High Glucose-stimulated aPKC Activation Promotes Pancreatic Cancer Cell Progression Through YAP Signaling.

BACKGROUND/AIM: Persistent hyperglycemia caused by diabetes mellitus is a risk factor for pancreatic cancer (PC). We have previously reported that aberrant activation of atypical protein kinase C (aPKC) enhances PC cell progression. However, no reports have elucidated whether hyperglycemia promotes PC cell progression and whether aPKC activation is related to PC cell progression mechanisms. MATERIALS AND METHODS: We examined whether high-glucose stimulation accelerates PC cell proliferation, migration, and invasion. Furthermore, to determine whether PC cells activate aPKC upon high-glucose stimulation, we measured the phosphorylation of aPKC at T560 in PC cells. RESULTS: High-glucose stimulation accelerated PC cell proliferation, migration, and invasion. High-glucose treatment increased aPKC's activated form, with T560 phosphorylation, in PC cells. However, aPKC knockdown attenuated these effects. aPKC reportedly induces cell transformation through Yes-associated protein (YAP) activation. YAP expression was increased in high glucose-treated PC cells but not in aPKC-knockdown cells. aPKC interacts with partitioning defective 3 (Par-3), which aids in establishing cell polarity and inhibits aPKC by binding as a substrate. In Par-3-knockdown PC cells, YAP expression increased independently of high-glucose treatment. Over-expression of Par-3 and aPKC-dominant negative mutants prevented the high glucose-stimulated nuclear localization of YAP. YAP forms a complex with the zinc finger E-box binding homeobox 1 protein (ZEB1), an activator of epithelial-mesenchymal transition. ZEB1 expression was increased by high glucose treatment or Par-3 knockdown, but aPKC knockdown suppressed this increase. CONCLUSION: High glucose-induced aPKC activation promotes PC progression by enhancing the YAP signaling pathway.

Efficacy of indocyanine green systemic administration for bile leak detection after hepatectomy: a protocol for a prospective single-arm clinical trial with a historical control group.

INTRODUCTION: Bile leakage (BL) after hepatectomy cannot always be detected with conventional methods; moreover, BL cannot be completely prevented. Recently, navigation procedures with indocyanine green (ICG) have been reported. Furthermore, we previously reported the possibility of detecting BLs with high sensitivity during hepatectomy by administering ICG into the bloodstream, which is quickly excreted in the bile. This study aims to verify whether detecting and addressing ICG leakage from the hepatic dissection plane using an ICG camera can reduce the bilirubin concentration in the drainage fluid, and consequently, the incidence of BL. METHODS AND ANALYSIS: This prospective single-centre non-randomised single-arm trial will be conducted with historical controls. Overall, 85 patients will be enrolled, including 40 and 45 in the ICG and historical control groups, respectively. In the ICG group, 10 mg/2 mL of ICG will be transvenously or transportally administered during liver surgery. After its uptake by liver cells and excretion into bile, it will be visualised using a camera following the completion of hepatectomy, and the site of ICG leakage will be sutured. Moreover, we will record the number of bile leak spots detected by the naked eye and ICG camera. The primary endpoint of the study will be the total bilirubin concentration in the drain fluid on postoperative day 3, and we will determine whether the concentration differs significantly between the ICG and historical control groups. The results of our study will be used to suggest whether intraoperative ICG administration and evaluation at the hepatic dissection plane can be widely used in liver surgery for more reliable detection of BL and consequent reduction of biliary fistula. ETHICS AND DISSEMINATION: The protocol was approved by the Certified Review Board of Tottori University Hospital (approval number: 21C002). Findings from this trial will be published in peer-reviewed journals and presented at academic conferences. TRIAL REGISTRATION NUMBER: jRCTs061210043.

TYRO3 promotes chemoresistance via increased LC3 expression in pancreatic cancer.

