can involve the entire gastrointestinal tract,and although its prevalence is rapidly increasing its etiology remains unclear.Emerging biological and small-molecule drugs have advanced the treatment of CD;however,a considerable proportion of patients are non-responsive to all known drugs.To achieve a breakthrough in this field,innovations that could guide the further development of effective therapies are of utmost urgency.In this review,we first propose the innovative concept of pan-lymphatic dysfunction for the general distribution of lymphatic dysfunction in various diseases,and suggest that CD is the intestinal manifestation of pan-lymphatic dysfunction based on basic and clinical preliminary data.The supporting evidence is fully summarized,including the existence of lymphatic system dysfunction,recognition of the inside-out model,disorders of immune cells,changes in cell plasticity,partial overlap of the underlying mechanisms,and common gut-derived fatty and bile acid metabolism.Another benefit of this novel concept is that it proposes adopting the zebrafish model for studying intestinal diseases,especially CD,as this model is good at presenting and mimicking lymphatic dysfunction.More importantly,the ensuing focus on improving lymphatic function may lead to novel and promising therapeutic strategies for CD.
基金financially supported by the National Natural Science Foundation of China (22279083,22109166,52202183)Guangdong Basic and Applied Basic Research Foundation (Grant No.2019A1515011136,2022B1515120006,2023B1515120041,2414050001473)+3 种基金Guangdong Province Higher Vocational Colleges and Schools Pearl River Scholar Funded SchemeGuangdong Provincial Key Laboratory Program (2021B1212040001)from the Department of Science and Technology of Guangdong ProvinceBeijing Institute of TechnologySongshan Lake Materials Laboratory。
文摘Near-infrared(NIR)transparent inverted all-inorganic perovskite solar cells(PSCs)are excellent top cell candidates in tandem applications.An essential challenge is the replacement of metal contacts with transparent conductive oxide(TCO)electrodes,which requires the introduction of a buffer layer to prevent sputtering damage.In this study,we show that the conventional buffers(i.e.,small organic molecules and atomic layer deposited metal oxides)used for organic-inorganic hybrid perovskites are not applicable to all-inorganic perovskites,due to non-uniform coverage of the vulnerable layers underneath,deterioration upon ion bombardment and moisture induced perovskite phase transition,A thin film of metal oxide nanoparticles by the spin-coating method serves as a non-destructive buffer layer for inorganic PSCs.All-inorganic inverted near-infrared-transparent PSCs deliver a PCE of 17.46%and an average transmittance of 73.7%between 780 and 1200 nm.In combination with an 18.56%Cu(In,Ga)Se_(2) bottom cell,we further demonstrate the first all-inorganic perovskite/CIGS 4-T tandem solar cell with a PCE of 24.75%,which exhibits excellent illumination stability by maintaining 86.7%of its initial efficiency after 1400 h.The non-destructive buffer lays the foundation for efficient and stable NIR-transparent inverted inorganic perovskite solar cells and perovskite-based tandems.
基金National Key R&D Plan(2023YFC3403200)National Natural Science Foundation of China(82070784,81702536,81974099 and 82170785)+4 种基金Science&Technology Department of Sichuan Province,China(2022JDRC0040,21GJHZ0246)Young Investigator Award of Sichuan University 2017(2017SCU04A17)Sichuan University-Panzhihua Science and Technology Cooperation Special Fund(2020CDPZH-4)China Postdoctoral Science Foundation(2021M692306)Post-Doctor Research Project of West China Hospital of Sichuan University(2021HXBH025).
