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The recent emphasis on circadian rhythmicity in critical skin cell functions related to homeostasis, regeneration and aging has shed light on the importance of the PER2 circadian clock gene as a vital antitumor gene. Furthermore, delta-opioid receptors (DOPrs) have been identified as playing a crucial role in skin differentiation, proliferation and migration, which are not only essential for wound healing but also contribute to cancer development. In this study, we propose a significant association between cutaneous opioid receptor (OPr) activity and circadian rhythmicity. To investigate this link, we conducted a 48 h circadian rhythm experiment, during which RNA samples were collected every 5 h. We discovered that the activation of DOPr by its endogenous agonist Met-Enkephalin in N/TERT-1 keratinocytes, synchronized by dexamethasone, resulted in a statistically significant 5.6 h delay in the expression of the core clock gene PER2 . Confocal microscopy further confirmed the simultaneous nuclear localization of the DOPr-β-arrestin-1 complex. Additionally, DOPr activation not only enhanced but also induced a phase shift in the rhythmic binding of β-arrestin-1 to the PER2 promoter. Furthermore, we observed that β-arrestin-1 regulates the transcription of its target genes, including PER2 , by facilitating histone-4 acetylation. Through the ChIP assay, we determined that Met-Enkephalin enhances β-arrestin-1 binding to acetylated H4 in the PER2 promoter. In summary, our findings suggest that DOPr activation leads to a phase shift in PER2 expression via β-arrestin-1-facilitated chromatin remodeling. Consequently, these results indicate that DOPr, much like its role in wound healing, may also play a part in cancer development by influencing PER2 .

In this study, we used a compact, high-resolution, and MRI-compatible PET camera (VersaPET) to assess the feasibility of measuring the image-derived input function (IDIF) from arteries in the leg with the ultimate goal of enabling fully quantitative PET brain imaging without blood sampling. We used this approach in five 18 F-FDG PET/MRI brain studies in which the input function was also acquired using the gold standard of serial arterial blood sampling. After accounting for partial volume, dispersion, and calibration effects, we compared the metabolic rates of glucose (MRglu) quantified from VersaPET IDIFs in 80 brain regions to those using the gold standard and achieved a bias and variability of <5% which is within the range of reported test-retest values for this type of study. We also achieved a strong linear relationship (R 2 >0.97) against the gold standard across regions. The results of this preliminary study are promising and support further studies to optimize methods, validate in a larger cohort, and extend to the modeling of other radiotracers., Competing Interests: Conflicts of Interest No potential conflicts of interest relevant to this article exist.

Backgrounds/aims: As populations age, an increased incidence of colorectal cancer will generate an increase in colorectal cancer liver metastases (CRLM). In order to guide treatment decisions, this study aimed to identify the contemporary complication rates of elderly patients undergoing liver resection for CRLM in a, centralised, UK centre., Methods: All patients undergoing operative procedures for CRLM between January 2013 and January 2019 were included. Patient, tumour and operative data were analysed, including the prognostic marker; tumour burden score., Results: 339 operations were performed on 289 consecutive patients with CRLM (272 patients ＜75 years old, 67 patients ≥75 years old). Median age was 66 years (range 20-93). There was no difference in major complication rates between the two age cohorts (6.65 vs. 6.0%, p =0.847) or operative mortality (1.1% vs. 1.4%, p =0.794). Younger patients had higher R1 resection rates (20.4% vs. 4.5%, p =0.002) and post-operative chemotherapy rates (60.3% vs. 35.8%, p < 0.001). The 1, 3 and 5-year OS was 90.2%, 70.5% and 52.3% respectively, median 70 months, with no difference between age cohorts ( p =0.772). Tumour Burden score and operation type were independent predictors of overall survival., Conclusions: Liver resection for CRLM in patients 75 years and older is feasible, safe and confers a similar 5-year survival rate to younger patients. The current outcomes from surgery are better than historical datasets.

Mitchell-Riley syndrome (MRS) is caused by recessive mutations in the regulatory factor X6 gene ( RFX6 ) and is characterised by pancreatic hypoplasia and neonatal diabetes. To determine why individuals with MRS specifically lack pancreatic endocrine cells, we micro-CT imaged a 12-week-old foetus homozygous for the nonsense mutation RFX6 c.1129C>T, which revealed loss of the pancreas body and tail. From this foetus, we derived iPSCs and show that differentiation of these cells in vitro proceeds normally until generation of pancreatic endoderm, which is significantly reduced. We additionally generated an RFX6 HA reporter allele by gene targeting in wild-type H9 cells to precisely define RFX6 expression and in parallel performed in situ hybridisation for RFX6 in the dorsal pancreatic bud of a Carnegie stage 14 human embryo. Both in vitro and in vivo , we find that RFX6 specifically labels a subset of PDX1-expressing pancreatic endoderm. In summary, RFX6 is essential for efficient differentiation of pancreatic endoderm, and its absence in individuals with MRS specifically impairs formation of endocrine cells of the pancreas head and tail., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)