Pancreatic cancer (PC) is an aggressive malignancy with few treatment options, and improved treatment strategies are urgently required. TYRO3, a member of the TAM receptor tyrosine kinase family, is a known oncogene; however, the relationship between TYRO3 expression and PC chemoresistance remains to be elucidated. We performed gain- and loss-of-function experiments on TYRO3 to examine whether it is involved in chemoresistance in PC cells. TYRO3 knockdown decreased cell viability and enhanced apoptosis following treatment of PC cells with gemcitabine and 5-fluorouracil (5-FU). In contrast, no such effects were observed in TYRO3-overexpressing PC cells. It is known that autophagy is associated with cancer chemoresistance. We then examined effects of TYRO3 on autophagy in PC cells. TYRO3 overexpression increased LC3 mRNA levels and induced LC3 puncta in PC cells. Inhibition of autophagy by chloroquine mitigated cell resistance to gemcitabine and 5-FU. In a xenograft mouse model, TYRO3 silencing significantly increased sensitivity of the cells to gemcitabine and 5-FU. To further investigate the involvement of autophagy in patients with PC, we immunohistochemically analyzed LC3 expression in the tissues of patients who underwent pancreatectomy and compared it with disease prognosis and TYRO3 expression. LC3 expression was negatively and positively correlated with prognosis and TYRO3 expression, respectively. Furthermore, LC3- and TYRO3-positive patients had a significantly worse prognosis among patients with PC who received chemotherapy after recurrence. These results indicated that the TYRO3-autophagy signaling pathway confers PC resistance to gemcitabine and 5-FU, and could be a novel therapeutic target to resolve PC chemoresistance.

Influence of the water jet system vs cavitron ultrasonic surgical aspirator for liver resection on the remnant liver.

BACKGROUND: Several methods, such as finger fracture, Pean crush, cavitron ultrasonic surgical aspirator (CUSA), and water jet (WJ), are used for hepatic parenchymal dissection in liver surgery. CUSA is the conventional method in Japan. WJ is a relatively novel method for parenchymal dissection. Although it has several advantages, such as lower volume of blood loss and shorter operative time, the effect of the WJ system for hepatic dissection on the remnant liver has not yet been investigated. AIM: To investigate and compare the effect of the WJ method vs CUSA on the remnant liver cut surface. METHODS: This observational study compared the two types of parenchymal transection methods (WJ vs CUSA) in liver surgery. In total, 24 and 40 patients who underwent hepatectomy using the WJ method and CUSA, respectively, were included in the analysis. Accordingly, the clinicopathological characteristics and clinical outcomes of 24 and 40 patients were compared. Furthermore, postoperative contrast-enhanced computed tomography (CT) scan was performed to assess the cut surface length of the remnant liver and the degenerative thickness of the areas with a reduced contrast effect in the dissected plane. Then, the two groups were compared. RESULTS: On CT scan, the median areas of denaturation in the liver dissection planes were 522 (range: 109.5-1242) mm2 in the CUSA group and 324 (range: 93.6-1529) mm2 in the WJ group. The area did not significantly differ between the two groups; however, the denaturation thickness of the WJ group was significantly lower than that of the CUSA group [5.8 (range: 0.7-11.1) mm vs 3.3 (range: 1.7-10.4) mm, P < 0.001]. CONCLUSION: The WJ group had significantly thinner contrast-enhanced areas in the post hepatectomy detached section than the CUSA group.

Modified geriatric nutritional risk index in patients with pancreatic cancer: a propensity score-matched analysis.

