Effects of mesenchymal stem cell on dopaminergic neurons,motor and memory functions in animal models of Parkinson's disease:a systematic review and meta-analysis

Parkinson’s disease is chara cterized by the loss of dopaminergic neurons in the substantia nigra pars com pacta,and although restoring striatal dopamine levels may improve symptoms,no treatment can cure or reve rse the disease itself.Stem cell therapy has a regenerative effect and is being actively studied as a candidate for the treatment of Parkinson’s disease.Mesenchymal stem cells are considered a promising option due to fewer ethical concerns,a lower risk of immune rejection,and a lower risk of teratogenicity.We performed a meta-analysis to evaluate the therapeutic effects of mesenchymal stem cells and their derivatives on motor function,memory,and preservation of dopamine rgic neurons in a Parkinson’s disease animal model.We searched bibliographic databases(PubMed/MEDLINE,Embase,CENTRAL,Scopus,and Web of Science)to identify articles and included only pee r-reviewed in vivo interve ntional animal studies published in any language through J une 28,2023.The study utilized the random-effect model to estimate the 95%confidence intervals(CI)of the standard mean differences(SMD)between the treatment and control groups.We use the systematic review center for laboratory animal expe rimentation’s risk of bias tool and the collaborative approach to meta-analysis and review of animal studies checklist for study quality assessment.A total of 33studies with data from 840 Parkinson’s disease model animals were included in the meta-analysis.Treatment with mesenchymal stem cells significantly improved motor function as assessed by the amphetamine-induced rotational test.Among the stem cell types,the bone marrow MSCs with neurotrophic factor group showed la rgest effect size(SMD[95%CI]=-6.21[-9.50 to-2.93],P=0.0001,I^(2)=0.0%).The stem cell treatment group had significantly more tyrosine hydroxylase positive dopamine rgic neurons in the striatum([95%CI]=1.04[0.59 to 1.49],P=0.0001,I^(2)=65.1%)and substantia nigra(SMD[95%CI]=1.38[0.89 to 1.87],P=0.0001,I^(2)=75.3%),indicating a protective effect on dopaminergic neurons.Subgroup analysis of the amphetamine-induced rotation test showed a significant reduction only in the intracranial-striatum route(SMD[95%CI]=-2.59[-3.25 to-1.94],P=0.0001,I^(2)=74.4%).The memory test showed significant improvement only in the intravenous route(SMD[95%CI]=4.80[1.84 to 7.76],P=0.027,I^(2)=79.6%).Mesenchymal stem cells have been shown to positively impact motor function and memory function and protect dopaminergic neurons in preclinical models of Parkinson’s disease.Further research is required to determine the optimal stem cell types,modifications,transplanted cell numbe rs,and delivery methods for these protocols.

Interplay between mesenchymal stromal cells and the immune system after transplantation: implications for advanced cell therapy in the retina

Advanced mesenchymal stromal cell-based therapies for neurodegenerative diseases are widely investigated in preclinical models.Mesenchymal stromal cells are well positioned as therapeutics because they address the underlying mechanisms of neurodegeneration,namely trophic factor deprivation and neuroinflammation.Most studies have focused on the beneficial effects of mesenchymal stromal cell transplantation on neuronal survival or functional improvement.However,little attention has been paid to the interaction between mesenchymal stromal cells and the host immune system due to the immunomodulatory properties of mesenchymal stromal cells and the long-held belief of the immunoprivileged status of the central nervous system.Here,we review the crosstalk between mesenchymal stromal cells and the immune system in general and in the context of the central nervous system,focusing on recent work in the retina and the importance of the type of transplantation.

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.

Use of machine learning models for the prognostication of liver transplantation: A systematic review

