BACKGROUND Colorectal cancer(CRC)ranks among the most prevalent malignant tumors globally.Recent reports suggest that Fusobacterium nucleatum(F.nucleatum)contributes to the initiation,progression,and prognosis of CRC....BACKGROUND Colorectal cancer(CRC)ranks among the most prevalent malignant tumors globally.Recent reports suggest that Fusobacterium nucleatum(F.nucleatum)contributes to the initiation,progression,and prognosis of CRC.Butyrate,a short-chain fatty acid derived from the bacterial fermentation of soluble dietary fiber,is known to inhibit various cancers.This study is designed to explore whether F.nucleatum influences the onset and progression of CRC by impacting the intestinal metabolite butyric acid.AIM To investigate the mechanism by which F.nucleatum affects CRC occurrence and development.METHODS Alterations in the gut microbiota of BALB/c mice were observed following the oral administration of F.nucleatum.Additionally,DLD-1 and HCT116 cell lines were exposed to sodium butyrate(NaB)and F.nucleatum in vitro to examine the effects on proliferative proteins and mitochondrial function.RESULTS Our research indicates that the prevalence of F.nucleatum in fecal samples from CRC patients is significantly greater than in healthy counterparts,while the prevalence of butyrate-producing bacteria is notably lower.In mice colonized with F.nucleatum,the population of butyrate-producing bacteria decreased,resulting in altered levels of butyric acid,a key intestinal metabolite of butyrate.Exposure to NaB can impair mitochondrial morphology and diminish mitochondrial membrane potential in DLD-1 and HCT116 CRC cells.Consequently,this leads to modulated production of adenosine triphosphate and reactive oxygen species,thereby inhibiting cancer cell prolif-eration.Additionally,NaB triggers the adenosine monophosphate-activated protein kinase(AMPK)signaling pathway,blocks the cell cycle in HCT116 and DLD-1 cells,and curtails the proliferation of CRC cells.The combined presence of F.nucleatum and NaB attenuated the effects of the latter.By employing small interfering RNA to suppress AMPK,it was demonstrated that AMPK is essential for NaB’s inhibition of CRC cell proliferation.CONCLUSION F.nucleatum can promote cancer progression through its inhibitory effect on butyric acid,via the AMPK signaling pathway.展开更多
Background:This study aimed to construct and characterize a humanized influenza mouse model expressing hST6GAL1.Methods:Humanized fragments,consisting of the endothelial cell-specific K18 promoter,human ST6GAL1-encodi...Background:This study aimed to construct and characterize a humanized influenza mouse model expressing hST6GAL1.Methods:Humanized fragments,consisting of the endothelial cell-specific K18 promoter,human ST6GAL1-encoding gene,and luciferase gene,were microinjected into the fertilized eggs of mice.The manipulated embryos were transferred into the oviducts of pseudopregnant female mice.The offspring were identified using PCR.Mice exhibiting elevated expression of the hST6GAL1 gene were selectively bred for propagation,and in vivo analysis was performed for screening.Expression of the humanized gene was tested by performing immunohistochemical(IHC)analysis.Hematologic and biochemical analyses using the whole blood and serum of humanized hST6GAL1 mice were performed.Results:Successful integration of the human ST6GAL1 gene into the mouse genome led to the overexpression of human SiaT ST6GAL1.Seven mice were identified as carrying copies of the humanized gene,and the in vivo analysis indicated that hST6GAL1gene expression in positive mice mirrored influenza virus infection characteristics.The IHC results revealed that hST6GAL1 was expressed in the lungs of humanized mice.Moreover,the hematologic and biochemical parameters of the positive mice were within the normal range.Conclusion:A humanized influenza mouse model expressing the hST6GAL1 gene was successfully established and characterized.展开更多
BACKGROUND Heterogeneous ribonucleoprotein A1(hnRNPA1)has been reported to enhance the Warburg effect and promote colon cancer(CC)cell proliferation,but the role and mechanism of the miR-490-3p/hnRNPA1-b/PKM2 axis in ...BACKGROUND Heterogeneous ribonucleoprotein A1(hnRNPA1)has been reported to enhance the Warburg effect and promote colon cancer(CC)cell proliferation,but the role and mechanism of the miR-490-3p/hnRNPA1-b/PKM2 axis in CC have not yet been elucidated.AIM To investigate the role and mechanism of a novel miR-490-3p/hnRNPA1-b/PKM2 axis in enhancing the Warburg effect and promoting CC cell proliferation through the PI3K/AKT pathway.METHODS Paraffin-embedded pathological sections from 220 CC patients were collected and subjected to immunohistochemical analysis to determine the expression of hnRNPA1-b.The relationship between the expression values and the clinicopathological features of the patients was investigated.Differences in mRNA expression were analyzed using quantitative real-time polymerase chain reaction,while differences in protein expression were analyzed using western blot.Cell proliferation was evaluated using the cell counting kit-8 and 5-ethynyl-2’-deoxyuridine assays,and cell cycle and apoptosis were detected using flow cytometric assays.The targeted binding of miR-490-3p to hnRNPA1-b was validated using a dual luciferase reporter assay.The Warburg effect was evaluated by glucose uptake and lactic acid production assays.RESULTS The expression of hnRNPA1-b was significantly increased in CC tissues and cells compared to normal controls(P<0.05).Immunohistochemical results demonstrated significant variations in the expression of the hnRNPA1-b antigen in different stages of CC,including stage I,II-III,and IV.Furthermore,the clinicopathologic characterization revealed a significant correlation between hnRNPA1-b expression and clinical stage as well as T classification.HnRNPA1-b was found to enhance the Warburg effect through the PI3K/AKT pathway,thereby promoting proliferation of HCT116 and SW620 cells.However,the proliferation of HCT116 and SW620 cells was inhibited when miR-490-3p targeted and bound to hnRNPA1-b,effectively blocking the Warburg effect.CONCLUSION These findings suggest that the novel miR-490-3p/hnRNPA1-b/PKM2 axis could provide a new strategy for the diagnosis and treatment of CC.展开更多
BACKGROUND Transient elastography(FibroScan)is a new and non-invasive test,which has been widely recommended by the guidelines of chronic hepatitis B virus(HBV)management for assessing hepatic fibrosis staging.However...BACKGROUND Transient elastography(FibroScan)is a new and non-invasive test,which has been widely recommended by the guidelines of chronic hepatitis B virus(HBV)management for assessing hepatic fibrosis staging.However,some confounders may affect the diagnostic accuracy of the FibroScan device in fibrosis staging.AIM To evaluate the diagnostic value of the FibroScan device and the effect of hepatic inflammation on the accuracy of FibroScan in assessing the stage of liver fibrosis in patients with HBV infection.METHODS The data of 416 patients with chronic HBV infection who accepted FibroScan,liver biopsy,clinical,and biological examination were collected from two hospitals retrospectively.Receiver operating characteristic(ROC)curves were used to analyze the diagnostic performance of FibroScan for assessing the stage of liver fibrosis.Any discordance in fibrosis staging by FibroScan and pathological scores was statistically analyzed.Logistic regression and ROC analyses were used to analyze the accuracy of FibroScan in assessing the stage of fibrosis in patients with different degrees of liver inflammation.A non-invasive model was constructed to predict the risk of misdiagnosis of fibrosis stage using FibroScan.RESULTS In the overall cohort,the optimal diagnostic values of liver stiffness measurement(LSM)using FibroScan for significant fibrosis(≥F2),severe fibrosis(≥F3),and cirrhosis(F4)were 7.3 kPa[area under the curve(AUC)=0.863],9.7 kPa(AUC=0.911),and 11.3 kPa(AUC=0.918),respectively.The rate of misdiagnosis of fibrosis stage using FibroScan was 34.1%(142/416 patients).The group of patients who showed discordance between fibrosis staging using FibroScan and pathological scores had significantly higher alanine aminotransferase and aspartate aminotransferase levels,and a higher proportion of moderate to severe hepatic inflammation,compared with the group of patients who showed concordance in fibrosis staging between the two methods.Liver inflammation activity over 2(OR=3.53)was an independent risk factor for misdiagnosis of fibrosis stage using FibroScan.Patients with liver inflammation activity≥2 showed higher LSM values using FibroScan and higher rates of misdiagnosis of fibrosis stage,whereas the diagnostic performance of FibroScan for different fibrosis stages was significantly lower than that in patients with inflammation activity<2(all P<0.05).A non-invasive prediction model was established to assess the risk of misdiagnosis of fibrosis stage using FibroScan,and the AUC was 0.701.CONCLUSION Liver inflammation was an independent risk factor affecting the diagnostic accuracy of FibroScan for fibrosis stage.A combination of other related noninvasive factors can predict the risk of misdiagnosis of fibrosis staging using FibroScan.展开更多
