Robotic versus laparoscopic hepatectomy: A single-center, propensity score- matched study.

BACKGROUND: Although the effectiveness of robotic hepatectomy (RH) has been evaluated in several studies, the superiority of RH over other approaches has not been definitely established. Therefore, in the present propensity score-matched cohort study, we compared RH and laparoscopic hepatectomy (LH) in terms of perioperative and oncologic outcomes. METHODS: This retrospective study included patients who underwent RH or LH for benign and malignant liver lesions at a single center in Taiwan at any time between 2014 and 2020. Confounding factors, specifically age, sex, body mass index, American Society of Anesthesiologists score, IWATE criteria, and Charlson comorbidity index, were adjusted through propensity score matching (PSM). RESULTS: A total of 329 patients were finally included in this study. Two homogeneous groups (RH and LH; n, 72 each) were formed using PSM. The RH group had a longer operative time (median: 231 vs.180 min, respectively; P = .001) and lower conversion (to open surgery) rate (9.7% vs.0.0%, respectively; P = .013) than did the LH group. However, the two groups did not differ in terms of other perioperative outcomes, specifically blood loss, hospital stay, intensive care unit admission, mortality, morbidity, or tumor margin status. CONCLUSIONS: The rate of conversion to open surgery is lower in RH than in LH. Although operative time is longer in RH than in LH, RH is feasible and safe for patients with benign or malignant liver lesion. Our study also demonstrated comparable oncological results in patients with hepatocellular carcinoma between LH and RH group.

2,3,5,4'-Tetrahydroxystilbene (TG1), a Novel Compound Derived from 2,3,5,4'-Tetrahydroxystilbene-2-O-ß-D-glucoside (THSG), Inhibits Colorectal Cancer Progression by Inducing Ferroptosis, Apoptosis, and Autophagy.

BACKGROUND: Colorectal cancer (CRC) is one of the deadliest cancers worldwide and long-term survival is not guaranteed in metastatic disease despite current multidisciplinary therapies. A new compound 2,3,5,4'-Tetrahydroxystilbene (TG1), derived from THSG (2,3,5,4'-Tetrahydroxystilbene-2-O-ß-D-Glucoside), has been developed, and its anticancer ability against CRC is verified in this study. METHODS: HCT116, HT-29, and DLD-1 were treated with TG1 and the IC50 was measured using a sulforhodamine B assay. A Xenograft mouse model was used to monitor tumor growth. Apoptosis and autophagy, induced by TG1 in CRC cells, were examined. RNA-sequencing analysis of CRC cells treated with TG1 was performed to discover underlying pathways and mechanisms. RESULTS: The results demonstrated that treatment with TG1 inhibited CRC proliferation in vitro and in vivo and induced apoptotic cell death, which was confirmed by Annexin V-FITC/PI staining and Western blotting. Additionally, TG1 treatment increased the level of autophagy in cells. RNA-sequencing and GSEA analyses revealed that TG1 was associated with MYC and the induction of ferroptosis. Furthermore, the ferroptosis inhibitor Bardoxolone abrogated the cytotoxic effect of TG1 in CRC cells, indicating that ferroptosis played a crucial role in TG1-induced cytotoxicity. CONCLUSIONS: These findings suggest that TG1 might be a potential and potent compound for clinical use in the treatment of CRC by inhibiting proliferation and inducing ferroptosis through the MYC pathway.

Efficacy and safety of once-daily prolonged-release tacrolimus versus twice-daily tacrolimus in kidney transplant recipients: A meta-analysis and trial sequential analysis.

