Objective To investigate the role and molecular mechanism of exosomal miR-224-5p in colorectal cancer(CRC).Methods The miR-224-5p expression in CRC patient tissues and cell-derived exosomes was measured by laser captu...Objective To investigate the role and molecular mechanism of exosomal miR-224-5p in colorectal cancer(CRC).Methods The miR-224-5p expression in CRC patient tissues and cell-derived exosomes was measured by laser capture microdissection and qRT-PCR,respectively.Dual-luciferase reporter gene assay was used to determine the target gene of miR-224-5p.The protein expressions of p53 and unc-51 like kinase 2(ULK2)in CRC cells were detected by western blot.Flow cytometry was used to detect cell cycle and apoptosis.Cell proliferation was measured by CCK8 and EdU assay.Results The miR-224-5p expression was upregulated in CRC tissues and increased progressively with the rise of CRC stage.CRC cells secreted extracellular miR-224-5p mainly in an exosome-dependent manner,and then miR-224-5p could be transferred to surrounding tumor cells to regulate cell proliferation in the form of autocrine or paracrine.Moreover,ULK2 was characterized as a direct target of miR-224-5p and was downregulated in CRC tissues.Interestingly,ULK2 inhibited CRC cell proliferation in a p53-dependent manner.Furthermore,exosome-derived miR-224-5p partially reversed the proliferation regulation of ULK2 on CRC cells.Conclusion Our findings demonstrate that exosome-transmitted miR-224-5p promotes p53-dependent cell proliferation by targeting ULK2 in CRC,which may offer promising targets for CRC prevention and therapy.展开更多
Objective: To evaluate the population attributable risks(PARs) between cigarette smoking and deaths of all causes, all cancers, lung cancer and other chronic diseases in urban Shanghai.Methods: In total, 61,480 men ag...Objective: To evaluate the population attributable risks(PARs) between cigarette smoking and deaths of all causes, all cancers, lung cancer and other chronic diseases in urban Shanghai.Methods: In total, 61,480 men aged 40-74 years from 2002 to 2006 and 74,941 women aged 40-70 years from 1997 to 2000 were recruited to undergo baseline surveys in urban Shanghai, with response rates of 74.0% and 92.3%, respectively. A Cox proportional hazards regression model was used to estimate relative risks(RRs) and 95% confidence intervals(95% CIs) of deaths associated with cigarette smoking. PARs and 95% CIs for deaths were estimated from smoking exposure rates and the estimated RRs.Results: Cigarette smoking was responsible for 23.9%(95% CI: 19.4-28.3%) and 2.4%(95% CI: 1.6-3.2%) of all deaths in men and women, respectively, in our study population. Respiratory disease had the highest PAR in men [37.5%(95% CI: 21.5-51.6%)], followed by cancer [31.3%(95% CI: 24.6-37.7%)] and cardiovascular disease(CVD) [24.1%(95% CI: 16.7-31.2%)]. While the top three PARs were 12.7%(95% CI: 6.1-19.3%), 4.0%(95% CI: 2.4-5.6%), and 1.1%(95% CI: 0.0-2.3%), for respiratory disease, CVD, and cancer, respectively in women. For deaths of lung cancer, the PAR of smoking was 68.4%(95% CI: 58.2-76.5%) in men.Conclusions: In urban Shanghai, 23.9% and 2.4% of all deaths in men and women could have been prevented if no people had smoked in the area. Effective control programs against cigarette smoking should be strongly advocated to reduce the increasing smoking-related death burden.展开更多
Background: Open pancreaticoduodenectomy(OPD) with portal or superior mesenteric vein resection and reconstruction has been applied in pancreatic cancer patients with tumor infiltration or adherence. However, it is co...Background: Open pancreaticoduodenectomy(OPD) with portal or superior mesenteric vein resection and reconstruction has been applied in pancreatic cancer patients with tumor infiltration or adherence. However, it is controversial whether laparoscopic pancreaticoduodenectomy(LPD) with major vascular resection and reconstruction is feasible. This study aimed to evaluate the safety and feasibility of LPD with major vascular resection compared with OPD with major vascular resection. Methods: We reviewed data for all pancreatic cancer patients undergoing LPD or OPD with vascular resection at Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, between February 2018 and May 2022. We compared the preoperative, intraoperative, and postoperative clinicopathological data of the two groups to conduct a comprehensive evaluation of LPD with major vascular resection. Results: A total of 63 patients underwent pancreaticoduodenectomy(PD) with portal or superior mesenteric vein resection and reconstruction, including 25 LPDs and 38 OPDs. The LPD group had less intraoperative blood loss(200 vs. 400 m L, P < 0.001), lower proportion of intraoperative blood transfusion(16.0% vs. 39.5%, P = 0.047), longer operation time(390 vs. 334 min, P = 0.004) and shorter postoperative hospital stay(11 vs. 14 days, P = 0.005). There was no perioperative death in all patients. There was no significant difference in the incidence of total postoperative complications, grade B/C postoperative pancreatic fistula, delayed gastric emptying and abdominal infection between the two groups. No postpancreatectomy hemorrhage nor bile leakage occurred during perioperative period. There was no significant difference in R0 resection rate and number of lymph nodes harvested between the two groups. Patency of reconstructed vessels in the two groups were 96.0% and 92.1%, respectively( P = 0.927). Conclusions: LPD with portal or superior mesenteric vein resection and reconstruction was safe, feasible and oncologically acceptable for selected patients with pancreatic cancer, and it can achieve similar or even better perioperative results compared to open approach.展开更多
Triple-negative breast cancer(TNBC)is the most difficult type of breast cancer to treat.TNBC is defined by the lack of expression of three receptors:estrogen receptor(ER);progesterone receptor(PR);and human epidermal ...Triple-negative breast cancer(TNBC)is the most difficult type of breast cancer to treat.TNBC is defined by the lack of expression of three receptors:estrogen receptor(ER);progesterone receptor(PR);and human epidermal growth factor receptor 2(HER2).Chemotherapy is currently first-line treatment for TNBC;however,due to the high heterogeneity of TNBC,most patients eventually develop chemotherapy resistance,which is associated with a poor prognosisl-2.Emerging immune checkpoint blockade(ICB)therapies have been shown to have promising therapeutic efficacy in treating solid tumors.A phase III clinical trial reported that the combination of ICB and chemotherapy lengthened progression-free survival in patients with metastatic PD-L1+TNBC3;however,most patients had primary resistance or acquired resistance to ICB.Thus,the intrinsic mechanisms underlying ICB resistance are still under investigation4.展开更多
Objective To investigate the roles of theγ-aminobutyric acid(GABA) in the metastasis of hepatocellular carcinoma(HCC) and to explore the potential of a novel therapeutic approach for the treatment of HCC. Methods The...Objective To investigate the roles of theγ-aminobutyric acid(GABA) in the metastasis of hepatocellular carcinoma(HCC) and to explore the potential of a novel therapeutic approach for the treatment of HCC. Methods The expression levels of GABA receptor subunit genes in various HCC cell lines and patients’ tissues were detected by quantitative real-time polymerase chain reaction and Western blot analysis.Transwell cell migration and invasion assays were carried out for functional analysis.The effects of GABA on liver cancer cell cytoskeletal were determined by immunofluorescence staining. And the effects of GABA on HCC metastasis in nude mice were evaluated using an in vivo orthotopic model of liver cancer. Results The mRNA level of GABA receptor subunits varied between the primary hepatocellular carcinoma tissue and the adjacent non-tumor liver tissue.GABA inhibited human liver cancer cell migration and invasion via the ionotropic GABAa receptor as a result of the induction of liver cancer cell cytoskeletal reorganization.Pretreatment with GABA also significantly reduced intrahepatic liver metastasis and primary tumor formation in vivo. Conclusions These findings introduce a potential and novel therapeutic approach for the treatment of cancer patients based on the modulation of the GABAergic system.展开更多
