GPR37 promotes colorectal cancer liver metastases by enhancing the glycolysis and histone lactylation via Hippo pathway.

Liver metastases are commonly detected in a range of malignancies including colorectal cancer (CRC), unfortunately no effectively strategies for CRC liver metastasis (CRLM). In this study, we found GPR37 expression dramatically increased in human CRLM specimens and associated poor prognosis. GPR37 depletion greatly suppressed the liver metastasis in the mouse models of CRLM. Functional experiments showed that GPR37 knockdown inhibited the growth by reducing the glycolysis of CRC cells. Also, GPR37 knockdown in tumor cells produced decreased levels of two chemokines involved in neutrophil accumulation, which abrogated neutrophil recruitment in the tumor microenvironment of CRLM. Finally, the mechanism studies revealed that GPR37 could activate the hippo pathway, thereby promoting LDHA expression and glycolysis. This leads to increased lactylation of H3K18la, resulting in up-regulation of CXCL1 and CXCL5. These results support a role of the GPR37 in modulating the tumor metabolism and microenvironment in CRLM and GPR37 could be a potential therapeutic target.

ZNF655 promotes the progression of hepatocellular carcinoma through PSMB8.

Hepatocellular carcinoma (HCC) is a type of liver cancer that is associated with high mortality rates. This study aims to investigate the role of ZNF655, a member of the zinc finger protein family, in the development of HCC. Immunohistochemical staining analysis was conducted to evaluate the expression of ZNF655 in HCC patient samples. Lentivirus-mediated ZNF655 knockdown was established in HCC cell lines (BEL-7402 and HCCLM3). The effects of ZNF655 on different aspects of HCC cell behavior such as proliferation, apoptosis, cycle, migration and tumor formation were examined. Downstream targets of ZNF655 in HCC were identified and verified through loss/gain-of-function experiments. Clinically, ZNF655 expression was elevated in HCC and increased with the severity of the disease. Functionally, inhibition of ZNF655 expression reduced the progression of HCC cells by decreasing proliferation, causing apoptosis, arresting cell cycle retention in G2, suppressing migration, and attenuating tumor formation in mice. Mechanistically, the proteasome subunit beta type-8 (PSMB8) was found to be co-expressed with ZNF655 in HCC, and PSMB8 knockdown weakened the promotion of ZNF655 overexpression on HCC. In summary, these findings suggest that ZNF655 promotes the progression of HCC through PSMB8, and inhibition of its expression may be a promising therapeutic target for HCC.

Safety and efficacy of GEMOX plus donafenib and tislelizumab as first-line therapy for advanced epithelial malignant biliary tract cancer.

AIM: This study was aimed to evaluate the safety and the efficacy of gemcitabine and oxaliplatin (GEMOX) combined with donafenib plus tislelizumab as the first-line treatment for patients with unresectable biliary tract cancer (BTC). METHODS: This is a prospective single-center exploratory study. Eligible patients (Stage III/IV BTC, at least one measurable disease according to RECIST v1.1, etc.) received gemcitabine 1000 mg/m2 IV Q3W, oxaliplatin 100 mg/m2 IV Q3W, donafenib 200 mg PO BID, and tislelizumab 200 mg IV Q3W until disease progression, unacceptable toxicity, or withdrawal of consent whichever occurred first. The primary endpoint was safety and secondary endpoints included disease control rate (DCR), objective response rate (ORR), conversion rate, and overall survival (OS). RESULTS: A total of 13 patients were enrolled. The median follow-up time was 420 days (range 345-487). The median duration of treatment was four cycles (range 1-15). The incidence of ≥Grade 3 treatment-related adverse events (TRAEs) was 53.8% and no Grade 5 TRAE. The most frequent Grade 3-4 TRAEs were rash (4/13, 30.8%), platelet count decreased (2/13, 15.4%), and fatigue (2/13, 15.4%). Tumor response was assessed in eight evaluable patients; ORR was 25.0% (95% CI, 3.2%-65.1%) and DCR 87.5% (95% CI, 47.3%-99.7%). The median PFS was 4.8 months (95% CI, 1.25-NE). Three Stage III patients underwent subsequent surgery with a conversion rate of 23.1%. The median OS was not estimable. CONCLUSIONS: GEMOX combined with donafenib plus tislelizumab as the first-line therapy for unresectable BTC showed manageable toxicity and encouraging efficacy especially in terms of promising conversion rate in Stage III patients.

