Study of liver cirrhosis over twenty consecutive years in adults in Southern China

BACKGROUND Liver cirrhosis(LC)is a prevalent and severe disease in China.The burden of LC is changing with widespread vaccination of hepatitis B virus(HBV)and antiviral therapy.However,the recent transition in etiologies and clinical features of LC cases requiring hospitalization is unclear.AIM To identify the transition in etiologies and clinical characteristics of hospitalized LC patients in Southern China.METHODS In this retrospective,cross-sectional study we included LC inpatients admitted between January 2001 and December 2020.Medical data indicating etiological diagnosis and LC complications,and demographic,laboratory,and imaging data were collected from our hospital-based dataset.The etiologies of LC were mainly determined according to the discharge diagnosis,and upper gastrointestinal bleeding,ascites,hepatic encephalopathy,spontaneous bacterial peritonitis,hepatocellular carcinoma(HCC),portal vein thrombosis,hepatorenal syndrome,and acute-on-chronic liver failure(ACLF)were considered LC-related complications in our study.Changing trends in the etiologies and clinical characteristics were investigated using logistic regression,and temporal trends in proportions of separated years were investigated using the Cochran-Armitage test.In-hospital prognosis and risk factors associated with in-hospital mortality were also invest igated.RESULTS A total of 33143 patients were included in the study[mean(SD)age,51.7(11.9)years],and 82.2%were males.The mean age of the study population increased from 51.0 years in 2001-2010 to 52.0 years in 2011-2020(P<0.001),and the proportion of female patients increased from 16.7%in 2001-2010 to 18.2%in 2011-2020(P=0.003).LC patients in the decompensated stage at diagnosis decreased from 68.1%in 2001-2010 to 64.6%in 2011-2020(P<0.001),and the median score of model for end-stage liver disease also decreased from 14.0 to 11.0(P<0.001).HBV remained the major etiology of LC(75.0%)and the dominant cause of viral hepatitis-LC(94.5%)during the study period.However,the proportion of HBV-LC decreased from 82.4%in 2001-2005 to 74.2%in 2016-2020,and the proportion of viral hepatitis-LC decreased from 85.2%in 2001-2005 to 78.1%in 2016-2020(both P for trend<0.001).Meanwhile,the proportions of LC caused by alcoholic liver disease,autoimmune hepatitis and mixed etiology increased by 2.5%,0.8%and 4.5%,respectively(all P for trend<0.001).In-hospital mortality was stable at 1.0%in 2011-2020,whereas HCC and ACLF manifested the highest increases in prevalence among all LC complications(35.8%to 41.0%and 5.7%to 12.4%,respectively)and were associated with 6-fold and 4-fold increased risks of mortality(odds ratios:6.03 and 4.22,respectively).CONCLUSION LC inpatients have experienced changes in age distribution and etiologies of cirrhosis over the last 20 years in Southern China.HCC and ACLF are associated with the highest risk of in-hospital mortality among LC complications.

Non-invasive assessment of liver fibrosis using twodimensional shear wave elastography in patients with autoimmune liver diseases

AIM To determine the diagnostic accuracy of two-dimensional shear wave elastography(2D-SWE) for the noninvasive assessment of liver fibrosis in patients with autoimmune liver diseases(AILD) using liver biopsy as the reference standard.METHODS Patients with AILD who underwent liver biopsy and 2D-SWE were consecutively enrolled. Receiver operating characteristic(ROC) curves were constructed to assess the overall accuracy and to identify optimal cut-off values.RESULTS The characteristics of the diagnostic performance were determined for 114 patients with AILD. The areas under the ROC curves for significant fibrosis, severe fibrosis, and cirrhosis were 0.85, 0.85, and 0.86, respectively, and the optimal cut-off values associated with significant fibrosis(≥ F2), severe fibrosis(≥ F3), and cirrhosis(F4) were 9.7 k Pa, 13.2 k Pa and 16.3 k Pa, respectively. 2D-SWE showed sensitivity values of 81.7% for significant fibrosis, 83.0% for severe fibrosis,and 87.0% for cirrhosis, and the respective specificity values were 81.3%, 74.6%, and 80.2%. The overall concordance rate of the liver stiffness measurements obtained using 2D-SWE vs fibrosis stages was 53.5%.CONCLUSION2D-SWE showed promising diagnostic performance for assessing liver fibrosis stages and exhibited high cut-off values in patients with AILD. Low overall concordance rate was observed in the liver stiffness measurements obtained using 2D-SWE vs fibrosis stages.

