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Sample records for absolute lung resistivity

  1. Method for estimating absolute lung volumes at constant inflation pressure.

    PubMed

    Hills, B A; Barrow, R E

    1979-10-01

    A method has been devised for measuring functional residual capacity in the intact killed animal or absolute lung volumes in any excised lung preparation without changing the inflation pressure. This is achieved by titrating the absolute pressure of a chamber in which the preparation is compressed until a known volume of air has entered the lungs. This technique was used to estimate the volumes of five intact rabbit lungs and five rigid containers of known dimensions by means of Boyle's law. Results were found to agree to within +/- 1% with values determined by alternative methods. In the discussion the advantage of determining absolute lung volumes at almost any stage in a study of lung mechanics without the determination itself changing inflation pressure and, hence, lung volume is emphasized. PMID:511699

  2. Prognostic significance of the absolute monocyte counts in lung cancer patients with venous thromboembolism.

    PubMed

    Go, Se-Il; Kim, Rock Bum; Song, Haa-Na; Kang, Myoung Hee; Lee, Un Seok; Choi, Hye Jung; Jo, Wonyong; Lee, Seung Jun; Cho, Yu Ji; Jeong, Yi Yeong; Kim, Ho Cheol; Lee, Jong Deog; Kim, Seok-Hyun; Kang, Jung-Hun; Lee, Gyeong-Won

    2015-09-01

    We investigated the clinical significance of the absolute monocyte count (AMC) as a predictor of the response to anticoagulation and survival in lung cancer patients with venous thromboembolism (VTE). We retrospectively reviewed 1707 patients with pathologically proven lung cancer who visited the hospital between July 2008 and May 2014. Among them, the clinical data of patients newly diagnosed with VTE and treated with anticoagulation were compared between the low and high AMC groups according to the median value of AMC (640/μL) at the time of VTE diagnosis. The incidence of VTE was 7.9 % during the study period. Most of the patients had non-small-cell lung cancer (82.1 %), stage IV (64.2 %), and pulmonary thromboembolism (76.1 %) and were incidentally diagnosed with VTE (76.9 %). The patients' characteristics and laboratory values were not significantly different between the low and high AMC groups. Among patients available for evaluation of the response to anticoagulation, the high AMC group was significantly more refractory to anticoagulation than the low AMC group (no response to anticoagulation, 21.7 vs. 6.8 %, respectively; p = 0.044). Additionally, the high AMC group showed worse overall survival (OS) than the low AMC group (median, 9.6 vs. 5.9 months; p = 0.038). On multivariate analysis, high AMC, low albumin, and advanced stage were independent poor prognostic factors for OS. High AMC is associated with refractoriness to anticoagulation and poor prognosis in lung cancer patients with VTE.

  3. Effects of Three Resistance Training Programs on Muscular Strength and Absolute and Relative Endurance.

    ERIC Educational Resources Information Center

    Anderson, Tim; Kearney, Jay T.

    1982-01-01

    The effects of three resistance training programs on male college students' muscular strength and absolute and relative muscular endurance were investigated. Results show that human skeletal muscle makes both general and specific adaptations to a training stimulus, and that the balance of these adaptations is to some extent dependent upon the…

  4. Absolute quantification of lung cancer related microRNA by droplet digital PCR.

    PubMed

    Wang, Ping; Jing, Fengxiang; Li, Gang; Wu, Zhenhua; Cheng, Zule; Zhang, Jishen; Zhang, Honglian; Jia, Chunping; Jin, Qinghui; Mao, Hongju; Zhao, Jianlong

    2015-12-15

    Digital polymerase chain reaction (digital PCR) enables the absolute quantification of nucleic acids through the counting of single molecules, thus eliminating the need for standard curves or endogenous controls. In this study, we developed a droplet digital PCR (ddPCR) system based on an oil saturated PDMS (OSP) microfluidic chip platform for quantification of lung cancer related microRNA (miRNA). The OSP chip was made with PDMS and was oil saturated to constrain oil swallow and maintain the stability of droplets. Two inlets were designed for oil and sample injection with a syringe pump at the outlet. Highly uniform monodisperse water-in-oil emulsion droplets to be used for subsequent detection and analysis were generated at the cross section of the channel. We compared miRNA quantification by the ddPCR system and quantitative real-time PCR (qPCR) to demonstrate that the ddPCR system was superior to qPCR both in its detection limit and smaller fold changes measurement. This droplet PCR system provides new possibilities for highly sensitive and efficient detection of cancer-related genes. PMID:26232679

  5. Can resistive breathing injure the lung? Implications for COPD exacerbations

    PubMed Central

    Vassilakopoulos, Theodoros; Toumpanakis, Dimitrios

    2016-01-01

    In obstructive lung diseases, airway inflammation leads to bronchospasm and thus resistive breathing, especially during exacerbations. This commentary discusses experimental evidence that resistive breathing per se (the mechanical stimulus) in the absence of underlying airway inflammation leads to lung injury and inflammation (mechanotransduction). The potential implications of resistive breathing-induced mechanotrasduction in COPD exacerbations are presented along with the available clinical evidence. PMID:27713628

  6. Basic Mechanisms of Therapeutic Resistance to Radiation and Chemotherapy in Lung Cancer

    PubMed Central

    Willers, Henning; Azzoli, Christopher G.; Santivasi, Wil L.; Xia, Fen

    2013-01-01

    In recent years, there have been multiple breakthroughs in our understanding of lung cancer biology. Despite significant advances in molecular targeted therapies DNA-damaging cytotoxic therapies will remain the mainstay of lung cancer management for the foreseeable future. Similar to the concept of personalized targeted therapies there is mounting evidence that perturbations in DNA repair pathways are common in lung cancers, altering the resistance of the affected tumors to many chemotherapeutics as well as radiation. Defects in DNA repair may be due to a multitude of mechanisms including gene mutations, epigenetic events, and alterations in signal transduction pathways such as EGFR and PI3K/AKT. Functional biomarkers that assess the subcellular localization of central repair proteins in response to DNA damage may prove useful for individualization of cytotoxic therapies including PARP inhibitors. A better mechanistic understanding of cellular sensitivity and resistance to DNA damaging agents should facilitate the development of novel, individualized treatment approaches. Absolute resistance to radiation therapy, however, does not exist. To some extent, radiation therapy will always have to remain unselective and indiscriminant to eradicate persistent, drug-resistant tumor stem cell pools. PMID:23708066

  7. Association between absolute volumes of lung spared from low-dose irradiation and radiation-induced lung injury after intensity-modulated radiotherapy in lung cancer: a retrospective analysis

    PubMed Central

    Chen, Jinmei; Hong, Jinsheng; Zou, Xi; Lv, Wenlong; Guo, Feibao; Hong, Hualan; Zhang, Weijian

    2015-01-01

    The aim of this study was to investigate the association between absolute volumes of lung spared from low-dose irradiation and radiation-induced lung injury (RILI) after intensity-modulated radiotherapy (IMRT) for lung cancer. The normal lung relative volumes receiving greater than 5, 10, 20 and 30 Gy (V5–30) mean lung dose (MLD), and absolute volumes spared from greater than 5, 10, 20 and 30 Gy (AVS5–30) for the bilateral and ipsilateral lungs of 83 patients were recorded. Any association of clinical factors and dose–volume parameters with Grade ≥2 RILI was analyzed. The median follow-up was 12.3 months; 18 (21.7%) cases of Grade 2 RILI, seven (8.4%) of Grade 3 and two (2.4%) of Grade 4 were observed. Univariate analysis revealed the located lobe of the primary tumor. V5, V10, V20, MLD of the ipsilateral lung, V5, V10, V20, V30 and MLD of the bilateral lung, and AVS5 and AVS10 of the ipsilateral lung were associated with Grade ≥2 RILI (P < 0.05). Multivariate analysis indicated AVS5 of the ipsilateral lung was prognostic for Grade ≥2 RILI (P = 0.010, OR = 0.272, 95% CI: 0.102–0.729). Receiver operating characteristic curves indicated Grade ≥2 RILI could be predicted using AVS5 of the ipsilateral lung (area under curve, 0.668; cutoff value, 564.9 cm3; sensitivity, 60.7%; specificity, 70.4%). The incidence of Grade ≥2 RILI was significantly lower with AVS5 of the ipsilateral lung ≥564.9 cm3 than with AVS5 < 564.9 cm3 (P = 0.008). Low-dose irradiation relative volumes and MLD of the bilateral or ipsilateral lung were associated with Grade ≥2 RILI, and AVS5 of the ipsilateral lung was prognostic for Grade ≥2 RILI for lung cancer after IMRT. PMID:26454068

  8. Understanding the resistivity and absolute thermoelectric power of disordered metals and alloys

    NASA Astrophysics Data System (ADS)

    Gasser, Jean-Georges

    2008-03-01

    We recall definitions of the electronic transport properties, direct coefficients like electrical and thermal transport conductivities and crossed thermoelectric coefficients like the Seebeck, Peltier and Thomson coefficients. We discuss the links between the different electronic transport coefficients and the experimental problems in measuring these properties in liquid metals. The electronic transport properties are interpreted in terms of the scattering of electrons by 'pseudo-atoms'. The absolute thermoelectric power (ATP), thermopower or Seebeck coefficient is known as the derivative of the electrical resistivity versus energy. The key is to understand the concept of resistivity versus energy. We show that the resistivity follows approximately a 1/E curve. The structure factor modulates this curve and, for a Fermi energy corresponding to noble and divalent metals, induces a positive thermopower when the free electron theory predicts a negative one. A second modulation is introduced by the pseudopotential squared form factor or equivalently by the squared t matrix of the scattering potential. This term sometimes introduces an anti-resonance (divalent metals) which lowers the resistivity, and sometimes a resonance having an important effect on the transition metals. Following the position of the Fermi energy, the thermopower can be positive or negative. For heavy semi-metals, the density of states splits into an s and a p band, themselves different from a free electron E0.5 curve. The electrons available to be scattered enter the Ziman formula. Thus if the density of states is not a free electron one, a third modulation of the \\rho \\cong 1/E curve is needed, which also can change the sign of the thermopower. For alloys, different contributions weighted by the concentrations are needed to explain the concentration dependent resistivity or thermopower. The formalism is the same for amorphous metals. It is possible that this mechanism can be extended to high

  9. Indirectly estimated absolute lung cancer mortality rates by smoking status and histological type based on a systematic review

    PubMed Central

    2013-01-01

    Background National smoking-specific lung cancer mortality rates are unavailable, and studies presenting estimates are limited, particularly by histology. This hinders interpretation. We attempted to rectify this by deriving estimates indirectly, combining data from national rates and epidemiological studies. Methods We estimated study-specific absolute mortality rates and variances by histology and smoking habit (never/ever/current/former) based on relative risk estimates derived from studies published in the 20th century, coupled with WHO mortality data for age 70–74 for the relevant country and period. Studies with populations grossly unrepresentative nationally were excluded. 70–74 was chosen based on analyses of large cohort studies presenting rates by smoking and age. Variations by sex, period and region were assessed by meta-analysis and meta-regression. Results 148 studies provided estimates (Europe 59, America 54, China 22, other Asia 13), 54 providing estimates by histology (squamous cell carcinoma, adenocarcinoma). For all smoking habits and lung cancer types, mortality rates were higher in males, the excess less evident for never smokers. Never smoker rates were clearly highest in China, and showed some increasing time trend, particularly for adenocarcinoma. Ever smoker rates were higher in parts of Europe and America than in China, with the time trend very clear, especially for adenocarcinoma. Variations by time trend and continent were clear for current smokers (rates being higher in Europe and America than Asia), but less clear for former smokers. Models involving continent and trend explained much variability, but non-linearity was sometimes seen (with rates lower in 1991–99 than 1981–90), and there was regional variation within continent (with rates in Europe often high in UK and low in Scandinavia, and higher in North than South America). Conclusions The indirect method may be questioned, because of variations in definition of smoking and

  10. Dynamics of Lung Defense in Pneumonia: Resistance, Resilience, and Remodeling

    PubMed Central

    Quinton, Lee J.; Mizgerd, Joseph P.

    2015-01-01

    Pneumonia is initiated by microbes in the lung, but physiological processes integrating responses across diverse cell types and organ systems dictate the outcome of respiratory infection. Resistance, or actions of the host to eradicate living microbes, in the lungs involves a combination of innate and adaptive immune responses triggered by air-space infection. Resilience, or the ability of the host tissues to withstand the physiologically damaging effects of microbial and immune activities, is equally complex, precisely regulated, and determinative. Both immune resistance and tissue resilience are dynamic and change throughout the lifetime, but we are only beginning to understand such remodeling and how it contributes to the incidence of severe pneumonias, which diminishes as childhood progresses and then increases again among the elderly. Here, we review the concepts of resistance, resilience, and remodeling as they apply to pneumonia, highlighting recent advances and current significant knowledge gaps. PMID:25148693

  11. Easy Absolute Values? Absolutely

    ERIC Educational Resources Information Center

    Taylor, Sharon E.; Mittag, Kathleen Cage

    2015-01-01

    The authors teach a problem-solving course for preservice middle-grades education majors that includes concepts dealing with absolute-value computations, equations, and inequalities. Many of these students like mathematics and plan to teach it, so they are adept at symbolic manipulations. Getting them to think differently about a concept that they…

  12. TCRP1 contributes to cisplatin resistance by preventing Pol β degradation in lung cancer cells.

    PubMed

    Liu, Xiaorong; Wang, Chengkun; Gu, Yixue; Zhang, Zhijie; Zheng, Guopei; He, Zhimin

    2015-01-01

    Cisplatin (DDP) is the first-line chemotherapy drug widely used for the treatment of lung cancer patients, whereas the majority of cancer patients will eventually show resistance to DDP. The mechanisms responsible for DDP resistance are not fully understood. Tongue cancer resistance-associated protein 1 (TCRP1) gene was recently cloned and reported to specially mediate DDP resistance in human oral squamous cell carcinoma (OSCC) cells. However, the mechanisms of TCRP1-mediated DDP resistance are far from clear, and whether TCRP1 participates in DDP resistance in lung cancer cells remains unknown. Here, we show that TCRP1 contributes to DDP resistance in lung cancer cells. Knockdown of TCRP1 sensitizes the cells to DDP and increases the DDP-induced DNA damage. We have identified that Pol β is associated with DDP resistance, and Pol β knockdown delays the repair of DDP-induced DNA damage in A549/DDP cells. We find TCRP1 interacts with Pol β in lung cancer cells. Moreover, TCRP1 knockdown decreases the level of Pol β and increases the level of its ubiquitination. These results suggest that TCRP1 contributes to DDP resistance through the prevention of Pol β degradation in lung cancer cells. These findings provide new insights into chemoresistance and may contribute to prevention and reversal of DDP resistance in treatment of lung cancer in the future.

  13. Behavior of vascular resistance undergoing various pressure insufflation and perfusion on decellularized lungs.

    PubMed

    da Palma, Renata Kelly; Nonaka, Paula Naomi; Campillo, Noelia; Uriarte, Juan J; Urbano, Jessica Julioti; Navajas, Daniel; Farré, Ramon; Oliveira, Luis V F

    2016-05-01

    Bioengineering of functional lung tissue by using whole lung scaffolds has been proposed as a potential alternative for patients awaiting lung transplant. Previous studies have demonstrated that vascular resistance (Rv) could be altered to optimize the process of obtaining suitable lung scaffolds. Therefore, this work was aimed at determining how lung inflation (tracheal pressure) and perfusion (pulmonary arterial pressure) affect vascular resistance. This study was carried out using the lungs excised from 5 healthy male Sprague-Dawley rats. The trachea was cannulated and connected to a continuous positive airway pressure (CPAP) device to provide a tracheal pressure ranging from 0 to 15cmH2O. The pulmonary artery was cannulated and connected to a controlled perfusion system with continuous pressure (gravimetric level) ranging from 5 to 30cmH2O. Effective Rv was calculated by ratio of pulmonary artery pressure (PPA) by pulmonary artery flow (V'PA). Rv in the decellularized lungs scaffolds decreased at increasing V'PA, stabilizing at a pulmonary arterial pressure greater than 20cmH2O. On the other hand, CPAP had no influence on vascular resistance in the lung scaffolds after being subjected to pulmonary artery pressure of 5cmH2O. In conclusion, compared to positive airway pressure, arterial lung pressure markedly influences the mechanics of vascular resistance in decellularized lungs.

  14. A Functional Landscape of Resistance to ALK Inhibition in Lung Cancer

    PubMed Central

    Wilson, Frederick H.; Johannessen, Cory M.; Piccioni, Federica; Tamayo, Pablo; Kim, Jong Wook; Van Allen, Eliezer M.; Corsello, Steven M.; Capelletti, Marzia; Calles, Antonio; Butaney, Mohit; Sharifnia, Tanaz; Gabriel, Stacey B.; Mesirov, Jill P.; Hahn, William C.; Engelman, Jeffrey A.; Meyerson, Matthew; Root, David E.; Jänne, Pasi A.; Garraway, Levi A.

    2015-01-01

    Summary We conducted a large-scale functional genetic study to characterize mechanisms of resistance to ALK inhibition in ALK-dependent lung cancer cells. We identify members of known resistance pathways and additional putative resistance drivers. Among the latter were members of the P2Y purinergic receptor family of G-protein coupled receptors (P2Y1, P2Y2, and P2Y6). P2Y receptors mediated resistance in part through a protein kinase C (PKC)-dependent mechanism. Moreover, PKC activation alone was sufficient to confer resistance to ALK inhibitors whereas combined ALK and PKC inhibition restored sensitivity. We observed enrichment of gene signatures associated with several resistance drivers (including P2Y receptors) in crizotinib-resistant ALK-rearranged lung tumors compared to treatment-naïve controls, supporting a role for identified resistance mechanisms in clinical resistance. PMID:25759024

  15. An etoposide-resistant lung cancer subline overexpresses the multidrug resistance-associated protein.

    PubMed Central

    Doyle, L. A.; Ross, D. D.; Ordonez, J. V.; Yang, W.; Gao, Y.; Tong, Y.; Belani, C. P.; Gutheil, J. C.

    1995-01-01

    We have characterised an etoposide-resistant subline of the small-cell lung cancer cell line, UMCC-1, derived at our centre. Subline UMCC-1/VP was developed by culturing the parent line in increasing concentrations of etoposide over 16 months. UMCC-1/VP is 20-fold resistant to etoposide by MTT assays, relative to the parent line, and is cross-resistant to doxorubicin, vincristine and actinomycin D, but not to taxol, cisplatin, melphalan, thiotepa or idarubicin. Topoisomerase II immunoblotting demonstrates a 50% reduction of the protein in the resistant subline. The UMCC-1/VP subline demonstrates a marked decrease in the accumulation of [3H]etoposide relative to the parent line, as well as a modest reduction in the accumulation of daunorubicin. Reverse transcription-polymerase chain reaction assays demonstrate no detectable mdr1 expression but marked expression of the multidrug resistance-associated protein (MRP) gene in the resistant subline. Northern blotting with an MRP cDNA probe confirms marked overexpression of the MRP gene only in the UMCC-1/VP subline. Western blotting with antisera against MRP peptide confirms a 195 kDa protein band in the UMCC-1/VP subline. Southern blotting experiments demonstrate a 10-fold amplification of the MRP gene in the resistant subline. Depletion of glutathione with buthionine sulphoximine sensitised UMCC-1/VP cells to daunorubicin and etoposide. Our studies indicate that MRP gene expression may be induced by etoposide and may lead to reduced accumulation of the drug. Images Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 PMID:7669558

  16. EPHA2 Blockade Overcomes Acquired Resistance to EGFR Kinase Inhibitors in Lung Cancer.

    PubMed

    Amato, Katherine R; Wang, Shan; Tan, Li; Hastings, Andrew K; Song, Wenqiang; Lovly, Christine M; Meador, Catherine B; Ye, Fei; Lu, Pengcheng; Balko, Justin M; Colvin, Daniel C; Cates, Justin M; Pao, William; Gray, Nathanael S; Chen, Jin

    2016-01-15

    Despite the success of treating EGFR-mutant lung cancer patients with EGFR tyrosine kinase inhibitors (TKI), all patients eventually acquire resistance to these therapies. Although various resistance mechanisms have been described, there are currently no FDA-approved therapies that target alternative mechanisms to treat lung tumors with acquired resistance to first-line EGFR TKI agents. Here we found that EPHA2 is overexpressed in EGFR TKI-resistant tumor cells. Loss of EPHA2 reduced the viability of erlotinib-resistant tumor cells harboring EGFR(T790M) mutations in vitro and inhibited tumor growth and progression in an inducible EGFR(L858R+T790M)-mutant lung cancer model in vivo. Targeting EPHA2 in erlotinib-resistant cells decreased S6K1-mediated phosphorylation of cell death agonist BAD, resulting in reduced tumor cell proliferation and increased apoptosis. Furthermore, pharmacologic inhibition of EPHA2 by the small-molecule inhibitor ALW-II-41-27 decreased both survival and proliferation of erlotinib-resistant tumor cells and inhibited tumor growth in vivo. ALW-II-41-27 was also effective in decreasing viability of cells with acquired resistance to the third-generation EGFR TKI AZD9291. Collectively, these data define a role for EPHA2 in the maintenance of cell survival of TKI-resistant, EGFR-mutant lung cancer and indicate that EPHA2 may serve as a useful therapeutic target in TKI-resistant tumors.

  17. EPHA2 Blockade Overcomes Acquired Resistance to EGFR Kinase Inhibitors in Lung Cancer.

    PubMed

    Amato, Katherine R; Wang, Shan; Tan, Li; Hastings, Andrew K; Song, Wenqiang; Lovly, Christine M; Meador, Catherine B; Ye, Fei; Lu, Pengcheng; Balko, Justin M; Colvin, Daniel C; Cates, Justin M; Pao, William; Gray, Nathanael S; Chen, Jin

    2016-01-15

    Despite the success of treating EGFR-mutant lung cancer patients with EGFR tyrosine kinase inhibitors (TKI), all patients eventually acquire resistance to these therapies. Although various resistance mechanisms have been described, there are currently no FDA-approved therapies that target alternative mechanisms to treat lung tumors with acquired resistance to first-line EGFR TKI agents. Here we found that EPHA2 is overexpressed in EGFR TKI-resistant tumor cells. Loss of EPHA2 reduced the viability of erlotinib-resistant tumor cells harboring EGFR(T790M) mutations in vitro and inhibited tumor growth and progression in an inducible EGFR(L858R+T790M)-mutant lung cancer model in vivo. Targeting EPHA2 in erlotinib-resistant cells decreased S6K1-mediated phosphorylation of cell death agonist BAD, resulting in reduced tumor cell proliferation and increased apoptosis. Furthermore, pharmacologic inhibition of EPHA2 by the small-molecule inhibitor ALW-II-41-27 decreased both survival and proliferation of erlotinib-resistant tumor cells and inhibited tumor growth in vivo. ALW-II-41-27 was also effective in decreasing viability of cells with acquired resistance to the third-generation EGFR TKI AZD9291. Collectively, these data define a role for EPHA2 in the maintenance of cell survival of TKI-resistant, EGFR-mutant lung cancer and indicate that EPHA2 may serve as a useful therapeutic target in TKI-resistant tumors. PMID:26744526

  18. Erlotinib resistance in mouse models of epidermal growth factor receptor-induced lung adenocarcinoma

    PubMed Central

    Politi, Katerina; Fan, Pang-Dian; Shen, Ronglai; Zakowski, Maureen; Varmus, Harold

    2010-01-01

    SUMMARY Seventy-five percent of lung adenocarcinomas with epidermal growth factor receptor (EGFR) mutations respond to treatment with the tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib; however, drug-resistant tumors eventually emerge. In 60% of cases, resistant tumors carry a secondary mutation in EGFR (T790M), amplification of MET, or both. Here, we describe the establishment of erlotinib resistance in lung tumors, which were induced by mutant EGFR, in transgenic mice after multiple cycles of drug treatment; we detect the T790M mutation in five out of 24 tumors or Met amplification in one out of 11 tumors in these mice. This preclinical mouse model, therefore, recapitulates the molecular changes responsible for resistance to TKIs in human tumors and holds promise for the discovery of additional mechanisms of drug resistance in lung cancer. PMID:20007486

  19. Erlotinib resistance in mouse models of epidermal growth factor receptor-induced lung adenocarcinoma.

    PubMed

    Politi, Katerina; Fan, Pang-Dian; Shen, Ronglai; Zakowski, Maureen; Varmus, Harold

    2010-01-01

    Seventy-five percent of lung adenocarcinomas with epidermal growth factor receptor (EGFR) mutations respond to treatment with the tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib; however, drug-resistant tumors eventually emerge. In 60% of cases, resistant tumors carry a secondary mutation in EGFR (T790M), amplification of MET, or both. Here, we describe the establishment of erlotinib resistance in lung tumors, which were induced by mutant EGFR, in transgenic mice after multiple cycles of drug treatment; we detect the T790M mutation in five out of 24 tumors or Met amplification in one out of 11 tumors in these mice. This preclinical mouse model, therefore, recapitulates the molecular changes responsible for resistance to TKIs in human tumors and holds promise for the discovery of additional mechanisms of drug resistance in lung cancer.

  20. Significant blood resistance to nitric oxide transfer in the lung.

    PubMed

    Borland, Colin D R; Dunningham, Helen; Bottrill, Fiona; Vuylsteke, Alain; Yilmaz, Cuneyt; Dane, D Merrill; Hsia, Connie C W

    2010-05-01

    Lung diffusing capacity for nitric oxide (DLNO) is used to measure alveolar membrane conductance (DMNO), but disagreement remains as to whether DMNO=DLNO, and whether blood conductance (thetaNO)=infinity. Our previous in vitro and in vivo studies suggested that thetaNOresistance to alveolar-capillary NO uptake. DLNO is sensitive to dynamic hematological factors and is not a pure index of conductance of the alveolar tissue membrane. With successive exchange transfusion, the estimated in vivo thetaNO [5.1 ml NO.(ml blood.min.Torr)(-1)] approached 4.5 ml NO.(ml blood.min.Torr)(-1), which was derived from in vitro measurements by Carlsen and Comroe (J Gen Physiol 42: 83-107, 1958). Therefore, we suggest use of thetaNO=4.5 ml NO.(min.Torr.ml blood)(-1) for calculation of DM(NO) and pulmonary capillary blood volume from DLNO and DLCO.

  1. Role of GSTM1 in Resistance for Lung Inflammation

    EPA Science Inventory

    Lung inflammation resulting from oxidant/antioxidant imbalance is a common feature of many lung diseases. In particular, the role of enzymes regulated by the NF-E2-related factor 2 (Nrf2) transcription factor has recently received increased attention. Among these antioxidant gene...

  2. The differential effects of inspiratory, expiratory, and combined resistive breathing on healthy lung

    PubMed Central

    Loverdos, Konstantinos; Toumpanakis, Dimitrios; Litsiou, Eleni; Karavana, Vassiliki; Glynos, Constantinos; Magkou, Christina; Theocharis, Stamatios; Vassilakopoulos, Theodoros

    2016-01-01

    Combined resistive breathing (CRB) is the hallmark of obstructive airway disease pathophysiology. We have previously shown that severe inspiratory resistive breathing (IRB) induces acute lung injury in healthy rats. The role of expiratory resistance is unknown. The possibility of a load-dependent type of resistive breathing-induced lung injury also remains elusive. Our aim was to investigate the differential effects of IRB, expiratory resistive breathing (ERB), and CRB on healthy rat lung and establish the lowest loads required to induce injury. Anesthetized tracheostomized rats breathed through a two-way valve. Varying resistances were connected to the inspiratory, expiratory, or both ports, so that the peak inspiratory pressure (IRB) was 20%–40% or peak expiratory (ERB) was 40%–70% of maximum. CRB was assessed in inspiratory/expiratory pressures of 30%/50%, 40%/50%, and 40%/60% of maximum. Quietly breathing animals served as controls. At 6 hours, respiratory system mechanics were measured, and bronchoalveolar lavage was performed for measurement of cell and protein concentration. Lung tissue interleukin-6 and interleukin-1β levels were estimated, and a lung injury histological score was determined. ERB produced significant, load-independent neutrophilia, without mechanical or permeability derangements. IRB 30% was the lowest inspiratory load that provoked lung injury. CRB increased tissue elasticity, bronchoalveolar lavage total cell, macrophage and neutrophil counts, protein and cytokine levels, and lung injury score in a dose-dependent manner. In conclusion, CRB load dependently deranges mechanics, increases permeability, and induces inflammation in healthy rats. ERB is a putative inflammatory stimulus for the lung. PMID:27499619

  3. Response and resistance to NF-κB inhibitors in mouse models of lung adenocarcinoma

    PubMed Central

    Xue, Wen; Meylan, Etienne; Oliver, Trudy G.; Feldser, David M.; Winslow, Monte M.; Bronson, Roderick; Jacks, Tyler

    2011-01-01

    Lung adenocarcinoma is a frequently diagnosed cancer type and a leading cause of cancer death worldwide. We recently demonstrated in an autochthonous mouse model of this disease that genetic inhibition of the NF-κB pathway affects both the initiation and maintenance of lung cancer, identifying this pathway as a promising therapeutic target. In this study, we tested the efficacy of small molecule NF-κB inhibitors in mouse models of lung cancer. In murine lung adenocarcinoma cell lines with high NF-κB activity, the proteasome inhibitor Bortezomib efficiently reduced nuclear p65, repressed NF-κB target genes and rapidly induced apoptosis. Bortezomib also induced lung tumor regression in vivo and prolonged the survival of tumor bearing KrasLSL-G12D/wt;p53flox/flox mice. In contrast, KrasG12D/wt lung tumors, which have low levels of nuclear NF-κB, do not respond to Bortezomib, suggesting that nuclear NF-κB may be a biomarker to predict treatment response to drugs of this class. Following repeated treatment, initially sensitive lung tumors became resistant to Bortezomib. A second NF-κB inhibitor, Bay-117082, showed similar therapeutic efficacy and acquired-resistance in mice. Our results using preclinical mouse models support the NF-κB pathway as a potential therapeutic target for a defined subset of lung adenocarcinoma. PMID:21874163

  4. Significant blood resistance to nitric oxide transfer in the lung

    PubMed Central

    Dunningham, Helen; Bottrill, Fiona; Vuylsteke, Alain; Yilmaz, Cuneyt; Dane, D. Merrill; Hsia, Connie C. W.

    2010-01-01

    Lung diffusing capacity for nitric oxide (DlNO) is used to measure alveolar membrane conductance (DmNO), but disagreement remains as to whether DmNO = DlNO, and whether blood conductance (θNO) = ∞. Our previous in vitro and in vivo studies suggested that θNO < ∞. We now show in a membrane oxygenator model perfused with whole blood that addition of a cell-free bovine hemoglobin (Hb) glutamer-200 solution increased diffusing capacity of the circuit (D) for NO (Dno) by 39%, D for carbon monoxide (Dco) by 24%, and the ratio of Dno to Dco by 12% (all P < 0.001). In three anesthetized dogs, DlNO and DlCO were measured by a rebreathing technique before and after three successive equal volume-exchange transfusions with bovine Hb glutamer-200 (10 ml/kg each, total exchange 30 ml/kg). At baseline, DlNO/DlCO = 4.5. After exchange transfusion, DlNO rose 57 ± 16% (mean ± SD, P = 0.02) and DlNO/DlCO = 7.1, whereas DlCO remained unchanged. Thus, in vitro and in vivo data directly demonstrate a finite θNO. We conclude that the erythrocyte and/or its immediate environment imposes considerable resistance to alveolar-capillary NO uptake. DlNO is sensitive to dynamic hematological factors and is not a pure index of conductance of the alveolar tissue membrane. With successive exchange transfusion, the estimated in vivo θNO [5.1 ml NO·(ml blood·min·Torr)−1] approached 4.5 ml NO·(ml blood·min·Torr)−1, which was derived from in vitro measurements by Carlsen and Comroe (J Gen Physiol 42: 83–107, 1958). Therefore, we suggest use of θNO = 4.5 ml NO·(min·Torr·ml blood)−1 for calculation of DmNO and pulmonary capillary blood volume from DlNO and DlCO. PMID:20150569

  5. Lung-specific loss of the laminin α3 subunit confers resistance to mechanical injury.

    PubMed

    Urich, Daniela; Eisenberg, Jessica L; Hamill, Kevin J; Takawira, Desire; Chiarella, Sergio E; Soberanes, Saul; Gonzalez, Angel; Koentgen, Frank; Manghi, Tomas; Hopkinson, Susan B; Misharin, Alexander V; Perlman, Harris; Mutlu, Gokhan M; Budinger, G R Scott; Jones, Jonathan C R

    2011-09-01

    Laminins are heterotrimeric glycoproteins of the extracellular matrix that are secreted by epithelial cells and which are crucial for the normal structure and function of the basement membrane. We have generated a mouse harboring a conditional knockout of α3 laminin (Lama3(fl/fl)), one of the main laminin subunits in the lung basement membrane. At 60 days after intratracheal treatment of adult Lama3(fl/fl) mice with an adenovirus encoding Cre recombinase (Ad-Cre), the protein abundance of α3 laminin in whole lung homogenates was more than 50% lower than that in control-treated mice, suggesting a relatively long half-life for the protein in the lung. Upon exposure to an injurious ventilation strategy (tidal volume of 35 ml per kg of body weight for 2 hours), the mice with a knockdown of the α3 laminin subunit had less severe injury, as shown by lung mechanics, histology, alveolar capillary permeability and survival when compared with Ad-Null-treated mice. Knockdown of the α3 laminin subunit resulted in evidence of lung inflammation. However, this did not account for their resistance to mechanical ventilation. Rather, the loss of α3 laminin was associated with a significant increase in the collagen content of the lungs. We conclude that the loss of α3 laminin in the alveolar epithelium results in an increase in lung collagen, which confers resistance to mechanical injury. PMID:21878500

  6. Oncogenic miR-137 contributes to cisplatin resistance via repressing CASP3 in lung adenocarcinoma

    PubMed Central

    Su, Te-Jen; Ku, Wen-Hui; Chen, Hsuan-Yu; Hsu, Yi-Chiung; Hong, Qi-Sheng; Chang, Gee-Chen; Yu, Sung-Liang; Chen, Jeremy JW

    2016-01-01

    Although targeted therapy can prolong the survival of non-small cell lung cancer (NSCLC) patients with EGFR mutations, chemotherapy still is the choice for patients with wild-type EGFR or failure in targeted therapy. However, most of the patients will eventually develop chemoresistance. Our previous study showed that miR-137 is a risky microRNA and is associated with poor prognosis in NSCLC patients. Here we investigated the role of miR-137 in cisplatin resistance in lung adenocarcinoma patients. Our data indicated that miR-137 overexpression increases the survival of lung cancer cells exposed to cisplatin and decreases cisplatin-induced apoptosis. Through computational prediction and microarray, we identified caspase-3 (CASP3) as a potential target of miR-137. Luciferase reporter and site-directed mutagenesis assays demonstrated that miR-137 downregulates CASP3 through binding to its 3’-UTR. Moreover, the endogenous CASP3 can be modulated by overexpressing or silencing miR-137 in lung adenocarcinoma cell lines regardless of EGFR status. Suppression of CASP3 by miR-137 provides cancer cells with anti-apoptotic ability, leading to cisplatin resistance. Immunohistochemistry results revealed an inverse correlation between miR-137 and CASP3 expressions in lung adenocarcinoma patients. Together, our data provide a new chemoresistance mechanism in lung adenocarcinoma and a possible target to control chemoresistance in lung adenocarcinoma patients. PMID:27429846

  7. Transfer factor, lung volumes, resistance and ventilation distribution in healthy adults.

    PubMed

    Verbanck, Sylvia; Van Muylem, Alain; Schuermans, Daniel; Bautmans, Ivan; Thompson, Bruce; Vincken, Walter

    2016-01-01

    Monitoring of chronic lung disease requires reference values of lung function indices, including putative markers of small airway function, spanning a wide age range.We measured spirometry, transfer factor of the lung for carbon monoxide (TLCO), static lung volume, resistance and ventilation distribution in a healthy population, studying at least 20 subjects per sex and per decade between the ages of 20 and 80 years.With respect to the Global Lung Function Initiative reference data, our subjects had average z-scores for forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC of -0.12, 0.04 and -0.32, respectively. Reference equations were obtained which could account for a potential dependence of index variability on age and height. This was done for (but not limited to) indices that are pertinent to asthma and chronic obstructive pulmonary disease studies: forced expired volume in 6 s, forced expiratory flow, TLCO, specific airway conductance, residual volume (RV)/total lung capacity (TLC), and ventilation heterogeneity in acinar and conductive lung zones.Deterioration in acinar ventilation heterogeneity and lung clearance index with age were more marked beyond 60 years, and conductive ventilation heterogeneity showed the greatest increase in variability with age. The most clinically relevant deviation from published reference values concerned RV/TLC values, which were considerably smaller than American Thoracic Society/European Respiratory Society-endorsed reference values.

  8. Surfactant-based drug delivery systems for treating drug-resistant lung cancer.

    PubMed

    Kaur, Prabhjot; Garg, Tarun; Rath, Goutam; Murthy, R S R; Goyal, Amit K

    2016-01-01

    Among all cancers, lung cancer is the major cause of deaths. Lung cancer can be categorized into two classes for prognostic and treatment purposes: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Both categories of cancer are resistant to certain drugs. Various mechanisms behind drug resistance are over-expression of superficial membrane proteins [glycoprotein (P-gp)], lung resistance-associated proteins, aberration of the intracellular enzyme system, enhancement of the cell repair system and deregulation of cell apoptosis. Structure-performance relationships and chemical compatibility are consequently major fundamentals in surfactant-based formulations, with the intention that a great deal investigation is committed to this region. With the purpose to understand the potential of P-gp in transportation of anti-tumor drugs to cancer cells with much effectiveness and specificity, several surfactant-based delivery systems have been developed which may include microspheres, nanosized drug carriers (nanoparticles, nanoemulsions, stealth liposomes, nanogels, polymer-drug conjugates), novel powders, hydrogels and mixed micellar systems intended for systemic and/or localized delivery. PMID:25013959

  9. Vemurafenib resistance selects for highly malignant brain and lung-metastasizing melanoma cells.

    PubMed

    Zubrilov, Inna; Sagi-Assif, Orit; Izraely, Sivan; Meshel, Tsipi; Ben-Menahem, Shlomit; Ginat, Ravit; Pasmanik-Chor, Metsada; Nahmias, Clara; Couraud, Pierre-Olivier; Hoon, Dave S B; Witz, Isaac P

    2015-05-28

    V600E being the most common mutation in BRAF, leads to constitutive activation of the MAPK signaling pathway. The majority of V600E BRAF positive melanoma patients treated with the BRAF inhibitor vemurafenib showed initial good clinical responses but relapsed due to acquired resistance to the drug. The aim of the present study was to identify possible biomarkers associated with the emergence of drug resistant melanoma cells. To this end we analyzed the differential gene expression of vemurafenib-sensitive and vemurafenib resistant brain and lung metastasizing melanoma cells. The major finding of this study is that the in vitro induction of vemurafenib resistance in melanoma cells is associated with an increased malignancy phenotype of these cells. Resistant cells expressed higher levels of genes coding for cancer stem cell markers (JARID1B, CD271 and Fibronectin) as well as genes involved in drug resistance (ABCG2), cell invasion and promotion of metastasis (MMP-1 and MMP-2). We also showed that drug-resistant melanoma cells adhere better to and transmigrate more efficiently through lung endothelial cells than drug-sensitive cells. The former cells also alter their microenvironment in a different manner from that of drug-sensitive cells. Biomarkers and molecular mechanisms associated with drug resistance may serve as targets for therapy of drug-resistant cancer.

  10. Plasminogen activator inhibitor 1, fibroblast apoptosis resistance, and aging-related susceptibility to lung fibrosis.

    PubMed

    Huang, Wen-Tan; Akhter, Hasina; Jiang, Chunsun; MacEwen, Mark; Ding, Qiang; Antony, Veena; Thannickal, Victor John; Liu, Rui-Ming

    2015-01-01

    Idiopathic pulmonary fibrosis (IPF) is a fatal lung disorder with unknown cause and no effective treatment. The incidence of and mortality from IPF increase with age, suggesting that advanced age is a major risk factor for IPF. The mechanism underlying the increased susceptibility of the elderly to IPF, however, is unknown. In this study, we show for the first time that the protein level of plasminogen activator inhibitor 1 (PAI-1), a protease inhibitor which plays an essential role in the control of fibrinolysis, was significantly increased with age in mouse lung homogenate and lung fibroblasts. Upon bleomycin challenge, old mice experienced augmented PAI-1 induction and lung fibrosis as compared to young mice. Most interestingly, we show that fewer (myo)fibroblasts underwent apoptosis and more (myo)fibroblasts with increased level of PAI-1 accumulated in the lung of old than in young mice after bleomycin challenge. In vitro studies further demonstrate that fibroblasts isolated from lungs of old mice were resistant to H2O2 and tumor necrosis factor alpha-induced apoptosis and had augmented fibrotic responses to TGF-β1, compared to fibroblasts isolated from young mice. Inhibition of PAI-1 activity with a PAI-1 inhibitor, on the other hand, eliminated the aging-related apoptosis resistance and TGF-β1 sensitivity in isolated fibroblasts. Moreover, we show that knocking down PAI-1 in human lung fibroblasts with PAI-1 siRNA significantly increased their sensitivity to apoptosis and inhibited their responses to TGF-β1. Together, the results suggest that increased PAI-1 expression may underlie the aging-related sensitivity to lung fibrosis in part by protecting fibroblasts from apoptosis.

  11. Association between clinical antibiotic resistance and susceptibility of Pseudomonas in the cystic fibrosis lung

    PubMed Central

    Jansen, Gunther; Mahrt, Niels; Tueffers, Leif; Barbosa, Camilo; Harjes, Malte; Adolph, Gernot; Friedrichs, Anette; Krenz-Weinreich, Annegret; Rosenstiel, Philip; Schulenburg, Hinrich

    2016-01-01

    Background and objectives: Cystic fibrosis patients suffer from chronic lung infections that require long-term antibiotic therapy. Pseudomonas readily evolve resistance, rendering antibiotics ineffective. In vitro experiments suggest that resistant bacteria may be treated by exploiting their collateral sensitivity to other antibiotics. Here, we investigate correlations of sensitivity and resistance profiles of Pseudomonas aeruginosa that naturally adapted to antibiotics in the cystic fibrosis lung. Methodology: Resistance profiles for 13 antibiotics were obtained using broth dilution, E-test and VITEK mass spectroscopy. Genetic variants were determined from whole-genome sequences and interrelationships among isolates were analyzed using 13 MLST loci. Result: Our study focused on 45 isolates from 13 patients under documented treatment with antibiotics. Forty percent of these were clinically resistant and 15% multi-drug resistant. Colistin resistance was found once, despite continuous colistin treatment and even though colistin resistance can readily evolve experimentally in the laboratory. Patients typically harbored multiple genetically and phenotypically distinct clones. However, genetically similar clones often had dissimilar resistance profiles. Isolates showed mutations in genes encoding cell wall synthesis, alginate production, efflux pumps and antibiotic modifying enzymes. Cross-resistance was commonly observed within antibiotic classes and between aminoglycosides and β-lactam antibiotics. No evidence was found for consistent phenotypic resistance to one antibiotic and sensitivity to another within one genotype. Conclusions and implications: Evidence supporting potential collateral sensitivity in clinical P. aeruginosa isolates remains equivocal. However, cross-resistance within antibiotic classes is common. Colistin therapy is promising since resistance to it was rare despite its intensive use in the studied patients. PMID:27193199

  12. Mechanisms of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Resistance and Strategies to Overcome Resistance in Lung Adenocarcinoma

    PubMed Central

    Chang, Yoon Soo; Choi, Chang-Min

    2016-01-01

    Somatic mutations that lead to hyperactivation of epidermal growth factor receptor (EGFR) signaling are detected in approximately 50% of lung adenocarcinoma in people from the Far East population and tyrosine kinase inhibitors are now the standard first line treatment for advanced disease. They have led to a doubling of progression-free survival and an increase in overall survival by more than 2 years. However, emergence of resistant clones has become the primary cause for treatment failure, and has created a new challenge in the daily management of patients with EGFR mutations. Identification of mechanisms leading to inhibitor resistance has led to new therapeutic modalities, some of which have now been adapted for patients with unsuccessful tyrosine kinase inhibitor treatment. In this review, we describe mechanisms of tyrosine kinase inhibitor resistance and the available strategies to overcoming resistance. PMID:27790276

  13. JAK2 inhibition sensitizes resistant EGFR-mutant lung adenocarcinoma to tyrosine kinase inhibitors

    PubMed Central

    Gao, Sizhi P.; Chang, Qing; Mao, Ninghui; Daly, Laura A.; Vogel, Robert; Chan, Tyler; Liu, Shu Hui; Bournazou, Eirini; Schori, Erez; Zhang, Haiying; Brewer, Monica Red; Pao, William; Morris, Luc; Ladanyi, Marc; Arcila, Maria; Manova-Todorova, Katia; de Stanchina, Elisa; Norton, Larry; Levine, Ross L.; Altan-Bonnet, Gregoire; Solit, David; Zinda, Michael; Huszar, Dennis; Lyden, David; Bromberg, Jacqueline F.

    2016-01-01

    Lung adenocarcinomas with mutant epidermal growth factor receptor (EGFR) respond to EGFR-targeted tyrosine kinase inhibitors (TKIs), but resistance invariably occurs. We found that the Janus kinase (JAK)/signal transduction and activator of transcription 3 (STAT3) signaling pathway was aberrantly increased in TKI-resistant EGFR-mutant non–small cell lung cancer (NSCLC) cells. JAK2 inhibition restored sensitivity to the EGFR inhibitor erlotinib in TKI-resistant cell lines and xenograft models of EGFR-mutant TKI-resistant lung cancer. JAK2 inhibition uncoupled EGFR from its negative regulator, suppressor of cytokine signaling 5 (SOCS5), consequently increasing EGFR abundance and restoring the tumor cells’ dependence on EGFR signaling. Furthermore, JAK2 inhibition led to heterodimerization of mutant and wild-type EGFR subunits, the activity of which was then blocked by TKIs. Our results reveal a mechanism whereby JAK2 inhibition overcomes acquired resistance to EGFR inhibitors and support the use of combination therapy with JAK and EGFR inhibitors for the treatment of EGFR-dependent NSCLC. PMID:27025877

  14. Increased aquaglyceroporin 9 expression disrupts arsenic resistance in human lung cancer cells.

    PubMed

    Miao, Zhi-Feng; Chang, Eddy Essen; Tsai, Feng-Yuan; Yeh, Szu-Ching; Wu, Chia-Fang; Wu, Kuen-Yuh; Wang, Chien-Jen; Tsou, Tsui-Chun

    2009-03-01

    Resistance to chemotherapy is one of the major problems in treatment responses of lung cancer. This study explored the mechanism underlying the arsenic resistance of lung cancer. Four lung cancer cells with different proliferation activity were characterized for cytotoxicity, arsenic influx/efflux, and arsenic effects on intracellular glutathione and 8-hydroxy-2'-deoxyguanosine (8-OHdG) production. Our data revealed that relative proliferation potency of these cells was H1299>A549>CL3>H1355. Moreover, A549, H1299, and H1355 were markedly resistant to As(2)O(3) with IC50 approximately 100 microM, whereas CL3 was sensitive to As(2)O(3) with IC50 approximately 11.8 microM. After treatment with the respective As(2)O(3) at IC50, arsenic influx/efflux activity in CL3 was comparable to those in the other three arsenic-resistant cells. However, differences in glutathione levels and 8-OHdG production were also detected either before or after arsenic treatment, indicating that a certain degree of variation in anti-oxidative systems and/or 8-OHdG repair activity existed in these cell lines. By transfection of an aquaglyceroporin 9 (AQP9) gene, we showed that increased AQP9 expression significantly enhanced arsenic uptake and disrupted arsenic resistance of A549. The present study strongly suggests that membrane transporters responsible for arsenic uptake, such as AQP9, may play a critical role in development of arsenic resistance in human lung cancer cells.

  15. Derivation and preliminary characterisation of adriamycin resistant lines of human lung cancer cells.

    PubMed Central

    Twentyman, P. R.; Fox, N. E.; Wright, K. A.; Bleehen, N. M.

    1986-01-01

    We have produced adriamycin (ADM)-resistant variants of the human lung cancer cell lines NCI-H69 (small cell), MOR (adenocarcinoma) and COR-L23 (large cell) but have failed to produce resistant variants of two other small cell lines. In each case, the derivation protocol took 7-9 months and included a period of drug-free growth. All three resistant lines show reduced cellular content of ADM after 1 h exposure when compared with their controls. During prolonged incubation of control and resistant NCI-H69 cells in 0.4 microgram ml-1 ADM, the ADM content of resistant cells was 6-7 times lower than that of control cells. The ratio of ADM doses to suppress growth of the two lines, however, was in the range of 40-200X. The ADM-resistant variant of NCI-H69 was also resistant to vincristine, colchicine, VP16, mitozantrone, 4' epiadriamycin and 4' deoxyadriamycin, somewhat resistant to melphalan but not resistant to aclacinomycin A, bleomycin of CCNU. The resistance to ADM could be partially overcome by the use of verapamil, an inhibitor of calcium transport. PMID:3011054

  16. miR-206 regulates cisplatin resistance and EMT in human lung adenocarcinoma cells partly by targeting MET

    PubMed Central

    Tang, Xiali; Chen, Jun; Mou, Hao; Lu, Wei

    2016-01-01

    MicroRNAs (miRNAs) play a critical role in drug resistance and epithelial-mesenchymal transition (EMT). The aims of this study were to explore the potential role of miR-206 in governing cisplatin resistance and EMT in lung cancer cells. We found that both lung adenocarcinoma A549 cisplatin-resistant cells (A549/DDP) and H1299 cisplatin-resistant cells (H1299/DDP) acquired mesenchymal features and were along with low expression of miR-206 and high migration and invasion abilities. Ectopic expression of miR-206 mimics inhibited cisplatin resistance, reversed the EMT phenotype, decreased the migration and invasion in these DDP-resistant cells. In contrast, miR-206 inhibitors increased cisplatin resistance, EMT, cell migration and invasion in non-DDP-resistant cells. Furthermore, we found that MET is the direct target of miR-206 in lung cancer cells. Knockdown of MET exhibited an EMT and DDP resistant inhibitory effect on DDP-resistant cells. Conversely, overexpression of MET in non-DDP- resistant cells produced a promoting effect on cell EMT and DDP resistance. In lung adenocarcinoma tissues, we demonstrated that low expression of miR-206 were also correlated with increased cisplatin resistance and MET expression. In addition, we revealed that miR-206 overexpression reduced cisplatin resistance and EMT in DDP-resistant cells, partly due to inactivation of MET/PI3K/AKT/mTOR signaling pathway, and subsequent downregulation of MDR1, ZEB1 and Snail expression. Finally, we found that miR-206 could also sensitize A549/DDP cells to cisplatin in mice model. Taken together, our study implied that activation of miR-206 or inactivation of its target gene pathway could serve as a novel approach to reverse cisplatin resistance in lung adenocarcinomas cells. PMID:27014910

  17. Rapamycin induces Bad phosphorylation in association with its resistance to human lung cancer cells.

    PubMed

    Liu, Yan; Sun, Shi-Yong; Owonikoko, Taofeek K; Sica, Gabriel L; Curran, Walter J; Khuri, Fadlo R; Deng, Xingming

    2012-01-01

    Inhibition of mTOR signaling by rapamycin has been shown to activate extracellular signal-regulated kinase 1 or 2 (ERK1/2) and Akt in various types of cancer cells, which contributes to rapamycin resistance. However, the downstream effect of rapamycin-activated ERKs and Akt on survival or death substrate(s) remains unclear. We discovered that treatment of human lung cancer cells with rapamycin results in enhanced phosphorylation of Bad at serine (S) 112 and S136 but not S155 in association with activation of ERK1/2 and Akt. A higher level of Bad phosphorylation was observed in rapamycin-resistant cells compared with parental rapamycin-sensitive cells. Thus, Bad phosphorylation may contribute to rapamycin resistance. Mechanistically, rapamycin promotes Bad accumulation in the cytosol, enhances Bad/14-3-3 interaction, and reduces Bad/Bcl-XL binding. Rapamycin-induced Bad phosphorylation promotes its ubiquitination and degradation, with a significant reduction of its half-life (i.e., from 53.3-37.5 hours). Inhibition of MEK/ERK by PD98059 or depletion of Akt by RNA interference blocks rapamycin-induced Bad phosphorylation at S112 or S136, respectively. Simultaneous blockage of S112 and S136 phosphorylation of Bad by PD98059 and silencing of Akt significantly enhances rapamycin-induced growth inhibition in vitro and synergistically increases the antitumor efficacy of rapamycin in lung cancer xenografts. Intriguingly, either suppression of Bad phosphorylation at S112 and S136 sites or expression of the nonphosphorylatable Bad mutant (S112A/S136A) can reverse rapamycin resistance. These findings uncover a novel mechanism of rapamycin resistance, which may promote the development of new strategies for overcoming rapamycin resistance by manipulating Bad phosphorylation at S112 and S136 in human lung cancer.

  18. SKA1 regulates the metastasis and cisplatin resistance of non-small cell lung cancer

    PubMed Central

    SHEN, LIHUA; YANG, MIN; LIN, QIONGHUA; ZHANG, ZHONGWEI; MIAO, CHANGHONG; ZHU, BIAO

    2016-01-01

    Currently, chemotherapy with platinum-based drugs including cisplatin is the most effective therapy for the treatment of non-small cell lung carcinoma (NSCLC). However, the efficacy of chemotherapy is limited due to commonly developed drug resistance. Spindle and kinetochore-associated complex subunit 1 (SKA1) is part of a complex essential for stabilizing the attachment of spindle microtubules to kinetochores and for maintaining the metaphase plate during mitosis. In the present study, we aimed to investigate the role of SKA1 in the process of metastasis and drug resistance of NSCLC. We completed a series of experiments to investigate the function of SKA1 in NSCLC metastasis and drug resistance including qRT-PCR, immunohistochemistry and western blotting, as well as MTT, BrdU, wounded healing, Transwell and gelatin zymography assays. We demonstrated that the expression levels of SKA1 were elevated in NSCLC and were correlated with cancer progression and malignancy. We also reported that SKA1 positively regulated the proliferation and metastatic ability of NSCLC cells. In addition, we determined that SKA1 contributed to cisplatin resistance in NSCLC cells by protecting these cells from cisplatin-induced cell apoptosis. SKA1 also appeared to regulate the ERK1/2 and the Akt-mediated signaling pathways in NSCLC cells. SKA1 is required for metastasis and cisplatin resistance of non-small cell lung cancer. PMID:26985856

  19. S. mansoni Trapping in Lungs Contributes to Resistance to Reinfection

    PubMed Central

    Knopf, Paul Mark; Suri, Parmjeet Behl

    2015-01-01

    Worm transplantation studies show that physiological and reproductive status of the worm is influenced by the microenvironment of the host and critical for vaccine design. Worm migration studies in rats with 75Se-methionine labeled cercariae demonstrated that resistance to reinfection (R/R) requires a host immune response resulting in worm death. In permissive hosts, inflammation due to anti eggs immunity leads to host death, whereas in non-permissive hosts this is not the case due to reduced egg burdens. Eggs-induced pathology and inflammatory debris resulting from immune attack on worms are important for vaccine design. Protective immune responses are perhaps induced when naïve hosts are vaccinated with either schistosome-derived molecules or attenuated cercariae as suggested by the induction of protective anti-parasite antibodies and monoclonals. However, these immunological strategies rarely produce 85–90% R/R as is achievable by portal-caval shunting. Alternatively, induction of anti-schistosoma immunity may induce portacaval shunting, seems highly unlikely although not yet tested. Differential screening with sera from twice-infected rats, protective (F2x) from Fisher vs. non-protective (W2x) from Wistar–Furth rats, was used to identify candidate vaccine antigens. PMID:25954278

  20. Emerging Paradigms in the Development of Resistance to Tyrosine Kinase Inhibitors in Lung Cancer

    PubMed Central

    Gainor, Justin F.; Shaw, Alice T.

    2013-01-01

    The success of tyrosine kinase inhibitors (TKIs) in select patients with non–small-cell lung cancer (NSCLC) has transformed management of the disease, placing new emphasis on understanding the molecular characteristics of tumor specimens. It is now recognized that genetic alterations in the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) define two unique subtypes of NSCLC that are highly responsive to genotype-directed TKIs. Despite this initial sensitivity, however, the long-term effectiveness of such therapies is universally limited by the development of resistance. Identifying the mechanisms underlying this resistance is an area of intense, ongoing investigation. In this review, we provide an overview of recent experience in the field, focusing on results from preclinical resistance models and studies of patient-derived, TKI-resistant tumor specimens. Although diverse TKI resistance mechanisms have been identified within EGFR-mutant and ALK-positive patients, we highlight common principles of resistance shared between these groups. These include the development of secondary mutations in the kinase target, gene amplification of the primary oncogene, and upregulation of bypass signaling tracts. In EGFR-mutant and ALK-positive patients alike, acquired resistance may also be a dynamic and multifactorial process that may necessitate the use of treatment combinations. We believe that insights into the mechanisms of TKI resistance in patients with EGFR mutations or ALK rearrangements may inform the development of novel treatment strategies in NSCLC, which may also be generalizable to other kinase-driven malignancies. PMID:24101047

  1. New experimental methodology, setup and LabView program for accurate absolute thermoelectric power and electrical resistivity measurements between 25 and 1600 K: Application to pure copper, platinum, tungsten, and nickel at very high temperatures

    SciTech Connect

    Abadlia, L.; Mayoufi, M.; Gasser, F.; Khalouk, K.; Gasser, J. G.

    2014-09-15

    In this paper we describe an experimental setup designed to measure simultaneously and very accurately the resistivity and the absolute thermoelectric power, also called absolute thermopower or absolute Seebeck coefficient, of solid and liquid conductors/semiconductors over a wide range of temperatures (room temperature to 1600 K in present work). A careful analysis of the existing experimental data allowed us to extend the absolute thermoelectric power scale of platinum to the range 0-1800 K with two new polynomial expressions. The experimental device is controlled by a LabView program. A detailed description of the accurate dynamic measurement methodology is given in this paper. We measure the absolute thermoelectric power and the electrical resistivity and deduce with a good accuracy the thermal conductivity using the relations between the three electronic transport coefficients, going beyond the classical Wiedemann-Franz law. We use this experimental setup and methodology to give new very accurate results for pure copper, platinum, and nickel especially at very high temperatures. But resistivity and absolute thermopower measurement can be more than an objective in itself. Resistivity characterizes the bulk of a material while absolute thermoelectric power characterizes the material at the point where the electrical contact is established with a couple of metallic elements (forming a thermocouple). In a forthcoming paper we will show that the measurement of resistivity and absolute thermoelectric power characterizes advantageously the (change of) phase, probably as well as DSC (if not better), since the change of phases can be easily followed during several hours/days at constant temperature.

  2. New experimental methodology, setup and LabView program for accurate absolute thermoelectric power and electrical resistivity measurements between 25 and 1600 K: application to pure copper, platinum, tungsten, and nickel at very high temperatures.

    PubMed

    Abadlia, L; Gasser, F; Khalouk, K; Mayoufi, M; Gasser, J G

    2014-09-01

    In this paper we describe an experimental setup designed to measure simultaneously and very accurately the resistivity and the absolute thermoelectric power, also called absolute thermopower or absolute Seebeck coefficient, of solid and liquid conductors/semiconductors over a wide range of temperatures (room temperature to 1600 K in present work). A careful analysis of the existing experimental data allowed us to extend the absolute thermoelectric power scale of platinum to the range 0-1800 K with two new polynomial expressions. The experimental device is controlled by a LabView program. A detailed description of the accurate dynamic measurement methodology is given in this paper. We measure the absolute thermoelectric power and the electrical resistivity and deduce with a good accuracy the thermal conductivity using the relations between the three electronic transport coefficients, going beyond the classical Wiedemann-Franz law. We use this experimental setup and methodology to give new very accurate results for pure copper, platinum, and nickel especially at very high temperatures. But resistivity and absolute thermopower measurement can be more than an objective in itself. Resistivity characterizes the bulk of a material while absolute thermoelectric power characterizes the material at the point where the electrical contact is established with a couple of metallic elements (forming a thermocouple). In a forthcoming paper we will show that the measurement of resistivity and absolute thermoelectric power characterizes advantageously the (change of) phase, probably as well as DSC (if not better), since the change of phases can be easily followed during several hours/days at constant temperature.

  3. Absolute Summ

    NASA Astrophysics Data System (ADS)

    Phillips, Alfred, Jr.

    Summ means the entirety of the multiverse. It seems clear, from the inflation theories of A. Guth and others, that the creation of many universes is plausible. We argue that Absolute cosmological ideas, not unlike those of I. Newton, may be consistent with dynamic multiverse creations. As suggested in W. Heisenberg's uncertainty principle, and with the Anthropic Principle defended by S. Hawking, et al., human consciousness, buttressed by findings of neuroscience, may have to be considered in our models. Predictability, as A. Einstein realized with Invariants and General Relativity, may be required for new ideas to be part of physics. We present here a two postulate model geared to an Absolute Summ. The seedbed of this work is part of Akhnaton's philosophy (see S. Freud, Moses and Monotheism). Most important, however, is that the structure of human consciousness, manifest in Kenya's Rift Valley 200,000 years ago as Homo sapiens, who were the culmination of the six million year co-creation process of Hominins and Nature in Africa, allows us to do the physics that we do. .

  4. Interleukin-6 and Lung Inflammation: Evidences of A Causing Role in Inducing Respiratory System Resistance Increments.

    PubMed

    Rubini, Alessandro

    2013-07-10

    Interleukin-6 has been shown to be increased in various pathological conditions involving the lungs, both experimentally induced in animals, or spontaneously occurring in humans. Experimental data demonstrating a significant role of interleukin-6 in commonly occurring respiratory system inflammatory diseases are reviewed. These diseases, i.e. asthma and chronic obstructive pulmonary disease, are characterised by respiratory system mechanical derangement, most of all because increased elastance and airway resistance. Recent findings showing a causative role of interleukin-6 in determining an airway resistance increment are reviewed. By applying the end-inflation occlusion method to study respiratory system mechanical properties before and after interleukin-6 administration, it was shown that this cytokine induced significant increments in both the resistive pressure dissipation due to frictional forces opposing the airflow in the airway (ohmic resistance), and in the additional resistive pressure dissipation due to the visco-elastic properties of the system, i.e. stress relaxation (visco-elastic resistance). A dose-dependent effect was also demonstrated. No effects were instead detected on respiratory system elastance. Even solely administrated in healthy mammals, interleukin-6 exhibits a significant effect on respiratory system resistances, leading to increased inspiratory muscle mechanical work of breathing. Thus, IL-6 may play an active role in the pathogenesis of respiratory system diseases. The possible involved mechanisms are discussed.

  5. Female resistance to pneumonia identifies lung macrophage nitric oxide synthase-3 as a therapeutic target

    PubMed Central

    Yang, Zhiping; Huang, Yuh-Chin T; Koziel, Henry; de Crom, Rini; Ruetten, Hartmut; Wohlfart, Paulus; Thomsen, Reimar W; Kahlert, Johnny A; Sørensen, Henrik Toft; Jozefowski, Szczepan; Colby, Amy; Kobzik, Lester

    2014-01-01

    To identify new approaches to enhance innate immunity to bacterial pneumonia, we investigated the natural experiment of gender differences in resistance to infections. Female and estrogen-treated male mice show greater resistance to pneumococcal pneumonia, seen as greater bacterial clearance, diminished lung inflammation, and better survival. In vitro, lung macrophages from female mice and humans show better killing of ingested bacteria. Inhibitors and genetically altered mice identify a critical role for estrogen-mediated activation of lung macrophage nitric oxide synthase-3 (NOS3). Epidemiologic data show decreased hospitalization for pneumonia in women receiving estrogen or statins (known to activate NOS3). Pharmacologic targeting of NOS3 with statins or another small-molecule compound (AVE3085) enhanced macrophage bacterial killing, improved bacterial clearance, and increased host survival in both primary and secondary (post-influenza) pneumonia. The data identify a novel mechanism for host defense via NOS3 and suggest a potential therapeutic strategy to reduce secondary bacterial pneumonia after influenza. DOI: http://dx.doi.org/10.7554/eLife.03711.001 PMID:25317947

  6. Early response of gene clusters is associated with mouse lung resistance or sensitivity to cigarette smoke.

    PubMed

    Cavarra, Eleonora; Fardin, Paolo; Fineschi, Silvia; Ricciardi, Annamaria; De Cunto, Giovanna; Sallustio, Fabio; Zorzetto, Michele; Luisetti, Maurizio; Pfeffer, Ulrich; Lungarella, Giuseppe; Varesio, Luigi

    2009-03-01

    We have investigated the effects of cigarette smoke exposure in three different strains of mice. DBA/2 and C57BL/6J are susceptible to smoke and develop different lung changes in response to chronic exposure, whereas ICR mice are resistant to smoke and do not develop emphysema. The present study was carried out to determine early changes in the gene expression profile of mice exposed to cigarette smoke with either a susceptible or resistant phenotype. The three strains of mice were exposed to smoke from three cigarettes per day, 5 days/wk, for 4 wk. Microarray analysis was carried out on total RNA extracted from the lung using the Affymetrix platform. Cigarette smoke modulates several clusters of genes (i.e., proemphysematous, acute phase response, and cell adhesion) in smoke-sensitive DBA/2 or C57BL/6J strains, but the same genes are not altered by smoke in ICR resistant mice. Only a few genes were commonly modulated by smoke in the three strains of mice. This pattern of gene expression suggests that the response to smoke is strain-dependent and may involve different molecular signaling pathways. Real-time quantitative PCR was used to verify the pattern of modulation of selected genes and their potential biological relevance. We conclude that gene expression response to smoke is highly dependent on the mouse genetic background. We speculate that the definition of gene clusters associated, to various degrees, with mouse susceptibility or resistance to smoke may be instrumental in defining the molecular basis of the individual response to smoke-induced lung injury in humans.

  7. Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients.

    PubMed

    Chabon, Jacob J; Simmons, Andrew D; Lovejoy, Alexander F; Esfahani, Mohammad S; Newman, Aaron M; Haringsma, Henry J; Kurtz, David M; Stehr, Henning; Scherer, Florian; Karlovich, Chris A; Harding, Thomas C; Durkin, Kathleen A; Otterson, Gregory A; Purcell, W Thomas; Camidge, D Ross; Goldman, Jonathan W; Sequist, Lecia V; Piotrowska, Zofia; Wakelee, Heather A; Neal, Joel W; Alizadeh, Ash A; Diehn, Maximilian

    2016-01-01

    Circulating tumour DNA (ctDNA) analysis facilitates studies of tumour heterogeneity. Here we employ CAPP-Seq ctDNA analysis to study resistance mechanisms in 43 non-small cell lung cancer (NSCLC) patients treated with the third-generation epidermal growth factor receptor (EGFR) inhibitor rociletinib. We observe multiple resistance mechanisms in 46% of patients after treatment with first-line inhibitors, indicating frequent intra-patient heterogeneity. Rociletinib resistance recurrently involves MET, EGFR, PIK3CA, ERRB2, KRAS and RB1. We describe a novel EGFR L798I mutation and find that EGFR C797S, which arises in ∼33% of patients after osimertinib treatment, occurs in <3% after rociletinib. Increased MET copy number is the most frequent rociletinib resistance mechanism in this cohort and patients with multiple pre-existing mechanisms (T790M and MET) experience inferior responses. Similarly, rociletinib-resistant xenografts develop MET amplification that can be overcome with the MET inhibitor crizotinib. These results underscore the importance of tumour heterogeneity in NSCLC and the utility of ctDNA-based resistance mechanism assessment. PMID:27283993

  8. Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients

    PubMed Central

    Chabon, Jacob J.; Simmons, Andrew D.; Lovejoy, Alexander F.; Esfahani, Mohammad S.; Newman, Aaron M.; Haringsma, Henry J.; Kurtz, David M.; Stehr, Henning; Scherer, Florian; Karlovich, Chris A.; Harding, Thomas C.; Durkin, Kathleen A.; Otterson, Gregory A.; Purcell, W. Thomas; Camidge, D. Ross; Goldman, Jonathan W.; Sequist, Lecia V.; Piotrowska, Zofia; Wakelee, Heather A.; Neal, Joel W.; Alizadeh, Ash A.; Diehn, Maximilian

    2016-01-01

    Circulating tumour DNA (ctDNA) analysis facilitates studies of tumour heterogeneity. Here we employ CAPP-Seq ctDNA analysis to study resistance mechanisms in 43 non-small cell lung cancer (NSCLC) patients treated with the third-generation epidermal growth factor receptor (EGFR) inhibitor rociletinib. We observe multiple resistance mechanisms in 46% of patients after treatment with first-line inhibitors, indicating frequent intra-patient heterogeneity. Rociletinib resistance recurrently involves MET, EGFR, PIK3CA, ERRB2, KRAS and RB1. We describe a novel EGFR L798I mutation and find that EGFR C797S, which arises in ∼33% of patients after osimertinib treatment, occurs in <3% after rociletinib. Increased MET copy number is the most frequent rociletinib resistance mechanism in this cohort and patients with multiple pre-existing mechanisms (T790M and MET) experience inferior responses. Similarly, rociletinib-resistant xenografts develop MET amplification that can be overcome with the MET inhibitor crizotinib. These results underscore the importance of tumour heterogeneity in NSCLC and the utility of ctDNA-based resistance mechanism assessment. PMID:27283993

  9. Inhibition of TGF-β signaling in normal lung epithelial cells confers resistance to ionizing radiation

    PubMed Central

    Reeves, Anna; Zagurovskaya, Marianna; Gupta, Seema; Shareef, Mohammed M.; Mohiuddin, Mohammed; Ahmed, Mansoor M.

    2007-01-01

    Purpose To address the functional role of radiation-induced TGF-β signaling in normal epithelial background, we selected spontaneously immortalized lung epithelial cell line derived from the normal lung tissue of dominant-negative mutant of TGF-β RII (ΔRII) transgenic mouse that expressed conditionally ΔRII under the control of metallothionein promoter (MT-1) and assessed it's impact on radio-sensitivity. Method and Materials Spontaneously immortalized lung epithelial cell culture (SILECC) was established and all analyses were performed within 50 passages. Colony-forming and TUNEL assays were used to assess the clonogenic inhibition and apoptosis respectively. Western blot analysis was performed to assess the kinetics of p21, bax and RII proteins. TGF-β responsive promoter activity was measured using dual-luciferase reporter assay. Results Exposure to ZnSO4 inhibited TGF-β signaling induced either by recombinant TGF-β1 or ionizing radiation. SILECC treated either with ZnSO4 or neutralizing antibody against TGF-β showed a significant increase in radio-resistance when compared to untreated cells. Furthermore, the expression of the ΔRII inhibited the radiation-induced up-regulation of the TGF-β effector gene p21waf1/cip1.. Conclusions Our findings imply that inhibition of radiation-induced TGF-β signaling via abrogation of RII function enhances radio-resistance of the normal lung epithelial cells, and this can be directly attributed to the loss of TGF-β signaling function. PMID:17448872

  10. Encapsulation in lipid-core nanocapsules overcomes lung cancer cell resistance to tretinoin.

    PubMed

    Schultze, Eduarda; Ourique, Aline; Yurgel, Virginia Campello; Begnini, Karine Rech; Thurow, Helena; de Leon, Priscila Marques Moura; Campos, Vinicius Farias; Dellagostin, Odir Antônio; Guterres, Silvia R; Pohlmann, Adriana R; Seixas, Fabiana Kömmling; Beck, Ruy Carlos Ruver; Collares, Tiago

    2014-05-01

    Tretinoin is a retinoid derivative that has an antiproliferative effect on several kinds of tumours. Human lung adenocarcinoma epithelial cell lines (A549) exhibit a profound resistance to the effects of tretinoin. Nanocarriers seem to be a good alternative to overcomecellular resistance to drugs. The aim of this study was to test whether tretinoin-loaded lipid-core nanocapsules exert anantitumor effect on A549 cells. A549 cells were incubated with free tretinoin (TTN), blank nanocapsules (LNC) and tretinoin-loaded lipid-core nanocapsules (TTN-LNC). Data from evaluation of DNA content and Annexin V binding assay by flow cytometry showed that TTN-LNC induced apoptosis and cell cycle arrest at the G1-phase while TTN did not. TTN-LNC showed higher cytotoxic effects than TTN on A549 cells evaluated by MTT and LIVE/DEAD cell viability assay. Gene expression profiling identified up-regulated expression of gene p21 by TTN-LNC, supporting the cell cycle arrest effect. These results showed for the first time that TTN-LNC are able to overcome the resistance of adenocarcinoma cell line A549 to treatment with TTN by inducing apoptosis and cell cycle arrest, providing support for their use in applications in lung cancer therapy.

  11. RESISTANCE TO ALVEOLAR SHAPE CHANGE LIMITS RANGE OF FORCE PROPAGATION IN LUNG PARENCHYMA

    PubMed Central

    Ma, Baoshun; Smith, Bradford J.; Bates, Jason H.T.

    2015-01-01

    We have recently shown that if the lung parenchyma is modeled in 2 dimensions as a network of springs arranged in a pattern of repeating hexagonal cells, the distortional forces around a contracting airway propagate much further from the airway wall than classic continuum theory predicts. In the present study we tested the hypothesis that this occurs because of the negligible shear modulus of a hexagonal spring network. We simulated the narrowing of an airway embedded in a hexagonal network of elastic alveolar walls when the hexagonal cells of the network offered some resistance to a change in shape. We found that as the forces resisting shape change approach about 10% of the forces resisting length change of an individual spring the range of distortional force propagation in the spring network fell of rapidly as in an elastic continuum. We repeated these investigations in a 3-dimensional spring network composed of space-filling polyhedral cells and found similar results. This suggests that force propagation away from a point of local parenchymal distortion also falls off rapidly in real lung tissue. PMID:25812796

  12. Resistance to alveolar shape change limits range of force propagation in lung parenchyma.

    PubMed

    Ma, Baoshun; Smith, Bradford J; Bates, Jason H T

    2015-06-01

    We have recently shown that if the lung parenchyma is modeled in 2 dimensions as a network of springs arranged in a pattern of repeating hexagonal cells, the distortional forces around a contracting airway propagate much further from the airway wall than classic continuum theory predicts. In the present study we tested the hypothesis that this occurs because of the negligible shear modulus of a hexagonal spring network. We simulated the narrowing of an airway embedded in a hexagonal network of elastic alveolar walls when the hexagonal cells of the network offered some resistance to a change in shape. We found that as the forces resisting shape change approach about 10% of the forces resisting length change of an individual spring the range of distortional force propagation in the spring network fell of rapidly as in an elastic continuum. We repeated these investigations in a 3-dimensional spring network composed of space-filling polyhedral cells and found similar results. This suggests that force propagation away from a point of local parenchymal distortion also falls off rapidly in real lung tissue.

  13. Tumor heterogeneity and resistance to EGFR-targeted therapy in advanced nonsmall cell lung cancer: challenges and perspectives

    PubMed Central

    Cheng, Xinghua; Chen, Haiquan

    2014-01-01

    Lung cancer, mostly nonsmall cell lung cancer, continues to be the leading cause of cancer-related death worldwide. With the development of tyrosine kinase inhibitors that selectively target lung cancer-related epidermal growth factor receptor mutations, management of advanced nonsmall cell lung cancer has been greatly transformed. Improvements in progression-free survival and life quality of the patients were observed in numerous clinical studies. However, overall survival is not prolonged because of later-acquired drug resistance. Recent studies reveal a heterogeneous subclonal architecture of lung cancer, so it is speculated that the tumor may rapidly adapt to environmental changes via a Darwinian selection mechanism. In this review, we aim to provide an overview of both spatial and temporal tumor heterogeneity as potential mechanisms underlying epidermal growth factor receptor tyrosine kinase inhibitor resistance in nonsmall cell lung cancer and summarize the possible origins of tumor heterogeneity covering theories of cancer stem cells and clonal evolution, as well as genomic instability and epigenetic aberrations in lung cancer. Moreover, investigational measures that overcome heterogeneity-associated drug resistance and new assays to improve tumor assessment are also discussed. PMID:25285017

  14. Resistance to mycoplasmal lung disease in mice is a complex genetic trait.

    PubMed Central

    Cartner, S C; Simecka, J W; Briles, D E; Cassell, G H; Lindsey, J R

    1996-01-01

    Mouse strains differ markedly in resistance to Mycoplasma pulmonis infection, and investigation of these differences holds much promise for understanding the mechanisms of antimycoplasmal host defenses. To determine the potential genetic diversity of resistance to disease in murine respiratory mycoplasmosis (MRM) and to select disease-resistant and nonresistant mouse strains for further genetic analysis, we screened 17 inbred mouse strains of various Bcg and H-2 genotypes for resistance to M. pulmonis. Mice were inoculated intranasally with 10(4) CFU of M. pulmonis UAB CT and evaluated at 21 days postinfection for severities of the four histologic lung lesions characteristic of MRM: alveolar exudate, airway exudate, airway epithelial hyperplasia, and lymphoid infiltrate. On the basis of these assessments of MRM severity, one group of mouse strains was found to be extremely resistant to disease (C57BR/cdJ, C57BL/6NCr, C57BL/10ScNCr, and C57BL/6J). The remaining strains of mice (C57L/J, SJL/NCr, BALB/cAnNCr, A/JCr, C3H/HeJ, SWR/J, AKR/NCr, CBA/NCr, C58/J, DBA/2NCr, C3H/HeNCr, C3HeB/FeJ, and C3H/HeJCr) developed disease of widely varying severities. Furthermore, strains in the group with more disease varied in pattern of lesion severity. While the severities of all four lesions were correlated in most mouse strains, this was not always true. DBA/2NCr mice had one of the highest scores for alveolar exudate, only a moderate score for airway exudate, and significantly lower scores for both airway epithelial hyperplasia and lymphoid infiltrate than all other strains susceptible to lung disease. DBA/2NCr mice had one of the highest mortality rates. We concluded that resistance to MRM is a complex trait. The observed differences in lung disease severity could not be explained by known differences at the Bcg or H-2 locus in the strains of mice we studied. PMID:8945584

  15. The molecular and clinical verification of therapeutic resistance via the p38 MAPK–Hsp27 axis in lung cancer

    PubMed Central

    Liu, Chia-Lin; Wu, Min-Zu; Jao, Shu-Wen; Lin, Yaoh-Shiang; Yang, Chin-Yuh; Lee, Tsai-Yu; Wen, Lian-Wu; Lan, Guo-Lun

    2016-01-01

    Treatment failure followed by relapse and metastasis in patients with non-small cell lung cancer is often the result of acquired resistance to cisplatin-based chemotherapy. A cancer stem cell (CSC)-mediated anti-apoptotic phenomenon is responsible for the development of drug resistance. The underlying molecular mechanism related to cisplatin resistance is still controversial, and a new strategy is needed to counteract cisplatin resistance. We used a nonadhesive culture system to generate drug-resistant spheres (DRSPs) derived from cisplatin-resistant H23 lung cancer cells. The expressions of drug-resistance genes, properties of CSCs, and markers of anti-apoptotic proteins were compared between control cells and DRSPs. DRSPs exhibited upregulation of cisplatin resistance-related genes. Gradual morphological alterations showing epithelial-to-mesenchymal transition phenomenon and increased invasion and migration abilities were seen during induction of DRSPs. Compared with control cells, DRSPs displayed increased CSC and anti-apoptotic properties, greater resistance to cisplatin, and overexpression of p-Hsp27 via activation of p38 MAPK signaling. Knockdown of Hsp27 or p38 decreased cisplatin resistance and increased apoptosis in DRSPs. Clinical studies confirmed that the expression of p-Hsp27 was closely associated with prognosis. Overexpression of p-Hsp27 was usually detected in advanced-stage patients with lung cancer and indicated short survival. Summary DRSPs were useful for investigating drug resistance and may provide a practical model for studying the crucial role of p-Hsp27 in the p38 MAPK–Hsp27 axis in CSC-mediated cisplatin resistance. Targeting this axis using siRNA Hsp27 may provide a treatment strategy to improve prognosis and prolong survival in lung cancer patients. PMID:26872057

  16. Small cell lung cancer transformation and T790M mutation: complimentary roles in acquired resistance to kinase inhibitors in lung cancer.