Objective This study aimed to characterize the diagnostic and vaccine potential of a novel Mycobacterium tuberculosisantigen Rv0674. Methods To evaluate thediagnostic potential and antigenicity of Rv0674, IgG was eval...Objective This study aimed to characterize the diagnostic and vaccine potential of a novel Mycobacterium tuberculosisantigen Rv0674. Methods To evaluate thediagnostic potential and antigenicity of Rv0674, IgG was evaluated using ELISA and interferon (IFN)-γ was done by using ELISpot assay among TB patients and healthy donors. For immunogenicity evaluation, BALB/c mice were immunized with Rv0674. Cytokine production was determined by cytokine release assay using an ELISA kit, and the antibodies were tested using ELISA. Results The results of serum Elisa tests showed that Rv0674 specific immunoglobulin G (IgG) response was higher in TB patients than negative controls. And Rv0674 had good performance in serological test with sensitivity and specificity of 77.1% and 81.1%, respectively. While it shows poor sensitivity and specificity of 26.23% and 79.69% for IFN-γ tests. In BALB/c mice, Rv0674 adjuvant by DDA/PolyI:C could also induce a high level of IFN-γ, interleukin-2 and interleukin-6 as well as a high IgG titer in both high-and low-dose groups indicating that Rv0674 is essential in humoral and cellular immunity. Moreover, the cytokine profile and IgG isotypecharacterized Rv0674 as a Th1/Th2-mixed-type protective immunity with the predominance of Th1 cytokines. Conclusion Rv0674 may be a good potential candidate for the development of TB serological diagnosis and a new TB vaccine.展开更多
Objective In this study, milk from a cow with mastitis was analyzed to determine the presence of mycobacterial infection. Milk quality and security problems pertaining to the safe consumption of dairy products were al...Objective In this study, milk from a cow with mastitis was analyzed to determine the presence of mycobacterial infection. Milk quality and security problems pertaining to the safe consumption of dairy products were also discussed in this study. Methods Milk was preprocessed with 4% NaOH. Then, mycobacteria were isolated from the milk sample on L-J medium. The isolate was identified using multiple loci Polymerase Chain Reaction （PCR） and multi-locus sequence analysis with 16S rRNA, sodA, hsp65, and ITS genes. The drug sensitivity of the isolate to 27 antibiotics was tested through alamar blue assay. Results Smooth, moist, pale yellow colonies appeared on the L-J medium within a week after inoculation. Based on the results of multiple loci PCR analysis, the isolate was preliminarily identified as non-tuberculous mycobacteria. The 16S rRNA, SodA, hsp65, and ITS gene sequences of the isolate exhibited 99%, 99%, 99%, and 100% similarities, respectively, with those of the published reference strains of Mycobacteriurn elephantis （M. elephantis）. The drug sensitivity results showed that the strain is resistant to isoniazid, p-aminosalicylic acid, and trimesulf but is sensitive to ofloxacin, rifampicin, amikacin, capreomycin, moxifloxacin, kanamycin, levofloxacin, cycloserine, ethambutol, streptomycin, tobramycin, rifabutin, ciprofloxacin, linezolid, cefoxitin, clarithromycin, and minocycline. Conclusion To the best of our knowledge, this study is initially to report the isolation of M. elephantis from the milk of a cow with mastitis in China.展开更多
Objective Macrolide susceptibility and drug resistance mechanisms of clinical non-tuberculous mycobacteria（NTM） isolates were preliminarily investigated for more accurate diagnosis and treatment of the infection in ...Objective Macrolide susceptibility and drug resistance mechanisms of clinical non-tuberculous mycobacteria（NTM） isolates were preliminarily investigated for more accurate diagnosis and treatment of the infection in China. Methods Four macrolides, including clarithromycin（CLAR）, azithromycin（AZM）, roxithromycin（ROX）, and erythromycin（ERY）, were used to test the drug susceptibility of 310 clinical NTM isolates from six provinces of China with the broth microdilution method. Two resistance mechanisms, 23 S r RNA and erm, were analyzed with nucleotide sequence analysis. Results Varied effectiveness of macrolides and species-specific resistance patterns were observed. Most Mycobacterium abscessus subsp. massiliense were susceptible and all M. fortuitum were highly resistant to macrolides. All the drugs, except for erythromycin, exhibited excellent activities against slow-growing mycobacteria, and drug resistance rates were below 22.2%. Only four highly resistant strains harbored 2,058/2,059 substitutions on rrl and none of other mutations were related to macrolide resistance. G2191 A and T2221 C on rrl were specific for the M. abscessus complex（MABC）. Seven sites, G2140 A, G2210 C, C2217 G, T2238 C, T2322 C, T2404 C, and A2406 G, were specifically carried by M. avium and M. intracellulare. Three sites, A2192 G, T2358 G, and A2636 G, were observed only in M. fortuitum and one site G2152 A was specific for M. gordonae. The genes erm（39） and erm（41） were detected in M. fortuitum and M. abscessus and inducible resistance was observed in relevant sequevar. Conclusion The susceptibility profile of macrolides against NTM was demonstrated. The well-known macrolide resistance mechanisms, 23 S r RNA and erm, failed to account for all resistant NTM isolates, and further studies are warranted to investigate macrolide resistance mechanisms in various NTM species.展开更多
A water-soluble polysaccharide (OJP2) obtained from the roots of Ophiopogon japonicas, was precipitated with 95% ethanol and purified by DEAE-52 cellulose anion-exchange and Sephadex G-100 gel filtration chromatograph...A water-soluble polysaccharide (OJP2) obtained from the roots of Ophiopogon japonicas, was precipitated with 95% ethanol and purified by DEAE-52 cellulose anion-exchange and Sephadex G-100 gel filtration chromatography. The characteristics of OJP2 were determined by chemical analysis, high performance gel permeation chromatography (HPGPC), and gas chromatography-mass spectrometry (GC-MS). The results showed that the average molecular weight (Mw) of OJP2 was 35.2 kDa, and five kinds of monosaccharides including rhamnose, arabinose, xylose, glucose and galactose in a molar ratio of 0.5:5:4:1:10. Furthermore, the antioxidant activity of OJP2 was evaluated in H2O2-treated HaCaT cells and glucose-treated LO2 cells. The results show that OJP2 can increase the activity of SOD and NO production, and decrease the level of MDA in these two kinds of injury cells. OJP2 should be explored as a novel and potential natural antioxidant agent for use in functional foods or medicine.展开更多
Metabolic dysfunction-associated fatty liver disease(MAFLD) is characterized by deregulated hepatic lipid metabolism;however, the association between MAFLD development and mitochondrial dysfunction has yet to be confi...Metabolic dysfunction-associated fatty liver disease(MAFLD) is characterized by deregulated hepatic lipid metabolism;however, the association between MAFLD development and mitochondrial dysfunction has yet to be confirmed. Herein, we employed highresolution respirometry, blue native polyacrylamide gelelectrophoresis-basedin-gelactivity measurement and immunoblot analysis to assess mitochondrial function in obesity-induced mouse models with varying degrees of MAFLD. Results showed a slight but significant decrease in hepatic mitochondrial respiration in some MAFLD mice compared to mice fed a standard diet. However, the activities and levels of mitochondrial oxidative phosphorylation complexes remained unchanged during obesity-induced MAFLD progression. These results suggest that mitochondrial function,particularly oxidative phosphorylation, was mildly affected duringo besity-induced MAFLD development. Moreover, transcriptome profiling of mouse and human liver tissues with varying degrees of MAFLD revealed that the decreased activation of mitochondria-related pathways was only associated with MAFLD of a high histological grade, whereas the major regulators of mitochondrial biogenesis were not altered in mice or humans during MAFLD development. Collectively, our results suggest that impaired hepatic mitochondrial function is not closely associated with obesity-induced MAFLD. Therefore,therapeutic strategies targeting mitochondria for the treatment of MAFLD should be reconsidered.展开更多