LncRNA-EWSAT1 promotes hepatocellular carcinoma metastasis via activation of the Src-YAP signaling axis.

Regardless of the improvements in diagnostic and therapeutic methods, the clinical outcomes of hepatocellular carcinoma (HCC) patients remain poor. Although accumulating evidence indicates that lncRNAs (long noncoding RNAs) are essential within the control of tumorigenesis and the metastasis of cancer, the underlying mechanisms remain largely unknown. This work explored the pattern of expression and functional significance of a newly found lncRNA, Ewing sarcoma-associated transcript 1 (EWSAT1), in HCC metastasis. The results indicated that EWSAT1 was upregulated significantly in HCC relative to that in normal tissues and was correlated with an aggressive phenotype and low patient survival. Functional experiments demonstrated that EWSAT1 could promote proliferation and HCC cell metastasis both in vitro and in vivo. Mechanistically, EWSAT1 binds directly to Yes-associated protein (YAP), promotes Sarcoma gene (Src)-induced phosphorylation of YAP, facilitates nuclear translocation of YAP, and consequently, activates the transcription of Hippo-YAP signaling target genes involved in cancer evolution. This study found that EWSAT1 plays a crucial role in HCC metastasis and that it has the potential to be a prognosis biomarker and a target for therapeutics.

Development and experimental verification of a prognosis model for cuproptosis-related subtypes in HCC.

BACKGROUND: Cuproptosis is a recently discovered mechanism of programmed cell death caused by intracellular aggregation of mitochondrial lipoylated proteins and destabilization of iron-sulfur proteins triggered by copper. Hepatocellular carcinoma (HCC) is a common malignant tumor with a poor prognosis. We aimed to predict the survival of patients with HCC using the cuproptosis-related gene (CRG) expression. METHODS: We analyzed the expression, methylation, and mutation status of CRGs in 538 HCC patients and correlated the date with clinical prognosis. HCC patients were divided into two clusters based on their CRG expression. The relationship between CRGs, risk genes, and the immune microenvironment was analyzed using the CIBERSORT algorithm and the single-cell data analysis method. A cuproptosis risk model was constructed according to the five risk genes using the LASSO COX method. To facilitate the clinical applicability of the proposed risk model, we constructed a nomogram and conducted an antineoplastic drug sensitivity analysis. RESULTS: Our results suggest that the expression levels of CRGs in HCC are regulated by methylation. The prognoses were significantly different between the patients of the two clusters. The prognostic risk score positively correlated with memory T cell activation and negatively correlated with natural killer (NK) and regulatory T cell activation. CONCLUSION: Our findings indicate the involvement of CRG regulation in HCC and provide new insights into prognosis assessment. Drug sensitivity analysis predicted drug candidates for the treatment of patients with different HCC subtypes.

The Value of Laparoscopic Simultaneous Colorectal and Hepatic Resection for Synchronous Colorectal Cancer Liver Metastasis: A Propensity Score Matching Study.

