KDM5B promotes SMAD4 loss-driven drug resistance through activating DLG1/YAP to induce lipid accumulation in pancreatic ductal adenocarcinoma.

Inactivated suppressor of mothers against decapentaplegic homolog (SMAD) 4 significantly affects cancer development in pancreatic ductal adenocarcinoma (PDAC). However, the contribution of smad4 loss to drug resistance in PDAC is largely undetermined. In the present study, we reported that the loss of SMAD4 endows PDAC cells the ability to drug resistance through upregulating histone lysine demethylase, Lysine-Specific Demethylase 5B (KDM5B, also known as JARID1B or PLU1). Upregulated KDM5B was found in PDAC, associated with poor prognosis and recurrence of PDAC patients. Upregulated KDM5B promotes PDAC tumor malignancy, i.e. cancer cells stemness and drug resistance in vitro and in vivo, while KDM5B knockout exerts opposite effects. Mechanistically, loss of Smad4-mediated upregulation of KDM5B promotes drug resistance through inhibiting the discs-large homolog 1 (DLG1), thereby facilitating nuclear translocation of YAP to induce de novo lipogenesis. Moreover, m6A demethylase FTO is involved in the upregulation of KDM5B by maintaining KDM5B mRNA stability. Collectively, the present study suggested FTO-mediated KDM5B stabilization in the context of loss of Smad4 activate DLG1/YAP1 pathway to promote tumorigenesis by reprogramming lipid accumulation in PDAC. Our study confirmed that the KDM5B-DLG1-YAP1 pathway axis plays a crucial role in the genesis and progression of PDAC, and KDM5B was expected to become a target for the treatment of PDAC. The schematic diagram of KDM5B-DLG1-YAP pathway axis in regulating drug resistance of PDAC to gemcitabine (GEM). In the context of SMAD4 loss PDAC cells, FTO-mediated stabilization and upregulation of KDM5B promotes drug resistance through directly targeting DLG1 to promote YAP1 translocation to nucleus to induce de novo lipogenesis (DNL).

Massive extrapancreatic solid pseudopapillary neoplasm misdiagnosed as hepatic tumor: a case report and literature review.

Background: Solid pseudopapillary neoplasms (SPNs) of the pancreas are uncommon, low-malignancy neoplasms. Moreover, the occurrence of extrapancreatic SPNs is rarely encountered. Case summary: A 45-year-old female presented with a right upper abdominal mass and abdominal pain for 3 and 1 months as chief complaints, respectively. Initially, the patient was misdiagnosed with hepatocellular carcinoma based on her symptoms and results of physical and imaging examinations. Following multidisciplinary discussion and ruling out surgical contraindications, a decision was taken to proceed with surgical intervention. Interestingly, the tumor was found to originate from the retroperitoneum and had invaded the right half of the liver and the right wall of the inferior vena cava. The operation was uneventful, and the pathological findings confirmed the tumor as an extrapancreatic SPN. The patient remained asymptomatic after 15 months of follow-up. Conclusion: Surgical treatment remains the preferred option for extrapancreatic SPN. The preoperative misdiagnosis also highlights the importance of accurate diagnosis and the development of appropriate treatment strategies for liver masses.

C-reactive protein to albumin ratio predict responses to programmed cell death-1 inhibitors in hepatocellular carcinoma patients.

