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

Randomized phase II study of pemetrexed or pemetrexed plus bevacizumab for elderly patients with previously untreated non-squamous non-small cell lung cancer: Results of the Lung Oncology Group in Kyushu (LOGIK1201)

Objectives: To evaluate the efficacy and safety, we conducted a randomized phase II study of pemetrexed (Pem) versus Pem + bevacizumab (Bev) for elderly patients with non-squamous non-small cell lung cancer (NSqNSCLC). Patients and methods: The eligibility criteria were as follows: NSqNSCLC, no prior therapy,stage IIIB/IV disease or postoperative recurrence, age: ?75 years, performance status (PS): 0?1, and adequate bone marrow function. The patients were randomly assigned (1:1 ratio)to receive Pem or Pem + Bev. The primary endpoint was progression-free survival (PFS).The secondary endpoints were the response rate, OS, toxicities, and cost-effectiveness. Results: Forty-one patients were enrolled and 40 (20 from each group) were assessable. Their characteristics were as follows: male/female = 23/17; median age (range) = 78 (75?83); stage IIIB/IV/postoperative recurrence = 1/30/9; PS 0/1 = 11/29. All cases involved adenocarcinoma.There was no significant intergroup difference in PFS and the median PFS (95% confidence interval) values of the Pem and Pem + Bev groups were 5.4 (3.0?7.4) and 5.5 (3.6?9.9) months, respectively (p = 0.66). The response rate was significantly higher in the Pem + Bev group(15% vs. 55%, p = 0.0146), and there was no significant difference in OS (median: 16.0 vs. 16.4 months, p = 0.58). Grade 3 and 4 leukopenia, neutropenia,and thrombocytopenia were seen in 10 and 30, 20 and 55, and 5 and 5 cases, respectively. Drug costs were higher in the Pem + Bev group (median: 1,522,008 vs. 3,368,428 JPY, p = 0.01). No treatment-related deaths occurred. Conclusions: Adding Bev to Pem did not result in improved survival in the elderly NSqNSCLC patients. Compared with Pem + Bev, Pem monotherapy had similar effects on survival, a more favorable toxicity profile, and was more cost-effective in elderly NSqNSCLC patients. Pem monotherapy might be one of the optional regimen for NSqNSCLC patients aged ?75 years

Concentration Dependence of Permeability Coefficients to an Electrolyte Component across Bovine Lens Capsule In Vitro

Theoretical and experimental studies have been made on permeability coefficients to various kinds of electrolyte across lens capsules that are dissected from bovine eyes and that are found to be positively fixed charged membranes from our experiments of membrane potentials. The differential permeability coefficient, P(m), is defined as J(s) = P(m)(C(2) - C(1)), where J(s) is the flux of an electrolyte component in moles per sec across unit area of the lens capsule that separates two aqueous solutions of the same electrolyte at different concentrations, C(2) and C(1). Various types of strong electrolytes were studied; KCl, NaCl, Cacl(2), MgSO(4), MgCl(2) and LaCl(3). It was found that at C(2)/C(1) = constant, P(m) decreases to zero as C(2) decreases and P(m) increases to a limiting value, (P(m))(∞), that is characteristic for the system of the salt used and the membrane as C(2) increases, despite of electrolytes. We assumed in theory that single ion activity coefficients of co-ion and gegen-ion are ideal, that the systems studied are in electric neutrality, that the fixed charge density of the membrane is independent of concentrations C(2), and that Donnan equilibrium holds between the bulk solution and membrane surface. Although the concentration-dependent changes of P(m) were quantitatively different depending on the type of electrolyte used, general agreement between theory and experiment was obtained over a wide range of concentrations except for the case of very dilute solutions

