SPARC Stabilizes ApoE to Induce Cholesterol-Dependent Invasion and Sorafenib Resistance in Hepatocellular Carcinoma.

Dysregulation of cholesterol homeostasis is implicated in the development and progression of hepatocellular carcinoma (HCC) that is characterized by intrahepatic and early extrahepatic metastases. A better understanding of the underlying mechanisms regulating cholesterol metabolism in HCC could help identify strategies to circumvent the aggressive phenotype. Here, we found that high expression of intracellular SPARC (secreted protein acidic and rich in cysteine) was significantly associated with elevated cholesterol levels and an enhanced invasive phenotype in HCC. SPARC potentiated cholesterol accumulation in HCC cells during tumor progression by stabilizing the ApoE protein. Mechanistically, SPARC competitively bound to ApoE, impairing its interaction with the E3 ligase tripartite motif containing 21 (TRIM21) and preventing its ubiquitylation and subsequent degradation. ApoE accumulation led to cholesterol enrichment in HCC cells, stimulating PI3K-AKT signaling and inducing epithelial-mesenchymal transition (EMT). Importantly, sorafenib-resistant HCC cells were characterized by increased expression of intracellular SPARC, elevated cholesterol levels, and enhanced invasive capacity. Inhibiting SPARC expression or reducing cholesterol levels enhanced the sensitivity of HCC cells to sorafenib treatment. Together, these findings unveil interplay between SPARC and cholesterol homeostasis. Targeting SPARC-triggered cholesterol-dependent oncogenic signaling is a potential therapeutic strategy for advanced HCC. SIGNIFICANCE: Intracellular SPARC boosts cholesterol availability to fuel invasion and drug resistance in hepatocellular carcinoma, providing a rational approach to improve the treatment of advanced liver cancer.

Histone lactylation inhibits RARγ expression in macrophages to promote colorectal tumorigenesis through activation of TRAF6-IL-6-STAT3 signaling.

Macrophages are phenotypically and functionally diverse in the tumor microenvironment (TME). However, how to remodel macrophages with a protumor phenotype and how to manipulate them for therapeutic purposes remain to be explored. Here, we show that in the TME, RARγ is downregulated in macrophages, and its expression correlates with poor prognosis in patients with colorectal cancer (CRC). In macrophages, RARγ interacts with tumor necrosis factor receptor-associated factor 6 (TRAF6), which prevents TRAF6 oligomerization and autoubiquitination, leading to inhibition of nuclear factor κB signaling. However, tumor-derived lactate fuels H3K18 lactylation to prohibit RARγ gene transcription in macrophages, consequently enhancing interleukin-6 (IL-6) levels in the TME and endowing macrophages with tumor-promoting functions via activation of signal transducer and activator of transcription 3 (STAT3) signaling in CRC cells. We identified that nordihydroguaiaretic acid (NDGA) exerts effective antitumor action by directly binding to RARγ to inhibit TRAF6-IL-6-STAT3 signaling. This study unravels lactate-driven macrophage function remodeling by inhibition of RARγ expression and highlights NDGA as a candidate compound for treating CRC.

Application of extended criteria donor grafts in liver transplantation for acute-on-chronic liver failure: A retrospective cohort study.

BACKGROUND: There is no consensus on the usage of extended criteria donor (ECD) grafts in liver transplantation (LT) for acute-on-chronic liver failure (ACLF) patients. AIM: To summarize the experience of using ECD livers in ACLF-LT. METHODS: A retrospective cohort study was conducted, enrolling patients who underwent LT at the First Affiliated Hospital of Sun Yat-Sen University from January 2015 to November 2021. The patients were divided into ECD and non-ECD groups for analysis. RESULTS: A total of 145 recipients were enrolled in this study, of which ECD and non-ECD recipients accounted for 53.8% and 46.2%, respectively. Donation after cardiac death (DCD) recipients accounted for the minority compared with donation after brain death (DBD) recipients (16.6% vs 83.4%). Neither overall survival nor graft survival significantly differed between ECD and non-ECD and DCD and DBD recipients. ECD grafts were associated with a significantly higher incidence of early allograft dysfunction (EAD) than non-ECD grafts (67.9% vs 41.8%, P = 0.002). Postoperative outcomes between DCD and DBD recipients were comparable (P > 0.05). ECD graft (P = 0.009), anhepatic phase (P = 0.034) and recipient gamma glutamyltransferase (P = 0.016) were independent risk factors for EAD. Recipient preoperative number of extrahepatic organ failures > 2 (P = 0.015) and intraoperative blood loss (P = 0.000) were independent predictors of poor post-LT survival. CONCLUSION: Although related to a higher risk of EAD, ECD grafts can be safely used in ACLF-LT. The main factors affecting post-LT survival in ACLF patients are their own severe preoperative disease and intraoperative blood loss.