Background: In recent years, inflammation-based scoring systems have been reported to predict survival in Hepatocellular Carcinoma (HCC). The aim of our study was to validate combined preoperative Neutrophil-to-Lymphocyte ratio (NLR)-Platelet-to-Lymphocyte ratio (PLR) in predicting overall survival (OS) and recurrence free survival (RFS) in patients who underwent curative resection for HCC., Methods: We conducted a retrospective study of HCC patients underwent liver resection with curative intent from January 2010 to December 2013. Receiver-operating characteristic (ROC) curve analysis was used to determine the optimal cut-off values for NLR and PLR. Patients with both NLR and PLR elevated were allocated a score of 2; patients showing one or neither of these indices elevated were accorded a score of 1 or 0, respectively., Results: 132 patients with a median age of 66 years (range 18-87) underwent curative resection for HCC. Overall morbidity was 30.3%, 30-day mortality was 2.3%, and 90-day mortality was 6.8%. At a median follow-up of 24 months (range 1-88), 25% patients died, and 40.9% had recurrence. On multivariate analysis, elevated preoperative NLR-PLR was predictive of both OS (HR 2.496; CI 1.156-5.389; p =0.020) and RFS (HR 1.917; CI 1.161-3.166; p =0.011). The 5-year OS was 76% for NLR-PLR=0 group, 21.7% for the NLR-PLR=1 group, and 61.1% for the NLR-PLR=2 group, respectively. The 5-year RFS was 39.3% for the NLR-PLR=0 group, 18.4% for the NLR-PLR=1 group, and 21.1% for the NLR-PLR=2 group, respectively., Conclusion: The preoperative NLR-PLR is predictive of both OS and RFS in patients with HCC undergoing curative liver resection.

Backgrounds/aims: Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS) has generated controversy due to high morbidity and mortality. We present our series of patients with 30-40% parenchymal transection and minimal hilar dissection., Methods: Patients who had partial ALPPS between April 2015 and April 2016 were included. Patients with colorectal liver metastases (CRLM) had their future liver remnants (FLR) cleared with metastasectomies. The liver was divided along the future line of transection to 30-40%, right portal vein was stapled and divided without extensive hilar dissection, with minimal handling of right liver, which was not mobilised. We preserved the middle hepatic vein. Data were collected prospectively for hypertrophy of the FLR, morbidity and mortality., Results: Among the 8 patients (age 25-68) investigated, one patient with cholangiocarcinoma had portal vein embolization prior to partial ALPPS. All patients completed two stages with adequate FLR hypertrophy at a median of 28 days. No mortality was found. The median length of stay after stages 1 and 2 was 9 and 9.6 days, respectively. The median increase in FLR was 38%., Conclusions: A limited transection of 30-40%, minimal hilar dissection and longer wait between stages yielded adequate FLR hypertrophy with low morbidity and no mortality.

