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Background: Triple-negative breast cancer (TNBC), lacking expression of hormone and human epidermal growth factor receptor 2 receptors, is an aggressive subtype that frequently metastasizes to the brain and has no FDA-approved systemic therapies. Previous literature demonstrates mitogen-Activated protein kinase kinase (MEK) pathway activation in TNBC brain metastases. Thus, we aimed to discover rational combinatorial therapies with MEK inhibition, hypothesizing that co-inhibition using clinically available brain-penetrant inhibitors would improve survival in preclinical models of TNBC brain metastases. Methods: Using human-derived TNBC cell lines, synthetic lethal small interfering RNA kinase screens were evaluated with brain-penetrant inhibitors against MEK1/2 (selumetinib, AZD6244) or phosphatidylinositol-3 kinase (PI3K; buparlisib, BKM120). Mice bearing intracranial TNBC tumors (SUM149, MDA-MB-231Br, MDA-MB-468, or MDA-MB-436) were treated with MEK, PI3K, or platelet derived growth factor receptor (PDGFR; pazopanib) inhibitors alone or in combination. Tumors were analyzed by western blot and multiplexed kinase inhibitor beads/mass spectrometry to assess treatment effects. Results: Screens identified MEK+PI3K and MEK+PDGFR inhibitors as tractable, rational combinations. Dual treatment of selumetinib with buparlisib or pazopanib was synergistic in TNBC cells in vitro. Both combinations improved survival in intracranial SUM149 and MDA-MB-231Br, but not MDA-MB-468 or MDA-MB-436. Treatments decreased mitogen-Activated protein kinase (MAPK) and PI3K (Akt) signaling in sensitive (SUM149 and 231Br) but not resistant models (MDA-MB-468). Exploratory analysis of kinome reprogramming in SUM149 intracranial tumors after MEK PI3K inhibition demonstrates extensive kinome changes with treatment, especially in MAPK pathway members. Conclusions: Results demonstrate that rational combinations of the clinically available inhibitors selumetinib with buparlisib or pazopanib may prove to be promising therapeutic strategies for the treatment of some TNBC brain metastases. Additionally, effective combination treatments cause widespread alterations in kinase pathways, including targetable potential resistance drivers.

Prone position ventilation for acute hypoxemic respiratory failure (AHRF) improves oxygenation but not survival, except possibly when AHRF is severe. To determine effects of prone versus supine ventilation in AHRF and severe hypoxemia [partial pressure of arterial oxygen (PaO2)/inspired fraction of oxygen (FiO(2)) < 100 mmHg] compared with moderate hypoxemia (100 mmHg a parts per thousand currency sign PaO2/FiO(2) a parts per thousand currency sign 300 mmHg). Systematic review and meta-analysis. Electronic databases (to November 2009) and conference proceedings. Two authors independently selected and extracted data from parallel-group randomized controlled trials comparing prone with supine ventilation in mechanically ventilated adults or children with AHRF. Trialists provided subgroup data. The primary outcome was hospital mortality in patients with AHRF and PaO2/FiO(2) < 100 mmHg. Meta-analyses used study-level random-effects models. Ten trials (N = 1,867 patients) met inclusion criteria; most patients had acute lung injury. Methodological quality was relatively high. Prone ventilation reduced mortality in patients with PaO2/FiO(2) < 100 mmHg [risk ratio (RR) 0.84, 95% confidence interval (CI) 0.74-0.96; p = 0.01; seven trials, N = 555] but not in patients with PaO2/FiO(2) a parts per thousand yen100 mmHg (RR 1.07, 95% CI 0.93-1.22; p = 0.36; seven trials, N = 1,169). Risk ratios differed significantly between subgroups (interaction p = 0.012). Post hoc analysis demonstrated statistically significant improved mortality in the more hypoxemic subgroup and significant differences between subgroups using a range of PaO2/FiO(2) thresholds up to approximately 140 mmHg. Prone ventilation improved oxygenation by 27-39% over the first 3 days of therapy but increased the risks of pressure ulcers (RR 1.29, 95% CI 1.16-1.44), endotracheal tube obstruction (RR 1.58, 95% CI 1.24-2.01), and chest tube dislodgement (RR 3.14, 95% CI 1.02-9.69). There was no statistical between-trial heterogeneity for most clinical outcomes. Prone ventilation reduces mortality in patients with severe hypoxemia. Given associated risks, this approach should not be routine in all patients with AHRF, but may be considered for severely hypoxemic patients.

Background: Prone position ventilation for acute hypoxemic respiratory failure (AHRF) improves oxygenation but not survival, except possibly when AHRF is severe. Objective: To determine effects of prone versus supine ventilation in AHRF and severe hypoxemia [partial pressure of arterial oxygen (PaO 2)/inspired fraction of oxygen (FiO2)