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Adaptor proteins play a pivotal role in cellular signaling mediating a multitude of protein-protein interaction critical for cellular homeostasis. Dysregulation of these interactions has been linked to the onset of various cancer pathologies and exploited by viral pathogens during host cell takeover. CrkL is an adaptor protein composed of an N-terminal SH2 domain followed by two SH3 domains that mediate interactions with diverse partners through the recognition of specific binding motifs. In this study, we employed proteomic peptide-phage display (ProP-PD) to comprehensively explore the short linear motif (SLiM)-based interactions of CrkL. Furthermore, we scrutinized how the binding affinity for selected peptides was influenced in the context of the full-length CrkL versus the isolated N-SH3 domain. Importantly, our results provided insights into SLiM-binding sites within previously reported interactors, as well as revealing novel human and viral ligands, expanding our understanding of the interactions mediated by CrkL and highlighting the significance of SLiM-based interactions in mediating adaptor protein function, with implications for cancer and viral pathologies.

Inhaled nitric oxide (iNO) is a drug used to treat neonates with persistent pulmonary hypertension and as a rescue strategy for the treatment of severe hypoxemia. The clinical administration of iNO is challenging since the patient population is heterogeneous, ranging from critically ill patients intubated and mechanically ventilated to patients with chronic pulmonary hypertension receiving iNO at home [8]. In the intubated mechanically ventilated patients, airways are sealed by a cuffed endotracheal tube. Therefore, it is possible to precisely reach and maintain the target iNO concentration. Conversely, in nonintubated spontaneously breathing patients, the patient airways are not sealed by a cuffed endotracheal tube, so the instantaneous delivered dose cannot be accurately determined. A snug-fitting mask can be used to deliver NO as a patient interface in hospitalized patients with acute bacterial or viral pneumonia. In patients requiring long-term iNO administration, nasal cannula can be a suitable patient interface, which is also often used for long-term oxygen administration. To safely administer iNO, the continuous monitoring of the delivered NO and nitrogen dioxide (NO2) concentrations is recommended to avoid excessive NO2 delivery that is irritant for the airways. Further, blood oxygenation and methemoglobin concentration monitoring have to be considered during iNO administration to ensure an adequate tissue oxygenation.

Las distintas representaciones de mujeres delincuentes inscritas en relatos literarios inspirados en un crimen -real o o imaginario - configuran una caracterización tanto del delito como de los sujetos femeninos. En dicha narrativa las mujeres delincuentes suelen ser el revés o la contracara de las víctimas; son percibidas como la cara oscura de la feminidad, reforzando así el arquetipo de la mujer como sujeto pasivo y pacífico. De esta manera se establece un tabú sobre la violencia femenina y se construyen una serie de estereotipos sobre las mujeres violentas que las desnaturaliza y las transforma en la negación del propio género. Este ser 'contro natura' las hace aún más peligrosas, letales y malvadas. La imposibilidad de admitir la potencialidad de las mujeres de ejercer la violencia lleva a la invisibilidad o al sensacionalismo: las mujeres criminales son inexistentes o monstruos deshumanos. Se propone el texto literario como espacio en el que es posible preguntarse sobre el origen de la violencia y cuestionar críticamente el estereotipo social que impone a la mujer pacífica, pasiva y víctima de la violencia masculina. Un espacio en el cual no hay verdades absolutas, pero en el que es posible imaginarnos de otra manera, indagar en los motivos oscuros del acto criminal abriendo pistas interpretativas inéditas, dando voz a personajes olvidados, invisibles.

Background: Sigh is a cyclic brief recruitment maneuver: previous physiologic studies showed that its use could be an interesting addition to pressure support ventilation to improve lung elastance, decrease regional heterogeneity, and increase release of surfactant. Research Question: Is the clinical application of sigh during pressure support ventilation (PSV) feasible? Study Design and Methods: We conducted a multicenter noninferiority randomized clinical trial on adult intubated patients with acute hypoxemic respiratory failure or ARDS undergoing PSV. Patients were randomized to the no-sigh group and treated by PSV alone, or to the sigh group, treated by PSV plus sigh (increase in airway pressure to 30 cm H2O for 3 s once per minute) until day 28 or death or successful spontaneous breathing trial. The primary end point of the study was feasibility, assessed as noninferiority (5% tolerance) in the proportion of patients failing assisted ventilation. Secondary outcomes included safety, physiologic parameters in the first week from randomization, 28-day mortality, and ventilator-free days. Results: Two-hundred and fifty-eight patients (31% women; median age, 65 [54-75] years) were enrolled. In the sigh group, 23% of patients failed to remain on assisted ventilation vs 30% in the no-sigh group (absolute difference, –7%; 95% CI, –18% to 4%; P =. 015 for noninferiority). Adverse events occurred in 12% vs 13% in the sigh vs no-sigh group (P =. 852). Oxygenation was improved whereas tidal volume, respiratory rate, and corrected minute ventilation were lower over the first 7 days from randomization in the sigh vs no-sigh group. There was no significant difference in terms of mortality (16% vs 21%; P =. 337) and ventilator-free days (22 [7-26] vs 22 [3-25] days; P =. 300) for the sigh vs no-sigh group. Interpretation: Among hypoxemic intubated ICU patients, application of sigh was feasible and without increased risk.

