Conjugated foldamers with unusually high space-charge-limited current hole mobilities.

PubMed

Li, Yong; Dutta, Tanmoy; Gerasimchuk, Nikolay; Wu, Shijie; Shetye, Kuldeep; Jin, Lu; Wang, Ruixin; Zhu, Da-Ming; Peng, Zhonghua

2015-05-13

Charge carrier mobility and its optimization play a critical role in the development of cutting-edge organic electronic and optoelectronic devices. Even though space-charge-limited current (SCLC) hole mobilities as high as 1.4 cm(2) V(-1) s(-1) have been reported for microscopically sized highly ordered liquid-crystalline conjugated small molecules, the SCLC hole mobility of device-sized thin films of conjugated polymers is still much lower, ranging from 10(-6) to 10(-3) cm(2) V(-1) s(-1). Herein, we report the synthesis, characterizations, and thin-film SCLC mobility of three discotic conjugated polymers, INDT-TT, INDT-BT, and INDT-NDT. Optical studies indicate that polymer INDT-NDT adopts a folded conformation in solutions of good or poor solvents, whereas polymer INDT-TT stays as random monomeric chains in good solvents and interchain aggregates in poor solvents. INDT-BT polymer chains, however, stay as foldamers in dilute solutions of good solvents but interchain aggregates in concentrated solutions or poor solvents. Circular dichroism spectroscopy provides clear evidence for the helical folding of INDT-NDT in solutions. Thin films spin-coated from 1,2-dichlorobenzene solutions of the polymers show SCLC hole mobility of 2.20 × 10(-6), 8.79 × 10(-5), and 2.77 × 10(-2) cm(2) V(-1) s(-1) for INDT-TT, INDT-BT, and INDT-NDT, respectively. HRTEM and powder XRD measurements show that INDT-NDT pristine thin films contain nanocrystalline domains, whereas the INDT-TT and INDT-BT films are amorphous. Thin films of INDT-NDT:PC71BM blends show increased crystallinity and further improved SCLC hole mobility up to 1.29 × 10(-1) cm(2) V(-1) s(-1), one of the highest SCLC mobility values ever recorded on solution-processed organic semiconducting thin films. The persistent folding conformation of INDT-NDT is believed to be responsible for the high crystallinity of its thin films and its high SCLC mobilities.

Comprehensive genomic profiles of small cell lung cancer

PubMed Central

George, Julie; Lim, Jing Shan; Jang, Se Jin; Cun, Yupeng; Ozretić, Luka; Kong, Gu; Leenders, Frauke; Lu, Xin; Fernández-Cuesta, Lynnette; Bosco, Graziella; Müller, Christian; Dahmen, Ilona; Jahchan, Nadine S.; Park, Kwon-Sik; Yang, Dian; Karnezis, Anthony N.; Vaka, Dedeepya; Torres, Angela; Wang, Maia Segura; Korbel, Jan O.; Menon, Roopika; Chun, Sung-Min; Kim, Deokhoon; Wilkerson, Matt; Hayes, Neil; Engelmann, David; Pützer, Brigitte; Bos, Marc; Michels, Sebastian; Vlasic, Ignacija; Seidel, Danila; Pinther, Berit; Schaub, Philipp; Becker, Christian; Altmüller, Janine; Yokota, Jun; Kohno, Takashi; Iwakawa, Reika; Tsuta, Koji; Noguchi, Masayuki; Muley, Thomas; Hoffmann, Hans; Schnabel, Philipp A.; Petersen, Iver; Chen, Yuan; Soltermann, Alex; Tischler, Verena; Choi, Chang-min; Kim, Yong-Hee; Massion, Pierre P.; Zou, Yong; Jovanovic, Dragana; Kontic, Milica; Wright, Gavin M.; Russell, Prudence A.; Solomon, Benjamin; Koch, Ina; Lindner, Michael; Muscarella, Lucia A.; la Torre, Annamaria; Field, John K.; Jakopovic, Marko; Knezevic, Jelena; Castaños-Vélez, Esmeralda; Roz, Luca; Pastorino, Ugo; Brustugun, Odd-Terje; Lund-Iversen, Marius; Thunnissen, Erik; Köhler, Jens; Schuler, Martin; Botling, Johan; Sandelin, Martin; Sanchez-Cespedes, Montserrat; Salvesen, Helga B.; Achter, Viktor; Lang, Ulrich; Bogus, Magdalena; Schneider, Peter M.; Zander, Thomas; Ansén, Sascha; Hallek, Michael; Wolf, Jürgen; Vingron, Martin; Yatabe, Yasushi; Travis, William D.; Nürnberg, Peter; Reinhardt, Christian; Perner, Sven; Heukamp, Lukas; Büttner, Reinhard; Haas, Stefan A.; Brambilla, Elisabeth; Peifer, Martin; Sage, Julien; Thomas, Roman K.

2016-01-01

We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Δex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer. PMID:26168399

Risk of brain metastases in patients with nonmetastatic lung cancer: Analysis of the Metropolitan Detroit Surveillance, Epidemiology, and End Results (SEER) data.

PubMed

Goncalves, Priscila H; Peterson, Stephanie L; Vigneau, Fawn D; Shore, Ronald D; Quarshie, William O; Islam, Khairul; Schwartz, Ann G; Wozniak, Antoinette J; Gadgeel, Shirish M

2016-06-15

Brain metastases (BM) remain an important cause of morbidity and mortality in patients with lung cancer. The current study evaluated population-based incidence and outcomes of BM in patients with nonmetastatic lung cancer. Patients diagnosed with nonmetastatic first primary lung cancer between 1973 and 2011 in the Metropolitan Detroit Surveillance, Epidemiology, and End Results (SEER) registry were used for the current analysis. Age-adjusted odds ratios of developing BM based on various demographic characteristics and histology were calculated with 95% confidence intervals. Adjusted Cox proportional hazard ratios and log-rank tests of Kaplan-Meier survival curves were calculated to evaluate survival differences for non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). The incidence of BM in patients with nonmetastatic NSCLC and SCLC was 9% and 18%, respectively. There was variation in the incidence of BM according to NCSLC histology. The incidence of BM was higher in patients aged <60 years for both NSCLC and SCLC, but there were no differences noted by race for either histological group. Female patients with NSCLC were more likely to have BM than male patients. There was variation in the proportion of BM in both patients with NSCLC and SCLC over the three 13-year periods of diagnosis. The risk of death (hazard ratio) was found to be significantly higher for patients with NSCLC with BM, but was not significantly higher in patients with SCLC with BM. The incidence of BM in patients with nonmetastatic lung cancer varies according to histology, age, and sex. BM are associated with worse survival for patients with NSCLC but not those with SCLC. Cancer 2016;122:1921-7. © 2016 American Cancer Society. © 2016 American Cancer Society.

A Primary Xenograft Model of Small Cell Lung Cancer Reveals Irreversible Changes in Gene Expression Imposed by Culture In-Vitro

PubMed Central

Daniel, Vincent C.; Marchionni, Luigi; Hierman, Jared S.; Rhodes, Jonathan T.; Devereux, Wendy L.; Rudin, Charles M.; Yung, Rex; Parmigani, Giovanni; Dorsch, Marion; Peacock, Craig D.; Watkins, D. Neil

2009-01-01

Traditional approaches to the preclinical investigation of cancer therapies rely on the use of established cell lines maintained in serum-based growth media. This is particularly true of small cell lung cancer (SCLC), where surgically resected tissue is rarely available. Recent attention has focused on the need for better models that preserve the integrity of cancer stem cell populations, as well as three-dimensional tumor-stromal interactions. Here we describe a primary xenograft model of SCLC in which endobronchial tumor specimens obtained from chemo-naive patients are serially propagated in vivo in immunodeficient mice. In parallel, cell lines grown in conventional tissue culture conditions were derived from each xenograft line, passaged for 6 months, and then re-implanted to generate secondary xenografts. Using the Affymetrix platform, we analyzed gene expression in primary xenograft, xenograft-derived cell line, and secondary xenograft, and compared these data to similar analyses of unrelated primary SCLC samples and laboratory models. When compared to normal lung, primary tumors, xenografts and cell lines displayed a gene expression signature specific for SCLC. Comparison of gene expression within the xenograft model identified a group of tumor-specific genes expressed in primary SCLC and xenografts that was lost during the transition to tissue culture, and that was not regained when the tumors were re-established as secondary xenografts. Such changes in gene expression may be a common feature of many cancer cell culture systems, with functional implications for the use of such models for preclinical drug development. PMID:19351829

Genetically engineered humanized anti-ganglioside GM2 antibody against multiple organ metastasis produced by GM2-expressing small-cell lung cancer cells.

PubMed

Yamada, Tadaaki; Bando, Hideaki; Takeuchi, Shinji; Kita, Kenji; Li, Qi; Wang, Wei; Akinaga, Shiro; Nishioka, Yasuhiko; Sone, Saburo; Yano, Seiji

2011-12-01

Small-cell lung cancer (SCLC) grows rapidly and metastasizes to multiple organs. We examined the antimetastatic effects of the humanized anti-ganglioside GM2 (GM2) antibodies, BIW-8962 and KM8927, compared with the chimeric antibody KM966, in a SCID mouse model of multiple organ metastases induced by GM2-expressing SCLC cells. BIW-8962 and KM8927 induced higher antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity than KM966 against the GM2-expressing SCLC cell line SBC-3 in vitro. These humanized antibodies inhibited the production of multiple organ metastases, increased the number of apoptotic cells, and prolonged the survival of the SCID mice. Histological analyses using clinical specimens showed that SCLC cells expressed GM2. These findings suggest that humanized anti-GM2 antibodies could be therapeutically useful for controlling multiple organ metastases of GM2-expressing SCLC. © 2011 Japanese Cancer Association.

Hypotonic activation of short ClC3 isoform is modulated by direct interaction between its cytosolic C-terminal tail and subcortical actin filaments.

PubMed

McCloskey, Diana T; Doherty, Lynda; Dai, Yan-Ping; Miller, Lisa; Hume, Joseph R; Yamboliev, Ilia A

2007-06-08

Short ClC3 isoform (sClC3) functions as a volume-sensitive outwardly rectifying anion channel (VSOAC) in some cell types. In previous studies, we have shown that the hypotonic activation of sClC3 is linked to cell swelling-mediated remodeling of the actin cytoskeleton. In the present study, we have tested the hypothesis that the cytosolic tails of sClC3 bind to actin directly and that binding modulates the hypotonic activation of the channel. Co-sedimentation assays in vitro demonstrated a strong binding between the glutathione S-transferase-fused cytosolic C terminus of sClC3 (GST-sClC3-CT) to filamentous actin (F-actin) but not to globular monomeric actin (G-actin). The GST-fused N terminus (GST-sClC3-NT) exhibited low binding affinity to both G- and F-actin. Co-sedimentation experiments with progressively truncated GST-sClC3-CT indicated that the F-actin binding region is located between amino acids 690 and 760 of sClC3. Two synthetic peptides mapping basic clusters of the cytosolic sClC3-CT (CTP2, isoleucine 716 to leucine 734; and CTP3, proline 688 to proline 709) prevented binding of GST-sClC3-CT to F-actin in vitro. Dialysis into NIH/3T3 cells of these two peptides (but not of synthetic peptide CTP1 (isoleucine 737 to glutamine 748)) reduced the maximal current density by 60 and 38%, respectively. Based on these results, we have concluded that, by direct interaction with subcortical actin filaments, sClC3 contributes to the hypotonic stress-induced VSOACs in NIH/3T3 cells.

Modeling small cell lung cancer (SCLC) biology through deterministic and stochastic mathematical models.

PubMed

Salgia, Ravi; Mambetsariev, Isa; Hewelt, Blake; Achuthan, Srisairam; Li, Haiqing; Poroyko, Valeriy; Wang, Yingyu; Sattler, Martin

2018-05-25

Mathematical cancer models are immensely powerful tools that are based in part on the fractal nature of biological structures, such as the geometry of the lung. Cancers of the lung provide an opportune model to develop and apply algorithms that capture changes and disease phenotypes. We reviewed mathematical models that have been developed for biological sciences and applied them in the context of small cell lung cancer (SCLC) growth, mutational heterogeneity, and mechanisms of metastasis. The ultimate goal is to develop the stochastic and deterministic nature of this disease, to link this comprehensive set of tools back to its fractalness and to provide a platform for accurate biomarker development. These techniques may be particularly useful in the context of drug development research, such as combination with existing omics approaches. The integration of these tools will be important to further understand the biology of SCLC and ultimately develop novel therapeutics.

Dc and ac electrical response of MOCVD grown GaN in p-i-n structure, assessed through I-V and admittance measurement

NASA Astrophysics Data System (ADS)

Ayarcı Kuruoğlu, Neslihan; Özdemir, Orhan; Bozkurt, Kutsal; Sundaram, Suresh; Salvestrini, Jean-Paul; Ougazzaden, Abdallah; Gaimard, Quentin; Belahsene, Sofiane; Merghem, Kamel; Ramdane, Abderrahim

2017-12-01

The electrical response of gallium nitride (GaN), produced through metal-organic chemical vapor deposition in a p-i-n structure was investigated through temperature-dependent current-voltage (I-V) and admittance measurement. The I-V curves showed double diode behavior together with several distinct regions in which trap-assisted tunnelling current has been identified at low and moderate forward/reverse direction and space charge limited current (SCLC) at large forward/reverse bias. The value of extracted energy (˜200 meV in forward and  ˜70 meV in reverse direction) marked the tunnelling entity as electron and heavy hole in the present structure. These values were also obtained in space charge limited regime and considered as minority carriers which might originate the experimentally observed negative capacitance issue at low frequencies over the junction under both forward and reverse bias directions. Analytically derived expression for the admittance in the revised versions of SCLC model was also applied to explain the inductance effect, yielding good fits to the experimentally measured admittance data.

A framework for identification of actionable cancer genome dependencies in small cell lung cancer

PubMed Central

Sos, Martin L.; Dietlein, Felix; Peifer, Martin; Schöttle, Jakob; Balke-Want, Hyatt; Müller, Christian; Koker, Mirjam; Richters, André; Heynck, Stefanie; Malchers, Florian; Heuckmann, Johannes M.; Seidel, Danila; Eyers, Patrick A.; Ullrich, Roland T.; Antonchick, Andrey P.; Vintonyak, Viktor V.; Schneider, Peter M.; Ninomiya, Takashi; Waldmann, Herbert; Büttner, Reinhard; Rauh, Daniel; Heukamp, Lukas C.; Thomas, Roman K.

2012-01-01

Small cell lung cancer (SCLC) accounts for about 15% of all lung cancers. The prognosis of SCLC patients is devastating and no biologically targeted therapeutics are active in this tumor type. To develop a framework for development of specific SCLC-targeted drugs we conducted a combined genomic and pharmacological vulnerability screen in SCLC cell lines. We show that SCLC cell lines capture the genomic landscape of primary SCLC tumors and provide genetic predictors for activity of clinically relevant inhibitors by screening 267 compounds across 44 of these cell lines. We show Aurora kinase inhibitors are effective in SCLC cell lines bearing MYC amplification, which occur in 3–7% of SCLC patients. In MYC-amplified SCLC cells Aurora kinase inhibition associates with G2/M-arrest, inactivation of PI3-kinase (PI3K) signaling, and induction of apoptosis. Aurora dependency in SCLC primarily involved Aurora B, required its kinase activity, and was independent of depletion of cytoplasmic levels of MYC. Our study suggests that a fraction of SCLC patients may benefit from therapeutic inhibition of Aurora B. Thus, thorough chemical and genomic exploration of SCLC cell lines may provide starting points for further development of rational targeted therapeutic intervention in this deadly tumor type. PMID:23035247

Characterization of the cell of origin for small cell lung cancer

PubMed Central

Park, Kwon-Sik; Liang, Mei-Chih; Raiser, David M; Zamponi, Raffaella; Roach, Rebecca R; Curtis, Stephen J; Walton, Zandra; Schaffer, Bethany E; Roake, Caitlin M; Zmoos, Anne-Flore; Kriegel, Christina; Wong, Kwok-Kin

2011-01-01

Small cell lung carcinoma (SCLC) is a neuroendocrine subtype of lung cancer that affects more than 200,000 people worldwide every year with a very high mortality rate. Here, we used a mouse genetics approach to characterize the cell of origin for SCLC; in this mouse model, tumors are initiated by the deletion of the Rb and p53 tumor suppressor genes in the lung epithelium of adult mice. We found that mouse SCLCs often arise in the lung epithelium, where neuroendocrine cells are located, and that the majority of early lesions were composed of proliferating neuroendocrine cells. In addition, mice in which Rb and p53 are deleted in a variety of non-neuroendocrine lung epithelial cells did not develop SCLC. These data indicate that SCLC likely arises from neuroendocrine cells in the lung. PMID:21822053

ERK phosphorylation is predictive of resistance to IGF-1R inhibition in Small Cell Lung Cancer

PubMed Central

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

2013-01-01

New therapies are critically needed to improve the outcome for patients with small cell lung cancer (SCLC). 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 PI3K-Akt and MAPK. 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 (IR). Approximately one third of these cell lines were sensitive to OSI-906, with an IC50 < 1 μM. 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 to 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

Axial p-n junction and space charge limited current in single GaN nanowire.

PubMed

Fang, Zhihua; Donatini, Fabrice; Daudin, Bruno; Pernot, Julien

2018-01-05

The electrical characterizations of individual basic GaN nanostructures, such as axial nanowire (NW) p-n junctions, are becoming indispensable and crucial for the fully controlled realization of GaN NW based devices. In this study, electron beam induced current (EBIC) measurements were performed on two single axial GaN p-n junction NWs grown by plasma-assisted molecular beam epitaxy. I-V characteristics revealed that both ohmic and space charge limited current (SCLC) regimes occur in GaN p-n junction NW. Thanks to an improved contact process, both the electric field induced by the p-n junction and the SCLC in the p-part of GaN NW were disclosed and delineated by EBIC signals under different biases. Analyzing the EBIC profiles in the vicinity of the p-n junction under 0 V and reverse bias, we deduced a depletion width in the range of 116-125 nm. Following our previous work, the acceptor N a doping level was estimated to be 2-3 × 10 17 at cm -3 assuming a donor level N d of 2-3 × 10 18 at cm -3 . The hole diffusion length in n-GaN was determined to be 75 nm for NW #1 and 43 nm for NW #2, demonstrating a low surface recombination velocity at the m-plane facet of n-GaN NW. Under forward bias, EBIC imaging visualized the electric field induced by the SCLC close to p-side contact, in agreement with unusual SCLC previously reported in GaN NWs.

Axial p-n junction and space charge limited current in single GaN nanowire

NASA Astrophysics Data System (ADS)

Fang, Zhihua; Donatini, Fabrice; Daudin, Bruno; Pernot, Julien

2018-01-01

The electrical characterizations of individual basic GaN nanostructures, such as axial nanowire (NW) p-n junctions, are becoming indispensable and crucial for the fully controlled realization of GaN NW based devices. In this study, electron beam induced current (EBIC) measurements were performed on two single axial GaN p-n junction NWs grown by plasma-assisted molecular beam epitaxy. I-V characteristics revealed that both ohmic and space charge limited current (SCLC) regimes occur in GaN p-n junction NW. Thanks to an improved contact process, both the electric field induced by the p-n junction and the SCLC in the p-part of GaN NW were disclosed and delineated by EBIC signals under different biases. Analyzing the EBIC profiles in the vicinity of the p-n junction under 0 V and reverse bias, we deduced a depletion width in the range of 116-125 nm. Following our previous work, the acceptor N a doping level was estimated to be 2-3 × 1017 at cm-3 assuming a donor level N d of 2-3 × 1018 at cm-3. The hole diffusion length in n-GaN was determined to be 75 nm for NW #1 and 43 nm for NW #2, demonstrating a low surface recombination velocity at the m-plane facet of n-GaN NW. Under forward bias, EBIC imaging visualized the electric field induced by the SCLC close to p-side contact, in agreement with unusual SCLC previously reported in GaN NWs.

Probing of barrier induced deviations in current-voltage characteristics of polymer devices by impedance spectroscopy

NASA Astrophysics Data System (ADS)

Khan, Motiur Rahman; Rao, K. S. R. Koteswara; Menon, R.

2017-05-01

Temperature dependent current-voltage measurements have been performed on poly(3-methylthiophene) based devices in metal/polymer/metal geometry in temperature range 90-300 K. Space charge limited current (SCLC) controlled by exponentially distributed traps is observed at all the measured temperatures at intermediate voltage range. At higher voltages, trap-free SCLC is observed at 90 K only while slope less than 2 is observed at higher temperatures which is quiet unusual in polymer devices. Impedance measurements were performed at different bias voltages. The unusual behavior observed in current-voltage characteristics is explained by Cole-Cole plot which gives the signature of interface dipole on electrode/polymer interface. Two relaxation mechanisms are obtained from the real part of impedance vs frequency spectra which confirms the interface related phenomena in the device

Tract-based Spatial Statistics and fMRI Analysis in Patients with Small Cell Lung Cancer before Prophylactic Cranial Irradiation

NASA Astrophysics Data System (ADS)

Benezi, S.; Bromis, K.; Karavasilis, E.; Karanasiou, I. S.; Koutsoupidou, M.; Matsopoulos, G.; Ventouras, E.; Uzunoglu, N.; Kouloulias, V.; Papathanasiou, M.; Foteineas, A.; Efstathopoulos, E.; Kelekis, N.; Kelekis, D.

2015-09-01

Prophylactic cranial irradiation (PCI) is known to increase life expectancy to a significant degree in Small Cell Lung Cancer (SCLC) patients. The overall scope of this research is to investigate changes in structural and functional connectivity between SCLC patients and controls before and after PCI treatment. In the current study specifically we use diffusion tensor imaging (DTI) and functional Magnetic Resonance (fMRI) to identify potential alterations in white matter structure and brain function respectively, in SCLC patients before PCI compared to healthy participants. The results in DTI analysis have showed lower fractional anisotropy (FA) and higher eigenvalues in white matter regions in the patient group. Similarly, in fMRI analysis a lower level of activation in the primary somatosensory cortex was reported. The results presented herein are subject to further investigation with larger patient and control groups.

Poly(beta-amino ester) nanoparticle-delivery of p53 has activity against small cell lung cancer in vitro and in vivo

PubMed Central

Kamat, Chandrashekhar D.; Shmueli, Ron B.; Connis, Nick; Rudin, Charles M.; Green, Jordan J.; Hann, Christine L.

2013-01-01

Small cell lung cancer (SCLC) is an aggressive disease with one of the highest case-fatality rates among cancer. The recommended therapy for SCLC has not changed significantly over the past 30 years; new therapeutic approaches are a critical need. TP53 is mutated in the majority of SCLC cases and its loss is required in transgenic mouse models of the disease. We synthesized an array of biodegradable poly(beta-amino ester) (PBAE) polymers which self-assemble with DNA and assayed for transfection efficiency in the p53-mutant H446 SCLC cell line using high-throughput methodologies. Two of the top candidates were selected for further characterization and TP53 delivery in vitro and in vivo. Nanoparticle delivery of TP53 resulted in expression of exogenous p53, induction of p21, induction of apoptosis and accumulation of cells in sub-G1 consistent with functional p53 activity. Intratumoral injection of subcutaneous H446 xenografts with polymers carrying TP53 caused marked tumor growth inhibition. This is the first demonstration of TP53 gene therapy in SCLC using non-viral polymeric nanoparticles. This technology may have general applicability as a novel anti-cancer strategy based on restoration of tumor suppressor gene function. PMID:23364678

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. ©2013 AACR

A Multicenter Pilot Study Examining the Role of Circulating Tumor Cells as a Blood-Based Tumor Marker in Patients with Extensive Small-Cell Lung Cancer

PubMed Central

Huang, Chao H.; Wick, Jo A.; Sittampalam, Gurusingham Sitta; Nirmalanandhan, Victor Sanjit; Ganti, Apar Kishor; Neupane, Prakash C.; Williamson, Stephen K.; Godwin, Andrew K.; Schmitt, Sarah; Smart, Nora J.; Spencer, Sarah; Van Veldhuizen, Peter J.

