Targeting inflammasome by the inhibition of caspase-1 activity using capped mesoporous silica nanoparticles

[EN] Acute inflammation is a protective response of the body to harmful stimuli, such as pathogens or damaged cells. However, dysregulated inflammation can cause secondary damage and could thus contribute to the pathophysiology of many diseases. Inflammasomes, the macromolecular complexes responsible for caspase-1 activation, have emerged as key regulators of immune and inflammatory responses. Therefore, modulation of inflammasome activity has become an important therapeutic approach. Here we describe the design of a smart nanodevice that takes advantage of the passive targeting of nanoparticles to macrophages and enhances the therapeutic effect of caspase-1 inhibitor VX-765 in vivo. The functional hybrid systems consisted of MCM-41-based nanoparticles loaded with anti-inflammatory drug VX-765 (S2-P) and capped with poly-L-lysine, which acts as a molecular gate. S2-P activity has been evaluated in cellular and in vivo models of inflammation. The results indicated the potential advantage of using nanodevices to treat inflammatory diseases. (C) 2017 Elsevier B.V. All rights reserved.The authors wish to express their gratitude to the Spanish government (Projects MAT2015-64139-C4-1-R and SAF2014-52614-R (MINECO/FEDER)) and the Generalitat Valencia (Projects PROMETEOII/2014/061 and PROMETEOII/2014/047) for support. A.G-F. is grateful to the Spanish government for an FPU grant.García-Fernández, A.; García-Laínez, G.; Ferrandiz Manglano, ML.; Aznar, E.; Sancenón Galarza, F.; Alcaraz, MJ.; Murguía, JR.... (2017). Targeting inflammasome by the inhibition of caspase-1 activity using capped mesoporous silica nanoparticles. Journal of Controlled Release. 248:60-70. https://doi.org/10.1016/j.jconrel.2017.01.002S607024

Q-SAPS?: què saben sobre salut pública a l’atenció primària?

Malalties; Declaració obligatòria; Brots epidèmicsEnfermedades; Declaración obligatoria; Brotes epidémicosDiseases; Mandatory declaration; Epidemic outbreaksEl treball d’aquesta comunitat de pràctica (CoP) pretén ajudar a detectar mancances de coneixement sobre la salut pública entre els professionals de l’atenció primària i elaborar un document de propostes per millorar el coneixement referit en aquest àmbit. Amb les següents propostes de valor: 1-Conèixer les funcions de cada actor en les malalties de declaració obligatòria (MDO), emergents i brots epidèmics. 2-Detectar mancances de coneixement i dificultats per a declarar. 3-Saber la utilitat de declarar MDO i brots epidèmics, ja que no és només un simple registre sinó que hi ha una actuació al darrere. 4-Conèixer les actuacions comunitàries que cal fer en cada malaltia per controlar-la, i brots epidèmics.El trabajo de esta comunidad de práctica (CoP) pretende ayudar a detectar carencias de conocimiento sobre la salud pública entre los profesionales de la atención primaria y elaborar un documento de propuestas para mejorar el conocimiento referido en este ámbito. Con las siguientes propuestas de valor: 1-Conocer las funciones de cada actor en las enfermedades de declaración obligatoria (MDO), emergentes y brotes epidémicos. 2-Detectar carencias de conocimiento y dificultades para declarar. 3-Saber la utilidad de declarar EDO y brotes epidémicos, ya que no es sólo un simple registro sino que hay una actuación detrás. 4-Conocer las actuaciones comunitarias a realizar en cada enfermedad para controlarla, y brotes epidémicos.The work of this community of practice (CoP) aims to help detect gaps in knowledge about public health among primary care professionals and prepare a document of proposals to improve the knowledge referred to in this area. With the following value propositions: 1-Know the functions of each actor in notifiable diseases, emerging diseases and epidemic outbreaks. 2-Detect knowledge gaps and difficulties in declaring. 3-Know the usefulness of declaring notifiable diseases and epidemic outbreaks, since it is not just a simple record but there is an action behind it. 4-Know the community actions to be carried out in each disease to control it, and epidemic outbreaks

Final results from the PERUSE study of first-line pertuzumab plus trastuzumab plus a taxane for HER2-positive locally recurrent or metastatic breast cancer, with a multivariable approach to guide prognostication

