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• The role of mammalian target of rapamycin (mTOR)–induced autophagy takes part in allograft survival during heart transplant. • The use of mTOR-induced autophagy was associated with the downregulated expression of IL-1β, IL-2, and TNF-α. • The use of BEZ235 may be preferentially recommended in transplant patients with cancer considering that BEZ235 has been widely used in cancer treatment. BEZ235, a dual PI3K/mTOR inhibitor, has shown a critical impact in the treatment of cancers, with the ability to induce autophagy. However, the effects of BEZ235 in heart transplant have been rarely investigated. The aim of this study was to evaluate the potency of BEZ235 in cardiac allograft survival. BEZ235 was administered during the perioperative period of syngeneic or allogeneic heart transplant to assess survival time. Next, the autophagy signaling pathway and the proinflammatory cytokines were analyzed. Furthermore, a cardiomyocytes-specific ATG5 gene-ablated mouse was used to confirm the results. BEZ235 treatment significantly prolonged the survival of the cardiac graft and reduced the infiltration of inflammatory cells. The expression levels of autophagy proteins were increased in the BEZ235 treatment group compared to the control group, but the therapeutic effect of BEZ235 was weakened in the cardiomyocytes-specific ATG5 gene-ablated mice. Moreover, BEZ235 significantly downregulated the expression of IL-1β, IL-2, and TNF-α. It seems BEZ235 could induce autophagy and prolonged murine cardiac allograft survival in a mechanism that involved the autophagy pathway and changed multiple inflammatory factors. This study has proposed a theoretical foundation for the strong connection between mTOR-induced autophagy and heart transplant. [ABSTRACT FROM AUTHOR]

There is no specific evidence regarding the benefits of external and internal pancreatic duct stents after pancreaticoduodenectomy since pancreatic fistula (grade A) have been redefined with no clinical treatment effect. We aimed to reevaluate the prognostic value of external and internal stents in clinically relevant postoperative pancreatic fistula over pancreaticoduodenectomy. PubMed, Web of Science, EMBASE and the Cochrane Database were specifically searched for pertinent and original articles published before May 2019. The project has been registered in PROSPERO (Registration number: CRD42019137579). Four randomized controlled trials and six nonrandomized controlled trials with a total of 2101 patients were enrolled in this meta-analysis. The use of an external stent resulted in better performance than the use of an internal stent in terms of pancreatic fistula (grade C) (OR 0.58, P = 0.03) but did not reduce the rate of pancreatic fistula (grade B) (OR 0.99, P = 0.94) in all studies. The meta-analysis of randomized controlled trials found that the use of an external stent approached a level of significance for an increased rate of clinically relevant postoperative pancreatic fistula compared to the use of an internal stent (OR 1.40, P = 0.10) but had no significant effect on pancreatic fistula (grade B) (OR 1.34, P = 0.26) or pancreatic fistula (grade C) (OR 1.68, P = 0.62). Compared with internal stents, the use of external stent might be associated with a lower rate of pancreatic fistula (grade C). More randomized clinical trials are warranted to further explore safety and efficacy of pancreatic duct external stents. [ABSTRACT FROM AUTHOR]

Immunotherapy with immune checkpoint inhibitors (ICIs), including antibodies against programmed cell death protein‐1 (PD‐1) and its receptor programmed cell death ligand‐1 (PD‐L1), represents a promising systematic treatment for advanced human malignancies. Transplantation remains the ultimate therapy for end‐stage organ diseases. However, the efficacy of ICI treatment in solid organ transplant (SOT) recipients remains controversial. We established a transgenic primary liver cancer mouse model and performed allogeneic heterotopic heart transplantation. Different treatments were performed and survival curves were calculated. Graft samples were collected, and immune cells and the cell surface expression of PD‐L1 were analysed by flow cytometry. Inflammatory cytokine levels in the serum were measured by an inflammatory array. The specificity of the histochemical techniques was tested by staining sections. A combination immunotherapy comprising a BET protein inhibitor (JQ1) and an immune checkpoint inhibitor (anti‐PD‐L1 antibody) was administered to primary liver cancer model mice bearing cardiac allografts. Interestingly, the combination immunotherapy effectively suppressed the progression of primary liver cancer but did not accelerate allograft rejection. In accordance with our previous findings, BET protein inhibition enhances the expression of a putative membrane transporter (Rab8A), which upregulates the expression of PD‐L1 on the plasma membrane in a transgenic primary liver cancer mouse model. This may be a crucial mechanism of tumour progression arrest. Our data showed that heart transplantation upregulated the expression of the proinflammatory factor IFN‐γ and suggested that BET protein inhibition (with JQ1) decreased PD‐L1 expression in heart tissues after cardiac transplantation. This phenomenon was accompanied by enhanced infiltration of inflammatory IFN‐γ. Our study provides a novel and efficient therapeutic strategy for SOT recipients. [ABSTRACT FROM AUTHOR]