Background: Immunotherapy has shown promise against solid tumors. However, the clinical significance of programmed cell death 1(PD-1) and programmed cell death ligand 1(PD-L1) in pancreatic ductal adenocarcinoma(PDAC)...Background: Immunotherapy has shown promise against solid tumors. However, the clinical significance of programmed cell death 1(PD-1) and programmed cell death ligand 1(PD-L1) in pancreatic ductal adenocarcinoma(PDAC) remains unclear. This meta-analysis aimed to analyze the prognostic effect of PD-L1 in PDAC.Data sources: Electronic search of the Pub Med, Cochrane Library and Web of Science was performed until December 2016. Through database searches, we identified articles describing the relationship between PD-L1 status and PDAC patient prognosis. Meta-analysis was performed to investigate the relationship between PD-1 and overall survival(OS).Results: Nine studies with 989 PDAC patients were included for PD-L1 expression analysis. And 5 studies with 688 PDAC patients were included in the prognostic analysis. The PD-L1 positive rate measured by immunohistochemistry(IHC) was higher than that measured by polymerase chain reaction(PCR)(P < 0.001). PDAC patients with high expression levels of PD-L1 had significantly reduced OS(HR = 2.34;95% CI: 1.78–3.08). Subgroup analysis showed that the prognostic effect of PD-L1 levels was similar between the IHC and PCR methods. The PD-L1 positive rate was associated with PDAC T stages; the PD-L1 positive rate in the T3–4 group was higher than that in the T1-2 group(OR = 0.37; P = 0.001).Conclusions: High PD-L1 expression levels predicted a poor prognosis in PDAC patients. Thus, PD-L1 status helps determine treatment in PDAC patients.展开更多
This is first report about the simultaneous over-expression of both Insulin-like growth factor (IGF- I ) and its receptor (IGF- I R) at mRNA level in human primary hepatic Cancer (PHC). In 10 PHC samples from China, I...This is first report about the simultaneous over-expression of both Insulin-like growth factor (IGF- I ) and its receptor (IGF- I R) at mRNA level in human primary hepatic Cancer (PHC). In 10 PHC samples from China, IGF-I and IGF- I R were both over-expressed, whereas only a background signal was detected in normal liver. In 5 pairs of PHC and its non- tumorous adjacent liver tissues from South Africa, IGF- I and IGF- I R were also over-expressed in PHC. mRNA expression of IGF- I in all 5 cases and IGF- I R in 4 of 5 cases were higher in cancer than non- tumorous adjacent liver tissues. These results strongly implicate that an autocrine and/ or paracrine mechanism might be Involved in formation and progression of PHC.展开更多
ABO blood type has been associated with risk of several malignancies. However, results are not consistent. In this population-based case-control study including 1204 incident endometrial cancer cases and 1212 populati...ABO blood type has been associated with risk of several malignancies. However, results are not consistent. In this population-based case-control study including 1204 incident endometrial cancer cases and 1212 population controls, we examined the association of self-reported serologic blood type with endometrial cancer risk using a logistic regression model. Women with endometrial cancer were more likely to have blood type A. Compared to women with blood type O, the adjusted odds ratios for endometrial cancer were 1.00 [95% confidence interval (CI), 0.79-1.28] for type B, 1.24 (95% CI, 0.90-1.69) for type AB, and 1.50 (95% CI, 1.19-1.90) for type A. A significant dose-response relationship was observed for cancer risk and level of antigen A (P for trend = 0.0003). The positive association of blood type A with cancer risk was observed regardless of menopausal status, body mass index, oral contraceptive use, or family cancer history. Our results suggest that ABO blood type may be involved in the development of endometrial cancer.展开更多
A recent genome-wide association study identified a new susceptibility locus for breast cancer, rs2046210, which is a single nucleotide polymorphism (SNP) located upstream of the estrogen receptor α (ESR1) gene on ch...A recent genome-wide association study identified a new susceptibility locus for breast cancer, rs2046210, which is a single nucleotide polymorphism (SNP) located upstream of the estrogen receptor α (ESR1) gene on chromosome 6q25.1. Given that endometrial cancer shares many risk factors with breast cancer and both are related to estrogen exposure and that rs2046210 is in close proximity to the ESR1 gene, we evaluated the association of SNP rs2046210 with endometrial cancer risk among 953 cases and 947 controls in a population-based, case-control study conducted in Shanghai, China. Logistic regression models were used to derive odds ratios (ORs) and 95% confidence intervals (95% CIs) after adjusting for potential confounders. We found that the A allele of rs2046210, linked to an increased risk of breast cancer, was associated with increased but not statistically significant risk of endometrial cancer (OR = 1.16, 95% CI = 0.96-1.41 for the GA and AA genotypes compared with the GG genotype); the association was stronger among post-menopausal women (OR = 1.28, 95% CI = 1.00-1.65). The association tended to be stronger among women with higher or longer estrogen exposure than among women with relatively lower or shorter exposure to estrogen. Our study suggests that rs2046210 may play a role in the etiology of endometrial cancer. Additional studies are needed to confirm our findings.展开更多
AIM To uncover the roles of tumor-promoting gene ZEB1 in aerobic glycolysis regulation and shed light on the underlying molecular mechanism.METHODS Endogenous zinc finger E-box binding homeobox-1(ZEB1) was silenced us...AIM To uncover the roles of tumor-promoting gene ZEB1 in aerobic glycolysis regulation and shed light on the underlying molecular mechanism.METHODS Endogenous zinc finger E-box binding homeobox-1(ZEB1) was silenced using a lentivirus-mediated method, and the impact of ZEB1 and methyl-CpG binding domain protein 1(MBD1) on aerobic glycolysis was measured using seahorse cellular flux analyzers, reactive oxygen species quantification, and mitochondrial membrane potential measurement. The interaction between ZEB1 and MBD1 was assessed by co-immunoprecipitation and immunofluorescence assays. The impact of ZEB1 and MBD1 interaction on sirtuin 3(SIRT3) expression was confirmed by quantitative polymerase chain reaction, western blotting, and dual-luciferase and chromatinimmunoprecipitation assays.RESULTS ZEB1 was a positive regulator of aerobic glycolysis in pancreatic cancer. ZEB1 transcriptionally silenced expression of SIRT3, a mitochondrial-localized tumor suppressor, through interaction with MBD1. CONCLUSION ZEB1 silenced SIRT3 expression via interaction with MBD1 to promote aerobic glycolysis in pancreatic cancer.展开更多
Recently,in cooperation with the Netherlands Cancer Institute,we demonstrated that epidermal growth factor receptor(EGFR)activation limited the response of liver cancer to lenvatinib.The original article was published...Recently,in cooperation with the Netherlands Cancer Institute,we demonstrated that epidermal growth factor receptor(EGFR)activation limited the response of liver cancer to lenvatinib.The original article was published in Nature as a cover story,which resulted in considerable attention from major scientific journals.Here,we were invited by Cancer Biology&Medicine to provide comments on preclinical and clinical findings about the combination of lenvatinib plus EGFR inhibitors as a promising strategy for hepatocellular carcinoma(HCC)treatment.Primary liver cancer represents the sixth most common malignancy and the third leading cause of cancer-related mortality worldwide,with an estimated 906,000 new cases and 830,000 deaths in 20201.展开更多