    PubMed

    Suda, Kenichi; Murakami, Isao; Sakai, Kazuko; Mizuuchi, Hiroshi; Shimizu, Shigeki; Sato, Katsuaki; Tomizawa, Kenji; Tomida, Shuta; Yatabe, Yasushi; Nishio, Kazuto; Mitsudomi, Tetsuya

    2015-09-24

    Lung cancers often harbour a mutation in the epidermal growth factor receptor (EGFR) gene. Because proliferation and survival of lung cancers with EGFR mutation solely depend on aberrant signalling from the mutated EGFR, these tumours often show dramatic responses to EGFR tyrosine kinase inhibitors (TKIs). However, acquiring resistance to these drugs is almost inevitable, thus a better understanding of the underlying resistance mechanisms is critical. Small cell lung cancer (SCLC) transformation is a relatively rare acquired resistance mechanism that has lately attracted considerable attention. In the present study, through an in-depth analysis of multiple EGFR-TKI refractory lesions obtained from an autopsy case, we observed a complementary relationship between SCLC transformation and EGFR T790M secondary mutation (resistance mutation). We also identified analogies and differences in genetic aberration between a TKI-refractory lesion with SCLC transformation and one with EGFR T790M mutation. In particular, target sequencing revealed a TP53 P151S mutation in all pre- and post-treatment lesions. PTEN M264I mutation was identified only in a TKI-refractory lesion with SCLC transformation, while PIK3CA and RB1 mutations were identified only in pre-treatment primary tumour samples. These results provide the groundwork for understanding acquired resistance to EGFR-TKIs via SCLC transformation.

  17. Role of reaction resistance in limiting carbon monoxide uptake in rabbit lungs.

    PubMed

    Heller, H; Schuster, K

    1998-06-01

    The contribution of reaction resistance to overall resistance to pulmonary carbon monoxide (CO) uptake [DLCO/(ThetaCO . Vc), where DLCO is lung CO diffusing capacity, ThetaCO is CO uptake conductance of erythrocytes, and Vc is pulmonary capillary blood volume] was determined in 10 anesthetized, paralyzed, and artificially ventilated rabbits. On the basis of the classical double-reciprocal equation of F. G. W. Roughton and R. E. Forster (J. Appl. Physiol. 11: 290-302, 1957), DLCO/(ThetaCO . Vc) was obtained by solving the relation DLCO/(ThetaCO . Vc) = 1 - 2/(DLNO/DLCO), where DLNO/DLCO represents the ratio between the respective single-breath diffusing capacities (DL) of nitric oxide (NO) and CO pulmonary capillary blood. The lungs of eight rabbits were inflated, starting from residual volume, by using 55 ml of indicator gas mixture (0.2% CO and 0.05% NO in nitrogen). DL values were calculated by taking the end-tidal partial pressures of CO and NO as analyzed by using a respiratory mass spectrometer. The overall value was DLCO/(ThetaCO . Vc) = 0.4 +/- 0.025 (mean +/- SD). Because of the use of O2-free indicator gas mixtures, the end-tidal O2 partial pressures were approximately 21 Torr. In one other rabbit, the application of 0.2% CO and 0.001% NO yielded DLCO/(ThetaCO . Vc) = 0.39; in the tenth rabbit, however, inspiratory volume was varied, and an identical value was found at functional residual capacity. We conclude that the contribution of reaction resistance to overall resistance to pulmonary CO uptake is independent of the inspiratory NO concentration used, including, with respect to the pertinent literature, the conclusion that in rabbits, dogs, and humans this contribution amounts to 40% when determined at functional residual capacity.

  18. Hedgehog pathway maintains cell survival under stress conditions, and drives drug resistance in lung adenocarcinoma

    PubMed Central

    Lin, Erh-Hsuan; Kao, Yu-Rung; Lin, Chih-An; Kuo, Ting-Yu; Yang, Sheng-Ping; Hsu, Chiung-Fang; Chou, Teh-Ying; Ho, Chao-Chi; Wu, Cheng-Wen

    2016-01-01

    Hedgehog (HH) pathway plays an important role in embryonic development, but is largely inactive in adult except for tissue repair. Aberrant activation of HH pathway has been found in a variety of cancer types. In non-small cell lung cancer, however, the role and importance of HH pathway remain controversial. In the current study, we found that HH pathway was maintained in low activity in lung adenocarcinoma (LAC) cells under normal culture condition, but was highly induced in response to stress conditions. Activation of HH pathway promoted cell survival, growth, and invasion partially through HGF and MET signaling. Hedgehog-Interacting Protein (HHIP), a cell-surface negative regulator of HH pathway, was epigenetically silenced in LAC. Overexpression of HHIP blocked the activation of HH and HGF/MET pathways, and made cells significantly more susceptible to stress conditions. In LAC cells with acquired resistance to Epidermal Growth Factor Receptor Tyrosin Kinase Inhibitor (EGFR-TKI), we found that a part of tumor cells were much more sensitive to HH or HGF/MET inhibitors, suggesting an oncogenic addiction shift from EGFR to HH and HGF/MET pathways. In conclusion, this study showed that HH pathway is a survival signaling that drives LAC cell growth under stress conditions, and HHIP is a key regulator to block the induction of HH pathway. Targeting the HH pathway through inhibitors or HHIP thus holds promise to address EGFR-TKI resistance in LAC in clinic. PMID:27015549

  19. Hedgehog pathway maintains cell survival under stress conditions, and drives drug resistance in lung adenocarcinoma.

    PubMed

    Lin, Erh-Hsuan; Kao, Yu-Rung; Lin, Chih-An; Kuo, Ting-Yu; Yang, Sheng-Ping; Hsu, Chiung-Fang; Chou, Teh-Ying; Ho, Chao-Chi; Wu, Cheng-Wen

    2016-04-26

    Hedgehog (HH) pathway plays an important role in embryonic development, but is largely inactive in adult except for tissue repair. Aberrant activation of HH pathway has been found in a variety of cancer types. In non-small cell lung cancer, however, the role and importance of HH pathway remain controversial. In the current study, we found that HH pathway was maintained in low activity in lung adenocarcinoma (LAC) cells under normal culture condition, but was highly induced in response to stress conditions. Activation of HH pathway promoted cell survival, growth, and invasion partially through HGF and MET signaling. Hedgehog-Interacting Protein (HHIP), a cell-surface negative regulator of HH pathway, was epigenetically silenced in LAC. Overexpression of HHIP blocked the activation of HH and HGF/MET pathways, and made cells significantly more susceptible to stress conditions. In LAC cells with acquired resistance to Epidermal Growth Factor Receptor Tyrosin Kinase Inhibitor (EGFR-TKI), we found that a part of tumor cells were much more sensitive to HH or HGF/MET inhibitors, suggesting an oncogenic addiction shift from EGFR to HH and HGF/MET pathways. In conclusion, this study showed that HH pathway is a survival signaling that drives LAC cell growth under stress conditions, and HHIP is a key regulator to block the induction of HH pathway. Targeting the HH pathway through inhibitors or HHIP thus holds promise to address EGFR-TKI resistance in LAC in clinic. PMID:27015549

  20. TOPK promotes lung cancer resistance to EGFR tyrosine kinase inhibitors by phosphorylating and activating c-Jun

    PubMed Central

    Wang, Tao; Wang, Ting; Niu, Mengjie; Zhang, Shengli; Jia, Lintao; Li, Shengqing

    2016-01-01

    Tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) have shown promising clinical efficacy in non-squamous non-small cell lung cancer (NSCLC); however, resistance is frequently observed in malignant cells, operating through a mechanism that remains largely unknown. The present study shows that T-lymphokine-activated killer cell-originated protein kinase (TOPK) is upregulated in NSCLC and excessively activated in TKI-refractory cells. TOPK dictates the responsiveness of lung cancers to the EGFR-targeted TKI gefitinib through the transcription factor AP-1 component c-Jun. TOPK binds directly to and phosphorylates c-Jun, which consequently activates the transcription of AP-1 target genes, including CCND1 and CDC2. TOPK silencing sensitizes EGFR-TKI-resistant lung cancer cells to gefitinib and increases gefitinib efficacy in preclinical lung adenocarcinoma xenograft models. These findings represent a novel mechanism of lung cancer resistance to TKIs and suggest that TOPK may have value both as a predictive biomarker and as a therapeutic target: TOPK-targeted therapy may synergize with EGFR-targeted therapy in lung cancers. PMID:26745678

  1. Niclosamide overcomes acquired resistance to erlotinib through suppression of STAT3 in non-small cell lung cancer

    PubMed Central

    Li, Rui; Hu, Zhongliang; Sun, Shi-Yong; Chen, Zhuo G.; Owonikoko, Taofeek K.; Sica, Gabriel L.; Ramalingam, Suresh S.; Curran, Walter J.; Khuri, Fadlo R.; Deng, Xingming

    2013-01-01

    The emergence of resistance to epidermal growth factor receptor (EGFR) inhibitor therapy is a major clinical problem for patients with non-small cell lung cancer (NSCLC). The mechanisms underlying tumor resistance to inhibitors of the kinase activity of EGFR are not fully understood. Here we found that inhibition of EGFR by erlotinib induces STAT3 phosphorylation at Tyr705 in association with increased Bcl2/Bcl-XL at both mRNA and protein levels in various human lung cancer cells. PTPMeg2 is a physiologic STAT3 phosphatase that can directly dephosphorylate STAT3 at the Tyr705 site. Intriguingly, treatment of cells with erlotinib results in downregulation of PTPMeg2 without activation of STAT3 kinases (i.e. JAK2 or c-Src), suggesting that erlotinib enhanced phosphorylation of STAT3 may occur, at least in part, from suppression of PTPMeg2 expression. Since elevated levels of phosphorylated STAT3 (pSTAT3), Bcl2 and Bcl-XL were observed in erlotinib-resistant lung cancer (HCC827/ER) cells as compared to erlotinib-sensitive parental HCC827 cells, we postulate that erlotinib-activated STAT3/Bcl2/Bcl-XL survival pathway may contribute to acquired resistance to erlotinib. Both blockage of Tyr705 phosphorylation of STAT3 by niclosamide and depletion of STAT3 by RNA interference in HCC827/ER cells reverses erlotinib resistance. Niclosamide in combination with erlotinib potently represses erlotinib-resistant lung cancer xenografts in association with increased apoptosis in tumor tissues, suggesting that niclosamide can restore sensitivity to erlotinib. These findings uncover a novel mechanism of erlotinib resistance and provide a novel approach to overcome resistance by blocking the STAT3/Bcl2/Bcl-XL survival signaling pathway in human lung cancer. PMID:23894143

  2. The significant blood resistance to lung nitric oxide transfer lies within the red cell.

    PubMed

    Borland, Colin; Bottrill, Fiona; Jones, Aled; Sparkes, Chris; Vuylsteke, Alain

    2014-01-01

    The lung nitric oxide (NO) diffusing capacity (DlNO) mainly reflects alveolar-capillary membrane conductance (Dm). However, blood resistance has been shown in vitro and in vivo. To explore whether this resistance lies in the plasma, the red blood cell (RBC) membrane, or in the RBC interior, we measured the NO diffusing capacity (Dno) in a membrane oxygenator circuit containing ∼1 liter of horse or human blood exposed to 14 parts per million NO under physiological conditions on 7 separate days. We compared results across a 1,000-fold change in extracellular diffusivity using dextrans, plasma, and physiological salt solution. We halved RBC surface area by comparing horse and human RBCs. We altered the diffusive resistance of the RBC interior by adding sodium nitrite converting oxyhemoglobin to methemoglobin. Neither increased viscosity nor reduced RBC size reduced Dno. Adding sodium nitrite increased methemoglobin and was associated with a steady fall in Dno (P < 0.001). Similar results were obtained at NO concentrations found in vivo. The RBC interior appears to be the site of the blood resistance.

  3. Lipoxygenase Pathway Mediates Increases of Airway Resistance and Lung Inflation Induced by Exposure to Nanotitanium Dioxide in Rats

    PubMed Central

    Lee, Jyu-Feng; Tung, Shu-Ping; Wang, David; Yeh, Diana Yuwung; Fong, Yao; Young, Yu-Chung; Leu, Fur-Jiang

    2014-01-01

    Nanotitanium dioxide particle (nTiO2) inhalation has been reported to induce lung parenchymal injury. After inhalation of nTiO2, we monitored changes in 5-lipoxygenase, endothelial nitric oxide synthase (eNOS), and inducible nitric oxide synthase (iNOS) mRNA in rat lung tissue. Lung function parameters include specific airway resistance (SRaw), peak expiratory flow rate (PEF), functional residual capacity (FRC), and lung compliance (Cchord); blood white blood cell count (WBC), nitric oxide (NO), hydrogen peroxide, and lactic dehydrogenase (LDH); and lung lavage leukotriene C4, interleukin 6 (IL6), tumor necrotic factor α (TNFα), hydroxyl radicals, and NO. Leukotriene receptor antagonist MK571 and 5-lipoxygenase inhibitor MK886 were used for pharmacologic intervention. Compared to control, nTiO2 exposure induced near 5-fold increase in 5-lipoxygenase mRNA expression in lung tissue. iNOS mRNA increased while eNOS mRNA decreased. Lavage leukotriene C4; IL6; TNFα; NO; hydroxyl radicals; and blood WBC, NO, hydrogen peroxide, and LDH levels rose. Obstructive ventilatory insufficiency was observed. MK571 and MK886 both attenuated the systemic inflammation and lung function changes. We conclude that inhaled nTiO2 induces systemic inflammation, cytokine release, and oxidative and nitrosative stress in the lung. The lipoxygenase pathway products, mediated by oxygen radicals and WBC, play a critical role in the obstructive ventilatory insufficiency induced by nTiO2. PMID:24693335

  4. Measurement of the absolute penetration depth and surface resistance of superconductors and normal metals with the variable spacing parallel plate resonator

    NASA Astrophysics Data System (ADS)

    Talanov, Vladimir V.; Mercaldo, Lucia V.; Anlage, Steven M.; Claassen, John H.

    2000-05-01

    The variable spacing parallel plate resonator (VSPPR) is a microwave transmission line resonator with a continuously variable thickness of the dielectric spacer between the superconducting or metallic plates, filled by cryogenic liquid or vacuum. We measure the dielectric spacer thickness dependencies of the resonator frequency and quality factor, and fit them to theoretical forms, in order to extract the absolute values of penetration depth, λ, and surface resistance, Rs. A cryogenic micropositioning setup is developed to vary the spacer thickness from 0 to 100 μm with a resolution of 8.5 nm, and to maintain parallelism of the resonator plates. Measurement of ac capacitance between the plates is utilized to directly determine the separation between the resonator plates and to reduce the effect of their tilt and nonflatness on the accuracy of the measured Rs and λ. Because the operating temperature is fixed (77 K), the result for a superconductor is independent of an a priori model for the penetration depth versus temperature. This technique can also be employed as a surface impedance standard for characterization of high temperature superconducting films for microwave applications.

  5. Dynamic Surface Activity of a Fully Synthetic Phospholipase-Resistant Lipid/Peptide Lung Surfactant

    PubMed Central

    Walther, Frans J.; Waring, Alan J.; Hernandez-Juviel, Jose M.; Gordon, Larry M.; Schwan, Adrian L.; Jung, Chun-Ling; Chang, Yusuo; Wang, Zhengdong; Notter, Robert H.

    2007-01-01

    Background This study examines the surface activity and resistance to phospholipase degradation of a fully-synthetic lung surfactant containing a novel diether phosphonolipid (DEPN-8) plus a 34 amino acid peptide (Mini-B) related to native surfactant protein (SP)-B. Activity studies used adsorption, pulsating bubble, and captive bubble methods to assess a range of surface behaviors, supplemented by molecular studies using Fourier transform infrared (FTIR) spectroscopy, circular dichroism (CD), and plasmon resonance. Calf lung surfactant extract (CLSE) was used as a positive control. Results DEPN-8+1.5% (by wt.) Mini-B was fully resistant to degradation by phospholipase A2 (PLA2) in vitro, while CLSE was severely degraded by this enzyme. Mini-B interacted with DEPN-8 at the molecular level based on FTIR spectroscopy, and had significant plasmon resonance binding affinity for DEPN-8. DEPN-8+1.5% Mini-B had greatly increased adsorption compared to DEPN-8 alone, but did not fully equal the very high adsorption of CLSE. In pulsating bubble studies at a low phospholipid concentration of 0.5 mg/ml, DEPN-8+1.5% Mini-B and CLSE both reached minimum surface tensions <1 mN/m after 10 min of cycling. DEPN-8 (2.5 mg/ml)+1.5% Mini-B and CLSE (2.5 mg/ml) also reached minimum surface tensions <1 mN/m at 10 min of pulsation in the presence of serum albumin (3 mg/ml) on the pulsating bubble. In captive bubble studies, DEPN-8+1.5% Mini-B and CLSE both generated minimum surface tensions <1 mN/m on 10 successive cycles of compression/expansion at quasi-static and dynamic rates. Conclusions These results show that DEPN-8 and 1.5% Mini-B form an interactive binary molecular mixture with very high surface activity and the ability to resist degradation by phospholipases in inflammatory lung injury. These characteristics are promising for the development of related fully-synthetic lipid/peptide exogenous surfactants for treating diseases of surfactant deficiency or dysfunction. PMID

  6. Expression of lung resistance protein in epithelioid sarcoma in vitro and in vivo.

    PubMed

    Kusakabe, H; Iwasaki, H; Sano, K; Kiyokane, K

    2000-06-01

    The incidence of epithelioid sarcoma among patients with malignant soft tissue tumors is small, but the rates of recurrence and metastasis of this type of sarcoma are high. To date, effective chemotherapy for advanced epithelioid sarcoma has not been established and, furthermore, epithelioid sarcoma is known to exhibit multidrug resistance (MDR). The chemosensitivities to anticancer agents of two cell lines established from epithelioid sarcoma were examined in this study. The results showed that the ES-OMC-MN and SFT-8606 cell lines were resistant to vincristine (IC50 1190 nM and 872 nM, respectively) and Adriamycin (IC50 921 nM and 650 nM, respectively), but sensitive to actinomycin D (IC50 < 10 nM). P-glycoprotein (p-Gp) and MDR-associated protein (MRP) were not expressed in these cell lines, but a high expression level of lung resistance protein (LRP) was observed. The original tumor tissues from which the two cell lines were established were also found to be LRP-positive but not to express p-Gp or MRP. Their chemosensitivities to Adriamycin were not significantly altered in the presence of 2.5 microg/ml anti-LRP antibody (LRP-56), but the IC50 of vincristine was much less (IC50 128 nM and 27 nM, respectively) than that for an untreated cell line. It is thus suggested that the vincristine resistance in the two cell lines is LRP-mediated. Since cyclosporin A, known to be a modifier of p-Gp, also induced reversal of vincristine resistance in the ES-OMC-MN and SFT-8606 cell lines (IC50 6.2 nM and 17 nM, respectively), it is suggested that cyclosporin A acts as a modifier of MDR mediated by LRP.

  7. Correlation among regional ventilation, airway resistance and particle deposition in normal and severe asthmatic lungs

    NASA Astrophysics Data System (ADS)

    Choi, Sanghun; Hoffman, Eric A.; Tawhai, Merryn H.; Lin, Ching-Long

    2012-11-01

    Computational fluid dynamic simulations are performed to investigate flow characteristics and quantify particle deposition with normal and severe asthmatic lungs. Continuity and Navier-Stokes equations are solved with unstructured meshes and finite element method; a large eddy simulation model is adopted to capture turbulent and/or transitional flows created in the glottis. The human airway models are reconstructed from CT volumetric images, and the subject-specific boundary condition is imposed to the 3D ending branches with the aid of an image registration technique. As a result, several constricted airways are captured in CT images of severe asthmatic subjects, causing significant pressure drop with high air speed because the constriction of airways creates high flow resistance. The simulated instantaneous velocity fields obtained are then employed to track transport and deposition of 2.5 μm particles. It is found that high flow resistance regions are correlated with high particle-deposition regions. In other words, the constricted airways can induce high airway resistance and subsequently increase particle deposition in the regions. This result may be applied to understand the characteristics of deposition of pharmaceutical aerosols or bacteria. This work was supported in part by NIH grants R01-HL094315 and S10-RR022421.

  8. Overcoming the resistance to crizotinib in patients with non-small cell lung cancer harboring EML4/ALK translocation.

    PubMed

    Perez, Cesar A; Velez, Michel; Raez, Luis E; Santos, Edgardo S

    2014-05-01

    The large knowledge learned in molecular biology specifically in the oncology field during the last ten years has resulted in fruitful results for the treatment of non-small cell lung cancer. The first pathway to be effectively targeted in lung cancer was the epidermal growth factor receptor. The acceptance of epidermal growth factor receptor mutation as a strong predictive biomarker in non-small cell lung carcinoma has encouraged the search for more targets. In 2011, regulatory entities granted conditional approval to an anaplastic lymphoma kinase inhibitor (crizotinib) based on an impressive overall response rate in previously treated non-small cell lung cancer patients whose tumors harbored EML4/ALK translocations. The landmark approval of crizotinib based on early promising clinical data highlights the remarkable success of molecular medicine in lung cancer therapeutics. The cumulative data developed after that approval has confirmed the appropriateness of this decision as recently reported phase III has now demonstrated. Unfortunately, resistance to this agent invariably develops and we now face the challenge of understanding several resistance pathways and overcoming them with new and more potent compounds. New agents in clinical development such as alectinib, LDK378, AP26113, and AUY922 have not only demonstrated promising activity in crizotinib resistant patients, but also crossing new pharmacokinetic boundaries in ALK inhibition as potent CNS penetration.

  9. Overcoming the resistance to crizotinib in patients with non-small cell lung cancer harboring EML4/ALK translocation.

    PubMed

    Perez, Cesar A; Velez, Michel; Raez, Luis E; Santos, Edgardo S

    2014-05-01

    The large knowledge learned in molecular biology specifically in the oncology field during the last ten years has resulted in fruitful results for the treatment of non-small cell lung cancer. The first pathway to be effectively targeted in lung cancer was the epidermal growth factor receptor. The acceptance of epidermal growth factor receptor mutation as a strong predictive biomarker in non-small cell lung carcinoma has encouraged the search for more targets. In 2011, regulatory entities granted conditional approval to an anaplastic lymphoma kinase inhibitor (crizotinib) based on an impressive overall response rate in previously treated non-small cell lung cancer patients whose tumors harbored EML4/ALK translocations. The landmark approval of crizotinib based on early promising clinical data highlights the remarkable success of molecular medicine in lung cancer therapeutics. The cumulative data developed after that approval has confirmed the appropriateness of this decision as recently reported phase III has now demonstrated. Unfortunately, resistance to this agent invariably develops and we now face the challenge of understanding several resistance pathways and overcoming them with new and more potent compounds. New agents in clinical development such as alectinib, LDK378, AP26113, and AUY922 have not only demonstrated promising activity in crizotinib resistant patients, but also crossing new pharmacokinetic boundaries in ALK inhibition as potent CNS penetration. PMID:24598368

  10. Hinokitiol Induces DNA Damage and Autophagy followed by Cell Cycle Arrest and Senescence in Gefitinib-Resistant Lung Adenocarcinoma Cells

    PubMed Central

    Li, Lan-Hui; Wu, Ping; Lee, Jen-Yi; Li, Pei-Rong; Hsieh, Wan-Yu; Ho, Chao-Chi; Ho, Chen-Lung; Chen, Wan-Jiun; Wang, Chien-Chun; Yen, Muh-Yong; Yang, Shun-Min; Chen, Huei-Wen

    2014-01-01

    Despite good initial responses, drug resistance and disease recurrence remain major issues for lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) mutations taking EGFR-tyrosine kinase inhibitors (TKI). To discover new strategies to overcome this issue, we investigated 40 essential oils from plants indigenous to Taiwan as alternative treatments for a wide range of illnesses. Here, we found that hinokitiol, a natural monoterpenoid from the heartwood of Calocedrus formosana, exhibited potent anticancer effects. In this study, we demonstrated that hinokitiol inhibited the proliferation and colony formation ability of lung adenocarcinoma cells as well as the EGFR-TKI-resistant lines PC9-IR and H1975. Transcriptomic analysis and pathway prediction algorithms indicated that the main implicated pathways included DNA damage, autophagy, and cell cycle. Further investigations confirmed that in lung cancer cells, hinokitiol inhibited cell proliferation by inducing the p53-independent DNA damage response, autophagy (not apoptosis), S-phase cell cycle arrest, and senescence. Furthermore, hinokitiol inhibited the growth of xenograft tumors in association with DNA damage and autophagy but exhibited fewer effects on lung stromal fibroblasts. In summary, we demonstrated novel mechanisms by which hinokitiol, an essential oil extract, acted as a promising anticancer agent to overcome EGFR-TKI resistance in lung cancer cells via inducing DNA damage, autophagy, cell cycle arrest, and senescence in vitro and in vivo. PMID:25105411

  11. Chemosensitizing activities of cyclotides from Clitoria ternatea in paclitaxel-resistant lung cancer cells.

    PubMed

    Sen, Zhang; Zhan, Xiao Kai; Jing, Jin; Yi, Zhang; Wanqi, Zhou

    2013-02-01

    Cyclotides comprise a family of circular mini-peptides that have been isolated from various plants and have a wide range of bioactivities. Previous studies have demonstrated that cyclotides have antitumor effects and cause cell death by membrane permeabilization. The present study aimed to evaluate the cytotoxicity and chemosensitizing activities of cyclotides from Clitoria ternatea in paclitaxel-resistant lung cancer cells. In this study, a total of seven cyclotides were selected for colorimetric cell viability assay (MTT assay) to evaluate their anticancer and chemosensitizing activities in the lung cancer cell line A549 and its sub-line A549/paclitaxel. Results suggested that certain cyclotides had significant anticancer and chemosensitizing abilities; such cyclotides were capable of causing multi-fold decreases in the half maximal inhibitory concentration (IC(50)) value of cliotides in the presence of paclitaxel. More importantly, their bioactivities were found to be correlated with their net charge status. In conclusion, cyclotides from C. ternatea have potential in chemosensitization application. PMID:23419988

  12. Hypoxia-induced autophagy mediates cisplatin resistance in lung cancer cells

    PubMed Central

    Wu, Hui-Mei; Jiang, Zi-Feng; Ding, Pei-Shan; Shao, Li-Jie; Liu, Rong-Yu

    2015-01-01

    Hypoxia which commonly exists in solid tumors, leads to cancer cells chemoresistance via provoking adaptive responses including autophagy. Therefore, we sought to evaluate the role of autophagy and hypoxia as well as the underlying mechanism in the cisplatin resistance of lung cancer cells. Our study demonstrated that hypoxia significantly protected A549 and SPC-A1 cells from cisplatin-induced cell death in a Hif-1α- and Hif-2α- dependent manner. Moreover, compared with normoxia, cisplatin-induced apoptosis under hypoxia was markedly reduced. However, when autophagy was inhibited by 3-MA or siRNA targeted ATG5, this reduction was effectively attenuated, which means autophagy mediates cisplatin resisitance under hypoxia. In parallel, we showed that hypoxia robustly augmented cisplatin-induced autophagy activation, accompanying by suppressing cisplatin-induced BNIP3 death pathways, which was due to the more efficient autophagic process under hypoxia. Consequently, we proposed that autophagy was a protective mechanism after cisplatin incubation under both normoxia and hypoxia. However, under normoxia, autophagy activation ‘was unable to counteract the stress induced by cisplatin, therefore resulting in cell death, whereas under hypoxia, autophagy induction was augmented that solved the cisplatin-induced stress, allowing the cells to survival. In conclusion, augmented induction of autophagy by hypoxia decreased lung cancer cells susceptibility to cisplatin-induced apoptosis. PMID:26201611

  13. Immunization protected well nourished mice but not undernourished ones from lung injury in Methicillin-resistant Staphylococcus aureus (MRSA) infection

    PubMed Central

    2009-01-01

    Background Staphylococcus aureus methicillin-resistant (MRSA) has been frequently isolated from endotracheal and lung puncture aspirates in malnourished children with pneumonia. In this work we evaluated the susceptibility of undernourished BALB/c mice and its ability to mount a protective immunity against MRSA with emphasis on the lung involvement. Results BALB/c mice submitted to a 20% dietary restriction during 20 days presented a significant decrease in body weight, lymphocyte number and also atrophy in thymus and intestinal epithelium. Determination of bacterial load by the number of colony forming units (CFU) indicated a similar susceptibility whereas the findings of Gram stain clearly suggested a higher amount of bacteria in the lungs of normal mice than in the undernourished ones. Immunization reduced bacterial growth in the lungs of normal mice but not in the undernourished ones. Histopathological analysis showed that inflammation appeared in the lungs from normal mice only after infection and that immunization prevented this pulmonary inflammatory process. On the other hand, undernourished mice presented lung inflammation even before infection. In addition, the degree of this inflammatory process did not change with infection or previous immunization. Conclusion Our results indicated that lung injury during MRSA infection is prevented by previous immunization in well nourished but not in undernourished mice. PMID:19930660

  14. AUY922 Effectively Overcomes MET- and AXL-Mediated Resistance to EGFR-TKI in Lung Cancer Cells

    PubMed Central

    Choi, Yun Jung; Kim, Seon Ye; So, Kwang Sup; Baek, In-Jeoung; Kim, Woo Sung; Choi, Se Hoon; Lee, Jae Cheol; Bivona, Trever G.; Rho, Jin Kyung; Choi, Chang-Min

    2015-01-01

    The activation of bypass signals, such as MET and AXL, has been identified as a possible mechanism of EGFR-TKI resistance. Because various oncoproteins depend on HSP90 for maturation and stability, we investigated the effects of AUY922, a newly developed non-geldanamycin class HSP90 inhibitor, in lung cancer cells with MET- and AXL-mediated resistance. We established resistant cell lines with HCC827 cells harboring an exon 19-deletion mutation in of the EGFR gene via long-term exposure to increasing concentrations of gefitinib and erlotinib (HCC827/GR and HCC827/ER, respectively). HCC827/GR resistance was mediated by MET activation, whereas AXL activation caused resistance in HCC827/ER cells. AUY922 treatment effectively suppressed proliferation and induced cell death in both resistant cell lines. Accordingly, the downregulation of EGFR, MET, and AXL led to decreased Akt activation. The inhibitory effects of AUY922 on each receptor were confirmed in gene-transfected LK2 cells. AUY922 also effectively controlled tumor growth in xenograft mouse models containing HCC827/GR and HCC827/ER cells. In addition, AUY922 reduced invasion and migration by both types of resistant cells. Our study findings thus show that AUY922 is a promising therapeutic option for MET- and AXL-mediated resistance to EGFR-TKI in lung cancer. PMID:25780909

  15. Metformin restores crizotinib sensitivity in crizotinib-resistant human lung cancer cells through inhibition of IGF1-R signaling pathway

    PubMed Central

    Zhang, Kejun; Lin, Caiyu; Han, Rui; Lu, Conghua; He, Yong

    2016-01-01

    Aim Despite the impressive efficacy of crizotinib for the treatment of ALK-positive non-small cell lung cancer, patients invariably develop therapeutic resistance. Suppression of the IGF-1R signaling pathway may abrogate this acquired mechanism of drug resistance to crizotinib. Metformin, a widely used antidiabetic agent, may reverse crizotinib resistance through inhibition of IGF-1R signaling. Results The present study revealed that metformin effectively increased the sensitivity of both crizotinib-sensitive and -resistant non-small cell lung cancer cells to crizotinib, as evidenced by decreased proliferation and invasion and enhanced apoptosis. Metformin reduced IGF-1R signaling activation in crizotinib-resistant cells. Furthermore, the addition of IGF-1 to crizotinib-sensitive H2228 cells induced crizotinib resistance, which was overcome by metformin. Experimental design The effects of metformin to reverse crizotinib resistance were examined in vitro by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT), invasion assay, ki67 incorporation assay, flow cytometry analysis, Western blot analysis, and colony-forming assay. Conclusions Metformin may be used in combination with crizotinib in ALK+ NSCLC patients to overcome crizotinib resistance and prolong survival. PMID:27144340

  16. Activation of the Met kinase confers acquired drug resistance in FGFR-targeted lung cancer therapy.

    PubMed

    Kim, S-M; Kim, H; Yun, M R; Kang, H N; Pyo, K-H; Park, H J; Lee, J M; Choi, H M; Ellinghaus, P; Ocker, M; Paik, S; Kim, H R; Cho, B C

    2016-01-01

    Aberrant fibroblast growth factor receptor (FGFR) activation/expression is a common feature in lung cancer (LC). In this study, we evaluated the antitumor activity of and the mechanisms underlying acquired resistance to two potent selective FGFR inhibitors, AZD4547 and BAY116387, in LC cell lines. The antitumor activity of AZD4547 and BAY1163877 was screened in 24 LC cell lines, including 5 with FGFR1 amplification. Two cell lines containing FGFR1 amplifications, H1581 and DMS114, were sensitive to FGFR inhibitors (IC50<250 nm). Clones of FGFR1-amplified H1581 cells resistant to AZD4547 or BAY116387 (H1581AR and H1581BR cells, respectively) were established. Receptor tyrosine kinase (RTK) array and immunoblotting analyses showed strong overexpression and activation of Met in H1581AR/BR cells, compared with that in the parental cells. Gene set enrichment analysis against the Kyoto Encyclopedia of Genes and Genomes (KEGG) database showed that cytokine-cytokine receptor interaction pathways were significantly enriched in H1581AR/BR cells, with Met contributing significantly to the core enrichment. Genomic DNA quantitative PCR and fluorescent in situ hybridization analyses showed MET amplification in H1581AR, but not in H1581BR, cells. Met amplification drives acquired resistance to AZD4547 in H1581AR cells by activating ErbB3. Combination treatment with FGFR inhibitors and an anaplastic lymphoma kinase (ALK)/Met inhibitor, crizotinib, or Met-specific short interfering RNA (siRNA) synergistically inhibited cell proliferation in both H1581AR and H1581BR cells. Conversely, ectopic expression of Met in H1581 cells conferred resistance to AZD4547 and BAY1163877. Acquired resistance to FGFR inhibitors not only altered cellular morphology, but also promoted migration and invasion of resistant clones, in part by inducing epithelial-to-mesenchymal transition. Taken together, our data suggest that Met activation is sufficient to bypass dependency on FGFR signaling. Concurrent

  17. Chloroquine Enhances Gefitinib Cytotoxicity in Gefitinib-Resistant Nonsmall Cell Lung Cancer Cells

    PubMed Central

    Tang, Mei-Chuan; Wu, Mei-Yi; Hwang, Ming-Hung; Chang, Ya-Ting; Huang, Hui-Ju; Lin, Anya Maan-Yuh; Yang, James Chih-Hsin

    2015-01-01

    Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), including gefitinib, are effective for non-small cell lung cancer (NSCLC) patients with EGFR mutations. However, these patients eventually develop resistance to EGFR-TKI. The goal of the present study was to investigate the involvement of autophagy in gefitinib resistance. We developed gefitinib-resistant cells (PC-9/gef) from PC-9 cells (containing exon 19 deletion EGFR) after long-term exposure in gefitinib. PC-9/gef cells (B4 and E3) were 200-fold more resistant to gefitinib than PC-9/wt cells. Compared with PC-9/wt cells, both PC-9/gefB4 and PC-9/gefE3 cells demonstrated higher basal LC3-II levels which were inhibited by 3-methyladenine (3-MA, an autophagy inhibitor) and potentiated by chloroquine (CQ, an inhibitor of autophagolysosomes formation), indicating elevated autophagy in PC-9/gef cells. 3-MA and CQ concentration-dependently inhibited cell survival of both PC-9wt and PC-9/gef cells, suggesting that autophagy may be pro-survival. Furthermore, gefitinib increased LC3-II levels and autolysosome formation in both PC-9/wt cells and PC-9/gef cells. In PC-9/wt cells, CQ potentiated the cytotoxicity by low gefitinib (3nM). Moreover, CQ overcame the acquired gefitinib resistance in PC-9/gef cells by enhancing gefitinib-induced cytotoxicity, activation of caspase 3 and poly (ADP-ribose) polymerase cleavage. Using an in vivo model xenografting with PC-9/wt and PC-9/gefB4 cells, oral administration of gefitinib (50 mg/kg) completely inhibited the tumor growth of PC-9/wt but not PC-9/gefB4cells. Combination of CQ (75 mg/kg, i.p.) and gefitinib was more effective than gefitinib alone in reducing the tumor growth of PC-9/gefB4. Our data suggest that inhibition of autophagy may be a therapeutic strategy to overcome acquired resistance of gefitinib in EGFR mutation NSCLC patients. PMID:25807554

  18. Chloroquine enhances gefitinib cytotoxicity in gefitinib-resistant nonsmall cell lung cancer cells.

    PubMed

    Tang, Mei-Chuan; Wu, Mei-Yi; Hwang, Ming-Hung; Chang, Ya-Ting; Huang, Hui-Ju; Lin, Anya Maan-Yuh; Yang, James Chih-Hsin

    2015-01-01

    Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), including gefitinib, are effective for non-small cell lung cancer (NSCLC) patients with EGFR mutations. However, these patients eventually develop resistance to EGFR-TKI. The goal of the present study was to investigate the involvement of autophagy in gefitinib resistance. We developed gefitinib-resistant cells (PC-9/gef) from PC-9 cells (containing exon 19 deletion EGFR) after long-term exposure in gefitinib. PC-9/gef cells (B4 and E3) were 200-fold more resistant to gefitinib than PC-9/wt cells. Compared with PC-9/wt cells, both PC-9/gefB4 and PC-9/gefE3 cells demonstrated higher basal LC3-II levels which were inhibited by 3-methyladenine (3-MA, an autophagy inhibitor) and potentiated by chloroquine (CQ, an inhibitor of autophagolysosomes formation), indicating elevated autophagy in PC-9/gef cells. 3-MA and CQ concentration-dependently inhibited cell survival of both PC-9wt and PC-9/gef cells, suggesting that autophagy may be pro-survival. Furthermore, gefitinib increased LC3-II levels and autolysosome formation in both PC-9/wt cells and PC-9/gef cells. In PC-9/wt cells, CQ potentiated the cytotoxicity by low gefitinib (3 nM). Moreover, CQ overcame the acquired gefitinib resistance in PC-9/gef cells by enhancing gefitinib-induced cytotoxicity, activation of caspase 3 and poly (ADP-ribose) polymerase cleavage. Using an in vivo model xenografting with PC-9/wt and PC-9/gefB4 cells, oral administration of gefitinib (50 mg/kg) completely inhibited the tumor growth of PC-9/wt but not PC-9/gefB4cells. Combination of CQ (75 mg/kg, i.p.) and gefitinib was more effective than gefitinib alone in reducing the tumor growth of PC-9/gefB4. Our data suggest that inhibition of autophagy may be a therapeutic strategy to overcome acquired resistance of gefitinib in EGFR mutation NSCLC patients. PMID:25807554

  19. Role of Insulin-Like Growth Factor-1 Signaling Pathway in Cisplatin-Resistant Lung Cancer Cells

    SciTech Connect

    Sun Yunguang; Zheng Siyuan; Torossian, Artour; Speirs, Christina K.; Schleicher, Stephen; Giacalone, Nicholas J.; Carbone, David P.; Zhao Zhongming; Lu Bo

    2012-03-01

    Purpose: The development of drug-resistant phenotypes has been a major obstacle to cisplatin use in non-small-cell lung cancer. We aimed to identify some of the molecular mechanisms that underlie cisplatin resistance using microarray expression analysis. Methods and Materials: H460 cells were treated with cisplatin. The differences between cisplatin-resistant lung cancer cells and parental H460 cells were studied using Western blot, MTS, and clonogenic assays, in vivo tumor implantation, and microarray analysis. The cisplatin-R cells were treated with human recombinant insulin-like growth factor (IGF) binding protein-3 and siRNA targeting IGF-1 receptor. Results: Cisplatin-R cells illustrated greater expression of the markers CD133 and aldehyde dehydrogenase, more rapid in vivo tumor growth, more resistance to cisplatin- and etoposide-induced apoptosis, and greater survival after treatment with cisplatin or radiation than the parental H460 cells. Also, cisplatin-R demonstrated decreased expression of insulin-like growth factor binding protein-3 and increased activation of IGF-1 receptor signaling compared with parental H460 cells in the presence of IGF-1. Human recombinant IGF binding protein-3 reversed cisplatin resistance in cisplatin-R cells and targeting of IGF-1 receptor using siRNA resulted in sensitization of cisplatin-R-cells to cisplatin and radiation. Conclusions: The IGF-1 signaling pathway contributes to cisplatin-R to cisplatin and radiation. Thus, this pathway represents a potential target for improved lung cancer response to treatment.

  20. Potential role of Saudi red propolis in alleviating lung damage induced by methicillin resistant Staphylococcus aureus virulence in rats.

    PubMed

    Saddiq, Amna Ali; Mohamed, Azza Mostafa

    2016-07-01

    The aim of this study was to explore the protective impact of aqueous extract of Saudi red propolis against rat lung damage induced by the pathogenic bacteria namely methicillin resistant Staphylococcus aureus (MRSA) ATCC 6538 strain. Infected rats were received a single intraperitoneal (i.p.) injection of bacterial suspension at a dose of 1 X 10(6) CFU / 100g body weight. Results showed that oral administration of an aqueous extract of propolis (50mg/100g body weight) daily for two weeks to infected rats simultaneously with bacterial infection, effectively ameliorated the alteration of oxidative stress biomarker, malondialdehyde (MDA), as well as the antioxidant markers, glutathione peroxidase (GPx) and superoxide dismutase (SOD), in lungs of infected rats compared with infected untreated ones. Also, the used propolis extract successfully modulated the alterations in proinflammatory mediators, tumor necrosis factor-α (TNF- α) and vascular endothelial growth factor (VEGF) in serum. In addition, the propolis extract successfully modulated the oxidative DNA damage and the apoptosis biomarker, caspase 3, in lungs of S aureus infected rats compared with infected untreated animals. The biochemical results were supported by histo-pathological observation of lung tissues. In conclusion, the beneficial prophylactic role of the aqueous extract of Saudi red propolis against lung damage induced by methicillin resistant S aureus may be related to the antioxidant, anti-inflammatory, immunomodulatory and antiapoptosis of its active constituents.

  1. Teaching Absolute Value Meaningfully

    ERIC Educational Resources Information Center

    Wade, Angela

    2012-01-01

    What is the meaning of absolute value? And why do teachers teach students how to solve absolute value equations? Absolute value is a concept introduced in first-year algebra and then reinforced in later courses. Various authors have suggested instructional methods for teaching absolute value to high school students (Wei 2005; Stallings-Roberts…

  2. Cetuximab-modified mesoporous silica nano-medicine specifically targets EGFR-mutant lung cancer and overcomes drug resistance.

    PubMed

    Wang, Yuetong; Huang, Hsin-Yi; Yang, Liu; Zhang, Zhanxia; Ji, Hongbin

    2016-01-01

    Drug resistance to tyrosine kinase inhibitor (TKI) is the main obstacle for efficient treatment of epidermal growth factor receptor (EGFR)-mutant lung cancer patients. Here we design a cetuximab-capped mesoporous silica nanoparticle (MP-SiO2 NP) as the drug carrier to specifically target EGFR-mutant lung cancer cells and efficiently release loaded drugs including doxorubicin and gefitinib. This innovative nano-medicine can specifically target lung cancer cells with high EGFR expression rather than those with low EGFR level. Treatment of a gefitinib-resistant cell line derived from PC9 cell (PC9-DR) with the gefitinib-loaded cetuximab-capped MP-SiO2 NP showed a significant inhibition of cell growth. Moreover, this nano-medicine successfully suppressed the progression of PC9-DR xenograft tumors. This tumor suppression was due to the endocytosis of large amount of nano-medicine and the effective gefitinib release induced by high glutathione (GSH) level in PC9-DR cells. Collectively, our study provides a novel approach to overcome EGFR-TKI resistance using cetuximab modified MP-SiO2 NP, which holds strong potential for effective management of EGFR-mutant lung cancer. PMID:27151505

  3. Silibinin reverses drug resistance in human small-cell lung carcinoma cells

    PubMed Central

    Sadava, David; Kane, Susan E.

    2014-01-01

    Small-cell lung carcinoma (SCLC) has a dismal prognosis in part because of multidrug resistance (MDR). Silibinin is a flavonolignan extracted from milk thistle (Silybum marianum), extracts of which are used in traditional medicine. We tested the effects of silibinin on drug-sensitive (H69) and multi-drug resistant (VPA17) SCLC cells. VPA17 cells did not show resistance to silibinin (IC50 = 60µM for H69 and VPA17). Flow cytometry analysis after incubation in 30 µM silibinin showed no changes in cell cycle phases in VPA17 or H69 cells compared with untreated cells. Silibinin (30 µM) incubation was pro-apoptotic in VPA17 cells after >3 days, as measured by ELISA of BUdR labeled DNA fragments. Apoptosis was also indicated by an increase in caspase-3 specific activity and decrease in survivin in VPA17 MDR cells. VPA17 cells had increased Pgp -mediated efflux of calcein acetoxymethyl ester (calcein AM); however, this was inhibited in cells pre-incubated in silibinin for 5 days. Pre-incubation of VPA17 cells in 30 µM silibinin for 5 days also reversed resistance to etoposide (IC50 = 5.50 uM to 0.65 µM) and doxorubicin (IC50 = 0.620 µM to 0.035 µM). The possible synergistic relationship between silibinin and chemotherapy drugs was determined by exposure of VPA17 cells to 1:1 ratios of their respective IC50 values, with serial dilutions at 0.25–2.0 × IC50 and calculation of the combination index (CI). Silibinin and etoposide showed synergism (CI = 0.46 at ED50), as did silibinin and doxorubicin (CI = 0.24 at ED50). These data indicate that in SCLC, silibinin is pro-apoptotic, reverses MDR and acts synergistically with chemotherapy drugs. Silibinin, a non-toxic natural product may be useful in the treatment of drug-resistant SCLC. PMID:23879966

  4. TUCAN/CARDINAL/CARD8 and apoptosis resistance in non-small cell lung cancer cells

    PubMed Central

    Checinska, Agnieszka; Giaccone, Giuseppe; Hoogeland, Bas SJ; Ferreira, Carlos G; Rodriguez, Jose A; Kruyt, Frank AE

    2006-01-01

    Background Activation of caspase-9 in response to treatment with cytotoxic drugs is inhibited in NSCLC cells, which may contribute to the clinical resistance to chemotherapy shown in this type of tumor. The aim of the present study was to investigate the mechanism of caspase-9 inhibition, with a focus on a possible role of TUCAN as caspase-9 inhibitor and a determinant of chemosensitivity in NSCLC cells. Methods Caspase-9 processing and activation were investigated by Western blot and by measuring the cleavage of the fluorogenic substrate LEHD-AFC. Proteins interaction assays, and RNA interference in combination with cell viability and apoptosis assays were used to investigate the involvement of TUCAN in inhibition of caspase-9 and chemosensitivity NSCLC. Results Analysis of the components of the caspase-9 activation pathway in a panel of NSCLC and SCLC cells revealed no intrinsic defects. In fact, exogenously added cytochrome c and dATP triggered procaspase-9 cleavage and activation in lung cancer cell lysates, suggesting the presence of an inhibitor. The reported inhibitor of caspase-9, TUCAN, was exclusively expressed in NSCLC cells. However, interactions between TUCAN and procaspase-9 could not be demonstrated by any of the assays used. Furthermore, RNA interference-mediated down-regulation of TUCAN did not restore cisplatin-induced caspase-9 activation or affect cisplatin sensitivity in NSCLC cells. Conclusion These results indicate that procaspase-9 is functional and can undergo activation and full processing in lung cancer cell extracts in the presence of additional cytochrome c/dATP. However, the inhibitory protein TUCAN does not play a role in inhibition of procaspase-9 and in determining the sensitivity to cisplatin in NSCLC. PMID:16796750

  5. A novel paclitaxel-loaded poly(d,l-lactide-co-glycolide)-Tween 80 copolymer nanoparticle overcoming multidrug resistance for lung cancer treatment

    PubMed Central

    Yuan, Xun; Ji, Wenxiang; Chen, Si; Bao, Yuling; Tan, Songwei; Lu, Shun; Wu, Kongming; Chu, Qian

    2016-01-01

    Drug resistance has become a main obstacle for the effective treatment of lung cancer. To address this problem, a novel biocompatible nanoscale package, poly(d,l-lactide-co-glycolide)-Tween 80, was designed and synthesized to overcome paclitaxel (PTX) resistance in a PTX-resistant human lung cancer cell line. The poly(d,l-lactide-co-glycolide) (PLGA)-Tween 80 nanoparticles (NPs) could efficiently load PTX and release the drug gradually. There was an increased level of uptake of PLGA-Tween 80 in PTX-resistant lung cancer cell line A549/T, which achieved a significantly higher level of cytotoxicity than both PLGA NP formulation and Taxol®. The in vivo antitumor efficacy also showed that PLGA-Tween 80 NP was more effective than Taxol®, indicating that PLGA-Tween 80 copolymer was a promising carrier for PTX in resistant lung cancer. PMID:27307727

  6. The mechanism of acquired resistance to irreversible EGFR tyrosine kinase inhibitor-afatinib in lung adenocarcinoma patients

    PubMed Central

    Wu, Shang-Gin; Liu, Yi-Nan; Tsai, Meng-Feng; Chang, Yih-Leong; Yu, Chong-Jen; Yang, Pan-Chyr; Yang, James Chih-Hsin; Wen, Yueh-Feng; Shih, Jin-Yuan

    2016-01-01

    Introduction Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are associated with favorable response in EGFR mutant lung cancer. Acquired resistance to reversible EGFR TKIs remains a significant barrier, and acquired EGFR T790M-mutation is the major mechanism. Second-generation irreversible EGFR TKI, afatinib, had also been approved for treating EGFR mutant lung cancer patients, but the mechanism of acquired resistance to afatinib has not been well studied. Results Forty-two patients had tissue specimens taken after acquiring resistance to afatinib. The sensitizing EGFR mutation were all consistent between pre- and post-afatinib tissues. Twenty patients (47.6%) had acquired T790M mutation. T790M rate was not different between first-generation EGFR TKI-naïve patients (50%) and first-generation EGFR TKI-treated patients (46.4%) (p = 0.827). No clinical characteristics or EGFR mutation types were associated with the development of acquired T790M. No other second-site EGFR mutations were detected. There were no small cell or squamous cell lung cancer transformation. Other genetic mutations were not identified in PIK3CA, BRAF, HER2, KRAS, NRAS, MEK1, AKT2, LKB1 and JAK2. Methods Afatinib-prescription record of our department of pharmacy from January 2007 and December 2014 was retrieved. We investigated patients with tissue specimens available after acquiring resistance to afatinib. Enrolled patients should have partial response or durable stable disease of treatment response to afatinib. Various mechanisms of acquired resistance to first-generation EGFR TKIs were evaluated. Histology and cytology were reviewed. EGFR, PIK3CA, BRAF, HER2, KRAS, NRAS, MEK1, AKT2, LKB1 and JAK2 genetic alterations were evaluated by sequencing. Statistical analysis was performed using Chi-square test and Kaplan-Meier method. Conclusions T790M was detected in half of the lung adenocarcinoma after acquiring resistance to afatinib. T790M is still the major acquired

  7. FAT10 is associated with the malignancy and drug resistance of non-small-cell lung cancer

    PubMed Central

    Xue, Feng; Zhu, Lin; Meng, Qing-wei; Wang, Liyan; Chen, Xue-song; Zhao, Yan-bin; Xing, Ying; Wang, Xiao-yun; Cai, Li

    2016-01-01

    Lung cancer has become one of the leading causes of cancer mortality worldwide, and non-small-cell lung cancer (NSCLC) accounts for ~85% of all lung cancer cases. Currently, platinum-based chemotherapy drugs, including cisplatin and carboplatin, are the most effective treatment for NSCLC. However, the clinical efficacy of chemotherapy is markedly reduced later in the treatment because drug resistance develops during the treatment. Recently, a series of studies has suggested the involvement of FAT10 in the development and malignancy of multiple cancer types. In this study, we focused our research on the function of FAT10 in NSCLC, which has not been previously reported in the literature. We found that the expression levels of FAT10 were elevated in quick chemoresistance NSCLC tissues, and we demonstrated that FAT10 promotes NSCLC cell proliferation, migration, and invasion. Furthermore, the protein levels of FAT10 were elevated in cisplatin- and carboplatin-resistant NSCLC cells, and knockdown of FAT10 reduced the drug resistance of NSCLC cells. In addition, we gained evidence that FAT10 regulates NSCLC malignancy and drug resistance by modulating the activity of the nuclear factor kappa B signaling pathway. PMID:27499634

  8. miR-487b-5p Regulates Temozolomide Resistance of Lung Cancer Cells Through LAMP2-Medicated Autophagy.

    PubMed

    Bao, Liang; Lv, Lei; Feng, Jinping; Chen, Yuyu; Wang, Xinhua; Han, Shuguang; Zhao, Hongqing

    2016-08-01

    Temozolomide (TMZ) is a standard agent used in the treatment of various types of cancers, including lung carcinoma, but TMZ resistance is common and accounts for many treatment failures. We investigated miRNA-487b-5p (miR-487b-5p) was highly expressed in A549 and H1299 cells which acquired TMZ resistance. Suppression of miR-487b-5p had overt effects on cellular proliferation and migration in the presence of TMZ. On the other hand, knockdown of miR-487b-5p resulted in increased survival and moderate tumor growth in vivo. In addition, the decreased cellular proliferation following miR-487b-5p suppression was linked to enhanced autophagy, evident by drastically increased levels of LC3-II, BECLIN1, and LAMP2 when miR-487b-5p was knocked down. Further analysis revealed that LAMP2 might be the target gene of miR-487b-5p. In conclusion, our study suggested that miR-487b-5p may be a potential biomarker of acquired TMZ resistance in lung cancer cells, and miR-487b-5p inhibition can be further explored as a chemotherapy target in the treatment of TMZ-resistant lung carcinoma.

  9. IGFBP2/FAK pathway is causally associated with dasatinib resistance in non-small Cell Lung Cancer Cells

    PubMed Central

    Lu, Haibo; Wang, Li; Gao, Wen; Meng, Jieru; Dai, Bingbing; Wu, Shuhong; Minna, John; Roth, Jack A.; Hofstetter, Wayne L.; Swisher, Stephen G.; Fang, Bingliang

    2013-01-01

    IGFBP2 expression is increased in various types of cancers, including in a subset of lung cancer patients. Because IGFBP2 is involved in signal transduction of some critical cancer related pathways, we analyzed the association between IGFBP2 and response to pathway-targeted agents in seven human non–small cell lung cancer (NSCLC) cell lines. Western blot analysis and enzyme-linked immunosorbent assay (ELISA) showed that four of the seven NSCLC cell lines analyzed expressed high levels of IGFBP2, while the remaining three had barely detectable IGFBP2. Susceptibilities of those seven cell lines to nine anticancer agents targeting to IGF1R, Src, FAK, MEK, and AKT were determined by dose-dependent cell viability assay. The results showed that high IGFBP2 levels were associated with resistance to dasatinib, and to a lesser degree to sacaratinib, but not to other agents. Ectopic IGFBP2 overexpression or knockdown revealed that changing IGFBP2 expression levels reversed dasatinib susceptibility phenotype, suggesting a causal relationship between IGFBP2 expression and dasatinib resistance. Molecular characterization revealed that FAK activation was associated with increased IGFBP2 expression and partially contributed to IGFBP2-mediated dasatinib resistance. Treatment with a combination of dasatinib and FAK inhibitor led to enhanced antitumor activity in IGFBP2-overexpressing and dasatinib-resistant NSCLC cells in vitro and in vivo. Our results demonstrated that the IGFBP2/FAK pathway is causally associated with dasatinib resistance and may be used as biomarkers for identification of dasatinib responders among lung cancer patients. Simultaneous targeting on Src and FAK will likely improve the therapeutic efficacy of dasatinib for treatment of lung cancer. PMID:24130049

  10. Enhanced expression of stem cell markers and drug resistance in sphere-forming non-small cell lung cancer cells

    PubMed Central

    Sun, Feng-Feng; Hu, Yong-He; Xiong, Lv-Ping; Tu, Xiao-Yun; Zhao, Ji-Hua; Chen, Sheng-Song; Song, Juan; Ye, Xiao-Qun

    2015-01-01

    There is growing evidence suggesting that cancer stem cells (CSCs) are playing critical roles in tumor progression, metastasis and drug resistance. However, the role of CSCs in non-small cell lung cancer (NSCLC) remains elusive. In this study, we enriched for stem-like cells from tumor spheres derived from NSCLC cell line A549 cultured in serum-free medium. Our results showed that sphere-derived cells expressed various stem cell markers such as CD44, CD133, Sox2 and Oct4. Compared with the corresponding cells in monolayer cultures, sphere-derived cells showed marked morphologic changes and increased expression of the stem cell markers CD133. Furthermore, we found that sphere-derived cells exhibited increased proliferation, cell-cycle progression as well as drug-resistant properties as compared to A549 adherent cells. Consistently, expression of several drug resistance proteins, including lung resistance-related protein (LRP), glutathion-S-transferase-π (GST-π) and multidrug resistance proteins-1 (MRP1) were all significantly enhanced in sphere-derived cells. These results indicate the enrichment of CSCs in sphere cultures and support their role in regulating drug resistance in NSCLC. PMID:26261505

  11. ERK phosphorylation is predictive of resistance to IGF-1R inhibition in small cell lung cancer.

    PubMed

    Zinn, Rebekah L; Gardner, Eric E; Marchionni, Luigi; Murphy, Sara C; Dobromilskaya, Irina; Hann, Christine L; Rudin, Charles M

    2013-06-01

    New therapies are critically needed to improve the outcome for patients with small cell lung cancer (SCLC). Insulin-like growth factor 1 receptor (IGF-1R) inhibition is a potential treatment strategy for SCLC: the IGF-1R pathway is commonly upregulated in SCLC and has been associated with inhibition of apoptosis and stimulation of proliferation through downstream signaling pathways, including phosphatidylinositol-3-kinase-Akt and mitogen-activated protein kinase. To evaluate potential determinants of response to IGF-1R inhibition, we assessed the relative sensitivity of 19 SCLC cell lines to OSI-906, a small molecule inhibitor of IGF-1R, and the closely related insulin receptor. Approximately one third of these cell lines were sensitive to OSI-906, with an IC50 < 1 μmol/L. Cell line expression of IGF-1R, IR, IGF-1, IGF-2, IGFBP3, and IGFBP6 did not correlate with sensitivity to OSI-906. Interestingly, OSI-906 sensitive lines expressed significantly lower levels of baseline phospho-ERK relative to resistant lines (P = 0.006). OSI-906 treatment resulted in dose-dependent inhibition of phospho-IGF-1R and phospho-Akt in both sensitive and resistant cell lines, but induced apoptosis and cell-cycle arrest only in sensitive lines. We tested the in vivo efficacy of OSI-906 using an NCI-H187 xenograft model and two SCLC patient xenografts in mice. OSI-906 treatment resulted in 50% tumor growth inhibition in NCI-H187 and 30% inhibition in the primary patient xenograft models compared with mock-treated animals. Taken together our data support IGF-1R inhibition as a viable treatment strategy for a defined subset of SCLC and suggest that low pretreatment levels of phospho-ERK may be indicative of sensitivity to this therapeutic approach. PMID:23515613

  12. Atorvastatin overcomes gefitinib resistance in KRAS mutant human non-small cell lung carcinoma cells.

    PubMed

    Chen, J; Bi, H; Hou, J; Zhang, X; Zhang, C; Yue, L; Wen, X; Liu, D; Shi, H; Yuan, J; Liu, J; Liu, B

    2013-09-26

    The exact influence of statins on gefitinib resistance in human non-small cell lung cancer (NSCLC) cells with KRAS mutation alone or KRAS/PIK3CA and KRAS/PTEN comutations remains unclear. This work found that transfection of mutant KRAS plasmids significantly suppressed the gefitinib cytotoxicity in Calu3 cells (wild-type KRAS). Gefitinib disrupted the Kras/PI3K and Kras/Raf complexes in Calu3 cells, whereas not in Calu3 KRAS mutant cells. These trends were corresponding to the expression of pAKT and pERK in gefitinib treatment. Atorvastatin (1 μM) plus gefitinib treatment inhibited proliferation, promoted cell apoptosis, and reduced the AKT activity in KRAS mutant NSCLC cells compared with gefitinib alone. Atorvastatin (5 μM) further enhanced the gefitinib cytotoxicity through concomitant inhibition of AKT and ERK activity. Atorvastatin could interrupt Kras/PI3K and Kras/Raf complexes, leading to suppression of AKT and ERK activity. Similar results were also obtained in comutant KRAS/PTEN or KRAS/PIK3CA NSCLC cells. Furthermore, mevalonate administration reversed the effects of atorvastatin on the Kras/Raf and Kras/PI3K complexes, as well as AKT and ERK activity in both A549 and Calu1 cells. The in vivo results were similar to those obtained in vitro. Therefore, mutant KRAS-mediated gefitinib insensitivity is mainly derived from failure to disrupt the Kras/Raf and Kras/PI3K complexes in KRAS mutant NSCLC cells. Atorvastatin overcomes gefitinib resistance in KRAS mutant NSCLC cells irrespective of PIK3CA and PTEN statuses through inhibition of HMG-CoA reductase-dependent disruption of the Kras/Raf and Kras/PI3K complexes.

  13. Discovery of New Monocarbonyl Ligustrazine-Curcumin Hybrids for Intervention of Drug-Sensitive and Drug-Resistant Lung Cancer.

    PubMed

    Ai, Yong; Zhu, Bin; Ren, Caiping; Kang, Fenghua; Li, Jinlong; Huang, Zhangjian; Lai, Yisheng; Peng, Sixun; Ding, Ke; Tian, Jide; Zhang, Yihua

    2016-03-10

    The elevation of oxidative stress preferentially in cancer cells by inhibiting thioredoxin reductase (TrxR) and/or enhancing reactive oxygen species (ROS) production has emerged as an effective strategy for selectively targeting cancer cells. In this study, we designed and synthesized 21 ligustrazine-curcumin hybrids (10a-u). Biological evaluation indicated that the most active compound 10d significantly inhibited the proliferation of drug-sensitive (A549, SPC-A-1, LTEP-G-2) and drug-resistant (A549/DDP) lung cancer cells but had little effect on nontumor lung epithelial-like cells (HBE). Furthermore, 10d suppressed the TrxR/Trx system and promoted intracellular ROS accumulation and cancer cell apoptosis. Additionally, 10d inhibited the NF-κB, AKT, and ERK signaling, P-gp-mediated efflux of rhodamine 123, P-gp ATPase activity, and P-gp expression in A549/DDP cells. Finally, 10d repressed the growth of implanted human drug-resistant lung cancer in mice. Together, 10d acts a novel TrxR inhibitor and may be a promising candidate for intervention of lung cancer. PMID:26891099

  14. Acquisition of cancer stem cell-like properties in non-small cell lung cancer with acquired resistance to afatinib

    PubMed Central

    Hashida, Shinsuke; Yamamoto, Hiromasa; Shien, Kazuhiko; Miyoshi, Yuichiro; Ohtsuka, Tomoaki; Suzawa, Ken; Watanabe, Mototsugu; Maki, Yuho; Soh, Junichi; Asano, Hiroaki; Tsukuda, Kazunori; Miyoshi, Shinichiro; Toyooka, Shinichi

    2015-01-01

    Afatinib is an irreversible epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that is known to be effective against the EGFR T790M variant, which accounts for half of the mechanisms of acquired resistance to reversible EGFR-TKIs. However, acquired resistance to afatinib was also observed in clinical use. Thus, elucidating and overcoming the mechanisms of resistance are important issues in the treatment of non-small cell lung cancer. In this study, we established various afatinib-resistant cell lines and investigated the resistance mechanisms. EGFR T790M mutations were not detected using direct sequencing in established resistant cells. Several afatinib-resistant cell lines displayed MET amplification, and these cells were sensitive to the combination of afatinib plus crizotinib. As a further investigation, a cell line that acquired resistance to afatinib plus crizotinib, HCC827-ACR, was established from one of the MET amplified-cell lines. Several afatinib-resistant cell lines including HCC827-ACR displayed epithelial-to-mesenchymal transition (EMT) features and epigenetic silencing of miR-200c, which is a suppresser of EMT. In addition, these cell lines also exhibited overexpression of ALDH1A1 and ABCB1, which are putative stem cell markers, and resistance to docetaxel. In conclusion, we established afatinib-resistant cells and found that MET amplification, EMT, and stem cell-like features are observed in cells with acquired resistance to EGFR-TKIs. This finding may provide clues to overcoming resistance to EGFR-TKIs. PMID:26202045

  15. Eosinophil count - absolute

    MedlinePlus

    Eosinophils; Absolute eosinophil count ... the white blood cell count to give the absolute eosinophil count. ... than 500 cells per microliter (cells/mcL). Normal value ranges may vary slightly among different laboratories. Talk ...

  16. Pseudomonas aeruginosa adaptation to lungs of cystic fibrosis patients leads to lowered resistance to phage and protist enemies.

    PubMed

    Friman, Ville-Petri; Ghoul, Melanie; Molin, Søren; Johansen, Helle Krogh; Buckling, Angus

    2013-01-01

    Pathogenic life styles can lead to highly specialized interactions with host species, potentially resulting in fitness trade-offs in other ecological contexts. Here we studied how adaptation of the environmentally transmitted bacterial pathogen, Pseudomonas aeruginosa, to cystic fibrosis (CF) patients affects its survival in the presence of natural phage (14/1, ΦKZ, PNM and PT7) and protist (Tetrahymena thermophila and Acanthamoebae polyphaga) enemies. We found that most of the bacteria isolated from relatively recently intermittently colonised patients (1-25 months), were innately phage-resistant and highly toxic for protists. In contrast, bacteria isolated from long time chronically infected patients (2-23 years), were less efficient in both resisting phages and killing protists. Moreover, chronic isolates showed reduced killing of wax moth larvae (Galleria mellonella) probably due to weaker in vitro growth and protease expression. These results suggest that P. aeruginosa long-term adaptation to CF-lungs could trade off with its survival in aquatic environmental reservoirs in the presence of microbial enemies, while lowered virulence could reduce pathogen opportunities to infect insect vectors; factors that are both likely to result in poorer environmental transmission. From an applied perspective, phage therapy could be useful against chronic P. aeruginosa lung infections that are often characterized by multidrug resistance: chronic isolates were least resistant to phages and their poor growth will likely slow down the emergence of beneficial resistance mutations.

  17. CHARACTERIZATION OF VIRULENCE GENES AND ANTIMICROBIAL RESISTANCE OF LUNG PATHOGENIC ESCHERICHIA COLI ISOLATES IN FOREST MUSK DEER (MOSCHUS BEREZOVSKII).

    PubMed

    Luo, Xi; Wang, Peng; Cheng, Jian-guo; Luo, Yan; Dai, Lei; Zhou, Xin; Zou, Li-kou; Li, Bei; Xiao, Jiu-Jin

    2016-06-01

    This study investigated genotypic diversity, 26 virulence genes, and antimicrobial susceptibility of lung pathogenic Escherichia coli (LPEC) isolated from forest musk deer. Associations between virulence factors (VFs) and phylogenetic group, between antimicrobial resistance (AMR) and phylogenetic group, and between AMR and VFs were subsequently assessed. The results showed 30 LPEC isolated were grouped into seven different clusters (A, B, C, D, E, F, and G). The detection rates of crl (90%), kpsMT II (76.67%), mat (76.67%), and ompA (80%) were over 75%. The most frequent types of resistance were to amoxicillin (100%), sulfafurazole (100%), ampicillin (96.67%), and tetracycline (96.67%), with 93.33% (n = 28) of isolates resistant to more than eight types of drugs. There were significant relationships between resistance to cefalotin and the presence of iucD(a) (P < 0.001), papC (P = 0.032), and kpsMT II (P = 0.028); between resistance to chloromycetin and the presence of irp2 (P = 0.004) and vat (P = 0.047); between resistance to nalidixic acid and the presence of crl (P = 0.002) and iucD(a) (P = 0.004); and between resistance to ampicillin/sulbactam and the presence of vat (P = 0.013). These results indicated there could be some association between resistance and VFs, and there is a great need for the prudent use of antimicrobial agents in LPEC. PMID:27468027

  18. CHARACTERIZATION OF VIRULENCE GENES AND ANTIMICROBIAL RESISTANCE OF LUNG PATHOGENIC ESCHERICHIA COLI ISOLATES IN FOREST MUSK DEER (MOSCHUS BEREZOVSKII).

    PubMed

    Luo, Xi; Wang, Peng; Cheng, Jian-guo; Luo, Yan; Dai, Lei; Zhou, Xin; Zou, Li-kou; Li, Bei; Xiao, Jiu-Jin

    2016-06-01

    This study investigated genotypic diversity, 26 virulence genes, and antimicrobial susceptibility of lung pathogenic Escherichia coli (LPEC) isolated from forest musk deer. Associations between virulence factors (VFs) and phylogenetic group, between antimicrobial resistance (AMR) and phylogenetic group, and between AMR and VFs were subsequently assessed. The results showed 30 LPEC isolated were grouped into seven different clusters (A, B, C, D, E, F, and G). The detection rates of crl (90%), kpsMT II (76.67%), mat (76.67%), and ompA (80%) were over 75%. The most frequent types of resistance were to amoxicillin (100%), sulfafurazole (100%), ampicillin (96.67%), and tetracycline (96.67%), with 93.33% (n = 28) of isolates resistant to more than eight types of drugs. There were significant relationships between resistance to cefalotin and the presence of iucD(a) (P < 0.001), papC (P = 0.032), and kpsMT II (P = 0.028); between resistance to chloromycetin and the presence of irp2 (P = 0.004) and vat (P = 0.047); between resistance to nalidixic acid and the presence of crl (P = 0.002) and iucD(a) (P = 0.004); and between resistance to ampicillin/sulbactam and the presence of vat (P = 0.013). These results indicated there could be some association between resistance and VFs, and there is a great need for the prudent use of antimicrobial agents in LPEC.

  19. Effects of simulated microgravity on surfactant and water balance of lung in animals with different resistance to stress

    NASA Astrophysics Data System (ADS)

    Bryndina, Irina; Vasilieva, Natalia

    Weightlessness is accompanied by redistribution of blood flow in lung, changes of lung volumes and gas exchange (Prisk et al., 2002; Grigoriev, Baranov, 2003). On the other hand, it is known that microgravity is considered as a kind of moderate stress (Grigoriev et al., 2004). Stress response may differ in animals resistant or vulnerable to stress (Sudakov, 2007). To study the effects of simulated microgravity upon lung, we used 20 male albino rats tested for behavior in the "open field" and than divided into active (stress resistant - SR ) and passive (stress vulnerable - CV) groups. Two mouse lines were used with similar goal - C57Bl/6 and BALB/c mice (n=16). According to data obtained earlier, BALB/c mice referred as more stress vulnerable, in contrast to C57BL/6 mice, which are considered to be relatively stress resistant (Flint et al., 2007). We have previously shown that changes in lung surfactant system after psychosocial stress or long-term immobilization are less pronounced in stress resistant rats (Vasilieva, Bryndina, 2012). The aim of this work is to study the properties and biochemical composition of pulmonary surfactant and lung water balance in rats and mice with different stress resistance in antiorthostatic suspension (AOS) of short and long duration. Simulated microgravity was reproduced according to procedure of Ilyin-Novikov in modification of Morey-Holton. The duration of exposure was 10 days for rats and 30 days for mice. The properties of pulmonary surfactant were assessed by the evaluation of surface activity (surface tension - ST), the content of total phospholipids (PL) and their fractions. Simultaneously we calculated the gravimetric water balance indices: lung coefficient, "dry residue" and wet-to-dry ratio. Total and extravascular lung fluid and pulmonary blood supply were estimated as well. The experiments demonstrated that there was a decrease of surface tension of surfactant films after 10-day AOS in both groups of rats (to a greater

  20. Cardiovascular Disease Biomarkers Predict Susceptibility or Resistance to Lung Injury in World Trade Center Dust Exposed Firefighters

    PubMed Central

    Weiden, Michael D.; Naveed, Bushra; Kwon, Sophia; Cho, Soo Jung; Comfort, Ashley L.; Prezant, David J.; Rom, William N.; Nolan, Anna

    2013-01-01

    Pulmonary vascular loss is an early feature of chronic obstructive pulmonary disease. Biomarkers of inflammation and of metabolic syndrome, predicts loss of lung function in World Trade Center Lung Injury (WTC-LI). We investigated if other cardiovascular disease (CVD) biomarkers also predicted WTC-LI. This nested case-cohort study used 801 never smoker, WTC exposed firefighters with normal pre-9/11 lung function presenting for subspecialty pulmonary evaluation (SPE) before March, 2008. A representative sub-cohort of 124/801 with serum drawn within six months of 9/11 defined CVD biomarker distribution. Post-9/11/01 FEV1 at subspecialty exam defined cases: susceptible WTC-LI cases with FEV1≤77% predicted (66/801) and resistant WTC-LI cases with FEV1≥107% (68/801). All models were adjusted for WTC exposure intensity, BMI at SPE, age at 9/11, and pre-9/11 FEV1. Susceptible WTC-LI cases had higher levels of Apo-AII, CRP, and MIP-4 with significant RRs of 3.85, 3.93, and 0.26 respectively with an area under the curve (AUC) of 0.858. Resistant WTC-LI cases had significantly higher sVCAM and lower MPO with RRs of 2.24, and 2.89 respectively; AUC 0.830. Biomarkers of CVD in serum six-month post-9/11 predicted either susceptibility or resistance to WTC-LI. These biomarkers may define pathways producing or protecting subjects from pulmonary vascular disease and associated loss of lung function after an irritant exposure. PMID:22903969

  1. Triclosan Potentiates Epithelial-To-Mesenchymal Transition in Anoikis-Resistant Human Lung Cancer Cells

    PubMed Central

    Winitthana, Thidarat; Lawanprasert, Somsong; Chanvorachote, Pithi

    2014-01-01

    Alteration of cancer cell toward mesenchymal phenotype has been shown to potentiate tumor aggressiveness by increasing cancer cell metastasis. Herein, we report the effect of triclosan, a widely used antibacterial agent found in many daily products, in enhancing the epithelial-to-mesenchymal transition (EMT) in aggressive anoikis resistant human H460 lung cancer cells. EMT has been long known to increase abilities of the cells to increase migration, invasion, and survival in circulating system. The present study reveals that treatment of the cancer cells with triclosan at the physiologically related concentrations significantly increased the colony number of the cancer cells assessed by tumor formation assay. Also, the mesenchymal-like morphology and decrease in cell-to-cell adhesion were observed in triclosan-treated cells. Importantly, western blot analysis revealed that triclosan-treated cells exhibited decreased E-cadherin, while the levels of EMT markers, namely N-cadherin, vimentin, snail and slug were found to be significantly up-regulated. Furthermore, EMT induced by triclosan treatment was accompanied by the activation of focal adhesion kinase/ATP dependent tyrosine kinase (FAK/Akt) and Ras-related C3 botulinum toxin substrate 1 (Rac1), which enhanced the ability of the cells to migrate and invade. In conclusion, we demonstrated for the first time that triclosan may potentiate cancer cells survival in detached condition and motility via the process of EMT. As mentioned capabilities are required for success in metastasis, the present study provides the novel toxicological information and encourages the awareness of triclosan use in cancer patients. PMID:25329306

  2. Triclosan potentiates epithelial-to-mesenchymal transition in anoikis-resistant human lung cancer cells.

    PubMed

    Winitthana, Thidarat; Lawanprasert, Somsong; Chanvorachote, Pithi

    2014-01-01

    Alteration of cancer cell toward mesenchymal phenotype has been shown to potentiate tumor aggressiveness by increasing cancer cell metastasis. Herein, we report the effect of triclosan, a widely used antibacterial agent found in many daily products, in enhancing the epithelial-to-mesenchymal transition (EMT) in aggressive anoikis resistant human H460 lung cancer cells. EMT has been long known to increase abilities of the cells to increase migration, invasion, and survival in circulating system. The present study reveals that treatment of the cancer cells with triclosan at the physiologically related concentrations significantly increased the colony number of the cancer cells assessed by tumor formation assay. Also, the mesenchymal-like morphology and decrease in cell-to-cell adhesion were observed in triclosan-treated cells. Importantly, western blot analysis revealed that triclosan-treated cells exhibited decreased E-cadherin, while the levels of EMT markers, namely N-cadherin, vimentin, snail and slug were found to be significantly up-regulated. Furthermore, EMT induced by triclosan treatment was accompanied by the activation of focal adhesion kinase/ATP dependent tyrosine kinase (FAK/Akt) and Ras-related C3 botulinum toxin substrate 1 (Rac1), which enhanced the ability of the cells to migrate and invade. In conclusion, we demonstrated for the first time that triclosan may potentiate cancer cells survival in detached condition and motility via the process of EMT. As mentioned capabilities are required for success in metastasis, the present study provides the novel toxicological information and encourages the awareness of triclosan use in cancer patients. PMID:25329306

  3. Triclosan potentiates epithelial-to-mesenchymal transition in anoikis-resistant human lung cancer cells.

    PubMed

    Winitthana, Thidarat; Lawanprasert, Somsong; Chanvorachote, Pithi

    2014-01-01

    Alteration of cancer cell toward mesenchymal phenotype has been shown to potentiate tumor aggressiveness by increasing cancer cell metastasis. Herein, we report the effect of triclosan, a widely used antibacterial agent found in many daily products, in enhancing the epithelial-to-mesenchymal transition (EMT) in aggressive anoikis resistant human H460 lung cancer cells. EMT has been long known to increase abilities of the cells to increase migration, invasion, and survival in circulating system. The present study reveals that treatment of the cancer cells with triclosan at the physiologically related concentrations significantly increased the colony number of the cancer cells assessed by tumor formation assay. Also, the mesenchymal-like morphology and decrease in cell-to-cell adhesion were observed in triclosan-treated cells. Importantly, western blot analysis revealed that triclosan-treated cells exhibited decreased E-cadherin, while the levels of EMT markers, namely N-cadherin, vimentin, snail and slug were found to be significantly up-regulated. Furthermore, EMT induced by triclosan treatment was accompanied by the activation of focal adhesion kinase/ATP dependent tyrosine kinase (FAK/Akt) and Ras-related C3 botulinum toxin substrate 1 (Rac1), which enhanced the ability of the cells to migrate and invade. In conclusion, we demonstrated for the first time that triclosan may potentiate cancer cells survival in detached condition and motility via the process of EMT. As mentioned capabilities are required for success in metastasis, the present study provides the novel toxicological information and encourages the awareness of triclosan use in cancer patients.

