Protein kinase A antagonist inhibits β-catenin nuclear translocation, c-Myc and COX-2 expression and tumor promotion in ApcMin/+ mice

<p>Abstract</p> <p>Background</p> <p>The adenomatous polyposis coli (APC) protein is part of the destruction complex controlling proteosomal degradation of β-catenin and limiting its nuclear translocation, which is thought to play a gate-keeping role in colorectal cancer. The destruction complex is inhibited by Wnt-Frz and prostaglandin E₂(PGE₂) - PI-3 kinase pathways. Recent reports show that PGE₂-induced phosphorylation of β-catenin by protein kinase A (PKA) increases nuclear translocation indicating two mechanisms of action of PGE₂on β-catenin homeostasis.</p> <p>Findings</p> <p>Treatment of <it>Apc</it>^Min/+mice that spontaneously develop intestinal adenomas with a PKA antagonist (Rp-8-Br-cAMPS) selectively targeting only the latter pathway reduced tumor load, but not the number of adenomas. Immunohistochemical characterization of intestines from treated and control animals revealed that expression of β-catenin, β-catenin nuclear translocation and expression of the β-catenin target genes c-Myc and COX-2 were significantly down-regulated upon Rp-8-Br-cAMPS treatment. Parallel experiments in a human colon cancer cell line (HCT116) revealed that Rp-8-Br-cAMPS blocked PGE₂-induced β-catenin phosphorylation and c-Myc upregulation.</p> <p>Conclusion</p> <p>Based on our findings we suggest that PGE₂act through PKA to promote β-catenin nuclear translocation and tumor development in <it>Apc</it>^Min/+mice <it>in vivo</it>, indicating that the direct regulatory effect of PKA on β-catenin nuclear translocation is operative in intestinal cancer.</p

Cardiac dysfunction affects eye development and vision by reducing supply of lipids in fish

Developing organisms are especially vulnerable to environmental stressors. Crude oil exposure in early life stages of fish result in multiple functional and developmental defects, including cardiac dysfunction and abnormal and smaller eyes. Phenanthrene (Phe) has a reversible impact on cardiac function, and under exposure Phe reduces cardiac contractility. Exposure to a known L-type channel blocker, nicardipine hydrochloride (Nic) also disrupts cardiac function and creates eye deformities. We aimed to investigate whether cardiac dysfunction was the major underlying mechanism of crude oil-, Phe- and Nic-induced eye malformations. We exposed Atlantic haddock (Melanogrammus aeglefinus) early embryos to Nic and crude oil (Oil) and late embryos/early larvae to Phe exposure. All three exposures resulted in cardiac abnormalities and lead to severe, eye, jaw and spinal deformities at early larval stages. At 3 days post hatching, larvae from the exposures and corresponding controls were dissected. Eyes, trunk, head and yolk sac were subjected to lipid profiling, and eyes were also subjected to transcriptomic profiling. Among most enriched pathways in the eye transcriptomes were fatty acid metabolism, calcium signaling and phototransduction. Changes in lipid profiles and the transcriptome suggested that the dysfunctional and abnormal eyes in our exposures were due to both disruption of signaling pathways and insufficient supply of essential fatty acids and other nutrients form the yolk.publishedVersio

Preoperative Inflammatory Markers in Liver Resection for Colorectal Liver Metastases: A National Registry-Based Study

Background Preoperative inflammatory markers were shown to be associated with prognosis following surgery for hepato-pancreato-biliary cancer. Yet little evidence exists about their role in patients with colorectal liver metastases (CRLM). This study aimed to examine the association between selected preoperative inflammatory markers and outcomes of liver resection for CRLM. Methods Data from the Norwegian National Registry for Gastrointestinal Surgery (NORGAST) was used to capture all liver resections performed in Norway within the study period (November 2015–April 2021). Preoperative inflammatory markers were Glasgow prognostic score (GPS), modified Glasgow prognostic score (mGPS) and C-reactive protein to albumin ratio (CAR). The impact of these on postoperative outcomes, as well as on survival were studied. Results Liver resections for CRLM were performed in 1442 patients. Preoperative GPS C 1 and mGPS C 1 were present in 170 (11.8%) and 147 (10.2%) patients, respectively. Both were associated with severe complications but became non-significant in the multivariable model. GPS, mGPS, CAR were significant predictors for overall survival in the univariable analysis, but only CAR remained such in the multivariable model. When stratified by the type of surgical approach, CAR was a significant predictor for survival after open but not laparoscopic liver resections. Conclusions GPS, mGPS and CAR have no impact on severe complications after liver resection for CRLM. CAR outperforms GPS and mGPS in predicting overall survival in these patients, especially following open resections. The prognostic significance of CAR in CRLM should be tested against other clinical and pathology parameters relevant for prognosis