Developing the methodologies that allow for safe and effective delivery of therapeutic drugs to target sites is a very important research area in cancer therapy.In this study,polyethylene glycol(PEG)-coated magnetic p...Developing the methodologies that allow for safe and effective delivery of therapeutic drugs to target sites is a very important research area in cancer therapy.In this study,polyethylene glycol(PEG)-coated magnetic polymeric liposome(MPL)nanoparticles(NPs)assembled from octadecyl quatemized carboxymethyl chitosan(OQC),PEGylated OQC,cholesterol,and magnetic NPs,and functionalized with epithelial growth factor receptor(EGFR)peptide,were successfully prepared for in-vivo liver targeting.The two-step liver targeting strategy,based on both magnetic force and EGFR peptide conjugation,was evaluated in a subcutaneous hepatocellular carcinoma model of nude mouse.The results showed that EGFR-conjugated MPLs not only accumulated in the liver by magnetic force,but could also diffuse into tumor cells as a result of EGFR targeting.In addition,paclitaxel(PTX)was incorporated into small EGFR-conjugated MPLs(102.0土0.7 nm),resulting in spherical particles with high drug encapsulation efficiency(>90%).The use of the magnetic targeting for enhancing the transport of PTX-loaded EGFR-conjugated MPLs to the tumor site was further confirmed by detecting PTX levels.In conclusion,PTX-loaded EGFR-conjugated MPLs could potentially be used as an effective drug delivery system for targeted liver cancer therapy.展开更多
This review will describe the global patterns and trends of colorectal cancer survival,using data from the population-based studies or cancer registration.We performed a systematic search of China National Knowledge I...This review will describe the global patterns and trends of colorectal cancer survival,using data from the population-based studies or cancer registration.We performed a systematic search of China National Knowledge Infrastructure(CNKI),Wanfang Data,PubMed,Web of Science,EMBASE,and SEER and collected all population-based survival studies of colorectal cancer(up to June 2020).Estimates of observed and relative survival rates of colorectal cancer by sex,period,and country were extracted from original studies to describe the temporal patterns and trends from the late 1990s to the early 21st century.Globally,5-year observed survival rates were higher in Seoul,Republic of Korea(1993–1997;56.8%and 54.3%for colon and rectum cancers,respectively),Zhejiang province(2005–2010;52.9%for colon cancer),Tianjin(1991–1999;52.5%for colon cancer),Shanghai(2002–2006;50.0%for rectum cancer)of China,and in Japan(1993–1996,59.6%for colorectal cancer).Five-year relative survival rates of colorectal cancer in the Republic of Korea(2010–2014),Queensland,Australia(2005–2012),and the USA(2005–2009)ranked at relatively higher positions compared to other countries.In general,colorectal cancer survival rates are improving over time worldwide.Sex disparities in survival rates were also observed in the colon,rectum,and colorectal cancers in most countries or regions.The poorest age-specific 5-year relative survival rate was observed in patients>75 years of age.In conclusion,over the past 3 decades,colorectal cancer survival has gradually improved.Geographic variations,sex differences,and age gradients were also observed globally in colorectal cancer survival.Further studies are therefore warranted to investigate the prognostic factors of colorectal cancer.展开更多
BACKGROUND Cellular metabolism regulates stemness in health and disease.A reduced redox state is essential for self-renewal of normal and cancer stem cells(CSCs).However,while stem cells rely on glycolysis,different C...BACKGROUND Cellular metabolism regulates stemness in health and disease.A reduced redox state is essential for self-renewal of normal and cancer stem cells(CSCs).However,while stem cells rely on glycolysis,different CSCs,including pancreatic CSCs,favor mitochondrial metabolism as their dominant energy-producing pathway.This suggests that powerful antioxidant networks must be in place to detoxify mitochondrial reactive oxygen species(ROS)and maintain stemness in oxidative CSCs.Since glutathione metabolism is critical for normal stem cell function and CSCs from breast,liver and gastric cancer show increased glutathione content,we hypothesized that pancreatic CSCs also rely on this pathway for ROS detoxification.AIM To investigate the role of glutathione metabolism in pancreatic CSCs.METHODS Primary pancreatic cancer cells of patient-derived xenografts(PDXs)were cultured in adherent or CSC-enriching sphere conditions to determine the role of glutathione metabolism in stemness.Real-time polymerase chain reaction(PCR)was used to validate RNAseq results involving glutathione metabolism genes in adherent vs spheres,as well as the expression of pluripotency-related genes following treatment.Public TCGA and GTEx RNAseq data from pancreatic cancer vs normal tissue samples were analyzed using the webserver GEPIA2.The glutathione-sensitive fluorescent probe monochlorobimane was used to determine glutathione content by fluorimetry or flow cytometry.Pharmacological inhibitors of glutathione synthesis and recycling[buthionine-sulfoximine(BSO)and 6-Aminonicotinamide(6-AN),respectively]were used to investigate the impact of glutathione depletion on CSC-enriched cultures.Staining with propidium iodide(cell cycle),Annexin-V(apoptosis)and CD133(CSC content)were determined by flow cytometry.Self-renewal was assessed by sphere formation assay and response to gemcitabine treatment was used as a readout for chemoresistance.RESULTS Analysis of our previously published RNAseq dataset E-MTAB-3808 revealed upregulation of genes involved in the KEGG(Kyoto Encyclopedia of Genes and Genomes)Pathway Glutathione Metabolism in CSC-enriched cultures compared to their differentiated counterparts.Consistently,in pancreatic cancer patient samples the expression of most of these up-regulated genes positively correlated with a stemness signature defined by NANOG,KLF4,SOX2 and OCT4 expression(P<10-5).Moreover,3 of the upregulated genes(MGST1,GPX8,GCCT)were associated with reduced disease-free survival in patients[Hazard ratio(HR)2.2-2.5;P=0.03-0.0054],suggesting a critical role for this pathway in pancreatic cancer progression.CSC-enriched sphere cultures also showed increased expression of different glutathione metabolism-related genes,as well as enhanced glutathione content in its reduced form(GSH).Glutathione depletion with BSO induced cell cycle arrest and apoptosis in spheres,and diminished the expression of stemness genes.Moreover,treatment with either BSO or the glutathione recycling inhibitor 6-AN inhibited self-renewal and the expression of the CSC marker CD133.GSH content in spheres positively correlated with intrinsic resistance to gemcitabine treatment in different PDXs r=0.96,P=5.8×1011).Additionally,CD133+cells accumulated GSH in response to gemcitabine,which was abrogated by BSO treatment(P<0.05).Combined treatment with BSO and gemcitabine-induced apoptosis in CD133+cells to levels comparable to CD133-cells and significantly diminished self-renewal(P<0.05),suggesting that chemoresistance of CSCs is partially dependent on GSH metabolism.CONCLUSION Our data suggest that pancreatic CSCs depend on glutathione metabolism.Pharmacological targeting of this pathway showed that high GSH content is essential to maintain CSC functionality in terms of self-renewal and chemoresistance.展开更多
Objective:This study aimed to determine whether dietary fat intake increased liver cancer risk in Chinese women from a prospective population-based cohort.Methods:A total of 72,704 Chinese women were followed up from ...Objective:This study aimed to determine whether dietary fat intake increased liver cancer risk in Chinese women from a prospective population-based cohort.Methods:A total of 72,704 Chinese women were followed up from the time of baseline recruitment(1996–2000)to the end of 2016.Dietary fat intake was calculated using a validated food frequency questionnaire.The Cox regression model was used to assess the hazard ratio(HR)and 95%confidence intervals(CI)for dietary fat intake and liver cancer risk.Results:We identified 252 incident liver cancer cases out of 1,267,845 person-years during the overall follow-up time.Null associations,neither in quartiles nor per standard deviation(SD)increment,were detected between liver cancer risk and dietary total fat,fat subtypes and subtype ratios,and food sources.The HR(95%CI)of the 1-SD increment was 1.03(0.90–1.17)for total fat,1.06(0.93–1.20)for saturated fat,1.06(0.93–1.21)for monounsaturated fat,and 1.00(0.89–1.13)for polyunsaturated fat.Similar null associations were observed in stratification analyses according to body mass index and menopausal status.Conclusions:In our prospective cohort study,no significant association was observed in Chinese women between dietary fat and liver cancer risk,and in stratification and sensitivity analyses.展开更多