Background: The phase III CLinical Evaluation Of Pertuzumab And TRAstuzumab (CLEOPATRA) trial established the combination of pertuzumab, trastuzumab and docetaxel as standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-positive locally recurrent/metastatic breast cancer (LR/mBC). The multicentre single-arm PERtUzumab global SafEty (PERUSE) study assessed the safety and efficacy of pertuzumab and trastuzumab combined with investigator-selected taxane in this setting. Patients and methods: Eligible patients with inoperable HER2-positive LR/mBC and no prior systemic therapy for LR/mBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab and pertuzumab until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Prespecified subgroup analyses included subgroups according to taxane, hormone receptor (HR) status and prior trastuzumab. Exploratory univariable analyses identified potential prognostic factors; those that remained significant in multivariable analysis were used to analyse PFS and OS in subgroups with all, some or none of these factors. Results: Of 1436 treated patients, 588 (41%) initially received paclitaxel and 918 (64%) had HR-positive disease. The most common grade 653 adverse events were neutropenia (10%, mainly with docetaxel) and diarrhoea (8%). At the final analysis (median follow-up: 5.7 years), median PFS was 20.7 [95% confidence interval (CI) 18.9-23.1] months overall and was similar irrespective of HR status or taxane. Median OS was 65.3 (95% CI 60.9-70.9) months overall. OS was similar regardless of taxane backbone but was more favourable in patients with HR-positive than HR-negative LR/mBC. In exploratory analyses, trastuzumab-pretreated patients with visceral disease had the shortest median PFS (13.1 months) and OS (46.3 months). Conclusions: Mature results from PERUSE show a safety and efficacy profile consistent with results from CLEOPATRA and median OS exceeding 5 years. Results suggest that paclitaxel is a valid alternative to docetaxel as backbone chemotherapy. Exploratory analyses suggest risk factors that could guide future trial design

Demographic, clinical and antibody characteristics of patients with digital ulcers in systemic sclerosis: data from the DUO Registry

OBJECTIVES: The Digital Ulcers Outcome (DUO) Registry was designed to describe the clinical and antibody characteristics, disease course and outcomes of patients with digital ulcers associated with systemic sclerosis (SSc). METHODS: The DUO Registry is a European, prospective, multicentre, observational, registry of SSc patients with ongoing digital ulcer disease, irrespective of treatment regimen. Data collected included demographics, SSc duration, SSc subset, internal organ manifestations, autoantibodies, previous and ongoing interventions and complications related to digital ulcers. RESULTS: Up to 19 November 2010 a total of 2439 patients had enrolled into the registry. Most were classified as either limited cutaneous SSc (lcSSc; 52.2%) or diffuse cutaneous SSc (dcSSc; 36.9%). Digital ulcers developed earlier in patients with dcSSc compared with lcSSc. Almost all patients (95.7%) tested positive for antinuclear antibodies, 45.2% for anti-scleroderma-70 and 43.6% for anticentromere antibodies (ACA). The first digital ulcer in the anti-scleroderma-70-positive patient cohort occurred approximately 5 years earlier than the ACA-positive patient group. CONCLUSIONS: This study provides data from a large cohort of SSc patients with a history of digital ulcers. The early occurrence and high frequency of digital ulcer complications are especially seen in patients with dcSSc and/or anti-scleroderma-70 antibodies

Targeted drug distribution in tumor extracellular fluid of GD2-expressing neuroblastoma patient-derived xenografts using SN-38-loaded nanoparticles conjugated to the monoclonal antibody 3F8

Neuroblastoma is a pediatric solid tumor with high expression of the tumor associated antigen disialoganglioside GD2. Despite initial response to induction therapy, nearly 50% of high-risk neuroblastomas recur because of chemoresistance. Here we encapsulated the topoisomerase-I inhibitor SN-38 in polymeric nanoparticles (NPs) surface-decorated with the anti-GD2 mouse mAb 3F8 at a mean density of seven antibody molecules per NP. The accumulation of drug-loaded NPs targeted with 3F8 versus with control antibody was monitored by microdialysis in patient-derived GD2-expressing neuroblastoma xenografts. We showed that the extent of tumor penetration by SN-38 was significantly higher in mice receiving the targeted nano-drug delivery system when compared to non-targeted system or free drug. This selective penetration of the tumor extracellular fluid translated into a strong anti-tumor effect prolonging survival of mice bearing GD2-high neuroblastomas in vivo.Fil: Monterrubio, Carles. Institut de Recerca Sant Joan de Deu; España. Hospital Sant Joan de Deu Barcelona; EspañaFil: Paco, Sonia. Institut de Recerca Sant Joan de Deu; España. Hospital Sant Joan de Deu Barcelona; EspañaFil: Olaciregui, Nagore G.. Institut de Recerca Sant Joan de Deu; España. Hospital Sant Joan de Deu Barcelona; EspañaFil: Pascual Pasto, Guillem. Institut de Recerca Sant Joan de Deu; España. Hospital Sant Joan de Deu Barcelona; EspañaFil: Vila Ubach, Monica. Institut de Recerca Sant Joan de Deu; España. Hospital Sant Joan de Deu Barcelona; EspañaFil: Cuadrado Vilanova, Maria. Institut de Recerca Sant Joan de Deu; España. Hospital Sant Joan de Deu Barcelona; EspañaFil: Ferrandiz, M. Mar. Institut de Recerca Sant Joan de Deu; España. Hospital Sant Joan de Deu Barcelona; EspañaFil: Castillo Ecija, Helena. Institut de Recerca Sant Joan de Deu; España. Hospital Sant Joan de Deu Barcelona; EspañaFil: Glisoni, Romina Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Nanobiotecnología. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Nanobiotecnología; ArgentinaFil: Kuplennik, Nataliya. Technion-Israel Institute of Technology; IsraelFil: Jungbluth, Achim. Memorial Sloan-Kettering Cancer Center; Estados UnidosFil: de Torres, Carmen. Institut de Recerca Sant Joan de Deu; España. Hospital Sant Joan de Deu Barcelona; EspañaFil: Lavarino, Cinzia. Institut de Recerca Sant Joan de Deu; España. Hospital Sant Joan de Deu Barcelona; EspañaFil: Cheung, N. K. V.. Memorial Sloan-Kettering Cancer Center; Estados UnidosFil: Mora, Jaume. Institut de Recerca Sant Joan de Deu; España. Hospital Sant Joan de Deu Barcelona; EspañaFil: Sosnik, Alejandro Dario. Technion-Israel Institute of Technology; IsraelFil: Montero Carcaboso, Angel. Institut de Recerca Sant Joan de Deu; España. Hospital Sant Joan de Deu Barcelona; Españ

