Single-cell RNA sequencing-guided fate-mapping toolkit delineates the contribution of yolk sac erythro-myeloid progenitors.

Erythro-myeloid progenitors of the yolk sac that originates during early embryo development has been suggested to generate tissue-resident macrophage, mast cell, and even endothelial cell populations from fetal to adult stages. However, the heterogeneity of erythro-myeloid progenitors (EMPs) is not well characterized. Here, we adapt single-cell RNA sequencing to dissect the heterogeneity of EMPs and establish several fate-mapping tools for each EMP subset to trace the contributions of different EMP subsets. We identify two primitive and one definitive EMP subsets from the yolk sac. In addition, we find that primitive EMPs are decoupled from definitive EMPs. Furthermore, we confirm that primitive and definitive EMPs give rise to microglia and other tissue-resident macrophages, respectively. In contrast, only Kit+ Csf1r- primitive EMPs generate endothelial cells transiently during early embryo development. Overall, our results delineate the contribution of yolk sac EMPs more clearly based on the single-cell RNA sequencing (scRNA-seq)-guided fate-mapping toolkit.

[Living-donor intestinal transplantation].

Due to advances in surgical techniques, perioperative care, and new immunosuppressive agents, intestinal transplantation has become a valid therapeutic choice for chronic intestinal failure. Intestinal transplantation has been performed most commonly using deceased donation, while less than 2% of which have been from living donation. Living donor intestinal transplantation obtaining a segmental intestinal graft, usually from close relatives. Preliminary results show that acute/chronic rejection rates, postoperative opportunistic infections, and graft versus host disease are significantly reduced after living donor intestinal transplantation, contributing to improved graft and patient survivals. Due to a severe shortage of organ donation, especially in children, living donor intestinal transplantation has increasingly become an important treatment option for patients with chronic intestinal failure in China.

[Advances in combination strategies with oncolytic virotherapy].

Compared with conventional treatments, oncolytic virotherapy has the advantages of enhanced cytotoxicity, improved targeting, and minimal side effects. However, its efficacy is not as good as expected for the single drug treatment. The purpose of synergistic effect is one of the development directions of existing oncolytic virus therapy. In this paper, through a systematic review of the current preclinical and clinical trials progress of oncolytic virus combination therapy, the combined treatment strategies of oncolytic virus and immune checkpoint inhibitors, chemotherapy, targeted therapy,and cell therapy are reviewed to provide reference for further clinical application.

[Progress in perioperative management of ABO-incompatible pediatric liver transplantation].

ABO incompatible(ABO-I) liver grafts will affect the prognosis of liver transplantation. With the improvement of perioperative treatment,including plasma exchange,rituximab,splenectomy,etc.,the prognosis of ABO-I liver transplantation has been greatly improved. Because children's immune systems are not fully developed,the perioperative management of ABO-I pediatric liver transplantation is significantly different from that of adults. Reducing the perioperative anti-donor ABO antibody titer is the key to the perioperative management of ABO-I liver transplantation. This article summarizes literatures on the perioperative management of ABO-I pediatric liver transplantation, including the perioperative anti-rejection regimen in pediatric recipients of different ages, splenectomy, postoperative monitoring and postoperative complications, etc.

[Outcome of pediatric-to-adult liver transplantation:a single-center study in China].

