To identify changes in extracellular vesicles (EVs) secreted by the liver following druginduced liver injury (DILI), rats were treated with a subtoxic dose (500 mg/kg) of the analgesic drug, acetaminophen (APAP). EVs were collected by liver perfusion of sham and APAP-treated rats. Changes in EVs morphology were examined by transmission electron microscopic analysis of negatively stained vesicles. Results from morphometric analysis of EVs revealed striking differences in their size and distribution. Proteome composition of EVs collected by liver perfusion was determined by mass spectrometry using methods of sample preparation that enabled better detection of both highly hydrophobic proteins and proteins with complex post-translational modifications. The collection of EVs after liver perfusion is an approach that enables the isolation of EVs shed not only by isolated hepatocytes, but also by the entire complement of hepatic cells. EVs derived after DILI had a lower content of alpha-1-macroglobulin, ferritin, and members of cytochrome 450 family. Fibronectin, aminopeptidase N, metalloreductase STEAP4, integrin beta, and members of the annexin family were detected only in APAP-treated samples of EVs. These results show that the present approach can provide valuable insights into the response of the liver following drug-induced liver injury.
Background: Endemic nephropathy (EN) and associated urothelial cell cancers (UUC) are an environmental form of aristolochic acid nephropathy where the most probable rout of ingestion of aristolochic acid (AA) was made by bread contaminated with AA, leading to chronic dietary intoxication. Clinical courses of three members of the same family, similarly exposed to toxin, who exhibited different clinical courses of the disease are presented. Methods: Questionnaires on AA exposure were taken. Tissue samples were obtained during therapeutic nephrouretectomies. Histopathology, immunohistochemical detection of p53, p53 mutation screening in tumor DNA and analysis on the presence of aristolactam (AL)-DNA adducts were performed. Results: Case 1 had UUC with typical EN histopathological signs, whereas Case 2 had bilateral UUCs with typical EN histopathological signs. In contrast, the patient in Case 3 initially showed renal insufficiency, complicated afterwards by right UUC, and later on by left UUC with histopathological end-stage chronic changes but without typical EN changes. AA-DNA adducts and specific p53 mutational spectra (A:T→ T:A transversion) were found in tissues of cases 1 and 2. Conclusion: Diverse clinical courses seem to be related not to differences in exposure but to differences in metabolic activation or detoxification of AA and/or DNA repair resulting from different genetic polymorphisms.
We examined proteomic profiles of rat liver extracellular vesicles (EVs) shed following treatment with a sub-toxic dose (500 mg/kg) of the pain reliever drug, acetaminophen (APAP). EVs representing the entire complement of hepatic cells were isolated after perfusion of the intact liver and analyzed with LC-MS/MS. The investigation was focused on revealing the function and cellular origin of identified EVs proteins shed by different parenchymal and non-parenchymal liver cells and their possible role in an early response of this organ to a toxic environment. Comparison of EV proteomic profiles from control and APAP-treated animals revealed significant differences. Alpha-1-macroglobulin and members of the cytochrome P450 superfamily were highly abundant proteins in EVs shed by the normal liver. In contrast, proteins like aminopeptidase N, metalloreductase STEAP4, different surface antigens like CD14 and CD45, and most members of the annexin family were detected only in EVs that were shed by livers of APAP-treated animals. In EVs from treated livers, there was almost a complete disappearance of members of the cytochrome P450 superfamily and a major decrease in other enzymes involved in the detoxification of xenobiotics. Additionally, there were proteins that predominated in non-parenchymal liver cells and in the extracellular matrix, like fibronectin, receptor-type tyrosine-protein phosphatase C, and endothelial type gp91. These differences indicate that even treatment with a sub-toxic concentration of APAP initiates dramatic perturbation in the function of this vital organ.
Imatinib mesylate (IM), a tyrosine kinase inhibitor, is the treatment of choice in patients with chronic myeloid leukemia (CML). It is considered a very safe drug, with mostly mild and reversible side effects. Lately, it has been suggested that adverse events may occur after a long term. We report a case of a 72-year-old woman diagnosed with blastic phase of Philadelphia chromosome positive CML treated with IM for 28 months. The patient presented first with ascites as a side effect of the drug. When the ascites re-occurred, it was caused by neuroendocrine tumor (NET) with peritoneal carcinomatosis. We believe this is the first case of a NET as a secondary malignancy (SM) after IM treatment. SM have been described in patients on IM before. It is unclear whether these tumors are caused by imatinib or found more easily because of close follow-up.
Background: In the Republic of Croatia cancer is the second cause of mortality after cardiovascular disease. Patients with cancer have a 4 to 7-fold higher risk of developing venous thromboembolism (VTE) and those who developed VTE have poorer survival than those without VTE. The greatest risk of developing VTE is present in pancreatic, brain, stomach and ovarian cancer, while the lowest risk is with breast and prostate cancer.Aims: Analyze characteristics of patients with cancer who were treated for VTE in General Hospital Dr. Josip Bencˇevic´ for a period of five years. Methods: In the General Hospital Dr Josip Bencˇevic´ -location of Slavonski Brod longitudinal observational analyzes of patients with cancer and newly diagnosed VTE treated in hospital during 2011-2015. Results: A total of 546 cases of VTE were diagnosed in the period of 5 years, out of which 134 (25%) patients with cancer. In patients with cancer and VTE (134) 46% were female while the median age was 67 years, ranging from 38 to 89 years. 87 (65%) patients had deep vein thrombosis (DVT), pulmonary embolism (PE) had a 34 (25%) while 13 (10%) patients had PE and DVT simultaneously. Cancer was only risk factor for development of VTE in 44 (33%) patients, while others had one or more additional risk factors; 51 patients (38%) were treated with possible thrombogenic chemotherapy, 36 (27%) had surgery within 6 months of diagnosis, 15 (11%) patients had sepsis and 18 (13%) were immobilized. A total of 27 (20%) patients died, 16 out of pulmonary embolism, 10 from cancer and 1 from sepsis as a main cause of death. The most common primary cancer sites were: lung 17%, colon and rectum 16%, haematological malignancies 11%, pancreas 9%, ovary 8%, prostate 7%, breast 6%, liver and gallbladder 6%, urinary bladder 5 % and stomach 4%. Summary/Conclusion: The results of our analysis are consistent with data from the literature on VTE incidence and the percentage of VTE caused by cancer. Distrubution of patients with cancer and VTE according to primary cancer site is also like data from literature -most cases were with lung and colon cancer who are the most common cases of cancer in our population while the most thrombogenic cancer in our study was pancreas. VTE prevention in patients with high risk of developing VTE is a priority in today's treatment. Strong adherence of the appropriate thromboprophylaxis is required to reduce the incidence of VTE in the cancer patients.
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