BACKGROUND: Rescue therapies to treat or prevent progression of coronavirus disease 2019 (COVID-19) hypoxic respiratory failure in pregnant patients are lacking. METHOD: To treat pregnant patients meeting criteria for severe or critical COVID-19 with high-dose (160-200 ppm) nitric oxide by mask twice daily and report on their clinical response. EXPERIENCE: Six pregnant patients were admitted with severe or critical COVID-19 at Massachusetts General Hospital from April to June 2020 and received inhalational nitric oxide therapy. All patients tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A total of 39 treatments was administered. An improvement in cardiopulmonary function was observed after commencing nitric oxide gas, as evidenced by an increase in systemic oxygenation in each administration session among those with evidence of baseline hypoxemia and reduction of tachypnea in all patients in each session. Three patients delivered a total of four neonates during hospitalization. At 28-day follow-up, all three patients were home and their newborns were in good condition. Three of the six patients remain pregnant after hospital discharge. Five patients had two negative test results on nasopharyngeal swab for SARS-CoV-2 within 28 days from admission. CONCLUSION: Nitric oxide at 160-200 ppm is easy to use, appears to be well tolerated, and might be of benefit in pregnant patients with COVID-19 with hypoxic respiratory failure.

Background: There is an increasing interest in safely delivering high dose of inhaled nitric oxide (NO) as an antimicrobial and antiviral therapeutics for spontaneously breathing patients. A novel NO delivery system is described. Methods: We developed a gas delivery system that utilizes standard respiratory circuit connectors, a reservoir bag, and a scavenging chamber containing calcium hydroxide. The performance of the system was tested using a mechanical lung, assessing the NO concentration delivered at varying inspiratory flows. Safety was assessed in vitro and in vivo by measuring nitrogen dioxide (NO2) levels in the delivered NO gas. Lastly, we measured the inspired and expired NO and NO2 of this system in 5 healthy subjects during a 15-min administration of high dose NO (160 parts-per-million, ppm) using our delivery system. Results: The system demonstrated stable delivery of prescribed NO levels at various inspiratory flow rates (0–50 L/min). The reservoir bag and a high flow of entering air minimized the oscillation of NO concentrations during inspiration on average 4.6 ppm for each 10 L/min increment in lung inspiratory flow. The calcium hydroxide scavenger reduced the inhaled NO2 concentration on average 0.9 ppm (95% CI -1.58, −0.22; p =.01). We performed 49 NO administrations of 160 ppm in 5 subjects. The average concentration of inspired NO was 164.8±10.74 ppm, with inspired NO2 levels of 0.7±0.13 ppm. The subjects did not experience any adverse events; transcutaneous methemoglobin concentrations increased from 1.05±0.58 to 2.26±0.47%. Conclusions: The system we developed to administer high-dose NO for inhalation is easy to build, reliable, was well tolerated in healthy subjects.

Objective There is initial evidence that the use of volatile anesthetics can reduce the postoperative release of cardiac troponin I, the need for inotropic support, and the number of patients requiring prolonged hospitalization following coronary artery bypass graft (CABG) surgery. Nevertheless, small randomized controlled trials have failed to demonstrate a survival advantage. Thus, whether volatile anesthetics improve the postoperative outcome of cardiac surgical patients remains uncertain. An adequately powered randomized controlled trial appears desirable. Design Single blinded, international, multicenter randomized controlled trial with 1:1 allocation ratio. Setting Tertiary and University hospitals. Interventions Patients (n = 10,600) undergoing coronary artery bypass graft will be randomized to receive either volatile anesthetic as part of the anesthetic plan, or total intravenous anesthesia. Measurements and main results The primary end point of the study will be one-year mortality (any cause). Secondary endpoints will be 30-day mortality; 30-day death or non-fatal myocardial infarction (composite endpoint); cardiac mortality at 30 day and at one year; incidence of hospital re-admission during the one year follow-up period and duration of intensive care unit, and hospital stay. The sample size is based on the hypothesis that volatile anesthetics will reduce 1-year unadjusted mortality from 3% to 2%, using a two-sided alpha error of 0.05, and a power of 0.9. Conclusions The trial will determine whether the simple intervention of adding a volatile anesthetic, an intervention that can be implemented by all anesthesiologists, can improve one-year survival in patients undergoing coronary artery bypass graft surgery.