Aim: To investigate the hepatic microcirculatory changes due to Haemoxygenase (HO), effect of HO inhibition on remote ischemic preconditioning (RIPC) and modulation of CINC., Methods: Eight groups of animals were studied - Sham, ischemia reperfusion injury (IRI) the animals were subjected to 45 min of hepatic ischemia followed by three hours of reperfusion, RIPC (remote ischemic preconditioning) + IRI group, remote ischemic preconditioning in sham (RIPC + Sham), PDTC + IR (Pyridodithiocarbamate, HO donor), ZnPP + RIPC + IRI (Zinc protoporphyrin prior to preconditioning), IR-24 (45 min of ischemia followed by 24 h of reperfusion), RIPC + IR-24 (preconditioning prior to IR). After 3 and 24 h of reperfusion the animals were killed by exsanguination and samples were taken., Results: Velocity of flow (160.83 ± 12.24 μm/s), sinusoidal flow (8.42 ± 1.19) and sinusoidal perfusion index (42.12 ± 7.28) in hepatic IR were lower (P < 0.05) in comparison to RIPC and PDTC (HO inducer). RIPC increased velocity of flow (328.04 ± 19.13 μm/s), sinusoidal flow (17.75 ± 2.59) and the sinusoidal perfusion index (67.28 ± 1.82) (P < 0.05). PDTC (HO induction) reproduced the effects of RIPC in hepatic IR. PDTC restored RBC velocity (300.88 ± 22.109 μm/s), sinusoidal flow (17.66 ± 3.71) and sinusoidal perfusion (82.33 ± 3.5) to near sham levels. ZnPP (HO inhibition) reduced velocity of flow of RBC in the RIPC group (170.74 ± 13.43 μm/s and sinusoidal flow in the RIPC group (9.46 ± 1.34). ZnPP in RIPC (60.29 ± 1.82) showed a fall in perfusion only at 180 min of reperfusion. Neutrophil adhesion in IR injury is seen in both postsinusoidal venules (769.05 ± 87.48) and sinusoids (97.4 ± 7.49). Neutrophil adhesion in RIPC + IR injury is reduced in both postsinusoidal venules (219.66 ± 93.79) and sinusoids (25.69 ± 9.08) (P < 0.05). PDTC reduced neutrophil adhesion in both postsinusoidal venules (89.58 ± 58.32) and sinusoids (17.98 ± 11.01) (P < 0.05) reproducing the effects of RIPC. ZnPP (HO inhibition) increased venular (589.04 ± 144.36) and sinusoidal neutrophil adhesion in preconditioned animals (121.39 ± 30.65) (P < 0.05). IR after 24 h of reperfusion increased venular and sinusoidal neutrophil adhesion in comparison to the early phase and was significantly reduced by RIPC. Hepatocellular cell death in IRI (80.83 ± 13.03), RIPC + IR (17.35 ± 2.47), and PTDC + IR (11.66 ± 1.17) reduced hepatocellular death. ZnPP + RIPC + IR (41.33 ± 3.07) significantly increased hepatocellular death (P < 0.05 PTDC/RIPC vs ZnPP and IR). The CINC cytokine levels in sham (101.32 ± 6.42). RIPC + sham (412.18 ± 65.24) as compared to sham (P < 0.05). CINC levels in hepatic IR were (644.08 ± 181.24). PDTC and RIPC CINC levels were significantly lower than hepatic IR (P < 0.05). HO inhibition in preconditioned animals with Zinc protoporphyrin increased serum CINC levels (521.81 ± 74.9) (P < 0.05). The serum CINC levels were high in the late phase of hepatic IR (15306 ± 1222.04). RIPC reduced CINC levels in the late phase of IR (467.46 ± 26.06), P < 0.05., Conclusion: RIPC protects hepatic microcirculation by induction of HO and modulation of CINC in hepatic IR., Competing Interests: Conflict-of-interest statement: No conflict of interest.

Background: Venous thromboembolism (VTE) is a condition that has always been perceived to be rare in Asia. The aim of this systematic review was to gather the current available evidence on the incidence of VTE in this population. A secondary aim was to assess the efficacy of pharmacological prophylaxis, and hence determine its role, in the Asian population., Methods: A comprehensive literature search was performed using MEDLINE, Embase, and the Cochrane Database of Systematic Reviews in June 2014. Articles found using search terms related to venous thromboembolism (VTE), Asian countries and general surgery procedures and pathologies were screened using the following inclusion criteria: (1) either the population studied was primarily Asian or the study was conducted in an Asian country, (2) the subjects studied underwent a major gastrointestinal or other general surgery procedure, (3) the primary outcome was the incidence of deep vein thrombosis (DVT) or pulmonary embolus (PE), and (4) secondary outcomes assessed included mortality and complications due to the VTE or prophylaxis against VTE., Results: Fourteen publications with a total of 11,218 patients were analyzed. Nine of the fourteen were observational studies, with half being prospective in nature. There were five interventional studies of which two were randomized controlled trials. Among the observational studies, the median (range) incidence of above-knee DVT was 0.08 % (0-2.9 %), while the median (range) incidence of PE was 0.18 % (0-0.58 %). The rates of DVT in the control groups were reported to be between 0 and 7.4 %, while the incidence of PE in the control groups ranged from 0 to 1.9 %. Analysis of the comparative studies revealed that the incidence of bleeding-related complications varied from 0 to 18.1 % in the low-molecular-weight heparin (LMWH) group compared to 0-7.5 % in the control group. The difference in minor bleeding complications between the LMWH group and the control group was found to be statistically significant., Conclusion: Data from this systematic review suggest that the risk of VTE in Asian general surgery patients is low, even in the context of risk factors typically regarded as high risk.