文摘Background Cell metabolism plays a pivotal role in tumor progression,and targeting cancer metabolism might effectively kill cancer cells.We aimed to investigate the role of hexokinases in prostate cancer(PCa)and identify a crucial target for PCa treatment.Methods The Cancer Genome Atlas(TCGA)database,online tools and clinical samples were used to assess the expression and prognostic role of ADP-dependent glucokinase(ADPGK)in PCa.The effect of ADPGK expression on PCa cell malignant phenotypes was validated in vitro and in vivo.Quantitative proteomics,metabolomics,and extracellular acidification rate(ECAR)and oxygen consumption rate(OCR)tests were performed to evaluate the impact of ADPGK on PCa metabolism.The underlying mechanisms were explored through ADPGK overexpression and knockdown,co-immunoprecipitation(Co-IP),ECAR analysis and cell counting kit-8(CCK-8)assays.Results ADPGK was the only glucokinase that was both upregulated and predicted worse overall survival(OS)in prostate adenocarcinoma(PRAD).Clinical sample analysis demonstrated that ADPGK was markedly upregulated in PCa tissues vs.non-PCa tissues.High ADPGK expression indicates worse survival outcomes,and ADPGK serves as an independent factor of biochemical recurrence.In vitro and in vivo experiments showed that ADPGK overexpression promoted PCa cell proliferation and migration,and ADPGK inhibition suppressed malignant phenotypes.Metabolomics,proteomics,and ECAR and OCR tests revealed that ADPGK significantly accelerated glycolysis in PCa.Mechanistically,ADPGK binds aldolase C(ALDOC)to promote glycolysis via AMP-activated protein kinase(AMPK)phosphorylation.ALDOC was positively correlated with ADPGK,and high ALDOC expression was associated with worse survival outcomes in PCa.Conclusions In summary,ADPGK is a driving factor in PCa progression,and its high expression contributes to a poor prognosis in PCa patients.ADPGK accelerates PCa glycolysis and progression by activating ALDOC-AMPK signaling,suggesting that ADPGK might be an effective target and marker for PCa treatment and prognosis evaluation.
基金This work was supported by grants from the National Natural Science Foundation of China(Grant No.82103039)the Program of Shanghai Academic/Technology Research Leader(Grant No.20XD1421100)the Wu Jieping Medical Foundation(Grant No.320.6750.2021-10-64).
文摘Objective:Triple-negative breast cancer(TNBC)is a heterogeneous and aggressive cancer.Although our previous study classified primary TNBC into four subtypes,comprehensive longitudinal investigations are lacking.Methods:We assembled a large-scale,real-world cohort comprised of 880 TNBC patients[465 early-stage TNBC(eTNBC)and 415 metastatic TNBC(mTNBC)patients]who were treated at Fudan University Shanghai Cancer Center.The longitudinal dynamics of TNBC subtypes during disease progression were elucidated in this patient cohort.Comprehensive analysis was performed to compare primary and metastatic lesions within specific TNBC subtypes.Results:The recurrence and metastasis rates within 3 years after initial diagnosis in the eTNBC cohort were 10.1%(47/465).The median overall survival(OS)in the mTNBC cohort was 27.2 months[95%confidence interval(CI),24.4–30.2 months],which indicated a poor prognosis.The prognostic significance of the original molecular subtypes in both eTNBC and mTNBC patients was confirmed.Consistent molecular subtypes were maintained in 77.5%of the patients throughout disease progression with the mesenchymal-like(MES)subtype demonstrating a tendency for subtype transition and brain metastasis.Additionally,a precision treatment strategy based on the metastatic MES subtype of target lesions resulted in improved progression-free survival in the FUTURE trial.Conclusions:Our longitudinal study comprehensively revealed the clinical characteristics and survival of patients with the original TNBC subtypes and validated the consistency of most molecular subtypes throughout disease progression.However,we emphasize the major importance of repeat pathologic confirmation of the MES subtype.
基金supported by grants from the National Key Research and Development Project of China(Grant No.2020YFA0112304)the National Natural Science Foundation of China(Grant Nos.81922048,82072922,91959207,and 92159301)+3 种基金the Program of Shanghai Academic/Technology Research Leader(Grant No.20XD1421100)the Shanghai Key Laboratory of Breast Cancer(Grant No.12DZ2260100)the Clinical Research Plan of SHDC(Grant Nos.SHDC2020CR4002 and SHDC2020CR5005)the SHDC Municipal Project for Developing Emerging and Frontier Technology in Shanghai Hospitals(Grant No.SHDC12021103).