Objective: To explore the outcome of the pediatric-to-adult liver transplantation, including postoperative complications and relevant factors which affecting graft survival. Methods: Data of 55 patients undergoing pediatric-to-adult liver transplantation at the First Affiliated Hospital of Zhejiang University between January 2015 and August 2021 were retrospectively analyzed. The donors consisted of 34 males and 21 females, and the age was (11.8±4.7) years (range: 1 to 17 years). Among the cases,17 cases (30.9%) were donation of brain death,32 cases (58.2%) were donation of cardiac death, and 6 cases (10.9%) were donation after brain death plus cardiac death. The recipients consisted of 32 males and 23 females, and the age was (51.6±10.1) years (range: 27 to 70 years). Among the recipients,10 cases (18.2%) were ABO-incompatible liver transplantation.The influencing factors of early graft survival were analyzed by Student t test,Mann-Whitney U test or χ2 test,respectively.Survival curve was drawn by Kaplan-Meier method.Logistic multivariate analysis was used to analyze the independent relevant factors of early postoperative graft loss. Results: Up to October 31,2021,the follow-up time (M(IQR)) was 36.0(43.1)months(range:5.9 to 81.7 months).There were 13 cases with graft loss (two of them underwent re-transplantation due to acute liver failure).The monofactor analysis indicated that cold ischemia time and donor-recipient blood group matching were the relevant factors affecting the early graft survival rate(both P<0.05).Logistic multivariate analysis showed that cold ischemia time and history of recipient gastrointestinal bleeding were independent relevant factors(both P<0.05).Postoperative hepatic artery thrombosis occurred in 3 cases(5.5%), portal vein thrombosis diagnosed in 4 cases(7.3%), portal vein stenosis occurred in 2 cases(3.6%),biliary complications diagnosed in 7 cases(12.7%), and small liver syndrome was found in 8 cases(14.5%). Conclusions: Adult liver transplantation with pediatric donor liver is an effective method to treat end-stage liver disease.Cold ischemia time and history of recipient gastrointestinal bleeding were independent relevant factors for the early graft survival.

[Review of risk evaluation scores for benign end stage liver diseases recipients].

Liver transplant is an unreplaceable method for benign end-stage liver disease. The risk evaluation for the waiting list recipients and for post-transplant survival could provide practical indication for organ allocation. In recent years, there are two major kinds of evaluation scores. The first kind of evaluation scores is based on model for end-stage liver disease(MELD) score,including SOFT/P-SOFT score,UCLA-FRS score and BAR score. The other evaluation system is based on the concept of acute-on-chronic liver failure,including CLIF-C-ACLF score,TAM score,AARC-ACLF score and COSSH-ACLF score. The scores based on ACLF have been shown superior power in predicting waiting list survival and post-transplant prognosis than MELD. This article reviews the two kinds of evaluation scores,aiming for the better allocation policy and the better prognosis of benign end-stage liver disease.

[Review of risk evaluation scores for benign end stage liver diseases recipients].

Liver transplant is an unreplaceable method for benign end-stage liver disease. The risk evaluation for the waiting list recipients and for post-transplant survival could provide practical indication for organ allocation. In recent years, there are two major kinds of evaluation scores. The first kind of evaluation scores is based on model for end-stage liver disease(MELD) score,including SOFT/P-SOFT score,UCLA-FRS score and BAR score. The other evaluation system is based on the concept of acute-on-chronic liver failure,including CLIF-C-ACLF score,TAM score,AARC-ACLF score and COSSH-ACLF score. The scores based on ACLF have been shown superior power in predicting waiting list survival and post-transplant prognosis than MELD. This article reviews the two kinds of evaluation scores,aiming for the better allocation policy and the better prognosis of benign end-stage liver disease.

[Gastrointestinal reconstruction by intestinal auto-transplantation after radical resection of neoplasms involving superior mesenteric artery: a preliminary consideration].

When abdominal neoplasms originating from the pancreas or nearby organs locally involving the superior mesenteric artery (SMA), complete resection is still the only hope for cure. However, SMA resection and reconstruction is a complex surgical procedure associated with high postoperative morbidity and mortality. Intestinal autotransplantation has recently emerged in clinical practice as a treatment option for selected patients with neoplasms involving the SMA. The original procedure involved en bloc removal of a tumor together with the intestine, ex vivo resection and reconstruction of gastrointestinal tract by an intestinal autograft. To further refine this complex procedure, a modified method was developed in which a segmental bowel autograft is selected and harvested first during the initial stage of the operation, and radical resection of the neoplasm is carried out thereafter. The modification would better protect a healthy bowel autograft from potential damage due to prolonged warm ischemia and allow the subsequent lengthy process of dissection to be performed in an unrushed manner. Furthermore, this alteration would better adhere to the general principles of minimal tumor manipulation during operation and potentially decrease the risks of tumor implantation during in vitro organ perfusion. Although intestinal autotransplantation has expanded eligibility for resection of otherwise unresectable lesions involving the SMA, its operative complexity, high risks, and post-operative complications largely limit its clinical applications.