Infections in Moderate to Severe Psoriasis Patients Treated with Biological Drugs Compared to Classic Systemic Drugs: Findings from the BIOBADADERM Registry.

Information regarding the safety of biological drugs prescribed to psoriasis patients on daily and long-term bases is insufficient. We used data from the BIOBADADERM registry (Spanish Registry of Adverse Events for Biological Therapy in Dermatological Diseases) to generate crude rates of infection during therapy with systemic drugs, including biological drugs (infliximab, etanercept, adalimumab, and ustekinumab) and nonbiological drugs (acitretin, cyclosporine, and methotrexate). We also calculated unadjusted and adjusted risk ratios (RRs) (with propensity score adjustment) of infection, serious infections, and recurrent infections of systemic therapies compared with methotrexate, using Poisson regression. Our study included records of 2,153 patients (7,867.5 person-years). The adjusted RR of overall infection was significantly increased in the groups treated with adalimumab with methotrexate (adjusted RR = 2.13, 95% confidence interval [CI] = 1.2-3.7), infliximab (adjusted RR = 1.71, 95% CI = 1.1-2.65), cyclosporine (adjusted RR = 1.58, 95% CI = 1.17-2.15), ustekinumab with methotrexate (adjusted RR = 1.56, 95% CI = 1.08-2.25), and etanercept (adjusted RR = 1.34, 95% CI: 1.02-1.76) compared with methotrexate alone. Cyclosporine had a significant risk of serious infection (adjusted RR = 3.12, 95% CI = 1.1-8.8), followed by adalimumab combined with methotrexate (adjusted RR = 3.28, 95% CI = 0.8-13.5). Adalimumab in combination with methotrexate had the highest risk of infection recurrence (adjusted RR = 4.33, 95% CI = 2.27-8.24)

Evolution over Time of Ventilatory Management and Outcome of Patients with Neurologic Disease∗

OBJECTIVES: To describe the changes in ventilator management over time in patients with neurologic disease at ICU admission and to estimate factors associated with 28-day hospital mortality. DESIGN: Secondary analysis of three prospective, observational, multicenter studies. SETTING: Cohort studies conducted in 2004, 2010, and 2016. PATIENTS: Adult patients who received mechanical ventilation for more than 12 hours. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among the 20,929 patients enrolled, we included 4,152 (20%) mechanically ventilated patients due to different neurologic diseases. Hemorrhagic stroke and brain trauma were the most common pathologies associated with the need for mechanical ventilation. Although volume-cycled ventilation remained the preferred ventilation mode, there was a significant (p < 0.001) increment in the use of pressure support ventilation. The proportion of patients receiving a protective lung ventilation strategy was increased over time: 47% in 2004, 63% in 2010, and 65% in 2016 (p < 0.001), as well as the duration of protective ventilation strategies: 406 days per 1,000 mechanical ventilation days in 2004, 523 days per 1,000 mechanical ventilation days in 2010, and 585 days per 1,000 mechanical ventilation days in 2016 (p < 0.001). There were no differences in the length of stay in the ICU, mortality in the ICU, and mortality in hospital from 2004 to 2016. Independent risk factors for 28-day mortality were age greater than 75 years, Simplified Acute Physiology Score II greater than 50, the occurrence of organ dysfunction within first 48 hours after brain injury, and specific neurologic diseases such as hemorrhagic stroke, ischemic stroke, and brain trauma. CONCLUSIONS: More lung-protective ventilatory strategies have been implemented over years in neurologic patients with no effect on pulmonary complications or on survival. We found several prognostic factors on mortality such as advanced age, the severity of the disease, organ dysfunctions, and the etiology of neurologic disease