Rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART): Study protocol for a randomized controlled trial

Background: Acute respiratory distress syndrome (ARDS) is associated with high in-hospital mortality. Alveolar recruitment followed by ventilation at optimal titrated PEEP may reduce ventilator-induced lung injury and improve oxygenation in patients with ARDS, but the effects on mortality and other clinical outcomes remain unknown. This article reports the rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART). Methods/Design: ART is a pragmatic, multicenter, randomized (concealed), controlled trial, which aims to determine if maximum stepwise alveolar recruitment associated with PEEP titration is able to increase 28-day survival in patients with ARDS compared to conventional treatment (ARDSNet strategy). We will enroll adult patients with ARDS of less than 72 h duration. The intervention group will receive an alveolar recruitment maneuver, with stepwise increases of PEEP achieving 45 cmH(2)O and peak pressure of 60 cmH2O, followed by ventilation with optimal PEEP titrated according to the static compliance of the respiratory system. In the control group, mechanical ventilation will follow a conventional protocol (ARDSNet). In both groups, we will use controlled volume mode with low tidal volumes (4 to 6 mL/kg of predicted body weight) and targeting plateau pressure <= 30 cmH2O. The primary outcome is 28-day survival, and the secondary outcomes are: length of ICU stay; length of hospital stay; pneumothorax requiring chest tube during first 7 days; barotrauma during first 7 days; mechanical ventilation-free days from days 1 to 28; ICU, in-hospital, and 6-month survival. ART is an event-guided trial planned to last until 520 events (deaths within 28 days) are observed. These events allow detection of a hazard ratio of 0.75, with 90% power and two-tailed type I error of 5%. All analysis will follow the intention-to-treat principle. Discussion: If the ART strategy with maximum recruitment and PEEP titration improves 28-day survival, this will represent a notable advance to the care of ARDS patients. Conversely, if the ART strategy is similar or inferior to the current evidence-based strategy (ARDSNet), this should also change current practice as many institutions routinely employ recruitment maneuvers and set PEEP levels according to some titration method.Hospital do Coracao (HCor) as part of the Program 'Hospitais de Excelencia a Servico do SUS (PROADI-SUS)'Brazilian Ministry of Healt

The role of pro-inflammatory components, carcinoma-associated fibroblasts, and tumor-associated macrophages in ovarian cancer progression and metastasis

Ovarian cancer (OC) is associated with poor outcomes and challenges scientists and clinicians. It is usually diagnosed in advanced stages when it is frequently aggressive, chemoresistant, and metastatic. The most prevalent form of OC is epithelial ovarian cancer (EOC), which displays significant heterogeneity, enhancing the difficulty in managing the disease. Several factors have been associated with the disease’s development and progression, especially those related to the tumor microenvironment (TME). Here, we highlight components of the ovarian TME in the disease development process, including pro-inflammatory pathways activated by interleukins, cytokines and chemokines, cancer-associated fibroblasts, tumor-associated macrophages, and epithelial-mesenchymal transition. We compiled evidence identifying TME factors promoting the development, chemoresistance, and metastasis, including cytokines, chemokines, growth factors, and tumor-associated cells. We identify potential targets for treatment and improving outcomes. These targets block or alter pathways associated with OC (especially EOC) progression

Metformin synergistically enhances antiproliferative effects of cisplatin and etoposide in NCI-H460 human lung cancer cells

OBJECTIVE: To test the effectiveness of combining conventional antineoplastic drugs (cisplatin and etoposide) with metformin in the treatment of non-small cell lung cancer in the NCI-H460 cell line, in order to develop new therapeutic options with high efficacy and low toxicity.METHODS: We used the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and calculated the combination index for the drugs studied.RESULTS: We found that the use of metformin as monotherapy reduced the metabolic viability of the cell line studied. Combining metformin with cisplatin or etoposide produced a synergistic effect and was more effective than was the use of cisplatin or etoposide as monotherapy.CONCLUSIONS: Metformin, due to its independent effects on liver kinase B1, had antiproliferative effects on the NCI-H460 cell line. When metformin was combined with cisplatin or etoposide, the cell death rate was even higher

Improved photodynamic action of nanoparticles loaded with indium (III) phthalocyanine on MCF-7 breast cancer cells