2014-01-01

Background: Small-cell lung cancer (SCLC), a variant of lung cancer marked by early metastases, accounts for 13% of all lung cancers diagnosed in US. Despite high response rates to treatment, it is an aggressive disease with a median survival of 9–11 months for patients with extensive stage (EX-SCLC). Detection of circulating tumor cells (CTCs) is a novel laboratory technique currently in use to determine response to therapy and to predict prognosis in breast, colorectal, and prostate cancer. We initiated a pilot study to analyze the role of CTCs as a biomarker of response and relapse in patients with EX-SCLC. Methods: We collected blood samples from chemotherapy naïve patients with EX-SCLC prior to initiation of therapy, after completion of systemic therapy, and follow-up every 6–8 weeks and at relapse. The number of CTCs was determined using the cell search system in a central laboratory. The study was conducted in four different sites, and it was reviewed and approved by respective research review committees and IRBs. Results: We enrolled 26 patients with EX-SCLC, 1 was excluded due to ineligibility, all were treated with platinum and etoposide. We observed partial response in 16 patients, stable disease in 3 patients, 1 patient with disease progression, and 6 patients were not assessed (5 deceased, 1 not available). The overall median number of CTCs in 24 patients measured at baseline and post-tx was 75 (range 0–3430) and 2 (range 0–526), respectively. A significant reduction in CTCs from baseline to post-treatment was identified for 15 subjects; the median reduction was 97.4% (range −100 to +100%, p < 0.001). Higher baseline CTCs and percentage change in post-treatment CTCs were associated with decreased survival. Conclusion: We demonstrated that it is feasible to detect CTCs in EX-SCLC. If validated in other prospective studies, CTCs could be a useful biomarker in the management of EX-SCLC by predicting patients’ clinical responses to therapy. PMID:25353007

MicroRNA-138 Regulates DNA Damage Response in Small Cell Lung Cancer Cells by Directly Targeting H2AX.

PubMed

Yang, Huan; Luo, Jinwen; Liu, Zhiguang; Zhou, Rui; Luo, Hong

2015-04-01

Lung cancer is the leading cause of cancer death worldwide and small cell lung cancer (SCLC) accounts for a significant proportion of all lung cancer cases. Even so, the underlying mechanism governing SCLC development remains poorly understood and SCLC related cancer death stands high despite decades of intensive investigation. We noted that both miR-138 and H2AX have been implicated in development of various malignancies. Also, there is a recent report showing the role of miR-138 in mediating DNA damage response by targeting H2AX. In light of these data, we sought to characterize the role of miR-138 for SCLC cell growth and cell-cycle progression by regulating H2AX expression. Results showed that miR-138 is significantly down-regulated in SCLC tumor tissues as well as in three SCLC cell lines. After successfully engineering miR-138 overexpression in one of the SCLC cell lines, NCI-H2081, we observed a remarkable reduction of cell growth and a significant inhibition on cell-cycle progression. Moreover, we were able to show that miR-138 potently inhibits H2AX expression, which suggests that H2AX may serve as a downstream executor for miR-138. Consistent with this hypothesis, we found that engineered H2AX knockdown achieves a similar effect as observed for miR-138 overexpression in terms of SCLC growth and cell cycle regulation. We also showed that H2AX overexpression largely abolished miR-138-mediated SCLC cancer cell growth and cell-cycle progression inhibition, which strongly suggests, at least in vitro, that miR-138 potently regulates SCLC development by targeting H2AX. In addition, we found lower miR-138 expression confers SCLC cells with greater DNA damage repair capacity. Finally, we were able to show miR-138 overexpression inhibits DNA damage repair in SCLC cells while miR-138 knockdown further facilitates DNA damage repair in these cells after IR. To date, there has been no study showing the role of miR-138/H2AX machinery in SCLC development. Our results may shed a light to development of new lines of SCLC diagnosis and treatment approaches.

SU-F-R-54: CT-Texture Based Early Tumor Treatment Response Assessment During Radiation Therapy Delivery: Small Cell Versus Non-Small Cell Lung Cancers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Paul, J; Gore, E; Li, X

Purpose: Tumor treatment response may potentially be assessed during radiation therapy (RT) by analyzing changes in CT-textures. We investigated the different early RT-responses between small cell (SCLC) and non-small cell lung cancer (NSCLC) as assessed by CT-texture. Methods: Daily diagnostic-quality CT acquired during routine CT-guided RT using a CT-on-Rails for 13-NSCLC and 5-SCLC patients were analyzed. These patient had ages ranging from 45–78 and 38–63 years, respectively, for NSCLC and SCLC groups, and tumor-stages ranging from T2-T4, and were treated with either RT or chemotherapy and RT with 45–66Gy/ 20–34 fractions. Gross-tumor volume (GTV) contour was generated on each dailymore » CT by populating GTV contour from simulation to daily CTs with manual editing if necessary. CT-texture parameters, such as Hounsfield Unit (HU) histogram, mean HU, skewness, kurtosis, entropy, and short-run high-gray level emphasis (SRHGLE), were calculated in GTV from each daily CT-set using an in house software tool. Difference in changes of these texture parameters during RT between NSCLC and SCLC was analyzed and compared with GTV volume changes. Results: Radiation-induced changes in CT-texture were different between SCLC and NSCLC. Average changes from first to the last fractions for NSCLC and SCLC in GTV were 28±10(12–44) and 30±15(11–47) HU (mean HU reduction), 12.7% and 18.3% (entropy), 50% and 55% (SRHGLE), 19% and 22% (kurtosis), and 5.2% and 22% (skewness), respectively. Good correlation in kurtosis changes and GTV was seen (R{sup 2}=0.8923) for SCLC, but not for NSCLC (R{sup 2}=0.4748). SCLC had better correlations between GTV volume reduction and entropy (SCLC R{sup 2}=0.847; NSCLC R{sup 2}=0.6485), skewness (SCLC R{sup 2}=0.935; NSCLC R{sup 2}=0.7666), or SRHGLE (SCLC R{sup 2}=0.9619; NSCLC R{sup 2}=0.787). Conclusion: NSCLC and SCLC exhibited different early RT-responses as assessed by CT-texture changes during RT-delivery. The observed larger changes in various CT-texture parameters for SCLC indicate that SCLC may respond to RT more rapid than NSCLC.« less

The Antitumor Effect of C-terminus of Hsp70-Interacting Protein via Degradation of c-Met in Small Cell Lung Cancer.

PubMed

Cho, Sung Ho; Kim, Jong In; Kim, Hyun Su; Park, Sung Dal; Jang, Kang Won

2017-06-01

The mesenchymal-epithelial transition factor (MET) receptor can be overexpressed in solid tumors, including small cell lung cancer (SCLC). However, the molecular mechanism regulating MET stability and turnover in SCLC remains undefined. One potential mechanism of MET regulation involves the C-terminus of Hsp70-interacting protein (CHIP), which targets heat shock protein 90-interacting proteins for ubiquitination and proteasomal degradation. In the present study, we investigated the functional effects of CHIP expression on MET regulation and the control of SCLC cell apoptosis and invasion. To evaluate the expression of CHIP and c-Met, which is a protein that in humans is encoded by the MET gene (the MET proto-oncogene), we examined the expression pattern of c-Met and CHIP in SCLC cell lines by western blotting. To investigate whether CHIP overexpression reduced cell proliferation and invasive activity in SCLC cell lines, we transfected cells with CHIP and performed a cell viability assay and cellular apoptosis assays. We found an inverse relationship between the expression of CHIP and MET in SCLC cell lines (n=5). CHIP destabilized the endogenous MET receptor in SCLC cell lines, indicating an essential role for CHIP in the regulation of MET degradation. In addition, CHIP inhibited MET-dependent pathways, and invasion, cell growth, and apoptosis were reduced by CHIP overexpression in SCLC cell lines. CHIP is capable of regulating SCLC cell apoptosis and invasion by inhibiting MET-mediated cytoskeletal and cell survival pathways in NCI-H69 cells. CHIP suppresses MET-dependent signaling, and regulates MET-mediated SCLC motility.

Effective growth-suppressive activity of maternal embryonic leucine-zipper kinase (MELK) inhibitor against small cell lung cancer.

PubMed

Inoue, Hiroyuki; Kato, Taigo; Olugbile, Sope; Tamura, Kenji; Chung, Suyoun; Miyamoto, Takashi; Matsuo, Yo; Salgia, Ravi; Nakamura, Yusuke; Park, Jae-Hyun

2016-03-22

Maternal embryonic leucine zipper kinase (MELK), that plays a critical role in maintenance of cancer stem cells (CSCs), is predominantly expressed in various types of human cancer including small cell lung cancer (SCLC). SCLC usually acquires resistance to anti-cancer drugs and portends dismal prognosis. We have delineated roles of MELK in development/progression of SCLC and examined anti-tumor efficacy of OTS167, a highly potent MELK inhibitor, against SCLC. MELK expression was highly upregulated in both SCLC cell lines and primary tumors. siRNA-mediated MELK knockdown induced significant growth inhibition in SCLC cell lines. Concordantly, treatment with OTS167 exhibited strong cytotoxicity against eleven SCLC cell lines with IC50 of < 10 nM. As similar to siRNA knockdown, OTS167 treatment induced cytokinetic defects with intercellular bridges, and in some cell lines we observed formation of neuronal protrusions accompanied with increase of a neuronal differentiation marker (CD56), indicating that the compound induced differentiation of cancer cells to neuron-like cells. Furthermore, the MELK inhibition decreased its downstream FOXM1 activity and Akt expression in SCLC cells, and led to apoptotic cell death. OTS167 appeared to be more effective to CSCs as measured by the sphere formation assay, thus MELK inhibition might become a promising treatment modality for SCLC.

Venetoclax Is Effective in Small-Cell Lung Cancers with High BCL-2 Expression.

PubMed

Lochmann, Timothy L; Floros, Konstantinos V; Naseri, Mitra; Powell, Krista M; Cook, Wade; March, Ryan J; Stein, Giovanna T; Greninger, Patricia; Maves, Yuki Kato; Saunders, Laura R; Dylla, Scott J; Costa, Carlotta; Boikos, Sosipatros A; Leverson, Joel D; Souers, Andrew J; Krystal, Geoffrey W; Harada, Hisashi; Benes, Cyril H; Faber, Anthony C

2018-01-15

Purpose: Small-cell lung cancer (SCLC) is an often-fatal neuroendocrine carcinoma usually presenting as extensive disease, carrying a 3% 5-year survival. Despite notable advances in SCLC genomics, new therapies remain elusive, largely due to a lack of druggable targets. Experimental Design: We used a high-throughput drug screen to identify a venetoclax-sensitive SCLC subpopulation and validated the findings with multiple patient-derived xenografts of SCLC. Results: Our drug screen consisting of a very large collection of cell lines demonstrated that venetoclax, an FDA-approved BCL-2 inhibitor, was found to be active in a substantial fraction of SCLC cell lines. Venetoclax induced BIM-dependent apoptosis in vitro and blocked tumor growth and induced tumor regressions in mice bearing high BCL-2-expressing SCLC tumors in vivo BCL-2 expression was a predictive biomarker for sensitivity in SCLC cell lines and was highly expressed in a subset of SCLC cell lines and tumors, suggesting that a substantial fraction of patients with SCLC could benefit from venetoclax. Mechanistically, we uncover a novel role for gene methylation that helped discriminate high BCL-2-expressing SCLCs. Conclusions: Altogether, our findings identify venetoclax as a promising new therapy for high BCL-2-expressing SCLCs. Clin Cancer Res; 24(2); 360-9. ©2017 AACR . ©2017 American Association for Cancer Research.

Effective growth-suppressive activity of maternal embryonic leucine-zipper kinase (MELK) inhibitor against small cell lung cancer

PubMed Central

Inoue, Hiroyuki; Kato, Taigo; Olugbile, Sope; Tamura, Kenji; Chung, Suyoun; Miyamoto, Takashi; Matsuo, Yo; Salgia, Ravi; Nakamura, Yusuke; Park, Jae-Hyun

2016-01-01

Maternal embryonic leucine zipper kinase (MELK), that plays a critical role in maintenance of cancer stem cells (CSCs), is predominantly expressed in various types of human cancer including small cell lung cancer (SCLC). SCLC usually acquires resistance to anti-cancer drugs and portends dismal prognosis. We have delineated roles of MELK in development/progression of SCLC and examined anti-tumor efficacy of OTS167, a highly potent MELK inhibitor, against SCLC. MELK expression was highly upregulated in both SCLC cell lines and primary tumors. siRNA-mediated MELK knockdown induced significant growth inhibition in SCLC cell lines. Concordantly, treatment with OTS167 exhibited strong cytotoxicity against eleven SCLC cell lines with IC50 of < 10 nM. As similar to siRNA knockdown, OTS167 treatment induced cytokinetic defects with intercellular bridges, and in some cell lines we observed formation of neuronal protrusions accompanied with increase of a neuronal differentiation marker (CD56), indicating that the compound induced differentiation of cancer cells to neuron-like cells. Furthermore, the MELK inhibition decreased its downstream FOXM1 activity and Akt expression in SCLC cells, and led to apoptotic cell death. OTS167 appeared to be more effective to CSCs as measured by the sphere formation assay, thus MELK inhibition might become a promising treatment modality for SCLC. PMID:26871945

Two Novel Determinants of Etoposide Resistance in Small Cell Lung Cancer

PubMed Central

Lawson, Malcolm H; Cummings, Natalie M; Rassl, Doris M; Russell, Roslin; Brenton, James D; Rintoul, Robert C; Murphy, Gillian

2011-01-01

Patient survival in small cell lung cancer (SCLC) is limited by acquired chemoresistance. Here we report the use of a biologically relevant model to identify novel candidate genes mediating in vivo acquired resistance to etoposide. Candidate genes derived from a cDNA microarray analysis were cloned and transiently overexpressed to evaluate their potential functional roles. We identified two promising genes in the DNA repair enzyme DNA Polymerase β and in the neuroendocrine transcription factor NKX2.2. Specific inhibition of DNA Polymerase β reduced the numbers of cells surviving treatment with etoposide and increased the amount of DNA damage in cells. Conversely, stable overexpression of NKX2.2 increased cell survival in response to etoposide in SCLC cell lines. Consistent with these findings, we found that an absence of nuclear staining for NKX2.2 in SCLC primary tumors was an independent predictor of improved outcomes in chemotherapy-treated patients. Taken together, our findings justify future prospective studies to confirm the roles of these molecules in mediating chemotherapy resistance in SCLC. PMID:21642373

Noninvasive Interrogation of DLL3 Expression in Metastatic Small Cell Lung Cancer.

PubMed

Sharma, Sai Kiran; Pourat, Jacob; Abdel-Atti, Dalya; Carlin, Sean D; Piersigilli, Alessandra; Bankovich, Alexander J; Gardner, Eric E; Hamdy, Omar; Isse, Kumiko; Bheddah, Sheila; Sandoval, Joseph; Cunanan, Kristen M; Johansen, Eric B; Allaj, Viola; Sisodiya, Vikram; Liu, David; Zeglis, Brian M; Rudin, Charles M; Dylla, Scott J; Poirier, John T; Lewis, Jason S

2017-07-15

The Notch ligand DLL3 has emerged as a novel therapeutic target expressed in small cell lung cancer (SCLC) and high-grade neuroendocrine carcinomas. Rovalpituzumab teserine (Rova-T; SC16LD6.5) is a first-in-class DLL3-targeted antibody-drug conjugate with encouraging initial safety and efficacy profiles in SCLC in the clinic. Here we demonstrate that tumor expression of DLL3, although orders of magnitude lower in surface protein expression than typical oncology targets of immunoPET, can serve as an imaging biomarker for SCLC. We developed 89 Zr-labeled SC16 antibody as a companion diagnostic agent to facilitate selection of patients for treatment with Rova-T based on a noninvasive interrogation of the in vivo status of DLL3 expression using PET imaging. Despite low cell-surface abundance of DLL3, immunoPET imaging with 89 Zr-labeled SC16 antibody enabled delineation of subcutaneous and orthotopic SCLC tumor xenografts as well as distant organ metastases with high sensitivity. Uptake of the radiotracer in tumors was concordant with levels of DLL3 expression and, most notably, DLL3 immunoPET yielded rank-order correlation for response to SC16LD6.5 therapy in SCLC patient-derived xenograft models. Cancer Res; 77(14); 3931-41. ©2017 AACR . ©2017 American Association for Cancer Research.

Overexpression of pro-gastrin releasing peptide promotes the cell proliferation and progression in small cell lung cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gong, Zhiyun; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032; Lu, Renquan

Pro-gastrin releasing peptide (ProGRP) plays the role of oncogene in small cell lung cancer (SCLC). In this study, we aim to explore the biological function of ProGRP in SCLC cells and its potential mechanism. Expression of ProGRP in SCLC tissues and cell lines were detected by immunohistochemistry and western blot analysis, respectively. The transduced cell lines with ProGRP down-regulation were established using RNA interference technology. Cell viability, cologenic, apoptosis-associated assay and the biomarker levels determination for cell supernatant were performed in the transduced cells to elucidate the biological functions and mechanisms of ProGRP in SCLC cells. Our data showed thatmore » ProGRP protein was demonstrated a higher level in SCLC tissues and cells compared with the control, and its diagnostic efficiency was better than NSE, further, the higher levels of ProGRP were detected in the patients with extensive disease stage (P < 0.05), were also the unfavorable factor to the prognosis of SCLC patients. Additionally, the concentration of serum ProGRP is a useful biomarker in disease-monitoring of the patients with SCLC. Down-regulation of ProGRP significantly reduced SCLC cell growth, repressed colony formation, but increased cancer cell apoptosis. Additionally, repression of ProGRP also induced change in the cell cycle and output of NSE. Our data indicated that ProGRP serve as the useful biomarker in the management of SCLC and might be a potential therapeutic target. - Highlights: • ProGRP is overexpressed in the tissues and sera of the patients with SCLC. • Down-regulation of ProGRP inhibited cell proliferation. • Inhibition of ProGRP altered cell cycle distribution and triggers the apoptosis of lung cancer cells.« less

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 ...

[99mTc-octreotide receptor scintigraphy in NCI-H446 small cell lung cancer nude mice model].

PubMed

Li, Chao; Zuo, Shuyao; Wang, Xufu; Liu, Xinfeng; Wang, Guoming; Wu, Fengyu

2015-01-01

For highly aggressive small cell lung cancer (SCLC), early diagnosis is important for its prognosis, but the current inspection methods are more limited, with poor specificity of the traditional imaging methods, and the high cost of PET/CT, difficult to popularization and application. SCLC is kind of neuroendocrine tumors, high expression of somatostatin receptors, which is the cornerstone of its early molecular imaging diagnosis. The aim of this study is to observe the biodistribution and metabolism of 99mTc-octreotide in normal and the human SCLC bearing nude mice. Dynamic and static scintigraphy at 0.5 h, 2 h, 3 h, 4 h were performed in both normal and tumor bearing nude mice after intravenous injection of 99mTc-octreotide. The technique of drawing region of interest (ROI) was used to obtain the averaged pixel counts and the activity-time (A-T) curve of brain, heart, lung, liver, kidney, tumor, respectively. ① The biodistribution study in normal nude mice showed highest uptake in kidney and liver, lower in lung and heart, lowest in brain. Most 99mTc-octreotide was excreted via kidney. ② All tumors were displayed clearly at 3 h postinjection of 99mTc-octreotide. The averaged T/N ratio at 0.5 h, 2 h, 3 h, 4 h postinjection of 99mTc-octreotide was 1.163 ± 0.03, 2.08 ± 0.12, 3.03 ± 0.23, 2.689 ± 0.31, respectively (F=51.69, P<0.000,1). The radioactivity of tumor was lower than liver, and similar with the lung. The curve of tumor showed a radioactivity peak at 2 min-3 min postinjection. 99mTc-octreotide receptor imaging on nude mice bearing SCLC shares high positive rate, especially at 3 h postinjection.

Calcium channel autoantibodies in myasthenic syndrome and small cell lung cancer.

PubMed

Pelucchi, A; Ciceri, E; Clementi, F; Marazzini, L; Foresi, A; Sher, E

1993-05-01

Lambert-Eaton myasthenic syndrome (LEMS) is one of the neurologic paraneoplastic syndromes often found in patients with lung cancer. It is characterized by a generalized deficit of neurotransmitter release. Patients with small cell lung cancer (SCLC) in particular may develop LEMS, and SCLC is very often detected in patients affected by LEMS. LEMS is an autoimmune disease, and autoantibodies that interfere with neurotransmitter release by binding to presynaptic voltage-operated calcium channels (VOCCs) have been found in sera of patients with LEMS. Both human neuronal and SCLC cell lines express omega-conotoxin-sensitive VOCCs, and autoantibodies from patients affected by LEMS can precipitate these channels. We have now screened a large population of patients and control subjects in order to define the specificity and sensitivity of the anti-VOCC antibody assay. We have tested sera from 52 patients with LEMS with and without SCLC; 32 sera from patients with SCLC without LEMS, 31 from patients with non-SCLC, 34 from patients with inflammatory lung diseases, 17 from patients with other neurologic disorders, and 48 from healthy control subjects. We have found that a positive result with this radioimmunoassay is highly specific for LEMS, with or without SCLC, when the antibody titer is higher than 14.21 pM. Anti-VOCC antibodies have also been found in about 40% of patients with SCLC without LEMS, but they were absent in all the other populations tested. We can conclude that this serologic assay is a very useful aid in the diagnosis of LEMS, and it might be useful also for the early diagnosis of SCLC.

TOPK (T-LAK cell-originated protein kinase) inhibitor exhibits growth suppressive effect on small cell lung cancer.

PubMed

Park, Jae-Hyun; Inoue, Hiroyuki; Kato, Taigo; Zewde, Makda; Miyamoto, Takashi; Matsuo, Yo; Salgia, Ravi; Nakamura, Yusuke

2017-03-01

T-lymphokine-activated killer cell-originated protein kinase (TOPK) plays critical roles in cancer cell proliferation as well as maintenance of cancer stem cells (CSC). Small cell lung cancer (SCLC) has highly aggressive phenotype, reveals early spread to distant sites, and results in dismal prognosis with little effective treatment. In this study, we demonstrate that TOPK expression was highly upregulated in both SCLC cell lines and primary tumors. Similar to siRNA-mediated TOPK knockdown effects, treatment with a potent TOPK inhibitor, OTS514, effectively suppressed growth of SCLC cell lines (IC 50 ; 0.4-42.6 nM) and led to their apoptotic cell death. TOPK inhibition caused cell morphologic changes in SCLC cells, elongation of intercellular bridges caused by cytokinesis defects or neuronal protrusions induced by neuronal differentiation in a subset of CSC-like SCLC cells. Treatment with OTS514 suppressed forkhead box protein M1 (FOXM1) activity, which was involved in stemness of CSC. Furthermore, OTS514 treatment reduced CD90-positive SCLC cells and showed higher cytotoxic effect against lung sphere-derived CSC-like SCLC cells. Collectively, our results suggest that targeting TOPK is a promising approach for SCLC therapy. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Cisplatin and photodynamic therapy exert synergistic inhibitory effects on small-cell lung cancer cell viability and xenograft tumor growth

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, You-Shuang; Peng, Yin-Bo; Yao, Min

Lung cancer is the leading cause of cancer death worldwide. Small-cell lung cancer (SCLC) is an aggressive type of lung cancer that shows an overall 5-year survival rate below 10%. Although chemotherapy using cisplatin has been proven effective in SCLC treatment, conventional dose of cisplatin causes adverse side effects. Photodynamic therapy, a form of non-ionizing radiation therapy, is increasingly used alone or in combination with other therapeutics in cancer treatment. Herein, we aimed to address whether low dose cisplatin combination with PDT can effectively induce SCLC cell death by using in vitro cultured human SCLC NCI-H446 cells and in vivo tumor xenograft model.more » We found that both cisplatin and PDT showed dose-dependent cytotoxic effects in NCI-H446 cells. Importantly, co-treatment with low dose cisplatin (1 μM) and PDT (1.25 J/cm{sup 2}) synergistically inhibited cell viability and cell migration. We further showed that the combined therapy induced a higher level of intracellular ROS in cultured NCI-H446 cells. Moreover, the synergistic effect by cisplatin and PDT was recapitulated in tumor xenograft as revealed by a more robust increase in the staining of TUNEL (a marker of cell death) and decrease in tumor volume. Taken together, our findings suggest that low dose cisplatin combination with PDT can be an effective therapeutic modality in the treatment of SCLC patients.« less

Activity of the Monocarboxylate Transporter 1 inhibitor AZD3965 in Small Cell Lung Cancer

PubMed Central

Polański, Radosław; Hodgkinson, Cassandra L.; Fusi, Alberto; Nonaka, Daisuke; Priest, Lynsey; Kelly, Paul; Trapani, Francesca; Bishop, Paul W.; White, Anne; Critchlow, Susan E.; Smith, Paul D.; Blackhall, Fiona

2013-01-01

Purpose The monocarboxylate transporter 1 (MCT1) inhibitor AZD3965 is undergoing Phase I evaluation in the UK. AZD3965 is proposed, via lactate transport modulation, to kill tumor cells reliant on glycolysis. We investigated the therapeutic potential of AZD3965 in small cell lung cancer (SCLC) seeking rationale for clinical testing in this disease and putative predictive biomarkers for trial use. Experimental Design AZD3965 sensitivity was determined for 7 SCLC cell lines, in normoxia and hypoxia, and for a tumor xenograft model. Proof of mechanism was sought via changes in intracellular/tumor lactate. Expression of MCT1 and related transporter MCT4 were assessed by western blot. Drug resistance was investigated via MCT4 siRNAi and overexpression. The expression and clinical significance of MCT1 and MCT4 were explored in a tissue microarray from 78 SCLC patients. Results AZD3965 sensitivity varied in vitro and was highest in hypoxia. Resistance in hypoxia was associated with increased MCT4 expression. In vivo, AZD3965 reduced tumor growth and increased intra-tumor lactate. In the tissue microarray, high MCT1 expression was associated with worse prognosis (p=0.014). MCT1 and hypoxia marker CA IX expression in the absence of MCT4 was observed in 21% of SCLC tumors. Conclusions This study provides a rationale to test AZD3965 in SCLC patients. Our results suggest that patients with tumors expressing MCT1 and lacking in MCT4 are most likely to respond. PMID:24277449

Bradykinin-related compounds as new drugs for cancer and inflammation.

