Polymorphism of p16INK4a gene and rare mutation of p15INK4b gene exon2 in primary hepatocarcinoma

INTRODUCTION Hepatocellular carcinoma(HCC)is the mostcommon cause of death from cancer in China.Themechanisms of hepatocarcinogenesis are not yetknown clearly,p16INK4a gene,the multiple tumorsuppressor gene 1(MTS1),encodes P16 protein,which acts as an inhibitor by binding directly toCDK4 and CDK6 and preventing its association

Purification and characterization ofα-L-fucosidase from human primary hepatocarcinoma tissue

AIM: To purify and characterizeα-L-fucosidase from human liver cancer tissue and to detect the localization ofα-L-fucosidase in tumor tissue. METHODS: Cation exchange chromatography on CM-52 and ultrafiltration were used to separateα-Lfucosidase (AFU) from crude extract of liver cancer tissue. 4-methylumbelliferyl-α-L-fucopyranoside was used as a fluorescent substrate to quantify the purified AFU activity in each step. A polyclonal antibody (pAb) against the purified AFU was obtained by anion exchange chromatography on DEAE-52 after ammonium sulfate fractionation and ultrafiltration. Immuohistochemical staining was used to observe the expression of AFU in malignant and adjacent liver tissues. RESULTS: Humanα-L-fucosidase was purified 74-fold to apparent homogeneity with 15% yield. SDSPAGE indicated the presence of one subunit of molecular weight of 55 Ku. The specific activity of AFU in pooled fraction by chromatography was 10085 IU/mg. Western blot analysis indicated that the pAb could recognize one protein band of molecular weight of 55 Ku. The expression of AFU was observed in cytoplasm membrane of liver cancer tissue but not in that of adjacent tissue. CONCLUSION: The purifiedα-L-fucosidase from primary hepatocarcinoma (PHC) is different in its properties fromα-L-fucosidase in human other organs. The polyclonal antibody prepared in this experiment can be applied to the diagnosis of PHC.

Implantation of a drug delivery system during surgery for patients with primary hepatocarcinoma

BACKGROUND: Postoperative regional chemotherapy is one of the most effective methods to decrease the recurrent rate and improve the prognosis of primary hepatocarcinoma (PHC). This study was undertaken to assess the optimal pathway to implant the drug delivery system (DDS) in the different ways of resecting PHC so as to offer a valuable reference to clinical implantation of the DDS. METHODS: One hundred and ninety cases were divided into two groups according to whether the tumors were resected completely (A) or not (B). Groups A and B were subdivided into three groups a, b and c according to the pathway selected for DDS implantation. The patients in subgroup a received DDS implantation through both the hepatic artery and portal vein (A+P-implanted group), the patients in subgroup b received DDS implantation through the portal vein (P-implanted group), and the patients in subgroup c received DDS implantation through the hepatic artery (A-implanted group). RESULTS: The 1- and 3-year recurrent rates of subgroup c in group A were higher than those of subgroup b, and there was no significant difference between subgroups a and b. Compared with subgroups a and c, the 1- and 3-year survival rates of subgroup b were similar to those of group a but higher than those of group c. The 1- and 3-year survival rates between subgroups a and b in group B were significantly different. The prognosis of subgroup c was lower than that of subgroup a and no significant difference was observed between subgroups b and c. CONCLUSIONS: The DDS should be implanted into the portal vein when PHC is resected completely. It may be better to implant it into both portal vein and hepatic artery if the tumor cannot be completely resected.

Cell cycle and radiosensitivity of progeny of irradiated primary cultured human hepatocarcinoma cells

AIM： To evaluate the change of growth characteristics and radiosensitivity of irradiated primary cultured human hepatocarcinoma cells. METHODS： All tumor tissue samples were obtained from 39 hepatocarcinoma patients with a mean age of 49.6 years （range 22-76 years）. We divided the samples into irradiated group and non-irradiated group and measured their plating efficiency （PE）, population doubling time （PDT）, radiosensitivity index SF2 and cell RESULTS： The PDT of primary culture of hepatocardnoma cells was 91.0±6.6 h, PE was 12.0±1.4%, SF2 was 0.41±0.05%. The PDT of their inadiated progeny was 124.8±5.8 h, PE was 5.0±0.7%, SF2 was 0.65±0.09%. The pdmary cultured human hepatocarcinoma cells showed significant S reduction and G^2 arrest in a dose-dependent manner. The progeny of irradiated primary cultured hepatocarcinoma cells grew more slowly and its radiosensitivity increased. CONCLUSION： The progeny of irradiated primary cultured human hepatocarcinoma cells grows more slowly and its radiosensitivity increases.