Clinical strategies to improve the survival rate of liver recipients with acute-on-chronic liver failure

There are currently more than 100 million patients with liver disease in China,and 300000 patients are estimated to be diagnosed with end-stage liver diseases each year.Since Dr.Starzl,a professor from the University of Pittsburgh,completed the first liver transplant in 1963,liver transplantation has been recognized as the only effective treatment for patients with end-stage liver disease.

Elevated Kallistatin promotes the occurrence and progression of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease(NAFLD)is the most common chronic liver disease worldwide,and the development of nonalcoholic steatohepatitis(NASH)might cause irreversible hepatic damage.Hyperlipidemia(HLP)is the leading risk factor for NAFLD.This study aims to illuminate the causative contributor and potential mechanism of Kallistatin(KAL)mediating HLP to NAFLD.221 healthy control and 253 HLP subjects,62 healthy control and 44 NAFLD subjects were enrolled.The plasma KAL was significantly elevated in HLP subjects,especially in hypertriglyceridemia(HTG)subjects,and positively correlated with liver injury.Further,KAL levels of NAFLD patients were significantly up-regulated.KAL transgenic mice induced hepatic steatosis,inflammation,and fibrosis with time and accelerated inflammation development in high-fat diet(HFD)mice.In contrast,KAL knockout ameliorated steatosis and inflammation in high-fructose diet(HFruD)and methionine and choline-deficient(MCD)diet-induced NAFLD rats.Mechanistically,KAL induced hepatic steatosis and NASH by down-regulating adipose triglyceride lipase(ATGL)and comparative gene identification 58(CGl-58)by LRP6/Gas/PKA/GSK3βpathway through down-regulating peroxisome proliferator-activated receptor(PPARy)and up-regulating kruppel-like factor four(KLF4),respectively.CGl-58 is bound to NF-kB p65 in the cytoplasm,and diminishing CGl-58 facilitated p65 nuclear translocation and TNFa induction.Meanwhile,hepatic CGl-58-overexpress reverses NASH in KAL transgenic mice.Further,free fatty acids up-regulated KAL against thyroid hormone in hepatocytes.Moreover,Fenofibrate,one triglyceride-lowering drug,could reverse hepatic steatosis by down-regulating KAL.These results demonstrate that elevated KAL plays a crucial role in the development of HLP to NAFLD and may be served as a potential preventive and therapeutic target.

Cutting balloon treatment of anastomotic biliary stenosis after liver transplantation: Report of two cases

Biliary stenosis is a common complication after liver transplantation,and has an incidence rate ranging from4.7%to 12.5%based on our previous study.Three types of biliary stenosis(anastomotic stenosis,nonanastomotic peripheral stenosis and non-anastomotic central hilar stenosis)have been identified.We report the outcome of two patients with anastomotic stricture after liver transplantation who underwent successfulcutting balloon treatment.Case 1 was a 40-year-old male transplanted due to subacute fulminant hepatitis C.Case 2 was a 57-year-old male transplanted due to hepatitis B virus-related end-stage cirrhosis associated with hepatocellular carcinoma.Both patients had similar clinical scenarios:refractory anastomotic stenosis after orthotopic liver transplantation and failure of balloon dilation of the common bile duct to alleviate biliary stricture.

All roads lead to Rome-a review of the potential mechanisms by which exerkines exhibit neuroprotective effects in Alzheimer’s disease

Age-related neurodegenerative disorders such as Alzheimer’s disease(AD)have become a critical public health issue due to the significantly extended human lifespan,leading to considerable economic and social burdens.Traditional therapies for AD such as medicine and surgery remain ineffective,impractical,and expensive.Many studies have shown that a variety of bioactive substances released by physical exercise(called“exerkines”)help to maintain and improve the normal functions of the brain in terms of cognition,emotion,and psychomotor coordination.Increasing evidence suggests that exerkines may exert beneficial effects in AD as well.This review summarizes the neuroprotective effects of exerkines in AD,focusing on the underlying molecular mechanism and the dynamic expression of exerkines after physical exercise.The findings described in this review will help direct research into novel targets for the treatment of AD and develop customized exercise therapy for individuals of different ages,genders,and health conditions.