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 0.871 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.

TRIM21 is a druggable target for the treatment of metastatic colorectal cancer through ubiquitination and activation of MST2.

Metastatic colorectal cancer (mCRC) is characterized by poorer prognosis of patients and limited therapeutic approach, partly due to the lack of effective target. Using mouse models and tumor organoids, this study reported a tripartite motif 21 (TRIM21) protein, exerting potential inhibitory effects on the invasion and metastasis of CRC. Mechanistically, TRIM21 directly interacted with and ubiquitinated MST2 at lysine 473 (K473) via K63-linkage. This ubiquitination enabled the formation of MST2 homodimer and enhanced its kinase activity, ultimately resulting in the functional inactivation of yes-associated protein (YAP) and inhibition of an epithelial-mesenchymal transition (EMT) feature. We identified that vilazodone, an antidepressant, directly bound to TRIM21 to exert effective anti-metastatic action both in vitro and in vivo. Collectively, these findings revealed a previously unrecognized interplay between TRIM21 and the Hippo-YAP signaling. These results suggested that vilazodone could be repositioned as an anti-tumor drug to inhibit CRC metastasis by targeting TRIM21.

Oncogenic potential of BEST4 in colorectal cancer via activation of PI3K/Akt signaling.

BEST4 is a member of the bestrophin protein family that plays a critical role in human intestinal epithelial cells. However, its role and mechanism in colorectal cancer (CRC) remain largely elusive. Here, we investigated the role and clinical significance of BEST4 in CRC. Our results demonstrate that BEST4 expression is upregulated in clinical CRC samples and its high-level expression correlates with advanced TNM (tumor, lymph nodes, distant metastasis) stage, LNM (lymph node metastasis), and poor survival. Functional studies revealed that ectopic expression of BEST4 promoted CRC cell proliferation and metastasis, whereas the depletion of BEST4 had the opposite effect both in vitro and in vivo. Mechanistically, BEST4 binds to the p85α regulatory subunit of phosphatidylinositol-3-kinase (PI3K) and promotes p110 kinase activity; this leads to activation of Akt signaling and expression of MYC and CCND1, which are critical regulators of cell proliferation and metastasis. In clinical samples, the expression of BEST4 is positively associated with the expression of phosphorylated Akt, MYC and CCND1. Pharmacological inhibition of Akt activity markedly repressed BEST4-mediated Akt signaling and proliferation and metastasis of CRC cells. Importantly, the interaction between BEST4 and p85α was also enhanced by epidermal growth factor (EGF) in CRC cells. Therapeutically, BEST4 suppression effectively sensitized CRC cells to gefitinib treatment in vivo. Taken together, our findings indicate the oncogenic potential of BEST4 in colorectal carcinogenesis and metastasis by modulating BEST4/PI3K/Akt signaling, highlighting a potential strategy for CRC therapy.

Transcriptomic Analysis Identifies Complement Component 3 as a Potential Predictive Biomarker for Chemotherapy Resistance in Colorectal Cancer.