Detection of autoantibodies in the serum of primary hepatocarcinoma patients

Objective: To study the significance of detecting au-toantibodies in primary hepatocarcinoma(PHC) pa-tients.Methods: Autoantibodies were detected by indirect im-munofluorescence assay. Antigens and antibodies ofHBV were determined by enzymeimmune assay. Antibodyto HCV IgG was detected by enzyme-linked immunoab-sorbent assay.Results: The positive rate of autoantibody was 27.3%(38/139) in 139 PHC patients. The main type of au-toantibodies in PHC was anti-nuclear antibody (36/38, 94.7%); others included anti-smooth muscle anti-body(2/38, 5.3% ), anti-mitochondria antibody(1/38, 2.6%), anti-midbody antibody (1/38, 2.6%), andanti-liver cell membrane antibody(2/38, 5.3%).Conclusions: Detecting autoantibodies in PHC patientsis of significance in studying the mechanism of au-toimmune reaction and etiology in PHC. The diversityof autoantibodies might result from a wide variety ofetiological factors involved in PHC development, andfrom a wide variety of overexpressed or mutated pro-teins involved in repeated cycles of necrosis and regen-eration in hepatocarcinoma development.

Three-dimensional choroidal vascularity index and choroidal thickness in fellow eyes of acute and chronic primary angle-closure using swept-source optical coherence tomography

AIM:To compare the three-dimensional choroidal vascularity index(CVI)and choroidal thickness between fellow eyes of acute primary angle-closure(F-APAC)and chronic primary angle-closure glaucoma(F-CPACG)and the eyes of normal controls.METHODS:This study included 37 patients with unilateral APAC,37 with asymmetric CPACG without prior treatment,and 36 healthy participants.Using swept-source optical coherence tomography(SS-OCT),the macular and peripapillary choroidal thickness and three-dimensional CVI were measured and compared globally and sectorally.Pearson’s correlation analysis and multivariate regression models were used to evaluate choroidal thickness or CVI with related factors.RESULTS:The mean subfoveal CVIs were 0.35±0.10,0.33±0.09,and 0.29±0.04,and the mean subfoveal choroidal thickness were 315.62±52.92,306.22±59.29,and 262.69±45.55μm in the F-APAC,F-CPACG,and normal groups,respectively.All macular sectors showed significantly higher CVIs and choroidal thickness in the F-APAC and F-CPACG eyes than in the normal eyes(P<0.05),while there were no significant differences between the F-APAC and F-CPACG eyes.In the peripapillary region,the mean overall CVIs were 0.21±0.08,0.20±0.08,and 0.19±0.05,and the mean overall choroidal thickness were 180.45±54.18,174.82±50.67,and 176.18±37.94μm in the F-APAC,F-CPACG,and normal groups,respectively.There were no significant differences between any of the two groups in all peripapillary sectors.Younger age,shorter axial length,and the F-APAC or F-CPACG diagnosis were significantly associated with higher subfoveal CVI and thicker subfoveal choroidal thickness(P<0.05).CONCLUSION:The fellow eyes of unilateral APAC or asymmetric CPACG have higher macular CVI and choroidal thickness than those of the normal controls.Neither CVI nor choroidal thickness can distinguish between eyes predisposed to APAC or CPACG.A thicker choroid with a higher vascular volume may play a role in the pathogenesis of primary angle-closure glaucoma.