Exosomes,especially from mesenchymal stem cells,have attracted extensive attention in regeneration medicine.Mesenchymal stem cells derived exosomes(MSCs-exosomes)have shown anti-inflammatory,anti-oxidant,antiapoptosis...Exosomes,especially from mesenchymal stem cells,have attracted extensive attention in regeneration medicine.Mesenchymal stem cells derived exosomes(MSCs-exosomes)have shown anti-inflammatory,anti-oxidant,antiapoptosis and tissue regeneration effects in a variety of tissue injury repair models.MSCs-exosomes hold many excellent properties such as low immunogenicity,biocompatibility,and targeting capability.With the in-depth study on the generation and function of exosomes,MSCs-exosomes are considered to be the bright stars in the field of regenerative medicine.However,there are still many obstacles to overcome in terms of exosomes isolation,clinical trials and safety evaluation.In this article,what we should focus on about MSCs-exosomes in regeneration medicine will be discussed.展开更多
BACKGROUND Mixed infection of hepatic cystic and alveolar echinococcosis is extremely rare.This article reveals the typical imaging manifestations of cystic and alveolar echinococcosis and investigates the diagnosis a...BACKGROUND Mixed infection of hepatic cystic and alveolar echinococcosis is extremely rare.This article reveals the typical imaging manifestations of cystic and alveolar echinococcosis and investigates the diagnosis and surgical experience of mixed infection of hepatic cystic and alveolar echinococcosis.CASE SUMMARY From January 2017 to May 2019,4 cases with rare mixed infection of hepatic cystic and alveolar echinococcosis were admitted and treated by the Division of General Surgery of Qinghai Provincial People’s Hospital.Three of the patients occasionally had upper abdominal discomfort,but it did not affect their daily lives.However,hepatic echinococcosis was found in one patient by physical examination,and the patient had no discomfort.All 4 cases were Tibetans who had lived in pastoral areas of southern Qinghai for a long time.Enzyme-linked immunosorbent assay for echinococcosis was positive for all patients.Moreover,abdominal computed tomography showed typical imaging manifestations of cystic and alveolar echinococcosis including coexisting"honeycomb sign,"and"spotted calcification."Three of the patients underwent radical resection,and 1 case underwent palliative resection.All 4 patients developed different types of surgical complications after the operation,but all of them recovered and were discharged after symptomatic treatment.CONCLUSION There are no problems diagnosing mixed infection of hepatic cystic and alveolar echinococcosis.The difficulties involve preoperative evaluation and treatment of surgical complications.展开更多
Primary liver cancer is a severe and complex disease,leading to 800000 global deaths annually.Emerging evidence suggests that inflammation is one of the critical factors in the development of hepatocellular carcinoma(...Primary liver cancer is a severe and complex disease,leading to 800000 global deaths annually.Emerging evidence suggests that inflammation is one of the critical factors in the development of hepatocellular carcinoma(HCC).Patients with viral hepatitis,alcoholic hepatitis,and steatohepatitis symptoms are at higher risk of developing HCC.However,not all inflammatory factors have a pathogenic function in HCC development.The current study describes the process and mechanism of hepatitis development and its progression to HCC,particularly focusing on viral hepatitis,alcoholic hepatitis,and steatohepatitis.Furthermore,the roles of some essential inflammatory cytokines in HCC progression are described in addition to a summary of future research directions.展开更多
Background: Significant portal hypertension(SPH) is a relative contraindication for patients with resectable hepatocellular carcinoma(HCC). However, increasing evidence indicates that liver resection is feasible for H...Background: Significant portal hypertension(SPH) is a relative contraindication for patients with resectable hepatocellular carcinoma(HCC). However, increasing evidence indicates that liver resection is feasible for HCC patients with SPH. Methods: HCC patients with cirrhosis who underwent laparoscopic liver resection(LLR) in two centers from January 2013 to April 2018 were included. Surgical and survival outcomes were analyzed to explore potential prognostic factors. Propensity score matching(PSM) analysis was performed to minimize bias. Results: A total of 165 patients were divided into two groups based on the presence(SPH, n = 76) or absence(non-SPH, n = 89) of SPH. Patients in the SPH group had longer operative time, more blood loss, and more advanced TNM stage than patients in the non-SPH group( P < 0.05). However, there were no significant differences in the postoperative 90-day mortality rate( n = 0), overall postoperative complications(47.4% vs. 41.6%, P = 0.455), Clavien-Dindo classification( P = 0.347), conversion to open surgery(9.2% vs. 6.7%, P = 0.557), or length of hospitalization(16 vs. 15 days, P = 0.203) between the SPH and non-SPH groups before PSM. Similar results were obtained after PSM. The 1-, 3-, and 5-year overall survival(OS) and recurrence-free survival rates in the SPH group were not significantly different from those in the non-SPH group both before and after PSM(log-rank P > 0.05). After PSM, alpha-fetoprotein(AFP) ≥ 400 μg/L [hazard ratio(HR) = 4.71, 95% confidence interval(CI): 2.69-8.25], ascites(HR = 2.18, 95% CI: 1.30-3.66), American Society of Anesthesiologists(ASA) classification(Ⅲ vs. Ⅱ)(HR = 2.13, 95% CI: 1.11-4.07) and tumor diameter > 5 cm(HR = 3.91, 95% CI: 2.02-7.56) independently predicted worse OS. Conclusions: LLR for patients with HCC complicated with SPH appears feasible at the price of increasing operative time and blood loss. AFP, ascites, ASA classification and tumor diameter may predict the prognosis of HCC complicated with SPH after LLR.展开更多
Nonalcoholic fatty liver disease(NAFLD)is a long-lasting condition that affects the liver,destroying its function.Liver injury can cause steatosis and inflammation,and further activation of hepatic stellate cells(HSCs...Nonalcoholic fatty liver disease(NAFLD)is a long-lasting condition that affects the liver,destroying its function.Liver injury can cause steatosis and inflammation,and further activation of hepatic stellate cells(HSCs)often leads to the development of nonalcoholic liver fibrosis.The patient with NAFLD is at risk of developing advanced liver disease and complications,such as liver failure,hepatocellular carcinoma(HCC),and portal hypertension.Although our understanding of the cellular and molecular mechanisms of NAFLD has greatly improved in recent years,treatment remains limited.Analysis and characterization of protein posttranslational modifications(PTMs)could improve our understanding of NAFLD pathology and leading to the development of new and more effective treatments.In recent years,a number of studies have described how ubiquitin-like(Ubl)-PTMs change during NAFLD and how treatments targeting specific enzymes mediating these Ubl-PTMs can improve various liver diseases,particularly in relation to NAFLD and nonalcoholic liver fibrosis.New strategies for evaluating modified proteomes could provide novel insights into the roles of Ubl-PTMs in NAFLD progression and the therapeutic value of targeting the proteins involved in these Ubl-PTMs.展开更多