Objective: 5-fluorouracil- and oxaliplatin-based FOLFOX regimens are mainstay chemotherapeutics for colorectal cancer (CRC) but drug resistance represents a major therapeutic challenge. To improve patient survival, there is a need to identify resistance genes to better understand the mechanisms underlying chemotherapy resistance. Methods: Transcriptomic datasets were retrieved from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and combined with our own microarray data. Weighted gene co-expression network analysis (WGCNA) was used to dissect the functional networks and hub genes associated with FOLFOX resistance and cancer recurrence. We then conducted analysis of prognosis, profiling of tumor infiltrating immune cells, and pathway overrepresentation analysis to comprehensively elucidate the biological impact of the identified hub gene in CRC. Results: WGCNA analysis identified the complement component 3 (C3) gene as the only hub gene associated with both FOLFOX chemotherapy resistance and CRC recurrence after FOLFOX chemotherapy. Subsequent survival analysis confirmed that high C3 expression confers poor progression-free survival, disease-free survival, and recurrence-free survival. Further correlational analysis revealed significant negative association of C3 expression with sensitivity to oxaliplatin, but not 5-fluorouracil. Moreover, in silico analysis of tumor immune cell infiltration suggested the change of C3 expression could affect tumor microenvironment. Finally, gene set enrichment analysis (GSEA) revealed a hyperactivation of pathways contributing to invasion, metastasis, lymph node spread, and oxaliplatin resistance in CRC samples with C3 overexpression. Conclusion: Our results suggest that high C3 expression is a debilitating factor for FOLFOX chemotherapy, especially for oxaliplatin sensitivity, and C3 may represent a novel biomarker for treatment decision of CRC.

Prediction of post-transplant graft survival by different definitions of early allograft dysfunction.

BACKGROUND: The efficacy of early allograft dysfunction (EAD) definitions in predicting post-transplant graft survival in a Chinese population is still unclear. METHODS: A total of 607 orthotopic liver transplants (OLT) have been included in the current study. Model accuracy was evaluated using receiver operating characteristic (ROC) analysis. Risk factors for EAD was evaluated using univariable analysis and multivariable logistic regression model. RESULTS: The 3-, 6-, and 12-month patient/graft survival were 91.6%/91.4%, 91.1%/90%, and 87.5%/87.3%, respectively. MELDPOD5 had a superior discrimination of 3-month graft survival (C statistic, 0.83), compared with MEAF (C statistic, 0.77) and Olthoff criteria (C statistic, 0.72). Multivariate analysis of risk factors for EAD defined by MELDPOD5, showed that donor body mass index (P=0.001), donor risk index (P=0.006), intraoperative use of packed red blood cells (P=0.001), hypertension of recipient (P=0.004), and preoperative total bilirubin (P<0.001) were independent risk factors. CONCLUSIONS: The results suggest that MLEDPOD5 is a better criterion of EAD for the Chinese population, which might serve as a surrogate end-point for graft survival in clinical study.

The Role of TGF-ß Signaling Pathways in Cancer and Its Potential as a Therapeutic Target.

The transforming growth factor-ß (TGF-ß) signaling pathway mediates various biological functions, and its dysregulation is closely related to the occurrence of malignant tumors. However, the role of TGF-ß signaling in tumorigenesis and development is complex and contradictory. On the one hand, TGF-ß signaling can exert antitumor effects by inhibiting proliferation or inducing apoptosis of cancer cells. On the other hand, TGF-ß signaling may mediate oncogene effects by promoting metastasis, angiogenesis, and immune escape. This review summarizes the recent findings on molecular mechanisms of TGF-ß signaling. Specifically, this review evaluates TGF-ß's therapeutic potential as a target by the following perspectives: ligands, receptors, and downstream signaling. We hope this review can trigger new ideas to improve the current clinical strategies to treat tumors related to the TGF-ß signaling pathway.

Clinical Impacts and Outcomes With Possible Donor-Derived Infection in Infected Donor Liver Transplantation: A Single-Center Retrospective Study in China.