NHERF1 (Na+/H+ exchanger 3 regulating factor 1) is an integral membrane adaptor protein carrying two NH2-terminal PDZ (postsynaptic density 95/discs large/zona occludens 1) tandem domains. PDZ1 (11-97 amino acids) and PDZ2 (150-237 amino acids) show 74% identity to each other and bind to specific carboxyl-terminal motifs on target proteins, such as E-catenin and PTEN, that may have a pivotal role in tumorigenesis. Oncogenic activity of NHERF1 is strictly dictated by changes on its subcellular localization. A pharmacophore model was used to filter out an in-house training set of about 6000 compounds, leading to identify a potent inhibitor of NHERF1. We herein reported the design and synthesis of new NHERF1 inhibitors (Figure 1). The new compounds were synthesized by treating the appropriate indole with thionyl chloride and the proper amino derivative in the presence of pyridine in dichloromethane at room temperature for 12 h; alternatively, the coupling reaction was carried out using (benzotriazol-1- yloxy)tripyrrolidinophosphonium hexafluorophosphate and triethylamine in N,N-dimethylformamide at room temperature for 12 h. Compounds 5, 9, 10 and 13 exhibited a remarkable cytotoxicity in Ls174TshE-Cat cells. The binding to NHERF1 PDZ was confirmed by means of a dansylated peptide corresponding to the C-terminal sequence of E2-AR. When used in combination with antagonists of E-catenin, the new derivatives increased the apoptotic death of colorectal cancer cells refractory to currently available Wnt/E-catenintargeted agents.

BACKGROUND: Adding cyclic short sustained inflations (sigh) to assisted ventilation yields optimizes lung recruitment, decreases heterogeneity and reduces inspiratory effort in patients with acute hypoxemic respiratory failure (AHRF). These findings suggest that adding sigh to pressure support ventilation (PSV) might decrease the risk of lung injury, shorten weaning and improve clinical outcomes. Thus, we conceived a pilot trial to test the feasibility of adding sigh to PSV (the PROTECTION study). METHODS: PROTECTION is an international randomized controlled trial that will be conducted in 23 intensive care units (ICUs). Patients with AHRF who have been intubated from 24 h to 7 days and undergoing PSV from 4 to 24 h will be enrolled. All patients will first undergo a 30-min sigh test by adding sigh to clinical PSV for 30 min to identify early oxygenation responders. Then, patients will be randomized to PSV or PSV + sigh until extubation, ICU discharge, death or day 28. Sigh will be delivered as a 3-s pressure control breath delivered once per minute at 30 cmH2O. Standardized protocols will guide ventilation settings, switch back to controlled ventilation, use of rescue treatments, performance of spontaneous breathing trial, extubation and reintubation. The primary endpoint of the study will be to verify the feasibility of PSV + sigh evaluated through reduction of failure to remain on assisted ventilation during the first 28 days in the PSV + sigh group versus standard PSV (15 vs. 22%). Failure will be defined by switch back to controlled ventilation for more than 24 h or use of rescue treatments or reintubation within 48 h from elective extubation. Setting the power to 80% and first-risk order to 5%, the computed size of the trial is 129 patients per arm. DISCUSSION: PROTECTION is a pilot randomized controlled trial testing the feasibility of adding sigh to PSV. If positive, it will provide physicians with an effective addition to standard PSV for lung protection, a

Aim: To evaluate the long-term histological outcome of patients transplanted for HBV-related liver disease and given HBIg prophylaxis indefinitely after LT. Methods: Forty-two consecutive patients transplanted for hepatitis B were prospectively studied. HBsAg, HBV-DNA and liver function tests were evaluated in the serum 3, 6 and 12 mo after LT and then yearly. LB was obtained 6 and 12 mo after LT and yearly thereafter. Chronic hepatitis (CH) B after LT was classified as minimal, mild, moderate or severe. Results: HBV recurred in 7/42 (16.6%) patients after 6-96 mo of follow-up. A hundred and eighty-seven LB were evaluated. Four of 7 patients with graft reinfection, all with unknown HBV DNA status before LT, developed cirrhosis at 12-36 mo of follow-up. Of the 122 LB obtained from 28 HBsAg+/HCV- recipients with no HBV recurrence after LT, all biopsies were completely normal in only 2 patients (7.1%), minimal/non-specific changes were observed in 18 (64.2%), and at least 1 biopsy showed CH in the remaining 8 (28.5%). Twenty-nine LB obtained from 7 patients transplanted for HBV-HCV cirrhosis and remaining HBsAg- after LT revealed recurrent CH-C. Actuarial survival was similar in patients with HBsAg+ or HBsAg- liver diseases. Conclusion: Though protocol biopsies may enable the detection of graft dysfunction at an early stage, the risk of progression and the clinical significance of these findings remains to be determined.

