Nicotine Induces Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor by α1 Nicotinic Acetylcholine Receptor–Mediated Activation in PC9 Cells

IntroductionNicotine, the major component among the 4000 identified chemicals in cigarette smoke, binds to nicotinic acetylcholine receptors (nAChRs) on non–small-cell lung cancer (NSCLC) cells and regulates cellular proliferation by activating mitogen-activated protein kinases [AQ: MAPK has been expanded to mitogen-activated protein kinases. Please approve.]and PI3K/Akt pathways. In patients with smoking-related lung cancer who continue smoking, the anticancer effect of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is weaker than that in nonsmokers; however, the precise reason for this difference remains unclear. We investigated the role of α1 nAChR subunit in this phenomenon.MethodsWe screened for α1 nAChR mRNA in three NSCLC cell lines and analyzed the protein in resected primary NSCLC tissues. We used Western blot and RNA interference (siRNA) methodology to confirm the results.ResultsWe determined that α1 nAChR plays an essential role in nicotine-induced cell signaling and nicotine-induced resistance to EGFR-TKI. In addition, we showed that silencing of α1 nAChR subunit in NSCLC may suppress the nicotine-induced resistance to EGFR-TKI.ConclusionsThese results further implicate nicotine in lung carcinogenesis, and suggest that α1 nAChR may be a biomarker for EGFR-TKI treatment and also a personalizing target molecule for patients with smoking-related lung cancer

Ultraviolet Action Spectrum and Effect of EPC-K1 on Ultraviolet Radiation-induced Injury in Cultured Normal Human Epidermal Keratinocytes

This study was aimed to determine the ultraviolet (UV: 235-310nm) action spectrum for killing normal human epidermal keratinocytes (NHEK) and to investigate the preventive effect of EPC-K1, a phosphate diester of vitamin C and vitamin E on UV radiation-induced NHEK injury. NHEK were cultured in EpiLife medium supplemented with Human Keratinocyte Growth Supplement Kit. NHEK viability was determined by crystal violet (CV) staining 48 h after the UV irradiation. The mRNA expressions of the C/EBP homologous protein (Chop) transcription factor and endoplasmic reticulum-resident molecular chaperone, Bip, were determined by RT-PCR analyses. UV was especially effective in killing NHEK when applied in the wavelength region of 250-280nm. The minimum exposure dose required to kill 50% of cells (LD50) was 1.64mJ/cm2 at 269nm. At 235 and 310nm, the LD50 for NHEK was 6.62 and 293mJ/cm2, respectively. Irradiation of 660-mJ/cm2 at 310nm significantly decreased the cell viability to 30% of control (without irradiation). The addition of 0.1mM EPC-K1 after irradiation returned the cell viability to 118%. Six hours after the 660-mJ/cm2 irradiation at 310nm, Chop and Bip mRNA levels in NHEK were increased to 487% and 283%, respectively, and were not significantly affected by EPC-K1. Chop and Bip are responsive to ER stress. These results suggested that EPC-K1 exerts a protective effect against UV-induced NHEK injury, and further studies should investigate the molecular mechanism underlying this effect

Hospital death in dementia patients and regional provision of palliative and end-of-life care: National patient data analysis

Hospital death is associated with poor-quality end-of-life care, and hospital is the most common death location for dementia patients. However, end-of-life care is inappropriate for dementia, which is not a terminal condition. In Japan, dementia patients receive long-term hospital treatment, with few opportunities to return home. Therefore, we examined the association between hospital death in dementia patients and regional provision of home-based end-of-life care. We analyzed 12,933 discharged dementia patients’ data from the National Patient Survey, a nationally representative cross-sectional survey examining hospital discharges. Number of patients covered by home-based end-of-life care clinics per 1,000 population in their residential regions were calculated using regional statistics. Of the 12,933 patients, 20.6% died in hospitals (average hospitalization duration: 160 days). Regional provision of home-based end-of-life care was associated with hospital death in dementia patients. However, patients in regions with high numbers of patients covered by home-based end-of-life care clinics were likelier to die in hospital than at home. Such care clinics were unsuccessful in providing end-of-life care. Furthermore, despite regional availability of home-based end-of-life care clinics, patients were likelier to die in hospital than at home. Therefore, specific strategies are needed to improve home-care clinics for dementia patients who require end-of-life care

Tracking and quantification of dendritic cell migration and antigen trafficking between the skin and lymph nodes.

Skin-derived dendritic cells (DCs) play a crucial role in the maintenance of immune homeostasis due to their role in antigen trafficking from the skin to the draining lymph nodes (dLNs). To quantify the spatiotemporal regulation of skin-derived DCs in vivo, we generated knock-in mice expressing the photoconvertible fluorescent protein KikGR. By exposing the skin or dLN of these mice to violet light, we were able to label and track the migration and turnover of endogenous skin-derived DCs. Langerhans cells and CD103(+)DCs, including Langerin(+)CD103(+)dermal DCs (DDCs), remained in the dLN for 4-4.5 days after migration from the skin, while CD103(-)DDCs persisted for only two days. Application of a skin irritant (chemical stress) induced a transient >10-fold increase in CD103(-)DDC migration from the skin to the dLN. Tape stripping (mechanical injury) induced a long-lasting four-fold increase in CD103(-)DDC migration to the dLN and accelerated the trafficking of exogenous protein antigens by these cells. Both stresses increased the turnover of CD103(-)DDCs within the dLN, causing these cells to die within one day of arrival. Therefore, CD103(-)DDCs act as sentinels against skin invasion that respond with increased cellular migration and antigen trafficking from the skin to the dLNs

A case of immunoglobulin G4-related respiratory disease with multiple lung cysts: A case report

A 48-year-old man was admitted for evaluation of abnormal shadows on chest radiograph. Chest computed tomography (CT) showed cysts, nodules, and cervical and axillary lymphadenopathies. Elevated serum levels of IgG4 and interleukin (IL)-6 suggested IgG4-related disease (IgG4-RD) or multicentric Castleman's disease (MCD). Histologic findings of the cervical lymph node and right lung S6 biopsies revealed numerous IgG4-positive plasma cells. Although CT findings of the lungs were atypical for IgG4-RD, consistent histologic findings, clinical symptoms, and laboratory data made us conclude IgG4-RD. Because histologic findings of IgG4-RD and MCD have similarities, differentiating between the two diseases should consider the clinical presentation

Interstitial pneumonia caused by dabigatran

We describe the case of a 73-year-old man who experienced dry cough and exertional dyspnea after dabigatran administration. Chest radiographs revealed the development of bilateral consolidative and ground glass opacity, and transbronchial lung biopsy showed organized materials in the alveolar spaces with moderate inflammatory infiltrate and focal fibrosis. Lung opacity gradually disappeared after discontinuing dabigatran. To date, there has been only one report regarding dabigatran-induced lung injury, except for alveolar hemorrhage and eosinophilic pneumonia. Therefore, we should consider that any drug can cause various types of lung injuries. Keywords: Dabigatran, Interstitial pneumonia, Drug-induced lung injur