文摘Objective:Mammographic calcifications are a common feature of breast cancer,but their molecular characteristics and treatment implications in hormone receptor-positive(HR+)/human epidermal growth factor receptor 2-negative(HER2−)breast cancer remain unclear.Methods:We retrospectively collected mammography records of an HR+/HER2−breast cancer cohort(n=316)with matched clinicopathological,genomic,transcriptomic,and metabolomic data.On the basis of mammographic images,we grouped tumors by calcification status into calcification-negative tumors,tumors with probably benign calcifications,tumors with calcification of lowmoderate suspicion for maligancy and tumors with calcification of high suspicion for maligancy.We then explored the molecular characteristics associated with each calcification status across multiple dimensions.Results:Among the different statuses,tumors with probably benign calcifications exhibited elevated hormone receptor immunohistochemical staining scores,estrogen receptor(ER)pathway activation,lipid metabolism,and sensitivity to endocrine therapy.Tumors with calcifications of high suspicion for malignancy had relatively larger tumor sizes,elevated lymph node metastasis incidence,Ki-67 staining scores,genomic instability,cell cycle pathway activation,and may benefit from cyclin-dependent kinase 4 and 6(CDK4/6)inhibitors.Conclusions:Our research established links between tumor calcifications and molecular features,thus proposing potential precision treatment strategies for HR+/HER2−breast cancer.
基金National Natural Science Foundation of China,No.81370008 and No.81000169Natural Science Foundation of Zhejiang Province,No.R2110159,No.LY15H030006 and No.LY16H030003
文摘AIM To investigate the role of the miR-133a-UCP2 pathway in the pathogenesis of inflammatory bowel disease (IBD) and to explore the potential downstream mechanisms with respect to inflammation, oxidative stress and energy metabolism. METHODS C57BL/6 mice were fed dextran sulfate sodium (DSS) liquid for 7 consecutive days, followed by the administration of saline to the DSS group, UCP2 siRNA to the UCP2 group and a miR-133a mimic to the miR-133a group on days 8 and 11. Body weight, stool consistency and rectal bleeding were recorded daily, and these composed the disease activity index (DAI) score for the assessment of disease severity. After cervical dislocation was performed on day 14, the length of the colon in each mouse was measured, and colonic tissue was collected for further study, which included the following: haematoxylin and eosin staining, UCP2 and miR-133a detection by immunohistochemical staining, western blot and quantitative real-time PCR, measurement of apoptosis by TUNEL assay, and the assessment of inflammation (TNF-alpha, IL-1 beta, IL-6 and MCP1), oxidative stress (H2O2 and MDA) and metabolic parameters (ATP) by ELISA and colorimetric methods. RESULTS An animal model of IBD was successfully established, as shown by an increased DAI score, shortened colon length and specific pathologic changes, along with significantly increased UCP2 and decreased miR-133a levels. Compared with the DSS group, the severity of IBD was alleviated in the UCP2 and the miR-133a groups after successful UCP2 knockdown and miR-133a overexpression. The extent of apoptosis, as well as the levels of TNF-alpha, IL-1 beta, MDA and ATP, were significantly increased in both the UCP2 and miR-133a groups compared with the DSS group. CONCLUSION The miR-133a-UCP2 pathway participates in IBD by altering downstream inflammation, oxidative stress and markers of energy metabolism, which provides novel clues and potential therapeutic targets for IBD.
基金sponsored by the National Natural Science Foundation of China(No.41702127,41372148)the National Science and Technology Major Project of China(No.2017ZX05039001)+1 种基金Natural Science Foundation of Shaanxi Province(No.2017JQ4004)Science and Technology Innovation Foundation of Xi’an Shiyou University(No.2016BS19).
文摘The Shanxi Formation(Shan 1 and Shan 2 Members)shales show good prospects in shale gas development in the Yan'an area of Ordos Basin.Based on the simulation experiment of hydrocarbon generation of low maturity shale samples,the hydrocarbon generation characteristics of shale samples was studied systematically.Then,combined with the geochemical analysis of shale and gas generation simulation,shale gas potential was evaluated.The results reveal that Shan 1 and Shan 2 shale samples are favorable for shale gas enrichment by and large,with C_(1)-C_(5) maximum yields of 146.96-160.83 mg/g TOC and 148.48-148.67 mg/g TOC respectively at a heat rate of 20℃/h and 2℃/h.The Shan 1 and Shan 2 shales are basically the same in terms of organic carbon production potential of each unit.The carbon isotopic composition of alkane gas reveals that heteroatomic compounds(NSOs)cracking is an important mechanism for shale gas generation of Shanxi Formation shales,and conducive to gas generation at highto over-mature stages.Given thermal history and kinetic parameters of hydrocarbon generation,the shales of Shanxi Formation reached the maximum gas production potential in the Late Cretaceous,with a maximum yield of 160.3 mg/g TOC under present geological conditions.During geological history,the Shanxi Formation shales went through high-to over-maturity evolution,mainly producing dry gas,and their gas generation capacity was controlled by the organic matter abundance and cracking capacity.The gas generation potential of Shan 2 shale is higher than that of Shan 1,due to its higher TOC.
