Although gastrointestinal cancers are frequently associated with chronic inflammation, the underlying molecular links have not been comprehensively deciphered. Using loss- and gain-of-function mice ...in a colitis-associated cancer model, we establish here a link comprising the gp130/Stat3 transcription factor signaling axis. Mutagen-induced tumor growth and multiplicity are reduced following intestinal epithelial cell (IEC)-specific Stat3 ablation, while its hyperactivation promotes tumor incidence and growth. Conversely, IEC-specific Stat3 deficiency enhances susceptibility to chemically induced epithelial damage and subsequent mucosal inflammation, while excessive Stat3 activation confers resistance to colitis. Stat3 has the capacity to mediate IL-6- and IL-11-dependent IEC survival and to promote proliferation through G1 and G2/M cell-cycle progression as the common tumor cell-autonomous mechanism that bridges chronic inflammation to tumor promotion.
Adenoma detection is a highly personalized task that differs markedly among endoscopists. Technical advances are therefore desirable for the improvement of the adenoma detection rate (ADR). An ...automated computer-driven technology would offer the chance to objectively assess the presence of colorectal polyps during colonoscopy. We present here the application of a real-time automated polyp detection software (APDS) under routine colonoscopy conditions.
This was a prospective study at a university hospital in Germany. A prototype of a novel APDS (“KoloPol,” Fraunhofer IIS, Erlangen, Germany) was used for automated image-based polyp detection. The software functions by highlighting structures of possible polyp lesions in a color-coded manner during real-time colonoscopy procedures. Testing the feasibility of APDS deployment under real-time conditions was the primary goal of the study. APDS polyp detection rates (PDRs) were defined as secondary endpoints provided that endoscopists’ detection served as criterion standard.
The APDS was applied in 55 routine colonoscopies without the occurrence of any clinically relevant adverse events. Endoscopists’ PDRs and ADRs were 56.4% and 30.9%, respectively. The PDRs and ADRs of the APDS were 50.9% and 29.1%, respectively. The APDS detected 55 of 73 polyps (75.3%). Smaller polyp size and flat polyp morphology were correlated with insufficient polyp detection by the APDS.
Computer-assisted automated low-delay polyp detection is feasible during real-time colonoscopy. Efforts should be undertaken to improve the APDS with respect to smaller and flat shaped polyps. (Clinical trial registration number: NCT02838888.)
Display omitted
The Apuseni‐Banat‐Timok‐Srednogorie Late Cretaceous magmatic arc in the Carpathian‐Balkan orogen formed on the European margin during closure of the Neotethys Ocean. It was subsequently deformed into ...a complex orocline by continental collisions. The Cu‐Au mineralized arc consists of geologically distinct segments: the Apuseni, Banat, Timok, Panagyurishte, and Eastern Srednogorie segments. New U‐Pb zircon ages and geochemical whole rock data for the Banat and Apuseni segments are combined with previously published data to reconstruct the original arc geometry and better constrain its tectonic evolution. Trace element and isotopic signatures of the arc magmas indicate a subduction‐enriched source in all segments and variable contamination by continental crust. The magmatic arc was active for 25 Myr (~92–67 Ma). Across‐arc age trends of progressively younger ages toward the inferred paleo‐trench indicate gradual steepening of the subducting slab away from the upper plate European margin. This leads to asthenospheric corner flow in the overriding plate, which is recorded by decreasing 87Sr/86Sr (0.70577 to 0.70373) and increasing 143Nd/144Nd (0.51234 to 0.51264) ratios over time in some segments. The close spatial relationship between arc magmatism, large‐scale shear zones, and related strike‐slip sedimentary basins in the Timok and Pangyurishte segments indicates mild transtension in these central segments of the restored arc. In contrast, the Eastern Srednogorie segment underwent strong orthogonal intraarc extension. Segmental distribution of tectonic stress may account for the concentration of rich porphyry Cu deposits in the transtensional segments, where lower crustal magma storage and fractionation favored the evolution of volatile‐rich magmas.