Purpose: The aim of this study is to investigate the value of total laparoscopic simultaneous colorectal and hepatic resection in patients with synchronous colorectal cancer liver metastases (sCRLMs). Methods: sCRLM patients who underwent simultaneous resection from December 2014 to December 2018 in Shanghai Cancer Center, Fudan University were recruited and analyzed retrospectively. The patients were divided into laparoscopic, open, and hybrid surgery groups. The intraoperative information, postoperative short-term outcome, and long-term survival were compared among the three groups. Propensity score matching (PSM) was performed to balance baselines. Results: A total of 281 patients were recruited. After PSM, 34 patients were selected from both the laparoscopic and the open surgery group. Forty-seven patients were also selected from both the laparoscopic and the hybrid surgery group. The clinicopathologic baselines between the laparoscopic surgery group and the other two groups were well matched. All the operation-related indicators between laparoscopic surgery and hybrid surgery were similar. However, compared with open surgery, laparoscopic surgery showed significantly longer operation time (229.09 ± 10.94 min vs. 192.24 ± 9.49 min, p = 0.013) and less intraoperative blood loss [100.00 (50.00-300.00) ml vs. 200.00 (150.00-400.00) ml, p = 0.021]. For postoperative morbidity, there was no significant difference between the laparoscopic surgery group and the hybrid or the open surgery group (23.40% vs. 31.91% and 17.65% vs. 26.47%, p = 0.356 and p = 0.380). Long-term survival analysis showed that there were no significant differences in all 1-, 3-, and 5-year overall survival, liver recurrence-free survival (RFS), and whole RFS between laparoscopic surgery and hybrid surgery (p = 0.334, p = 0.286, and p = 0.558) or open surgery (p = 0.230, p = 0.348, and p = 0.450). Conclusions: Laparoscopic simultaneous resection for sCRLM shows slight advantages in surgical safety and short-term outcome, and does not compromise long-term survival.

Enhanced Recovery After Surgery in the Patients With Hepatocellular Carcinoma Undergoing Hemihepatectomy.

BACKGROUND: This study aims to compare the effectiveness and safety of enhanced recovery after surgery (ERAS) in patients with hepatocellular carcinoma (HCC) undergoing hemihepatectomy. METHODS: From January 2017 to June 2019, 54 and 56 patients were enrolled into the control and ERAS group, retrospectively. All the indicators related to operation, liver functions, and postoperative outcomes were included in the analysis. Propensity score matching (PSM) analysis identified 72 patients for further analysis. RESULTS: The clinicopathological characteristics were well-matched after PSM, and there were no significant differences in the operative duration, blood loss, blood transfusion, hospital costs, and most postoperative indicators in these 2 groups. In the ERAS group, D-dimer and fibrin degradation product values were significantly reduced (3.57 (2.874.60) µg/ml vs 4.81 (3.948.29) µg/ml and 11.90 (10.0418.02) µg/ml vs 15.80 (11.5529.24) µg/ml; P = .002 and P = .023, respectively). The days that semiliquid diet was allowed after surgery (2.00 (2.003.00) days vs 5.00 (4.006.00) days, P < .001), abdominal drainage tube indwelling duration (5.00 (4.005.00) days vs 5.00 (4.756.25) days, P = .004), and hospital stay after surgery (6.00 (6.007.00) days vs 8.00 (7.0010.00) days, P < .001) were also significantly shorter. The proportion of patients requiring analgesic treatment was significantly lower in the postoperative day 2 and day 4 (P < .001 and P = .025, respectively). The morbidity was significantly less (36.11% vs 69.44%, P = .005). CONCLUSIONS: ERAS programs are feasible and safe in HCC patients undergoing hemihepatectomy. Postoperative anticoagulant therapy may be one of the necessary steps.

Enhanced Recovery After Surgery in Patients With Hepatocellular Carcinoma Undergoing Laparoscopic Hepatectomy.

Objective: To compare the effectiveness and safety of enhanced recovery after surgery (ERAS) in patients with hepatocellular carcinoma (HCC) undergoing laparoscopic hepatectomy. Methods: From September 2016 to June 2019, 282 patients were enrolled, and ERAS was implemented since March 2018. All indicators related to surgery, liver function, and postoperative outcomes were included in the analysis. Propensity score matching (PSM) identified 174 patients for further comparison. Results: After PSM, the clinicopathological baselines were well-matched. The group showed significantly less intraoperative blood loss (100.00 [100.00-200.00] vs. 200.00 [100.00-300.00] ml, P = 0.001), fewer days before abdominal drainage tube removal (4.00 [3.00-4.00] days vs. 4.00 [3.00-5.00] days, P = 0.023), shorter hospital stay after surgery (6.00 [5.00-6.00] days vs. 6.00 [6.00-7.00] days, P < 0.001), and reduced postoperative morbidity (18.39 vs. 34.48%, P = 0.026). The proportion of patients with a pain score ≥ 4 was significantly lower in the ERAS group within the first 2 days after surgery (1.15 vs. 13.79% and 8.05 vs. 26.44%, P = 0.002 and P = 0.001, respectively). Pringle maneuver was performed more frequently in the ERAS group (70.11 vs. 18.39%, P < 0.001), and a significantly higher postoperative alanine aminotransferase level was also observed (183.40 [122.85-253.70] vs. 136.20 [82.93-263.40] U/l, P = 0.026). The 2-year recurrence-free survival was similar between the two groups (72 vs. 71%, P = 0.946). Conclusions: ERAS programs are feasible and safe and do not influence mid-term recurrence in HCC patients undergoing laparoscopic hepatectomy.