BACKGROUND: Kidney transplantation is the most important treatment for end-stage renal disease. Immunosuppressive therapies can prevent acute rejection for kidney transplant recipients. Tacrolimus is usually administered to prevent graft rejection after transplantation. Previous studies have indicated that once-daily tacrolimus may improve medication adherence. Therefore, this meta-analysis aimed to compare clinical outcomes between once-daily and twice-daily tacrolimus in de novo renal transplant patients. METHODS: Eligible studies were identified from the Cochrane Library Database, PubMed, and Embase until July 2022. Those randomized controlled trials (RCTs) evaluating once-daily versus twice-daily tacrolimus formulations in de novo renal transplantation were included. A summary risk ratio (RR) and standardized mean difference (SMD) with the 95% confidence interval (CI) were estimated using a random-effects model. RESULTS: In total, nine RCTs were included. There were no differences in biopsy-confirmed acute rejection rates between patients with once-daily and those with twice-daily tacrolimus (RR, 0.91; 95% CI, 0.73-1.13) in 12 months. Regarding renal function, there was no significant difference between the once-daily and twice-daily tacrolimus groups (SMD, -0.03; 95% CI, -0.12 to 0.07). In addition, the risk of graft failure, death, and adverse events in the first year was similar for the once-daily and twice-daily tacrolimus groups. CONCLUSION: Our major findings suggest that de novo renal transplantation recipients receiving once-daily tacrolimus immediately after transplantation have comparable efficacy and safety with those recipients who received twice-daily tacrolimus. Therefore, once-daily tacrolimus medication can be an alternative for de novo renal transplantation recipients.

Novel heavily fucosylated glycans as a promising therapeutic target in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is highly prevalent and lethal globally, and its prognosis remains unsatisfactory. Drug resistance is regarded as the main cause of treatment failure leading to tumor recurrence and metastasis. The overexpression of fucosylated epitopes, which are usually modifications of glycoproteins, was reported to occur in various epithelial cancers. However, the effects of treatments that target these antigens in colorectal cancer remain unclear. METHODS: This study investigated the expression of heavily fucosylated glycans (HFGs) in 30 clinical samples from patients with CRC and other normal human tissues. The complement-dependent cytotoxicity was explored in vitro through treatment with anti-HFG monoclonal antibody (mAb) alone or in combination with chemotherapeutic agents. In vivo inhibitory effects were also examined using a xenograft mouse model. RESULTS: Immunohistochemistry staining and western blotting revealed that HFG expression was higher in human colorectal cancer tissues than in normal tissues. In DLD-1 and SW1116 cells, which overexpress fucosylated epitopes, anti-HFG mAb produced observable cytotoxic effects, especially when it was combined with chemotherapeutic agents. The xenograft model also demonstrated that anti-HFG mAb had potent and dose-dependent inhibitory effects on colorectal tumor growth. CONCLUSIONS: As a novel cancer antigen, HFGs are a promising treatment target, and the implementation of anti-HFG mAb treatment for CRC warrants further investigation.

Galectin-1-mediated MET/AXL signaling enhances sorafenib resistance in hepatocellular carcinoma by escaping ferroptosis.

Sorafenib, a small-molecule inhibitor targeting several tyrosine kinase pathways, is the standard treatment for advanced hepatocellular carcinoma (HCC). However, not all patients with HCC respond well to sorafenib, and 30% of patients develop resistance to sorafenib after short-term treatment. Galectin-1 modulates cell-cell and cell-matrix interactions and plays a crucial role in HCC progression. However, whether Galectin-1 regulates receptor tyrosine kinases by sensitizing HCC to sorafenib remains unclear. Herein, we established a sorafenib-resistant HCC cell line (Huh-7/SR) and determined that Galectin-1 expression was significantly higher in Huh-7/SR cells than in parent cells. Galectin-1 knockdown reduced sorafenib resistance in Huh-7/SR cells, whereas Galectin-1 overexpression in Huh-7 cells increased sorafenib resistance. Galectin-1 regulated ferroptosis by inhibiting excessive lipid peroxidation, protecting sorafenib-resistant HCC cells from sorafenib-mediated ferroptosis. Galectin-1 expression was positively correlated with poor prognostic outcomes for HCC patients. Galectin-1 overexpression promoted the phosphorylation of AXL receptor tyrosine kinase (AXL) and MET proto-oncogene, receptor tyrosine kinase (MET) signaling, which increased sorafenib resistance. MET and AXL were highly expressed in patients with HCC, and AXL expression was positively correlated with Galectin-1 expression. These findings indicate that Galectin-1 regulates sorafenib resistance in HCC cells through AXL and MET signaling. Consequently, Galectin-1 is a promising therapeutic target for reducing sorafenib resistance and sorafenib-mediated ferroptosis in patients with HCC.