Key Points
Major magmatic arc concealed by postsubduction continental collision
Europe's active margin reconstructed using magma chemistry and geochronology
Distribution of magmatic‐hydrothermal ore deposits controlled by stress state
Background & Aims Early metastasis is a hallmark of pancreatic ductal adenocarcinoma and responsible for >90% of pancreatic cancer death. Because little is known about the biology and genetics of the ...metastatic process, we desired to elucidate molecular pathways mediating pancreatic cancer metastasis in vivo by an unbiased forward genetic approach. Methods Highly metastatic pancreatic cancer cell populations were selected by serial in vivo passaging of parental cells with low metastatic potential and characterized by global gene expression profiling, chromatin immunoprecipitation, and in vivo metastatic assay. Results In vivo selection of highly metastatic pancreatic cancer cells induced epithelial-mesenchymal transition (EMT), loss of E-cadherin expression, and up-regulation of mesenchymal genes such as Snail. Genetic inactivation of E-cadherin in parental cells induced EMT and increased metastasis in vivo. Silencing of E-cadherin in highly metastatic cells is mediated by a transcriptional repressor complex containing Snail and histone deacetylase 1 (HDAC1) and HDAC2. In line, mesenchymal pancreatic cancer specimens and primary cell lines from genetically engineered KrasG12D mice showed HDAC-dependent down-regulation of E-cadherin and high metastatic potential. Finally, transforming growth factor β-driven E-cadherin silencing and EMT of human pancreatic cancer cells depends on HDAC activity. Conclusions We provide the first in vivo evidence that HDACs and Snail play an essential role in silencing E-cadherin during the metastatic process of pancreatic cancer cells. These data link the epigenetic HDAC machinery to EMT and metastasis and provide preclinical evidence that HDACs are promising targets for antimetastatic therapy.
Hepatic fibrosis is a progressive pathological process involving the exhaustion of hepatocellular regenerative capacity and ultimately leading to the development of cirrhosis and even hepatocellular ...carcinoma. Brg1, the core subunit of the SWI/SNF chromatin-remodeling complex, was recently identified as important for liver regeneration. This study investigates the role of Brg1 in hepatic fibrosis development.
Hepatocyte-specific Brg1 knockout mice were generated and injected with carbon tetrachloride (CCl4) for 4, 6, 8, and 12 weeks to induce liver fibrosis. Afterwards, liver fibrosis and liver damage were assessed.
Brg1 expression was significantly increased in the fibrotic liver tissue of wild-type mice, as compared to that of untreated wild-type mice. The livers of the Brg1 knockout animals showed reduced liver inflammation, extracellular matrix accumulation, and liver fibrosis. TNF-α and NF-κB-mediated inflammatory response was reduced in Brg1 knockout animals.
Brg1 promotes the progression of liver fibrosis in mice and may therefore be used as a potential therapeutic target for treating patients with liver fibrosis due to chronic injury.
Background and aims: Clinical data suggest that the quality of optical diagnoses of colorectal polyps differs markedly among endoscopists. The aim of this study was to develop a computer program that ...was able to differentiate neoplastic from non-neoplastic polyps using unmagnified endoscopic pictures.
Methods: During colonoscopy procedures polyp photographies were performed using the unmagnified high-definition white light and narrow band image mode. All detected polyps (n = 275) were resected and sent to pathology. Histopathological diagnoses served as the ground truth. Machine learning was used in order to generate a computer-assisted optical biopsy (CAOB) approach. In the test phase pictures were presented to CAOB in order to obtain optical diagnoses. Altogether 788 pictures were available (602 for training the machine learning algorithm and 186 for CAOB testing). All test pictures were also presented to two experts in optical polyp characterization. The primary endpoint of the study was the accuracy of CAOB diagnoses in the test phase.
Results: A total of 100 polyps (of these 52% neoplastic) were used in the CAOB test phase. The mean size of test polyps was 4 mm. Accuracy of the CAOB approach was 78.0%. Sensitivity and negative predictive value were 92.3% and 88.2%, respectively. Accuracy obtained by two expert endoscopists was 84.0% and 77.0%. Regarding accuracy of optical diagnoses CAOB predictions did not differ significantly compared to experts (p = .307 and p = 1.000, respectively).
Conclusions: CAOB showed good accuracy on the basis of unmagnified endoscopic pictures. Performance of CAOB predictions did not differ significantly from experts' decisions. The concept of computer assistance for colorectal polyp characterization needs to evolve towards a real-time application prior of being used in a broader set-up.