RNA sequencing analysis reveals the competing endogenous RNAs interplay in resected hepatocellular carcinoma patients who received interferon-alpha therapy.

BACKGROUND: Interferon-alpha (IFN-α) is a general therapeutic regimen to be utilized in hepatocellular carcinoma (HCC). However, regulatory mechanisms of IFN-α on competing endogenous RNAs (ceRNAs) level in anti-HCC relapse are rarely understood. METHODS: HCC patients with and without IFN-α treatment were calculated to analyze the expression profile of mRNA, long non-coding RNA (lncRNA), microRNA (miRNA), and circular RNA (circRNA) by RNA sequence, and significant differential expression (DE) of these types of RNAs were selected for further analysis. A ceRNA regulatory network was constructed to explore the potential mechanisms of IFN-α intervention on anti-HCC relapse. Finally, the potential prognostic associated genes among these DE RNAs were identified. RESULTS: Totally, 556 mRNAs, 120 circRNAs, 87 lncRNAs, and 96 miRNAs were differentially expressed in patients who received IFN-α treatment. A ceRNA regulatory network including a circRNA-miRNA-mRNA network which composed of 4 up- and 10 down-regulated circRNAs, 8 up- and 5 down-regulated miRNAs, 28 up- and 9 down-regulated mRNAs, and a lncRNA-miRNA-mRNA network which composed of 10 up- and 3 down-regulated lncRNAs, 11 up- and 5 down-regulated miRNAs, 28 up- and 10 down-regulated mRNAs was constructed. Gene enrichment and pathway analysis revealed that the ceRNA network was associated with immune-related pathway and corresponding molecular function in patients who accepted IFN-α treatment. Next, we identified 3 most relevant to IFN-α treatment to HCC among these DE RNAs, namely FAM20A, IGFBP4 and MARCH3, as the prognostic associated genes for HCC. Furthermore, MARCH3 expression correlated with infiltrating levels of tumor infiltrating immune cells (TICCs) in HCC. MARCH3 expression also showed strong correlations with the gene markers of diverse immune cells in HCC. CONCLUSION: Our data discovered a novel ceRNA network in HCC patients receiving IFN-α therapy, which might lay the foundation for better understand the regulatory mechanism of IFN-α treatment.

Long noncoding RNA MALAT1 sponging miR-26a-5p to modulate Smad1 contributes to colorectal cancer progression by regulating autophagy.

Accumulating evidences have suggested that bone morphogenetic protein (BMP)-Smad have a functional role in regulating autophagy in the development of human colorectal cancer (CRC). However, the regulatory mechanisms controlling this process remain unclear. Here, we showed that Smad1, the key effector of BMP2-Smad signaling, induces autophagy by upregulating autophagy-related gene 5 (ATG5) expression, and Smad1 binds to the proximal promoter to induce its expression. Moreover, BMP2 induces autophagy in CRC. Overexpression of Smad1 promotes tumorigenesis and migration of CRC cells, and knockdown of ATG5 is able to rescue the Smad1-induced promotion of CRC proliferation and migration partially. Mechanistically, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) may act as a competing endogenous RNA by binding with miR-26a-5p competitively and thus modulating the de-repression of downstream target Smad1. Furthermore, clinical analysis results show that Smad1 is positively correlated with MALAT1 and negatively correlated with miR-26a-5p in CRC samples. In conclusion, our results demonstrated that Smad1 may serve as an oncogene in CRC through autophagy.