Potential application of ultrasound-guided thermal ablation in rare liver tumors

Background: With the advances of imaging techniques, the detection rate of rare liver tumor is increased. However, the therapeutic strategies of the rare liver tumors remain limited. Methods: We analyzed twelve pathologically confirmed rare liver tumors in 8 patients. All of the patients underwent ultrasound(US) guided biopsy and subsequent thermal ablation. The tumors were ablated according to the preoperative plans and monitored by real-time US. CT/MRI fused with contrast enhanced US(CEUS) or three-dimensional(3 D) US-CEUS images were used to guide and assess the ablation zone more accurately during thermal ablation. The rate of technical efficacy was assessed based on the contrast-enhance CT/MRI(CECT/MRI) results one month after ablation. Local tumor progression(LTP), recurrence and complications were followed up and recorded. Results: Among these twelve nodules, nine were subject to US-guided thermal ablation, whereas the other three inconspicuous nodules were subject to CEUS-guided thermal ablation. Intra-procedure CT/MRI-CEUS or 3 D US-CEUS fusion imaging assessments demonstrated that the ablation zone sufficiently covered the original tumor, and no immediate supplementary ablation was required. Additionally, no major complications were observed during the follow-up period. The postoperative CECT/MRI confirmed that the technique success rate was 100%. Within the surveillance period of 13 months, no LTP or recurrence was noted. Conclusions: US-guided thermal ablation was feasible and safe for rare liver tumors. The use of fusion imaging technique might make US-guided thermal ablation as effective as surgical resection, and this technique might serve as a potential therapeutic modality for rare liver tumors in the future.

Lowering the threshold of alanine aminotransferase for enhanced identification of significant hepatic injury in chronic hepatitis B patients

BACKGROUND The clinical and histological features of chronic hepatitis B(CHB)patients who fall into the"grey zone(GZ)"and do not fit into conventional natural phases are unclear.AIM To explore the impact of varying the threshold of alanine aminotransferase(ALT)levels in identifying significant liver injury among GZ patients.METHODS This retrospective analysis involved a cohort of 1617 adult patients diagnosed with CHB who underwent liver biopsy.The clinical phases of CHB patients were determined based on the European Association for the Study of the Liver 2017 Clinical Practice Guidelines.GZ CHB patients were classified into four groups:GZ-A(HBeAg positive,normal ALT levels,and HBV DNA≤10^(7) IU/mL),GZ-B(HBeAg positive,elevated ALT levels,and HBV DNA<10^(4) or>10^(7) IU/mL),GZC(HBeAg negative,normal ALT levels,and HBV DNA≥2000 IU/mL),and GZ-D(HBeAg negative,elevated ALT levels,and HBV DNA≤2000 IU/mL).Significant hepatic injury(SHI)was defined as the presence of notable liver inflammation(≥G2)and/or significant fibrosis(≥S2).RESULTS The results showed that 50.22%of patients were classified as GZ,and 63.7%of GZ patients developed SHI.The study also found that lowering the ALT treatment thresholds to the American Association for the Study of Liver Diseases 2018 treatment criteria(35 U/L for men and 25 U/L for women)can more accurately identify patients with significant liver damage in the GZ phases.In total,the proportion of patients with ALT≤40 U/L who required antiviral therapy was 64.86%[(221+294)/794].When we lowered the ALT treatment threshold to the new criteria(30 U/L for men and 19 U/L for women),the same outcome was revealed,and the proportion of patients with ALT≤40 U/L who required antiviral therapy was 75.44%[(401+198)/794].Additionally,the proportion of SHI was 49.1%in patients under 30 years old and increased to 55.3%in patients over 30 years old(P=0.136).CONCLUSION These findings suggest the importance of redefining the natural phases of CHB and using new ALT treatment thresholds for better diagnosis and management of CHB patients in the GZ phases.