Chronic myeloid leukemia(CML)is a common adult leukemia.Both the acute phase of the disease and the adverse effects of anti-cancer treatments can lead to a poor prognosis.The N6-methyladenine(m^(6)A)modification plays...Chronic myeloid leukemia(CML)is a common adult leukemia.Both the acute phase of the disease and the adverse effects of anti-cancer treatments can lead to a poor prognosis.The N6-methyladenine(m^(6)A)modification plays an important regulatory role in various physiological and pathological processes.KIAA1429 is a known m^(6)A regulator,but the biological role of KIAA1429 in CML is unclear.In this study,we observed that the m^(6)A levels and KIAA1429 expression were significantly up-regulated in patients with blast phase CML.Notably,KIAA1429 regulated the total level of RNA m^(6)A modification in the CML cells and promoted the malignant biological behaviors of CML cells,including proliferation,migration,and imatinib resistance.Inhibiting KIAA1429 in CML cells reduced the stability of RAB27B mRNA through the m^(6)A/YTHDF1 axis,consequently inhibiting CML proliferation and drug efflux,ultimately increasing the sensitivity of CML cells to imatinib.Moreover,the knockdown of RAB27B also inhibited the proliferation and drug resistance of CML cells and promoted their apoptosis.Rucaparib,a recently developed anti-cancer agent,suppressed the expression of KIAA1429 and CML cell proliferation and promoted cell apoptosis.Rucaparib also inhibited the tumorigenesis of CML cells in vivo.The combined use of rucaparib and imatinib enhanced the sensitivity of CML cells to imatinib.Our study provides evidence that elevated KIAA1429 expression in the blast phase of CML enhances the stability of RAB27B mRNA through the m^(6)A/YTHDF1 axis to up-regulate RAB27B expression,thereby promoting CML progression.Rucaparib exerts inhibitory effects on KIAA1429 expression and thus reduces CML progression.展开更多
Small cell lung cancer(SCLC),a highly aggressive malignancy,is rapidly at an extensive stage once diagnosed and is one of the leading causes of death from malignancy.In the past decade,the treatment of SCLC has largel...Small cell lung cancer(SCLC),a highly aggressive malignancy,is rapidly at an extensive stage once diagnosed and is one of the leading causes of death from malignancy.In the past decade,the treatment of SCLC has largely remained unchanged,and chemotherapy remains the cornerstone of SCLC treatment.The therapeutic value of adding immune checkpoint inhibitors to chemotherapy for SCLC is low,and only a few SCLC patients have shown a response to immune checkpoint inhibitors.Circulating tumor cells(CTCs)are tumor cells shed from solid tumor masses into the peripheral circulation and are key to tumor metastasis.Single-cell sequencing has revealed that the genetic profiles of individual CTCs are highly heterogeneous and contribute to the poor outcome and prognosis of SCLC patients.Theoretically,phenotypic analysis of CTCs may be able to predict the diagnostic significance of new potential targets for metastatic tumors.In this paper,we will discuss in depth the heterogeneity of CTCs in SCLC and the value of CTCs for the diagnosis and prognosis of SCLC and as relevant tumor markers in metastatic SCLC.展开更多
DNA not only plays a vital role in nature as fundamental hereditary material for storing genetic material,but also serves as well-defined functional material,for example,building blocks for the assembly of nanoscale b...DNA not only plays a vital role in nature as fundamental hereditary material for storing genetic material,but also serves as well-defined functional material,for example,building blocks for the assembly of nanoscale bio-architectures by Watson-Crick base-pairing interaction.With the development of molecular biology,biotechnology and nanoscience,structural DNA nanotechnology has achieved numerous advances,contributing to the construction of various DNA nanostructures ranging from discrete objects to one dimensional(1D),two dimensional(2D),and three dimensional(3D)architectures.Among them,DNA tetrahedral nanoarchitecture is intensively studied because of simple 3D structure,easy design and unique properties,such as high rigidity,desirable biostability and efficient cellular uptake without auxiliary species.This review summarizes the research progress in the assembly of DNA tetrahedral objects and outlines the applications in biosensing,drug delivery and targeted therapy.Moreover,the dependence of biological activity of biomolecules on DNA tetrahedron-mediated spatially-controlled arrangement and great potential applications are discussed.In addition,the challenges in the design and clinic applications of DNA tetrahedron-based platforms are described,the perspectives towards biomedical applications are foreseen,and our understandings on further studies of DNA tetrahedron are provided,aiming to motivate the development of DNA nanotechnology and interdisciplinary research.展开更多
Tumor-derived exosomes (TEXs) enriched in immune suppressive molecules predominantly drive T-cell dysfunction and impair antitumor immunity. Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising tr...Tumor-derived exosomes (TEXs) enriched in immune suppressive molecules predominantly drive T-cell dysfunction and impair antitumor immunity. Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising treatment for refractory and relapsed hematological malignancies, but whether lymphoma TEXs have the same impact on CAR T-cell remains unclear. Here, we demonstrated that B-cell lymphoma-derived exosomes induce the initial activation of CD19-CAR T-cells upon stimulation with exosomal CD19. However, lymphoma TEXs might subsequently induce CAR T-cell apoptosis and impair the tumor cytotoxicity of the cells because of the upregulated expression of the inhibitory receptors PD-1, TIM3, and LAG3 upon prolonged exposure. Similar results were observed in the CAR T-cells exposed to plasma exosomes from patients with lymphoma. More importantly, single-cell RNA sequencing revealed that CAR T-cells typically showed differentiated phenotypes and regulatory T-cell (Treg) phenotype conversion. By blocking transforming growth factor β (TGF-β)-Smad3 signaling with TGF-β inhibitor LY2109761, the negative effects of TEXs on Treg conversion, terminal differentiation, and immune checkpoint expression were rescued. Collectively, although TEXs lead to the initial activation of CAR T-cells, the effect of TEXs suppressed CAR T-cells, which can be rescued by LY2109761. A treatment regimen combining CAR T-cell therapy and TGF-β inhibitors might be a novel therapeutic strategy for refractory and relapsed B-cell lymphoma.展开更多
Pancreatic cancer is one of the most lethal malignant tumors in the world.Despite advances in diagnosis and treatment,the five-year survival rate for pancreatic cancer patients remains only 9%.1 Pancreatic adenocarcin...Pancreatic cancer is one of the most lethal malignant tumors in the world.Despite advances in diagnosis and treatment,the five-year survival rate for pancreatic cancer patients remains only 9%.1 Pancreatic adenocarcinoma(PAAD)belongs to pancreatic cancer,which occupies 85%of the whole pancreatic cancer.2 Reversible modification of Ne-methyladenosine(m^(6)A)has been shown to be involved in cancer progression,resulting in up-regulation of oncogene expression or down-regulation of tumor-suppressing genes and may affect the prognosis of patients with pancreatic cancer.展开更多
Chemotherapy is regarded as a widely used and effective treatment strategy for lung cancer,although most conventional chemotherapeutics cause severe toxic side-effects due to their indiscriminate attacks on both cance...Chemotherapy is regarded as a widely used and effective treatment strategy for lung cancer,although most conventional chemotherapeutics cause severe toxic side-effects due to their indiscriminate attacks on both cancerous and normal cells.Although nucleic acid nanomaterials are emerging as a promising drug delivery strategy,their clinical applications are limited by rapid degradation by nucleases and difficulties in targeting cancer cells.In this study,we have developed a Rhein-loaded aptamer-based DNA nanotube(DNT-S6@Rhein)for the targeted and efficient therapy of non-small cell lung cancer.Through the palindrome segments,two specified oligonucleotides were hybridized and folded into the well-defined nanotubes(DNT-S6),with the S6 aptamer distributed outside.The obtained nanotubes exhibited excellent serum stability and targeting ability towards A549 cells due to the firm structure and decoration of the S6 aptamer.Rhein,as an antitumor drug and DNA intercalator,can be effectively inserted into the DNT-S6.The drug-loaded nanotubes rapidly disassembled in intracellular environment and then the released Rhein was found to activate cellular apoptotic process and significantly suppress proliferation,migration and invasion of A549 cells.Moreover,DNT-S6@Rhein could efficiently accumulate in tumor regions,offering compelling therapeutic efficacy and biocompatibility under both in vitro and in vivo settings.These findings of this study provide a promising strategy for mitigating the inevitable systemic side-effects of chemotherapy and expand the potential application of DNA nanostructure on targeted drug delivery.展开更多
基金Supported by the Key Discipline of Zhejiang Province in Medical Technology(First Class,Category A)and the Health Project of the Science and Technology Department of Wenzhou,No.Y20220029.