[Progress and perspectives on adjuvant therapy after curative resection of hepatocellular carcinoma].

Tumor recurrence after curative resection of hepatocellular carcinoma(HCC) is a major challenge to patient survival. Postoperative adjuvant therapy has been proved to be an effective method in tackling tumor recurrence. However,its role in HCC remains unclear. First,there are many differences between Chinese and foreign guidelines in recommendations on adjuvant therapy of HCC. Chinese guidelines have made many recommendations on various modalities of adjuvant therapy of HCC,including anti-viral therapy,transarterial chemoembolization,and herbs. On the contrary,foreign guidelines don't make any recommendation on adjuvant therapy of HCC,except for anti-viral therapy. Second,clear definition of patients who have a higher risk of tumor recurrence is still unknown. In other words,patients who will benefit from adjuvant therapy is unclear. Although various kinds of adjuvant therapies have been proved to be efficient in preventing tumor recurrence and prolonging patient survival,a standard protocol is still lacking. There are many ongoing clinical trials investigating the value of adjuvant therapy in HCC. Emerging evidences will answer questions on the role of adjuvant therapy and how to perform it.

[Advances in perioperative systemic therapy for hepatocellular carcinoma].

The low surgical resection rate and high postoperative recurrence rate of hepatocellular carcinoma(HCC) are urgent clinical problems to be solved. Therefore, it is important to develop effective perioperative treatment. In recent years, a growing number of studies have shown that systemic therapy is expected to break through the limitations of traditional local treatment and play an important role in preoperative treatment. For example, some novel targeted agents and immunocheckpoint inhibitors have shown excellent potential as neoadjuvant treatment for HCC. Meanwhile, researchers have explored the application of systemic therapy as adjuvant therapy, but due to different criteria for patient selection, no consensus is reached on its efficacy. By far, there is no standard procedure for the application of systemic therapy in HCC perioperative period, little is known about the efficacy and safety of targeted drugs and immunotherapy. This article discusses the feasibility of systemic therapy as neoadjuvant and adjuvant treatment of HCC, as well as its adverse events, with an aim to provide new horizons of HCC systemic therapy in the perioperative period.

[Developments and controversies in neoadjuvant therapy for resectable pancreatic cancer].

Neoadjuvant therapy has been proved beneficial in patients with non-metastatic pancreatic cancer and it has received unprecedented attention in past years. However, the clinical value of neoadjuvant therapy in resectable pancreatic cancer patients remains controversial.Although the NCCN guideline has recommended that resectable pancreatic cancer patients with high-risk factors should be given preoperative neoadjuvant therapy, there is no consensus on specific criteria, treatment options, treatment duration and timing of surgery.More high-level evidences are strongly required.Recently, the development of new technologies such as liquid biopsy and radiomics analysis for pancreatic cancer will also help to address some clinical problems.This article reviewed the developments and controversies in neoadjuvant therapy for resectable pancreatic cancer.

[Effects of neoadjuvant therapy on postoperative complication of pancreatic cancer surgery].

Pancreatic cancer is a fatal disease with low resectability, high recurrence rate and despairing prognosis.Neoadjuvant therapy has been proven to improve resectability, especially R0 resection rate, and extend overall survival.It has become the hotspot in the field of pancreatic cancer in the last decade.However, the concomitant adverse effects on surgery and postoperative complication also draw wide attention.In this reivew, the indication and the effects of neoadjuvant therapy on pancreas and body composition according the latest studies are summarized.Futhermore, the effects of neoadjuvant therapy on postoperative complication from multiple aspects are discussed.

