Transcatheter Mitral Valve Implantation in Failed Transventricular Mitral Valve Repair.

An 84-year-old man presented with dyspnea at rest due to severe mitral regurgitation. He first underwent transventricular mitral valve repair with the Harpoon system, which relapsed owing to rupture of neochords. He was definitively treated with transcatheter mitral valve implantation of the Tendyne system 8 months later.

Clinical Impact of the Endo-aortic Clamp for Redo Mitral Valve Surgery.

Aim of this study was to compare redo MV surgery patients undergoing right mini-thoracotomy and EAC with redo MV patients undergoing surgery through other approaches. Redo MV patients from 7 European centers were analyzed. Primary endpoint was 30-day mortality; secondary endpoints were stroke, re-exploration, low cardiac output syndrome (LCOS), respiratory failure, and intensive care unit (ICU) and in-hospital length-of-stay. Forty-nine patients underwent right mini-thoracotomy and EAC (22.7%), and 167 (77.3%) underwent surgery through other approaches (112 sternotomy, 40 unclamped mini-thoracotomies, and 15 mini-thoracotomies with trans-thoracic clamp). Thirty-day mortality, stroke, re-exploration for bleeding, and weaning failure were comparable. The EAC group showed significant lower rate of LCOS (p = 0.03) and shorter ICU (p = 0.04) and in-hospital length of stay (p = 0.002). The EAC allows the surgeon to reach the aorta, to clamp it, and to deliver the cardioplegia with a "no-touch" technique, with significant improvement in outcomes.

Continuous stellate ganglion block for ventricular arrhythmias: case series, systematic review, and differences from thoracic epidural anaesthesia.

AIMS: Percutaneous stellate ganglion block (PSGB) through single-bolus injection and thoracic epidural anaesthesia (TEA) have been proposed for the acute management of refractory ventricular arrhythmias (VAs). However, data on continuous PSGB (C-PSGB) are scant. The aim of this study is to report our dual-centre experience with C-PSGB and to perform a systematic review on C-PSGB and TEA. METHODS AND RESULTS: Consecutive patients receiving C-PSGB at two centres were enrolled. The systematic literature review follows the latest Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. Our case series (26 patients, 88% male, 60 ± 16 years, all with advanced structural heart disease, left ventricular ejection fraction 23 ± 11%, 32 C-PSGBs performed, with a median duration of 3 days) shows that C-PSGB is feasible and safe and leads to complete VAs suppression in 59% and to overall clinical benefit in 94% of cases. Overall, 61 patients received 68 C-PSGBs and 22 TEA, with complete VA suppression in 63% of C-PSGBs (61% of patients). Most TEA procedures (55%) were performed on intubated patients, as opposed to 28% of C-PSGBs (P = 0.02); 63% of cases were on full anticoagulation at C-PSGB, none at TEA (P < 0.001). Ropivacaine and lidocaine were the most used drugs for C-PSGB, and the available data support a starting dose of 12 and 100 mg/h, respectively. No major complications occurred, yet TEA discontinuation rate due to side effects was higher than C-PSGB (18 vs. 1%, P = 0.01). CONCLUSION: Continuous PSGB seems feasible, safe, and effective for the acute management of refractory VAs. The antiarrhythmic effect may be accomplished with less concerns for concomitant anticoagulation compared with TEA and with a lower side-effect related discontinuation rate.

Epidemiology and Risk Factors for Nosocomial Infections in Left Ventricular Assist Device Recipients.

Left ventricular assist devices (LVADs) have been increasingly used as a valid option to improve the prognosis and reduce the symptoms of end-stage heart failure. However, long-term complications, mostly infections and coagulation disorders, are frequent. We described the epidemiology and risk factors for nosocomial infections (NIs) in a cohort of adult patients who underwent continuous-flow LVAD implant between January 2010 and December 2017 in Turin, Italy. Secondary outcomes were the prevalence of multidrug-resistant (MDR) bacteria and mortality. Results: Overall, 64 LVADs were implanted. A total of 32 (50%) patients experienced at least one episode of NI, with a total of 46 infectious events. VAD-related infections occurred in 22 patients (68.8%). Non VAD-related NIs occurred in 12 patients (37.5%), mainly low respiratory tract infections. Length of intensive care unit admission was a risk factor for NI (OR 1.224, 95%CI; 1.049, 1.429). Gram-negative bacilli were responsible for 58.8% of VAD-related infections and 79.5% of non-VAD related infections. In sixteen patients (50%), at least one episode of infection was related to an MDR strain. INTERMACS class and length of MV were independent risk factors for NIs by MDR strains (respectively, OR 2.12, 95%CI: 1.08, 6.80; p = 0.02 and OR 1.46, 95%CI: 1.07, 5.52, p = 0.047). In-hospital mortality was 6.3%. No differences in mortality were observed between infected and non-infected patients (p = 0.61) even when caused by MDR strains (p = 0.143). Conclusion: the rate of nosocomial infections in LVAD patients is associated with the length of ICU admission, and the etiology of nosocomial infection after LVAD implant is mainly due to GNB, including a high rate of MDR strains, especially KPC-KP and MDR PA.