Indium (III) phthalocyanine (InPc) was encapsulated into nanoparticles of PEGylated poly (D,L-lactide-co-glycolide) (PLGA-PEG) to improve the photobiological activity of the photosensitizer. the efficacy of nanoparticles loaded with InPc and their cellular uptake was investigated with MCF-7 breast tumor cells, and compared with the free InPc. the influence of photosensitizer (PS) concentration (1.8-7.5 mu mol/L), incubation time (1-2 h), and laser power (10-100 mW) were studied on the photodynamic effect caused by the encapsulated and the free InPc. Nanoparticles with a size distribution ranging from 61 to 243 nm and with InPc entrapment efficiency of 72 +/- 6 % were used in the experiments. Only the photodynamic effect of encapsulated InPc was dependent on PS concentration and laser power. the InPc-loaded nanoparticles were more efficient in reducing MCF-7 cell viability than the free PS. for a light dose of 7.5 J/cm(2) and laser power of 100 mW, the effectiveness of encapsulated InPc to reduce the viability was 34 +/- 3 % while for free InPc was 60 +/- 7 %. Confocal microscopy showed that InPc-loaded nanoparticles, as well as free InPc, were found throughout the cytosol. However, the nanoparticle aggregates and the aggregates of free PS were found in the cell periphery and outside of the cell. the nanoparticles aggregates were generated due to the particles concentration used in the experiment because of the small loading of the InPc while the low solubility of InPc caused the formation of aggregates of free PS in the culture medium. the participation of singlet oxygen in the photocytotoxic effect of InPc-loaded nanoparticles was corroborated by electron paramagnetic resonance experiments, and the encapsulation of photosensitizers reduced the photobleaching of InPc.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Federal Institute of Espirito SantoFed Inst Espirito Santo, BR-29192733 Aracruz, ES, BrazilUniv Fed Espirito Santo, Hlth Sci Ctr, Biotechnol Program RENORBIO, BR-29040090 Vitoria, ES, BrazilUniversidade Federal de São Paulo, Dept Exact Sci & Earth, BR-09972270 Diadema, SP, BrazilUniv Estadual Campinas, Dept Cellular Biol, BR-13083863 Campinas, SP, BrazilUniv Fed Espirito Santo, Dept Pharmaceut Sci, BR-29040090 Vitoria, ES, BrazilUniv Estadual Campinas, Inst Chem, Dept Phys Chem, BR-13083970 Campinas, SP, BrazilUniversidade Federal de São Paulo, Dept Exact Sci & Earth, BR-09972270 Diadema, SP, BrazilWeb of Scienc

Synthetic naphthoquinone derivatives as anticancer agents in ovarian cancer: cytotoxicity assay and investigation of possible biological mechanisms action

In this study, eight naphthoquinone derivatives were synthesized in yields ranging from 52 to 96% using easy, fast, and low-cost methodologies. All naphthoquinone derivatives were screened for their in vitro anti-proliferative activities against OVCA A2780 cancer cell lines. Amongst all analysed compounds, derivatives 3–5 presented the most prominent cytotoxic potential. Naphthoquinones 3 and 4, bearing sulfur-containing groups, were identified as having high potential for ROS production, in particular the superoxide anion. Furthermore, 3 and 4 compounds caused a decrease in the cell population in G0/G1 and induced more than 90% of the cell population to apoptosis. Compound 5 did not act in any of these processes. Finally, compounds 3–5 were tested for their inhibitory ability against PI3K and MAPK. Compounds 3 and 4 do not inhibit the PI3K enzyme. On the other hand, the naphthoquinone-polyphenol 5 was only able to inhibit the percentage of cells expressing pERK

Rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART): Study protocol for a randomized controlled trial

Background: Acute respiratory distress syndrome (ARDS) is associated with high in-hospital mortality. Alveolar recruitment followed by ventilation at optimal titrated PEEP may reduce ventilator-induced lung injury and improve oxygenation in patients with ARDS, but the effects on mortality and other clinical outcomes remain unknown. This article reports the rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART). Methods/Design: ART is a pragmatic, multicenter, randomized (concealed), controlled trial, which aims to determine if maximum stepwise alveolar recruitment associated with PEEP titration is able to increase 28-day survival in patients with ARDS compared to conventional treatment (ARDSNet strategy). We will enroll adult patients with ARDS of less than 72 h duration. The intervention group will receive an alveolar recruitment maneuver, with stepwise increases of PEEP achieving 45 cmH(2)O and peak pressure of 60 cmH2O, followed by ventilation with optimal PEEP titrated according to the static compliance of the respiratory system. In the control group, mechanical ventilation will follow a conventional protocol (ARDSNet). In both groups, we will use controlled volume mode with low tidal volumes (4 to 6 mL/kg of predicted body weight) and targeting plateau pressure <= 30 cmH2O. The primary outcome is 28-day survival, and the secondary outcomes are: length of ICU stay; length of hospital stay; pneumothorax requiring chest tube during first 7 days; barotrauma during first 7 days; mechanical ventilation-free days from days 1 to 28; ICU, in-hospital, and 6-month survival. ART is an event-guided trial planned to last until 520 events (deaths within 28 days) are observed. These events allow detection of a hazard ratio of 0.75, with 90% power and two-tailed type I error of 5%. All analysis will follow the intention-to-treat principle. Discussion: If the ART strategy with maximum recruitment and PEEP titration improves 28-day survival, this will represent a notable advance to the care of ARDS patients. Conversely, if the ART strategy is similar or inferior to the current evidence-based strategy (ARDSNet), this should also change current practice as many institutions routinely employ recruitment maneuvers and set PEEP levels according to some titration method.13Hospital do Coracao (HCor) as part of the Program 'Hospitais de Excelencia a Servico do SUS (PROADI-SUS)'Brazilian Ministry of Healt