文摘BACKGROUND Colorectal cancer(CRC)ranks among the most prevalent malignant tumors globally.Recent reports suggest that Fusobacterium nucleatum(F.nucleatum)contributes to the initiation,progression,and prognosis of CRC.Butyrate,a short-chain fatty acid derived from the bacterial fermentation of soluble dietary fiber,is known to inhibit various cancers.This study is designed to explore whether F.nucleatum influences the onset and progression of CRC by impacting the intestinal metabolite butyric acid.AIM To investigate the mechanism by which F.nucleatum affects CRC occurrence and development.METHODS Alterations in the gut microbiota of BALB/c mice were observed following the oral administration of F.nucleatum.Additionally,DLD-1 and HCT116 cell lines were exposed to sodium butyrate(NaB)and F.nucleatum in vitro to examine the effects on proliferative proteins and mitochondrial function.RESULTS Our research indicates that the prevalence of F.nucleatum in fecal samples from CRC patients is significantly greater than in healthy counterparts,while the prevalence of butyrate-producing bacteria is notably lower.In mice colonized with F.nucleatum,the population of butyrate-producing bacteria decreased,resulting in altered levels of butyric acid,a key intestinal metabolite of butyrate.Exposure to NaB can impair mitochondrial morphology and diminish mitochondrial membrane potential in DLD-1 and HCT116 CRC cells.Consequently,this leads to modulated production of adenosine triphosphate and reactive oxygen species,thereby inhibiting cancer cell prolif-eration.Additionally,NaB triggers the adenosine monophosphate-activated protein kinase(AMPK)signaling pathway,blocks the cell cycle in HCT116 and DLD-1 cells,and curtails the proliferation of CRC cells.The combined presence of F.nucleatum and NaB attenuated the effects of the latter.By employing small interfering RNA to suppress AMPK,it was demonstrated that AMPK is essential for NaB’s inhibition of CRC cell proliferation.CONCLUSION F.nucleatum can promote cancer progression through its inhibitory effect on butyric acid,via the AMPK signaling pathway.
基金National Key Research and Development Program of China,Grant/Award Number:2021YFC2301403 and 2022YFF0711000。
文摘Background:This study aimed to construct and characterize a humanized influenza mouse model expressing hST6GAL1.Methods:Humanized fragments,consisting of the endothelial cell-specific K18 promoter,human ST6GAL1-encoding gene,and luciferase gene,were microinjected into the fertilized eggs of mice.The manipulated embryos were transferred into the oviducts of pseudopregnant female mice.The offspring were identified using PCR.Mice exhibiting elevated expression of the hST6GAL1 gene were selectively bred for propagation,and in vivo analysis was performed for screening.Expression of the humanized gene was tested by performing immunohistochemical(IHC)analysis.Hematologic and biochemical analyses using the whole blood and serum of humanized hST6GAL1 mice were performed.Results:Successful integration of the human ST6GAL1 gene into the mouse genome led to the overexpression of human SiaT ST6GAL1.Seven mice were identified as carrying copies of the humanized gene,and the in vivo analysis indicated that hST6GAL1gene expression in positive mice mirrored influenza virus infection characteristics.The IHC results revealed that hST6GAL1 was expressed in the lungs of humanized mice.Moreover,the hematologic and biochemical parameters of the positive mice were within the normal range.Conclusion:A humanized influenza mouse model expressing the hST6GAL1 gene was successfully established and characterized.
基金Supported by the National Natural Science Foundation of China,No.82160405Jiangxi Provincial Natural Science Foundation,No.20232BAB206131,No.20212ACB206016,and No.20224BAB206114+1 种基金Jiangxi Provincial Health Commission Project,No.202310887the Development Fund of Jiangxi Cancer Hospital,No.2021J10.
文摘BACKGROUND Heterogeneous ribonucleoprotein A1(hnRNPA1)has been reported to enhance the Warburg effect and promote colon cancer(CC)cell proliferation,but the role and mechanism of the miR-490-3p/hnRNPA1-b/PKM2 axis in CC have not yet been elucidated.AIM To investigate the role and mechanism of a novel miR-490-3p/hnRNPA1-b/PKM2 axis in enhancing the Warburg effect and promoting CC cell proliferation through the PI3K/AKT pathway.METHODS Paraffin-embedded pathological sections from 220 CC patients were collected and subjected to immunohistochemical analysis to determine the expression of hnRNPA1-b.The relationship between the expression values and the clinicopathological features of the patients was investigated.Differences in mRNA expression were analyzed using quantitative real-time polymerase chain reaction,while differences in protein expression were analyzed using western blot.Cell proliferation was evaluated using the cell counting kit-8 and 5-ethynyl-2’-deoxyuridine assays,and cell cycle and apoptosis were detected using flow cytometric assays.The targeted binding of miR-490-3p to hnRNPA1-b was validated using a dual luciferase reporter assay.The Warburg effect was evaluated by glucose uptake and lactic acid production assays.RESULTS The expression of hnRNPA1-b was significantly increased in CC tissues and cells compared to normal controls(P<0.05).Immunohistochemical results demonstrated significant variations in the expression of the hnRNPA1-b antigen in different stages of CC,including stage I,II-III,and IV.Furthermore,the clinicopathologic characterization revealed a significant correlation between hnRNPA1-b expression and clinical stage as well as T classification.HnRNPA1-b was found to enhance the Warburg effect through the PI3K/AKT pathway,thereby promoting proliferation of HCT116 and SW620 cells.However,the proliferation of HCT116 and SW620 cells was inhibited when miR-490-3p targeted and bound to hnRNPA1-b,effectively blocking the Warburg effect.CONCLUSION These findings suggest that the novel miR-490-3p/hnRNPA1-b/PKM2 axis could provide a new strategy for the diagnosis and treatment of CC.
基金Science and Technology Department of Fujian Province,China,No.2019Y0015 and No.2019J01432Chinese National 13th Five-Year Plan's Science and Technology Projects,No.2017ZX10202201Quanzhou Science and Technology Project of Fujian Province,China,No.2018Z074.
文摘BACKGROUND Transient elastography(FibroScan)is a new and non-invasive test,which has been widely recommended by the guidelines of chronic hepatitis B virus(HBV)management for assessing hepatic fibrosis staging.However,some confounders may affect the diagnostic accuracy of the FibroScan device in fibrosis staging.AIM To evaluate the diagnostic value of the FibroScan device and the effect of hepatic inflammation on the accuracy of FibroScan in assessing the stage of liver fibrosis in patients with HBV infection.METHODS The data of 416 patients with chronic HBV infection who accepted FibroScan,liver biopsy,clinical,and biological examination were collected from two hospitals retrospectively.Receiver operating characteristic(ROC)curves were used to analyze the diagnostic performance of FibroScan for assessing the stage of liver fibrosis.Any discordance in fibrosis staging by FibroScan and pathological scores was statistically analyzed.Logistic regression and ROC analyses were used to analyze the accuracy of FibroScan in assessing the stage of fibrosis in patients with different degrees of liver inflammation.A non-invasive model was constructed to predict the risk of misdiagnosis of fibrosis stage using FibroScan.RESULTS In the overall cohort,the optimal diagnostic values of liver stiffness measurement(LSM)using FibroScan for significant fibrosis(≥F2),severe fibrosis(≥F3),and cirrhosis(F4)were 7.3 kPa[area under the curve(AUC)=0.863],9.7 kPa(AUC=0.911),and 11.3 kPa(AUC=0.918),respectively.The rate of misdiagnosis of fibrosis stage using FibroScan was 34.1%(142/416 patients).The group of patients who showed discordance between fibrosis staging using FibroScan and pathological scores had significantly higher alanine aminotransferase and aspartate aminotransferase levels,and a higher proportion of moderate to severe hepatic inflammation,compared with the group of patients who showed concordance in fibrosis staging between the two methods.Liver inflammation activity over 2(OR=3.53)was an independent risk factor for misdiagnosis of fibrosis stage using FibroScan.Patients with liver inflammation activity≥2 showed higher LSM values using FibroScan and higher rates of misdiagnosis of fibrosis stage,whereas the diagnostic performance of FibroScan for different fibrosis stages was significantly lower than that in patients with inflammation activity<2(all P<0.05).A non-invasive prediction model was established to assess the risk of misdiagnosis of fibrosis stage using FibroScan,and the AUC was 0.701.CONCLUSION Liver inflammation was an independent risk factor affecting the diagnostic accuracy of FibroScan for fibrosis stage.A combination of other related noninvasive factors can predict the risk of misdiagnosis of fibrosis staging using FibroScan.