Which ultrasound-guided parasternal intercostal nerve block for post-sternotomy pain? Results from a prospective observational study.

BACKGROUND: Parasternal intercostal blocks (PSB) have been proposed for postoperative analgesia in patients undergoing median sternotomy. PSB can be achieved using two different approaches, the superficial parasternal intercostal plane block (SPIP) and deep parasternal intercostal plane block (DPIP) respectively. METHODS: We designed the present prospective, observational cohort study to compare the analgesic efficacy of the two approaches. Cardiac surgical patients who underwent full sternotomy from January to September 2022 were enrolled and divided into three groups, according to pain control strategy: morphine, SPIP, and DPIP group. Primary outcomes were was postoperative pain evaluated as absolute value of NRS at 12 h. Secondary outcomes were the NRS at 24 and 48 h, the need for salvage analgesia (both opioids and NSAIDs), incidence of postoperative nausea and vomiting, time to extubation, mechanical ventilation duration, and bowel disfunction. RESULTS: Ninety-six were enrolled. There was no significant difference in terms of median Numeric Pain Rating Scale at 24 h and at 48 h between the study groups. Total postoperative morphine consumption was 1.00 (0.00-3.00), 2.00 (0.00-5.50), and 15.60 mg (9.60-30.00) in the SPIP, DPIP, and morphine group, respectively (SPIP and DPIP vs morphine: p < 0.001). Metoclopramide consumption was lower in SPIP and DPIP group compared with morphine group (p = 0.01). There was no difference in terms of duration of mechanical ventilation and of bowel activity between the study groups. Two pneumothorax occurred in the DPIP group. CONCLUSIONS: Both SPIP and DPIP seem able to guarantee an effective pain management in the postoperative phase of cardiac surgeries via full median sternotomy while ensuring a reduced consumption of opioids and antiemetic drugs.

Cytokines Removal During Ex-Vivo Lung Perfusion: Initial Clinical Experience.

Ex Vivo Lung Perfusion (EVLP) can be potentially used to manipulate organs and to achieve a proper reconditioning process. During EVLP pro-inflammatory cytokines have been shown to accumulate in perfusate over time and their production is correlated with poor outcomes of the graft. Aim of the present study is to investigate the feasibility and safety of cytokine adsorption during EVLP. From July 2011 to March 2020, 54 EVLP procedures have been carried out, 21 grafts treated with an adsorption system and 33 without. Comparing the grafts perfused during EVLP with or without cytokine adsorption, the use of a filter significantly decreased the levels of IL10 and GCSFat the end of the procedure. Among the 38 transplanted patients, the adsorption group experienced a significant decreased IL6, IL10, MCP1 and GCSF concentrations and deltas compared to the no-adsorption group, with a lower in-hospital mortality (p = 0.03) and 1-year death rate (p = 0.01). This interventional study is the first human experience suggesting the safety and efficacy of a porous polymer beads adsorption device in reducing the level of inflammatory mediators during EVLP. Clinical impact of cytokines reduction during EVLP must be evaluated in further studies.

Minimally Invasive Surgery: Standard of Care for Mitral Valve Endocarditis.

