AIM:To study the mechanism of 5-fluorouracil(5-FU)resistance in colon cancer cells and to develop strategies for overcoming such resistance by combination treatment.METHODS:We established and characterized a 5-FU resi...AIM:To study the mechanism of 5-fluorouracil(5-FU)resistance in colon cancer cells and to develop strategies for overcoming such resistance by combination treatment.METHODS:We established and characterized a 5-FU resistance(5-FU-R)cell line derived from continuous exposure(25μmol/L)to 5-FU for 20 wk in 5-FU sensitive HCT-116 cells.The proliferation and expression of different representative apoptosis and anti-apoptosis markers in 5-FU sensitive and 5-FU resistance cells were measured by the MTT assay and by Western blotting,respectively,after treatment with Resveratrol(Res)and/or 1,3-Bis(2-chloroethyl)-1-nitrosourea(BCNU).Apoptosis and cell cycle arrest was measured by 4',6'-diamidino-2-phenylindole hydrochloride staining and fluorescence-activated cell sorting analysis,respectively.The extent of DNA damage was measured by the Comet assay.We measured the visible changes in the DNA damage/repair cascade by Western blotting.RESULTS:The widely used chemotherapeutic agents BCNU and Res decreased the growth of 5-FU sensitive HCT-116 cells in a dose dependent manner.Combined application of BCNU and Res caused more apoptosis in5-FU sensitive cells in comparison to individual treatment.In addition,the combined application of BCNU and Res caused a significant decrease of major DNA base excision repair components in 5-FU sensitive cells.We established a 5-FU resistance cell line(5-FU-R)from 5-FU-sensitive HCT-116(mismatch repair deficient)cells that was not resistant to other chemotherapeutic agents(e.g.,BCNU,Res)except 5-FU.The 5-FU resistance of 5-FU-R cells was assessed by exposure to increasing concentrations of 5-FU followed by the MTT assay.There was no significant cell death noted in5-FU-R cells in comparison to 5-FU sensitive cells after5-FU treatment.This resistant cell line overexpressed anti-apoptotic[e.g.,AKT,nuclear factorκB,FLICE-like inhibitory protein),DNA repair(e.g.,DNA polymerase beta(POL-β),DNA polymerase eta(POLH),protein Flap endonuclease 1(FEN1),DNA damage-binding protein 2(DDB2)]and 5-FU-resistance proteins(thymidylate synthase)but under expressed pro-apoptotic proteins(e.g.,DAB2,CK1)in comparison to the parental cells.Increased genotoxicity and apoptosis were observed in resistant cells after combined application of BCNU and Res in comparison to untreated or parental cells.BCNU increased the sensitivity to Res of 5-FU resistant cells compared with parental cells.Fifty percent cell death were noted in parental cells when 18μmol/L of Res was associated with fixed concentration(20μmol/L)of BCNU,but a much lower concentration of Res(8μmol/L)was needed to achieve the same effect in 5-FU resistant cells.Interestingly,increased levels of adenomatous polyposis coli and decreased levels POL-β,POLH,FEN1 and DDB2 were noted after the same combined treatment in resistant cells.CONCLUSION:BCNU combined with Res exerts a synergistic effect that may prove useful for the treatment of colon cancer and to overcome drug resistance.展开更多
microRNAs （miRNAs） are a class of non-coding RNAs that function as endogenous triggers of the RNA interference pathway. Studies have shown that thousands of human protein-coding genes are regulated by miRNAs, indica...microRNAs （miRNAs） are a class of non-coding RNAs that function as endogenous triggers of the RNA interference pathway. Studies have shown that thousands of human protein-coding genes are regulated by miRNAs, indicating that miRNAs are master regulators of many important biological processes, such as cancer development, miRNAs frequently have deregulated expression in many types of human cancers, and play critical roles in tumorigenesis, which functions either as tumor suppressors or as oncogenes. Recent studies have shown that miRNAs are highly related with cancer progression, including initiating, growth, apoptosis, invasion, and metastasis. Furthermore, miRNAs are shown to be responsible for the cancer-related inflam- mation, anti-cancer drug resistance, and regulation of cancer stem ceils. Therefore, miRNAs have generated great interest as a novel strategy in cancer diagnosis and therapy. Here we review the versatile roles of miRNAs in cancers and their potential applications for diagnosis, prognosis, and treatment as biomarkers.展开更多
Objective： To evaluate the efficacy and feasibility of screening procedure for upper gastrointestinal cancer in both high-risk and non-high-risk areas in China. Setting： Seven cities/counties, representing three eco...Objective： To evaluate the efficacy and feasibility of screening procedure for upper gastrointestinal cancer in both high-risk and non-high-risk areas in China. Setting： Seven cities/counties, representing three economical-geographical regions （Eastern, Central and Western） in China, were selected as screening centers： three in high-risk areas and four in non-high-risk areas. Participants： Villages/communities in these seven centers regarded as clusters were randomly assigned to either intervention group （screening by endoscopic examination） or control group （with normal community care） in a 1：1 ratio stratified by each center. Eligible participants are local residents aged 40-69 years in the selected villages/communities with no history of cancer or endoscopic examination in the latest 3 years who are mentally and physically competent. Those who are not willing to take endoscopic examination or are unwilling to sign the consent form are excluded from the study. Totally 140,000 participants will be enrolled. Interventions： In high-risk areas of upper gastrointestinal cancer, all subjects in screening group will be screened by endoscopy. In non-high-risk areas, 30% of the subjects in screening group, identified through a survey, will be screened by endoscopy. Primary and secondary outcome measures： The primary outcome is the mortality caused by upper gastrointestinal cancer. The secondary outcomes include detection rate, incidence rate, survival rate, and clinical stage distribution. Additional data on quality of life and cost-effectiveness will also be collected to answer important questions regarding screening effects. Conclusions： Screening strategy evaluated in those areas with positive findings may be promoted nationally and applied to the majority of Chinese people. On the other hand, negative findings will provide scientific evidence for abandoning a test and shifting resources elsewhere. Trial registration： The study has been registered with the Protocol Registration System in Chinese Clinical Trial Registry （identifier： ChiCTR-EOR-16008577）.展开更多
Objective：We assessed the trends in lung cancer incidence over a 25-year period by socioeconomic groups for men in New South Wales（NSW）,Australia.Methods：Men diagnosed with lung cancer between 1987 and 2011 were d...Objective：We assessed the trends in lung cancer incidence over a 25-year period by socioeconomic groups for men in New South Wales（NSW）,Australia.Methods：Men diagnosed with lung cancer between 1987 and 2011 were divided into five quintiles according to an Index of Education and Occupation（IEO）.We assessed relative socioeconomic differences over time by calculating age-standardized incidence ratios（SIRs）by 5-year period of diagnosis,and estimated absolute differences by comparing the observed and expected numbers of cases using the highest IEO quintile as the reference.Results：Lung cancer incidence for men decreased from 1987 to 2011 for all IEO quintiles,with a greater rate of decline for men living in the highest IEO areas.Thus,the relative disparity increased significantly over the 25-year period（P=0.0006）.For example,the SIR for the lowest IEO quintile increased from 1.28 during 1987–1991 to 1.74during 2007–2011.Absolute differences also increased with the proportion of＂potentially preventable＂cases doubling from 14.5% in 1987–1991 to 30.2% in 2007–2011.Conclusions：Despite the overall decline in lung cancer incidence among men in NSW over the past 25 years,there was a significant increase in disparity across socioeconomic areas in both relative and absolute terms.展开更多