基金National Science and Technology Major Project of China [2018ZX10731301-002]
文摘Objective This study aimed to characterize the diagnostic and vaccine potential of a novel Mycobacterium tuberculosisantigen Rv0674. Methods To evaluate thediagnostic potential and antigenicity of Rv0674, IgG was evaluated using ELISA and interferon (IFN)-γ was done by using ELISpot assay among TB patients and healthy donors. For immunogenicity evaluation, BALB/c mice were immunized with Rv0674. Cytokine production was determined by cytokine release assay using an ELISA kit, and the antibodies were tested using ELISA. Results The results of serum Elisa tests showed that Rv0674 specific immunoglobulin G (IgG) response was higher in TB patients than negative controls. And Rv0674 had good performance in serological test with sensitivity and specificity of 77.1% and 81.1%, respectively. While it shows poor sensitivity and specificity of 26.23% and 79.69% for IFN-γ tests. In BALB/c mice, Rv0674 adjuvant by DDA/PolyI:C could also induce a high level of IFN-γ, interleukin-2 and interleukin-6 as well as a high IgG titer in both high-and low-dose groups indicating that Rv0674 is essential in humoral and cellular immunity. Moreover, the cytokine profile and IgG isotypecharacterized Rv0674 as a Th1/Th2-mixed-type protective immunity with the predominance of Th1 cytokines. Conclusion Rv0674 may be a good potential candidate for the development of TB serological diagnosis and a new TB vaccine.
基金supported by the project 81401647 of Natural Science Foundation of ChinaProject 2014SKLID104 of State Key Laboratory for Infectious Diseases Prevention and Controlprojects 16411967900 of Science and Technology Commission of Shanghai Municipality
文摘Objective In this study, milk from a cow with mastitis was analyzed to determine the presence of mycobacterial infection. Milk quality and security problems pertaining to the safe consumption of dairy products were also discussed in this study. Methods Milk was preprocessed with 4% NaOH. Then, mycobacteria were isolated from the milk sample on L-J medium. The isolate was identified using multiple loci Polymerase Chain Reaction （PCR） and multi-locus sequence analysis with 16S rRNA, sodA, hsp65, and ITS genes. The drug sensitivity of the isolate to 27 antibiotics was tested through alamar blue assay. Results Smooth, moist, pale yellow colonies appeared on the L-J medium within a week after inoculation. Based on the results of multiple loci PCR analysis, the isolate was preliminarily identified as non-tuberculous mycobacteria. The 16S rRNA, SodA, hsp65, and ITS gene sequences of the isolate exhibited 99%, 99%, 99%, and 100% similarities, respectively, with those of the published reference strains of Mycobacteriurn elephantis （M. elephantis）. The drug sensitivity results showed that the strain is resistant to isoniazid, p-aminosalicylic acid, and trimesulf but is sensitive to ofloxacin, rifampicin, amikacin, capreomycin, moxifloxacin, kanamycin, levofloxacin, cycloserine, ethambutol, streptomycin, tobramycin, rifabutin, ciprofloxacin, linezolid, cefoxitin, clarithromycin, and minocycline. Conclusion To the best of our knowledge, this study is initially to report the isolation of M. elephantis from the milk of a cow with mastitis in China.
基金supported by the Key Project of the State Key Laboratory for Infectious Disease Prevention and Control[2014SKLID104]the National Key Programs of Mega Infectious Diseases[2013ZX10003002-001]
文摘Objective Macrolide susceptibility and drug resistance mechanisms of clinical non-tuberculous mycobacteria（NTM） isolates were preliminarily investigated for more accurate diagnosis and treatment of the infection in China. Methods Four macrolides, including clarithromycin（CLAR）, azithromycin（AZM）, roxithromycin（ROX）, and erythromycin（ERY）, were used to test the drug susceptibility of 310 clinical NTM isolates from six provinces of China with the broth microdilution method. Two resistance mechanisms, 23 S r RNA and erm, were analyzed with nucleotide sequence analysis. Results Varied effectiveness of macrolides and species-specific resistance patterns were observed. Most Mycobacterium abscessus subsp. massiliense were susceptible and all M. fortuitum were highly resistant to macrolides. All the drugs, except for erythromycin, exhibited excellent activities against slow-growing mycobacteria, and drug resistance rates were below 22.2%. Only four highly resistant strains harbored 2,058/2,059 substitutions on rrl and none of other mutations were related to macrolide resistance. G2191 A and T2221 C on rrl were specific for the M. abscessus complex（MABC）. Seven sites, G2140 A, G2210 C, C2217 G, T2238 C, T2322 C, T2404 C, and A2406 G, were specifically carried by M. avium and M. intracellulare. Three sites, A2192 G, T2358 G, and A2636 G, were observed only in M. fortuitum and one site G2152 A was specific for M. gordonae. The genes erm（39） and erm（41） were detected in M. fortuitum and M. abscessus and inducible resistance was observed in relevant sequevar. Conclusion The susceptibility profile of macrolides against NTM was demonstrated. The well-known macrolide resistance mechanisms, 23 S r RNA and erm, failed to account for all resistant NTM isolates, and further studies are warranted to investigate macrolide resistance mechanisms in various NTM species.
文摘A water-soluble polysaccharide (OJP2) obtained from the roots of Ophiopogon japonicas, was precipitated with 95% ethanol and purified by DEAE-52 cellulose anion-exchange and Sephadex G-100 gel filtration chromatography. The characteristics of OJP2 were determined by chemical analysis, high performance gel permeation chromatography (HPGPC), and gas chromatography-mass spectrometry (GC-MS). The results showed that the average molecular weight (Mw) of OJP2 was 35.2 kDa, and five kinds of monosaccharides including rhamnose, arabinose, xylose, glucose and galactose in a molar ratio of 0.5:5:4:1:10. Furthermore, the antioxidant activity of OJP2 was evaluated in H2O2-treated HaCaT cells and glucose-treated LO2 cells. The results show that OJP2 can increase the activity of SOD and NO production, and decrease the level of MDA in these two kinds of injury cells. OJP2 should be explored as a novel and potential natural antioxidant agent for use in functional foods or medicine.
基金This research was supported by the National Natural Science Foundation of China(Key Program:81830071)Zhejiang Provincial Natural Science Foundation of China(LY19H040004 and Key Program:LR20H200001)Zhejiang Provincial Health Science and Technology Plan(2015KYB238)。
文摘Metabolic dysfunction-associated fatty liver disease(MAFLD) is characterized by deregulated hepatic lipid metabolism;however, the association between MAFLD development and mitochondrial dysfunction has yet to be confirmed. Herein, we employed highresolution respirometry, blue native polyacrylamide gelelectrophoresis-basedin-gelactivity measurement and immunoblot analysis to assess mitochondrial function in obesity-induced mouse models with varying degrees of MAFLD. Results showed a slight but significant decrease in hepatic mitochondrial respiration in some MAFLD mice compared to mice fed a standard diet. However, the activities and levels of mitochondrial oxidative phosphorylation complexes remained unchanged during obesity-induced MAFLD progression. These results suggest that mitochondrial function,particularly oxidative phosphorylation, was mildly affected duringo besity-induced MAFLD development. Moreover, transcriptome profiling of mouse and human liver tissues with varying degrees of MAFLD revealed that the decreased activation of mitochondria-related pathways was only associated with MAFLD of a high histological grade, whereas the major regulators of mitochondrial biogenesis were not altered in mice or humans during MAFLD development. Collectively, our results suggest that impaired hepatic mitochondrial function is not closely associated with obesity-induced MAFLD. Therefore,therapeutic strategies targeting mitochondria for the treatment of MAFLD should be reconsidered.