Prognostic alternative splicing regulatory network of RBM25 in hepatocellular carcinoma.

RNA-binding motif protein 25 (RBM25) is a poorly characterized RNA-binding protein that is involved in several biological processes and regulates the proliferation and metastasis of tumor cells. The regulatory role of RBM25 in hepatocellular carcinoma (HCC) is unknown. Here, RBM25 expression and outcomes in HCC patients were evaluated using The Cancer Genome Atlas database. RBM25 was overexpressed in HCC patients compared with the healthy group. The high expression of RBM25 in tumor tissues was significantly related to poor overall survival (P<0.001). Overexpression of RBM25 significantly contributed to poorer survival in male patients and N0 stage patients (P<0.001). Spearman analysis and weighted gene co-expression network analysis identified 694 RBM25-related genes. Protein-protein interaction network analysis revealed the Cluster with the highest score, which positively correlated with RBM25. CDCA5 and INCENP were identified as the core functional genes related to RBM25. The overexpression of CDCA5 and INCENP in HCC patients was examined using the Human Protein Atlas database. The findings collectively indicated that RBM25 may interact with CDCA5 and INCENP to regulate HCC. Our detailed characterization of RBM25 protein interactions and related core functional genes provides a basis for further studies aimed at identifying molecular regulatory pathways or splicing events.

LRP1B or TP53 mutations are associated with higher tumor mutational burden and worse survival in hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is one of the most leading causes of cancer-related mortality worldwide. Immune checkpoint inhibitors (ICIs) have been proved to be beneficial for advanced HCC. Tumor mutational burden (TMB) is an important predictor for efficacy of ICIs. However, the genetic landscape of Chinese HCC patients and the association between TMB and frequently mutated genes of HCC remain unclear. Methods: Whole-exome sequencing data of 369 liver tumors from the Cancer Genome Altas (TCGA) and next generation sequencing (NGS) data of 657 liver tumors from Chinese clinical dataset were included. Results: TP53 (61.8%) was the most frequently mutated gene in the Chinese cohort, followed by CTNNB1 (17.2%), RB1 (13.7%), and LRP1B (12.3%). The PI3K-Akt signaling (11.2%), the Rap1 signaling (8.1%), and Ras signaling (7.7%), were significantly mapped. LRP1B mutations were significantly associated with higher TMB in both TCGA cohort (P = 0.0003) and Chinese cohort (P = 0.0005). And TP53 mutations were also associated with higher TMB in the TCGA and Chinese cohort (P = 0.0005 and 0.0010, respectively). Prognosis analysis performed in TCGA cohort revealed LRP1B mutations were significantly associated with shorter overall survival (OS, median, 20.9 vs 61.7 months; HR, 2.22; P = 0.0012). TP53 mutation was an independent risk factor affecting both OS (HR 1.58, P = 0.0109) and PFS (HR 1.59, P = 0.0027). Conclusions: The results suggest that LRP1B or TP53 mutations are associated with higher TMB and a poor prognostic factor in HCC.

Prognostic value of resection margin length after surgical resection for intrahepatic cholangiocarcinoma.

BACKGROUND: The definition and prognostic value of a wide resection margin remains controversial. The aim of this study was to assess the relevance of resection margin length for survival following intrahepatic cholangiocarcinoma (ICC) resection. METHODS: Patients scheduled for curative resection for ICC between 2015 and 2018 were identified from an institutional database. Demographic data, pathological margin length, and oncologic outcomes were collected and analyzed. RESULTS: This study included 126 patients, of whom 78% underwent anatomical hepatectomy. The resection margin was <0.5, <1.0, and <1.5 cm in 73 (60%), 92 (73%), and 109 (87%) patients, respectively. A resection margin ≥1.0 cm was associated with favorable overall survival (OS) (HR: 0.403; 95% CI: 0.191-0.854; P = 0.018) and recurrence-free survival (RFS) (HR: 0.436; 95% CI: 0.232-0.817; P = 0.010). In the anatomical hepatectomy group, a resection margin ≥1.0 cm was an independent predictor of superior OS (HR: 0.451; 95% CI: 0.208-0.977; P = 0.043) and RFS (HR: 0.470; 95% CI: 0.242-0.914; P = 0.026). CONCLUSIONS: A resection margin ≥1.0 cm was associated with significantly improved survival in ICC. Therefore, a clear margin of at least 1.0 cm should be achieved during ICC resection.