Management of biliary tract cancer remains challenging. Tumors show high recurrence rates and therapeutic resistance, leading to dismal prognosis and short survival. The cancer stem cell model states that a tumor is a...Management of biliary tract cancer remains challenging. Tumors show high recurrence rates and therapeutic resistance, leading to dismal prognosis and short survival. The cancer stem cell model states that a tumor is a heterogeneous conglomerate of cells, in which a certain subpopulation of cells-the cancer stem cells-possesses stem cell properties. Cancer stem cells have high clinical relevance due to their potential contributions to development, progression and aggressiveness as well as recurrence and metastasis of malignant tumors. Consequently, reliable identification of as well as pharmacological intervention with cancer stem cells is an intensively investigated and promising research field. The involvement of cancer stem cells in biliary tract cancer is likely as a number of studies demonstrated their existence and the obvious clinical relevance of several established cancer stem cell markers in biliary tract cancer models and tissues. In the present article, we review and discuss the currently available literature addressing the role of putative cancer stem cells in biliary tract cancer as well as the connection between known contributors of biliary tract tumorigenesis such as oncogenic signaling pathways, micro-RNAs and the tumor microenvironment with cancer stem cells.展开更多
Prostate cancer (PCa) represents the most frequent urologic diagnosis in elderly males. We have previously shown that exposure of prostate to lipopolysaccharide (LPS) promotes cancer risk. We investigated the effect o...Prostate cancer (PCa) represents the most frequent urologic diagnosis in elderly males. We have previously shown that exposure of prostate to lipopolysaccharide (LPS) promotes cancer risk. We investigated the effect of non-selective cyclooxygenase (COX) inhibition on prostate inflammation-mediated cancer risk in vivo. The prostates of male rats were inoculated with E. coli as sources of inflammatory molecules (LPS) and were treated with COX inhibitor, aspirin 2 mg/Kg orally for 14 days or PBS. Oxidative stress was induced with two 2 mls of hydrogen peroxide orally twice daily or PBS for 14 days;they were either treated with COX inhibitor or PBS for another 14 days. Blood was collected and analyzed for acid phosphatase and PSA. Data showed presences of LPS in the prostate of the rats resulted in gradual increase in PSA when compared to control (P < 0.0001). However, COX inhibition resulted in statistically significant reduction in concentration of PSA level compared to control group (P < 0.0001). To understand if oxidative stress mechanism was involved in the inflammation mediated increase in PSA, data showed that rats exposed to H<sub>2</sub>O<sub>2</sub> had 2.5 fold increase in acid phosphatase (ACP) compared control (P < 0.0001), and by inhiting COX activity, a statistically significant reduction in ACP from 11.2 IU/L ± 0.67 to 5.7 IU/L ± 0.347 (P < 0.0034) was observed. Thus since increased in PSA was associated to cancer risk, our data suggested that inflammation mediated prostate cancer risk was reversible by Inhibition of COX Activity in rats.展开更多
Objective Several epidemiological observational studies have related particulate matter(PM)exposure to Inflammatory bowel disease(IBD),but many confounding factors make it difficult to draw causal links from observati...Objective Several epidemiological observational studies have related particulate matter(PM)exposure to Inflammatory bowel disease(IBD),but many confounding factors make it difficult to draw causal links from observational studies.The objective of this study was to explore the causal association between PM_(2.5)exposure,its absorbance,and IBD.Methods We assessed the association of PM_(2.5)and PM_(2.5)absorbance with the two primary forms of IBD(Crohn’s disease[CD]and ulcerative colitis[UC])using Mendelian randomization(MR)to explore the causal relationship.We conducted two-sample MR analyses with aggregated data from the UK Biobank genome-wide association study.Single-nucleotide polymorphisms linked with PM_(2.5)concentrations or their absorbance were used as instrumental variables(IVs).We used inverse variance weighting(IVW)as the primary analytical approach and four other standard methods as supplementary analyses for quality control.Results The results of MR demonstrated that PM_(2.5)had an adverse influence on UC risk(odds ratio[OR]=1.010;95%confidence interval[CI]=1.001–1.019,P=0.020).Meanwhile,the results of IVW showed that PM_(2.5)absorbance was also causally associated with UC(OR=1.012;95%CI=1.004–1.019,P=0.002).We observed no causal relationship between PM_(2.5),PM_(2.5)absorbance,and CD.The results of sensitivity analysis indicated the absence of heterogeneity or pleiotropy,ensuring the reliability of MR results.Conclusion Based on two-sample MR analyses,there are potential positive causal relationships between PM_(2.5),PM_(2.5)absorbance,and UC.展开更多
Cervical cancer is a worldwide disease that constitutes a significant public health problem, especially in developing countries, not only due to its high incidence but also because the most affected population compris...Cervical cancer is a worldwide disease that constitutes a significant public health problem, especially in developing countries, not only due to its high incidence but also because the most affected population comprises women who belong to marginalized socio-economic classes. Clinical and molecular research has identified immunological impairment in squamous intraepithelial cervical lesions and cervical cancer patients. Human Papillomavirus(HPV) has several mechanisms for avoiding the immune system: it down-regulates the expression of interferon and upregulates interleukin(IL)-10and transforming growth factor(TGF)-β1 to produce a local immunosuppressive environment, which, along with altered tumor surface antigens, forms an immunosuppressive network that inhibits the antitumor immune response. In this review we analyzed the available data on several deregulated cellular immune functions in patients with NIC Ⅰ, NIC Ⅱ and NIC Ⅲ and cervical cancer. The effects of immunosuppressive cytokines on innate immune response, T-cell activation and cellular factors that promote tumor cell proliferation in cervical cancer patients are summarized. We discuss the functional consequences of HPV E2, E6, and E7 protein interactions with IL-10 and TGF-β1 promoters in the induction of these cytokines and postulate its effect on the cellular immune response in squamous intraepithelial cervical lesions and cervical cancer patients. This review provides a comprehensive picture of the immunological functions of IL-10 and TGF-β1 in response to HPV in humans.展开更多