Background. Minimally invasive surgery via right mini-thoracotomy has become the standard of care for the treatment of mitral valve disease worldwide, particularly at high-volume centers. In recent years, the spectrum of indications has progressively shifted and extended to fragile and higher-risk patients, also addressing more complex mitral valve disease and ultimately including patients with native or prosthetic infective endocarditis. The rationale for the adoption of the minimally invasive approach is to minimize surgical trauma, promote an earlier postoperative recovery, and reduce the incidence of surgical wound infection and other nosocomial infections. The aim of this retrospective observational study is to evaluate the effectiveness and the early and late outcome in patients undergoing minimally invasive surgery for mitral valve infective endocarditis. Methods. Prospectively collected data regarding minimally invasive surgery in patients with mitral valve infective endocarditis were entered into a dedicated database for the period between January 2007 and December 2022 and retrospectively analyzed. All comers during the study period underwent a preoperative evaluation based on their clinical history and anatomy for the allocation to the most appropriate surgical strategy. The selection of the mini-thoracotomy approach was primarily driven by a thorough transthoracic and especially transesophageal echocardiographic evaluation, coupled with total body and vascular imaging. Results. During the study period, 92 patients underwent right mini-thoracotomy to treat native (80/92, 87%) or prosthetic (12/92, 13%) mitral valve endocarditis at our institution, representing 5% of the patients undergoing minimally invasive mitral surgery. Twenty-six (28%) patients had undergone previous cardiac operations, whereas 18 (20%) presented preoperatively with complications related to endocarditis, most commonly systemic embolization. Sixty-nine and twenty-three patients, respectively, underwent early surgery (75%) or were operated on after the completion of the targeted antibiotic treatment (25%). A conservative procedure was feasible in 16/80 (20%) patients with native valve endocarditis. Conversion to standard sternotomy was necessary in a single case (1.1%). No cases of intraoperative iatrogenic aortic dissection were reported. Four patients died perioperatively, accounting for a thirty-day mortality of 4.4%. The causes of death were refractory heart or multiorgan failure and/or septic shock. A new onset stroke was observed postoperatively in one case (1.1%). Overall actuarial survival rate at 1 and 5 years after operation was 90.8% and 80.4%, whereas freedom from mitral valve reoperation at 1 and 5 years was 96.3% and 93.2%, respectively. Conclusions. This present study shows good early and long-term results in higher-risk patients undergoing minimally invasive surgery for mitral valve infective endocarditis. Total body, vascular, and echocardiographic screening represent the key points to select the optimal approach and allow for the extension of indications for minimally invasive surgery to sicker patients, including active endocarditis and sepsis.

Lysosomal lipid switch sensitises to nutrient deprivation and mTOR targeting in pancreatic cancer.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with limited therapeutic options. However, metabolic adaptation to the harsh PDAC environment can expose liabilities useful for therapy. Targeting the key metabolic regulator mechanistic target of rapamycin complex 1 (mTORC1) and its downstream pathway shows efficacy only in subsets of patients but gene modifiers maximising response remain to be identified. DESIGN: Three independent cohorts of PDAC patients were studied to correlate PI3K-C2γ protein abundance with disease outcome. Mechanisms were then studied in mouse (KPC mice) and cellular models of PDAC, in presence or absence of PI3K-C2γ (WT or KO). PI3K-C2γ-dependent metabolic rewiring and its impact on mTORC1 regulation were assessed in conditions of limiting glutamine availability. Finally, effects of a combination therapy targeting mTORC1 and glutamine metabolism were studied in WT and KO PDAC cells and preclinical models. RESULTS: PI3K-C2γ expression was reduced in about 30% of PDAC cases and was associated with an aggressive phenotype. Similarly, loss of PI3K-C2γ in KPC mice enhanced tumour development and progression. The increased aggressiveness of tumours lacking PI3K-C2γ correlated with hyperactivation of mTORC1 pathway and glutamine metabolism rewiring to support lipid synthesis. PI3K-C2γ-KO tumours failed to adapt to metabolic stress induced by glutamine depletion, resulting in cell death. CONCLUSION: Loss of PI3K-C2γ prevents mTOR inactivation and triggers tumour vulnerability to RAD001 (mTOR inhibitor) and BPTES/CB-839 (glutaminase inhibitors). Therefore, these results might open the way to personalised treatments in PDAC with PI3K-C2γ loss.

Clinical performance of lung ultrasound in predicting time-dependent changes in lung aeration in ARDS patients.