Comprehensive molecular profiling of intrahepatic cholangiocarcinoma in the Chinese population and therapeutic experience.

BACKGROUND: The genomic alterations of intrahepatic cholangiocarcinoma (ICC) in the Chinese population have not been fully revealed. Molecular profiling may provide a reference for clinical management, especially targeted therapy. METHODS: A retrospective study was conducted in 122 ICC patients. All patients' samples underwent next-generation sequencing (NGS), which analyzed 417 genes. The genetic characteristics, clinical management and therapeutic responses were analyzed. RESULTS: The most commonly mutated genes were TP53 (34%), KRAS (25%) and ARID1A (17%). Targeted agents were used referring to molecular profiling, in combination with chemotherapy. Twenty-two patients with wild-type KRAS/NRAS/BRAF were treated with cetuximab. The disease control and response rates were 78% and 47%, respectively, which were higher than those achieved with chemotherapy alone (72% and 11%, P = 0.16). Fifty-four patients underwent anti-VEGF treatment with bevacizumab. The disease control and response rates were 85% and 60%, respectively. Better therapeutic efficiency (P = 0.001) and longer progression-free survival (PFS) were observed in the bevacizumab-treated group compared to chemotherapy alone group (15.4 and 6.7 months, respectively; P = 0.04). The PFS of ten patients who underwent hepatectomy after combined treatment with chemotherapy and bevacizumab was longer than that of 139 patients who underwent surgical treatment (28.9 vs 18.0 months, P = 0.03). Two patients (1.6%) had signatures of microsatellite instability (MSI-H), and both benefited from immunotherapy. CONCLUSIONS: This study provides an overview of genetic alterations in Chinese ICC patients and indicates the potential clinical implications for NGS-based personalized therapies.

Enhanced recovery after surgery program in the patients undergoing hepatectomy for benign liver lesions.

BACKGROUND: Enhanced recovery after surgery (ERAS) has shown effectiveness in terms of reducing the hospital stay and cost. However, the benefit of ERAS in patients undergoing hepatectomy for benign liver lesions is still unclear. METHODS: ERAS was implemented in our center since March 1st, 2018. From September 2016 to February 2018, 109 patients were enrolled into the control group, and from March 2018 to June 2019, 124 patients were enrolled into the ERAS group. All the indicators related to operation, liver functions, and postoperative outcomes were included in the analysis. RESULTS: The clinicopathologic baselines were similar in these two groups. A significantly higher proportion of patients underwent laparoscopic surgery in the ERAS group. On the whole, intraoperative blood loss (100.00 mL vs. 200.00 mL, P < 0.001), blood transfusion (3.23% vs. 10.09%, P = 0.033), total bilirubin (17.10 µmol/L vs. 21.00 µmol/L, P = 0.041), D-dimer (2.08 µg/mL vs. 2.57 µg/mL, P = 0.031), postoperative hospital stay (5.00 d vs. 6.00 d, P < 0.001), and postoperative morbidity (16.13% vs. 32.11%, P = 0.008) were significantly shorter or less in the ERAS group than those in the control group. After stratified by operation methods, ERAS group showed significantly shorter postoperative hospital stay in both open and laparoscopic operation (both P < 0.001). In patients underwent open surgery, ERAS group demonstrated significantly shorter operative duration (131.76 ± 8.75 min vs. 160.73 ± 7.23 min, P = 0.016), less intraoperative blood loss (200.00 mL vs. 450.00 mL, P = 0.008) and less postoperative morbidity (16.00% vs. 44.44%, P = 0.040). CONCLUSIONS: ERAS program may be safe and effective for the patients underwent hepatectomy, especially open surgery, for benign liver lesions.