BACKGROUND: The modified nutritional geriatric risk index (mGNRI) was developed as a novel index and provides a more appropriate prognostic index than the original GNRI, which was reported to be a useful index for predicting prognoses for various malignancies. This study investigated the prognostic significance of the mGNRI compared with that of the GNRI in patients with pancreatic cancer and the association with psoas muscle volume (PMV) for survival outcomes. METHODS: This retrospective study included 137 patients who had undergone pancreatectomy for pancreatic cancer. The enrolled patients were grouped as high mGNRI (≥ 85.3) or low mGNRI (< 85.3), and high GNRI (≥ 92) or low GNRI (< 92) for prognostic analysis based on cutoff values. A propensity-matched analysis was performed in this study. RESULTS: The 5-year overall survival of patients in the high mGNRI group or high GNRI group was significantly longer than those in the low mGNRI group or low GNRI group. Statistically significant differences for the 5-year OS were observed in the three groups with respect to the combination of mGNRI and PMV. Patients with low mGNRI/low PMV had a worse 5-year OS rate compared with patients with high GNRI/high PMV or those with high GNRI or high PMV, but not both. The concordance index of the mGNRI to predict the 5-year overall survival was greater than that of the GNRI or the combination of the GNRI and PMV, but lower than that of the combination of the mGNRI and PMV. Multivariate analysis revealed that the mGNRI was an independent prognostic factor for patients with pancreatic cancer (P = 0.005). CONCLUSIONS: The mGNRI might be a more useful prognostic factor than the GNRI for patients with pancreatic cancer, and might predict prognostic outcomes more accurately when combined with PMV.

Geriatric nutritional risk index as a prognostic factor in patients with recurrent pancreatic cancer.

The aim of this study is to investigate the prognostic significance of geriatric nutritional risk index (GNRI) at the time of recurrence in patients with recurrent pancreatic cancer, and the relationship between GNRI and skeletal muscle mass for survival outcomes after recurrence. This study enrolled 77 patients who developed postoperative recurrence. The skeletal muscle mass index (SMI) was used in this study. The patients were divided into a high-GNRI group (n = 36) and a low-GNRI group (n = 41) for the GNRI, and were divided into a high-SMI group (n = 38) and a low-SMI group (n = 39) for SMI. The 2-year post-recurrence overall survival of patients in the high-GNRI group was significantly longer than that of patients in the low-GNRI group (P = 0.001). No significant difference for the 2-year post-recurrence OS curves between the high-SMI group and the low-SMI group was observed (P = 0.125). Upon stratifying the patients with high GNRI or low GNRI according to SMI, There was no significant difference in the 2-year post-recurrence OS curves between the patients with both high GNRI and high SMI and the patients with high GNRI and low SMI (P = 0.399). Similarly, There was no significant difference in the 2-year post-recurrence OS curves between the patients with low GNRI and high SMI and the patients with both low GNRI and low SMI (P = 0.256). Multivariate analysis revealed that the GNRI at the time of recurrence was an independent prognostic risk factor in patients with recurrent pancreatic cancer (P = 0.019). The GNRI at the time of recurrence is useful for predicting the prognosis in patients with recurrence pancreatic cancer. Skeletal muscle mass at the time of recurrence is not contributed to predict post-recurrence survival of patients with recurrent pancreatic cancer.

Molecular mechanisms underlying the promotion of wound repair by coenzyme Q10: PI3K/Akt signal activation via alterations to cell membrane domains.

Coenzyme Q10 (CoQ10) promotes wound healing in vitro and in vivo. However, the molecular mechanisms underlying the promoting effects of CoQ10 on wound repair remain unknown. In the present study, we investigated the molecular mechanisms through which CoQ10 induces wound repair using a cellular wound-healing model. CoQ10 promoted wound closure in a dose-dependent manner and wound-mediated cell polarization after wounding in HaCaT cells. A comparison with other CoQ homologs, benzoquinone derivatives, and polyisoprenyl compounds suggested that the whole structure of CoQ10 is required for potent wound repair. The phosphorylation of Akt after wounding and the plasma membrane translocation of Akt were elevated in CoQ10-treated cells. The promoting effect of CoQ10 on wound repair was abrogated by co-treatment with a phosphatidylinositol 3-kinase (PI3K) inhibitor. Immuno-histochemical and biochemical analyses showed that CoQ10 increased the localization of caveolin-1 (Cav-1) to the apical membrane domains of the cells and the Cav-1 content in the membrane-rich fractions. Depletion of Cav-1 suppressed CoQ10-mediated wound repair and PI3K/Akt signaling activation in HaCaT cells. These results indicated that CoQ10 increases the translocation of Cav-1 to the plasma membranes, activating the downstream PI3K/Akt signaling pathway, and resulting in wound closure in HaCaT cells.