Breast cancer susceptibility gene 1(BRCA1)is a tumor suppressor gene,and its protein BRCA1 plays a role in DNA repair[1].BRCA1 is generally expressed in the cells of mammary glands and other tissues,helping to repair ...Breast cancer susceptibility gene 1(BRCA1)is a tumor suppressor gene,and its protein BRCA1 plays a role in DNA repair[1].BRCA1 is generally expressed in the cells of mammary glands and other tissues,helping to repair damaged DNA or disrupting cells when DNA cannot be repaired.When BRCA1 is mutated and cannot function and therefore the damaged DNA cannot be repaired展开更多
Background:Neoadjuvant therapy is associated with nodal downstaging and improved oncological outcomes in patients with lymph node(LN)-positive pancreatic cancer.This study aimed to develop and validate a nomogram to p...Background:Neoadjuvant therapy is associated with nodal downstaging and improved oncological outcomes in patients with lymph node(LN)-positive pancreatic cancer.This study aimed to develop and validate a nomogram to preoperatively predict LN-positive disease.Methods:A total of 558 patients with resected pancreatic cancer were randomly and equally divided into development and internal validation cohorts.Multivariate logistic regression analysis was used to construct the nomogram.Model performance was evaluated by discrimination,calibration,and clinical usefulness.An independent multicenter cohort consisting of 250 patients was used for external validation.Results:A four-marker signature was built consisting of carbohydrate antigen 19–9(CA19–9),CA125,CA50,and CA242.A nomogram was constructed to predict LN metastasis using three predictors identified by multivariate analysis:risk score of the four-marker signature,computed tomography-reported LN status,and clinical tumor stage.The prediction model exhibited good discrimination ability,with C-indexes of 0.806,0.742 and 0.763 for the development,internal validation,and external validation cohorts,respectively.The model also showed good calibration and clinical usefulness.A cut-off value(0.72)for the probability of LN metastasis was determined to separate low-risk and high-risk patients.Kaplan-Meier survival analysis revealed a good agreement of the survival curves between the nomogram-predicted status and the true LN status.Conclusions:This nomogram enables the identification of pancreatic cancer patients at high risk for LN positivity who may have more advanced disease and thus could potentially benefit from neoadjuvant therapy.展开更多
Rat-1 cells were transfected with DNA from human esophageal cancer 2K, 4K, 6K, 7K. 8K. The transforming foci were obtained and the transforming cell lines were established. The cell lines can form larger colony in sof...Rat-1 cells were transfected with DNA from human esophageal cancer 2K, 4K, 6K, 7K. 8K. The transforming foci were obtained and the transforming cell lines were established. The cell lines can form larger colony in soft agar. Those nude mice injected subcutaneously with the cells suffered from larger fibrous sarcoma. This indicates that the cell lines have carcinogenicity. The experimental results suggest that human DNA sequence and human Ha-ras special 616Kb (BamHI) band are present in the DNA of the transforming cells. The over-expression of ras gene products P21 were found in the tissues of exophageal cancer, the tissues adjacent to tumor and the transforming cells.展开更多
C/EBP is a sequence-specific DNA-binding protein.In order to identify its distribu-tion,localization and function,immunocytochemical technique(ABC method)was done usinganti-C/EBP polypeptide antibodies 1103~#,425~# in...C/EBP is a sequence-specific DNA-binding protein.In order to identify its distribu-tion,localization and function,immunocytochemical technique(ABC method)was done usinganti-C/EBP polypeptide antibodies 1103~#,425~# in liver specimens from 20 normal adult,5neonatal,6 patients with hepatitis,25 patients with liver cirrhosis,80 patients with hepatocellu-lar carcinoma(40 cases were associated with surrounding nontumorous tissues)and 26 patientswith cholangiocarcinoma(15 cases were associated with surrounding nontumorous tissues).Theresults showed that C/EBP was diffusely distributed in nuclei and cytoplasm of differentiated liv-er cells and very low or undetectable in liver cancer cells.The expression of C/EBP was in pro-portion to differentiated degree of tumor cells,and was obviously weaker than that in surround-ing nontumorous tissues.C/EBP positive staining has also been found in regenerating epithelialcells of bile ductules.The results suggested that C/EBP might play an important role in estab-lishing and maintaining the differentiation of liver cells and might exert an inhibiting effect againsttransformation of liver cells and proliferation of neoplastic tissue.展开更多
An amphotropic pseudotype retrovirus containing human N-ras antisense gene was constructed and packaged with helper cells. It has been previously demonstrated that the virus did inhibit the growth of human hepatocarci...An amphotropic pseudotype retrovirus containing human N-ras antisense gene was constructed and packaged with helper cells. It has been previously demonstrated that the virus did inhibit the growth of human hepatocarcinoma cell line PLC PRF/5 in vitro accompanied with the blockage of p21 expression. Based on these results, further study was carried on to examine the effect of these viruses on the growth of human hepatoma transplanted LTNM4 in nude mice. It has been shown that the retrovirus containing human antisense N-ras gene could inhibit the hepatoma in nude mice at a rate of 78% (P【0.05) as compared with saline control. No inhibition was observed in group treated with retrovirus which contained no N-ras sequence. These results in vivo lend further support that human N-ras antisense gene mediated by retrovirus could block the expression of the relevant oncogene and lead to the inhibition of cancer growth. It also provided the basis for further approaches of gene therapy for human cancer.展开更多
基金supported by the National Natural Science Foundation of China[Grant Number:81972803]。
文摘Objective To investigate the role and molecular mechanism of exosomal miR-224-5p in colorectal cancer(CRC).Methods The miR-224-5p expression in CRC patient tissues and cell-derived exosomes was measured by laser capture microdissection and qRT-PCR,respectively.Dual-luciferase reporter gene assay was used to determine the target gene of miR-224-5p.The protein expressions of p53 and unc-51 like kinase 2(ULK2)in CRC cells were detected by western blot.Flow cytometry was used to detect cell cycle and apoptosis.Cell proliferation was measured by CCK8 and EdU assay.Results The miR-224-5p expression was upregulated in CRC tissues and increased progressively with the rise of CRC stage.CRC cells secreted extracellular miR-224-5p mainly in an exosome-dependent manner,and then miR-224-5p could be transferred to surrounding tumor cells to regulate cell proliferation in the form of autocrine or paracrine.Moreover,ULK2 was characterized as a direct target of miR-224-5p and was downregulated in CRC tissues.Interestingly,ULK2 inhibited CRC cell proliferation in a p53-dependent manner.Furthermore,exosome-derived miR-224-5p partially reversed the proliferation regulation of ULK2 on CRC cells.Conclusion Our findings demonstrate that exosome-transmitted miR-224-5p promotes p53-dependent cell proliferation by targeting ULK2 in CRC,which may offer promising targets for CRC prevention and therapy.