Spatiotemporal changes of gross primary productivity and its response to drought in the Mongolian Plateau under climate change

Gross primary productivity(GPP)of vegetation is an important constituent of the terrestrial carbon sinks and is significantly influenced by drought.Understanding the impact of droughts on different types of vegetation GPP provides insight into the spatiotemporal variation of terrestrial carbon sinks,aiding efforts to mitigate the detrimental effects of climate change.In this study,we utilized the precipitation and temperature data from the Climatic Research Unit,the standardized precipitation evapotranspiration index(SPEI),the standardized precipitation index(SPI),and the simulated vegetation GPP using the eddy covariance-light use efficiency(EC-LUE)model to analyze the spatiotemporal change of GPP and its response to different drought indices in the Mongolian Plateau during 1982-2018.The main findings indicated that vegetation GPP decreased in 50.53% of the plateau,mainly in its northern and northeastern parts,while it increased in the remaining 49.47%area.Specifically,meadow steppe(78.92%)and deciduous forest(79.46%)witnessed a significant decrease in vegetation GPP,while alpine steppe(75.08%),cropland(76.27%),and sandy vegetation(87.88%)recovered well.Warming aridification areas accounted for 71.39% of the affected areas,while 28.53% of the areas underwent severe aridification,mainly located in the south and central regions.Notably,the warming aridification areas of desert steppe(92.68%)and sandy vegetation(90.24%)were significant.Climate warming was found to amplify the sensitivity of coniferous forest,deciduous forest,meadow steppe,and alpine steppe GPP to drought.Additionally,the drought sensitivity of vegetation GPP in the Mongolian Plateau gradually decreased as altitude increased.The cumulative effect of drought on vegetation GPP persisted for 3.00-8.00 months.The findings of this study will improve the understanding of how drought influences vegetation in arid and semi-arid areas.

Abnormally activated wingless/integrated signaling modulates tumor-associated macrophage polarization and potentially promotes hepatocarcinoma cell growth

In this article,we comment on the article by Huang et al.The urgent development of new therapeutic strategies targeting macrophage polarization is critical in the fight against liver cancer.Tumor-associated macrophages(TAMs),primarily of the M2 subtype,are instrumental in cellular communication within the tumor microenvironment and are influenced by various signaling pathways,including the wingless/integrated(Wnt)pathway.Activation of the Wnt signaling pathway is pivotal in promoting M2 TAMs polarization,which in turn can exacerbate hepatocarcinoma cell proliferation and migration.This manuscript emphasizes the burgeoning significance of the Wnt signaling pathway and M2 TAMs polarization in the pathogenesis and progression of liver cancer,highlighting the potential therapeutic benefits of inhibiting the Wnt pathway.Lastly,we point out areas in Huang et al’s study that require further research,providing guidance and new directions for similar studies.

Acute primary angle closure during the Omicron outbreak

AIM:To investigate Omicron’s impact on clinical presentation of acute primary angle closure(APAC)in China.METHODS:A consecutive case series with historical controls was conducted at Shenzhen Eye Hospital,the largest specialized hospital in Shenzhen,China.Medical records from a two-month period during the Omicron pandemic(December 1,2022,to January 31,2023)were compared with records from two control groups(12/2018–1/2019 and 12/2021–1/2022)before pandemic.Patients with APAC were included,and the prevalence of APAC and demographic characteristics in Omicron-infected and noninfected patients were compared.RESULTS:Seventy-one(23.43%)out of 303 patients were diagnosed with APAC in the pandemic cohort,which was 2.98 and 2.61 times higher than that in control cohorts(7.87%in 2019,8.96%in 2022,P<0.001).The pandemic cohort has significantly higher Omicron-infected rate(78.87%vs 0 vs 0;P<0.001),lower proportion of glaucoma history(16.90%vs 42.86%vs 41.67%,P=0.005),higher surgical rate(95.77%vs 83.33%vs 78.57%,P=0.024),higher total medical costs and larger pupil diameter(5.63±0.15 vs 4.68±0.15 vs 4.69±0.22 mm,P<0.01).In 83%Omicron-infected patients,ocular symptoms appeared within 3d after systemic symptoms onset.In multivariate analysis,Omicron infection(P<0.001)was the only independent predictor of pupil diameter.CONCLUSION:In the Omicron epidemic in China,there is an increase of prevalence and severity of APAC,particularly focusing on the first 3d following infection.