  4. Intrinsic resistance to EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer with activating EGFR mutations

    PubMed Central

    Wang, Jun; Wang, Baocheng; Chu, Huili; Yao, Yunfeng

    2016-01-01

    Identifying activating EGFR mutations is a useful predictive strategy that helps select a population of advanced non-small-cell lung cancer (NSCLC) patients for treatment with EGFR tyrosine kinase inhibitors (TKIs). Patients with sensitizing EGFR mutations (predominantly an in-frame deletion in exon 19 and an L858R substitution) are highly responsive to first-generation EGFR TKIs, such as gefitinib and erlotinib, and show improved progression-free survival without serious side effects. However, all patients with activating EGFR mutations who are initially responsive to EGFR TKIs eventually develop acquired resistance after a median progression-free survival of 10–16 months, followed by disease progression. Moreover, ~20%–30% of NSCLC patients have no objective tumor regression on initial EGFR TKI treatment, although they harbor an activating EGFR mutation. These patients represent an NSCLC subgroup that is defined as having intrinsic or primary resistance to EGFR TKIs. Different mechanisms of acquired EGFR TKI resistance have been identified, and several novel compounds have been developed to reverse acquired resistance, but little is known about EGFR TKI intrinsic resistance. In this review, we summarize the latest findings involving mechanisms of intrinsic resistance to EGFR TKIs in advanced NSCLC with activating EGFR mutations and present possible therapeutic strategies to overcome this resistance. PMID:27382309

  5. Decreased glutathione biosynthesis contributes to EGFR T790M-driven erlotinib resistance in non-small cell lung cancer

    PubMed Central

    Li, Hongde; Stokes, William; Chater, Emily; Roy, Rajat; de Bruin, Elza; Hu, Yili; Liu, Zhigang; Smit, Egbert F; Heynen, Guus JJE; Downward, Julian; Seckl, Michael J; Wang, Yulan; Tang, Huiru; Pardo, Olivier E

    2016-01-01

    Epidermal growth factor receptor (EGFR) inhibitors such as erlotinib are novel effective agents in the treatment of EGFR-driven lung cancer, but their clinical impact is often impaired by acquired drug resistance through the secondary T790M EGFR mutation. To overcome this problem, we analysed the metabonomic differences between two independent pairs of erlotinib-sensitive/resistant cells and discovered that glutathione (GSH) levels were significantly reduced in T790M EGFR cells. We also found that increasing GSH levels in erlotinib-resistant cells re-sensitised them, whereas reducing GSH levels in erlotinib-sensitive cells made them resistant. Decreased transcription of the GSH-synthesising enzymes (GCLC and GSS) due to the inhibition of NRF2 was responsible for low GSH levels in resistant cells that was directly linked to the T790M mutation. T790M EGFR clinical samples also showed decreased expression of these key enzymes; increasing intra-tumoural GSH levels with a small-molecule GST inhibitor re-sensitised resistant tumours to erlotinib in mice. Thus, we identified a new resistance pathway controlled by EGFR T790M and a therapeutic strategy to tackle this problem in the clinic. PMID:27721983

  6. The insulin-like growth factor 1 receptor causes acquired resistance to erlotinib in lung cancer cells with the wild-type epidermal growth factor receptor.

    PubMed

    Suda, Kenichi; Mizuuchi, Hiroshi; Sato, Katsuaki; Takemoto, Toshiki; Iwasaki, Takuya; Mitsudomi, Tetsuya

    2014-08-15

    Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy often provides a dramatic response in lung cancer patients with EGFR mutations. In addition, moderate clinical efficacy of the EGFR-TKI, erlotinib, has been shown in lung cancer patients with the wild-type EGFR. Numerous molecular mechanisms that cause acquired resistance to EGFR-TKIs have been identified in lung cancers with the EGFR mutations; however, few have been reported in lung cancers with the wild-type EGFR. We used H358 lung adenocarcinoma cells lacking EGFR mutations that showed modest sensitivity to erlotinib. The H358 cells acquired resistance to erlotinib via chronic exposure to the drug. The H358 erlotinib-resistant (ER) cells do not have a secondary EGFR mutation, neither MET gene amplification nor PTEN downregulation; these have been identified in lung cancers with the EGFR mutations. From comprehensive screening of receptor tyrosine kinase phosphorylation, we observed increased phosphorylation of insulin-like growth factor 1 receptor (IGF1R) in H358ER cells compared with parental H358 cells. H358ER cells responded to combined therapy with erlotinib and NVP-AEW541, an IGF1R-TKI. Our results indicate that IGF1R activation is a molecular mechanism that confers acquired resistance to erlotinib in lung cancers with the wild-type EGFR.

  7. Novel targeted therapies for resistant ALK-rearranged non-small-cell lung cancer: ceritinib and beyond.

    PubMed

    Kanaan, Zeyad; Kloecker, Goetz H; Paintal, Ajit; Perez, Cesar A

    2015-01-01

    Lung cancer is the leading cause of cancer-related mortality in both sexes, accounting for over one quarter of cancer deaths. Non-small-cell lung cancer (NSCLC) comprises 85%-90% of lung cancer diagnoses and despite advances in multimodality therapies, 5-year survival rates remain dismal with a median survival for patients with metastatic disease of 1 year. The positive outcomes of targeted therapies against the kinase domain of epidermal growth factor receptor in NSCLC triggered consistent efforts to identify the so-called driver mutations as other potential targets. Anaplastic large-cell kinase (ALK) gene rearrangements were identified and targeted resulting in promising response rates in early studies. Unfortunately, most of the patients treated with crizotinib, the first-generation ALK inhibitor, progressed within 9 months. Ceritinib is a second-generation ALK inhibitor that has demonstrated activity in crizotinib-resistant patients, becoming a promising treatment option in this population. Furthermore, additional novel ALK inhibitors and agents targeting alternative pathways have been recruited to rechallenge this evasive disease post-crizotinib resistance.

  8. Novel targeted therapies for resistant ALK-rearranged non-small-cell lung cancer: ceritinib and beyond

    PubMed Central

    Kanaan, Zeyad; Kloecker, Goetz H; Paintal, Ajit; Perez, Cesar A

    2015-01-01

    Lung cancer is the leading cause of cancer-related mortality in both sexes, accounting for over one quarter of cancer deaths. Non-small-cell lung cancer (NSCLC) comprises 85%–90% of lung cancer diagnoses and despite advances in multimodality therapies, 5-year survival rates remain dismal with a median survival for patients with metastatic disease of 1 year. The positive outcomes of targeted therapies against the kinase domain of epidermal growth factor receptor in NSCLC triggered consistent efforts to identify the so-called driver mutations as other potential targets. Anaplastic large-cell kinase (ALK) gene rearrangements were identified and targeted resulting in promising response rates in early studies. Unfortunately, most of the patients treated with crizotinib, the first-generation ALK inhibitor, progressed within 9 months. Ceritinib is a second-generation ALK inhibitor that has demonstrated activity in crizotinib-resistant patients, becoming a promising treatment option in this population. Furthermore, additional novel ALK inhibitors and agents targeting alternative pathways have been recruited to rechallenge this evasive disease post-crizotinib resistance. PMID:25945060

  9. Suppression of Rev3, the catalytic subunit of Pol{zeta}, sensitizes drug-resistant lung tumors to chemotherapy.

    PubMed

    Doles, Jason; Oliver, Trudy G; Cameron, Eleanor R; Hsu, Gerald; Jacks, Tyler; Walker, Graham C; Hemann, Michael T

    2010-11-30

    Platinum-based chemotherapeutic drugs are front-line therapies for the treatment of non-small cell lung cancer. However, intrinsic drug resistance limits the clinical efficacy of these agents. Recent evidence suggests that loss of the translesion polymerase, Polζ, can sensitize tumor cell lines to cisplatin, although the relevance of these findings to the treatment of chemoresistant tumors in vivo has remained unclear. Here, we describe a tumor transplantation approach that enables the rapid introduction of defined genetic lesions into a preclinical model of lung adenocarcinoma. Using this approach, we examined the effect of impaired translesion DNA synthesis on cisplatin response in aggressive late-stage lung cancers. In the presence of reduced levels of Rev3, an essential component of Polζ, tumors exhibited pronounced sensitivity to cisplatin, leading to a significant extension in overall survival of treated recipient mice. Additionally, treated Rev3-deficient cells exhibited reduced cisplatin-induced mutation, a process that has been implicated in the induction of secondary malignancies following chemotherapy. Taken together, our data illustrate the potential of Rev3 inhibition as an adjuvant therapy for the treatment of chemoresistant malignancies, and highlight the utility of rapid transplantation methodologies for evaluating mechanisms of chemotherapeutic resistance in preclinical settings.

  10. Interleukin 6 augments lung cancer chemotherapeutic resistance via ataxia-telangiectasia mutated/NF-kappaB pathway activation.

    PubMed

    Yan, Hong Qiong; Huang, Xiao Bo; Ke, Shi Zhong; Jiang, Yi Na; Zhang, Yue Hua; Wang, Yi Nan; Li, Juan; Gao, Feng Guang

    2014-09-01

    Although it is known that ataxia-telangiectasia mutated (ATM) and interleukin 6 (IL-6) contribute to multiple drug resistance (MDR) in tumor chemotherapy, the exact role of ATM activation in MDR resulting from increased IL-6 expression is still unclear. In the present study, we demonstrate that the activation of the ATM-NF-kappaB pathway, resulting from increased IL-6 expression, plays a central role in augmented chemoresistance in lung cancer cell lines. This result was supported by the increased expressions of Bcl-2, Mcl-1, Bcl-xl, and the upregulation of MDR-associated protein ABCG2. The higher level of IL-6 reveals not only higher ATM/NF-kappaB activity but also increased expressions of ABCG2, Bcl-2, Mcl-1 and Bcl-xl. Most importantly, lung cancer cells themselves upregulated IL-6 secretion by activating the p38/NF-kappaB pathway through treatment with cisplatin and camptothecin. Taken together, these findings demonstrate that chemotherapeutic agents increase IL-6 expression, hence activating the ATM/NF-kappaB pathway, augmenting anti-apoptotic protein expression and contributing to MDR. This indicates that both IL-6 and ATM are potential targets for the treatment of chemotherapeutic resistance in lung cancer. PMID:24988892

  11. Interleukin 6 augments lung cancer chemotherapeutic resistance via ataxia-telangiectasia mutated/NF-kappaB pathway activation

    PubMed Central

    Yan, Hong Qiong; Huang, Xiao Bo; Ke, Shi Zhong; Jiang, Yi Na; Zhang, Yue Hua; Wang, Yi Nan; Li, Juan; Gao, Feng Guang

    2014-01-01

    Although it is known that ataxia-telangiectasia mutated (ATM) and interleukin 6 (IL-6) contribute to multiple drug resistance (MDR) in tumor chemotherapy, the exact role of ATM activation in MDR resulting from increased IL-6 expression is still unclear. In the present study, we demonstrate that the activation of the ATM-NF-kappaB pathway, resulting from increased IL-6 expression, plays a central role in augmented chemoresistance in lung cancer cell lines. This result was supported by the increased expressions of Bcl-2, Mcl-1, Bcl-xl, and the upregulation of MDR-associated protein ABCG2. The higher level of IL-6 reveals not only higher ATM/NF-kappaB activity but also increased expressions of ABCG2, Bcl-2, Mcl-1 and Bcl-xl. Most importantly, lung cancer cells themselves upregulated IL-6 secretion by activating the p38/NF-kappaB pathway through treatment with cisplatin and camptothecin. Taken together, these findings demonstrate that chemotherapeutic agents increase IL-6 expression, hence activating the ATM/NF-kappaB pathway, augmenting anti-apoptotic protein expression and contributing to MDR. This indicates that both IL-6 and ATM are potential targets for the treatment of chemotherapeutic resistance in lung cancer. PMID:24988892

  12. Interleukin 6 augments lung cancer chemotherapeutic resistance via ataxia-telangiectasia mutated/NF-kappaB pathway activation.

    PubMed

    Yan, Hong Qiong; Huang, Xiao Bo; Ke, Shi Zhong; Jiang, Yi Na; Zhang, Yue Hua; Wang, Yi Nan; Li, Juan; Gao, Feng Guang

    2014-09-01

    Although it is known that ataxia-telangiectasia mutated (ATM) and interleukin 6 (IL-6) contribute to multiple drug resistance (MDR) in tumor chemotherapy, the exact role of ATM activation in MDR resulting from increased IL-6 expression is still unclear. In the present study, we demonstrate that the activation of the ATM-NF-kappaB pathway, resulting from increased IL-6 expression, plays a central role in augmented chemoresistance in lung cancer cell lines. This result was supported by the increased expressions of Bcl-2, Mcl-1, Bcl-xl, and the upregulation of MDR-associated protein ABCG2. The higher level of IL-6 reveals not only higher ATM/NF-kappaB activity but also increased expressions of ABCG2, Bcl-2, Mcl-1 and Bcl-xl. Most importantly, lung cancer cells themselves upregulated IL-6 secretion by activating the p38/NF-kappaB pathway through treatment with cisplatin and camptothecin. Taken together, these findings demonstrate that chemotherapeutic agents increase IL-6 expression, hence activating the ATM/NF-kappaB pathway, augmenting anti-apoptotic protein expression and contributing to MDR. This indicates that both IL-6 and ATM are potential targets for the treatment of chemotherapeutic resistance in lung cancer.

  13. Acquired resistance of non-small cell lung cancer to epidermal growth factor receptor tyrosine kinase inhibitors.

    PubMed

    Nurwidya, Fariz; Takahashi, Fumiyuki; Murakami, Akiko; Kobayashi, Isao; Kato, Motoyasu; Shukuya, Takehito; Tajima, Ken; Shimada, Naoko; Takahashi, Kazuhisa

    2014-03-01

    Activation of epidermal growth factor receptor (EGFR) triggers anti-apoptotic signaling, proliferation, angiogenesis, invasion, metastasis, and drug resistance, which leads to development and progression of human epithelial cancers, including non-small cell lung cancer (NSCLC). Inhibition of EGFR by tyrosine kinase inhibitors such as gefitinib and erlotinib has provided a new hope for the cure of NSCLC patients. However, acquired resistance to gefitinib and erlotinib via EGFR-mutant NSCLC has occurred through various molecular mechanisms such as T790M secondary mutation, MET amplification, hepatocyte growth factor (HGF) overexpression, PTEN downregulation, epithelial-mesenchymal transition (EMT), and other mechanisms. This review will discuss the biology of receptor tyrosine kinase inhibition and focus on the molecular mechanisms of acquired resistance to tyrosine kinase inhibitors of EGFR-mutant NSCLC.

  14. Absolute nuclear material assay

    DOEpatents

    Prasad, Manoj K.; Snyderman, Neal J.; Rowland, Mark S.

    2012-05-15

    A method of absolute nuclear material assay of an unknown source comprising counting neutrons from the unknown source and providing an absolute nuclear material assay utilizing a model to optimally compare to the measured count distributions. In one embodiment, the step of providing an absolute nuclear material assay comprises utilizing a random sampling of analytically computed fission chain distributions to generate a continuous time-evolving sequence of event-counts by spreading the fission chain distribution in time.

  15. Absolute nuclear material assay

    DOEpatents

    Prasad, Manoj K.; Snyderman, Neal J.; Rowland, Mark S.

    2010-07-13

    A method of absolute nuclear material assay of an unknown source comprising counting neutrons from the unknown source and providing an absolute nuclear material assay utilizing a model to optimally compare to the measured count distributions. In one embodiment, the step of providing an absolute nuclear material assay comprises utilizing a random sampling of analytically computed fission chain distributions to generate a continuous time-evolving sequence of event-counts by spreading the fission chain distribution in time.

  16. Lung cancer tumorigenicity and drug resistance are maintained through ALDH(hi)CD44(hi) tumor initiating cells.

    PubMed

    Liu, Jing; Xiao, Zhijie; Wong, Sunny Kit-Man; Tin, Vicky Pui-Chi; Ho, Ka-Yan; Wang, Junwen; Sham, Mai-Har; Wong, Maria Pik

    2013-10-01

    Limited improvement in long term survival of lung cancer patients has been achieved by conventional chemotherapy or targeted therapy. To explore the potentials of tumor initiating cells (TIC)-directed therapy, it is essential to identify the cell targets and understand their maintenance mechanisms. We have analyzed the performance of ALDH/CD44 co-expression as TIC markers and treatment targets of lung cancer using well-validated in vitro and in vivo analyses in multiple established and patient-derived lung cancer cells. The ALDH(hi)CD44(hi) subset showed the highest enhancement of stem cell phenotypic properties compared to ALDH(hi)CD44(lo), ALDH(lo)CD44(hi), ALDH(lo)CD44(lo) cells and unsorted controls. They showed higher invasion capacities, pluripotency genes and epithelial-mesenchymal transition transcription factors expression, lower intercellular adhesion protein expression and higher G2/M phase cell cycle fraction. In immunosuppressed mice, the ALDH(hi)CD44(hi)xenografts showed the highest tumor induction frequency, serial transplantability, shortest latency, largest volume and highest growth rates. Inhibition of sonic Hedgehog and Notch developmental pathways reduced ALDH+CD44+ compartment. Chemotherapy and targeted therapy resulted in higher AALDH(hi)CD44(hi) subset viability and ALDH(lo)CD44(lo) subset apoptosis fraction. ALDH inhibition and CD44 knockdown led to reduced stemness gene expression and sensitization to drug treatment. In accordance, clinical lung cancers containing a higher abundance of ALDH and CD44-coexpressing cells was associated with lower recurrence-free survival. Together, results suggested theALDH(hi)CD44(hi)compartment was the cellular mediator of tumorigenicity and drug resistance. Further investigation of the regulatory mechanisms underlying ALDH(hi)CD44(hi)TIC maintenance would be beneficial for the development of long term lung cancer control.

  17. Elevated Cellular PD1/PD-L1 Expression Confers Acquired Resistance to Cisplatin in Small Cell Lung Cancer Cells.

    PubMed

    Yan, Fei; Pang, Jiuxia; Peng, Yong; Molina, Julian R; Yang, Ping; Liu, Shujun

    2016-01-01

    Although small cell lung cancer (SCLC) is highly responsive to chemotherapies (e.g., cisplatin-etoposide doublet), virtually almost all responsive SCLC patients experience disease recurrence characterized by drug resistance. The mechanisms underlying cisplatin resistance remain elusive. Here we report that cell-intrinsic expression of PD1 and PD-L1, two immune checkpoints, is required for sustained expansion of SCLC cells under cisplatin selection. Indeed, PD1 and PD-L1 were expressed at a higher level in lung cancer cell lines, tumor tissues, and importantly, in SCLC cells resistant to cisplatin (H69R, H82R), when compared to respective controls. Genetic abrogation of PD1 and PD-L1 in H69R and H82R cells decreased their proliferation rate, and restored their sensitivity to cisplatin. Mechanistically, PD-L1 upregulation in H69R and H82R cells was attributed to the overexpression of DNA methyltransferase 1 (DNMT1) or receptor tyrosine kinase KIT, as knockdown of DNMT1 or KIT in H69R and H82R cells led to PD-L1 downregulation. Consequently, combined knockdown of PD-L1 with KIT or DNMT1 resulted in more pronounced inhibition of H69R and H82R cell growth. Thus, cell intrinsic PD1/PD-L1 signaling may be a predictor for poor efficacy of cisplatin treatment, and targeting the cellular PD1/PD-L1 axis may improve chemosensitization of aggressive SCLC.

  18. Sera from patients with colon, breast and lung cancer induce resistance to lysis mediated by NK cytotoxic factors (NKCF).

    PubMed Central

    Marubayashi, M.; Solana, R.; Ramirez, R.; Aranda, E.; Galan, F.; Peña, J.

    1991-01-01

    Natural killer (NK) cells are involved in the antitumoral immunologic mechanism. These cells act through the release of cytotoxic molecules defined as NK cytotoxic factors (NKCF). Inhibitory factors of NK and NKCF mediated lysis have been described in in vitro assays. This study evaluates the induction of resistance to NKCF cytotoxicity by sera from 27 patients with colon, breast and lung cancer. Addition of these sera to the cytolytic assay where K562 cells and concentrated NKCF were used, induced resistance to NKCF mediated cytotoxicity in 21 cases (77%). The sera from the group with metastasis blocked NKCF lysis more markedly than the group with local tumours. However, no differences were observed when the groups with colon, breast and lung cancers were compared. This blocking effect was not found to be related to gamma interferon (IFN) levels. In a previous study, we described a tumour factor (NK-RIF) produced by human cell lines derived from metastatic adenocarcinomas. This factor blocked lysis of tumour target cells by NK cells. Consequently, it is proposed that the release of similar tumour factors with a capacity to induce resistance to NKCF may be involved in tumour growth and metastatic spreading in in vivo. PMID:1906292

  19. Fisetin, a dietary bioflavonoid, reverses acquired Cisplatin-resistance of lung adenocarcinoma cells through MAPK/Survivin/Caspase pathway

    PubMed Central

    Zhuo, Wenlei; Zhang, Liang; Zhu, Yi; Zhu, Bo; Chen, Zhengtang

    2015-01-01

    Cisplatin has been a key chemotherapy drug for treatment of non-small cell lung cancer (NSCLC) for decades. However, the efficacy of Cisplatin is usually reduced by the occurrence of drug-resistance of cancer cells. Fisetin is a flavonol naturally found in many fruits and vegetables, which has been reported to suppress cell proliferation and induce apoptosis in various cancers. In this study, we aimed to investigate whether Fisetin was capable of enhancing cytotoxicity of Cisplatin in Cisplatin-resistant NSCLC cells, and explore the possible signaling pathways involved. Cisplatin-resistant NSCLC cells, A549-CR, was established by repeated subculturing of A549 cells with increasing Cisplatin. Proliferation ability was assessed by MTT analysis and apoptosis was detected by flow cytometry. The results showed that Fisetin effectively increased sensitivity of A549-CR cells to Cisplatin, possibly mediated by inhibiting aberrant activation of MAPK signaling pathways. This increases the possibility of Fisetin as a promising agent for lung cancer therapy. PMID:26692948

  20. Drug Resistance to EGFR Inhibitors in Lung Cancer | Office of Cancer Genomics

    Cancer.gov

    The discovery of mutations in epidermal growth factor receptor (EGFR) has dramatically changed the treatment of patients with non-small-cell lung cancer (NSCLC), the leading cause of cancer deaths worldwide.

  1. Acquired resistance mechanisms to tyrosine kinase inhibitors in lung cancer with activating epidermal growth factor receptor mutation--diversity, ductility, and destiny.

    PubMed

    Suda, Kenichi; Mizuuchi, Hiroshi; Maehara, Yoshihiko; Mitsudomi, Tetsuya

    2012-12-01

    Lung cancers that harbor somatic activating mutations in the gene for the epidermal growth factor receptor (EGFR) depend on mutant EGFR for their proliferation and survival; therefore, lung cancer patients with EGFR mutations often dramatically respond to orally available EGFR tyrosine kinase inhibitors (TKIs). However, emergence of acquired resistance is virtually inevitable, thus limiting improvement in patient outcomes. To elucidate and overcome this acquired resistance, multidisciplinary basic and clinical investigational approaches have been applied, using in vitro cell line models or samples obtained from lung cancer patients treated with EGFR-TKIs. These efforts have revealed several acquired resistance mechanisms and candidates, including EGFR secondary mutations (T790M and other rare mutations), MET amplification, PTEN downregulation, CRKL amplification, high-level HGF expression, FAS-NFκB pathway activation, epithelial-mesenchymal transition, and conversion to small cell lung cancer. Interestingly, cancer cells harbor potential destiny and ductility together in acquiring resistance to EGFR-TKIs, as shown in in vitro acquired resistance models. Molecular mechanisms of "reversible EGFR-TKI tolerance" that occur in early phase EGFR-TKI exposure have been identified in cell line models. Furthermore, others have reported molecular markers that can predict response to EGFR-TKIs in clinical settings. Deeper understanding of acquired resistance mechanisms to EGFR-TKIs, followed by the development of molecular target drugs that can overcome the resistance, might turn this fatal disease into a chronic disorder.

  2. FHIT loss confers cisplatin resistance in lung cancer via the AKT/NF-κB/Slug-mediated PUMA reduction.

    PubMed

    Wu, D-W; Lee, M-C; Hsu, N-Y; Wu, T-C; Wu, J-Y; Wang, Y-C; Cheng, Y-W; Chen, C-Y; Lee, H

    2015-05-01

    Fragile histidine triad (FHIT) loss by the two-hit mechanism of loss of heterozygosity and promoter hypermethylation commonly occurrs in non-small cell lung cancer (NSCLC) and may confer cisplatin resistance in NSCLC cells. However, the underlying mechanisms of FHIT loss in cisplatin resistance and the response to cisplatin-based chemotherapy in NSCLC patients have not yet been reported. In the present study, inhibition concentration of 50% cell viability induced by cisplatin (IC50) and soft agar growth and invasion capability were increased and decreased in FHIT-knockdown and -overexpressing cells, respectively. Mechanistically, Slug transcription is upregulated by AKT/NF-κB activation due to FHIT loss and, in turn, Slug suppresses PUMA expression; this decrease of PUMA by FHIT loss is responsible for cisplatin resistance. In addition, cisplatin resistance due to FHIT loss can be conquered by AKT inhibitor-perifosine in xenograft tumors. Among NSCLC patients, low FHIT, high p-AKT, high Slug and low PUMA were correlated with shorter overall survival, relapse-free survival and poorer response to cisplatin-based chemotherapy. Therefore, the AKT inhibitor perifosine might potentially overcome the resistance to cisplatin-based chemotherapy in NSCLC patients with low-FHIT tumors, and consequently improve the outcome. PMID:24998847

  3. FHIT loss confers cisplatin resistance in lung cancer via the AKT/NF-κB/Slug-mediated PUMA reduction.

    PubMed

    Wu, D-W; Lee, M-C; Hsu, N-Y; Wu, T-C; Wu, J-Y; Wang, Y-C; Cheng, Y-W; Chen, C-Y; Lee, H

    2015-05-01

    Fragile histidine triad (FHIT) loss by the two-hit mechanism of loss of heterozygosity and promoter hypermethylation commonly occurrs in non-small cell lung cancer (NSCLC) and may confer cisplatin resistance in NSCLC cells. However, the underlying mechanisms of FHIT loss in cisplatin resistance and the response to cisplatin-based chemotherapy in NSCLC patients have not yet been reported. In the present study, inhibition concentration of 50% cell viability induced by cisplatin (IC50) and soft agar growth and invasion capability were increased and decreased in FHIT-knockdown and -overexpressing cells, respectively. Mechanistically, Slug transcription is upregulated by AKT/NF-κB activation due to FHIT loss and, in turn, Slug suppresses PUMA expression; this decrease of PUMA by FHIT loss is responsible for cisplatin resistance. In addition, cisplatin resistance due to FHIT loss can be conquered by AKT inhibitor-perifosine in xenograft tumors. Among NSCLC patients, low FHIT, high p-AKT, high Slug and low PUMA were correlated with shorter overall survival, relapse-free survival and poorer response to cisplatin-based chemotherapy. Therefore, the AKT inhibitor perifosine might potentially overcome the resistance to cisplatin-based chemotherapy in NSCLC patients with low-FHIT tumors, and consequently improve the outcome.

  4. Combination of gambogic acid with cisplatin enhances the antitumor effects on cisplatin-resistant lung cancer cells by downregulating MRP2 and LRP expression

    PubMed Central

    Zhang, Wendian; Zhou, Hechao; Yu, Ying; Li, Jingjing; Li, Haiwen; Jiang, Danxian; Chen, Zihong; Yang, Donghong; Xu, Zumin; Yu, Zhonghua

    2016-01-01

    Cisplatin resistance is a main clinical problem of lung cancer therapy. Gambogic acid (GA) could prohibit the proliferation of a variety of human cancer cells. However, the effects of GA on cisplatin-resistant lung cancer are still unclear. The objective of the present study was to find out the antitumor effects of GA on cisplatin-resistant human lung cancer A549/DDP cells and further explore its underlying mechanisms. Cell Counting Kit-8 assay was used to observe the impacts of GA and/or cisplatin on the proliferation of lung cancer cells; flow cytometry was used to detect the effects of GA on cell cycle and apoptosis; Western blot was used to examine the effects of GA on the expression of lung resistance protein (LRP) and multidrug resistance-associated protein 2 (MRP2) protein in A549/DDP cells. Our results showed that GA dose- and time-dependently prohibited the proliferation and induced significant cell apoptosis in A549 and A549/DDP cells. GA also induced G0/G1 arrest in both A549/DDP and A549 cells. Moreover, GA upregulated protein expression level of cleaved caspase-3 and Bax and downregulated protein expression level of pro-caspase-9 and Bcl-2 in time- and dose-dependent way in A549/DDP cells. GA combined with cisplatin enhanced the cells apoptotic rate and reduced the cisplatin resistance index in A549/DDP cells. In addition, GA reduced the MRP2 and LRP protein expression level in A549/DDP cells. GA inhibits the proliferation, induces cell cycle arrest and apoptosis in A549/DDP cells. Combination of GA with cisplatin enhances the antitumor effects on cisplatin-resistant lung cancer cells by downregulating MRP2 and LRP expression. PMID:27330316

  5. 5-Aza-CdR can reverse gefitinib resistance caused by DAPK gene promoter methylation in lung adenocarcinoma cells.

    PubMed

    Yang, Bo; Yang, Zhi-Guang; Gao, Bao; Shao, Guo-Guang; Li, Guang-Hu

    2015-01-01

    To explore the relationship between death associated protein kinase (DAPK) gene promoter methylation and gefitinib resistance in Lung adenocarcinoma cell lines. EGFR-mutation lung adenocarcinoma cell lines PC9 and the gefitinib-resistant with T790M Mutation cell lines PC9/GR were chosen as cell models, and PC9/GR were treated with 5-aza-CdR (1 μmol/L). The experiments were divided into three groups: PC9 group, PC9/GR group and PC9/GR with 5-Aza-CdR pretreatment group. Treat three groups cell with different concentrations gefitinib, the cell proliferation was determined by MTT assay. The apoptotic rates were detected by flow cytometry. The methylation of DAPK gene promoter region was examined by methylation-specific PCR (MSP). The expressions of DAPK protein were detected by Western blot. MTT results showed that the half maximal inhibitory concentration (IC50) of PC9 and PC9/GR cell lines increase from 0.12 μmol/L to 8.52 μmol/L. But after treated with 5-aza-CdR, the IC50 of PC9/GR cell lines decrease to 4.35 μmol/L, and the resistance index (RI) decrease from 71 to 36 (P<0.05). Flow cytometry results showed that the apoptosis rate were 24.80% ± 0.28%, 12.70% ± 0.31%, 19.8% ± 0.15% respectively. MSP results showed that DAPK gene promoter region was un-methylated in PC9 cells and methylated in PC9/GR cells, when treated with 5-aza-CdR, DAPK gene promoter region was partly methylated in PC9/GR cells (P<0.05). Western blot results showed that the levels of DAPK protein were reduced significantly in PC9/GR cell lines compared with PC9, and after treated with 5-aza-CdR, the expression levels of DAPK protein in PC9/GR were increased (P<0.05). In conclusion, DAPK gene promoter methylation may contribute to the downregulation of DAPK gene and protein, and consequently affect the sensitivity of gefitinib in lung adenocarcinoma lines, induced gefitinib resistance. But 5-Aza-CdR can reverse gefitinib resistance by demethylation of DAPK gene promoter.

  6. Mechanism of Resistance and Novel Targets Mediating Resistance to EGFR and c-Met Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer

    PubMed Central

    Chhabra, Gagan; Nlend, Marie

    2015-01-01

    Tyrosine kinase inhibitors (TKIs) against EGFR and c-Met are initially effective when administered individually or in combination to non-small cell lung cancer (NSCLC) patients. However, the overall efficacies of TKIs are limited due to the development of drug resistance. Therefore, it is important to elucidate mechanisms of EGFR and c-Met TKI resistance in order to develop more effective therapies. Model NSCLC cell lines H1975 and H2170 were used to study the similarities and differences in mechanisms of EGFR/c-Met TKI resistance. H1975 cells are positive for the T790M EGFR mutation, which confers resistance to current EGFR TKI therapies, while H2170 cells are EGFR wild-type. Previously, H2170 cells were made resistant to the EGFR TKI erlotinib and the c-Met TKI SU11274 by exposure to progressively increasing concentrations of TKIs. In H2170 and H1975 TKI-resistant cells, key Wnt and mTOR proteins were found to be differentially modulated. Wnt signaling transducer, active β-catenin was upregulated in TKI-resistant H2170 cells when compared to parental cells. GATA-6, a transcriptional activator of Wnt, was also found to be upregulated in resistant H2170 cells. In H2170 erlotinib resistant cells, upregulation of inactive GSK3β (p-GSK3β) was observed, indicating activation of Wnt and mTOR pathways which are otherwise inhibited by its active form. However, in H1975 cells, Wnt modulators such as active β-catenin, GATA-6 and p-GSK3β were downregulated. Additional results from MTT cell viability assays demonstrated that H1975 cell proliferation was not significantly decreased after Wnt inhibition by XAV939, but combination treatment with everolimus (mTOR inhibitor) and erlotinib resulted in synergistic cell growth inhibition. Thus, in H2170 cells and H1975 cells, simultaneous inhibition of key Wnt or mTOR pathway proteins in addition to EGFR and c-Met may be a promising strategy for overcoming EGFR and c-Met TKI resistance in NSCLC patients. PMID:26301867

  7. DNA Repair Genes ERCC1 and BRCA1 Expression in Non-Small Cell Lung Cancer Chemotherapy Drug Resistance.

    PubMed

    Wang, Shuai; Liu, Feng; Zhu, Jingyan; Chen, Peng; Liu, Hongxing; Liu, Qi; Han, Junqing

    2016-06-12

    BACKGROUND Surgery combined with chemotherapy is an important therapy for non-small cell lung cancer (NSCLC). However, chemotherapy drug resistance seriously hinders the curative effect. Studies show that DNA repair genes ERCC1 and BRCA1 are associated with NSCLC chemotherapy, but their expression and mechanism in NSCLC chemotherapy drug-resistant cells has not been elucidated. MATERIAL AND METHODS NSCLC cell line A549 and drug resistance cell line A549/DDP were cultured. Real-time PCR and Western blot analyses were used to detect ERCC1 and BRCA1 mRNA expression. A549/DDP cells were randomly divided into 3 groups: the control group; the siRNA-negative control group (scramble group); and the siRNA ERCC1 and BRCA1siRNA transfection group. Real-time PCR and Western blot analyses were used to determine ERCC1 and BRCA1 mRNA and protein expression. MTT was used to detect cell proliferation activity. Caspase 3 activity was tested by use of a kit. Western blot analysis was performed to detect PI3K, AKT, phosphorylated PI3K, and phosphorylated AKT protein expression. RESULTS ERCC1 and BRCA1 were overexpressed in A549/DDP compared with A549 (P<0.05). ERCC1 and BRCA1siRNA transfection can significantly reduce ERCC1 and BRCA1 mRNA and protein expression (P<0.05). Downregulating ERCC1 and BRCA1 expression obviously inhibited cell proliferation and increased caspase 3 activity (P<0.05). Downregulating ERCC1 and BRCA1 significantly decreased PI3K and AKT phosphorylation levels (P<0.05). CONCLUSIONS ERCC1 and BRCA1 were overexpressed in NSCLC drug-resistant cells, and they regulated lung cancer occurrence and development through the phosphorylating PI3K/AKT signaling pathway.

  8. DNA Repair Genes ERCC1 and BRCA1 Expression in Non-Small Cell Lung Cancer Chemotherapy Drug Resistance

    PubMed Central

    Wang, Shuai; Liu, Feng; Zhu, Jingyan; Chen, Peng; Liu, Hongxing; Liu, Qi; Han, Junqing

    2016-01-01

    Background Surgery combined with chemotherapy is an important therapy for non-small cell lung cancer (NSCLC). However, chemotherapy drug resistance seriously hinders the curative effect. Studies show that DNA repair genes ERCC1 and BRCA1 are associated with NSCLC chemotherapy, but their expression and mechanism in NSCLC chemotherapy drug-resistant cells has not been elucidated. Material/Methods NSCLC cell line A549 and drug resistance cell line A549/DDP were cultured. Real-time PCR and Western blot analyses were used to detect ERCC1 and BRCA1 mRNA expression. A549/DDP cells were randomly divided into 3 groups: the control group; the siRNA-negative control group (scramble group); and the siRNA ERCC1 and BRCA1siRNA transfection group. Real-time PCR and Western blot analyses were used to determine ERCC1 and BRCA1 mRNA and protein expression. MTT was used to detect cell proliferation activity. Caspase 3 activity was tested by use of a kit. Western blot analysis was performed to detect PI3K, AKT, phosphorylated PI3K, and phosphorylated AKT protein expression. Results ERCC1 and BRCA1 were overexpressed in A549/DDP compared with A549 (P<0.05). ERCC1 and BRCA1siRNA transfection can significantly reduce ERCC1 and BRCA1 mRNA and protein expression (P<0.05). Downregulating ERCC1 and BRCA1 expression obviously inhibited cell proliferation and increased caspase 3 activity (P<0.05). Downregulating ERCC1 and BRCA1 significantly decreased PI3K and AKT phosphorylation levels (P<0.05). Conclusions ERCC1 and BRCA1 were overexpressed in NSCLC drug-resistant cells, and they regulated lung cancer occurrence and development through the phosphorylating PI3K/AKT signaling pathway. PMID:27289442

  9. Clinical heterogeneity of dominant chronic mucocutaneous candidiasis disease: presenting as treatment-resistant candidiasis and chronic lung disease.

    PubMed

    Dotta, Laura; Scomodon, Omar; Padoan, Rita; Timpano, Silviana; Plebani, Alessandro; Soresina, Annarosa; Lougaris, Vassilios; Concolino, Daniela; Nicoletti, Angela; Giardino, Giuliana; Licari, Amelia; Marseglia, Gianluigi; Pignata, Claudio; Tamassia, Nicola; Facchetti, Fabio; Vairo, Donatella; Badolato, Raffaele

    2016-03-01

    In gain-of-function STAT1 mutations, chronic mucocutaneous candidiasis disease (CMCD) represents the phenotypic manifestation of a complex immunodeficiency characterized by clinical and immunological heterogeneity. We aimed to study clinical manifestations, long-term complications, molecular basis, and immune profile of patients with dominant CMCD. We identified nine patients with heterozygous mutations in STAT1, including novel amino acid substitutions (L283M, L351F, L400V). High risk of azole-resistance was observed, particularly when intermittent regimens of antifungal treatment or use of suboptimal dosage occurs. We report a case of Cryptococcosis and various bacterial and viral infections. Risk of developing bronchiectasis in early childhood or gradually evolving to chronic lung disease in adolescent or adult ages emerges. Lymphopenia is variable, likely progressing by adulthood. We conclude that continuous antifungal prophylaxis associated to drug monitoring might prevent resistance to treatment; prompt diagnosis and therapy of lung disease might control long-term progression; careful monitoring of lymphopenia-related infections might improve prognosis.

  10. Role of WNT1-inducible-signaling pathway protein 1 in etoposide resistance in lung adenocarcinoma A549 cells

    PubMed Central

    Xu, Yunhua; Lu, Shun

    2015-01-01

    Object: The aim of this study was to explore the role of WNT1-inducible-signaling Pathway Protein 1 (WISP-1) in etoposide resistance in lung adenocarcinoma A549 cells. Methods: WISP-1 overexpression A549 lung adenocarcinoma cell was established. After exposure to ultraviolet (UV) and etoposide, cell viability and apoptosis were evaluated. Moreover, western-blot was employed to examine the expression of apoptotic pathway proteins. In addition, a nude mice tumor model was established to examine the effect of WISP-1 overexpression in vivo and TUNEL staining was used to assess cell apoptosis of tumor tissue. Results: WISP-1 overexpression significantly increased cell viability and decreased cell apoptosis after treatment with UV and etoposide. Decreased expression of Bad and Bax and increased expression of Bcl-2 was found after etoposide treatment in WISP-1 overexpressed cells. A significantly increasing of tumor volume in WISP-1 overexpressed group was found and TUNEL staining revealed that decreased cell apoptosis in WISP-1 overexpressed group. Conclusion: Our results demonstrated that WISP-1 may have a facilitating role in etoposide resistance through increasing cell viability and decreasing cell apoptosis. PMID:26628978

  11. Caveolin-1 regulates cell apoptosis and invasion ability in paclitaxel-induced multidrug-resistant A549 lung cancer cells

    PubMed Central

    Han, Fei; Zhang, Long; Zhou, Yongxin; Yi, Xianghua

    2015-01-01

    The aim of the study was to investigate the effect and potential mechanism of caveolin-1 (Cav1) knockdown in paclitaxel-resistant lung cancer A549/Taxol cells. The human paclitaxel-resistant lung cancer cell line A549/Taxol was transfected with a Cav1 shRNA lentiviral vector. Interference efficiency for Cav1 was detected by real-time PCR and Western blotting. A MTT assay was used to determine cell proliferation, and flow cytometry was used to detect the cell cycle stage and apoptosis. Cell migration and invasion capability were detected by a transwell assay. Protein levels of related signaling molecules were detected by Western blotting. We successfully constructed a stable A549/Taxol cell line expressing low levels of Cav1. Cav1 knockdown significantly inhibited cell proliferation and induced G0/G1 arrest and cell apoptosis in vitro and in vivo. In addition, these effects correlated significantly with a reduction in cyclin D1 expression and activation of the Bcl-2/Bax-mediated mitochondrial apoptosis pathway. Furthermore, knockdown of Cav1 inhibited cell migration and invasion, and this may be related to the inhibition of AKT and the subsequent decreased protein expression of MMP2, MMP7 and MMP9. PMID:26464635

  12. Blocking the epithelial-to-mesenchymal transition pathway abrogates resistance to anti-folate chemotherapy in lung cancer

    PubMed Central

    Liang, S-Q; Marti, T M; Dorn, P; Froment, L; Hall, S R R; Berezowska, S; Kocher, G; Schmid, R A; Peng, R-W

    2015-01-01

    Anticancer therapies currently used in the clinic often can neither eradicate the tumor nor prevent disease recurrence due to tumor resistance. In this study, we showed that chemoresistance to pemetrexed, a multi-target anti-folate (MTA) chemotherapeutic agent for non-small cell lung cancer (NSCLC), is associated with a stem cell-like phenotype characterized by an enriched stem cell gene signature, augmented aldehyde dehydrogenase activity and greater clonogenic potential. Mechanistically, chemoresistance to MTA requires activation of epithelial-to-mesenchymal transition (EMT) pathway in that an experimentally induced EMT per se promotes chemoresistance in NSCLC and inhibition of EMT signaling by kaempferol renders the otherwise chemoresistant cancer cells susceptible to MTA. Relevant to the clinical setting, human primary NSCLC cells with an elevated EMT signaling feature a significantly enhanced potential to resist MTA, whereas concomitant administration of kaempferol abrogates MTA chemoresistance, regardless of whether it is due to an intrinsic or induced activation of the EMT pathway. Collectively, our findings reveal that a bona fide activation of EMT pathway is required and sufficient for chemoresistance to MTA and that kaempferol potently regresses this chemotherapy refractory phenotype, highlighting the potential of EMT pathway inhibition to enhance chemotherapeutic response of lung cancer. PMID:26181204

  13. Decoding the EGFR mutation-induced drug resistance in lung cancer treatment by local surface geometric properties.

    PubMed

    Ma, Lichun; Wang, Debby D; Huang, Yiqing; Wong, Maria P; Lee, Victor H F; Yan, Hong

    2015-08-01

    Epidermal growth factor receptor (EGFR) mutation-induced drug resistance leads to a limited efficacy of tyrosine kinase inhibitors during lung cancer treatments. In this study, we explore the correlations between the local surface geometric properties of EGFR mutants and the progression-free survival (PFS). The geometric properties include local surface changes (four types) of the EGFR mutants compared with the wild-type EGFR, and the convex degrees of these local surfaces. Our analysis results show that the Spearman׳s rank correlation coefficients between the PFS and three types of local surface properties are all greater than 0.6 with small P-values, implying a high significance. Moreover, the number of atoms with solid angles in the ranges of [0.71, 1], [0.61, 1] or [0.5, 1], indicating the convex degree of a local EGFR surface, also shows a strong correlation with the PFS. Overall, these characteristics can be efficiently applied to the prediction of drug resistance in lung cancer treatments, and easily extended to other cancer treatments.

  14. A Novel Bispecific Antibody Targeting EGFR and cMet Is Effective against EGFR Inhibitor-Resistant Lung Tumors.

    PubMed

    Moores, Sheri L; Chiu, Mark L; Bushey, Barbara S; Chevalier, Kristen; Luistro, Leopoldo; Dorn, Keri; Brezski, Randall J; Haytko, Peter; Kelly, Thomas; Wu, Sheng-Jiun; Martin, Pauline L; Neijssen, Joost; Parren, Paul W H I; Schuurman, Janine; Attar, Ricardo M; Laquerre, Sylvie; Lorenzi, Matthew V; Anderson, G Mark

    2016-07-01

    Non-small cell lung cancers (NSCLC) with activating EGFR mutations become resistant to tyrosine kinase inhibitors (TKI), often through second-site mutations in EGFR (T790M) and/or activation of the cMet pathway. We engineered a bispecific EGFR-cMet antibody (JNJ-61186372) with multiple mechanisms of action to inhibit primary/secondary EGFR mutations and the cMet pathway. JNJ-61186372 blocked ligand-induced phosphorylation of EGFR and cMet and inhibited phospho-ERK and phospho-AKT more potently than the combination of single receptor-binding antibodies. In NSCLC tumor models driven by EGFR and/or cMet, JNJ-61186372 treatment resulted in tumor regression through inhibition of signaling/receptor downmodulation and Fc-driven effector interactions. Complete and durable regression of human lung xenograft tumors was observed with the combination of JNJ-61186372 and a third-generation EGFR TKI. Interestingly, treatment of cynomolgus monkeys with JNJ-61186372 resulted in no major toxicities, including absence of skin rash observed with other EGFR-directed agents. These results highlight the differentiated potential of JNJ-61186372 to inhibit the spectrum of mutations driving EGFR TKI resistance in NSCLC. Cancer Res; 76(13); 3942-53. ©2016 AACR.

  15. Chitotriosidase is a Biomarker for the Resistance to World Trade Center Lung Injury in New York City Firefighters

    PubMed Central

    Cho, Soo Jung; Nolan, Anna; Echevarria, Ghislaine C.; Kwon, Sophia; Naveed, Bushra; Schenck, Edward; Tsukiji, Jun; Prezant, David J.; Rom, William N.; Weiden, Michael D.

    2013-01-01

    Purpose World Trade Center (WTC) exposure caused airflow obstruction years after exposure. Chitinases and IgE are innate and humoral mediators of obstructive airway disease. We investigated if serum expression of chitinases and IgE early after WTC exposure predicts subsequent obstruction. Methods With a nested case-control design, 251 FDNY personnel had chitotriosidase, YKL-40 and IgE measured in serum drawn within months of 9/11/2001. The main outcome was subsequent Forced Expiratory Volume after one second/Forced Vital Capacity (FEV1/FVC) less than the lower limit of normal (LLN). Cases (N=125) had abnormal FEV1/FVC whereas controls had normal FEV1/FVC (N=126). In a secondary analysis, resistant cases (N=66) had FEV1 (≥107%) one standard deviation above the mean. Logistic regression adjusted for age, BMI, exposure intensity and post-exposure FEV1/FVC modeled the association between early biomarkers and later lung function. Results Cases and Controls initially lost lung function. Controls recovered to pre-9/11 FEV1 and FVC while cases continue to decline. Cases expressed lower serum chitotriosidase and higher IgE levels. Increase in IgE increased the odds of airflow obstruction and decreased the odds of above average FEV1. Alternately, increasing chitotriosidase decreased the odds of abnormal FEV1/FVC and increased the odds of FEV1≥107%. Serum YKL-40 was not associated with FEV1/FVC or FEV1 in this cohort. Conclusions Increased serum chitotriosidase reduces the odds of developing obstruction after WTC-particulate matter exposure and is associated with recovery of lung function. Alternately, elevated IgE is a risk factor for airflow obstruction and progressive lung function decline. PMID:23744081

  16. Valproic acid, an inhibitor of class I histone deacetylases, reverses acquired Erlotinib-resistance of lung adenocarcinoma cells: a Connectivity Mapping analysis and an experimental study.

    PubMed

    Zhuo, Wenlei; Zhang, Liang; Zhu, Yi; Xie, Qichao; Zhu, Bo; Chen, Zhengtang

    2015-01-01

    Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have been used as a powerful targeting therapeutic agent for treatment of lung adenocarcinoma for years. Nevertheless, the efficacy of TKI was hampered by the appearance of acquired TKI-resistance. In the present study, we aimed to search, predict, and screen the agents that can overcome the acquired TKI-resistance of lung adenocarcinoma by using the expression profiles of differentially expressed genes (DEGs) and Connectivity map (CMAP). The profiles of DEGs were obtained by searching GEO microarray database, and then, they were submitted to CMAP for analysis in order to predict and screen the agent that might reverse the TKI-resistance of lung cancer cells. Next, the effects of the selected agent on TKI-resistant cancer cells were tested and the possible signaling pathways were also evaluated. As a result, valproic acid (VPA) was selected. Then, we used a low-concentration of VPA that has little effect on the cell growth for analysis. Interestingly, the results showed that treatment with a combination of VPA and Erlotinib significantly led to a decrease in cell viability and an increase in cell apoptosis for TKI-resistant HCC827-ER cells, relative to those treated with VPA or Erlotinib alone. Further experiments confirmed that inhibition of MAPK and AKT might be involved in this process. Analyzing the DEGs through the CMAP is a good strategy for exploitation of anti-tumor agents. VPA might markedly increase the sensitivity of TKI-resistant lung adenocarcinoma cells to Erlotinib, thus reversing the acquired TKI-resistance of cancer cells and raising VPA as a potential agent for TKI-resistant lung cancer therapy.

  17. Valproic acid, an inhibitor of class I histone deacetylases, reverses acquired Erlotinib-resistance of lung adenocarcinoma cells: a Connectivity Mapping analysis and an experimental study

    PubMed Central

    Zhuo, Wenlei; Zhang, Liang; Zhu, Yi; Xie, Qichao; Zhu, Bo; Chen, Zhengtang

    2015-01-01

    Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have been used as a powerful targeting therapeutic agent for treatment of lung adenocarcinoma for years. Nevertheless, the efficacy of TKI was hampered by the appearance of acquired TKI-resistance. In the present study, we aimed to search, predict, and screen the agents that can overcome the acquired TKI-resistance of lung adenocarcinoma by using the expression profiles of differentially expressed genes (DEGs) and Connectivity map (CMAP). The profiles of DEGs were obtained by searching GEO microarray database, and then, they were submitted to CMAP for analysis in order to predict and screen the agent that might reverse the TKI-resistance of lung cancer cells. Next, the effects of the selected agent on TKI-resistant cancer cells were tested and the possible signaling pathways were also evaluated. As a result, valproic acid (VPA) was selected. Then, we used a low-concentration of VPA that has little effect on the cell growth for analysis. Interestingly, the results showed that treatment with a combination of VPA and Erlotinib significantly led to a decrease in cell viability and an increase in cell apoptosis for TKI-resistant HCC827-ER cells, relative to those treated with VPA or Erlotinib alone. Further experiments confirmed that inhibition of MAPK and AKT might be involved in this process. Analyzing the DEGs through the CMAP is a good strategy for exploitation of anti-tumor agents. VPA might markedly increase the sensitivity of TKI-resistant lung adenocarcinoma cells to Erlotinib, thus reversing the acquired TKI-resistance of cancer cells and raising VPA as a potential agent for TKI-resistant lung cancer therapy. PMID:26328250

  18. Valproic acid, an inhibitor of class I histone deacetylases, reverses acquired Erlotinib-resistance of lung adenocarcinoma cells: a Connectivity Mapping analysis and an experimental study.

    PubMed

    Zhuo, Wenlei; Zhang, Liang; Zhu, Yi; Xie, Qichao; Zhu, Bo; Chen, Zhengtang

    2015-01-01

    Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have been used as a powerful targeting therapeutic agent for treatment of lung adenocarcinoma for years. Nevertheless, the efficacy of TKI was hampered by the appearance of acquired TKI-resistance. In the present study, we aimed to search, predict, and screen the agents that can overcome the acquired TKI-resistance of lung adenocarcinoma by using the expression profiles of differentially expressed genes (DEGs) and Connectivity map (CMAP). The profiles of DEGs were obtained by searching GEO microarray database, and then, they were submitted to CMAP for analysis in order to predict and screen the agent that might reverse the TKI-resistance of lung cancer cells. Next, the effects of the selected agent on TKI-resistant cancer cells were tested and the possible signaling pathways were also evaluated. As a result, valproic acid (VPA) was selected. Then, we used a low-concentration of VPA that has little effect on the cell growth for analysis. Interestingly, the results showed that treatment with a combination of VPA and Erlotinib significantly led to a decrease in cell viability and an increase in cell apoptosis for TKI-resistant HCC827-ER cells, relative to those treated with VPA or Erlotinib alone. Further experiments confirmed that inhibition of MAPK and AKT might be involved in this process. Analyzing the DEGs through the CMAP is a good strategy for exploitation of anti-tumor agents. VPA might markedly increase the sensitivity of TKI-resistant lung adenocarcinoma cells to Erlotinib, thus reversing the acquired TKI-resistance of cancer cells and raising VPA as a potential agent for TKI-resistant lung cancer therapy. PMID:26328250

  19. Novel method for conscious airway resistance and ventilation estimation in neonatal rodents using plethysmography and a mechanical lung.

    PubMed

    Zhang, Boyang; McDonald, Fiona B; Cummings, Kevin J; Frappell, Peter B; Wilson, Richard J A

    2014-09-15

    In unrestrained whole body plethysmography, tidal volume is commonly determined using the barometric method, which assumes that temperature and humidity changes (the 'barometric component') are solely responsible for breathing-related chamber pressure fluctuations. However, in small animals chamber pressure is also influenced by a 'mechanical component' dependent on airway resistance and airflow. We devised a novel 'mechanical lung' capable of simulating neonatal mouse breathing in the absence of temperature or humidity changes. Using this device, we confirm that the chamber pressure fluctuations produced by breathing of neonatal mice are dominated by the mechanical component, precluding direct quantitative assessment of tidal volume. Recognizing the importance of airway resistance to the chamber pressure signal and the ability of our device to simulate neonatal breathing at different frequencies and tidal volumes, we invented a novel in vivo, non-invasive method for conscious airway resistance and ventilation estimation (CARVE) in neonatal rodents. This technique will allow evaluation of developmental, pathological and pharmaceutical effects on airway resistance.

  20. Targeting MDR in breast and lung cancer: discriminating its potential importance from the failure of drug resistance reversal studies.

    PubMed

    Amiri-Kordestani, Laleh; Basseville, Agnes; Kurdziel, Karen; Fojo, Antonio Tito; Bates, Susan E

    2012-01-01

    This special issue of Drug Resistance Updates is dedicated to multidrug resistance protein 1 (MDR-1), 35 years after its discovery. While enormous progress has been made and our understanding of drug resistance has become more sophisticated and nuanced, after 35 years the role of MDR-1 in clinical oncology remains a work in progress. Despite clear in vitro evidence that P-glycoprotein (Pgp), encoded by MDR-1, is able to dramatically reduce drug concentrations in cultured cells, and that drug accumulation can be increased by small molecule inhibitors, clinical trials testing this paradigm have mostly failed. Some have argued that it is no longer worthy of study. However, repeated analyses have demonstrated MDR-1 expression in a tumor is a poor prognostic indicator leading some to conclude MDR-1 is a marker of a more aggressive phenotype, rather than a mechanism of drug resistance. In this review we will re-evaluate the MDR-1 story in light of our new understanding of molecular targeted therapy, using breast and lung cancer as examples. In the end we will reconcile the data available and the knowledge gained in support of a thesis that we understand far more than we realize, and that we can use this knowledge to improve future therapies.

  1. Novel method for conscious airway resistance and ventilation estimation in neonatal rodents using plethysmography and a mechanical lung.

    PubMed

    Zhang, Boyang; McDonald, Fiona B; Cummings, Kevin J; Frappell, Peter B; Wilson, Richard J A

    2014-09-15

    In unrestrained whole body plethysmography, tidal volume is commonly determined using the barometric method, which assumes that temperature and humidity changes (the 'barometric component') are solely responsible for breathing-related chamber pressure fluctuations. However, in small animals chamber pressure is also influenced by a 'mechanical component' dependent on airway resistance and airflow. We devised a novel 'mechanical lung' capable of simulating neonatal mouse breathing in the absence of temperature or humidity changes. Using this device, we confirm that the chamber pressure fluctuations produced by breathing of neonatal mice are dominated by the mechanical component, precluding direct quantitative assessment of tidal volume. Recognizing the importance of airway resistance to the chamber pressure signal and the ability of our device to simulate neonatal breathing at different frequencies and tidal volumes, we invented a novel in vivo, non-invasive method for conscious airway resistance and ventilation estimation (CARVE) in neonatal rodents. This technique will allow evaluation of developmental, pathological and pharmaceutical effects on airway resistance. PMID:25017785

  2. Geraniin inhibits TGF-β1-induced epithelial-mesenchymal transition and suppresses A549 lung cancer migration, invasion and anoikis resistance.

    PubMed

    Ko, Hyeonseok

    2015-09-01

    The epithelial-mesenchymal transition (EMT) is an important cellular process during which epithelial polarized cells become motile mesenchymal-appeared cells, which, in turn, induces the metastatic of cancer. Geraniin is a polyphenolic component isolated from Phyllanthus amarus, which exhibits a wide range of pharmacological and physiological activities, such as antitumor, anti-hyperglycemic, anti-hypertensive, antimicrobial, and antiviral activities. However, the possible role of geraniin in the EMT is unclear. We investigated the effect of geraniin on the EMT. Transforming growth factor-beta 1 (TGF-β1) induces the EMT to promote lung adenocarcinoma migration, invasion, and anoikis resistance. To understand the suppressive role of geraniin in lung cancer migration, invasion, and anoikis resistance, we investigated the use of geraniin as inhibitors of TGF-β1-induced EMT in A549 lung cancer cells in vitro. Here, we show that geraniin remarkably increased expression of the epithelial marker E-cadherin and repressed Snail upregulation and expression of the mesenchymal marker N-cadherin and vimentin during the TGF-β1-induced EMT. Geraniin also inhibited the TGF-β1-induced increase in cell migration, invasion, and anoikis resistance of A549 lung cancer cells. Additionally, geraniin markedly inhibited TGF-β1-regulated activation of Smad2. Taken together, our findings provide new evidence that geraniin suppresses lung cancer migration, invasion, and anoikis resistance in vitro by inhibiting the TGF-β1-induced EMT.

  3. Feroniellin A-induced autophagy causes apoptosis in multidrug-resistant human A549 lung cancer cells.

    PubMed

    Kaewpiboon, Chutima; Surapinit, Serm; Malilas, Waraporn; Moon, Jeong; Phuwapraisirisan, Preecha; Tip-Pyang, Santi; Johnston, Randal N; Koh, Sang Seok; Assavalapsakul, Wanchai; Chung, Young-Hwa

    2014-04-01

    During the screening of natural chemicals that can reverse multidrug resistance in human A549 lung cancer cells resistant to etoposide (A549RT-eto), we discovered that Feroniellin A (FERO), a novel furanocoumarin, shows toxicity toward A549RT-eto cells in a dose- and time-dependent manner. FERO reduced the expression of NF-κB, leading to downregulation of P-glycoprotein (P-gp), encoded by MDR1, which eventually sensitized A549RT-eto cells to apoptosis. FERO specifically diminished transcription and promoter activity of MDR1 but did not inhibit the expression of other multidrug resistance genes MRP2 and BCRP. Moreover, co-administration of FERO with Bay11-7802, an inhibitor of NF-κB, accelerated apoptosis of A549RT-eto cells through decreased expression of P-gp, indicating that NF-κB is involved in multidrug resistance. Conversely, addition of Z-VAD, a pan-caspase inhibitor, blocked FERO-induced apoptosis in A549RT-eto cells but did not block downregulation of P-gp, indicating that a decrease in P-gp expression is necessary but not sufficient for FERO-induced apoptosis. Interestingly, we found that FERO also induces autophagy, which is characterized by the conversion of LC3 I to LC3 II, induction of GFP-LC3 puncta, enhanced expression of Beclin-1 and ATG5, and inactivation of mTOR. Furthermore, suppression of Beclin-1 by siRNA reduced FERO-induced apoptosis in A549RT-eto cells and activation of autophagy by rapamycin accelerated FERO-induced apoptosis, suggesting that autophagy plays an active role in FERO-induced apoptosis. Herein, we report that FERO reverses multidrug resistance in A549RT-eto cells and exerts its cytotoxic effect by induction of both autophagy and apoptosis, which suggests that FERO can be a useful anticancer drug for multidrug-resistant lung cancer. PMID:24535083

  4. Feroniellin A-induced autophagy causes apoptosis in multidrug-resistant human A549 lung cancer cells.

    PubMed

    Kaewpiboon, Chutima; Surapinit, Serm; Malilas, Waraporn; Moon, Jeong; Phuwapraisirisan, Preecha; Tip-Pyang, Santi; Johnston, Randal N; Koh, Sang Seok; Assavalapsakul, Wanchai; Chung, Young-Hwa

    2014-04-01

    During the screening of natural chemicals that can reverse multidrug resistance in human A549 lung cancer cells resistant to etoposide (A549RT-eto), we discovered that Feroniellin A (FERO), a novel furanocoumarin, shows toxicity toward A549RT-eto cells in a dose- and time-dependent manner. FERO reduced the expression of NF-κB, leading to downregulation of P-glycoprotein (P-gp), encoded by MDR1, which eventually sensitized A549RT-eto cells to apoptosis. FERO specifically diminished transcription and promoter activity of MDR1 but did not inhibit the expression of other multidrug resistance genes MRP2 and BCRP. Moreover, co-administration of FERO with Bay11-7802, an inhibitor of NF-κB, accelerated apoptosis of A549RT-eto cells through decreased expression of P-gp, indicating that NF-κB is involved in multidrug resistance. Conversely, addition of Z-VAD, a pan-caspase inhibitor, blocked FERO-induced apoptosis in A549RT-eto cells but did not block downregulation of P-gp, indicating that a decrease in P-gp expression is necessary but not sufficient for FERO-induced apoptosis. Interestingly, we found that FERO also induces autophagy, which is characterized by the conversion of LC3 I to LC3 II, induction of GFP-LC3 puncta, enhanced expression of Beclin-1 and ATG5, and inactivation of mTOR. Furthermore, suppression of Beclin-1 by siRNA reduced FERO-induced apoptosis in A549RT-eto cells and activation of autophagy by rapamycin accelerated FERO-induced apoptosis, suggesting that autophagy plays an active role in FERO-induced apoptosis. Herein, we report that FERO reverses multidrug resistance in A549RT-eto cells and exerts its cytotoxic effect by induction of both autophagy and apoptosis, which suggests that FERO can be a useful anticancer drug for multidrug-resistant lung cancer.

  5. Synthetic lung surfactants containing SP-B and SP-C peptides plus novel phospholipase-resistant lipids or glycerophospholipids

    PubMed Central

    Notter, Robert H.; Gupta, Rohun; Schwan, Adrian L.; Wang, Zhengdong; Shkoor, Mohanad Gh

    2016-01-01

    Background This study examines the biophysical and preclinical pulmonary activity of synthetic lung surfactants containing novel phospholipase-resistant phosphonolipids or synthetic glycerophospholipids combined with Super Mini-B (S-MB) DATK and/or SP-Css ion-lock 1 peptides that replicate the functional biophysics of surfactant proteins (SP)-B and SP-C. Phospholipase-resistant phosphonolipids used in synthetic surfactants are DEPN-8 and PG-1, molecular analogs of dipalmitoyl phosphatidylcholine (DPPC) and palmitoyl-oleoyl phosphatidylglycerol (POPG), while glycerophospholipids used are active lipid components of native surfactant (DPPC:POPC:POPG 5:3:2 by weight). The objective of the work is to test whether these novel lipid/peptide synthetic surfactants have favorable preclinical activity (biophysical, pulmonary) for therapeutic use in reversing surfactant deficiency or dysfunction in lung disease or injury. Methods Surface activity of synthetic lipid/peptide surfactants was assessed in vitro at 37 °C by measuring adsorption in a stirred subphase apparatus and dynamic surface tension lowering in pulsating and captive bubble surfactometers. Shear viscosity was measured as a function of shear rate on a Wells-Brookfield micro-viscometer. In vivo pulmonary activity was determined by measuring lung function (arterial oxygenation, dynamic lung compliance) in ventilated rats and rabbits with surfactant deficiency/dysfunction induced by saline lavage to lower arterial PO2 to <100 mmHg, consistent with clinical acute respiratory distress syndrome (ARDS). Results Synthetic surfactants containing 5:3:2 DPPC:POPC:POPG or 9:1 DEPN-8:PG-1 combined with 3% (by wt) of S-MB DATK, 3% SP-Css ion-lock 1, or 1.5% each of both peptides all adsorbed rapidly to low equilibrium surface tensions and also reduced surface tension to ≤1 mN/m under dynamic compression at 37 °C. However, dual-peptide surfactants containing 1.5% S-MB DATK + 1.5% SP-Css ion-lock 1 combined with 9:1 DEPN-8

  6. Absolute biological needs.

    PubMed

    McLeod, Stephen

    2014-07-01

    Absolute needs (as against instrumental needs) are independent of the ends, goals and purposes of personal agents. Against the view that the only needs are instrumental needs, David Wiggins and Garrett Thomson have defended absolute needs on the grounds that the verb 'need' has instrumental and absolute senses. While remaining neutral about it, this article does not adopt that approach. Instead, it suggests that there are absolute biological needs. The absolute nature of these needs is defended by appeal to: their objectivity (as against mind-dependence); the universality of the phenomenon of needing across the plant and animal kingdoms; the impossibility that biological needs depend wholly upon the exercise of the abilities characteristic of personal agency; the contention that the possession of biological needs is prior to the possession of the abilities characteristic of personal agency. Finally, three philosophical usages of 'normative' are distinguished. On two of these, to describe a phenomenon or claim as 'normative' is to describe it as value-dependent. A description of a phenomenon or claim as 'normative' in the third sense does not entail such value-dependency, though it leaves open the possibility that value depends upon the phenomenon or upon the truth of the claim. It is argued that while survival needs (or claims about them) may well be normative in this third sense, they are normative in neither of the first two. Thus, the idea of absolute need is not inherently normative in either of the first two senses. PMID:23586876

  7. Absolute biological needs.

    PubMed

    McLeod, Stephen

    2014-07-01

    Absolute needs (as against instrumental needs) are independent of the ends, goals and purposes of personal agents. Against the view that the only needs are instrumental needs, David Wiggins and Garrett Thomson have defended absolute needs on the grounds that the verb 'need' has instrumental and absolute senses. While remaining neutral about it, this article does not adopt that approach. Instead, it suggests that there are absolute biological needs. The absolute nature of these needs is defended by appeal to: their objectivity (as against mind-dependence); the universality of the phenomenon of needing across the plant and animal kingdoms; the impossibility that biological needs depend wholly upon the exercise of the abilities characteristic of personal agency; the contention that the possession of biological needs is prior to the possession of the abilities characteristic of personal agency. Finally, three philosophical usages of 'normative' are distinguished. On two of these, to describe a phenomenon or claim as 'normative' is to describe it as value-dependent. A description of a phenomenon or claim as 'normative' in the third sense does not entail such value-dependency, though it leaves open the possibility that value depends upon the phenomenon or upon the truth of the claim. It is argued that while survival needs (or claims about them) may well be normative in this third sense, they are normative in neither of the first two. Thus, the idea of absolute need is not inherently normative in either of the first two senses.

  8. Elevated Cellular PD1/PD-L1 Expression Confers Acquired Resistance to Cisplatin in Small Cell Lung Cancer Cells

    PubMed Central

    Yan, Fei; Pang, Jiuxia; Peng, Yong; Molina, Julian R.; Yang, Ping; Liu, Shujun

    2016-01-01

    Although small cell lung cancer (SCLC) is highly responsive to chemotherapies (e.g., cisplatin-etoposide doublet), virtually almost all responsive SCLC patients experience disease recurrence characterized by drug resistance. The mechanisms underlying cisplatin resistance remain elusive. Here we report that cell-intrinsic expression of PD1 and PD-L1, two immune checkpoints, is required for sustained expansion of SCLC cells under cisplatin selection. Indeed, PD1 and PD-L1 were expressed at a higher level in lung cancer cell lines, tumor tissues, and importantly, in SCLC cells resistant to cisplatin (H69R, H82R), when compared to respective controls. Genetic abrogation of PD1 and PD-L1 in H69R and H82R cells decreased their proliferation rate, and restored their sensitivity to cisplatin. Mechanistically, PD-L1 upregulation in H69R and H82R cells was attributed to the overexpression of DNA methyltransferase 1 (DNMT1) or receptor tyrosine kinase KIT, as knockdown of DNMT1 or KIT in H69R and H82R cells led to PD-L1 downregulation. Consequently, combined knockdown of PD-L1 with KIT or DNMT1 resulted in more pronounced inhibition of H69R and H82R cell growth. Thus, cell intrinsic PD1/PD-L1 signaling may be a predictor for poor efficacy of cisplatin treatment, and targeting the cellular PD1/PD-L1 axis may improve chemosensitization of aggressive SCLC. PMID:27610620

  9. Elevated Cellular PD1/PD-L1 Expression Confers Acquired Resistance to Cisplatin in Small Cell Lung Cancer Cells.

    PubMed

    Yan, Fei; Pang, Jiuxia; Peng, Yong; Molina, Julian R; Yang, Ping; Liu, Shujun

    2016-01-01

    Although small cell lung cancer (SCLC) is highly responsive to chemotherapies (e.g., cisplatin-etoposide doublet), virtually almost all responsive SCLC patients experience disease recurrence characterized by drug resistance. The mechanisms underlying cisplatin resistance remain elusive. Here we report that cell-intrinsic expression of PD1 and PD-L1, two immune checkpoints, is required for sustained expansion of SCLC cells under cisplatin selection. Indeed, PD1 and PD-L1 were expressed at a higher level in lung cancer cell lines, tumor tissues, and importantly, in SCLC cells resistant to cisplatin (H69R, H82R), when compared to respective controls. Genetic abrogation of PD1 and PD-L1 in H69R and H82R cells decreased their proliferation rate, and restored their sensitivity to cisplatin. Mechanistically, PD-L1 upregulation in H69R and H82R cells was attributed to the overexpression of DNA methyltransferase 1 (DNMT1) or receptor tyrosine kinase KIT, as knockdown of DNMT1 or KIT in H69R and H82R cells led to PD-L1 downregulation. Consequently, combined knockdown of PD-L1 with KIT or DNMT1 resulted in more pronounced inhibition of H69R and H82R cell growth. Thus, cell intrinsic PD1/PD-L1 signaling may be a predictor for poor efficacy of cisplatin treatment, and targeting the cellular PD1/PD-L1 axis may improve chemosensitization of aggressive SCLC. PMID:27610620

  10. Integrated Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC) and Isobaric Tags for Relative and Absolute Quantitation (iTRAQ) Quantitative Proteomic Analysis Identifies Galectin-1 as a Potential Biomarker for Predicting Sorafenib Resistance in Liver Cancer.

    PubMed

    Yeh, Chao-Chi; Hsu, Chih-Hung; Shao, Yu-Yun; Ho, Wen-Ching; Tsai, Mong-Hsun; Feng, Wen-Chi; Chow, Lu-Ping

    2015-06-01

    Sorafenib has become the standard therapy for patients with advanced hepatocellular carcinoma (HCC). Unfortunately, most patients eventually develop acquired resistance. Therefore, it is important to identify potential biomarkers that could predict the efficacy of sorafenib. To identify target proteins associated with the development of sorafenib resistance, we applied stable isotope labelling with amino acids in cell culture (SILAC)-based quantitative proteomic approach to analyze differences in protein expression levels between parental HuH-7 and sorafenib-acquired resistance HuH-7 (HuH-7(R)) cells in vitro, combined with an isobaric tags for relative and absolute quantitation (iTRAQ) quantitative analysis of HuH-7 and HuH-7(R) tumors in vivo. In total, 2,450 quantified proteins were identified in common in SILAC and iTRAQ experiments, with 81 showing increased expression (>2.0-fold) with sorafenib resistance and 75 showing decreased expression (<0.5-fold). In silico analyses of these differentially expressed proteins predicted that 10 proteins were related to cancer with involvements in cell adhesion, migration, and invasion. Knockdown of one of these candidate proteins, galectin-1, decreased cell proliferation and metastasis in HuH-7(R) cells and restored sensitivity to sorafenib. We verified galectin-1 as a predictive marker of sorafenib resistance and a downstream target of the AKT/mTOR/HIF-1α signaling pathway. In addition, increased galectin-1 expression in HCC patients' serum was associated with poor tumor control and low response rate. We also found that a high serum galectin-1 level was an independent factor associated with poor progression-free survival and overall survival. In conclusion, these results suggest that galectin-1 is a possible biomarker for predicting the response of HCC patients to treatment with sorafenib. As such, it may assist in the stratification of HCC and help direct personalized therapy.

  11. Integrated Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC) and Isobaric Tags for Relative and Absolute Quantitation (iTRAQ) Quantitative Proteomic Analysis Identifies Galectin-1 as a Potential Biomarker for Predicting Sorafenib Resistance in Liver Cancer*

    PubMed Central

    Yeh, Chao-Chi; Hsu, Chih-Hung; Shao, Yu-Yun; Ho, Wen-Ching; Tsai, Mong-Hsun; Feng, Wen-Chi; Chow, Lu-Ping

    2015-01-01

    Sorafenib has become the standard therapy for patients with advanced hepatocellular carcinoma (HCC). Unfortunately, most patients eventually develop acquired resistance. Therefore, it is important to identify potential biomarkers that could predict the efficacy of sorafenib. To identify target proteins associated with the development of sorafenib resistance, we applied stable isotope labelling with amino acids in cell culture (SILAC)-based quantitative proteomic approach to analyze differences in protein expression levels between parental HuH-7 and sorafenib-acquired resistance HuH-7 (HuH-7R) cells in vitro, combined with an isobaric tags for relative and absolute quantitation (iTRAQ) quantitative analysis of HuH-7 and HuH-7R tumors in vivo. In total, 2,450 quantified proteins were identified in common in SILAC and iTRAQ experiments, with 81 showing increased expression (>2.0-fold) with sorafenib resistance and 75 showing decreased expression (<0.5-fold). In silico analyses of these differentially expressed proteins predicted that 10 proteins were related to cancer with involvements in cell adhesion, migration, and invasion. Knockdown of one of these candidate proteins, galectin-1, decreased cell proliferation and metastasis in HuH-7R cells and restored sensitivity to sorafenib. We verified galectin-1 as a predictive marker of sorafenib resistance and a downstream target of the AKT/mTOR/HIF-1α signaling pathway. In addition, increased galectin-1 expression in HCC patients' serum was associated with poor tumor control and low response rate. We also found that a high serum galectin-1 level was an independent factor associated with poor progression-free survival and overall survival. In conclusion, these results suggest that galectin-1 is a possible biomarker for predicting the response of HCC patients to treatment with sorafenib. As such, it may assist in the stratification of HCC and help direct personalized therapy. PMID:25850433

  12. Triptolide reverses the Taxol resistance of lung adenocarcinoma by inhibiting the NF-κB signaling pathway and the expression of NF-κB-regulated drug-resistant genes.

    PubMed

    Jiang, Ning; Dong, Xiao-Peng; Zhang, Suo-Lin; You, Qing-Yong; Jiang, Xing-Tao; Zhao, Xiao-Gang

    2016-01-01

    Paclitaxel (or Taxol®) is a first-line chemotherapeutic drug for the treatment of non-small cell lung cancer; however, resistance to the drug is an important factor, which influences the outcome of chemotherapy. The present study aimed to investigate the role of triptolide (TPL) in reversing Taxol‑resistant human lung adenocarcinoma and to elucidate the underlying molecular mechanism of resistance reversal mediated by TPL. It was hypothesized that this experimental approach would assist in solving the problem of chemotherapeutic resistance in non‑small cell lung cancer, thereby improving the clinical outcomes. The human Taxol‑resistant lung adenocarcinoma cell line, A549/Taxol, was established. The resistance index of the cell line was calculated, according to the half maximal inhibitory concentration (IC50) of A549/Taxol IC50 of A549, to be 51.87. The levels of apoptosis and the cell cycle in the A549/Taxol cell line were assessed to confirm the effects of TPL at three different concentrations (0.03, 0.3 and 3 µmol/l) and treatment durations (2, 4, 6 and 12 h) by flow cytometric analysis, and the inhibition of the NF‑κB signaling pathway and the expression of NF‑κB‑regulated drug‑resistant proteins were determined by immunofluorescence and western blotting, respectively. The administration of TPL promoted cell apoptosis in the A549/Taxol lung adenocarcinoma Taxol‑resistant cell line and also promoted cell cycle regulation. The drug was also able to elicit a reversal of the drug resistance. TPL inhibited the nuclear factor‑κB (NF‑κB) signaling pathway and the expression of NF‑κB‑regulated drug‑resistant genes, including those for FLICE‑like inhibitory protein, X‑linked inhibitor of apoptosis protein, Bcl‑2, Bcl‑xL and cyclo‑oxygenase‑2. TPL exerted a marked drug‑resistance‑reversal effect on human lung adenocarcinoma Taxol resistance, and the effect was revealed to be dose‑ and time‑dependent. In conclusion, TPL

  13. Crosstalk with cancer-associated fibroblasts induces resistance of non-small cell lung cancer cells to epidermal growth factor receptor tyrosine kinase inhibition

    PubMed Central

    Choe, Chungyoul; Shin, Yong-Sung; Kim, Changhoon; Choi, So-Jung; Lee, Jinseon; Kim, So Young; Cho, Yong Beom; Kim, Jhingook

    2015-01-01

    Although lung cancers with activating mutations in the epidermal growth factor receptor (EGFR) are highly sensitive to selective EGFR tyrosine kinase inhibitors (TKIs), these tumors invariably develop acquired drug resistance. Host stromal cells have been found to have a considerable effect on the sensitivity of cancer cells to EGFR TKIs. Little is known, however, about the signaling mechanisms through which stromal cells contribute to the response to EGFR TKI in non-small cell lung cancer. This work examined the role of hedgehog signaling in cancer-associated fibroblast (CAF)-mediated resistance of lung cancer cells to the EGFR TKI erlotinib. PC9 cells, non-small cell lung cancer cells with EGFR-activating mutations, became resistant to the EGFR TKI erlotinib when cocultured in vitro with CAFs. Polymerase chain reaction and immunocytochemical assays showed that CAFs induced epithelial to mesenchymal transition phenotype in PC9 cells, with an associated change in the expression of epithelial to mesenchymal transition marker proteins including vimentin. Importantly, CAFs induce upregulation of the 7-transmembrane protein smoothened, the central signal transducer of hedgehog, suggesting that the hedgehog signaling pathway is active in CAF-mediated drug resistance. Indeed, downregulation of smoothened activity with the smoothened antagonist cyclopamine induces remodeling of the actin cytoskeleton independently of Gli-mediated transcriptional activity in PC9 cells. These findings indicate that crosstalk with CAFs plays a critical role in resistance of lung cancer to EGFR TKIs through induction of the epithelial to mesenchymal transition and may be an ideal therapeutic target in lung cancer. PMID:26676152

  14. Inhalable self-assembled albumin nanoparticles for treating drug-resistant lung cancer.

    PubMed

    Choi, Seong Ho; Byeon, Hyeong Jun; Choi, Ji Su; Thao, Lequang; Kim, Insoo; Lee, Eun Seong; Shin, Beom Soo; Lee, Kang Choon; Youn, Yu Seok

    2015-01-10

    Direct pulmonary delivery of anti-cancer agents is viewed as an effective way of treating lung cancer. Here, we fabricated inhalable nanoparticles made of human serum albumin (HSA) conjugated with doxorubicin and octyl aldehyde and adsorbed with apoptotic TRAIL protein (TRAIL/Dox HSA-NP). The octyl aldehyde and doxorubicin endowed HSA with significant hydrophobicity that facilitated self-assembly. TRAIL/Dox HSA-NP was found to have excellent particle size (~340nm), morphology, dispersability, and aerosolization properties. TRAIL/Dox HSA-NP displayed synergistic cytotoxicity and apoptotic activity in H226 lung cancer cells vs. HSA-NP containing TRAIL or Dox alone. TRAIL/Dox HSA-NP was well deposited in the mouse lungs using an aerosolizer, and TRAIL and Dox-HSA were found to be gradually released over 3days. The anti-tumor efficacy of pulmonary administered TRAIL/Dox HSA-NP was evaluated in BALB/c nu/nu mice bearing H226 cell-induced metastatic tumors. It was found that the tumors of H226-implanted mice treated with TRAIL/Dox HSA-NP were remarkably smaller and lighter than those of mice treated with TRAIL or Dox HSA-NP alone (337.5±7.5; 678.2±51.5; and 598.9±24.8mg, respectively). Importantly, this improved anti-tumor efficacy was found to be due to the synergistic apoptotic effects of Dox and TRAIL. In the authors' opinion, TRAIL/Dox HSA-NP offers a potential inhalable anti-lung cancer drug delivery system. Furthermore, the synergism displayed by combined use of Dox and TRAIL could be used to markedly reduce doxorubicin doses and minimize its side effects.

