Andrea Costamagna

Feasibility and safety of low-flow extracorporeal carbon dioxide removal to facilitate ultra-protective ventilation in patients with moderate acute respiratory distress sindrome

BackgroundMechanical ventilation with a tidal volume (VT) of 6 mL/kg/predicted body weight (PBW), to maintain plateau pressure (Pplat) lower than 30 cmH2O, does not completely avoid the risk of ventilator induced lung injury (VILI). The aim of this study was to evaluate safety and feasibility of a ventilation strategy consisting of very low VT combined with extracorporeal carbon dioxide removal (ECCO2R).MethodsIn fifteen patients with moderate ARDS, VT was reduced from baseline to 4 mL/kg PBW while PEEP was increased to target a plateau pressure – (Pplat) between 23 and 25 cmH2O. Low-flow ECCO2R was initiated when respiratory acidosis developed (pH < 7.25, PaCO2 > 60 mmHg). Ventilation parameters (VT, respiratory rate, PEEP), respiratory compliance (CRS), driving pressure (DeltaP = VT/CRS), arterial blood gases, and ECCO2R system operational characteristics were collected during the period of ultra-protective ventilation. Patients were weaned from ECCO2R when PaO2/FiO2 was higher than 200 and could tolerate conventional ventilation settings. Complications, mortality at day 28, need for prone positioning and extracorporeal membrane oxygenation, and data on weaning from both MV and ECCO2R were also collected.ResultsDuring the 2 h run in phase, VT reduction from baseline (6.2 mL/kg PBW) to approximately 4 mL/kg PBW caused respiratory acidosis (pH < 7.25) in all fifteen patients. At steady state, ECCO2R with an average blood flow of 435 mL/min and sweep gas flow of 10 L/min was effective at correcting pH and PaCO2 to within 10 % of baseline values. PEEP values tended to increase at VT of 4 mL/kg from 12.2 to 14.5 cmH2O, but this change was not statistically significant. Driving pressure was significantly reduced during the first two days compared to baseline (from 13.9 to 11.6 cmH2O; p < 0.05) and there were no significant differences in the values of respiratory system compliance. Rescue therapies for life threatening hypoxemia such as prone position and ECMO were necessary in four and two patients, respectively. Only two study-related adverse events were observed (intravascular hemolysis and femoral catheter kinking).ConclusionsThe low-flow ECCO2R system safely facilitates a low volume, low pressure ultra-protective mechanical ventilation strategy in patients with moderate ARDS.

Epidemics spreading in predator–prey systems

In this paper, we consider an ecosystem in which two disease-affected populations thrive and in which the epidemics can spread from one species to the other one by contact. The feasibility and stability conditions of the equilibria of the system are investigated analytically. The model does not possess Hopf bifurcations. Numerical simulations are performed to investigate the role of the main epidemiological and demographic parameters in the model, thus discovering that the predation of healthy or diseased predators on an infected prey allows some kind of control of the prey, if the latter, for instance, represents a pest.

Dysregulation of Blimp1 transcriptional repressor unleashes p130Cas/ErbB2 breast cancer invasion

ErbB2 overexpression is detected in approximately 20% of breast cancers and is correlated with poor survival. It was previously shown that the adaptor protein p130Cas/BCAR1 is a crucial mediator of ErbB2 transformation and that its overexpression confers invasive properties to ErbB2-positive human mammary epithelial cells. We herein prove, for the first time, that the transcriptional repressor Blimp1 is a novel mediator of p130Cas/ErbB2-mediated invasiveness. Indeed, high Blimp1 expression levels are detected in invasive p130Cas/ErbB2 cells and correlate with metastatic status in human breast cancer patients. The present study, by using 2D and 3D breast cancer models, shows that the increased Blimp1 expression depends on both MAPK activation and miR-23b downmodulation. Moreover, we demonstrate that Blimp1 triggers cell invasion and metastasis formation via its effects on focal adhesion and survival signaling. These findings unravel the previously unidentified role that transcriptional repressor Blimp1 plays in the control of breast cancer invasiveness.