Clinical analysis of multiple primary gastrointestinal malignant tumors:A 10-year case review of a single-center

BACKGROUND Multiple primary malignant tumors(MPMTs)was first described by Billroth as early as 1889,with the first report published by Warren and Gates in 1932.Since then,numerous cases have been reported.A literature review of 1104269 patients with cancer revealed that the incidence of MPMTs ranged from 0.73 to 11.7%.In recent years,however,there has been a significant upward trend in the incidence of this phenomenon,which may be associated with many different factors,including the advancement of modern diagnostic procedures facilitating the examination and diagnosis of more MPMTs,increased exposure to chemotherapy and radiotherapy that exacerbate the risk of new malignant tumors in patients with cancer,and prolonged survival of patients with cancer allowing sufficient time for the development of new primary cancers.AIM To analyze the incidence,clinical features,treatment factors,prevalence,and prognosis of patients with MPMTs in the gastrointestinal tract treated in a single center.Additionally,we analyzed the different tumor combinations,time interval between the occurrence of tumors,and staging.METHODS This retrospective cohort study analyzed 8059 patients with pathologically confirmed gastrointestinal malignant tumors treated at the Gansu Province Hospital in Lanzhou,Gansu,China between June 2011 and June 2020.Of these,85 patients had MPMTs.The clinical features,treatment factors,prevalence,and prognosis of this latter cohort were analyzed.RESULTS The incidence of MPMTs in patients with gastrointestinal malignant tumors was 1.05%(85/8059),including 83 double primary malignant tumors and two triple primary malignant tumors of which 57(67.06%)were synchronous MPMTs(SMPMTs)and 28(32.94%)were metachronous MPMTs(MMPMTs).The most frequent associations were found between the rectum colon cancers within the SMPMT category and the gastric-colon cancers within the MMPMT category.For the MMPMTs,the median interval was 53 months.The overall 1-,3-and 5-year survival rates from diagnosis of the first primary cancer were 91.36%,65.41%,and 45.97%,respectively;those from diagnosis of the second primary cancer were 67.90%,29.90%,and 17.37%,respectively.CONCLUSION MPMTs in the gastrointestinal tract have a high incidence and poor prognosis.Thus,it is necessary to perform both gastroscopy and colonoscopy in patients with gastrointestinal tumors.Multidisciplinary comprehensive diagnosis and treatment may improve the diagnosis rate and treatment efficiency of MPMTs.

Efficacy and safety of transhepatic arterial chemoembolization with drug-loaded microspheres in unresectable primary liver cancer

BACKGROUND Transhepatic arterial chemoembolization(TACE),as a local treatment,has been widely used in the treatment of unresectable liver cancer.The introduction of drug carrier microspheres has brought new hope for the therapeutic effect of TACE.Microspheres can realize the slow release and directional delivery of drugs,reduce systemic toxicity and improve local curative effect.AIM To compare the effectiveness of traditional transcatheter arterial chemoembolization against microsphere-assisted transcatheter arterial chemoembolization in the treatment of hepatocellular carcinoma that is incurable.METHODS We searched the PubMed,Embase,Cochrane Library,and CNKI databases for clinical trials of drug-luting beads TACE(DEB-TACE)vs conventional TACE(cTACE)for the treatment of unresectable liver cancer.We screened references based on inclusion and exclusion criteria and then selected valid data for meta-analysis using RevMan 53 software.The complete response(CR)rate,partial response(PR)rate,postoperative stable disease(SD)rate,and 6-month and 12-month survival rates were compared.RESULTS A total of 12 articles were included,including 1177 patients,519 of whom received DEB-TACE and 658 of whom received cTACE.The CR rate in the DEB-TACE group was much greater than that in the cTACE group[relative risk(RR)=1.42,95%CI:1.18-1.72,P=0.0002].The 12-month survival rate significantly increased(RR=1.09;95%CI:1.01-1.17,P=0.03);the PR rate(RR=1.13;95%CI:0.97-1.30,P=0.12);the SD rate(RR=0.82;95%CI:0.64-1.05,P=0.12);and the 6-month survival rate(RR=1.05;95%CI:1.00-1.10,P=0.07).There was no significant difference(P<0.05).CONCLUSION Compared with those of iodized oil TACE,the drug-loaded microspheres tended to have therapeutic advantages.