Predictive Value of Intraoperative Indocyanine Green Clearance Measurement on Postoperative Liver Function After Anatomic Major Liver Resection.

BACKGROUND: The aim of this study was to evaluate the predictive value of measuring indocyanine green (ICG) clearance during intraoperative partial occlusion of liver lobes to be resected on postoperative liver function following major anatomic liver resection. METHODS: We prospectively included 46 patients, and 35 patients ultimately underwent anatomic major liver resection. ICG clearance was measured preoperatively and intraoperatively. Intraoperative ICG clearance was measured immediately after selective occlusion of hepatic arterial, portal, and hepatic venous blood flow to the liver lobes to be resected. The albumin-bilirubin (ALBI) grade, albumin-indocyanine green evaluation (ALICE) grade, platelet count, remnant liver volume per kilogram of weight (RLV/kg), and future liver remnant plasma clearance rate of ICG (ICGK-FLR) were measured preoperatively. RESULTS: An intraoperative ICG retention at 15 min (I-R15) greater than 13.8% indicates transient posthepatectomy liver failure (PHLF) and Clavien-Dindo > grade I complications. Receiver operating characteristic (ROC) curve analysis revealed that the area under the curve (AUC) for predicting PHLF and Clavien-Dindo > grade I complications was 0.797 and 0.734, respectively (p = 0.001 and 0.014). Furthermore, an I-R15 greater than 22.7% indicates mid-term PHLF, and the AUC was 0.911 (p < 0.0001). The I-R15 is a better predictor of PHLF than the ALBI grade, ALICE grade, platelet count, RLV/kg, and ICGK-FLR. CONCLUSIONS: Intraoperative ICG clearance measurements during partial occlusion of blood flow accurately predict postoperative liver function and could be new criteria for determining the feasibility and safety of anatomic major liver resection.

Surgical treatment of ovarian cancer liver metastasis.

In addition to hepatocellular carcinoma, metastatic liver cancer (MLC) is another focus of hepatic surgeon. Good outcome of patients with liver metastasis (LM) from colorectal cancer or neuroendocrine tumor have been achieved. Ovarian cancer liver metastasis (OCLM) has its unique oncological characteristics and a variety of metastasis patterns, which brings a challenge to hepatic surgeon. Hepatic surgeons hold different views and techniques from gynecologists, which makes differences in the evaluation and treatment of the disease. We reviewed recent studies and, in combination with our own clinical experience, attempted to introduce the progress of surgical treatment of liver metastases from OC. In our experience, both preoperative imaging and surgical procedures are based on the assurance of R0 resection. R0 cytoreductive surgery (CRS) is the most favorable determinant for the prognosis of OC patients, and R0 liver resection (LR) is a component of R0 CRS. Gynecologists and hepatic surgeons should do their own preoperative and intraoperative evaluation for the extrahepatic and intrahepatic metastasis respectively. During the operation, regardless of the miliary nodules dissemination between the right hemidiaphragm and liver capsule, liver parenchymal infiltration (LPI) or liver parenchymal metastasis (LPM), 1-2 cm resection margin should be emphasized. For patients with liver portal lymph node metastasis (LPLNM), hepatic portal skeletonization should be performed, rather than portal lymph node dissection. The operation should be as radical as possible to ensure the patients to achieve good prognosis.

Probing the cooperative mechanism of the µ-δ opioid receptor heterodimer by multiscale simulation.