BACKGROUND: Information on possible donor-derived transmission events in China is limited. We evaluated the impacts of liver transplantation from infected deceased-donors, analyzed possible donor-derived bacterial or fungal infection events in recipients, and evaluated the etiologic agents' characteristics and cases outcomes. METHODS: A single-center observational study was performed from January 2015 to March 2017 to retrospectively collect data from deceased-donors diagnosed with infection. Clinical data were recorded for each culture-positive donor and the matched liver recipient. The microorganisms were isolated and identified, and antibiotic sensitivity testing was performed. The pathogens distribution and incidence of possible donor-derived infection (P-DDI) events were analyzed and evaluated. RESULTS: Information from 211 donors was collected. Of these, 82 donors were infected and classified as the donation after brain death category. Overall, 149 and 138 pathogens were isolated from 82 infected donors and 82 matched liver recipients, respectively. Gram-positive bacteria, Gram-negative bacteria, and fungi accounted for 42.3% (63 of 149), 46.3% (69 of 149), and 11.4% (17 of 149) of pathogens in infected donors. The incidence of multidrug-resistant bacteria was high and Acinetobacter baumannii was the most concerning species. Infections occurred within the first 2 weeks after liver transplantation with an organ from an infected donor. Compared with the noninfection recipient group, the infection recipient group experienced a longer mechanical ventilation time (P = .004) and intensive care unit stay (P = .003), a higher incidence of renal dysfunction (P = .026) and renal replacement therapy (P = .001), and higher hospital mortality (P = .015). Possible donor-derived infection was observed in 14.6% of cases. Recipients with acute-on-chronic liver failure were more prone to have P-DDI than recipients with other diseases (P = .007; odds ratio = 0.114; 95% confidence interval, .025-.529). CONCLUSIONS: When a liver recipient receives a graft from an infected deceased-donor, the postoperative incidence of infection is high and the infection interval is short. In addition, when a possible donor-derived, drug-resistant bacterial infection occurs, recipients may have serious complications and poor outcomes.

Tumor Necrosis Factor Receptor-Associated Factor 6 Promotes Hepatocarcinogenesis by Interacting With Histone Deacetylase 3 to Enhance c-Myc Gene Expression and Protein Stability.

The oncogene c-Myc is aberrantly expressed and plays a key role in malignant transformation and progression of hepatocellular carcinoma (HCC). Here, we report that c-Myc is significantly up-regulated by tumor necrosis factor receptor-associated factor 6 (TRAF6), an E3 ubiquitin ligase, in hepatocarcinogenesis. High TRAF6 expression in clinical HCC samples correlates with poor prognosis, and the loss of one copy of the Traf6 gene in Traf6+/- mice significantly impairs liver tumorigenesis. Mechanistically, TRAF6 first interacts with and ubiquitinates histone deacetylase 3 (HDAC3) with K63-linked ubiquitin chains, which leads to the dissociation of HDAC3 from the c-Myc promoter and subsequent acetylation of histone H3 at K9, thereby epigenetically enhancing the mRNA expression of c-Myc. Second, the K63-linked ubiquitination of HDAC3 impairs the HDAC3 interaction with c-Myc and promotes c-Myc protein acetylation, which thereby enhances c-Myc protein stability by inhibiting carboxyl terminus of heat shock cognate 70-kDa-interacting protein-mediated c-Myc ubiquitination and degradation. Importantly, TRAF6/HDAC3/c-Myc signaling is also primed in hepatitis B virus-transgenic mice, unveiling a critical role for a mechanism in inflammation-cancer transition. In clinical specimens, TRAF6 positively correlates with c-Myc at both the mRNA and protein levels, and high TRAF6 and c-Myc expression is associated with an unfavorable prognosis, suggesting that TRAF6 collaborates with c-Myc to promote human hepatocarcinogenesis. Consistently, curbing c-Myc expression by inhibition of TRAF6 activity with a TRAF6 inhibitor peptide or the silencing of c-Myc by small interfering RNA significantly suppressed tumor growth in mice. Conclusion: These findings demonstrate the oncogenic potential of TRAF6 during hepatocarcinogenesis by modulating TRAF6/HDAC3/c-Myc signaling, with potential implications for HCC therapy.

Targeting TF-AKT/ERK-EGFR Pathway Suppresses the Growth of Hepatocellular Carcinoma.