To evaluate whether lung ultrasound is reliable bedside tool to monitor changes of lung aeration at the early and late stages of ARDS. LUS was performed in ARDS patients that underwent at least two consecutive CT scan at ICU admission and at least 1 week after admission. Twelve fields were evaluated and graded from 0 (normal) to 3 (consolidation). Changes of LUS score in twelve fields (ΔLUStot) and in four ventral (ΔLUSV), intermediate (ΔLUSI) and dorsal (ΔLUSD) zones were calculated at each time points. Three categories were described: Improve (ΔLUS < 0), Equal (ΔLUS = 0) or Worse (ΔLUS > 0). LUS scores were correlated with total changes in lung CT aeration (ΔCTair) and with normally, poorly and not aerated regions (ΔCTnorm, ΔCTpoor and ΔCTnot, respectively). Eleven patients were enrolled. ΔLUStot had significant correlation with ΔCTair (r = - 0.74, p < 0.01). ΔLUSV, ΔLUSI and ΔLUSD showed significant correlations with ΔCTair (r = - 0.66, r = - 0.69, r = - 0.63, respectively; p < 0.05). Compared to Equal, Improve and Worse categories had significantly higher (p < 0.01) and lower (p < 0.05) ΔCTair values, respectively. Compared to Equal, Improve and Worse categories had lower (p < 0.01) and higher (p < 0.01) ΔCTnot values, respectively. LUS score had a good correlation with lung CT in detecting changes of lung aeration.

Dual Role of Extracellular Vesicles in Sepsis-Associated Kidney and Lung Injury.

Extracellular vesicles form a complex intercellular communication network, shuttling a variety of proteins, lipids, and nucleic acids, including regulatory RNAs, such as microRNAs. Transfer of these molecules to target cells allows for the modulation of sets of genes and mediates multiple paracrine and endocrine actions. EVs exert broad pro-inflammatory, pro-oxidant, and pro-apoptotic effects in sepsis, mediating microvascular dysfunction and multiple organ damage. This deleterious role is well documented in sepsis-associated acute kidney injury and acute respiratory distress syndrome. On the other hand, protective effects of stem cell-derived extracellular vesicles have been reported in experimental models of sepsis. Stem cell-derived extracellular vesicles recapitulate beneficial cytoprotective, regenerative, and immunomodulatory properties of parental cells and have shown therapeutic effects in experimental models of sepsis with kidney and lung involvement. Extracellular vesicles are also likely to play a role in deranged kidney-lung crosstalk, a hallmark of sepsis, and may be key to a better understanding of shared mechanisms underlying multiple organ dysfunction. In this review, we analyze the state-of-the-art knowledge on the dual role of EVs in sepsis-associated kidney/lung injury and repair. PubMed library was searched from inception to July 2022, using a combination of medical subject headings (MeSH) and keywords related to EVs, sepsis, acute kidney injury (AKI), acute lung injury (ALI), and acute respiratory distress syndrome (ARDS). Key findings are summarized into two sections on detrimental and beneficial mechanisms of actions of EVs in kidney and lung injury, respectively. The role of EVs in kidney-lung crosstalk is then outlined. Efforts to expand knowledge on EVs may pave the way to employ them as prognostic biomarkers or therapeutic targets to prevent or reduce organ damage in sepsis.

Is continuous Erector Spinae Plane Block (ESPB) better than continuous Serratus Anterior Plane Block (SAPB) for mitral valve surgery via mini-thoracotomy? Results from a prospective observational study.

Aims: Chest wall blocks are effective alternatives for postoperative pain control in mitral valve surgery in right mini-thoracotomy (mini-MVS). We compared the efficacy of Serratus Anterior plane block (SAPB) and Erector Spinae plane block (ESPB) on postoperative pain relief after mini-MVS. Settings and Design: It is a prospective, observational study. Material and Methods: A total of 85 consecutive patients undergoing continuous SAPB and continuous ESPB for mini-MVS from March 2019 to October 2020 were included. The primary outcome was the assessment of postoperative pain evaluated as absolute value of NRS at 12, 24 and 48 h. Secondary outcomes were assessment of salvage analgesia (both opioids and NSAIDs), incidence of mild adverse effects (i.e. nausea, vomiting, and incorrect catheter placement) and timing of postoperative course (ICU and hospital length of stay, duration of mechanical ventilation, ventilator-free days). Results: The median NRS was 0.00 (0.00-3.00) at 12 h and 0.00 (0.00-2.00) at 24 and 48 h. No significant differences were observed between groups. Postoperative morphine consumption in the first 24 h was similar in both groups (P = 0.76), whereas between 24 and 48 h was significantly less in the ESPB group compared with SAPB group, P = 0.013. NSAIDs median consumption and Metoclopramide consumption were significantly lower in the ESPB group compared to SAPB group (P = 0.002 and P = 0.048, respectively). Conclusions: ESPB, even more than SAPB, appears to be a feasible and effective strategy for the management of postoperative pain, allowing good quality analgesia with low consumption of opioids, NSAIDs and antiemetic drugs.