Different techniques for harvesting grafts for living donor liver transplantation: A systematic review and meta-analysis

AIM To perform a systematic review and meta-analysis on minimally vs conventional invasive techniques for harvesting grafts for living donor liver transplantation.METHODS Pub Med,Web of Science,EMBASE,and the Cochrane Library were searched comprehensively for studies comparing MILDH with conventional living donor hepatectomy(CLDH).Intraoperative and postoperative outcomes(operative time,estimated blood loss,postoperative liver function,length of hospital stay,analgesia use,complications,and survival rate)were analyzed in donors and recipients.Articles were included if they:(1)compared the outcomes of MILDH and CLDH;and(2)reported at least some of the above outcomes.RESULTS Of 937 articles identified,13,containing 1592 patients,met our inclusion criteria and were included in the meta-analysis.For donors,operative time[weighted mean difference(WMD)=20.68,95%CI:-6.25-47.60, =0.13]and blood loss(WMD=-32.61,95%CI:-80.44-5.21, =0.18)were comparable in the two groups.In contrast,analgesia use(WMD=-7.79,9 5%C I:-1 4.0 6-1.8 7, =0.0 1),posto pera tive complications[odds ratio(OR)=0.62,95%CI:0.44-0.89, =0.009],and length of hospital stay(W M D):-1.2 5,9 5%C I:-2.3 5-0.1 4, =0.0 3)significantly favored MILDH.No differences were observed in recipient outcomes,including postoperative complications(OR=0.93,95%CI:0.66-1.31, =0.68)and survival rate(HR=0.96,95%CI:0.27-3.47, =0.95).Funnel plot and statistical methods showed a low probability of publication bias.CONCLUSION MILDH is safe,effective,and feasible for living donor liver resection with fewer donor postoperative complications,reduced length of hospital stay and analgesia requirement than CLDH.

Achievement of complete response to nivolumab in a patient with advanced sarcomatoid hepatocellular carcinoma:A case report

BACKGROUND Sarcomatoid hepatocellular carcinoma(SHC)is a rare subtype of hepatocellular carcinoma(HCC),with a high recurrence rate after surgery.In addition to limited effective treatment for the advanced stage of SHC,the prognosis of patients with this malignancy is worse than that of patients with conventional HCC.CASE SUMMARY We present the case of a 54-year-old man with SHC who underwent radical segmental hepatectomy,which relapsed 4 mo after surgery due to lymphatic metastasis in the porta hepatis.Although a second surgery was performed,new metastasis developed in the mediastinal lymph nodes.Therefore,sorafenib and lenvatinib were sequentially administered as first-and second-line systemic therapies,respectively.However,progressive disease was confirmed based on a recurrent hepatic lesion and new metastatic lesion in the abdominal cavity.Percutaneous transhepatic cholangial drainage was performed to alleviate the biliary obstruction.Because the tumor was strongly positive for programmed death-ligand 1,the patient was started on nivolumab.Imaging studies revealed that after two cycles of immunotherapy,the metastatic lesions decreased to undetectable levels.CONCLUSION The patient experienced continuous complete remission for 8 mo.Immune checkpoint inhibitors are useful for the treatment of advanced SHC.

Reversal Effect of BM-cyclin 1 on Multidrug Resistance by Down-regulating MRP2 in BALB/C Nude Mice Bearing C-A120 Cells

Our previous study demonstrated that BM-cyclin 1, a traditional anti-mycoplasma drug, could effectively reverse the multidrug resistance （MDR） of C-A120 cells. The present study aims to explore the reversal effect of BM-cyclin 1 on MDR and its mechanisms in BALB/C nude mice bearing C-A120 cells. Irnmunoblotting analysis and reverse transcription-polymerase chain reaction （RT-PCR） were used to study the change in multidrug resistance-associated protein 2 （MRP2） induced by BM-cyclin 1. We found that the expression levels of MRP2 protein and mRNA in C-A120 cells treated with BM-cyclin 1 were reduced significantly. Chemical colorimetry revealed no significant change in the level of glutathione （GSH）. In the xenografl model, the inhibitory rate of C-A120 cells growth in BM-cyclin 1 plus adriamycin （ADM） group was 52%, which was significantly higher than in control group （P〈0.01）. The immunoblotting and RT-PCR results conclusively demonstrated that BM-cycin 1 could significantly reduce the expression of MRP2 in transplanted tumor. In conclusion, BM-cyclin 1 could effectively reverse the MDR of C-A 120 cells in vivo by suppressing the expression of MRP2.

