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According to the fibrotic characteristics of HEWL, a water-soluble stimulus-responsive AIE polymer was designed and successfully used for oligomer detection.

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.

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.

PurposeThe 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).MethodssCRLM 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.ResultsA 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).ConclusionsLaparoscopic simultaneous resection for sCRLM shows slight advantages in surgical safety and short-term outcome, and does not compromise long-term survival.

BackgroundThe survival benefit of primary and metastatic resection for patients with colorectal cancer with liver metastasis (CRLM) has been observed, but methods for discriminating which individuals would benefit from surgery have been poorly defined. Herein, a predictive model was developed to stratify patients into sub-population based on their response to surgery.MethodsWe assessed the survival benefits for adults diagnosed with colorectal liver metastasis by comparing patients with curative surgery vs. those without surgery. CRLM patients enrolled in the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015 were identified for model construction. Other data including CRLM patients from our center were obtained for external validation. Calibration plots, the area under the curve (AUC), and decision curve analysis (DCA) were used to evaluate the performance of the nomogram compared with the tumor–node–metastasis (TNM) classification. The Kaplan–Meier analysis was performed to examine whether this model would distinguish patients who could benefit from surgery.ResultsA total of 1,220 eligible patients were identified, and 881 (72.2%) underwent colorectal and liver resection. Cancer-specific survival (CSS) for the surgery group was significantly better than that for the no-surgery group (41 vs. 14 months, p < 0.001). Five factors were found associated with CSS and adopted to build the nomograms, i.e., age, T stage, N stage, neoadjuvant chemotherapy, and primary tumor position. The AUC of the CRLM nomogram showed a better performance in identifying patients who could obtain benefits in the surgical treatment, compared with TNM classification (training set, 0.826 [95% CI, 0.786–0.866] vs. 0.649 [95% CI, 0.598–0.701]; internal validation set, 0.820 [95% CI, 0.741–0.899] vs. 0.635 [95% CI, 0.539–0.731]; external validation set, 0.763 [95% CI, 0.691–0.836] vs. 0.626 [95% CI, 0.542–0.710]). The calibration curves revealed excellent agreement between the predicted and actual survival outcomes. The DCA showed that the nomogram exhibited more clinical benefits than the TNM staging system. The beneficial and surgery group survived longer significantly than the non-beneficial and surgery group (HR = 0.21, 95% CI, 0.17–0.27, p < 0.001), but no difference was observed between the non-beneficial and surgery and non-surgery groups (HR = 0.89, 95% CI, 0.71–1.13, p = 0.344).ConclusionsAn accurate and easy-to-use CRLM nomogram has been developed and can be applied to identify optimal candidates for the resection of primary and metastatic lesions among CRLM patients.

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.

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.

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. 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. 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

ImportanceSimultaneous or delayed resection of synchronous liver metastasis (SLM) with primary colorectal cancer (CRC) remains a controversial topic.ObjectiveTo investigate the outcomes of simultaneous vs delayed resection in patients with resectable SLM.Design, Setting, and ParticipantsThis comparative effectiveness research study included 1569 patients with resectable SLM who underwent curative-intent liver resection at 3 independent centers in China between January 1, 2000, to December 31, 2019. A 1:1 propensity score matching was performed. Follow-up was completed on August 31, 2021, and the data were analyzed from April 1 to 30, 2022.Main Outcomes and MeasuresPrimary outcome was the percentage of patients with at least 1 major complication within 60 days after surgery. Secondary outcomes were intraoperative and postoperative complications, overall survival (OS), and cancer-specific survival (CSS) rates.ResultsAmong the 1569 patients included, 1057 (67.4%) underwent delayed resection (719 men [68.0%] with a mean [SD] age of 57.4 [11.2] years), and 512 patients (310 men [60.5%] with a mean [SD] age of 57.1 [10.5] years) underwent simultaneous resection. Matching yielded 495 pairs of patients underwent simultaneous resection. The percentage of major perioperative complications did not differ between the simultaneous and delayed resection groups (34.1% vs 30.0%; P = .89). The OS rates were 65.2% at 3 years, 47.1% at 5 years, and 38.0% at 8 years for the delayed resection group and 78.0% at 3 years, 65.4% at 5 years, and 63.1% at 8 years for the simultaneous resection group (hazard ratio [HR], 1.42; 95% CI, 1.10-1.85, P = .003). The CSS rates were 68.3% at 3 years, 48.5% at 5 years, and 37.1% at 8 years for the delayed resection group and 79.2% at 3 years, 67.2% at 5 years, and 65.9% at 8 years for the simultaneous resection group (HR, 1.45; 95% CI, 1.14-1.98; P = .004). On subgroup analysis comparing the 2 strategies according to the KRAS sequence variation status, the OS rates (HR, 1.61; 95% CI, 1.45-2.18; P P = .003]) in the simultaneous resection group were significantly better than those in the delayed resection group in patients with KRAS wild-type tumors.Conclusions and RelevanceResults of this study suggest that complication rates did not differ when CRC and SLM were resected simultaneously and that the survival benefits of simultaneous resection were restricted to patients with KRAS wild-type tumors. Integrating molecular features into the treatment decision is a basis for accurate, individualized treatments.