Bloodstream Infections Caused by Carbapenem-Resistant Pathogens in Intensive Care Units: Risk Factors Analysis and Proposal of a Prognostic Score.

Considering the growing prevalence of carbapenem-resistant Gram-negative bacteria (CR-GNB) bloodstream infection (BSI) in intensive care units (ICUs), the identification of specific risk factors and the development of a predictive model allowing for the early identification of patients at risk for CR-Klebsiella pneumoniae, Acinetobacter baumannii or Pseudomonas aeruginosa are essential. In this retrospective case-control study including all consecutive patients showing an episode of BSI in the ICUs of a university hospital in Italy in the period January-December 2016, patients with blood culture positive for CR-GNB pathogens and for any other bacteria were compared. A total of 106 patients and 158 episodes of BSI were identified. CR-GNBs induced BSI in 49 patients (46%) and 58 episodes (37%). Prognosis score and disease severity at admission, parenteral nutrition, cardiovascular surgery prior to admission to ICU, the presence of sepsis and septic shock, ventilation-associated pneumonia and colonization of the urinary or intestinal tract were statistically significant in the univariate analysis. The duration of ventilation and mortality at 28 days were significantly higher among CR-GNB cases. The prognostic model based on age, presence of sepsis, previous cardiovascular surgery, SAPS II, rectal colonization and invasive respiratory infection from the same pathogen showed a C-index of 89.6%. The identified risk factors are in line with the international literature. The proposal prognostic model seems easy to use and shows excellent performance but requires further studies to be validated.

Is there life on the airway tree? A pilot study of bronchial cell vitality and tissue morphology in the ex vivo lung perfusion (EVLP) era of lung transplantation.

BACKGROUND: Ex vivo lung perfusion (EVLP) is a relevant procedure to increase the lung donor pool but could potentially increase the airway tree ischemic injury risk. METHODS: This study aimed to evaluate the direct effect of EVLP on the airway tree by evaluating bronchial cell vitality and tissue signs of injury on a series of 117 bronchial rings collected from 40 conventional and 19 EVLP-treated lung grafts. Bronchial rings and related scraped bronchial epithelial cells were collected before the EVLP procedure and surgical anastomosis. RESULTS: The preimplantation interval was significantly increased in the EVLP graft group (p < 0.01). Conventional grafts presented cell viability percentages of 47.07 ± 23.41 and 49.65 ± 21.25 in the first and second grafts which did not differ significantly from the EVLP group (first graft 50.54 ± 25.83 and second graft 50.22 ± 20.90 cell viability percentage). No significant differences in terms of histopathological features (edema, inflammatory infiltrate, and mucosa ulceration) were observed comparing conventional and EVLP samples. A comparison of bronchial cell viability and histopathology of EVLP samples retrieved at different time intervals revealed no significant differences. Accordingly, major bronchial complications after lung transplant were not observed in both groups. CONCLUSIONS: Based on these data, we observed that EVLP did not significantly impact bronchial cell vitality and airway tissue preservation nor interfere with bronchial anastomosis healing, further supporting it as a safe and useful procedure.

Effectiveness of an Active and Continuous Surveillance Program for Intensive Care Units Infections Based on the EPIC III (Extended Prevalence of Infection in Intensive Care) Approach.

We evaluated the effectiveness of the Extended Prevalence of Infection in Intensive Care (EPIC) III data collection protocol as an active surveillance tool in the eight Intensive Care Units (ICUs) of the Intensive and Critical Care Department of the University Hospital of Turin. A total of 435 patients were included in a six-day study over 72 ICU beds. 42% had at least one infection: 69% at one site, 26% at two sites and 5% at three or more sites. ICU-acquired infections were the most common (64%), followed by hospital-associated infections (22%) and community-acquired (20%), considering that each patient may have developed more than one infection type. 72% of patients were receiving at least one antibiotic: 48% for prophylaxis and 52% for treatment. Mortality, the length of ICU and hospital stays were 13%, 14 and 29 days, respectively, being all estimated to be significantly different in patients without and with infection (8% vs. 20%; 4 vs. 20 and 11 vs. 50 (p < 0.001). Our data confirm a high prevalence of infections, sepsis and the use of antimicrobials. The repeated punctual prevalence survey seems an effective method to carry out the surveillance of infections and the use of antimicrobials in the ICU. The use of the European Centre for Disease Prevention and Control (ECDC) definitions and the EPIC III protocol seems strategic to allow comparisons with national and international contexts.