[Clinical features, diagnosis and treatment of intraductal papillary neoplasm of the bile duct].

Objective: To study the clinicopathologic features of intraductal papillary neoplasm of the bile duct(IPNB) and to analyze the diagnostic and therapeutic patterns. Methods: The data of 46 patients with IPNB undergoing surgery in Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital of Zhejiang University School of Medicine from January 2013 to November 2017 were retrospectively analyzed.There were 23 males and 23 females with age of (64±8)years.Patients were followed up by clinics and telephone inquiry.Categorical data were compared with χ(2) test or Fisher's exact test. Results: Abdominal pain(in 31 patients), fever (in 15 patients) and jaundice (in 11 patients) were the most common symptoms.Twenty-five patients were accompanied with cholangiolithiasis and 25 were accompanied with liver atrophy.Preoperative laboratory examination was mainly manifested as the abnormal liver function caused by biliary obstruction.Typical imaging findings included bile duct dilation (in 45 patients) and mass within bile duct (in 22 patients). All the patients were diagnosed as IPNB histopathologically.Among them, high-grade intraepithelial neoplasia and related adenocarcinoma were more common in mucus-hypersecretion IPNB ((13/15 vs. 51.6%(16/31))(χ(2)=5.331, P=0.021). Hepatectomy was performed in 25 patients, hepatectomy combined with biliary resection and reconstruction in 12 cases, biliary resection and reconstruction in 3 cases, pancreatoduodenectomy in 3 cases, hepatopancreaticoduodenectomy in 1 case, liver transplantation in 1 case and radiofrequency ablation in 1 case.Forty-one patients were followed up with a median of 30 (12, 41) months.Seven patients suffered recurrence and 6 died. Conclusion: IPNB is a rare disease with limited knowledge currently.Images are the main diagnositc means and surgery is the first choice.

Review of radiological classifications of pancreatic cancer with peripancreatic vessel invasion: are new grading criteria required?

Pancreatic cancer is mainly diagnosed at an advanced stage when adjacent vessel invasion is present; however, radical resection is potentially curative for selected patients with adjacent vessel invasion. Therefore, accurately judging the resectability of patients with adjacent vessel invasion represents a crucially important step in diagnosis and treatment. Currently, decisions regarding resectability are based on imaging studies, commonly contrast computed tomography (CT). Several radiological classifications have been published for vascular infiltration in pancreatic cancer. However, radiologists always formulate these CT grading systems according to their own experience, resulting in different judgment methods and parameters. And it is controversial in evaluating performance and clinical application. Besides, the conventional CT grading systems mainly focus on the evaluation of vessel invasion so as to less on the outcome of patient evaluation. In this review, we summarize the mainstream CT grading systems for vascular invasion in pancreatic cancer, with the aim of improving the clinical value of CT grading systems for predicting resectability and survival.

[Advances in immunotherapy of pancreatic ductal adenocarcinoma].

The morbidity of pancreatic ductal adenocarcinoma (PDAC) has been increasing over years, while the treatment efficacy and prognosis of PDAC remain far from satisfying. The newly-ermerged tumor immunotherapy has not only made lots of breakthroughs in various malignancies, but also brought an opportunity to the treatment of pancreatic cancer.PDAC immunotherapies, mainly including vaccine therapy, adoptive T cell thanfer therapy, checkpoint blockade therapy, have achieved a certain effect, however, the clinical outcomes have not been satisfactory. Therefore, the combination of immunotherapies based on different theoretical views is important and is likely to be the trend in the future. Carcinoma associated fibroblast (CAF) is the most common cell in pancreatic cancer stromal component. It will be helpful to develop more potential therapeutic targets by further exploring CAF and the mechanism of fibrosis mediated immunosuppression.

Myocyte enhancer factor 2C regulation of hepatocellular carcinoma via vascular endothelial growth factor and Wnt/ß-catenin signaling.