Background Interferon-alpha (IFN-α) is a general therapeutic regimen to be utilized in HCC. However, regulatory mechanisms of IFN-α on competing endogenous RNAs (ceRNAs) level in HCC are rarely understood. Methods HCC patients with and without IFN-α treatment were calculated to analyze the expression profile of mRNA, lncRNA, miRNA, and circRNA by RNA sequence, and significant differential expression (DE) of these types of RNAs were screened out for the following analysis. A ceRNA regulatory network was constructed to explore effects of IFN-α intervention on HCC. Furthermore, the potential prognostic factors among these DE RNAs were identified. Results In total, 60 (0.37%) mRNAs, 23 (0.08%) circRNAs, 15 (0.11%) lncRNAs, and 23 (0.91%) 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 factors of HCC. Furthermore, MARCH3 expression was positively correlated with infiltrating levels of CD4 + T and CD8 + T cells, macrophages, neutrophils, and dendritic cells (DCs) in HCC. MARCH3 expression showed strong correlations with diverse immune marker sets 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.

Millions of patients benefit from surgery and are exposed to surgical stress. However, ample studies suggest that surgical stress contributes to tumor recurrence or distant metastases. Surgical stress suppresses CD8+ T cells (CTL) function which is vital for eliminating the malignant cells. Anti-programmed cell death 1 (PD-1) therapy is an effective and safe treatment that increases survival rate of patients with multiple cancers, however, whether anti-PD-1 therapy is able to reverse the immunosuppression following surgery remains largely unknown. Using a surgical stress mice model, we found that surgical stress reduced CD8+ T cell total numbers in the spleen and impaired CTLs function. Surgical induced CD8+ T cells had impaired anti-tumor effects in a tumor bearing models. Blockade of PD-1 with specific antibody restored CD8+ T cell numbers and secretion ability. PGE2 expression was dramatically upregulated in the postoperative serum, and anti-PD-1 together with PGE2 inhibitor restored CTLs dysfunction induced by surgery. Collectively, blockade of PD-1 with monoclonal antibody may be an effective treatment during the postoperative period for restoring surgery-induced immunosuppression.

Additional file 1: Table S1. Gene list of the 417-gene panel.

Additional file 2: Table S2. Therapeutic strategies.

Hyperglycemia-mediated reactive oxygen species (ROS) accumulation plays an important role in hyperglycemia-induced endothelial injury. Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway inhibition participates in hyperglycemia-induced ROS accumulation. Our previous study indicated that SET8 overexpression inhibits high glucose-mediated ROS accumulation in human umbilical vein endothelial cells (HUVECs). In the present study, we hypothesize that SET8 may play a major role in high glucose-induced ROS accumulation via modulation of Keap1/Nrf2/ARE pathway. Our data indicated that high glucose mediated cell viability reduction, ROS accumulation, and Nrf2/ARE signal pathway inhibition via upregulation of Keap1 expression in HUVECs. Moreover, high glucose inhibited the expressions of SET8 and H4K20me1 (a downstream target of SET8). SET8 overexpression improved high glucose-mediated Keap1/Nrf2/ARE pathway inhibition and endothelial oxidation. Consistently, the effects of sh-SET8 were similar to that of high glucose treatment and were reversed by si-Keap1. A mechanistic study found that H4K20me1 was enriched at the Keap1 promoter region. SET8 overexpression attenuated Keap1 promoter activity and its expression, while mutant SET8 R259G did not affect Keap1 promoter activity and expression. The results of this study demonstrated that SET8 negatively regulates Keap1 expression, thus participating in high glucose-mediated Nrf2/ARE signal pathway inhibition and oxidative injury in HUVECs.

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.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.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, P0.001), 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, P0.001), 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 P0.001). 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).ERAS program may be safe and effective for the patients underwent hepatectomy, especially open surgery, for benign liver lesions.

To study the modulation in number and function of endothelial progenitor cell (EPC) in multiple organ dysfunction syndrome (MODS) after trauma in swine, and to investigate its pathogenesis.Forty pigs were divided into sham group and MODS group (each, n=20). The model of MODS of "two-hit" injury, namely hemorrhagic shock and endotoxemia, was reproduced. The peripheral blood was collected before hemorrhage (T1) and endotoxin injection (T2), and 1 hour (T3), 24 hours (T4), 48 hours (T5) after endotoxin injection. Phosphorylation of p38 mitogen-activated protein kinase (p-p38MAPK ) in mononuclear cell was determined by Western Blot, the content of tumor necrosis factor-α (TNF-α) was determined with enzyme linked immunosorbent assay (ELISA), and the number of EPC was determined with flow cytometry.Model of MODS was successfully reproduced in 17 pigs. In model group, the expression of p-p38MAPK (A value) peaked at T3 (4.83±0.52), and gradually declined at T4 and T5 (4.36±0.43, 1.93±0.33), and the expression of p-p38MAPK at T3-T5 was significantly higher than that at T1 (1.00±0.22, all P0.01). The plasma concentration of TNF-α (ng/L) at T3 in MODS group was obviously elevated compared with that of sham group (532.43±52.17 vs. 129.03±20.45, t=31.163, P0.001), and it peaked at T3, it then gradually lowered, and it was significantly higher at T4 and T5 than that in sham group (T4: 398.93±35.75 vs. 131.12±29.53, t=26.562, P0.001; T5: 287.48±27.26 vs. 126.44±26.96, t=17.861, P0.001). The number of EPC (×10(7)/L) was apparently increased in MODS group at T3 compared with sham group (4.832±0.624 vs. 3.545±0.363, t=9.542, P0.001), and it peaked at T3, then gradually decreased, and the number of EPC at T4 and T5 was significantly lower than that in sham group (T4: 2.628±0.627 vs. 3.442±0.325, t=5.043, P0.001; T5: 2.203±0.711 vs. 3.471±0.323, t=2.972, P0.001).Phosphorylation of p38MAPK could increase the plasma concentration of TNF-αand decrease the quantity of EPC in MODS,which may be one of the mechanisms of MODS.