Chronic postsurgical pain and quality of life after right minithoracotomy mitral valve operations.

OBJECTIVES: Chronic postsurgical pain (CPSP) is a relatively common complication after cardio-thoracic operations with well-known consequences in terms of return to normal activities and quality of life. Little is known about the prevalence and severity of CPSP after minimally invasive cardiac surgery. The aim of this study was to measure the rate of CPSP in patients undergoing right minithoracotomy mitral valve (MV) surgery and to compare the effectiveness of different approaches to pain control. METHODS: A prospective observational study was conducted between March 2019 and September 2020. All patients undergoing right minithoracotomy MV surgery treated with morphine, continuous serratus anterior plane block (SAPB), or continuous erector spinae plane block (ESPB) were included. The Brief Pain Inventory questionnaire was used to evaluate 6-month CPSP and quality of life. RESULTS: A total of 100 patients were enrolled: postoperative pain control was obtained with morphine in 26 cases, with SAPB in 37 cases, and with ESPB in 37 cases. Median intensive care unit and hospital length of stay were 1 day and 6 days, respectively. Pain severity index was lower than 10 in 81 patients, and no differences were recorded between groups (p = .59). No patients reported chronic use of medications for pain management or severe pain interference in daily activities at follow-up. DISCUSSION: Right minithoracotomy approach is not burdened by a high incidence of CPSP: pain severity index was lower than 10 in more than 90% of patients. Then, in our experience, chronic pain seems not to be related to the type of perioperative analgesia adopted.

A PI3Kγ mimetic peptide triggers CFTR gating, bronchodilation, and reduced inflammation in obstructive airway diseases.

Cyclic adenosine 3',5'-monophosphate (cAMP)-elevating agents, such as ß2-adrenergic receptor (ß2-AR) agonists and phosphodiesterase (PDE) inhibitors, remain a mainstay in the treatment of obstructive respiratory diseases, conditions characterized by airway constriction, inflammation, and mucus hypersecretion. However, their clinical use is limited by unwanted side effects because of unrestricted cAMP elevation in the airways and in distant organs. Here, we identified the A-kinase anchoring protein phosphoinositide 3-kinase γ (PI3Kγ) as a critical regulator of a discrete cAMP signaling microdomain activated by ß2-ARs in airway structural and inflammatory cells. Displacement of the PI3Kγ-anchored pool of protein kinase A (PKA) by an inhaled, cell-permeable, PI3Kγ mimetic peptide (PI3Kγ MP) inhibited a pool of subcortical PDE4B and PDE4D and safely increased cAMP in the lungs, leading to airway smooth muscle relaxation and reduced neutrophil infiltration in a murine model of asthma. In human bronchial epithelial cells, PI3Kγ MP induced unexpected cAMP and PKA elevations restricted to the vicinity of the cystic fibrosis transmembrane conductance regulator (CFTR), the ion channel controlling mucus hydration that is mutated in cystic fibrosis (CF). PI3Kγ MP promoted the phosphorylation of wild-type CFTR on serine-737, triggering channel gating, and rescued the function of F508del-CFTR, the most prevalent CF mutant, by enhancing the effects of existing CFTR modulators. These results unveil PI3Kγ as the regulator of a ß2-AR/cAMP microdomain central to smooth muscle contraction, immune cell activation, and epithelial fluid secretion in the airways, suggesting the use of a PI3Kγ MP for compartment-restricted, therapeutic cAMP elevation in chronic obstructive respiratory diseases.

Lung Ultrasound and Electrical Impedance Tomography During Ventilator-Induced Lung Injury.