  15. Nicotine-induced resistance of non-small cell lung cancer to treatment--possible mechanisms.

    PubMed

    Czyżykowski, Rafał; Połowinczak-Przybyłek, Joanna; Potemski, Piotr

    2016-01-01

    Cigarette smoking is the leading risk factor of lung cancer. Data from several clinical studies suggest that continuation of smoking during therapy of tobacco-related cancers is associated with lower response rates to chemotherapy and/or radiotherapy, and even with decreased survival. Although nicotine--an addictive component of tobacco--is not a carcinogen, it may influence cancer development and progression or effectiveness of anti-cancer therapy. Several in vitro and in vivo trials have evaluated the influence of nicotine on lung cancer cells. The best known mechanisms by which nicotine impacts cancer biology involve suppression of apoptosis induced by certain drugs or radiation, promotion of proliferation, angiogenesis, invasion and migration of cancer cells. This effect is mainly mediated by membranous nicotinic acetylcholine receptors whose stimulation leads to sustained activation of such intracellular pathways as PI3K/Akt/mTOR, RAS/RAF/MEK/ERK and JAK/STAT, induction of NF-κB activity, enhanced transcription of mitogenic promoters, inhibition of the mitochondrial death pathway or stimulation of pro-angiogenic factors. We herein summarize the mechanisms underlying nicotine's influence on biology of lung cancer cells and the effectiveness of anti-cancer therapy. PMID:26943316

  16. Do glutathione and related enzymes play a role in drug resistance in small cell lung cancer cell lines?

    PubMed Central

    Campling, B. G.; Baer, K.; Baker, H. M.; Lam, Y. M.; Cole, S. P.

    1993-01-01

    Small cell lung cancer (SCLC) is treated primarily with combination chemotherapy. Despite high initial response rates, most patients eventually die with drug resistant disease. In some tumours, resistance to multiple chemotherapeutic agents is attributed to overexpression of P-glycoprotein (P-gp). However, this does not appear to be a frequent occurrence in drug resistant SCLC. Increased levels of glutathione (GSH) and related enzymes may play a role in resistance to alkylating agents as well as natural product drugs. We measured levels of GSH, glutathione S-transferase (GST), glutathione reductase (GSH Red), glutathione peroxidase (GSH Px), and gamma-glutamyl transpeptidase (gamma-GT) in a panel of 20 SCLC cell lines. Most of these lines were established from patients treated at this centre. Each cell line had a characteristic and reproducible profile of GSH and related enzyme levels. Immunoblot analysis indicated that the predominant GST in the cell lines was the anionic pi isoenzyme. The relative sensitivity of each of these cell lines to 16 different chemotherapeutic agents was measured using a modified MTT assay. Spearman rank correlation analysis was used to determine the relationships between the relative chemosensitivity of these cell lines and the levels of GSH and related enzymes. The number of positive correlations was no greater than expected by chance alone. Furthermore, there was no correlation with the treatment history of the patients from whom the cell lines were derived. These data suggest that alterations in glutathione metabolism do not play a major role in resistance to chemotherapeutic agents in these human SCLC cell lines. Images Figure 1 PMID:8102244

  17. Profiling Analysis of Histone Modifications and Gene Expression in Lewis Lung Carcinoma Murine Cells Resistant to Anti-VEGF Treatment

    PubMed Central

    Du, Yanhua; Chen, Kaiming; Liu, Zhenping; Li, Bing; Li, Jie; Tao, Fei; Gu, Hua; Jiang, Cizhong; Fang, Jianmin

    2016-01-01

    Tumor cells become resistant after long-term use of anti-VEGF (vascular endothelial growth factor) agents. Our previous study shows that treatment with a VEGF inhibitor (VEGF-Trap) facilitates to develop tumor resistance through regulating angiogenesis-related genes. However, the underlying molecular mechanisms remain elusive. Histone modifications as a key epigenetic factor play a critical role in regulation of gene expression. Here, we explore the potential epigenetic gene regulatory functions of key histone modifications during tumor resistance in a mouse Lewis lung carcinoma (LLC) cell line. We generated high resolution genome-wide maps of key histone modifications in sensitive tumor sample (LLC-NR) and resistant tumor sample (LLC-R) after VEGF-Trap treatment. Profiling analysis of histone modifications shows that histone modification levels are effectively predictive for gene expression. Composition of promoters classified by histone modification state is different between LLC-NR and LLC-R cell lines regardless of CpG content. Histone modification state change between LLC-NR and LLC-R cell lines shows different patterns in CpG-rich and CpG-poor promoters. As a consequence, genes with different level of CpG content whose gene expression level are altered are enriched in distinct functions. Notably, histone modification state change in promoters of angiogenesis-related genes consists with their expression alteration. Taken together, our findings suggest that treatment with anti-VEGF therapy results in extensive histone modification state change in promoters with multiple functions, particularly, biological processes related to angiogenesis, likely contributing to tumor resistance development. PMID:27362259

  18. Effect of Ganoderma on drug-sensitive and multidrug-resistant small-cell lung carcinoma cells.

    PubMed

    Sadava, David; Still, David W; Mudry, Ryan R; Kane, Susan E

    2009-05-18

    Multidrug resistance is a major problem in small-cell lung cancer (SCLC). Ganoderma lucidum is a widely used herb in traditional Chinese medicine. We tested the effects of Ganoderma on drug-sensitive (H69) and multi-drug resistant (VPA) human SCLC cells. Both cells showed equal cytotoxicity when incubated with extracts of mycelia of 9 species of Ganoderma, including G. lucidum. Cells treated with the IC(50) of cytotoxic Ganoderma and analyzed by flow cytometry-PI staining showed increases in S phase. When compared untreated controls or SCLC cells treated with extracts of non-cytotoxic Ganoderma species, cells treated with extracts of cytotoxic Ganoderma species responded with an induction of apoptosis similar to cells treated with the chemotherapeutic drugs etoposide and doxorubicin. This was shown by four criteria: increased DNA fragmentation within cells as measured by ELISA; increased TUNEL staining for DNA breaks; increased specific activities of caspases 3 and 9, but not caspase 8 by colorimetric assays, indicating the endogenous pathway; and similar patterns changes in the expressions of 9 genes involved in the cell cycle/apoptosis, as measured by RT-PCR and capillary electrophoresis. Pre-incubation of drug-resistant SCLC cells with cytotoxic Ganoderma reduced the IC(50) for etoposide (3.4-0.21 microM) and doxorubicin (0.19-0.04 microM). These results show that extracts of several species of Ganoderma are cytotoxic to both drug-sensitive and drug-resistant SCLC cells, are pro-apoptotic, induce gene expression patterns that are similar to SCLC cells treated with chemotherapeutic drugs, and can reverse resistance to chemotherapeutic drugs.

  19. Hyaluronic Acid-Modified Multifunctional Q-Graphene for Targeted Killing of Drug-Resistant Lung Cancer Cells.

    PubMed

    Luo, Yanan; Cai, Xiaoli; Li, He; Lin, Yuehe; Du, Dan

    2016-02-17

    Considering the urgent need to explore multifunctional drug delivery system for overcoming multidrug resistance, we prepared a new nanocarbon material Q-Graphene as a nanocarrier for killing drug-resistant lung cancer cells. Attributing to the introduction of hyaluronic acid and rhodamine B isothiocyanate (RBITC), the Q-Graphene-based drug delivery system was endowed with dual function of targeted drug delivery and fluorescence imaging. Additionally, doxorubicin (DOX) as a model drug was loaded on the surface of Q-Graphene via π-π stacking. Interestingly, the fluorescence of DOX was quenched by Q-Graphene due to its strong electron-accepting capability, and a significant recovery of fluorescence was observed, while DOX was released from Q-Graphene. Because of the RBITC labeling and the effect of fluorescence quenching/restoring of Q-Graphene, the uptake of nanoparticles and intracellular DOX release can be tracked. Overall, a highly promising multifunctional nanoplatform was developed for tracking and monitoring targeted drug delivery for efficiently killing drug-resistant cancer cells. PMID:26785717

  20. RAC1 inhibition as a therapeutic target for gefitinib-resistant non-small-cell lung cancer

    PubMed Central

    Kaneto, Naoki; Yokoyama, Satoru; Hayakawa, Yoshihiro; Kato, Shinichiro; Sakurai, Hiroaki; Saiki, Ikuo

    2014-01-01

    Although epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (EGFR-TKI), including gefitinib, provide a significant clinical benefit in non-small-cell lung cancer (NSCLC) patients, the acquisition of drug resistance has been known to limit the efficacy of EGFR-TKI therapy. In this study, we demonstrated the involvement of EGF-EGFR signaling in NSCLC cell migration and the requirement of RAC1 in EGFR-mediated progression of NSCLC. We showed the significant role of RAC1 pathway in the cell migration or lamellipodia formation by using gene silencing of RAC1 or induction of constitutive active RAC1 in EGFR-mutant NSCLC cells. Importantly, the RAC1 inhibition suppressed EGFR-mutant NSCLC cell migration and growth in vitro, and growth in vivo even in the gefitinib-resistant cells. In addition, these suppressions by RAC1 inhibition were mediated through MEK or PI3K independent mechanisms. Collectively, these results open up a new opportunity to control the cancer progression by targeting the RAC1 pathway to overcome the resistance to EGFR-TKI in NSCLC patients. PMID:24750242

  1. Interleukin-6 and lung inflammation: evidence for a causative role in inducing respiratory system resistance increments.

    PubMed

    Rubini, Alessandro

    2013-10-01

    Interleukin-6 is a multifunctional cytokine that has been shown to be increased in some pathological conditions involving the respiratory system such as those experimentally induced in animals or spontaneously occurring in humans. Experimental data demonstrating that interleukin-6 plays a significant role in commonly occurring respiratory system inflammatory diseases are reviewed here. Those diseases, i.e. asthma and chronic obstructive pulmonary disease, are characterised by mechanical derangements of the respiratory system, for the most part due to increased elastance and airway resistance. Recent findings showing that interleukin-6 has a causative role in determining an increase in airway resistance are reviewed. The end-inflation occlusion method was used to study the mechanical properties of the respiratory system before and after interleukin-6 administration. The cytokine was shown to induce significant, dose-dependent increments in both the resistive pressure dissipation due to frictional forces opposing the airflow in the airway (ohmic resistance) and the additional resistive pressure dissipation due to the visco-elastic properties of the system, i.e. stress relaxation (visco-elastic resistance). There were no alterations in respiratory system elastance. Even when administered to healthy mammals, interleukin-6 determines a significant effect on respiratory system resistance causing an increase in the mechanical work of breathing during inspiration. IL-6 hypothetically plays an active role in the pathogenesis of respiratory system diseases and the mechanisms that may be involved are discussed here.

  2. The absolute path command

    2012-05-11

    The ap command traveres all symlinks in a given file, directory, or executable name to identify the final absolute path. It can print just the final path, each intermediate link along with the symlink chan, and the permissions and ownership of each directory component in the final path. It has functionality similar to "which", except that it shows the final path instead of the first path. It is also similar to "pwd", but it canmore » provide the absolute path to a relative directory from the current working directory.« less

  3. The absolute path command

    SciTech Connect

    Moody, A.

    2012-05-11

    The ap command traveres all symlinks in a given file, directory, or executable name to identify the final absolute path. It can print just the final path, each intermediate link along with the symlink chan, and the permissions and ownership of each directory component in the final path. It has functionality similar to "which", except that it shows the final path instead of the first path. It is also similar to "pwd", but it can provide the absolute path to a relative directory from the current working directory.

  4. Increasing Capacity: Practice Effects in Absolute Identification

    ERIC Educational Resources Information Center

    Dodds, Pennie; Donkin, Christopher; Brown, Scott D.; Heathcote, Andrew

    2011-01-01

    In most of the long history of the study of absolute identification--since Miller's (1956) seminal article--a severe limit on performance has been observed, and this limit has resisted improvement even by extensive practice. In a startling result, Rouder, Morey, Cowan, and Pfaltz (2004) found substantially improved performance with practice in the…

  5. EGFR inhibition evokes innate drug resistance in lung cancer cells by preventing Akt activity and thus inactivating Ets-1 function.

    PubMed

    Phuchareon, Janyaporn; McCormick, Frank; Eisele, David W; Tetsu, Osamu

    2015-07-21

    Nonsmall cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. About 14% of NSCLCs harbor mutations in epidermal growth factor receptor (EGFR). Despite remarkable progress in treatment with tyrosine kinase inhibitors (TKIs), only 5% of patients achieve tumor reduction >90%. The limited primary responses are attributed partly to drug resistance inherent in the tumor cells before therapy begins. Recent reports showed that activation of receptor tyrosine kinases (RTKs) is an important determinant of this innate drug resistance. In contrast, we demonstrate that EGFR inhibition promotes innate drug resistance despite blockade of RTK activity in NSCLC cells. EGFR TKIs decrease both the mitogen-activated protein kinase (MAPK) and Akt protein kinase pathways for a short time, after which the Ras/MAPK pathway becomes reactivated. Akt inhibition selectively blocks the transcriptional activation of Ets-1, which inhibits its target gene, dual specificity phosphatase 6 (DUSP6), a negative regulator specific for ERK1/2. As a result, ERK1/2 is activated. Furthermore, elevated c-Src stimulates Ras GTP-loading and activates Raf and MEK kinases. These observations suggest that not only ERK1/2 but also Akt activity is essential to maintain Ets-1 in an active state. Therefore, despite high levels of ERK1/2, Ets-1 target genes including DUSP6 and cyclins D1, D3, and E2 remain suppressed by Akt inhibition. Reduction of DUSP6 in combination with elevated c-Src renews activation of the Ras/MAPK pathway, which enhances cell survival by accelerating Bim protein turnover. Thus, EGFR TKIs evoke innate drug resistance by preventing Akt activity and inactivating Ets-1 function in NSCLC cells.

  6. Molecular Characterization of a Voriconazole-Resistant, Posaconazole-Susceptible Aspergillus fumigatus Isolate in a Lung Transplant Recipient in the United States

    PubMed Central

    Vazquez, Jose A.

    2015-01-01

    Molecular characterization of cyp51A from the azole-resistant Aspergillus fumigatus isolate 50593 from a lung transplant patient showed Y121F/T289A changes coupled with a 46-bp tandem repeat (TR46) on the promoter, whereas cyp51A from the pretherapy isolate, A. fumigatus 47381, showed no changes. This is the first reported case of A. fumigatus azole resistance due to Y121F/T289A/TR46 in the United States, suggesting that multiple mutational alterations of cyp51A resulting in high-level azole resistance could occur during prolonged antifungal therapy. PMID:26574014

  7. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer

    PubMed Central

    Cross, Darren A. E.; Ashton, Susan E.; Ghiorghiu, Serban; Eberlein, Cath; Nebhan, Caroline A.; Spitzler, Paula J.; Orme, Jonathon P.; Finlay, M. Raymond V.; Ward, Richard A.; Mellor, Martine J.; Hughes, Gareth; Rahi, Amar; Jacobs, Vivien N.; Brewer, Monica Red; Ichihara, Eiki; Sun, Jing; Jin, Hailing; Ballard, Peter; Al-Kadhimi, Katherine; Rowlinson, Rachel; Klinowska, Teresa; Richmond, Graham H. P.; Cantarini, Mireille; Kim, Dong-Wan; Ranson, Malcolm R.; Pao, William

    2014-01-01

    First generation EGF receptor tyrosine kinase inhibitors (EGFR TKIs) provide significant clinical benefit in patients with advanced EGFR mutant (EGFRm+) non-small cell lung cancer (NSCLC). Patients ultimately develop disease progression, often driven by acquisition of a second T790M EGFR TKI resistance mutation. AZD9291 is a novel oral, potent and selective third generation irreversible inhibitor of both EGFRm+ sensitizing and T790M resistance mutants that spares wild-type EGFR. This monoanilino-pyrimidine compound is structurally distinct from other third generation EGFR TKIs and offers a pharmacologically differentiated profile from earlier generation EGFR TKIs. Pre-clinically, the drug potently inhibits signaling pathways and cellular growth in both EGFRm+ and EGFRm+/T790M mutant cell lines in vitro, with lower activity against wild-type EGFR lines, translating into profound and sustained tumor regression in EGFR mutant tumor xenograft and transgenic models. The treatment of two patients with advanced EGFRm T790M+ NSCLC is described as proof of principle. PMID:24893891

  8. Activation of the BMP-BMPR pathway conferred resistance to EGFR-TKIs in lung squamous cell carcinoma patients with EGFR mutations.

    PubMed

    Wang, Zhijie; Shen, Zhirong; Li, Zhenxiang; Duan, Jianchun; Fu, Shuai; Liu, Zhentao; Bai, Hua; Zhang, Zemin; Zhao, Jun; Wang, Xiaodong; Wang, Jie

    2015-08-11

    The empirical criteria for defining a clinical subtype of lung cancer are gradually transiting from histopathology to genetic variations in driver genes. Targeting these driver mutations, such as sensitizing epidermal growth factor receptor (EGFR) mutations, has dramatically improved the prognosis of advanced non-small cell lung cancer (NSCLC). However, the clinical benefit of molecularly targeted therapy on NSCLC appears to be different between lung adenocarcinomas and squamous cell carcinomas (SqCCs). We report here that the resistance of lung SqCC harboring EGFR mutations to EGFR tyrosine kinase inhibitors (EGFR-TKIs) was due to the activation of BMP-BMPR-Smad1/5-p70S6K. The combined treatment of these tumor cells with EGFR-TKI, together with inhibitors specific to BMPR or downstream mTOR, effectively reversed the resistance to EGFR-TKI. Moreover, blocking the whole PI3K-AKT-mTOR pathway with the PI3K/mTOR dual inhibitor BEZ235 also showed efficacy in treating this subtype of lung SqCC. This study details the empirical basis for a feasible clinical solution for squamous cell carcinomas with EGFR mutations.

  9. Activation of the BMP-BMPR pathway conferred resistance to EGFR-TKIs in lung squamous cell carcinoma patients with EGFR mutations

    PubMed Central

    Wang, Zhijie; Shen, Zhirong; Li, Zhenxiang; Duan, Jianchun; Fu, Shuai; Liu, Zhentao; Bai, Hua; Zhang, Zemin; Zhao, Jun; Wang, Xiaodong; Wang, Jie

    2015-01-01

    The empirical criteria for defining a clinical subtype of lung cancer are gradually transiting from histopathology to genetic variations in driver genes. Targeting these driver mutations, such as sensitizing epidermal growth factor receptor (EGFR) mutations, has dramatically improved the prognosis of advanced non–small cell lung cancer (NSCLC). However, the clinical benefit of molecularly targeted therapy on NSCLC appears to be different between lung adenocarcinomas and squamous cell carcinomas (SqCCs). We report here that the resistance of lung SqCC harboring EGFR mutations to EGFR tyrosine kinase inhibitors (EGFR-TKIs) was due to the activation of BMP-BMPR-Smad1/5-p70S6K. The combined treatment of these tumor cells with EGFR-TKI, together with inhibitors specific to BMPR or downstream mTOR, effectively reversed the resistance to EGFR-TKI. Moreover, blocking the whole PI3K-AKT-mTOR pathway with the PI3K/mTOR dual inhibitor BEZ235 also showed efficacy in treating this subtype of lung SqCC. This study details the empirical basis for a feasible clinical solution for squamous cell carcinomas with EGFR mutations. PMID:26216950

  10. Activation of the BMP-BMPR pathway conferred resistance to EGFR-TKIs in lung squamous cell carcinoma patients with EGFR mutations.

    PubMed

    Wang, Zhijie; Shen, Zhirong; Li, Zhenxiang; Duan, Jianchun; Fu, Shuai; Liu, Zhentao; Bai, Hua; Zhang, Zemin; Zhao, Jun; Wang, Xiaodong; Wang, Jie

    2015-08-11

    The empirical criteria for defining a clinical subtype of lung cancer are gradually transiting from histopathology to genetic variations in driver genes. Targeting these driver mutations, such as sensitizing epidermal growth factor receptor (EGFR) mutations, has dramatically improved the prognosis of advanced non-small cell lung cancer (NSCLC). However, the clinical benefit of molecularly targeted therapy on NSCLC appears to be different between lung adenocarcinomas and squamous cell carcinomas (SqCCs). We report here that the resistance of lung SqCC harboring EGFR mutations to EGFR tyrosine kinase inhibitors (EGFR-TKIs) was due to the activation of BMP-BMPR-Smad1/5-p70S6K. The combined treatment of these tumor cells with EGFR-TKI, together with inhibitors specific to BMPR or downstream mTOR, effectively reversed the resistance to EGFR-TKI. Moreover, blocking the whole PI3K-AKT-mTOR pathway with the PI3K/mTOR dual inhibitor BEZ235 also showed efficacy in treating this subtype of lung SqCC. This study details the empirical basis for a feasible clinical solution for squamous cell carcinomas with EGFR mutations. PMID:26216950

  11. Curcumin promotes apoptosis in A549/DDP multidrug-resistant human lung adenocarcinoma cells through an miRNA signaling pathway

    SciTech Connect

    Zhang, Jian; Zhang, Tao; Ti, Xinyu; Shi, Jieran; Wu, Changgui; Ren, Xinling; Yin, Hong

    2010-08-13

    Research highlights: {yields} Curcumin had anti-cancer effects on A549/DDP multidrug-resistant human lung adenocarcinoma cells {yields} Curcumin promotes apoptosis in A549/DDP cells through a miRNA signaling pathway {yields} Curcumin induces A549/DDP cell apoptosis by downregulating miR-186* {yields} miR-186* may serve as a potential gene therapy target for refractory lung cancer that is sensitive to curcumin -- Abstract: Curcumin extracted from the rhizomes of Curcuma longa L. has been shown to have inhibitory effects on cancers through its anti-proliferative and pro-apoptotic activities. Emerging evidence demonstrates that curcumin can overcome drug resistance to classical chemotherapies. Thus, the mechanisms underlying the anti-tumor activities of curcumin require further study. In our study, we first demonstrated that curcumin had anti-cancer effects on A549/DDP multidrug-resistant human lung adenocarcinoma cells. Further studies showed that curcumin altered miRNA expression; in particular, significantly downregulated the expression of miR-186* in A549/DDP. In addition, transfection of cells with a miR-186* inhibitor promoted A549/DDP apoptosis, and overexpression of miR-186* significantly inhibited curcumin-induced apoptosis in A549/DDP cells. These observations suggest that miR-186* may serve as a potential gene therapy target for refractory lung cancer that is sensitive to curcumin.

  12. Identification of Up- and Down-Regulated Proteins in Pemetrexed-Resistant Human Lung Adenocarcinoma: Flavin Reductase and Calreticulin Play Key Roles in the Development of Pemetrexed-Associated Resistance.

    PubMed

    Chou, Hsiu-Chuan; Chen, Jing-Yi; Lin, Dai-Ying; Wen, Yueh-Feng; Lin, Chi-Chen; Lin, Sheng-Hao; Lin, Ching-Hsiung; Chung, Ting-Wen; Liao, En-Chi; Chen, Ying-Jen; Wei, Yu-Shan; Tsai, Yi-Ting; Chan, Hong-Lin

    2015-11-01

    Drug resistance is one of the major causes of cancer chemotherapy failure. In the current study, we used a pair of lung adenocarcinoma cell lines, A549 and the pemetrexed-resistant A549/PEM cells, as a model to monitor resistance-dependent cellular responses and identify potential therapeutic targets. By means of 2D differential gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS), we investigated the global protein expression alterations induced by pemetrexed treatment and resistance. The proteomic result revealed that pemetrexed exposure obviously altered the expression of 81 proteins in the A549 cells, whereas no significant response was observed in the similarly treated A549/PEM cells, hence implying an association between these proteins and the drug-specific response. Moreover, 72 proteins including flavin reductase and calreticulin demonstrated differential expression between the A549 and A549/PEM cells, indicating baseline resistance. Additional tests employed siRNA silencing, protein overexpression, cell viability analysis, and analysis of apoptosis to examine and confirm the potency of flavin reductase and calreticulin proteins in the development of pemetrexed resistance. In summary, by using a proteomic approach, we identified numerous proteins, including flavin reductase and calreticulin, involved in pemetrexed drug resistance-developing mechanisms. Our results provide useful diagnostic markers and therapeutic candidates for pemetrexed-resistant lung cancer treatment.

  13. Biotin-targeted Pluronic(®) P123/F127 mixed micelles delivering niclosamide: A repositioning strategy to treat drug-resistant lung cancer cells.

    PubMed

    Russo, Annapina; Pellosi, Diogo Silva; Pagliara, Valentina; Milone, Maria Rita; Pucci, Biagio; Caetano, Wilker; Hioka, Noboru; Budillon, Alfredo; Ungaro, Francesca; Russo, Giulia; Quaglia, Fabiana

    2016-09-10

    With the aim to develop alternative therapeutic tools for the treatment of resistant cancers, here we propose targeted Pluronic(®) P123/F127 mixed micelles (PMM) delivering niclosamide (NCL) as a repositioning strategy to treat multidrug resistant non-small lung cancer cell lines. To build multifunctional PMM for targeting and imaging, Pluronic(®) F127 was conjugated with biotin, while Pluronic(®) P123 was fluorescently tagged with rhodamine B, in both cases at one of the two hydroxyl end groups. This design intended to avoid any interference of rhodamine B on biotin exposition on PMM surface, which is a key fundamental for cell trafficking studies. Biotin-decorated PMM were internalized more efficiently than non-targeted PMM in A549 lung cancer cells, while very low internalization was found in NHI3T3 normal fibroblasts. Biotin-decorated PMM entrapped NCL with good efficiency, displayed sustained drug release in protein-rich media and improved cytotoxicity in A549 cells as compared to free NCL (P<0.01). To go in depth into the actual therapeutic potential of NCL-loaded PMM, a cisplatin-resistant A549 lung cancer cell line (CPr-A549) was developed and its multidrug resistance tested against common chemotherapeutics. Free NCL was able to overcome chemoresistance showing cytotoxic effects in this cell line ascribable to nucleolar stress, which was associated to a significant increase of the ribosomal protein rpL3 and consequent up-regulation of p21. It is noteworthy that biotin-decorated PMM carrying NCL at low doses demonstrated a significantly higher cytotoxicity than free NCL in CPr-A549. These results point at NCL-based regimen with targeted PMM as a possible second-line chemotherapy for lung cancer showing cisplatin or multidrug resistance.

  14. Biotin-targeted Pluronic(®) P123/F127 mixed micelles delivering niclosamide: A repositioning strategy to treat drug-resistant lung cancer cells.

    PubMed

    Russo, Annapina; Pellosi, Diogo Silva; Pagliara, Valentina; Milone, Maria Rita; Pucci, Biagio; Caetano, Wilker; Hioka, Noboru; Budillon, Alfredo; Ungaro, Francesca; Russo, Giulia; Quaglia, Fabiana

    2016-09-10

    With the aim to develop alternative therapeutic tools for the treatment of resistant cancers, here we propose targeted Pluronic(®) P123/F127 mixed micelles (PMM) delivering niclosamide (NCL) as a repositioning strategy to treat multidrug resistant non-small lung cancer cell lines. To build multifunctional PMM for targeting and imaging, Pluronic(®) F127 was conjugated with biotin, while Pluronic(®) P123 was fluorescently tagged with rhodamine B, in both cases at one of the two hydroxyl end groups. This design intended to avoid any interference of rhodamine B on biotin exposition on PMM surface, which is a key fundamental for cell trafficking studies. Biotin-decorated PMM were internalized more efficiently than non-targeted PMM in A549 lung cancer cells, while very low internalization was found in NHI3T3 normal fibroblasts. Biotin-decorated PMM entrapped NCL with good efficiency, displayed sustained drug release in protein-rich media and improved cytotoxicity in A549 cells as compared to free NCL (P<0.01). To go in depth into the actual therapeutic potential of NCL-loaded PMM, a cisplatin-resistant A549 lung cancer cell line (CPr-A549) was developed and its multidrug resistance tested against common chemotherapeutics. Free NCL was able to overcome chemoresistance showing cytotoxic effects in this cell line ascribable to nucleolar stress, which was associated to a significant increase of the ribosomal protein rpL3 and consequent up-regulation of p21. It is noteworthy that biotin-decorated PMM carrying NCL at low doses demonstrated a significantly higher cytotoxicity than free NCL in CPr-A549. These results point at NCL-based regimen with targeted PMM as a possible second-line chemotherapy for lung cancer showing cisplatin or multidrug resistance. PMID:27374195

  15. Curcumin reverses cis-platin resistance and promotes human lung adenocarcinoma A549/DDP cell apoptosis through HIF-1α and caspase-3 mechanisms.

    PubMed

    Ye, Ming-Xiang; Zhao, Yi-Lin; Li, Yan; Miao, Qing; Li, Zhi-Kui; Ren, Xin-Ling; Song, Li-Qiang; Yin, Hong; Zhang, Jian

    2012-06-15

    Curcumin, a yellow pigment derived from Curcuma longa Linn, has been favored by the Eastern as dietary ingredients for centuries. During the past decade, extensive investigations have revealed curcumin sensitized various chemotherapeutic agents in human breast, colon, pancreas, gastric, liver, brain and hematological malignant disorders in vivo and in vitro. Several pathways and specific targets including NF-κB, STAT3, COX-2, Akt and multidrug resistant protein have been identified to facilitate curcumin as a chemosensitizer. Recent studies suggest HIF-1α participated in the development of drug resistance in cancer cells and targeting HIF-1α either by RNAi or siRNA successfully overcame chemotherapeutic resistance. To investigate the mechanism basis of curcumin as a chemosensitizer in lung cancer, we examined curcumin's effects on HIF-1α in cis-platin (DDP) sensitive A549 and resistant A549/DDP cell lines by RT-PCR and Western blot. HIF-1α in A549/DDP cells was found to be overexpressed at both mRNA and protein levels together with a poor response to DDP. Results from transient transfection and flow cytometry showed the HIF-1α abnormality contributed to DDP resistance in A549/DDP lung cancer cells. Combined curcumin and DDP treatment markedly inhibited A549/DDP cells proliferation, reversed DDP resistance and triggered apoptotic death by promoting HIF-1α degradation and activating caspase-3, respectively. Expression of HIF-1α-dependent P-gp also seemed to decrease as response to curcumin in a dose-dependent manner. Our findings shed light on drug resistant reversing effect of curcumin in lung cancer cells by inhibiting HIF-1α expression and activating caspase-3. PMID:22483553

  16. Targeting Tyrosine Kinase Inhibitor-Resistant Non-Small Cell Lung Cancer by Inducing Epidermal Growth Factor Receptor Degradation via Methionine 790 Oxidation

    PubMed Central

    Leung, Elaine Lai-Han; Fan, Xing-Xing; Wong, Maria Pik; Jiang, Zhi-Hong; Liu, Zhong-Qiu; Yao, Xiao-Jun; Lu, Lin-Lin; Zhou, Yan-Ling; Yau, Li-Fong; Tin, Vicky Pui-Chi

    2016-01-01

    Abstract Aims: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been developed to treat non-small cell lung cancer (NSCLC) patients with EGFR mutation, but TKI resistance is common. Almost half of the acquired resistance patients are due to additional T790M mutation on EGFR (EGFRT790M), thus overcoming TKI resistance is important. In this study, we aim to investigate the role of reactive oxygen species (ROS) in TKI resistance as well as the molecular and biological effects of EGFRT790M after redox manipulation. Results: The basal ROS levels in EGFRT790M-containing TKI-resistant NSCLC cell lines were substantially high. Sixty-three human lung tumors showed higher NADPH oxidase isoform 2 (NOX2) expression than normal lung tissues, which may contribute to high basal ROS in cancer and poor survival. Interestingly, only NOX3 was upregulated by sanguinarine, a pharmacological agent to elevate ROS, and resulted in EGFR overoxidation, degradation, and apoptosis. By contrast, such responses were lacking in EGFRWT cells. Selective EGFRT790M degradation was manipulated by redox imbalance between NOX3 and methionine reductase A (MsrA). Furthermore, the in vivo tumor suppression effect of sanguinarine, NOX3 upregulation, and EGFR degradation were confirmed. Innovation: We have found a new treatment strategy to overcome TKI resistance by selectively inducing EGFRT790M degradation via specific stimulation of methionine 790 (M790) oxidation. It can be achieved via manipulating redox imbalance between NOX3 and MsrA. Conclusion: Targeting EGFR by elevating ROS and redox imbalance is a potential new strategy to develop a new EGFR inhibitor for TKI-resistant patients with a wide therapeutic window between EGFRT790M and EGFRWT. Antioxid. Redox Signal. 24, 263–279. PMID:26528827

  17. Global Oct4 target gene analysis reveals novel downstream PTEN and TNC genes required for drug-resistance and metastasis in lung cancer.

    PubMed

    Tang, Yen-An; Chen, Chi-Hsin; Sun, H Sunny; Cheng, Chun-Pei; Tseng, Vincent S; Hsu, Han-Shui; Su, Wu-Chou; Lai, Wu-Wei; Wang, Yi-Ching

    2015-02-18

    Overexpression of Oct4, a stemness gene encoding a transcription factor, has been reported in several cancers. However, the mechanism by which Oct4 directs transcriptional program that leads to somatic cancer progression remains unclear. In this study, we provide mechanistic insight into Oct4-driven transcriptional network promoting drug-resistance and metastasis in lung cancer cell, animal and clinical studies. Through an integrative approach combining our Oct4 chromatin-immunoprecipitation sequencing and ENCODE datasets, we identified the genome-wide binding regions of Oct4 in lung cancer at promoter and enhancer of numerous genes involved in critical pathways which promote tumorigenesis. Notably, PTEN and TNC were previously undefined targets of Oct4. In addition, novel Oct4-binding motifs were found to overlap with DNA elements for Sp1 transcription factor. We provided evidence that Oct4 suppressed PTEN in an Sp1-dependent manner by recruitment of HDAC1/2, leading to activation of AKT signaling and drug-resistance. In contrast, Oct4 transactivated TNC independent of Sp1 and resulted in cancer metastasis. Clinically, lung cancer patients with Oct4 high, PTEN low and TNC high expression profile significantly correlated with poor disease-free survival. Our study reveals a critical Oct4-driven transcriptional program that promotes lung cancer progression, illustrating the therapeutic potential of targeting Oc4 transcriptionally regulated genes.

  18. Met gene amplification and protein hyperactivation is a mechanism of resistance to both first and third generation EGFR inhibitors in lung cancer treatment.

    PubMed

    Shi, Puyu; Oh, You-Take; Zhang, Guojing; Yao, Weilong; Yue, Ping; Li, Yikun; Kanteti, Rajani; Riehm, Jacob; Salgia, Ravi; Owonikoko, Taofeek K; Ramalingam, Suresh S; Chen, Mingwei; Sun, Shi-Yong

    2016-10-01

    The 3rd generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs; e.g., AZD9291), which selectively and irreversibly inhibit EGFR activating and T790M mutants, represent very promising therapeutic options for patients with non-small cell lung cancer (NSCLC) that has become resistant to 1st generation EGFR-TKIs due to T790M mutation. However, eventual resistance to the 3rd generation EGFR-TKIs has already been described in the clinic, resulting in disease progression. Therefore, there is a great challenge and urgent need to understand how this resistance occurs and to develop effective strategies to delay or overcome the resistance. The current study has demonstrated that Met amplification and hyperactivation is a resistance mechanism to both 1st and 3rd generation EGFR-TKIs since both erlotinib- and AZD9291-resistant HCC827 cell lines possessed amplified Met gene and hyperactivated Met, and were cross-resistant to AZD9291 or erlotinib. Met inhibition overcame the resistance of these cell lines to AZD9291 both in vitro and in vivo, including enhancement of apoptosis or G1 cell cycle arrest. Hence, we suggest that Met inhibition is also an effective strategy to overcome resistance of certain EGFR-mutated NSCLCs with Met amplification to AZD9291, warranting the further clinical validation of our findings. PMID:27450722

  19. [Advances in the Research of Autophagy in EGFR-TKI Treatment and Resistance 
in Lung Cancer].

    PubMed

    Zhang, Qicheng; Xu, Ke

    2016-09-20

    Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is a group of targeted-drugs which effectively inhibits the growth of tumor cells with sensitive mutations in EGFR. However, the innate and acquired resistance are major obstacles of the efficiency. Autophagy is a highly conserved self-digesting process in cells, which is considered to be associated with cancer development andchemoresistance. The activation of EGFR may regulate autophagy through multiple signal pathways. EGFR-TKIs can induce autophagy, however, the function of the inducted autophagy remains biphasic. On one hand, autophagy induced by EGFR-TKI acts as a cytoprotective response in cancer cells, and autophagy inhibitors can enhance the cytotoxic effects of EGFR-TKI. On the other hand, a high level of autophagy after treatment of EGFR-TKI can also result in autophagic cell death lacking features of apoptosis, and the combination of EGFR-TKI with autophagy inducer might be beneficial. Thus, autophagy regulation represents a promising approach for improving the efficiency of EGFR-TKI in the treatment of cancer patients. Here we summarized the signaling pathways involved in EGFR-TKI induced autophagy, and reviewed the roles of autophagy in the treatment and chemoresistance of EGFR-TKI treatment in lung cancer. PMID:27666552

  20. Cancer stem cells and cisplatin-resistant cells isolated from non-small-lung cancer cell lines constitute related cell populations

    PubMed Central

    Lopez-Ayllon, Blanca D; Moncho-Amor, Veronica; Abarrategi, Ander; de Cáceres, Inmaculada Ibañez; Castro-Carpeño, Javier; Belda-Iniesta, Cristobal; Perona, Rosario; Sastre, Leandro

    2014-01-01

    Lung cancer is the top cause of cancer-related deceases. One of the reasons is the development of resistance to the chemotherapy treatment. In particular, cancer stem cells (CSCs), can escape treatment and regenerate the bulk of the tumor. In this article, we describe a comparison between cancer cells resistant to cisplatin and CSCs, both derived from the non-small-cell lung cancer cell lines H460 and A549. Cisplatin-resistant cells were obtained after a single treatment with the drug. CSCs were isolated by culture in defined media, under nonadherent conditions. The isolated CSCs were clonogenic, could be differentiated into adherent cells and were less sensitive to cisplatin than the original cells. Cisplatin resistant and CSCs were able to generate primary tumors and to metastasize when injected into immunodeficient Nu/Nu mice, although they formed smaller tumors with a larger latency than untreated cells. Notably, under appropriated proportions, CSCs synergized with differentiated cells to form larger tumors. CSCs also showed increased capacity to induce angiogenesis in Nu/Nu mice. Conversely, H460 cisplatin-resistant cells showed increased tendency to develop bone metastasis. Gene expression analysis showed that several genes involved in tumor development and metastasis (EGR1, COX2, MALAT1, AKAP12, ADM) were similarly induced in CSC and cisplatin-resistant H460 cells, in agreement with a close similarity between these two cell populations. Cells with the characteristic growth properties of CSCs were also isolated from surgical samples of 18 out of 44 lung cancer patients. A significant correlation (P = 0.028) was found between the absence of CSCs and cisplatin sensitivity. PMID:24961511

  1. ABSOLUTE POLARIMETRY AT RHIC.

    SciTech Connect

    OKADA; BRAVAR, A.; BUNCE, G.; GILL, R.; HUANG, H.; MAKDISI, Y.; NASS, A.; WOOD, J.; ZELENSKI, Z.; ET AL.

    2007-09-10

    Precise and absolute beam polarization measurements are critical for the RHIC spin physics program. Because all experimental spin-dependent results are normalized by beam polarization, the normalization uncertainty contributes directly to final physics uncertainties. We aimed to perform the beam polarization measurement to an accuracy Of {Delta}P{sub beam}/P{sub beam} < 5%. The absolute polarimeter consists of Polarized Atomic Hydrogen Gas Jet Target and left-right pairs of silicon strip detectors and was installed in the RHIC-ring in 2004. This system features proton-proton elastic scattering in the Coulomb nuclear interference (CNI) region. Precise measurements of the analyzing power A{sub N} of this process has allowed us to achieve {Delta}P{sub beam}/P{sub beam} = 4.2% in 2005 for the first long spin-physics run. In this report, we describe the entire set up and performance of the system. The procedure of beam polarization measurement and analysis results from 2004-2005 are described. Physics topics of AN in the CNI region (four-momentum transfer squared 0.001 < -t < 0.032 (GeV/c){sup 2}) are also discussed. We point out the current issues and expected optimum accuracy in 2006 and the future.

  2. Down-regulation of SerpinB2 is associated with gefitinib resistance in non-small cell lung cancer and enhances invadopodia-like structure protrusions

    PubMed Central

    Bae, Song Yi; Park, Hyen Joo; Hong, Ji-Young; Lee, Hye-Jung; Lee, Sang Kook

    2016-01-01

    The failure of targeted therapy due to the resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, is considered a major problem in the treatment of non-small cell lung cancer (NSCLC) patients. SerpinB2, a component of the urokinase plasminogen activator (uPA) system, has been recognized as a biomarker for the progression and metastasis of lung cancer. Nevertheless, the relationship between SerpinB2 and EGFR-TKI resistance has not been elucidated. Here, we report that SerpinB2 is down-regulated in gefitinib-resistant (H292-Gef) cells compared to gefitinib-sensitive (H292) cells. The low SerpinB2 levels in H292-Gef cells were also associated with an enhancement in invasiveness and increase in the length of invadopodia-like structures in the cells. The effect on invasiveness and gefitinib sensitivity was confirmed by knockdown and overexpression of SerpinB2. In addition, the possibility to overcome the resistance through the up-regulation of SerpinB2 was supported by employing an antitumor agent yuanhuadine (YD). Treatment with YD effectively elevated SerpinB2 levels and suppressed invasive properties in H292-Gef cells. Collectively, these findings demonstrate the prospective role of SerpinB2 as a novel biomarker for acquired gefitinib resistance and a potential target for NSCLC treatment. PMID:27558531

  3. Homoharringtonine induces apoptosis and inhibits STAT3 via IL-6/JAK1/STAT3 signal pathway in Gefitinib-resistant lung cancer cells

    PubMed Central

    Cao, Wei; Liu, Ying; Zhang, Ran; Zhang, Bo; Wang, Teng; Zhu, Xianbing; Mei, Lin; Chen, Hongbo; Zhang, Hongling; Ming, Pinghong; Huang, Laiqiang

    2015-01-01

    Tyrosine kinase inhibitors (TKIs) are mostly used in non-small cell lung cancer (NSCLC) treatment. Unfortunately, treatment with Gefitinib for a period of time will result in drug resistance and cause treatment failure in clinic. Therefore, exploring novel compounds to overcome this resistance is urgently required. Here we investigated the antitumor effect of homoharringtonine (HHT), a natural compound extracted from Cephalotaxus harringtonia, on Gefitinib-resistant NSCLC cell lines in vitro and in vivo. NCI-H1975 cells with EGFR T790M mutation are more sensitive to HHT treatment compared with that of A549 cells with wild type EGFR. HHT inhibited cells growth, cell viability and colony formation, as well as induced cell apoptosis through mitochondria pathway. Furthermore, we explored the mechanism of HHT inhibition on NSCLC cells. Higher level of interleukin-6 (IL-6) existed in lung cancer patients and mutant EGFR and TGFβ signal requires the upregulation of IL-6 through the gp130/JAK pathway to overactive STAT3, an oncogenic protein which has been considered as a potential target for cancer therapy. HHT reversiblely inhibited IL-6-induced STAT3 Tyrosine 705 phosphorylation and reduced anti-apoptotic proteins expression. Gefitinib-resistant NSCLC xenograft tests also confirmed the antitumor effect of HHT in vivo. Consequently, HHT has the potential in Gefitinib-resistant NSCLC treatment. PMID:26166037

  4. Utilization of arsenic trioxide as a treatment of cisplatin-resistant non-small cell lung cancer PC-9/CDDP and PC-14/CDDP cells

    PubMed Central

    SUZUKI, TOSHIHIRO; ISHIBASHI, KENICHI; YUMOTO, ATSUSHI; NISHIO, KAZUTO; OGASAWARA, YUKI

    2015-01-01

    Cisplatin is a commonly used drug in combination chemotherapy. However, various malignant tumors frequently acquire resistance to cisplatin. Arsenic trioxide (ATO) has been approved as a chemotherapeutic drug for the treatment of acute promyelocytic leukemia, and the combination of ATO and cisplatin has been revealed to demonstrate synergistic effects in ovarian and small cell lung cancer cells. Thus, it was hypothesized that ATO may also be active against cisplatin-resistant non-small cell lung cancer (NSCLC) PC-9/CDDP and PC-14/CDDP cells. The present study also evaluated the effects of ATO on the cisplatin-sensitive NSCLC PC-9 and PC-14 cell lines. Notably, ATO demonstrated a markedly decreased IC50 in the cisplatin-resistant PC-9/CDDP and PC-14/CDDP cells compared with the IC50 in the cisplatin-sensitive parental PC-9 and PC-14 cells. Additionally, it was found that arsenite accumulation in the PC-9 cell line was affected through the downregulation of GS-X pump systems. Although it is likely that cisplatin resistance in PC-9 cells does not depend on the GS-X pump systems, ATO was effective against cisplatin-resistant NSCLC PC-9/CDDP and PC-14/CDDP cells in combination chemotherapy. PMID:26622574

  5. Genome-wide profiling of long non-coding RNA expression patterns in the EGFR-TKI resistance of lung adenocarcinoma by microarray.

    PubMed

    Wu, Ying; Yu, Dan-Dan; Hu, Yong; Yan, Dali; Chen, Xiu; Cao, Hai-Xia; Yu, Shao-Rong; Wang, Zhuo; Feng, Ji-Feng

    2016-06-01

    Mutations in the epidermal growth factor receptor (EGFR) make lung adenocarcinoma cells sensitive to EGFR tyrosine kinase inhibitors (TKIs). Long-term cancer therapy may cause the occurrence of acquired resistance to EGFR TKIs. Long non-coding RNAs (lncRNAs) play important roles in tumor formation, tumor metastasis and the development of EGFR-TKI resistance in lung cancer. To gain insight into the molecular mechanisms of EGFR-TKI resistance, we generated an EGFR-TKI-resistant HCC827-8-1 cell line and analyzed expression patterns by lncRNA microarray and compared it with its parental HCC827 cell line. A total of 1,476 lncRNA transcripts and 1,026 mRNA transcripts were dysregulated in the HCC827‑8-1 cells. The expression levels of 7 chosen lncRNAs were validated by real-time quantitative PCR. As indicated by functional analysis, several groups of lncRNAs may be involved in the bio-pathways associated with EGFR-TKI resistance through their cis- and/or trans‑regulation of protein-coding genes. Thus, lncRNAs may be used as novel candidate biomarkers and potential targets in EGFR-TKI therapy in the future.

  6. p38 MAPK-induced MDM2 degradation confers paclitaxel resistance through p53-mediated regulation of EGFR in human lung cancer cells

    PubMed Central

    Park, Shin-Hyung; Seong, Myeong-A; Lee, Ho-Young

    2016-01-01

    Paclitaxel (PTX) is a chemotherapeutic agent that is used to treat a variety of cancers, including non-small cell lung cancer (NSCLC). However, the emergence of drug resistance limits the utility of PTX. This study determined the signaling pathway that contributes to PTX resistance. We first established PTX resistant cell lines (H460/R and 226B/R) using a dose-escalating maintenance of PTX. We found that p38 MAPK and epidermal growth factor receptor (EGFR) were constitutively activated in these cell lines. The inhibition of p38 MAPK activity by SB203580 treatment or the transfection of dominant-negative p38 MAPK sensitized both cell lines to PTX treatment. Erlotinib, an EGFR inhibitor, also increased PTX-induced apoptosis in PTX resistant cells, which suggests a role for p38 MAPK and EGFR in the development of PTX resistance. We demonstrated that p38 MAPK enhanced EGFR expression via the induction of the rapid degradation of mouse double-minute 2 homolog (MDM2) and the consequent stabilization of p53, a transcription factor of EGFR. These results suggest for the first time that the p38 MAPK/p53/EGFR axis is crucial for the facilitation of PTX resistance in NSCLCs. We also propose a mechanism for the role of the tumor-suppressor p53 in drug resistance. These results provide a foundation for the future development of potential therapeutic strategies to regulate the p38 MAPK/p53/EGFR pathway for the treatment of lung cancer patients with PTX resistance. PMID:26799187

  7. Matrine induces mitochondrial apoptosis in cisplatin-resistant non-small cell lung cancer cells via suppression of β-catenin/survivin signaling.

    PubMed

    Wang, Huan-Qin; Jin, Jian-Jun; Wang, Jing

    2015-05-01

    Matrine is an alkaloid isolated from Sophora flavescens and shows anticancer activities. The present study was carried out to determine the cytotoxic effects of matrine on cisplatin-resistant non-small cell lung cancer (NSCLC) cells and the associated molecular mechanisms. Parental and cisplatin-resistant A549 and H460 NSCLC cells were treated with 1 or 2 g/l of matrine for 48 h, and cell viability and apoptosis were assessed. β-catenin-mediated transcriptional activity, mitochondrial membrane potential (ΔΨm) changes, activation of caspases, and survivin expression were examined. The effect of overexpression of survivin on the anticancer activity of matrine was investigated. Compared to the parental cells, cisplatin-resistant NSCLC cells showed increased β-catenin transcriptional activity. Matrine treatment resulted in a significant reduction in β-catenin activation and survivin expression in the cisplatin-resistant cells. Matrine caused apoptotic death in the cisplatin-resistant NSCLC cells, coupled with loss of ΔΨm and activation of caspase-9 and -3. Matrine-induced apoptosis of the cisplatin-resistant NSCLC cells was significantly reversed by overexpression of survivin. In conclusion, matrine exposure induces mitochondrial apoptosis in cisplatin-resistant NSCLC cells, which is largely mediated through inactivation of β-catenin/survivin signaling. Further investigation of the therapeutic benefit of matrine in overcoming cisplatin resistance in NSCLC is warranted.

  8. Non-Invasive Methods to Monitor Mechanisms of Resistance to Tyrosine Kinase Inhibitors in Non-Small-Cell Lung Cancer: Where Do We Stand?

    PubMed Central

    Ulivi, Paola

    2016-01-01

    The induction of resistance mechanisms represents an important problem for the targeted therapy of patients with non-small-cell lung cancer (NSCLC). The best-known resistance mechanism induced during treatment with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is EGFR T790M mutation for which specific drugs are have been developed. However, other molecular alterations have also been reported as induced resistance mechanisms to EGFR-TKIs. Similarly, there is growing evidence of acquired resistance mechanisms to anaplastic lymphoma kinase (ALK)-TKI treatment. A better understanding of these acquired resistance mechanisms is essential in clinical practice as patients could be treated with specific drugs that are active against the induced alterations. The use of free circulating tumor nucleic acids or circulating tumor cells (CTCs) enables resistance mechanisms to be characterized in a non-invasive manner and reduces the need for tumor re-biopsy. This review discusses the main resistance mechanisms to TKIs and provides a comprehensive overview of innovative strategies to evaluate known resistance mechanisms in free circulating nucleic acids or CTCs and potential future orientations for these non-invasive approaches. PMID:27455248

  9. Sodium/iodide symporter gene transfection increases radionuclide uptake in human cisplatin-resistant lung cancer cells.

    PubMed

    Chai, W; Yin, X; Ren, L; Cai, M; Long, T; Zhou, M; Tang, Y; Yang, N; Hu, S

    2015-10-01

    The sodium/iodide symporter (NIS) is involved in iodide uptake and has been used for the diagnosis and treatment of thyroid cancer. Transfection of the NIS gene in A549 human lung cancer cells can induce radioactive iodine ((131)I) and radioactive technetium ((99m)Tc) uptake. The aim of the present study was to assess the role of NIS in (99m)Tc and (131)I uptake by the A549/DDP human cisplatin-resistant lung cancer cell line. To do so, recombinant adenovirus, adenovirus-enhanced green fluorescent protein-human NIS (Ad-eGFP-hNIS) and Ad-eGFP-rat NIS (Ad-eGFP-rNIS) vectors were established. These vectors were transfected into A549/DDP cells and xenograft tumors in nude mice. Assessment of (99m)Tc and (131)I uptake was performed. Results showed that the transfection efficiency of Ad-eGFP-hNIS and Ad-eGFP-rNIS in A549/DDP cells was at least 90 % in all experiments, and that the uptake ability of (99m)Tc and (131)I was highly enhanced (14-18 folds for (99m)Tc, and 12-16 folds for (131)I). However, the radionuclide concentration in transfected NIS genes' A549/DDP cells reached a plateau within 30-60 min, indicating that NIS transport led rapidly to (99m)Tc and (131)I saturation in cells. In xenograft tumor models, uptake of (99m)TcO4 (-) was obviously higher in the hNIS and rNIS groups compared with controls. In conclusion, these results support the hypothesis that A549/DDP cells can effectively uptake (99m)Tc and (131)I when transfected with the hNIS and rNIS gene. The rNIS or hNIS gene could be used as an effective method for the effective delivery of radioactive products to specific tissues for imagery and/or treatment.

  10. Absolute Equilibrium Entropy

    NASA Technical Reports Server (NTRS)

    Shebalin, John V.

    1997-01-01

    The entropy associated with absolute equilibrium ensemble theories of ideal, homogeneous, fluid and magneto-fluid turbulence is discussed and the three-dimensional fluid case is examined in detail. A sigma-function is defined, whose minimum value with respect to global parameters is the entropy. A comparison is made between the use of global functions sigma and phase functions H (associated with the development of various H-theorems of ideal turbulence). It is shown that the two approaches are complimentary though conceptually different: H-theorems show that an isolated system tends to equilibrium while sigma-functions allow the demonstration that entropy never decreases when two previously isolated systems are combined. This provides a more complete picture of entropy in the statistical mechanics of ideal fluids.

  11. Noninvasive detection of response and resistance in EGFR-mutant lung cancer using quantitative next-generation genotyping of cell-free plasma DNA

    PubMed Central

    Kuang, Yanan; Mach, Stacy L.; O'Connell, Allison; Messineo, Melissa M.; Luke, Jason J.; Butaney, Mohit; Kirschmeier, Paul; Jackman, David M.; Jänne, Pasi A.

    2014-01-01

    Purpose Tumor genotyping using cell free plasma DNA (cfDNA) has the potential to allow noninvasive assessment of tumor biology, yet many existing assays are cumbersome and vulnerable to false positive results. We sought to determine whether droplet digital PCR (ddPCR) of cfDNA would allow highly specific and quantitative assessment of tumor genotype. Experimental Design ddPCR assays for EGFR, KRAS, and BRAF mutations were developed using plasma collected from patients with advanced lung cancer or melanoma of a known tumor genotype. Sensitivity and specificity were determined using cancers with non-overlapping genotypes as positive and negative controls. Serial assessment of response and resistance was studied in EGFR-mutant lung cancer patients on a prospective trial of erlotinib. Results We identified a reference range for EGFR L858R and exon 19 deletions in specimens from KRAS-mutant lung cancer, allowing identification of candidate thresholds with high sensitivity and 100% specificity. Received operative characteristic (ROC) curve analysis of 4 assays demonstrated an area under the curve in the range of 0.80-0.94. Sensitivity improved in specimens with optimal cfDNA concentrations. Serial plasma genotyping of EGFR-mutant lung cancer on erlotinib demonstrated pretreatment detection of EGFR mutations, complete plasma response in most cases, and increasing levels of EGFR T790M emerging prior to objective progression. Conclusions Noninvasive genotyping of cfDNA using ddPCR demonstrates assay qualities that could allow effective translation into a clinical diagnostic. Serial quantification of plasma genotype allows noninvasive assessment of response and resistance, including detection of resistance mutations up to 16 weeks prior to radiographic progression. PMID:24429876

  12. The Role of PIK3CA Mutations among Lung Adenocarcinoma Patients with Primary and Acquired Resistance to EGFR Tyrosine Kinase Inhibition

    PubMed Central

    Wu, Shang-Gin; Chang, Yih-Leong; Yu, Chong-Jen; Yang, Pan-Chyr; Shih, Jin-Yuan

    2016-01-01

    To understand the impact of PIK3CA mutations on clinical characteristics and treatment response to epidermal growth factor tyrosine kinase inhibitors (EGFR TKIs) of lung adenocarcinoma, we examined PIK3CA and EGFR mutations in lung adenocarcinoma patients, and analyzed their clinical outcomes. Surgically excised tumor, bronchoscopy biopsy/brushing specimens and pleural effusions were prospectively collected from 1029 patients. PIK3CA and EGFR mutations were analyzed by RT-PCR and direct sequencing. In EGFR TKI-nave specimens, PIK3CA mutation rate was 1.8% (14/760). Twelve patients had coexisting PIK3CA and EGFR mutations. Among the 344 EGFR TKI-treated EGFR mutant patients, there was no significant difference in treatment response (p = 0.476) and progression-free survival (p = 0.401) of EGFR TKI between PIK3CA mutation-positive and negative patients. The PIK3CA mutation rate in lung adenocarcinoma with acquired resistance to EGFR TKI is not higher than that in EGFR TKI-naïve tissue specimens (2.9% (6/207) vs. 1.8%; p = 0.344). Of the 74 patients with paired specimens (TKI-naïve and acquired resistance to TKIs) only one patient (1.4%) developed acquired PIK3CA (E545K) mutation, and he also had acquired EGFR (T790M) mutation. In conclusion, PIK3CA mutation may not be associated with primary resistance to EGFR TKI among lung adenocarcinoma patients. Acquired PIK3CA mutation related to EGFR TKI treatment is rare. PMID:27734950

  13. Elucidation of Resistance Mechanisms to Second-Generation ALK Inhibitors Alectinib and Ceritinib in Non-Small Cell Lung Cancer Cells.

    PubMed

    Dong, Xuyuan; Fernandez-Salas, Ester; Li, Enxiao; Wang, Shaomeng

    2016-03-01

    Crizotinib is the first anaplastic lymphoma kinase (ALK) inhibitor to have been approved for the treatment of non-small cell lung cancer (NSCLC) harboring an ALK fusion gene, but it has been found that, in the clinic, patients develop resistance to it. Alectinib and ceritinib are second-generation ALK inhibitors which show remarkable clinical responses in both crizotinib-naive and crizotinib-resistant NSCLC patients harboring an ALK fusion gene. Despite their impressive activity, clinical resistance to alectinib and ceritinib has also emerged. In the current study, we elucidated the resistance mechanisms to these second-generation ALK inhibitors in the H3122 NSCLC cell line harboring the EML4-ALK variant 1 fusion in vitro. Prolonged treatment of the parental H3122 cells with alectinib and ceritinib led to two cell lines which are 10 times less sensitive to alectinib and ceritinib than the parental H3122 cell line. Although mutations of ALK in its kinase domain are a common resistance mechanism for crizotinib, we did not detect any ALK mutation in these resistant cell lines. Rather, overexpression of phospho-ALK and alternative receptor tyrosine kinases such as phospho-EGFR, phospho-HER3, and phospho-IGFR-1R was observed in both resistant cell lines. Additionally, NRG1, a ligand for HER3, is upregulated and responsible for resistance by activating the EGFR family pathways through the NRG1-HER3-EGFR axis. Combination treatment with EGFR inhibitors, in particular afatinib, was shown to be effective at overcoming resistance. Our study provides new mechanistic insights into adaptive resistance to second-generation ALK inhibitors and suggests a potential clinical strategy to combat resistance to these second-generation ALK inhibitors in NSCLC.

  14. Elucidation of Resistance Mechanisms to Second-Generation ALK Inhibitors Alectinib and Ceritinib in Non–Small Cell Lung Cancer Cells

    PubMed Central

    Dong, Xuyuan; Fernandez-Salas, Ester; Li, Enxiao; Wang, Shaomeng

    2016-01-01

    Crizotinib is the first anaplastic lymphoma kinase (ALK) inhibitor to have been approved for the treatment of non–small cell lung cancer (NSCLC) harboring an ALK fusion gene, but it has been found that, in the clinic, patients develop resistance to it. Alectinib and ceritinib are second-generation ALK inhibitors which show remarkable clinical responses in both crizotinib-naive and crizotinib-resistant NSCLC patients harboring an ALK fusion gene. Despite their impressive activity, clinical resistance to alectinib and ceritinib has also emerged. In the current study, we elucidated the resistance mechanisms to these second-generation ALK inhibitors in the H3122 NSCLC cell line harboring the EML4-ALK variant 1 fusion in vitro. Prolonged treatment of the parental H3122 cells with alectinib and ceritinib led to two cell lines which are 10 times less sensitive to alectinib and ceritinib than the parental H3122 cell line. Although mutations of ALK in its kinase domain are a common resistance mechanism for crizotinib, we did not detect any ALK mutation in these resistant cell lines. Rather, overexpression of phospho-ALK and alternative receptor tyrosine kinases such as phospho-EGFR, phospho-HER3, and phospho-IGFR-1R was observed in both resistant cell lines. Additionally, NRG1, a ligand for HER3, is upregulated and responsible for resistance by activating the EGFR family pathways through the NRG1-HER3-EGFR axis. Combination treatment with EGFR inhibitors, in particular afatinib, was shown to be effective at overcoming resistance. Our study provides new mechanistic insights into adaptive resistance to second-generation ALK inhibitors and suggests a potential clinical strategy to combat resistance to these second-generation ALK inhibitors in NSCLC. PMID:26992917

  15. hnRNPK inhibits GSK3β Ser9 phosphorylation, thereby stabilizing c-FLIP and contributes to TRAIL resistance in H1299 lung adenocarcinoma cells

    PubMed Central

    Gao, Xuejuan; Feng, Junxia; He, Yujiao; Xu, Fengmei; Fan, Xiaoqin; Huang, Wensi; Xiong, Haiting; Liu, Qiuyu; Liu, Wanting; Liu, Xiaohui; Sun, Xuesong; He, Qing-Yu; Zhang, Qihao; Liu, Langxia

    2016-01-01

    c-FLIP (cellular FLICE-inhibitory protein) is the pivotal regulator of TRAIL resistance in cancer cells, It is a short-lived protein degraded through the ubiquitin/proteasome pathway. The discovery of factors and mechanisms regulating its protein stability is important for the comprehension of TRAIL resistance by tumor cells. In this study, we show that, when H1299 lung adenocarcinoma cells are treated with TRAIL, hnRNPK is translocated from nucleus to cytoplasm where it interacts and co-localizes with GSK3β. We find that hnRNPK is able to inhibit the Ser9 phosphorylation of GSK3β by PKC. This has the effect of activating GSK3β and thereby stabilizing c-FLIP protein which contributes to the resistance to TRAIL in H1299 cells. Our immunohistochemical analysis using tissue microarray provides the clinical evidence of this finding by establishing a negative correlation between the level of hnRNPK expression and the Ser9 phosphorylation of GSK3β in both lung adenocarcinoma tissues and normal tissues. Moreover, in all cancer tissues examined, hnRNPK was found in the cytoplasm whereas it is exclusively nuclear in the normal tissues. Our study sheds new insights on the molecular mechanisms governing the resistance to TRAIL in tumor cells, and provides new clues for the combinatorial chemotherapeutic interventions with TRAIL. PMID:26972480

  16. Pharmacodynamic Profile of GSK2140944 against Methicillin-Resistant Staphylococcus aureus in a Murine Lung Infection Model

    PubMed Central

    So, Wonhee; Crandon, Jared L.

    2015-01-01

    GSK2140944 is a novel bacterial type II topoisomerase inhibitor with in vitro activity against key causative respiratory pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). We described the pharmacodynamics of GSK2140944 against MRSA in the neutropenic murine lung infection model. MICs of GSK2140944 were determined by broth microdilution. Plasma and epithelial lining fluid (ELF) pharmacokinetics were evaluated to allow determination of pulmonary distribution. Six MRSA isolates were tested. GSK2140944 doses of 1.56 to 400 mg/kg of body weight every 6 h (q6h) were utilized. Efficacy as the change in log10 CFU at 24 h compared with 0 h controls and the area under the concentration-time curve for the free, unbound fraction of a drug (fAUC)/MIC required for various efficacy endpoints were determined. GSK2140944 MICs were 0.125 to 0.5 mg/liter against the six MRSA isolates. ELF penetration ratios ranged from 1.1 to 1.4. Observed maximal decreases were 1.1 to 3.1 log10 CFU in neutropenic mice. The mean fAUC/MIC ratios required for stasis and 1-log-unit decreases were 59.3 ± 34.6 and 148.4 ± 83.3, respectively. GSK2140944 displayed in vitro and in vivo activity against MRSA. The pharmacodynamic profile of GSK2140944, as determined, supports its further development as a potential treatment option for pulmonary infections, including those caused by MRSA. PMID:26055376

  17. Neuropilin 1 expression correlates with the Radio-resistance of human non-small-cell lung cancer cells.

    PubMed

    Dong, Juan Cong; Gao, Hui; Zuo, Si Yao; Zhang, Hai Qin; Zhao, Gang; Sun, Shi Long; Han, Hai Ling; Jin, Lin Lin; Shao, Li Hong; Wei, Wei; Jin, Shun Zi

    2015-09-01

    The purpose of this study was to determine the correlation between over-expression of the neuropilin 1 (NRP1) gene and growth, survival, and radio-sensitivity of non-small cell lung carcinoma (NSCLC) cells. 3-[4,5-dimethylthylthiazol-2-yl]-2,5 diphenyltetrazolium broide (MTT) and colony assays were then performed to determine the effect of NRP1 inhibition on the in vitro growth of NSCLC cells. The Annexin V-Fluorescein Isothiocyanate (FITC) apoptosis detection assay was performed to analyse the effect of NRP1 enhancement on apoptosis of NSCLC cells. Transwell invasion and migration assays were employed to examine the metastatic ability of A549 cells post X-ray irradiation. In addition, Western blot assays were carried out to detect the protein level of VEGFR2, PI3K and NF-κB. Finally, to examine the effect of shNRP1 on proliferation and radio-sensitivity in vivo, a subcutaneous tumour formation assay in nude mice was performed. Microvessel density in tumour tissues was assessed by immunohistochemistry. The stable transfected cell line (shNRP1-A549) showed a significant reduction in colony-forming ability and proliferation not only in vitro, but also in vivo. Moreover, shRNA-mediated NRP1 inhibition also significantly enhanced the radio-sensitivity of NSCLC cells both in vitro and in vivo. The over-expression of NRP1 was correlated with growth, survival and radio-resistance of NSCLC cells via the VEGF-PI3K- NF-κB pathway, and NRP1 may be a molecular therapeutic target for gene therapy or radio-sensitization of NSCLC.

  18. [A case of non-acquired immunodeficiency syndrome-defining lung adenocarcinoma in a multidrug-resistant human immunodeficiency virus-positive patient].

    PubMed

    Mori, Naoyoshi; Maeda, Hikaru; Fujiwara, Kentarou; Taniguchi, Haruki

    2013-10-01

    We report a case of non-acquired immunodeficiency syndrome-defining lung adenocarcinoma in a multidrug-resistant human immunodeficiency virus (HIV)-positive patient. The patient was a 47-year-old Japanese woman who received salvage combination anti-retroviral therapy with darunavir plus ritonavir plus raltegravir plus tenofovir/emtricitabine in May 2009. She was diagnosed with lung adenocarcinoma (T3N3M1, stage IV) in November 2010 and was not found to possess any activating mutations in the epidermal growth factor receptor gene. Therefore, 6 courses of carboplatin plus pemetrexed and 3 courses of gemcitabine followed by erlotinib were administrated, and therapy was changed to home medical care. The only drug-related adverse event was grade 1 neutropenia, and drug interaction between the simultaneously administered anti-retroviral and chemotherapeutic agents was not confirmed. The patient battled lung adenocarcinoma for 1 year after the diagnosis and died of cancer progression in October 2011. Her performance status was stable and the CD4 (+) lymphocyte count and HIV load were well controlled throughout the course of treatment. In conclusion, the agents used for this patient show high tolerability and can be used as an effective treatment strategy for lung cancer occurring in HIV-positive patients.

  19. Absolute neutrino mass measurements

    SciTech Connect

    Wolf, Joachim

    2011-10-06

    The neutrino mass plays an important role in particle physics, astrophysics and cosmology. In recent years the detection of neutrino flavour oscillations proved that neutrinos carry mass. However, oscillation experiments are only sensitive to the mass-squared difference of the mass eigenvalues. In contrast to cosmological observations and neutrino-less double beta decay (0v2{beta}) searches, single {beta}-decay experiments provide a direct, model-independent way to determine the absolute neutrino mass by measuring the energy spectrum of decay electrons at the endpoint region with high accuracy.Currently the best kinematic upper limits on the neutrino mass of 2.2eV have been set by two experiments in Mainz and Troitsk, using tritium as beta emitter. The next generation tritium {beta}-experiment KATRIN is currently under construction in Karlsruhe/Germany by an international collaboration. KATRIN intends to improve the sensitivity by one order of magnitude to 0.2eV. The investigation of a second isotope ({sup 137}Rh) is being pursued by the international MARE collaboration using micro-calorimeters to measure the beta spectrum. The technology needed to reach 0.2eV sensitivity is still in the R and D phase. This paper reviews the present status of neutrino-mass measurements with cosmological data, 0v2{beta} decay and single {beta}-decay.

  20. Overcoming drug-resistant lung cancer by paclitaxel loaded dual-functional liposomes with mitochondria targeting and pH-response.

    PubMed

    Jiang, Lei; Li, Li; He, Xiaodan; Yi, Qiangying; He, Bin; Cao, Jun; Pan, Weisan; Gu, Zhongwei

    2015-06-01

    Mitochondrion-orientated transportation of smart liposomes has been developed as a promising strategy to deliver anticancer drugs directly to tumor sites, and these have a tremendous potential for killing cancer cells, especially those with multidrug resistance (MDR). Herein we report a novel dual-functional liposome system possessing both extracellular pH response and mitochondrial targeting properties to enhance drug accumulation in mitochondria and trigger apoptosis of drug-resistant cancer cells. Briefly, peptide D[KLAKLAK]2 (KLA) was modified with 2, 3-dimethylmaleic anhydride (DMA) and combined with 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) to yield a DSPE-KLA-DMA (DKD) lipid. This dual-functional DKD was then mixed with other commercially available lipids to fabricate liposomes. In vitro anticancer efficacy of this liposome system was evaluated in human lung cancer A549 cells and drug-resistant lung cancer A549/Taxol cells. At tumor extracellular pH (∼6.8), liposomes could reverse their surface charge (negative to positive), facilitating liposome internalization. After cellular uptake, KLA peptide directed delivery-enabled selective accumulation of these liposomes into mitochondria and favored release of their cargo paclitaxel (PTX) into desired sites. Specifically, enhanced apoptosis of MDR cancer cells through mitochondrial signaling pathways was evidenced by release of cytochrome c and increased activity of caspase-9 and -3. These dual-functional liposomes had the greatest efficacy for treating A549 cells and A549/Taxol cells in vitro, and in treating drug-resistant lung cancer A549/Taxol cells xenografted onto nude mice (tumor growth inhibition 86.7%). In conclusion, dual-functional liposomes provide a novel and versatile approach for overcoming MDR in cancer treatment.

  1. Overcoming resistance to first/second generation epidermal growth factor receptor tyrosine kinase inhibitors and ALK inhibitors in oncogene-addicted advanced non-small cell lung cancer

    PubMed Central

    Romanidou, Ourania; Landi, Lorenza; Cappuzzo, Federico; Califano, Raffaele

    2016-01-01

    Epidermal growth factor receptor (EGFR) activating mutations and anaplastic lymphoma kinase (ALK) gene rearrangement in advanced non-small cell lung cancer (NSCLC) represent the two oncogenic events with an impact on current clinical practice. EGFR tyrosine kinase inhibitors (TKIs) and crizotinib are the standard of care for the treatment of EGFR mutant and ALK gene rearranged advanced NSCLC patients. Unfortunately, despite initial clinical benefit, acquired resistance to EGFR-TKIs or crizotinib usually develops after an average of 10–12 months of treatment. The aim of this review is to describe the mechanisms of resistance to first/second generation EGFR-TKIs and crizotinib. In particular, we focus on strategies to overcome resistance due to secondary EGFR T790M mutation and mutations of the ALK domain. PMID:27239236

  2. Acquired Resistance to EGFR Kinase Inhibitors Associated with a Novel T854A Mutation in a Patient with EGFR-Mutant Lung Adenocarcinoma

    PubMed Central

    Bean, James; Riely, Gregory J.; Balak, Marissa; Marks, Jenifer L.; Ladanyi, Marc; Miller, Vincent A.; Pao, William

    2008-01-01

    Purpose Somatic mutations in the tyrosine kinase domain of EGFR are associated with sensitivity of lung adenocarcinomas to the EGFR tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib. Acquired drug resistance is frequently associated with a secondary somatic mutation that leads to substitution of methionine for threonine at position 790 (T790M). We aimed to identify additional second-site alterations associated with acquired resistance. Experimental Design Tumor samples were obtained from 48 patients with acquired resistance. Tumor cell DNA was analyzed for EGFR kinase domain mutations. Molecular analyses were then performed to characterize biological properties of a novel mutant EGFR allele. Results A previously unreported mutation in exon 21 of EGFR, which leads to substitution of alanine for threonine at position 854 (T854A), was identified in one patient with a drug-sensitive EGFR L858R-mutant lung adenocarcinoma after long-term treatment with TKIs. The T854A mutation was not detected in a pretreatment tumor sample. Crystal structure analyses of EGFR suggest that the T854 side chain is within contact distance of gefitinib and erlotinib. Surrogate kinase assays demonstrate that the EGFR T854A mutation abrogates inhibition of tyrosine phosphorylation by erlotinib. Such resistance appears to be overcome by a new irreversible dual EGFR/HER2 inhibitor, BIBW 2992. Conclusions The T854A mutation is the second reported second-site acquired resistance mutation that is within contact distance of gefitinib and erlotinib. These data suggest that acquired resistance to ATP-mimetic EGFR kinase inhibitors may often be associated with amino acid substitutions that alter drug contact residues in the EGFR ATP-binding pocket. PMID:19010870

  3. JAK2 inhibitor TG101348 overcomes erlotinib-resistance in non-small cell lung carcinoma cells with mutated EGF receptor.

    PubMed

    Zhang, Fu-quan; Yang, Wen-tao; Duan, Shan-zhou; Xia, Ying-chen; Zhu, Rong-ying; Chen, Yong-bing

    2015-06-10

    Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations are responsive to EGFR-tyrosine kinase inhibitor (EGFR-TKI). However, NSCLC patients with secondary somatic EGFR mutations are resistant to EGFR-TKI treatment. In this study, we investigated the effect of TG101348 (a JAK2 inhibitor) on the tumor growth of erlotinib-resistant NSCLC cells. Cell proliferation, apoptosis, gene expression and tumor growth were evaluated by diphenyltetrazolium bromide (MTT) assay, flow cytometry, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) staining, Western Blot and a xenograft mouse model, respectively. Results showed that erlotinib had a stronger impact on the induction of apoptosis in erlotinib-sensitive PC-9 cells but had a weaker effect on erlotinib-resistant H1975 and H1650 cells than TG101348. TG101348 significantly enhanced the cytotoxicity of erlotinib to erlotinib-resistant NSCLC cells, stimulated erlotinib-induced apoptosis and downregulated the expressions of EGFR, p-EGFR, p-STAT3, Bcl-xL and survivin in erlotinib-resistant NSCLC cells. Moreover, the combined treatment of TG101348 and erlotinib induced apoptosis, inhibited the activation of p-EGFR and p-STAT3, and inhibited tumor growth of erlotinib-resistant NSCLC cells in vivo. Our results indicate that TG101348 is a potential adjuvant for NSCLC patients during erlotinib treatment.

  4. TM4SF4 overexpression in radiation-resistant lung carcinoma cells activates IGF1R via elevation of IGF1.

    PubMed

    Choi, Soo-Im; Kim, Seo-Yeon; Lee, Jaeha; Cho, Eun-Wie; Kim, In-Gyu

    2014-10-30

    Transmembrane 4 L six family member 4 (TM4SF4) is a member of the tetraspanin L6 domain family. Other members of this family, TM4SF1 (also known as L6-Ag) and TM4SF5, have been shown to be upregulated in multiple tumors and involved in epithelial-to-mesenchymal transition and cell migration. However, unlike its homologs, little is known about TM4SF4. Here, we show that TM4SF4 was highly expressed in radiation-resistant lung adenocarcinoma cells, such as A549 and Calu-3 cells, and its expression activated cell growth, migration, and invasion. Overexpression of TM4SF4 in A549 cells increased the activation of PI3K, AKT, and NF-kappaB and the expression of PTEN. IGF1R was clearly activated by overexpression of TM4SF4, although EGFR was also slightly activated. TM4SF4 expression was correlated with the increased expression of IGF1, consequently resulting in IGF1R activation. Tumorigenic activity of TM4SF4 in lung adenocarcinoma cells was also demonstrated by xenograft assay; however, this activity was almost completely suppressed by treatment with anti-TM4SF4 antibody. Our results suggest that TM4SF4 overexpression in lung carcinoma cells results in resistance to radiotherapy via IGF1-induced IGF1R activation and blocking the activity of TM4SF4 using specific antibody can be a promising therapeutics against TM4SF4-overexpressing lung adenocarcinoma. PMID:25344917

  5. TM4SF4 overexpression in radiation-resistant lung carcinoma cells activates IGF1R via elevation of IGF1

    PubMed Central

    Choi, Soo-Im; Kim, Seo-Yeon; Lee, Jaeha; Cho, Eun-Wie; Kim, In-Gyu

    2014-01-01

    Transmembrane 4 L six family member 4 (TM4SF4) is a member of the tetraspanin L6 domain family. Other members of this family, TM4SF1 (also known as L6-Ag) and TM4SF5, have been shown to be upregulated in multiple tumors and involved in epithelial-to-mesenchymal transition and cell migration. However, unlike its homologs, little is known about TM4SF4. Here, we show that TM4SF4 was highly expressed in radiation-resistant lung adenocarcinoma cells, such as A549 and Calu-3 cells, and its expression activated cell growth, migration, and invasion. Overexpression of TM4SF4 in A549 cells increased the activation of PI3K, AKT, and NF-kappaB and the expression of PTEN. IGF1R was clearly activated by overexpression of TM4SF4, although EGFR was also slightly activated. TM4SF4 expression was correlated with the increased expression of IGF1, consequently resulting in IGF1R activation. Tumorigenic activity of TM4SF4 in lung adenocarcinoma cells was also demonstrated by xenograft assay; however, this activity was almost completely suppressed by treatment with anti-TM4SF4 antibody. Our results suggest that TM4SF4 overexpression in lung carcinoma cells results in resistance to radiotherapy via IGF1-induced IGF1R activation and blocking the activity of TM4SF4 using specific antibody can be a promising therapeutics against TM4SF4-overexpressing lung adenocarcinoma. PMID:25344917

  6. Influence of inoculum size and marbofloxacin plasma exposure on the amplification of resistant subpopulations of Klebsiella pneumoniae in a rat lung infection model.