Background:   Remote ischaemic preconditioning (RIPC) is a novel method of protecting the liver from ischaemia-reperfusion (I-R) injury. Protective effects in the early phase (4-6 h) have been demonstrated, but no studies have focused on the late phase (24 h) of hepatic I-R. This study analysed events in the late phase of I-R following RIPC and focused on the microcirculation, inflammatory cascade and the role of cytokine-induced neutrophil chemoattractant-1 (CINC-1)., Methods:   A standard animal model was used. Remote preconditioning prior to I-R was induced by intermittent limb ischaemia. Ischaemia was induced in the left and median lobes of the liver (70%). The animals were recovered after 45 min of liver ischaemia. At 24 h, the animals were re-evaluated under anaesthesia. Hepatic microcirculation, sinusoidal leukocyte adherence and hepatocellular death were assessed by intravital microscopy, hepatocellular injury by standard biochemistry and serum CINC-1 by enzyme-linked immunosorbent assay (ELISA)., Results:   At 24 h post I-R, RIPC was found to have improved sinusoidal flow by increasing the sinusoidal diameter. There was no effect of preconditioning on the velocity of red blood cells, by contrast with the early phase of hepatic I-R. Remote ischaemic preconditioning significantly reduced hepatocellular injury, neutrophil-induced endothelial injury and serum CINC-1 levels., Conclusions:   Remote ischaemic preconditioning is amenable to translation into clinical practice and may improve outcomes in liver resection surgery and transplantation., (© 2011 International Hepato-Pancreato-Biliary Association.)

Background: The optimal treatment for patients with suspected biliary dyskinesia is controversial. Some studies found that cholecystectomy produced symptomatic improvement in patients with gallbladder dyskinesia (diagnosed by low gallbladder ejection fraction) while others found no significant benefit. Some studies have shown that gallbladder ejection fraction can discriminate patients who would benefit from cholecystectomy. Other studies have not confirmed this., Objectives: The aim of this review was to compare the benefits and harms of cholecystectomy for patients with suspected gallbladder dyskinesia., Search Strategy: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded until March 2008., Selection Criteria: We considered for inclusion all randomised clinical trials comparing cholecystectomy versus no cholecystectomy on patients with gallbladder dyskinesia., Data Collection and Analysis: We collected the data on the characteristics, methodological quality, mortality, number of patients in whom symptoms were improved or cured from the one identified trial. We planned to analyse the data using the fixed-effect and the random-effects models using RevMan Analysis. For each outcome we planned to calculate the risk ratio (RR) with 95% confidence intervals based on intention-to-treat analysis., Main Results: We included one trial with 21 patients randomised: 11 to cholecystectomy and 10 to control (no cholecystectomy). This trial was considered to be of high risk of bias as patients were not blinded and the procedure-related morbidity was not reported. There was no mortality in either group. All patients in the cholecystectomy group and only one patient in the control group had improvement in symptoms (P = 0.0001) after a mean follow-up period of 33.6 months., Authors' Conclusions: The evidence for the benefits and harms of cholecystectomy in gallbladder dyskinesia from randomised clinical trials is based on a single small trial at risk of bias. Further randomised clinical trials with improved bias control are necessary to confirm or reject the promising results.

Background: Although day-case elective laparoscopic cholecystectomy can save bed costs, its safety remains to be established., Objectives: To assess the safety and benefits of day-case surgery compared to overnight stay in patients undergoing elective laparoscopic cholecystectomy., Search Strategy: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded until April 2008 for identifying randomised trials using search strategies., Selection Criteria: Only randomised clinical trials, irrespective of language, blinding, or publication status, comparing day-case and overnight stay in elective laparoscopic cholecystectomy were considered for the review., Data Collection and Analysis: We collected the data on the characteristics of the trial, methodological quality of the trials, morbidity, prolonged hospitalisation, re-admissions, pain and quality of life from each trial. We analysed the data with both the fixed-effect and the random-effects models using RevMan Analysis. For each outcome we calculated the risk ratio, weighted mean difference, or standardised mean difference with 95% confidence intervals (CI) based on available case-analysis., Main Results: Five trials with 429 patients randomised to the day-case group (215) and overnight stay group (214) were included in the review. All the trials were of high risk of bias. The trials recruited 49% of patients undergoing cholecystectomy. The selection criteria varied, but most included only patients without other diseases. The patients were living in easy reach of the hospital and with a responsible adult to take care of them. On the day of surgery, 81% of day-case patients were discharged. The drop-out rate after randomisation varied from 6.5% to 12.7%. There was no significant difference between day-case and overnight stay group as regards to morbidity, prolongation of hospital stay, re-admission rates, pain, quality of life, patient satisfaction and return to normal activity and work., Authors' Conclusions: Day-case elective laparoscopic cholecystectomy seems to be a safe and effective intervention in selected patients (with no or minimal systemic disease and within easy reach of the hospital) with symptomatic gallstones. Because of the decreased hospital stay, it is likely to save costs.

