Biliary Migration, Colonization, and Pathogenesis of O. viverrini Co-Infected with CagA+ Helicobacter pylori

Co-infection with the cagA strain of Helicobacter pylori exacerbates the pathology of human liver fluke Opisthorchis viverrini (OV) infection leading to cholangiocarcinoma. However, underlying mechanisms remain unclear. We report a significant increase in cagA-positive and cagA-negative H. pylori in the stomach, blood, bile, and in the OV worms of co-infected Syrian golden hamsters at one hour, three hours, and one month, post-infection, compared to hamsters infected with either OV or H. pylori alone. Except in the worms, H. pylori numbers declined at three months post-infection, particularly in the bile fluid of co-infected animals. Both strains of H. pylori were immunohistochemically detected in the tegument of the worm, as well as in the bile duct epithelium when co-infected with O. viverrine, but not in H. pylori infection alone. Interestingly, only the cagA-positive strain was detected in the gut of the worm. Co-infection between cagA-positive H. pylori and O. viverrini resulted in a more severe biliary pathology and decreased E-cadherin expression in vivo and in vitro than those of the cagA-negative strain. These data suggest that O. viverrini acts as a carrier of cagA-positive H. pylori and co-migrates to the bile ducts, whereas O. viverrini facilitates H. pylori colonization and enhances the biliary pathogenesis and carcinogenesis.

Examining the Use of Radiation Therapy for Cholangiocarcinoma: Benefits through Modern Techniques

<b><i>Background:</i></b> Cholangiocarcinoma (CCA) is a rare malignant tumor of the bile duct epithelium. At first diagnosis, only a minority of patients are eligible for surgery, which is regarded as the only curative treatment. This study examines the role of radiation therapy (RT) and chemoradiotherapy (CRT) in the definitive and adjuvant treatment situation. <b><i>Methods:</i></b> The monocentric, retrospective analysis included 39 patients with CCA undergoing 53 RT courses. Data were collected from January 2005 to September 2018. There were 11 cases of CRT, 6 of which were definitive. Surgery was either palliative (<i>n</i> = 6) or radical (<i>n</i> = 15). <b><i>Results:</i></b> After RT, the median overall survival (OS) was 10.4 months (m), median progression-free survival was 5.6 m, and median duration of local control (DOLC) was 8.9 m. There was a significant difference in survival between patients with and without locoregional lymph node metastasis (OS: 4.3 vs. 15.4 m, <i>p</i> = 0.031). After treatment of a primary tumor, DOLC was about twice as long as in the recurrent situation (10.4 vs. 5.4 m, <i>p</i> = 0.032). Conservative therapy significantly elevated the risk of local recurrence compared to radical surgery in univariate and multivariate analyses. Side effects were mostly classified as mild to moderate. Termination of RT and increased alanine aminotransferase were significantly less frequent after stereotactic body radiation therapy and hypofractionation. <b><i>Conclusion:</i></b> RT can achieve local control in patients with CCA. Toxicities of RT are manageable but require close clinical and laboratory follow-up.

Feasibility of using tissue autolysis to estimate the postmortem interval in horses

Estimation of the postmortem interval (PMI) is a poorly studied field in veterinary pathology. The development of field-applicable methods is needed given that animal cruelty investigations are increasing continually. We evaluated various histologic criteria in equine brain, liver, and muscle tissue to aid the estimation of PMI in horses, which is central to forensic investigations of suspicious death. After death, autolysis proceeds predictably, depending on environmental conditions. Currently, no field-applied methods exist that accurately estimate the PMI using histology in animals or humans through quantification of autolysis. Brain, liver, and skeletal muscle from 12 freshly euthanized horses were held at 22°C and 8°C for 72 h. Tissues were sampled at T0h, T1h, T2h, T4h, T6h, T12h, T24h, T36h, T48h, T60h, and T72h. For each tissue, we quantified 5 to 7 criteria associated with autolysis, based on the percentage of microscopic field involved. Each criterion was modeled, with temperature and time as independent variables. Changes were most predictable in liver and muscle over the first 72 h postmortem. The criteria for autolysis that were present most extensively at both temperatures were hepatocyte individualization and the separation of bile duct epithelium from the basement membrane. The changes that were present next most extensively were disruption of myofiber continuity, hypereosinophilia, and loss of striation. Brain changes were highly variable. The high statistical correlation between the parameter “autolysis” and the variables “time/temperature”, indicates that autolysis is progressive and predictable. Further investigation of these criteria is needed to establish histologic algorithms for PMI.

A redox probe screens MTHFD1 as a determinant of gemcitabine chemoresistance in cholangiocarcinoma

Cholangiocarcinoma (CCA) is a type of solid tumor derived from the bile duct epithelium that features universal gemcitabine resistance. Here, we utilized a gene-encoded ROS biosensor probe (HyPer3 probe) to sort subpopulations with different redox statuses from CCA cells. The isolated HyPer-low subpopulation CCA cells, which exhibited relatively lower cellular ROS levels, exhibited higher chemoresistance to gemcitabine than HyPer-high subpopulation CCA cells in vitro and in vivo. Mechanistically, increased expression of MTHFD1 was found in HyPer-low cells. Knocking down MTHFD1 in HyPer-low cells enhanced cellular ROS and restored sensitivity to gemcitabine. Furthermore, the MTHFD1 inhibitor antifolate compound methotrexate (MTX) increased cellular ROS, and combining gemcitabine with MTX effectively suppressed cholangiocarcinoma cell growth. In summary, the MTHFD1 level mediated the heterogeneous cellular redox status in CCA, which resulted in chemoresistance to gemcitabine. Our data suggest a novel strategy for CCA chemotherapy.

Drug-induced Bile Duct Injury - A Short Review

: The liver represents the major site of drug metabolism, i.e. the key organ in the processes of detoxification and elimination of drugs from the organism. It is therefore often affected by toxic metabolites and suffers sometimes fatal consequences. The spectrum of pathologies differs by the cell type primarily damaged and the group of the cholangiopathies includes those conditions affecting the bile duct epithelium or the cholangiocytes. They can range from transient cholestasis to vanishing bile duct syndrome and sclerosing cholangitis, both leading eventually to the development of biliary fibrosis and cirrhosis. : In this review article, we focus on the etiology, predisposing factors, clinical manifestations, and histopathological characteristics of bile duct injury as a consequence of drug treatment and discuss separately the different bile duct pathologies.