45 research outputs found

    Glutathione-responsive cyclodextrin-nanosponges as drug delivery systems for doxorubicin:Evaluation of toxicity and transport mechanisms in the liver

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    The potential mammalian hepatotoxicity of a new class of GSH-responsive cyclodextrin-based nanosponges loaded with the anticancer drug doxorubicin (Dox-GSH-NS) was investigated. Previous studies showed that these nanosponges can release medicaments preferentially in cells having high GSH content, a common feature of chemoresistant cells, and showed enhanced anti-tumoral activity compared to free Dox in vitro and in vivo in cells with high GSH content. Following these promising results, we investigated here the Dox-GSH-NS hepatotoxicity in human HepG2 cells (in vitro) and in the organotypic cultures of rat precision-cut liver slices (PCLS, ex vivo), while their accumulation in rat liver was assessed in vivo. Moreover, the transport in Dox uptake, as well as its efflux, was studied in vitro. Overall, benefiting of the integration of different investigational models, a good safety profile of Dox-GSH-NSs was evidenced, and their hepatotoxicity resulted to be comparable with respect to free Dox both in vitro and ex vivo. Furthermore, in vivo studies showed that the hepatic accumulation of the Dox loaded in the NS is comparable with respect to the free drug. In addition, Dox-GSH-NSs are taken up by active mechanisms, and can escape the efflux drug pump, thus, contributing to overcoming drug resistance.</p

    Elective cancer surgery in COVID-19-free surgical pathways during the SARS-CoV-2 pandemic: An international, multicenter, comparative cohort study

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    PURPOSE As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19–free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19–free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19–free surgical pathways. Patients who underwent surgery within COVID-19–free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19–free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score–matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19–free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION Within available resources, dedicated COVID-19–free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks

    Elective Cancer Surgery in COVID-19-Free Surgical Pathways During the SARS-CoV-2 Pandemic: An International, Multicenter, Comparative Cohort Study.

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    PURPOSE: As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19-free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS: This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19-free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS: Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19-free surgical pathways. Patients who underwent surgery within COVID-19-free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19-free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score-matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19-free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION: Within available resources, dedicated COVID-19-free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks

    In vivo whole body and organ arginine metabolism during endotoxemia (sepsis) is dependent on mouse strain and gender

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    In vivo whole body and organ arginine metabolism during endotoxemia (sepsis) is dependent on mouse strain and gender. Luiking YC, Hallemeesch MM, Vissers YL, Lamers WH, Deutz NE. Maastricht University, Department of Surgery, The Netherlands. Arginine metabolism involves various organs such as the kidney, the intestines, and the liver, which act together in an interorgan axis. Major pathways for arginine production are protein breakdown and de novo arginine production from citrulline; disposal of arginine is mainly used for protein synthesis or used by the enzymes arginase and nitric oxide synthase (NOS). To assess in vivo organ arginine metabolism under normal conditions and during endotoxemia we used a mouse model, and analyzed for gender and strain differences. Male and female inbred FVB and C57BL6/J mice were anesthetized and catheterized to study whole body, gut, liver, renal and muscle metabolism, using a stable isotope infusion protocol. Animals were treated with saline or lipopolysaccharide. Plasma arginine levels tended to be higher in female mice, although levels were not significantly different from male mice (P = 0.09). Although not all significantly different, whole body arginine production and arginine clearance tended to be higher in C57BL6/J mice (P < 0.1), while citrulline (P = 0.05), NO (P = 0.08), and de novo arginine (P < 0.01) production were higher in FVB mice. During endotoxemia, NO production increased in general (P < 0.05), while whole body arginine clearance increased in FVB mice, but decreased in C57BL6/J mice (P < 0.01). At the organ level, portal-drained viscera (PDV) arginine metabolism was higher in FVB than in C57BL6/J mice (P < 0.05). During endotoxemia, liver arginine metabolism decreased in general (P < 0.05), while strain differences existed for PDV, muscle, and renal arginine metabolism. In conclusion, stable isotope techniques in multicatheterized mice allow measurements of arginine metabolism on whole body and organ level. Strain and gender differences are present in arginine metabolism under physiological conditions and during endotoxemia

    Flutamide Attenuates Pro-inflammatory Cytokine Production and Hepatic Injury Following Trauma-Hemorrhage via Estrogen Receptor-related Pathway

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    Although flutamide attenuates hepatic injury following trauma-hemorrhage, the mechanisms of its salutary effects are unknown. This study suggests that the flutamide mediates its salutary effects on hepatic function following trauma-hemorrhage via estrogen receptor-dependent down-regulation of hepatic chemokine and cytokine production, nuclear factor-ÎşB DNA binding activity, and neutrophil accumulation
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