基金supported by the funds of Key Discipline and Specialty Foundation of Shanghai Municipal Commission of Health and Family Planningthe National Key Basic Research Program "973 project" (2015CB554000)grants from US National Institutes of Health (R37 CA070867, R01 CA82729, UM1CA173640, and UM1 CA182910)
文摘Objective: To evaluate the population attributable risks(PARs) between cigarette smoking and deaths of all causes, all cancers, lung cancer and other chronic diseases in urban Shanghai.Methods: In total, 61,480 men aged 40-74 years from 2002 to 2006 and 74,941 women aged 40-70 years from 1997 to 2000 were recruited to undergo baseline surveys in urban Shanghai, with response rates of 74.0% and 92.3%, respectively. A Cox proportional hazards regression model was used to estimate relative risks(RRs) and 95% confidence intervals(95% CIs) of deaths associated with cigarette smoking. PARs and 95% CIs for deaths were estimated from smoking exposure rates and the estimated RRs.Results: Cigarette smoking was responsible for 23.9%(95% CI: 19.4-28.3%) and 2.4%(95% CI: 1.6-3.2%) of all deaths in men and women, respectively, in our study population. Respiratory disease had the highest PAR in men [37.5%(95% CI: 21.5-51.6%)], followed by cancer [31.3%(95% CI: 24.6-37.7%)] and cardiovascular disease(CVD) [24.1%(95% CI: 16.7-31.2%)]. While the top three PARs were 12.7%(95% CI: 6.1-19.3%), 4.0%(95% CI: 2.4-5.6%), and 1.1%(95% CI: 0.0-2.3%), for respiratory disease, CVD, and cancer, respectively in women. For deaths of lung cancer, the PAR of smoking was 68.4%(95% CI: 58.2-76.5%) in men.Conclusions: In urban Shanghai, 23.9% and 2.4% of all deaths in men and women could have been prevented if no people had smoked in the area. Effective control programs against cigarette smoking should be strongly advocated to reduce the increasing smoking-related death burden.
基金supported by grants from the National Natural Science Foundation of China (82072693, 81902417 and 82172884)the Scientific Innovation Project of Shanghai Education Commit-tee (2019-01-07-00-07-E00057)+2 种基金Clinical and Scientific Innovation Project of Shanghai Hospital Development Center (SHDC12018109)Clinical Research Plan of Shanghai Hospital Development Center (SHDC2020CR1006A)National Key Research and Development Program of China (2020YFA0803202)。
文摘Background: Open pancreaticoduodenectomy(OPD) with portal or superior mesenteric vein resection and reconstruction has been applied in pancreatic cancer patients with tumor infiltration or adherence. However, it is controversial whether laparoscopic pancreaticoduodenectomy(LPD) with major vascular resection and reconstruction is feasible. This study aimed to evaluate the safety and feasibility of LPD with major vascular resection compared with OPD with major vascular resection. Methods: We reviewed data for all pancreatic cancer patients undergoing LPD or OPD with vascular resection at Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, between February 2018 and May 2022. We compared the preoperative, intraoperative, and postoperative clinicopathological data of the two groups to conduct a comprehensive evaluation of LPD with major vascular resection. Results: A total of 63 patients underwent pancreaticoduodenectomy(PD) with portal or superior mesenteric vein resection and reconstruction, including 25 LPDs and 38 OPDs. The LPD group had less intraoperative blood loss(200 vs. 400 m L, P < 0.001), lower proportion of intraoperative blood transfusion(16.0% vs. 39.5%, P = 0.047), longer operation time(390 vs. 334 min, P = 0.004) and shorter postoperative hospital stay(11 vs. 14 days, P = 0.005). There was no perioperative death in all patients. There was no significant difference in the incidence of total postoperative complications, grade B/C postoperative pancreatic fistula, delayed gastric emptying and abdominal infection between the two groups. No postpancreatectomy hemorrhage nor bile leakage occurred during perioperative period. There was no significant difference in R0 resection rate and number of lymph nodes harvested between the two groups. Patency of reconstructed vessels in the two groups were 96.0% and 92.1%, respectively( P = 0.927). Conclusions: LPD with portal or superior mesenteric vein resection and reconstruction was safe, feasible and oncologically acceptable for selected patients with pancreatic cancer, and it can achieve similar or even better perioperative results compared to open approach.
基金supported by the National Natural Science Foundation of China(Grant Nos.82171774 and 82172736)the innovative research team of high-level local universities in Shanghai(Grant No.SHSMU-ZDCX20210600)。
文摘Triple-negative breast cancer(TNBC)is the most difficult type of breast cancer to treat.TNBC is defined by the lack of expression of three receptors:estrogen receptor(ER);progesterone receptor(PR);and human epidermal growth factor receptor 2(HER2).Chemotherapy is currently first-line treatment for TNBC;however,due to the high heterogeneity of TNBC,most patients eventually develop chemotherapy resistance,which is associated with a poor prognosisl-2.Emerging immune checkpoint blockade(ICB)therapies have been shown to have promising therapeutic efficacy in treating solid tumors.A phase III clinical trial reported that the combination of ICB and chemotherapy lengthened progression-free survival in patients with metastatic PD-L1+TNBC3;however,most patients had primary resistance or acquired resistance to ICB.Thus,the intrinsic mechanisms underlying ICB resistance are still under investigation4.