Cytotoxic properties of unfractionated and fractionated bromelain alone or in combination with chemotherapeutic agents in colorectal cancer cells.

BACKGROUND: Colorectal cancer (CRC) is one of the most lethal cancers worldwide. Long-term survival is not achieved in metastatic CRC despite the current multidisciplinary therapies. Bromelain, a compound extracted from the pineapple plant, has multiple functions and anticancer properties. Previously, bromelain has been chromatographically separated into four fractions. Fraction 3 (F3) exhibits the highest proteolytic activity. The anticancer effects of F3 bromelain in CRC cells is unknown. METHODS: In vitro cytotoxicity was verified through a sulforhodamine B assay. Apoptosis in CRC cells induced by unfractionated or F3 bromelain was examined using Annexin V-FITC/PI staining and Western blot analysis. ROS status, autophagy and lysosome formation were determined by specific detection kit. RESULTS: The cytotoxicity of F3 bromelain in CRC cells was found to be comparable to that of unfractionated bromelain. F3 bromelain induces caspase-dependent apoptosis in CRC cells. Treatment with unfractionated or F3 bromelain increased superoxide and oxidative stress levels and autophagy and lysosome formation. ATG5/12 and beclin-1 were upregulated, and the conversion of LC3B-I to LC3B-II was increased significantly by treatment with F3 bromelain. Treated CQ, autophagy inhibitor, with unfractionated or F3 bromelain enhances the cytotoxic effects. Finally, the combination of unfractionated and F3 bromelain with a routine chemotherapeutic agent (5-fluourouracil, irinotecan, or oxaliplatin) resulted in synergistically higher cytotoxic potency in CRC cells. CONCLUSION: Unfractionated and F3 bromelain inhibits CRC cell proliferation in vitro, and the cytotoxic effects of unfractionated bromelain are equivalent to F3 bromelain. F3 bromelain may be a potential and potent drug for clinical use due to its anticancer efficacy and high synergistic cytotoxicity when combined with a routine chemotherapeutic agent for CRC.

Chaperone-mediated autophagy degrade Dicer to promote breast cancer metastasis.

Metastasis in breast cancer usually lead to the majority of deaths on clinical patients. Accordingly, diagnosis of metastasis at the early stage in breast cancer is important to improve the prognosis. We observed that Dicer protein levels are significant decrease in highly invasive breast cancer cells and usually correlated with poor clinical outcomes. Following, we aim to clarify the molecular regulatory mechanism of this phenomenon in breast cancer to provide a new therapeutic target. In this study, we obtained that Dicer expression correlated with metastasis and invasion without affect cell stability in breast cancer cells. Importantly, we identified the regulatory mechanism of Dicer protein degradation, the chaperone-mediated autophagy (CMA)-mediated degradation that is major mechanism to decrease Dicer protein expression and lead to cancer metastasis. We discovered that heat shock cognate 71-kDa protein (Hsc70) which as a CMA-related factor interacts with the CMA-targeting motif I333A/K334A on Dicer to promote degradation through CMA. Taken together, our findings hint that Dicer highly correlated with cancer metastasis, we reveal the tumor-promoting effect of CMA-mediated Dicer degradation in breast cancer.

Organic cation transporter 2 activation enhances sensitivity to oxaliplatin in human pancreatic ductal adenocarcinoma.