BACKGROUND Liver transplantation(LT)is a life-saving intervention for patients with end-stage liver disease.However,the equitable allocation of scarce donor organs remains a formidable challenge.Prognostic tools are pivotal in identifying the most suitable transplant candidates.Traditionally,scoring systems like the model for end-stage liver disease have been instrumental in this process.Nevertheless,the landscape of prognostication is undergoing a transformation with the integration of machine learning(ML)and artificial intelligence models.AIM To assess the utility of ML models in prognostication for LT,comparing their performance and reliability to established traditional scoring systems.METHODS Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines,we conducted a thorough and standardized literature search using the PubMed/MEDLINE database.Our search imposed no restrictions on publication year,age,or gender.Exclusion criteria encompassed non-English studies,review articles,case reports,conference papers,studies with missing data,or those exhibiting evident methodological flaws.RESULTS Our search yielded a total of 64 articles,with 23 meeting the inclusion criteria.Among the selected studies,60.8%originated from the United States and China combined.Only one pediatric study met the criteria.Notably,91%of the studies were published within the past five years.ML models consistently demonstrated satisfactory to excellent area under the receiver operating characteristic curve values(ranging from 0.6 to 1)across all studies,surpassing the performance of traditional scoring systems.Random forest exhibited superior predictive capabilities for 90-d mortality following LT,sepsis,and acute kidney injury(AKI).In contrast,gradient boosting excelled in predicting the risk of graft-versus-host disease,pneumonia,and AKI.CONCLUSION This study underscores the potential of ML models in guiding decisions related to allograft allocation and LT,marking a significant evolution in the field of prognostication.

Efficacy and safety of fecal microbiota transplantation for treatment of ulcerative colitis:A post-consensus systematic review and metaanalysis

BACKGROUND Numerous studies have assessed the efficacy and safety of fecal microbiota transplantation(FMT)as a therapy for ulcerative colitis(UC).However,the treatment processes and outcomes of these studies vary.AIM To evaluate the efficacy and safety of FMT for treating UC by conducting a systematic meta-analysis.METHODS The inclusion criteria involved reports of adult patients with UC treated with FMT,while studies that did not report clinical outcomes or that included patients with infection were excluded.Clinical remission(CR)and endoscopic remission(ER)were the primary and secondary outcomes,respectively.RESULTS We included nine studies retrieved from five electronic databases.The FMT group had better CR than the control group[relative risk(RR)=1.53;95%confidence interval(CI):1.19-1.94;P<0.0008].ER was statistically significantly different between the two groups(RR=2.80;95%CI:1.93-4.05;P<0.00001).Adverse events did not differ significantly between the two groups.CONCLUSION FMT demonstrates favorable performance and safety;however,well-designed randomized clinical trials are still needed before the widespread use of FMT can be recommended.Furthermore,standardizing the FMT process is urgently needed for improved safety and efficacy.

Vaccination for solid organ transplanted patients:Recommendations,efficacy,and safety

Solid organ transplant recipients face unique challenges in managing their im-munosuppressed status,making vaccination a critical consideration.This review aimed to comprehensively analyze current recommendations,evaluate the effi-cacy of vaccinations in this population,and assess safety concerns.We explored the latest evidence on vaccine types,timing,and potential benefits for transplant patients,highlighting the importance of individualized approaches for routinely used vaccines as well as coronavirus disease 2019 vaccines.By synthesizing avai-lable data,this review underscored the pressing need to optimize vaccination strategies,ensuring that transplant recipients can obtain the full protection against many pathogens while minimizing risks associated with their post-transplant immunosuppression.

Palliative care for end-stage liver disease and acute on chronic liver failure:A systematic review

BACKGROUND End stage liver disease(ESLD)represents a growing health concern characterized by elevated morbidity and mortality,particularly among individual ineligible for liver transplantation.The demand for palliative care(PC)is pronounced in patients grappling with ESLD and acute on chronic liver failure(ACLF).Unfortunately,the historical underutilization of PC in ESLD patients,despite their substantial needs and those of their family caregivers,underscores the imperative of seamlessly integrating PC principles into routine healthcare practices across the entire disease spectrum.AIM To comprehensively investigate the evidence surrounding the benefits of incorporating PC into the comprehensive care plan for individuals confronting ESLD and/or ACLF.METHODS A systematic search in the Medline(PubMed)database was performed using a predetermined search command,encompassing studies published in English without any restrictions on the publication date.Subsequently,the retrieved studies were manually examined.Simple descriptive analyses were employed to summarize the results.RESULTS The search strategies yielded 721 references.Following the final analysis,32 fulllength references met the inclusion criteria and were consequently incorporated into the study.Meticulous data extraction from these 32 studies was undertaken,leading to the execution of a comprehensive narrative systematic review.The review found that PC provides significant benefits,reducing symptom burden,depressive symptoms,readmission rates,and hospital stays.Yet,barriers like the appeal of transplants and misconceptions about PC hinder optimal utilization.Integrating PC early,upon the diagnosis of ESLD and ACLF,regardless of transplant eligibility and availability,improves the quality of life for these patients.CONCLUSION Despite the substantial suffering and poor prognosis associated with ESLD and ACLF,where liver transplantation stands as the only curative treatment,albeit largely inaccessible,PC services have been overtly provided too late in the course of the illness.A comprehensive understanding of PC's pivotal role in treating ESLD and ACLF is crucial for overcoming these barriers,involving healthcare providers,patients,and caregivers.