MicroRNA-122-functionalized DNA tetrahedron stimulate hepatic differentiation of human mesenchymal stem cells for acute liver failure therapy

As the most abundant liver-specific microRNA, microRNA-122 (miR122) played a crucial role in the differentiation of stem cells into hepatocytes. However, highly efficient miR122 delivery still confronts challenges including poor cellular uptake and easy biodegradation. Herein, we for the first time demonstrated that the tetrahedral DNA (TDN) nanoplatform had great potential in inducing the differentiation of human mesenchymal stem cells (hMSCs) into functional hepatocyte-like cells (HLCs) by transferring the liver-specific miR122 to hMSCs efficiently without any extrinsic factors. As compared with miR122, miR122-functionalized TDN (TDN-miR122) could significantly up-regulate the protein expression levels of mature hepatocyte markers and hepatocyte-specific marker genes in hMSCs, indicating that TDN-miR122 could particularly activate the hepatocyte-specific properties of hMSCs for developing cell-based therapies in vitro. The transcriptomic analysis further indicated the potential mechanism that TDN-miR122 assisted hMSCs differentiated into functional HLCs. The TDN-miR122-hMSCs exhibited hepatic cell morphology phenotype, significantly up-regulated specific hepatocyte genes and hepatic biofunctions in comparison with the undifferentiated MSCs. Preclinical in vivo transplantation appeared that TDN-miR122-hMSCs in combination with or without TDN could efficiently rescue acute liver failure injury through hepatocyte function supplement, anti-apoptosis, cellular proliferation promotion, and anti-inflammatory. Collectively, our findings may provide a new and facile approach for hepatic differentiation of hMSCs for acute liver failure therapy. Further large animal model explorations are needed to study their potential in clinical translation in the future.

Stem cell-derived hepatocyte therapy using versatile biomimetic nanozyme incorporated nanofiber-reinforced decellularized extracellular matrix hydrogels for the treatment of acute liver failure

Reactive oxygen species(ROS)-associated oxidative stress,inflammation storm,and massive hepatocyte necrosis are the typical manifestations of acute liver failure(ALF),therefore specific therapeutic interventions are essential for the devastating disease.Here,we developed a platform consisting of versatile biomimetic copper oxide nanozymes(Cu NZs)-loaded PLGA nanofibers(Cu NZs@PLGA nanofibers)and decellularized extracellular matrix(dECM)hydrogels for delivery of human adipose-derived mesenchymal stem/stromal cells-derived hepatocyte-like cells(hADMSCs-derived HLCs)(HLCs/Cu NZs@fiber/dECM).Cu NZs@PLGA nanofibers could conspicuously scavenge excessive ROS at the early stage of ALF,and reduce the massive accumulation of pro-inflammatory cytokines,herein efficiently preventing the deterioration of hepatocytes necrosis.Moreover,Cu NZs@PLGA nanofibers also exhibited a cytoprotection effect on the transplanted HLCs.Meanwhile,HLCs with hepatic-specific biofunctions and anti-inflammatory activity acted as a promising alternative cell source for ALF therapy.The dECM hydrogels further provided the desirable 3D environment and favorably improved the hepatic functions of HLCs.In addition,the pro-angiogenesis activity of Cu NZs@PLGA nanofibers also facilitated the integration of the whole implant with the host liver.Hence,HLCs/Cu NZs@fiber/dECM performed excellent synergistic therapeutic efficacy on ALF mice.This strategy using Cu NZs@PLGA nanofiber-reinforced dECM hydrogels for HLCs in situ delivery is a promising approach for ALF therapy and shows great potential for clinical translation.

A multidimensional platform of patient-derived tumors identifies drug susceptibilities for clinical lenvatinib resistance

Lenvatinib,a second-generation multi-receptor tyrosine kinase inhibitor approved by the FDA for first-line treatment of advanced liver cancer,facing limitations due to drug resistance.Here,we applied a multidimensional,high-throughput screening platform comprising patient-derived resistant liver tumor cells(PDCs),organoids(PDOs),and xenografts(PDXs)to identify drug susceptibilities for conquering lenvatinib resistance in clinically relevant settings.Expansion and passaging of PDCs and PDOs from resistant patient liver tumors retained functional fidelity to lenvatinib treatment,expediting drug repurposing screens.Pharmacological screening identified romidepsin,YM155,apitolisib,NVP-TAE684 and dasatinib as potential antitumor agents in lenvatinib-resistant PDC and PDO models.Notably,romidepsin treatment enhanced antitumor response in syngeneic mouse models by triggering immunogenic tumor cell death and blocking the EGFR signaling pathway.A combination of romidepsin and immunotherapy achieved robust and synergistic antitumor effects against lenvatinib resistance in humanized immunocompetent PDX models.Collectively,our findings suggest that patient-derived liver cancer models effectively recapitulate lenvatinib resistance observed in clinical settings and expedite drug discovery for advanced liver cancer,providing a feasible multidimensional platform for personalized medicine.