Intratracheal administration of small interfering RNA targeting fas reduces lung ischemia-reperfusion injury

Objectives:Lung ischemia-reperfusion injury is the main cause of primary graft dysfunction after lung transplantation and results in increased morbidity and mortality. Fas-mediated apoptosis is one of the pathologic mechanisms involved in the development of ischemia-reperfusion injury. We hypothesized that the inhibition of Fas gene expression in lungs by intratracheal administration of small interfering RNA could reduce lung ischemia-reperfusion injury in an ex vivo model reproducing the procedural sequence of lung transplantation. Design:Prospective, randomized, controlled experimental study. Setting:University research laboratory. Subjects:C57/BL6 mice weighing 28–30 g. Interventions:Ischemia-reperfusion injury was induced in lungs isolated from mice, 48 hours after treatment with intratracheal small interfering RNA targeting Fas, control small interfering RNA, or vehicle. Isolated lungs were exposed to 6 hours of cold ischemia (4°C), followed by 2 hours of warm (37°C) reperfusion with a solution containing 10% of fresh whole blood and mechanical ventilation with constant low driving pressure. Measurements and Main Results:Fas gene expression was significantly silenced at the level of messenger RNA and protein after ischemia-reperfusion in lungs treated with small interfering RNA targeting Fas compared with lungs treated with control small interfering RNA or vehicle. Silencing of Fas gene expression resulted in reduced edema formation (bronchoalveolar lavage protein concentration and lung histology) and improvement in lung compliance. These effects were associated with a significant reduction of pulmonary cell apoptosis of lungs treated with small interfering RNA targeting Fas, which did not affect cytokine release and neutrophil infiltration. Conclusions:Fas expression silencing in the lung by small interfering RNA is effective against ischemia-reperfusion injury. This approach represents a potential innovative strategy of organ preservation before lung transplantation.

p130Cas scaffold protein regulates ErbB2 stability by altering breast cancer cell sensitivity to autophagy

Overexpression of the ErbB2/HER2 receptor tyrosine kinase occurs in up to 20% of human breast cancers and correlates with aggressive disease. Several efficacious targeted therapies, including antibodies and kinase inhibitors, have been developed but the occurring of resistance to these agents is often observed. New therapeutic agents targeting the endocytic recycling and intracellular trafficking of membrane in tumor cells overexpressing ErbB2 are actually in clinical development. Nevertheless the mechanisms underlying ErbB2 downregulation are still obscure. We have previously demonstrated that the overexpression of the p130Cas adaptor protein in ErbB2 positive breast cancer, promotes tumor aggressiveness and progression. Here we demonstrate that lowering p130Cas expression in breast cancer cells is sufficient to induce ErbB2 degradation by autophagy. Conversely, p130Cas overexpression protects ErbB2 from degradation by autophagy. Furthermore, this autophagy-dependent preferential degradation of ErbB2 in absence of p130Cas is due to an increased ErbB2 ubiquitination. Indeed, the overexpression of p130Cas impairs ErbB2 ubiquitination by inhibiting the binding of Cbl and CHIP E3 ligases to ErbB2. Finally, our results indicate that p130Cas-dependent ErbB2 protection from degradation by autophagy may alter the sensitivity to the humanized monoclonal antibody trastuzumab. Consistently, in human ErbB2 positive breast cancers that develop resistance to trastuzumab, p130Cas expression is significantly increased suggesting that elevated levels of p130Cas can be involved in trastuzumab resistance.

Extracorporeal CO2 Removal May Improve Renal Function of Patients with ARDS and Acute Kidney Injury