Systemic lupus erythematosus following virological response to peginterferon alfa-2b in a transplanted patient with chronic hepatitis C recurrence

Autoimmune manifestations are common both in patients chronically infected by hepatitis C virus, and in patients transplanted for non-autoimmune diseases. A correlation between interferon based treatment and autoimmune diseases or the development of autoantibodies is well established in non-transplanted patients, but few data are available about transplanted patients. It is unclear whether interferon may increase the incidence of acute cellular rejection and there are few reports on the development of atypical autoimmune manifestations during post-liver transplantation interferon or pegylated interferon treatment. We describe a case of systemic lupus erythematosus following treatment with pegylated interferon alfa-2b in a transplanted patient with recurrence of chronic hepatitis C. Our experience suggest that pegylated interferon may induce autoimmune diseases in the immunosuppressed host, different from acute cellular rejection and call for a great attention to possible autoimmune disorders development during interferon based treatments in liver transplanted patients.

Fecal microbiota transplantation for the treatment of irritable bowel syndrome:A systematic review and meta-analysis

BACKGROUND Irritable bowel syndrome(IBS)is the most prevalent gastrointestinal disorder in developed countries and reduces patients’quality of life,hinders their ability to work,and increases health care costs.A growing number of trials have demonstrated an aberrant gut microbiota composition in IBS,also known as‘gut dysbiosis’.Fecal microbiota transplantation(FMT)has been suggested as a treatment for IBS.AIM To assess the efficacy and safety of FMT for the treatment of IBS.METHODS We searched Cochrane Central,MEDLINE,EMBASE and Web of Science up to 24 October 2022 for randomised controlled trials(RCTs)investigating the effectiveness of FMT compared to placebo(including autologous FMT)in treating IBS.The primary outcome was the number of patients with improvements of symptoms measured using a validated,global IBS symptoms score.Secondary outcomes were changes in quality-of-life scores,non-serious and serious adverse events.Risk ratios(RR)and corresponding 95%CI were calculated for dichotomous outcomes,as were the mean differences(MD)and 95%CI for continuous outcomes.The Cochrane risk of bias tool was used to assess the quality of the trials.GRADE criteria were used to assess the overall quality of the evidence.RESULTS Eight RCTs(484 participants)were included in the review.FMT resulted in no significant benefit in IBS symptoms three months after treatment compared to placebo(RR 1.19,95%CI:0.68-2.10).Adverse events were reported in 97 participants in the FMT group and in 45 participants in the placebo group(RR 1.17,95%CI:0.63-2.15).One serious adverse event occurred in the FMT group and two in the placebo group(RR 0.42,95%CI:0.07-2.60).Endoscopic FMT delivery resulted in a significant improvement in symptoms,while capsules did not.FMT did not improve the quality of life of IBS patients but,instead,appeared to reduce it,albeit non significantly(MD-6.30,95%CI:-13.39-0.79).The overall quality of the evidence was low due to moderate-high inconsistency,the small number of patients in the studies,and imprecision.CONCLUSION We found insufficient evidence to support or refute the use of FMT for IBS.Larger trials are needed.