Platelets:A review of their function and effects in liver diseases

Platelets are small fragments of the cytoplasm and are detached from the cytoplasm of mature megakaryocytes.They play an important role in the function of blood coagulation in humans.Recent studies have shown that in addition to participating in hemostasis,platelets play a critical role in liver regeneration,liver inflammation,liver tumors,injury,and other liver diseases by regulating the activation of stellate cells and the interaction between Kupffer cells and sinusoidal endothelial cells.Targeting platelets and their related molecules is a promising treatment strategy in the management of liver diseases.Here,we review the role of platelets and their related molecules in the development of liver diseases and the application of targeted drugs.

Laparoscopic VS open hepatectomy for hepatolithiasis: An updated systematic review and meta-analysis

AIM To perform a meta-analysis on laparoscopic hepatectomy VS conventional liver resection for treating hepatolithiasis.METHODS We conducted a systematic literature search on Pub Med,Embase,Web of Science and Cochrane Library,and undertook a meta-analysis to compare the efficacy and safety of laparoscopic hepatectomy V S conventional open liver resection for local hepatolithiasis in the left or right lobe. Intraoperative and postoperative outcomes(time,estimated blood loss,blood transfusion rate,postoperative intestinal function recovery time,length of hospital stay,postoperative complication rate,initial residual stone,final residual stone and stone recurrence) were analyzed systematically.RESULTS A comprehensive literature search retrieved 16 publications with a total of 1329 cases. Meta-analysis of these studies showed that the laparoscopic approach for hepatolithiasis was associated with significantly less intraoperative estimated blood loss [weighted mean difference(WMD): 61.56,95% confidence interval(CI): 14.91-108.20,P = 0.01],lower blood transfusion rate [odds ratio(OR): 0.41,95%CI: 0.22-0.79,P = 0.008],shorter intestinal function recovery time(WMD: 0.98,95%CI: 0.47-1.48,P = 0.01),lower total postoperative complication rate(OR: 0.52,95%CI: 0.39-0.70,P < 0.0001) and shorter stay in hospital(WMD: 3.32,95%CI: 2.32-4.32,P < 0.00001). In addition,our results showed no significant differences between the two groups in operative time(WMD: 21.49,95%CI: 0.27-43.24,P = 0.05),residual stones(OR: 0.79,95%CI: 0.50-1.25,P = 0.31) and stone recurrence(OR: 0.34,95%CI: 0.11-1.08,P = 0.07). Furthermore,with subgroups analysis,our results proved that the laparoscopic approach for hepatolithiasis in the left lateral lobe and left side could achieve satisfactory therapeutic effects. CONCLUSION The laparoscopic approach is safe and effective,with less intraoperative estimated blood loss,fewer postoperative complications,reduced length of hospital stay and shorter intestinal function recovery time than with conventional approaches.

Cancer-associated fibroblasts in digestive tumors

The significant influence of tumor stroma on malignant cells has been extensively investigated in this era of targeted therapy.The tumor microenvironment,as a dynamic system,is orchestrated by various cells including tumor vascular composing cells,inflammatory cells and fibroblasts.As a major and important component in tumor stroma,increasing evidence has shown that spindle-shaped cancer-associated fibroblasts(CAFs)are a significant modifier of cancer evolution,and promote tumorigenesis,tumor invasion and metastasis by stimulating angiogenesis,malignant cell survival,epithelial-mesenchymal transition(EMT)and proliferation via direct cell-to-cell contact or secretion of soluble factors in most digestive solid tumors.CAFs are thought to be activated,characterized bythe expression ofα-smooth muscle actin,fibroblast activated protein,fibroblast specific protein,vimentin,fibronectin,etc.They are hypothesized to originate from normal or aged fibroblasts,bone marrow-derived mesenchymal cells,or vascular endothelial cells.EMT may also be an important process generating CAFs,and most probably,CAFs may originate from multiple cells.A close link exists between EMT,tumor stem cells,and chemo-resistance of tumor cells,which is largely orchestrated by CAFs.CAFs significantly induce immunosuppression,and may be a prognostic marker in various malignancies.Targeted therapy toward CAFs has displayed promising anticancer efficacy,which further reinforces the necessity to explore the relationship between CAFs and their hosts.