BACKGROUND: Over the years, programmed cell death-1 (PD-1) inhibitors have been routinely used for hepatocellular carcinoma (HCC) treatment and yielded improved survival outcomes. Nonetheless, significant heterogeneity surrounds the outcomes of most studies. Therefore, it is critical to search for biomarkers that predict the efficacy of PD-1 inhibitors in patients with HCC. AIM: To investigate the role of the C-reactive protein to albumin ratio (CAR) in evaluating the efficacy of PD-1 inhibitors for HCC. METHODS: The clinical data of 160 patients with HCC treated with PD-1 inhibitors from January 2018 to November 2022 at the First Affiliated Hospital of Guangxi Medical University were retrospectively analyzed. RESULTS: The optimal cut-off value for CAR based on progression-free survival (PFS) was determined to be 1.20 using x-tile software. Cox proportional risk model was used to determine the factors affecting prognosis. Eastern Cooperative Oncology Group performance status [hazard ratio (HR) = 1.754, 95% confidence interval (95%CI) = 1.045-2.944, P = 0.033], CAR (HR = 2.118, 95%CI = 1.057-4.243, P = 0.034) and tumor number (HR = 2.932, 95%CI = 1.246-6.897, P = 0.014) were independent prognostic factors for overall survival. CAR (HR = 2.730, 95%CI = 1.502-4.961, P = 0.001), tumor number (HR = 1.584, 95%CI = 1.003-2.500, P = 0.048) and neutrophil to lymphocyte ratio (HR = 1.120, 95%CI = 1.022-1.228, P = 0.015) were independent prognostic factors for PFS. Two nomograms were constructed based on independent prognostic factors. The C-index index and calibration plots confirmed that the nomogram is a reliable risk prediction tool. The ROC curve and decision curve analysis confirmed that the nomogram has a good predictive effect as well as a net clinical benefit. CONCLUSION: Overall, we reveal that the CAR is a potential predictor of short- and long-term prognosis in patients with HCC treated with PD-1 inhibitors. If further verified, CAR-based nomogram may increase the number of markers that predict individualized prognosis.

[Retracted] Downregulation of δ opioid receptor by RNA interference enhances the sensitivity of BEL/FU drug­resistant human hepatocellular carcinoma cells to 5­FU.

Subsequently to the publication of the above article, and a Corrigendum that was published with the intention of showing corrected data for the flow cytometric plots shown in Fig. 3 (DOI: 10.3892/mmr.2018.9415; published online on August 21, 2018), it was drawn to the Editors' attention by a concerned reader that the ß­actin agarose gel electrophoretic blots shown in Fig. 1A were strikingly similar to data appearing in different form in another article by different authors at a different research institute which had already been published elsewhere prior to this paper's submission to Molecular Medicine Reports. Owing to the fact that the contentious data had already been published else prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a satisfactory reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 13: 59­66, 2016; DOI: 10.3892/mmr.2015.4511].

Complement inhibition alleviates donor brain death-induced liver injury and posttransplant cascade injury by regulating phosphoinositide 3-kinase signaling.

Brain death (BD) donors are the primary source of donor organs for liver transplantation. However, the effects of BD on donor livers and outcomes after liver transplantation remain unclear. Here, we explored the role of complement and the therapeutic effect of complement inhibition in BD-induced liver injury and posttransplantation injury in a mouse BD and liver transplantation model. For complement inhibition, we used complement receptor 2 (CR2)-Crry, a murine inhibitor of C3 activation that specifically targets sites of complement activation. In the mouse model, BD resulted in complement activation and liver injury in donor livers and a cascade liver injury posttransplantation, mediated in part through the C3a-C3aR (C3a receptor) signaling pathway, which was ameliorated by treatment with CR2-Crry. Treatment of BD donors with CR2-Crry improved graft survival, which was further improved when recipients received an additional dose of CR2-Crry posttransplantation. Mechanistically, we determined that complement inhibition alleviated BD-induced donor liver injury and posttransplant cascade injury by regulating phosphoinositide 3-kinase (PI3K) signaling pathways. Together, BD induced donor liver injury and cascade injury post-transplantation, which was mediated by complement activation products acting on PI3K signaling pathways. Our study provides an experimental basis for developing strategies to improve the survival of BD donor grafts in liver transplantation.

Electron-transfer-based peroxymonosulfate activation on defect-rich carbon nanotubes: Understanding the substituent effect on the selective oxidation of phenols.