Background: Although day-case laparoscopic cholecystectomy can save bed costs, its safety has to be established. The aim of this meta-analysis is to assess the advantages and disadvantages of day-case surgery compared with overnight stay in patients undergoing elective laparoscopic cholecystectomy., Methods: Randomized clinical trials addressing the above issue were identified from The Cochrane Library trials register, Medline, Embase, Science Citation Index Expanded and reference lists. Data were extracted from these trials by two independent reviewers. For each outcome the relative risk, weighted mean difference or standardized mean difference was calculated with 95 per cent confidence intervals based on available case analysis., Results: Five trials with 215 patients randomized to the day-case group and 214 to the overnight-stay group were included in the review. Four of the five trials were of low risk of bias. The trials recruited 49.1 per cent of patients presenting for cholecystectomy. There was no significant difference between day case and overnight stay with respect to morbidity, prolongation of hospital stay, readmission rates, pain, quality of life, patient satisfaction, and return to normal activity and work. In the day-case group 80.5 per cent of patients were discharged on the day of surgery., Conclusion: Day-case laparoscopic cholecystectomy is a safe and effective treatment for symptomatic gallstones., (2008 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.)

Background: Although day-case elective laparoscopic cholecystectomy can save bed costs, its safety remains to be established., Objectives: To assess the safety and benefits of day-case surgery compared to overnight stay in patients undergoing elective laparoscopic cholecystectomy., Search Strategy: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded until February 2007 for identifying randomised trials using search strategies., Selection Criteria: Only randomised clinical trials, irrespective of language, blinding, or publication status, comparing day-case and overnight stay in elective laparoscopic cholecystectomy were considered for the review., Data Collection and Analysis: We collected the data on the characteristics of the trial, methodological quality of the trials, morbidity, prolonged hospitalisation, re-admissions, pain and quality of life from each trial. We analysed the data with both the fixed-effect and the random-effects models using RevMan Analysis. For each outcome we calculated the relative risk, weighted mean difference, or standardised mean difference with 95% confidence intervals (CI) based on available case-analysis., Main Results: Five trials with 429 patients randomised to the day-case group (215) and overnight stay group (214) were included in the review. Four of the five trials were of low risk of bias regarding randomisation and follow up, but all lacked blinding. The trials recruited 49% of patients undergoing cholecystectomy. The selection criteria varied, but most included only patients without other diseases. The patients were living in easy reach of the hospital and with a responsible adult to take care of them. On the day of surgery, 81% of day-case patients were discharged. The drop-out rate after randomisation varied from 6.5% to 12.7%. There was no significant difference between day-case and overnight stay group as regards to morbidity, prolongation of hospital stay, re-admission rates, pain, quality of life, patient satisfaction and return to normal activity and work., Authors' Conclusions: Day-case elective laparoscopic cholecystectomy seems to be a safe and effective intervention in selected patients (with no or minimal systemic disease and within easy reach of the hospital) with symptomatic gallstones. Because of the decreased hospital stay, it is likely to save costs.

Purpose: To compare endovascular (EVR) to open repair (OR) of abdominal aortic aneurysm (AAA) for cytokine activation, changes in the intestinal mucosal barrier, and renal dysfunction., Methods: In a prospective nonrandomized study, 15 patients admitted to a university hospital for elective infrarenal AAA repair (8 OR and 7 EVR) were recruited. Intestinal permeability was assessed preoperatively (PO), at day 1 (D1), and at day 3 (D3) after surgery using the lactulose/mannitol differential excretion (LMR) test. Renal damage was assessed from measurements of the urinary albumin:creatinine ratio (ACR); cytokine activation was based on the urinary concentration of tumor necrosis factor receptor p55 (TNF-Rp55) at the same time points. Serum creatinine and urea concentrations were measured preoperatively and daily for 5 days postoperatively., Results: A significant increase in LMR was found in the OR group at D1 and D3 compared to PO (p<0.05). The LMR increase at D3 was significantly greater in the OR group (p<0.01). A significant difference was observed in the percentage rise in ACR on D1 in the OR group compared to the EVR group (p<0.005). The urinary TNF-Rp55 concentration was significantly elevated in the OR group at D1 (p<0.05) and D3 (p<0.05) compared to baseline; in the EVR group, it was elevated at D1 (p<0.05) compared to PO. The difference was also significant for this marker between the 2 groups at D1 (p<0.01). No significant change was observed in the serum creatinine or urea concentrations in either group perioperatively., Conclusions: Endovascular AAA repair is associated with less cytokine production and less intestinal and renal dysfunction compared to the open approach.