Bromodomain and extraterminal (BET) proteins are promising therapeutic targets for hematological and solid tumors. However, BET inhibitor monotherapy did not show a significant therapeutic benefit for hepatocellular carcinoma (HCC) in preclinical trials. Here, we identified YAP/TAZ genes, as determinants for sensitivity to BET inhibitors. YAP/TAZ expression, especially TAZ, promote resistance to BET inhibitor. In addition, we analyzed that the mRNA level of PDE5 was positively correlated with YAP/TAZ based on TCGA database and demonstrated tadalafil, a PDE5 inhibitor, could block YAP/TAZ protein expression by activating Hippo pathway. Cotreatment with tadalafil and JQ-1 synergistically reduced YAP/TAZ protein expression, suppressed proliferation and induced G0-G1 arrest of cultured HCC cells. JQ-1 alone does not show significant benefits in a mouse model of HCC induced by c-Myc/N-Ras plasmids. In contrast, the combination, tadalafil and JQ-1, successfully suppressed tumor progression, enhanced antitumor immunity by improving the ratio of activated CD8 and extended the survival time of mice. Our data define the key role of YAP/TAZ in mediating resistance to BET inhibitor, described the PDE5/PKG/Hippo/YAP/TAZ axis and identified a common clinical drug that can be developed as an effective combined strategy to overcome BET inhibitor resistance in MYC/Ras-driven HCC. • The upregulation of YAP/TAZ is correlated with the poor prognosis in HCC. • Overexpressed YAP/TAZ leads to BET inhibitors resistance. • PDE5/PKG/Hippo axis regulates the expression of YAP/TAZ. • Tadalafil enhances the sensitization of BET inhibitors to the treatment of HCC. [ABSTRACT FROM AUTHOR]

Dysbiosis of the gut microbiota has important roles in various diseases and pathological states of the host. However, the changes of the gut microbiota during partial hepatectomy (PH)-induced acute liver injury have so far remained elusive. The present study investigated the gut microbiome and its related pathways following PH-induced acute liver injury. A total of 50 male C57/BL6 mice were divided into a normal control (NC), sham-operation and liver resection (LR) group (50% PH). Samples were collected at 3 and 14 days post-operation to obtain specimens for the Sham3, Sham14, LR3 and LR14 groups (10 mice/group). Specimens of NC group (n=10) were obtained at the same time as those of Sham3 group. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined using an automatic chemical analyzer and the gut microbiota was assessed by 16S ribosomal RNA gene sequencing of small intestinal contents. The serum levels of ALT and AST in the LR3 group were significantly increased, while those in the LR14 group were decreased again to near-normal levels. In the LR3 group, the operational taxonomic units, species richness (Chao1) and species diversity (Shannon and Simpson indices) were decreased, although without any significant difference. Furthermore, in the LR3 group, significant Cyanobacteria enrichment and Fusobacteria depletion compared with the NC and Sham3 groups was observed, while in the LR14 group, a significant depletion of the abundance of Verrucomicrobia, Chloroflexi and Deferribacteres compared to the LR3 group was obtained. The abundance of Firmicutes was increased in the LR3 group and decreased again in the LR14 group. However, the abundance of Bacteroidetes and Actinobacteria decreased in the LR3 group and increased again in the LR14 group. The alterations of the gut microbiota at the genus level were also revealed, as significant increases in Chloroplast, Curvibacter, Pelomonas, Ruminococcaceae UCG-005 and Blautia and a sharp decrease in Akkermansia and Eubacterium coprostanoligenes were caused by acute liver injury. Furthermore, functional metagenome prediction was performed by Phylogenetic Investigation of Communities by Reconstruction of Unobserved States based on the Greengenes database, revealing alterations in signal transduction, transcription and cell motility, as well as metabolism of amino acids, lipids, glucose, cofactors and terpenoids, and xenobiotics pathways. An improved understanding of the structural and functional changes of the gut microbiota following 50% PH-induced acute liver injury and repair may provide novel strategies for the recovery of hosts undergoing hepatectomy. [ABSTRACT FROM AUTHOR]