新規バブルジェット式霧化装置を用いたインスリンの経気道的投与

本実験で我々は, キヤノン株式会社がインクジェットプリンター技術を応用して開発した, 新規バブルジェット式霧化装置を用いてインスリンの経気道的投与を試みた. 本実験の目的は, この新規霧化装置を用いて正常ラットに吸入インスリンを投与し, その血糖降下作用の有効性を確認することである. 実験方法 : バブルジェット式霧化装置を用いて, Wistar ラットに吸入インスリン（15U/kg）, またはインスリンを含まないコントロール溶液を気管内投与した. インスリンまたはコントロール溶液投与後, 0, 10, 20, 30, 60, 90, 120分の血糖値を測定した. 実験結果 : 吸入インスリン群の血糖値は63 ± 10mg/dl（20 分）, 43 ± 8mg/dl（60 分）, 35 ±9mg/dl（120分）であった. 一方, コントロール溶液群の血糖値は80± 9mg/dl（p = 0.016）, 75±10mg/dl（p < 0.001）, 85 ± 27mg/dl（p < 0.001）であった. 吸入インスリン群の血糖値は, 0分と10分を除き全ての測定値においてコントロール溶液群より有意に低かった（p < 0.001）. 結論 : 我々は新規バブルジェット式霧化装置を用いた吸入インスリンの投与において, その血糖降下作用の有効性を確認した. これらの結果より, 新規装置はその生物活性を失うことなくインスリンを霧化できることが証明された.In this study, we attempted to perform inhalative administration of insulin using a newwbubble jetxatomization device based on ink jet printing technology and developed by Canon Inc. The aim of this study was to confirm the usefulness of the new device for achieving a hypoglycemic effect by insulin inhalation in normal rats. Methods : Inhaled insulin (15 U/kg) or a control solution without insulin was administrated to each Wistar rat intratracheally using the bubble-jet atomization device. Blood glucose concentrations were measured at 0, 10, 20, 30, 60, 90 and 120 min after administration of insulin or control solution. Results : The blood glucose concentrations in the inhaled insulin group were 63 ±10 mg/dl (20 min), 43 ± 8 mg/dl (60 min) and 35 ± 9 mg/dl (120 min), while those in the control solution group were 80±9 mg/dl (p = 0.016), 75 ± 10 mg/dl (p < 0.001) and 85 ± 27 mg/dl (p < 0.001). The blood glucose concentrations after administration of inhaled insulin were significantly lower than those after administration of control solution at all time points (p < 0.05) except 0 and 10 min. Conclusions : We confirmed the hypoglycemic effect of inhaled insulin using the new bubble jet atomization device. These results proved that the new device could atomize insulin while maintaining its bioactivity

National trends in the outcomes of subarachnoid haemorrhage and the prognostic influence of stroke centre capability in Japan: retrospective cohort study

Objectives To examine the national, 6-year trends in in-hospital clinical outcomes of patients with subarachnoid haemorrhage (SAH) who underwent clipping or coiling and the prognostic influence of temporal trends in the Comprehensive Stroke Center (CSC) capabilities on patient outcomes in Japan.Design Retrospective study.Setting Six hundred and thirty-one primary care institutions in Japan.Participants Forty-five thousand and eleven patients with SAH who were urgently hospitalised, identified using the J-ASPECT Diagnosis Procedure Combination database.Primary and secondary outcome measures Annual number of patients with SAH who remained untreated, or who received clipping or coiling, in-hospital mortality and poor functional outcomes (modified Rankin Scale: 3–6) at discharge. Each CSC was assessed using a validated scoring system (CSC score: 1–25 points).Results In the overall cohort, in-hospital mortality decreased (year for trend, OR (95% CI): 0.97 (0.96 to 0.99)), while the proportion of poor functional outcomes remained unchanged (1.00 (0.98 to 1.02)). The proportion of patients who underwent clipping gradually decreased from 46.6% to 38.5%, while that of those who received coiling and those left untreated gradually increased from 16.9% to 22.6% and 35.4% to 38%, respectively. In-hospital mortality of coiled (0.94 (0.89 to 0.98)) and untreated (0.93 (0.90 to 0.96)) patients decreased, whereas that of clipped patients remained stable. CSC score improvement was associated with increased use of coiling (per 1-point increase, 1.14 (1.08 to 1.20)) but not with short-term patient outcomes regardless of treatment modality.Conclusions The 6-year trends indicated lower in-hospital mortality for patients with SAH (attributable to better outcomes), increased use of coiling and multidisciplinary care for untreated patients. Further increasing CSC capabilities may improve overall outcomes, mainly by increasing the use of coiling. Additional studies are necessary to determine the effect of confounders such as aneurysm complexity on outcomes of clipped patients in the modern endovascular era