Oxaliplatin, a third-generation platinum derivative, has become one of the main chemotherapeutic treatments for esophagus, gastric and colorectal cancer; however, it is still unclear the potential effectiveness for pancreatic ductal adenocarcinoma (PDAC) with gemcitabine resistance. Here, we observed that PDAC tumors have low level of organic cation transporter 2 (OCT2, also known as SLC22A2) compared with non-tumor tissues and identified that OCT2 expression is positively correlated with oxaliplatin sensitivity in PDAC cells. Treatment of OCT2 inhibitors or knockdown of OCT2 expression significantly decreased the sensitivity to oxaliplatin in PANC-1 cells. In addition, bisulfite sequencing polymerase chain reaction analysis revealed that higher methylation frequency represses OCT2 expression in gemcitabine-resistant PANC-1 (PANC-1/GR) cells. Moreover, we found that treatment of DNA methyltransferase (DNMT) inhibitors, decitabine or 5-azacytidine recover OCT2 expression and oxaliplatin sensitivity in PANC-1/GR cells, and DNMT1 level has inverse correlation with OCT2 expression in PDAC cells and tumors. Our findings jointly suggest that OCT2 expression is a potential and predictive marker for evaluating oxaliplatin sensitivity and developing alternative treatments for PDAC patients with gemcitabine resistance.

Phosphomimetic Dicer S1016E triggers a switch to glutamine metabolism in gemcitabine-resistant pancreatic cancer.

OBJECTIVE: Dicer is an enzyme that processes microRNAs (miRNAs) precursors into mature miRNAs, which have been implicated in various aspects of cancer progressions, such as clinical aggressiveness, prognosis, and survival outcomes. We previously showed that high expression of Dicer is associated with gemcitabine (GEM) resistance in pancreatic ductal adenocarcinoma (PDAC); thus, in this study, we aimed to focus on how Dicer is involved in GEM resistance in PDAC, including cancer prognosis, cell proliferation, and metabolic regulation. METHODS: We generated stable shRNA knockdown of Dicer in GEM-resistant PANC-1 (PANC-1 GR) cells and explored cell viability by MTT and clonogenicity assays. Metabolomic profiling was employed to investigate metabolic changes between parental cells, PANC-1, and PANC-1 GR cells, and further implied to compare their sensitivity to the glutaminase inhibitor, CB839, and GEM treatments. To identify putative phosphorylation site involves with Dicer and its effects on GEM resistance in PDAC cells, we further generated phosphomimetic or phosphomutant Dicer at S1016 site and examined the changes in drug sensitivity, metabolic alteration, and miRNA regulation. RESULTS: We observed that high Dicer levels in pancreatic ductal adenocarcinoma cells were positively correlated with advanced pancreatic cancer and acquired resistance to GEM. Metabolomic analysis indicated that PANC-1 GR cells rapidly utilised glutamine as their major fuel and increased levels of glutaminase (GLS): glutamine synthetase (GLUL) ratio which is related to high Dicer expression. In addition, we found that phosphomimetic Dicer S1016E but not phosphomutant Dicer S1016A facilitated miRNA maturation, causing an imbalance in GLS and GLUL and resulting in an increased response to GLS inhibitors. CONCLUSION: Our results suggest that phosphorylation of Dicer on site S1016 affects miRNA biogenesis and glutamine metabolism in GEM-resistant pancreatic cancer.

Dicer-mediated miR-200b expression contributes to cell migratory/invasive abilities and cancer stem cells properties of breast cancer cells.

Distant metastasis is the leading cause of death in patients with breast cancer. Despite considerable treatment advances, the clinical outcomes of patients with metastatic breast cancer remain poor. CSCs can self-renew, enhancing cancer progression and metastasis. Dicer, a microRNA (miRNA) processing-related enzyme, is required for miRNA maturation. Imbalanced Dicer expression may be pivotal in cancer progression. However, whether and how Dicer affects the stemness of metastatic breast cancer cells remains unclear. Here, we hypothesized that Dicer regulates the migration, invasion, and stemness of breast cancer cells. We established highly invasive cell lines (MCF-7/I-3 and MDA-MB-231/I-3) and observed that Dicer expression was conspicuously lower in the highly invasive cells than in the parental cells. The silencing of Dicer significantly enhanced the cell migratory/invasive abilities and CSCs properties of the breast cancer cells. Conversely, the overexpression of Dicer in the highly invasive cells reduced their migration, invasion, and CSCs properties. Our bioinformatics analyses demonstrated that low Dicer levels were correlated with increased breast cancer risk. Suppression of Dicer inhibited miR-200b expression, whereas miR-200b suppression recovered Dicer knockdown-induced migration, invasion, and cancer stem cells (CSCs) properties of the breast cancer cells. Thus, our findings reveal that Dicer is a crucial regulator of the migration, invasion, and CSCs properties of breast cancer cells and is significantly associated with poor survival in patients with breast cancer.