PubMed

Stewart, John M; Gera, Lajos; Chan, Daniel C; Bunn, Paul A; York, Eunice J; Simkeviciene, Vitalija; Helfrich, Barbara

2002-04-01

Bradykinin (BK) (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) is an important growth factor for small-cell lung cancer (SCLC) and prostate cancer (PC). These cancers have cells of neuroendocrine origin and express receptors for a variety of neuropeptides. BK receptors are expressed on almost all lung cancer cell lines and on many PC cells. Our very potent BK antagonist B9430 (D-Arg-Arg-Pro-Hyp-Gly-lgl-Ser-D-Igl-Oic-Arg) (Hyp, trans-4-hydroxy-L-proline; Ig1, alpha-2-indanylglycine; Oic, octahydroindole-2-carboxylic acid) is a candidate anti-inflammatory drug but does not inhibit growth of SCLC or PC. When B9430 is dimerized by N-terminal cross-linking with a suberimide linker, the product B9870 is a potent growth inhibitor for SCLC both in vitro and in vivo in athymic nude mice. Daily i.p. injection at 5 mg x kg(-1) day(-1) beginning on day 8 after SCLC SHP-77 cell implantation gave 65% inhibition of tumor growth. B9870 stimulates apoptosis in SCLC by a novel "biased agonist" action. We have also developed new small mimetic antagonists. BKM-570 (F5C-OC2Y-Atmp) (F5C, pentafluorocinnamic acid; OC2Y, O-2,6-dichlorobenzyl tyrosine; Atmp, 4-amino-2,2,6,6-tetramethylpiperidine) is very potent for inhibition of SHP-77 growth in nude mice. When injected daily i.p. at 5 mg x kg(-1), M-570 gave 90% suppression of tumor growth. M-570 is more potent than the well-known anticancer drug cisPlatin (60% inhibition) or the recently developed SU5416 (40% inhibition) in this model. M-570 also showed activity against various other cancer cell lines in vitro (SCLC, non-SCLC, lung, prostate, colon, cervix) and inhibited growth of prostate cell line PC3 in nude mice. M-570 and related compounds evidently act in vivo through pathways other than BK receptors. These compounds have clinical potential for treatment of human lung and prostate cancers.

NCAM polysialylation during adherence transitions: live cell monitoring using an antibody-mimetic EGFP-endosialidase and the viability dye DRAQ7.

PubMed

Smith, Paul J; Furon, Emeline; Wiltshire, Marie; Chappell, Sally; Patterson, Laurence H; Shnyder, Steven D; Falconer, Robert A; Errington, Rachel J

2013-07-01

Polysialylation of neural cell adhesion molecule (NCAM) in small-cell lung cancer (SCLC) is thought to regulate NCAM-mediated cell-surface interactions, imparting antiadhesive properties to cells. However, SCLC cells in culture demonstrate anchorage-independent growth and spontaneously generate adherent forms. Here, the ability of polySia-NCAM to influence cell proliferation and adherence is unclear. We analyzed live SCLC cell polySia-NCAM expression by flow cytometry, using the novel combination of a polySia antibody-mimetic eGFP-tagged endosialidase and the viability dye DRAQ7. Enrichment for adherence (<30 population doublings) in SCLC cell lines resolved populations with increased (SHP-77 and COR-L279) or negligible (NCI-H69) polysialylation compared with nonadherent parent populations. Adherent forms retained NCAM expression as confirmed by immunofluorescence and immunoblotting. Initial transition to adherence and loss of polysialylation in NCI-H69 was linked to a reduced proliferation rate with no increase in cell death. This reduced proliferation rate was reiterated in vivo as determined by the growth of noninvasive subcutaneous xenografts in mice. Continued selection for enhanced substrate adherence in NCI-H69 (>150 population doublings) resolved cells with stable re-expression of polySia and increased growth rates both in vitro and in vivo. Endoneuraminidase removal of polySia from re-expressing cells showed that rapid adherence to extracellular matrix components was functionally independent of polySia. PolySia expression was not altered when isolated adherent forms underwent enforced cell-cell contact in three-dimensional culture. Coculture of polySia expression variants modulated overall polySia expression profiles indicating an influence of SCLC microcommunity composition independent of substrate adherence potential. We conclude that an obligatory linkage between substrate adherence potential and polySia expression is rejected for SCLC cells. We suggest that a degree of homeostasis operates to regulate polysialylation within heterogeneous cell populations. The findings suggest a new model for SCLC progression while the application of live cell profiling of polysialylation could be used to assess polySia-NCAM-targeted therapies. Copyright © 2013 International Society for Advancement of Cytometry.

Towards a unified description of the charge transport mechanisms in conductive atomic force microscopy studies of semiconducting polymers.

PubMed

Moerman, D; Sebaihi, N; Kaviyil, S E; Leclère, P; Lazzaroni, R; Douhéret, O

2014-09-21

In this work, conductive atomic force microscopy (C-AFM) is used to study the local electrical properties in thin films of self-organized fibrillate poly(3-hexylthiophene) (P3HT), as a reference polymer semiconductor. Depending on the geometrical confinement in the transport channel, the C-AFM current is shown to be governed either by the charge transport in the film or by the carrier injection at the tip-sample contact, leading to either bulk or local electrical characterization of the semiconducting polymer, respectively. Local I-V profiles allow discrimination of the different dominating electrical mechanisms, i.e., resistive in the transport regime and space charge limited current (SCLC) in the local regime. A modified Mott-Gurney law is analytically derived for the contact regime, taking into account the point-probe geometry of the contact and the radial injection of carriers. Within the SCLC regime, the probed depth is shown to remain below 12 nm with a lateral electrical resolution below 5 nm. This confirms that high resolution is reached in those C-AFM measurements, which therefore allows for the analysis of single organic semiconducting nanostructures. The carrier density and mobility in the volume probed under the tip under steady-state conditions are also determined in the SCLC regime.

The microRNA expression signature of small cell lung cancer: tumor suppressors of miR-27a-5p and miR-34b-3p and their targeted oncogenes.

PubMed

Mizuno, Keiko; Mataki, Hiroko; Arai, Takayuki; Okato, Atsushi; Kamikawaji, Kazuto; Kumamoto, Tomohiro; Hiraki, Tsubasa; Hatanaka, Kazuhito; Inoue, Hiromasa; Seki, Naohiko

2017-07-01

Small cell lung cancer (SCLC) constitutes approximately 15% of all diagnosed lung cancers. SCLC is a particularly lethal malignancy, as the 2-year survival rate after appropriate treatment is less than 5%. The patients with SCLC have not been received a benefit of the recently developed molecular targeted treatment. Therefore, a new treatment strategy is necessary for the patients. The molecular mechanisms underlying the aggressiveness of SCLC cells and their development of treatment-resistance are still ambiguous. In this study, we newly constructed a microRNA (miRNA) expression signature of SCLC by analysis of autopsy specimens. Based on the resultant signature, four miRNAs (miR-27a-5p, miR-485-3p, miR-34-5p and miR-574-3p) were found to be candidate anti-tumor miRNAs. To investigate their functional importance, we first validated the downregulation of miR-27a-5p and miR-34b-3p in SCLC clinical specimens. Next, we demonstrated that ectopic expression of both miR-27a-5p and miR-34b-3p significantly inhibited cancer cell aggressiveness. Our in silico analyses showed that four genes (topoisomerase 2 alpha (TOP2A), maternal embryonic leucine zipper kinase (MELK), centromere protein F (CENPF) and SRY-box 1 (SOX1) were identified as miR-27a-5p- and miR-34b-3p-regulated genes. Based on immunohistochemical analysis, TOP2A, MELK and CENPF were involved in SCLC pathogenesis. These genes might contribute to high proliferation and early metastatic spread of SCLC cells. Elucidation of differentially expressed miRNA-mediated cancer pathways based on SCLC signature may provide new insights into the mechanisms of SCLC pathogenesis.

Pro-gastrin-releasing peptide (ProGRP) as a biomarker in small-cell lung cancer diagnosis, monitoring and evaluation of treatment response.

PubMed

Wojcik, Ewa; Kulpa, Jan Kanty

2017-01-01

Lung cancer belongs to malignant tumors that possess the highest rates of morbidity and mortality in the world. A number of morphological, biological and clinical features justify the distinction of small-cell carcinoma with respect to the other histological types of lung cancer. The predominant neuroendocrine phenotype is critical for the selection of biomarkers used in diagnostics, monitoring and evaluation of treatment response; early onset relapses in patients with small-cell lung cancer (SCLC) and the evaluation of their prognosis. Although for a long time the neuron-specific enolase (NSE) was considered to be the marker of choice for this tumor, it is now increasingly important to pay attention to concentrations of pro-gastrin-releasing peptide (ProGRP). The results of this marker have been implicated in the differential diagnosis of non-small lung cancer and SCLC, chemotherapy and radiotherapy monitoring as well as evaluation of treatment response. The subject of this series of studies is to determine the usefulness of ProGRP in the evaluation of patients' prognosis and its predictive value. The current aim for the optimization of the effectiveness of biochemical diagnostics of SCLC is recommended by complementary ProGRP and NSE studies. The present work is a summary of the latest reports regarding diagnostic utility of these markers in SCLC.

CD13 as target for tissue factor induced tumor vascular infarction in small cell lung cancer.

PubMed

Schmidt, Lars Henning; Stucke-Ring, Janine; Brand, Caroline; Schliemann, Christoph; Harrach, Saliha; Muley, Thomas; Herpel, Esther; Kessler, Torsten; Mohr, Michael; Görlich, Dennis; Kreuter, Michael; Lenz, Georg; Wardelmann, Eva; Thomas, Michael; Berdel, Wolfgang E; Schwöppe, Christian; Hartmann, Wolfgang

2017-11-01

Zinc-binding protease aminopeptidase N (CD13) is expressed on tumor vascular cells and tumor cells. It represents a potential candidate for molecular targeted therapy, e.g. employing truncated tissue factor (tTF)-NGR, which can bind CD13 and thereby induce tumor vascular infarction. We performed a comprehensive analysis of CD13 expression in a clinically well characterized cohort of patients with small cell lung cancer (SCLC) to evaluate its potential use for targeted therapies in this disease. CD13 expression was analyzed immunohistochemically in 27 SCLC patients and correlated with clinical course and outcome. In CD-1 nude mice bearing human HTB119 SCLC xenotransplants, the systemic effects of the CD13-targeting fusion protein tTF-NGR on tumor growth were tested. In 52% of the investigated SCLC tissue samples, CD13 was expressed in tumor stroma cells, while the tumor cells were negative for CD13. No prognostic effect was found in the investigated SCLC study collective with regard to overall survival (p>0.05). In CD-1 nude mice, xenografts of CD13 negative HTB119 SCLC cells showed CD13 expression in the intratumoral vascular and perivascular cells, and the systemic application of CD13-targeted tissue factor tTF-NGR led to a significant reduction of tumor growth. We here present first data on the expression of CD13 in SCLC tumor samples. Our results strongly recommend the further investigation of tTF-NGR and other molecules targeted by NGR-peptides in SCLC patients. Considering the differential expression of CD13 in SCLC samples pre-therapeutic CD13 analysis is proposed for testing as investigational predictive biomarker for patient selection. Copyright © 2017 Elsevier B.V. All rights reserved.

Small Cell Lung Cancer Exhibits Frequent Inactivating Mutations in the Histone Methyltransferase KMT2D/MLL2: CALGB 151111 (Alliance)

PubMed Central

Augert, Arnaud; Zhang, Qing; Bates, Breanna; Cui, Min; Wang, Xiaofei; Wildey, Gary; Dowlati, Afshin; MacPherson, David

2017-01-01

Introduction SCLC is a lethal neuroendocrine tumor type that is highly prone to metastasis. There is an urgency to understand the mutated genes that promote SCLC, as there are no approved targeted therapies yet available. SCLC is rarely resected, limiting the number of samples available for genomic analyses of somatic mutations. Methods To identify potential driver mutations in human SCLC we sequenced the whole exomes of 18 primary SCLCs and seven cell lines along with matched normal controls. We extended these data by resequencing a panel of genes across 40 primary SCLCs and 48 cell lines. Results We report frequent mutations in the lysine methyltransferase 2D gene (KMT2D) (also known as MLL2), a key regulator of transcriptional enhancer function. KMT2D exhibited truncating nonsense/frameshift/splice site mutations in 8% of SCLC tumors and 17% of SCLC cell lines. We found that KMT2D mutation in human SCLC cell lines was associated with reduced lysine methyltransferase 2D protein levels and reduced monomethylation of histone H3 lysine 4, a mark associated with transcriptional enhancers. We also found mutations in other genes associated with transcriptional enhancer control, including CREB binding protein gene (CREBBP), E1A binding protein p300 gene (EP300), and chromodomain helicase DNA binding protein 7 gene (CHD7), and we report mutations in additional chromatin remodeling genes such as polybromo 1 gene (PBRM1). Conclusions These data indicate that KMT2D is one of the major mutated genes in SCLC, and they point to perturbation of transcriptional enhancer control as potentially contributing to SCLC. PMID:28007623

Is the canonical RAF-MEK-ERK signaling pathway a therapeutic target in SCLC?

PubMed Central

Cristea, Sandra; Sage, Julien

2017-01-01

The activity of the RAF-MEK-ERK signaling pathway is critical for the proliferation of normal and cancerous cells. Oncogenic mutations driving the development of lung adenocarcinoma often activate this signaling pathway. In contrast, pathway activity levels and their biological roles are not well established in small cell lung cancer (SCLC), a fast-growing neuroendocrine lung cancer subtype. Here we discuss the function of the RAF-MEK-ERK kinase pathway and the mechanisms leading to its activation in SCLC cells. In particular, we argue that activation of this pathway may be beneficial to the survival, proliferation and spread of SCLC cells in response to multiple stimuli. We also consider evidence that high levels of RAF-MEK-ERK pathway activity may be detrimental to SCLC tumors, including in part by interfering with their neuroendocrine fate. Based on these observations, we examine when small molecules targeting kinases in the RAF-MEK-ERK pathway may be useful therapeutically in SCLC patients, including in combination with other therapeutic agents. PMID:27133774

Therapeutic strategies and genetic profile comparisons in small cell carcinoma and large cell neuroendocrine carcinoma of the lung using next-generation sequencing.

PubMed

Ito, Masaoki; Miyata, Yoshihiro; Hirano, Shoko; Kimura, Shingo; Irisuna, Fumiko; Ikeda, Kyoko; Kushitani, Kei; Tsutani, Yasuhiro; Ueda, Daisuke; Tsubokawa, Norifumi; Takeshima, Yukio; Okada, Morihito

2017-12-12

Small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) of the lung are classified as variants of endocrine carcinoma and subdivided into pure or combined type. Clinical benefit of target therapy has not been established in these tumors. This study aimed to compare genetic and clinicopathological features between SCLC and LCNEC or pure and combined types, and explore the possibility of target therapy using next-generation sequencing. In 13 SCLC and 22 LCNEC cases, 72 point mutations, 19 deletions, and 3 insertions were detected. As therapeutically targetable variants, mutations in EGFR (L858R), KRAS (G12D, G12A, G12V), and PIK3CA (E545K) were detected in 5 cases. The case harboring EGFR mutation showed response to EGFR-tyrosine kinase inhibitor. However, there are no clinicopathological features associated with therapeutically targetable cases. And there was no significant genetic feature between SCLC and LCNEC or pure and combined types. In conclusion, although patients with SCLC and LCNEC may benefit from target therapy, they were not identifiable by clinicopathologic background. And there was not significant genetic difference between SCLC and LCNEC, including between pure and combined types. Classifying SCLC and LCNEC in same category is reasonable. However, distinguishing the pure type from combined type was not validated. Comprehensive genetic analysis should be performed to detect targetable variants in any type of SCLC and LCNEC.

Expression of Notch1 and Numb in small cell lung cancer.

PubMed

Kikuchi, Hajime; Sakakibara-Konishi, Jun; Furuta, Megumi; Yokouchi, Hiroshi; Nishihara, Hiroshi; Yamazaki, Shigeo; Uramoto, Hidetaka; Tanaka, Fumihiro; Harada, Masao; Akie, Kenji; Sugaya, Fumiko; Fujita, Yuka; Takamura, Kei; Kojima, Tetsuya; Harada, Toshiyuki; Higuchi, Mitsunori; Honjo, Osamu; Minami, Yoshinori; Watanabe, Naomi; Oizumi, Satoshi; Suzuki, Hiroyuki; Ishida, Takashi; Dosaka-Akita, Hirotoshi; Isobe, Hiroshi; Munakata, Mitsuru; Nishimura, Masaharu

2017-02-07

Notch signaling in tumorigenesis functions as an oncogene or tumor suppressor according to the type of malignancy. Numb represses intracellular Notch signaling. Previous studies have demonstrated that Notch signaling suppresses the proliferation of small cell lung cancer (SCLC) cell lines. However, in SCLC, the association between Notch1 and Numb expression and clinicopathological factors or prognosis has remained unclear. In this study, we evaluated the expression of Notch1 and Numb in SCLC. We immunohistochemically assessed 125 SCLCs that were surgically resected at 16 institutions participating in either the Hokkaido Lung Cancer Clinical Study Group Trial (HOT) or the Fukushima Investigative Group for Healing Thoracic Malignancy (FIGHT) between 2003 and 2013. Correlations between Notch1 or Numb expression and various clinicopathological features were evaluated. Notch1 expression was associated with ECOG performance status. Numb expression was associated with age, sex, and pathological histology (SCLC or Combined SCLC). Analysis of cellular biological expression did not demonstrate a significant correlation between the expression of Notch1 and of Numb. Multivariate Cox regression analysis showed that high Notch1 expression was an independent favorable prognostic factor for SCLC(hazard ratio = 0.503, P = 0.023). High Notch1 expression, but not Numb expression, is associated with favorable prognosis in SCLC.

Small cell lung cancer growth is inhibited by miR-342 through its effect of the target gene IA-2.

PubMed

Xu, Huanyu; Cai, Tao; Carmona, Gilberto N; Abuhatzira, Liron; Notkins, Abner L

2016-09-26

Small cell lung cancers (SCLC) are tumors of neuroendocrine origin. Previous in vitro studies from our laboratory showed that SCLC expresses high levels of the transmembrane dense core vesicle protein IA-2 (islet cell antigen-2) as compared to normal lung cells. IA-2, through its effect on dense core vesicles (DCVs), is known to be involved in the secretion of hormones and neurotransmitters. It is believed that the dysregulated release of the neurotransmitter Acetylcholine (ACh) by DCVs has an autocrine effect on SCLC cell growth. Recently, we found that IA-2 is a target of the microRNA miR-342 and that miR-342 mimics suppress the expression of IA-2. The present experiments were initiated to see whether IA-2 and/or miR-342 affect the growth of SCLC. SCLC cell growth was evaluated following the knockdown of endogenous IA-2 with RNAi or by overexpressing miR-342 with a mimic. The secretion and content of ACh in SCLC cells was analyzed using a human acetylcholine ELISA (enzyme-linked immunosorbent assay) kit. The knockdown of endogenous IA-2 by RNAi reduced SCLC cell growth within 4 days by 40 % or more. Similar results were obtained when these cell lines were transfected with a miR-342 mimic. The knockdown of IA-2 by RNAi or miR-342 with a mimic also resulted in a significant decrease in the secretion of ACh, one of the autocrine hormones secreted by SCLC. Further studies revealed that the growth of SCLC cell lines that had been treated with the miR-342 mimic was restored to nearly normal levels by treatment with ACh. Our studies show for the first time that both miR-342 and its target gene IA-2 are involved in the growth process of SCLC cells and act by their effect on autocrine secretion. These findings point to possible new therapeutic approaches for the treatment of autocrine-induced tumor proliferation.

Lemongrass essential oil and citral inhibit Src/Stat3 activity and suppress the proliferation/survival of small-cell lung cancer cells, alone or in combination with chemotherapeutic agents.

PubMed

Maruoka, Takayuki; Kitanaka, Akira; Kubota, Yoshitsugu; Yamaoka, Genji; Kameda, Tomohiro; Imataki, Osamu; Dobashi, Hiroaki; Bandoh, Shuji; Kadowaki, Norimitsu; Tanaka, Terukazu

2018-03-13

Small-cell lung cancer (SCLC) is intractable due to its high propensity for relapse. Novel agents are thus needed for SCLC treatment. Lemongrass essential oil (LG-EO) and its major constituent, citral, have been reported to inhibit the proliferation and survival of several types of cancer cells. However, the precise mechanisms through which LG-EO and citral exert their effects on SCLC cells have not been fully elucidated. SCLC cells express Src and have high levels of Src-tyrosine kinase (Src-TK) activity. In most SCLC cell lines, constitutive phosphorylation of Stat3(Y705), which is essential for its activation, has been detected. Src-TK can phosphorylate Stat3(Y705), and activated Stat3 promotes the expression of the anti-apoptotic factors Bcl-xL and Mcl-1. In the present study, LG-EO and citral prevented Src-TK from phosphorylating Stat3(Y705), resulting in decreased Bcl-xL and Mcl-1 expression, in turn suppressing the proliferation/survival of SCLC cells. To confirm these findings, the wild-type-src gene was transfected into the LU135 SCLC cell line (LU135‑wt-src), in which Src and activated phospho-Stat3(Y705) were overexpressed. The suppression of cell proliferation and the induction of apoptosis by treatment with LG-EO or citral were significantly attenuated in the LU135-wt-src cells compared with the control LU135-mock cells. The signal transducer and activator of transcription 3 (Stat3) signaling pathway is also associated with intrinsic drug resistance. LU135-wt-src cells were significantly resistant to conventional chemotherapeutic agents compared with LU135-mock cells. The combined effects of citral and each conventional chemotherapeutic agent on SCLC cells were also evaluated. The combination treatment exerted additive or more prominent effects on LU135-wt-src, LU165 and MN1112 cells, which are relatively chemoresistant SCLC cells. These findings suggest that either LG-EO or citral, alone or in combination with chemotherapeutic agents, may be a novel therapeutic option for SCLC patients.