MP-3 microperimeter in early primary open angle glaucoma with a new pattern

AIM:To investigate macular microperimetry in patients with early primary open angle glaucoma(POAG)using a new custom-made pattern,and analyze the characteristics of macular sensitivity.METHODS:This case-control study included 38 patients with POAG,who were divided into pre-perimetric glaucoma(18 eyes of 18 patients),early-stage(20 eyes of 20 patients),and control(20 eyes of 20 patients)groups.All subjects underwent standard 24-2 humphrey visual field test.An MP-3 microperimeter with a new custom-made pattern(28 testing points distributed in four quadrants,covering the central 10°of the retina)was used to evaluate macular sensitivity.Ganglion cell complex(GCC)thicknesses were examined using an RS-3000 Advance OCT system.The features of structure and function were analysed per quadrant.RESULTS:The pre-perimetric glaucoma group had significantly lower inferior hemifield macular sensitivity compared to controls(P<0.05).The early-stage POAG group had significantly lower average,inferior hemifield,inferonasal,and inferotemporal mean sensitivities compared to the pre-perimetric glaucoma group(P<0.05),and lower macular sensitivity in all sectors compared to controls(P<0.05).Regarding GCC thickness,all sectors in the early-stage POAG group became thinner compared to those in controls(P<0.05);whereas all sectors in the early-stage POAG group,except the superonasal quadrant,became thinner compared to those in the pre-perimetric glaucoma group(P<0.05).Macular sensitivity and GCC thickness were significantly associated in each sector.The inferotemporal quadrant had the highest correlation coefficients(0.840).The structure-function relationship for the inferonasal and inferotemporal sectors was stronger compared to the corresponding superior sectors.CONCLUSION:Microperimetry reveals variations in macular sensitivity in patients with early glaucoma earlier than conventional perimetry,particularly in pre-perimetric glaucoma cases in which it might be undetectable by conventional methods.The new custom-made pattern may improve the accuracy of microperimetry by enhancing point arrangement and reducing fatigue effects.Macular sensitivity measured by MP-3 with this pattern shows statistically significant structural and functional associations with the thicknesses of the GCC.

Evaluation of Well Spacing for Primary Development of Fractured Horizontal Wells in Tight Sandstone Gas Reservoirs

Methods for horizontal well spacing calculation in tight gas reservoirs are still adversely affected by the complexity of related control factors,such as strong reservoir heterogeneity and seepage mechanisms.In this study,the stress sensitivity and threshold pressure gradient of various types of reservoirs are quantitatively evaluated through reservoir seepage experiments.On the basis of these experiments,a numerical simulation model(based on the special seepage mechanism)and an inverse dynamic reserve algorithm(with different equivalent drainage areas)were developed.The well spacing ranges of Classes I,II,and III wells in the Q gas field are determined to be 802–1,000,600–662,and 285–400 m,respectively,with their average ranges as 901,631,and 342.5 m,respectively.By considering both the pairs of parallel well groups and series well groups as examples,the reliability of the calculation results is verified.It is shown that the combination of the two models can reduce errors and provide accurate results.

Bruton’s tyrosine kinase inhibitors in primary central nervous system lymphoma:New hopes on the horizon

In this editorial,we comment on the article by Wang et al.This manuscript explores the potential synergistic effects of combining zanubrutinib,a novel oral inhibitor of Bruton’s tyrosine kinase,with high-dose methotrexate(HD-MTX)as a therapeutic intervention for primary central nervous system lymphoma(PCNSL).The study involves a retrospective analysis of 19 PCNSL patients,highlighting clinicopathological characteristics,treatment outcomes,and genomic biomarkers.The results indicate the combination’s good tolerance and strong antitumor activity,with an 84.2%overall response rate.The authors emphasize the potential of zanubrutinib to modulate key genomic features of PCNSL,particularly mutations in myeloid differentiation primary response 88 and cluster of differentiation 79B.Furthermore,the study investigates the role of circulating tumor DNA in cerebrospinal fluid for disease surveillance and treatment response monitoring.In essence,the study provides valuable insights into the potential of combining zanubrutinib with HD-MTX as a frontline therapeutic regimen for PCNSL.The findings underscore the importance of exploring alternative treatment modalities and monitoring genomic and liquid biopsy markers to optimize patient outcomes.While the findings suggest promise,the study’s limitations should be considered,and further research is needed to establish the clinical relevance of this therapeutic approach for PCNSL.

