We previously demonstrated that the transcription factor NF-E2-related factor2 (Nrf2), expressed abundantly in non-small-cell lung cancer (NSCLC) cells, plays a pivotal role in the proliferation and ...chemoresistance of NSCLC. Here we show that Nrf2-mediated NSCLC cell proliferation is dually regulated by epidermal growth factor receptor (EGFR) signaling and an Nrf2 repressor protein Keap1 (Kelch-like ECH-associated protein-1). NSCLC cells expressing wild-type EGFR and Keap1 genes show enhanced proliferation on stimulation with EGFR ligand under non-stress conditions. Exposure to cigarette smoke extract (CSE) enhanced cell proliferation by modification of the Nrf2/Keap1 interaction. Although EGFR-tyrosine kinase inhibitor (TKI) inhibited the proliferation of these cells, exposure to CSE attenuated its efficacy. In NSCLC cells with Keap1 gene mutations, Nrf2 was constitutively activated owing to dysfunction of Keap1 and cells proliferated independently of EGFR signaling. Furthermore, EGFR-TKI was unable to inhibit their proliferation. In NSCLC cells with EGFR gene mutations, Nrf2 was constitutively activated by EGFR signaling. In these cells, proliferation was largely dependent on the EGFR signaling pathway. Although these cells were highly sensitive to EGFR-TKI, exposure to CSE or knockdown of Keap1 mRNA reduced sensitivity to EGFR-TKI. We found a case of NSCLC showing resistance to EGFR-TKI despite having EGFR-TKI-sensitive EGFR gene mutation because of dysfunctional mutation in Keap1 gene. Results indicate that oxidative stress reduces the anticancer effects of EGFR-TKI in wild-type Keap1 NSCLC cells. Analysis of Keap1 dysfunction may become a novel molecular marker to predict resistance to EGFR-TKI in NSCLC cells having EGFR-TKI-sensitive EGFR mutations. Finally, as the downstream molecule of both EGFR and Keap1 signaling, Nrf2 is an important molecular target for the treatment of NSCLC, where cells have mutations in EGFR, KRAS or Keap1 genes.
We search for the signature of parity-violating physics in the cosmic microwave background, called cosmic birefringence, using the Planck data release 4. We initially find a birefringence angle of ...β=0.30°±0.11° (68% C.L.) for nearly full-sky data. The values of β decrease as we enlarge the Galactic mask, which can be interpreted as the effect of polarized foreground emission. Two independent ways to model this effect are used to mitigate the systematic impact on β for different sky fractions. We choose not to assign cosmological significance to the measured value of β until we improve our knowledge of the foreground polarization.
Background Endothelial progenitor cells (EPCs) play an important role in the maintenance of vascular integrity. Lipid lowering therapy (LLT) with statins may contribute to biologically relevant ...activities including the proliferation of endothelial cells. The physiological role of microRNA (miR)‐221/222, a newly discovered class of small RNA, is closely linked to the proliferation of endothelial cells. We therefore investigated whether LLT with statins might affect miR‐221/222 expression in EPCs obtained from patients with coronary artery disease (CAD).
Materials and methods This study included 44 patients with stable CAD and 22 subjects without CAD (non‐CAD). Patients with CAD were randomized to 12 months of LLT with atorvastatin (10 mg day−1) or pravastatin (10 mg day−1). EPCs were obtained from peripheral blood at baseline and after 12 months of statin therapy. Levels of miR‐221/222 in EPCs were measured by real‐time RT‐PCR.
Results Levels of miR‐221/222 were significantly higher in the CAD group than in the non‐CAD group (P < 0·01). Levels of miR‐221/222 were weakly negatively correlated with EPC number in the CAD group. After 12 months of therapy, changes in lipid profiles were greater in the atorvastatin group than in the pravastatin group. LLT with atorvastatin markedly increased EPC numbers and decreased miR‐221/222 levels (all P < 0·05), whereas LLT with pravastatin did not change EPC numbers or miR‐221/222 levels.
Conclusions This study demonstrates that LLT with atorvastatin increases EPC numbers and decreases miR‐221/222 levels in patients with CAD, possibly contributing to the beneficial effects of LLT with atorvastatin in this disorder.
Ultracold neutrons (UCNs) can be bound by the potential of terrestrial gravity and a reflecting mirror. The wave function of the bound state has characteristic modulations. We carried out an ...experiment to observe the vertical distribution of the UCNs above such a mirror at the Institut Laue-Langevin in 2011. The observed modulation is in good agreement with that prediction by quantum mechanics using the Wigner function. The spatial resolution of the detector system is estimated to be 0.7 μm. This is the first observation of gravitationally bound states of UCNs with submicron spatial resolution.
The role of adult weight change in breast cancer (BC) risk is unclear in Japanese women.
A total of 10,106 postmenopausal women aged 40-64 years (the Miyagi Cohort) were followed from 1990 to 2003, ...and 108 BC cases were identified. Hazard ratios (HRs) were estimated according to body mass index (BMI) at the current age and at the of age 20 years, and weight change since age 20 years.
Higher current BMI was associated with an increased risk of BC (P for trend=0.02), whereas higher BMI at the age 20 years was inversely associated with this risk (P for trend=0.002). There was a significant association between weight change since age 20 years and BC risk (P for trend=0.0086). Compared with stable weight, HR was 0.35 for weight loss of 5 kg or more (P for weight loss trend=0.04) and 1.55 for weight gain of 12 kg or more (P for weight gain trend=0.05).
Adiposity at younger and current age has differential effects on BC risk among postmenopausal women; weight gain in adulthood being associated with an increased, and weight loss with a decreased risk.
Using only cosmic microwave background polarization data from the polarbear experiment, we measure B-mode polarization delensing on subdegree scales at more than 5σ significance. We achieve a 14% ...B-mode power variance reduction, the highest to date for internal delensing, and improve this result to 22% by applying for the first time an iterative maximum a posteriori delensing method. Our analysis demonstrates the capability of internal delensing as a means of improving constraints on inflationary models, paving the way for the optimal analysis of next-generation primordial B-mode experiments.
PDF