An extremely rare case of small-cell lung cancer harboring variant 2 of the EML4-ALK fusion gene.

PubMed

Toyokawa, Gouji; Takenoyama, Mitsuhiro; Taguchi, Kenichi; Toyozawa, Ryo; Inamasu, Eiko; Kojo, Miyako; Shiraishi, Yoshimasa; Morodomi, Yosuke; Takenaka, Tomoyoshi; Hirai, Fumihiko; Yamaguchi, Masafumi; Seto, Takashi; Shimokawa, Mototsugu; Ichinose, Yukito

2013-09-01

Anaplastic lymphoma kinase (ALK) fuses echinoderm microtubule-associated protein-like 4 (EML4) to acquire a transforming activity in lung adenocarcinomas. However, the presence of an EML4-ALK fusion gene in other lung cancer histologies is an extremely rare phenomenon. A 43-year-old female was referred to our department due to dyspnea on effort and left back pain. Computed tomography (CT) showed a large mass in the upper lobe of the left lung and a massive left pleural effusion, while a CT-guided needle biopsy confirmed a diagnosis of small-cell lung cancer (SCLC). Surprisingly, the tumor was genetically considered to harbor the EML4-ALK fusion gene (variant 2). Although the patient underwent two regimens of cytotoxic chemotherapy for SCLC, she died approximately seven months after the administration of first-line chemotherapy. Our analysis of 30 consecutive patients with SCLC for EML4-ALK revealed that two patients, including the current patient and a patient we previously reported, harbored the EML4-ALK fusion gene. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Neurotensin may function as a regulatory peptide in small cell lung cancer.

PubMed

Davis, T P; Crowell, S; McInturff, B; Louis, R; Gillespie, T

1991-01-01

Neurotensin (NT) has been postulated to act as a modulatory agent in the central nervous system. Besides its presence in mammalian brain, NT is produced by small cell carcinoma of the lung (SCLC) and cell lines derived from these tumors. Receptors have also been characterized in some SCLC cell lines leading to the suggestion that NT could regulate the growth of SCLC in an autocrine fashion similar to bombesin/GRP. Previously, we had reported that a 10 nM dose of NT and NT(8-13), but not NT(1-8), elevated cytosolic Ca2+, indicating that SCLC NT receptors may use Ca2+ as a second messenger. Using intact SCLC cells we report that time-course incubations with NT lead to the formation of the amino-terminal fragment NT(1-8) and small amounts of the C-terminal fragment NT(9-13). These fragments are formed by metalloendopeptidase 3.4.24.15 cleaving enzyme at the Arg8-Arg9 bond of NT. Significant levels of soluble 3.4.24.15 (10-17 nmoles/mg Pr-/min) are present in SCLC cell lines. Using the in vitro clonogenic assay we tested the effect of 0.5, 5.0 and 10.0 nM doses of NT, NT(1-8) and NT(8-13) on SCLC clonal growth. NT and the C-terminal fragment NT(8-13) stimulated colony formation whereas the N-terminal fragment did not. In summary, NT may function as a regulatory peptide in SCLC through the formation of peptide fragments.

Carfilzomib demonstrates broad anti-tumor activity in pre-clinical non-small cell and small cell lung cancer models.

PubMed

Baker, Amanda F; Hanke, Neale T; Sands, Barbara J; Carbajal, Liliana; Anderl, Janet L; Garland, Linda L

2014-12-31

Carfilzomib (CFZ) is a proteasome inhibitor that selectively and irreversibly binds to its target and has been approved in the US for treatment of relapsed and refractory multiple myeloma. Phase 1B studies of CFZ reported signals of clinical activity in solid tumors, including small cell lung cancer (SCLC). The aim of this study was to investigate the activity of CFZ in lung cancer models. A diverse panel of human lung cancer cell lines and a SHP77 small cell lung cancer xenograft model were used to investigate the anti-tumor activity of CFZ. CFZ treatment inhibited both the constitutive proteasome and the immunoproteasome in lung cancer cell lines. CFZ had marked anti-proliferative activity in A549, H1993, H520, H460, and H1299 non-small cell lung cancer (NSCLC) cell lines, with IC50 values after 96 hour exposure from <1.0 nM to 36 nM. CFZ had more variable effects in the SHP77 and DMS114 SCLC cell lines, with IC50 values at 96 hours from <1 nM to 203 nM. Western blot analysis of CFZ-treated H1993 and SHP77 cells showed cleavage of poly ADP ribose polymerase (PARP) and caspase-3, indicative of apoptosis, and induction of microtubule-associated protein-1 light chain-3B (LC3B), indicative of autophagy. In SHP77 flank xenograft tumors, CFZ monotherapy inhibited tumor growth and prolonged survival, while no additive or synergistic anti-tumor efficacy was observed for CFZ + cisplatin (CDDP). CFZ demonstrated anti-proliferative activity in lung cancer cell lines in vitro and resulted in a significant survival advantage in mice with SHP77 SCLC xenografts, supporting further pre-clinical and clinical investigations of CFZ in NSCLC and SCLC.

Albendazole sensitizes cancer cells to ionizing radiation

PubMed Central

2011-01-01

Background Brain metastases afflict approximately half of patients with metastatic melanoma (MM) and small cell lung cancer (SCLC) and represent the direct cause of death in 60 to 70% of those affected. Standard of care remains ineffective in both types of cancer with the challenge of overcoming the blood brain barrier (BBB) exacerbating the clinical problem. Our purpose is to determine and characterize the potential of albendazole (ABZ) as a cytotoxic and radiosensitizing agent against MM and SCLC cells. Methods Here, ABZ's mechanism of action as a DNA damaging and microtubule disrupting agent is assessed through analysis of histone H2AX phosphorylation and cell cyle progression. The cytotoxicity of ABZ alone and in combination with radiation therapy is determined though clonogenic cell survival assays in a panel of MM and SCLC cell lines. We further establish ABZ's ability to act synergistically as a radio-sensitizer through combination index calculations and apoptotic measurements of poly (ADP-ribose) polymerase (PARP) cleavage. Results ABZ induces DNA damage as measured by increased H2AX phosphorylation. ABZ inhibits the growth of MM and SCLC at clinically achievable plasma concentrations. At these concentrations, ABZ arrests MM and SCLC cells in the G2/M phase of the cell cycle after 12 hours of treatment. Exploiting the notion that cells in the G2/M phase are the most sensitive to radiation therapy, we show that treatment of MM and SCLC cells treated with ABZ renders them more sensitive to radiation in a synergistic fashion. Additionally, MM and SCLC cells co-treated with ABZ and radiation exhibit increased apoptosis at 72 hours. Conclusions Our study suggests that the orally available antihelminthic ABZ acts as a potent radiosensitizer in MM and SCLC cell lines. Further evaluation of ABZ in combination with radiation as a potential treatment for MM and SCLC brain metastases is warranted. PMID:22094106

Leakage current phenomena in Mn-doped Bi(Na,K)TiO{sub 3}-based ferroelectric thin films

DOE Office of Scientific and Technical Information (OSTI.GOV)

Walenza-Slabe, J.; Gibbons, B. J., E-mail: brady.gibbons@oregonstate.edu

2016-08-28

Mn-doped 80(Bi{sub 0.5}Na{sub 0.5})TiO{sub 3}-20(Bi{sub 0.5}K{sub 0.5})TiO{sub 3} thin films were fabricated by chemical solution deposition on Pt/TiO{sub 2}/SiO{sub 2}/Si substrates. Steady state and time-dependent leakage current were investigated from room temperature to 180 °C. Undoped and low-doped films showed space-charge-limited current (SCLC) at high temperatures. The electric field marking the transition from Ohmic to trap-filling-limited current increased monotonically with Mn-doping. With 2 mol. % Mn, the current was Ohmic up to 430 kV/cm, even at 180 °C. Modeling of the SCLC showed that all films exhibited shallow trap levels and high trap concentrations. In the regime of steady state leakage, theremore » were also observations of negative differential resistivity and positive temperature coefficient of resistivity near room temperature. Both of these phenomena were confined to relatively low temperatures (below ∼60 °C). Transient currents were observed in the time-dependent leakage data, which was measured out to several hundred seconds. In the undoped films, these were found to be a consequence of oxygen vacancy migration modulating the electronic conductivity. The mobility and thermal activation energy for oxygen vacancies was extracted as μ{sub ion} ≈ 1.7 × 10{sup −12} cm{sup 2} V{sup −1} s{sup −1} and E{sub A,ion} ≈ 0.92 eV, respectively. The transient current displayed different characteristics in the 1 mol. % Mn-doped films which were not readily explained by oxygen vacancy migration.« less

Combinational Therapy Enhances the Effects of Anti-IGF-1R mAb Figitumumab to Target Small Cell Lung Cancer

PubMed Central

Shen, Hongchang; Xu, Jun; Zhu, Linhai; Liu, Qi; Du, Jiajun

2015-01-01

Background Small cell lung cancer (SCLC) is a recalcitrant malignancy with distinct biologic properties. Antibody targeting therapy has been actively investigated as a new drug modality. Methods We tested the expression of IGF-1R and calculated the survival in 61 SCLC patients. We also evaluated the anti-tumor effects of anti-IGF-1R monoclonal antibody Figitumumab (CP) on SCLC, and tried two drug combinations to improve CP therapy. Results Our clinical data suggested that high IGF-1R expression was correlated with low SCLC patient survival. We then demonstrated the effect of CP was likely through IGF-1R blockage and down-regulation without IGF-1R auto-phosphorylation and PI3K/AKT activation. However, we observed elevated MEK/ERK activation upon CP treatment in SCLC cells, and this MEK/ERK activation was enhanced by ß-arrestin1 knockdown while attenuated by ß-arrestin2 knockdown. We found both MEK/ERK inhibitor and metformin could enhance CP treatment in SCLC cells. We further illustrated the additive effect of metformin was likely through promoting further IGF-1R down-regulation. Conclusion Our results highlighted the potential of anti-IGF-1R therapy and the adjuvant therapy strategy with either MEK/ERK inhibitor or metformin to target SCLC, warranting further studies. PMID:26287334

Utility of the quantitative Ki-67 proliferation index and CD56 together in the cytologic diagnosis of small cell lung carcinoma and other lung neuroendocrine tumors.

PubMed

Zheng, Gang; Ettinger, David S; Maleki, Zahra

2013-01-01

Distinction of small cell lung carcinoma (SCLC) from non-small cell lung carcinoma (NSCLC) is critical because of the differences in prognosis and management. Patients with SCLC usually present with distant metastasis, and clinicians demand an accurate diagnosis in order to initiate appropriate therapy. Limited cytology material, occasionally with crush artifact, is not uncommon. Therefore, robust cytomorphologic features and a small immunostaining panel would be ideal to differentiate SCLC from NSCLC and other neuroendocrine neoplasms. We evaluated CD56 and the quantitative Ki-67 immunohistochemical panel in comparison to synaptophysin and chromogranin, along with cytomorphology to diagnose SCLC. Eighty-eight cases of SCLC were retrieved from the cytology archives of The Johns Hopkins Hospital. Forty neuroendocrine neoplasms were used as control cases. SCLCs included 33 lung cases and 55 metastatic lesions. The specimens were obtained by fine needle aspiration, thoracocentesis, bronchoalveolar lavage and abdominal paracentesis. CD56 was expressed in 98.9% of SCLCs, which is significantly more sensitive than synaptophysin and chromogranin. The Ki-67 labeling index was high (>70%) in all cases, which is a reliable marker to differentiate SCLC from other neuroendocrine neoplasms and NSCLC. CD56 and quantitative Ki-67 along with cytomorphology is a robust immunohistochemical panel to differentiate SCLC from other neuroendocrine neoplasms and NSCLC. Copyright © 2013 S. Karger AG, Basel.

Prophylactic Cranial Irradiation (PCI) versus Active MRI Surveillance for Small Cell Lung Cancer: The Case for Equipoise.

PubMed

Rusthoven, Chad G; Kavanagh, Brian D

2017-12-01

Prophylactic cranial irradiation (PCI) for SCLC offers a consistent reduction in the incidence of brain metastases at the cost of measurable toxicity to neurocognitive function and quality of life, in the setting of characteristic pathologic changes to the brain. The sequelae of PCI have historically been justified by the perception of an overall survival advantage specific to SCLC. This rationale has now been challenged by a randomized trial in extensive-stage SCLC demonstrating equivalent progression-free survival and a trend toward improved overall survival with PCI omission in the context of modern magnetic resonance imaging (MRI) staging and surveillance. In this article, we critically examine the randomized trials of PCI in extensive-stage SCLC and discuss their implications on the historical data supporting PCI for limited-stage SCLC from the pre-MRI era. Further, we review the toxicity of moderate doses of radiation to the entire brain that underlie the growing interest in active MRI surveillance and PCI omission. Finally, the evidence supporting prospective investigation of radiosurgery for limited brain metastases in SCLC is reviewed. Overall, our aim is to provide an evidence-based assessment of the debate over PCI versus active MRI surveillance and to highlight the need for contemporary trials evaluating optimal central nervous system management in SCLC. Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Mutation patterns in small cell and non-small cell lung cancer patients suggest a different level of heterogeneity between primary and metastatic tumors.

PubMed

Saber, Ali; Hiltermann, T Jeroen N; Kok, Klaas; Terpstra, M Martijn; de Lange, Kim; Timens, Wim; Groen, Harry J M; van den Berg, Anke

2017-02-01

Several studies have shown heterogeneity in lung cancer, with parallel existence of multiple subclones characterized by their own specific mutational landscape. The extent to which minor clones become dominant in distinct metastasis is not clear. The aim of our study was to gain insight in the evolution pattern of lung cancer by investigating genomic heterogeneity between primary tumor and its distant metastases. Whole exome sequencing (WES) was performed on 24 tumor and five normal samples of two small cell lung carcinoma (SCLC) and three non-SCLC (NSCLC) patients. Validation of somatic variants in these 24 and screening of 33 additional samples was done by single primer enrichment technology. For each of the three NSCLC patients, about half of the mutations were shared between all tumor samples, whereas for SCLC patients, this percentage was around 95. Independent validation of the non-ubiquitous mutations confirmed the WES data for the vast majority of the variants. Phylogenetic trees indicated more distance between the tumor samples of the NSCLC patients as compared to the SCLC patients. Analysis of 30 independent DNA samples of 16 biopsies used for WES revealed a low degree of intra-tumor heterogeneity of the selected sets of mutations. In the primary tumors of all five patients, variable percentages (19-67%) of the seemingly metastases-specific mutations were present albeit at low read frequencies. Patients with advanced NSCLC have a high percentage of non-ubiquitous mutations indicative of branched evolution. In contrast, the low degree of heterogeneity in SCLC suggests a parallel and linear model of evolution. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Development of targeted therapy and immunotherapy for treatment of small cell lung cancer.

PubMed

Saito, Motonobu; Shiraishi, Kouya; Goto, Akiteru; Suzuki, Hiroyuki; Kohno, Takashi; Kono, Koji

2018-05-14

Targeted therapy against druggable genetic aberrations has shown a significantly positive response rate and longer survival in various cancers, including lung cancer. In lung adenocarcinoma (LADC), specific thyroxin kinase inhibitors against EGFR mutations and ALK fusions are used as a standard treatment regimen and show significant positive efficacy. On the other hand, targeted therapy against driver gene aberrations has not been adapted yet in small cell lung cancer (SCLC). This is because driver genes and druggable aberrations are rarely identified by next generation sequencing in SCLC. Recent advances in the understanding of molecular biology have revealed several candidate therapeutic targets. To date, poly [ADP-ribose] polymerase (PARP), enhancer of zeste homologue 2 (EZH2) or delta-like canonical Notch ligand 3 (DLL3) are considered to be druggable targets in SCLC. In addition, another candidate of personalized therapy for SCLC is immune blockade therapy of programmed death-1 (PD-1) and its ligand, PD-L1. PD-1/PD-L1 blockade therapy is not a standard therapy for SCLC, so many clinical trials have been performed to investigate its efficacy. Herein, we review gene aberrations exploring the utility of targeted therapy and discuss blockade of immune checkpoints therapy in SCLC.

Dispersive electron transport in tris(8-hydroxyquinoline) aluminum (Alq3) probed by impedance spectroscopy.

PubMed

Berleb, Stefan; Brütting, Wolfgang

2002-12-31

Electron transport in tris(8-hydroxyquinoline) aluminum (Alq3) is investigated by impedance spectroscopy under conditions of space-charge limited conduction (SCLC). Existing SCLC models are extended to include the field dependence of the charge carrier mobility and energetically distributed trap states. The dispersive nature of electron transport is revealed by a frequency-dependent mobility with a dispersion parameter alpha in the range 0.4-0.5, independent of temperature. This indicates that positional rather than energetic disorder is the dominant mechanism for the dispersive transport of electrons in Alq3.

The anti-apoptotic BAG3 protein is expressed in lung carcinomas and regulates small cell lung carcinoma (SCLC) tumor growth.

PubMed

Chiappetta, Gennaro; Basile, Anna; Barbieri, Antonio; Falco, Antonia; Rosati, Alessandra; Festa, Michelina; Pasquinelli, Rosa; Califano, Daniela; Palma, Giuseppe; Costanzo, Raffaele; Barcaroli, Daniela; Capunzo, Mario; Franco, Renato; Rocco, Gaetano; Pascale, Maria; Turco, Maria Caterina; De Laurenzi, Vincenzo; Arra, Claudio

2014-08-30

BAG3, member the HSP70 co-chaperones family, has been shown to play a relevant role in the survival, growth and invasiveness of different tumor types. In this study, we investigate the expression of BAG3 in 66 specimens from different lung tumors and the role of this protein in small cell lung cancer (SCLC) tumor growth. Normal lung tissue did not express BAG3 while we detected the expression of BAG3 by immunohistochemistry in all the 13 squamous cell carcinomas, 13 adenocarcinomas and 4 large cell carcinomas. Furthermore, we detected BAG3 expression in 22 of the 36 SCLCs analyzed. The role on SCLC cell survival was determined by down-regulating BAG3 levels in two human SCLC cell lines, i.e. H69 and H446, in vitro and measuring cisplatin induced apoptosis. Indeed down-regulation of BAG3 determines increased cell death and sensitizes cells to cisplatin treatment. The effect of BAG3 down-regulation on tumor growth was also investigated in an in vivo xenograft model by treating mice with an adenovirus expressing a specific bag3 siRNA. Treatment with bag3 siRNA-Ad significantly reduced tumor growth and improved animal survival. In conclusion we show that a subset of SCLCs over express BAG3 that exerts an anti-apoptotic effect resulting in resistance to chemotherapy.

Prognostic value of chemotherapy-induced leukopenia in small-cell lung cancer

PubMed Central

Liu, Wei; Zhang, Cui-Cui; Li, Kai

2013-01-01

Objective Chemotherapy is the standard treatment for small-cell lung cancer (SCLC), and leukopenia is a common side effect. This study assesses whether chemotherapy-induced leukopenia is a predictor of efficacy and whether it is associated with the survival of SCLC patients. Methods A retrospective analysis was conducted on data from 445 patients with SCLC who received standard chemotherapy for 4 to 10 cycles. The World Health Organization grading system classifies leukopenia during chemotherapy as follows: absent (grade 0), mild (grades 1 and 2), or severe (grades 3 and 4). The primary endpoint is overall survival (OS). Results The association between chemotherapy-induced leukopenia and OS was assessed. According to a multivariate Cox model with time-varying covariates, the hazard ratio of death was significantly lower among patients with mild leukopenia than among patients with severe leukopenia at 0.687 (0.506 to 0.943) and 1.414 (1.147 to 1.744), respectively. The median survival was 13 months (95% CI: 11 to 15 months) for patients who did not experience leukopenia, 17 months (95% CI: 14 to 18 months) for those with mild leukopenia, and 14 months (95% CI: 13 to 16 months) for those with severe leukopenia (absent vs. mild vs. severe leukopenia, P=0.047). Conclusion Leukopenia during chemotherapy is associated with the survival of SCLC patients. Mild leukopenia is strongly associated with longer survival time. PMID:23882424

[Prediction of soil adsorption coefficients of organic compounds in a wide range of soil types by soil column liquid chromatography].

PubMed

Guo, Rongbo; Chen, Jiping; Zhang, Qing; Wu, Wenzhong; Liang, Xinmiao

2004-01-01

Using the methanol-water mixtures as mobile phases of soil column liquid chromatography (SCLC), prediction of soil adsorption coefficients (K(d)) by SCLC was validated in a wide range of soil types. The correlations between the retention factors measured by SCLC and soil adsorption coefficients measured by batch experiments were studied for five soils with different properties, i.e., Eurosoil 1#, 2#, 3#, 4# and 5#. The results show that good correlations existed between the retention factors and soil adsorption coefficients for Eurosoil 1#, 2#, 3# and 4#. For Eurosoil 5# which has a pH value of near 3, the correlation between retention factors and soil adsorption coefficients was unsatisfactory using methanol-water as mobile phase of SCLC. However, a good correlation was obtained using a methanol-buffer mixture with pH 3 as the mobile phase. This study proved that the SCLC is suitable for the prediction of soil adsorption coefficients.

Helping Smokers Quit: New Partners and New Strategies from the University of California, San Francisco Smoking Cessation Leadership Center.

PubMed

Schroeder, Steven A; Clark, Brian; Cheng, Christine; Saucedo, Catherine B

2018-01-01

The Smoking Cessation Leadership Center (SCLC) was established in 2003 to increase the rate of smoking cessation attempts and the likelihood those efforts would succeed. Although smoking remains the number one cause of preventable death and disability, clinicians underperform in smoking cessation. Furthermore, many clinical organizations, governmental agencies, and advocacy groups put little effort into smoking cessation. Initially targeted at increasing the efforts of primary care physicians, SCLC efforts expanded to include many other medical and non-physician disciplines, ultimately engaging 21 separate specialties. Most clinicians and their organizations are daunted by efforts required to become cessation experts. A compromise solution, Ask, Advise, Refer (to telephone quitlines), was crafted. SCLC also stimulated smoking cessation projects in governmental, not-for-profit, and industry groups, including the Veterans Administration, the Health Resources Services Administration, Los Angeles County, and the Joint Commission. SCLC helped CVS pharmacies to stop selling tobacco products and other pharmacies to increase smoking cessation efforts, provided multiple educational offerings, and distributed $6.4 million in industry-supported smoking cessation grants to 55 organizations plus $4 million in direct SCLC grants. Nevertheless, smoking still causes 540,000 annual deaths in the US. SCLC's work in the field of behavioral health is described in a companion article.

The pitfalls in cytology diagnosis of poorly differentiated neuroendocrine carcinoma of lung and their treatment response.

PubMed

Saha, Debarshi; Kumar, Ankit; Banerjee, Sourjya; Nirupama, M; Sridevi, H B; Garg, Priya; Lobo, Flora D

2017-01-01

Lung is the most common site of small cell carcinoma (SCLC) - a poorly differentiated neuroendocrine carcinoma (PDNEC). SCLC comprises 15-20% of the invasive cancers of the lung. This study was conducted to appraise the accuracy and pitfalls of the diagnosis of PDNEC on cytology along with treatment responses if available. Retrospective study for 2 years yielded 21 cases on cytology. Slides of fine-needle aspiration of lymph nodes, the tumor, bronchial brush, and bronchoalveolar lavage specimens were used. The histological correlation was obtained as were treatment responses. Eighteen SCLCs were confirmed on review. Of these, 13 initial reports were concordant and five, discordant. The rest three cases which initially reported as SCLC were found to be negative (2) and combined SCLC (1). One SCLC with concordant initial and reviewed diagnoses failed to confirm on histopathology. The patients, all heavy smokers, were predominantly males in the seventh to eighth decade age group. The sensitivity and specificity of reviewed diagnoses were better than that of the original. The difference between histopathology and cytology diagnoses (reviewed and original) was statistically insignificant. All patients were categorized as "extensive stage" by positron emission tomography-computerized tomography, and five were treated with etoposide and cisplatin with/without radiotherapy. Age group (61-70) and gender (males) distribution were statistically significant. Intermediate variants of SCLC may be misdiagnosed as adenocarcinoma. Similarly, combined SCLC may be missed on cytology if the observer does not sustain a high index of suspicion. Unequivocal cytology diagnosis opposed to negative histopathology report demands repeat biopsy.