Temporal Dynamics of Antioxidant Defence System in Relation to Polyamine Catabolism in Rice under Direct-Seeded and Transplanted Conditions

Six rice cultivars viz. PR120, PR116, Feng Ai Zan, PR115, PAU201 and Punjab Mehak 1 under the direct-seeded and transplanted conditions were used to investigate the involvement of antioxidative defence system in relation to polyamine catabolism in temporal regulation of developing grains. Activities of ascorbate peroxidase （APx）, guaiacol peroxidase （GPx）, catalase （CAT）, superoxide dismutase （SOD）, polyamine oxidases （PAO） and contents of ascorbate, a-tocopherol, proline and polyamines increased gradually until mid-milky stage and then declined towards maturity stage under both planting conditions. The transplanted condition led to higher activities of antioxidative enzymes （APx, GPx and CAT） and contents of ascorbate, a-tocopherol and proline whereas the direct-seeded condition had elevated levels of PAO and SOD activities and contents of polyamines, lipid peroxide and hydrogen peroxide. Cultivars Feng Ai Zan and PR120 exhibited superior tolerance over other cultivars by accumulating higher contents of ascorbate, a-tocopherol and proline with increasing level of PAO and SOD activities under the direct-seeded condition. However, under the transplanted condition PR116 and PAU201 showed higher activities of antioxidative enzymes with decreasing content of lipid peroxide. Therefore, we concluded that under the direct-seeded condition, enhancements of polyamines content and PAO activity enabled rice cultivars more tolerant to oxidative stress, while under the transplanted condition, antioxidative defence with decreasing of lipid peroxide content was closely associated with the protection of grains by maintaining membrane integrity during rice grain filling. The results indicated that temporal dynamics of H2O2 metabolic machinery was strongly up-regulated especially at the mid-milky stage.

Corrected QT interval in cirrhosis:A systematic review and metaanalysis

BACKGROUND Corrected QT(QTc)interval is prolonged in patients with liver cirrhosis and has been proposed to correlate with the severity of the disease.However,the effects of sex,age,severity,and etiology of cirrhosis on QTc have not been elucidated.At the same time,the role of treatment,acute illness,and liver transplantation(Tx)remains largely unknown.AIM To determine the mean QTc in patients with cirrhosis,assess whether QTc is prolonged in patients with cirrhosis,and investigate whether QTc is affected by factors such as sex,age,severity,etiology,treatment,acute illness,and liver Tx.METHODS In the present systematic review and meta-analysis,the searching protocol“{[QTc]OR[QT interval]OR[QT-interval]OR[Q-T syndrome]}AND{[cirrhosis]OR[Child-Pugh]OR[MELD]}”was applied in PubMed,EMBASE,and Google Scholar databases to identify studies that reported QTc in patients with cirrhosis and published after 1998.Seventy-three studies were considered eligible.Data concerning first author,year of publication,type of study,method used,sample size,mean age,female ratio,alcoholic etiology of cirrhosis ratio,Child-Pugh A/B/C ratio,mean model for end-stage liver disease(MELD)score,treatment withβ-blockers,episode of acute gastrointestinal bleeding,formula for QT correction,mean pulse rate,QTc in patients with cirrhosis and controls,and QTc according to etiology of cirrhosis,sex,Child-Pugh stage,MELD score,and liver Tx status(pre-Tx/post-Tx)were retrieved.The Newcastle-Ottawa quality assessment scale appraised the quality of the eligible studies.Effect estimates,expressed as proportions or standardized mean differences,were combined using the randomeffects,generic inverse variance method of DerSimonian and Laird.Subgroup,sensitivity analysis,and meta-regressions were applied to assess heterogeneity.RESULTS QTc combined mean in patients with cirrhosis was 444.8 ms[95%confidence interval(CI):440.4-449.2;P<0.001 when compared with the upper normal limit of 440 ms],presenting high heterogeneity(I2=97.5%;95%CI:97.2%-97.8%);both Egger’s and Begg’s tests showed non-significance.QTc was elongated in patients with cirrhosis compared with controls(P<0.001).QTc was longer in patients with Child-Pugh C cirrhosis when compared with Child-Pugh B and A(P<0.001);Child-Pugh B patients presented longer QTc when compared with Child-Pugh A patients(P=0.003).The MELD score was higher in patients with cirrhosis with QTc>440 ms when compared with QTc≤440 ms(P<0.001).No correlation of QTc with age(P=0.693),sex(P=0.753),or etiology(P=0.418)was detected.β-blockers shortened QTc(P<0.001).QTc was prolonged during acute gastrointestinal bleeding(P=0.020).Tx tended to improve QTc(P<0.001).No other sources of QTc heterogeneity were revealed.CONCLUSION QTc is prolonged in cirrhosis independently of sex,age,and etiology but is correlated with severity and affected byβ-blockers and acute gastrointestinal bleeding.QTc is improved after liver Tx.