Laparoscopic versus open liver resection for intrahepatic cholangiocarcinoma: a multicenter propensity score-matched study

Background: The role of laparoscopy in the treatment of intrahepatic cholangiocarcinoma (ICC) remains unclear. This multicenter study examined the outcomes of laparoscopic liver resection for ICC. Methods: Patients with ICC who had undergone laparoscopic or open liver resection between 2012 and 2019 at four European expert centers were included in the study. Laparoscopic and open approaches were compared in terms of surgical and oncological outcomes. Propensity score matching was used for minimizing treatment selection bias and adjusting for confounders (age, ASA grade, tumor size, location, number of tumors and underlying liver disease). Results: Of 136 patients, 50 (36.7%) underwent laparoscopic resection, whereas 86 (63.3%) had open surgery. Median tumor size was larger (73.6 vs 55.1 mm, p¼ 0.01) and the incidence of bi-lobar tumors was higher (36.6 vs 6%, p< 0.01) in patients undergoing open surgery. After propensity score matching baseline characteristics were comparable although open surgery was associated with a larger fraction of major liver resections (74 vs 38%, p< 0.01), lymphadenectomy (60 vs 20%, p< 0.01) and longer operative time (294 vs 209 min, p< 0.01). Tumor characteristics were similar. Laparoscopic resection resulted in less complications (30 vs 52%, p¼ 0.025), fewer reoperations (4 vs 16%, p¼ 0.046) and shorter hospital stay (5 vs 8 days, p< 0.01). No differences were found in terms of recurrence, recurrence-free and overall survival. Conclusion: Laparoscopic resection seems to be associated with improved short-term and with similar long-term outcomes compared with open surgery in patients with ICC. However, possible selection criteria for laparoscopic surgery are yet to be defined

Patient-Derived Organoids from Multiple Colorectal Cancer Liver Metastases Reveal Moderate Intra-patient Pharmacotranscriptomic Heterogeneity

Peer reviewe

Nomogram predicting macroscopic finding with limited or no clinical implication in 19175 patients referred to esophagogastroduodenoscopy

Objective: The diagnostic yield of esophagogastroduodenoscopy (EGD) depends on appropriate patient selection. The aim of the current study was to create a nomogram predicting findings with limited or no clinical implication in patients referred to EGD. Patients and methods: Indications and findings were registered prospectively in patients who underwent first-time EGD from 1994 to 2013. All findings were classified as “finding with limited or no clinical implication” or “finding with or possibly with clinical implication,” and used to create a predicting nomogram. Results: A total of 19175 patients were included (female: 59.0% [n = 11,312], male: 41.0% [n = 7,863]) with 30821 combinations of indications and findings, of which 20,512 (66.6%) constituted findings with limited or no clinical implication. The median age was 61 (58.9 ± 20.6 [mean ± standard deviation]) years and age was the strongest factor associated with normal EGD. Risk relationships were determined for age and indications by sex and used to create a nomogram. Receiver operating characteristics analysis was used to validate the nomogram-calculated probability of a finding with limited or no clinical implication (area under curve: 0.721; p < 0.001). Conclusion: The present nomogram may clarify the EGD yield challenges to referring physicians and patients. Early use of the nomogram may prevent unnecessary EDGs and assist to increase the diagnostic yield of the procedure

Aggressive Treatment of Patients with Metastatic Colorectal Cancer Increases Survival: A Scandinavian Single-Center Experience

Background. We examined overall and disease-free survivals in a cohort of patients subjected to resection of liver metastasis from colorectal cancer (CRLM) in a 10-year period when new treatment strategies were implemented. Methods. Data from 239 consecutive patients selected for liver resection of CRLM during the period from 2002 to 2011 at a single center were used to estimate overall and disease-free survival. The results were assessed against new treatment strategies and established risk factors. Results. The 5-year cumulative overall and disease-free survivals were 46 and 24%. The overall survival was the same after reresection, independently of the number of prior resections and irrespectively of the location of the recurrent disease. The time intervals between each recurrence were similar (11 ± 1 months). Patients with high tumor load given neoadjuvant chemotherapy had comparable survival to those with less extensive disease without neoadjuvant chemotherapy. Positive resection margin or resectable extrahepatic disease did not affect overall survival. Conclusion. Our data support that one still, and perhaps to an even greater extent, should seek an aggressive therapeutic strategy to achieve resectable status for recurrent hepatic and extrahepatic metastases. The data should be viewed in the context of recent advances in the understanding of cancer biology and the metastatic process