    PubMed

    Kesteman, Anne-Sylvie; Ferran, Aude A; Perrin-Guyomard, Agnès; Laurentie, Michel; Sanders, Pascal; Toutain, Pierre-Louis; Bousquet-Mélou, Alain

    2009-11-01

    We tested the hypothesis that the bacterial load at the infection site could impact considerably on the pharmacokinetic/pharmacodynamic (PK/PD) parameters of fluoroquinolones. Using a rat lung infection model, we measured the influence of different marbofloxacin dosage regimens on selection of resistant bacteria after infection with a low (10(5) CFU) or a high (10(9) CFU) inoculum of Klebsiella pneumoniae. For daily fractionated doses of marbofloxacin, prevention of resistance occurred for an area-under-the-concentration-time-curve (AUC)/MIC ratio of 189 h for the low inoculum, whereas for the high inoculum, resistant-subpopulation enrichment occurred for AUC/MIC ratios up to 756 h. For the high-inoculum-infected rats, the AUC/MIC ratio, C(max)/MIC ratio, and time within the mutant selection window (T(MSW)) were not found to be effective predictors of resistance prevention upon comparison of fractionated and single administrations. An index corresponding to the ratio of the time that the drug concentrations were above the mutant prevention concentration (MPC) over the time that the drug concentrations were within the MSW (T(>MPC)/T(MSW)) was the best predictor of the emergence of resistance: a T(>MPC)/T(MSW) ratio of 0.54 was associated with prevention of resistance for both fractionated and single administrations. These results suggest that the enrichment of resistant bacteria depends heavily on the inoculum size at the start of an antimicrobial treatment and that classical PK/PD parameters cannot adequately describe the impact of different dosage regimens on enrichment of resistant bacteria. We propose an original index, the T(>MPC)/T(MSW) ratio, which reflects the ratio of the time that the less susceptible bacterial subpopulation is killed over the time that it is selected, as a potentially powerful indicator of prevention of enrichment of resistant bacteria. This ratio is valid only if plasma concentrations achieve the MPC.

  7. Targeting glucosylceramide synthase induction of cell surface globotriaosylceramide (Gb3) in acquired cisplatin-resistance of lung cancer and malignant pleural mesothelioma cells

    SciTech Connect

    Tyler, Andreas; Johansson, Anders; Karlsson, Terese; Gudey, Shyam Kumar; Brännström, Thomas; Grankvist, Kjell; Behnam-Motlagh, Parviz

    2015-08-01

    Background: Acquired resistance to cisplatin treatment is a caveat when treating patients with non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM). Ceramide increases in response to chemotherapy, leading to proliferation arrest and apoptosis. However, a tumour stress activation of glucosylceramide synthase (GCS) follows to eliminate ceramide by formation of glycosphingolipids (GSLs) such as globotriaosylceramide (Gb3), the functional receptor of verotoxin-1. Ceramide elimination enhances cell proliferation and apoptosis blockade, thus stimulating tumor progression. GSLs transactivate multidrug resistance 1/P-glycoprotein (MDR1) and multidrug resistance-associated protein 1 (MRP1) expression which further prevents ceramide accumulation and stimulates drug efflux. We investigated the expression of Gb3, MDR1 and MRP1 in NSCLC and MPM cells with acquired cisplatin resistance, and if GCS activity or MDR1 pump inhibitors would reduce their expression and reverse cisplatin-resistance. Methods: Cell surface expression of Gb3, MDR1 and MRP1 and intracellular expression of MDR1 and MRP1 was analyzed by flow cytometry and confocal microscopy on P31 MPM and H1299 NSCLC cells and subline cells with acquired cisplatin resistance. The effect of GCS inhibitor PPMP and MDR1 pump inhibitor cyclosporin A for 72 h on expression and cisplatin cytotoxicity was tested. Results: The cisplatin-resistant cells expressed increased cell surface Gb3. Cell surface Gb3 expression of resistant cells was annihilated by PPMP whereas cyclosporin A decreased Gb3 and MDR1 expression in H1299 cells. No decrease of MDR1 by PPMP was noted in using flow cytometry, whereas a decrease of MDR1 in H1299 and H1299res was indicated with confocal microscopy. No certain co-localization of Gb3 and MDR1 was noted. PPMP, but not cyclosporin A, potentiated cisplatin cytotoxicity in all cells. Conclusions: Cell surface Gb3 expression is a likely tumour biomarker for acquired cisplatin

  8. Liposome armed with herpes virus-derived gH625 peptide to overcome doxorubicin resistance in lung adenocarcinoma cell lines

    PubMed Central

    Falanga, Annarita; Zappavigna, Silvia; Stiuso, Paola; Tirino, Virginia; Desiderio, Vincenzo; Papaccio, Gianpaolo; Galdiero, Massimiliano; Giordano, Antonio; Galdiero, Stefania; Caraglia, Michele

    2016-01-01

    New delivery systems including liposomes have been developed to circumvent drug resistance. To enhance the antitumor efficacy of liposomes encapsulating anti-cancer agents, we used liposomes externally conjugated to the 20 residue peptide gH625. Physicochemical characterization of the liposome system showed a size of 140 nm with uniform distribution and high doxorubicin encapsulation efficiency. We evaluated the effects of increasing concentrations of liposomes encapsulating Doxo (LipoDoxo), liposomes encapsulating Doxo conjugated to gH625 (LipoDoxo-gH625), empty liposomes (Lipo) or free Doxo on growth inhibition of either wild type (A549) or doxorubicin-resistant (A549 Dx) human lung adenocarcinoma. After 72 h, we found that the growth inhibition induced by LipoDoxo-gH625 was higher than that caused by LipoDoxo with an IC50 of 1 and 0.3 μM in A549 and A549 Dx cells, respectively. The data on cell growth inhibition were paralleled by an higher oxidative stress and an increased uptake of Doxo induced by LipoDoxo-gH625 compared to LipoDoxo, above all in A549 Dx cells. Cytometric analysis showed that the antiproliferative effects of each drug treatment were mainly due to the induction of apoptosis. In conclusion, liposomes armed with gH625 are able to overcome doxorubicin resistance in lung adenocarcinoma cell lines. PMID:26554306

  9. Sendai virus-induced alterations in lung structure/function correlate with viral loads and reveal a wide resistance/susceptibility spectrum among mouse strains.

    PubMed

    Faisca, Pedro; Anh, Dao Bui Tran; Desmecht, Daniel J-M

    2005-11-01

    The Paramyxoviridae family includes some of the most important and ubiquitous disease-causing viruses of infants and children, most of which cause significant infections of the respiratory tract. Evidence is accumulating in humans that genetic factors are involved in the severity of clinical presentation. As a first step toward the identification of the genes involved, this study was undertaken to establish whether laboratory mouse strains differ in susceptibility to Sendai virus, the murine counterpart of human type-1 parainfluenza virus which, historically, has been used extensively in studies that have defined the basic biological properties of paramyxoviruses in general. With this purpose in mind, double-chamber plethysmography data were collected daily for 7 days after inoculation of Sendai virus in six inbred strains of mice. In parallel, histological examinations and lung viral titration were carried out from day 5 to day 7 after inoculation. Pulmonary structure/function values closely reflected the success of viral replication in the lungs and revealed a pattern of continuous variation with resistant, intermediate, and susceptible strains. The results unambiguously suggest that BALB/c (resistant) and 129Sv (susceptible) strains should be used in crossing experiments aimed at identifying the genes involved in resistance to Paramyxoviridae by the positional cloning approach.

  10. Screening and identification of novel compounds with potential anti-proliferative effects on gallium-resistant lung cancer through an AXL kinase pathway.

    PubMed

    Oyewumi, Moses O; Alazizi, Adnan; Liva, Sophia; Lin, Li; Geldenhuys, Werner J

    2014-09-15

    The clinical application of gallium compounds as anticancer agents is hampered by development of resistance. As a potential strategy to overcome the limitation, eight series of compounds were identified through virtual screening of AXL kinase homology model. Anti-proliferative studies were carried using gallium-sensitive (S) and gallium-resistant (R) human lung adenocarcinoma (A549) cells. Compounds 5476423 and 7919469 were identified as leads. The IC50 values from treating R-cells showed compounds 5476423 and 7919469 had 80 fold and 13 fold increased potency, respectively, compared to gallium acetylacetonate (GaAcAc). The efficacy of GaAcAc against R-cells was increased 2 fold and 1.2 fold when combined with compounds 5476423 and 7919469, respectively. Compared with S-cells, R-cells showed elevated expression of AXL protein, which was significantly suppressed through treatments with the lead compounds. It is anticipated that the lead compounds could be applied in virtual screening programs to identify novel scaffolds for new therapeutic agents as well as combinatorial therapy agents in gallium resistant lung cancer.

  11. Absolute Identification by Relative Judgment

    ERIC Educational Resources Information Center

    Stewart, Neil; Brown, Gordon D. A.; Chater, Nick

    2005-01-01

    In unidimensional absolute identification tasks, participants identify stimuli that vary along a single dimension. Performance is surprisingly poor compared with discrimination of the same stimuli. Existing models assume that identification is achieved using long-term representations of absolute magnitudes. The authors propose an alternative…

  12. Be Resolute about Absolute Value

    ERIC Educational Resources Information Center

    Kidd, Margaret L.

    2007-01-01

    This article explores how conceptualization of absolute value can start long before it is introduced. The manner in which absolute value is introduced to students in middle school has far-reaching consequences for their future mathematical understanding. It begins to lay the foundation for students' understanding of algebra, which can change…

  13. Does the Clearance of Inhaled (99m)Tc-Sestamibi Correlate with Multidrug Resistance Protein 1 Expression in the Human Lung?

    PubMed

    Mohan, Hosahalli K; Routledge, Thomas; Cane, Paul; Livieratos, Lefteris; Ballinger, James R; Peters, Adrien M

    2016-09-01

    Purpose To examine the relation between the lung elimination rate of inhaled technetium 99m ((99m)Tc)-sestamibi and immunohistochemical expression of bronchopulmonary multidrug resistance protein 1 (MRP1) and permeability glycoprotein (P-gp) and assess the repeatability of the inhaled (99m)Tc-sestamibi clearance technique. Materials and Methods (99m)Tc-sestamibi is a known substrate for P-gp and MRP1, which are established cellular drug efflux transporters. The elimination rate of (99m)Tc-sestamibi from the lungs after inhalation as an aerosol has been hypothesized to be regulated by expression of these transporters. Institutional ethics committee approval was received for this prospective study. Written informed consent was obtained from all participants. The clearance of inhaled (99m)Tc-sestamibi from the lungs of 13 patients due to undergo surgery for primary lung cancer (five of 13) or spontaneous pneumothorax (eight of 13) was estimated after dynamic imaging of the lungs during a period of 40 minutes. The time taken to clear 50% of inhaled sestamibi (T1/2) was compared with a semiquantitative immunohistochemical assessment (grade 0-3) of MRP1 and P-gp expression in the lung by using parametric and nonparametric tests. The study was repeated in five participants to assess the repeatability of the technique by using a Bland Altman analysis method. Results MRP1 expression was seen in 12 of 13 patients, while P-gp expression was seen in only two. The mean (99m)Tc-sestamibi elimination rate was faster in patients (n = 6) with low levels of MRP1 expression (grade 0-1) and mean T1/2 of 105 minutes ± 20 (standard deviation), compared with those with higher levels of MRP1 expression (grade 2-3, n = 7) and mean T1/2 of 149 minutes ± 28 (P = .008). Bland-Altman analysis revealed excellent agreement between test and retest values. Conclusion Inhaled (99m)Tc-sestamibi clearance study is a repeatable technique demonstrating significant correlation with MRP1 expression in

  14. Extract of Bryophyllum laetivirens reverses etoposide resistance in human lung A549 cancer cells by downregulation of NF-κB.

    PubMed

    Kaewpiboon, Chutima; Srisuttee, Ratakorn; Malilas, Waraporn; Moon, Jeong; Kaowinn, Sirichat; Cho, Il-Rae; Johnston, Randal N; Assavalapsakul, Wanchai; Chung, Young-Hwa

    2014-01-01

    Since multidrug resistance (MDR) is one of the main reasons for failure in cancer treatment, its suppression may increase the efficacy of cancer therapy. In the present study we attempted to identify a new and effective anticancer drug against MDR cancer cells. We first found that lung cancer A549 cells resistant to etoposide (A549RT-eto) exhibit upregulation of NF-κB and SIRT1 in comparison to A549 parental cells. During a search for anticancer drug candidates from medicinal plant sources, we found that an extract fraction (F14) of Bryophyllum laetivirens leaves downregulated expression of NF-κB and SIRT1, sensitizing the levels of A549RT-eto cells to apoptosis through downregulation of P-glycoprotein (P-gp), which is encoded by the MDR1 gene. To address whether NF-κB is involved in resistance to etoposide through P-gp, we treated A549RT-eto cells with Bay11-7802, an inhibitor of NF-κB. We then observed that Bay11-7802 treatment reduced P-gp expression levels, and furthermore combined treatment with the F14 extract and Bay11-7802 accelerated apoptosis through a decrease in P-gp levels, suggesting that NF-κB is involved in MDR. To address whether upregulation of SIRT1 is involved in resistance to etoposide through P-gp, we treated A549RT-eto cells with SIRT1 siRNA or nicotinamide (NAM), an inhibitor of SIRT1. we found that suppression of SIRT1 did not reduce P-gp levels. furthermore, the combined treatment with the F14 extract, and SIRT1 siRNA or NAM did not accelerate apoptosis, indicating that SIRT1 is not involved in the regulation of P-gp levels in A549RT-eto cells. Taken together, we suggest that upregulation of NF-κB determines etoposide resistance through P-gp expression in human A549 lung cancer cells. We herein demonstrated that B. laetivirens extract reverses etoposide resistance in human A549 lung cancer cells through downregulation of NF-κB. PMID:24220725

  15. Extract of Bryophyllum laetivirens reverses etoposide resistance in human lung A549 cancer cells by downregulation of NF-κB.

    PubMed

    Kaewpiboon, Chutima; Srisuttee, Ratakorn; Malilas, Waraporn; Moon, Jeong; Kaowinn, Sirichat; Cho, Il-Rae; Johnston, Randal N; Assavalapsakul, Wanchai; Chung, Young-Hwa

    2014-01-01

    Since multidrug resistance (MDR) is one of the main reasons for failure in cancer treatment, its suppression may increase the efficacy of cancer therapy. In the present study we attempted to identify a new and effective anticancer drug against MDR cancer cells. We first found that lung cancer A549 cells resistant to etoposide (A549RT-eto) exhibit upregulation of NF-κB and SIRT1 in comparison to A549 parental cells. During a search for anticancer drug candidates from medicinal plant sources, we found that an extract fraction (F14) of Bryophyllum laetivirens leaves downregulated expression of NF-κB and SIRT1, sensitizing the levels of A549RT-eto cells to apoptosis through downregulation of P-glycoprotein (P-gp), which is encoded by the MDR1 gene. To address whether NF-κB is involved in resistance to etoposide through P-gp, we treated A549RT-eto cells with Bay11-7802, an inhibitor of NF-κB. We then observed that Bay11-7802 treatment reduced P-gp expression levels, and furthermore combined treatment with the F14 extract and Bay11-7802 accelerated apoptosis through a decrease in P-gp levels, suggesting that NF-κB is involved in MDR. To address whether upregulation of SIRT1 is involved in resistance to etoposide through P-gp, we treated A549RT-eto cells with SIRT1 siRNA or nicotinamide (NAM), an inhibitor of SIRT1. we found that suppression of SIRT1 did not reduce P-gp levels. furthermore, the combined treatment with the F14 extract, and SIRT1 siRNA or NAM did not accelerate apoptosis, indicating that SIRT1 is not involved in the regulation of P-gp levels in A549RT-eto cells. Taken together, we suggest that upregulation of NF-κB determines etoposide resistance through P-gp expression in human A549 lung cancer cells. We herein demonstrated that B. laetivirens extract reverses etoposide resistance in human A549 lung cancer cells through downregulation of NF-κB.

  16. The role of epithelial to mesenchymal transition in resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer.

    PubMed

    Jakobsen, Kristine Raaby; Demuth, Christina; Sorensen, Boe Sandahl; Nielsen, Anders Lade

    2016-04-01

    Inhibition of the epidermal growth factor receptor (EGFR) is an important strategy when treating non-small cell lung cancer (NSCLC) patients. However, intrinsic resistance or development of resistance during the course of treatment constitutes a major challenge. The knowledge on EGFR-directed tyrosine kinase inhibitors (TKIs) and their biological effect keeps increasing. Within the group of patients with EGFR mutations some benefit to a much higher degree than others, and for patients lacking EGFR mutations a subset experience an effect. Up to 70% of patients with EGFR mutations and 10-20% of patients without EGFR mutations initially respond to the EGFR-TKI erlotinib, but there is a severe absence of good prognostic markers. Despite initial effect, all patients acquire resistance to EGFR-TKIs. Multiple mechanisms have implications in resistance development, but much is still to be explored. Epithelial to mesenchymal transition (EMT) is a transcriptionally regulated phenotypic shift rendering cells more invasive and migratory. Within the EMT process lays a need for external or internal stimuli to give rise to changes in central signaling pathways. Expression of mesenchymal markers correlates to a bad prognosis and an inferior response to EGFR-TKIs in NSCLC due to the contribution to a resistant phenotype. A deeper understanding of the role of EMT in NSCLC and especially in EGFR-TKI resistance-development constitute one opportunity to improve the benefit of TKI treatment for the individual patient. Many scientific studies have linked the EMT process to EGFR-TKI resistance in NSCLC and our aim is to review the role of EMT in both intrinsic and acquired resistance to EGFR-TKIs.

  17. The role of epithelial to mesenchymal transition in resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer

    PubMed Central

    Jakobsen, Kristine Raaby; Demuth, Christina; Sorensen, Boe Sandahl

    2016-01-01

    Inhibition of the epidermal growth factor receptor (EGFR) is an important strategy when treating non-small cell lung cancer (NSCLC) patients. However, intrinsic resistance or development of resistance during the course of treatment constitutes a major challenge. The knowledge on EGFR-directed tyrosine kinase inhibitors (TKIs) and their biological effect keeps increasing. Within the group of patients with EGFR mutations some benefit to a much higher degree than others, and for patients lacking EGFR mutations a subset experience an effect. Up to 70% of patients with EGFR mutations and 10–20% of patients without EGFR mutations initially respond to the EGFR-TKI erlotinib, but there is a severe absence of good prognostic markers. Despite initial effect, all patients acquire resistance to EGFR-TKIs. Multiple mechanisms have implications in resistance development, but much is still to be explored. Epithelial to mesenchymal transition (EMT) is a transcriptionally regulated phenotypic shift rendering cells more invasive and migratory. Within the EMT process lays a need for external or internal stimuli to give rise to changes in central signaling pathways. Expression of mesenchymal markers correlates to a bad prognosis and an inferior response to EGFR-TKIs in NSCLC due to the contribution to a resistant phenotype. A deeper understanding of the role of EMT in NSCLC and especially in EGFR-TKI resistance-development constitute one opportunity to improve the benefit of TKI treatment for the individual patient. Many scientific studies have linked the EMT process to EGFR-TKI resistance in NSCLC and our aim is to review the role of EMT in both intrinsic and acquired resistance to EGFR-TKIs. PMID:27186512

  18. 3,6,2',4',5'-Pentahydroxyflavone, an orally bioavailable multiple protein kinase inhibitor, overcomes gefitinib resistance in non-small cell lung cancer.

    PubMed

    Sheng, Yuqiao; Li, Wei; Zhu, Feng; Liu, Kangdong; Chen, Hanyong; Yao, Ke; Reddy, Kanamata; Lim, Do Young; Oi, Naomi; Li, Haitao; Peng, Cong; Ma, Wei-Ya; Bode, Ann M; Dong, Ziming; Dong, Zigang

    2014-10-10

    Non-small cell lung cancer (NSCLC) is the most lethal cancer, causing more than 150,000 deaths in the United States in 2013. The receptor tyrosine kinase inhibitors such as gefitinib are not perfect clinical therapeutic agents for NSCLC treatment due to primary or acquired tyrosine kinase inhibitor resistance. Herein, 3,6,2',4',5'-pentahydroxyflavone (36245-PHF) was identified as a multiple kinase inhibitor for NSCLC treatment based on the computational screening of a natural products database. 36245-PHF was shown to inhibit PI3K and Aurora A and B kinases and overcome gefitinib-resistant NSCLC growth. Our data clearly showed that 36245-PHF markedly inhibited anchorage-independent growth of gefitinib-resistant NSCLC cell lines and exerted a substantial chemotherapeutic effect following oral administration in a gefitinib-resistant NSCLC xenograft model. The evidence from three different subsequent methodological approaches, in vitro, ex vivo, and in vivo, all confirmed that 36245-PHF as a multiple protein kinase inhibitor. Overall, we identified 36245-PHF as a multiple protein kinase inhibitor and as a novel therapeutic agent to overcome gefitinib-resistant NSCLC growth, which could provide a new option for clinical NSCLC oral treatment.

  19. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M.

    PubMed

    Thress, Kenneth S; Paweletz, Cloud P; Felip, Enriqueta; Cho, Byoung Chul; Stetson, Daniel; Dougherty, Brian; Lai, Zhongwu; Markovets, Aleksandra; Vivancos, Ana; Kuang, Yanan; Ercan, Dalia; Matthews, Sarah E; Cantarini, Mireille; Barrett, J Carl; Jänne, Pasi A; Oxnard, Geoffrey R

    2015-06-01

    Here we studied cell-free plasma DNA (cfDNA) collected from subjects with advanced lung cancer whose tumors had developed resistance to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) AZD9291. We first performed next-generation sequencing of cfDNA from seven subjects and detected an acquired EGFR C797S mutation in one; expression of this mutant EGFR construct in a cell line rendered it resistant to AZD9291. We then performed droplet digital PCR on serial cfDNA specimens collected from 15 AZD9291-treated subjects. All were positive for the T790M mutation before treatment, but upon developing AZD9291 resistance three molecular subtypes emerged: six cases acquired the C797S mutation, five cases maintained the T790M mutation but did not acquire the C797S mutation and four cases lost the T790M mutation despite the presence of the underlying EGFR activating mutation. Our findings provide insight into the diversity of mechanisms through which tumors acquire resistance to AZD9291 and highlight the need for therapies that are able to overcome resistance mediated by the EGFR C797S mutation.

  20. Oridonin inhibits gefitinib-resistant lung cancer cells by suppressing EGFR/ERK/MMP-12 and CIP2A/Akt signaling pathways.

    PubMed

    Xiao, Xiangling; He, Zhongwei; Cao, Wei; Cai, Fen; Zhang, Liang; Huang, Qiuyue; Fan, Chunsheng; Duan, Chao; Wang, Xiaobo; Wang, Jiu; Liu, Ying

    2016-06-01

    Oridonin (Ori), a diterpenoid compound extracted from traditional medicinal herbs, elicits antitumor effects on many cancer types. However, whether Ori can be used in gefitinib-resistant non-small cell lung cancer (NSCLC) cells remains unclear. This study investigated the antitumor activity and underlying mechanisms of Ori. Results demonstrated that this compound dose-dependently inhibited the proliferation, invasion, and migration of the gefitinib-resistant NSCLC cells in vitro. Ori also significantly downregulated the phosphorylation of EGFR, ERK, Akt, expression levels of matrix metalloproteinase-12 (MMP-12), and the cancerous inhibitor of protein phosphatase 2A (CIP2A). In addition, Ori upregulated protein phosphatase 2A (PP2A) activity of gefitinib-resistant NSCLC cells. Ori combined with docetaxel synergistically inhibited these cells. Ori also inhibited tumor growth in murine models. Immunohistochemistry results further revealed that Ori downregulated phospho-EGFR, MMP-12, and CIP2A in vivo. These findings indicated that Ori can inhibit the proliferation, invasion, and migration of gefitinib-resistant NSCLC cells by suppressing EGFR/ERK/MMP-12 and CIP2A/PP2A/Akt signaling pathways. Thus, Ori may be a novel effective candidate to treat gefitinib-resistant NSCLC.

  1. Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer: a new era begins.

    PubMed

    Remon, J; Morán, T; Majem, M; Reguart, N; Dalmau, E; Márquez-Medina, D; Lianes, P

    2014-02-01

    The discovery of mutated oncogenes has opened up a new era for the development of more effective treatments for non-small cell lung cancer patients (NSCLC) harbouring EGFR mutations. However, patients with EGFR-activating mutation ultimately develop acquired resistance (AR). Several studies have identified some of the mechanisms involved in the development of AR to EGFR tyrosine kinase inhibitors (TKI) that can be potential therapeutic strategies, although in up to 30% of cases, the underlying mechanism of AR are still unexplained. In this review we aim to summarize the main mechanisms of AR to EGFR TKI and some clinical strategies that can be used in the daily clinical practice to overcome this resistance and try to prolong the outcomes in this subgroup of patients.

  2. Toll-Like Receptor 9 Enhances Bacterial Clearance and Limits Lung Consolidation in Murine Pneumonia Caused by Methicillin-Resistant Staphylococcus aureus

    PubMed Central

    van der Meer, Anne Jan; Achouiti, Achmed; van der Ende, Arie; Soussan, Aicha Ait; Florquin, Sandrine; de Vos, Alex; Zeerleder, Sacha S; van der Poll, Tom

    2016-01-01

    Methicillin-resistant Staphylococcus aureus (MRSA) is an important pathogen in pneumonia associated with severe lung damage. Tissue injury causes release of damage-associated molecular patterns (DAMPs), which may perpetuate inflammation. DNA has been implicated as a DAMP that activates inflammation through Toll-like receptor 9 (TLR9). The aim of this study was to evaluate the role of TLR9 in MRSA pneumonia. Wild-type (Wt) and TLR9 knockout (tlr9−/−) mice were infected intranasally with MRSA USA300 (BK 11540) (5E7 CFU) and euthanized at 6, 24, 48 or 72 h for analyses. MRSA pneumonia was associated with profound release of cell-free host DNA in the airways, as reflected by increases in nucleosome and DNA levels in bronchoalveolar lavage fluid (BALF), accompanied by transient detection of pathogen DNA in MRSA-free BALF supernatants. In BALF, as compared with Wt mice, tlr9−/− mice showed reduced tumor necrosis factor α and IL-6 levels at 6 h and reduced bacterial clearance at 6 and 24 h postinfection. Furthermore, tlr9−/− mice exhibited a greater influx of neutrophils in BALF and increased lung consolidation at 24 and 48 h. This study demonstrates the release of host- and pathogen-derived TLR9 ligands (DNA) into the alveolar space after infection with MRSA via the airways and suggests that TLR9 has proinflammatory effects during MRSA pneumonia associated with enhanced bacterial clearance and limitation of lung consolidation. PMID:27508882

  3. ROS/Autophagy/Nrf2 Pathway Mediated Low-Dose Radiation Induced Radio-Resistance in Human Lung Adenocarcinoma A549 Cell.

    PubMed

    Chen, Ni; Wu, Lijun; Yuan, Hang; Wang, Jun

    2015-01-01

    Low-dose ionizing radiation (LDIR) can induce radio-resistance to following high dose radiation in various mammalian cells. The protective role of LDIR has been thought to be associated with the overall outcomes of cancer radiotherapy. NF-E2 related factor 2 (Nrf2) is a transcription factor that plays pivotal roles in maintaining cellular oxidative equilibrium. Since oxidative stress has been indicated to be a mediator of LDIR induced radio-resistance, the role of Nrf2 in this process was investigated in this research. Our results showed that in human lung adenocarcinoma A549 cell, 5cGy alpha particle induced radio-resistance to following 75cGy alpha particle radiation. The expression level of Nrf2 and its target Heme Oxygenase-1(HO-1) increased after 5cGy radiation. Both the shRNA of Nrf2 and the chemical inhibitor of HO-1 suppressed the induced radio-resistance, indicating the involvement of Nrf2 antioxidant pathway in this process. Further, we found 5cGy radiation stimulated autophagy process in A549. Inhibition of the autophagy process resulted in suppression of the radio-resistance and the induced expression of Nrf2 and HO-1. ROS scavenger N-acetyl-L-cysteine (NAC) blocked the autophagy process induced by 5cGy alpha particle, the upregulation of Nrf2 and HO-1, as well as the induced radio-resistance. In conclusion, ROS elevation caused by LDIR promoted Autophagy/Nrf2-HO-1 and conferred radio-resistance in A549.

  4. The TNF Family Molecules LIGHT and Lymphotoxin αβ Induce a Distinct Steroid-Resistant Inflammatory Phenotype in Human Lung Epithelial Cells.

    PubMed

    da Silva Antunes, Ricardo; Madge, Lisa; Soroosh, Pejman; Tocker, Joel; Croft, Michael

    2015-09-01

    Lung epithelial cells are considered important sources of inflammatory molecules and extracellular matrix proteins that contribute to diseases such as asthma. Understanding the factors that stimulate epithelial cells may lead to new insights into controlling lung inflammation. This study sought to investigate the responsiveness of human lung epithelial cells to the TNF family molecules LIGHT and lymphotoxin αβ (LTαβ). Bronchial and alveolar epithelial cell lines, and primary human bronchial epithelial cells, were stimulated with LIGHT and LTαβ, and expression of inflammatory cytokines and chemokines and markers of epithelial-mesenchymal transition and fibrosis/remodeling was measured. LTβ receptor, the receptor shared by LIGHT and LTαβ, was constitutively expressed on all epithelial cells. Correspondingly, LIGHT and LTαβ strongly induced a limited but highly distinct set of inflammatory genes in all epithelial cells tested, namely the adhesion molecules ICAM-1 and VCAM-1; the chemokines CCL5, CCL20, CXCL1, CXCL3, CXCL5, and CXCL11; the cytokines IL-6, activin A and GM-CSF; and metalloproteinases matrix metalloproteinase-9 and a disintegrin and metalloproteinase domain-8. Importantly, induction of the majority of these inflammatory molecules was insensitive to the suppressive effects of the corticosteroid budesonide. LIGHT and LTαβ also moderately downregulated E-cadherin, a protein associated with maintaining epithelial integrity, but did not significantly drive production of extracellular matrix proteins or α-smooth muscle actin. Thus, LIGHT and LTαβ induce a distinct steroid-resistant inflammatory signature in airway epithelial cells via constitutively expressed LTβ receptor. These findings support our prior murine studies that suggested the receptors for LIGHT and LTαβ contribute to development of lung inflammation characteristic of asthma and idiopathic pulmonary fibrosis.

  5. Targeting Heat Shock Protein 90 Overrides the Resistance of Lung Cancer Cells by Blocking Radiation-induced Stabilization of Hypoxia-inducible Factor 1α

    PubMed Central

    Kim, Woo-Young; Oh, Seung Hyun; Woo, Jong-Kyu; Hong, Waun Ki; Lee, Ho-Young

    2008-01-01

    Hypoxia-inducible factor-1 (HIF-1) has been suggested to play a major role in tumor radioresistance. However, the mechanisms through which irradiation regulates HIF-1α expression remain unclear. The purpose of this study was to investigate the mechanisms that mediate HIF-1 activation and thus radioresistance. Here we show that irradiation induces survival and angiogenic activity in a subset of radioresistant lung cancer cell lines by elevating HIF-1α protein expression. Radiation induced HIF-1α protein expression mainly through two distinct pathways, including an increase in de novo protein synthesis via activation of PI3K/Akt/mTOR and stabilization of HIF-1α protein via augmenting the interaction between heat shock protein 90 (Hsp90) and HIF-1α protein. While the PI3K/Akt/mTOR pathway was activated by irradiation in all the lung cancer cells examined, the HSP90-HIF-1α interaction was enhanced in the resistant cells only. Inhibition of Hsp90 function by 17-AAG or deguelin, a novel natural inhibitor of HSP90, suppressed increases in HIF-1α/Hsp90 interaction and HIF-1α expression in radioresistant cells. Furthermore, combined treatment of radiation with deguelin significantly decreased the survival and angiogenic potential of radioresistant lung cancer cells in vitro. We finally determined in vivo that systemic administration of deguelin resulted in profound inhibition of tumor growth and angiogenesis when combined with radiation. These results provide a strong rationale to target Hsp90 as a means to block radiation-induced HIF-1α and thus to circumvent radioresistance in lung cancer cells. PMID:19176399

  6. NF-{kappa}B signaling is activated and confers resistance to apoptosis in three-dimensionally cultured EGFR-mutant lung adenocarcinoma cells

    SciTech Connect

    Sakuma, Yuji; Yamazaki, Yukiko; Nakamura, Yoshiyasu; Yoshihara, Mitsuyo; Matsukuma, Shoichi; Koizume, Shiro; Miyagi, Yohei

    2012-07-13

    Highlights: Black-Right-Pointing-Pointer EGFR-mutant cells in 3D culture resist EGFR inhibition compared with suspended cells. Black-Right-Pointing-Pointer Degradation of I{kappa}B and activation of NF-{kappa}B are observed in 3D-cultured cells. Black-Right-Pointing-Pointer Inhibiting NF-{kappa}B enhances the efficacy of the EGFR inhibitor in 3D-cultured cells. -- Abstract: Epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells in suspension undergo apoptosis to a greater extent than adherent cells in a monolayer when EGFR autophosphorylation is inhibited by EGFR tyrosine kinase inhibitors (TKIs). This suggests that cell adhesion to a culture dish may activate an anti-apoptotic signaling pathway other than the EGFR pathway. Since the microenvironment of cells cultured in a monolayer are substantially different to that of cells existing in three-dimension (3D) in vivo, we assessed whether two EGFR-mutant lung adenocarcinoma cell lines, HCC827 and H1975, were more resistant to EGFR TKI-induced apoptosis when cultured in a 3D extracellular matrix (ECM) as compared with in suspension. The ECM-adherent EGFR-mutant cells in 3D were significantly less sensitive to treatment with WZ4002, an EGFR TKI, than the suspended cells. Further, a marked degradation of I{kappa}B{alpha}, the inhibitor of nuclear factor (NF)-{kappa}B, was observed only in the 3D-cultured cells, leading to an increase in the activation of NF-{kappa}B. Moreover, the inhibition of NF-{kappa}B with pharmacological inhibitors enhanced EGFR TKI-induced apoptosis in 3D-cultured EGFR-mutant cells. These results suggest that inhibition of NF-{kappa}B signaling would render ECM-adherent EGFR-mutant lung adenocarcinoma cells in vivo more susceptible to EGFR TKI-induced cell death.

  7. Singular perturbation of absolute stability.

    NASA Technical Reports Server (NTRS)

    Siljak, D. D.

    1972-01-01

    It was previously shown (author, 1969) that the regions of absolute stability in the parameter space can be determined when the parameters appear on the right-hand side of the system equations, i.e., the regular case. Here, the effect on absolute stability of a small parameter attached to higher derivatives in the equations (the singular case) is studied. The Lur'e-Postnikov class of nonlinear systems is considered.

  8. Anticancer Effects of Paris Saponins by Apoptosis and PI3K/AKT Pathway in Gefitinib-Resistant Non-Small Cell Lung Cancer

    PubMed Central

    Zhu, Xinhai; Jiang, Hao; Li, Jinhui; Xu, Ji; Fei, Zhenghua

    2016-01-01

    Background Paris saponins have been studied for their anticancer effects in various cancer types, but the mechanisms underlying the cytotoxic effects, especially in EGFR-TKI-resistant cells, are still unclear. We explored the potential mechanism of the antitumor effects of PSI, II, VI, VII in EGFR-TKI-resistant cells and attempted to develop PSI, II, VI, VII as a systemic treatment strategy for EGFR-TKI-resistant lung cancer. Material/Methods Growth inhibition was detected by MTT assay. The apoptosis assay was detected using annexin-V/PI and Hoechst staining. The level of PI3K, pAKT, Bax, Bcl-2, caspase-3, and caspase-9 protein expression were detected using Western blot analysis. Results The results revealed that PSI, II, VI, VII inhibited the proliferation of PC-9-ZD cells. Furthermore, PSI, II, VI, VII induced significant cell apoptosis. The levels of PI3K, pAKT, Bcl-2 protein decreased, while the Bax, caspase-3, and caspase-9 protein was increased by PSI, II, PSVI, PSVII treatment and resulted in increased sensitivity to gefitinib in PC-9-ZD cells. Conclusions The underlying mechanism of Paris saponins may be related to targeting the PI3K/AKT pathways to cause apoptosis. Our results suggest a therapeutic potential of Paris saponins in clinical settings for gefitinib-resistant NSCLC. PMID:27125283

  9. Anticancer Effects of Paris Saponins by Apoptosis and PI3K/AKT Pathway in Gefitinib-Resistant Non-Small Cell Lung Cancer.

    PubMed

    Zhu, XinHai; Jiang, Hao; Li, Jinhui; Xu, Ji; Fei, Zhenghua

    2016-01-01

    BACKGROUND Paris saponins have been studied for their anticancer effects in various cancer types, but the mechanisms underlying the cytotoxic effects, especially in EGFR-TKI-resistant cells, are still unclear. We explored the potential mechanism of the antitumor effects of PSI, II, VI, VII in EGFR-TKI-resistant cells and attempted to develop PSI, II, VI, VII as a systemic treatment strategy for EGFR-TKI-resistant lung cancer. MATERIAL AND METHODS Growth inhibition was detected by MTT assay. The apoptosis assay was detected using annexin-V/PI and Hoechst staining. The level of PI3K, pAKT, Bax, Bcl-2, caspase-3, and caspase-9 protein expression were detected using Western blot analysis. RESULTS The results revealed that PSI, II, VI, VII inhibited the proliferation of PC-9-ZD cells. Furthermore, PSI, II, VI, VII induced significant cell apoptosis. The levels of PI3K, pAKT, Bcl-2 protein decreased, while the Bax, caspase-3, and caspase-9 protein was increased by PSI, II, PSVI, PSVII treatment and resulted in increased sensitivity to gefitinib in PC-9-ZD cells. CONCLUSIONS The underlying mechanism of Paris saponins may be related to targeting the PI3K/AKT pathways to cause apoptosis. Our results suggest a therapeutic potential of Paris saponins in clinical settings for gefitinib-resistant NSCLC. PMID:27125283

  10. Intrinsic resistance to selumetinib, a selective inhibitor of MEK1/2, by cAMP-dependent protein kinase A activation in human lung and colorectal cancer cells

    PubMed Central

    Troiani, T; Vecchione, L; Martinelli, E; Capasso, A; Costantino, S; Ciuffreda, L P; Morgillo, F; Vitagliano, D; D'Aiuto, E; De Palma, R; Tejpar, S; Van Cutsem, E; De Lorenzi, M; Caraglia, M; Berrino, L; Ciardiello, F

    2012-01-01

    Background: MEK is activated in ∼40% colorectal cancer (CRC) and 20–30% non-small cell lung cancer (NSCLC). Selumetinib is a selective inhibitor of MEK1/2, which is currently in clinical development. Methods: We evaluated the effects of selumetinib in vitro and in vivo in CRC and NSCLC cell lines to identify cancer cell characteristics correlating with sensitivity to MEK inhibition. Results: Five NSCLC and six CRC cell lines were treated with selumetinib and classified according to the median inhibitory concentration (IC50) values as sensitive (⩽1 μℳ) or resistant (>1 μℳ). In selumetinib-sensitive cancer cell lines, selumetinib treatment induced G1 cell-cycle arrest and apoptosis and suppression of tumour growth as xenografts in immunodeficient mice. Evaluation of intracellular effector proteins and analysis of gene mutations showed no correlation with selumetinib sensitivity. Microarray gene expression profiles revealed that the activation of cAMP-dependent protein kinase A (PKA) was associated with MEK inhibitor resistance. Combined targeting of both MEK and PKA resulted in cancer cell growth inhibition of MEK inhibitor-resistant cancer cell lines in vitro and in vivo. Conclusion: This study provides molecular insights to explain resistance to an MEK inhibitor in human cancer cell lines. PMID:22569000

  11. Uncommon epidermal growth factor receptor mutations in non-small cell lung cancer and their mechanisms of EGFR tyrosine kinase inhibitors sensitivity and resistance.

    PubMed

    Massarelli, Erminia; Johnson, Faye M; Erickson, Heidi S; Wistuba, Ignacio I; Papadimitrakopoulou, Vassiliki

    2013-06-01

    Therapy targeted against the epidermal growth factor receptor (EGFR) has demonstrated dramatic tumor responses and favorable clinical outcomes in a select group of non-small cell lung cancer (NSCLC) patients whose tumors harbor EGFR activating mutations. The best characterized of the mutations conferring sensitivity to EGFR tyrosine kinase inhibitors (TKIs) are deletions in exon 19 and a point mutation in exon 21 (L858R). Likewise, the most common mutation that confers resistance is the T790M point mutation. However several other mutations have been reported and several have been characterized as regards their role in sensitivity or resistance to EGFR TKIs. Resistance to the EGFR TKIs erlotinib and gefitinib, and the newer irreversible EGFR TKIs is a problem of fundamental importance. Recognition of the presence and significance of specific EGFR mutations is important for appropriate therapeutic implementation of EGFR TKIs and research and development of mutation-specific inhibitors. We summarize the literature and present an overview of the subject of less common EGFR mutations and their clinical significance, with an emphasis on EGFR TKI sensitivity or resistance.

  12. Abscess in the Lungs

    MedlinePlus

    ... abscesses are streptococci and staphylococci, including methicillin-resistant Staphylococcus aureus (MRSA), which is a serious infection. Obstruction ... night sweats. In contrast, lung abscesses caused by Staphylococcus aureus or MRSA can be fatal within days, ...

  13. Rapid detection of the epidermal growth factor receptor mutation in non-small-cell lung cancer for analysis of acquired resistance using molecular beacons.

    PubMed

    Oh, Young-Hee; Kim, Youngwook; Kim, Young-Pil; Seo, Soo-Won; Mitsudomi, Tetsuya; Ahn, Myung-Ju; Park, Keunchil; Kim, Hak-Sung

    2010-09-01

    A secondary mutation (T790M) in epidermal growth factor receptor (EGFR) is a hallmark of acquired resistance to EGFR inhibitors used to treat non-small-cell lung cancer (NSCLC). Therefore, identifying the T790M mutation is crucial to guide treatment decisions. Given that DNA sequencing methods are time-consuming and insensitive, we developed and investigated the feasibility of using molecular beacons for the detection of the T790M mutation in EGFR. A molecular beacon complementary to the region of the secondary EGFR mutation (T790M) was designed and used in NSCLC samples bearing drug-sensitive and -resistant EGFR mutations. For a rapid and simple assay, we attempted to use the molecular beacon with real-time PCR and in situ fluorescence imaging. The ability of the designed molecular beacon to specifically detect the T790M mutation of EGFR was tested for samples from two patients with drug resistance and compared with conventional DNA sequencing methods. The molecular beacon successfully detected the T790M mutation in patient samples with drug resistance. The sensitivity of the molecular beacon, which detected as little as 2% of genomic DNA from the drug-resistant cells (H1975), was much higher than direct sequencing. Furthermore, in situ fluorescence imaging with the molecular beacon gave rise to a distinguishable signal for the T790M mutation in drug-resistant cells. The molecular beacon-based approach enabled rapid and sensitive detection of the EGFR mutation (T790M) in NSCLC with in situ fluorescence imaging, which can be directed to determine various treatment options in patients with cancer.

  14. Long-term Exposure to PM10 and NO2 in Association with Lung Volume and Airway Resistance in the MAAS Birth Cohort

    PubMed Central

    Agius, Raymond M.; de Vocht, Frank; Lindley, Sarah; Gerrard, William; Lowe, Lesley; Belgrave, Danielle; Custovic, Adnan; Simpson, Angela

    2013-01-01

    Background: Findings from previous studies on the effects of air pollution exposure on lung function during childhood have been inconsistent. A common limitation has been the quality of exposure data used, and few studies have modeled exposure longitudinally throughout early life. Objectives: We sought to study the long-term effects of exposure to particulate matter with an aerodynamic diameter ≤ 10 μm (PM10) and to nitrogen dioxide (NO2) on specific airway resistance (sRaw) and forced expiratory volume in 1 sec (FEV1) before and after bronchodilator treatment. Subjects were from the Manchester Asthma and Allergy Study (MAAS) birth cohort (n = 1,185). Methods: Spirometry was performed during clinic visits at ages 3, 5, 8, and 11 years. Individual-level PM10 and NO2 exposures were estimated from birth to 11 years of age through a microenvironmental exposure model. Longitudinal and cross-sectional associations were estimated using generalized estimating equations and multivariable linear regression models. Results: Lifetime exposure to PM10 and NO2 was associated with significantly less growth in FEV1 (percent predicted) over time, both before (–1.37%; 95% CI: –2.52, –0.23 for a 1-unit increase in PM10 and –0.83%; 95% CI: –1.39, –0.28 for a 1-unit increase in NO2) and after bronchodilator treatment (–3.59%; 95% CI: –5.36, –1.83 and –1.20%; 95% CI: –1.97, –0.43, respectively). We found no association between lifetime exposure and sRaw over time. Cross-sectional analyses of detailed exposure estimates for the summer and winter before 11 years of age and lung function at 11 years indicated no significant associations. Conclusions: Long-term PM10 and NO2 exposures were associated with small but statistically significant reductions in lung volume growth in children of elementary-school age. Citation: Mölter A, Agius RM, de Vocht F, Lindley S, Gerrard W, Lowe L, Belgrave D, Custovic A, Simpson A. 2013. Long-term exposure to PM10 and NO2 in

  15. Absolute flux scale for radioastronomy

    SciTech Connect

    Ivanov, V.P.; Stankevich, K.S.

    1986-07-01

    The authors propose and provide support for a new absolute flux scale for radio astronomy, which is not encumbered with the inadequacies of the previous scales. In constructing it the method of relative spectra was used (a powerful tool for choosing reference spectra). A review is given of previous flux scales. The authors compare the AIS scale with the scale they propose. Both scales are based on absolute measurements by the ''artificial moon'' method, and they are practically coincident in the range from 0.96 to 6 GHz. At frequencies above 6 GHz, 0.96 GHz, the AIS scale is overestimated because of incorrect extrapolation of the spectra of the primary and secondary standards. The major results which have emerged from this review of absolute scales in radio astronomy are summarized.

  16. Yu Ping Feng San reverses cisplatin-induced multi-drug resistance in lung cancer cells via regulating drug transporters and p62/TRAF6 signalling

    PubMed Central

    Lou, Jian-Shu; Yan, Lu; Bi, Cathy W. C.; Chan, Gallant K. L.; Wu, Qi-Yun; Liu, Yun-Le; Huang, Yun; Yao, Ping; Du, Crystal Y. Q.; Dong, Tina T. X.; Tsim, Karl W. K.

    2016-01-01

    Yu Ping Feng San (YPFS), an ancient Chinese herbal decoction composed of Astragali Radix, Atractylodis Macrocephalae Rhizoma and Saposhnikoviae Radix, has been used in the clinic for treating immune deficiency. In cancer therapy, YPFS is being combined with chemotherapy drugs to achieve improved efficacy; however, scientific evidence to illustrate this combination effect is lacking. The present study aims to demonstrate the anti-drug resistance of YPFS in cisplatin (DDP)-resistant non-small cell lung cancer cells (A549/DDP). The application of YPFS exhibited a synergistic enhancement of DDP-induced cytotoxicity as well as of the apoptotic signalling molecules. DDP-induced expression of the multi-drug-resistance efflux transporters was markedly reduced in the presence of YPFS, resulting in a higher intracellular concentration of DDP. In addition, the application of YPFS increased DDP-induced ROS accumulation and MMP depletion, decreased p62/TRAF6 signalling in DDP-treated A549/DDP cells. The co-treatment of DDP and YPFS in tumour-bearing mice reduced the tumour size robustly (by more than 80%), which was much better than the effect of DDP alone. These results indicate that YPFS can notably improve the DDP-suppressed cancer effect, which may be a consequence of the elevation of intracellular DDP via the drug transporters as well as the down regulation of p62/TRAF6 signalling. PMID:27558312

  17. Immunomodulatory Protein from Ganoderma microsporum Induces Pro-Death Autophagy through Akt-mTOR-p70S6K Pathway Inhibition in Multidrug Resistant Lung Cancer Cells.

    PubMed

    Chiu, Ling-Yen; Hu, Ming-E; Yang, Tsung-Ying; Hsin, I-Lun; Ko, Jiunn-Liang; Tsai, Kan-Jen; Sheu, Gwo-Tarng

    2015-01-01

    Chemoresistance in cancer therapy is an unfavorable prognostic factor in non-small cell lung cancer (NSCLC). Elevation of intracellular calcium level in multidrug resistant (MDR) sublines leads to sensitization of MDR sublines to cell death. We demonstrated that a fungal protein from Ganoderma microsporum, GMI, elevates the intracellular calcium level and reduces the growth of MDR subline via autophagy and apoptosis, regardless of p-glycoprotein (P-gp) overexpression, in mice xenograft tumors. In addition, we examined the roles of autophagy in the death of MDR A549 lung cancer sublines by GMI, thapsigargin (TG) and tunicamycin (TM) in vitro. Cytotoxicity of TG was inhibited by overexpressed P-gp. However, TM-induced death of MDR sublines was independent of P-gp level. Combinations of TG and TM with either docetaxel or vincristine showed no additional cytotoxic effects on MDR sublines. TG- and TM-mediated apoptosis of MDR sublines was demonstrated on Annexin-V assay and Western blot and repressed by pan-caspase inhibitor (Z-VAD-FMK). Treatment of MDR sublines with TG and TM also augmented autophagy with accumulation of LC3-II proteins, breakdown of p62 and formation of acidic vesicular organelles (AVOs). Inhibition of ATG5 by shRNA silencing significantly reduced autophagy and cell death but not apoptosis following TG or TM treatment. GMI treatment inhibited the phosphorylation of Akt/S473 and p70S6K/T389. Interestingly, the phosphorylation of ERK was not associated with GMI-induced autophagy. We conclude that autophagy plays a pro-death role in acquired MDR and upregulation of autophagy by GMI via Akt/mTOR inhibition provides a potential strategy for overcoming MDR in the treatment of lung cancers.

  18. Lung Emergencies

    MedlinePlus

    ... Emergencies Cardiac Emergencies Eye Emergencies Lung Emergencies Surgeries Lung Emergencies People with Marfan syndrome can be at ... should be considered an emergency. Symptoms of sudden lung collapse (pneumothorax) Symptoms of a sudden lung collapse ...

  19. Lung Cancer

    MedlinePlus

    ... version of this page please turn Javascript on. Lung Cancer What is Lung Cancer? How Tumors Form The body is made ... button on your keyboard.) Two Major Types of Lung Cancer There are two major types of lung ...

  20. Lung metastases

    MedlinePlus

    Metastases to the lung; Metastatic cancer to the lung ... Metastatic tumors in the lungs are cancers that developed at other places in the body (or other parts of the lungs) and spread through the ...

  1. Adenovirus vector infection of non-small-cell lung cancer cells is a trigger for multi-drug resistance mediated by P-glycoprotein.

    PubMed

    Tomono, Takumi; Kajita, Masahiro; Yano, Kentaro; Ogihara, Takuo

    2016-08-01

    P-glycoprotein (P-gp) is an ATP-binding cassette protein involved in cancer multi-drug resistance (MDR). It has been reported that infection with some bacteria and viruses induces changes in the activities of various drug-metabolizing enzymes and transporters, including P-gp. Although human adenoviruses (Ad) cause the common cold, the effect of Ad infection on MDR in cancer has not been established. In this study, we investigated whether Ad infection is a cause of MDR in A549, H441 and HCC827 non-small-cell lung cancer (NSCLC) cell lines, using an Ad vector system. We found that Ad vector infection of NSCLC cell lines induced P-gp mRNA expression, and the extent of induction was dependent on the number of Ad vector virus particles and the infection time. Heat-treated Ad vector, which is not infectious, did not alter P-gp mRNA expression. Uptake experiments with doxorubicin (DOX), a P-gp substrate, revealed that DOX accumulation was significantly decreased in Ad vector-infected A549 cells. The decrease of DOX uptake was blocked by verapamil, a P-gp inhibitor. Our results indicated that Ad vector infection of NSCLC cells caused MDR mediated by P-gp overexpression. The Ad vector genome sequence is similar to that of human Ad, and therefore human Ad infection of lung cancer patients may lead to chemoresistance in the clinical environment.

  2. Cerium-144-induced lung gumors in two strains of mice

    SciTech Connect

    Hahn, F.F.; Griffith, W.C.

    1995-12-01

    A major problem in the extrapolation of radiation cancer risk factors from one species or population to another is the choice of the risk model to use, either absolute or relative. The purpose of this study was to compare absolute and relative risk models in predicting the lung-tumor risks between a low lung-tumor incidence strain of mice and a high-incidence strain of mice. The conclusion from this study is that absolute risk is more accurate than relative risk for predicting lung tumor risk from high to low lung-tumor incidence strains of mice.

  3. The DNA Methyltransferase DNMT1 and Tyrosine-Protein Kinase KIT Cooperatively Promote Resistance to 5-Aza-2'-deoxycytidine (Decitabine) and Midostaurin (PKC412) in Lung Cancer Cells.

    PubMed

    Yan, Fei; Shen, Na; Pang, Jiuxia; Molina, Julian R; Yang, Ping; Liu, Shujun

    2015-07-24

    Lung cancer cells are sensitive to 5-aza-2'-deoxycytidine (decitabine) or midostaurin (PKC412), because decitabine restores the expression of methylation-silenced tumor suppressor genes, whereas PKC412 inhibits hyperactive kinase signaling, which is essential for cancer cell growth. Here, we demonstrated that resistance to decitabine (decitabine(R)) or PKC412 (PKC412(R)) eventually results from simultaneously remethylated DNA and reactivated kinase cascades. Indeed, both decitabine(R) and PKC412(R) displayed the up-regulation of DNA methyltransferase DNMT1 and tyrosine-protein kinase KIT, the enhanced phosphorylation of KIT and its downstream effectors, and the increased global and gene-specific DNA methylation with the down-regulation of tumor suppressor gene epithelial cadherin CDH1. Interestingly, decitabine(R) and PKC412(R) had higher capability of colony formation and wound healing than parental cells in vitro, which were attributed to the hyperactive DNMT1 or KIT, because inactivation of KIT or DNMT1 reciprocally blocked decitabine(R) or PKC412(R) cell proliferation. Further, DNMT1 knockdown sensitized PKC412(R) cells to PKC412; conversely, KIT depletion synergized with decitabine in eliminating decitabine(R). Importantly, when engrafted into nude mice, decitabine(R) and PKC412(R) had faster proliferation with stronger tumorigenicity that was caused by the reactivated KIT kinase signaling and further CDH1 silencing. These findings identify functional cross-talk between KIT and DNMT1 in the development of drug resistance, implying the reciprocal targeting of protein kinases and DNA methyltransferases as an essential strategy for durable responses in lung cancer.

  4. Electroneutral composite polymersomes self-assembled by amphiphilic polyphosphazenes for effective miR-200c in vivo delivery to inhibit drug resistant lung cancer.

    PubMed

    Peng, Yan; Zhu, Xiumei; Qiu, Liyan

    2016-11-01

    MiR-200c has been confirmed to display remarkable effects on proliferation inhibition and apoptosis induction of certain cancer cells, but the main challenge for its successful translation into the clinic remains its effective delivery to the action site in vivo. In this study, a novel composite polyphosphazene vesicle system composed of amphiphilic [NP(PEG)0.3(EAB)1.7]n (PEEP) and weakly cationic [NP(PEG)0.5(DPA)1.5]n (PEDP) was prepared via a very simple dialysis method. The loading of miR-200c was accomplished with high efficiency by taking advantage of the combination effect of physical encapsulation and electrostatic interaction between vectors and miR-200c. The resultant miR-200c-loaded PEEP-PEDP polymersome (Nano-ED-200c) displayed suitable particle size, electric neutrality, excellent Ribonuclease stability and hemocompatibility. We also evaluated its subsequent miR-200c function in paclitaxel resistance human lung cancer (A549/T) cells in culture and tumor xenografts in nude mice. The results showed that Nano-ED-200c could achieve a higher miR-200c level and the enhanced antitumor efficacy with 68% tumor inhibition ratio at a very low dose of 1.0 mg/kg than PEEP nanoparticle, PEDP nanoparticle, even than Lipo2000. All these evidences indicated that this miR-200c delivery via polyphosphazene vesicles could act as a potential new therapeutic option for paclitaxel resistant human lung cancer.

  5. Low or high doses of cefquinome targeting low or high bacterial inocula cure Klebsiella pneumoniae lung infections but differentially impact the levels of antibiotic resistance in fecal flora.

    PubMed

    Vasseur, Maleck V; Laurentie, Michel; Rolland, Jean-Guy; Perrin-Guyomard, Agnès; Henri, Jérôme; Ferran, Aude A; Toutain, Pierre-Louis; Bousquet-Mélou, Alain

    2014-01-01

    The combination of efficacious treatment against bacterial infections and mitigation of antibiotic resistance amplification in gut microbiota is a major challenge for antimicrobial therapy in food-producing animals. In rats, we evaluated the impact of cefquinome, a fourth-generation cephalosporin, on both Klebsiella pneumoniae lung infection and intestinal flora harboring CTX-M-producing Enterobacteriaceae. Germfree rats received a fecal flora specimen from specific-pathogen-free pigs, to which a CTX-M-producing Escherichia coli strain had been added. K. pneumoniae cells were inoculated in the lungs of these gnotobiotic rats by using either a low (10(5) CFU) or a high (10(9) CFU) inoculum. Without treatment, all animals infected with the low or high K. pneumoniae inoculum developed pneumonia and died before 120 h postchallenge. In the treated groups, the low-inoculum rats received a 4-day treatment of 5 mg/kg of body weight cefquinome beginning at 24 h postchallenge (prepatent phase of the disease), and the high-inoculum rats received a 4-day treatment of 50 mg/kg cefquinome beginning when the animals expressed clinical signs of infection (patent phase of the disease). The dose of 50 mg/kg targeting the high K. pneumoniae inoculum cured all the treated rats and resulted in a massive amplification of CTX-M-producing Enterobacteriaceae. A dose of 5 mg/kg targeting the low K. pneumoniae inoculum cured all the rats and averted an outbreak of clinical disease, all without any amplification of CTX-M-producing Enterobacteriaceae. These findings might have implications for the development of new antimicrobial treatment strategies that ensure a cure for bacterial infections while avoiding the amplification of resistance genes of human concern in the gut microbiota of food-producing animals.

  6. Electroneutral composite polymersomes self-assembled by amphiphilic polyphosphazenes for effective miR-200c in vivo delivery to inhibit drug resistant lung cancer.

    PubMed

    Peng, Yan; Zhu, Xiumei; Qiu, Liyan

    2016-11-01

    MiR-200c has been confirmed to display remarkable effects on proliferation inhibition and apoptosis induction of certain cancer cells, but the main challenge for its successful translation into the clinic remains its effective delivery to the action site in vivo. In this study, a novel composite polyphosphazene vesicle system composed of amphiphilic [NP(PEG)0.3(EAB)1.7]n (PEEP) and weakly cationic [NP(PEG)0.5(DPA)1.5]n (PEDP) was prepared via a very simple dialysis method. The loading of miR-200c was accomplished with high efficiency by taking advantage of the combination effect of physical encapsulation and electrostatic interaction between vectors and miR-200c. The resultant miR-200c-loaded PEEP-PEDP polymersome (Nano-ED-200c) displayed suitable particle size, electric neutrality, excellent Ribonuclease stability and hemocompatibility. We also evaluated its subsequent miR-200c function in paclitaxel resistance human lung cancer (A549/T) cells in culture and tumor xenografts in nude mice. The results showed that Nano-ED-200c could achieve a higher miR-200c level and the enhanced antitumor efficacy with 68% tumor inhibition ratio at a very low dose of 1.0 mg/kg than PEEP nanoparticle, PEDP nanoparticle, even than Lipo2000. All these evidences indicated that this miR-200c delivery via polyphosphazene vesicles could act as a potential new therapeutic option for paclitaxel resistant human lung cancer. PMID:27541441

  7. Relativistic Absolutism in Moral Education.

    ERIC Educational Resources Information Center

    Vogt, W. Paul

    1982-01-01

    Discusses Emile Durkheim's "Moral Education: A Study in the Theory and Application of the Sociology of Education," which holds that morally healthy societies may vary in culture and organization but must possess absolute rules of moral behavior. Compares this moral theory with current theory and practice of American educators. (MJL)

  8. Absolute transition probabilities of phosphorus.

    NASA Technical Reports Server (NTRS)

    Miller, M. H.; Roig, R. A.; Bengtson, R. D.

    1971-01-01

    Use of a gas-driven shock tube to measure the absolute strengths of 21 P I lines and 126 P II lines (from 3300 to 6900 A). Accuracy for prominent, isolated neutral and ionic lines is estimated to be 28 to 40% and 18 to 30%, respectively. The data and the corresponding theoretical predictions are examined for conformity with the sum rules.-

  9. Lung cancer

    SciTech Connect

    Aisner, J.

    1985-01-01

    This book contains 13 chapters. Some of the chapter titles are: The Pathology of Lung Cancer; Radiotherapy for Non-Small-Cell Cancer of the Lung; Chemotherapy for Non-Small-Cell Lung Cancer; Immunotherapy in the Management of Lung Cancer; Preoperative Staging and Surgery for Non-Small-Cell Lung Cancer; and Prognostic Factors in Lung Cancer.

  10. Modulation of intrinsic in vitro resistance to carboplatin by edatrexate in the A549 human nonsmall cell lung cancer cell line.

    PubMed

    Perez, E A; Hack, F M; Fletcher, T S; Chou, T C

    1994-01-01

    Edatrexate (10-ethyl-deazaaminopterin) is a methotrexate analog that has been shown to have greater antitumor activity and improved therapeutic index compared to its parent compound in preclinical systems. We have evaluated the ability of edatrexate to modulate the intrinsic resistance of the lung adenocarcinoma A549 cell line to carboplatin. Concentration effects, exposure time and schedule dependence were assessed. Modulation of resistance was observed with edatrexate treatment (0.2 microM for 1 h) prior to carboplatin. The concentrations of carboplatin to achieve IC50 at the 1-, 3-, and 24-h IC50 were decreased by a mean of 16.8 times (12.2-22.2) with edatrexate preexposure. In contrast, there was little modulation observed of carboplatin resistance when carboplatin was administered prior to edatrexate. In addition, schedule dependency experiments were performed using the method described by Chou and Talalay, in which the ratio of carboplatin to edatrexate was constant or nonconstant, and both the potency of effects and the shapes of the concentration-effect curves were taken into account in a computerized analysis. These experiments also demonstrated schedule dependency. Although both treatments resulted in a reduced IC50 vs. carboplatin alone, the reduction was much greater when edatrexate was added first (12.59 vs. 2.59 times). We conclude that the combination of edatrexate and carboplatin demonstrates schedule-dependent modulation of intrinsic carboplatin resistance in this in vitro model at clinically achievable edatrexate plasma levels (0.01 to 10 microM). The greatest modulatory synergism was observed in the setting of edatrexate treatment before carboplatin. Our findings suggest a potentially useful schedule when combining edatrexate and carboplatin for the treatment of malignant disease.

  11. Clonal dissemination, emergence of mutator lineages and antibiotic resistance evolution in Pseudomonas aeruginosa cystic fibrosis chronic lung infection.

    PubMed

    López-Causapé, Carla; Rojo-Molinero, Estrella; Mulet, Xavier; Cabot, Gabriel; Moyà, Bartolomé; Figuerola, Joan; Togores, Bernat; Pérez, José L; Oliver, Antonio

    2013-01-01

    Chronic respiratory infection by Pseudomonas aeruginosa is a major cause of mortality in cystic fibrosis (CF). We investigated the interplay between three key microbiological aspects of these infections: the occurrence of transmissible and persistent strains, the emergence of variants with enhanced mutation rates (mutators) and the evolution of antibiotic resistance. For this purpose, 10 sequential isolates, covering up to an 8-year period, from each of 10 CF patients were studied. As anticipated, resistance significantly accumulated overtime, and occurred more frequently among mutator variants detected in 6 of the patients. Nevertheless, highest resistance was documented for the nonmutator CF epidemic strain LES-1 (ST-146) detected for the first time in Spain. A correlation between resistance profiles and resistance mechanisms evaluated [efflux pump (mexB, mexD, mexF, and mexY) and ampC overexpression and OprD production] was not always obvious and hypersusceptibility to certain antibiotics (such as aztreonam or meropenem) was frequently observed. The analysis of whole genome macrorestriction fragments through Pulsed-Field Gel Electrophoresis (PFGE) revealed that a single genotype (clone FQSE-A) produced persistent infections in 4 of the patients. Multilocus Sequence typing (MLST) identified clone FQSE-A as the CF epidemic clone ST-274, but striking discrepancies between PFGE and MLST profiles were evidenced. While PFGE macrorestriction patterns remained stable, a new sequence type (ST-1089) was detected in two of the patients, differing from ST-274 by only two point mutations in two of the genes, each leading to a nonpreviously described allele. Moreover, detailed genetic analyses revealed that the new ST-1089 is a mutS deficient mutator lineage that evolved from the epidemic strain ST-274, acquired specific resistance mechanisms, and underwent further interpatient spread. Thus, presented results provide the first evidence of interpatient dissemination of mutator

  12. Drug resistance to paclitaxel is not only associated with ABCB1 mRNA expression but also with drug accumulation in intracellular compartments in human lung cancer cell lines.

    PubMed

    Shimomura, Masanori; Yaoi, Takeshi; Itoh, Kyoko; Kato, Daishiro; Terauchi, Kunihiko; Shimada, Junichi; Fushiki, Shinji

    2012-04-01

    In order to clarify the mechanisms of resistance to paclitaxel in lung cancer, three human lung cancer cell lines which exhibit different sensitivity to paclitaxel were investigated from the following viewpoints: overexpression of ATP-binding cassette, sub-family B, member 1 (ABCB1), mutations on paclitaxel binding site of β-tubulin genes, quantity of polymerized tubulin and the intracellular localization of paclitaxel. ABCB1 expression was evaluated by real-time RT-PCR. No correlations were noted between the ABCB1 expression in the sensitive and resistant cell lines at the mRNA level. No mutations on the paclitaxel binding site of the β-tubulin genes were detected in either the resistant or sensitive cells. Live cell images obtained by confocal laser microscopy revealed that the resistant cell line, RERF-LC-KJ, had more accumulation of Oregon Green® 488 conjugated paclitaxel in the lysosomal and extra-lysosomal compartments of cytoplasm than other cell lines. The results obtained in this study indicated that the changes in the subcellular localization could contribute to the production of paclitaxel resistance in lung cancer cell lines. Further studies should be conducted to elucidate the molecular mechanisms that differentiate the intracellular localization of paclitaxel. PMID:22179563

  13. Drug resistance to paclitaxel is not only associated with ABCB1 mRNA expression but also with drug accumulation in intracellular compartments in human lung cancer cell lines

    PubMed Central

    SHIMOMURA, MASANORI; YAOI, TAKESHI; ITOH, KYOKO; KATO, DAISHIRO; TERAUCHI, KUNIHIKO; SHIMADA, JUNICHI; FUSHIKI, SHINJI

    2012-01-01

    In order to clarify the mechanisms of resistance to paclitaxel in lung cancer, three human lung cancer cell lines which exhibit different sensitivity to paclitaxel were investigated from the following viewpoints: overexpression of ATP-binding cassette, sub-family B, member 1 (ABCB1), mutations on paclitaxel binding site of β-tubulin genes, quantity of polymerized tubulin and the intracellular localization of paclitaxel. ABCB1 expression was evaluated by real-time RT-PCR. No correlations were noted between the ABCB1 expression in the sensitive and resistant cell lines at the mRNA level. No mutations on the paclitaxel binding site of the β-tubulin genes were detected in either the resistant or sensitive cells. Live cell images obtained by confocal laser microscopy revealed that the resistant cell line, RERF-LC-KJ, had more accumulation of Oregon Green® 488 conjugated paclitaxel in the lysosomal and extra-lysosomal compartments of cytoplasm than other cell lines. The results obtained in this study indicated that the changes in the subcellular localization could contribute to the production of paclitaxel resistance in lung cancer cell lines. Further studies should be conducted to elucidate the molecular mechanisms that differentiate the intracellular localization of paclitaxel. PMID:22179563

  14. Bcl-2 anti-apoptotic oncoprotein suppresses angiogenesis in non-small cell lung cancer: implications in resistance to photodynamic treatment?

    NASA Astrophysics Data System (ADS)

    Koukourakis, M. I.; Giatromanolaki, A.; Skarlatos, J.; Kosma, L.; Apostolikas, N.; Beroukas, K.

    1998-07-01

    PDT cytotoxicity is likely to occur through photooxidative reactions. In that way mechanisms that define poor oxygenation should be involved in defining resistance to photo-dynamic treatment (PDT). On the other hand bcl-2 anti- apoptotic protein has been shown to delay cell death and protect cells from toxic oxidative products. We examined 134 specimens from T1,2-NO,1 staged patients treated with surgery alone. Specimens were immunohistochemically examined for vascular grade using the JC70 MoAb, and bcl-2 oncoprotein expression. Bcl-2 expression correlated with low vascular grade. Only 3/27 of bcl2+ case had high angiogenesis vs. 34/107 of cases without bcl-2 expression. In the present study we provide evidence that bcl-2 overexpression directly suppresses angiogenesis in non-small cell lung cancer, which obviously results in decreased blood supply and oxygenation. This finding implies that reduced intratumoral angiogenesis and immortalizing oncoprotein overexpression are linked to each other and may have a role in defining tumors resistant to PDT.

  15. Advances in molecular-based personalized non-small-cell lung cancer therapy: targeting epidermal growth factor receptor and mechanisms of resistance

    PubMed Central

    Jotte, Robert M; Spigel, David R

    2015-01-01

    Molecularly targeted therapies, directed against the features of a given tumor, have allowed for a personalized approach to the treatment of advanced non-small-cell lung cancer (NSCLC). The reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib had undergone turbulent clinical development until it was discovered that these agents have preferential activity in patients with NSCLC harboring activating EGFR mutations. Since then, a number of phase 3 clinical trials have collectively shown that EGFR-TKI monotherapy is more effective than combination chemotherapy as first-line therapy for EGFR mutation-positive advanced NSCLC. The next generation of EGFR-directed agents for EGFR mutation-positive advanced NSCLC is irreversible TKIs against EGFR and other ErbB family members, including afatinib, which was recently approved, and dacomitinib, which is currently being tested in phase 3 trials. As research efforts continue to explore the various proposed mechanisms of acquired resistance to EGFR-TKI therapy, agents that target signaling pathways downstream of EGFR are being studied in combination with EGFR TKIs in molecularly selected advanced NSCLC. Overall, the results of numerous ongoing phase 3 trials involving the EGFR TKIs will be instrumental in determining whether further gains in personalized therapy for advanced NSCLC are attainable with newer agents and combinations. This article reviews key clinical trial data for personalized NSCLC therapy with agents that target the EGFR and related pathways, specifically based on molecular characteristics of individual tumors, and mechanisms of resistance. PMID:26310719

  16. Advances in molecular-based personalized non-small-cell lung cancer therapy: targeting epidermal growth factor receptor and mechanisms of resistance.

    PubMed

    Jotte, Robert M; Spigel, David R

    2015-11-01

    Molecularly targeted therapies, directed against the features of a given tumor, have allowed for a personalized approach to the treatment of advanced non-small-cell lung cancer (NSCLC). The reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib had undergone turbulent clinical development until it was discovered that these agents have preferential activity in patients with NSCLC harboring activating EGFR mutations. Since then, a number of phase 3 clinical trials have collectively shown that EGFR-TKI monotherapy is more effective than combination chemotherapy as first-line therapy for EGFR mutation-positive advanced NSCLC. The next generation of EGFR-directed agents for EGFR mutation-positive advanced NSCLC is irreversible TKIs against EGFR and other ErbB family members, including afatinib, which was recently approved, and dacomitinib, which is currently being tested in phase 3 trials. As research efforts continue to explore the various proposed mechanisms of acquired resistance to EGFR-TKI therapy, agents that target signaling pathways downstream of EGFR are being studied in combination with EGFR TKIs in molecularly selected advanced NSCLC. Overall, the results of numerous ongoing phase 3 trials involving the EGFR TKIs will be instrumental in determining whether further gains in personalized therapy for advanced NSCLC are attainable with newer agents and combinations. This article reviews key clinical trial data for personalized NSCLC therapy with agents that target the EGFR and related pathways, specifically based on molecular characteristics of individual tumors, and mechanisms of resistance. PMID:26310719

  17. Optomechanics for absolute rotation detection

    NASA Astrophysics Data System (ADS)

    Davuluri, Sankar

    2016-07-01

    In this article, we present an application of optomechanical cavity for the absolute rotation detection. The optomechanical cavity is arranged in a Michelson interferometer in such a way that the classical centrifugal force due to rotation changes the length of the optomechanical cavity. The change in the cavity length induces a shift in the frequency of the cavity mode. The phase shift corresponding to the frequency shift in the cavity mode is measured at the interferometer output to estimate the angular velocity of absolute rotation. We derived an analytic expression to estimate the minimum detectable rotation rate in our scheme for a given optomechanical cavity. Temperature dependence of the rotation detection sensitivity is studied.

  18. Moral absolutism and ectopic pregnancy.

    PubMed

    Kaczor, C

    2001-02-01

    If one accepts a version of absolutism that excludes the intentional killing of any innocent human person from conception to natural death, ectopic pregnancy poses vexing difficulties. Given that the embryonic life almost certainly will die anyway, how can one retain one's moral principle and yet adequately respond to a situation that gravely threatens the life of the mother and her future fertility? The four options of treatment most often discussed in the literature are non-intervention, salpingectomy (removal of tube with embryo), salpingostomy (removal of embryo alone), and use of methotrexate (MXT). In this essay, I review these four options and introduce a fifth (the milking technique). In order to assess these options in terms of the absolutism mentioned, it will also be necessary to discuss various accounts of the intention/foresight distinction. I conclude that salpingectomy, salpingostomy, and the milking technique are compatible with absolutist presuppositions, but not the use of methotrexate.

  19. Moral absolutism and ectopic pregnancy.

    PubMed

    Kaczor, C

    2001-02-01

    If one accepts a version of absolutism that excludes the intentional killing of any innocent human person from conception to natural death, ectopic pregnancy poses vexing difficulties. Given that the embryonic life almost certainly will die anyway, how can one retain one's moral principle and yet adequately respond to a situation that gravely threatens the life of the mother and her future fertility? The four options of treatment most often discussed in the literature are non-intervention, salpingectomy (removal of tube with embryo), salpingostomy (removal of embryo alone), and use of methotrexate (MXT). In this essay, I review these four options and introduce a fifth (the milking technique). In order to assess these options in terms of the absolutism mentioned, it will also be necessary to discuss various accounts of the intention/foresight distinction. I conclude that salpingectomy, salpingostomy, and the milking technique are compatible with absolutist presuppositions, but not the use of methotrexate. PMID:11262641

  20. The Absolute Spectrum Polarimeter (ASP)

    NASA Technical Reports Server (NTRS)

    Kogut, A. J.

    2010-01-01

    The Absolute Spectrum Polarimeter (ASP) is an Explorer-class mission to map the absolute intensity and linear polarization of the cosmic microwave background and diffuse astrophysical foregrounds over the full sky from 30 GHz to 5 THz. The principal science goal is the detection and characterization of linear polarization from an inflationary epoch in the early universe, with tensor-to-scalar ratio r much greater than 1O(raised to the power of { -3}) and Compton distortion y < 10 (raised to the power of{-6}). We describe the ASP instrument and mission architecture needed to detect the signature of an inflationary epoch in the early universe using only 4 semiconductor bolometers.

  1. Classification images predict absolute efficiency.

    PubMed

    Murray, Richard F; Bennett, Patrick J; Sekuler, Allison B

    2005-02-24

    How well do classification images characterize human observers' strategies in perceptual tasks? We show mathematically that from the classification image of a noisy linear observer, it is possible to recover the observer's absolute efficiency. If we could similarly predict human observers' performance from their classification images, this would suggest that the linear model that underlies use of the classification image method is adequate over the small range of stimuli typically encountered in a classification image experiment, and that a classification image captures most important aspects of human observers' performance over this range. In a contrast discrimination task and in a shape discrimination task, we found that observers' absolute efficiencies were generally well predicted by their classification images, although consistently slightly (approximately 13%) higher than predicted. We consider whether a number of plausible nonlinearities can account for the slight under prediction, and of these we find that only a form of phase uncertainty can account for the discrepancy.

  2. Absolute calibration of optical flats

    DOEpatents

    Sommargren, Gary E.

    2005-04-05

    The invention uses the phase shifting diffraction interferometer (PSDI) to provide a true point-by-point measurement of absolute flatness over the surface of optical flats. Beams exiting the fiber optics in a PSDI have perfect spherical wavefronts. The measurement beam is reflected from the optical flat and passed through an auxiliary optic to then be combined with the reference beam on a CCD. The combined beams include phase errors due to both the optic under test and the auxiliary optic. Standard phase extraction algorithms are used to calculate this combined phase error. The optical flat is then removed from the system and the measurement fiber is moved to recombine the two beams. The newly combined beams include only the phase errors due to the auxiliary optic. When the second phase measurement is subtracted from the first phase measurement, the absolute phase error of the optical flat is obtained.

  3. Pyrazine, 2-ethylpyridine, and 3-ethylpyridine are cigarette smoke components that alter the growth of normal and malignant human lung cells, and play a role in multidrug resistance development.

    PubMed

    Liu, Min; Poo, Wak-Kim; Lin, Yu-Ling

    2015-02-01

    Lung cancer is one of the few human diseases for which the primary etiological agent, cigarette smoke (CS), has been described; however, the precise role of individual cigarette smoke toxicant in tumor development and progression remains to be elusive. The purpose of this study was to assess in vitro the effects of previously identified cigarette smoke components, pyrazine, 2-ethylpyridine, and 3-ethylpyridine, on non-tumorigenic (MRC5) and adenocarcinomic (A549) human lung cell lines. Our data showed that the administration of three cigarette smoke components in combination perturbed the proliferation of both normal and adenocarcinomic cells. Study of malignant cells revealed that CS components were cytotoxic at high concentration (10(-6) M) and stimulatory in a dose-dependent manner at lower concentrations (10(-8) M to 10(-10) M). This adverse effect was enhanced when adenocarcinomic cells were maintained in hypoxia resembling intratumoral environment. Furthermore, exposure to pyrazine, 2-ethylpyridine, and 3-ethylpyridine induced oxidative stress in both normal and malignant cells. Finally, assessment of P-gp activity revealed that multidrug resistance was induced in CS component exposed adenocarcinomic lung cells and the induction was augmented in hypoxia. Taken together, pyrazine, 2-ethylpyridine, and 3-ethylpyridine adversely altered both normal and diseased lung cells in vitro and data collected from this study may help lung cancer patients to understand the importance of quitting smoking during lung cancer treatment.

  4. Chemotherapy of non-small cell lung carcinoma guided by an in vitro drug resistance assay measuring total tumour cell kill.

    PubMed Central

    Wilbur, D. W.; Camacho, E. S.; Hilliard, D. A.; Dill, P. L.; Weisenthal, L. M.