基金supported by the Ministry of Health of China (No.2008ZX10002-022)the Doctoral Innovation Fund of Shanghai Cancer Institute(No.SB-09-02)
文摘Objective To investigate the roles of theγ-aminobutyric acid(GABA) in the metastasis of hepatocellular carcinoma(HCC) and to explore the potential of a novel therapeutic approach for the treatment of HCC. Methods The expression levels of GABA receptor subunit genes in various HCC cell lines and patients’ tissues were detected by quantitative real-time polymerase chain reaction and Western blot analysis.Transwell cell migration and invasion assays were carried out for functional analysis.The effects of GABA on liver cancer cell cytoskeletal were determined by immunofluorescence staining. And the effects of GABA on HCC metastasis in nude mice were evaluated using an in vivo orthotopic model of liver cancer. Results The mRNA level of GABA receptor subunits varied between the primary hepatocellular carcinoma tissue and the adjacent non-tumor liver tissue.GABA inhibited human liver cancer cell migration and invasion via the ionotropic GABAa receptor as a result of the induction of liver cancer cell cytoskeletal reorganization.Pretreatment with GABA also significantly reduced intrahepatic liver metastasis and primary tumor formation in vivo. Conclusions These findings introduce a potential and novel therapeutic approach for the treatment of cancer patients based on the modulation of the GABAergic system.
基金supported by grants from the National Natural Science Foundation of China(81472670,81172005,81402397,81402398 and 81172276)the National Natural Science Foundation of Shanghai(14ZR1407600)+1 种基金the“Yang-Fan”Plan for Young Scientists of Shanghai(14YF1401100)the Ph D Programs Foundation of the Ministry of Education of China(20110071120096)
文摘Background: Immunotherapy has shown promise against solid tumors. However, the clinical significance of programmed cell death 1(PD-1) and programmed cell death ligand 1(PD-L1) in pancreatic ductal adenocarcinoma(PDAC) remains unclear. This meta-analysis aimed to analyze the prognostic effect of PD-L1 in PDAC.Data sources: Electronic search of the Pub Med, Cochrane Library and Web of Science was performed until December 2016. Through database searches, we identified articles describing the relationship between PD-L1 status and PDAC patient prognosis. Meta-analysis was performed to investigate the relationship between PD-1 and overall survival(OS).Results: Nine studies with 989 PDAC patients were included for PD-L1 expression analysis. And 5 studies with 688 PDAC patients were included in the prognostic analysis. The PD-L1 positive rate measured by immunohistochemistry(IHC) was higher than that measured by polymerase chain reaction(PCR)(P < 0.001). PDAC patients with high expression levels of PD-L1 had significantly reduced OS(HR = 2.34;95% CI: 1.78–3.08). Subgroup analysis showed that the prognostic effect of PD-L1 levels was similar between the IHC and PCR methods. The PD-L1 positive rate was associated with PDAC T stages; the PD-L1 positive rate in the T3–4 group was higher than that in the T1-2 group(OR = 0.37; P = 0.001).Conclusions: High PD-L1 expression levels predicted a poor prognosis in PDAC patients. Thus, PD-L1 status helps determine treatment in PDAC patients.
文摘This is first report about the simultaneous over-expression of both Insulin-like growth factor (IGF- I ) and its receptor (IGF- I R) at mRNA level in human primary hepatic Cancer (PHC). In 10 PHC samples from China, IGF-I and IGF- I R were both over-expressed, whereas only a background signal was detected in normal liver. In 5 pairs of PHC and its non- tumorous adjacent liver tissues from South Africa, IGF- I and IGF- I R were also over-expressed in PHC. mRNA expression of IGF- I in all 5 cases and IGF- I R in 4 of 5 cases were higher in cancer than non- tumorous adjacent liver tissues. These results strongly implicate that an autocrine and/ or paracrine mechanism might be Involved in formation and progression of PHC.
基金supported by United States Public Health Service (USPHS) grant R01CA92585 from the National Cancer Institute
文摘ABO blood type has been associated with risk of several malignancies. However, results are not consistent. In this population-based case-control study including 1204 incident endometrial cancer cases and 1212 population controls, we examined the association of self-reported serologic blood type with endometrial cancer risk using a logistic regression model. Women with endometrial cancer were more likely to have blood type A. Compared to women with blood type O, the adjusted odds ratios for endometrial cancer were 1.00 [95% confidence interval (CI), 0.79-1.28] for type B, 1.24 (95% CI, 0.90-1.69) for type AB, and 1.50 (95% CI, 1.19-1.90) for type A. A significant dose-response relationship was observed for cancer risk and level of antigen A (P for trend = 0.0003). The positive association of blood type A with cancer risk was observed regardless of menopausal status, body mass index, oral contraceptive use, or family cancer history. Our results suggest that ABO blood type may be involved in the development of endometrial cancer.
基金supported in part by the Vanderbilt-Ingram Cancer Center (P30 CA68485)supported by a National Cancer Institute grant (R01 CA92585, PI: Xiao-Ou Shu)
文摘A recent genome-wide association study identified a new susceptibility locus for breast cancer, rs2046210, which is a single nucleotide polymorphism (SNP) located upstream of the estrogen receptor α (ESR1) gene on chromosome 6q25.1. Given that endometrial cancer shares many risk factors with breast cancer and both are related to estrogen exposure and that rs2046210 is in close proximity to the ESR1 gene, we evaluated the association of SNP rs2046210 with endometrial cancer risk among 953 cases and 947 controls in a population-based, case-control study conducted in Shanghai, China. Logistic regression models were used to derive odds ratios (ORs) and 95% confidence intervals (95% CIs) after adjusting for potential confounders. We found that the A allele of rs2046210, linked to an increased risk of breast cancer, was associated with increased but not statistically significant risk of endometrial cancer (OR = 1.16, 95% CI = 0.96-1.41 for the GA and AA genotypes compared with the GG genotype); the association was stronger among post-menopausal women (OR = 1.28, 95% CI = 1.00-1.65). The association tended to be stronger among women with higher or longer estrogen exposure than among women with relatively lower or shorter exposure to estrogen. Our study suggests that rs2046210 may play a role in the etiology of endometrial cancer. Additional studies are needed to confirm our findings.
基金the National Science Fund for Distinguished Young Scholars of China,No.81625016the National Science Foundation of China,No.81502031 and No.81772555+1 种基金Shanghai Municipal Commission of Health and Family Planning Grant,No.20154Y0090Youth Research Foundation of Shanghai Municipal Commission of Health and Family Planning,No.Z0124Y074
文摘AIM To uncover the roles of tumor-promoting gene ZEB1 in aerobic glycolysis regulation and shed light on the underlying molecular mechanism.METHODS Endogenous zinc finger E-box binding homeobox-1(ZEB1) was silenced using a lentivirus-mediated method, and the impact of ZEB1 and methyl-CpG binding domain protein 1(MBD1) on aerobic glycolysis was measured using seahorse cellular flux analyzers, reactive oxygen species quantification, and mitochondrial membrane potential measurement. The interaction between ZEB1 and MBD1 was assessed by co-immunoprecipitation and immunofluorescence assays. The impact of ZEB1 and MBD1 interaction on sirtuin 3(SIRT3) expression was confirmed by quantitative polymerase chain reaction, western blotting, and dual-luciferase and chromatinimmunoprecipitation assays.RESULTS ZEB1 was a positive regulator of aerobic glycolysis in pancreatic cancer. ZEB1 transcriptionally silenced expression of SIRT3, a mitochondrial-localized tumor suppressor, through interaction with MBD1. CONCLUSION ZEB1 silenced SIRT3 expression via interaction with MBD1 to promote aerobic glycolysis in pancreatic cancer.