AIM To elucidate the role of STAT3 in hepatocarcinogenesis and biliary ductular proliferation following chronic liver injury. METHODS We investigated thioacetamide(TAA)-induced liver injury, compensatory hepatocyte pr...AIM To elucidate the role of STAT3 in hepatocarcinogenesis and biliary ductular proliferation following chronic liver injury. METHODS We investigated thioacetamide(TAA)-induced liver injury, compensatory hepatocyte proliferation, and hepatocellular carcinoma(HCC) development in hepatic STAT3-deficient mice. In addition, we evaluated TAAinduced biliary ductular proliferation and analyzed the activation of sex determining region Y-box9(SOX9) and Yes-associated protein(YAP), which regulate the transdifferentiation of hepatocytes to cholangiocytes.RESULTS Both compensatory hepatocyte proliferation and HCC formation were significantly decreased in hepatic STAT3-deficient mice as compared with control mice. STAT3 deficiency resulted in augmentation of hepatic necrosis and fibrosis. On the other hand, biliary ductular proliferation increased in hepatic STAT3-deficient livers as compared with control livers. SOX9 and YAP were upregulated in hepatic STAT3-deficient hepatocytes.CONCLUSION STAT3 may regulate hepatocyte proliferation as well as transdifferentiation into cholangiocytes and serve as a therapeutic target for HCC inhibition and biliary regeneration.展开更多
AIM: To investigate whether vascular endothelial growth factor (VEGF) and basic fibroblastic growth factor (bFGF) are associated wibh spider angiomas in patients wibh liver cirrhosis. METHODS: Eighty-six patients with...AIM: To investigate whether vascular endothelial growth factor (VEGF) and basic fibroblastic growth factor (bFGF) are associated wibh spider angiomas in patients wibh liver cirrhosis. METHODS: Eighty-six patients with liver cirrhosis were enrolled and the number and size of the spider angiomas were recorded. Fifty-three healthy subjects were selected as controls. Plasma levels of VEGF and bFGF were measured in both the cirrhotics and the controls. RESULTS: Plasma VEGF and bFGF were increased in cirrhotics compared with controls (122±13 vs. 71±11 pg/mL, P=0.003 for VEGF; 5.1±0.5 vs. 3.4±0.5 pg/mL, P=0.022 for bFGF). In cirrhotics, plasma VEGF and bFGF were also higher in patients with spider angiomas compared with patients without spider angiomas (185±28 vs. 90±10 pg/mL, P=-0.003 for VEGF; 6.8±1.0 vs. 4.1±0.5 pg/mL, P=0.017 for bFGF). Multivariate logistic regression showed that young age and increased plasma levels of VEGF and bFGF were the most significant predictors for the presence of spider angiomas in cirrhotic patients (odds ratio [OR]=6.64, 95% confidence interval[CI]=2.02-21.79, P=0.002; OR=4.35, 95% CI=1.35-14.01,P=0.014; OR=5.66, 95% CI=1.72-18.63, P=0.004, respectively). CONCLUSION: Plasma VEGF and bFGF are elevated inpatients with liver cirrhosis. Age as well as plasma levels of VEGF and bFGF are significant predictors for spider angiomas in cirrhotic patients.展开更多
AIM: To systematically review the available evidence regarding cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC) for colorectal peritoneal metastases (CPM).
Background The COVID-19 pandemic has drastically increased demands on healthcare workers(HCWs)leaving them vulnerable to acute psychological distress,burnout and post-traumatic stress.In response,supportive services i...Background The COVID-19 pandemic has drastically increased demands on healthcare workers(HCWs)leaving them vulnerable to acute psychological distress,burnout and post-traumatic stress.In response,supportive services in a central London hospital mobilised mental health support specifically for HCWs.Aims This rapid evaluation assessed HCW psychological welfare during the acute phase of the COVID-19 pandemic and their use of supportive services made available.Methods During the acute phase of COVID-19(April to May 2020)all staff working for the hospital were invited to complete an online survey assessing well-being(self-rated health,moral distress exposure,symptoms of burnout and psychological distress)and use of available supportive services(awareness of,use and perceived helpfulness).Associations among personal characteristics and psychological well-being were explored using correlations and linear regression.Results A total of 1127 staff participated in the rapid evaluation.On average,psychological distress was high(mean(SD):22(7.57))regardless of role,with 84%of this sample scoring above the general population mean(14.5).Nearly half of the sample reported feeling emotionally drained and a profile emerged displaying higher levels of psychological distress and burnout in those who were younger and exposed to morally distressing situations,with this group also exhibiting greater support service use.Greater levels of burnout were associated with increased psychological distress when controlling for personal factors.During this acute phase of the pandemic,majority of staff used at least one service and rated it as helpful.Conclusion HCWs experienced high levels of psychological distress requiring continued support as the COVID-19 pandemic evolved.Although HCWs were aware of supportive services,uptake varied.In order to mitigate the risk of burnout and post-traumatic stress,long-term,effective strategies that facilitate staff accessing support are urgently required.展开更多
A 73-year-old man underwent endoscopic mucosal resection(EMR) of a 20-mm flat elevated lesion on the transverse colon. The morning after the procedure, he started to have severe right upper quadrant pain after his fir...A 73-year-old man underwent endoscopic mucosal resection(EMR) of a 20-mm flat elevated lesion on the transverse colon. The morning after the procedure, he started to have severe right upper quadrant pain after his first meal. A computed tomography scan revealed free air and a stomach filled with food. He was diagnosed to have delayed post-EMR intestinal perforation. He underwent emergent colonoscopy and clipping of the perforated site. He was discharged 8 d after the endoscopic closure without the need for surgical intervention. The meal was not the cause of the colon transversum perforation.展开更多
A series of 8-substituted alkyl xanthines were evaluated in vitro to test the cytotoxocity in cells. For this experiment, we utilized different mammalian cancer cell lines primarily representing prostrate and lung. On...A series of 8-substituted alkyl xanthines were evaluated in vitro to test the cytotoxocity in cells. For this experiment, we utilized different mammalian cancer cell lines primarily representing prostrate and lung. One of the compounds synthesized, viz. 8-tertbutyl caffeine showed potent anticancer activity at low concentrations against DU145 when compared to adriamycin. Further experiments were carried out to check the cell cycle arrest in the DU145 cells treated with adriamycin, caffeine and 8-tert butyl caffeine. We observed that there was an arrest in G1 phase of cell cycle at 24 hours while at 48 hours of incubation, the cells were constantly distributed (59.71% -70.79%). We conclude that the effect of 8-tertbutyl caffeine is relatively comparable to caffeine whereas in adriamycin treated cells, we observed the cells underwent G2 arrest. We evaluate the studies on these effects by showing potent analogues which could be used as promising anticancer agents.展开更多