Tissue factor (TF) is a transmembrane glycoprotein to initiate blood coagulation and frequently overexpressed in a variety of tumors. Our previous study has showed that the expression of TF is upregulated and correlated with prognosis in hepatocellular carcinoma (HCC). However, the role and molecular mechanism of TF in the growth of HCC are still unclear. In vitro and in vivo functional experiments were performed to determine the effect of TF on the growth of HCC cells. A panel of biochemical assays was used to elucidate the underlying mechanisms. TF could promote the growth of HCC in vitro and in vivo by activating both ERK and AKT signaling pathways. TF induced EGFR upregualtion, and inhibition of EGFR suppressed TF-mediated HCC growth. In addition, TF protein expression was correlated with EGFR in HCC tissues. TF promotes HCC growth by upregulation of EGFR, and TF as well as EGFR may be potential therapeutic targets of HCC.

TRAF6 inhibits colorectal cancer metastasis through regulating selective autophagic CTNNB1/ß-catenin degradation and is targeted for GSK3B/GSK3ß-mediated phosphorylation and degradation.

Aberrant CTNNB1 signaling is one of the fundamental processes in cancers, especially colorectal cancer (CRC). Here, we reported that TRAF6, an E3 ubiquitin ligase important for inflammatory signaling, inhibited epithelial-mesenchymal transition (EMT) and CRC metastasis through driving a selective autophagic CTNNB1 degradation machinery. Mechanistically, TRAF6 interacted with MAP1LC3B/LC3B through its LC3-interacting region 'YxxL' and catalyzed K63-linked polyubiquitination of LC3B. The K63-linked ubiquitination of LC3B promoted the formation of the LC3B-ATG7 complex and was critical to the subsequent recognition of CTNNB1 by LC3B for the selective autophagic degradation. However, TRAF6 was phosphorylated at Thr266 by GSK3B in most clinical CRC, which triggered K48-linked polyubiquitination and degradation of TRAF6 and thereby attenuated its inhibitory activity towards the autophagy-dependent CTNNB1 signaling. Clinically, decreased expression of TRAF6 was associated with elevated GSK3B protein levels and activity and reduced overall survival in CRC patients. Pharmacological inhibition of GSK3B activity stabilized the TRAF6 protein, promoted CTNNB1 degradation, and effectively suppressed EMT and CRC metastasis. Thus, targeting TRAF6 and its pathway may be meaningful for treating advanced CRC. Abbreviations: AMBRA1: autophagy and beclin 1 regulator 1; AOM: azoxymethane; ATG5: autophagy related 5; ATG7: autophagy related 7; Baf A1: bafilomycin A1; BECN1: beclin 1; CoIP: co-immunoprecipitation; CQ: chloroquine; CRC: colorectal cancer; CTNNB1/ß-catenin: catenin beta 1; DSS: dextran sodium sulfate; EMT: epithelial-mesenchymal transition; FBS: fetal bovine serum; GFP: green fluorescent protein; GSK3B/GSK3ß: glycogen synthase kinase 3 beta; IgG: Immunoglobulin G; IHC: immunohistochemistry; LIR: LC3-interacting region; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; RFP: red fluorescent protein; RT: room temperature; shRNA: short hairpin RNA; siRNA: small interfering RNA; TRAF6: TNF receptor-associated factor 6; WT: wild-type; ZEB1: zinc finger E-box binding homeobox 1.

Orphan nuclear receptor Nur77 inhibits poly (I:C)-triggered acute liver inflammation by inducing the ubiquitin-editing enzyme A20.