OBJECTIVES: Lung damage during mechanical ventilation involves lung volume and alveolar water content, and lung ultrasound (LUS) and electrical impedance tomography changes are related to these variables. We investigated whether these techniques may detect any signal modification during the development of ventilator-induced lung injury (VILI). DESIGN: Experimental animal study. SETTING: Experimental Department of a University Hospital. SUBJECTS: Forty-two female pigs (24.2 ± 2.0 kg). INTERVENTIONS: The animals were randomized into three groups (n = 14): high tidal volume (TV) (mean TV, 803.0 ± 121.7 mL), high respiratory rate (RR) (mean RR, 40.3 ± 1.1 beats/min), and high positive-end-expiratory pressure (PEEP) (mean PEEP, 24.0 ± 1.1 cm H2O). The study lasted 48 hours. At baseline and at 30 minutes, and subsequently every 6 hours, we recorded extravascular lung water, end-expiratory lung volume, lung strain, respiratory mechanics, hemodynamics, and gas exchange. At the same time-point, end-expiratory impedance was recorded relatively to the baseline. LUS was assessed every 12 hours in 12 fields, each scoring from 0 (presence of A-lines) to 3 (consolidation). MEASUREMENTS AND MAIN RESULTS: In a multiple regression model, the ratio between extravascular lung water and end-expiratory lung volume was significantly associated with the LUS total score (p < 0.002; adjusted R2, 0.21). The variables independently associated with the end-expiratory difference in lung impedance were lung strain (p < 0.001; adjusted R2, 0.18) and extravascular lung water (p < 0.001; adjusted R2, 0.11). CONCLUSIONS: Data suggest as follows. First, what determines the LUS score is the ratio between water and gas and not water alone. Therefore, caution is needed when an improvement of LUS score follows a variation of the lung gas content, as after a PEEP increase. Second, what determines the end-expiratory difference in lung impedance is the strain level that may disrupt the intercellular junction, therefore altering lung impedance. In addition, the increase in extravascular lung water during VILI development contributed to the observed decrease in impedance.

Docking Protein p130Cas Regulates Acinar to Ductal Metaplasia During Pancreatic Adenocarcinoma Development and Pancreatitis.

BACKGROUND & AIMS: Acinar to ductal metaplasia is the prerequisite for the initiation of Kras-driven pancreatic ductal adenocarcinoma (PDAC), and candidate genes regulating this process are emerging from genome-wide association studies. The adaptor protein p130Cas emerged as a potential PDAC susceptibility gene and a Kras-synthetic lethal interactor in pancreatic cell lines; however, its role in PDAC development has remained largely unknown. METHODS: Human PDAC samples and murine KrasG12D-dependent pancreatic cancer models of increasing aggressiveness were used. p130Cas was conditionally ablated in pancreatic cancer models to investigate its role during Kras-induced tumorigenesis. RESULTS: We found that high expression of p130Cas is frequently detected in PDAC and correlates with higher histologic grade and poor prognosis. In a model of Kras-driven PDAC, loss of p130Cas inhibits tumor development and potently extends median survival. Deletion of p130Cas suppresses acinar-derived tumorigenesis and progression by means of repressing PI3K-AKT signaling, even in the presence of a worsening condition like pancreatitis. CONCLUSIONS: Our observations finally demonstrated that p130Cas acts downstream of Kras to boost the PI3K activity required for acinar to ductal metaplasia and subsequent tumor initiation. This demonstrates an unexpected driving role of p130Cas downstream of Kras through PI3K/AKT, thus indicating a rational therapeutic strategy of targeting the PI3K pathway in tumors with high expression of p130Cas.

p130Cas/BCAR1 and p140Cap/SRCIN1 Adaptors: The Yin Yang in Breast Cancer?

p130Cas/BCAR1 is an adaptor protein devoid of any enzymatic or transcriptional activity, whose modular structure with various binding motifs, allows the formation of multi-protein signaling complexes. This results in the induction and/or maintenance of signaling pathways with pleiotropic effects on cell motility, cell adhesion, cytoskeleton remodeling, invasion, survival, and proliferation. Deregulation of p130Cas/BCAR1 adaptor protein has been extensively demonstrated in a variety of human cancers in which overexpression of p130Cas/BCAR1 correlates with increased malignancy. p140Cap (p130Cas associated protein), encoded by the SRCIN1 gene, has been discovered by affinity chromatography and mass spectrometry analysis of putative interactors of p130Cas. It came out that p140Cap associates with p130Cas not directly but through its interaction with the Src Kinase. p140Cap is highly expressed in neurons and to a lesser extent in epithelial tissues such as the mammary gland. Strikingly, in vivo and in vitro analysis identified its tumor suppressive role in breast cancer and in neuroblastoma, showing an inverse correlation between p140Cap expression in tumors and tumor progression. In this review, a synopsis of 15 years of research on the role of p130Cas/BCAR1 and p140Cap/SRCIN1 in breast cancer will be presented.