Nanocarbon-based persulfate oxidation technologies are promising for green elimination of phenolic pollutants. Previous studies revealed the electron transfer via defective carbon nanotube (CNTs) for selective oxidation of various phenols. However, an underlying relationship between the molecular structure of phenols and the selectivity of electron transfer-induced oxidation has not been well understood. Herein, we report that defect-rich CNTs could initiate electron-transfer regime from phenols to peroxymonosulfate (PMS), resulting in the efficient degradation of phenols. Further studies uncover a distinctive substituent group-dependent selective oxidation of phenols via the CNT-mediated electron transfer process. Specifically, the degradation rate of para-substituted phenols with electron-donating groups (e.g., -NH2 and -OCH3) is faster than those with electron-withdrawing groups (e.g., -NO2 and -COOH). For a kind of substituted phenols, the substituent position has a great influence on the phenols degradation and their degradation rates follow this sequence: para > ortho > meta -position. Besides, increasing the number of the substituent group can accelerate the degradation of substituted phenols. This study elucidates the substituent effect on the electron transfer-dominated selective oxidation of phenols for the first time, which guides the application of carbon/persulfate system for the targeted remediation of phenols-polluted wastewater.

Da Vinci robot-assisted pancreato-duodenectomy in a patient with situs inversus totalis: A case report and review of literature.

BACKGROUND: Situs inversus totalis (SIT) is an extremely rare congenital malformation characterized by mirror displacement of the thoracoabdominal organs such as the heart, liver, spleen, and stomach. Herein, we describe a patient with SIT complicated with cholangiocarcinoma who underwent successful pancreaticoduodenectomy with the assistance of a da Vinci robot. CASE SUMMARY: A 58-year-old female presented to the hospital with paroxysmal pain in her left upper abdomen, accompanied by jaundice and staining of the sclera as chief complaints. Imaging examination detected a mass at the distal end of the common bile duct, with inverted thoracic and abdominal organs. Endoscopic retrograde cholangiopancreatography forceps biopsy revealed the presence of a well-differentiated adenocarcinoma. The patient successfully underwent robotic-assisted pancreaticoduodenectomy; the operation lasted 300 min, the intraoperative blood loss was 500 mL, and there were no intraoperative and postoperative complications. CONCLUSION: SIT is not directly related to the formation of cholangiocarcinoma. Detailed preoperative imaging examination is conducive to disease diagnosis and also convenient for determining the feasibility of tumor resection. Robot-assisted pancreaticoduodenectomy for SIT complicated with cholangiocarcinoma provides a safe, feasible, minimally invasive, and complication-free alternative with adequate preoperative planning combined with meticulous intraoperative procedures.

Comparison of surgical outcomes among open, laparoscopic, and robotic pancreatoduodenectomy: a single-center retrospective study.

BACKGROUND: There is no general consensus on the feasibility and safety of robotic pancreatoduodenectomy (RPD) and whether it increases surgical risks. The purpose of this study was to assess the safety, feasibility, and rationality of RPD by comparing perioperative data among open pancreatoduodenectomy (OPD), laparoscopic pancreatoduodenectomy (LPD), and RPD performed in our center in recent years. METHODS: Clinical data of patients had undergone RPD (n = 32), LPD (n = 21), and OPD (n = 86) in The First Affiliated Hospital of Guangxi Medical University between January 2016 and June 2020 were retrospectively collected and analyzed. RESULTS: RPD required more time for operation (537.2 min vs. 441.5 min, p < 0.001) than OPD did, but less time to remove abdominal drainage tube (12.5 d vs. 17.3 d, p = 0.001). The differences between the RPD group and LPD group were interesting, as the two groups had similar operation time (537.2 min vs. 592.9 min, p = 1.000) and blood loss (482.8 ml vs. 559.5 ml, p > 0.05), but the RPD group had a higher activity of daily living score on postoperative day 3 (35.8 vs. 25.7, p = 0.0017) and a lower rate of conversion to OPD (6.5% vs. 38.1%, p = 0.011). Regarding complications, such as the postoperative pancreatic fistula, abdominal hemorrhage, intra-abdominal infection, bile leakage, reoperation, and perioperative mortality, there were no significant differences among the three groups. CONCLUSIONS: Not only is RPD feasible and reliable, it also offers significant advantages in that it improves postoperative recovery of skills needed for everyday life, has a low conversion rate to open surgery, and does not increase surgical risks.