Inflammation is a key contributor to various types of acute and chronic liver disease. We recently reported that lack of Nur77, an orphan nuclear receptor, contributes to the pathogenesis of inflammatory diseases including inflammatory bowel disease and sepsis. However, whether Nur77 plays a critical role in liver inflammation remains to be fully understood. Employing in vivo acute liver inflammation model in wild-type (Nur77+/+) and Nur77-/- mice, we here found that Nur77 deficiency dramatically increased the production of pro-inflammatory cytokines and accelerated liver injury induced by poly (I:C)/D-GalN in Nur77-/- mice. Mechanistically, Nur77 acts as a negative regulator of NF-κB signaling by inducing the expression of ubiquitin-editing enzyme A20, a novel target gene of Nur77. Notably, in inflammatory cells, overexpression of A20 enhanced, whereas knockdown of A20 by siRNA approach impaired, the inhibitory effect of Nur77 on poly (I:C)-triggered inflammation. Collectively, our data suggest that the orphan nuclear receptor Nur77 plays a protective role in poly (I:C)-triggered liver inflammation by inducing A20, thus making it a promising target for the prevention and treatment of liver inflammation.

The long non-coding RNA NONHSAT062994 inhibits colorectal cancer by inactivating Akt signaling.

The aberrant expression of long noncoding RNAs (lncRNAs) is implicated in cancer development and progression. However, the clinical significance and mechanism by which NONHSAT062994 regulates colorectal cancer (CRC) is unknown. We here reported that NONHSAT062994 was significantly downregulated in human CRC tissues and cell lines. Moreover, its expression was inversely correlated with tumor size and overall survival (OS) time in CRC patients. In CRC cells, the overexpression and knockdown of NONHSAT062994 inhibited and enhanced CRC cell growth, respectively, in vitro and in vivo. Mechanistically, NONHSAT062994 functioned as a tumor suppressor to inhibit CRC cell growth by inactivating Akt signaling. Notably, the NONHSAT062994 expression status was negatively correlated with the Akt downstream targets c-Myc and Cyclin D1 in clinical CRC samples. The current findings suggest that NONHSAT062994 plays a critical role in the development of CRC by regulating Akt signaling, and identified a candidate prognostic biomarker or potential therapeutic target for CRC patients.

MiR-486-5p negatively regulates oncogenic NEK2 in hepatocellular carcinoma.

NEK2 is a member of the NIMA-related family of serine/threonine centrosomal kinases. We analyzed the relationship between differential expression of NEK2 and hepatocellular carcinoma (HCC) patient outcomes after liver transplants. We also studied the microRNAs that affect NEK2 expression. Analysis of multiple microarrays in the Oncomine database revealed that NEK2 expression was higher in HCC tissues than adjacent normal liver tissues. High NEK2 expression correlated with tumor size, pathological grade and macro- and microvascular invasion. Consequently, patients exhibiting high NEK2 expression had poorer prognosis. This was corroborated by our multivariate analysis that showed NEK2 to be an independent prognostic factor for HCC patient survival. Further, high NEK2 expression promoted proliferation, colony formation, migration and invasion of HCC cell lines. Tumor xenograft data from Balb/c nude mice demonstrated that HCC cells with high NEK2 expression formed larger tumors than those with low NEK2 expression. Finally, we showed that miR-486-5p suppressed NEK2 by directly binding to its transcript 3'UTR. We also demonstrated an inverse relationship between miR-486-5p and NEK2 expression in HCC patients. These findings suggest miR-486-5p negatively regulates NEK2, which is a critical prognostic indicator of HCC patient survival after liver transplantation.

Kidney transplantation from donors with rhabdomyolysis and acute renal failure.

Rhabdomyolysis in deceased donors usually causes acute renal failure (ARF), which may be considered a contraindication for kidney transplantation. From January 2012 to December 2016, 30 kidneys from 15 deceased donors with severe rhabdomyolysis and ARF were accepted for transplantation at our center. The peak serum creatinine (SCr) kinase, myoglobin, and SCr of the these donors were 15 569±8597 U/L, 37 092±42 100 µg/L, and 422±167 µmol/L, respectively. Two donors received continuous renal replacement therapy due to anuria. Six kidneys exhibited a discolored appearance (from brown to glossy black) due to myoglobin casts. The kidney transplant results from the donors with rhabdomyolysis donors were compared with those of 90 renal grafts from standard criteria donors (SCD). The estimated glomerular filtration rate at 2 years was similar between kidney transplants from donors with rhabdomyolysis and SCD (70.3±14.6 mL/min/1.73 m2 vs 72.3±15.1 mL/min/1.73 m2 ). We conclude that excellent graft function can be achieved from kidneys donors with ARF caused by rhabdomyolysis.