MHC class II expression in lung cancer.

PubMed

He, Yayi; Rozeboom, Leslie; Rivard, Christopher J; Ellison, Kim; Dziadziuszko, Rafal; Yu, Hui; Zhou, Caicun; Hirsch, Fred R

2017-10-01

Immunotherapy is an exciting development in lung cancer research. In this study we described major histocompatibility complex (MHC) Class II protein expression in lung cancer cell lines and patient tissues. We studied MHC Class II (DP, DQ, DR) (CR3/43, Abcam) protein expression in 55 non-small cell lung cancer (NSCLC) cell lines, 42 small cell lung cancer (SCLC) cell lines and 278 lung cancer patient tissues by immunohistochemistry (IHC). Seven (12.7%) NSCLC cell lines were positive for MHC Class II. No SCLC cell lines were found to be MHC Class II positive. We assessed 139 lung cancer samples available in the Hirsch Lab for MHC Class II. There was no positive MHC Class II staining on SCLC tumor cells. MHC Class II expression on TILs in SCLC was significantly lower than that on TILs in NSCLC (P＜0.001). MHC Class II was also assessed in an additional 139 NSCLC tumor tissues from Medical University of Gdansk, Poland. Patients with positive staining of MHC Class II on TILs had longer regression-free survival (RFS) and overall survival (OS) than those whose TILs were MHC Class II negative (2.980 years, 95% CI 1.628-4.332 vs. 1.050 years, 95% CI 0.556-1.554, P=0.028) (3.230 years, 95% CI 2.617-3.843 vs. 1.390 years, 95% CI 0.629-2.151, P=0.014). MHC Class II was expressed both in NSCLC cell lines and tissues. However, MHC Class II was not detected in SCLC cell lines or tissue tumor cells. MHC Class II expression was lower on SCLC TILs than on NSCLC TILs. Loss of expression of MHC Class II on SCLC tumor cells and reduced expression on SCLC TILs may be a means of escaping anti-cancer immunity. Higher MHC Class II expression on TILs was correlated with better prognosis in patients with NSCLC. Copyright © 2017. Published by Elsevier B.V.

From Bench to Bedside: Attempt to Evaluate Repositioning of Drugs in the Treatment of Metastatic Small Cell Lung Cancer (SCLC)

PubMed Central

Lohinai, Zoltan; Dome, Peter; Szilagyi, Zsuzsa; Ostoros, Gyula; Moldvay, Judit; Hegedus, Balazs

2016-01-01

Backgrounds Based on in vitro data and results of a recent drug repositioning study, some medications approved by the FDA for the treatment of various non-malignant disorders were demonstrated to have anti-SCLC activity in preclinical models. The aim of our study is to confirm whether use of these medications is associated with survival benefit. Methods Consecutive patients with pathologically confirmed, stage 4 SCLC were analyzed in this retrospective study. Patients that were prescribed statins, aspirin, clomipramine (tricyclic antidepressant; TCA), selective serotonin reuptake inhibitors (SSRIs), doxazosin or prazosin (α1-adrenergic receptor antagonists; ADRA1) were identified. Results There were a total of 876 patients. Aspirin, statins, SSRIs, ADRA1, and TCA were administered in 138, 72, 20, 28, and 5 cases, respectively. A statistically significant increase in median OS was observed only in statin-treated patients when compared to those not receiving any of the aforementioned medications (OS, 8.4 vs. 6.1 months, respectively; p = 0.002). The administration of SSRIs, aspirin, and ADRA1 did not result in a statistically significant OS benefit (median OS, 8.5, 6.8, and 6.0 months, respectively). The multivariate Cox model showed that, besides age and ECOG PS, radiotherapy was an independent survival predictor (Hazard Ratio, 2.151; 95% confidence interval, 1.828–2.525; p <0.001). Conclusions Results of drug repositioning studies using only preclinical data or small numbers of patients should be treated with caution before application in the clinic. Our data demonstrated that radiotherapy appears to be an independent survival predictor in stage 4 SCLC, therefore confirming the results of other prospective and retrospective studies. PMID:26735301

Capsaicin Displays Anti-Proliferative Activity against Human Small Cell Lung Cancer in Cell Culture and Nude Mice Models via the E2F Pathway

PubMed Central

Hardman, W. Elaine; Luo, Haitao; Chen, Yi C.; Carpenter, A. Betts; Lau, Jamie K.; Dasgupta, Piyali

2010-01-01

Background Small cell lung cancer (SCLC) is characterized by rapid progression and low survival rates. Therefore, novel therapeutic agents are urgently needed for this disease. Capsaicin, the active ingredient of chilli peppers, displays anti-proliferative activity in prostate and epidermoid cancer in vitro. However, the anti-proliferative activity of capsaicin has not been studied in human SCLCs. The present manuscript fills this void of knowledge and explores the anti-proliferative effect of capsaicin in SCLC in vitro and in vivo. Methodology/Principal Findings BrdU assays and PCNA ELISAs showed that capsaicin displays robust anti-proliferative activity in four human SCLC cell lines. Furthermore, capsaicin potently suppressed the growth of H69 human SCLC tumors in vivo as ascertained by CAM assays and nude mice models. The second part of our study attempted to provide insight into molecular mechanisms underlying the anti-proliferative activity of capsaicin. We found that the anti-proliferative activity of capsaicin is correlated with a decrease in the expression of E2F-responsive proliferative genes like cyclin E, thymidylate synthase, cdc25A and cdc6, both at mRNA and protein levels. The transcription factor E2F4 mediated the anti-proliferative activity of capsaicin. Ablation of E2F4 levels by siRNA methodology suppressed capsaicin-induced G1 arrest. ChIP assays demonstrated that capsaicin caused the recruitment of E2F4 and p130 on E2F-responsive proliferative promoters, thereby inhibiting cell proliferation. Conclusions/Significance Our findings suggest that the anti-proliferative effects of capsaicin could be useful in the therapy of human SCLCs. PMID:20421925

Direct observation of hole transfer from semiconducting polymer to carbon nanotubes.

PubMed

Lan, Fei; Li, Guangyong

2013-05-08

Carbon nanotubes have been proven to play significant roles in polymer-based solar cells. However, there is intensive debate on whether carbon nanotube behaves as a donor or acceptor in the semiconducting polymer:carbon nanotube composite. In this paper, we report a direct observation via Kelvin probe force microscopy (KPFM) that single walled carbon nanotubes (SWNTs) behave as hole transporting channels in poly(3-hexylthiophene-2,5-diyl) (P3HT)/SWNT heterojunctions. By comparing the surface potential (SP) change of SWNT in dark and under illumination, we observed that electrons are blocked from SWNT while holes are transferred to SWNT. This observation can be well-explained by our proposed band alignment model of P3HT/SWNT heterojunction. The finding is further verified by hole mobility measurement using the space charge limited current (SCLC) method. SCLC results indicate that the existence of small amount of SWNT (wt 0.5%) promotes device hole mobility to around 15-fold, indicating SWNT act as hole transfer channel. Our finding of hole transporting behavior of SWNT in P3HT/SWNT blend will provide a useful guidance for enhancing the performance of polymer solar cells by carbon nanotubes.

Risk of Hippocampal Metastases in Small Cell Lung Cancer Patients at Presentation and After Cranial Irradiation: A Safety Profile Study for Hippocampal Sparing During Prophylactic or Therapeutic Cranial Irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kundapur, Vijayananda, E-mail: Vijayananda.kundapur@saskcancer.ca; Ellchuk, Tasha; Ahmed, Shahid

2015-03-15

Purpose: Neurocognitive impairment (NI) in patients with small cell lung cancer (SCLC) after whole brain radiation treatment (WBRT) is a significant cause of morbidity. Hippocampal avoidance (HA) during WBRT may mitigate or prevent NI in such patients. However, this has not been tested in SCLC patients. The estimated risk of metastases in the HA region (HM) in patients with SCLC at diagnosis or after WBRT is unknown. Our study aimed to determine the risk of HM in patients with SCLC and to assess correlated clinical factors. Methods and Materials: Patients with SCLC who experienced brain metastases (BM) at presentation (demore » novo) or after WBRT treated at the Saskatoon Cancer Centre between 2005 and 2012 were studied. Relevant neuroimaging was independently reviewed by a neuroradiologist. HM was defined as metastases within 5 mm of the hippocampus. Logistic regression analysis was performed to assess correlation between various clinical variables and HM. Results: Seventy eligible patients were identified. Of 59 patients presenting with de novo BM, 3 patients (5%, 95% confidence interval [CI]: 0%-10.7%) had HM. Collectively there were 359 (range, 1-33) de novo BM with 3 (0.8%, 95% CI: 0%-1.7%) HM deposits. Twenty patients experienced progression of metastatic disease in the brain after WBRT. Of the 20 patients, only 1 patient (5%, 95% CI: 0%-14.5%) experienced HM. On logistic regression, no factors significantly correlated with HM. Conclusion: The overall incidence of HM before or after WBRT in SCLC patients is low, providing preliminary support for the safety of HA during planned clinical trials of HA-WBRT for SCLC.« less

Targeted therapy with apatinib in a patient with relapsed small cell lung cancer

PubMed Central

Zhao, Jun; Zhang, Xiaoling; Gong, Chaojie; Zhang, Jialei

2017-01-01

Abstract Rationale: Small cell lung cancer (SCLC) is a lethal malignancy. Once relapsed, the disease is irreversible and most of the patients will die of cancer aggravation in 1 to 2 months. In the past several decades, little progress has been made in the systemic treatment of SCLC. Apatinib, as a novel small-molecule tyrosine kinase inhibitor specifically targeting the vascular endothelial growth factor receptor 2 (VEGFR2), has achieved progress in treatment of a variety of cancers. However, there has been no report of the targeted therapy with apatinib in SCLC yet. Patient concerns: A 63-year-old man, an ex-smoker, presented with a slight hoarseness and cough. The patient was admitted to our department with a primary diagnosis of SCLC at an extensive stage (ES-SCLC). After 17 months of successful first-, second-, and third-line chemotherapy, the disease eventually became relapsed. Then, apatinib treatment started promptly on demand by the patient and his family. Intervention: After presenting an informed consent, the patient received apatinib treatment immediately at a dose of 250 mg/day orally. Outcomes: (1) On the 28th day of apatinib therapy, the symptoms of dyspnea and poor appetite of the patient were notably improved. (2) The CT scan taken on the 70th day showed that the pleural effusion in the left lung almost disappeared. (3) The elevated serum neuron-specific enolase (NSE) level was decreased. The patient died of acute respiratory failure on the 172nd day of apatinib treatment. Importantly, the tumor mass did not enlarge obviously during apatinib treatment. Lessons: Here, we presented a case with relapsed SCLC who unexpectedly responded to single-agent apatinib treatment. Therefore, this report will shed light on future studies of targeted therapy with apatinib in SCLC at different stages. PMID:29390367

Study of small-cell lung cancer cell-based sensor and its applications in chemotherapy effects rapid evaluation for anticancer drugs.

PubMed

Guohua, Hui; Hongyang, Lu; Zhiming, Jiang; Danhua, Zhu; Haifang, Wan

2017-11-15

Small cell lung cancer (SCLC) is a smoking-related cancer disease. Despite improvement in clinical survival, SCLC outcome remains extremely poor. Cisplatin (DDP) is the first-line chemotherapy drug for SCLC, but the choice of second-line chemotherapy drugs is not clear. In this paper, a SCLC cell-based sensor was proposed, and its applications in chemotherapy effects rapid evaluation for anticancer drugs were investigated. SCLC cell lines lung adenocarcinoma cell (LTEP-P) and DDP-resistant lung adenocarcinoma cell (LTEP-P/DDP-1.0) are cultured on carbon screen-printed electrode (CSPE) to fabricate integrated cell-based sensor. Several chemotherapy anticancer drugs, including cisplatin, ifosmamide, gemcitabine, paclitaxel, docetaxel, vinorelbine, etoposide, camptothecin, and topotecan, are selected as experimental chemicals. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) tests are conducted to evaluate chemotherapy drug effects on LTEP-P and LTEP-P/DDP-1.0 cell lines. Electrical cell-substrate impedance sensing (ECIS) responses to anti-tumor chemicals are measured and processed by double-layered cascaded stochastic resonance (DCSR). Cisplatin solutions in different concentrations measurement results demonstrate that LTEP-P cell-based sensor presents quantitative analysis abilities for cisplatin and topotecan. Cisplatin and its mixtures can also be discriminated. Results demonstrate that LTEP-P cell-based sensor sensitively evaluates chemotherapy drugs' apoptosis function to SCLC cells. LTEP-P/DDP-1.0 cell-based sensor responses demonstrate that gemcitabine, vinorelbine, and camptothecin are ideal second-line drugs for clinical post-cisplatin therapy than other drugs according to MTT test results. This work provides a novel way for SCLC second-line clinical chemotherapy drug screening. Copyright © 2017 Elsevier B.V. All rights reserved.

Identification of deregulation of apoptosis and cell cycle in neuroendocrine tumors of the lung via NanoString nCounter expression analysis.

PubMed

Walter, Robert Fred Henry; Werner, Robert; Ting, Saskia; Vollbrecht, Claudia; Theegarten, Dirk; Christoph, Daniel Christian; Schmid, Kurt Werner; Wohlschlaeger, Jeremias; Mairinger, Fabian Dominik

2015-09-22

Neuroendocrine tumors of the lung comprise typical (TC) and atypical carcinoids (AC), large-cell neuroendocrine cancer (LCNEC) and small-cell lung cancer (SCLC). Cell cycle and apoptosis are key pathways of multicellular homeostasis and deregulation of these pathways is associated with cancerogenesis. Sixty representative FFPE-specimens (16 TC, 13 AC, 16 LCNEC and 15 SCLC) were used for mRNA expression analysis using the NanoString technique. Eight genes related to apoptosis and ten genes regulating key points of cell cycle were investigated. ASCL1, BCL2, CASP8, CCNE1, CDK1, CDK2, CDKN1A and CDKN2A showed lower expression in carcinoids compared to carcinomas. In contrast, CCNE1 and CDK6 showed elevated expression in carcinoids compared to carcinomas. The calculated BCL2/BAX ratio showed increasing values from TC to SCLC. Between SCLC and LCNEC CDK2, CDKN1B, CDKN2A and PNN expression was significantly different with higher expression in SCLC. Carcinoids have increased CDK4/6 and CCND1 expression controlling RB1 phosphorylation via this signaling cascade. CDK2 and CCNE1 were increased in carcinomas showing that these use the opposite way to control RB1. BAX and BCL2 are antagonists in regulating apoptosis. BCL2 expression increased over BAX expression with increasing malignancy of the tumor from TC to SCLC.

Small cell lung cancer transformation from EGFR-mutated lung adenocarcinoma: A case report and literatures review.

PubMed

Liu, Yangyang

2018-06-03

Epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have markedly improved the response of non-small cell lung cancer (NSCLC) with EGFR-mutant patients. However, these patients inevitably come cross acquired resistance to EGFR-TKIs. The transformation of lung adenocarcinoma to small cell lung cancer (SCLC) following treatment with EGFR-TKIs is rare, which leads to resistance to EGFR-TKIs. The present case concerns a case of a 38-year-old man presenting with cough and dyspnea. Radical resection was performed and confirmed an EGFR exon 21 L858R lung adenocarcinoma. However, the patient suffered pleural metastasis after successful treatment with surgery and adjuvant treatment. So, erlotinib was administered with 18 months. Because of enlarged pleural nodule, repeat biopsy identified an SCLC and chemotherapy was started. However, despite the brief success of chemotherapy, our patient suffered brain metastasis. Our case emaphsizes both the profile of transformation from NSCLC to SCLC and the importance of repeat biopsy dealing with drug resistance. We also summarize the clinical characteristics, mechanisms, predictors of SCLC transformation, treatment after transformation and other types of transformation to SCLC.

Whole-genome analysis of a patient with early-stage small-cell lung cancer.

PubMed

Han, J-Y; Lee, Y-S; Kim, B C; Lee, G K; Lee, S; Kim, E-H; Kim, H-M; Bhak, J

2014-12-01

We performed whole-genome sequencing (WGS) of a case of early-stage small-cell lung cancer (SCLC) to analyze the genomic features. WGS revealed a lot of single-nucleotide variations (SNVs), small insertion/deletions and chromosomal abnormality. Chromosomes 4p, 5q, 13q, 15q, 17p and 22q contained many block deletions. Especially, copy loss was observed in tumor suppressor genes RB1 and TP53, and copy gain in oncogene hTERT. Somatic mutations were found in TP53 and CREBBP. Novel nonsynonymous (ns) SNVs in C6ORF103 and SLC5A4 genes were also found. Sanger sequencing of the SLC5A4 gene in 23 independent SCLC samples showed another nsSNV in the SLC5A4 gene, indicating that nsSNVs in the SLC5A4 gene are recurrent in SCLC. WGS of an early-stage SCLC identified novel recurrent mutations and validated known variations, including copy number variations. These findings provide insight into the genomic landscape contributing to SCLC development.

Clinical evaluation of a novel microfluidic device for epitope-independent enrichment of circulating tumour cells in patients with small cell lung cancer.

PubMed

Chudziak, Jakub; Burt, Deborah J; Mohan, Sumitra; Rothwell, Dominic G; Mesquita, Bárbara; Antonello, Jenny; Dalby, Suzanne; Ayub, Mahmood; Priest, Lynsey; Carter, Louise; Krebs, Matthew G; Blackhall, Fiona; Dive, Caroline; Brady, Ged

2016-01-21

Circulating tumour cells (CTCs) have potential utility as minimally-invasive biomarkers to aid cancer treatment decision making. However, many current CTC technologies enrich CTCs using specific surface epitopes that do not necessarily reflect CTC heterogeneity. Here we evaluated the epitope-independent Parsortix system which enriches CTCs based on size and rigidity using both healthy normal volunteer blood samples spiked with tumour cells and blood samples from patients with small cell lung cancer (SCLC). Blood samples were maintained unfractionated at room temperature for up to 4 days followed by plasma removal for circulating free DNA (cfDNA) isolation and direct application of the remaining cell component to the Parsortix system. For tumour cells expressing the EpCAM cell surface marker the numbers of spiked cells retained using the Parsortix system and by EpCAM-positive selection using CellSearch® were not significantly different, whereas only the Parsortix system showed strong enrichment of cells with undetectable EpCAM expression. In a pilot clinical study we banked both enriched CTCs as well as plasma from SCLC patient blood samples. Upon retrieval of the banked Parsortix cellular samples we could detect cytokeratin positive CTCs in all 12 SCLC patients tested. Interestingly, processing parallel samples from the same patients by EpCAM enrichment using CellSearch® revealed only 83% (10/12) with cytokeratin positive CTCs indicating the Parsortix system is enriching for EpCAM negative SCLC CTCs. Our combined results indicate the Parsortix system is a valuable tool for combined cfDNA isolation and CTC enrichment that enables CTC analysis to be extended beyond dependence on surface epitopes.

Charge Transport in Carbon Nanotubes-Polymer Composite Photovoltaic Cells

PubMed Central

Ltaief, Adnen; Bouazizi, Abdelaziz; Davenas, Joel

2009-01-01

We investigate the dark and illuminated current density-voltage (J/V) characteristics of poly(2-methoxy-5-(2’-ethylhexyloxy)1-4-phenylenevinylene) (MEH-PPV)/single-walled carbon nanotubes (SWNTs) composite photovoltaic cells. Using an exponential band tail model, the conduction mechanism has been analysed for polymer only devices and composite devices, in terms of space charge limited current (SCLC) conduction mechanism, where we determine the power parameters and the threshold voltages. Elaborated devices for MEH-PPV:SWNTs (1:1) composites showed a photoresponse with an open-circuit voltage Voc of 0.4 V, a short-circuit current density JSC of 1 µA/cm² and a fill factor FF of 43%. We have modelised the organic photovoltaic devices with an equivalent circuit, where we calculated the series and shunt resistances.

Vasoactive Intestinal Peptide Inhibits Human Small-Cell Lung Cancer Proliferation in vitro and in vivo

NASA Astrophysics Data System (ADS)

Maruno, Kaname; Absood, Afaf; Said, Sami I.

1998-11-01

Small-cell lung carcinoma (SCLC) is an aggressive, rapidly growing and metastasizing, and highly fatal neoplasm. We report that vasoactive intestinal peptide inhibits the proliferation of SCLC cells in culture and dramatically suppresses the growth of SCLC tumor-cell implants in athymic nude mice. In both cases, the inhibition was mediated apparently by a cAMP-dependent mechanism, because the inhibition was enhanced by the adenylate cyclase activator forskolin and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine in proportion to increases in intracellular cAMP levels, and the inhibition was abolished by selective inhibition of cAMP-dependent protein kinase. If confirmed in clinical trials, this antiproliferative action of vasoactive intestinal peptide may offer a new and promising means of suppressing SCLC in human subjects, without the toxic side effects of chemotherapeutic agents.

Identification of deregulation of apoptosis and cell cycle in neuroendocrine tumors of the lung via NanoString nCounter expression analysis

PubMed Central

Walter, Robert Fred Henry; Werner, Robert; Ting, Saskia; Vollbrecht, Claudia; Theegarten, Dirk; Christoph, Daniel Christian; Schmid, Kurt Werner; Wohlschlaeger, Jeremias; Mairinger, Fabian Dominik

2015-01-01

Background Neuroendocrine tumors of the lung comprise typical (TC) and atypical carcinoids (AC), large-cell neuroendocrine cancer (LCNEC) and small-cell lung cancer (SCLC). Cell cycle and apoptosis are key pathways of multicellular homeostasis and deregulation of these pathways is associated with cancerogenesis. Materials and Methods Sixty representative FFPE-specimens (16 TC, 13 AC, 16 LCNEC and 15 SCLC) were used for mRNA expression analysis using the NanoString technique. Eight genes related to apoptosis and ten genes regulating key points of cell cycle were investigated. Results ASCL1, BCL2, CASP8, CCNE1, CDK1, CDK2, CDKN1A and CDKN2A showed lower expression in carcinoids compared to carcinomas. In contrast, CCNE1 and CDK6 showed elevated expression in carcinoids compared to carcinomas. The calculated BCL2/BAX ratio showed increasing values from TC to SCLC. Between SCLC and LCNEC CDK2, CDKN1B, CDKN2A and PNN expression was significantly different with higher expression in SCLC. Conclusion Carcinoids have increased CDK4/6 and CCND1 expression controlling RB1 phosphorylation via this signaling cascade. CDK2 and CCNE1 were increased in carcinomas showing that these use the opposite way to control RB1. BAX and BCL2 are antagonists in regulating apoptosis. BCL2 expression increased over BAX expression with increasing malignancy of the tumor from TC to SCLC. PMID:26008974

Proteasome inhibitor bortezomib enhances the effect of standard chemotherapy in small cell lung cancer

PubMed Central

Taromi, Sanaz; Lewens, Florentine; Arsenic, Ruza; Sedding, Dagmar; Sänger, Jörg; Kunze, Almut; Möbs, Markus; Benecke, Joana; Freitag, Helma; Christen, Friederike; Kaemmerer, Daniel; Lupp, Amelie; Heilmann, Mareike; Lammert, Hedwig; Schneider, Claus-Peter; Richter, Karen; Hummel, Michael; Siegmund, Britta; Burger, Meike; Briest, Franziska; Grabowski, Patricia

2017-01-01

Small cell lung cancer (SCLC) is an aggressive cancer showing a very poor prognosis because of metastasis formation at an early stage and acquisition of chemoresistance. One key driver of chemoresistance is the transcription factor Forkhead box protein M1 (FOXM1) that regulates cell cycle proliferation, maintenance of genomic stability, DNA damage response, and cell differentiation in numerous tumor entities. In this study we investigated the role of FOXM1 in SCLC progression and analyzed the effect of FOXM1 inhibition using two proteasome inhibitors, bortezomib and siomycin A. FOXM1 was strongly expressed in patient-derived SCLC samples (n=123) and its nuclear localization was associated with the proliferation marker Ki-67. Both proteasome inhibitors successfully inhibited FOXM1 expression leading to a significantly reduced proliferation and a decreased mitotic rate along with cell cycle arrest and apoptosis induction. These effects were further enhanced by addition of bortezomib to standard chemotherapy. Treatment of mice bearing chemoresistant SCLC xenografts with bortezomib reduced the mean bioluminescence signal of tumors by 54%. Similarly, treatment with cisplatin as a standard chemotherapy reduced the mean bioluminescence signal of tumors by 58%. However, in combination with standard chemotherapy bortezomib further reduced the mean bioluminescence signal by 93% (p=0.0258). In conclusion, we demonstrate the effect of bortezomib in inhibiting FOXM1 expression and thus in sensitizing resistant SCLC cells to standard chemotherapy. Thus, addition of bortezomib to standard chemotherapy might potently improve SCLC therapy, particularly in an extensive cancer stage. PMID:29228593

Proteasome inhibitor bortezomib enhances the effect of standard chemotherapy in small cell lung cancer.