Nuclear factor-κB(NF-κB) and p53 critically determine cancer development and progression. Defining the cross talk between these transcription factors can expand our knowledge on molecular mechanisms ...of tumorigenesis. Here, we show that induction of replicational stress activates NF-κB p65 and triggers its interaction with p53 in the nucleus. Experiments with knockout cells show that p65 and p53 are both required for enhanced NF-κ activity during S-phase checkpoint activation involving ataxiatelangiectasia mutated and checkpoint kinase-1. Accordingly, the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) also triggers formation of a transcriptionally active complex containing nuclear p65 and p53 on kB response elements. Gene expression analyses revealed that, independent of NF-κB activation in the cytosol, TNF-induced NF-κB-directed gene expression relies on p53. Hence, p53 is unexpectedly necessary for NF-κB-mediated gene expression induced by atypical and classical stimuli. Remarkably, data from gain- and loss-of function approaches argue that anti-apoptotic NF-κB p65 activity is constitutively evoked by a p53 hot-spot mutant frequently found in tumors. Our observations suggest explanations for the outstanding question why p53 mutations rather than p53 deletions arise in tumors of various origins. Oncogene (2010) 29, 2795-2806; doi: 10.1038/onc.2010.46; published online 1 March 2010 Keywords: NF-kB; p53; S-phase; hydroxyurea; TNF-a; apoptosis
Bacterial colonization of biliary stents is one of the driving forces behind sludge formation which may result in stent occlusion. Major focus of the study was to analyze the spectrum and number of ...microorganisms in relation to the indwelling time of stents and the risk factors for sludge formation. 343 stents were sonicated to optimize the bacterial release from the biofilm and identified by matrix-associated laser desorption/ionization-time of flight mass spectrometer (MALDI-TOF). 2283 bacteria were analyzed in total. The most prevalent microorganisms were Enterococcus species (spp.) (504;22%), followed by Klebsiella spp. (218;10%) and Candida spp. (188;8%). Colonization of the stents mainly began with aerobic gram-positive bacteria (43/49;88%) and Candida spp. (25/49;51%), whereas stents with an indwelling time>60 days(d) showed an almost equal colonization rate by aerobic gram-negative (176/184;96%) and aerobic gram-positive bacteria (183/184;99%) and a high proportion of anaerobes (127/184;69%). Compared to stents without sludge, more Clostridium spp. (P = 0.02; Odds Ratio (OR): 2.4; 95% confidence interval (95%CI): (1.1-4.9)) and Staphylococcus spp. (P = 0.03; OR (95%CI): 4.3 (1.1-16.5) were cultured from stents with sludge. Multivariate analysis revealed a significant relationship between the number of microorganisms P<0.01; OR (95%CI): 1.3(1.1-1.5), the indwelling time P<0.01; 1-15 d vs. 20-59 d: OR (95%CI): 5.6(1.4-22), 1-15 d vs. 60-3087 d: OR (95% CI): 9.5(2.5-35.7), the presence of sideholes P<0.01; OR (95%CI): 3.5(1.6-7.9) and the occurrence of sludge. Stent occlusion was found in 70/343(20%) stents. In 35% of cases, stent occlusion resulted in a cholangitis or cholestasis. In conclusion, microbial colonization of the stents changed with the indwelling time. Sludge was associated with an altered spectrum and an increasing number of microorganisms, a long indwelling time and the presence of sideholes. Interestingly, stent occlusion did not necessarily lead to a symptomatic biliary obstruction.
Percutaneous transhepatic biliary drainage (PTBD) plays a significant role especially in the palliation of an endoscopically inaccessible biliary system. Since a standard technique of PTBD is not ...defined, we compared a fluoroscopically guided technique (F-PTBD) with an ultrasound (US-PTBD) guided approach.
Procedure characteristics, success-rates and complication-rates of the different PTBD techniques were compared in patients who underwent PTBD between October 1, 2006, and -December 31, 2014.
In 195 patients, 251 PTBDs (207 F-PTBDs, 44 US-PTBDs) were performed. F-PTBDs were mostly inserted from the right and US-PTBDs from the left. Patient age, gender and physical status were comparable in both techniques. There was no difference regarding overall procedure success (90%/86.4%), overall interventional complication rates (10.6%/9.1%), fluoroscopy times, intervention times or sedatives dosages. However, major complications were only encountered in F-PTBDs. There was a higher success rate for F-PTBD vs. US-PTBD from the right side (91.9 vs. 75%; p = 0.033) and a trend towards a higher success rate for US guidance from the left side (82.9 vs. 95.8%; p = 0.223).
For drainage of the right biliary system F-PTBD seems superior over the US-PTBD technique used in this study. However, major complications can occur more frequently in F-PTBD.
AIM： To evaluate the sensitivity of brush cytology and forceps biopsy in a homogeneous patient group with hilar cholangiocarcinoma.METHODS： Brush cytology and forceps biopsy were routinely performed ...in patients with suspected malignant biliary strictures. Fifty-eight consecutive patients undergoing endoscopic retrograde cholangio-pancreatography （ERCP） including forceps biopsy and brush cytology in patients with hilar cholangiocarcinoma between 1995-2005.RESULTS： Positive results for malignancy were obtained in 24/58 patients （41.4%） by brush cytology and in 31/58 patients （53.4%） by forceps biopsy. The combination of both techniques brush cytology and forceps biopsy resulted only in a minor increase in diagnostic sensitivity to 60.3% （35/58 patients）. In 20/58 patients （34.5%）, diagnosis were obtained by both positive cytology and positive histology, in 11/58 （19%） by positive histology （negative cytology） and only 4/58 patients （6.9%） were confirmed by positive cytology （negative histology）.CONCLUSION： Brush cytology and forceps biopsy have only limited sensitivity for the diagnosis of malignant hilar tumors. In our eyes, additional diagnostic techniques should be evaluated and should become routine in patients with negative cytological and histological findings.
PDF
