Profound variation in dihydropyrimidine dehydrogenase activity in human blood cells: major implications for the detection of partly deficient patients

Dihydropyrimidine dehydrogenase (DPD) is responsible for the breakdown of the widely used antineoplastic agent 5-fluorouracil (5FU), thereby limiting the efficacy of the therapy. To identify patients suffering from a complete or partial DPD deficiency, the activity of DPD is usually determined in peripheral blood mononuclear cells (PBM cells). In this study, we demonstrated that the highest activity of DPD was found in monocytes followed by that of lymphocytes, granulocytes and platelets, whereas no significant activity of DPD could be detected in erythrocytes. The activity of DPD in PBM cells proved to be intermediate compared with the DPD activity observed in monocytes and lymphocytes. The mean percentage of monocytes in the PBM cells obtained from cancer patients proved to be significantly higher than that observed in PBM cells obtained from healthy volunteers. Moreover, a profound positive correlation was observed between the DPD activity of PBM cells and the percentage of monocytes, thus introducing a large inter- and intrapatient variability in the activity of DPD and hindering the detection of patients with a partial DPD deficiency. © 1999 Cancer Research Campaig

Parkinson’s disease mouse models in translational research

Animal models with high predictive power are a prerequisite for translational research. The closer the similarity of a model to Parkinson’s disease (PD), the higher is the predictive value for clinical trials. An ideal PD model should present behavioral signs and pathology that resemble the human disease. The increasing understanding of PD stratification and etiology, however, complicates the choice of adequate animal models for preclinical studies. An ultimate mouse model, relevant to address all PD-related questions, is yet to be developed. However, many of the existing models are useful in answering specific questions. An appropriate model should be chosen after considering both the context of the research and the model properties. This review addresses the validity, strengths, and limitations of current PD mouse models for translational research

Rapid In-vitro Testing for Chemotherapy Sensitivity in Leukaemia Patients

© Springer-Verlag Berlin Heidelberg 2014. Bioluminescent bacterial biosensors can be used in a rapid in vitro assay to predict sensitivity to commonly used chemotherapy drugs in acute myeloid leukemia (AML). The nucleoside analog cytarabine (ara-C) is the key agent for treating AML; however, up to 30% of patients fail to respond to treatment. Screening of patient blood samples to determine drug response before commencement of treatment is needed. To achieve this aim, a self-bioluminescent reporter strain of Escherichia coli has been constructed and evaluated for use as an ara-C biosensor and an in vitro assay has been designed to predict ara-C response in clinical samples. Transposition mutagenesis was used to create a cytidine deaminase (cdd)-deficient mutant of E. coli MG1655 that responded to ara-C. The strain was transformed with the luxCDABE operon and used as a whole-cell biosensor for development an 8-h assay to determine ara-C uptake and phosphorylation by leukemic cells. Intracellular concentrations of 0.025 lmol/L phosphorylated ara-C were detected by significantly increased light output (P\0.05) from the bacterial biosensor. Results using AML cell lines with known response to ara-C showed close correlation between the 8-h assay and a 3-day cytotoxicity test for ara-C cell killing. In retrospective tests with 24 clinical samples of bone marrow or peripheral blood, the biosensor-based assay predicted leukemic cell response to ara-C within 8 h. The biosensor-based assay may offer a predictor for evaluating the sensitivity of leukemic cells to ara-C before patients undergo chemotherapy and allow customized treatment of drug-sensitive patients with reduced ara-C dose levels. The 8-h assay monitors intracellular ara-CTP (cytosine arabinoside triphosphate) levels and, if fully validated, may be suitable for use in clinical settings

Laparoscopic peritoneal lavage versus laparoscopic sigmoidectomy in complicated acute diverticulitis: a multicenter prospective observational study

11sinonePurpose: Laparoscopic peritoneal lavage (LPL) is feasible in selected patients with pelvic abscess and generalized purulent peritonitis caused by acute diverticulitis. We aimed to compare LPL and laparoscopic sigmoidectomy (LS) in complicated acute diverticulitis. Methods: This prospective, observational, multicenter study included patients with a pelvic abscess not amenable to conservative management and patients with Hinchey III acute diverticulitis, from 2015 to 2018. Sixty-six patients were enrolled: 28 (42%) underwent LPL and 38 (58%) underwent LS. In LS, patients had a primary anastomosis, with or without ileostomy, or an end colostomy (HA). Major outcomes were mortality, morbidity, failure of source control, reoperation, length of stay, and diverticulitis recurrence. Results: Patient demographics were similar in the two groups. In LPL, ASA score > 2 and Mannheim Peritonitis Index were significantly higher (p = 0.05 and 0.004). In LS, 24 patients (63%) had a PA and 14 (37%) an HA. No death was recorded. Overall, morbidity was 33% in LPL and 18% in LS (p = 0.169). However, failure to achieve source control of the peritoneal infection and the need to return to the operating room were more frequent in LPL (p = 0.002 and p = 0.006). Mean postoperative length of stay was comparable (p = 0.08). Diverticular recurrence was significantly higher in LPL (p = 0.003). Conclusion: LPL is related to a higher reoperation rate, more frequent postoperative ongoing sepsis, and higher recurrence rates. Therefore, laparoscopic lavage for perforated diverticulitis carries a high risk of failure in daily practice.noneTartaglia D.; Di Saverio S.; Stupalkowska W.; Giannessi S.; Robustelli V.; Coccolini F.; Ioannidis O.; Nita G.E.; Munoz-Cruzado V.M.D.; Ciuro F.P.; Chiarugi M.Tartaglia, D.; Di Saverio, S.; Stupalkowska, W.; Giannessi, S.; Robustelli, V.; Coccolini, F.; Ioannidis, O.; Nita, G. E.; Munoz-Cruzado, V. M. D.; Ciuro, F. P.; Chiarugi, M