Heterochronous multiple primary prostate cancer and lymphoma:A case report

BACKGROUND Multiple primary malignant tumors(MPMTs)are rare type of cancer,especially when solid tumors are the first and lymphoma is the second primary malignancy.We report a patient with heterochronous MPMTs consisting of prostate cancer and rectal diffuse large B-cell lymphoma(DLBCL).CASE SUMMARY We report a 77-year-old male patient diagnosed with prostate cancer who was treated with radiation therapy and one year of endocrine therapy with bicalutamide(50 mg per day)and an extended-release implant of goserelin(1/28 d).Seven years later,rectal DLBCL with lung metastases was found.CONCLUSION Although rare,the possibility of prostate cancer combined with a double primary cancer of DLBCL can provide a deeper understanding.

Three novel rare TP53 fusion mutations in a patient with multiple primary cancers:a case report

As survival rates improve and detection technologies advance,the occurrence of multiple primary cancers(MPCs)has been increasing.Approximately 16%of cancer survivors develop a subsequent malignancy,with lung cancer often developing after esophageal cancer due to potential“field cancerization”effects.Despite this observation,the genetic heterogeneity underlying MPCs remains understudied.However,the recent emergence of genetic testing has expanded the scope of investigations into MPCs to investigate signatures underlying cancer predisposition.This report reveals 3 unprecedented TP53 fusion mutations in a Chinese patient afflicted by MPCs,namely,AP1M2–TP53(A1;T11)fusion,TP53–ILF3(T10;I13)fusion,and SLC44A2–TP53(S5;T11)fusion.This patient exhibited an extended period of survival after diagnosis of extensive-stage small cell lung cancer,which occurred 6 years after the diagnosis of esophageal squamous cell cancer.This unique reportmay provide supplementary data that enhance our understanding of the genetic landscape ofMPCs.

Upadacitinib for refractory ulcerative colitis with primary nonresponse to infliximab and vedolizumab:A case report

BACKGROUND Many patients with ulcerative colitis(UC)do not respond well to,or tolerate conventional and biological therapies.There is currently no consensus on the treatment of refractory UC.Studies have demonstrated that the selective Janus kinase 1 inhibitor upadacitinib,a small-molecule drug,is effective and safe for treating UC.However,no studies have revealed that upadacitinib is effective in treating refractory UC with primary nonresponse to infliximab and vedolizumab.CASE SUMMARY We report the case of a 44-year-old male patient with a chief complaint of bloody diarrhoea with mucus and pus,in addition to dizziness.The patient had recurrent disease after receiving mesalazine,prednisone,azathioprine,infliximab and vedolizumab over four years.Based on the endoscopic findings and pathological biopsy,the patient was diagnosed with refractory UC.In particular,the patient showed primary nonresponse to infliximab and vedolizumab.Based on the patient’s history and recurrent disease,we decided to administer upadacitinib.During hospitalisation,the patient was received upadacitinib under our guidance.Eight weeks after the initiation of upadacitinib treatment,the patient’s symptoms and endoscopic findings improved significantly.No notable adverse reactions have been reported to date.CONCLUSION Our case report suggests that upadacitinib may represent a valuable strategy for treating refractory UC with primary nonresponse.

Validation and performance of three scoring systems for predicting primary non-function and early allograft failure after liver transplantation

