SETD2 in cancer:functions,molecular mechanisms,and therapeutic regimens

In recent years,the histone methyltransferase SET domain containing 2(SETD2)has garnered significant attention for its involvement in carcinogenesis.Herein we aim to summarize the research advances regarding SETD2 in tumors,elucidate the role in global epigenetic regulation,highlight potential therapeutic regimens for patients with SETD2 deficiency,and outline future research directions.

Genomic profiling of colorectal cancer in large-scale Chinese patients:amplification and somatic mutations in ERBB2

Objectives:Human epidermal growth factor receptor 2(HER2)-targeted therapies have demonstrated potential benefits for metastatic colorectal cancer(mCRC)patients with HER2 amplification,but are not satisfactory in cases of HER2 mutant CRCs.Methods:Consequently,further elucidation of amplifications and somatic mutations in erythroblastic oncogene B-2(ERBB2)is imperative.Comprehensive genomic profiling was conducted on 2454 Chinese CRC cases to evaluate genomic alterations in 733 cancer-related genes,tumor mutational burden,microsatellite instability,and programmed death ligand 1(PD-L1)expression.Results:Among 2454 CRC patients,85 cases(3.46%)exhibited ERBB2 amplification,and 55 cases(2.24%)carried ERBB2 mutation.p.R678Q(28%),p.V8421(24%),and p.S310F/Y(12%)were the most prevalent of the 16 detected mutation sites.In comparison to the ERBB2 altered(alt)group,KRAS/BRAF mutations were more prevalent in ERBB2 wild-type(wt)samples(ERBB2wt vs.ERBB2alt,KRAS:50.9%vs.25.6%,p<0.05;BRAF:8.5%vs.2.3%,p<0.05).32.7%(18/55)of CRCs with ERBB2 mutation exhibited microsatellite instability high(MSI-H),while no cases with HER2 amplification displayed MSI-H.Mutant genes varied between ERBB2 copy number variation(CNV)and ERBB2 single nucleotide variant(SNV);TP53 alterations tended to co-occur with ERBB2 amplification(92.3%)as opposed to ERBB2 mutation(58.3%).KRAS and PIK3CA alterations were more prevalent in ERBB2 SNV cases(KRAS/PIK3CA:45.8%/31.2%)compared to ERBB2 amplification cases(KRAS/PIK3CA:14.1%/7.7%).Conclusion:Our study delineates the landscape of HER2 alterations in a large-scale cohort of CRC patients from China.These findings enhance our understanding of the molecular features of Chinese CRC patients and offer valuable implications for further investigation.

Long-Term Survival Trend of Gynecological Cancer:A Systematic Review of Population-Based Cancer Registration Data

Gynecological cancer significantly affect the health of women.This review aimed to describe the global patterns and trends in the survival of patients with gynecological cancers.We searched PubMed,Embase,Web of Science,SinoMed,and SEER for survival analyses of cancer registration data of cervical,endometrial,and ovarian cancers published between 1980 and 2022.Globally,the highest 5-year observed survival rate for cervical cancer was 76.5% in Anshan,Liaoning,China(2008-2017).The 5-year observed survival rates of endometrial and ovarian cancers were higher in Finland(1995-1999,82.5%)and Singapore(1988-1992,62.0%).The 5-year relative survival rate of cervical cancer patients was higher in Haining,Zhejiang,China(2011-2014,85.8%).Korea ranked first at 89.0% and 64.5% for endometrial and ovarian cancers,respectively.Survival rates have improved for cervical,endometrial,and ovarian cancers.Patients aged≥75 years and those with advancedstage disease had the worst 5-year survival rates.Survival rates were better for squamous cell carcinoma in cervical cancer,for endometrial carcinoma and mucinous adenocarcinoma in endometrial cancer,and for germ cell and sex-cord stromal tumors in ovarian cancer.Over the past four decades,the survival rates of gynecological cancers have increased globally,with notable increases in cervical and endometrial cancers.Survival rates are higher in developed countries,with a slow-growing trend.Future studies should focus on improving survival,especially in ovarian cancer patients.

Exosome-Transmitted miR-224-5p Promotes Colorectal Cancer Cell Proliferation via Targeting ULK2 in p53-Dependent Manner

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.

Population attributable risks of cigarette smoking for deaths of all causes, all cancers and other chronic diseases among adults aged 40-74 years in urban Shanghai, China

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% Ch 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% Ch 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.

Laparoscopic pancreaticoduodenectomy with portal or superior mesenteric vein resection and reconstruction for pancreatic cancer:A single-center experience

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.

