Somatic mutations that activate phosphoinositide 3-kinase (PI3K) have been identified in the p110-α catalytic subunit (PIK3CA) 1. They are most frequently observed in two hotspots: the helical domain (E545K and E542K) and the kinase domain (H1047R). Although the PIK3CA mutants are transforming in vitro, their oncogenic potential has not been assessed in genetically engineered mouse models. Furthermore, clinical trials with PI3K inhibitors have recently been initiated, and it is unknown if their efficacy will be restricted to specific, genetically defined malignancies. In this study, we engineered an inducible bitransgenic mouse model that develops lung adenocarcinomas initiated and maintained by expression of p110-α H1047R. Treatment of these tumors with NVP-BEZ235, a dual pan PI3K/mTOR inhibitor in clinical development, led to marked tumor regression as shown by PET-CT, MRI and microscopic examination. In contrast, mouse lung cancers driven by mutant K-Ras did not substantially respond to single-agent NVP-BEZ235. However, when NVP-BEZ235 was combined with a MEK inhibitor, ARRY-142886, there was dramatic synergy in shrinking these K-Ras mutant cancers. These in vivo studies suggest that inhibitors of the PI3K/mTOR pathway may be active in cancers with PIK3CA mutations, and, when combined with MEK inhibitors, may effectively treat K-RAS mutated lung cancers.
Background
Self-collected specimens has been advocated to avoid infectious exposure to healthcare workers. Self-induced sputum in those with a productive cough, and saliva in those without a productive cough have been proposed, but sensitivity remains uncertain.
Methods
We performed a prospective study in two regional hospitals in Hong Kong
Results
We prospectively examined 563 serial samples collected during the virus shedding periods of 50 patients: 150 deep-throat saliva (DTS), 309 pooled-nasopharyngeal (NP) and throat swabs, and 104 sputum. DTS had the lowest overall RT-PCR positive rate (68.7% vs. 89.4% [sputum] and 80.9% [pooled NP and throat swabs]), and the lowest viral RNA concentration (mean log copy/mL 3.54 vs. 5.03 [sputum] and 4.63 [pooled NP and throat swabs]). Analyses with respect to time from symptom onset and severity also revealed similar results. Virus yield of DTS correlated with that of sputum (Pearson correlation index [95% CI]: 0.76 [0.62 – 0.86]). We estimated the overall false-negative rate of DTS could be 31.3%, and increased 2.7 times among patients without sputum.
Conclusion
DTS produced the lowest viral RNA concentration and RT-PCR positive rate compared to conventional respiratory specimens in all phases of illness. Self-collect sputum should be the choice for patients with sputum.
is the research leader for the Exotic and Emerging Avian Viral Disease Research Unit of the Agricultural Research Service, USDA. His primary research interests are in the understanding and control of avian influenza and Newcastle disease viruses in poultry and other emerging viral diseases that threaten the poultry industry.
A combined computational and experimental study is presented that investigates the mechanism of the anti-Markovnikov hydration of phenylacetylene by [Ru(η(5)-C5H5)(6-DPPAP)(3-DPICon)](+) (where 6-DPPAP = 6-(diphenylphosphino)-N-pivaloyl-2-aminopyridine) and 3-DPICon = 3-diphenylphosphinoisoquinolone). The proposed mechanism, modelled using density functional calculations, involves an initial alkyne-vinylidene tautomerism, which occurs via a ligand-assisted proton shuttle (LAPS) mechanism. Intramolecular ligand assistance from the 6-DPPAP and 3-DPICon ligands, particularly the basic nitrogen of 6-DPPAP, is also involved in subsequent stages of the mechanism and three LAPS processes in total are observed. The self-assembled ligand backbone helps to create a water-binding pocket close to the metal centre, which facilitates nucleophilic attack of water at the vinylidene α-carbon and mediates protonation and deprotonation of subsequent acyl and vinyl intermediates. Experimental evidence is also presented for a novel non-productive catalyst deactivation pathway, which appears to arise from an initial lactam-lactim tautomerism of the 3-DPICon ligand followed by coupling with a vinylidene.
Anti-nucleosome antibodies demonstrate greater fidelity as a biomarker for changes in SLE disease activity than traditional biomarkers, supporting the routine monitoring of this antibody in clinical practice.
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