基金This work was supported by grants from the National Natural Science Foundation of China(Grant No.81920108025)the Shanghai Municipal Science and Technology Project(Grant No.20JC1411100)the 111 Project(Grant No.B21024).
文摘Recently,in cooperation with the Netherlands Cancer Institute,we demonstrated that epidermal growth factor receptor(EGFR)activation limited the response of liver cancer to lenvatinib.The original article was published in Nature as a cover story,which resulted in considerable attention from major scientific journals.Here,we were invited by Cancer Biology&Medicine to provide comments on preclinical and clinical findings about the combination of lenvatinib plus EGFR inhibitors as a promising strategy for hepatocellular carcinoma(HCC)treatment.Primary liver cancer represents the sixth most common malignancy and the third leading cause of cancer-related mortality worldwide,with an estimated 906,000 new cases and 830,000 deaths in 20201.
基金the Research Program Foundation of the Department of Education of Fujian Province for Young Talents(No.JK2017021)the Training Program of Department of Health of Fujian Province for Young Talents(No.2017-ZQN-41).
文摘Developing the methodologies that allow for safe and effective delivery of therapeutic drugs to target sites is a very important research area in cancer therapy.In this study,polyethylene glycol(PEG)-coated magnetic polymeric liposome(MPL)nanoparticles(NPs)assembled from octadecyl quatemized carboxymethyl chitosan(OQC),PEGylated OQC,cholesterol,and magnetic NPs,and functionalized with epithelial growth factor receptor(EGFR)peptide,were successfully prepared for in-vivo liver targeting.The two-step liver targeting strategy,based on both magnetic force and EGFR peptide conjugation,was evaluated in a subcutaneous hepatocellular carcinoma model of nude mouse.The results showed that EGFR-conjugated MPLs not only accumulated in the liver by magnetic force,but could also diffuse into tumor cells as a result of EGFR targeting.In addition,paclitaxel(PTX)was incorporated into small EGFR-conjugated MPLs(102.0土0.7 nm),resulting in spherical particles with high drug encapsulation efficiency(>90%).The use of the magnetic targeting for enhancing the transport of PTX-loaded EGFR-conjugated MPLs to the tumor site was further confirmed by detecting PTX levels.In conclusion,PTX-loaded EGFR-conjugated MPLs could potentially be used as an effective drug delivery system for targeted liver cancer therapy.
基金This work was supported by funding from the National Key Project of Research and Development Program of China(Grant No.2016YFC1302503)the National Key Basic Research Program of China“973 Program”(Grant No.2015CB554000).
文摘This review will describe the global patterns and trends of colorectal cancer survival,using data from the population-based studies or cancer registration.We performed a systematic search of China National Knowledge Infrastructure(CNKI),Wanfang Data,PubMed,Web of Science,EMBASE,and SEER and collected all population-based survival studies of colorectal cancer(up to June 2020).Estimates of observed and relative survival rates of colorectal cancer by sex,period,and country were extracted from original studies to describe the temporal patterns and trends from the late 1990s to the early 21st century.Globally,5-year observed survival rates were higher in Seoul,Republic of Korea(1993–1997;56.8%and 54.3%for colon and rectum cancers,respectively),Zhejiang province(2005–2010;52.9%for colon cancer),Tianjin(1991–1999;52.5%for colon cancer),Shanghai(2002–2006;50.0%for rectum cancer)of China,and in Japan(1993–1996,59.6%for colorectal cancer).Five-year relative survival rates of colorectal cancer in the Republic of Korea(2010–2014),Queensland,Australia(2005–2012),and the USA(2005–2009)ranked at relatively higher positions compared to other countries.In general,colorectal cancer survival rates are improving over time worldwide.Sex disparities in survival rates were also observed in the colon,rectum,and colorectal cancers in most countries or regions.The poorest age-specific 5-year relative survival rate was observed in patients>75 years of age.In conclusion,over the past 3 decades,colorectal cancer survival has gradually improved.Geographic variations,sex differences,and age gradients were also observed globally in colorectal cancer survival.Further studies are therefore warranted to investigate the prognostic factors of colorectal cancer.
文摘BACKGROUND Cellular metabolism regulates stemness in health and disease.A reduced redox state is essential for self-renewal of normal and cancer stem cells(CSCs).However,while stem cells rely on glycolysis,different CSCs,including pancreatic CSCs,favor mitochondrial metabolism as their dominant energy-producing pathway.This suggests that powerful antioxidant networks must be in place to detoxify mitochondrial reactive oxygen species(ROS)and maintain stemness in oxidative CSCs.Since glutathione metabolism is critical for normal stem cell function and CSCs from breast,liver and gastric cancer show increased glutathione content,we hypothesized that pancreatic CSCs also rely on this pathway for ROS detoxification.AIM To investigate the role of glutathione metabolism in pancreatic CSCs.METHODS Primary pancreatic cancer cells of patient-derived xenografts(PDXs)were cultured in adherent or CSC-enriching sphere conditions to determine the role of glutathione metabolism in stemness.Real-time polymerase chain reaction(PCR)was used to validate RNAseq results involving glutathione metabolism genes in adherent vs spheres,as well as the expression of pluripotency-related genes following treatment.Public TCGA and GTEx RNAseq data from pancreatic cancer vs normal tissue samples were analyzed using the webserver GEPIA2.The glutathione-sensitive fluorescent probe monochlorobimane was used to determine glutathione content by fluorimetry or flow cytometry.Pharmacological inhibitors of glutathione synthesis and recycling[buthionine-sulfoximine(BSO)and 6-Aminonicotinamide(6-AN),respectively]were used to investigate the impact of glutathione depletion on CSC-enriched cultures.Staining with propidium iodide(cell cycle),Annexin-V(apoptosis)and CD133(CSC content)were determined by flow cytometry.Self-renewal was assessed by sphere formation assay and response to gemcitabine treatment was used as a readout for chemoresistance.RESULTS Analysis of our previously published RNAseq dataset E-MTAB-3808 revealed upregulation of genes involved in the KEGG(Kyoto Encyclopedia of Genes and Genomes)Pathway Glutathione Metabolism in CSC-enriched cultures compared to their differentiated counterparts.Consistently,in pancreatic cancer patient samples the expression of most of these up-regulated genes positively correlated with a stemness signature defined by NANOG,KLF4,SOX2 and OCT4 expression(P<10-5).Moreover,3 of the upregulated genes(MGST1,GPX8,GCCT)were associated with reduced disease-free survival in patients[Hazard ratio(HR)2.2-2.5;P=0.03-0.0054],suggesting a critical role for this pathway in pancreatic cancer progression.CSC-enriched sphere cultures also showed increased expression of different glutathione metabolism-related genes,as well as enhanced glutathione content in its reduced form(GSH).Glutathione depletion with BSO induced cell cycle arrest and apoptosis in spheres,and diminished the expression of stemness genes.Moreover,treatment with either BSO or the glutathione recycling inhibitor 6-AN inhibited self-renewal and the expression of the CSC marker CD133.GSH content in spheres positively correlated with intrinsic resistance to gemcitabine treatment in different PDXs r=0.96,P=5.8×1011).Additionally,CD133+cells accumulated GSH in response to gemcitabine,which was abrogated by BSO treatment(P<0.05).Combined treatment with BSO and gemcitabine-induced apoptosis in CD133+cells to levels comparable to CD133-cells and significantly diminished self-renewal(P<0.05),suggesting that chemoresistance of CSCs is partially dependent on GSH metabolism.CONCLUSION Our data suggest that pancreatic CSCs depend on glutathione metabolism.Pharmacological targeting of this pathway showed that high GSH content is essential to maintain CSC functionality in terms of self-renewal and chemoresistance.