Up-Regulation of HMGB1 Exacerbates Renal Ischemia-Reperfusion Injury by Stimulating Inflammatory and Immune Responses through the TLR4 Signaling Pathway in Mice.

BACKGROUND/AIMS: The aim of this study was to elucidate how high-mobility group box 1 (HMGB1) exacerbates renal ischemic-reperfusion injury (IRI) by inflammatory and immune responses through the toll-like receptor 4 (TLR4) signaling pathway. METHODS: A total of 30 wild-type (WT) mice and 30 TLR4 knockout (TLR4-/-) mice were selected and then randomly assigned to the Sham, I/R or HMGB1 groups. The serum and kidney tissues of all mice were collected 24 h after the perfusion. The fully automatic biochemical detector and ELISA were applied to determine the blood urea nitrogen (BUN) and serum creatinine (Scr) levels, and TNF-α, IL-1ß, IL-6, IFN-γ and IL-10 levels, respectively. HE staining was used to evaluate kidney tissue damage, immunofluorescence and immunohistochemical staining were performed to observe CD68 and MPO cell infiltration, and flow cytometry was applied to detect immune cells. qRT-PCR and Western blotting were used to detect the expressions of TLR signaling pathway-related genes and proteins, respectively. RESULTS: Compared with the Sham group, the levels of BUN, Scr, TNF-α, IL-1ß, IL-6, IFN-γ and IL-10, kidney tissue damage score, CD68 and MPO cell infiltration, the numbers of immune cells, and the expressions of TLR signaling pathway-related genes and proteins in the I/R and HMGB1 groups were significantly up-regulated. In the I/R and HMGB1 groups, the levels of BUN and Scr, TNF-α, IL-1ß, IL-6 and IFN-γ, kidney tissue damage score, CD68 and MPO cell infiltration, immune cell numbers, and TLR signaling pathway-related gene and protein expressions in the WT mice were all higher than those in the TLR4-/- mice, but IL-10 level was significantly lower. Similarly, all aforementioned indexes but IL-10 level in the WT and TLR4-/- mice were higher in the HMGB1 group than in the I/R group. CONCLUSION: Our study indicated that the up-regulation of HMGB1 could exacerbate renal IRI by stimulating inflammatory and immune responses through the TLR4 signaling pathway.c.

A simplified multivisceral transplantation procedure for patients with combined end-stage liver disease and type 2 diabetes mellitus.

In liver transplant patients with type 2 diabetes mellitus (DM), the disease worsens after transplantation because of longterm use of diabetogenic immunosuppressive drugs, making management of those patients a great challenge. The objective of our study was to evaluate the safety and efficacy of a simplified multivisceral transplantation (SMT) procedure for the treatment of patients with end-stage liver disease and concurrent type 2 DM. Forty-four patients who had pretransplant type 2 DM were included. A total of 23 patients received SMT, and 21 patients received orthotopic liver transplantation (OLT). Patient and graft survivals, complications, diabetic control, and quality of life (QOL) were retrospectively analyzed in both groups. The 1-, 3-, and 5-year cumulative patient and graft survival rates were 91.5%, 75.4%, and 75.4% in the SMT group and were 94.4%, 64.4%, and 64.4% in the OLT group, respectively (P = 0.70). Interestingly, 95.7% (22/23) of patients achieved complete remission from DM after SMT compared with 16.7% (3/18) of patients after OLT. The occurrence of biliary complication was significantly higher in the OLT group than that in the SMT group (23.8% versus 0.0%; P = 0.01). Moreover, better QOL was observed in the SMT group than that in the OLT group. In conclusion, the SMT procedure we described here is a safe and viable option for patients with end-stage live disease and concurrent type 2 DM. This SMT procedure offers excellent transplant outcomes and QOL. Liver Transplantation 23 1161-1170 2017 AASLD.