Inter-rater and intra-rater reliability of the current assessment model and tools for laparoscopic suturing.

BACKGROUND: Moorthy checklist (MC) and laparoscopic skill competency assessment tool (LS-CAT) are tools commonly used to evaluate the quality of laparoscopic suturing. The current assessment model is single measurement by multiple raters. Our aim is to examine the reliability of the current assessment model and tools. METHODS: With IRB approval, participants of three different backgrounds, namely medical students, trainees, and surgeons, were enrolled. The participants each accomplished a standardized laparoscopic suturing task. The performances were video-recorded and reviewed with LS-CAT and MC independently by three blinded raters. Intraclass correlation coefficients (ICC) were calculated for inter-rater and intra-rater reliability. RESULTS: 26 participants were enrolled, comprising 10 students, 10 trainees and 6 surgeons. In regard of inter-rater reliability, ICC values (95% CI) were 0.909 (0.768-0.961) and 0.868 (0.608-0.948) in LS-CAP and MC, respectively. For students, ICC values were 0.908 (0.682-0.976) and 0.815 (0.408-0.951) in LS-CAT and MC, respectively. For trainees, ICC values were 0.812 (0.426-0.947) and 0.717 (0.102-0.925), respectively. For surgeons, ICC values were 0.720 (0.064-0.955) and 0.868 (0.608-0.948), respectively. In regard of intra-rater reliability, ICC values of the mean scores from the three raters were 0.956 (0.905-0.980) and 0.925 (0.842-0.966) in LS-CAP and MC, respectively. CONCLUSION: LS-CAT and MC are both qualified assessment tools for laparoscopic suturing. LS-CAT is more reliable particularly for medical students and trainees. The current assessment model of single measurement by multiple raters provides excellent reliability.

Routine intraoperative cholangiography during laparoscopic cholecystectomy: application of the 2016 WSES guidelines for predicting choledocholithiasis.

BACKGROUND: Routine use of intraoperative cholangiography (IOC) during laparoscopic cholecystectomy (LC) for detecting common bile duct stones remains controversial. The 2016 World Society of Emergency Surgery (WSES) guidelines on acute calculous cholecystitis proposed a risk stratification for choledocholithiasis. Our present study aimed to (1) examine the findings of common bile duct (CBD) stones in patients underwent LC with routine use of IOC, and (2) validate the 2016 WSES risk classes for predicting choledocholithiasis. METHODS: All patients had LC with IOC routinely performed from November 2012 to December 2017 were reviewed retrospectively. Patients were classified into high-, intermediate-, and low-risk groups based on the 2016 WSES risk classes with modification. RESULTS: A total of 990 patients with LC and routine IOC were enrolled. CBD stones were detected in 197 (19.9%) patients. The rate of CBD stone detected in low-, intermediate-, high-risk groups were 0%, 14.2%, and 89.6%, respectively. Predictors as following: evidence of CBD stones on abdominal ultrasound or computed tomography, CBD diameter > 6 mm, total bilirubin > 4 mg/dL, bilirubin level = 1.8-4 mg/dL, abnormal liver biochemical test result other than bilirubin, presence of clinical gallstone pancreatitis had statistical significance between patients with and without CBD stones. Major bile duct injury was found in 4 patients (0.4%). All 4 patients had uneventful recovery after repair surgery. CONCLUSIONS: Based on our study results, the 2016 WSES risk classes for choledocholithiasis could be an effective approach for predicting the risk of choledocholithiasis. Considering its advantages for detecting CBD stones and biliary injuries, the routine use of IOC is still suggested.