PubMed

Taromi, Sanaz; Lewens, Florentine; Arsenic, Ruza; Sedding, Dagmar; Sänger, Jörg; Kunze, Almut; Möbs, Markus; Benecke, Joana; Freitag, Helma; Christen, Friederike; Kaemmerer, Daniel; Lupp, Amelie; Heilmann, Mareike; Lammert, Hedwig; Schneider, Claus-Peter; Richter, Karen; Hummel, Michael; Siegmund, Britta; Burger, Meike; Briest, Franziska; Grabowski, Patricia

2017-11-14

Small cell lung cancer (SCLC) is an aggressive cancer showing a very poor prognosis because of metastasis formation at an early stage and acquisition of chemoresistance. One key driver of chemoresistance is the transcription factor Forkhead box protein M1 (FOXM1) that regulates cell cycle proliferation, maintenance of genomic stability, DNA damage response, and cell differentiation in numerous tumor entities. In this study we investigated the role of FOXM1 in SCLC progression and analyzed the effect of FOXM1 inhibition using two proteasome inhibitors, bortezomib and siomycin A. FOXM1 was strongly expressed in patient-derived SCLC samples (n=123) and its nuclear localization was associated with the proliferation marker Ki-67. Both proteasome inhibitors successfully inhibited FOXM1 expression leading to a significantly reduced proliferation and a decreased mitotic rate along with cell cycle arrest and apoptosis induction. These effects were further enhanced by addition of bortezomib to standard chemotherapy. Treatment of mice bearing chemoresistant SCLC xenografts with bortezomib reduced the mean bioluminescence signal of tumors by 54%. Similarly, treatment with cisplatin as a standard chemotherapy reduced the mean bioluminescence signal of tumors by 58%. However, in combination with standard chemotherapy bortezomib further reduced the mean bioluminescence signal by 93% (p=0.0258). In conclusion, we demonstrate the effect of bortezomib in inhibiting FOXM1 expression and thus in sensitizing resistant SCLC cells to standard chemotherapy. Thus, addition of bortezomib to standard chemotherapy might potently improve SCLC therapy, particularly in an extensive cancer stage.

Acetylcholine receptor antibody-positive myasthenia gravis associated with small-cell lung cancer

PubMed Central

Yamasaki, Masahiro; Funaishi, Kunihiko; Saito, Naomi; Yonekawa, Tomomi; Yamawaki, Takemori; Ihara, Daisuke; Daido, Wakako; Ishiyama, Sayaka; Deguchi, Naoko; Taniwaki, Masaya; Hattori, Noboru

2018-01-01

Abstract Rationale: Only few cases of myasthenia gravis (MG) associated with small-cell lung cancer (SCLC) have been reported, and cases positive for acetylcholine receptor antibody (AChR-ab) are even rarer. The efficacy of standard MG treatment, such as cholinesterase inhibitor therapy, immunosuppressive therapy using steroids and immunosuppressive drugs, plasma exchange, and intravenous immune globulin (IVIg), for these cases is unclear. Patient concerns and diagnoses: A 71-year-old man complained of bilateral eyelid ptosis. He also presented with dysphagia and masticatory muscle fatigue after chewing. The edrophonium test was positive, and the serum AChR-ab level was increased; therefore, the patient was diagnosed with MG. Computed tomography scan showed a nodule on the left upper lobe of the lung and mediastinal lymphadenopathy. Further examination revealed the lesion as SCLC. Finally, he was diagnosed with AChR-ab-positive MG associated with SCLC. Interventions and outcomes: Oral pyridostigmine and tacrolimus were administered to treat MG; however, his symptoms worsened. Therefore, methylprednisolone and IVIg were administrated, which temporarily improved his symptoms. However, they remained uncontrolled. Meanwhile, chemotherapy with carboplatin and etoposide was administered to treat his SCLC. The lesions shrunk, and the MG symptoms and serum AChR-ab level also improved. Lessons: AChR-ab-positive MG may develop as a comorbidity of SCLC. In such cases, management might require treatment for SCLC in addition to the standard MG treatment to stabilize the MG symptoms. PMID:29703032

Liquid crystalline perylene diimide outperforming nonliquid crystalline counterpart: higher power conversion efficiencies (PCEs) in bulk heterojunction (BHJ) cells and higher electron mobility in space charge limited current (SCLC) devices.

PubMed

Zhang, Youdi; Wang, Helin; Xiao, Yi; Wang, Ligang; Shi, Dequan; Cheng, Chuanhui

2013-11-13

In this work, we propose the application of liquid crystalline acceptors as a potential means to improve the performances of bulk heterojunction (BHJ) organic solar cells. LC-1, a structurally-simple perylene diimide (PDI), has been adopted as a model for thorough investigation. It exhibits a broad temperature range of liquid crystalline (LC) phase from 41 °C to 158 °C, and its LC properties have been characterized by differental scanning calorimetry (DSC), polarization optical microscopy (POM), and X-ray diffraction (XRD). The BHJ devices, using P3HT:LC-1 (1:2) as an organic photovoltaic active layer undergoing thermal annealing at 120 °C, shows an optimized efficiency of 0.94 %. By contrast, the devices based on PDI-1, a nonliquid crystalline PDI counterpart, only obtain a much lower efficiency of 0.22%. Atomic force microscopy (AFM) images confirm that the active layers composed of P3HT:LC-1 have smooth and ordered morphology. In space charge limited current (SCLC) devices fabricated via a spin-coating technique, LC-1 shows the intrinsic electron mobility of 2.85 × 10(-4) cm(2)/(V s) (at 0.3 MV/cm) which is almost 5 times that of PDI-1 (5.83 × 10(-5) cm(2)/(V s)) under the same conditions for thermal annealing at 120 °C.

Surgery for limited-stage small-cell lung cancer.

PubMed

Barnes, Hayley; See, Katharine; Barnett, Stephen; Manser, Renée

2017-04-21

Current treatment guidelines for limited-stage small-cell lung cancer (SCLC) recommend concomitant platinum-based chemo-radiotherapy plus prophylactic cranial irradiation, based on the premise that SCLC disseminates early, and is chemosensitive. However, although there is usually a favourable initial response, relapse is common and the cure rate for limited-stage SCLC remains relatively poor. Some recent clinical practice guidelines have recommended surgery for stage 1 (limited) SCLC followed by adjuvant chemotherapy, but this recommendation is largely based on the findings of observational studies. To determine whether, in patients with limited-stage SCLC, surgical resection of cancer improves overall survival and treatment-related deaths compared with radiotherapy or chemotherapy, or a combination of radiotherapy and chemotherapy, or best supportive care. We performed searches on CENTRAL, MEDLINE, Embase, CINAHL, and Web of Science up to 11 January 2017. We handsearched review articles, clinical trial registries, and reference lists of retrieved articles. We included randomised controlled trials (RCTs) with adults diagnosed with limited-stage SCLC, confirmed by cytology or histology, and radiological assessment, considered medically suitable for resection and radical radiotherapy, which randomised participants to surgery versus any other intervention. We imported studies identified by the search into a reference manager database. We retrieved the full-text version of relevant studies, and two review authors independently extracted data. The primary outcome measures were overall survival and treatment-related deaths; and secondary outcome measures included loco-regional progression, quality of life, and adverse events. We included three trials with 330 participants. We judged the quality of the evidence as very low for all the outcomes. The quality of the data was limited by the lack of complete outcome reporting, unclear risk of bias in the methods in which the studies were conducted, and the age of the studies (> 20 years). The methods of cancer staging and types of surgical procedures, which do not reflect current practice, reduced our confidence in the estimation of the effect.Two studies compared surgery to radiation therapy, and in one study chemotherapy was administered to both arms. One study administered initial chemotherapy, then responders were randomised to surgery versus control; following, both groups underwent chest and whole brain irradiation.Due to the clinical heterogeneity of the trials, we were unable to pool results for meta-analysis.All three studies reported overall survival. One study reported a mean overall survival of 199 days in the surgical arm, compared to 300 days in the radiotherapy arm (P = 0.04). One study reported overall survival as 4% in the surgical arm, compared to 10% in the radiotherapy arm at two years. Conversely, one study reported overall survival at two years as 52% in the surgical arm, compared to 18% in the radiotherapy arm. However this difference was not statistically significant (P = 0.12).One study reported early postoperative mortality as 7% for the surgical arm, compared to 0% mortality in the radiotherapy arm. One study reported the difference in mean degree of dyspnoea as -1.2 comparing surgical intervention to radiotherapy, indicating that participants undergoing radiotherapy are likely to experience more dyspnoea. This was measured using a non-validated scale. Evidence from currently available RCTs does not support a role for surgical resection in the management of limited-stage small-cell lung cancer; however our conclusions are limited by the quality of the available evidence and the lack of contemporary data. The results of the trials included in this review may not be generalisable to patients with clinical stage 1 small-cell lung cancer carefully staged using contemporary staging methods. Although some guidelines currently recommend surgical resection in clinical stage 1 small-cell lung cancer, prospective randomised controlled trials are needed to determine if there is any benefit in terms of short- and long-term mortality and quality of life compared with chemo-radiotherapy alone.

Change from lung adenocarcinoma to small cell lung cancer as a mechanism of resistance to afatinib.

PubMed

Manca, Paolo; Russano, Marco; Pantano, Francesco; Tonini, Giuseppe; Santini, Daniele

2017-08-29

We report the case of a patient affected by advanced EGFR mutation-positive lung who experienced resistance to therapy during treatment with Afatinib through the occurrence of a switch of tumor histotype to small cell lung cancer (SCLC) with features of a G3 neuroendocrine carcinoma. Unexpectedly, the switch to SCLC histotype occurred in the only site not responsive to afatinib and subsequently the most responsive to chemotherapy. Our case shows that occurrence of switch to SCLC is a possible mechanism of resistance during treatment with Afatinib.

Targeted therapy with apatinib in a patient with relapsed small cell lung cancer: A case report and literature review.

PubMed

Zhao, Jun; Zhang, Xiaoling; Gong, Chaojie; Zhang, Jialei

2017-12-01

Small cell lung cancer (SCLC) is a lethal malignancy. Once relapsed, the disease is irreversible and most of the patients will die of cancer aggravation in 1 to 2 months. In the past several decades, little progress has been made in the systemic treatment of SCLC. Apatinib, as a novel small-molecule tyrosine kinase inhibitor specifically targeting the vascular endothelial growth factor receptor 2 (VEGFR2), has achieved progress in treatment of a variety of cancers. However, there has been no report of the targeted therapy with apatinib in SCLC yet. A 63-year-old man, an ex-smoker, presented with a slight hoarseness and cough. The patient was admitted to our department with a primary diagnosis of SCLC at an extensive stage (ES-SCLC). After 17 months of successful first-, second-, and third-line chemotherapy, the disease eventually became relapsed. Then, apatinib treatment started promptly on demand by the patient and his family. After presenting an informed consent, the patient received apatinib treatment immediately at a dose of 250 mg/day orally. (1) On the 28th day of apatinib therapy, the symptoms of dyspnea and poor appetite of the patient were notably improved. (2) The CT scan taken on the 70th day showed that the pleural effusion in the left lung almost disappeared. (3) The elevated serum neuron-specific enolase (NSE) level was decreased. The patient died of acute respiratory failure on the 172nd day of apatinib treatment. Importantly, the tumor mass did not enlarge obviously during apatinib treatment. Here, we presented a case with relapsed SCLC who unexpectedly responded to single-agent apatinib treatment. Therefore, this report will shed light on future studies of targeted therapy with apatinib in SCLC at different stages. Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.

Distinct Characteristics of Small Cell Lung Cancer Correlate With Central or Peripheral Origin: Subtyping Based on Location and Expression of Transcription Factor TTF-1.

PubMed

Miyauchi, Eisaku; Motoi, Noriko; Ono, Hiroshi; Ninomiya, Hironori; Ohyanagi, Fumiyoshi; Nishio, Makoto; Okumura, Sakae; Ichinose, Masakazu; Ishikawa, Yuichi

2015-12-01

Small-cell lung carcinoma (SCLC) is a type of lung cancer with neuroendocrine differentiation and a poor prognosis that is widely believed to arise in the central lung. Thyroid transcription factor-1 (TTF-1) is a peripheral marker of lung adenocarcinoma that is also highly expressed in SCLC. In this study, we examined whether SCLC is really a central-type tumor and the relationship between tumor location, TTF-1 expression and prognosis of SCLC.Ninety six SCLCs, diagnosed from biopsies or surgical materials, for which detailed computed tomography (CT) images were available, were collected consecutively from Japanese patients between 2004 and 2011. We examined the location of the primary tumor (central or peripheral) using thin-sliced CT, a TTF-1 immunohistochemical expression, and clinicopathology including prognosis.Of the 96 SCLCs, 74% (71/96) were of the peripheral type and found to have a significantly worse prognosis than central-type tumors. TTF-1 immunoreactivity was identified in 79 tumors (82%), 78% of which (62/79) were of the peripheral type and 22% of which were central. TTF-1 expression was significantly correlated with peripheral location (P = 0.030). Multivariate analysis revealed that high TNM stages and the peripheral location were independent markers for poor survival.The majority of SCLCs were of the peripheral type. The peripheral-type SCLC expressed TTF-1 more frequently and had a poorer prognosis than central-type tumors did. Further analysis on original sites of SCLC, using molecular methodology, or based on another ethnicity, should be warranted.

MRP- and BCL-2-mediated drug resistance in human SCLC: effects of apoptotic sphingolipids in vitro.

PubMed

Khodadadian, M; Leroux, M E; Auzenne, E; Ghosh, S C; Farquhar, D; Evans, R; Spohn, W; Zou, Y; Klostergaard, J

2009-10-01

Multidrug-resistance-associated protein (MRP) and BCL-2 contribute to drug resistance expressed in SCLC. To establish whether MRP-mediated drug resistance affects sphingolipid (SL)-induced apoptosis in SCLC, we first examined the human SCLC cell line, UMCC-1, and its MRP over-expressing, drug-resistant subline, UMCC-1/VP. Despite significantly decreased sensitivity to doxorubicin (Dox) and to the etoposide, VP-16, the drug-selected line was essentially equally as sensitive to treatment with exogenous ceramide (Cer), sphingosine (Sp) or dimethyl-sphingosine (DMSP) as the parental line. Next, we observed that high BCL-2-expressing human H69 SCLC cells, that were approximately 160-fold more sensitive to Dox than their combined BCL-2 and MRP-over-expressing (H69AR) counterparts, were only approximately 5-fold more resistant to DMSP. Time-lapse fluorescence microscopy of either UMCC cell line treated with DMSP-Coumarin revealed comparable extents and kinetics of SL uptake, further ruling out MRP-mediated effects on drug uptake. DMSP potentiated the cytotoxic activity of VP-16 and Taxol, but not Dox, in drug-resistant UMCC-1/VP cells. However, this sensitization did not appear to involve DMSP-mediated effects on the function of MRP in drug export; nor did DMSP strongly shift the balance of pro-apoptotic Sps and anti-apoptotic Sp-1-Ps in these cells. We conclude that SL-induced apoptosis markedly overcomes or bypasses MRP-mediated drug resistance relevant to SCLC and may suggest a novel therapeutic approach to chemotherapy for these tumors.

Second-Line Therapy of Small-Cell Lung Cancer: Topotecan Compared to a Combination Treatment with Adriamycin, Cyclophosphamide And Vincristine (ACO) - a Single Center Experience

PubMed Central

Hagmann, Raphael; Hess, Viviane; Zippelius, Alfred; Rothschild, Sacha I.

2015-01-01

Background: Randomized trials established topotecan and the combination of adriamycin, cyclophosphamide and vincristine (ACO) as second-line therapy options for small-cell lung cancer. We retrospectively evaluated the outcome of SCLC patients undergoing second-line chemotherapy. Patients and Methods: 92 consecutive patients with a diagnosis of SCLC between 2000 and 2010 were analyzed. Results: 86 patients (93.5%) were evaluable for outcome analysis. All patients diagnosed with limited disease (LD) SCLC received platinum-based chemotherapy as first-line treatment. 69 patients (98.6%) diagnosed with extensive disease (ED) SCLC received first-line palliative chemotherapy. In the total cohort, the median overall survival (OS) was 10.3 months (19.2 months and 9.2 months for LD-SCLC and ED-SCLC, respectively). 42 patients received second-line therapy (ACO in 47.6% and topotecan in 31.0% of patients, respectively). Eight patients (19.0%) were re-challenged with platinum/etoposide. Neither the overall response rate (52.9% vs. 22.2%; p=0.128) nor progression-free survival (2.4 vs. 2.4 months; p=0.794) or OS (5.5 vs. 5.0 months; p=0.997) were significantly different between ACO and topotecan. ACO-treated patients showed a trend towards a longer duration of inpatient care. Conclusion: We showed similar outcomes as reported in clinical trials. Second-line combination chemotherapy with ACO did not show superiority to intravenous topotecan, but was associated with a clinically relevant longer hospitalization time. PMID:26516363

Penetration of Recommended Procedures for Lung Cancer Staging and Management in the United States over 10 Years: A Quality Research in Radiation Oncology Survey

PubMed Central

Komaki, Ritsuko; Khalid, Najma; Langer, Corey J.; Kong, Feng-Ming (Spring); Owen, Jean B.; Crozier, Cheryl L.; Wilson, J. Frank; Wei, Xiong; Movsas, Benjamin

2013-01-01

Purpose To document the penetration of clinical trial results, practice guidelines, and appropriateness criteria into national practice, we compared the use of components of staging and treatment for lung cancer among patients treated in 2006–2007 versus in 1998–1999. Methods Patient, staging work-up, and treatment characteristics were extracted from the process survey database of the Quality Research in Radiation Oncology (QRRO), comprising records from 340 patients with locally advanced non-small cell lung cancer (LA-NSCLC) at 44 institutions and 144 patients with limited-stage small cell lung cancer (LS-SCLC) at 39 institutions. Data were compared for patients treated in 2006–2007 versus patients treated in 1998–1999. Results Use of all recommended procedures for staging and treatment was more common in 2006–2007. Specifically, disease was staged with brain imaging (magnetic resonance imaging or computed tomography) and whole-body imaging (positron emission tomography or bone scanning) in 66% of patients with LA-NSCLC in 2006–2007 (vs. 42% in 1998–1999, p=0.0001) and in 84% of patients with LS-SCLC in 2006–2007 (vs. 58.3% in 1998–1999, p=0.0011). Concurrent chemoradiation was used for 77% of LA-NSCLC patients (vs. 45% in 1998–1999, p<0.0001) and for 90% of LS-SCLC patients (vs. 62.5% in 1998–1999, p<0.0001). Use of the recommended radiation dose (59–74 Gy for NSCLC and 60–70 Gy as once-daily therapy for SCLC) did not change appreciably, being 88% for NSCLC in both periods and 51% (2006–2007) vs. 43% (1998–1999) for SCLC. Twice-daily radiation for SCLC was used for 21% of patients in 2006–2007 vs. 8% in 1998–1999. Finally, 49% of patients with LS-SCLC received prophylactic cranial irradiation (PCI) in 2006–2007 (vs. 21% in 1998–1999). Conclusion Although adherence to all quality indicators improved over time, brain imaging and recommended radiation doses for stage III NSCLC were used in <90% of cases. Use of full thoracic doses and PCI for LS-SCLC also require improvement. PMID:23273996

Penetration of Recommended Procedures for Lung Cancer Staging and Management in the United States Over 10 Years: A Quality Research in Radiation Oncology Survey

DOE Office of Scientific and Technical Information (OSTI.GOV)

Komaki, Ritsuko, E-mail: rkomaki@mdanderson.org; Khalid, Najma; Langer, Corey J.

2013-03-15

Purpose: To document the penetration of clinical trial results, practice guidelines, and appropriateness criteria into national practice, we compared the use of components of staging and treatment for lung cancer among patients treated in 2006-2007 with those used in patients treated in 1998-1999. Methods and Materials: Patient, staging work-up, and treatment characteristics were extracted from the process survey database of the Quality Research in Radiation Oncology (QRRO), consisting of records of 340 patients with locally advanced non-small cell lung cancer (LA-NSCLC) at 44 institutions and of 144 patients with limited-stage small cell lung cancer (LS-SCLC) at 39 institutions. Data weremore » compared for patients treated in 2006-2007 versus those for patients treated in 1998-1999. Results: Use of all recommended procedures for staging and treatment was more common in 2006-2007. Specifically, disease was staged with brain imaging (magnetic resonance imaging or computed tomography) and whole-body imaging (positron emission tomography or bone scanning) in 66% of patients with LA-NSCLC in 2006-2007 (vs 42% in 1998-1999, P=.0001) and in 84% of patients with LS-SCLC in 2006-2007 (vs 58.3% in 1998-1999, P=.0011). Concurrent chemoradiation was used for 77% of LA-NSCLC patients (vs 45% in 1998-1999, P<.0001) and for 90% of LS-SCLC patients (vs 62.5% in 1998-1999, P<.0001). Use of the recommended radiation dose (59-74 Gy for NSCLC and 60-70 Gy as once-daily therapy for SCLC) did not change appreciably, being 88% for NSCLC in both periods and 51% (2006-2007) versus 43% (1998-1999) for SCLC. Twice-daily radiation for SCLC was used for 21% of patients in 2006-2007 versus 8% in 1998-1999. Finally, 49% of patients with LS-SCLC received prophylactic cranial irradiation (PCI) in 2006-2007 (vs 21% in 1998-1999). Conclusions: Although adherence to all quality indicators improved over time, brain imaging and recommended radiation doses for stage III NSCLC were used in <90% of cases. Use of full thoracic doses and PCI for LS-SCLC also requires improvement.« less

Immune checkpoint inhibitors in small cell lung cancer.

PubMed

Pakkala, Suchita; Owonikoko, Taofeek K

2018-02-01

Small cell lung cancer (SCLC) is a rapidly progressive cancer that often debilitates patients within months of detection and quickly becomes refractory to the limited options of therapy. While SCLC is not generally considered an immunogenic tumor, clinical experience suggests that patients with robust immune response manifesting as paraneoplastic syndrome are more likely to present with limited stage of the disease and tend to have a better prognosis. Monoclonal antibodies targeting critical negative regulators of immune response, so called immune checkpoints, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD-1) have expanded the application of immune-based therapies to increasing number of advanced stage cancers. These agents overcome the inhibitory immune signals leading to a heightened immune response against cancer cells. These immune checkpoint inhibitors have established efficacy leading to regulatory approval for their use in many cancer types including non-small cell lung cancer (NSCLC). Evaluation of the CTLA-4 inhibitor, ipilimumab and PD-1 inhibitors, nivolumab and pembrolizumab in SCLC have shown encouraging signal but definitive studies are still ongoing. In this review, we discuss the rationale behind the use of checkpoint inhibitors in SCLC, contextualize the results of early trials of immunotherapy agents in SCLC and project the future evolution of this strategy.