Background: Primary non-function(PNF) and early allograft failure(EAF) after liver transplantation(LT) seriously affect patient outcomes. In clinical practice, effective prognostic tools for early identifying recipients at high risk of PNF and EAF were urgently needed. Recently, the Model for Early Allograft Function(MEAF), PNF score by King's College(King-PNF) and Balance-and-Risk-Lactate(BAR-Lac) score were developed to assess the risks of PNF and EAF. This study aimed to externally validate and compare the prognostic performance of these three scores for predicting PNF and EAF. Methods: A retrospective study included 720 patients with primary LT between January 2015 and December 2020. MEAF, King-PNF and BAR-Lac scores were compared using receiver operating characteristic(ROC) and the net reclassification improvement(NRI) and integrated discrimination improvement(IDI) analyses. Results: Of all 720 patients, 28(3.9%) developed PNF and 67(9.3%) developed EAF in 3 months. The overall early allograft dysfunction(EAD) rate was 39.0%. The 3-month patient mortality was 8.6% while 1-year graft-failure-free survival was 89.2%. The median MEAF, King-PNF and BAR-Lac scores were 5.0(3.5–6.3),-2.1(-2.6 to-1.2), and 5.0(2.0–11.0), respectively. For predicting PNF, MEAF and King-PNF scores had excellent area under curves(AUCs) of 0.872 and 0.891, superior to BAR-Lac(AUC = 0.830). The NRI and IDI analyses confirmed that King-PNF score had the best performance in predicting PNF while MEAF served as a better predictor of EAD. The EAF risk curve and 1-year graft-failure-free survival curve showed that King-PNF was superior to MEAF and BAR-Lac scores for stratifying the risk of EAF. Conclusions: MEAF, King-PNF and BAR-Lac were validated as practical and effective risk assessment tools of PNF. King-PNF score outperformed MEAF and BAR-Lac in predicting PNF and EAF within 6 months. BAR-Lac score had a huge advantage in the prediction for PNF without post-transplant variables. Proper use of these scores will help early identify PNF, standardize grading of EAF and reasonably select clinical endpoints in relative studies.

Research progress of ferroptosis regulating lipid peroxidation and metabolism in occurrence and development of primary liver cancer

As a highly aggressive tumor,the pathophysiological mechanism of primary liver cancer has attracted much attention.In recent years,factors such as ferroptosis regulation,lipid peroxidation and metabolic abnormalities have emerged in the study of liver cancer,providing a new perspective for understanding the development of liver cancer.Ferroptosis regulation,lipid peroxidation and metabolic abnormalities play important roles in the occurrence and development of liver cancer.The regulation of ferroptosis is involved in apoptosis and necrosis,affecting cell survival and death.Lipid peroxidation promotes oxidative damage and promotes the invasion of liver cancer cells.Metabolic abnormalities,especially the disorders of glucose and lipid metabolism,directly affect the proliferation and growth of liver cancer cells.Studies of ferroptosis regulation and lipid peroxidation may help to discover new therapeutic targets and improve therapeutic outcomes.The understanding of metabolic abnormalities can provide new ideas for the prevention of liver cancer,and reduce the risk of disease by adjusting the metabolic process.This review focuses on the key roles of ferroptosis regulation,lipid peroxidation and metabolic abnormalities in this process.

MSC-derived exosomes attenuate hepatic fibrosis in primary sclerosing cholangitis through inhibition of Th17 differentiation

Primary sclerosing cholangitis(PSC)is an autoimmune cholangiopathy characterized by chronic inflammation of the biliary epithelium and periductal fibrosis,with no curative treatment available,and liver transplantation is inevitable for end-stage patients.Human placentalmesenchymal stem cell(hpMSC)-derived exosomes have demonstrated the ability to prevent fibrosis,inhibit collagen production and possess immunomodulatory properties in autoimmune liver disease.Here,we prepared hpMSC-derived exosomes(Exo^(MSC))and further investigated the anti-fibrotic effects and detailed mechanism on PSC based on Mdr2^(−/−)mice and multicellular organoids established from PSC patients.The results showed that Exo^(MSC) ameliorated liver fibrosis in Mdr2^(−/−)mice with significant collagen reduction in the preductal area where Th17 differentiation was inhibited as demonstrated by RNAseq analysis,and the percentage of CD4+IL-17A+T cells was reduced both in Exo^(MSC)-treated Mdr2^(−/−)mice(Mdr2^(−/−)-Exo)in vivo and Exo^(MSC)-treated Th17 differentiation progressed in vitro.Furthermore,Exo^(MSC) improved the hypersecretory phenotype and intercellular interactions in the hepatic Th17 microenvironment by regulating PERK/CHOP signaling as supported by multicellular organoids.Thus,our data demonstrate the antifibrosis effect of Exo^(MSC) in PSC disease by inhibiting Th17 differentiation,and ameliorating the Th17-induced microenvironment,indicating the promising potential therapeutic role of Exo^(MSC) in liver fibrosis of PSC or Th17-related diseases.