Laparoscopic cholecystectomy after percutaneous transhepatic gallbladder drainage for acute cholecystitis in a patient with a left ventricle assist device: A case report and brief review of the literature (with video).

For acute cholecystitis in patients with left ventricular assist devices, the use of percutaneous transhepatic gallbladder drainage to calm inflammation before planned laparoscopic cholecystectomy may be helpful in safely adjusting anticoagulation and in performing safe laparoscopic cholecystectomy, as demonstrated in this case.

The Significance of Surgical Intervention for Metasynchronous Liver Metastasis in Gastric Cancer: A Single-centre Analysis.

BACKGROUND/AIM: This study investigated the influence of surgery for metasynchronous liver metastasis in gastric cancer on prognosis. PATIENTS AND METHODS: A retrospective study was conducted involving 21 consecutive patients with gastric cancer with metasynchronous distant metastasis only in the liver after curative gastrectomy. The patients were divided into two groups: those who underwent hepatic resection and those who did not. The clinicopathological characteristics, recurrence-free survival (RFS), overall survival (OS), and disease-specific survival (DSS) were analysed. RESULTS: Among 981 gastrectomies performed in Tottori University Hospital between 2005 and 2019, 930 were curative. Among 153 cases of recurrence during the follow-up, 21 consecutive cases involving the liver only and metasynchronous recurrent metastasis on imaging were included in this study. The study included 16 males and five females with a median age of 70 years. No statistical difference in RFS (237 vs. 201 days; p=0.788) was observed between the hepatectomy and non-hepatectomy groups; however, OS (1,564 vs. 608 days, p=0.008) and DSS (1,597 vs. 608 days, p=0.006) were significantly prolonged in the hepatectomy group. Univariate and multivariate analyses revealed that hepatectomy was the only independent prognostic factor (hazard ratio=0.33; p=0.042). CONCLUSION: Hepatic resection of heterogeneous liver metastases in gastric cancer seems to be a useful option that can be expected to cure the disease, which cannot be achieved by chemotherapy alone.

Transabdominal preperitoneal repair for an adolescent patient with Hunter syndrome: a case report.

BACKGROUND: Hunter syndrome is an X-linked disorder caused by a deficit of the lysosomal enzyme iduronate-2-sulfatase and is associated with many disorders. Patients with Hunter syndrome often develop inguinal hernias in early childhood and undergo Potts' method, laparoscopic percutaneous extraperitoneal closure (LPEC), or laparoscopic direct suture. CASE PRESENTATION: An 18-year-old male visited our hospital for evaluation of a palpable mass in the right groin hernia. Computed tomography revealed a right indirect inguinal hernia. He had a history of repeated admission to our hospital and pediatric treatments for pneumonia, heart failure, and convulsions after birth. Because he has stopped growing and a wide hernia orifice was present with no apparent hernia on the left side, we performed TAPP repair. During surgery, we noted softness of the abdominal wall, similar to children's abdominal wall, and laparoscopy revealed well-developed veins around the spermatic cord and testicular artery. The softness of the abdominal wall made insertion of the trocars difficult and well-developed veins needed our special care to avoid hemorrhage. After surgery, the patient developed a convulsion due to Hunter syndrome and subsequent aspiration pneumonia; however, he recovered with medical treatments administered in cooperation with specialists and was discharged on postoperative day 9. CONCLUSION: This is the first reported patient with Hunter syndrome whose inguinal hernia was treated by TAPP repair. TAPP repair might be a useful procedure even for adolescent patients with Hunter syndrome, although adequate care is needed for symptoms due to Hunter syndrome.