基金This work was supported by the National Natural Science Foundation of China(81871496,81971757)Zhenjiang Key Laboratory of High Technology Research on Exosomes Foundation and Transformation Application(ss2018003)Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD III).
文摘Exosomes,especially from mesenchymal stem cells,have attracted extensive attention in regeneration medicine.Mesenchymal stem cells derived exosomes(MSCs-exosomes)have shown anti-inflammatory,anti-oxidant,antiapoptosis and tissue regeneration effects in a variety of tissue injury repair models.MSCs-exosomes hold many excellent properties such as low immunogenicity,biocompatibility,and targeting capability.With the in-depth study on the generation and function of exosomes,MSCs-exosomes are considered to be the bright stars in the field of regenerative medicine.However,there are still many obstacles to overcome in terms of exosomes isolation,clinical trials and safety evaluation.In this article,what we should focus on about MSCs-exosomes in regeneration medicine will be discussed.
文摘BACKGROUND Mixed infection of hepatic cystic and alveolar echinococcosis is extremely rare.This article reveals the typical imaging manifestations of cystic and alveolar echinococcosis and investigates the diagnosis and surgical experience of mixed infection of hepatic cystic and alveolar echinococcosis.CASE SUMMARY From January 2017 to May 2019,4 cases with rare mixed infection of hepatic cystic and alveolar echinococcosis were admitted and treated by the Division of General Surgery of Qinghai Provincial People’s Hospital.Three of the patients occasionally had upper abdominal discomfort,but it did not affect their daily lives.However,hepatic echinococcosis was found in one patient by physical examination,and the patient had no discomfort.All 4 cases were Tibetans who had lived in pastoral areas of southern Qinghai for a long time.Enzyme-linked immunosorbent assay for echinococcosis was positive for all patients.Moreover,abdominal computed tomography showed typical imaging manifestations of cystic and alveolar echinococcosis including coexisting"honeycomb sign,"and"spotted calcification."Three of the patients underwent radical resection,and 1 case underwent palliative resection.All 4 patients developed different types of surgical complications after the operation,but all of them recovered and were discharged after symptomatic treatment.CONCLUSION There are no problems diagnosing mixed infection of hepatic cystic and alveolar echinococcosis.The difficulties involve preoperative evaluation and treatment of surgical complications.
基金Supported by the National Natural Science Foundation of China,No.82260567Science and Technology Fund of Guizhou Provincial Health Commission,No.gzwkj2022-082+2 种基金Excellent Young Talents Plan of Guizhou Medical University,No.2023(112)Taizhou Social Development Science and Technology Plan Project,No.23ywb146and Start-up Fund of Guizhou Medical University,No.J2021032.
文摘Primary liver cancer is a severe and complex disease,leading to 800000 global deaths annually.Emerging evidence suggests that inflammation is one of the critical factors in the development of hepatocellular carcinoma(HCC).Patients with viral hepatitis,alcoholic hepatitis,and steatohepatitis symptoms are at higher risk of developing HCC.However,not all inflammatory factors have a pathogenic function in HCC development.The current study describes the process and mechanism of hepatitis development and its progression to HCC,particularly focusing on viral hepatitis,alcoholic hepatitis,and steatohepatitis.Furthermore,the roles of some essential inflammatory cytokines in HCC progression are described in addition to a summary of future research directions.
基金supported by grants from the National Natu-ral Science Foundation of China(81701950 and 82172135)Medi-cal Research Projects of Chongqing for staffagainst the epidemic(2020FYYX248)the Kuanren Talents Program of the Second Affiliated Hospital,Chongqing Medical University(KY2019Y002).
文摘Background: Significant portal hypertension(SPH) is a relative contraindication for patients with resectable hepatocellular carcinoma(HCC). However, increasing evidence indicates that liver resection is feasible for HCC patients with SPH. Methods: HCC patients with cirrhosis who underwent laparoscopic liver resection(LLR) in two centers from January 2013 to April 2018 were included. Surgical and survival outcomes were analyzed to explore potential prognostic factors. Propensity score matching(PSM) analysis was performed to minimize bias. Results: A total of 165 patients were divided into two groups based on the presence(SPH, n = 76) or absence(non-SPH, n = 89) of SPH. Patients in the SPH group had longer operative time, more blood loss, and more advanced TNM stage than patients in the non-SPH group( P < 0.05). However, there were no significant differences in the postoperative 90-day mortality rate( n = 0), overall postoperative complications(47.4% vs. 41.6%, P = 0.455), Clavien-Dindo classification( P = 0.347), conversion to open surgery(9.2% vs. 6.7%, P = 0.557), or length of hospitalization(16 vs. 15 days, P = 0.203) between the SPH and non-SPH groups before PSM. Similar results were obtained after PSM. The 1-, 3-, and 5-year overall survival(OS) and recurrence-free survival rates in the SPH group were not significantly different from those in the non-SPH group both before and after PSM(log-rank P > 0.05). After PSM, alpha-fetoprotein(AFP) ≥ 400 μg/L [hazard ratio(HR) = 4.71, 95% confidence interval(CI): 2.69-8.25], ascites(HR = 2.18, 95% CI: 1.30-3.66), American Society of Anesthesiologists(ASA) classification(Ⅲ vs. Ⅱ)(HR = 2.13, 95% CI: 1.11-4.07) and tumor diameter > 5 cm(HR = 3.91, 95% CI: 2.02-7.56) independently predicted worse OS. Conclusions: LLR for patients with HCC complicated with SPH appears feasible at the price of increasing operative time and blood loss. AFP, ascites, ASA classification and tumor diameter may predict the prognosis of HCC complicated with SPH after LLR.
基金This work was funded by the National Natural Science Foundation of China(81670549)Jiangsu Provincial Key Research and Development Program(BE2020775)+2 种基金Zhenjiang Key Research and Development Program(SH2020002)Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)333 Talent Project of Jiangsu Province,Six Talent Peaks Project of Jiangsu Province and the Backbone Teacher of the Blue Project in Jiangsu Province.
文摘Nonalcoholic fatty liver disease(NAFLD)is a long-lasting condition that affects the liver,destroying its function.Liver injury can cause steatosis and inflammation,and further activation of hepatic stellate cells(HSCs)often leads to the development of nonalcoholic liver fibrosis.The patient with NAFLD is at risk of developing advanced liver disease and complications,such as liver failure,hepatocellular carcinoma(HCC),and portal hypertension.Although our understanding of the cellular and molecular mechanisms of NAFLD has greatly improved in recent years,treatment remains limited.Analysis and characterization of protein posttranslational modifications(PTMs)could improve our understanding of NAFLD pathology and leading to the development of new and more effective treatments.In recent years,a number of studies have described how ubiquitin-like(Ubl)-PTMs change during NAFLD and how treatments targeting specific enzymes mediating these Ubl-PTMs can improve various liver diseases,particularly in relation to NAFLD and nonalcoholic liver fibrosis.New strategies for evaluating modified proteomes could provide novel insights into the roles of Ubl-PTMs in NAFLD progression and the therapeutic value of targeting the proteins involved in these Ubl-PTMs.
基金supported by grants from the National Natural Science Foundation of China(No.81860034,82160405,82160038,82260035)the Natural Science Foundations of Jiangxi Province,China(No.20224BAB216037,20212ACB 206016).