A case-control study in Taiwanese cohort and meta-analysis of serum ferritin in pancreatic cancer.

Pancreatic cancer is one of the most lethal diseases which lack an early diagnostic marker. We investigated whether serum ferritin (SF) reflects risk for pancreatic cancer and potential genes that may contribute ferritin and pancreatic cancer risks. We performed a meta-analysis of relevant studies on SF and pancreatic cancer risk by searching articles in PUBMED and EMBASE published up to 1 March 2020. We also collected serum samples from Taipei Medical University Joint Biobank and compared SF levels in 34 healthy controls and 34 pancreatic cancer patients. An Oncomine database was applied as a platform to explore a series of genes that exhibited strong associations between ferritin and pancreatic cancer. Herein, we show that high levels of SF can indicate risk of pancreatic cancer, suggesting SF as the new tumor marker that may be used to help pancreatic cancer diagnosis. We also found that expressions of iron homeostasis genes (MYC, FXN) and ferroptosis genes (ALOX15, CBS, FDFT1, LPCAT3, RPL8, TP53, TTC35) are significantly altered with pancreatic tumor grades, which may contribute to differential expression of ferritin related to pancreatic cancer prognosis.

Hsa-miR-107 regulates chemosensitivity and inhibits tumor growth in hepatocellular carcinoma cells.

Hepatocellular carcinoma is a common type of liver cancer. Resistance to chemotherapeutic agents is a major problem in cancer therapy. MicroRNAs have been reported in cancer development and tumor growth; however, the relationship between chemoresistance and hepatocellular carcinoma needs to be fully investigated. Here, we treated hepatocellular carcinoma cell line (HA22T) with a histone deacetylase inhibitor to establish hepatocellular carcinoma-resistant cells (HDACi-R) and investigated the molecular mechanisms of chemoresistance in HCC cells. Although histone deacetylase inhibitor could not enhance cell death in HDACi-R but upregulation of miR-107 decreased cell viability both in parental cells and resistance cells, decreased the expression of cofilin-1, enhanced ROS-induced cell apoptosis, and dose-dependently sensitized HDACi-R to HDACi. Further, miR-107 upregulation resulted in tumor cell disorganization in both HA22T and HDACi-R in a mice xenograft model. Our findings demonstrated that miR-107 downregulation leads to hepatocellular carcinoma cell resistance in HDACi via a cofilin-1-dependent molecular mechanism and ROS accumulation.

Comparison of surgical outcomes for laparoscopic liver resection of large hepatocellular carcinomas: A retrospective observation from single-center experience.

BACKGROUND/PURPOSE: Although laparoscopic liver resection (LLR) is a common surgical procedure for hepatocellular carcinoma (HCC), its suitability for large HCCs (≥5 cm) remains controversial. This study compared surgical outcomes of open hepatectomy with LLR for large HCCs. METHODS: A total of 313 patients with HCC who underwent hepatectomy between January 2010 and June 2017 were analyzed retrospectively. Demographic data, short-term outcomes, and long-term survivals were analyzed. RESULTS: Among patients with large HCCs (n = 122), the open group (n = 85) had larger tumor sizes (10.91 ± 4.72 vs. 7.45 ± 2.95 cm; p < 0.001) and more advanced stages (stages 3/4: 71.8% vs. 45.9%; p = 0.029) than the LLR group (n = 37), while LLR group achieved less blood loss (623.24 ± 841.75 mL vs. 1091.76 ± 1004.72 mL, p = 0.014) and shorter LOS (9.00 ± 5.13 d vs. 12.82 ± 8.51 d, p = 0.013). There were no significant differences in complication and mortality rates between groups. The 5-year overall and recurrence-free survival rates between the two groups were not significantly different (p = 0.408 and 0.644 respectively). The surgical outcomes showed equal benefit of the two operation types. CONCLUSION: With sufficient surgeon experience and appropriate patient selection, LLR is a feasible treatment choice for large HCCs.