Transplanted choroidal plexus epithelial cells can integrate with organotypic spinal cord slices into a new system

This study aimed to evaluate the integration of transplanted choroidal plexus epithelial cells with organotypic spinal cord slices.Organotypic spinal cord slices,normally cultured for 6 days,were divided into control group(Ctrl)and transplanted group(T).The choroidal plexus epithelial cells were dissociated and primary cultured(C group).The choroidal plexus epithelial cells cultured for 6–7 days were labeled by 1,1’-dioctadecyl-3,3,3’,3’-tetramethylindocarbocyanineperchlorate(CM-Dil),and were identified by transthyretin(TTR)in immunocytochemistry.They were adjusted to the density of 0.5–1×107/ml,then 2μl cells suspension were transplanted to the spinal cord slices in the T group.The same amount of basal medium was dripped on the spinal cord slices in the Ctrl group.After 14 days of transplantation,the differentiations into neurons and astrocytes,and the synapses were identified by immunofluorescence histochemistry.At the same time,the ratios of cell differentiations and synapses in new system,and the changes of MAPK signaling pathway were tested by western blotting.The choroid plexus epithelial cells were well labeled by CM-Dil and were immune-stained by TTR in immunocytochemistry.The choroid plexus epithelial cells bodies were small when transplanted on the spinal cord slices,but big when transplanted on the polyester membrane inserts.The transplanted cells could differentiate into astrocytes,and possibly differentiate into neurons,and there were a large number of synaptophysin positive vesicles between transplanted cells and organotypic spinal cord slices in immunofluorescence histochemistry.The levels of GFAP,TUB-III and synaptophysin in the T group were higher than which in the Ctrl and C groups in western blotting(P<0.05).And the ratios of p-JNK/JNK and p-P38/P38 in the T group were significantly lower than which in the Ctrl and C groups(P<0.05).But the ratio of p-ERK/ERK in the three groups was of no significant difference.The transplanted choroidal plexus epithelial cells can integrate with organotypic spinal cord slices into a new system.

The emerging roles of transplanted radial glial cells in regenerating the central nervous system

Scientists conclude that a combination of treatments involving rehabilitation,drug delivery,surgery and cell transplantation are necessary to achieve significant progress in regenerating the injured central nervous system（CNS）.

Anesthetic Management of a Percutaneous Mitral Valve Repair (MVR) with the MitraClip System in a Twice Renal Transplanted Patient

Chronic renal failure is strongly related to poor outcomes, in cardiovascular system, such as: cardiac dilatation, left ventricular dysfunction and mitral valve regurgitation. Mitral calcification and regurgitation play an important role in prediction of morbidity and mortality in patients on dialysis. Percutaneous mitral valve repair (MVR) with the MitraClip system, which has begun to be used in severe mitral insufficiency patients with multiple comorbid medical conditions, including renal disease, is a new, alternative method. This intervention is not associated with cardiopulmonary bypass, thus;it has been proven to be safe and effective in risky patients. In this report, we would like to share our anesthetic experience in successful mitral valve repair by MitraClip system in a patient who had undergone renal transplantation twice.

Donor-Derived Transmission of Scedosporiosis in Kidney Transplant Recipients from a Systemic lupus erythematosus donor

Donor-derived infection(DDI)associated with Scedosporium spp is extremely rare,and results in a very poor prognosis.The present study reports a probable DDI due to Scedosporium boydii(S.boydii)from a donor with neuropsychiatric systemic lupus erythematosus.Two recipients developed Scedosporiosis after kidney transplantation from the same donor.Recipient 1 died of central nervous system infection due to S.boydii based on the clinical presentations,and the positive metagenomic next-generation sequencing(mNGS)and culture results for the cerebrospinal fluid.The other recipient with urinary tract obstruction due to S.boydii,which was identified through the positive culture and mNGS results of the removed stents,was successfully treated by stent replacement and voriconazole administration.Undiagnosed disseminated donor infection and the transmission of S.boydii should be given attention,particularly when the donor and recipients have primary immunodeficiency disease.The screening of donors and recipients for S.boydii using mNGS may be helpful in guiding antifungal prophylaxis and treatment recipients,due to its higher sensitivity and shorter diagnostic time relative to other traditional techniques.