文摘Chronic myeloid leukemia(CML)is a common adult leukemia.Both the acute phase of the disease and the adverse effects of anti-cancer treatments can lead to a poor prognosis.The N6-methyladenine(m^(6)A)modification plays an important regulatory role in various physiological and pathological processes.KIAA1429 is a known m^(6)A regulator,but the biological role of KIAA1429 in CML is unclear.In this study,we observed that the m^(6)A levels and KIAA1429 expression were significantly up-regulated in patients with blast phase CML.Notably,KIAA1429 regulated the total level of RNA m^(6)A modification in the CML cells and promoted the malignant biological behaviors of CML cells,including proliferation,migration,and imatinib resistance.Inhibiting KIAA1429 in CML cells reduced the stability of RAB27B mRNA through the m^(6)A/YTHDF1 axis,consequently inhibiting CML proliferation and drug efflux,ultimately increasing the sensitivity of CML cells to imatinib.Moreover,the knockdown of RAB27B also inhibited the proliferation and drug resistance of CML cells and promoted their apoptosis.Rucaparib,a recently developed anti-cancer agent,suppressed the expression of KIAA1429 and CML cell proliferation and promoted cell apoptosis.Rucaparib also inhibited the tumorigenesis of CML cells in vivo.The combined use of rucaparib and imatinib enhanced the sensitivity of CML cells to imatinib.Our study provides evidence that elevated KIAA1429 expression in the blast phase of CML enhances the stability of RAB27B mRNA through the m^(6)A/YTHDF1 axis to up-regulate RAB27B expression,thereby promoting CML progression.Rucaparib exerts inhibitory effects on KIAA1429 expression and thus reduces CML progression.
基金Jiangxi Province Key R&D Program Project,Grant/Award Number:20203BBGL73149Jiangxi Province Postgraduate Innovation Special Funds,Grant/Award Number:YC2022-s16。
文摘Small cell lung cancer(SCLC),a highly aggressive malignancy,is rapidly at an extensive stage once diagnosed and is one of the leading causes of death from malignancy.In the past decade,the treatment of SCLC has largely remained unchanged,and chemotherapy remains the cornerstone of SCLC treatment.The therapeutic value of adding immune checkpoint inhibitors to chemotherapy for SCLC is low,and only a few SCLC patients have shown a response to immune checkpoint inhibitors.Circulating tumor cells(CTCs)are tumor cells shed from solid tumor masses into the peripheral circulation and are key to tumor metastasis.Single-cell sequencing has revealed that the genetic profiles of individual CTCs are highly heterogeneous and contribute to the poor outcome and prognosis of SCLC patients.Theoretically,phenotypic analysis of CTCs may be able to predict the diagnostic significance of new potential targets for metastatic tumors.In this paper,we will discuss in depth the heterogeneity of CTCs in SCLC and the value of CTCs for the diagnosis and prognosis of SCLC and as relevant tumor markers in metastatic SCLC.
基金supported by National Natural Science Foundation of China(NSFC)(grant NO:22174020)Key Project of Natural Science Foundation of Fujian Province(Grant NO:2019J02005)。
文摘DNA not only plays a vital role in nature as fundamental hereditary material for storing genetic material,but also serves as well-defined functional material,for example,building blocks for the assembly of nanoscale bio-architectures by Watson-Crick base-pairing interaction.With the development of molecular biology,biotechnology and nanoscience,structural DNA nanotechnology has achieved numerous advances,contributing to the construction of various DNA nanostructures ranging from discrete objects to one dimensional(1D),two dimensional(2D),and three dimensional(3D)architectures.Among them,DNA tetrahedral nanoarchitecture is intensively studied because of simple 3D structure,easy design and unique properties,such as high rigidity,desirable biostability and efficient cellular uptake without auxiliary species.This review summarizes the research progress in the assembly of DNA tetrahedral objects and outlines the applications in biosensing,drug delivery and targeted therapy.Moreover,the dependence of biological activity of biomolecules on DNA tetrahedron-mediated spatially-controlled arrangement and great potential applications are discussed.In addition,the challenges in the design and clinic applications of DNA tetrahedron-based platforms are described,the perspectives towards biomedical applications are foreseen,and our understandings on further studies of DNA tetrahedron are provided,aiming to motivate the development of DNA nanotechnology and interdisciplinary research.
基金supported by the funds from the National Natural Science Foundation of China(Nos.81830006,82170219,and 81830004)the Science Technology Department of Zhejiang Province(No.2021C03117).
文摘Tumor-derived exosomes (TEXs) enriched in immune suppressive molecules predominantly drive T-cell dysfunction and impair antitumor immunity. Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising treatment for refractory and relapsed hematological malignancies, but whether lymphoma TEXs have the same impact on CAR T-cell remains unclear. Here, we demonstrated that B-cell lymphoma-derived exosomes induce the initial activation of CD19-CAR T-cells upon stimulation with exosomal CD19. However, lymphoma TEXs might subsequently induce CAR T-cell apoptosis and impair the tumor cytotoxicity of the cells because of the upregulated expression of the inhibitory receptors PD-1, TIM3, and LAG3 upon prolonged exposure. Similar results were observed in the CAR T-cells exposed to plasma exosomes from patients with lymphoma. More importantly, single-cell RNA sequencing revealed that CAR T-cells typically showed differentiated phenotypes and regulatory T-cell (Treg) phenotype conversion. By blocking transforming growth factor β (TGF-β)-Smad3 signaling with TGF-β inhibitor LY2109761, the negative effects of TEXs on Treg conversion, terminal differentiation, and immune checkpoint expression were rescued. Collectively, although TEXs lead to the initial activation of CAR T-cells, the effect of TEXs suppressed CAR T-cells, which can be rescued by LY2109761. A treatment regimen combining CAR T-cell therapy and TGF-β inhibitors might be a novel therapeutic strategy for refractory and relapsed B-cell lymphoma.
基金approved by the Medical Research Ethics Committee of the First Affiliated Hospital of Nanchang University[reference number:(2023)CDYFYYLK(05-023)].
文摘Pancreatic cancer is one of the most lethal malignant tumors in the world.Despite advances in diagnosis and treatment,the five-year survival rate for pancreatic cancer patients remains only 9%.1 Pancreatic adenocarcinoma(PAAD)belongs to pancreatic cancer,which occupies 85%of the whole pancreatic cancer.2 Reversible modification of Ne-methyladenosine(m^(6)A)has been shown to be involved in cancer progression,resulting in up-regulation of oncogene expression or down-regulation of tumor-suppressing genes and may affect the prognosis of patients with pancreatic cancer.
基金the support from the First Affiliated Hospital of Wenzhou Medical University Medical Research Center。
文摘Chemotherapy is regarded as a widely used and effective treatment strategy for lung cancer,although most conventional chemotherapeutics cause severe toxic side-effects due to their indiscriminate attacks on both cancerous and normal cells.Although nucleic acid nanomaterials are emerging as a promising drug delivery strategy,their clinical applications are limited by rapid degradation by nucleases and difficulties in targeting cancer cells.In this study,we have developed a Rhein-loaded aptamer-based DNA nanotube(DNT-S6@Rhein)for the targeted and efficient therapy of non-small cell lung cancer.Through the palindrome segments,two specified oligonucleotides were hybridized and folded into the well-defined nanotubes(DNT-S6),with the S6 aptamer distributed outside.The obtained nanotubes exhibited excellent serum stability and targeting ability towards A549 cells due to the firm structure and decoration of the S6 aptamer.Rhein,as an antitumor drug and DNA intercalator,can be effectively inserted into the DNT-S6.The drug-loaded nanotubes rapidly disassembled in intracellular environment and then the released Rhein was found to activate cellular apoptotic process and significantly suppress proliferation,migration and invasion of A549 cells.Moreover,DNT-S6@Rhein could efficiently accumulate in tumor regions,offering compelling therapeutic efficacy and biocompatibility under both in vitro and in vivo settings.These findings of this study provide a promising strategy for mitigating the inevitable systemic side-effects of chemotherapy and expand the potential application of DNA nanostructure on targeted drug delivery.