Hepatocellular carcinoma (HCC) is one of the leading malignancies worldwide. Myocyte enhancer factor 2C (MEF2C) was traditionally regarded as a development-associated factor and was recently reported to be an oncogene candidate. We have previously reported overexpression of MEF2C in HCC; however, the roles of MEF2C in HCC remain to be clarified. In this study, HCC cell lines and a xenograft mouse model were used to determine the functions of MEF2C in vitro and in vivo, respectively. Specific plasmids and small interfering RNA were used to upregulate and downregulate MEF2C expression, respectively. Functional assays were performed to assess the influence of MEF2C on cell proliferation, and VEGF-induced vasculogenic mimicry, migration/invasion as well as angiogenesis. Co-immunoprecipitation was conducted to identify the interaction of MEF2C and ß-catenin. Human HCC tissue microarrays were used to investigate correlations among MEF2C, ß-catenin and involved biomarkers. MEF2C was found to mediate VEGF-induced vasculogenic mimicry, angiogenesis and migration/invasion, with involvement of the p38 MAPK and PKC signaling pathways. However, MEF2C itself inhibited tumor growth in vitro and in vivo. MEF2C was upregulated by and directly interacted with ß-catenin. The nuclear translocation of ß-catenin blocked by MEF2C was responsible for MEF2C-mediated growth inhibition. The nuclear translocation of MEF2C was associated with intracellular calcium signaling induced by ß-catenin. HCC microarrays showed correlations of nuclear MEF2C with the angiogenesis-associated biomarker, CD31, and cytosolic MEF2C with the proliferation-associated biomarker, Ki-67. MEF2C showed double-edged activities in HCC, namely mediating VEGF-induced malignancy enhancement while inhibiting cancer proliferation via blockade of Wnt/ß-catenin signaling. The overall effect of MEF2C in HCC progression regulation was dictated by its subcellular distribution. This should be determined prior to any MEF2C-associated intervention in HCC.

National rates of Helicobacter pylori recurrence are significantly and inversely correlated with human development index.

BACKGROUND: Helicobacter pylori infection is a worldwide threat to human health with recurrence rates that vary widely. The precise correlation between H. pylori recurrence and socioeconomic development has not been determined. AIM: To determine H. pylori recurrence rates after successful eradication and their association with socioeconomic development metrics. METHODS: Bibliographical searches were performed in the MEDLINE database. We reviewed all results, filtered by inclusion criteria, extracted primary results to calculate H. pylori recurrence rates and calculated national Human Development Index (HDI) values for the periods during which the studies were conducted. RESULTS: One thousand two hundred and twenty six cases of H. pylori recurrence in 77 eligible studies were observed in 43 525.1 follow-up patient-years after successful eradication therapy, giving a recurrence rate of 2.82 ± 1.16% per patient-year (weighted mean ± 95% confidence interval). H. pylori recurrence rate was inversely correlated with national HDI on linear (r = -0.633) and weighted least square (r = -0.546) regression analysis. Countries with very high HDI had a mean recurrence rate significantly lower than that of high, medium and low HDI countries (P < 0.01, 0.001, and 0.001, respectively). CONCLUSIONS: Less-developed areas, as measured by HDI, are more likely to have high H. pylori recurrence rates. A different approach to follow-up after H. pylori eradication is needed in developing countries where reinfection is highly prevalent, paying special attention to sources of reinfection and high-risk groups.

Establishment of an acute graft-versus-host disease model following liver transplantation in donor-dominant one-way major histocompatibility complex matching rats.