Outcome of split liver transplantation vs living donor liver transplantation:A systematic review and meta-analysis

BACKGROUND The outcomes of liver transplantation(LT)from different grafts have been studied individually and in combination,but the reports were conflicting with some researchers finding no difference in both short-term and long-term outcomes between the deceased donor split LT(DD-SLT)and living donor LT(LDLT).AIM To compare the outcomes of DD-SLT and LDLT we performed this systematic review and meta-analysis.METHODS This systematic review was performed in compliance with the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines.The following databases were searched for articles comparing outcomes of DD-SLT and LDLT:PubMed;Google Scholar;Embase;Cochrane Central Register of Controlled Trials;the Cochrane Database of Systematic Reviews;and Reference Citation Analysis(https://www.referencecitationanalysis.com/).The search terms used were:“liver transplantation;”“liver transplant;”“split liver transplant;”“living donor liver transplant;”“partial liver transplant;”“partial liver graft;”“ex vivo splitting;”and“in vivo splitting.”RESULTS Ten studies were included for the data synthesis and meta-analysis.There were a total of 4836 patients.The overall survival rate at 1 year,3 years and 5 years was superior in patients that received LDLT compared to DD-SLT.At 1 year,the hazard ratios was 1.44(95%confidence interval:1.16-1.78;P=0.001).The graft survival rate at 3 years and 5 years was superior in the LDLT group(3 year hazard ratio:1.28;95%confidence interval:1.01-1.63;P=0.04).CONCLUSION This meta-analysis showed that LDLT has better graft survival and overall survival when compared to DD-SLT.

Exercise training as an intervention for frailty in cirrhotic patients on the liver transplant waiting list:A systematic review

BACKGROUND The existing literature suggests that exercise for cirrhotic patients is safe and favours significant improvement to their physical capacity.However,exercise training for this population and how to deliver activities,especially in severe stages of the disease and while waiting for a liver transplant(LT),remain undefined.AIM To review the existing exercise prescriptions for cirrhotic patients on the waiting list for LT,their results for frailty evolution and their effect on clinical outcomes.METHODS A systematic review was performed following the Preferred Reporting Review and Meta-Analysis guidelines and searching the PubMed,MEDLINE,and Scopus databases.The keyword“liver transplant”was used in combination with the free terms“frailty”and“exercise”for the literature review.Clinical studies that evaluated the effect of a regular training program,independent of supervision or the duration or intensity of physical exercise,in cirrhotic patients on the waiting list for LT were reviewed.The data on safe physical activity prescriptions following Frequency,Intensity,Time,and Type recommendations were extracted and summarised.RESULTS Nine articles met the inclusion criteria for this review.Various instruments for frailty assessment were used,frequently in combination.Five studies prescribed physical activity for patients,one in-person and four to be performed remotely and unsupervised.The remaining four studies only used a self-report instrument to assess the level of physical activity.None reported adverse events related to exercise training.The exercise frequency mainly varied from daily to a minimum of twice per week.The intensity depended on frailty and included increasing levels of activity.The type of exercise was predominantly a combination of aerobic and resistance training.The duration of exercise varied from 4 to 12 wk.Three articles evaluated the effect of the exercise program on clinical outcomes,reporting a reduction in 90-d readmission rates post-transplant and improved frailty scores,as well as improved survival of cirrhotic patients waiting for LT.CONCLUSION Routine frailty assessment is essential for this population.Although more robust evidence is required,the prescription of exercise is safe and can improve patients’functional capacity,improving pre-and post-LT outcomes.

Mechanism of AiTongXiao granule in the treatment of hepatocellular carcinoma based on network pharmacology and rat transplanted liver cancer model