System analysis identifies distinct and common functional networks governed by transcription factor ASCL1, in glioma and small cell lung cancer.

PubMed

Donakonda, Sainitin; Sinha, Swati; Dighe, Shrinivas Nivrutti; Rao, Manchanahalli R Satyanarayana

2017-07-25

ASCL1 is a basic Helix-Loop-Helix transcription factor (TF), which is involved in various cellular processes like neuronal development and signaling pathways. Transcriptome profiling has shown that ASCL1 overexpression plays an important role in the development of glioma and Small Cell Lung Carcinoma (SCLC), but distinct and common molecular mechanisms regulated by ASCL1 in these cancers are unknown. In order to understand how it drives the cellular functional network in these two tumors, we generated a gene expression profile in a glioma cell line (U87MG) to identify ASCL1 gene targets by an si RNA silencing approach and then compared this with a publicly available dataset of similarly silenced SCLC (NCI-H1618 cells). We constructed TF-TF and gene-gene interactions, as well as protein interaction networks of ASCL1 regulated genes in glioma and SCLC cells. Detailed network analysis uncovered various biological processes governed by ASCL1 target genes in these two tumor cell lines. We find that novel ASCL1 functions related to mitosis and signaling pathways influencing development and tumor growth are affected in both glioma and SCLC cells. In addition, we also observed ASCL1 governed functional networks that are distinct to glioma and SCLC.

Peptide hormones and lung cancer.

PubMed

Moody, T W

2006-03-01

Several peptide hormones have been identified which alter the proliferation of lung cancer. Small cell lung cancer (SCLC), which is a neuroendocrine cancer, produces and secretes gastrin releasing peptide (GRP), neurotensin (NT) and adrenomedullin (AM) as autocrine growth factors. GRP, NT and AM bind to G-protein coupled receptors causing phosphatidylinositol turnover or elevated cAMP in SCLC cells. Addition of GRP, NT or AM to SCLC cells causes altered expression of nuclear oncogenes, such as c-fos, and stimulation of growth. Antagonists have been developed for GRP, NT and AM receptors which function as cytostatic agents and inhibit SCLC growth. Growth factor antagonists, such as the NT1 receptor antagonist SR48692, facilitate the ability of chemotherapeutic drugs to kill lung cancer cells. It remains to be determined if GRP, NT and AM receptors will served as molecular targets, for development of new therapies for the treatment of SCLC patients. Non-small cell lung cancer (NSCLC) cells also have a high density of GRP, NT, AM and epidermal growth factor (EGF) receptors. Several NSCLC patients with EGF receptor mutations respond to gefitinib, a tyrosine kinase inhibitor. Gefitinib relieves NSCLC symptoms, maintaining stable disease in patients who are not eligible for systemic chemotherapy. It is important to develop new therapeutic approaches using translational research techniques for the treatment of lung cancer patients.

Most high-grade neuroendocrine tumours of the lung are likely to secondarily develop from pre-existing carcinoids: innovative findings skipping the current pathogenesis paradigm.

PubMed

Pelosi, Giuseppe; Bianchi, Fabrizio; Dama, Elisa; Simbolo, Michele; Mafficini, Andrea; Sonzogni, Angelica; Pilotto, Sara; Harari, Sergio; Papotti, Mauro; Volante, Marco; Fontanini, Gabriella; Mastracci, Luca; Albini, Adriana; Bria, Emilio; Calabrese, Fiorella; Scarpa, Aldo

2018-04-01

Among lung neuroendocrine tumours (Lung-NETs), typical carcinoid (TC) and atypical carcinoid (AC) are considered separate entities as opposed to large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC). By means of two-way clustering analysis of previously reported next-generation sequencing data on 148 surgically resected Lung-NETs, six histology-independent clusters (C1 → C6) accounting for 68% of tumours were identified. Low-grade Lung-NETs were likely to evolve into high-grade tumours following two smoke-related paths. Tumour composition of the first path (C5 → C1 → C6) was coherent with the hypothesis of an evolution of TC to LCNEC, even with a conversion of SCLC-featuring tumours to LCNEC. The second path (C4 → C2-C3) had a tumour composition supporting the evolution of AC to SCLC-featuring tumours. The relevant Ki-67 labelling index varied accordingly, with median values being 5%, 9% and 50% in the cluster sequence C5 → C1 → C6, 12% in cluster C4 and 50-60% in cluster C2-C3. This proof-of-concept study suggests an innovative view on the progression of pre-existing TC or AC to high-grade NE carcinomas in most Lung-NET instances.

Mesenchymal-Epithelial Transition and Circulating Tumor Cells in Small Cell Lung Cancer.

PubMed

Hamilton, Gerhard; Rath, Barbara

2017-01-01

Cancer patients die of metastatic disease but knowledge regarding individual steps of this complex process of intravasation, spread and extravasation leading to secondary lesions is incomplete. Subpopulations of tumor cells are supposed to undergo an epithelial-mesenchymal transition (EMT), to enter the bloodstream and eventually establish metastases in a reverse process termed mesenchymal-epithelial transition (MET). Small cell lung cancer (SCLC) represents a unique model to study metastatic spread due to early dissemination and relapse, as well as availability of a panel of circulating cancer cell (CTC) lines recently. Additionally, chemosensitive SCLC tumor cells switch to a completely resistant phenotype during cancer recurrence. In advanced disease, SCLC patients display extremely high blood counts of CTCs in contrast to other tumors, like breast, prostate and colon cancer. Local inflammatory conditions at the primary tumor site and recruitment of macrophages seem to increase the shedding of tumor cells into the circulation in processes which may proceed independently of EMT. Since millions of cells are released by tumors into the circulation per day, analysis of a limited number of CTCs at specific time points are difficult to be related to the development of metastatic lesions which may occur approximately one year later. We have obtained a panel of SCLC CTC cell line from patients with relapsing disease, which share characteristic markers of this malignancy and a primarily epithelial phenotype with unique formation of large tumorospheres, containing quiescent and hypoxic cells. Although smoking and inflammation promote EMT, partial expression of vimentin indicates a transitional state with partial EMT in these cell lines at most. The CTC lines exhibit high expression of EpCAM , absent phosphorylation of β-catenin and background levels of Snail. Provided that these tumor cells had ever undergone EMT, here in advanced disease MET seem to have occurred already in the peripheral circulation. Alternative explanations for the expression of mesenchymal markers of the CTC lines are the heterogeneity of SCLC cells, cooperative migration or altered gene expression in response to the inflammatory tumor microenvironment allowing for tumor spread without EMT/MET.

Expressions of topoisomerase IIα and BCRP in metastatic cells are associated with overall survival in small cell lung cancer patients.

PubMed

Rijavec, Matija; Silar, Mira; Triller, Nadja; Kern, Izidor; Cegovnik, Urška; Košnik, Mitja; Korošec, Peter

2011-09-01

The aim of this study was to investigate the mRNA expression levels of multidrug resistance-associated proteins in chemo-naïve metastatic lung cancer cells and to determine the correlation with response to chemotherapy and overall survival. Metastatic cells were obtained by transbronchial fine needle aspiration biopsy of enlarged mediastinal lymph nodes in 14 patients with small cell lung cancer (SCLC) and 7 patients with non-small cell lung cancer (NSCLC). After cytological confirmation of lung cancer type, total RNA was extracted from biopsy samples and reverse transcribed to cDNA, and real-time PCR for the genes of interest [P-glycoprotein (P-gp), multidrug resistance protein 1 (MRP1), breast cancer resistance protein (BCRP), lung resistance protein (LRP) and topoisomerase IIα (TOPIIα)], was performed. We observed significantly decreased expression of BCRP and significantly increased expression of TOPIIα in metastatic SCLC cells compared to NSCLC. Furthermore, in SCLC high topoisomerase IIα and low BCRP expression levels positively correlated with longer overall survival. Our results showed higher expression levels of BCRP as well as lower levels of topoisomerase IIα in chemo-naïve metastatic cells in NSCLC than in SCLC. These results correlate with previous observations that metastatic SCLC cells at the beginning of chemotherapy are potentially more sensitive to chemotherapeutic agents while in metastatic NSCLC cells resistance is usually inherent. We also showed that altered levels of topoisomerase IIα and BCRP in SCLC are important factors that contribute to resistance to chemotherapeutics that interfere with the enzyme and/or DNA and are highly associated with overall survival.

Heterogeneity in Immune Marker Expression after Acquisition of Resistance to EGFR Kinase Inhibitors: Analysis of a Case with Small Cell Lung Cancer Transformation.

PubMed

Suda, Kenichi; Murakami, Isao; Yu, Hui; Kim, Jihye; Ellison, Kim; Rivard, Christopher J; Mitsudomi, Tetsuya; Hirsch, Fred R

2017-06-01

Expression of immune markers is of scientific interest because of their potential roles as predictive biomarkers for immunotherapy. Although the microenvironment of metastatic tumors and/or therapy-inducible histological transformation may affect the expression of these immune markers, there are few data regarding this context. A 76-year-old never-smoking female with EGFR-mutated lung adenocarcinoma (AC) acquired resistance to gefitinib. After her death, an autopsy revealed SCLC transformation and EGFR T790M secondary mutation (T790M) as mutually exclusive resistance mechanisms occurring differently in different metastases; two liver metastases (SCLC versus AC with T790M) and two lymph node metastases (SCLC versus AC with T790M) were analyzed to compare the expression status of immune markers by immunohistochemistry and by an immune oncology gene expression panel. Programmed death ligand 1 (PD-L1) protein was partially expressed in tumor cells with AC lesions (T790M) but not in tumor cells with SCLC transformation. The liver metastasis with SCLC transformation showed no stromal PD-L1 expression and scant tumor-infiltrating lymphocytes, whereas the other lesions demonstrated stromal PD-L1 staining and infiltration of CD8-positive T cells. Data generated using an immuno-oncology gene expression panel indicated a higher level of T-cell costimulatory molecules and lower expression of type I interferon-regulated genes in lesions with SCLC transformation. These data highlight the heterogeneity of expression of immune markers depending on the metastatic sites and histological transformation and indicate that the biopsy specimen from one lesion may not be representative of immune marker status for all lesions. Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Role of Immune Checkpoint Inhibitors in Small Cell Lung Cancer.

PubMed

Cooper, Maryann R; Alrajhi, Abdullah M; Durand, Cheryl R

Small cell lung cancer (SCLC) accounts for approximately 13% of all lung cancer diagnoses each year. SCLC is characterized by a rapid doubling time, early metastatic spread, and an unfavorable prognosis overall. Most patients with SCLC will respond to initial treatment; however, the majority will experience a disease recurrence and response to second-line therapies is poor. Immune checkpoint inhibitors may be an option given the success in other diseases. A literature search was conducted using Medline (1946-July week 1, 2017) and Embase (1996-2017 week 28) with the search terms small cell lung cancer combined with nivolumab or ipilimumab or pembrolizumab or atezolizumab or tremelimumab or durvalumab. Five clinical trials, including extended follow-up for 2, that evaluated immune checkpoint inhibitors in limited stage or extensive stage SCLC were included. In 2 phase 2 trials, ipilimumab was added to upfront chemotherapy. In both trials, an improvement in progression-free survival was seen. Toxicity, when combined with a platinum and etoposide, was significant. In a confirmatory phase 3 trial, ipilimumab did not prolong overall survival when added to first-line chemotherapy. Overall, response rates were similar between the placebo and ipilimumab groups. A phase 1/2 trial evaluated nivolumab alone or in combination with ipilimumab in recurrent SCLC. Results revealed that nivolumab monotherapy and the combination of nivolumab and ipilimumab were relatively safe and had antitumor activity. Pembrolizumab has been evaluated in a multicohort, phase 1b trial. Preliminary data showed a durable response in the second-line setting. Given the lack of overall survival data and significant toxicity associated with the combination of ipilimumab with first-line chemotherapy, this treatment is not a reasonable option at this time. Nivolumab alone or in combination with ipilimumab is a valid option for recurrent SCLC.

Evaluation of role of Notch3 signaling pathway in human lung cancer cells.

PubMed

Hassan, Wael Abdo; Yoshida, Ryoji; Kudoh, Shinji; Motooka, Yamato; Ito, Takaaki

2016-05-01

There is still a debate on the extent to which Notch3 signaling is involved in lung carcinogenesis and whether such function is dependent on cancer type or not. To evaluate Notch3 expression in different types of human lung cancer cells. Notch3 was detected in human lung cancer cell lines and in tissues. Then, small interfering RNA (siRNA) was used to down-regulate the expression of Notch3 in H69AR small cell lung carcinoma (SCLC) cells; two non-small cell lung carcinoma (NSCLC) cells; A549 adenocarcinoma (ADC); and H2170 squamous cell carcinoma (SCC). In addition, Notch3 intracellular domain (N3ICD) plasmid was transfected into H1688 human SCLC cells. We observed the effect of deregulating Notch3 signaling on the following cell properties: Notch-related proteins, cell morphology, adhesion, epithelial-mesenchymal transition (EMT), motility, proliferation and neuroendocrine (NE) features of SCLC. Notch3 is mainly expressed in NSCLC, and the expression of Notch1, Hes1 and Jagged1 is affected by Notch3. Notch3 has opposite functions in SCLC and NSCLC, being a tumor suppressor in the former and tumor promoting in the latter, in the context of cell adhesion, EMT and motility. Regarding cell proliferation, we found that inhibiting Notch3 in NSCLC decreases cell proliferation and induces apoptosis in NSCLC. Notch3 has no effect on cell proliferation or NE features of SCLC. Notch3 signaling in lung carcinoma is dependent on cell type. In SCLC, Notch3 behaves as a tumor suppressor pathway, while in NSCLC it acts as a tumor-promoting pathway.

Acquired resistance L747S mutation in an epidermal growth factor receptor-tyrosine kinase inhibitor-naïve patient: A report of three cases.

PubMed

Yamaguchi, Fumihiro; Fukuchi, Kunihiko; Yamazaki, Yohei; Takayasu, Hiromi; Tazawa, Sakiko; Tateno, Hidetsugu; Kato, Eisuke; Wakabayashi, Aya; Fujimori, Mami; Iwasaki, Takuya; Hayashi, Makoto; Tsuchiya, Yutaka; Yamashita, Jun; Takeda, Norikazu; Kokubu, Fumio

2014-02-01

The purpose of the present study was to report cases of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-naïve patients carrying a mutation associated with acquired resistance to the drug. Gene alterations in 77 lung carcinoma patients were analyzed by collecting and studying curette lavage fluid at the time of diagnosis. PCRs were performed to amplify mutation hotspot regions in EGFR genes. The PCR products were direct-sequenced and the mutations confirmed by resequencing using different primers. Case 1 was a 78-year-old Japanese male diagnosed with stage IB lung adenocarcinoma who was found to have two EGFR mutations, G719S and L747S. Case 2 was a 73-year-old Japanese male diagnosed with stage IV squamous cell lung carcinoma and bone metastasis who had the EGFR mutation, L747S. Case 3 was an 82-year-old Japanese male diagnosed with hyponatremia due to inappropriate secretion of antidiuretic hormone and stage IIIB small cell lung carcinoma (SCLC) who had the EGFR mutation, L747S. Thus, the EGFR mutation L747S associated with acquired EGFR-TKI resistance was detected in two non-small cell lung carcinoma (NSCLC) patients and one SCLC patient, none of whom had ever received EGFR-TKI. The patients were current smokers with stages at diagnosis ranging from IB to IV, and their initial tumors contained resistant clones carrying L747S. L747S may be associated with primary resistance. To the best of our knowledge, this study is the first report of an EGFR mutation associated with resistance to EGFR-TKI in SCLC patients. The early detection of EGFR-TKI resistance mutations may be beneficial in making treatment decisions for lung carcinoma patients, including those with SCLC.

[Small-cell lung cancer: epidemiology, diagnostics and therapy].

PubMed

Pešek, Miloš; Mužík, Jan

Authors present actual overview of information on diagnostic and therapeutic procedures in small-cell lung cancer (SCLC). This highly aggressive type of lung cancer is diagnosed in 14.8 % of Czech lung cancer patients. Vast majority of those patients (87 %) suffer from advanced and metastatic disease in the time of diagnosis. In this issue are presented prognostic factors, staging diagnostic procedures and therapeutic recommendations. The backbone of actual SCLC treatment is combined chemotherapy and radiotherapy and less frequently, carefully in selected cases, surgical procedures. SCLC should be have as chemosensitive, chemoresistent or chemorefractory disease. Actual cytostatic combinations used in 1st line treatment, different schedules of chemoradiotherapy, drugs used in second line treatment and schedules and timing of prophylactic brain irradiation are presented. In near future, perspectively, there are some promissible data on antitumour immunotherapy based on anti CTLA-4 and anti PD-1/PE-L1 antibodies also in SCLC patients.Key words: cancer immunotherapy - concomitant chemoradiotherapy - chemotherapy - chest radiotherapy - lung resections - prophylactic brain irradiation - small cell lung cancer.

Prohormone convertase and autocrine growth factor mRNAs are coexpressed in small cell lung carcinoma.

PubMed

Rounseville, M P; Davis, T P

2000-08-01

A hallmark of small cell lung carcinoma (SCLC) is the expression of autocrine growth factors such as neurotensin and gastrin-releasing peptide, which bind to cellular receptors and stimulate cell division. The biological activity of autocrine growth factors requires the concurrent expression of prohormone convertases that cleave the growth factors to their active form, suggesting the expression of these genes is linked in SCLCs. RNase protection assays were used to detect the expression of autocrine growth factor and prohormone convertase mRNAs in a panel of lung cancer cell lines. These mRNAs are coexpressed in SCLC and lung carcinoid cell lines, but not in normal lung epithelium or in non-small cell lung cancers. These findings, together with earlier results from our laboratory, suggest the expression of prohormone convertases has an important role in the development and maintenance of the SCLC phenotype and that autocrine growth factor and prohormone convertase genes respond to a common transcriptional activator in SCLC.

Longitudinal Brain Changes Associated with Prophylactic Cranial Irradiation in Lung Cancer.

PubMed

Simó, Marta; Vaquero, Lucía; Ripollés, Pablo; Gurtubay-Antolin, Ane; Jové, Josep; Navarro, Arturo; Cardenal, Felipe; Bruna, Jordi; Rodríguez-Fornells, Antoni

2016-04-01

The toxic effects of prophylactic cranial irradiation (PCI) and platinum-based chemotherapy on cognition in the lung cancer population have not yet been well established. In the present study we examined the longitudinal neuropsychological and brain structural changes observed in patients with lung cancer who were undergoing these treatments. Twenty-two patients with small cell lung cancer (SCLC) who underwent platinum-based chemotherapy and PCI were compared with two control groups: an age- and education-matched group of healthy controls (n = 21) and a group of patients with non-SCLC (NSCLC, n = 13) who underwent platinum-based chemotherapy. All groups were evaluated using a neuropsychological battery and multimodal structural magnetic resonance imaging: T1-weighted and diffusion tensor imaging at baseline (before PCI for SCLC and chemotherapy for NSCLC) and at 3 months after treatment. T1 voxel-based morphometry and tract-based spatial statistics were used to analyze microstructural changes in gray matter (GM) and white matter (WM). The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core Questionnaire was also completed. Patients with SCLC exhibited cognitive deterioration in verbal fluency over time. Structural magnetic resonance imaging showed decreases in GM at 3 months in the right subcortical regions, bilateral insular cortex, and superior temporal gyrus in patients with SCLC compared with both control groups. Additionally, patients with SCLC showed decreases in GM over time in the aforementioned regions plus in the right parahippocampal gyrus and hippocampus, together with changes in the WM microstructure of the entire corpus callosum. These changes had a limited impact on responses to the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core Questionnaire, however. Patients with NSCLC showed no cognitive or brain structural differences after chemotherapy. This longitudinal study documents moderate neuropsychological deficits together with notable brain-specific structural changes (in GM and WM) in patients with SCLC after chemotherapy and PCI, suggesting that chemotherapy and especially PCI are associated with the development of cognitive and structural brain toxic effects. Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Neutral endopeptidase: variable expression in human lung, inactivation in lung cancer, and modulation of peptide-induced calcium flux.

PubMed

Cohen, A J; Bunn, P A; Franklin, W; Magill-Solc, C; Hartmann, C; Helfrich, B; Gilman, L; Folkvord, J; Helm, K; Miller, Y E

1996-02-15

Neutral endopeptidase (NEP; CALLA, CD10, EC 3.4.24.11) is a cell surface endopeptidase that hydrolyses bioactive peptides, including the bombesin-like peptides, as well as other neuropeptides. Bombesin-like peptides and other neuropeptides are autocrine growth factors for both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Low expression of NEP has been reported in SCLC and NSCLC cell lines. NEP inhibition has been shown to increase proliferation in one cell line. To date, NEP expression has not been quantitatively evaluated in normal adult lung, SCLC or NSCLC tumors, paired uninvolved lung from the same patient, or in other pulmonary neoplasms such as mesotheliomas and carcinoids. We examined the expression of NEP in these tissues and human cell lines using immunohistochemistry, flow cytometry, enzyme activity, ELISA, Western blot, and reverse transcription (RT)-PCR. Uninvolved lung tissue from different individuals displayed considerable variation in NEP activity and protein. By immunohistochemistry, NEP expression was detectable in alveolar and airway epithelium, fibroblasts of normal lung, and in mesotheliomas, whereas it was undetectable in most SCLC, adenocarcinoma, squamous cell carcinoma, and carcinoid tumors of the lung. NEP activity and protein levels were lower in all SCLC and adenocarcinoma tumors when compared to adjacent uninvolved lung, often at levels consistent with expression derived from contaminating stroma. NEP expression and activity were reduced or undetectable in most SCLC and lung adenocarcinoma cell lines. NEP mRNA by RT-PCR was not expressed or was in low abundance in the majority of lung cancer cell lines. The majority of lung tumors did not express NEP by RT-PCR as compared with normal adjacent lung. In addition, recombinant NEP abolished, whereas an NEP inhibitor potentiated, the calcium flux generated by neuropeptides in some lung cancer cell lines, demonstrating potential physiological significance for low NEP expression. NEP, therefore, is a signal transduction and possibly a growth modulator for both SCLC and NSCLC, emphasizing the role of neuropeptides in the pathogenesis of the major histological forms of lung cancer.

Prophylactic cranial irradiation in small cell lung cancer: a single institution experience.

PubMed

Naidoo, J; Kehoe, M; Sasiadek, W; Hacking, D; Calvert, P

2014-03-01

Prophylactic cranial irradiation (PCI) is used to prevent the development of brain metastases in small cell lung carcinoma. PCI confers an overall survival (OS) benefit in both limited and extensive stage disease. We analyze the incidence of symptomatic brain metastases, progression-free survival (PFS) and OS in a cohort of patients who received PCI, in a 5-year period. A retrospective review of all patients who had received PCI between 2006 and 2011 at the Whitfield Clinic was completed. Patient- and disease-related characteristics, the number of patients who developed brain metastases, PFS and OS data were collected. 24 patients were identified. 14 (58.3 %) patients were male, 10 (41.7 %) were female, with a mean age of 62.5 years (range 31-78). All patients were smokers. 12 (50 %) patients had limited stage small cell lung cancer (SCLC), 12 (50 %) had extensive stage disease. 2 (8.2 %) patients developed brain metastases post PCI (p = 0.478.) The median PFS for limited stage SCLC was 13 months (range 3-20) and 10 months (range 5-18) for extensive stage SCLC. Median OS was 15 months (range 4-29) in limited stage SCLC, and 11 months (range 5-29) in extensive stage SCLC. Our study demonstrated a low incidence of symptomatic brain metastases and favourable median PFS and OS in the patients that received PCI, when compared to published phase III data.