Acute graft-versus-host disease is an uncommon but devastating complication following liver transplantation (LTx-aGVHD). We investigated whether a rat model of LTx-aGVHD could be established using Lewis rat donors and (LewisXBN)F1 rats as recipients, which provides favorable conditions for studies of graft-versus-host reaction or disease. Replacement of (LewisXBN)F1 livers by Lewis livers alone was not sufficient to induce aGVHD; all recipients grew in a normal pattern as the syngeneic liver transplantation (LT) from Lewis to Lewis rat. However, when various numbers of donor splenocytes (1 x 10(8), 2 x 10(8), 3 x 10(8), 4 x 10(8)) were transferred simultaneously with the LT, the morbidities of lethal aGVHD were 16.7%, 50%, 83.3%, and 100%, respectively. The clinical courses as well as histologic analyses of skin and colon showed typical aGVHD characteristics. However, unlike transfusion-associated aGVHD, the liver graft was not involved. These clinical and histologic characteristics of aGVHD were consistent with those in humans who develop aGVHD after LT. Thus, a reproducible rat model of LTx-aGVHD was developed by performing LT from Lewis to (LewisXBN)F1 rats in combination with donor splenocyte transfusion. This model may be useful for further studies on the mechanisms and effective treatment modalities for LTx-aGVHD.

Elevation of intact parathyroid hormone level is a risk factor for low bone mineral density in pretransplant patients with liver diseases.

The purpose of this study was to investigate the frequency and risk factors for low bone mineral density (BMD) among patients awaiting liver transplantation. BMD of the lumbar spine (LS) and femoral neck (FN), measured by dual-energy X-ray absorptiometery (DEXA), were obtained in 64 pretransplant patients. We measured markers of bone metabolism including serum calcium, phosphorus, serum 25-hydroxyvitamin D (25-OH D), intact parathyroid hormone (iPTH), bone alkaline phosphatase (BAP), osteocalcin (OC), and urinary deoxypyridinoline/creatinine (DPD/Cr) ratio. Osteoporosis and osteopenia (low BMD) were observed in 36 patients (36/64, 56.2%), including 6 cases of osteoporosis (6/64, 9.3%) and 30 cases of osteopenia (30/64, 46.9%). Of all variables, cholestatic liver disease and elevated levels of iPTH were significantly associated with low BMD. Moreover, elevated iPTH level was identified as an independent risk factor for low BMD (P<.05, OR=1.017, 95% CI=1.001-1.032) by multivariate analysis. The median level of iPTH was increased to 55.6 pg/mL (range, 7.8-337 pg/mL) in the low BMD group, while the median level was 33 pg/mL (range, 3-162 pg/mL) in the normal BMD group (P<.05). This study revealed a high incidence of low BMD in the pretransplant patients with liver diseases. The elevated iPTH level was the predominant risk factor for low BMD. We suggest that both BMD and iPTH examinations be considered routine tests to identify the status of bone mass and bone metabolism among recipients prior to liver transplantation.

Early postoperative hemorrhage requiring urgent surgical reintervention after orthotopic liver transplantation.

Hemorrhage is a common complication in the early postoperative period after orthotopic liver transplantation (OLT) and surgical reintervention may be necessary. We sought to assess the incidence as well as to identify potential risk factors for bleeding requiring surgical reintervention in the early postoperative period. From January 2003 to December 2005, we retrospectively reviewed the courses of 261 patients who underwent OLT. We analyzed the pretransplantation parameters, transplantation features, and clinical data for surgical reintervention due to early postoperative hemorrhage. Twenty-two of 261 patients (8.4%) had early postoperative hemorrhage requiring urgent surgical reintervention during the initial hospital stay. In-hospital mortality of the patients with hemorrhage (9/22; 41%) was significantly higher than that of other patients (29/239; 12.1%; P < .001). The surgical problem was the main cause of hemorrhage (18/22; 81.8%). More intraoperative blood transfusions were necessary for patients with hemorrhage than for other patients. Furthermore, a greater number of blood transfusions, including red blood cells, plasma, and platelet concentrates, during the transplantation procedure correlated with a greater mortality. In conclusion, early postoperative hemorrhage requiring urgent surgical reintervention is a severe complication with a high mortality. It is mainly caused by errors in surgical technique. Blood transfusion during transplantation was correlated with a higher mortality.