1. Sedgwick P, Joekes K. Kaplan-Meier survival curves: interpretation and communication of risk. BMJ 2013; 347. 2. Sedgwick P. The log rank test. BMJ 2010; 341. 3. Sedgwick P, Joekes K. Interpreting hazard ratios. BMJ 2015;351: h4631. 4. Dehbi HM, Royston P, Hackshaw A. Life expectancy difference and life expectancy ratio: two measures of treatment effects in randomised trials with non-proportional hazards. BMJ 2017;357: j2250. 5. Royston P, Parmar MK. The use of restricted mean survival time to estimate the treatment effect in randomized clinical trials when the proportional hazards assumption is in doubt. Stat Med 2011;30: 2409–2421. 6. Uno H, Wittes J, Fu H, Solomon SD, Claggett B, Tian L, et al. Alternatives to hazard ratios for comparing the efficacy or safety of therapies in noninferiority studies. Ann Intern Med 2015;163: 127–134. 7. Uno H, Claggett B, Tian L, Inoue E, Gallo P, Miyata T, et al. Moving beyond the hazard ratio in quantifying the between-group difference in survival analysis. J Clin Oncol 2014;32:2380–2385. 8. Pak K, Uno H, Kim DH, Tian L, Kane RC, Takeuchi M, et al. Interpretability of cancer clinical trial results using restricted mean survival time as an alternative to the hazard ratio. JAMA Oncol 2017;3:1692–1696. 9. Zhao L, Claggett B, Tian L, Uno H, Pfeffer MA, Solomon SD, et al. On the restricted mean survival time curve in survival analysis. Biometrics 2016;72:215–221. 10. Kim DH, Uno H, Wei LJ. Restricted mean survival time as a measure to interpret clinical trial results. JAMA Cardiol 2017;2:1179–1180. 11. Uno H. Vignette for survRM2 package: comparing two survival curves using the restricted mean survival time. 2017 [accessed 2018 Apr 7]. Available from: https://cran.r-project.org/web/packages/survRM2/ vignettes/survRM2-vignette3-2.html. 12. Cronin A, Tian L, Uno H. strmst2 and strmst2pw: New commands to compare survival curves using the restricted mean survival time. Stata J 2016;16:702–716. 13. Tian L, Fu H, Ruberg SJ, Uno H, Wei LJ. Efficiency of two sample tests via the restricted mean survival time for analyzing event time observations. Biometrics 2018;74:694–702. 14. Royston P, Parmar MK. Restricted mean survival time: an alternative to the hazard ratio for the design and analysis of randomized trials with a time-to-event outcome. BMC Med Res Methodol 2013;13:152.

Ecoepidemics overcoming the species barrier and being subject to harvesting

An ecoepidemiological model in which the disease can be transmitted from one population to another one is considered. Linear harvesting on all the populations is considered. By means of numerical simulations, the role of the epidemiological parameters as well as that of harvesting are investigated. Some relevant consequences of harvesting on the system dynamics are discovered.

Extracorporeal Carbon Dioxide Removal

Abstract Mechanical ventilation (MV) represents a lifesaving treatment for patients with respiratory failure, but it could be harmful through the development of ventilator-induced lung injury (VILI). In patients with acute respiratory distress syndrome (ARDS), protective MV strategies with low tidal volume to minimize VILI have been demonstrated to reduce lung injury and mortality. However, they can be limited by the emergence of uncontrolled hypercapnia. Similarly, in COPD patients, noninvasive MV failure often is associated with a progressive rise in arterial CO 2 and need for endotracheal intubation, with higher risk of hospital mortality. Minimally invasive extracorporeal CO 2 removal systems (ECCO 2 R) theoretically can remove the entire amount of the CO 2 produced in the body per minute. In ARDS patients, ECCO 2 R may further reduce the risk of VILI ensuring ultraprotective MV and avoiding hypercapnia. In patients with exacerbation of COPD, ECCO 2 R may help to avoid intubation or facilitate weaning from invasive MV. In intensive care unit, concomitant renal and respiratory failure with MV is one of the strongest risk factors for hospital mortality. Combining ECCO 2 R and renal replacement therapy may support respiratory and renal functions and limit the side effects of MV. However, the need for systemic anticoagulation and the related risk of bleeding still represent a concern for a wider application of ECCO 2 R devices. In conclusion, ECCO 2 R is an effective support therapy to MV to limit its invasiveness and side effects, but its efficacy and safety must be proven in well-designed clinical trials.

Low-Flow ECMO and CO2 Removal

In 1952, the outbreak of poliomyelitis in Copenhagen recalls the first clinical scenario in which positive pressure mechanical ventilation (MV) was extensively applied to patients with acute respiratory failure. MV was able to restore the balance between weak respiratory muscles and inspiratory workload [1]. Paradoxically, depending on the impairment of respiratory system mechanics, the ventilator setting, per se, may cause macroscopic and microscopic lung injury, negatively affecting patient outcome [2, 3].

A Simple Model for Vector‐Borne Ecoepidemics

We mathematically investigate the effects of a disease which is spread in an interacting population system by the action of an external carrier.