基金supported by the National Key Project of Research and Development Program of China(Grant No.2016YFC1302503)the National Key Basic Research Program of China“973 Program”(Grant No.2015CB554000)+1 种基金the State Key Project Specialized for Infectious Diseases of China(Grant Nos.2008ZX10002-015 and 2012ZX10002008-002)the US National Institutes of Health(Grant No.UM1 CA173640).
文摘Objective:This study aimed to determine whether dietary fat intake increased liver cancer risk in Chinese women from a prospective population-based cohort.Methods:A total of 72,704 Chinese women were followed up from the time of baseline recruitment(1996–2000)to the end of 2016.Dietary fat intake was calculated using a validated food frequency questionnaire.The Cox regression model was used to assess the hazard ratio(HR)and 95%confidence intervals(CI)for dietary fat intake and liver cancer risk.Results:We identified 252 incident liver cancer cases out of 1,267,845 person-years during the overall follow-up time.Null associations,neither in quartiles nor per standard deviation(SD)increment,were detected between liver cancer risk and dietary total fat,fat subtypes and subtype ratios,and food sources.The HR(95%CI)of the 1-SD increment was 1.03(0.90–1.17)for total fat,1.06(0.93–1.20)for saturated fat,1.06(0.93–1.21)for monounsaturated fat,and 1.00(0.89–1.13)for polyunsaturated fat.Similar null associations were observed in stratification analyses according to body mass index and menopausal status.Conclusions:In our prospective cohort study,no significant association was observed in Chinese women between dietary fat and liver cancer risk,and in stratification and sensitivity analyses.
基金supported by National Natural Science Foundation of China grants(Nos.81530075 and 81472741)the National Key Research and Development Program of China(Stem Cell and Translational Research 2016YFA0101202)the Ministry of Science and Technology(MOST) grant (No.2015CB553800)
文摘Breast cancer susceptibility gene 1(BRCA1)is a tumor suppressor gene,and its protein BRCA1 plays a role in DNA repair[1].BRCA1 is generally expressed in the cells of mammary glands and other tissues,helping to repair damaged DNA or disrupting cells when DNA cannot be repaired.When BRCA1 is mutated and cannot function and therefore the damaged DNA cannot be repaired
基金supported by grants from the National Natural Science Foundation of China(81772555,81802352 and 81902428)the National Science Foundation for Distinguished Young Scholars of China(81625016)+4 种基金the Shanghai Sailing Program(19YF1409400 and 20YF1409000)the Shanghai Rising-Star Program(20QA1402100)the Shanghai Anticancer Association Young Eagle Program(SACA-CY19A06)the Clinical and Scientific Innovation Project of Shanghai Hospital Development Center(SHDC12018109 and SHDC12019109)the Scientific Innovation Project of Shanghai Education Committee(2019-01-07-00-07-E00057)。
文摘Background:Neoadjuvant therapy is associated with nodal downstaging and improved oncological outcomes in patients with lymph node(LN)-positive pancreatic cancer.This study aimed to develop and validate a nomogram to preoperatively predict LN-positive disease.Methods:A total of 558 patients with resected pancreatic cancer were randomly and equally divided into development and internal validation cohorts.Multivariate logistic regression analysis was used to construct the nomogram.Model performance was evaluated by discrimination,calibration,and clinical usefulness.An independent multicenter cohort consisting of 250 patients was used for external validation.Results:A four-marker signature was built consisting of carbohydrate antigen 19–9(CA19–9),CA125,CA50,and CA242.A nomogram was constructed to predict LN metastasis using three predictors identified by multivariate analysis:risk score of the four-marker signature,computed tomography-reported LN status,and clinical tumor stage.The prediction model exhibited good discrimination ability,with C-indexes of 0.806,0.742 and 0.763 for the development,internal validation,and external validation cohorts,respectively.The model also showed good calibration and clinical usefulness.A cut-off value(0.72)for the probability of LN metastasis was determined to separate low-risk and high-risk patients.Kaplan-Meier survival analysis revealed a good agreement of the survival curves between the nomogram-predicted status and the true LN status.Conclusions:This nomogram enables the identification of pancreatic cancer patients at high risk for LN positivity who may have more advanced disease and thus could potentially benefit from neoadjuvant therapy.
文摘Rat-1 cells were transfected with DNA from human esophageal cancer 2K, 4K, 6K, 7K. 8K. The transforming foci were obtained and the transforming cell lines were established. The cell lines can form larger colony in soft agar. Those nude mice injected subcutaneously with the cells suffered from larger fibrous sarcoma. This indicates that the cell lines have carcinogenicity. The experimental results suggest that human DNA sequence and human Ha-ras special 616Kb (BamHI) band are present in the DNA of the transforming cells. The over-expression of ras gene products P21 were found in the tissues of exophageal cancer, the tissues adjacent to tumor and the transforming cells.
文摘C/EBP is a sequence-specific DNA-binding protein.In order to identify its distribu-tion,localization and function,immunocytochemical technique(ABC method)was done usinganti-C/EBP polypeptide antibodies 1103~#,425~# in liver specimens from 20 normal adult,5neonatal,6 patients with hepatitis,25 patients with liver cirrhosis,80 patients with hepatocellu-lar carcinoma(40 cases were associated with surrounding nontumorous tissues)and 26 patientswith cholangiocarcinoma(15 cases were associated with surrounding nontumorous tissues).Theresults showed that C/EBP was diffusely distributed in nuclei and cytoplasm of differentiated liv-er cells and very low or undetectable in liver cancer cells.The expression of C/EBP was in pro-portion to differentiated degree of tumor cells,and was obviously weaker than that in surround-ing nontumorous tissues.C/EBP positive staining has also been found in regenerating epithelialcells of bile ductules.The results suggested that C/EBP might play an important role in estab-lishing and maintaining the differentiation of liver cells and might exert an inhibiting effect againsttransformation of liver cells and proliferation of neoplastic tissue.
文摘An amphotropic pseudotype retrovirus containing human N-ras antisense gene was constructed and packaged with helper cells. It has been previously demonstrated that the virus did inhibit the growth of human hepatocarcinoma cell line PLC PRF/5 in vitro accompanied with the blockage of p21 expression. Based on these results, further study was carried on to examine the effect of these viruses on the growth of human hepatoma transplanted LTNM4 in nude mice. It has been shown that the retrovirus containing human antisense N-ras gene could inhibit the hepatoma in nude mice at a rate of 78% (P【0.05) as compared with saline control. No inhibition was observed in group treated with retrovirus which contained no N-ras sequence. These results in vivo lend further support that human N-ras antisense gene mediated by retrovirus could block the expression of the relevant oncogene and lead to the inhibition of cancer growth. It also provided the basis for further approaches of gene therapy for human cancer.