Application of da Vinci robot and laparoscopy on repeat hepatocellular carcinoma.

Background: Repeat laparoscopic liver resection has been used safely and effectively on hepatocellular carcinoma (HCC). However, few studies have been performed on repeat HCC surgery by a da Vinci robot. This study aims to evaluate the outcomes of the patients with repeat HCC treated using a da Vinci robot or laparoscopic system at a single centre. Methods: All of the patients with repeat HCC treated using a da Vinci robotic or laparoscopic system between April 2017 and April 2020 were included in this retrospective study. Results: There were 24 patients with a mean age of 56 years who underwent da Vinci robotic or laparoscopic surgery for treatment of repeat HCC who were included in this study. The operations lasted 152 ± 25 min and 142 ± 34 min. The average intraoperative blood loss was 284 ± 89 ml and 251 ± 92 ml. The average hospitalisation stay lasted 9 ± 2 days and 9 ± 3 days. The rates at which surgeons switched to open surgery were 9% and 23%. No serious perioperative or post-operative complications were encountered. Conclusion: Da Vinci robots can provide a precise dissection of the tissue under a perfect view. It is a technically feasible procedure for less rates at which surgeons switched to open surgery on repeat HCC.

Defect-rich porous carbon with anti-interference capability for adsorption of bisphenol A via long-range hydrophobic interaction synergized with short-range dispersion force.

Wastewater features-directed design of an adsorbent is promising but challenging strategy for sustainable remediation of actual bisphenol A (BPA)-polluted water. Herein, we report that the discarded cigarette butt-derived porous carbon (AC-800) exhibit high capacity (865 mg/g), rapid reaction rate (186.9 mg/g/min) and outstanding durability for adsorption of BPA. Different from the most reported carbon-based adsorbents, quantitative structure-activity relationship studies unveil that graphitic defect plays a crucial role in the improvement of adsorptivity. Further studies illuminate that π-π interactions, electrostatic attraction and hydrogen-bond interaction play a negligible role whereas long-range hydrophobic interaction synergized with short-range dispersion force make a substantial contribution to BPA adsorption on AC-800. Benefited from this unique adsorption mechanism, AC-800 features a remarkable anti-interference capability and realizes the efficient clean-up of BPA from actual wastewater with complex backgrounds. This work sheds new light on mechanistic insight into the BPA adsorption on carbon-based materials and develops a fit-for-purpose designed adsorbent toward green remediation of practical wastewater.

Potential Difference Driving Electron Transfer via Defective Carbon Nanotubes toward Selective Oxidation of Organic Micropollutants.

Nanocarbon-based persulfate oxidation emerges as a promising technology for the elimination of organic micropollutants (OMPs). However, the nature of the active site and its working mechanism remain elusive, impeding developments of high-performance oxidative technology for water treatment practice. Here, we report that defect-rich carbon nanotubes (CNTs) exhibit a superior activity in the activation of peroxymonosulfate (PMS) for OMP oxidation. Quantitative structure-activity relationship studies combined with theoretical calculations unveil that the double-vacancy defect on CNTs may be the intrinsic active site, which works as a conductive bridge to facilitate the potential difference-dominated electron transfer from the highest occupied molecular orbital of OMPs to the lowest unoccupied molecular orbital of PMS. Based on this unique mechanism, the established CNTs@PMS oxidative system achieves outstanding selectivity and realizes the target-oriented elimination of specific OMPs in a complicated aquatic environment. This work sheds new light on the mechanism of carbocatalysis for selective oxidation and develops an innovative technology toward remediation of practical wastewater.

Correction: JARID1B promotes metastasis and epithelial-mesenchymal transition via PTEN/AKT signaling in hepatocellular carcinoma cells.

[This corrects the article DOI: 10.18632/oncotarget.3713.].

The application of Compont gel in chronic obstructive jaundice rats model.