Objective:To investigate the mechanism of action and material basis of AiTongXiao granule in the treatment of hepatocellular carcinoma(HCC)based on network pharmacology and transplanted liver cancer rat model.Methods:TCMSP database was used to screen out effective components and its corresponding potential pharmaceutical targets,and databases including Gene Cards,OMIM,Drugbank and TTD were further used to collect HCC-related drug targets.The intersecting targets were obtained by mapping the drug and disease targets.The component-targets network was constructed and visualized by Cytoscape 3.8.2 software.Protein-protein interaction(PPI)network was built by STRING online platform,and the topological relationship and core targets was analyzed and screened by using CytoNCA software.In addition,Metascape database was used to perform gene ontology(GO)enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analysis of the core targets.At last,rat liver transplanted liver cancer model was established by using Walker-256 cell line and treated by AiTongXiao granule for 15 days.Western blot was used to further compare the expression levels of AKT,pAKT,p53,p-p53,ERK1/2 and ERK1/2 in the tumor between treatment group and the control group.Results:257 active components were obtained from AiTongXiao granule,corresponding to 294 drug targets.Meanwhile,233 of the 7993 HCC disease targets were screened out between AiTongXiao granule drug and HCC disease targets.11 core targets including AKT1,IL6,TP53,MAPK3,TNF,JUN,CASP3,MAPK1,MYC,PTGS2,MMP9 were further obtained by median screening.GO and KEGG analysis results showed that these core targets enriched to HBV,TNF and cancer related pathways.The rat transplanted liver cancer model results indicated significant down regulation for AKT,p-AKT,pERK1/2,and significant up regulation of p-p53 after AiTongXiao granule treatment(P<0.05).Conclusion:AiTongXiao granule could act to multiple cancer related pathways,and AKT,p53 and ERK1/2 were validated to be regulated by ATXF in rat model.The mechanism may be through the regulation of the above signaling pathways to exert anti-liver cancer effect.

Hepatic ischemia-reperfusion syndrome and its effect on the cardiovascular system: The role of treprostinil, a synthetic prostacyclin analog

Hepatic ischemia-reperfusion syndrome has been the subject of intensive study and experimentation in recent decades since it is responsible for the outcome of several clinical entities,such as major hepatic resections and liver transplantation.In addition to the organ’s post reperfusion injury,this syndrome appears to play a central role in the dysfunction of distant tissues and systems.Thus,continuous research should be directed toward finding effective therapeutic options to improve the outcome and reduce the postoperative morbidity and mortality rates.Treprostinil is a synthetic analog of prostaglandin I2,and its experimental administration has shown encouraging results.It has already been approved by the Food and Drug Administration in the United States for pulmonary arterial hypertension and has been used in liver transplantation,where preliminary encouraging results showed its safety and feasibility by using continuous intravenous administration at a dose of 5 ng/kg/min.Treprostinil improves renal and hepatic function,diminishes hepatic oxidative stress and lipid peroxidation,reduces hepatictoll-like receptor 9 and inflammation,inhibits hepatic apoptosis and restores hepatic adenosine triphosphate(ATP)levels and ATP synthases,which is necessary for functional maintenance of mitochondria.Treprostinil exhibits vasodilatory properties and antiplatelet activity and regulates proinflam-matory cytokines;therefore,it can potentially minimize ischemia-reperfusion injury.Additionally,it may have beneficial effects on cardiovascular parameters,and much current research interest is concentrated on this compound.

Primary cutaneous anaplastic large cell lymphoma with overexpressed Ki-67 transitioning into systemic anaplastic large cell lymphoma:A case report

BACKGROUND Primary cutaneous anaplastic large cell lymphoma(PC-ALCL)differs from systemic anaplastic large cell lymphoma(sALCL)in cell biological behavior,clinical features,treatment,and outcome.PC-ALCL has been reported to rarely transition into sALCL,but the underlying mechanism is not clear.Here we report such a case with certain characteristics that shed light on this.CASE SUMMARY Herein,we report a 43-year-old male with symptoms of a skin nodule and histologically confirmed PC-ALCL with high expression of Ki-67.After three months of observation,two skin nodules re-appeared with muscle layer involvement and was histologically confirmed as sALCL.Seventeen months after receiving six cycles of CHOP regimen,the patient had pain in the chest and back,cough,shortness of breath,and night sweats.This was confirmed as relapse of sALCL by immunohistochemistry and several organs,such as the lung were involved as shown by positron emission tomography/computed tomography.After four cycles of DICE plus chidamide regimens followed by auto-hematopoietic stem cell transplantation(ASCT),complete remission(CR)duration was achieved for twelve months while the patient was on maintenance with chidamide(20 mg)pills.CONCLUSION This case had significantly high expression of Ki-67 when diagnosed as PC-ALCL initially and then transitioned into sALCL,which is rare.Auto-ASCT combined with demethylation drugs effectively maintained CR and prolonged progression free survival.