This research was designed to analyze the possible associations of Arg389 Gly ADRB1 and Trp64 Arg ADRB3polymorphisms in children with obesity.A cross-sectional study included 1,046 school-age Mexican participants（6-1...This research was designed to analyze the possible associations of Arg389 Gly ADRB1 and Trp64 Arg ADRB3polymorphisms in children with obesity.A cross-sectional study included 1,046 school-age Mexican participants（6-12 years old） from the cities of San Luis Potosi and Leon.Children were classified as non-obese or obese according to their body mass index（BMI） percentile;obese children had a BMI≥95th percentile for sex and age.Biochemical data were collected.Polymorphisms were detected using TaqMan qPCR assay.A logistic regression analysis was used to calculate the risk of obesity based on genotypes.Differences were found between groups where obese children had a significant increase in systolic and diastolic blood pressure,fasting plasma glucose,insulin,HOMAIR,LDL-cholesterol,triglycerides,and lower HDL-cholesterol compared with the normal weight group（P 〈 0.05）.The distribution of allele frequency in the population was Arg = 87.4 and Gly = 12.6（Hardy Weinberg equilibrium x^2= 3.16,P = 0.07）;Trp = 81.5 and Arg= 18.5（Hardy Weinberg equilibrium x^2 = 2.2,P = 0.14） for ADRB1 and ADRB3,respectively.Even though no different frequencies of Arg389 Gly polymoiphism between groups were found（P = 0.08）,children carriers of one Gly389,ADRB1 allele had a risk for obesity of OR = 1.40（95%CI,1.03-1.90,P =0.03） after adjustment for age and gender.No other association was found for Trp64 Arg ADRB3 polymorphism.Only the Arg389 Gly ADRB1 polymorphism was associated with risk for obesity in Mexican children.展开更多
Context Drug-induced hepatotoxicity represents a significant proportion of liver disease cases. Currently, there is no effective treatment. To date efforts to identify treatment regimen that can reverse progressive da...Context Drug-induced hepatotoxicity represents a significant proportion of liver disease cases. Currently, there is no effective treatment. To date efforts to identify treatment regimen that can reverse progressive damage have not been successful. We have previously shown that extract from Moringa (M) oleifera possesses clinically relevant antidiabetic and electrolyte modulators. Objective The aim of the current studies is to create experimental model of xenobiotic induced liver damage and investigate if treatment with lipophilic extract of M. oleifera could biochemically reverse progressive liver damage. Materials and Method For two groups of healthy rats, 7 in each group received 200 mg of extract or vehicle twice daily for 14 days. Acute toxicity, hepatotoxicity and hematologic/endothelial toxicity were monitored. Then 30 rats weighing 130 - 200 g received repeated dose of acetaminophen (xenobiotics) (640 mg/kg) for 5 days. Hepatotoxicity was confirmed biochemically by an established protocol. Treatment with M. oleifera extract resulted in mean weight of 132.2 ± 5.05 compared to the control with 134.1 ± 5.08 (P > 0.8115) among the healthy rats. Their LDH levels were 170.7 ± 13.02 and 133.8 ± 7.17 (P > 0.0698) for controls group, while the mean serum (ALT) level was 12.4 ± 1.2 or 25.6 ± 5.644 (P M. oleifera resulted in 100% biochemical recovery from hepatitis compared to the control group (P M. oleifera could effectively and biochemically abrogate xenobiotics induced liver damage in animal model.展开更多
We aimed to evaluate the efficacy and safety of adding apatinib,to sintilimab and chemotherapy in the neoadjuvant treatment of early triple-negative breast cancer(TNBC).In the phase 2 NeoSAC trial,patients with early ...We aimed to evaluate the efficacy and safety of adding apatinib,to sintilimab and chemotherapy in the neoadjuvant treatment of early triple-negative breast cancer(TNBC).In the phase 2 NeoSAC trial,patients with early TNBC received six cycles of apatinib,sintilimab,nab-paclitaxel,and carboplatin followed by surgery.The primary endpoint was pathological complete response(pCR)rate.Specimens collected pre-neoadjuvant therapy and post-surgery were retained for comprehensive analysis of predictive biomarkers and the impact on the tumor microenvironment.Among 34 enrolled patients,24 achieved pCR(70.6%;95%confidence interval(CI),53.0-85.3),and 79.4%(95%CI,65.1-93.7)had residual cancer burden 0-I.Imaging evaluation showed 21 complete responses(61.8%)and 13 partial responses(38.2%).The most common grade 3-4 adverse events were leukopenia(47%),neutropenia(36%),and thrombocytopenia(24%).The 36-month disease-free survival rate stood at 94.1%with a median follow-up of 39.1 months.Notably,baseline high ImmuneScore,immune cell infiltration,and enrichment of interferon-related pathways correlated with pCR.Comparison of pre-neoadjuvant and post-surgery data revealed that the pCR group treated with this novel regimen exhibited an upregulation of distinct immune cell subsets,thereby activating the tumor microenvironment.Moreover,higher oxeiptosis scores were associated with an increased likelihood of achieving pCR.Following neoadjuvant therapy,the pCR group showed a decrease in oxeiptosis score,whereas the non-pCR group exhibited an increase.Our study suggests that apatinib,sintilimab combined with carboplatin and nab-paclitaxel chemotherapy showed a promising clinical activity and manageable safety profile in early TNBC and merits further study.ClinicalTrials.gov registration:NCT04722718.展开更多
Gastric cancer is a major global health challenge,associated with high mortality and limited therapeutic options.Ginsenoside Rg3(Rg3),a bioactive compound derived from ginseng,has been shown to possess significant ant...Gastric cancer is a major global health challenge,associated with high mortality and limited therapeutic options.Ginsenoside Rg3(Rg3),a bioactive compound derived from ginseng,has been shown to possess significant anticancer properties,particularly through immune modulation.In this study,we explored the therapeutic potential of Ginsenoside Rg3 hydrogel in the treatment of gastric cancer,focusing on its ability to target fibroblast activation protein(FAP),a key mediator of tumor progression.Using reverse molecular docking and gene expression analysis,we identified FAP as a primary molecular target of Rg3.Preclinical evaluations revealed that Rg3 hydrogel effectively inhibited the proliferation and invasion of gastric cancer cells in vitro.Furthermore,the hydrogel promoted immunogenic cell death,resulting in a robust immune response against the tumor.Our findings suggest that Ginsenoside Rg3 hydrogel holds promise as a novel immune-based therapeutic strategy for gastric cancer,offering a potential pathway to improved clinical outcomes and treatment strategies.展开更多
Background:Breast cancer is a highly heterogeneous disease,characterized by tumor and nontumor cells at various cell states.Ecotyper is an innovative machine learning framework that quantifies the tumor microenvironme...Background:Breast cancer is a highly heterogeneous disease,characterized by tumor and nontumor cells at various cell states.Ecotyper is an innovative machine learning framework that quantifies the tumor microenvironment and delineates the tumor ecosystem,demonstrating clinical significance.However,further validation is needed in breast cancer.Methods:Ecotyper was applied to identify multiple cellular states and tumor ecotypes using large-scale breast cancer bulk sequencing data,followed by a detailed analysis of their associations with clinical classification,molecular subtypes,survival prognosis,and immunotherapy response.Identified subtypes were further characterized using single-cell and spatial data sets to reveal molecular profiles.Results:In a comprehensive analysis of 6578 breast cancer samples from four data sets,Ecotyper identified 69 cellular states and 10 tumor ecotypes.Of these,37 cellular states significantly correlated with overall survival.Notably,specific states within epithelial cells,macrophages/monocytes,and fibroblasts were linked to a worse prognosis.CE2 abundance was identified as the most significant marker indicating unfavorable prognosis and was further validated in an additional data set of 116 HER2-negative patients.These biomarkers also indicated the efficacy of neoadjuvant immunotherapy in breast cancer.CE2-high cancers were characterized by an abundance of basal-like epithelial cells,scant lymphocytic infiltration,and activation of hypoxia signaling.Single-cell analysis showed that CE2-high areas were rich in SPP1-positive tumor-associated macrophages(TAM),basal-like epithelial cells,and hypoxic cancer-associated fibroblasts(CAF).Spatially,these regions were often peripheral in triple-negative breast cancer,adjacent to fibrotic/necrotic zones.Multiplex immunofluorescence confirmed the enrichment of SPP1+CD68+TAM and HIF1A+SMA+CAF in hypoxic triple-negative breast cancer(TNBC)regions.展开更多