Natural Pregnancy and Successful Delivery in A Woman with Endometrial Stromal Sarcoma After Sequential Therapy with Heavy Dosage of Chinese Medicine: A Case Report

Endometrial stromal sarcoma(ESS)is an extremely rare(<10%)malignancy of female reproductive system,(1,2)The diagnosis of ESS is mainly depended on the morphology and immunohistochemistry techniques.On the basis of mitotic index,it has been classified into two categories:low-and high-grade ESS.The management of ESS includes surgical resection with or without adjuvant therapy.

Serum from Acute-on-chronic Liver Failure Patients May Affect Mesenchymal Stem Cells Transplantation by Impairing the Immunosuppressive Function of Cells

Background and Aims:The safety and efficacy of mesenchymal stem cells(MSCs)in the treatment of acute-onchronic liver failure(ACLF)have been validated.However,the impact of the pathological ACLF microenvironment on MSCs is less well understood.This study was designed to explore the changes in the functional properties of MSCs exposed to ACLF serum.Methods:MSCs were cultured in the presence of 10%,30%and 50%serum concentrations from ACLF patients and healthy volunteers.Then,the cell morphology,phenotype,apoptosis and proliferation of MSCs were evaluated,including the immunosuppressive effects.Subsequently,mRNA sequencing analysis was used to identify the molecules and pathways involved in MSC functional changes in the context of ACLF.Results:In the presence of ACLF serum,MSC morphology significantly changed but phenotype did not.Besides,MSC proliferation activity was weakened,while the apoptosis rate was lightly increased.Most importantly,the immunosuppressive function of MSCs was enhanced in a lowconcentration serum environment but transformed into a proinflammatory response in a high-concentration serum environment.RNA sequencing indicated that 10%serum concentration from ACLF patients mediated the PI3K-Akt pathway to enhance the anti-inflammatory effect of MSCs,while the 50%serum concentration from ACLF patients promoted the conversion of MSCs into a proinflammatory function by affecting the cell cycle.Conclusions:The 50%ACLF serum concentration is more similar to the environment in the human body,which means that direct peripheral blood intravenous infusion of MSCs may reduce the effect of transplantation.Combining treatments of plasma exchange to reduce harmful substances in serum may promote MSCs to exert a stronger anti-inflammatory effect.

A scoring model based on plasma fibrinogen concentration for predicting recurrence of hepatocellular carcinoma after liver transplantation

Background:We investigated the prognostic value of preoperative fibrinogen levels in hepatocellular carcinoma patients receiving liver transplantation by building a scoring model for predicting tumor recurrence.Methods:Cox regression analysis was used to identify factors that predicted tumor recurrence,and a scoring model was generated by assigning a value of 0 or 1 to each independent risk factor.The cut-off value for fibrinogen was determined by receiver operating characteristic curve analysis.Results:Preoperative fibrinogen concentration was significantly higher in patients with vs.without tumor recurrence(3.27 g/L vs.2.34 g/L,P<0.001),with vs.without macrovascular invasion(3.54 g/L vs.2.82 g/L,P?0.007),and with>400 vs.400 ng/mL plasma alpha-fetoprotein concentration(3.43 g/L vs.2.76 g/L,P?0.007).The 5-year disease-free survival rate was significantly lower for patients with elevated(2.68 g/L)vs.normal(<2.68 g/L)fibrinogen concentration(37.2%vs.78.4%,P?0.001).Macrovascular invasion,>3 tumor nodules,and elevated fibrinogen concentration were independent risk factors for tumor recurrence.A scoring model based on these risk factors predicted recurrence with a sensitivity of 68.3%and a specificity of 87.5%.Conclusions:Elevated preoperative plasma fibrinogen concentration is associated with tumor recurrence in HCC patients after liver transplantation.A new scoring model predicted recurrence with good sensitivity and specificity.