基金This work was supported by the Hunan Provincial Natural Science Foundation(2021JJ30915).
文摘Fos-related antigen 1(Fra-1)is a nuclear transcription factor that regulates cell growth,differentiation,and apoptosis.It is involved in the proliferation,invasion,apoptosis and epithelial mesenchymal transformation of malignant tumor cells.Fra-1 is highly expressed in gastric cancer(GC),affects the cycle distribution and apoptosis of GC cells,and participates in GC occurrence and development.However,the detailed mechanism of Fra-1 in GC is unclear,such as the identification of Fra-1-interacting proteins and their role in GC pathogenesis.In this study,we identified tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein eta(YWHAH)as a Fra-1-interacting protein in GC cells using co-immunoprecipitation combined with liquid chromatography-tandem mass spectrometry.Experiments showed that YWHAH positively regulated Fra-1 mRNA and protein expression,and affected GC cell proliferation.Whole proteome analysis showed that Fra-1 affected the activity of the high mobility group AT-hook 1(HMGA1)/phosphatidylinositol-4,5-bisphosphate 3-kinase(PI3K)/protein kinase B(AKT)/mechanistic target of rapamycin(mTOR)signaling pathway in GC cells.Western blotting and flow cytometry confirmed that YWHAH activated HMGA1/PI3K/AKT/mTOR signaling pathway by positively regulating Fra-1 to affect GC cell proliferation.These results will help to discover new molecular targets for the early diagnosis,treatment,and prognosis prediction of GC.
基金the Natural Science Foundation of Zhejiang Province,No.LZ21H030002。
文摘BACKGROUND Obesity plays a vital role in the occurrence and development of non-alcoholic steatohepatitis(NASH).However,the underlining mechanism is still unclear,where adipose tissue(AT)derived exosomes may actively participate.MicroRNAs(miRNAs)are commonly secreted from exosomes for cell communication.Though the regulation of miR-103 on insulin sensitivity has been reported,the specific role of AT-derived exosomes miR-103 in NASH is still vague and further investigation may provide novel therapeutic choices.AIM To determine the specific role of AT-derived exosomes miR-103 in developing NASH through various methods.METHODS The expression levels of miR-103 in the AT-derived exosomes and livers were detected and compared between NASH mice and control.The effect of miR-103 on NASH progression was also explored by antagonizing miR-103,including steatosis and inflammation degree changes.The interaction between miR-103 and the autophagy-related gene phosphatase and tensin homolog(PTEN)was confirmed by dual-luciferase reporter assay.The role of the interaction between miR-103 and PTEN on autophagy was verified in NASH-like cells.Finally,the effects of miR-103 from adipose-derived exosomes on NASH and autophagy were analyzed through animal experiments.RESULTS The expression of miR-103 was increased in NASH mice,compared to the control,and inhibition of miR-103 could alleviate NASH.The results of the dual-luciferase reporter assay showed miR-103 could interact with PTEN.MiR-103-anta decreased p-AMPKa,p-mammalian target of rapamycin(mTOR),and p62 but increased the protein levels of PTEN and LC3-II/I and the number of autophagosomes in NASH mice.Similar results were also observed in NASH-like cells,and further experiments showed PTEN silencing inhibited the effect of miR-103-anta.AT derivedexosome miR-103 aggravated NASH and increased the expressions of p-AMPKa,p-mTOR,and p62 but decreased the protein levels of PTEN and LC3-II/I and the number of autophagosomes in mice.CONCLUSION AT derived-exosome increased the levels of miR-103 in the liver,and miR-103 aggravated NASH.Mechanically,miR-103 could interact with PTEN and inhibit autophagy.