PURPOSE: To establish a new rat model, the pathogenesis of which is closer to the clinical occurrence of chronic obstructive jaundice with liver fibrosis. METHODS: 90 SD rats were randomly divided into 3 groups. Group A common bile duct ligation, group B common bile duct injection compont and group C injection saline. The serum of three groups was extracted, and the liver function was detected by ELISA. HE staining, Masson staining and immunohistochemistry were used to detect liver pathology. RESULTS: Group B showed a fluctuant development of jaundice, obstructive degree reached a peak at 2 weeks, and decreased from 3 weeks. HA, LA and PCIII were significantly higher than control group. 3 weeks after surgery, liver tissue fibrosis occurred in group B, and a wide range of fiber spacing was formed at 5 weeks. Immunohistochemistry showed that hepatic stellate cells were more active than the control group. CONCLUSION: Intra-biliary injection of Compont gel is different from the classic obstructive jaundice animal model caused by classic bile duct ligation, which can provide an ideal rat model of chronic obstructive jaundice with liver fibrosis.

Complement C3 activation regulates the production of tRNA-derived fragments Gly-tRFs and promotes alcohol-induced liver injury and steatosis.

Complement is known to play a role in alcoholic fatty liver disease (AFLD), but the underlying mechanisms are poorly understood, thereby constraining the development of a rational approach for therapeutic intervention in the complement system. C3 deficiency has been shown to impart protective effects against ethanol-induced hepatic steatosis and inflammation. Here we demonstrate a protection effect in wild-type mice by treatment with CR2-Crry, a specific inhibitor of C3 activation. The expression of glycine transfer (t) RNA-derived fragments (Gly-tRFs) is upregulated in ethanol-fed mice and inhibition of Gly-tRFs in vivo decreases chronic ethanol feeding-induced hepatosteatosis without affecting inflammation. The expression of Gly-tRF was downregulated in C3-deficient or CR2-Crry-treated mice, but not in C5-deficient mice; Gly-tRF expression was restored by the C3 activation products C3a or Asp (C3a-des-Arg) via the regulation of CYP2E1. Transcriptome profiling of hepatic tissues showed that Gly-tRF inhibitors upregulate the expression of sirtuin1 (Sirt1) and subsequently affect downstream lipogenesis and ß-oxidation pathways. Mechanistically, Gly-tRF interacts with AGO3 to downregulate Sirt1 expression via sequence complementarity in the 3' UTR. Notably, the expression levels of C3d, CYP2E1 and Gly-tRF are upregulated, whereas Sirt1 is decreased in AFLD patients compared to healthy controls. Collectively, our findings suggest that C3 activation products contribute to hepatosteatosis by regulating the expression of Gly-tRF. Complement inhibition at the C3 activation step and treatment with Gly-tRF inhibitors may be potential and precise therapeutic approaches for AFLD.

CBX8 exhibits oncogenic properties and serves as a prognostic factor in hepatocellular carcinoma.

Polycomb group family is a class of proteins that have important roles in both physiological and pathological processes, and its family member Chromobox homolog 8 (CBX8) regulates cell differentiation, aging, and cell cycle progression in numerous carcinomas; however, the effects and underlying mechanisms of CBX8 in hepatocellular carcinoma (HCC) are rarely reported. We found that CBX8 expression in clinical HCC specimens correlates inversely with patient survival. In HCC cells, we found that enforced overexpression of CBX8 induces epithelial-mesenchymal transition, invasive migration, and stem cell-like traits, which are associated with increased tumor growth and metastasis in mice. Conversely, CBX8 silencing inhibits the aggressive phenotype of HCC cells that have high CBX8 expression. Mechanistically, CBX8 modulates H3K27me3 in the gene promoter of bone morphogenetic protein 4 (BMP4), which is associated with active BMP4 transcription and, consequently, the activation of Smads and mitogen-activated protein kinases. BMP4 expression reverses the effects of CBX8 silencing in inhibiting epithelial-mesenchymal transition, stemness, and metastasis. Our results establish CBX8 as a critical driver of HCC stem cell-like and metastatic behaviors and characterize its role in modulating BMP4 expression. These findings have implications for the targeting of CBX8 as an approach to HCC prognosis and treatment.