Background/aims. The prognosis of hepatocellular carcinoma (HCC) on cirrhosis is hard to predict as it depends on tumour stage, underlying liver disease, type of treatment and, possibly, biological factors of the tumour itself. Methods. We prospectively evaluated the survival of 91 consecutive patients with HCC on cirrhosis, diagnosed between January 1998 and December 1999. Clinical features and histological/biological aspects, including histotype, grade, p53 overexpression, cytoproliferation and apoptotic markers were analysed. Results. Child-Pugh (P = 0.01), Okuda (P < 0.0001), Cancer of the Liver Italian Program (CLIP) staging (P < 0.0001) and type of treatment (P = 0.0001) were significantly related to survival. In the Cox model, CLIP staging was included as independent predictor of survival at step 1 (P < 0.0001) with Okuda at step 2 (P = 0.013). Amongst the biological factors, p53 overexpression and histotype were significantly related with survival (P = 0.0044 and 0.017 respectively). When clinical and biological variables were examined together in the Cox model, CLIP and Okuda were confirmed as being statistically related with survival (P < 0.0001 and =0.012) followed by histotype and p53 overexpression (P = 0.019 and 0.02). Conclusions. CLIP, Okuda, histotype and p53 overexpression are the strongest predictors of survival in this series of patients. These data confirm that staging of the tumour and underlying liver disease are strictly related to prognosis but support the concurrent role of clinical and biological factors in upgrading our capacity of predicting the fate of HCC patients.

Background. Liver transplantation is the standard treatment for patients with end-stage liver disease no longer responsive to conventional medical treatment Aims. To report the long-term experience of liver transplantation in Italy. Patients and Methods. Data were obtained retrospectively by means of a multiple-item form collected from 15 Italian liver transplant centres. The filing centre was centralized. Results. A total of 3323 liver transplants were performed on 3026 patients, with a cumulative proportional survival of 72.4%. Three, 5 and 10 years'patient survival rates were 72.3%, 68.8% and 61.3%, respectively. The most common indication for liver transplantation were hepatitis B virus (± hepatitis D virus]- and hepatitis C virus-related cirrhosis (59.4%). Excellent survival rates were observed particularly in controversial indications, such as alcoholic cirrhosis, hepatitis B virus-related cirrhosis and hepatocellular carcinoma. Retransplantation was required in 8.9% of the cases. The overall prevalence of acute cellular rejection episodes was 43.5%. In our study population, primary non-function and disease recurrence were the most common causes of graft failure (28.7% and 25.4%, respectively). Infections and/or sepsis were the most common causes of death after transplantation (42%). Conclusion. This study confirms that patients with controversial indications to liver transplantation such as alcoholic cirrhosis, HBV-related cirrhosis and hepatocellular carcinoma can achieve excellent survival when properly selected.

Se analizan dos novelas, la primera, escrita por un conocido historiador, Jean Meyer, trata de una de las figuras más emblemáticas de la lucha de independencia: José Miguel Hidalgo y Costilla. Se analiza la representación literaria que se hace de la figura histórica, los recursos que permiten trazar un retarato mucho más humano que rompe con la historiografía oficial. La segunda novela, de la escritora mexicana Carmen Boullosa, es una amplia reelaboración ficcional de tres momentos históricos de México, la guerra de independencia de 1810, la revolución de 1910 y la guerra al narcotráfico de 2010. La voz narrante es la de una casa, metáfora de la patria, que reconstruye con la libertad que da la creación literaria, la historia de México. Ambas novelas se publicaron durante las celebraciones como conmemoración editorial y literaria del Bicentenario de la Independencia y Centenario de la Revolución.

Se explica el valor de la mirada literaria hacia las revoluciones mexicanas de 1810 y 1910, que dialoga con la historia creando una narración nueva que permite decir lo que los datos objetivos de la investigación histórica impiden, enriqueciendo la representación y reelaboración de la historia nacional. Se plantea la relación entre literatura e histórica, entre la verdad ficcional y la verdad histórica.