基金Supported by Indian Council of Medical Research and Department of Biotechnology,Government of India
文摘AIM:To study the mechanism of 5-fluorouracil(5-FU)resistance in colon cancer cells and to develop strategies for overcoming such resistance by combination treatment.METHODS:We established and characterized a 5-FU resistance(5-FU-R)cell line derived from continuous exposure(25μmol/L)to 5-FU for 20 wk in 5-FU sensitive HCT-116 cells.The proliferation and expression of different representative apoptosis and anti-apoptosis markers in 5-FU sensitive and 5-FU resistance cells were measured by the MTT assay and by Western blotting,respectively,after treatment with Resveratrol(Res)and/or 1,3-Bis(2-chloroethyl)-1-nitrosourea(BCNU).Apoptosis and cell cycle arrest was measured by 4',6'-diamidino-2-phenylindole hydrochloride staining and fluorescence-activated cell sorting analysis,respectively.The extent of DNA damage was measured by the Comet assay.We measured the visible changes in the DNA damage/repair cascade by Western blotting.RESULTS:The widely used chemotherapeutic agents BCNU and Res decreased the growth of 5-FU sensitive HCT-116 cells in a dose dependent manner.Combined application of BCNU and Res caused more apoptosis in5-FU sensitive cells in comparison to individual treatment.In addition,the combined application of BCNU and Res caused a significant decrease of major DNA base excision repair components in 5-FU sensitive cells.We established a 5-FU resistance cell line(5-FU-R)from 5-FU-sensitive HCT-116(mismatch repair deficient)cells that was not resistant to other chemotherapeutic agents(e.g.,BCNU,Res)except 5-FU.The 5-FU resistance of 5-FU-R cells was assessed by exposure to increasing concentrations of 5-FU followed by the MTT assay.There was no significant cell death noted in5-FU-R cells in comparison to 5-FU sensitive cells after5-FU treatment.This resistant cell line overexpressed anti-apoptotic[e.g.,AKT,nuclear factorκB,FLICE-like inhibitory protein),DNA repair(e.g.,DNA polymerase beta(POL-β),DNA polymerase eta(POLH),protein Flap endonuclease 1(FEN1),DNA damage-binding protein 2(DDB2)]and 5-FU-resistance proteins(thymidylate synthase)but under expressed pro-apoptotic proteins(e.g.,DAB2,CK1)in comparison to the parental cells.Increased genotoxicity and apoptosis were observed in resistant cells after combined application of BCNU and Res in comparison to untreated or parental cells.BCNU increased the sensitivity to Res of 5-FU resistant cells compared with parental cells.Fifty percent cell death were noted in parental cells when 18μmol/L of Res was associated with fixed concentration(20μmol/L)of BCNU,but a much lower concentration of Res(8μmol/L)was needed to achieve the same effect in 5-FU resistant cells.Interestingly,increased levels of adenomatous polyposis coli and decreased levels POL-β,POLH,FEN1 and DDB2 were noted after the same combined treatment in resistant cells.CONCLUSION:BCNU combined with Res exerts a synergistic effect that may prove useful for the treatment of colon cancer and to overcome drug resistance.
基金supported by National Natural Science Foundation of China grants (No. 30872889, 81072215, 81001210, 81172580)Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry (No. 20098-8-2)+1 种基金State Key Laboratory of Oral Diseases Open Funding (SKLODOF2010-05)the Fundamental Research Funds of the Central Universities of China (2011)
文摘microRNAs （miRNAs） are a class of non-coding RNAs that function as endogenous triggers of the RNA interference pathway. Studies have shown that thousands of human protein-coding genes are regulated by miRNAs, indicating that miRNAs are master regulators of many important biological processes, such as cancer development, miRNAs frequently have deregulated expression in many types of human cancers, and play critical roles in tumorigenesis, which functions either as tumor suppressors or as oncogenes. Recent studies have shown that miRNAs are highly related with cancer progression, including initiating, growth, apoptosis, invasion, and metastasis. Furthermore, miRNAs are shown to be responsible for the cancer-related inflam- mation, anti-cancer drug resistance, and regulation of cancer stem ceils. Therefore, miRNAs have generated great interest as a novel strategy in cancer diagnosis and therapy. Here we review the versatile roles of miRNAs in cancers and their potential applications for diagnosis, prognosis, and treatment as biomarkers.
基金supported by the Special Fund for Health Research in the Public Interest(No.201502001)
文摘Objective： To evaluate the efficacy and feasibility of screening procedure for upper gastrointestinal cancer in both high-risk and non-high-risk areas in China. Setting： Seven cities/counties, representing three economical-geographical regions （Eastern, Central and Western） in China, were selected as screening centers： three in high-risk areas and four in non-high-risk areas. Participants： Villages/communities in these seven centers regarded as clusters were randomly assigned to either intervention group （screening by endoscopic examination） or control group （with normal community care） in a 1：1 ratio stratified by each center. Eligible participants are local residents aged 40-69 years in the selected villages/communities with no history of cancer or endoscopic examination in the latest 3 years who are mentally and physically competent. Those who are not willing to take endoscopic examination or are unwilling to sign the consent form are excluded from the study. Totally 140,000 participants will be enrolled. Interventions： In high-risk areas of upper gastrointestinal cancer, all subjects in screening group will be screened by endoscopy. In non-high-risk areas, 30% of the subjects in screening group, identified through a survey, will be screened by endoscopy. Primary and secondary outcome measures： The primary outcome is the mortality caused by upper gastrointestinal cancer. The secondary outcomes include detection rate, incidence rate, survival rate, and clinical stage distribution. Additional data on quality of life and cost-effectiveness will also be collected to answer important questions regarding screening effects. Conclusions： Screening strategy evaluated in those areas with positive findings may be promoted nationally and applied to the majority of Chinese people. On the other hand, negative findings will provide scientific evidence for abandoning a test and shifting resources elsewhere. Trial registration： The study has been registered with the Protocol Registration System in Chinese Clinical Trial Registry （identifier： ChiCTR-EOR-16008577）.