    1992-01-01

    Specimens from 45 patients with previously-untreated non-small cell lung cancer (NSCLC) were tested for in vitro chemosensitivity to ten drugs utilising the DiSC assay, which measures cell kill in the total (largely non-dividing) tumour cell population. Thirty-five assays were successful and 25 patients with advanced disease subsequently received chemotherapy with the 'best' three drugs selected by the assay. Six patients were Karnofsky performance status 60 or less and the median pretreatment weight loss was 8.5%. Nine patients had a partial response (response rate = 36%; 95% confidence interval = 17-55%) and the median survival of all patients was 202 days. Specimens from responding patients were significantly more sensitive in the assay to drugs in general (especially to etoposide and to 'natural product' drugs) and to the drugs used in treatment than were specimens from non-responding patients. In vitro drug resistance differences between responding and non-responding patients were of greater significance than were differences between other clinical and laboratory measurements. Assay results classified patients into two cohorts, having relatively high and low probabilities of responding to chemotherapy. Assay results also identified patient cohorts with above average and below average durations of survival. Five patients (20%) were found to have tumours with extreme drug resistance (EDR), defined as assay results for the average of all ten tested drugs falling greater than one standard deviation more resistant than the median for all tumours assayed, and none of these patients with EDR responded to chemotherapy. PMID:1310250

  5. Chemotherapy With Erlotinib or Chemotherapy Alone in Advanced Non-Small Cell Lung Cancer With Acquired Resistance to EGFR Tyrosine Kinase Inhibitors

    PubMed Central

    Oxnard, Geoffrey R.; Digumarthy, Subba; Muzikansky, Alona; Jackman, David M.; Lennes, Inga T.; Sequist, Lecia V.

    2013-01-01

    Purpose. Epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer has an oncogene-addicted biology that confers sensitivity to EGFR tyrosine kinase inhibitors (TKIs). Published data suggest that EGFR addiction persists after development of TKI acquired resistance, leading many clinicians to continue TKI with subsequent chemotherapy; however, this strategy has not been formally evaluated. Methods. We retrospectively reviewed an institutional database to identify patients with advanced EGFR mutation with acquired resistance who subsequently received chemotherapy. Patients were classified as receiving chemotherapy with continued erlotinib or chemotherapy alone. We assessed differences in outcomes between the two strategies. Results. Seventy-eight patients were included, 34 treated with chemotherapy and erlotinib and 44 treated with chemotherapy alone. Objective response rate was evaluable in 57 patients and was 41% for those treated with chemotherapy and erlotinib and 18% for those treated with chemotherapy alone. After adjusting for chemotherapy regimen and length of initial TKI course, the odds ratio for the response rate was 0.20 (95% confidence interval: 0.05–0.78; p = .02) favoring treatment with chemotherapy and erlotinib. The median progression-free survival was 4.4 months on chemotherapy and erlotinib and 4.2 months on chemotherapy alone (adjusted hazard ratio = 0.79; 95% confidence interval: 0.48–1.29; p = .34). There was no difference in overall survival. Conclusion. This is the first study, to our knowledge, to demonstrate that continuation of EGFR TKI with chemotherapy in patients with acquired resistance improves outcomes compared with chemotherapy alone. We observed an improved response rate but no difference in progression-free survival or overall survival. A larger prospective clinical trial is needed to evaluate this promising strategy further. PMID:24072220

  6. The AFGL absolute gravity program

    NASA Technical Reports Server (NTRS)

    Hammond, J. A.; Iliff, R. L.

    1978-01-01

    A brief discussion of the AFGL's (Air Force Geophysics Laboratory) program in absolute gravity is presented. Support of outside work and in-house studies relating to gravity instrumentation are discussed. A description of the current transportable system is included and the latest results are presented. These results show good agreement with measurements at the AFGL site by an Italian system. The accuracy obtained by the transportable apparatus is better than 0.1 microns sq sec 10 microgal and agreement with previous measurements is within the combined uncertainties of the measurements.

  7. Familial Aggregation of Absolute Pitch

    PubMed Central

    Baharloo, Siamak; Service, Susan K.; Risch, Neil; Gitschier, Jane; Freimer, Nelson B.

    2000-01-01

    Absolute pitch (AP) is a behavioral trait that is defined as the ability to identify the pitch of tones in the absence of a reference pitch. AP is an ideal phenotype for investigation of gene and environment interactions in the development of complex human behaviors. Individuals who score exceptionally well on formalized auditory tests of pitch perception are designated as “AP-1.” As described in this report, auditory testing of siblings of AP-1 probands and of a control sample indicates that AP-1 aggregates in families. The implications of this finding for the mapping of loci for AP-1 predisposition are discussed. PMID:10924408

  8. Lung disease

    MedlinePlus

    ... the lungs to take in oxygen and release carbon dioxide. People with this type of lung disorder often ... the lungs to take up oxygen and release carbon dioxide. These diseases may also affect heart function. An ...

  9. Collapsed Lung

    MedlinePlus

    A collapsed lung happens when air enters the pleural space, the area between the lung and the chest wall. If it is a ... is called pneumothorax. If only part of the lung is affected, it is called atelectasis. Causes of ...

  10. Integrin β1-mediated acquired gefitinib resistance in non-small cell lung cancer cells occurs via the phosphoinositide 3-kinase-dependent pathway

    PubMed Central

    DENG, QIN-FANG; SU, BO; ZHAO, YIN-MIN; TANG, LIANG; ZHANG, JIE; ZHOU, CAI-CUN

    2016-01-01

    The present study aimed to explore the role of integrin β1 and the relevant signaling pathways in acquired gefitinib resistance in non-small cell lung cancer (NSCLC). The inhibitory effects of gefitinib, with or without LY294002, on cellular proliferation were evaluated by 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide assay. Cell cycle progression and apoptosis were analyzed by flow cytometry, while western blotting was used to evaluate the expression of EGFR, phosphorylated (phospho)-EGFR, protein kinase B (Akt), phospho-Akt, extracellular signal-regulated kinase (Erk) and phospho-Erk. The gene expression profiles of PC9 and PC9/G cells were determined by DNA microarray. Integrin β1 was knocked down in PC9/G cells by transiently transfected short interfering RNA (siRNA). A scrambled siRNA sequence was used as a control. Apoptosis of transfected cells was determined by Annexin V-phycoerythrin-Cy5/propidium iodide staining. Sequencing products were amplified by nested PCR. The resistant index of PC9/G cells to gefitinib was ~138- to 256-fold higher than that of PC9 cells, and this resistance was accompanied by significant increase in integrin β1 expression in PC9/G cells. Knockdown of integrin β1 with short hairpin RNA in PC9/G cells markedly inhibited proliferation and enhanced apoptosis in response to gefitinib, restoring the sensitivity of PC9/G cells gefitinib. Phosphoinositide 3-kinase (PI3K)/Akt activation was observed in PC9/G cells in the presence of gefitinib and the sensitivity of PC9/G cells to gefitinib was also able to be restored by PI3K/Akt pathway inhibitor LY294002. Finally, knockdown of integrin β1 significantly reduced the levels of phospho-Akt. These findings suggest that integrin β1 signaling via the PI3K/Akt pathway may be a significant mechanism underlying gefitinib resistance, and may potentially present an alternative therapeutic target for the treatment of NSCLC unresponsive to EGFR inhibitors. PMID:26870244

  11. TRAIL-coated lipid-nanoparticles overcome resistance to soluble recombinant TRAIL in non-small cell lung cancer cells

    NASA Astrophysics Data System (ADS)

    De Miguel, Diego; Gallego-Lleyda, Ana; María Ayuso, José; Erviti-Ardanaz, Sandra; Pazo-Cid, Roberto; del Agua, Celia; José Fernández, Luis; Ochoa, Ignacio; Anel, Alberto; Martinez-Lostao, Luis

    2016-05-01

    Purpose. Non-small cell lung cancer (NSCLC) is one the types of cancer with higher prevalence and mortality. Apo2-Ligand/TRAIL is a TNF family member able to induce apoptosis in tumor cells but not in normal cells. It has been tested in clinical trials against different types of human cancer including NSCLC. However, results of clinical trials have shown a limited efficacy of TRAIL-based therapies. Recently we have demonstrated that artificial lipid nanoparticles coated with bioactive Apo2L/TRAIL (LUV-TRAIL) greatly improved TRAIL cytotoxic ability being capable of killing chemoresistant hematological cancer cells. In the present work we have extended the study to NSCLC. Methods/patients. LUV-TRAIL-induced cytotoxicity was assessed on different NSCLC cell lines with different sensitivity to soluble TRAIL and on primary human tumor cells from three patients suffering from NSCLC cancer. We also tested LUV-TRAIL-cytotoxic ability in combination with several anti-tumor agents. Results. LUV-TRAIL exhibited a greater cytotoxic effect compared to soluble TRAIL both in A549 cells and primary human NSCLC cells. LUV-TRAIL-induced cell death was dependent on caspase-8 and caspase-3 activation. Moreover, combination of LUV-TRAIL with other anti-tumor agents such as flavopiridol, and SNS-032 clearly enhanced LUV-TRAIL-induced cytotoxicity against NSCLC cancer cells. Conclusion. The novel formulation of TRAIL based on displaying it on the surface of lipid nanoparticles greatly increases its anti-tumor activity and has clinical potential in cancer treatment.

  12. Mechanisms of collateral sensitivity to fluorouracil of a cis-diamminedichloroplatinum(II)-resistant human non-small lung cancer cell line.

    PubMed Central

    Sugimoto, Y.; Ohe, Y.; Nishio, K.; Ohmori, T.; Morikage, T.; Fujiwara, Y.; Saijo, N.

    1992-01-01

    A cisplatin(CDDP)-resistant subline of a human lung cancer cell line, PC-7/CDDP, was 4.7-fold more resistant to CDDP than the parent line in a colony-forming assay. The sensitivity of this cell line to anthracyclines, vinca-alkaloid, etoposide, mitomycin C, and bleomycin was similar to that of the parental line, PC-7. However, PC-7/CDDP exhibited 4-fold higher sensitivity to fluorouracil (FUra). Possible mechanisms associated with the collateral sensitivity to FUra were studied in PC-7/CDDP cells. The sensitivity of both cell lines to FUra did not correlate with the effect of FUra on RNA. On the other hand, FUra induced a greater reduction in dTTP pools and more single strand breaks in PC-7/CDDP than in PC-7 cells. These results suggest that the pathway for de novo deoxyribonucleotide synthesis may be a target for FUra in PC-7/CDDP cells. However, inhibition of thymidylate synthase after FUra treatment did not correlate with the DNA-directed activity of FUra. Based on the above findings, the decreased salvage synthesis of dTTP was considered a possible mechanism of the greater reduction of dTTP pools in PC-7/CDDP cells. However, the activity of dThd kinase was the same in both cell lines. In the presence of physiological concentrations of exogenous dThd in the serum, uptake of dThd was less in PC-7/CDDP cells than that in PC-7 cells. Our data suggest that FUra-induced cytotoxicity in PC-7/CDDP cells is associated with the inhibition of dTTP synthesis and that the decreased uptake of dThd is a possible mechanism of the collateral sensitivity to FUra in PC-7/CDDP cells. PMID:1319727

  13. Levofloxacin-Ceftriaxone Combination Attenuates Lung Inflammation in a Mouse Model of Bacteremic Pneumonia Caused by Multidrug-Resistant Streptococcus pneumoniae via Inhibition of Cytolytic Activities of Pneumolysin and Autolysin

    PubMed Central

    Majhi, Arnab; Adhikary, Rana; Bhattacharyya, Aritra; Mahanti, Sayantika

    2014-01-01

    In this study, our objective was to determine whether a synergistic antimicrobial combination in vitro would be beneficial in the downregulation of pneumococcal virulence genes and whether the associated inflammation of the lung tissue induced by multidrug-resistant Streptococcus pneumoniae infection in vivo needs to be elucidated in order to consider this mode of therapy in case of severe pneumococcal infection. We investigated in vivo changes in the expression of these virulence determinants using an efficacious combination determined in previous studies. BALB/c mice were infected with 106 CFU of bacteria. Intravenous levofloxacin at 150 mg/kg and/or ceftriaxone at 50 mg/kg were initiated 18 h postinfection; the animals were sacrificed 0 to 24 h after the initiation of treatment. The levels of cytokines, chemokines, and C-reactive protein (CRP) in the serum and lungs, along with the levels of myeloperoxidase and nitric oxide the inflammatory cell count in bronchoalveolar lavage fluid (BALF), changes in pneumolysin and autolysin gene expression and COX-2 and inducible nitric oxide synthase (iNOS) protein expression in the lungs were estimated. Combination therapy downregulated inflammation and promoted bacterial clearance. Pneumolysin and autolysin expression was downregulated, with a concomitant decrease in the expression of COX-2 and iNOS in lung tissue. Thus, the combination of levofloxacin and ceftriaxone can be considered for therapeutic use even in cases of pneumonia caused by drug-resistant isolates. PMID:24957840

  14. Jonquailine, a new pretazettine-type alkaloid isolated from Narcissus jonquilla quail, with activity against drug-resistant cancer

    PubMed Central

    Masi, Marco; Frolova, Liliya V.; Yu, Xiaojie; Mathieu, Véronique; Cimmino, Alessio; De Carvalho, Annelise; Kiss, Robert; Rogelj, Snezna; Pertsemlidis, Alexander; Kornienko, Alexander; Evidente, Antonio

    2016-01-01

    A new alkaloid, belonging to the pretazettine group of Amaryllidaceae alkaloids, was isolated from dried bulbs of Narcissus jonquilla quail and named jonquailine. Its structure, including the absolute configuration, was elucidated using various NMR, ECD and ESI MS techniques. Initial biological evaluation revealed significant antiproliferative effects against glioblastoma, melanoma, uterine sarcoma and non-small-cell lung cancer cells displaying various forms of drug resistance, including resistance to apoptosis and multi-drug resistance. Jonquailine was also found to synergize with paclitaxel in its antiproliferative action against drug-resistant lung cancer cells. The results obtained compared with literature data also showed that the hydroxylation at C-8 is an important feature for the anticancer activity but this seems unaffected by the stereochemistry or the acetalization of the lactol. PMID:25598189

  15. Cosmology with negative absolute temperatures

    NASA Astrophysics Data System (ADS)

    Vieira, J. P. P.; Byrnes, Christian T.; Lewis, Antony

    2016-08-01

    Negative absolute temperatures (NAT) are an exotic thermodynamical consequence of quantum physics which has been known since the 1950's (having been achieved in the lab on a number of occasions). Recently, the work of Braun et al. [1] has rekindled interest in negative temperatures and hinted at a possibility of using NAT systems in the lab as dark energy analogues. This paper goes one step further, looking into the cosmological consequences of the existence of a NAT component in the Universe. NAT-dominated expanding Universes experience a borderline phantom expansion (w < ‑1) with no Big Rip, and their contracting counterparts are forced to bounce after the energy density becomes sufficiently large. Both scenarios might be used to solve horizon and flatness problems analogously to standard inflation and bouncing cosmologies. We discuss the difficulties in obtaining and ending a NAT-dominated epoch, and possible ways of obtaining density perturbations with an acceptable spectrum.

  16. Apparatus for absolute pressure measurement

    NASA Technical Reports Server (NTRS)

    Hecht, R. (Inventor)

    1969-01-01

    An absolute pressure sensor (e.g., the diaphragm of a capacitance manometer) was subjected to a superimposed potential to effectively reduce the mechanical stiffness of the sensor. This substantially increases the sensitivity of the sensor and is particularly useful in vacuum gauges. An oscillating component of the superimposed potential induced vibrations of the sensor. The phase of these vibrations with respect to that of the oscillating component was monitored, and served to initiate an automatic adjustment of the static component of the superimposed potential, so as to bring the sensor into resonance at the frequency of the oscillating component. This establishes a selected sensitivity for the sensor, since a definite relationship exists between resonant frequency and sensitivity.

  17. Cosmology with negative absolute temperatures

    NASA Astrophysics Data System (ADS)

    Vieira, J. P. P.; Byrnes, Christian T.; Lewis, Antony

    2016-08-01

    Negative absolute temperatures (NAT) are an exotic thermodynamical consequence of quantum physics which has been known since the 1950's (having been achieved in the lab on a number of occasions). Recently, the work of Braun et al. [1] has rekindled interest in negative temperatures and hinted at a possibility of using NAT systems in the lab as dark energy analogues. This paper goes one step further, looking into the cosmological consequences of the existence of a NAT component in the Universe. NAT-dominated expanding Universes experience a borderline phantom expansion (w < -1) with no Big Rip, and their contracting counterparts are forced to bounce after the energy density becomes sufficiently large. Both scenarios might be used to solve horizon and flatness problems analogously to standard inflation and bouncing cosmologies. We discuss the difficulties in obtaining and ending a NAT-dominated epoch, and possible ways of obtaining density perturbations with an acceptable spectrum.

  18. EGF‑stimulated AKT activation is mediated by EGFR recycling via an early endocytic pathway in a gefitinib‑resistant human lung cancer cell line.

    PubMed

    Nishimura, Yukio; Takiguchi, Soichi; Ito, Shigeru; Itoh, Kazuyuki

    2015-04-01

    The receptor tyrosine kinase epidermal growth factor receptor (EGFR) and its ligand epidermal growth factor (EGF) are known to play important roles in malignant tumor cells, and the EGFR signaling pathway is one of the most important targets in various tumors, including non-small cell lung cancer (NSCLC). We reported recently that an aberration in certain steps of EGF-stimulated phosphorylated epidermal growth factor receptor (pEGFR) endocytic trafficking from the early endosomes to the late endosomes occurs in the gefitinib-resistant NSCLC cells, in which large amounts of sorting nexin 1 (SNX1) are colocalized with EGFR in the aggregated early endosomes where the internalized pEGFR is also accumulated of these cells. To further investigate the role of SNX1 in EGF‑stimulated pEGFR endocytosis, followed by downstream signaling leading to the activation of phosphatidylinositol 3-kinase (PI3K)--the serine/threonine kinase AKT pathway, we examined the effect of depletion of SNX1 knock-down expression by siRNA and an inhibition of targeting membrane recycling using monensin. Using immunofluorescence, we observed an efficient endocytic transport of pEGFR from early endosomes to late endosomes/lysosomes after EGF-stimulation in the cells transfected with siRNA‑SNX1, whereas the delayed endocytic delivery of pEGFR was evident in the siRNA-control-transfected cells. Furthermore, a large amount of endocytosed pEGFR was accumulated in the presence of monensin in the early endosomes of the SNX1 knock-down cells. In western blot analysis, EGF stimulation of both control and cells transfected with siRNA-SNX1 resulted in rapid phosphorylation of EGFR and enhanced AKT phosphorylation. Monensin-dependent inhibition of AKT phosphorylation was stronger in SNX1 knock-down cells than in controls. In contrast, however, monensin had no effect on AKT phosphorylation triggered by activation of the MET receptor tyrosine kinase. Collectively, we suggest that EGF-stimulated recycling of

  19. Genome-Wide Gene Expression Profiles in Lung Tissues of Pig Breeds Differing in Resistance to Porcine Reproductive and Respiratory Syndrome Virus

    PubMed Central

    Zhang, Chenhua; Zhang, Yujie; Wang, Nan; Li, Yanping; Yang, Lijuan; Jiang, Chenglan; Zhang, Chaoyang; Wen, Changhong; Jiang, Yunliang

    2014-01-01

    Porcine reproductive and respiratory syndrome (PRRS) caused by PRRS virus (PRRSV) is an infectious disease characterized by severe reproductive deficiency in pregnant sows, typical respiratory symptoms in piglets, and high mortality rate of piglets. In this study, we employed an Affymetrix microarray chip to compare the gene expression profiles of lung tissue samples from Dapulian (DPL) pigs (a Chinese indigenous pig breed) and Duroc×Landrace×Yorkshire (DLY) pigs after infection with PRRSV. During infection with PRRSV, the DLY pigs exhibited a range of clinical features that typify the disease, whereas the DPL pigs showed only mild signs of the disease. Overall, the DPL group had a lower percentage of CD4+ cells and lower CD4+/CD8+ratios than the DLY group (p<0.05). For both IL-10 and TNF-α, the DLY pigs had significantly higher levels than the DPL pigs (p<0.01). The DLY pigs have lower serum IFN-γ levels than the DPL pigs (p<0.01). The serum IgG levels increased slightly from 0 dpi to 7 dpi, and peaked at 14 dpi (p<0.0001). Microarray data analysis revealed 16 differentially expressed (DE) genes in the lung tissue samples from the DLY and DPL pigs (q≤5%), of which LOC100516029 and LOC100523005 were up-regulated in the PRRSV-infected DPL pigs, while the other 14 genes were down-regulated in the PRRSV-infected DPL pigs compared with the PRRSV-infected DLY pigs. The mRNA expression levels of 10 out of the 16 DE genes were validated by real-time quantitative RT-PCR and their fold change was consistent with the result of microarray data analysis. We further analyzed the mRNA expression level of 8 differentially expressed genes between the DPL and DLY pigs for both uninfected and infected groups, and found that TF and USP18 genes were important in underlying porcine resistance or susceptibility to PRRSV. PMID:24465897

  20. Absolute configuration of isovouacapenol C

    PubMed Central

    Fun, Hoong-Kun; Yodsaoue, Orapun; Karalai, Chatchanok; Chantrapromma, Suchada

    2010-01-01

    The title compound, C27H34O5 {systematic name: (4aR,5R,6R,6aS,7R,11aS,11bR)-4a,6-dihy­droxy-4,4,7,11b-tetra­methyl-1,2,3,4,4a,5,6,6a,7,11,11a,11b-dodeca­hydro­phenanthro[3,2-b]furan-5-yl benzoate}, is a cassane furan­oditerpene, which was isolated from the roots of Caesalpinia pulcherrima. The three cyclo­hexane rings are trans fused: two of these are in chair conformations with the third in a twisted half-chair conformation, whereas the furan ring is almost planar (r.m.s. deviation = 0.003 Å). An intra­molecular C—H⋯O inter­action generates an S(6) ring. The absolute configurations of the stereogenic centres at positions 4a, 5, 6, 6a, 7, 11a and 11b are R, R, R, S, R, S and R, respectively. In the crystal, mol­ecules are linked into infinite chains along [010] by O—H⋯O hydrogen bonds. C⋯O [3.306 (2)–3.347 (2) Å] short contacts and C—H⋯π inter­actions also occur. PMID:21588364

  1. Frequency-domain analysis of absolute gravimeters

    NASA Astrophysics Data System (ADS)

    Svitlov, S.

    2012-12-01

    An absolute gravimeter is analysed as a linear time-invariant system in the frequency domain. Frequency responses of absolute gravimeters are derived analytically based on the propagation of the complex exponential signal through their linear measurement functions. Depending on the model of motion and the number of time-distance coordinates, an absolute gravimeter is considered as a second-order (three-level scheme) or third-order (multiple-level scheme) low-pass filter. It is shown that the behaviour of an atom absolute gravimeter in the frequency domain corresponds to that of the three-level corner-cube absolute gravimeter. Theoretical results are applied for evaluation of random and systematic measurement errors and optimization of an experiment. The developed theory agrees with known results of an absolute gravimeter analysis in the time and frequency domains and can be used for measurement uncertainty analyses, building of vibration-isolation systems and synthesis of digital filtering algorithms.

  2. MiR-134/487b/655 cluster regulates TGF-β-induced epithelial-mesenchymal transition and drug resistance to gefitinib by targeting MAGI2 in lung adenocarcinoma cells.

    PubMed

    Kitamura, Kazuhiro; Seike, Masahiro; Okano, Tetsuya; Matsuda, Kuniko; Miyanaga, Akihiko; Mizutani, Hideaki; Noro, Rintaro; Minegishi, Yuji; Kubota, Kaoru; Gemma, Akihiko

    2014-02-01

    Epithelial-mesenchymal transition (EMT) has recently been recognized as a key element of cell invasion, migration, metastasis, and drug resistance in several types of cancer, including non-small cell lung cancer (NSCLC). Our aim was to clarify microRNA (miRNA)-related mechanisms underlying EMT followed by acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) in NSCLC. miRNA expression profiles were examined before and after transforming growth factor β1 (TGF-β1) exposure in four human adenocarcinoma cell lines with or without EMT. Correlation between expressions of EMT-related miRNAs and resistance to EGFR-TKI gefitinib was evaluated. miRNA array and real-time quantitative reverse transcription PCR (qRT-PCR) revealed that TGF-β1 significantly induced overexpression of miR-134, miR-487b, and miR-655, which belong to the same cluster located on chromosome 14q32, in lung adenocarcinoma cells with EMT. MAGI2 (membrane-associated guanylate kinase, WW, and PDZ domain-containing protein 2), a predicted target of these miRNAs and a scaffold protein required for PTEN, was diminished in A549 cells with EMT after the TGF-β1 stimulation. Overexpression of miR-134 and miR-487b promoted the EMT phenomenon and affected the drug resistance to gefitinib, whereas knockdown of these miRNAs inhibited the EMT process and reversed TGF-β1-induced resistance to gefitinib. Our study demonstrated that the miR-134/487b/655 cluster contributed to the TGF-β1-induced EMT phenomenon and affected the resistance to gefitinib by directly targeting MAGI2, in which suppression subsequently caused loss of PTEN stability in lung cancer cells. The miR-134/miR-487b/miR-655 cluster may be a new therapeutic target in patients with advanced lung adenocarcinoma, depending on the EMT phenomenon. PMID:24258346

  3. Activation of the IGF1R pathway potentially mediates acquired resistance to mutant-selective 3rd-generation EGF receptor tyrosine kinase inhibitors in advanced non-small cell lung cancer

    PubMed Central

    Park, Ji Hyun; Choi, Yun Jung; Kim, Seon Ye; Lee, Jung-Eun; Sung, Ki Jung; Park, Sojung; Kim, Woo Sung; Song, Joon Seon; Choi, Chang-Min; Sung, Young Hoon; Rho, Jin Kyung; Lee, Jae Cheol

    2016-01-01

    Mutant-selective, 3rd-generation EGFR-TKIs were recently developed to control lung cancer cells harboring T790M-mediated resistance. However, the development of resistance to these novel drugs seems inevitable. Thus, we investigated the mechanism of acquired resistance to the mutant-selective EGFR-TKI WZ4002. We established five WZ4002-resistant cells, derived from cells harboring both EGFR and T790M mutations by long-term exposure to increasing doses of WZ4002. Compared with the parental cells, all resistant cells showed 10–100-folds higher resistance to WZ4002, as well as cross-resistance to other mutant-selective inhibitors. Among them, three resistant cells (HCC827/WR, PC-9/WR and H1975/WR) showed dependency on EGFR signaling, but two other cells (PC-9/GR/WR and PC-9/ER/WR) were not. Notably, insulin-like growth factor-1 receptor (IGF1R) was aberrantly activated in PC-9/GR/WR cells in phospho-receptor tyrosine kinase array, consistently accompanied by loss of IGF binding protein-3 (IGFBP3). Down-regulation of IGF1R by shRNA, as well as inhibition of IGF1R activity either by AG-1024 (a small molecule IGF1R inhibitor) or BI 836845 (a monoclonal anti-IGF1/2 blocking antibody), restored the sensitivity to WZ4002 both in vitro and xenograft. Taken together, these results suggest that activation of the IGF1R pathway associated with IGFBP3 loss can induce an acquired resistance to the mutant-selective EGFR-TKI, WZ4002. Therefore, a combined therapy of IGF1R inhibitors and mutant-selective EGFR-TKIs might be a viable treatment strategy for overcoming acquired resistance. PMID:26980747

  4. Lung transplant

    MedlinePlus

    Solid organ transplant - lung ... the new lung Have severe disease of other organs Cannot reliably take their medicines Are unable to ... medicines Damage to your kidneys, liver, or other organs from anti-rejection medicines Future risk of certain ...

  5. Lung surgery

    MedlinePlus

    ... Pneumonectomy; Lobectomy; Lung biopsy; Thoracoscopy; Video-assisted thoracoscopic surgery; VATS ... You will have general anesthesia before surgery. You will be asleep and unable to feel pain. Two common ways to do surgery on your lungs are thoracotomy and video- ...

  6. Absolute Income, Relative Income, and Happiness

    ERIC Educational Resources Information Center

    Ball, Richard; Chernova, Kateryna

    2008-01-01

    This paper uses data from the World Values Survey to investigate how an individual's self-reported happiness is related to (i) the level of her income in absolute terms, and (ii) the level of her income relative to other people in her country. The main findings are that (i) both absolute and relative income are positively and significantly…

  7. Investigating Absolute Value: A Real World Application

    ERIC Educational Resources Information Center

    Kidd, Margaret; Pagni, David

    2009-01-01

    Making connections between various representations is important in mathematics. In this article, the authors discuss the numeric, algebraic, and graphical representations of sums of absolute values of linear functions. The initial explanations are accessible to all students who have experience graphing and who understand that absolute value simply…

  8. Preschoolers' Success at Coding Absolute Size Values.

    ERIC Educational Resources Information Center

    Russell, James

    1980-01-01

    Forty-five 2-year-old and forty-five 3-year-old children coded relative and absolute sizes using 1.5-inch, 6-inch, and 18-inch cardboard squares. Results indicate that absolute coding is possible for children of this age. (Author/RH)

  9. Introducing the Mean Absolute Deviation "Effect" Size

    ERIC Educational Resources Information Center

    Gorard, Stephen

    2015-01-01

    This paper revisits the use of effect sizes in the analysis of experimental and similar results, and reminds readers of the relative advantages of the mean absolute deviation as a measure of variation, as opposed to the more complex standard deviation. The mean absolute deviation is easier to use and understand, and more tolerant of extreme…

  10. Monolithically integrated absolute frequency comb laser system

    DOEpatents

    Wanke, Michael C.

    2016-07-12

    Rather than down-convert optical frequencies, a QCL laser system directly generates a THz frequency comb in a compact monolithically integrated chip that can be locked to an absolute frequency without the need of a frequency-comb synthesizer. The monolithic, absolute frequency comb can provide a THz frequency reference and tool for high-resolution broad band spectroscopy.

  11. Estimating the absolute wealth of households

    PubMed Central

    Gerkey, Drew; Hadley, Craig

    2015-01-01

    Abstract Objective To estimate the absolute wealth of households using data from demographic and health surveys. Methods We developed a new metric, the absolute wealth estimate, based on the rank of each surveyed household according to its material assets and the assumed shape of the distribution of wealth among surveyed households. Using data from 156 demographic and health surveys in 66 countries, we calculated absolute wealth estimates for households. We validated the method by comparing the proportion of households defined as poor using our estimates with published World Bank poverty headcounts. We also compared the accuracy of absolute versus relative wealth estimates for the prediction of anthropometric measures. Findings The median absolute wealth estimates of 1 403 186 households were 2056 international dollars per capita (interquartile range: 723–6103). The proportion of poor households based on absolute wealth estimates were strongly correlated with World Bank estimates of populations living on less than 2.00 United States dollars per capita per day (R2 = 0.84). Absolute wealth estimates were better predictors of anthropometric measures than relative wealth indexes. Conclusion Absolute wealth estimates provide new opportunities for comparative research to assess the effects of economic resources on health and human capital, as well as the long-term health consequences of economic change and inequality. PMID:26170506

  12. Absolute optical metrology : nanometers to kilometers

    NASA Technical Reports Server (NTRS)

    Dubovitsky, Serge; Lay, O. P.; Peters, R. D.; Liebe, C. C.

    2005-01-01

    We provide and overview of the developments in the field of high-accuracy absolute optical metrology with emphasis on space-based applications. Specific work on the Modulation Sideband Technology for Absolute Ranging (MSTAR) sensor is described along with novel applications of the sensor.

  13. Absolute instability of the Gaussian wake profile

    NASA Technical Reports Server (NTRS)

    Hultgren, Lennart S.; Aggarwal, Arun K.

    1987-01-01

    Linear parallel-flow stability theory has been used to investigate the effect of viscosity on the local absolute instability of a family of wake profiles with a Gaussian velocity distribution. The type of local instability, i.e., convective or absolute, is determined by the location of a branch-point singularity with zero group velocity of the complex dispersion relation for the instability waves. The effects of viscosity were found to be weak for values of the wake Reynolds number, based on the center-line velocity defect and the wake half-width, larger than about 400. Absolute instability occurs only for sufficiently large values of the center-line wake defect. The critical value of this parameter increases with decreasing wake Reynolds number, thereby indicating a shrinking region of absolute instability with decreasing wake Reynolds number. If backflow is not allowed, absolute instability does not occur for wake Reynolds numbers smaller than about 38.

  14. Which patients are candidates for lung transplantation? Indications for unilateral, bilateral, and heart-lung procedures.

    PubMed

    Ettinger, N A

    1994-01-01

    Single-lung transplantation, long successful in resolving interstitial lung disease, can now be used in COPD patients and shows promise in managing pulmonary hypertension. The bilateral procedure, which often avoids cardiopulmonary bypass, is preferred when chronic airway infection is present. Heart-lung transplants, now rare, are used when pulmonary hypertension is complicated by congestive cardiomyopathy or irreparable cardiac defects. Mechanical ventilation, prior cardiothoracic surgery, and corticosteroid use no longer constitute absolute contraindications to lung transplantation. The growing scarcity of donor organs is increasing waiting times; thus, earlier recognition of potential recipients is necessary.

  15. Lung Organogenesis

    PubMed Central

    Warburton, David; El-Hashash, Ahmed; Carraro, Gianni; Tiozzo, Caterina; Sala, Frederic; Rogers, Orquidea; De Langhe, Stijn; Kemp, Paul J.; Riccardi, Daniela; Torday, John; Bellusci, Saverio; Shi, Wei; Lubkin, Sharon R; Jesudason, Edwin

    2011-01-01

    Developmental lung biology is a field that has the potential for significant human impact: lung disease at the extremes of age continues to cause major morbidity and mortality worldwide. Understanding how the lung develops holds the promise that investigators can use this knowledge to aid lung repair and regeneration. In the decade since the “molecular embryology” of the lung was first comprehensively reviewed, new challenges have emerged—and it is on these that we focus the current review. Firstly, there is a critical need to understand the progenitor cell biology of the lung in order to exploit the potential of stem cells for the treatment of lung disease. Secondly, the current familiar descriptions of lung morphogenesis governed by growth and transcription factors need to be elaborated upon with the reinclusion and reconsideration of other factors, such as mechanics, in lung growth. Thirdly, efforts to parse the finer detail of lung bud signaling may need to be combined with broader consideration of overarching mechanisms that may be therapeutically easier to target: in this arena, we advance the proposal that looking at the lung in general (and branching in particular) in terms of clocks may yield unexpected benefits. PMID:20691848

  16. An Autopsy Case of Two Distinct, Acquired Drug Resistance Mechanisms in Epidermal Growth Factor Receptor-mutant Lung Adenocarcinoma: Small Cell Carcinoma Transformation and Epidermal Growth Factor Receptor T790M Mutation.

    PubMed

    Furugen, Makoto; Uechi, Kayoko; Hirai, Jun; Aoyama, Hajime; Saio, Masanao; Yoshimi, Naoki; Kinjo, Takeshi; Miyagi, Kazuya; Haranaga, Shusaku; Higa, Futoshi; Tateyama, Masao; Fujita, Jiro

    2015-01-01

    We herein describe the case of a 63-year-old man who died from relapsed epidermal growth factor receptor gene (EGFR) exon 19 deletion lung adenocarcinoma treated with erlotinib. According to the autopsy results, he was confirmed to have small cell carcinoma without the EGFR T790M mutation in his pancreas and left kidney metastatic specimens, while the adenocarcinoma metastatic lesion in his right kidney had the EGFR T790M mutation; both retained the somatic EGFR exon 19 deletion. We herein report an autopsy case of resistance to an EGFR tyrosine kinase inhibitor via small cell carcinoma transformation and the EGFRT790M mutation in separate metastatic organs. PMID:26424310

  17. [Advances in Lung Stem Cells and Lung Cancer Stem Cells].

    PubMed

    Yin, Huijing; Deng, Jiong

    2015-10-20

    Cancer stem cells (CSCs) are emerging as a hot topic for cancer research. Lung CSCs share many characteristics with normal lung stem cells (SCs), including self-renewal and multi-potency for differentiation. Many molecular markers expressed in various types of CSCs were also found in lung CSCs, such as CD133, CD44, aldehyde dehydrogenase (ALDH) and ATP-binding cassette sub-family G member 2 (ABCG2). Similarly, proliferation and expansion of lung CSCs are regulated not only by signal transduction pathways functioning in normal lung SCs, such as Notch, Hedgehog and Wnt pathways, but also by those acting in tumor cells, such as epidermal growth factor receptor (EGFR), signal transducer and activator of transcription 3 (STAT3) and phosphatidylinositol 3 kinase (PI3K) pathways. As CSC plays an critical role in tumor recurrence, metastasis and drug-resistance, understanding the difference between lung CSCs and normal lung SCs, identifying and targeting CSC markers or related signaling pathways may increase the efficacy of therapy on lung cancer and improved survival of lung cancer patients.

  18. The lung tumor promoter, butylated hydroxytoluene (BHT), causes chronic inflammation in promotion-sensitive BALB/cByJ mice but not in promotion-resistant CXB4 mice.

    PubMed

    Bauer, A K; Dwyer-Nield, L D; Hankin, J A; Murphy, R C; Malkinson, A M

    2001-12-01

    An inflammatory response accompanies the reversible pneumotoxicity caused by butylated hydroxytoluene (BHT) administration to mice. Lung tumor formation is promoted by BHT administration following an initiating agent in BALB/cByJ mice, but not in CXB4 mice. To assess the contribution of inflammation to this differential susceptibility, we quantitatively characterized inflammation after one 150 mg/kg body weight, followed by three weekly 200 mg/kg ip injections of BHT into male mice of both strains. This examination included inflammatory cell infiltrate and protein contents in bronchoalveolar lavage (BAL) fluid, cyclooxygenase (COX)-1 and COX-2 expression in lung extracts, and PGE(2) and PGI(2) production by isolated bronchiolar Clara cells. BAL macrophage and lymphocyte numbers increased in BALB mice (P<0.0007 and 0.02, respectively), as did BAL protein content (P<0.05), COX-1 and COX-2 expression (P<0.05 for each), and PGI(2) production (P<0.05); conversely, these indices were not perturbed by BHT in CXB4 mice. BALB mice fed aspirin (400 mg/kg of chow) for two weeks prior to BHT treatment had reduced inflammatory cell infiltration. Our results support a hypothesis that resistance to BHT-induced inflammation in CXB4 mice accounts, at least in part, for the lack of effect of BHT on lung tumor multiplicity in this strain.

  19. Absolute magnitudes of trans-neptunian objects

    NASA Astrophysics Data System (ADS)

    Duffard, R.; Alvarez-candal, A.; Pinilla-Alonso, N.; Ortiz, J. L.; Morales, N.; Santos-Sanz, P.; Thirouin, A.

    2015-10-01

    Accurate measurements of diameters of trans- Neptunian objects are extremely complicated to obtain. Radiomatric techniques applied to thermal measurements can provide good results, but precise absolute magnitudes are needed to constrain diameters and albedos. Our objective is to measure accurate absolute magnitudes for a sample of trans- Neptunian objects, many of which have been observed, and modelled, by the "TNOs are cool" team, one of Herschel Space Observatory key projects grantes with ~ 400 hours of observing time. We observed 56 objects in filters V and R, if possible. These data, along with data available in the literature, was used to obtain phase curves and to measure absolute magnitudes by assuming a linear trend of the phase curves and considering magnitude variability due to rotational light-curve. In total we obtained 234 new magnitudes for the 56 objects, 6 of them with no reported previous measurements. Including the data from the literature we report a total of 109 absolute magnitudes.

  20. A New Gimmick for Assigning Absolute Configuration.

    ERIC Educational Resources Information Center

    Ayorinde, F. O.

    1983-01-01

    A five-step procedure is provided to help students in making the assignment absolute configuration less bothersome. Examples for both single (2-butanol) and multi-chiral carbon (3-chloro-2-butanol) molecules are included. (JN)

  1. The Simplicity Argument and Absolute Morality

    ERIC Educational Resources Information Center

    Mijuskovic, Ben

    1975-01-01

    In this paper the author has maintained that there is a similarity of thought to be found in the writings of Cudworth, Emerson, and Husserl in his investigation of an absolute system of morality. (Author/RK)

  2. Antitumor activity of pimasertib, a selective MEK 1/2 inhibitor, in combination with PI3K/mTOR inhibitors or with multi-targeted kinase inhibitors in pimasertib-resistant human lung and colorectal cancer cells.

    PubMed

    Martinelli, Erika; Troiani, Teresa; D'Aiuto, Elena; Morgillo, Floriana; Vitagliano, Donata; Capasso, Anna; Costantino, Sarah; Ciuffreda, Loreta Pia; Merolla, Francesco; Vecchione, Loredana; De Vriendt, Veerle; Tejpar, Sabine; Nappi, Anna; Sforza, Vincenzo; Martini, Giulia; Berrino, Liberato; De Palma, Raffaele; Ciardiello, Fortunato

    2013-11-01

    The RAS/RAF/MEK/MAPK and the PTEN/PI3K/AKT/mTOR pathways are key regulators of proliferation and survival in human cancer cells. Selective inhibitors of different transducer molecules in these pathways have been developed as molecular targeted anti-cancer therapies. The in vitro and in vivo anti-tumor activity of pimasertib, a selective MEK 1/2 inhibitor, alone or in combination with a PI3K inhibitor (PI3Ki), a mTOR inhibitor (everolimus), or with multi-targeted kinase inhibitors (sorafenib and regorafenib), that block also BRAF and CRAF, were tested in a panel of eight human lung and colon cancer cell lines. Following pimasertib treatment, cancer cell lines were classified as pimasertib-sensitive (IC50 for cell growth inhibition of 0.001 µM) or pimasertib-resistant. Evaluation of basal gene expression profiles by microarrays identified several genes that were up-regulated in pimasertib-resistant cancer cells and that were involved in both RAS/RAF/MEK/MAPK and PTEN/PI3K/AKT/mTOR pathways. Therefore, a series of combination experiments with pimasertib and either PI3Ki, everolimus, sorafenib or regorafenib were conducted, demonstrating a synergistic effect in cell growth inhibition and induction of apoptosis with sustained blockade in MAPK- and AKT-dependent signaling pathways in pimasertib-resistant human colon carcinoma (HCT15) and lung adenocarcinoma (H1975) cells. Finally, in nude mice bearing established HCT15 and H1975 subcutaneous tumor xenografts, the combined treatment with pimasertib and BEZ235 (a dual PI3K/mTOR inhibitor) or with sorafenib caused significant tumor growth delays and increase in mice survival as compared to single agent treatment. These results suggest that dual blockade of MAPK and PI3K pathways could overcome intrinsic resistance to MEK inhibition.

  3. Combined targeting of EGFR/HER promotes anti-tumor efficacy in subsets of KRAS mutant lung cancer resistant to single EGFR blockade

    PubMed Central

    Umelo, Ijeoma Adaku; De Wever, Olivier; Kronenberger, Peter; Van Deun, Jan; Noor, Alfiah; Singh, Kshitiz; Teugels, Erik; Chen, Gang; Bracke, Marc; De Grève, Jacques

    2015-01-01

    KRAS is a frequently mutated oncogene in lung cancer and among the most refractory to EGFR targeted therapy. Recently, preclinical evidence in pancreatic cancer has demonstrated that mutant KRAS can be regulated by EGFR. However, the distinct correlation between the EGFR/HER family members and mutant KRAS has not been investigated. Here, we show that non-small cell lung cancer cell lines harboring differing isoforms of mutant KRAS, can be broadly divided into EGFR/HER dependent and EGFR/HER independent groups. Combined therapeutic targeting of EGFR, HER2 and HER3 in isoforms regulated by extracellular growth signals promotes in vitro and in vivo efficacy. We also provide evidence that depletion of EGFR via RNA interference specifically abolishes the EGFR/KRAS interaction in the dependent subset. Taken together, these findings suggest that upstream inhibition of the EGFR/HER receptors may be effective in treating a subset of KRAS mutant lung cancers. PMID:25992771

  4. Precision absolute value amplifier for a precision voltmeter

    DOEpatents

    Hearn, William E.; Rondeau, Donald J.

    1985-01-01

    Bipolar inputs are afforded by the plus inputs of first and second differential input amplifiers. A first gain determining resister is connected between the minus inputs of the differential amplifiers. First and second diodes are connected between the respective minus inputs and the respective outputs of the differential amplifiers. First and second FETs have their gates connected to the outputs of the amplifiers, while their respective source and drain circuits are connected between the respective minus inputs and an output lead extending to a load resister. The output current through the load resister is proportional to the absolute value of the input voltage difference between the bipolar input terminals. A third differential amplifier has its plus input terminal connected to the load resister. A second gain determining resister is connected between the minus input of the third differential amplifier and a voltage source. A third FET has its gate connected to the output of the third amplifier. The source and drain circuit of the third transistor is connected between the minus input of the third amplifier and a voltage-frequency converter, constituting an output device. A polarity detector is also provided, comprising a pair of transistors having their inputs connected to the outputs of the first and second differential amplifiers. The outputs of the polarity detector are connected to gates which switch the output of the voltage-frequency converter between up and down counting outputs.

  5. Jasminum flexile flower absolute from India--a detailed comparison with three other jasmine absolutes.

    PubMed

    Braun, Norbert A; Kohlenberg, Birgit; Sim, Sherina; Meier, Manfred; Hammerschmidt, Franz-Josef

    2009-09-01

    Jasminum flexile flower absolute from the south of India and the corresponding vacuum headspace (VHS) sample of the absolute were analyzed using GC and GC-MS. Three other commercially available Indian jasmine absolutes from the species: J. sambac, J. officinale subsp. grandiflorum, and J. auriculatum and the respective VHS samples were used for comparison purposes. One hundred and twenty-one compounds were characterized in J. flexile flower absolute, with methyl linolate, benzyl salicylate, benzyl benzoate, (2E,6E)-farnesol, and benzyl acetate as the main constituents. A detailed olfactory evaluation was also performed.

  6. Peroxisome proliferator-activated receptor γ agonist efatutazone impairs transforming growth factor β2-induced motility of epidermal growth factor receptor tyrosine kinase inhibitor-resistant lung cancer cells.

    PubMed

    Serizawa, Masakuni; Murakami, Haruyasu; Watanabe, Masaru; Takahashi, Toshiaki; Yamamoto, Nobuyuki; Koh, Yasuhiro

    2014-06-01

    Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) are effective for non-small cell lung cancers (NSCLC) with EGFR-activating mutations. However, most responders develop resistance. Efatutazone, a novel peroxisome proliferator-activated receptor gamma (PPARγ) agonist, is currently under clinical evaluation; it has antiproliferative effects and induces cellular morphological changes and differentiation. The present study investigated the effects of efatutazone in EGFR-TKI-resistant NSCLC cells, while focusing on cell motility. The PC-9-derived NSCLC cell lines PC-9ER and PC-9ZD, resistant to EGFR-TKI due to v-crk avian sarcoma virus CT10 oncogene homolog-like (CRKL) amplification-induced phosphatidylinositol 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homolog (AKT) activation and an EGFR T790M mutation, respectively, were used. These cells exhibit enhanced cell motility due to transforming growth factor β (TGF-β)/Smad2 family member 2 (Smad2) pathway activation. Efatutazone had no growth-inhibitory effect on the tested cells but inhibited the motility of EGFR-TKI-resistant cells in wound closure and transwell assays. Efatutazone plus erlotinib treatment provided greater inhibition of PC-9ER cell migration than efatutazone or erlotinib alone. Efatutazone suppressed increased TGF-β2 secretion from both cell lines (shown by ELISA) and downregulation of TGF-β2 transcription (observed by quantitative RT-PCR). Immunoblot analysis and luciferase assays revealed that efatutazone suppressed Smad2 phosphorylation and its transcriptional activity. These results suggest that efatutazone inhibits cell motility by antagonizing the TGF-β/Smad2 pathway and effectively prevents metastasis in NSCLC patients with acquired resistance to EGFR-TKI regardless of the resistance mechanism.

  7. Lung transplantation

    PubMed Central

    Afonso, José Eduardo; Werebe, Eduardo de Campos; Carraro, Rafael Medeiros; Teixeira, Ricardo Henrique de Oliveira Braga; Fernandes, Lucas Matos; Abdalla, Luis Gustavo; Samano, Marcos Naoyuki; Pêgo-Fernandes, Paulo Manuel

    2015-01-01

    ABSTRACT Lung transplantation is a globally accepted treatment for some advanced lung diseases, giving the recipients longer survival and better quality of life. Since the first transplant successfully performed in 1983, more than 40 thousand transplants have been performed worldwide. Of these, about seven hundred were in Brazil. However, survival of the transplant is less than desired, with a high mortality rate related to primary graft dysfunction, infection, and chronic graft dysfunction, particularly in the form of bronchiolitis obliterans syndrome. New technologies have been developed to improve the various stages of lung transplant. To increase the supply of lungs, ex vivo lung reconditioning has been used in some countries, including Brazil. For advanced life support in the perioperative period, extracorporeal membrane oxygenation and hemodynamic support equipment have been used as a bridge to transplant in critically ill patients on the waiting list, and to keep patients alive until resolution of the primary dysfunction after graft transplant. There are patients requiring lung transplant in Brazil who do not even come to the point of being referred to a transplant center because there are only seven such centers active in the country. It is urgent to create new centers capable of performing lung transplantation to provide patients with some advanced forms of lung disease a chance to live longer and with better quality of life. PMID:26154550

  8. Lung Diseases

    MedlinePlus

    When you breathe, your lungs take in oxygen from the air and deliver it to the bloodstream. The cells in your body need oxygen to ... you breathe nearly 25,000 times. People with lung disease have difficulty breathing. Millions of people in ...

  9. Lung Cancer

    MedlinePlus

    Lung cancer is one of the most common cancers in the world. It is a leading cause of cancer death in men and women in the United States. Cigarette smoking causes most lung cancers. The more cigarettes you smoke per day and ...

  10. Integrin beta 1 enhances the epithelial-mesenchymal transition in association with gefitinib resistance of non-small cell lung cancer.

    PubMed

    Ju, Lixia; Zhou, Caicun

    2013-01-01

    We have previously shown that integrinβ1 associates with gefitinib resistance. As epithelial-mesenchymal transition (EMT) also induces gefitinib resistance in vitro, we wished to determine the relation of them in gefitinib resistance. In this study, we show that integrinβ1 induced epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance in xenograft tumors and gefitinib-resistant NSCLC tumors acquired EMT phenotype. Furthermore, inhibition of integrinβ1 reverses EMT, meanwhile overexpression and activation of integrinβ1 aggravates EMT. Lastly, we further identified that integrinβ1 enhanced EMT via FAK-AKT signaling pathway. These findings highlight a novel relation of integrinβ1 and EMT in EGFR TKI resistant NSCLC. PMID:24440972

  11. Universal Cosmic Absolute and Modern Science

    NASA Astrophysics Data System (ADS)

    Kostro, Ludwik

    The official Sciences, especially all natural sciences, respect in their researches the principle of methodic naturalism i.e. they consider all phenomena as entirely natural and therefore in their scientific explanations they do never adduce or cite supernatural entities and forces. The purpose of this paper is to show that Modern Science has its own self-existent, self-acting, and self-sufficient Natural All-in Being or Omni-Being i.e. the entire Nature as a Whole that justifies the scientific methodic naturalism. Since this Natural All-in Being is one and only It should be considered as the own scientifically justified Natural Absolute of Science and should be called, in my opinion, the Universal Cosmic Absolute of Modern Science. It will be also shown that the Universal Cosmic Absolute is ontologically enormously stratified and is in its ultimate i.e. in its most fundamental stratum trans-reistic and trans-personal. It means that in its basic stratum. It is neither a Thing or a Person although It contains in Itself all things and persons with all other sentient and conscious individuals as well, On the turn of the 20th century the Science has begun to look for a theory of everything, for a final theory, for a master theory. In my opinion the natural Universal Cosmic Absolute will constitute in such a theory the radical all penetrating Ultimate Basic Reality and will substitute step by step the traditional supernatural personal Absolute.

  12. Lung diffusion testing

    MedlinePlus

    Lung diffusion testing measures how well the lungs exchange gases. This is an important part of lung testing , because ... gases do not move normally across the lung tissues into the blood vessels of the lung. This ...

  13. Collapsed lung (pneumothorax)

    MedlinePlus

    Air around the lung; Air outside the lung; Pneumothorax dropped lung; Spontaneous pneumothorax ... Collapsed lung can be caused by an injury to the lung. Injuries can include a gunshot or knife wound ...

  14. Lung disease - resources

    MedlinePlus

    Resources - lung disease ... The following organizations are good resources for information on lung disease : American Lung Association -- www.lung.org National Heart, Lung, and Blood Institute -- www.nhlbi.nih.gov ...

  15. Quantum theory allows for absolute maximal contextuality

    NASA Astrophysics Data System (ADS)

    Amaral, Barbara; Cunha, Marcelo Terra; Cabello, Adán

    2015-12-01

    Contextuality is a fundamental feature of quantum theory and a necessary resource for quantum computation and communication. It is therefore important to investigate how large contextuality can be in quantum theory. Linear contextuality witnesses can be expressed as a sum S of n probabilities, and the independence number α and the Tsirelson-like number ϑ of the corresponding exclusivity graph are, respectively, the maximum of S for noncontextual theories and for the theory under consideration. A theory allows for absolute maximal contextuality if it has scenarios in which ϑ /α approaches n . Here we show that quantum theory allows for absolute maximal contextuality despite what is suggested by the examination of the quantum violations of Bell and noncontextuality inequalities considered in the past. Our proof is not constructive and does not single out explicit scenarios. Nevertheless, we identify scenarios in which quantum theory allows for almost-absolute-maximal contextuality.

  16. Absolute calibration in vivo measurement systems

    SciTech Connect

    Kruchten, D.A.; Hickman, D.P.

    1991-02-01

    Lawrence Livermore National Laboratory (LLNL) is currently investigating a new method for obtaining absolute calibration factors for radiation measurement systems used to measure internally deposited radionuclides in vivo. Absolute calibration of in vivo measurement systems will eliminate the need to generate a series of human surrogate structures (i.e., phantoms) for calibrating in vivo measurement systems. The absolute calibration of in vivo measurement systems utilizes magnetic resonance imaging (MRI) to define physiological structure, size, and composition. The MRI image provides a digitized representation of the physiological structure, which allows for any mathematical distribution of radionuclides within the body. Using Monte Carlo transport codes, the emission spectrum from the body is predicted. The in vivo measurement equipment is calibrated using the Monte Carlo code and adjusting for the intrinsic properties of the detection system. The calibration factors are verified using measurements of existing phantoms and previously obtained measurements of human volunteers. 8 refs.

  17. Stimulus probability effects in absolute identification.

    PubMed

    Kent, Christopher; Lamberts, Koen

    2016-05-01

    This study investigated the effect of stimulus presentation probability on accuracy and response times in an absolute identification task. Three schedules of presentation were used to investigate the interaction between presentation probability and stimulus position within the set. Data from individual participants indicated strong effects of presentation probability on both proportion correct and response times. The effects were moderated by the ubiquitous stimulus position effect. The accuracy and response time data were predicted by an exemplar-based model of perceptual cognition (Kent & Lamberts, 2005). The bow in discriminability was also attenuated when presentation probability for middle items was relatively high, an effect that will constrain future model development. The study provides evidence for item-specific learning in absolute identification. Implications for other theories of absolute identification are discussed. (PsycINFO Database Record

  18. Quantitative standards for absolute linguistic universals.

    PubMed

    Piantadosi, Steven T; Gibson, Edward

    2014-01-01

    Absolute linguistic universals are often justified by cross-linguistic analysis: If all observed languages exhibit a property, the property is taken to be a likely universal, perhaps specified in the cognitive or linguistic systems of language learners and users. In many cases, these patterns are then taken to motivate linguistic theory. Here, we show that cross-linguistic analysis will very rarely be able to statistically justify absolute, inviolable patterns in language. We formalize two statistical methods--frequentist and Bayesian--and show that in both it is possible to find strict linguistic universals, but that the numbers of independent languages necessary to do so is generally unachievable. This suggests that methods other than typological statistics are necessary to establish absolute properties of human language, and thus that many of the purported universals in linguistics have not received sufficient empirical justification.

  19. Absolute photoacoustic thermometry in deep tissue.

    PubMed

    Yao, Junjie; Ke, Haixin; Tai, Stephen; Zhou, Yong; Wang, Lihong V

    2013-12-15

    Photoacoustic thermography is a promising tool for temperature measurement in deep tissue. Here we propose an absolute temperature measurement method based on the dual temperature dependences of the Grüneisen parameter and the speed of sound in tissue. By taking ratiometric measurements at two adjacent temperatures, we can eliminate the factors that are temperature irrelevant but difficult to correct for in deep tissue. To validate our method, absolute temperatures of blood-filled tubes embedded ~9 mm deep in chicken tissue were measured in a biologically relevant range from 28°C to 46°C. The temperature measurement accuracy was ~0.6°C. The results suggest that our method can be potentially used for absolute temperature monitoring in deep tissue during thermotherapy.

  20. Molecular iodine absolute frequencies. Final report

    SciTech Connect

    Sansonetti, C.J.

    1990-06-25

    Fifty specified lines of {sup 127}I{sub 2} were studied by Doppler-free frequency modulation spectroscopy. For each line the classification of the molecular transition was determined, hyperfine components were identified, and one well-resolved component was selected for precise determination of its absolute frequency. In 3 cases, a nearby alternate line was selected for measurement because no well-resolved component was found for the specified line. Absolute frequency determinations were made with an estimated uncertainty of 1.1 MHz by locking a dye laser to the selected hyperfine component and measuring its wave number with a high-precision Fabry-Perot wavemeter. For each line results of the absolute measurement, the line classification, and a Doppler-free spectrum are given.

  1. Absolute Stability And Hyperstability In Hilbert Space

    NASA Technical Reports Server (NTRS)

    Wen, John Ting-Yung

    1989-01-01

    Theorems on stabilities of feedback control systems proved. Paper presents recent developments regarding theorems of absolute stability and hyperstability of feedforward-and-feedback control system. Theorems applied in analysis of nonlinear, adaptive, and robust control. Extended to provide sufficient conditions for stability in system including nonlinear feedback subsystem and linear time-invariant (LTI) feedforward subsystem, state space of which is Hilbert space, and input and output spaces having finite numbers of dimensions. (In case of absolute stability, feedback subsystem memoryless and possibly time varying. For hyperstability, feedback system dynamical system.)

  2. Hidden Treasures in “Ancient” Microarrays: Gene-Expression Portrays Biology and Potential Resistance Pathways of Major Lung Cancer Subtypes and Normal Tissue

    PubMed Central

    Kerkentzes, Konstantinos; Lagani, Vincenzo; Tsamardinos, Ioannis; Vyberg, Mogens; Røe, Oluf Dimitri

    2014-01-01

    Objective: Novel statistical methods and increasingly more accurate gene annotations can transform “old” biological data into a renewed source of knowledge with potential clinical relevance. Here, we provide an in silico proof-of-concept by extracting novel information from a high-quality mRNA expression dataset, originally published in 2001, using state-of-the-art bioinformatics approaches. Methods: The dataset consists of histologically defined cases of lung adenocarcinoma (AD), squamous (SQ) cell carcinoma, small-cell lung cancer, carcinoid, metastasis (breast and colon AD), and normal lung specimens (203 samples in total). A battery of statistical tests was used for identifying differential gene expressions, diagnostic and prognostic genes, enriched gene ontologies, and signaling pathways. Results: Our results showed that gene expressions faithfully recapitulate immunohistochemical subtype markers, as chromogranin A in carcinoids, cytokeratin 5, p63 in SQ, and TTF1 in non-squamous types. Moreover, biological information with putative clinical relevance was revealed as potentially novel diagnostic genes for each subtype with specificity 93–100% (AUC = 0.93–1.00). Cancer subtypes were characterized by (a) differential expression of treatment target genes as TYMS, HER2, and HER3 and (b) overrepresentation of treatment-related pathways like cell cycle, DNA repair, and ERBB pathways. The vascular smooth muscle contraction, leukocyte trans-endothelial migration, and actin cytoskeleton pathways were overexpressed in normal tissue. Conclusion: Reanalysis of this public dataset displayed the known biological features of lung cancer subtypes and revealed novel pathways of potentially clinical importance. The findings also support our hypothesis that even old omics data of high quality can be a source of significant biological information when appropriate bioinformatics methods are used. PMID:25325012

  3. Absolute Points for Multiple Assignment Problems

    ERIC Educational Resources Information Center

    Adlakha, V.; Kowalski, K.

    2006-01-01

    An algorithm is presented to solve multiple assignment problems in which a cost is incurred only when an assignment is made at a given cell. The proposed method recursively searches for single/group absolute points to identify cells that must be loaded in any optimal solution. Unlike other methods, the first solution is the optimal solution. The…

  4. Absolute partial photoionization cross sections of ozone.

    SciTech Connect

    Berkowitz, J.; Chemistry

    2008-04-01

    Despite the current concerns about ozone, absolute partial photoionization cross sections for this molecule in the vacuum ultraviolet (valence) region have been unavailable. By eclectic re-evaluation of old/new data and plausible assumptions, such cross sections have been assembled to fill this void.

  5. Stimulus Probability Effects in Absolute Identification

    ERIC Educational Resources Information Center

    Kent, Christopher; Lamberts, Koen

    2016-01-01

    This study investigated the effect of stimulus presentation probability on accuracy and response times in an absolute identification task. Three schedules of presentation were used to investigate the interaction between presentation probability and stimulus position within the set. Data from individual participants indicated strong effects of…

  6. Teaching Absolute Value Inequalities to Mature Students

    ERIC Educational Resources Information Center

    Sierpinska, Anna; Bobos, Georgeana; Pruncut, Andreea

    2011-01-01

    This paper gives an account of a teaching experiment on absolute value inequalities, whose aim was to identify characteristics of an approach that would realize the potential of the topic to develop theoretical thinking in students enrolled in prerequisite mathematics courses at a large, urban North American university. The potential is…

  7. Solving Absolute Value Equations Algebraically and Geometrically

    ERIC Educational Resources Information Center

    Shiyuan, Wei

    2005-01-01

    The way in which students can improve their comprehension by understanding the geometrical meaning of algebraic equations or solving algebraic equation geometrically is described. Students can experiment with the conditions of the absolute value equation presented, for an interesting way to form an overall understanding of the concept.

  8. Absolute Radiometric Calibration Of The Thematic Mapper

    NASA Astrophysics Data System (ADS)

    Slater, P. N.; Biggar, S. F.; Holm, R. G.; Jackson, R. D.; Mao, Y.; Moran, M. S.; Palmer, J. M.; Yuan, B.

    1986-11-01

    The results are presented of five in-flight absolute radiometric calibrations, made in the period July 1984 to November 1985, at White Sands, New Mexico, of the solar reflective bands of the Landsat-5 Thematic Mapper (TM) . The 23 bandcalibrations made on the five dates show a ± 2.8% RMS variation from the mean as a percentage of the mean.

  9. On Relative and Absolute Conviction in Mathematics

    ERIC Educational Resources Information Center

    Weber, Keith; Mejia-Ramos, Juan Pablo

    2015-01-01

    Conviction is a central construct in mathematics education research on justification and proof. In this paper, we claim that it is important to distinguish between absolute conviction and relative conviction. We argue that researchers in mathematics education frequently have not done so and this has lead to researchers making unwarranted claims…

  10. (Z)3,4,5,4‧-trans-tetramethoxystilbene, a new analogue of resveratrol, inhibits gefitinb-resistant non-small cell lung cancer via selectively elevating intracellular calcium level

    NASA Astrophysics Data System (ADS)

    Fan, Xing-Xing; Yao, Xiao-Jun; Xu, Su Wei; Wong, Vincent Kam-Wai; He, Jian-Xing; Ding, Jian; Xue, Wei-Wei; Mujtaba, Tahira; Michelangeli, Francesco; Huang, Min; Huang, Jun; Xiao, Da-Kai; Jiang, Ze-Bo; Zhou, Yan-Ling; Kin-Ting Kam, Richard; Liu, Liang; Lai-Han Leung, Elaine

    2015-11-01

    Calcium is a second messenger which is required for regulation of many cellular processes. However, excessive elevation or prolonged activation of calcium signaling would lead to cell death. As such, selectively regulating calcium signaling could be an alternative approach for anti-cancer therapy. Recently, we have identified an effective analogue of resveratrol, (Z)3,4,5,4‧-trans-tetramethoxystilbene (TMS) which selectively elevated the intracellular calcium level in gefitinib-resistant (G-R) non-small-cell lung cancer (NSCLC) cells. TMS exhibited significant inhibitory effect on G-R NSCLC cells, but not other NSCLC cells and normal lung epithelial cells. The phosphorylation and activation of EGFR were inhibited by TMS in G-R cells. TMS induced caspase-independent apoptosis and autophagy by directly binding to SERCA and causing endoplasmic reticulum (ER) stress and AMPK activation. Proteomics analysis also further confirmed that mTOR pathway, which is the downstream of AMPK, was significantly suppressed by TMS. JNK, the cross-linker of ER stress and mTOR pathway was significantly activated by TMS. In addition, the inhibition of JNK activation can partially block the effect of TMS. Taken together, TMS showed promising anti-cancer activity by mediating calcium signaling pathway and inducing apoptosis as well as autophagy in G-R NSCLC cells, providing strategy in designing multi-targeting drug for treating G-R patients.

  11. (Z)3,4,5,4′-trans-tetramethoxystilbene, a new analogue of resveratrol, inhibits gefitinb-resistant non-small cell lung cancer via selectively elevating intracellular calcium level

    PubMed Central

    Fan, Xing-Xing; Yao, Xiao-Jun; Xu, Su Wei; Wong, Vincent Kam-Wai; He, Jian-Xing; Ding, Jian; Xue, Wei-Wei; Mujtaba, Tahira; Michelangeli, Francesco; Huang, Min; Huang, Jun; Xiao, Da-Kai; Jiang, Ze-Bo; Zhou, Yan-Ling; Kin-Ting Kam, Richard; Liu, Liang; Lai-Han Leung, Elaine

    2015-01-01

    Calcium is a second messenger which is required for regulation of many cellular processes. However, excessive elevation or prolonged activation of calcium signaling would lead to cell death. As such, selectively regulating calcium signaling could be an alternative approach for anti-cancer therapy. Recently, we have identified an effective analogue of resveratrol, (Z)3,4,5,4′-trans-tetramethoxystilbene (TMS) which selectively elevated the intracellular calcium level in gefitinib-resistant (G-R) non-small-cell lung cancer (NSCLC) cells. TMS exhibited significant inhibitory effect on G-R NSCLC cells, but not other NSCLC cells and normal lung epithelial cells. The phosphorylation and activation of EGFR were inhibited by TMS in G-R cells. TMS induced caspase-independent apoptosis and autophagy by directly binding to SERCA and causing endoplasmic reticulum (ER) stress and AMPK activation. Proteomics analysis also further confirmed that mTOR pathway, which is the downstream of AMPK, was significantly suppressed by TMS. JNK, the cross-linker of ER stress and mTOR pathway was significantly activated by TMS. In addition, the inhibition of JNK activation can partially block the effect of TMS. Taken together, TMS showed promising anti-cancer activity by mediating calcium signaling pathway and inducing apoptosis as well as autophagy in G-R NSCLC cells, providing strategy in designing multi-targeting drug for treating G-R patients. PMID:26542098

  12. Ganoderma tsugae Induces S Phase Arrest and Apoptosis in Doxorubicin-Resistant Lung Adenocarcinoma H23/0.3 Cells via Modulation of the PI3K/Akt Signaling Pathway

    PubMed Central

    Yu, Yang-Hao; Kuo, Han-Peng; Hsieh, Hui-Hsia; Li, Jhy-Wei; Hsu, Wu-Huei; Chen, Shih-Jung; Su, Muh-Hwan; Liu, Shwu-Huey; Cheng, Yung-Chi; Chen, Chih-Yi; Kao, Ming-Ching

    2012-01-01

    Ganoderma tsugae (GT) is a traditional Chinese medicine that exhibits significant antitumor activities against many types of cancer. This study investigated the molecular mechanism by which GT suppresses the growth of doxorubicin-resistant lung adenocarcinoma H23/0.3 cells. Our results reveal that GT inhibits the viability of H23/0.3 cells in vitro and in vivo and sensitizes the growth suppression effect of doxorubicin on H23/0.3 cells. The data also show that GT induces S phase arrest by interfering with the protein expression of cyclin A, cyclin E, CDK2, and CDC25A. Furthermore, GT induces cellular apoptosis via induction of a mitochondria/caspase pathway. In addition, we also demonstrate that the suppression of cell proliferation by GT is through down-regulation of the PI3K/Akt signaling pathway. In conclusion, this study suggests that GT may be a useful adjuvant therapeutic agent in the treatment of lung cancer. PMID:22792123

  13. Usefulness of texture features for segmentation of lungs with severe diffuse interstitial lung disease

    NASA Astrophysics Data System (ADS)

    Wang, Jiahui; Li, Feng; Li, Qiang

    2010-03-01

    We developed an automated method for the segmentation of lungs with severe diffuse interstitial lung disease (DILD) in multi-detector CT. In this study, we would like to compare the performance levels of this method and a thresholdingbased segmentation method for normal lungs, moderately abnormal lungs, severely abnormal lungs, and all lungs in our database. Our database includes 31 normal cases and 45 abnormal cases with severe DILD. The outlines of lungs were manually delineated by a medical physicist and confirmed by an experienced chest radiologist. These outlines were used as reference standards for the evaluation of the segmentation results. We first employed a thresholding technique for CT value to obtain initial lungs, which contain normal and mildly abnormal lung parenchyma. We then used texture-feature images derived from co-occurrence matrix to further segment lung regions with severe DILD. The segmented lung regions with severe DILD were combined with the initial lungs to generate the final segmentation results. We also identified and removed the airways to improve the accuracy of the segmentation results. We used three metrics, i.e., overlap, volume agreement, and mean absolute distance (MAD) between automatically segmented lung and reference lung to evaluate the performance of our segmentation method and the thresholding-based segmentation method. Our segmentation method achieved a mean overlap of 96.1%, a mean volume agreement of 98.1%, and a mean MAD of 0.96 mm for the 45 abnormal cases. On the other hand the thresholding-based segmentation method achieved a mean overlap of 94.2%, a mean volume agreement of 95.8%, and a mean MAD of 1.51 mm for the 45 abnormal cases. Our new method obtained higher performance level than the thresholding-based segmentation method.

  14. The DNA Methyltransferase DNMT1 and Tyrosine-Protein Kinase KIT Cooperatively Promote Resistance to 5-Aza-2′-deoxycytidine (Decitabine) and Midostaurin (PKC412) in Lung Cancer Cells*

    PubMed Central

    Yan, Fei; Shen, Na; Pang, Jiuxia; Molina, Julian R.; Yang, Ping; Liu, Shujun

    2015-01-01

    Lung cancer cells are sensitive to 5-aza-2′-deoxycytidine (decitabine) or midostaurin (PKC412), because decitabine restores the expression of methylation-silenced tumor suppressor genes, whereas PKC412 inhibits hyperactive kinase signaling, which is essential for cancer cell growth. Here, we demonstrated that resistance to decitabine (decitabineR) or PKC412 (PKC412R) eventually results from simultaneously remethylated DNA and reactivated kinase cascades. Indeed, both decitabineR and PKC412R displayed the up-regulation of DNA methyltransferase DNMT1 and tyrosine-protein kinase KIT, the enhanced phosphorylation of KIT and its downstream effectors, and the increased global and gene-specific DNA methylation with the down-regulation of tumor suppressor gene epithelial cadherin CDH1. Interestingly, decitabineR and PKC412R had higher capability of colony formation and wound healing than parental cells in vitro, which were attributed to the hyperactive DNMT1 or KIT, because inactivation of KIT or DNMT1 reciprocally blocked decitabineR or PKC412R cell proliferation. Further, DNMT1 knockdown sensitized PKC412R cells to PKC412; conversely, KIT depletion synergized with decitabine in eliminating decitabineR. Importantly, when engrafted into nude mice, decitabineR and PKC412R had faster proliferation with stronger tumorigenicity that was caused by the reactivated KIT kinase signaling and further CDH1 silencing. These findings identify functional cross-talk between KIT and DNMT1 in the development of drug resistance, implying the reciprocal targeting of protein kinases and DNA methyltransferases as an essential strategy for durable responses in lung cancer. PMID:26085088

  15. Combined Use of Absolute and Differential Seismic Arrival Time Data to Improve Absolute Event Location

    NASA Astrophysics Data System (ADS)

    Myers, S.; Johannesson, G.

    2012-12-01

    Arrival time measurements based on waveform cross correlation are becoming more common as advanced signal processing methods are applied to seismic data archives and real-time data streams. Waveform correlation can precisely measure the time difference between the arrival of two phases, and differential time data can be used to constrain relative location of events. Absolute locations are needed for many applications, which generally requires the use of absolute time data. Current methods for measuring absolute time data are approximately two orders of magnitude less precise than differential time measurements. To exploit the strengths of both absolute and differential time data, we extend our multiple-event location method Bayesloc, which previously used absolute time data only, to include the use of differential time measurements that are based on waveform cross correlation. Fundamentally, Bayesloc is a formulation of the joint probability over all parameters comprising the multiple event location system. The Markov-Chain Monte Carlo method is used to sample from the joint probability distribution given arrival data sets. The differential time component of Bayesloc includes scaling a stochastic estimate of differential time measurement precision based the waveform correlation coefficient for each datum. For a regional-distance synthetic data set with absolute and differential time measurement error of 0.25 seconds and 0.01 second, respectively, epicenter location accuracy is improved from and average of 1.05 km when solely absolute time data are used to 0.28 km when absolute and differential time data are used jointly (73% improvement). The improvement in absolute location accuracy is the result of conditionally limiting absolute location probability regions based on the precise relative position with respect to neighboring events. Bayesloc estimates of data precision are found to be accurate for the synthetic test, with absolute and differential time measurement

  16. An absolute measure for a key currency

    NASA Astrophysics Data System (ADS)

    Oya, Shunsuke; Aihara, Kazuyuki; Hirata, Yoshito

    It is generally considered that the US dollar and the euro are the key currencies in the world and in Europe, respectively. However, there is no absolute general measure for a key currency. Here, we investigate the 24-hour periodicity of foreign exchange markets using a recurrence plot, and define an absolute measure for a key currency based on the strength of the periodicity. Moreover, we analyze the time evolution of this measure. The results show that the credibility of the US dollar has not decreased significantly since the Lehman shock, when the Lehman Brothers bankrupted and influenced the economic markets, and has increased even relatively better than that of the euro and that of the Japanese yen.

  17. Probing absolute spin polarization at the nanoscale.

    PubMed

    Eltschka, Matthias; Jäck, Berthold; Assig, Maximilian; Kondrashov, Oleg V; Skvortsov, Mikhail A; Etzkorn, Markus; Ast, Christian R; Kern, Klaus

    2014-12-10

    Probing absolute values of spin polarization at the nanoscale offers insight into the fundamental mechanisms of spin-dependent transport. Employing the Zeeman splitting in superconducting tips (Meservey-Tedrow-Fulde effect), we introduce a novel spin-polarized scanning tunneling microscopy that combines the probing capability of the absolute values of spin polarization with precise control at the atomic scale. We utilize our novel approach to measure the locally resolved spin polarization of magnetic Co nanoislands on Cu(111). We find that the spin polarization is enhanced by 65% when increasing the width of the tunnel barrier by only 2.3 Å due to the different decay of the electron orbitals into vacuum. PMID:25423049

  18. Absolute radiometry and the solar constant

    NASA Technical Reports Server (NTRS)

    Willson, R. C.

    1974-01-01

    A series of active cavity radiometers (ACRs) are described which have been developed as standard detectors for the accurate measurement of irradiance in absolute units. It is noted that the ACR is an electrical substitution calorimeter, is designed for automatic remote operation in any environment, and can make irradiance measurements in the range from low-level IR fluxes up to 30 solar constants with small absolute uncertainty. The instrument operates in a differential mode by chopping the radiant flux to be measured at a slow rate, and irradiance is determined from two electrical power measurements together with the instrumental constant. Results are reported for measurements of the solar constant with two types of ACRs. The more accurate measurement yielded a value of 136.6 plus or minus 0.7 mW/sq cm (1.958 plus or minus 0.010 cal/sq cm per min).

  19. From Hubble's NGSL to Absolute Fluxes

    NASA Technical Reports Server (NTRS)

    Heap, Sara R.; Lindler, Don

    2012-01-01

    Hubble's Next Generation Spectral Library (NGSL) consists of R-l000 spectra of 374 stars of assorted temperature, gravity, and metallicity. Each spectrum covers the wavelength range, 0.18-1.00 microns. The library can be viewed and/or downloaded from the website, http://archive.stsci.edu/prepds/stisngsll. Stars in the NGSL are now being used as absolute flux standards at ground-based observatories. However, the uncertainty in the absolute flux is about 2%, which does not meet the requirements of dark-energy surveys. We are therefore developing an observing procedure that should yield fluxes with uncertainties less than 1 % and will take part in an HST proposal to observe up to 15 stars using this new procedure.

  20. Impact of Winko on absolute discharges.

    PubMed

    Balachandra, Krishna; Swaminath, Sam; Litman, Larry C

    2004-01-01

    In Canada, case laws have had a significant impact on the way mentally ill offenders are managed, both in the criminal justice system and in the forensic mental health system. The Supreme Court of Canada's decision with respect to Winko has set a major precedent in the application of the test of significant risk to the safety of the public in making dispositions by the Ontario Review Board and granting absolute discharges to the mentally ill offenders in the forensic health system. Our study examines the impact of the Supreme Court of Canada's decision before and after Winko. The results show that the numbers of absolute discharges have increased post-Winko, which was statistically significant, but there could be other factors influencing this increase.

  1. Asteroid absolute magnitudes and slope parameters

    NASA Technical Reports Server (NTRS)

    Tedesco, Edward F.

    1991-01-01

    A new listing of absolute magnitudes (H) and slope parameters (G) has been created and published in the Minor Planet Circulars; this same listing will appear in the 1992 Ephemerides of Minor Planets. Unlike previous listings, the values of the current list were derived from fits of data at the V band. All observations were reduced in the same fashion using, where appropriate, a single basis default value of 0.15 for the slope parameter. Distances and phase angles were computed for each observation. The data for 113 asteroids was of sufficiently high quality to permit derivation of their H and G. These improved absolute magnitudes and slope parameters will be used to deduce the most reliable bias-corrected asteroid size-frequency distribution yet made.

  2. Absolute-magnitude distributions of supernovae

    SciTech Connect

    Richardson, Dean; Wright, John; Jenkins III, Robert L.; Maddox, Larry

    2014-05-01

    The absolute-magnitude distributions of seven supernova (SN) types are presented. The data used here were primarily taken from the Asiago Supernova Catalogue, but were supplemented with additional data. We accounted for both foreground and host-galaxy extinction. A bootstrap method is used to correct the samples for Malmquist bias. Separately, we generate volume-limited samples, restricted to events within 100 Mpc. We find that the superluminous events (M{sub B} < –21) make up only about 0.1% of all SNe in the bias-corrected sample. The subluminous events (M{sub B} > –15) make up about 3%. The normal Ia distribution was the brightest with a mean absolute blue magnitude of –19.25. The IIP distribution was the dimmest at –16.75.

  3. Absolute and relative dosimetry for ELIMED

    SciTech Connect

    Cirrone, G. A. P.; Schillaci, F.; Scuderi, V.; Cuttone, G.; Candiano, G.; Musumarra, A.; Pisciotta, P.; Romano, F.; Carpinelli, M.; Presti, D. Lo; Raffaele, L.; Tramontana, A.; Cirio, R.; Sacchi, R.; Monaco, V.; Marchetto, F.; Giordanengo, S.