Lnc-PDZD7 contributes to stemness properties and chemosensitivity in hepatocellular carcinoma through EZH2-mediated ATOH8 transcriptional repression.

BACKGROUND: Hepatocellular carcinoma (HCC) with stemness features are pivotal for tumorigenesis, chemoresistance, and progression. Long non-coding RNAs have been implicated in the regulation of HCC stemness features; however, their mechanisms remain largely unknown. Here, we found that Lnc-PDZD7 is a potential oncogene. We systematically analyzed the clinical significance and mechanism of Lnc-PDZD7 in stemness and chemosensitivity regulation. METHODS: We analyzed the Lnc-PDZD7 expression levels in liver cancer tissues and cell line by qRT-PCR and In situ hybridization. Gain- and loss-of-function experiments were conducted to investigate the biological functions of Lnc-PDZD7 in stemness and chemosensitivity regulation. Bioinformatics analysis, dual-luciferase reporter assays were performed to validate that Lnc-PDZD7 competitively regulates EZH2, Moreover, chromatin immunoprecipitation assays, bisulfite genomic sequencing and Western blot were performed to evaluate the mechanisms of EZH2 repressing ATOH8. RESULTS: Lnc-PDZD7 is frequently upregulated in HCC tissues. Patients with high Lnc-PDZD7 expression had poorer prognoses and a poor response to adjuvant TACE therapy. Lnc-PDZD7 could promote stemness features and suppress the sensitivity of HCC cells to anticancer drugs in vitro and in vivo. Mechanistically, Lnc-PDZD7 functioned as a molecular sponge for miR-101, antagonizing its ability to repress EZH2 expression. Subsequently, EZH2 can further inhibit the expression of the stemness regulator ATOH8 via elevating its H3K27 trimethylation and DNA methylation. CONCLUSION: Lnc-PDZD7 promotes stemness properties and suppresses chemosensitivity though the miR-101/EZH2/ATOH8 pathway, providing new biomarkers for diagnosis and potential drug targets for HCC.

Surgery strategy of 13 cases to control bleeding from the liver on laparoscopic repeat liver resection for recurrent hepatocellular carcinoma.

INTRODUCTION: Laparoscopic repeat liver resection (LRLR) is a safe and effective treatment in recurrent hepatocellular carcinoma (rHCC) in particular patients. However, there are less reports about surgery strategy of LRLR for rHCC. The aim of this study was to perform a systematic strategy for bleeding of liver to increase the safety and feasibility of LRLR for rHCC. METHODS: In this study, a total of 13 cases of LRLR for rHCC, including 8 males and 5 females; aged 28-72 years, mean age 54 years, who were received at least one laparotomy due to HCC. We employ to block the local blood flow, ligation of the left or right hepatic artery and/or approach of Pringle according to the assessment of the degree of adhesions in the abdominal and the first hepatic portal, the location of the tumour (edge/central). RESULTS: Three cases were less adhesions, nine cases were dense adhesions but 1 case was serious adhesions. Two cases were employed to block the local blood flow, 3 cases were employed to ligation of the left or right hepatic artery and 7 cases were employed to approach of Pringle. Twelve cases were successfully completed by LRLR whereas 1 case was completed by transfer to the open resection, including massive resection in 3 cases (the diameter of resection ≥3 cm), small hepatectomy in 10 cases (the diameter of resection <3 cm), no severe perioperative complication. The average operative time was (142 ± 34) min, the average intraoperative blood loss was (251 ± 92) ml and the average post-operative hospital time was (9 ± 3) d. The mean follow-up time was 25 months. Until the last follow-up, 11 cases survived while 2 cases died because of tumour recurrence. CONCLUSIONS: It can improve the safety and feasibility of LRLR for rHCC, according to the degree of adhesion of the peritoneal adhesions and the first hepatic portal, then selecting the appropriate technique to control the bleeding of the hepatectomy.