文摘Objective：We assessed the trends in lung cancer incidence over a 25-year period by socioeconomic groups for men in New South Wales（NSW）,Australia.Methods：Men diagnosed with lung cancer between 1987 and 2011 were divided into five quintiles according to an Index of Education and Occupation（IEO）.We assessed relative socioeconomic differences over time by calculating age-standardized incidence ratios（SIRs）by 5-year period of diagnosis,and estimated absolute differences by comparing the observed and expected numbers of cases using the highest IEO quintile as the reference.Results：Lung cancer incidence for men decreased from 1987 to 2011 for all IEO quintiles,with a greater rate of decline for men living in the highest IEO areas.Thus,the relative disparity increased significantly over the 25-year period（P=0.0006）.For example,the SIR for the lowest IEO quintile increased from 1.28 during 1987–1991 to 1.74during 2007–2011.Absolute differences also increased with the proportion of＂potentially preventable＂cases doubling from 14.5% in 1987–1991 to 30.2% in 2007–2011.Conclusions：Despite the overall decline in lung cancer incidence among men in NSW over the past 25 years,there was a significant increase in disparity across socioeconomic areas in both relative and absolute terms.
基金Supported by Studies of the authors Mayr C,Pichler M,Neureiter D and Kiesslich T in the research field of this review were supported by research grants of the Jubilaumsfonds derosterreichischen Nationalbank,No.12677 and No.14842the research fund of the Paracelsus Medical University Salzburg,No.08/07/037,No.A-12/02/006-KIE and No.R-16/03/083-MAY
文摘Management of biliary tract cancer remains challenging. Tumors show high recurrence rates and therapeutic resistance, leading to dismal prognosis and short survival. The cancer stem cell model states that a tumor is a heterogeneous conglomerate of cells, in which a certain subpopulation of cells-the cancer stem cells-possesses stem cell properties. Cancer stem cells have high clinical relevance due to their potential contributions to development, progression and aggressiveness as well as recurrence and metastasis of malignant tumors. Consequently, reliable identification of as well as pharmacological intervention with cancer stem cells is an intensively investigated and promising research field. The involvement of cancer stem cells in biliary tract cancer is likely as a number of studies demonstrated their existence and the obvious clinical relevance of several established cancer stem cell markers in biliary tract cancer models and tissues. In the present article, we review and discuss the currently available literature addressing the role of putative cancer stem cells in biliary tract cancer as well as the connection between known contributors of biliary tract tumorigenesis such as oncogenic signaling pathways, micro-RNAs and the tumor microenvironment with cancer stem cells.
文摘Prostate cancer (PCa) represents the most frequent urologic diagnosis in elderly males. We have previously shown that exposure of prostate to lipopolysaccharide (LPS) promotes cancer risk. We investigated the effect of non-selective cyclooxygenase (COX) inhibition on prostate inflammation-mediated cancer risk in vivo. The prostates of male rats were inoculated with E. coli as sources of inflammatory molecules (LPS) and were treated with COX inhibitor, aspirin 2 mg/Kg orally for 14 days or PBS. Oxidative stress was induced with two 2 mls of hydrogen peroxide orally twice daily or PBS for 14 days;they were either treated with COX inhibitor or PBS for another 14 days. Blood was collected and analyzed for acid phosphatase and PSA. Data showed presences of LPS in the prostate of the rats resulted in gradual increase in PSA when compared to control (P < 0.0001). However, COX inhibition resulted in statistically significant reduction in concentration of PSA level compared to control group (P < 0.0001). To understand if oxidative stress mechanism was involved in the inflammation mediated increase in PSA, data showed that rats exposed to H<sub>2</sub>O<sub>2</sub> had 2.5 fold increase in acid phosphatase (ACP) compared control (P < 0.0001), and by inhiting COX activity, a statistically significant reduction in ACP from 11.2 IU/L ± 0.67 to 5.7 IU/L ± 0.347 (P < 0.0034) was observed. Thus since increased in PSA was associated to cancer risk, our data suggested that inflammation mediated prostate cancer risk was reversible by Inhibition of COX Activity in rats.
基金supported by the National Natural Science Foundation of China(No.82303169)the Key Research and Development Program of Shaanxi(No.2021ZDLSF02-06).
文摘Objective Several epidemiological observational studies have related particulate matter(PM)exposure to Inflammatory bowel disease(IBD),but many confounding factors make it difficult to draw causal links from observational studies.The objective of this study was to explore the causal association between PM_(2.5)exposure,its absorbance,and IBD.Methods We assessed the association of PM_(2.5)and PM_(2.5)absorbance with the two primary forms of IBD(Crohn’s disease[CD]and ulcerative colitis[UC])using Mendelian randomization(MR)to explore the causal relationship.We conducted two-sample MR analyses with aggregated data from the UK Biobank genome-wide association study.Single-nucleotide polymorphisms linked with PM_(2.5)concentrations or their absorbance were used as instrumental variables(IVs).We used inverse variance weighting(IVW)as the primary analytical approach and four other standard methods as supplementary analyses for quality control.Results The results of MR demonstrated that PM_(2.5)had an adverse influence on UC risk(odds ratio[OR]=1.010;95%confidence interval[CI]=1.001–1.019,P=0.020).Meanwhile,the results of IVW showed that PM_(2.5)absorbance was also causally associated with UC(OR=1.012;95%CI=1.004–1.019,P=0.002).We observed no causal relationship between PM_(2.5),PM_(2.5)absorbance,and CD.The results of sensitivity analysis indicated the absence of heterogeneity or pleiotropy,ensuring the reliability of MR results.Conclusion Based on two-sample MR analyses,there are potential positive causal relationships between PM_(2.5),PM_(2.5)absorbance,and UC.
基金Supported by The Instituto Nacional de Salud PúblicaMexicoby the grant from CONACYT-FOSISS SALUD2008-C01-494 87701,Mexico
文摘Cervical cancer is a worldwide disease that constitutes a significant public health problem, especially in developing countries, not only due to its high incidence but also because the most affected population comprises women who belong to marginalized socio-economic classes. Clinical and molecular research has identified immunological impairment in squamous intraepithelial cervical lesions and cervical cancer patients. Human Papillomavirus(HPV) has several mechanisms for avoiding the immune system: it down-regulates the expression of interferon and upregulates interleukin(IL)-10and transforming growth factor(TGF)-β1 to produce a local immunosuppressive environment, which, along with altered tumor surface antigens, forms an immunosuppressive network that inhibits the antitumor immune response. In this review we analyzed the available data on several deregulated cellular immune functions in patients with NIC Ⅰ, NIC Ⅱ and NIC Ⅲ and cervical cancer. The effects of immunosuppressive cytokines on innate immune response, T-cell activation and cellular factors that promote tumor cell proliferation in cervical cancer patients are summarized. We discuss the functional consequences of HPV E2, E6, and E7 protein interactions with IL-10 and TGF-β1 promoters in the induction of these cytokines and postulate its effect on the cellular immune response in squamous intraepithelial cervical lesions and cervical cancer patients. This review provides a comprehensive picture of the immunological functions of IL-10 and TGF-β1 in response to HPV in humans.