Cutting the root:the next generation of T cells engagers against cancer stem cells to overcome drug resistance in triple-negative breast cancer

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.

Food-derived exosomes as the future of drug delivery

Exosomes are a kind of nanoscale membrane vesicles that can be secreted by many types of cells in both normal and pathological states and play a very important role in intercellular information exchange and transmission by transporting proteins, nucleic acids, lipids, and other biologically active substances to act on the receptor cells. Recent studies have shown that exosomes from some plants, animals, microorganisms, and other food sources can also be extracted like the structure of exosomes secreted by mammalian cells, which are named food-derived exosomes (FDEs) and can be absorbed by intestinal cells and further transported to other organs through blood circulation. With the advantages of high biocompatibility, low immunogenicity, low toxicity, high cargo capacity, and the ability to cross biological barriers, FDEs can be involved in a variety of applications such as immune response, cell migration, and tumor invasion, and have attracted a lot of attention as biotherapeutic agents and drug delivery carriers in the treatment of human diseases. This article reviews the classification, preparation characterization, physiological processes in the human body, biological functions, and application prospects of FDEs. It aims to provide a reference for the research and application of FDEs in disease treatment.

Impacts of different pancreatic resection ranges on endocrine function in Suncus murinus

BACKGROUND Surgical intervention involving the pancreas can lead to impaired glucose tolerance and other types of endocrine dysfunction.The scope of pancreatectomy and whether it includes the ventral pancreas are the key factors in the development of postoperative diabetes.The ventral and dorsal pancreases are almost separated in Suncus murinus(S.murinus).AIM To investigate the effects of different extents of pancreatic resection on endocrine function in S.murinus.METHODS Eight-week-old male S.murinus shrews were randomly divided into three experimental groups according to different pancreatic resection ranges as follows:ventral pancreatectomy(VPx)group;partial pancreatectomy(PPx)group;subtotal pancreatectomy(SPx)group;and a sham-operated group.Postprandial serum insulin,glucagon-like peptide-1(GLP-1),pancreatic polypeptide(PP),and somatostatin(SST)levels,as well as food intake,weight,blood glucose,and glucose tolerance were regularly measured for each animal.RESULTS S.murinus treated with PPx and SPx suffered from varying degrees of impaired glucose tolerance,but only a small proportion of the SPx group developed diabetes.Only S.murinus in the SPx group showed a significant decrease in food intake accompanied by severe weight loss,as well as a significant increase in postprandial serum GLP-1 levels.Postprandial serum PP levels decreased in both the VPx and PPx groups,but not in the SPx group.Postprandial serum SST levels decreased in both VPx and PPx groups,but the decrease was marginal.CONCLUSION Severe weight loss after pancreatectomy may be related to loss of appetite caused by compensatory elevation of GLP-1.PP and GLP-1 may play a role in resisting blood glucose imbalance.

Suppression of Human Liver Cancer Cell Migration and Invasion via the GABA_A Receptor

Objective To investigate the roles of the y-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.

Global pattern and trends of colorectal cancer survival: a systematic review of population-based registration data

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.

The clinicopathological and prognostic significance of PD-L1 expression in pancreatic cancer:A meta-analysis

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.

ABO blood type is associated with endometrial cancer risk in Chinese women

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.

Association of a single nucleotide polymorphism at 6q25.1, rs2046210, with endometrial cancer risk among Chinese women

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.

SIMULTANEOUS OVER-EXPRESSION OF INSULIN-LIKE GROWTH FACTOR- Ⅱ (IGF- Ⅱ ) AND IGF- Ⅱ RECEPTOR(IGF- Ⅱ R) GENES IN HUMAN PRIMARY CANCER-IMPLICATION OF AUTOCRINE AND PARACRINE MECHANISM IN AUTONOMOUS GROWTH OF HEPATIC CANCER

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.

Glutathione metabolism is essential for self-renewal and chemoresistance of pancreatic cancer stem cells

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.

A CRISPR-Cas9 screen shows the combination efficacy of lenvatinib plus epidermal growth factor receptor inhibitors for treatment of liver cancer

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.

Application of Paclitaxel-loaded EGFR Peptide-conjugated Magnetic Polymeric Liposomes for Liver Cancer Therapy

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.

Zinc finger E-box-binding homeobox 1 mediates aerobic glycolysis via suppression of sirtuin 3 in pancreatic cancer

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 and the impact of ZEB1 and lentivirus-mediated method, methyI-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.

Dietary fat intake and liver cancer risk: A prospective cohort study in Chinese women

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.