AXL is crucial for E1A-enhanced therapeutic efficiency of EGFR tyrosine kinase inhibitors through NFI in breast cancer.

AXL which is a chemosensitizer protein for breast cancer cells in response to epidermal growth factor receptor-tyrosine kinase inhibitor and suppresses tumor growth. The clinical information show nuclear factor I (NFI)-C and NFI-X expression correlate with AXL expression in breast cancer patients. Following, we establish serial deletions of AXL promoter to identify regions required for Adenovirus-5 early region 1A (E1A)-mediated AXL suppression. All of the NFI family members were extensively studied for their expression and functions in regulating AXL. Moreover, E1A post-transcriptionally downregulates AXL expression through NFI. NFI-C and NFI-X, not NFI-A and NFI-B, resulting in cell death in response to EGFR-TKI. Our finding suggests that NFI-C and NFI-X are crucial regulators for AXL and significantly correlated with poor survival of breast cancer patients.

ERK-mediated transcriptional activation of Dicer is involved in gemcitabine resistance of pancreatic cancer.

Gemcitabine has been a commonly used therapeutic agent for treatment of pancreatic cancer. In the clinic, a growing resistance to gemcitabine has been observed in patients with pancreatic cancer, and investigation of the underlying mechanism of gemcitabine resistance is urgently required. The microRNA (miRNA)-producing enzyme, Dicer, is crucial for the maturation of miRNAs, and is involved in clinical aggressiveness, poor prognosis, and survival outcomes in various cancers, however, the role of Dicer in acquired gemcitabine resistance of pancreatic cancer is still not clear. Here, we found that Dicer expression was significantly increased in gemcitabine-resistant PANC-1 (PANC-1/GEM) cells compared with parental PANC-1 cells and observed a high level of Dicer correlated with increased risk of pancreatic cancer. Suppression of Dicer obviously decreased gemcitabine resistance in PANC-1/GEM cells; consistently, overexpression of Dicer in PANC-1 cells increased gemcitabine resistance. Moreover, we identified that transcriptional factor Sp1 targeted the promoter region of Dicer and found ERK/Sp1 signaling regulated Dicer expression in PANC-1/GEM cells, as well as positively correlated with pancreatic cancer progression and suggest that targeting the ERK/Sp1/Dicer pathway has potential therapeutic value for pancreatic cancer with acquired resistance to gemcitabine.

Cryptanshinone Inhibits the Glycolysis and Inhibits Cell Migration Through PKM2/ß-Catenin Axis in Breast Cancer.

BACKGROUND: Breast cancer is one of the most prevalent gynecologic malignancies worldwide. Despite the high sensitivity in response to chemotherapy, drug resistance occurred frequently in clinical treatment. Cryptotanshinone (CTS) is a herbal medicine and has been identified as an anti-inflammatory and anti-oxidative drug. METHODS: In vitro assays, including the cell proliferation assay, colony formation assay, Western blot analysis, transwell migration/invasion assays, and cell scratch assay were used to explore the biological activities and working mechanism of CTS. Breast cancer cells were also transfected with PKM2 expressing vectors to define the molecular mechanisms involved in CTS-mediated anti-tumor activity. RESULTS: We found that CTS shows anti-proliferative effects and decreases the clonogenic ability of breast cancer cells. We also found that CTS inhibited the migration and invasion activity of MCF-7 and MDA-MB-231 cells by different analyzed methods. CTS also downregulated the levels of glycolysis-related proteins, such as PKM2, LDHA, and HK2. In addition, overexpression of PKM2 recovered CTS-mediated suppression of cell proliferation, colony formation, and cell mobility of breast cancer cells. We also found PKM2 was significantly overexpressed in tumor tissues and invasive ductal breast carcinoma compared to normal tissues and patients with high PKM2 expression had worse overall survival and metastasis-free survival outcomes. CONCLUSION: CTS inhibited the proliferation, migration, and invasion of breast cancer cells. The involved mechanism may refer to the downregulation of the PKM2/ß-catenin axis.