基金Supported by JSp S Grant-in-Aid for Scientific Research(C)No.16K09385 to Torimura T
文摘AIM To elucidate the role of STAT3 in hepatocarcinogenesis and biliary ductular proliferation following chronic liver injury. METHODS We investigated thioacetamide(TAA)-induced liver injury, compensatory hepatocyte proliferation, and hepatocellular carcinoma(HCC) development in hepatic STAT3-deficient mice. In addition, we evaluated TAAinduced biliary ductular proliferation and analyzed the activation of sex determining region Y-box9(SOX9) and Yes-associated protein(YAP), which regulate the transdifferentiation of hepatocytes to cholangiocytes.RESULTS Both compensatory hepatocyte proliferation and HCC formation were significantly decreased in hepatic STAT3-deficient mice as compared with control mice. STAT3 deficiency resulted in augmentation of hepatic necrosis and fibrosis. On the other hand, biliary ductular proliferation increased in hepatic STAT3-deficient livers as compared with control livers. SOX9 and YAP were upregulated in hepatic STAT3-deficient hepatocytes.CONCLUSION STAT3 may regulate hepatocyte proliferation as well as transdifferentiation into cholangiocytes and serve as a therapeutic target for HCC inhibition and biliary regeneration.
基金grant NSC 89-2315-B-075-004 from the National Science Councilgrant VGH 90-070 from Taipei Veterans General Hospital,Taiwan
文摘AIM: To investigate whether vascular endothelial growth factor (VEGF) and basic fibroblastic growth factor (bFGF) are associated wibh spider angiomas in patients wibh liver cirrhosis. METHODS: Eighty-six patients with liver cirrhosis were enrolled and the number and size of the spider angiomas were recorded. Fifty-three healthy subjects were selected as controls. Plasma levels of VEGF and bFGF were measured in both the cirrhotics and the controls. RESULTS: Plasma VEGF and bFGF were increased in cirrhotics compared with controls (122±13 vs. 71±11 pg/mL, P=0.003 for VEGF; 5.1±0.5 vs. 3.4±0.5 pg/mL, P=0.022 for bFGF). In cirrhotics, plasma VEGF and bFGF were also higher in patients with spider angiomas compared with patients without spider angiomas (185±28 vs. 90±10 pg/mL, P=-0.003 for VEGF; 6.8±1.0 vs. 4.1±0.5 pg/mL, P=0.017 for bFGF). Multivariate logistic regression showed that young age and increased plasma levels of VEGF and bFGF were the most significant predictors for the presence of spider angiomas in cirrhotic patients (odds ratio [OR]=6.64, 95% confidence interval[CI]=2.02-21.79, P=0.002; OR=4.35, 95% CI=1.35-14.01,P=0.014; OR=5.66, 95% CI=1.72-18.63, P=0.004, respectively). CONCLUSION: Plasma VEGF and bFGF are elevated inpatients with liver cirrhosis. Age as well as plasma levels of VEGF and bFGF are significant predictors for spider angiomas in cirrhotic patients.
基金Supported by Cancer Research United KingdomWessex Medical Research
文摘AIM: To systematically review the available evidence regarding cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC) for colorectal peritoneal metastases (CPM).
文摘Background The COVID-19 pandemic has drastically increased demands on healthcare workers(HCWs)leaving them vulnerable to acute psychological distress,burnout and post-traumatic stress.In response,supportive services in a central London hospital mobilised mental health support specifically for HCWs.Aims This rapid evaluation assessed HCW psychological welfare during the acute phase of the COVID-19 pandemic and their use of supportive services made available.Methods During the acute phase of COVID-19(April to May 2020)all staff working for the hospital were invited to complete an online survey assessing well-being(self-rated health,moral distress exposure,symptoms of burnout and psychological distress)and use of available supportive services(awareness of,use and perceived helpfulness).Associations among personal characteristics and psychological well-being were explored using correlations and linear regression.Results A total of 1127 staff participated in the rapid evaluation.On average,psychological distress was high(mean(SD):22(7.57))regardless of role,with 84%of this sample scoring above the general population mean(14.5).Nearly half of the sample reported feeling emotionally drained and a profile emerged displaying higher levels of psychological distress and burnout in those who were younger and exposed to morally distressing situations,with this group also exhibiting greater support service use.Greater levels of burnout were associated with increased psychological distress when controlling for personal factors.During this acute phase of the pandemic,majority of staff used at least one service and rated it as helpful.Conclusion HCWs experienced high levels of psychological distress requiring continued support as the COVID-19 pandemic evolved.Although HCWs were aware of supportive services,uptake varied.In order to mitigate the risk of burnout and post-traumatic stress,long-term,effective strategies that facilitate staff accessing support are urgently required.
文摘A 73-year-old man underwent endoscopic mucosal resection(EMR) of a 20-mm flat elevated lesion on the transverse colon. The morning after the procedure, he started to have severe right upper quadrant pain after his first meal. A computed tomography scan revealed free air and a stomach filled with food. He was diagnosed to have delayed post-EMR intestinal perforation. He underwent emergent colonoscopy and clipping of the perforated site. He was discharged 8 d after the endoscopic closure without the need for surgical intervention. The meal was not the cause of the colon transversum perforation.
文摘A series of 8-substituted alkyl xanthines were evaluated in vitro to test the cytotoxocity in cells. For this experiment, we utilized different mammalian cancer cell lines primarily representing prostrate and lung. One of the compounds synthesized, viz. 8-tertbutyl caffeine showed potent anticancer activity at low concentrations against DU145 when compared to adriamycin. Further experiments were carried out to check the cell cycle arrest in the DU145 cells treated with adriamycin, caffeine and 8-tert butyl caffeine. We observed that there was an arrest in G1 phase of cell cycle at 24 hours while at 48 hours of incubation, the cells were constantly distributed (59.71% -70.79%). We conclude that the effect of 8-tertbutyl caffeine is relatively comparable to caffeine whereas in adriamycin treated cells, we observed the cells underwent G2 arrest. We evaluate the studies on these effects by showing potent analogues which could be used as promising anticancer agents.
基金supports by Consejo Nacional de Ciencia y Tecnologia(CONACYT) No.Approval 2002020201
文摘This research was designed to analyze the possible associations of Arg389 Gly ADRB1 and Trp64 Arg ADRB3polymorphisms in children with obesity.A cross-sectional study included 1,046 school-age Mexican participants（6-12 years old） from the cities of San Luis Potosi and Leon.Children were classified as non-obese or obese according to their body mass index（BMI） percentile;obese children had a BMI≥95th percentile for sex and age.Biochemical data were collected.Polymorphisms were detected using TaqMan qPCR assay.A logistic regression analysis was used to calculate the risk of obesity based on genotypes.Differences were found between groups where obese children had a significant increase in systolic and diastolic blood pressure,fasting plasma glucose,insulin,HOMAIR,LDL-cholesterol,triglycerides,and lower HDL-cholesterol compared with the normal weight group（P 〈 0.05）.The distribution of allele frequency in the population was Arg = 87.4 and Gly = 12.6（Hardy Weinberg equilibrium x^2= 3.16,P = 0.07）;Trp = 81.5 and Arg= 18.5（Hardy Weinberg equilibrium x^2 = 2.2,P = 0.14） for ADRB1 and ADRB3,respectively.Even though no different frequencies of Arg389 Gly polymoiphism between groups were found（P = 0.08）,children carriers of one Gly389,ADRB1 allele had a risk for obesity of OR = 1.40（95%CI,1.03-1.90,P =0.03） after adjustment for age and gender.No other association was found for Trp64 Arg ADRB3 polymorphism.Only the Arg389 Gly ADRB1 polymorphism was associated with risk for obesity in Mexican children.