    2013-07-26

    The definition of detectors, methods and procedures for the absolute and relative dosimetry of laser-driven proton beams is a crucial step toward the clinical use of this new kind of beams. Hence, one of the ELIMED task, will be the definition of procedures aiming to obtain an absolute dose measure at the end of the transport beamline with an accuracy as close as possible to the one required for clinical applications (i.e. of the order of 5% or less). Relative dosimetry procedures must be established, as well: they are necessary in order to determine and verify the beam dose distributions and to monitor the beam fluence and the energetic spectra during irradiations. Radiochromic films, CR39, Faraday Cup, Secondary Emission Monitor (SEM) and transmission ionization chamber will be considered, designed and studied in order to perform a fully dosimetric characterization of the ELIMED proton beam.

  4. Absolute photoionization cross sections of atomic oxygen

    NASA Technical Reports Server (NTRS)

    Samson, J. A. R.; Pareek, P. N.

    1985-01-01

    The absolute values of photoionization cross sections of atomic oxygen were measured from the ionization threshold to 120 A. An auto-ionizing resonance belonging to the 2S2P4(4P)3P(3Do, 3So) transition was observed at 479.43 A and another line at 389.97 A. The experimental data is in excellent agreement with rigorous close-coupling calculations that include electron correlations in both the initial and final states.

  5. Absolute photoionization cross sections of atomic oxygen

    NASA Technical Reports Server (NTRS)

    Samson, J. A. R.; Pareek, P. N.

    1982-01-01

    The absolute values of photoionization cross sections of atomic oxygen were measured from the ionization threshold to 120 A. An auto-ionizing resonance belonging to the 2S2P4(4P)3P(3Do, 3So) transition was observed at 479.43 A and another line at 389.97 A. The experimental data is in excellent agreement with rigorous close-coupling calculations that include electron correlations in both the initial and final states.

  6. Relative errors can cue absolute visuomotor mappings.

    PubMed

    van Dam, Loes C J; Ernst, Marc O

    2015-12-01

    When repeatedly switching between two visuomotor mappings, e.g. in a reaching or pointing task, adaptation tends to speed up over time. That is, when the error in the feedback corresponds to a mapping switch, fast adaptation occurs. Yet, what is learned, the relative error or the absolute mappings? When switching between mappings, errors with a size corresponding to the relative difference between the mappings will occur more often than other large errors. Thus, we could learn to correct more for errors with this familiar size (Error Learning). On the other hand, it has been shown that the human visuomotor system can store several absolute visuomotor mappings (Mapping Learning) and can use associated contextual cues to retrieve them. Thus, when contextual information is present, no error feedback is needed to switch between mappings. Using a rapid pointing task, we investigated how these two types of learning may each contribute when repeatedly switching between mappings in the absence of task-irrelevant contextual cues. After training, we examined how participants changed their behaviour when a single error probe indicated either the often-experienced error (Error Learning) or one of the previously experienced absolute mappings (Mapping Learning). Results were consistent with Mapping Learning despite the relative nature of the error information in the feedback. This shows that errors in the feedback can have a double role in visuomotor behaviour: they drive the general adaptation process by making corrections possible on subsequent movements, as well as serve as contextual cues that can signal a learned absolute mapping. PMID:26280315

  7. The absolute spectrophotometric catalog by Anita Cochran

    NASA Astrophysics Data System (ADS)

    Burnashev, V. I.; Burnasheva, B. A.; Ruban, E. V.; Hagen-Torn, E. I.

    2014-06-01

    The absolute spectrophotometric catalog by Anita Cochran is presented in a machine-readable form. The catalog systematizes observations acquired at the McDonald Observatory in 1977-1978. The data are compared with other sources, in particular, the calculated broadband stellar magnitudes are compared with photometric observations by other authors, to show that the observational data given in the catalog are reliable and suitable for a variety of applications. Observations of variable stars of different types make Cochran's catalog especially valuable.

  8. Absolute magnitudes and kinematics of barium stars.

    NASA Astrophysics Data System (ADS)

    Gomez, A. E.; Luri, X.; Grenier, S.; Prevot, L.; Mennessier, M. O.; Figueras, F.; Torra, J.

    1997-03-01

    The absolute magnitude of barium stars has been obtained from kinematical data using a new algorithm based on the maximum-likelihood principle. The method allows to separate a sample into groups characterized by different mean absolute magnitudes, kinematics and z-scale heights. It also takes into account, simultaneously, the censorship in the sample and the errors on the observables. The method has been applied to a sample of 318 barium stars. Four groups have been detected. Three of them show a kinematical behaviour corresponding to disk population stars. The fourth group contains stars with halo kinematics. The luminosities of the disk population groups spread a large range. The intrinsically brightest one (M_v_=-1.5mag, σ_M_=0.5mag) seems to be an inhomogeneous group containing barium binaries as well as AGB single stars. The most numerous group (about 150 stars) has a mean absolute magnitude corresponding to stars in the red giant branch (M_v_=0.9mag, σ_M_=0.8mag). The third group contains barium dwarfs, the obtained mean absolute magnitude is characteristic of stars on the main sequence or on the subgiant branch (M_v_=3.3mag, σ_M_=0.5mag). The obtained mean luminosities as well as the kinematical results are compatible with an evolutionary link between barium dwarfs and classical barium giants. The highly luminous group is not linked with these last two groups. More high-resolution spectroscopic data will be necessary in order to better discriminate between barium and non-barium stars.

  9. Chemical composition of French mimosa absolute oil.

    PubMed

    Perriot, Rodolphe; Breme, Katharina; Meierhenrich, Uwe J; Carenini, Elise; Ferrando, Georges; Baldovini, Nicolas

    2010-02-10

    Since decades mimosa (Acacia dealbata) absolute oil has been used in the flavor and perfume industry. Today, it finds an application in over 80 perfumes, and its worldwide industrial production is estimated five tons per year. Here we report on the chemical composition of French mimosa absolute oil. Straight-chain analogues from C6 to C26 with different functional groups (hydrocarbons, esters, aldehydes, diethyl acetals, alcohols, and ketones) were identified in the volatile fraction. Most of them are long-chain molecules: (Z)-heptadec-8-ene, heptadecane, nonadecane, and palmitic acid are the most abundant, and constituents such as 2-phenethyl alcohol, methyl anisate, and ethyl palmitate are present in smaller amounts. The heavier constituents were mainly triterpenoids such as lupenone and lupeol, which were identified as two of the main components. (Z)-Heptadec-8-ene, lupenone, and lupeol were quantified by GC-MS in SIM mode using external standards and represents 6%, 20%, and 7.8% (w/w) of the absolute oil. Moreover, odorant compounds were extracted by SPME and analyzed by GC-sniffing leading to the perception of 57 odorant zones, of which 37 compounds were identified by their odorant description, mass spectrum, retention index, and injection of the reference compound. PMID:20070087

  10. Measurement of absolute gravity acceleration in Firenze

    NASA Astrophysics Data System (ADS)

    de Angelis, M.; Greco, F.; Pistorio, A.; Poli, N.; Prevedelli, M.; Saccorotti, G.; Sorrentino, F.; Tino, G. M.

    2011-01-01

    This paper reports the results from the accurate measurement of the acceleration of gravity g taken at two separate premises in the Polo Scientifico of the University of Firenze (Italy). In these laboratories, two separate experiments aiming at measuring the Newtonian constant and testing the Newtonian law at short distances are in progress. Both experiments require an independent knowledge on the local value of g. The only available datum, pertaining to the italian zero-order gravity network, was taken more than 20 years ago at a distance of more than 60 km from the study site. Gravity measurements were conducted using an FG5 absolute gravimeter, and accompanied by seismic recordings for evaluating the noise condition at the site. The absolute accelerations of gravity at the two laboratories are (980 492 160.6 ± 4.0) μGal and (980 492 048.3 ± 3.0) μGal for the European Laboratory for Non-Linear Spectroscopy (LENS) and Dipartimento di Fisica e Astronomia, respectively. Other than for the two referenced experiments, the data here presented will serve as a benchmark for any future study requiring an accurate knowledge of the absolute value of the acceleration of gravity in the study region.

  11. A Methodology for Absolute Isotope Composition Measurement

    NASA Astrophysics Data System (ADS)

    Shen, J. J.; Lee, D.; Liang, W.

    2007-12-01

    Double spike technique was a well defined method for isotope composition measurement by TIMS of samples which have natural mass fractionation effect, but it is still a problem to define the isotope composition for double spike itself. In this study, we modified the old double spike technique and found that we could use the modified technique to solve the ¡§true¡¨ isotope composition of double spike itself. According the true isotope composition of double spike, we can measure the absolute isotope composition if the sample has natural fractionation effect. A new vector analytical method has been developed in order to obtain the true isotopic composition of a 42Ca-48Ca double spike, and this is achieved by using two different sample-spike mixtures combined with the double spike and the natural Ca data. Because the natural sample, the two mixtures, and the spike should all lie on a single mixing line, we are able to constrain the true isotopic composition of our double spike using this new approach. This method not only can be used in Ca system but also in Ti, Cr, Fe, Ni, Zn, Mo, Ba and Pb systems. The absolute double spike isotopic ratio is important, which can save a lot of time to check different reference standards. Especially for Pb, radiogenic isotope system, the decay systems embodied in three of four naturally occurring isotopes induce difficult to obtain true isotopic ratios for absolute dating.

  12. Chemical composition of French mimosa absolute oil.

    PubMed

    Perriot, Rodolphe; Breme, Katharina; Meierhenrich, Uwe J; Carenini, Elise; Ferrando, Georges; Baldovini, Nicolas

    2010-02-10

    Since decades mimosa (Acacia dealbata) absolute oil has been used in the flavor and perfume industry. Today, it finds an application in over 80 perfumes, and its worldwide industrial production is estimated five tons per year. Here we report on the chemical composition of French mimosa absolute oil. Straight-chain analogues from C6 to C26 with different functional groups (hydrocarbons, esters, aldehydes, diethyl acetals, alcohols, and ketones) were identified in the volatile fraction. Most of them are long-chain molecules: (Z)-heptadec-8-ene, heptadecane, nonadecane, and palmitic acid are the most abundant, and constituents such as 2-phenethyl alcohol, methyl anisate, and ethyl palmitate are present in smaller amounts. The heavier constituents were mainly triterpenoids such as lupenone and lupeol, which were identified as two of the main components. (Z)-Heptadec-8-ene, lupenone, and lupeol were quantified by GC-MS in SIM mode using external standards and represents 6%, 20%, and 7.8% (w/w) of the absolute oil. Moreover, odorant compounds were extracted by SPME and analyzed by GC-sniffing leading to the perception of 57 odorant zones, of which 37 compounds were identified by their odorant description, mass spectrum, retention index, and injection of the reference compound.

  13. The Carina Project: Absolute and Relative Calibrations

    NASA Astrophysics Data System (ADS)

    Corsi, C. E.; Bono, G.; Walker, A. R.; Brocato, E.; Buonanno, R.; Caputo, F.; Castellani, M.; Castellani, V.; Dall'Ora, M.; Marconi, M.; Monelli, M.; Nonino, M.; Pulone, L.; Ripepi, V.; Smith, H. A.

    We discuss the reduction strategy adopted to perform the relative and the absolute calibration of the Wide Field Imager (WFI) available at the 2.2m ESO/MPI telescope and of the Mosaic Camera (MC) available at the 4m CTIO Blanco telescope. To properly constrain the occurrence of deceptive systematic errors in the relative calibration we observed with each chip the same set of stars. Current photometry seems to suggest that the WFI shows a positional effect when moving from the top to the bottom of individual chips. Preliminary results based on an independent data set collected with the MC suggest that this camera is only marginally affected by the same problem. To perform the absolute calibration we observed with each chip the same set of standard stars. The sample covers a wide color range and the accuracy both in the B and in the V-band appears to be of the order of a few hundredths of magnitude. Finally, we briefly outline the observing strategy to improve both relative and absolute calibrations of mosaic CCD cameras.

  14. Open lung biopsy

    MedlinePlus

    Biopsy - open lung ... An open lung biopsy is done in the hospital using general anesthesia , which means you are asleep and pain- ... The open lung biopsy is done to evaluate lung problems seen on x-ray or CT scan .

  15. Lung cancer - small cell

    MedlinePlus

    Cancer - lung - small cell; Small cell lung cancer; SCLC ... About 15% of all lung cancer cases are SCLC. Small cell lung cancer is slightly more common in men than women. Almost all cases of SCLC are ...

  16. Identification of a novel HIP1-ALK fusion variant in Non-Small-Cell Lung Cancer (NSCLC) and discovery of ALK I1171 (I1171N/S) mutations in two ALK-rearranged NSCLC patients with resistance to Alectinib.

    PubMed

    Ou, Sai-Hong Ignatius; Klempner, Samuel J; Greenbowe, Joel R; Azada, Michele; Schrock, Alexa B; Ali, Siraj M; Ross, Jeffrey S; Stephens, Philip J; Miller, Vincent A

    2014-12-01

    Huntingtin-interacting protein 1 (HIP1) has recently been identified as a new fusion partner fused to anaplastic lymphoma kinase (ALK) in non-small-cell lung cancer (NSCLC). To date, two variants of HIP1-ALK (H21; A20) and (H28; A20) have been identified in NSCLC. However, the response of patients with NSCLC harboring HIP1-ALK to ALK inhibitors and potential resistance mechanisms to such remain unknown. Here, we report a patient with NSCLC harboring a novel HIP1-ALK fusion variant (H30; A20). This patient and another patient with EML4-ALK variant 3a/b initially responded sequentially to crizotinib and then alectinib, a next-generation ALK inhibitor, but developed acquired resistance to alectinib with the presence of a mutation in amino acid residue 1171 (I1171N and I1171S respectively) located in the hydrophobic regulatory spine (R-spine) of the ALK kinase in both the cases as identified by a comprehensive next-generation sequencing-based assay performed on biopsies of new liver metastases that developed during alectinib treatment.

  17. Tsunami lung.

    PubMed

    Inoue, Yoshihiro; Fujino, Yasuhisa; Onodera, Makoto; Kikuchi, Satoshi; Shozushima, Tatsuyori; Ogino, Nobuyoshi; Mori, Kiyoshi; Oikawa, Hirotaka; Koeda, Yorihiko; Ueda, Hironobu; Takahashi, Tomohiro; Terui, Katsutoshi; Nakadate, Toshihide; Aoki, Hidehiko; Endo, Shigeatsu

    2012-04-01

    We encountered three cases of lung disorders caused by drowning in the recent large tsunami that struck following the Great East Japan Earthquake. All three were females, and two of them were old elderly. All segments of both lungs were involved in all the three patients, necessitating ICU admission and endotracheal intubation and mechanical ventilation. All three died within 3 weeks. In at least two cases, misswallowing of oil was suspected from the features noted at the time of the detection. Sputum culture for bacteria yielded isolation of Stenotrophomonas maltophilia, Legionella pneumophila, Burkholderia cepacia, and Pseudomonas aeruginosa. The cause of tsunami lung may be a combination of chemical induced pneumonia and bacterial pneumonia.

  18. Resistance to Therapy.

    PubMed

    Rivera, Gabriel; Wakelee, Heather A

    2016-01-01

    Identification of driver mutations in adenocarcinoma of the lung has revolutionized the treatment of this disease. It is now standard of care to look for activating mutations in epidermal growth factor receptor (EGFR), and translocations in anaplastic lymphoma kinase (ALK) or ROS1 in all newly diagnosed adenocarcinoma of the lung, and in many patients with squamous cell carcinoma as well. Recognition of multiple other lung cancer driver mutations has also expanded treatment options. Targeted treatments of these mutations lead to rapid and prolonged responses, but resistance inevitably develops. Until recently, traditional chemotherapy was the only alternative at that time, but better understanding of resistance mechanisms has lead to additional therapeutic options. These mechanisms of resistance and treatments are the focus of this chapter. Understanding of mechanisms of chemotherapy resistance is touched upon, along with a brief discussion of immune checkpoint inhibitors. PMID:27535395

  19. Non-adherent culture induces paclitaxel resistance in H460 lung cancer cells via ERK-mediated up-regulation of βIVa-tubulin.

    PubMed

    Atjanasuppat, Korakot; Lirdprapamongkol, Kriengsak; Jantaree, Phatcharida; Svasti, Jisnuson

    2015-10-23

    Circulating tumor cells (CTCs) are metastasizing epithelial cancer cells that adapt to survive when floating in bloodstream during metastasis. This condition can be mimicked in vitro by using non-adherent cell culture. The chemosensitivity of CTCs appears to correlate with the response of metastatic cancer patients to therapy, but chemoresistance is also frequently observed in advanced stage cancer patients, who have never previously received chemotherapy. We hypothesize that adaptation of epithelial cancer cells to become floating CTCs could lead to development of chemoresistance. Here, we explore whether chemoresistance is induced in epithelial cancer cells when cultured under non-adherent conditions. Increased paclitaxel-specific resistance was observed in floating cells compared to attached cells in H460, MCF-7, and HepG2 human cancer cell lines, by 15.6-, 3.9-, and 2.6-fold increases in IC50 values, respectively. qRT-PCR analysis showed that a paclitaxel-resistant β-tubulin isotype, βIVa-tubulin, was the most up-regulated gene compared with other β-tubulin isotypes in H460 floating cells, concomitant with elevated ERK activation. ERK inhibitor treatment could attenuate the up-regulation of βIVa-tubulin, and decreased the paclitaxel resistance of H460 floating cells, even though other β-tubulin isotypes were up-regulated when the ERK activation was blocked. In conclusion, we show induction of paclitaxel resistance in epithelial cancer cells, when floating in non-adherent culture, and this might occur with CTCs of cancer patients.

  20. Comparison of the respiratory responses to external resistive loading and bronchoconstriction.

    PubMed Central

    Kelsen, S G; Prestel, T F; Cherniack, N S; Chester, E H; Deal, E C

    1981-01-01

    The effects of resistive loads applied at the mouth were compared to the effects of bronchospasm on ventilation, respiratory muscle force (occlusion pressure), and respiratory sensations in 6 normal and 11 asthmatic subjects breathing 100% O2. External resistive loads ranging from 0.65 to 13.33 cm H2O/liter per s were applied during both inspiration and expiration. Bronchospasm was induced by inhalation of aerosolized methacholine. Bronchospasm increased ventilation, inspiratory airflow, respiratory rate, and lowered PACO2. External resistive loading, on the other hand, reduced respiratory rate and inspiratory flow, but left ventilation and PACO2 unaltered. FRC increased to a greater extent with bronchospasm than external flow resistive loads. With both bronchospasm and external loading, occlusion pressure increased in proportion to the rise in resistance to airflow. However, the change in occlusion pressure produced by a given change in resistance and the absolute level of occlusion pressure at comparable levels of airway resistance were greater during bronchospasm than during external loading. These differences in occlusion pressure responses to the two forms of obstruction were not explained by differences in chemical drive or respiratory muscle mechanical advantage. Although the subjects' perception of the effort involved in breathing was heightened during both forms of obstruction to airflow, at any given level of resistance the sense of effort was greater with bronchospasm than external loading. Inputs from mechanoreceptors in the lungs (e.g., irritant receptors) and/or greater stimulation of chest wall mechanoreceptors as a result of increases in lung elastance may explain the differing responses elicited by the two forms of resistive loading. PMID:6787083

  1. The role of cMet in non-small cell lung cancer resistant to EGFR-inhibitors: did we really find the target?

    PubMed

    Passiglia, Francesco; Van Der Steen, Nele; Raez, Luis; Pauwels, Patrick; Gil-Bazo, Ignacio; Santos, Edgardo; Santini, Daniele; Tesoriere, Giovanni; Russo, Antonio; Bronte, Giuseppe; Zwaenepoel, Karen; Cappuzzo, Federico; Rolfo, Christian

    2014-01-01

    The advent of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) represented the most important innovation in NSCLC treatment over the last years. However, despite a great initial activity, secondary mutations in the same target, or different alterations in other molecular pathways, inevitably occur, leading to the emergence of acquired resistance, in median within the first year of treatment. In this scenario, the mesenchymal-epidermal transition (cMET) tyrosine kinase receptor and its natural ligand, the hepatocyte growth factor (HGF), seem to play an important role. Indeed either the overexpression or the amplification of cMET, as well as the overexpression of the HGF, have been reported in a substantial subgroup of NSCLC patients resistant to EGFR-TKIs. Several cMET-inhibitors have been developed as potential therapeutic candidates, and are currently under investigation in clinical trials. These compounds include both monoclonal antibodies and TKIs, and most of them have been investigated as dual combinations including an anti-EGFR TKI, to improve the efficacy of the available treatments, and ultimately overcome acquired resistance to EGFR-inhibitors.

  2. Absolute Radiometric Calibration of EUNIS-06

    NASA Technical Reports Server (NTRS)

    Thomas, R. J.; Rabin, D. M.; Kent, B. J.; Paustian, W.

    2007-01-01

    The Extreme-Ultraviolet Normal-Incidence Spectrometer (EUNIS) is a soundingrocket payload that obtains imaged high-resolution spectra of individual solar features, providing information about the Sun's corona and upper transition region. Shortly after its successful initial flight last year, a complete end-to-end calibration was carried out to determine the instrument's absolute radiometric response over its Longwave bandpass of 300 - 370A. The measurements were done at the Rutherford-Appleton Laboratory (RAL) in England, using the same vacuum facility and EUV radiation source used in the pre-flight calibrations of both SOHO/CDS and Hinode/EIS, as well as in three post-flight calibrations of our SERTS sounding rocket payload, the precursor to EUNIS. The unique radiation source provided by the Physikalisch-Technische Bundesanstalt (PTB) had been calibrated to an absolute accuracy of 7% (l-sigma) at 12 wavelengths covering our bandpass directly against the Berlin electron storage ring BESSY, which is itself a primary radiometric source standard. Scans of the EUNIS aperture were made to determine the instrument's absolute spectral sensitivity to +- 25%, considering all sources of error, and demonstrate that EUNIS-06 was the most sensitive solar E W spectrometer yet flown. The results will be matched against prior calibrations which relied on combining measurements of individual optical components, and on comparisons with theoretically predicted 'insensitive' line ratios. Coordinated observations were made during the EUNIS-06 flight by SOHO/CDS and EIT that will allow re-calibrations of those instruments as well. In addition, future EUNIS flights will provide similar calibration updates for TRACE, Hinode/EIS, and STEREO/SECCHI/EUVI.

  3. Clock time is absolute and universal

    NASA Astrophysics Data System (ADS)

    Shen, Xinhang

    2015-09-01

    A critical error is found in the Special Theory of Relativity (STR): mixing up the concepts of the STR abstract time of a reference frame and the displayed time of a physical clock, which leads to use the properties of the abstract time to predict time dilation on physical clocks and all other physical processes. Actually, a clock can never directly measure the abstract time, but can only record the result of a physical process during a period of the abstract time such as the number of cycles of oscillation which is the multiplication of the abstract time and the frequency of oscillation. After Lorentz Transformation, the abstract time of a reference frame expands by a factor gamma, but the frequency of a clock decreases by the same factor gamma, and the resulting multiplication i.e. the displayed time of a moving clock remains unchanged. That is, the displayed time of any physical clock is an invariant of Lorentz Transformation. The Lorentz invariance of the displayed times of clocks can further prove within the framework of STR our earth based standard physical time is absolute, universal and independent of inertial reference frames as confirmed by both the physical fact of the universal synchronization of clocks on the GPS satellites and clocks on the earth, and the theoretical existence of the absolute and universal Galilean time in STR which has proved that time dilation and space contraction are pure illusions of STR. The existence of the absolute and universal time in STR has directly denied that the reference frame dependent abstract time of STR is the physical time, and therefore, STR is wrong and all its predictions can never happen in the physical world.

  4. Achieving Climate Change Absolute Accuracy in Orbit

    NASA Technical Reports Server (NTRS)

    Wielicki, Bruce A.; Young, D. F.; Mlynczak, M. G.; Thome, K. J; Leroy, S.; Corliss, J.; Anderson, J. G.; Ao, C. O.; Bantges, R.; Best, F.; Bowman, K.; Brindley, H.; Butler, J. J.; Collins, W.; Dykema, J. A.; Doelling, D. R.; Feldman, D. R.; Fox, N.; Huang, X.; Holz, R.; Huang, Y.; Jennings, D.; Jin, Z.; Johnson, D. G.; Jucks, K.; Kato, S.; Kratz, D. P.; Liu, X.; Lukashin, C.; Mannucci, A. J.; Phojanamongkolkij, N.; Roithmayr, C. M.; Sandford, S.; Taylor, P. C.; Xiong, X.

    2013-01-01

    The Climate Absolute Radiance and Refractivity Observatory (CLARREO) mission will provide a calibration laboratory in orbit for the purpose of accurately measuring and attributing climate change. CLARREO measurements establish new climate change benchmarks with high absolute radiometric accuracy and high statistical confidence across a wide range of essential climate variables. CLARREO's inherently high absolute accuracy will be verified and traceable on orbit to Système Internationale (SI) units. The benchmarks established by CLARREO will be critical for assessing changes in the Earth system and climate model predictive capabilities for decades into the future as society works to meet the challenge of optimizing strategies for mitigating and adapting to climate change. The CLARREO benchmarks are derived from measurements of the Earth's thermal infrared spectrum (5-50 micron), the spectrum of solar radiation reflected by the Earth and its atmosphere (320-2300 nm), and radio occultation refractivity from which accurate temperature profiles are derived. The mission has the ability to provide new spectral fingerprints of climate change, as well as to provide the first orbiting radiometer with accuracy sufficient to serve as the reference transfer standard for other space sensors, in essence serving as a "NIST [National Institute of Standards and Technology] in orbit." CLARREO will greatly improve the accuracy and relevance of a wide range of space-borne instruments for decadal climate change. Finally, CLARREO has developed new metrics and methods for determining the accuracy requirements of climate observations for a wide range of climate variables and uncertainty sources. These methods should be useful for improving our understanding of observing requirements for most climate change observations.

  5. Absolute calibration of the Auger fluorescence detectors

    SciTech Connect

    Bauleo, P.; Brack, J.; Garrard, L.; Harton, J.; Knapik, R.; Meyhandan, R.; Rovero, A.C.; Tamashiro, A.; Warner, D.

    2005-07-01

    Absolute calibration of the Pierre Auger Observatory fluorescence detectors uses a light source at the telescope aperture. The technique accounts for the combined effects of all detector components in a single measurement. The calibrated 2.5 m diameter light source fills the aperture, providing uniform illumination to each pixel. The known flux from the light source and the response of the acquisition system give the required calibration for each pixel. In the lab, light source uniformity is studied using CCD images and the intensity is measured relative to NIST-calibrated photodiodes. Overall uncertainties are presently 12%, and are dominated by systematics.

  6. Absolute rate theories of epigenetic stability

    NASA Astrophysics Data System (ADS)

    Walczak, Aleksandra M.; Onuchic, José N.; Wolynes, Peter G.

    2005-12-01

    Spontaneous switching events in most characterized genetic switches are rare, resulting in extremely stable epigenetic properties. We show how simple arguments lead to theories of the rate of such events much like the absolute rate theory of chemical reactions corrected by a transmission factor. Both the probability of the rare cellular states that allow epigenetic escape and the transmission factor depend on the rates of DNA binding and unbinding events and on the rates of protein synthesis and degradation. Different mechanisms of escape from the stable attractors occur in the nonadiabatic, weakly adiabatic, and strictly adiabatic regimes, characterized by the relative values of those input rates. rate theory | stochastic gene expression | gene switches

  7. Characterization of the DARA solar absolute radiometer

    NASA Astrophysics Data System (ADS)

    Finsterle, W.; Suter, M.; Fehlmann, A.; Kopp, G.

    2011-12-01

    The Davos Absolute Radiometer (DARA) prototype is an Electrical Substitution Radiometer (ESR) which has been developed as a successor of the PMO6 type on future space missions and ground based TSI measurements. The DARA implements an improved thermal design of the cavity detector and heat sink assembly to minimize air-vacuum differences and to maximize thermal symmetry of measuring and compensating cavity. The DARA also employs an inverted viewing geometry to reduce internal stray light. We will report on the characterization and calibration experiments which were carried out at PMOD/WRC and LASP (TRF).

  8. Absolute Priority for a Vehicle in VANET

    NASA Astrophysics Data System (ADS)

    Shirani, Rostam; Hendessi, Faramarz; Montazeri, Mohammad Ali; Sheikh Zefreh, Mohammad

    In today's world, traffic jams waste hundreds of hours of our life. This causes many researchers try to resolve the problem with the idea of Intelligent Transportation System. For some applications like a travelling ambulance, it is important to reduce delay even for a second. In this paper, we propose a completely infrastructure-less approach for finding shortest path and controlling traffic light to provide absolute priority for an emergency vehicle. We use the idea of vehicular ad-hoc networking to reduce the imposed travelling time. Then, we simulate our proposed protocol and compare it with a centrally controlled traffic light system.

  9. Absolute method of measuring magnetic susceptibility

    USGS Publications Warehouse

    Thorpe, A.; Senftle, F.E.

    1959-01-01

    An absolute method of standardization and measurement of the magnetic susceptibility of small samples is presented which can be applied to most techniques based on the Faraday method. The fact that the susceptibility is a function of the area under the curve of sample displacement versus distance of the magnet from the sample, offers a simple method of measuring the susceptibility without recourse to a standard sample. Typical results on a few substances are compared with reported values, and an error of less than 2% can be achieved. ?? 1959 The American Institute of Physics.

  10. Sentinel-2/MSI absolute calibration: first results

    NASA Astrophysics Data System (ADS)

    Lonjou, V.; Lachérade, S.; Fougnie, B.; Gamet, P.; Marcq, S.; Raynaud, J.-L.; Tremas, T.

    2015-10-01

    Sentinel-2 is an optical imaging mission devoted to the operational monitoring of land and coastal areas. It is developed in partnership between the European Commission and the European Space Agency. The Sentinel-2 mission is based on a satellites constellation deployed in polar sun-synchronous orbit. It will offer a unique combination of global coverage with a wide field of view (290km), a high revisit (5 days with two satellites), a high resolution (10m, 20m and 60m) and multi-spectral imagery (13 spectral bands in visible and shortwave infra-red domains). CNES is involved in the instrument commissioning in collaboration with ESA. This paper reviews all the techniques that will be used to insure an absolute calibration of the 13 spectral bands better than 5% (target 3%), and will present the first results if available. First, the nominal calibration technique, based on an on-board sun diffuser, is detailed. Then, we show how vicarious calibration methods based on acquisitions over natural targets (oceans, deserts, and Antarctica during winter) will be used to check and improve the accuracy of the absolute calibration coefficients. Finally, the verification scheme, exploiting photometer in-situ measurements over Lacrau plain, is described. A synthesis, including spectral coherence, inter-methods agreement and temporal evolution, will conclude the paper.

  11. Experimental results for absolute cylindrical wavefront testing

    NASA Astrophysics Data System (ADS)

    Reardon, Patrick J.; Alatawi, Ayshah

    2014-09-01

    Applications for Cylindrical and near-cylindrical surfaces are ever-increasing. However, fabrication of high quality cylindrical surfaces is limited by the difficulty of accurate and affordable metrology. Absolute testing of such surfaces represents a challenge to the optical testing community as cylindrical reference wavefronts are difficult to produce. In this paper, preliminary results for a new method of absolute testing of cylindrical wavefronts are presented. The method is based on the merging of the random ball test method with the fiber optic reference test. The random ball test assumes a large number of interferograms of a good quality sphere with errors that are statistically distributed such that the average of the errors goes to zero. The fiber optic reference test utilizes a specially processed optical fiber to provide a clean high quality reference wave from an incident line focus from the cylindrical wave under test. By taking measurements at different rotation and translations of the fiber, an analogous procedure can be employed to determine the quality of the converging cylindrical wavefront with high accuracy. This paper presents and discusses the results of recent tests of this method using a null optic formed by a COTS cylindrical lens and a free-form polished corrector element.

  12. Absolute Electron Extraction Efficiency of Liquid Xenon

    NASA Astrophysics Data System (ADS)

    Kamdin, Katayun; Mizrachi, Eli; Morad, James; Sorensen, Peter

    2016-03-01

    Dual phase liquid/gas xenon time projection chambers (TPCs) currently set the world's most sensitive limits on weakly interacting massive particles (WIMPs), a favored dark matter candidate. These detectors rely on extracting electrons from liquid xenon into gaseous xenon, where they produce proportional scintillation. The proportional scintillation from the extracted electrons serves to internally amplify the WIMP signal; even a single extracted electron is detectable. Credible dark matter searches can proceed with electron extraction efficiency (EEE) lower than 100%. However, electrons systematically left at the liquid/gas boundary are a concern. Possible effects include spontaneous single or multi-electron proportional scintillation signals in the gas, or charging of the liquid/gas interface or detector materials. Understanding EEE is consequently a serious concern for this class of rare event search detectors. Previous EEE measurements have mostly been relative, not absolute, assuming efficiency plateaus at 100%. I will present an absolute EEE measurement with a small liquid/gas xenon TPC test bed located at Lawrence Berkeley National Laboratory.

  13. Why to compare absolute numbers of mitochondria.

    PubMed

    Schmitt, Sabine; Schulz, Sabine; Schropp, Eva-Maria; Eberhagen, Carola; Simmons, Alisha; Beisker, Wolfgang; Aichler, Michaela; Zischka, Hans

    2014-11-01

    Prompted by pronounced structural differences between rat liver and rat hepatocellular carcinoma mitochondria, we suspected these mitochondrial populations to differ massively in their molecular composition. Aiming to reveal these mitochondrial differences, we came across the issue on how to normalize such comparisons and decided to focus on the absolute number of mitochondria. To this end, fluorescently stained mitochondria were quantified by flow cytometry. For rat liver mitochondria, this approach resulted in mitochondrial protein contents comparable to earlier reports using alternative methods. We determined similar protein contents for rat liver, heart and kidney mitochondria. In contrast, however, lower protein contents were determined for rat brain mitochondria and for mitochondria from the rat hepatocellular carcinoma cell line McA 7777. This result challenges mitochondrial comparisons that rely on equal protein amounts as a typical normalization method. Exemplarily, we therefore compared the activity and susceptibility toward inhibition of complex II of rat liver and hepatocellular carcinoma mitochondria and obtained significant discrepancies by either normalizing to protein amount or to absolute mitochondrial number. Importantly, the latter normalization, in contrast to the former, demonstrated a lower complex II activity and higher susceptibility toward inhibition in hepatocellular carcinoma mitochondria compared to liver mitochondria. These findings demonstrate that solely normalizing to protein amount may obscure essential molecular differences between mitochondrial populations.

  14. Absolute Proper Motions of Southern Globular Clusters

    NASA Astrophysics Data System (ADS)

    Dinescu, D. I.; Girard, T. M.; van Altena, W. F.

    1996-05-01

    Our program involves the determination of absolute proper motions with respect to galaxies for a sample of globular clusters situated in the southern sky. The plates cover a 6(deg) x 6(deg) area and are taken with the 51-cm double astrograph at Cesco Observatory in El Leoncito, Argentina. We have developed special methods to deal with the modelling error of the plate transformation and we correct for magnitude equation using the cluster stars. This careful astrometric treatment leads to accuracies of from 0.5 to 1.0 mas/yr for the absolute proper motion of each cluster, depending primarily on the number of measurable cluster stars which in turn is related to the cluster's distance. Space velocities are then derived which, in association with metallicities, provide key information for the formation scenario of the Galaxy, i.e. accretion and/or dissipational collapse. Here we present results for NGC 1851, NGC 6752, NGC 6584, NGC 6362 and NGC 288.

  15. Relational versus absolute representation in categorization.

    PubMed

    Edwards, Darren J; Pothos, Emmanuel M; Perlman, Amotz

    2012-01-01

    This study explores relational-like and absolute-like representations in categorization. Although there is much evidence that categorization processes can involve information about both the particular physical properties of studied instances and abstract (relational) properties, there has been little work on the factors that lead to one kind of representation as opposed to the other. We tested 370 participants in 6 experiments, in which participants had to classify new items into predefined artificial categories. In 4 experiments, we observed a predominantly relational-like mode of classification, and in 2 experiments we observed a shift toward an absolute-like mode of classification. These results suggest 3 factors that promote a relational-like mode of classification: fewer items per group, more training groups, and the presence of a time delay. Overall, we propose that less information about the distributional properties of a category or weaker memory traces for the category exemplars (induced, e.g., by having smaller categories or a time delay) can encourage relational-like categorization.

  16. Transient absolute robustness in stochastic biochemical networks.

    PubMed

    Enciso, German A

    2016-08-01

    Absolute robustness allows biochemical networks to sustain a consistent steady-state output in the face of protein concentration variability from cell to cell. This property is structural and can be determined from the topology of the network alone regardless of rate parameters. An important question regarding these systems is the effect of discrete biochemical noise in the dynamical behaviour. In this paper, a variable freezing technique is developed to show that under mild hypotheses the corresponding stochastic system has a transiently robust behaviour. Specifically, after finite time the distribution of the output approximates a Poisson distribution, centred around the deterministic mean. The approximation becomes increasingly accurate, and it holds for increasingly long finite times, as the total protein concentrations grow to infinity. In particular, the stochastic system retains a transient, absolutely robust behaviour corresponding to the deterministic case. This result contrasts with the long-term dynamics of the stochastic system, which eventually must undergo an extinction event that eliminates robustness and is completely different from the deterministic dynamics. The transiently robust behaviour may be sufficient to carry out many forms of robust signal transduction and cellular decision-making in cellular organisms. PMID:27581485

  17. Aerosol-derived lung morphometry: comparisons with a lung model and lung function indexes.

    PubMed

    Blanchard, J D; Heyder, J; O'Donnell, C R; Brain, J D

    1991-10-01

    This study evaluated the ability of aerosol-derived lung morphometry to noninvasively probe airway and acinar dimensions. Effective air-space diameters (EAD) were calculated from the time-dependent gravitational losses of 1-microns particles from inhaled aerosol boluses during breath holding. In 17 males [33 +/- 7 (SD) yr] the relationship between EAD and volumetric penetration of the bolus into the lungs (Vp) could be expressed by the linear power-law function, log (EAD) alpha beta log (Vp). Our EAD values were consistent with Weibel's symmetric lung model A for small airways and more distal air spaces. As lung volume increased from 57 to 87% of total lung capacity (TLC), EAD at Vp of 160 and 550 cm3 increased 70 and 41%, respectively. At 57% TLC, log (EAD) at 160 cm3 was significantly correlated with airway resistance (r = -0.57, P less than 0.0204) but not with forced expired flow between 25 and 75% of vital capacity. Log (EAD) at 400 cm3 was correlated with deposition of 1-micron particles (r = -0.73, P less than 0.0009). We conclude that aerosol-derived lung morphometry is a responsive noninvasive probe of peripheral air-space diameters. PMID:1757343

  18. The autophagy inhibitor chloroquine overcomes the innate resistance to erlotinib of non-small cell lung cancer cells with wild-type EGFR

    PubMed Central

    Zou, Yiyu; Ling, Yi-He; Sironi, Juan; Schwartz, Edward L.; Perez-Soler, Roman; Piperdi, Bilal

    2013-01-01

    Introduction The EGFR inhibitor erlotinib is much less effective in NSCLC tumors with wild-type EGFR than in tumors with activating EGFR mutations. Autophagy is a tightly regulated lysosomal self-digestion process that may alternatively promote cell survival or type II cell death. This study assessed the role of autophagy in erlotinib-mediated cytotoxicity. Methods We used wild-type EGFR erlotinib-sensitive and -resistant NSCLC cell lines to determine if inhibiting autophagy by a therapeutic agent potentiated the antitumor activity of erlotinib in vitro and in vivo. Results Erlotinib at a clinically relevant concentration (2 μM) induced autophagy in NSCLC cells with wild type EGFR, and the degree of induction was greater in resistant than in sensitive cells, suggesting that autophagy is cytoprotective. This was confirmed by knockdown of the autophagy-related gene Atg-5 and by using the autophagy inhibitor chloroquine (CQ), both of which increased the cytotoxicity of erlotinib. The synergistic activity of CQ was not due to the potentiation of erlotinib’s effects on autophagy, cell cycle arrest, inhibition of EGF receptor, or the inhibition of signaling downstream of the EGFR. Rather CQ markedly activated apoptosis in the cells. The ability of CQ to potentiate the antitumor activity of erlotinib was also seen in mice bearing NSCLC tumor xenografts. Conclusions The ability to adapt to anti-EGFR therapy by triggering autophagy may be a key determinant of resistance to erlotinib in wild-type EGFR NSCLC. Inhibition of autophagy by CQ represents a novel strategy to broaden the spectrum of erlotinib efficacy in wild-type EGFR NSCLC tumors. PMID:23575415

  19. A Conceptual Approach to Absolute Value Equations and Inequalities

    ERIC Educational Resources Information Center

    Ellis, Mark W.; Bryson, Janet L.

    2011-01-01

    The absolute value learning objective in high school mathematics requires students to solve far more complex absolute value equations and inequalities. When absolute value problems become more complex, students often do not have sufficient conceptual understanding to make any sense of what is happening mathematically. The authors suggest that the…

  20. Using, Seeing, Feeling, and Doing Absolute Value for Deeper Understanding

    ERIC Educational Resources Information Center

    Ponce, Gregorio A.

    2008-01-01

    Using sticky notes and number lines, a hands-on activity is shared that anchors initial student thinking about absolute value. The initial point of reference should help students successfully evaluate numeric problems involving absolute value. They should also be able to solve absolute value equations and inequalities that are typically found in…

  1. The Absolute Radiometric Calibration of Space - Sensors.

    NASA Astrophysics Data System (ADS)

    Holm, Ronald Gene

    1987-09-01

    The need for absolute radiometric calibration of space-based sensors will continue to increase as new generations of space sensors are developed. A reflectance -based in-flight calibration procedure is used to determine the radiance reaching the entrance pupil of the sensor. This procedure uses ground-based measurements coupled with a radiative transfer code to characterize the effects the atmosphere has on the signal reaching the sensor. The computed radiance is compared to the digital count output of the sensor associated with the image of a test site. This provides an update to the preflight calibration of the system and a check on the on-board internal calibrator. This calibration procedure was used to perform a series of five calibrations of the Landsat-5 Thematic Mapper (TM). For the 12 measurements made in TM bands 1-3, the RMS variation from the mean as a percentage of the mean is (+OR-) 1.9%, and for measurements in the IR, TM bands 4,5, and 7, the value is (+OR-) 3.4%. The RMS variation for all 23 measurements is (+OR-) 2.8%. The absolute calibration techniques were put to another test with a series of three calibration of the SPOT-1 High Resolution Visible, (HRV), sensors. The ratio, HRV-2/HRV-1, of absolute calibration coefficients compared very well with ratios of histogrammed data obtained when the cameras simultaneously imaged the same ground site. Bands PA, B1 and B3 agreed to within 3%, while band B2 showed a 7% difference. The procedure for performing a satellite calibration was then used to demonstrate how a calibrated satellite sensor can be used to quantitatively evaluate surface reflectance over a wide range of surface features. Predicted reflectance factors were compared to values obtained from aircraft -based radiometer data. This procedure was applied on four dates with two different surface conditions per date. A strong correlation, R('2) = .996, was shown between reflectance values determined from satellite imagery and low-flying aircraft

  2. Use of Absolute and Comparative Performance Feedback in Absolute and Comparative Judgments and Decisions

    ERIC Educational Resources Information Center

    Moore, Don A.; Klein, William M. P.

    2008-01-01

    Which matters more--beliefs about absolute ability or ability relative to others? This study set out to compare the effects of such beliefs on satisfaction with performance, self-evaluations, and bets on future performance. In Experiment 1, undergraduate participants were told they had answered 20% correct, 80% correct, or were not given their…

  3. Gli1-Mediated Regulation of Sox2 Facilitates Self-Renewal of Stem-Like Cells and Confers Resistance to EGFR Inhibitors in Non-Small Cell Lung Cancer.

    PubMed

    Bora-Singhal, Namrata; Perumal, Deepak; Nguyen, Jonathan; Chellappan, Srikumar

    2015-07-01

    Non-small cell lung cancer (NSCLC) patients have very low survival rates because the current therapeutic strategies are not fully effective. Although EGFR tyrosine kinase inhibitors are effective for NSCLC patients harboring EGFR mutations, patients invariably develop resistance to these agents. Alterations in multiple signaling cascades have been associated with the development of resistance to EGFR inhibitors. Sonic Hedgehog and associated Gli transcription factors play a major role in embryonic development and have recently been found to be reactivated in NSCLC, and elevated Gli1 levels correlate with poor prognosis. The Hedgehog pathway has been implicated in the functions of cancer stem cells, although the underlying molecular mechanisms are not clear. In this context, we demonstrate that Gli1 is a strong regulator of embryonic stem cell transcription factor Sox2. Depletion of Gli1 or inhibition of the Hedgehog signaling significantly abrogated the self-renewal of stem-like side-population cells from NSCLCs as well as vascular mimicry of such cells. Gli1 was found to transcriptionally regulate Sox2 through its promoter region, and Gli1 could be detected on the Sox2 promoter. Inhibition of Hedgehog signaling appeared to work cooperatively with EGFR inhibitors in markedly reducing the viability of NSCLC cells as well as the self-renewal of stem-like cells. Thus, our study demonstrates a cooperative functioning of the EGFR signaling and Hedgehog pathways in governing the stem-like functions of NSCLC cancer stem cells and presents a novel therapeutic strategy to combat NSCLC harboring EGFR mutations.

  4. Proteomic biomarkers in lung cancer.

    PubMed

    Pastor, M D; Nogal, A; Molina-Pinelo, S; Carnero, A; Paz-Ares, L

    2013-09-01

    The correct understanding of tumour development relies on the comprehensive study of proteins. They are the main orchestrators of vital processes, such as signalling pathways, which drive the carcinogenic process. Proteomic technologies can be applied to cancer research to detect differential protein expression and to assess different responses to treatment. Lung cancer is the number one cause of cancer-related death in the world. Mostly diagnosed at late stages of the disease, lung cancer has one of the lowest 5-year survival rates at 15 %. The use of different proteomic techniques such as two-dimensional gel electrophoresis (2D-PAGE), isotope labelling (ICAT, SILAC, iTRAQ) and mass spectrometry may yield new knowledge on the underlying biology of lung cancer and also allow the development of new early detection tests and the identification of changes in the cancer protein network that are associated with prognosis and drug resistance. PMID:23606351

  5. Absolute radiometric calibration of the CCRS SAR

    NASA Astrophysics Data System (ADS)

    Ulander, Lars M. H.; Hawkins, Robert K.; Livingstone, Charles E.; Lukowski, Tom I.

    1991-11-01

    Determining the radar scattering coefficients from SAR (synthetic aperture radar) image data requires absolute radiometric calibration of the SAR system. The authors describe an internal calibration methodology for the airborne Canada Centre for Remote Sensing (CCRS) SAR system, based on radar theory, a detailed model of the radar system, and measurements of system parameters. The methodology is verified by analyzing external calibration data acquired over a 6-month period in 1988 by the C-band radar using HH polarization. The results indicate that the overall error is +/- 0.8 dB (1-sigma) for incidence angles +/- 20 deg from antenna boresight. The dominant error contributions are due to the antenna radome and uncertainties in the elevation angle relative to the antenna boresight.

  6. Absolute calibration of ultraviolet filter photometry

    NASA Technical Reports Server (NTRS)

    Bless, R. C.; Fairchild, T.; Code, A. D.

    1972-01-01

    The essential features of the calibration procedure can be divided into three parts. First, the shape of the bandpass of each photometer was determined by measuring the transmissions of the individual optical components and also by measuring the response of the photometer as a whole. Secondly, each photometer was placed in the essentially-collimated synchrotron radiation bundle maintained at a constant intensity level, and the output signal was determined from about 100 points on the objective. Finally, two or three points on the objective were illuminated by synchrotron radiation at several different intensity levels covering the dynamic range of the photometers. The output signals were placed on an absolute basis by the electron counting technique described earlier.

  7. Absolute measurements of fast neutrons using yttrium

    SciTech Connect

    Roshan, M. V.; Springham, S. V.; Rawat, R. S.; Lee, P.; Krishnan, M.

    2010-08-15

    Yttrium is presented as an absolute neutron detector for pulsed neutron sources. It has high sensitivity for detecting fast neutrons. Yttrium has the property of generating a monoenergetic secondary radiation in the form of a 909 keV gamma-ray caused by inelastic neutron interaction. It was calibrated numerically using MCNPX and does not need periodic recalibration. The total yttrium efficiency for detecting 2.45 MeV neutrons was determined to be f{sub n}{approx}4.1x10{sup -4} with an uncertainty of about 0.27%. The yttrium detector was employed in the NX2 plasma focus experiments and showed the neutron yield of the order of 10{sup 8} neutrons per discharge.

  8. Absolute geostrophic currents in global tropical oceans

    NASA Astrophysics Data System (ADS)

    Yang, Lina; Yuan, Dongliang

    2016-11-01

    A set of absolute geostrophic current (AGC) data for the period January 2004 to December 2012 are calculated using the P-vector method based on monthly gridded Argo profiles in the world tropical oceans. The AGCs agree well with altimeter geostrophic currents, Ocean Surface Current Analysis-Real time currents, and moored current-meter measurements at 10-m depth, based on which the classical Sverdrup circulation theory is evaluated. Calculations have shown that errors of wind stress calculation, AGC transport, and depth ranges of vertical integration cannot explain non-Sverdrup transport, which is mainly in the subtropical western ocean basins and equatorial currents near the Equator in each ocean basin (except the North Indian Ocean, where the circulation is dominated by monsoons). The identified non-Sverdrup transport is thereby robust and attributed to the joint effect of baroclinicity and relief of the bottom (JEBAR) and mesoscale eddy nonlinearity.

  9. Absolute Measurement of Electron Cloud Density

    SciTech Connect

    Covo, M K; Molvik, A W; Cohen, R H; Friedman, A; Seidl, P A; Logan, G; Bieniosek, F; Baca, D; Vay, J; Orlando, E; Vujic, J L

    2007-06-21

    Beam interaction with background gas and walls produces ubiquitous clouds of stray electrons that frequently limit the performance of particle accelerator and storage rings. Counterintuitively we obtained the electron cloud accumulation by measuring the expelled ions that are originated from the beam-background gas interaction, rather than by measuring electrons that reach the walls. The kinetic ion energy measured with a retarding field analyzer (RFA) maps the depressed beam space-charge potential and provides the dynamic electron cloud density. Clearing electrode current measurements give the static electron cloud background that complements and corroborates with the RFA measurements, providing an absolute measurement of electron cloud density during a 5 {micro}s duration beam pulse in a drift region of the magnetic transport section of the High-Current Experiment (HCX) at LBNL.

  10. Micron Accurate Absolute Ranging System: Range Extension

    NASA Technical Reports Server (NTRS)

    Smalley, Larry L.; Smith, Kely L.

    1999-01-01

    The purpose of this research is to investigate Fresnel diffraction as a means of obtaining absolute distance measurements with micron or greater accuracy. It is believed that such a system would prove useful to the Next Generation Space Telescope (NGST) as a non-intrusive, non-contact measuring system for use with secondary concentrator station-keeping systems. The present research attempts to validate past experiments and develop ways to apply the phenomena of Fresnel diffraction to micron accurate measurement. This report discusses past research on the phenomena, and the basis of the use Fresnel diffraction distance metrology. The apparatus used in the recent investigations, experimental procedures used, preliminary results are discussed in detail. Continued research and equipment requirements on the extension of the effective range of the Fresnel diffraction systems is also described.

  11. Absolute calibration of remote sensing instruments

    NASA Astrophysics Data System (ADS)

    Biggar, S. F.; Bruegge, C. J.; Capron, B. A.; Castle, K. R.; Dinguirard, M. C.; Holm, R. G.; Lingg, L. J.; Mao, Y.; Palmer, J. M.; Phillips, A. L.

    1985-12-01

    Source-based and detector-based methods for the absolute radiometric calibration of a broadband field radiometer are described. Using such a radiometer, calibrated by both methods, the calibration of the integrating sphere used in the preflight calibration of the Thematic Mapper was redetermined. The results are presented. The in-flight calibration of space remote sensing instruments is discussed. A method which uses the results of ground-based reflectance and atmospheric measurements as input to a radiative transfer code to predict the radiance at the instrument is described. A calibrated, helicopter-mounted radiometer is used to determine the radiance levels at intermediate altitudes to check the code predictions. Results of such measurements for the calibration of the Thematic Mapper on Landsat 5 and an analysis that shows the value of such measurements are described.

  12. Absolute radiometric calibration of the Thematic Mapper

    NASA Technical Reports Server (NTRS)

    Slater, P. N.; Biggar, S. F.; Holm, R. G.; Jackson, R. D.; Mao, Y.

    1986-01-01

    Calibration data for the solar reflective bands of the Landsat-5 TM obtained from five in-flight absolute radiometric calibrations from July 1984-November 1985 at White Sands, New Mexico are presented and analyzed. Ground reflectance and atmospheric data were utilized to predict the spectral radiance at the entrance pupil of the TM and the average number of digital counts in each TM band. The calibration of each of the TM solar reflective bands was calculated in terms of average digital counts/unit spectral radiance for each band. It is observed that for the 12 reflectance-based measurements the rms variation from the means as a percentage of the mean is + or - 1.9 percent; for the 11 measurements in the IR bands, it is + or - 3.4 percent; and the rms variation for all 23 measurements is + or - 2.8 percent.

  13. Swarm's Absolute Scalar Magnetometer metrological performances

    NASA Astrophysics Data System (ADS)

    Leger, J.; Fratter, I.; Bertrand, F.; Jager, T.; Morales, S.

    2012-12-01

    The Absolute Scalar Magnetometer (ASM) has been developed for the ESA Earth Observation Swarm mission, planned for launch in November 2012. As its Overhauser magnetometers forerunners flown on Oersted and Champ satellites, it will deliver high resolution scalar measurements for the in-flight calibration of the Vector Field Magnetometer manufactured by the Danish Technical University. Latest results of the ground tests carried out to fully characterize all parameters that may affect its accuracy, both at instrument and satellite level, will be presented. In addition to its baseline function, the ASM can be operated either at a much higher sampling rate (burst mode at 250 Hz) or in a dual mode where it also delivers vector field measurements as a by-product. The calibration procedure and the relevant vector performances will be discussed.

  14. MAGSAT: Vector magnetometer absolute sensor alignment determination

    NASA Technical Reports Server (NTRS)

    Acuna, M. H.

    1981-01-01

    A procedure is described for accurately determining the absolute alignment of the magnetic axes of a triaxial magnetometer sensor with respect to an external, fixed, reference coordinate system. The method does not require that the magnetic field vector orientation, as generated by a triaxial calibration coil system, be known to better than a few degrees from its true position, and minimizes the number of positions through which a sensor assembly must be rotated to obtain a solution. Computer simulations show that accuracies of better than 0.4 seconds of arc can be achieved under typical test conditions associated with existing magnetic test facilities. The basic approach is similar in nature to that presented by McPherron and Snare (1978) except that only three sensor positions are required and the system of equations to be solved is considerably simplified. Applications of the method to the case of the MAGSAT Vector Magnetometer are presented and the problems encountered discussed.

  15. Combinatorial-Designed Epidermal Growth Factor Receptor-Targeted Chitosan Nanoparticles for Encapsulation and Delivery of Lipid-Modified Platinum Derivatives in Wild-Type and Resistant Non-Small-Cell Lung Cancer Cells.

    PubMed

    Nascimento, Ana Vanessa; Singh, Amit; Bousbaa, Hassan; Ferreira, Domingos; Sarmento, Bruno; Amiji, Mansoor M

    2015-12-01

    Development of efficient and versatile drug delivery platforms to overcome the physical and biological challenges in cancer therapeutics is an area of great interest, and novel materials are actively sought for such applications. Recent strides in polymer science have led to a combinatorial approach for generating a library of materials with different functional identities that can be "mixed and matched" to attain desired characteristics of a delivery vector. We have applied the combinatorial design to chitosan (CS), where the polymer backbone has been modified with polyethylene glycol, epidermal growth factor receptor-binding peptide, and lipid derivatives of varying chain length to encapsulate hydrophobic drugs. Cisplatin, cis-([PtCl2(NH3)2]), is one of the most potent chemotherapy drugs broadly administered for cancer treatment. Cisplatin is a hydrophilic drug, and in order for it to be encapsulated in the developed nanosystems, it was modified with lipids of varying chain length. The library of four CS derivatives and six platinum derivatives was self-assembled in aqueous medium and evaluated for physicochemical characteristics and cytotoxic effects in platinum-sensitive and -resistant lung cancer cells. The results show that the lipid-modified platinate encapsulation into CS nanoparticles significantly improved cellular cytotoxicity of the drug. In this work, we have also reinforced the idea that CS is a multifaceted system that can be as successful in delivering small molecules as it has been as a nucleic acids carrier.

  16. Lung volumes: measurement, clinical use, and coding.

    PubMed

    Flesch, Judd D; Dine, C Jessica

    2012-08-01

    Measurement of lung volumes is an integral part of complete pulmonary function testing. Some lung volumes can be measured during spirometry; however, measurement of the residual volume (RV), functional residual capacity (FRC), and total lung capacity (TLC) requires special techniques. FRC is typically measured by one of three methods. Body plethysmography uses Boyle's Law to determine lung volumes, whereas inert gas dilution and nitrogen washout use dilution properties of gases. After determination of FRC, expiratory reserve volume and inspiratory vital capacity are measured, which allows the calculation of the RV and TLC. Lung volumes are commonly used for the diagnosis of restriction. In obstructive lung disease, they are used to assess for hyperinflation. Changes in lung volumes can also be seen in a number of other clinical conditions. Reimbursement for measurement of lung volumes requires knowledge of current procedural terminology (CPT) codes, relevant indications, and an appropriate level of physician supervision. Because of recent efforts to eliminate payment inefficiencies, the 10 previous CPT codes for lung volumes, airway resistance, and diffusing capacity have been bundled into four new CPT codes. PMID:22871760

  17. Rheumatoid lung disease

    MedlinePlus

    Lung disease - rheumatoid arthritis; Rheumatoid nodules; Rheumatoid lung ... Elsevier Saunders; 2016:chap 65. Lake F, Proudman S. Rheumatoid arthritis and lung disease: from mechanisms to a practical approach. Semin Respir ...

  18. How Lungs Work

    MedlinePlus

    ... Health and Diseases > How Lungs Work How Lungs Work The Respiratory System Your lungs are part of ... Parts of the Respiratory System and How They Work Airways SINUSES are hollow spaces in the bones ...

  19. Lung Carcinoid Tumor: Surgery

    MedlinePlus

    ... for lung carcinoid tumor symptoms Surgery to treat lung carcinoid tumors Surgery is the main treatment for ... often be cured by surgery alone. Types of lung surgery Different operations can be used to treat ( ...

  20. Lung surgery - discharge

    MedlinePlus

    Thoracotomy - discharge; Lung tissue removal - discharge; Pneumonectomy - discharge; Lobectomy - discharge; Lung biopsy - discharge; Thoracoscopy - discharge; Video-assisted thoracoscopic surgery - discharge; VATS - ...

  1. Interstitial lung disease

    MedlinePlus

    Diffuse parenchymal lung disease; Alveolitis; Idiopathic pulmonary pneumonitis (IPP) ... The lungs contain tiny air sacs (alveoli), which is where oxygen is absorbed. These air sacs expand with each ...

  2. Lung Circulation.

    PubMed

    Suresh, Karthik; Shimoda, Larissa A

    2016-04-01

    The circulation of the lung is unique both in volume and function. For example, it is the only organ with two circulations: the pulmonary circulation, the main function of which is gas exchange, and the bronchial circulation, a systemic vascular supply that provides oxygenated blood to the walls of the conducting airways, pulmonary arteries and veins. The pulmonary circulation accommodates the entire cardiac output, maintaining high blood flow at low intravascular arterial pressure. As compared with the systemic circulation, pulmonary arteries have thinner walls with much less vascular smooth muscle and a relative lack of basal tone. Factors controlling pulmonary blood flow include vascular structure, gravity, mechanical effects of breathing, and the influence of neural and humoral factors. Pulmonary vascular tone is also altered by hypoxia, which causes pulmonary vasoconstriction. If the hypoxic stimulus persists for a prolonged period, contraction is accompanied by remodeling of the vasculature, resulting in pulmonary hypertension. In addition, genetic and environmental factors can also confer susceptibility to development of pulmonary hypertension. Under normal conditions, the endothelium forms a tight barrier, actively regulating interstitial fluid homeostasis. Infection and inflammation compromise normal barrier homeostasis, resulting in increased permeability and edema formation. This article focuses on reviewing the basics of the lung circulation (pulmonary and bronchial), normal development and transition at birth and vasoregulation. Mechanisms contributing to pathological conditions in the pulmonary circulation, in particular when barrier function is disrupted and during development of pulmonary hypertension, will also be discussed. PMID:27065170

  3. On the absolute alignment of GONG images

    NASA Astrophysics Data System (ADS)

    Toner, C. G.

    2001-01-01

    In order to combine data from the six instruments in the GONG network the alignment of all of the images must be known to a fairly high precision (~0°.1 for GONG Classic and ~0°.01 for GONG+). The relative orientation is obtained using the angular cross-correlation method described by (Toner & Harvey, 1998). To obtain the absolute orientation the Project periodically records a day of drift scans, where the image of the Sun is allowed to drift across the CCD repeatedly throughout the day. These data are then analyzed to deduce the direction of Terrestrial East-West as a function of hour angle (i.e., time) for that instrument. The transit of Mercury on Nov. 15, 1999, which was recorded by three of the GONG instruments, provided an independent check on the current alignment procedures. Here we present a comparison of the alignment of GONG images as deduced from both drift scans and the Mercury transit for two GONG sites: Tucson (GONG+ camera) and Mauna Loa (GONG Classic camera). The agreement is within ~0°.01 for both cameras, however, the scatter is substantially larger for GONG Classic: ~0°.03 compared to ~0°.01 for GONG+.

  4. Climate Absolute Radiance and Refractivity Observatory (CLARREO)

    NASA Technical Reports Server (NTRS)

    Leckey, John P.

    2015-01-01

    The Climate Absolute Radiance and Refractivity Observatory (CLARREO) is a mission, led and developed by NASA, that will measure a variety of climate variables with an unprecedented accuracy to quantify and attribute climate change. CLARREO consists of three separate instruments: an infrared (IR) spectrometer, a reflected solar (RS) spectrometer, and a radio occultation (RO) instrument. The mission will contain orbiting radiometers with sufficient accuracy, including on orbit verification, to calibrate other space-based instrumentation, increasing their respective accuracy by as much as an order of magnitude. The IR spectrometer is a Fourier Transform spectrometer (FTS) working in the 5 to 50 microns wavelength region with a goal of 0.1 K (k = 3) accuracy. The FTS will achieve this accuracy using phase change cells to verify thermistor accuracy and heated halos to verify blackbody emissivity, both on orbit. The RS spectrometer will measure the reflectance of the atmosphere in the 0.32 to 2.3 microns wavelength region with an accuracy of 0.3% (k = 2). The status of the instrumentation packages and potential mission options will be presented.

  5. Absolute flux measurements for swift atoms

    NASA Technical Reports Server (NTRS)

    Fink, M.; Kohl, D. A.; Keto, J. W.; Antoniewicz, P.

    1987-01-01

    While a torsion balance in vacuum can easily measure the momentum transfer from a gas beam impinging on a surface attached to the balance, this measurement depends on the accommodation coefficients of the atoms with the surface and the distribution of the recoil. A torsion balance is described for making absolute flux measurements independent of recoil effects. The torsion balance is a conventional taut suspension wire design and the Young modulus of the wire determines the relationship between the displacement and the applied torque. A compensating magnetic field is applied to maintain zero displacement and provide critical damping. The unique feature is to couple the impinging gas beam to the torsion balance via a Wood's horn, i.e., a thin wall tube with a gradual 90 deg bend. Just as light is trapped in a Wood's horn by specular reflection from the curved surfaces, the gas beam diffuses through the tube. Instead of trapping the beam, the end of the tube is open so that the atoms exit the tube at 90 deg to their original direction. Therefore, all of the forward momentum of the gas beam is transferred to the torsion balance independent of the angle of reflection from the surfaces inside the tube.

  6. Gyrokinetic Statistical Absolute Equilibrium and Turbulence

    SciTech Connect

    Jian-Zhou Zhu and Gregory W. Hammett

    2011-01-10

    A paradigm based on the absolute equilibrium of Galerkin-truncated inviscid systems to aid in understanding turbulence [T.-D. Lee, "On some statistical properties of hydrodynamical and magnetohydrodynamical fields," Q. Appl. Math. 10, 69 (1952)] is taken to study gyrokinetic plasma turbulence: A finite set of Fourier modes of the collisionless gyrokinetic equations are kept and the statistical equilibria are calculated; possible implications for plasma turbulence in various situations are discussed. For the case of two spatial and one velocity dimension, in the calculation with discretization also of velocity v with N grid points (where N + 1 quantities are conserved, corresponding to an energy invariant and N entropy-related invariants), the negative temperature states, corresponding to the condensation of the generalized energy into the lowest modes, are found. This indicates a generic feature of inverse energy cascade. Comparisons are made with some classical results, such as those of Charney-Hasegawa-Mima in the cold-ion limit. There is a universal shape for statistical equilibrium of gyrokinetics in three spatial and two velocity dimensions with just one conserved quantity. Possible physical relevance to turbulence, such as ITG zonal flows, and to a critical balance hypothesis are also discussed.

  7. Who Needs a Lung Transplant?

    MedlinePlus

    ... from the NHLBI on Twitter. Who Needs a Lung Transplant? Your doctor may recommend a lung transplant ... lungs to pick up oxygen. Applying to a Lung Transplant Program Lung transplants are done in medical ...

  8. Issues in Absolute Spectral Radiometric Calibration: Intercomparison of Eight Sources

    NASA Technical Reports Server (NTRS)

    Goetz, Alexander F. H.; Kindel, Bruce; Pilewskie, Peter

    1998-01-01

    The application of atmospheric models to AVIRIS and other spectral imaging data to derive surface reflectance requires that the sensor output be calibrated to absolute radiance. Uncertainties in absolute calibration are to be expected, and claims of 92% accuracy have been published. Measurements of accurate surface albedos and cloud absorption to be used in radiative balance calculations depend critically on knowing the absolute spectral-radiometric response of the sensor. The Earth Observing System project is implementing a rigorous program of absolute radiometric calibration for all optical sensors. Since a number of imaging instruments that provide output in terms of absolute radiance are calibrated at different sites, it is important to determine the errors that can be expected among calibration sites. Another question exists about the errors in the absolute knowledge of the exoatmospheric spectral solar irradiance.

  9. Absolute nuclear material assay using count distribution (LAMBDA) space

    SciTech Connect

    Prasad, Mano K.; Snyderman, Neal J.; Rowland, Mark S.

    2015-12-01

    A method of absolute nuclear material assay of an unknown source comprising counting neutrons from the unknown source and providing an absolute nuclear material assay utilizing a model to optimally compare to the measured count distributions. In one embodiment, the step of providing an absolute nuclear material assay comprises utilizing a random sampling of analytically computed fission chain distributions to generate a continuous time-evolving sequence of event-counts by spreading the fission chain distribution in time.

  10. Absolute nuclear material assay using count distribution (LAMBDA) space

    DOEpatents

    Prasad, Manoj K.; Snyderman, Neal J.; Rowland, Mark S.

    2012-06-05

    A method of absolute nuclear material assay of an unknown source comprising counting neutrons from the unknown source and providing an absolute nuclear material assay utilizing a model to optimally compare to the measured count distributions. In one embodiment, the step of providing an absolute nuclear material assay comprises utilizing a random sampling of analytically computed fission chain distributions to generate a continuous time-evolving sequence of event-counts by spreading the fission chain distribution in time.

  11. Antifungal activity of tuberose absolute and some of its constituents.

    PubMed

    Nidiry, Eugene Sebastian J; Babu, C S Bujji

    2005-05-01

    The antifungal activity of the absolute of tuberose (Polianthes tuberosa ) and some of its constituents were evaluated against the mycelial growth of Colletotrichum gloeosporioides on potato-dextrose-agar medium. Tuberose absolute showed only mild activity at a concentration of 500 mg/L. However, three constituents present in the absolute, namely geraniol, indole and methyl anthranilate exhibited significant activity showing total inhibition of the mycelial growth at this concentration.

  12. The absolute disparity anomaly and the mechanism of relative disparities.

    PubMed

    Chopin, Adrien; Levi, Dennis; Knill, David; Bavelier, Daphne

    2016-06-01

    There has been a long-standing debate about the mechanisms underlying the perception of stereoscopic depth and the computation of the relative disparities that it relies on. Relative disparities between visual objects could be computed in two ways: (a) using the difference in the object's absolute disparities (Hypothesis 1) or (b) using relative disparities based on the differences in the monocular separations between objects (Hypothesis 2). To differentiate between these hypotheses, we measured stereoscopic discrimination thresholds for lines with different absolute and relative disparities. Participants were asked to judge the depth of two lines presented at the same distance from the fixation plane (absolute disparity) or the depth between two lines presented at different distances (relative disparity). We used a single stimulus method involving a unique memory component for both conditions, and no extraneous references were available. We also measured vergence noise using Nonius lines. Stereo thresholds were substantially worse for absolute disparities than for relative disparities, and the difference could not be explained by vergence noise. We attribute this difference to an absence of conscious readout of absolute disparities, termed the absolute disparity anomaly. We further show that the pattern of correlations between vergence noise and absolute and relative disparity acuities can be explained jointly by the existence of the absolute disparity anomaly and by the assumption that relative disparity information is computed from absolute disparities (Hypothesis 1).

  13. The absolute disparity anomaly and the mechanism of relative disparities

    PubMed Central

    Chopin, Adrien; Levi, Dennis; Knill, David; Bavelier, Daphne

    2016-01-01

    There has been a long-standing debate about the mechanisms underlying the perception of stereoscopic depth and the computation of the relative disparities that it relies on. Relative disparities between visual objects could be computed in two ways: (a) using the difference in the object's absolute disparities (Hypothesis 1) or (b) using relative disparities based on the differences in the monocular separations between objects (Hypothesis 2). To differentiate between these hypotheses, we measured stereoscopic discrimination thresholds for lines with different absolute and relative disparities. Participants were asked to judge the depth of two lines presented at the same distance from the fixation plane (absolute disparity) or the depth between two lines presented at different distances (relative disparity). We used a single stimulus method involving a unique memory component for both conditions, and no extraneous references were available. We also measured vergence noise using Nonius lines. Stereo thresholds were substantially worse for absolute disparities than for relative disparities, and the difference could not be explained by vergence noise. We attribute this difference to an absence of conscious readout of absolute disparities, termed the absolute disparity anomaly. We further show that the pattern of correlations between vergence noise and absolute and relative disparity acuities can be explained jointly by the existence of the absolute disparity anomaly and by the assumption that relative disparity information is computed from absolute disparities (Hypothesis 1). PMID:27248566

  14. NADPH:cytochrome c (P450) reductase activates tirapazamine (SR4233) to restore hypoxic and oxic cytotoxicity in an aerobic resistant derivative of the A549 lung cancer cell line

    PubMed Central

    Saunders, M P; Patterson, A V; Chinje, E C; Harris, A L; Stratford, I J

    2000-01-01

    Tirapazamine (TPZ, SR4233, WIN 59075) is a bioreductive drug that is activated in regions of low oxygen tension to a cytotoxic radical intermediate. This labile metabolite shows high selective toxicity towards hypoxic cells, such as those found in solid tumours. Under aerobic conditions, redox cycling occurs with subsequent generation of superoxide radicals, which are also cytotoxic. NADPH:cytochrome c (P450) reductase (P450R) is a one-electron reducing enzyme that efficiently activates TPZ. Recently a derivative of the A549 non-small cell lung cancer cell line (A549c50) was generated that showed substantially reduced P450R activity compared to its parental line (Elwell et al (1997) Biochem Pharmacol54: 249–257). Here, it is demonstrated that the A549c50 cells are markedly more resistant to TPZ under both aerobic and hypoxic conditions. In addition, these cells have a dramatically impaired ability to metabolize TPZ to its two-electron reduction product, SR4317, under hypoxic conditions when compared to wild-type cells. P450R activity in the A549c50 cells was reintroduced to similar levels as that seen in the parental A549 cells by transfection of the full-length cDNA for human P450R. These P450R over-expressing cells exhibit restored sensitivity to TPZ under both aerobic and hypoxic conditions, comparable to that found in the original parental A549 cells. Further, the ability of the transfected cells to metabolize TPZ to SR4317 under hypoxic conditions is also shown to be restored. This provides further evidence that P450R can play an important role in the activation, metabolism and toxicity of this lead bioreductive drug. © 2000 Cancer Research Campaign PMID:10682679

  15. Absolute Plate Velocities from Seismic Anisotropy

    NASA Astrophysics Data System (ADS)

    Kreemer, Corné; Zheng, Lin; Gordon, Richard

    2015-04-01

    The orientation of seismic anisotropy inferred beneath plate interiors may provide a means to estimate the motions of the plate relative to the sub-asthenospheric mantle. Here we analyze two global sets of shear-wave splitting data, that of Kreemer [2009] and an updated and expanded data set, to estimate plate motions and to better understand the dispersion of the data, correlations in the errors, and their relation to plate speed. We also explore the effect of using geologically current plate velocities (i.e., the MORVEL set of angular velocities [DeMets et al. 2010]) compared with geodetically current plate velocities (i.e., the GSRM v1.2 angular velocities [Kreemer et al. 2014]). We demonstrate that the errors in plate motion azimuths inferred from shear-wave splitting beneath any one tectonic plate are correlated with the errors of other azimuths from the same plate. To account for these correlations, we adopt a two-tier analysis: First, find the pole of rotation and confidence limits for each plate individually. Second, solve for the best fit to these poles while constraining relative plate angular velocities to consistency with the MORVEL relative plate angular velocities. The SKS-MORVEL absolute plate angular velocities (based on the Kreemer [2009] data set) are determined from the poles from eight plates weighted proportionally to the root-mean-square velocity of each plate. SKS-MORVEL indicates that eight plates (Amur, Antarctica, Caribbean, Eurasia, Lwandle, Somalia, Sundaland, and Yangtze) have angular velocities that differ insignificantly from zero. The net rotation of the lithosphere is 0.25±0.11° Ma-1 (95% confidence limits) right-handed about 57.1°S, 68.6°E. The within-plate dispersion of seismic anisotropy for oceanic lithosphere (σ=19.2° ) differs insignificantly from that for continental lithosphere (σ=21.6° ). The between-plate dispersion, however, is significantly smaller for oceanic lithosphere (σ=7.4° ) than for continental

  16. Lung surfactant.

    PubMed Central

    Rooney, S A

    1984-01-01

    Aspects of pulmonary surfactant are reviewed from a biochemical perspective. The major emphasis is on the lipid components of surfactant. Topics reviewed include surfactant composition, cellular and subcellular sites as well as pathways of biosynthesis of phosphatidylcholine, disaturated phosphatidylcholine and phosphatidylglycerol. The surfactant system in the developing fetus and neonate is considered in terms of phospholipid content and composition, rates of precursor incorporation, activities of individual enzymes of phospholipid synthesis and glycogen content and metabolism. The influence of the following hormones and other factors on lung maturation and surfactant production is discussed: glucocorticoids, thyroid hormone, estrogen, prolactin, cyclic AMP, beta-adrenergic and cholinergic agonists, prostaglandins and growth factors. The influence of maternal diabetes, fetal sex, stress and labor are also considered. Nonphysiologic and toxic agents which influence surfactant in the fetus, newborn and adult are reviewed. PMID:6145585

  17. Evaluation of the Absolute Regional Temperature Potential

    NASA Technical Reports Server (NTRS)

    Shindell, D. T.

    2012-01-01

    The Absolute Regional Temperature Potential (ARTP) is one of the few climate metrics that provides estimates of impacts at a sub-global scale. The ARTP presented here gives the time-dependent temperature response in four latitude bands (90-28degS, 28degS-28degN, 28-60degN and 60-90degN) as a function of emissions based on the forcing in those bands caused by the emissions. It is based on a large set of simulations performed with a single atmosphere-ocean climate model to derive regional forcing/response relationships. Here I evaluate the robustness of those relationships using the forcing/response portion of the ARTP to estimate regional temperature responses to the historic aerosol forcing in three independent climate models. These ARTP results are in good accord with the actual responses in those models. Nearly all ARTP estimates fall within +/-20%of the actual responses, though there are some exceptions for 90-28degS and the Arctic, and in the latter the ARTP may vary with forcing agent. However, for the tropics and the Northern Hemisphere mid-latitudes in particular, the +/-20% range appears to be roughly consistent with the 95% confidence interval. Land areas within these two bands respond 39-45% and 9-39% more than the latitude band as a whole. The ARTP, presented here in a slightly revised form, thus appears to provide a relatively robust estimate for the responses of large-scale latitude bands and land areas within those bands to inhomogeneous radiative forcing and thus potentially to emissions as well. Hence this metric could allow rapid evaluation of the effects of emissions policies at a finer scale than global metrics without requiring use of a full climate model.

  18. Absolute Radiometric Calibration of KOMPSAT-3A

    NASA Astrophysics Data System (ADS)

    Ahn, H. Y.; Shin, D. Y.; Kim, J. S.; Seo, D. C.; Choi, C. U.

    2016-06-01

    This paper presents a vicarious radiometric calibration of the Korea Multi-Purpose Satellite-3A (KOMPSAT-3A) performed by the Korea Aerospace Research Institute (KARI) and the Pukyong National University Remote Sensing Group (PKNU RSG) in 2015.The primary stages of this study are summarized as follows: (1) A field campaign to determine radiometric calibrated target fields was undertaken in Mongolia and South Korea. Surface reflectance data obtained in the campaign were input to a radiative transfer code that predicted at-sensor radiance. Through this process, equations and parameters were derived for the KOMPSAT-3A sensor to enable the conversion of calibrated DN to physical units, such as at-sensor radiance or TOA reflectance. (2) To validate the absolute calibration coefficients for the KOMPSAT-3A sensor, we performed a radiometric validation with a comparison of KOMPSAT-3A and Landsat-8 TOA reflectance using one of the six PICS (Libya 4). Correlations between top-of-atmosphere (TOA) radiances and the spectral band responses of the KOMPSAT-3A sensors at the Zuunmod, Mongolia and Goheung, South Korea sites were significant for multispectral bands. The average difference in TOA reflectance between KOMPSAT-3A and Landsat-8 image over the Libya 4, Libya site in the red-green-blue (RGB) region was under 3%, whereas in the NIR band, the TOA reflectance of KOMPSAT-3A was lower than the that of Landsat-8 due to the difference in the band passes of two sensors. The KOMPSAT-3Aensor includes a band pass near 940 nm that can be strongly absorbed by water vapor and therefore displayed low reflectance. Toovercome this, we need to undertake a detailed analysis using rescale methods, such as the spectral bandwidth adjustment factor.

  19. Orion Absolute Navigation System Progress and Challenge

    NASA Technical Reports Server (NTRS)

    Holt, Greg N.; D'Souza, Christopher

    2012-01-01

    The absolute navigation design of NASA's Orion vehicle is described. It has undergone several iterations and modifications since its inception, and continues as a work-in-progress. This paper seeks to benchmark the current state of the design and some of the rationale and analysis behind it. There are specific challenges to address when preparing a timely and effective design for the Exploration Flight Test (EFT-1), while still looking ahead and providing software extensibility for future exploration missions. The primary onboard measurements in a Near-Earth or Mid-Earth environment consist of GPS pseudo-range and delta-range, but for future explorations missions the use of star-tracker and optical navigation sources need to be considered. Discussions are presented for state size and composition, processing techniques, and consider states. A presentation is given for the processing technique using the computationally stable and robust UDU formulation with an Agee-Turner Rank-One update. This allows for computational savings when dealing with many parameters which are modeled as slowly varying Gauss-Markov processes. Preliminary analysis shows up to a 50% reduction in computation versus a more traditional formulation. Several state elements are discussed and evaluated, including position, velocity, attitude, clock bias/drift, and GPS measurement biases in addition to bias, scale factor, misalignment, and non-orthogonalities of the accelerometers and gyroscopes. Another consideration is the initialization of the EKF in various scenarios. Scenarios such as single-event upset, ground command, and cold start are discussed as are strategies for whole and partial state updates as well as covariance considerations. Strategies are given for dealing with latent measurements and high-rate propagation using multi-rate architecture. The details of the rate groups and the data ow between the elements is discussed and evaluated.