Accumulated experimental evidence indicated that G-protein coupled receptors (GPCRs) could form biologically relevant oligomers and hetero-oligomers possess different functional properties from monomers and homo-oligomers, for example, unique pharmacology. However, the urgent lack of crystal structures of the GPCR oligomers results in very limited knowledge about their structural and functional mechanisms. In this work, we utilized a multiscale simulation strategy coupled with principal component analysis, correlation analysis and a protein structure network to study the hetero-dimerization of the µ-OR and δ-OR. We probed the cooperative mechanism involved in their activations, the allosteric communication pathways, the impact of the interface and differences from the µ-OR homodimer. The result indicates that TM1-TM2-H8 is a stable interface, but some residues of TM7 also participate in the dimer interface. Similar to the homodimer, the hetero-dimerization of the two inactive receptors would enhance the constitutive activation of one subunit but weaken that of the other subunit, both presenting a negative cooperativity. However, in contrast to the homodimer, the hetero-dimerization of the active protomer with the inactive one would weaken the constitutive activation of the inactive unit but maintain the activity of the active subunit. In addition, the hetero-dimerization and the activation of one subunit could significantly alter the types and the numbers of residues participating in the allosteric pathway from the ligand-binding pocket to the G-protein region and the pathway between two subunits. Some important residues were identified, which play important roles in modulating activations and cooperativity between two subunits. The observations from this work indicate that the negative cooperativity should be a common feature for the homodimers and the heterodimers, but the cooperative results would be significantly different between them, depending on the activated extent of one subunit.

Interferon-α Combined With Herbal Compound "Songyou Yin" Effectively Inhibits the Increased Invasiveness and Metastasis by Insufficient Radiofrequency Ablation of Hepatocellular Carcinoma in an Animal Model.

OBJECTIVE: We had previously proved that insufficient radiofrequency ablation (RFA) could enhance invasiveness and metastasis of hepatocellular carcinoma (HCC) through epithelial-mesenchymal transition (EMT), which is mediated by activating ß-catenin signaling. Thus, the aim of the present study was to demonstrate whether the combined treatment of interferon-α (IFN-α) and "Songyou Yin" (SYY) minimizes the pro-metastatic effects of insufficient RFA, as well as to explore its underlying mechanism. METHODS: Insufficient RFA was performed in an orthotopic nude mice model of HCCLM3 with high metastatic potential. The effects of IFN-α, SYY, and combined IFN-α and SYY were observed in the animal model. Tumor sizes, lung metastasis, and survival time were assessed. Immunochemistry staining, real-time polymerase chain reaction, and Western blot were used to examine gene expression related to metastasis and angiogenesis in residual cancer after insufficient RFA. RESULTS: For up to 8 weeks of treatment, the combined therapy significantly decreased the residual cancer sizes, minimized the lung metastasis rate, and prolonged the survival time of nude mice, which might be due to suppression of the EMT via ß-catenin signal blockade, in addition to attenuating angiogenesis in residual cancer after insufficient RFA. CONCLUSION: IFN-α combined with SYY significantly weakened the enhanced metastatic potential of residual cancer after insufficient RFA by attenuating EMT, which is mediated through inhibiting activation of ß-catenin. In addition, decreasing angiogenesis of residual cancer might also play a certain role.

Use multiscale simulation to explore the effects of the homodimerizations between different conformation states on the activation and allosteric pathway for the µ-opioid receptor.

Recently, oligomers of G-protein coupled receptors (GPCRs) have been an important topic in the GPCR fields. However, knowledge about their structures and activation mechanisms is very limited due to the absence of crystal structures reported. In this work, we used multiscale simulations to study the effects of homodimerization between different conformation states on their activation, dynamic behaviors, and allosteric communication pathways for µ-OR. The results indicated that the dimerization of one inactive monomer with either one inactive monomer or one active one could enhance its constitutive activation. However, the conformation state of the other protomer (e.g., active or inactive) can influence the activated extent. The dimerization between the two inactive protomers leads to a negative cooperativity for their activation, which should contribute to the asymmetric activation of GPCR dimers observed in some experiments. On the other hand, for the active monomer, its dimerization with one inactive receptor could alleviate its deactivation, whereby negative and positive cooperativities can be observed between the two subunits of the dimer, depending on the different regions. Observations from protein structure network (PSN) analysis indicated that the dimerization of one inactive monomer with one active one would cause a significant drop in the number of main pathways from the ligand binding pocket to the G-protein coupled region for the inactive protomer, while the impact is minor for the active protomer. But, for the active monomer or the inactive one, its dimerization with one inactive monomer would significantly change the types of residues participating in the pathway with the highest frequency.