文摘Context Drug-induced hepatotoxicity represents a significant proportion of liver disease cases. Currently, there is no effective treatment. To date efforts to identify treatment regimen that can reverse progressive damage have not been successful. We have previously shown that extract from Moringa (M) oleifera possesses clinically relevant antidiabetic and electrolyte modulators. Objective The aim of the current studies is to create experimental model of xenobiotic induced liver damage and investigate if treatment with lipophilic extract of M. oleifera could biochemically reverse progressive liver damage. Materials and Method For two groups of healthy rats, 7 in each group received 200 mg of extract or vehicle twice daily for 14 days. Acute toxicity, hepatotoxicity and hematologic/endothelial toxicity were monitored. Then 30 rats weighing 130 - 200 g received repeated dose of acetaminophen (xenobiotics) (640 mg/kg) for 5 days. Hepatotoxicity was confirmed biochemically by an established protocol. Treatment with M. oleifera extract resulted in mean weight of 132.2 ± 5.05 compared to the control with 134.1 ± 5.08 (P > 0.8115) among the healthy rats. Their LDH levels were 170.7 ± 13.02 and 133.8 ± 7.17 (P > 0.0698) for controls group, while the mean serum (ALT) level was 12.4 ± 1.2 or 25.6 ± 5.644 (P M. oleifera resulted in 100% biochemical recovery from hepatitis compared to the control group (P M. oleifera could effectively and biochemically abrogate xenobiotics induced liver damage in animal model.
基金funded by the Provincial-Level Clinical Key Specialty Construction in Qinghai Province in China.
文摘We aimed to evaluate the efficacy and safety of adding apatinib,to sintilimab and chemotherapy in the neoadjuvant treatment of early triple-negative breast cancer(TNBC).In the phase 2 NeoSAC trial,patients with early TNBC received six cycles of apatinib,sintilimab,nab-paclitaxel,and carboplatin followed by surgery.The primary endpoint was pathological complete response(pCR)rate.Specimens collected pre-neoadjuvant therapy and post-surgery were retained for comprehensive analysis of predictive biomarkers and the impact on the tumor microenvironment.Among 34 enrolled patients,24 achieved pCR(70.6%;95%confidence interval(CI),53.0-85.3),and 79.4%(95%CI,65.1-93.7)had residual cancer burden 0-I.Imaging evaluation showed 21 complete responses(61.8%)and 13 partial responses(38.2%).The most common grade 3-4 adverse events were leukopenia(47%),neutropenia(36%),and thrombocytopenia(24%).The 36-month disease-free survival rate stood at 94.1%with a median follow-up of 39.1 months.Notably,baseline high ImmuneScore,immune cell infiltration,and enrichment of interferon-related pathways correlated with pCR.Comparison of pre-neoadjuvant and post-surgery data revealed that the pCR group treated with this novel regimen exhibited an upregulation of distinct immune cell subsets,thereby activating the tumor microenvironment.Moreover,higher oxeiptosis scores were associated with an increased likelihood of achieving pCR.Following neoadjuvant therapy,the pCR group showed a decrease in oxeiptosis score,whereas the non-pCR group exhibited an increase.Our study suggests that apatinib,sintilimab combined with carboplatin and nab-paclitaxel chemotherapy showed a promising clinical activity and manageable safety profile in early TNBC and merits further study.ClinicalTrials.gov registration:NCT04722718.
文摘Gastric cancer is a major global health challenge,associated with high mortality and limited therapeutic options.Ginsenoside Rg3(Rg3),a bioactive compound derived from ginseng,has been shown to possess significant anticancer properties,particularly through immune modulation.In this study,we explored the therapeutic potential of Ginsenoside Rg3 hydrogel in the treatment of gastric cancer,focusing on its ability to target fibroblast activation protein(FAP),a key mediator of tumor progression.Using reverse molecular docking and gene expression analysis,we identified FAP as a primary molecular target of Rg3.Preclinical evaluations revealed that Rg3 hydrogel effectively inhibited the proliferation and invasion of gastric cancer cells in vitro.Furthermore,the hydrogel promoted immunogenic cell death,resulting in a robust immune response against the tumor.Our findings suggest that Ginsenoside Rg3 hydrogel holds promise as a novel immune-based therapeutic strategy for gastric cancer,offering a potential pathway to improved clinical outcomes and treatment strategies.
基金supported by National Natural Science Foundation of China(Grant No.82172650)Chinese Academy of Medical Sciences Clinical Translational and Medical Research Fund(Grant No.2022-I2M-C&T-A-014)+2 种基金Beijing Hospitals Authority Youth Programme(Grant No.QML20231110)Natural Science Foundation of Shandong Province(Grant No.ZR2023QH359)the Taishan Scholars Young Experts Fund(Grant No.tsqn202306388).
文摘Background:Breast cancer is a highly heterogeneous disease,characterized by tumor and nontumor cells at various cell states.Ecotyper is an innovative machine learning framework that quantifies the tumor microenvironment and delineates the tumor ecosystem,demonstrating clinical significance.However,further validation is needed in breast cancer.Methods:Ecotyper was applied to identify multiple cellular states and tumor ecotypes using large-scale breast cancer bulk sequencing data,followed by a detailed analysis of their associations with clinical classification,molecular subtypes,survival prognosis,and immunotherapy response.Identified subtypes were further characterized using single-cell and spatial data sets to reveal molecular profiles.Results:In a comprehensive analysis of 6578 breast cancer samples from four data sets,Ecotyper identified 69 cellular states and 10 tumor ecotypes.Of these,37 cellular states significantly correlated with overall survival.Notably,specific states within epithelial cells,macrophages/monocytes,and fibroblasts were linked to a worse prognosis.CE2 abundance was identified as the most significant marker indicating unfavorable prognosis and was further validated in an additional data set of 116 HER2-negative patients.These biomarkers also indicated the efficacy of neoadjuvant immunotherapy in breast cancer.CE2-high cancers were characterized by an abundance of basal-like epithelial cells,scant lymphocytic infiltration,and activation of hypoxia signaling.Single-cell analysis showed that CE2-high areas were rich in SPP1-positive tumor-associated macrophages(TAM),basal-like epithelial cells,and hypoxic cancer-associated fibroblasts(CAF).Spatially,these regions were often peripheral in triple-negative breast cancer,adjacent to fibrotic/necrotic zones.Multiplex immunofluorescence confirmed the enrichment of SPP1+CD68+TAM and HIF1A+SMA+CAF in hypoxic triple-negative breast cancer(TNBC)regions.