Background: The outcomes of large‐sized graft mismatch in deceased donor liver transplantation (LT) have been rarely studied. The aim of this study was to determine whether a large‐sized graft for recipient influenced the post‐transplant outcomes. Methods: A total of 273 patients undergoing LT were enrolled and divided into a large and a normal‐sized graft group by graft weight to recipient weight (GWRW) >2.5% (n = 76) or GWRW ≤2.5% (n = 197). Post‐operative complications and outcomes were retrospectively analysed. Results: The two groups were comparable in demographic characteristics. The rate of complications was significantly higher in the large‐sized graft group including early allograft dysfunction (36.8% versus 17.8%, P = 0.001), hepatic necrosis (26.3% versus 13.7%, P = 0.01) and massive hydrothorax (25% versus 14.7%, P = 0.04). The large‐sized graft group suffered higher early mortality compared with the normal‐sized graft group (30 days: 14.5% versus 5.6%, P = 0.02, 90 days: 21.1% versus 9.6%, P = 0.01). The primary causes of early death were multiple organ failure (10.5% versus 2%, P = 0.002) and sepsis (2.6% versus 1.5%, P = 0.54). Four parameters including donor alanine transaminase, GWRW, estimated blood loss and model for end‐stage liver disease score were significant on multivariate analysis, and indicated significant risk factors for the early mortality of recipients. Conclusion: In deceased donor LT, GWRW >2.5% is associated with increased liver injury, risk of early mortality and other adverse outcomes. Thus, donor livers should be allocated to recipients with GWRW ≤2.5%. [ABSTRACT FROM AUTHOR]

Background: The present study aimed to assess the risk factors of cholesterol and premalignancy in polypoid lesions of the gallbladder (PLGs) and to establish an appropriate treatment strategy. Methods: Data from patients who underwent cholecystectomy at the First Affiliated Hospital, School of Medicine, Zhejiang University, between January 2011 and July 2017, were collected retrospectively. Results: A total of 1561 patients were included in the present study. The cohort comprised of 636 (40.7%) males and 925 (59.3%) females, with a mean age of 49.5 (range 16–88) years; 65.6% (1024/1561) demonstrated cholesterol lesions in this cohort, among which cholesterol polyps accounted for 81.0%. Age younger than 50 years and multiple number of polyps were found to be independent predictive variables for cholesterol lesions (odds ratio (OR) 3.461, 95% confidence interval (CI) 2.058–5.820, P < 0.001 and OR 3.321, 95% CI 1.988–5.547, P < 0.001, respectively). The presence of polyp growth was associated with premalignancy (OR 5.366, 95% CI 1.466–19.637, P = 0.011), and the presence of clinical symptoms indicated benign non‐cholesterol lesions (OR 0.368, 95% CI 0.153–0.885, P = 0.026). Conclusion: In the case of patients ≥50 years old with single asymptomatic polyp, cholecystectomy was recommended if the polyp presented growth at a rate above 3–4 mm within 6 months. If not, trimonthly ultrasound follow up was recommended, and clinicians should carefully assess the risk factors for premalignancy in PLGs. This study aimed to develop a strategy to discriminate cholesterol and premalignancy in polypoid lesions of the gallbladder. In the case of patients aged ≥50 years with single asymptomatic polyp, cholecystectomy was recommended if the polyp presented growth at a rate above 3–4 mm within 6 months. [ABSTRACT FROM AUTHOR]

A solitary fibrous tumor (SFT) is a rare mesenchymal tumor. Ex situ hepatectomy and liver autotransplantation are novel methods for the treatment of complicated liver tumors, for example, those involving vascular structures, including the inferior vena cava, which are unresectable by conventional approaches. The present study describes a rare case of a massive hepatic SFT in a 32-year-old female who underwent ex situ hepatectomy and liver autotransplantation to achieve a radical resection. The surgery was without complications. Post-operative histopathological and immunohistochemical examinations revealed an SFT of the liver. The patient was discharged 29 days after the surgery with fully recovered liver function. The routine check-up 3 months after surgery indicated normal liver function and no evidence of recurrence. Additionally, an exhaustive review of available literature was performed to provide a complete overview of the current status of SFTs. In summary, the present study found that ex situ hepatectomy and liver autotransplantation are suitable surgical techniques for treating a giant SFT, as well as other liver neoplasms that are considered unresectable by conventional surgery. [ABSTRACT FROM AUTHOR]

Acute cellular rejection (ACR) is a major barrier to the long-term survival of cardiac allografts. Although immune cells are well known to play critical roles in ACR, the dynamic cellular landscape of allografts with ACR remains obscure. Single-cell RNA sequencing (scRNA-seq) was carried out for mouse cardiac allografts with ACR. Bioinformatic analysis was performed, and subsequent transplant experiments were conducted to validate the findings. Despite an overall large depletion of cardiac fibroblasts (CFBs), highly expanded cytotoxic T lymphocytes and a CXCL10+Gbp2+ subcluster of CFBs were enriched within grafts at the late stage. CXCL10+Gbp2+ CFBs featured strong interferon responsiveness and high expression of chemokines and major histocompatibility complex molecules, implying their involvement in the recruitment and activation of immune cells. Cell‒cell communication analysis revealed that CXCL9/CXCL10-CXCR3 might contribute to regulating CXCL10+Gbp2+ CFB-induced chemotaxis and immune cell recruitment. In vivo transplant studies revealed the therapeutic potential of CXCR3 antagonism in transplant rejection. The findings of our study unveiled a novel CFB subcluster that might mediate acute cardiac rejection. Targeting CXCR3 could prolong allograft survival. [ABSTRACT FROM AUTHOR]