Long-term and short-term surgical outcomes of single-incision laparoscopic hepatectomy on anterolateral liver segments.

BACKGROUND: Laparoscopic liver resection yields improved short-term surgical outcomes, whereas the reports about clinical benefits of single-incision laparoscopic hepatectomy (SILH) are scarce. This retrospective study is to compare the surgical outcomes of SILH with those of multi-incision laparoscopic hepatectomy (MILH). METHODS: The study included 54 patients who had undergone SILH and 184 patients who had undergone MILH between January 2010 and December 2017. Short-term outcomes were compared in those of patients who underwent left lateral sectionectomy and partial hepatectomy of segment 5-6. A subgroup analysis of hepatocellular carcinoma (HCC) was also performed for long-term outcome comparisons. RESULTS: In those of patients who underwent left lateral sectionectomy, SILH group had less chronic hepatitis B (15.2 vs. 45.8%; p = 0.004), less liver cirrhosis (12.1 vs. 50.0%; p = 0.002), less tumor proximal to major vessel (6.1 vs. 29.2%; p = 0.018), shorter surgical time (113.2 ± 37.9 vs. 146.0 ± 50.5 min; p = 0.007), and shorter postoperative hospital stays (4.4 ± 1.1 vs. 5.4 ± 1.3 days; p = 0.002) compared with MILH group. In those of patients with tumor located at segment 5-6, no significant differences were observed in surgical time, blood loss, complications, and mortality. Single-incision laparoscopic partial hepatectomy was only associated with wider surgical margins (11.8 ± 7.0 vs. 5.3 ± 5.2 mm; p = 0.003). In the HCC subgroup, SILH had similar 1-, 3-, and 5-year overall survival and 1-, 3-, and 5-year recurrence-free survival rates compared with patients who had undergone MILH. CONCLUSIONS: The study demonstrates the safety and feasibility of single-incision laparoscopic liver resection for left lateral sectionectomy and partial hepatectomy for segment 5-6. In selected patients within the group and by experienced surgical team, the SILH technique results in comparable short-term surgical outcomes and long-term oncological outcomes.

Smoking as an Independent Risk Factor for Hepatocellular Carcinoma Due to the α7-Nachr Modulating the JAK2/STAT3 Signaling Axis.

BACKGROUND: Hepatocellular carcinoma (HCC) is a worldwide health problem. Currently, there is no effective clinical therapeutic strategy for HCC. Smoking is associated with several malignant diseases including cancers. EXPERIMENTAL APPROACH: However, the impact of smoking on HCC is still unresolved. Retrospectively reviewed HCC patients diagnosed between 1 January 2010 and 31 December 2015 at Taipei Medical University-Shuang Ho Hospital (Ministry of Health and Welfare). We found that smoking was associated with a poor prognosis, especially recurrence and patient survival after curative surgery using a clinicopathological analysis. RESULTS: Our univariate and multivariate analyses showed that the α7-nicotinic acetylcholine receptor (α7-nAChR) was an oncogene and risk factor for post-resection recurrence. The α7-nAChR was overexpressed in HCC tissues compared to their non-tumor counterparts. Silencing the α7-nAChR reduced the viability of HCC cells, suppressed cellular proliferation, attenuated migration and invasion, and diminished the tumor's sphere-formation ability, with concurrent downregulation of expression levels of the TGR5, p-JAK2, p-STAT3 (Tyr705/Ser727), RhoA, ROCK1, MMP2, and MMP9 proteins. Furthermore, a positive correlation was found between α7-nAChR and JAK2 expressions (p = 0.01) in HCC specimens, as well as their membranous co-localization. CONCLUSION: Together, we demonstrated that the α7-nAChR may be an independent prognosticator of the progression and prognosis of HCC patients. These findings suggest that the α7-nAChR drives the progression and recurrence of HCC through JAK2/STAT3 signaling and is a novel target for anti-HCC therapy.