  20. Absolute determination of local tropospheric OH concentrations

    NASA Technical Reports Server (NTRS)

    Armerding, Wolfgang; Comes, Franz-Josef

    1994-01-01

    Long path absorption (LPA) according to Lambert Beer's law is a method to determine absolute concentrations of trace gases such as tropospheric OH. We have developed a LPA instrument which is based on a rapid tuning of the light source which is a frequency doubled dye laser. The laser is tuned across two or three OH absorption features around 308 nm with a scanning speed of 0.07 cm(exp -1)/microsecond and a repetition rate of 1.3 kHz. This high scanning speed greatly reduces the fluctuation of the light intensity caused by the atmosphere. To obtain the required high sensitivity the laser output power is additionally made constant and stabilized by an electro-optical modulator. The present sensitivity is of the order of a few times 10(exp 5) OH per cm(exp 3) for an acquisition time of a minute and an absorption path length of only 1200 meters so that a folding of the optical path in a multireflection cell was possible leading to a lateral dimension of the cell of a few meters. This allows local measurements to be made. Tropospheric measurements have been carried out in 1991 resulting in the determination of OH diurnal variation at specific days in late summer. Comparison with model calculations have been made. Interferences are mainly due to SO2 absorption. The problem of OH self generation in the multireflection cell is of minor extent. This could be shown by using different experimental methods. The minimum-maximum signal to noise ratio is about 8 x 10(exp -4) for a single scan. Due to the small size of the absorption cell the realization of an open air laboratory is possible in which by use of an additional UV light source or by additional fluxes of trace gases the chemistry can be changed under controlled conditions allowing kinetic studies of tropospheric photochemistry to be made in open air.

  1. Lung Cancer Screening

    MedlinePlus

    ... Cancer Treatment Small Cell Lung Cancer Treatment Lung cancer is the leading cause of cancer death in the United States. Lung cancer is ... non- skin cancer in the United States. Lung cancer is the leading cause of cancer death in men and in women. ...

  2. Interstitial Lung Diseases

    MedlinePlus

    Interstitial lung disease is the name for a large group of diseases that inflame or scar the lungs. The inflammation and scarring make it hard to ... air is responsible for some types of interstitial lung diseases. Specific types include Black lung disease among ...

  3. The lung microbiome after lung transplantation.

    PubMed

    Becker, Julia; Poroyko, Valeriy; Bhorade, Sangeeta

    2014-04-01

    Lung transplantation survival remains significantly impacted by infections and the development of chronic rejection manifesting as bronchiolitis obliterans syndrome (BOS). Traditional microbiologic data has provided insight into the role of infections in BOS. Now, new non-culture-based techniques have been developed to characterize the entire population of microbes resident on the surfaces of the body, also known as the human microbiome. Early studies have identified that lung transplant patients have a different lung microbiome and have demonstrated the important finding that the transplant lung microbiome changes over time. Furthermore, both unique bacterial populations and longitudinal changes in the lung microbiome have now been suggested to play a role in the development of BOS. In the future, this technology will need to be combined with functional assays and assessment of the immune responses in the lung to help further explain the microbiome's role in the failing lung allograft.

  4. Targeting Lung Cancer Stem Cells with Antipsychological Drug Thioridazine

    PubMed Central

    Yue, Haiying; Huang, Dongning; Qin, Li; Zheng, Zhiyong; Hua, Li; Wang, Guodong; Huang, Jian

    2016-01-01

    Lung cancer stem cells are a subpopulation of cells critical for lung cancer progression, metastasis, and drug resistance. Thioridazine, a classical neurological drug, has been reported with anticancer ability. However, whether thioridazine could inhibit lung cancer stem cells has never been studied. In our current work, we used different dosage of thioridazine to test its effect on lung cancer stem cells sphere formation. The response of lung cancer stem cells to chemotherapy drug with thioridazine treatment was measured. The cell cycle distribution of lung cancer stem cells after thioridazine treatment was detected. The in vivo inhibitory effect of thioridazine was also measured. We found that thioridazine could dramatically inhibit sphere formation of lung cancer stem cells. It sensitized the LCSCs to chemotherapeutic drugs 5-FU and cisplatin. Thioridazine altered the cell cycle distribution of LCSCs and decreased the proportion of G0 phase cells in lung cancer stem cells. Thioridazine inhibited lung cancer stem cells initiated tumors growth in vivo. This study showed that thioridazine could inhibit lung cancer stem cells in vitro and in vivo. It provides a potential drug for lung cancer therapy through targeting lung cancer stem cells. PMID:27556038

  5. Mid-infrared absolute spectral responsivity scale based on an absolute cryogenic radiometer and an optical parametric oscillator laser

    NASA Astrophysics Data System (ADS)

    Zhao, Kun; Shi, Xueshun; Chen, Haidong; Liu, Yulong; Liu, Changming; Chen, Kunfeng; Li, Ligong; Gan, Haiyong; Ma, Chong

    2016-06-01

    We are reporting on a laser-based absolute spectral responsivity scale in the mid-infrared spectral range. By using a mid-infrared tunable optical parametric oscillator as the laser source, the absolute responsivity scale has been established by calibrating thin-film thermopile detectors against an absolute cryogenic radiometer. The thin-film thermopile detectors can be then used as transfer standard detectors. The extended uncertainty of the absolute spectral responsivity measurement has been analyzed to be 0.58%–0.68% (k  =  2).

  6. Mid-infrared absolute spectral responsivity scale based on an absolute cryogenic radiometer and an optical parametric oscillator laser

    NASA Astrophysics Data System (ADS)

    Zhao, Kun; Shi, Xueshun; Chen, Haidong; Liu, Yulong; Liu, Changming; Chen, Kunfeng; Li, Ligong; Gan, Haiyong; Ma, Chong

    2016-06-01

    We are reporting on a laser-based absolute spectral responsivity scale in the mid-infrared spectral range. By using a mid-infrared tunable optical parametric oscillator as the laser source, the absolute responsivity scale has been established by calibrating thin-film thermopile detectors against an absolute cryogenic radiometer. The thin-film thermopile detectors can be then used as transfer standard detectors. The extended uncertainty of the absolute spectral responsivity measurement has been analyzed to be 0.58%-0.68% (k  =  2).

  7. PREOPERATIVE PREDICTION OF LUNG FUNCTION IN PNEUMONECTOMY BY SPIROMETRY AND LUNG PERFUSION SCINTIGRAPHY

    PubMed Central

    Cukic, Vesna

    2012-01-01

    Introduction: Nowadays an increasing number of lung resections are being done because of the rising prevalence of lung cancer that occurs mainly in patients with limited lung function, what is caused by common etiologic factor - smoking cigarettes. Loss of lung tissue in such patients can worsen much the postoperative pulmonary function. So it is necessary to asses the postoperative pulmonary function especially after maximal resection, i.e. pneumonectomy. Objective: To check over the accuracy of preoperative prognosis of postoperative lung function after pneumonectomy using spirometry and lung perfusion scinigraphy. Material and methods: The study was done on 17 patients operated at the Clinic for thoracic surgery, who were treated previously at the Clinic for Pulmonary Diseases “Podhrastovi” in the period from 01. 12. 2008. to 01. 06. 2011. Postoperative pulmonary function expressed as ppoFEV1 (predicted postoperative forced expiratory volume in one second) was prognosticated preoperatively using spirometry, i.e.. simple calculation according to the number of the pulmonary segments to be removed and perfusion lung scintigraphy. Results: There is no significant deviation of postoperative achieved values of FEV1 from predicted ones obtained by both methods, and there is no significant differences between predicted values (ppoFEV1) obtained by spirometry and perfusion scintigraphy. Conclusion: It is necessary to asses the postoperative pulmonary function before lung resection to avoid postoperative respiratory failure and other cardiopulmonary complications. It is absolutely necessary for pneumonectomy, i.e.. maximal pulmonary resection. It can be done with great possibility using spirometry or perfusion lung scintigraphy. PMID:23378687

  8. Ex vivo lung perfusion.

    PubMed

    Reeb, Jeremie; Cypel, Marcelo

    2016-03-01

    Lung transplantation is an established life-saving therapy for patients with end-stage lung disease. Unfortunately, greater success in lung transplantation is hindered by a shortage of lung donors and the relatively poor early-, mid-, and long-term outcomes associated with severe primary graft dysfunction. Ex vivo lung perfusion has emerged as a modern preservation technique that allows for a more accurate lung assessment and improvement in lung quality. This review outlines the: (i) rationale behind the method; (ii) techniques and protocols; (iii) Toronto ex vivo lung perfusion method; (iv) devices available; and (v) clinical experience worldwide. We also highlight the potential of ex vivo lung perfusion in leading a new era of lung preservation. PMID:26700566

  9. On the Error Sources in Absolute Individual Antenna Calibrations

    NASA Astrophysics Data System (ADS)

    Aerts, Wim; Baire, Quentin; Bilich, Andria; Bruyninx, Carine; Legrand, Juliette

    2013-04-01

    The two main methods for antenna calibration currently in use, are anechoic chamber measurements on the one hand and outdoor robot calibration on the other hand. Both techniques differ completely in approach, setup and data processing. Consequently, the error sources for both techniques are totally different as well. Except for the (near field) multi path error, caused by the antenna positioning device, that alters results for both calibration methods. But not necessarily with the same order of magnitude. Literature states a (maximum deviation) repeatability for robot calibration of choke ring antennas of 0.5 mm on L1 and 1 mm on L2 [1]. For anechoic chamber calibration, a value of 1.5 mm on L2 for a resistive ground plane antenna can be found in [2]. Repeatability however masks systematic errors linked with the calibration technique. Hence, comparing an individual calibration obtained with a robot to a calibration of the same antenna in an anechoic chamber, may result in differences that surpass these repeatability thresholds. This was the case at least for all six choke ring antennas studied. The order of magnitude of the differences moreover corresponded well to the values given for a LEIAT504GG in [3]. For some error sources, such as the GNSS receiver measurement noise or the VNA measurement noise, estimates can be obtained from manufacturer specifications in data sheets. For other error sources, such as the finite distance between transmit and receive antenna, or the limited attenuation of reflections on wall absorber, back-of-the-envelope calculations can be made to estimate their order of magnitude. For the error due to (near field) multi path this is harder to do, if not impossible. The more because this strongly depends on the antenna type and its mount. Unfortunately it is, again, this (near field) multi path influence that might void the calibration once the antenna is installed at the station. Hence it can be concluded that at present, due to (near

  10. Epidemiology of Lung Cancer

    PubMed Central

    Ridge, Carole A.; McErlean, Aoife M.; Ginsberg, Michelle S.

    2013-01-01

    Incidence and mortality attributed to lung cancer has risen steadily since the 1930s. Efforts to improve outcomes have not only led to a greater understanding of the etiology of lung cancer, but also the histologic and molecular characteristics of individual lung tumors. This article describes this evolution by discussing the extent of the current lung cancer epidemic including contemporary incidence and mortality trends, the risk factors for development of lung cancer, and details of promising molecular targets for treatment. PMID:24436524

  11. Novalis' Poetic Uncertainty: A "Bildung" with the Absolute

    ERIC Educational Resources Information Center

    Mika, Carl

    2016-01-01

    Novalis, the Early German Romantic poet and philosopher, had at the core of his work a mysterious depiction of the "absolute." The absolute is Novalis' name for a substance that defies precise knowledge yet calls for a tentative and sensitive speculation. How one asserts a truth, represents an object, and sets about encountering things…

  12. Absolute Pitch in Infant Auditory Learning: Evidence for Developmental Reorganization.

    ERIC Educational Resources Information Center

    Saffran, Jenny R.; Griepentrog, Gregory J.

    2001-01-01

    Two experiments examined 8-month-olds' use of absolute and relative pitch cues in a tone-sequence statistical learning task. Results suggest that, given unsegmented stimuli that do not conform to rules of musical composition, infants are more likely to track patterns of absolute pitches than of relative pitches. A third experiment found that adult…

  13. Supplementary and Enrichment Series: Absolute Value. Teachers' Commentary. SP-25.

    ERIC Educational Resources Information Center

    Bridgess, M. Philbrick, Ed.

    This is one in a series of manuals for teachers using SMSG high school supplementary materials. The pamphlet includes commentaries on the sections of the student's booklet, answers to the exercises, and sample test questions. Topics covered include addition and multiplication in terms of absolute value, graphs of absolute value in the Cartesian…

  14. Supplementary and Enrichment Series: Absolute Value. SP-24.

    ERIC Educational Resources Information Center

    Bridgess, M. Philbrick, Ed.

    This is one in a series of SMSG supplementary and enrichment pamphlets for high school students. This series is designed to make material for the study of topics of special interest to students readily accessible in classroom quantity. Topics covered include absolute value, addition and multiplication in terms of absolute value, graphs of absolute…

  15. Absolute dimensions of unevolved O type close binaries

    SciTech Connect

    Doom, C.; de Loore, C.

    1984-03-15

    A method is presented to derive the absolute dimensions of early-type detached binaries by combining the observed parameters with results of evolutionary computations. The method is used to obtain the absolute dimensions of nine close binaries. We find that most systems have an initial masss ratio near 1.

  16. Absolute Humidity and the Seasonality of Influenza (Invited)

    NASA Astrophysics Data System (ADS)

    Shaman, J. L.; Pitzer, V.; Viboud, C.; Grenfell, B.; Goldstein, E.; Lipsitch, M.

    2010-12-01

    Much of the observed wintertime increase of mortality in temperate regions is attributed to seasonal influenza. A recent re-analysis of laboratory experiments indicates that absolute humidity strongly modulates the airborne survival and transmission of the influenza virus. Here we show that the onset of increased wintertime influenza-related mortality in the United States is associated with anomalously low absolute humidity levels during the prior weeks. We then use an epidemiological model, in which observed absolute humidity conditions temper influenza transmission rates, to successfully simulate the seasonal cycle of observed influenza-related mortality. The model results indicate that direct modulation of influenza transmissibility by absolute humidity alone is sufficient to produce this observed seasonality. These findings provide epidemiological support for the hypothesis that absolute humidity drives seasonal variations of influenza transmission in temperate regions. In addition, we show that variations of the basic and effective reproductive numbers for influenza, caused by seasonal changes in absolute humidity, are consistent with the general timing of pandemic influenza outbreaks observed for 2009 A/H1N1 in temperate regions. Indeed, absolute humidity conditions correctly identify the region of the United States vulnerable to a third, wintertime wave of pandemic influenza. These findings suggest that the timing of pandemic influenza outbreaks is controlled by a combination of absolute humidity conditions, levels of susceptibility and changes in population mixing and contact rates.

  17. Determination of Absolute Zero Using a Computer-Based Laboratory

    ERIC Educational Resources Information Center

    Amrani, D.

    2007-01-01

    We present a simple computer-based laboratory experiment for evaluating absolute zero in degrees Celsius, which can be performed in college and undergraduate physical sciences laboratory courses. With a computer, absolute zero apparatus can help demonstrators or students to observe the relationship between temperature and pressure and use…

  18. Absolute radiometric calibration of advanced remote sensing systems

    NASA Technical Reports Server (NTRS)

    Slater, P. N.

    1982-01-01

    The distinction between the uses of relative and absolute spectroradiometric calibration of remote sensing systems is discussed. The advantages of detector-based absolute calibration are described, and the categories of relative and absolute system calibrations are listed. The limitations and problems associated with three common methods used for the absolute calibration of remote sensing systems are addressed. Two methods are proposed for the in-flight absolute calibration of advanced multispectral linear array systems. One makes use of a sun-illuminated panel in front of the sensor, the radiance of which is monitored by a spectrally flat pyroelectric radiometer. The other uses a large, uniform, high-radiance reference ground surface. The ground and atmospheric measurements required as input to a radiative transfer program to predict the radiance level at the entrance pupil of the orbital sensor are discussed, and the ground instrumentation is described.

  19. Lung hyperinflation: foe or friend?

    PubMed

    Eichinger, M; Walterspacher, S; Scholz, T; Tetzlaff, K; Röcker, K; Muth, C-M; Puderbach, M; Kauczor, H-U; Sorichter, S

    2008-10-01

    Breath-hold divers employ glossopharyngeal insufflation (GI) in order to prevent the lungs from compressing at great depth and to increase intrapulmonary oxygen stores, thus increasing breath-hold time. The presented case study shows the physiological data and dynamic magnetic resonance imaging (dMRI) findings of acute hyperinflation, deliberately induced by GI, in a breath-hold diver and discusses the current state of knowledge regarding the associated hazards of this unique competitive sport. Static and dynamic lung volumes and expiratory flows were within the normal range, with vital capacity and peak expiratory flow being higher than the predicted values. Airway resistance and diffusing capacity of the lung for carbon monoxide were normal. Static compliance was normal and increased five-fold with hyperinflation. dMRI revealed a preserved shape of the thorax and diaphragm with hyperinflation. A herniation of the lung beneath the sternum and enlargement of the costodiaphragmatic angle were additional findings during the GI manoeuvre. After expiration, complete resolution to baseline was demonstrated. Hyperinflation can be physiological and even protective under abnormal physical conditions in the sense of acute adaptation to deep breath-hold diving. Dynamic magnetic resonance imaging is adequate for visualisation of the sequence of the glossopharyngeal insufflation manoeuvre and the complete reversibility of deliberate hyperinflation.

  20. Interstitial lung disease - adults - discharge

    MedlinePlus

    Diffuse parenchymal lung disease - discharge; Alveolitis - discharge; Idiopathic pulmonary pneumonitis - discharge; IPP - discharge; Chronic interstitial lung - discharge; Chronic respiratory interstitial lung - ...

  1. [Lung cancer in elderly patients: lung cancer and lung function].

    PubMed

    Tanita, Tatsuo

    2005-07-01

    The incidence of bronchogenic carcinoma is increasing as life expectancy rises. With increase in the aged population in Japan, the number of patients suffering from lung cancer and candidates for lung resections are increasing. In this paper, the author lists up indispensable procedures for diagnosis, namely, lung function tests, unilateral pulmonary arterial occlusion test and exercise tolerance test. The cut-offs for identifying candidates for elderly patients for lung resections can be applied the same cut-offs for younger patients. Also the author indicates the importance of postoperative management for lung lobe resections. In order to prevent postoperative problems such as congestive heart failure that might be a fetal complication, the most useful check values after the lung surgery for elderly patients are rate of transfusion and urine volume. In conclusion, when elderly patients assert their rights to undergo lung surgery, we, the thoracic surgeons, should reply their requests under the equal quality of safe surgery as that for younger patients. Besides, it is desirable that even elderly patients, over 80 years old, who undergo lung surgery should guarantee their quality of daily life after surgery.

  2. The promise of microfluidic artificial lungs.

    PubMed

    Potkay, Joseph A

    2014-11-01

    Microfluidic or microchannel artificial lungs promise to enable a new class of truly portable, therapeutic artificial lungs through feature sizes and blood channel designs that closely mimic those found in their natural counterpart. These new artificial lungs could potentially: 1) have surface areas and priming volumes that are a fraction of current technologies thereby decreasing device size and reducing the foreign body response; 2) contain blood flow networks in which cells and platelets experience pressures, shear stresses, and branching angles that copy those in the human lung thereby improving biocompatibility; 3) operate efficiently with room air, eliminating the need for gas cylinders and complications associated with hyperoxemia; 4) exhibit biomimetic hydraulic resistances, enabling operation with natural pressures and eliminating the need for blood pumps; and, 5) provide increased gas exchange capacity enabling respiratory support for active patients. This manuscript reviews recent research efforts in microfluidic artificial lungs targeted at achieving the advantages above, investigates the ultimate performance and scaling limits of these devices using a proven mathematical model, and discusses the future challenges that must be overcome in order for microfluidic artificial lungs to be applied in the clinic. If all of these promising advantages are realized and the remaining challenges are met, microfluidic artificial lungs could revolutionize the field of pulmonary rehabilitation.

  3. Epidemiology of Lung Cancer

    PubMed Central

    Brock, Malcolm V.; Ford, Jean G.; Samet, Jonathan M.; Spivack, Simon D.

    2013-01-01

    Background: Ever since a lung cancer epidemic emerged in the mid-1900s, the epidemiology of lung cancer has been intensively investigated to characterize its causes and patterns of occurrence. This report summarizes the key findings of this research. Methods: A detailed literature search provided the basis for a narrative review, identifying and summarizing key reports on population patterns and factors that affect lung cancer risk. Results: Established environmental risk factors for lung cancer include smoking cigarettes and other tobacco products and exposure to secondhand tobacco smoke, occupational lung carcinogens, radiation, and indoor and outdoor air pollution. Cigarette smoking is the predominant cause of lung cancer and the leading worldwide cause of cancer death. Smoking prevalence in developing nations has increased, starting new lung cancer epidemics in these nations. A positive family history and acquired lung disease are examples of host factors that are clinically useful risk indicators. Risk prediction models based on lung cancer risk factors have been developed, but further refinement is needed to provide clinically useful risk stratification. Promising biomarkers of lung cancer risk and early detection have been identified, but none are ready for broad clinical application. Conclusions: Almost all lung cancer deaths are caused by cigarette smoking, underscoring the need for ongoing efforts at tobacco control throughout the world. Further research is needed into the reasons underlying lung cancer disparities, the causes of lung cancer in never smokers, the potential role of HIV in lung carcinogenesis, and the development of biomarkers. PMID:23649439

  4. The wind god promotes lung cancer.

    PubMed

    Frisch, Steven M; Schaller, Michael D

    2014-05-12

    In this issue of Cancer Cell, Li and colleagues demonstrate that the hematopoietic transcription factor Aiolos (named after the Wind God of Greek mythology) confers anoikis resistance in lung tumor cells through repression of cell adhesion-related genes including the mechanosensor p66Shc.

  5. The wind god promotes lung cancer.

    PubMed

    Frisch, Steven M; Schaller, Michael D

    2014-05-12

    In this issue of Cancer Cell, Li and colleagues demonstrate that the hematopoietic transcription factor Aiolos (named after the Wind God of Greek mythology) confers anoikis resistance in lung tumor cells through repression of cell adhesion-related genes including the mechanosensor p66Shc. PMID:24823631

  6. Epidemiology of Lung Cancer.

    PubMed

    Mao, Yousheng; Yang, Ding; He, Jie; Krasna, Mark J

    2016-07-01

    Lung cancer has been transformed from a rare disease into a global problem and public health issue. The etiologic factors of lung cancer become more complex along with industrialization, urbanization, and environmental pollution around the world. Currently, the control of lung cancer has attracted worldwide attention. Studies on the epidemiologic characteristics of lung cancer and its relative risk factors have played an important role in the tertiary prevention of lung cancer and in exploring new ways of diagnosis and treatment. This article reviews the current evolution of the epidemiology of lung cancer. PMID:27261907

  7. Mini-implants and miniplates generate sub-absolute and absolute anchorage

    PubMed Central

    Consolaro, Alberto

    2014-01-01

    The functional demand imposed on bone promotes changes in the spatial properties of osteocytes as well as in their extensions uniformly distributed throughout the mineralized surface. Once spatial deformation is established, osteocytes create the need for structural adaptations that result in bone formation and resorption that happen to meet the functional demands. The endosteum and the periosteum are the effectors responsible for stimulating adaptive osteocytes in the inner and outer surfaces.Changes in shape, volume and position of the jaws as a result of skeletal correction of the maxilla and mandible require anchorage to allow bone remodeling to redefine morphology, esthetics and function as a result of spatial deformation conducted by orthodontic appliances. Examining the degree of changes in shape, volume and structural relationship of areas where mini-implants and miniplates are placed allows us to classify mini-implants as devices of subabsolute anchorage and miniplates as devices of absolute anchorage. PMID:25162561

  8. Minimal requirements for the molecular testing of lung cancer.

    PubMed

    Popper, Helmut H; Tímár, József; Ryska, Ales; Olszewski, Wlodzimierz

    2014-10-01

    From the aspect of the contemporary pathologic diagnostics of lung cancer, it is a key issue of the tissue obtained since small biopsies and cytology still play a major role. In the non-small cell lung cancer era, cytology considered equal to biopsy. However, in recent years it is unable to provide quality diagnosis and must be replaced by biopsy. Various molecular techniques can handle various different tissue samples which must be considered during molecular pathology diagnosis. Besides, tumor cell-normal cell ratio in the obtained tissue as well as the absolute tumor cell number have great significance whose information must be provided in the primary lung cancer diagnosis. Last but not least, for continuous sustainable molecular diagnostics of lung cancer rational algorythms, affordable technology and appropriate reimbursement are equally necessary.

  9. Lung carcinogenesis from chronic obstructive pulmonary disease: characteristics of lung cancer from COPD and contribution of signal transducers and lung stem cells in the inflammatory microenvironment.

    PubMed

    Sekine, Yasuo; Hata, Atsushi; Koh, Eitetsu; Hiroshima, Kenzo

    2014-07-01

    Chronic obstructive pulmonary disease (COPD) and lung cancer are closely related. The annual incidence of lung cancer arising from COPD has been reported to be 0.8-1.7 %. Treatment of lung cancer from COPD is very difficult due to low cardiopulmonary function, rapid tumor growth, and resistance to molecularly targeted therapies. Chronic inflammation caused by toxic gases can induce COPD and lung cancer. Carcinogenesis in the inflammatory microenvironment occurs during cycles of tissue injury and repair. Cellular damage can induce induction of necrotic cell death and loss of tissue integrity. Quiescent normal stem cells or differentiated progenitor cells are introduced to repair injured tissues. However, inflammatory mediators may promote the growth of bronchioalveolar stem cells, and activation of NF-κB and signal transducer and activator of transcription 3 (STAT3) play crucial roles in the development of lung cancer from COPD. Many of the protumorgenic effects of NF-κB and STAT3 activation in immune cells are mediated through paracrine signaling. NF-κB and STAT3 also contribute to epithelial-mesenchymal transition. To improve lung cancer treatment outcomes, lung cancer from COPD must be overcome. In this article, we review the characteristics of lung cancer from COPD and the mechanisms of carcinogenesis in the inflammatory microenvironment. We also propose the necessity of identifying the mechanisms underlying progression of COPD to lung cancer, and comment on the clinical implications with respect to lung cancer prevention, screening, and therapy.

  10. An All Fiber White Light Interferometric Absolute Temperature Measurement System

    PubMed Central

    Kim, Jeonggon Harrison

    2008-01-01

    Recently the author of this article proposed a new signal processing algorithm for an all fiber white light interferometer. In this article, an all fiber white light interferometric absolute temperature measurement system is presented using the previously proposed signal processing algorithm. Stability and absolute temperature measurement were demonstrated. These two tests demonstrated the feasibility of absolute temperature measurement with an accuracy of 0.015 fringe and 0.0005 fringe, respectively. A hysteresis test from 373K to 873K was also presented. Finally, robustness of the sensor system towards laser diode temperature drift, AFMZI temperature drift and PZT non-linearity was demonstrated.

  11. Measurement of Disintegration Rates and Absolute {gamma}-ray Intensities

    SciTech Connect

    DeVries, Daniel J.; Griffin, Henry C.

    2006-03-13

    The majority of practical radioactive materials decay by modes that include {gamma}-ray emission. For questions of 'how much' or 'how pure', one must know the absolute intensities of the major radiations. We are using liquid scintillation counting (LSC) to measurements of disintegration rates, coupled with {gamma}-ray spectroscopy to measure absolute {gamma}-ray emission probabilities. Described is a study of the 227Th chain yielding absolute {gamma}-ray intensities with {approx}0.5% accuracy and information on LSC efficiencies.

  12. Absolute Antenna Calibration at the US National Geodetic Survey

    NASA Astrophysics Data System (ADS)

    Mader, G. L.; Bilich, A. L.

    2012-12-01

    Geodetic GNSS applications routinely demand millimeter precision and extremely high levels of accuracy. To achieve these accuracies, measurement and instrument biases at the centimeter to millimeter level must be understood. One of these biases is the antenna phase center, the apparent point of signal reception for a GNSS antenna. It has been well established that phase center patterns differ between antenna models and manufacturers; additional research suggests that the addition of a radome or the choice of antenna mount can significantly alter those a priori phase center patterns. For the more demanding GNSS positioning applications and especially in cases of mixed-antenna networks, it is all the more important to know antenna phase center variations as a function of both elevation and azimuth in the antenna reference frame and incorporate these models into analysis software. Determination of antenna phase center behavior is known as "antenna calibration". Since 1994, NGS has computed relative antenna calibrations for more than 350 antennas. In recent years, the geodetic community has moved to absolute calibrations - the IGS adopted absolute antenna phase center calibrations in 2006 for use in their orbit and clock products, and NGS's CORS group began using absolute antenna calibration upon the release of the new CORS coordinates in IGS08 epoch 2005.00 and NAD 83(2011,MA11,PA11) epoch 2010.00. Although NGS relative calibrations can be and have been converted to absolute, it is considered best practice to independently measure phase center characteristics in an absolute sense. Consequently, NGS has developed and operates an absolute calibration system. These absolute antenna calibrations accommodate the demand for greater accuracy and for 2-dimensional (elevation and azimuth) parameterization. NGS will continue to provide calibration values via the NGS web site www.ngs.noaa.gov/ANTCAL, and will publish calibrations in the ANTEX format as well as the legacy ANTINFO

  13. The development of a Compton lung densitometer

    SciTech Connect

    Loo, B.W.; Goulding, F.S.; Madden, N.W.; Simon, D.S.

    1988-11-01

    A field instrument is being developed for the non-invasive determination of absolute lung density using unique Compton backscattering techniques. A system consisting of a monoenergetic gamma-ray beam and a shielded high resolution high-purity-germanium (HPGe) detector in a close-coupled geometry is designed to minimize errors due to multiple scattering and uncontrollable attenuation in the chestwall. Results of studies on system performance with phantoms, the optimization of detectors, and the fabrication of a practical gamma-ray source are presented. 3 refs., 6 figs., 2 tabs.

  14. Asymmetric Synthesis and Absolute Configuration Assignment of a New Type of Bedaquiline Analogue.

    PubMed

    Qiao, Chang-Jiang; Wang, Xiao-Kui; Xie, Fei; Zhong, Wu; Li, Song

    2015-01-01

    Bedaquiline is the first FDA-approved new chemical entity to fight multidrug-resistant tuberculosis in the last forty years. Our group replaced the quinoline ring with a naphthalene ring, leading to a new type of triarylbutanol skeleton. An asymmetric synthetic route was established for our bedaquiline analogues, and the goal of assigning their absolute configurations was achieved by comparison of experimental and calculated electronic circular dichroism spectra, and was confirmed by the combined use of circular dichroism and NMR spectroscopy. PMID:26690407

  15. Lung cancer epidemiology: contemporary and future challenges worldwide.

    PubMed

    Didkowska, Joanna; Wojciechowska, Urszula; Mańczuk, Marta; Łobaszewski, Jakub

    2016-04-01

    Over the last century, lung cancer from the rarest of diseases became the biggest cancer killer of men worldwide and in some parts of the world also of women (North America, East Asia, Northern Europe, Australia and New Zealand). In 2012 over 1.6 million of people died due to lung cancer. The cause-effect relationship between tobacco smoking and lung cancer occurrence has been proven in many studies, both ecological and clinical. In global perspective one can see the increasing tobacco consumption trend followed by ascending trends of lung cancer mortality, especially in developing countries. In some more developed countries, where the tobacco epidemics was on the rise since the beginning of the 20th century and peaked in its mid, in male population lung cancer incidence trend reversed or leveled off. Despite predicted further decline of incidence rates, the absolute number of deaths will continue to grow in these countries. In the remaining parts of the world the tobacco epidemics is still evolving what brings rapid increase of the number of new lung cancer cases and deaths. Number of lung cancer deaths worldwide is expected to grow up to 3 million until 2035. The figures will double both in men (from 1.1 million in 2012 to 2.1 million in 2035) and women (from 0.5 million in 2012 to 0.9 million in 2035) and the two-fold difference between sexes will persist. The most rapid increase is expected in Africa region (AFRO) and East Mediterranean region (EMRO). The increase of the absolute number of lung cancer deaths in more developed countries is caused mostly by population aging and in less developed countries predominantly by the evolving tobacco epidemic.

  16. Lung cancer epidemiology: contemporary and future challenges worldwide

    PubMed Central

    Wojciechowska, Urszula; Mańczuk, Marta; Łobaszewski, Jakub

    2016-01-01

    Over the last century, lung cancer from the rarest of diseases became the biggest cancer killer of men worldwide and in some parts of the world also of women (North America, East Asia, Northern Europe, Australia and New Zealand). In 2012 over 1.6 million of people died due to lung cancer. The cause-effect relationship between tobacco smoking and lung cancer occurrence has been proven in many studies, both ecological and clinical. In global perspective one can see the increasing tobacco consumption trend followed by ascending trends of lung cancer mortality, especially in developing countries. In some more developed countries, where the tobacco epidemics was on the rise since the beginning of the 20th century and peaked in its mid, in male population lung cancer incidence trend reversed or leveled off. Despite predicted further decline of incidence rates, the absolute number of deaths will continue to grow in these countries. In the remaining parts of the world the tobacco epidemics is still evolving what brings rapid increase of the number of new lung cancer cases and deaths. Number of lung cancer deaths worldwide is expected to grow up to 3 million until 2035. The figures will double both in men (from 1.1 million in 2012 to 2.1 million in 2035) and women (from 0.5 million in 2012 to 0.9 million in 2035) and the two-fold difference between sexes will persist. The most rapid increase is expected in Africa region (AFRO) and East Mediterranean region (EMRO). The increase of the absolute number of lung cancer deaths in more developed countries is caused mostly by population aging and in less developed countries predominantly by the evolving tobacco epidemic. PMID:27195268

  17. Ex vivo lung perfusion in Brazil

    PubMed Central

    Abdalla, Luis Gustavo; Braga, Karina Andrighetti de Oliveira; Nepomuceno, Natalia Aparecida; Fernandes, Lucas Matos; Samano, Marcos Naoyuki; Pêgo-Fernandes, Paulo Manuel

    2016-01-01

    Objective: To evaluate the use of ex vivo lung perfusion (EVLP) clinically to prepare donor lungs for transplantation. Methods: A prospective study involving EVLP for the reconditioning of extended-criteria donor lungs, the criteria for which include aspects such as a PaO2/FiO2 ratio < 300 mmHg. Between February of 2013 and February of 2014, the lungs of five donors were submitted to EVLP for up to 4 h each. During EVLP, respiratory mechanics were continuously evaluated. Once every hour during the procedure, samples of the perfusate were collected and the function of the lungs was evaluated. Results: The mean PaO2 of the recovered lungs was 262.9 ± 119.7 mmHg at baseline, compared with 357.0 ± 108.5 mmHg after 3 h of EVLP. The mean oxygenation capacity of the lungs improved slightly over the first 3 h of EVLP-246.1 ± 35.1, 257.9 ± 48.9, and 288.8 ± 120.5 mmHg after 1, 2, and 3 h, respectively-without significant differences among the time points (p = 0.508). The mean static compliance was 63.0 ± 18.7 mmHg, 75.6 ± 25.4 mmHg, and 70.4 ± 28.0 mmHg after 1, 2, and 3 h, respectively, with a significant improvement from hour 1 to hour 2 (p = 0.029) but not from hour 2 to hour 3 (p = 0.059). Pulmonary vascular resistance remained stable during EVLP, with no differences among time points (p = 0.284). Conclusions: Although the lungs evaluated remained under physiological conditions, the EVLP protocol did not effectively improve lung function, thus precluding transplantation. PMID:27167429

  18. Isolated lung perfusion.

    PubMed

    Cypel, Marcelo; Keshavjee, Shaf

    2012-01-01

    Isolated lung perfusion (ILP) has been historically used as a method to study basic lung physiologic concepts using animal models. More recently, ILP has been applied in lung transplantation and thoracic oncology. In lung transplantation, ILP has been used to assess physiological integrity of donor lungs after the organ is removed from the donor. This procedure is called Ex vivo Lung Perfusion (EVLP), and it has also been proposed as a method for active treatment and repair of injured unsuitable donor organs ex vivo. In oncology, ILP is an attractive method to deliver high dose chemotherapy to treat pulmonary metastatic disease. Since the lung vasculature is isolated in vivo, this technique is called in vivo lung perfusion (IVLP). This review will focus on the rationale, technical aspects, experimental and clinical experience of EVLP and IVLP. A perspective on the future use of these techniques is described. PMID:22202033

  19. Ex vivo lung perfusion.

    PubMed

    Machuca, Tiago N; Cypel, Marcelo

    2014-08-01

    Lung transplantation (LTx) is an established treatment option for eligible patients with end-stage lung disease. Nevertheless, the imbalance between suitable donor lungs available and the increasing number of patients considered for LTx reflects in considerable waitlist mortality. Among potential alternatives to address this issue, ex vivo lung perfusion (EVLP) has emerged as a modern preservation technique that allows for more accurate lung assessment and also improvement of lung function. Its application in high-risk donor lungs has been successful and resulted in safe expansion of the donor pool. This article will: (I) review the technical details of EVLP; (II) the rationale behind the method; (III) report the worldwide clinical experience with the EVLP, including the Toronto technique and others; (IV) finally, discuss the growing literature on EVLP application for donation after cardiac death (DCD) lungs. PMID:25132972

  20. Lung Diseases and Conditions

    MedlinePlus

    ... Share this page from the NHLBI on Twitter. Lung Diseases and Conditions Breathing is a complex process. ... your bronchial tubes ( bronchitis ) or deep in your lungs ( pneumonia ). These infections cause a buildup of mucus ...

  1. Lung needle biopsy

    MedlinePlus

    ... not improve, a chest tube is inserted to expand your lung. In rare cases, pneumothorax can be ... Philadelphia, PA: Elsevier Saunders; 2011:chap 197. Silvestri GA, Jett JR. Clinical aspects of lung cancer. In: ...

  2. American Lung Association

    MedlinePlus

    ... Washington DC West Virginia Wisconsin Wyoming November Is Lung Cancer Awareness Month If you or someone you ... RESEARCH Our vision is a world FREE OF LUNG DISEASE Make Each Breath Count: Learn, Engage, Act! ...

  3. Ex vivo lung perfusion

    PubMed Central

    Machuca, Tiago N.

    2014-01-01

    Lung transplantation (LTx) is an established treatment option for eligible patients with end-stage lung disease. Nevertheless, the imbalance between suitable donor lungs available and the increasing number of patients considered for LTx reflects in considerable waitlist mortality. Among potential alternatives to address this issue, ex vivo lung perfusion (EVLP) has emerged as a modern preservation technique that allows for more accurate lung assessment and also improvement of lung function. Its application in high-risk donor lungs has been successful and resulted in safe expansion of the donor pool. This article will: (I) review the technical details of EVLP; (II) the rationale behind the method; (III) report the worldwide clinical experience with the EVLP, including the Toronto technique and others; (IV) finally, discuss the growing literature on EVLP application for donation after cardiac death (DCD) lungs. PMID:25132972

  4. Absolute pitch in infant auditory learning: evidence for developmental reorganization.

    PubMed

    Saffran, J R; Griepentrog, G J

    2001-01-01

    To what extent do infants represent the absolute pitches of complex auditory stimuli? Two experiments with 8-month-old infants examined the use of absolute and relative pitch cues in a tone-sequence statistical learning task. The results suggest that, given unsegmented stimuli that do not conform to the rules of musical composition, infants are more likely to track patterns of absolute pitches than of relative pitches. A 3rd experiment tested adults with or without musical training on the same statistical learning tasks used in the infant experiments. Unlike the infants, adult listeners relied primarily on relative pitch cues. These results suggest a shift from an initial focus on absolute pitch to the eventual dominance of relative pitch, which, it is argued, is more useful for both music and speech processing.

  5. Absolute calibration of sniffer probes on Wendelstein 7-X

    NASA Astrophysics Data System (ADS)

    Moseev, D.; Laqua, H. P.; Marsen, S.; Stange, T.; Braune, H.; Erckmann, V.; Gellert, F.; Oosterbeek, J. W.

    2016-08-01

    Here we report the first measurements of the power levels of stray radiation in the vacuum vessel of Wendelstein 7-X using absolutely calibrated sniffer probes. The absolute calibration is achieved by using calibrated sources of stray radiation and the implicit measurement of the quality factor of the Wendelstein 7-X empty vacuum vessel. Normalized absolute calibration coefficients agree with the cross-calibration coefficients that are obtained by the direct measurements, indicating that the measured absolute calibration coefficients and stray radiation levels in the vessel are valid. Close to the launcher, the stray radiation in the empty vessel reaches power levels up to 340 kW/m2 per MW injected beam power. Furthest away from the launcher, i.e., half a toroidal turn, still 90 kW/m2 per MW injected beam power is measured.

  6. Temporal Dynamics of Microbial Rhodopsin Fluorescence Reports Absolute Membrane Voltage

    PubMed Central

    Hou, Jennifer H.; Venkatachalam, Veena; Cohen, Adam E.

    2014-01-01

    Plasma membrane voltage is a fundamentally important property of a living cell; its value is tightly coupled to membrane transport, the dynamics of transmembrane proteins, and to intercellular communication. Accurate measurement of the membrane voltage could elucidate subtle changes in cellular physiology, but existing genetically encoded fluorescent voltage reporters are better at reporting relative changes than absolute numbers. We developed an Archaerhodopsin-based fluorescent voltage sensor whose time-domain response to a stepwise change in illumination encodes the absolute membrane voltage. We validated this sensor in human embryonic kidney cells. Measurements were robust to variation in imaging parameters and in gene expression levels, and reported voltage with an absolute accuracy of 10 mV. With further improvements in membrane trafficking and signal amplitude, time-domain encoding of absolute voltage could be applied to investigate many important and previously intractable bioelectric phenomena. PMID:24507604

  7. Absolute Value Boundedness, Operator Decomposition, and Stochastic Media and Equations

    NASA Technical Reports Server (NTRS)

    Adomian, G.; Miao, C. C.

    1973-01-01

    The research accomplished during this period is reported. Published abstracts and technical reports are listed. Articles presented include: boundedness of absolute values of generalized Fourier coefficients, propagation in stochastic media, and stationary conditions for stochastic differential equations.

  8. Absolute calibration of sniffer probes on Wendelstein 7-X.

    PubMed

    Moseev, D; Laqua, H P; Marsen, S; Stange, T; Braune, H; Erckmann, V; Gellert, F; Oosterbeek, J W

    2016-08-01

    Here we report the first measurements of the power levels of stray radiation in the vacuum vessel of Wendelstein 7-X using absolutely calibrated sniffer probes. The absolute calibration is achieved by using calibrated sources of stray radiation and the implicit measurement of the quality factor of the Wendelstein 7-X empty vacuum vessel. Normalized absolute calibration coefficients agree with the cross-calibration coefficients that are obtained by the direct measurements, indicating that the measured absolute calibration coefficients and stray radiation levels in the vessel are valid. Close to the launcher, the stray radiation in the empty vessel reaches power levels up to 340 kW/m(2) per MW injected beam power. Furthest away from the launcher, i.e., half a toroidal turn, still 90 kW/m(2) per MW injected beam power is measured. PMID:27587121

  9. Preparation of an oakmoss absolute with reduced allergenic potential.

    PubMed

    Ehret, C; Maupetit, P; Petrzilka, M; Klecak, G

    1992-06-01

    Synopsis Oakmoss absolute, an extract of the lichen Evernia prunastri, is known to cause allergenic skin reactions due to the presence of certain aromatic aldehydes such as atranorin, chloratranorin, ethyl hematommate and ethyl chlorohematommate. In this paper it is shown that treatment of Oakmoss absolute with amino acids such as lysine and/or leucine, lowers considerably the content of these allergenic constituents including atranol and chloratranol. The resulting Oakmoss absolute, which exhibits an excellent olfactive quality, was tested extensively in comparative studies on guinea pigs and on man. The results of the Guinea Pig Maximization Test (GPMT) and Human Repeated Insult Patch Test (HRIPT) indicate that, in comparison with the commercial test sample, the allergenicity of this new quality of Oakmoss absolute was considerably reduced, and consequently better skin tolerance of this fragrance for man was achieved. PMID:19272096

  10. Modelling and measurement of the absolute level of power radiated by antenna integrated THz UTC photodiodes.

    PubMed

    Natrella, Michele; Liu, Chin-Pang; Graham, Chris; van Dijk, Frederic; Liu, Huiyun; Renaud, Cyril C; Seeds, Alwyn J

    2016-05-30

    We determine the output impedance of uni-travelling carrier (UTC) photodiodes at frequencies up to 400 GHz by performing, for the first time, 3D full-wave modelling of detailed UTC photodiode structures. In addition, we demonstrate the importance of the UTC impedance evaluation, by using it in the prediction of the absolute power radiated by an antenna integrated UTC, over a broad frequency range and confirming the predictions by experimental measurements up to 185 GHz. This is done by means of 3D full-wave modelling and is only possible since the source (UTC) to antenna impedance match is properly taken into account. We also show that, when the UTC-to-antenna coupling efficiency is modelled using the classical junction-capacitance/series-resistance concept, calculated and measured levels of absolute radiated power are in substantial disagreement, and the maximum radiated power is overestimated by a factor of almost 7 dB. The ability to calculate the absolute emitted power correctly enables the radiated power to be maximised through optimisation of the UTC-to-antenna impedance match.

  11. Modelling and measurement of the absolute level of power radiated by antenna integrated THz UTC photodiodes.

    PubMed

    Natrella, Michele; Liu, Chin-Pang; Graham, Chris; van Dijk, Frederic; Liu, Huiyun; Renaud, Cyril C; Seeds, Alwyn J

    2016-05-30

    We determine the output impedance of uni-travelling carrier (UTC) photodiodes at frequencies up to 400 GHz by performing, for the first time, 3D full-wave modelling of detailed UTC photodiode structures. In addition, we demonstrate the importance of the UTC impedance evaluation, by using it in the prediction of the absolute power radiated by an antenna integrated UTC, over a broad frequency range and confirming the predictions by experimental measurements up to 185 GHz. This is done by means of 3D full-wave modelling and is only possible since the source (UTC) to antenna impedance match is properly taken into account. We also show that, when the UTC-to-antenna coupling efficiency is modelled using the classical junction-capacitance/series-resistance concept, calculated and measured levels of absolute radiated power are in substantial disagreement, and the maximum radiated power is overestimated by a factor of almost 7 dB. The ability to calculate the absolute emitted power correctly enables the radiated power to be maximised through optimisation of the UTC-to-antenna impedance match. PMID:27410104

  12. Absolute Free Energies for Biomolecules in Implicit or Explicit Solvent

    NASA Astrophysics Data System (ADS)

    Berryman, Joshua T.; Schilling, Tanja

    Methods for absolute free energy calculation by alchemical transformation of a quantitative model to an analytically tractable one are discussed. These absolute free energy methods are placed in the context of other methods, and an attempt is made to describe the best practice for such calculations given the current state of the art. Calculations of the equilibria between the four free energy basins of the dialanine molecule and the two right- and left-twisted basins of DNA are discussed as examples.

  13. Heat capacity and absolute entropy of iron phosphides

    SciTech Connect

    Dobrokhotova, Z.V.; Zaitsev, A.I.; Litvina, A.D.

    1994-09-01

    There is little or no data on the thermodynamic properties of iron phosphides despite their importance for several areas of science and technology. The information available is of a qualitative character and is based on assessments of the heat capacity and absolute entropy. In the present work, we measured the heat capacity over the temperature range of 113-873 K using a differential scanning calorimeter (DSC) and calculated the absolute entropy.

  14. Mortality and survival of lung cancer in Denmark: Results from the Danish Lung Cancer Group 2000-2012.

    PubMed

    Jakobsen, Erik; Rasmussen, Torben Riis; Green, Anders

    2016-06-01

    Background In the 1990s outcomes in Danish lung cancer patients were poor compared with the other Nordic countries. The five-year survival was only about 5%, only 10% of patients were operated on and less than 60% received active surgical or oncologic treatment. This paper describes trends in mortality and survival of lung cancer in Denmark from 2000 to 2012. Methods The study population comprised 52 435 patients with a diagnosis of cancer of the trachea and the lung, primarily ascertained from the Danish Lung Cancer Register and grouped into three cohorts by year of diagnosis. The outcome measures covered the first year as well as the first full five-year period after diagnosis and comprised absolute mortality rate (per 100 patient years), absolute survival, and the relative survival. All outcomes were estimated for the overall patient population as well as after stratification by covariates. Results Overall, the mortality rates have declined significantly over time from 117 per 100 patient years to 88 for the one-year mortality and from 75 to 65 for the five-year mortality rates, respectively. With the exception of patients with advanced stage, declining mortality was observed for all strata by gender, comorbidity, stage and surgery status and was accompanied by corresponding improvements in both absolute and relative survival. Conclusions The mortality has been significantly declining and the prognosis correspondingly improving in lung cancer in Denmark since the turn of the millennium. As of today, survival after lung cancer in Denmark is probably in line with the international standard. Based on our results we recommend introducing mortality indicators based on all-cause mortality within the patient population in international benchmarking studies as comparisons based on cancer-specific mortality relative to the total general population may be misleading when interpreted in the context of outcomes and quality of care. PMID:27056247

  15. Global absolut gravity reference system as replacement of IGSN 71

    NASA Astrophysics Data System (ADS)

    Wilmes, Herbert; Wziontek, Hartmut; Falk, Reinhard

    2015-04-01

    The determination of precise gravity field parameters is of great importance in a period in which earth sciences are achieving the necessary accuracy to monitor and document global change processes. This is the reason why experts from geodesy and metrology joined in a successful cooperation to make absolute gravity observations traceable to SI quantities, to improve the metrological kilogram definition and to monitor mass movements and smallest height changes for geodetic and geophysical applications. The international gravity datum is still defined by the International Gravity Standardization Net adopted in 1971 (IGSN 71). The network is based upon pendulum and spring gravimeter observations taken in the 1950s and 60s supported by the early free fall absolute gravimeters. Its gravity values agreed in every case to better than 0.1 mGal. Today, more than 100 absolute gravimeters are in use worldwide. The series of repeated international comparisons confirms the traceability of absolute gravity measurements to SI quantities and confirm the degree of equivalence of the gravimeters in the order of a few µGal. For applications in geosciences where e.g. gravity changes over time need to be analyzed, the temporal stability of an absolute gravimeter is most important. Therefore, the proposition is made to replace the IGSN 71 by an up-to-date gravity reference system which is based upon repeated absolute gravimeter comparisons and a global network of well controlled gravity reference stations.

  16. Experimental lung injury promotes alterations in energy metabolism and respiratory mechanics in the lungs of rats: prevention by exercise.

    PubMed

    da Cunha, Maira J; da Cunha, Aline A; Scherer, Emilene B S; Machado, Fernanda Rossato; Loureiro, Samanta O; Jaenisch, Rodrigo B; Guma, Fátima; Lago, Pedro Dal; Wyse, Angela T S

    2014-04-01

    In the present study we investigated the effects of lung injury on energy metabolism (succinate dehydrogenase, complex II, cytochrome c oxidase, and ATP levels), respiratory mechanics (dynamic and static compliance, elastance and respiratory system resistance) in the lungs of rats, as well as on phospholipids in bronchoalveolar lavage fluid. The protective effect of physical exercise on the alterations caused by lung injury, including lung edema was also evaluated. Wistar rats were submitted to 2 months of physical exercise. After this period the lung injury was induced by intratracheal instillation of lipopolysaccharide. Adult Wistar rats were submitted to 2 months of physical exercise and after this period the lung injury was induced by intratracheal instillation of lipopolysaccharide in dose 100 μg/100 g body weight. The sham group received isotonic saline instillation. Twelve hours after the injury was performed the respiratory mechanical and after the rats were decapitated and samples were collected. The rats subjected to lung injury presented a decrease in activities of the enzymes of the electron transport chain and ATP levels in lung, as well as the formation of pulmonary edema. A decreased lung dynamic and static compliance, as well as an increase in respiratory system resistance, and a decrease in phospholipids content were observed. Physical exercise was able to totally prevent the decrease in succinate dehydrogenase and complex II activities and the formation of pulmonary edema. It also partially prevented the increase in respiratory system resistance, but did not prevent the decrease in dynamic and static compliance, as well as in phospholipids content. These findings suggest that the mitochondrial dysfunction may be one of the important contributors to lung damage and that physical exercise may be beneficial in this pathology, although it did not prevent all changes present in lung injury.

  17. Method to obtain absolute impurity density profiles combining charge exchange and beam emission spectroscopy without absolute intensity calibrationa)

    NASA Astrophysics Data System (ADS)

    Kappatou, A.; Jaspers, R. J. E.; Delabie, E.; Marchuk, O.; Biel, W.; Jakobs, M. A.

    2012-10-01

    Investigation of impurity transport properties in tokamak plasmas is essential and a diagnostic that can provide information on the impurity content is required. Combining charge exchange recombination spectroscopy (CXRS) and beam emission spectroscopy (BES), absolute radial profiles of impurity densities can be obtained from the CXRS and BES intensities, electron density and CXRS and BES emission rates, without requiring any absolute calibration of the spectra. The technique is demonstrated here with absolute impurity density radial profiles obtained in TEXTOR plasmas, using a high efficiency charge exchange spectrometer with high etendue, that measures the CXRS and BES spectra along the same lines-of-sight, offering an additional advantage for the determination of absolute impurity densities.

  18. CFTR and lung homeostasis.

    PubMed

    Collawn, James F; Matalon, Sadis

    2014-12-15

    CFTR is a cAMP-activated chloride and bicarbonate channel that is critical for lung homeostasis. Decreases in CFTR expression have dire consequences in cystic fibrosis (CF) and have been suggested to be a component of the lung pathology in chronic obstructive pulmonary disease. Decreases or loss of channel function often lead to mucus stasis, chronic bacterial infections, and the accompanying chronic inflammatory responses that promote progressive lung destruction, and, eventually in CF, lung failure. Here we discuss CFTR's functional role airway surface liquid hydration and pH, in regulation of other channels such as the epithelial sodium channel, and in regulating inflammatory responses in the lung. PMID:25381027

  19. Lung cancer in women.

    PubMed

    Coscio, Angela M; Garst, Jennifer

    2006-07-01

    Lung cancer is the most common cancer in both men and women; however, there are some clear gender-based differences. As the incidence of lung cancer is declining in men, the incidence of lung cancer is increasing in women. Women are more likely than men to have adenocarcinoma, a histologic subtype that correlates with worsened prognosis, but women have improved survival compared with men. Genetic predisposition and the presence of estrogen receptors in lung cancer cells may predispose women to developing lung cancer. Further studies are needed to understand the mechanism and significance of these findings. PMID:17254523

  20. The lung in space

    NASA Technical Reports Server (NTRS)

    Prisk, G. Kim

    2005-01-01

    The lung is exquisitely sensitive to gravity, which induces gradients in ventilation, blood flow, and gas exchange. Studies of lungs in microgravity provide a means of elucidating the effects of gravity. They suggest a mechanism by which gravity serves to match ventilation to perfusion, making for a more efficient lung than anticipated. Despite predictions, lungs do not become edematous, and there is no disruption to, gas exchange in microgravity. Sleep disturbances in microgravity are not a result of respiratory-related events; obstructive sleep apnea is caused principally by the gravitational effects on the upper airways. In microgravity, lungs may be at greater risk to the effects of inhaled aerosols.

  1. Xenogeneic lung transplantation models

    PubMed Central

    Burdorf, Lars; Azimzadeh, Agnes M.; Pierson, Richard N.

    2014-01-01

    Summary Study of lung xenografts has proven useful to understand the remaining barriers to successful transplantation of other organ xenografts. In this chapter, the history and current status of lung xenotransplantation will be briefly reviewed and two different experimental models, the ex vivo porcine-to-human lung perfusion and the in vivo xenogeneic lung transplantation, will be presented. We will focus on the technical details of these lung xenograft models in sufficient detail, list the needed materials and mention analysis techniques to allow others to adopt them with minimal learning curve. PMID:22565996

  2. Lung Cancer Screening.

    PubMed

    Deffebach, Mark E; Humphrey, Linda

    2015-10-01

    Screening for lung cancer in high-risk individuals with annual low-dose computed tomography has been shown to reduce lung cancer mortality by 20% and is recommended by multiple health care organizations. Lung cancer screening is not a specific test; it is a process that involves appropriate selection of high-risk individuals, careful interpretation and follow-up of imaging, and annual testing. Screening should be performed in the context of a multidisciplinary program experienced in the diagnosis and management of lung nodules and early-stage lung cancer.

  3. The lung mucosa: A critical environmental battleground

    SciTech Connect

    Bergofsky, E.H. )

    1991-10-21

    The entirety of the lung mucous membrane and epithelial surface are exposed to the environment; react to noxious environmental gases, vapors, and particles; and are under physiologic and humoral mediator control. In recent years much information has been gained regarding the mucous membrane of the tracheobronchial tree, its physiology, and its reaction to environmental hazards. The pharmacologic control of secretion, ciliary beat rate, and net mucus flow governs both the clearance of mucus and the clearance of particles. The physiologic factors that govern this clearance mechanism can be influenced by pharmacologic agents in patients with lung disease and presumably also in patients with purely environmental injury. The effects of ozone on lung function, lung compliance, and airway resistance have been well documented in adults and children. Environmental ozone also alters mucous membrane function, increasing mucociliary secretion rate and peripheral lung clearance. The speed-up in clearance implies an increase in mucous gland secretion, which may act unfavorably when ciliary beat is damaged, glandular hypertrophy is present, or flow-limiting segments exist, as is usually the case in bronchial asthma and chronic obstructive pulmonary disease. Thus, whereas the consequences of ozone may be modest for a normal, healthy individual, they presumably increase hazards for the individual with lung disease or damage. For this reason, efforts should be made to control or limit damage by ozone or other environmental inhalants in such individuals. This goal may be facilitated by a wider knowledge of the pharmacologic control of the mucous membrane.30 references.

  4. The impact of respiratory gating on lung dosimetry in stereotactic body radiotherapy for lung cancer.

    PubMed

    Jang, Seong Soon; Huh, Gil Ja; Park, Suk Young; Yang, Po Song; Cho, Eun Youn

    2014-09-01

    The purpose of this study was to evaluate the impacts of respiratory gating and different gating windows (GWs) on lung dosimetry in stereotactic body radiotherapy (SBRT) for lung cancer. Gated SBRT plans were developed using the four-dimensional computed tomography data from 17 lung cancer patients treated with SBRT. Using amplitude-based end-exhalation gating, we established 2 fixed GWs with approximate duty cycles of 50% (50% GW) and 25% (25% GW), respectively, for this study. For highly mobile tumors (3D mobility > 10 mm), additional benefits in lung-dose reductions were achieved with the 25% GW, as a result of inadequate mobility and planning target volume reductions obtained with the 50% GW. In these tumors, the absolute differences compared to the non-gated and 50% gated plans, were 0.5 Gy and 0.33 Gy for the mean lung dose and 1.11% and 0.71% for the V20, respectively. Dosimetric benefits were achieved with the 50% GW, compared with the non-gated plan, for tumors with both low mobility and small volume (gross tumor volume ≤ 10 cc). Among the identified predictive factors of dosimetric benefits, the lateral distance from midspinal canal and the motion range in anterior-posterior direction might be stronger factors because of their correlations with many of the lung-dose parameters and greater predictive capacity. The results of the present study might facilitate the selection of appropriate patients and the optimal GW according to the tumor characteristics for gated lung SBRT.

  5. Lung function tests in neonates and infants with chronic lung disease: lung and chest-wall mechanics.

    PubMed

    Gappa, Monika; Pillow, J Jane; Allen, Julian; Mayer, Oscar; Stocks, Janet

    2006-04-01

    This is the fifth paper in a review series that summarizes available data and critically discusses the potential role of lung function testing in infants and young children with acute neonatal respiratory disorders and chronic lung disease of infancy (CLDI). This review focuses on respiratory mechanics, including chest-wall and tissue mechanics, obtained in the intensive care setting and in infants during unassisted breathing. Following orientation of the reader to the subject area, we focused comments on areas of enquiry proposed in the introductory paper to this series. The quality of the published literature is reviewed critically with respect to relevant methods, equipment and study design, limitations and strengths of different techniques, and availability and appropriateness of reference data. Recommendations to guide future investigations in this field are provided. Numerous different methods have been used to assess respiratory mechanics with the aims of describing pulmonary status in preterm infants and assessing the effect of therapeutic interventions such as surfactant treatment, antenatal or postnatal steroids, or bronchodilator treatment. Interpretation of many of these studies is limited because lung volume was not measured simultaneously. In addition, populations are not comparable, and the number of infants studied has generally been small. Nevertheless, results appear to support the pathophysiological concept that immaturity of the lung leads to impaired lung function, which may improve with growth and development, irrespective of the diagnosis of chronic lung disease. To fully understand the impact of immaturity on the developing lung, it is unlikely that a single parameter such as respiratory compliance or resistance will accurately describe underlying changes. Assessment of respiratory mechanics will have to be supplemented by assessment of lung volume and airway function. New methods such as the low-frequency forced oscillation technique, which

  6. [Lung cancer screening].

    PubMed

    Sánchez González, M

    2014-01-01

    Lung cancer is a very important disease, curable in early stages. There have been trials trying to show the utility of chest x-ray or computed tomography in Lung Cancer Screening for decades. In 2011, National Lung Screening Trial results were published, showing a 20% reduction in lung cancer mortality in patients with low dose computed tomography screened for three years. These results are very promising and several scientific societies have included lung cancer screening in their guidelines. Nevertheless we have to be aware of lung cancer screening risks, such as: overdiagnosis, radiation and false positive results. Moreover, there are many issues to be solved, including choosing the appropriate group to be screened, the duration of the screening program, intervals between screening and its cost-effectiveness. Ongoing trials will probably answer some of these questions. This article reviews the current evidence on lung cancer screening.

  7. Partitioning of respiratory mechanical impedance by absolute and differential body plethysmography.

    PubMed

    Peslin, R; Duvivier, C

    1999-11-01

    We have recently demonstrated the feasibility of partitioning total respiratory impedance (Zrs) into its airway (Zaw) and tissular (Zti) components by measuring alveolar gas compression (Vpl) plethysmographically during pressure oscillations at the airway opening (Peslin et al.). The aim of this study was to comparatively evaluate an alternative approach: the measurement of Zrs and of the transfer function (FTF) between airway flow and body surface flow obtained by absolute body plethysmography. The two approaches are theoretically equivalent, provided thermal and other artifacts are properly eliminated. Zrs and Vpl (method 1) and Zrs and FTF (method 2) were measured in 11 healthy subjects from 4 to 29 Hz, using a pressure-type and a flow-type plethysmograph, respectively. Inspired gas was conditioned to body temperature and pressure, saturated with water vapor in both instances to minimize thermal factors. Zaw and Zti spectra computed from both sets of data were quite similar in shape. Neither airway resistance nor tissue compliance differed significantly; tissue resistance, however, was about 14% lower with method 1, which may be due to imperfect gas conditioning. The reproducibility of the data was similar with the two approaches. We conclude that absolute body plethysmography is as reliable as differential body plethysmography to partition Zrs. PMID:10582419

  8. Cannabidiol improves lung function and inflammation in mice submitted to LPS-induced acute lung injury.

    PubMed

    Ribeiro, A; Almeida, V I; Costola-de-Souza, C; Ferraz-de-Paula, V; Pinheiro, M L; Vitoretti, L B; Gimenes-Junior, J A; Akamine, A T; Crippa, J A; Tavares-de-Lima, W; Palermo-Neto, J

    2015-02-01

    We have previously shown that the prophylactic treatment with cannabidiol (CBD) reduces inflammation in a model of acute lung injury (ALI). In this work we analyzed the effects of the therapeutic treatment with CBD in mice subjected to the model of lipopolysaccharide (LPS)-induced ALI on pulmonary mechanics and inflammation. CBD (20 and 80 mg/kg) was administered (i.p.) to mice 6 h after LPS-induced lung inflammation. One day (24 h) after the induction of inflammation the assessment of pulmonary mechanics and inflammation were analyzed. The results show that CBD decreased total lung resistance and elastance, leukocyte migration into the lungs, myeloperoxidase activity in the lung tissue, protein concentration and production of pro-inflammatory cytokines (TNF and IL-6) and chemokines (MCP-1 and MIP-2) in the bronchoalveolar lavage supernatant. Thus, we conclude that CBD administered therapeutically, i.e. during an ongoing inflammatory process, has a potent anti-inflammatory effect and also improves the lung function in mice submitted to LPS-induced ALI. Therefore the present and previous data suggest that in the future cannabidiol might become a useful therapeutic tool for the attenuation and treatment of inflammatory lung diseases.

  9. Absolute irradiance of the Moon for on-orbit calibration

    USGS Publications Warehouse

    Stone, T.C.; Kieffer, H.H.; ,

    2002-01-01

    The recognized need for on-orbit calibration of remote sensing imaging instruments drives the ROLO project effort to characterize the Moon for use as an absolute radiance source. For over 5 years the ground-based ROLO telescopes have acquired spatially-resolved lunar images in 23 VNIR (Moon diameter ???500 pixels) and 9 SWIR (???250 pixels) passbands at phase angles within ??90 degrees. A numerical model for lunar irradiance has been developed which fits hundreds of ROLO images in each band, corrected for atmospheric extinction and calibrated to absolute radiance, then integrated to irradiance. The band-coupled extinction algorithm uses absorption spectra of several gases and aerosols derived from MODTRAN to fit time-dependent component abundances to nightly observations of standard stars. The absolute radiance scale is based upon independent telescopic measurements of the star Vega. The fitting process yields uncertainties in lunar relative irradiance over small ranges of phase angle and the full range of lunar libration well under 0.5%. A larger source of uncertainty enters in the absolute solar spectral irradiance, especially in the SWIR, where solar models disagree by up to 6%. Results of ROLO model direct comparisons to spacecraft observations demonstrate the ability of the technique to track sensor responsivity drifts to sub-percent precision. Intercomparisons among instruments provide key insights into both calibration issues and the absolute scale for lunar irradiance.

  10. Absolute neutrophil values in malignant patients on cytotoxic chemotherapy.

    PubMed

    Madu, A J; Ibegbulam, O G; Ocheni, S; Madu, K A; Aguwa, E N

    2011-01-01

    A total of eighty patients with various malignancies seen between September 2008 and April 2009 at the University of Nigeria Teaching Hospital (UNTH) Ituku Ozalla, Enugu, Nigeria, had their absolute neutrophil counts, done at Days 0 and 12 of the first cycle of their various chemotherapeutic regimens. They were adult patients who had been diagnosed of various malignancies, consisting of Breast cancer 36 (45%), Non-Hodgkin's lymphoma 8 (10%), Hodgkin's lymphoma 13 (16.25%), Colorectal carcinoma 6 (7.5%), Multiple myeloma 7 (8.75%), Cervical carcinoma 1 (1.25%) and other malignancies 9 (11.25%), Manual counting of absolute neutrophil count was done using Turks solution and improved Neubauer counting chamber and Galen 2000 Olympus microscope. The socio demographic data of the patients were assessed from a questionnaire. There were 27 males (33.75%) and 53 females (66.25%). Their ages ranged from 18 - 80 years with a median of 45 years. The mean absolute neutrophil count of the respondents pre-and post chemotherapy was 3.7 +/- 2.1 x 10(9)/L and 2.5 +/- 1.6 x 10(9)/L respectively. There were significant differences in both the absolute neutrophil count (p=0.00) compared to the pre-chemotherapy values. Chemotherapeutic combinations containing cyclophosphamide and Adriamycin were observed to cause significant reduction in absolute neutrophil.

  11. The Application of Optimisation Methods to Constrain Absolute Plate Motions

    NASA Astrophysics Data System (ADS)

    Tetley, M. G.; Williams, S.; Hardy, S.; Müller, D.

    2015-12-01

    Plate tectonic reconstructions are an excellent tool for understanding the configuration and behaviour of continents through time on both global and regional scales, and are relatively well understood back to ~200 Ma. However, many of these models represent only relative motions between continents, providing little information of absolute tectonic motions and their relationship with the deep Earth. Significant issues exist in solving this problem, including how to combine constraints from multiple, diverse data into a unified model of absolute plate motions; and how to address uncertainties both in the available data, and in the assumptions involved in this process (e.g. hotspot motion, true polar wander). In deep time (pre-Pangea breakup), plate reconstructions rely more heavily on paleomagnetism, but these data often imply plate velocities much larger than those observed since the breakup of the supercontinent Pangea where plate velocities are constrained by the seafloor spreading record. Here we present two complementary techniques to address these issues, applying parallelized numerical methods to quantitatively investigate absolute plate motions through time. Firstly, we develop a data-fit optimized global absolute reference frame constrained by kinematic reconstruction data, hotspot-trail observations, and trench migration statistics. Secondly we calculate optimized paleomagnetic data-derived apparent polar wander paths (APWPs) for both the Phanerozoic and Precambrian. Paths are generated from raw pole data with optimal spatial and temporal pole configurations calculated using all known uncertainties and quality criteria to produce velocity-optimized absolute motion paths through deep time.

  12. Lung injury mediated by antibodies to endothelium. I. In the rabbit a repeated interaction of heterologous anti-angiotensin-converting enzyme antibodies with alveolar endothelium results in resistance to immune injury through antigenic modulation

    PubMed Central

    1983-01-01

    To study the effects of relatively long-term interaction of antibodies with surface antigens of lung endothelium, rabbits were intravenously injected for a maximum of 4 d with goat anti-rabbit lung angiotensin- converting enzyme (Gt anti-RbACE) antibodies. On day 1 69%, on day 2 13%, and on days 3 and 4 of injection none of the rabbits developed lethal pulmonary edema. By immunofluorescence microscopy, deposits of GtIgG, frequently in association with RbC3, were found along the endothelium of alveolar capillary walls in all rabbits studied on day 1, in 57% on day 2, in 33% on day 3, and in none of them on day 4. While in vitro anti-ACE antibodies bound in a linear pattern to the lung endothelium, the binding pattern in vivo was distinctly granular. The in vivo interaction of antibodies with ACE also redistributed ACE in a granular pattern along capillary walls. In contrast to the granular deposition of injected anti-ACE IgG and F(ab')2 fragments of anti-ACE IgG, Fab fragments of anti-ACE IgG localized, without fixing C3, in a linear pattern along the endothelium of lung capillaries and did not modify the normal distribution of ACE. However, when the injection of Fab fragments of Gt anti-RbACE IgG was followed by an injection of Rb anti-GtIgG serum, granular deposits of Gt Fab fragments, RbIgG and RbC3 were seen along alveolar capillary walls. Biochemical measurement of ACE activity in lung homogenates provided data in agreement with those obtained by immunofluorescence microscopy, showing diminished activity to none on day 4, with some return of ACE activity on day 5, 24 h after the last injection of antibody, and normal values on day 21. The results obtained indicate that divalent antibodies to an antigen expressed on the plasma membrane of rabbit lung endothelial cells promotes a rapid redistribution of antigenic receptors, fixation of complement and, in surviving rabbits, disappearance of the antigen from the endothelial cells that are no longer susceptible to

  13. Absolute and allometric relationships between internal morphology and body mass in the adult collared peccary, Tayassu tajacu (Tayassuidae).

    PubMed

    Lochmiller, R L; Hellgren, E C; Grant, W E

    1986-01-01

    Selected morphological features of 8 adult male and 8 adult female collared peccaries (Tayassu tajacu) shot from southern Texas during March 1983 are described. A total of 16 adult peccaries with an average body mass of 18.68 +/- 0.61 (SE) Kg was examined. Significant differences between males and females were observed for absolute and relative mass of liver and lungs, and relative heart mass. These visceral organs were heavier among females than males. Significant sex effects were also found for absolute and relative mass of the dorsal scent gland. The dorsal scent gland contributed twice as much to total body mass in males as in females. No sexual dimorphisms of the gastrointestinal tract were noted. Females had a significantly greater portion of total visceral fat deposited around the kidneys than did males. Relative mass of the mandible was significantly greater in males than in females. Adult males had extremely large accessory sex glands. The bulbourethral and seminal vesicle glands comprised 0.27 per cent of the total body mass. Allometric growth coefficients (b) varied among the various organs and glands examined, ranging from below (eyes, b = 0.34) to well above (seminal vesicles, b = 1.87) unity. Growth coefficients of lungs, kidneys, pituitary gland, and thyroid gland during adulthood greatly exceeded respective values in developing nurslings.

  14. Expected indoor sup 222 Rn levels in counties with very high and very low lung cancer rates

    SciTech Connect

    Cohen, B.L. )

    1989-12-01

    Counties in the US with high lung cancer rates should have higher average {sup 222}Rn levels than counties with low lung cancer rates, assuming the average {sup 222}Rn level in a county is not correlated with other factors that cause lung cancer. The magnitude of this effect was calculated, using the absolute risk model, the relative risk model, and an intermediate model, for females who died in 1950-1969. The results were similar for all three models. We concluded that, ignoring migration, the average Rn level in the highest lung cancer counties should be about three times higher than in the lowest lung cancer counties according to the theory. Preliminary data are presented indicating that the situation is quite the opposite: The average Rn level in the highest lung cancer counties was only about one-half that in the lowest lung cancer counties.

  15. System and method for calibrating a rotary absolute position sensor

    NASA Technical Reports Server (NTRS)

    Davis, Donald R. (Inventor); Permenter, Frank Noble (Inventor); Radford, Nicolaus A (Inventor)

    2012-01-01

    A system includes a rotary device, a rotary absolute position (RAP) sensor generating encoded pairs of voltage signals describing positional data of the rotary device, a host machine, and an algorithm. The algorithm calculates calibration parameters usable to determine an absolute position of the rotary device using the encoded pairs, and is adapted for linearly-mapping an ellipse defined by the encoded pairs to thereby calculate the calibration parameters. A method of calibrating the RAP sensor includes measuring the rotary position as encoded pairs of voltage signals, linearly-mapping an ellipse defined by the encoded pairs to thereby calculate the calibration parameters, and calculating an absolute position of the rotary device using the calibration parameters. The calibration parameters include a positive definite matrix (A) and a center point (q) of the ellipse. The voltage signals may include an encoded sine and cosine of a rotary angle of the rotary device.

  16. Method and apparatus for two-dimensional absolute optical encoding

    NASA Technical Reports Server (NTRS)

    Leviton, Douglas B. (Inventor)

    2004-01-01

    This invention presents a two-dimensional absolute optical encoder and a method for determining position of an object in accordance with information from the encoder. The encoder of the present invention comprises a scale having a pattern being predetermined to indicate an absolute location on the scale, means for illuminating the scale, means for forming an image of the pattern; and detector means for outputting signals derived from the portion of the image of the pattern which lies within a field of view of the detector means, the field of view defining an image reference coordinate system, and analyzing means, receiving the signals from the detector means, for determining the absolute location of the object. There are two types of scale patterns presented in this invention: grid type and starfield type.

  17. Neural Sensitivity to Absolute and Relative Anticipated Reward in Adolescents

    PubMed Central

    Vaidya, Jatin G.; Knutson, Brian; O'Leary, Daniel S.; Block, Robert I.; Magnotta, Vincent

    2013-01-01

    Adolescence is associated with a dramatic increase in risky and impulsive behaviors that have been attributed to developmental differences in neural processing of rewards. In the present study, we sought to identify age differences in anticipation of absolute and relative rewards. To do so, we modified a commonly used monetary incentive delay (MID) task in order to examine brain activity to relative anticipated reward value (neural sensitivity to the value of a reward as a function of other available rewards). This design also made it possible to examine developmental differences in brain activation to absolute anticipated reward magnitude (the degree to which neural activity increases with increasing reward magnitude). While undergoing fMRI, 18 adolescents and 18 adult participants were presented with cues associated with different reward magnitudes. After the cue, participants responded to a target to win money on that trial. Presentation of cues was blocked such that two reward cues associated with $.20, $1.00, or $5.00 were in play on a given block. Thus, the relative value of the $1.00 reward varied depending on whether it was paired with a smaller or larger reward. Reflecting age differences in neural responses to relative anticipated reward (i.e., reference dependent processing), adults, but not adolescents, demonstrated greater activity to a $1 reward when it was the larger of the two available rewards. Adults also demonstrated a more linear increase in ventral striatal activity as a function of increasing absolute reward magnitude compared to adolescents. Additionally, reduced ventral striatal sensitivity to absolute anticipated reward (i.e., the difference in activity to medium versus small rewards) correlated with higher levels of trait Impulsivity. Thus, ventral striatal activity in anticipation of absolute and relative rewards develops with age. Absolute reward processing is also linked to individual differences in Impulsivity. PMID:23544046

  18. Neural sensitivity to absolute and relative anticipated reward in adolescents.

    PubMed

    Vaidya, Jatin G; Knutson, Brian; O'Leary, Daniel S; Block, Robert I; Magnotta, Vincent

    2013-01-01

    Adolescence is associated with a dramatic increase in risky and impulsive behaviors that have been attributed to developmental differences in neural processing of rewards. In the present study, we sought to identify age differences in anticipation of absolute and relative rewards. To do so, we modified a commonly used monetary incentive delay (MID) task in order to examine brain activity to relative anticipated reward value (neural sensitivity to the value of a reward as a function of other available rewards). This design also made it possible to examine developmental differences in brain activation to absolute anticipated reward magnitude (the degree to which neural activity increases with increasing reward magnitude). While undergoing fMRI, 18 adolescents and 18 adult participants were presented with cues associated with different reward magnitudes. After the cue, participants responded to a target to win money on that trial. Presentation of cues was blocked such that two reward cues associated with $.20, $1.00, or $5.00 were in play on a given block. Thus, the relative value of the $1.00 reward varied depending on whether it was paired with a smaller or larger reward. Reflecting age differences in neural responses to relative anticipated reward (i.e., reference dependent processing), adults, but not adolescents, demonstrated greater activity to a $1 reward when it was the larger of the two available rewards. Adults also demonstrated a more linear increase in ventral striatal activity as a function of increasing absolute reward magnitude compared to adolescents. Additionally, reduced ventral striatal sensitivity to absolute anticipated reward (i.e., the difference in activity to medium versus small rewards) correlated with higher levels of trait Impulsivity. Thus, ventral striatal activity in anticipation of absolute and relative rewards develops with age. Absolute reward processing is also linked to individual differences in Impulsivity. PMID:23544046

  19. Non-Invasive Method of Determining Absolute Intracranial Pressure

    NASA Technical Reports Server (NTRS)

    Yost, William T. (Inventor); Cantrell, John H., Jr. (Inventor); Hargens, Alan E. (Inventor)

    2004-01-01

    A method is presented for determining absolute intracranial pressure (ICP) in a patient. Skull expansion is monitored while changes in ICP are induced. The patient's blood pressure is measured when skull expansion is approximately zero. The measured blood pressure is indicative of a reference ICP value. Subsequently, the method causes a known change in ICP and measured the change in skull expansion associated therewith. The absolute ICP is a function of the reference ICP value, the known change in ICP and its associated change in skull expansion; and a measured change in skull expansion.

  20. Absolutely maximally entangled states, combinatorial designs, and multiunitary matrices

    NASA Astrophysics Data System (ADS)

    Goyeneche, Dardo; Alsina, Daniel; Latorre, José I.; Riera, Arnau; Życzkowski, Karol

    2015-09-01

    Absolutely maximally entangled (AME) states are those multipartite quantum states that carry absolute maximum entanglement in all possible bipartitions. AME states are known to play a relevant role in multipartite teleportation, in quantum secret sharing, and they provide the basis novel tensor networks related to holography. We present alternative constructions of AME states and show their link with combinatorial designs. We also analyze a key property of AME states, namely, their relation to tensors, which can be understood as unitary transformations in all of their bipartitions. We call this property multiunitarity.