Prophylactic cranial irradiation in resected small cell lung cancer: A systematic review with meta-analysis

PubMed Central

Yang, Yang; Zhang, Danhong; Zhou, Xia; Bao, Wuan; Ji, Yonglin; Sheng, Liming; Cheng, Lei; Chen, Ying; Du, Xianghui; Qiu, Guoqin

2018-01-01

Background: The use of PCI in early operable patients with small cell lung cancer (SCLC) is still controversial. Therefore, we conducted a systematic review with meta-analysis to investigate the effects of PCI in resected SCLC patients. Methods: Relevant studies were identified from PubMed and EMBASE databases, the pooled hazard risks were obtained by the random-effects model. We also analyzed the brain metastasis (BM) risk in p-stage I patients without PCI. Results: Five retrospective studies were identified and a total of 1691 patients were included in our analysis, 315 of them received PCI. For all the resected patients, PCI was associated with improved overall survival (HR: 0.52, 95% CI: 0.33-0.82), and reduced brain metastasis risk (RR: 0.50, 95%CI: 0.32-0.78). However, with regard to p-stage I patients, no survival benefit was brought by PCI (HR: 0.87, 95% CI: 0.34-2.24). Moreover, the pooled analysis of 7 studies found that the 5-year brain metastasis risk was relatively low (12%, 95% CI: 8%-17%) for p-stage I patients without PCI. Conclusions: PCI might be associated with a favorable survival advantage and reduced BM risk in complete resected SCLC patients, except for p-stage I patients. PMID:29344290

De novo activating epidermal growth factor mutations (EGFR) in small-cell lung cancer.

PubMed

Thai, Alesha; Chia, Puey L; Russell, Prudence A; Do, Hongdo; Dobrovic, Alex; Mitchell, Paul; John, Thomas

2017-09-01

In Australia, mutations in epidermal growth factor mutations (EGFR) occur in 15% of patients diagnosed with non-small-cell lung cancer and are found with higher frequency in female, non-smokers of Asian ethnicity. Activating mutations in the EGFR gene are rarely described in SCLC. We present two cases of de novo EGFR mutations in patients with SCLC detected in tissue and in plasma cell free DNA, both of whom were of Asian ethnicity and never-smokers. These two cases add to the growing body of evidence suggesting that screening for EGFR mutations in SCLC should be considered in patients with specific clinical features. © 2017 Royal Australasian College of Physicians.

INVESTIGATION OF LEAKAGE CURRENT BEHAVIOR OF Pt/Bi0.975La0.025Fe0.975Ni0.025O3/Pt CAPACITOR MEASURED AT DIFFERENT TEMPERATURES

NASA Astrophysics Data System (ADS)

Dai, Xiu Hong; Zhao, Hong Dong; Zhang, Lei; Zhu, Hui Juan; Li, Xiao Hong; Zhao, Ya Jun; Guo, Jian Xin; Zhao, Qing Xun; Wang, Ying Long; Liu, Bao Ting; Ma, Lian Xi

2014-03-01

Polycrystalline Bi0.975La0.025Fe0.975Ni0.025O3 (BLFNO) film is fabricated on Pt/Ti/SiO2/Si(111) substrate by sol-gel method. It is found that the well-crystallized BLFNO film is polycrystalline, and the Pt/BLFNO/Pt capacitor possesses good ferroelectric properties with remnant polarization of 74 μC/cm2 at electric field of 833 kV/cm. Moreover, it is also found that the leakage current density of the Pt/BLFNO/Pt capacitor increases with the increase of measurement temperature ranging from 100 to 300 K. The leakage density of the Pt/BLFNO/Pt capacitor satisfies space-charge-limited conduction (SCLC) at higher electric field and shows little dependence on voltage polarity and temperature, but shows polarity and temperature dependence at lower applied electric field. With temperature increasing from 100 to 300 K at lower applied electric field, the most likely conduction mechanism is from Ohmic behavior to SCLC for positive biases, but no clear dominant mechanism for negative biases is shown.

Reusable Floating-Electrode Sensor for Real-Time Electrophysiological Monitoring of Nonadherent Cells

NASA Astrophysics Data System (ADS)

Pham Ba, Viet Anh; Ta, Van-Thao; Park, Juhun; Park, Eun Jin; Hong, Seunghun

2015-03-01

We herein report the development of a reusable floating-electrode sensor (FES) based on aligned single-walled carbon nanotubes, which allowed quantitatively monitoring the electrophysiological responses from nonadherent cells. The FES was used to measure the real-time responses of normal lung cells and small-cell lung cancer (SCLC) cells to the addition of nicotine. The SCLC cells exhibited rather large electrophysiological responses to nicotine compared to normal cells, which was attributed to the overexpressed nicotinic acetylcholine receptors (nAChRs) in the SCLC cells. Importantly, using only a single device could measure repeatedly the responses of multiple individual cells to various drugs, enabling statistically meaningful measurements without errors from the device-to-device variations of the sensor characteristics. As results, that the treatment with drugs such as genistin or daidzein reduced Ca2+ influx in SCLC cells was found. Moreover, tamoxifen, has been known as an anti-estrogen compound, was found to only partly block the binding of daidzein to nAChRs. Our FES can be a promising tool for various biomedical applications such as drug screening and therapy monitoring.

The Prognosis of Small Cell Lung Cancer in Patients with Pulmonary Fibrosis.

PubMed

Matsumoto, Yoko; Ohara, Sayaka; Furukawa, Ryutaro; Usui, Kazuhiro

2017-10-01

The purpose of this study was to assess the prognosis of small cell lung cancer (SCLC) based on the underlying pulmonary disease. A total of 204 patients with SCLC were reviewed and categorized into three groups: normal, emphysema and fibrosis. The median overall survival duration (OS) in patients with normal lungs (n=57), with emphysema (n=105) and fibrosis (n=42) was 21.3, 16.4 and 10.8 months (p=0.063). In limited-stage disease (LD), the median OS in patients with fibrosis (7.4 months) was shorter than normal (52.7 months) or emphysema patients (26.4 months) (p=0.034). In extensive-stage disease (ED), the median OS in patients with fibrosis (12.7 months) was not significantly different from normal (11.4 months) or emphysema patients (13.5 months) (p=0.600). Patients with fibrosis had a poorer prognosis than normal or emphysema patients in LD-SCLC, but the coexistence of pulmonary fibrosis did not affect the prognostic outcomes in ED-SCLC. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

MicroRNA-134 regulates lung cancer cell H69 growth and apoptosis by targeting WWOX gene and suppressing the ERK1/2 signaling pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Tianjun; Gao, Fei; Feng, Sifang

2015-08-28

MicroRNAs have been shown to act as crucial modulators during carcinogenesis. Recent studies have implied that miR-134 expression associated with epithelial-to-mesenchymal transition phenotype and invasive potential of NSCLC cells. Our study investigated the pathogenic implications of miR-134 in small cell lung cancer (SCLC). Overexpression or inhibition MiR-134 expression by miR-134 mimics or miR-134 inhibitors (anti-miR-134) in SCLC cell lines was detected using qRT-PCR. Lactate dehydrogenase (LDH) assay, MTT assays and flow cytometry were performed in order to clarify the growth and apoptosis of SCLC cells which had been transfected with miR-134 mimics or anti-miR-134. WWOX expression in H69 cells wasmore » detected by qRT-PCR and western blot, respectively. The results showed that overexpression miR-134 was significantly promoting SCLC cells growth and inhibit its apoptosis. In addition, reduced miR-134 expression was significantly correlated with cell growth inhibition and apoptosis promotion. Furthermore, transfection of miR-134 mimics into the SCLC cells markedly down-regulated the level of WWOX, whereas, anti-miR-134 up-regulated WWOX expression. We also found that overexpression WWOX attenuate miR-134 induced H69 cells growth, and promote cell apoptosis. Moreover, miR-134 promoted cell proliferation and inhibit apoptosis via the activation of ERK1/2 pathway. These findings suggest that miR-134 may be an ideal diagnostic and prognostic marker, and may be attributed to the molecular therapy of SCLC. - Highlights: • MiR-134 play roles in small cell lung cancer cell growth and apoptosis. • MiR-134 negative regulated the level of WWOX in H69 cells. • WWOX overexpression attenuate miR-134 induced H69 cells growth. • MiR-134 promotes cell growth via the activation of ERK1/2 pathway.« less

Genomic alterations in neuroendocrine cancers of the ovary.

PubMed

Yaghmour, George; Prouet, Philippe; Wiedower, Eric; Jamy, Omer Hassan; Feldman, Rebecca; Chandler, Jason C; Pandey, Manjari; Martin, Mike G

2016-08-26

As we have previously reported, small cell carcinoma of the ovary (SCCO) is a rare, aggressive form of ovarian cancer associated with poor outcomes. In an effort to identify new treatment options, we utilized comprehensive genomic profiling to assess the potential for novel therapies in SCCO. Patients with SCCO, SCCO-HT (hypercalcemic type), neuroendocrine tumors of the ovary (NET-O), and small cell carcinoma of the lung (SCLC) profiled by Caris Life Sciences between 2007-2015 were identified. Tumors were assessed with up to 21 IHC stains, in situ hybridization of cMET, EGFR, HER2 and PIK3CA, and next-generation sequencing (NGS) as well as Sanger sequencing of selected genes. Forty-six patients with SCCO (10 SCCO, 18 SCCO-HT, 18 NET-O) were identified as well as 58 patients with SCLC for comparison. Patients with SCCO and SCCO-HT were younger (median 42 years [range 12-75] and 26 years [range 8-40], respectively) than patients with NET-O 62 [range 13-76] or SCLC 66 [range 36-86]. SCCO patients were more likely to be metastatic (70 %) than SCCO-HT (50 %) or NET-O (33 %) patients, but at a similar rate to SCLC patients (65 %). PD1 expression varied across tumor type with SCCO (100 %), SCCO-HT (60 %), NET-O (33 %) vs SCLC (42 %). PDL1 expression also varied with SCCO (50 %), SCCO-HT (20 %), NET-O (33 %) and SCLC (0 %). No amplifications were identified in cMET, EGFR, or HER2 and only 1 was found in PIK3CA (NET-O). Actionable mutations were rare with 1 patient with SCCO having a BRCA2 mutation and 1 patient with NET-O having a PIK3CA mutation. No other actionable mutations were identified. No recurrent actionable mutations or rearrangements were identified using this platform in SCCO. IHC patterns may help guide the use of chemotherapy in these rare tumors.

In vivo synergistic cytogenetic effects of aminophylline on lymphocyte cultures from patients with lung cancer undergoing chemotherapy.

PubMed

Mylonaki, Effie; Manika, Katerina; Zarogoulidis, Paul; Domvri, Kalliopi; Voutsas, Vasilis; Zarogoulidis, Kostas; Mourelatos, Dionysios

2012-12-01

The anti-cancer and cytogenetic effects of aminophylline (AM) have been demonstrated in several clinical trials. The aim of the present study was to investigate the in vivo cytogenetic effects of AM in newly diagnosed patients with small cell (SCLC) and non-small cell lung cancer (NSCLC), receiving chemotherapy for the first time. Sister chromatid exchanges (SCEs) and proliferation rate index (PRI) were evaluated in peripheral blood lymphocyte cultures from six patients with SCLC and six patients with NSCLC after the in vitro addition of AM and after the in vivo administration of AM in patients receiving chemotherapy. The in vitro addition of AM significantly increased SCEs only in SCLC patients (p<0.001). The in vivo administration of AM after chemotherapy increased SCEs in both cancer types (SCLC: p<0.001, NSCLC: p=0.003) and this increase was synergistic, the rates of SCEs in the presence of AM were higher than the expected SCE values if the increases above background for chemotherapy and AM were independent and additive (SCLC: p<0.001, NSCLC: p=0.008). Although in both groups of patients cell division delays were observed after the combined chemotherapy plus in vivo AM treatment, the correlation between the magnitude of the SCE response and the PRI depression was not statistically significant (p>0.05). These observations suggest that AM enhances the results of concurrently administered chemotherapy by synergistically increasing its cytogenetic effects in patients with lung cancer. Copyright © 2012 Elsevier B.V. All rights reserved.

A prospective pilot study of genome-wide exome and transcriptome profiling in patients with small cell lung cancer progressing after first-line therapy.

PubMed

Weiss, Glen J; Byron, Sara A; Aldrich, Jessica; Sangal, Ashish; Barilla, Heather; Kiefer, Jeffrey A; Carpten, John D; Craig, David W; Whitsett, Timothy G

2017-01-01

Small cell lung cancer (SCLC) that has progressed after first-line therapy is an aggressive disease with few effective therapeutic strategies. In this prospective study, we employed next-generation sequencing (NGS) to identify therapeutically actionable alterations to guide treatment for advanced SCLC patients. Twelve patients with SCLC were enrolled after failing platinum-based chemotherapy. Following informed consent, genome-wide exome and RNA-sequencing was performed in a CLIA-certified, CAP-accredited environment. Actionable targets were identified and therapeutic recommendations made from a pharmacopeia of FDA-approved drugs. Clinical response to genomically-guided treatment was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The study completed its accrual goal of 12 evaluable patients. The minimum tumor content for successful NGS was 20%, with a median turnaround time from sample collection to genomics-based treatment recommendation of 27 days. At least two clinically actionable targets were identified in each patient, and six patients (50%) received treatment identified by NGS. Two had partial responses by RECIST 1.1 on a clinical trial involving a PD-1 inhibitor + irinotecan (indicated by MLH1 alteration). The remaining patients had clinical deterioration before NGS recommended therapy could be initiated. Comprehensive genomic profiling using NGS identified clinically-actionable alterations in SCLC patients who progressed on initial therapy. Recommended PD-1 therapy generated partial responses in two patients. Earlier access to NGS guided therapy, along with improved understanding of those SCLC patients likely to respond to immune-based therapies, should help to extend survival in these cases with poor outcomes.

Activated Raf-1 causes growth arrest in human small cell lung cancer cells.

PubMed Central

Ravi, R K; Weber, E; McMahon, M; Williams, J R; Baylin, S; Mal, A; Harter, M L; Dillehay, L E; Claudio, P P; Giordano, A; Nelkin, B D; Mabry, M

1998-01-01

Small cell lung cancer (SCLC) accounts for 25% of all lung cancers, and is almost uniformly fatal. Unlike other lung cancers, ras mutations have not been reported in SCLC, suggesting that activation of ras-associated signal transduction pathways such as the raf-MEK mitogen-activated protein kinases (MAPK) are associated with biological consequences that are unique from other cancers. The biological effects of raf activation in small cell lung cancer cells was determined by transfecting NCI-H209 or NCI-H510 SCLC cells with a gene encoding a fusion protein consisting of an oncogenic form of human Raf-1 and the hormone binding domain of the estrogen receptor (DeltaRaf-1:ER), which can be activated with estradiol. DeltaRaf-1:ER activation resulted in phosphorylation of MAPK. Activation of this pathway caused a dramatic loss of soft agar cloning ability, suppression of growth capacity, associated with cell accumulation in G1 and G2, and S phase depletion. Raf activation in these SCLC cells was accompanied by a marked induction of the cyclin-dependent kinase (cdk) inhibitor p27(kip1), and a decrease in cdk2 protein kinase activities. Each of these events can be inhibited by pretreatment with the MEK inhibitor PD098059. These data demonstrate that MAPK activation by DeltaRaf-1:ER can activate growth inhibitory pathways leading to cell cycle arrest. These data suggest that raf/MEK/ MAPK pathway activation, rather than inhibition, may be a therapeutic target in SCLC and other neuroendocrine tumors. PMID:9421477

Prognostic effect of liver metastasis in lung cancer patients with distant metastasis.

PubMed

Ren, Yijiu; Dai, Chenyang; Zheng, Hui; Zhou, Fangyu; She, Yunlang; Jiang, Gening; Fei, Ke; Yang, Ping; Xie, Dong; Chen, Chang

2016-08-16

Because the need of clinical prognostic evaluation by specific metastatic organ, we aim to analyze the prognostic factors in lung cancer patients with M1b disease with Surveillance Epidemiology and End-Results database (SEER). This retrospective study evaluated lung cancer patients of adenocarcinoma (AD), squamous cell carcinoma (SQCC), and small cell lung cancer (SCLC) selected from SEER. We provided the prognostic correlates of overall survival (OS) and lung cancer-specific survival (LCSS) in this population. 23,679 eligible patients were included. Bone was the most common metastatic site in AD (63.1%) and SQCC (61.1%), while liver was the most prevalent site (61.9%) in SCLC. Single site metastasis was significantly associated with better outcome compared to multiple sites metastases in all patients. Among patients with single site metastasis, OS and LCSS were longer for AD and SCLC if involving brain or bone, with median survival time of 5 to 7 months, comparing to 3 months if invloving liver (all p-values < 0.001). Similarly, among patients with multiple metastases, better outcomes were observed in AD patients (4 vs 3 months; OS and LCSS, p < 0.001) and SCLC patients (6 vs 4 months; OS, p = 0.017; LCSS, p = 0.023) without liver metastasis compared to those with liver metastasis. In conclusion, we estimated multiple survival outcomes by histology of primary tumor and sites of metastasis. Liver metastasis is found to be the worst prognostic factor for AD and SCLC patients with distant metastasis. More in-depth research is warranted to identify patients who are prone to develop distance metastasis, especially to liver.

Brain Functional Connectivity in Small Cell Lung Cancer Population after Chemotherapy Treatment: an ICA fMRI Study

NASA Astrophysics Data System (ADS)

Bromis, K.; Kakkos, I.; Gkiatis, K.; Karanasiou, I. S.; Matsopoulos, G. K.

2017-11-01

Previous neurocognitive assessments in Small Cell Lung Cancer (SCLC) population, highlight the presence of neurocognitive impairments (mainly in attention processing and executive functioning) in this type of cancer. The majority of these studies, associate these deficits with the Prophylactic Cranial Irradiation (PCI) that patients undergo in order to avoid brain metastasis. However, there is not much evidence exploring cognitive impairments induced by chemotherapy in SCLC patients. For this reason, we aimed to investigate the underlying processes that may potentially affect cognition by examining brain functional connectivity in nineteen SCLC patients after chemotherapy treatment, while additionally including fourteen healthy participants as control group. Independent Component Analysis (ICA) is a functional connectivity measure aiming to unravel the temporal correlation between brain regions, which are called brain networks. We focused on two brain networks related to the aforementioned cognitive functions, the Default Mode Network (DMN) and the Task-Positive Network (TPN). Permutation tests were performed between the two groups to assess the differences and control for familywise errors in the statistical parametric maps. ICA analysis showed functional connectivity disruptions within both of the investigated networks. These results, propose a detrimental effect of chemotherapy on brain functioning in the SCLC population.

Factors Affecting the Risk of Brain Metastasis in Small Cell Lung Cancer With Surgery: Is Prophylactic Cranial Irradiation Necessary for Stage I-III Disease?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gong Linlin; Wang, Q.I.; Zhao Lujun

2013-01-01

Purpose: The use of prophylactic cranial irradiation (PCI) in small cell lung cancer (SCLC) with surgical resection has not been fully identified. This study undertook to assess the factors affecting the risk of brain metastases in patients with stage I-III SCLC after surgical resection. The implications of PCI treatment for these patients are discussed. Methods and Materials: One hundred twenty-six patients treated with surgical resection for stage I-III SCLC from January 1998-December 2009 were retrospectively analyzed to elucidate the risk factors of brain metastases. Log-rank test and Cox regression model were used to determine the risk factors of brain metastases.more » Results: The median survival time for this patient population was 34 months, and the 5-year overall survival rate was 34.9%. For the whole group, 23.0% (29/126) of the patients had evidence of metastases to brain. Pathologic stage not only correlated with overall survival but also significantly affected the risk of brain metastases. The 5-year survival rates for patients with pathologic stages I, II, and III were 54.8%, 35.6%, and 14.1%, respectively (P=.001). The frequency of brain metastases in patients with pathologic stages I, II, and III were 6.25% (2/32), 28.2% (11/39), and 29.1% (16/55) (P=.026), respectively. A significant difference in brain metastases between patients with complete resection and incomplete resection was also observed (20.5% vs 42.9%, P=.028). The frequency of brain metastases was not found to be correlated with age, sex, pathologic type, induction chemotherapy, adjuvant chemotherapy, or adjuvant radiation therapy. Conclusions: Stage I SCLC patients with complete resection had a low incidence of brain metastases and a favorable survival rate. Stage II-III disease had a higher incidence of brain metastases. Thus, PCI might have a role for stage II-III disease but not for stage I disease.« less

Optoelectronic properties of dicyanofluorene-based n-type polymers.

PubMed

Vijayakumar, Chakkooth; Saeki, Akinori; Seki, Shu

2012-08-01

Three new donor-acceptor-type copolymers (P1-P3) consisting of dicyanofluorene as acceptor and various donor moieties were designed and synthesized. Optoelectronic properties were studied in detail by means of UV-visible absorption and fluorescence spectroscopy, cyclic voltammetry, space-charge-limited current (SCLC), flash-photolysis time-resolved microwave conductivity (FP-TRMC), and density functional theory (DFT). All polymers showed strong absorption in the UV-visible region and the absorption maximum undergoes redshift with an increasing number of thiophene units in the polymer backbone. SCLC analysis showed that the electron mobilities of the polymers in the bulk state were 1 to 2 orders higher than that of the corresponding hole mobilities, which indicated the n-type nature of the materials. By using FP-TRMC, the intrapolymer charge-carrier mobility was assessed and compared with the interpolymer mobility obtained by SCLC. The polymers exhibited good electron-accepting properties sufficiently high enough to oxidize the excited states of regioregular poly(3-hexylthiophene) (P3HT (donor)), as evident from the FP-TRMC analysis. The P3 polymer exhibited the highest FP-TRMC transients in the pristine form as well as when blended with P3HT. Use of these polymers as n-type materials in all-polymer organic solar cells was also explored in combination with P3HT. In accordance with the TRMC results, P3 exhibited superior electron-transport and photovoltaic properties to the other two polymers, which is explained by the distribution of the energy levels of the polymers by using DFT calculations. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Space electric field concentrated effect for Zr:SiO2 RRAM devices using porous SiO2 buffer layer

PubMed Central

2013-01-01

To improve the operation current lowing of the Zr:SiO2 RRAM devices, a space electric field concentrated effect established by the porous SiO2 buffer layer was investigated and found in this study. The resistive switching properties of the low-resistance state (LRS) and high-resistance state (HRS) in resistive random access memory (RRAM) devices for the single-layer Zr:SiO2 and bilayer Zr:SiO2/porous SiO2 thin films were analyzed and discussed. In addition, the original space charge limited current (SCLC) conduction mechanism in LRS and HRS of the RRAM devices using bilayer Zr:SiO2/porous SiO2 thin films was found. Finally, a space electric field concentrated effect in the bilayer Zr:SiO2/porous SiO2 RRAM devices was also explained and verified by the COMSOL Multiphysics simulation model. PMID:24330524

Fabricate heterojunction diode by using the modified spray pyrolysis method to deposit nickel-lithium oxide on indium tin oxide substrate.

PubMed

Wu, Chia-Ching; Yang, Cheng-Fu

2013-06-12

P-type lithium-doped nickel oxide (p-LNiO) thin films were deposited on an n-type indium tin oxide (ITO) glass substrate using the modified spray pyrolysis method (SPM), to fabricate a transparent p-n heterojunction diode. The structural, optical, and electrical properties of the p-LNiO and ITO thin films and the p-LNiO/n-ITO heterojunction diode were characterized by field emission scanning electron microscopy (FE-SEM), X-ray diffraction (XRD), UV-visible spectroscopy, Hall effect measurement, and current-voltage (I-V) measurements. The nonlinear and rectifying I-V properties confirmed that a heterojunction diode characteristic was successfully formed in the p-LNiO/n-ITO (p-n) structure. The I-V characteristic was dominated by space-charge-limited current (SCLC), and the Anderson model demonstrated that band alignment existed in the p-LNiO/n-ITO heterojunction diode.

Amrubicin for relapsed small-cell lung cancer: a systematic review and meta-analysis of 803 patients

PubMed Central

Horita, Nobuyuki; Yamamoto, Masaki; Sato, Takashi; Tsukahara, Toshinori; Nagakura, Hideyuki; Tashiro, Ken; Shibata, Yuji; Watanabe, Hiroki; Nagai, Kenjiro; Nakashima, Kentaro; Ushio, Ryota; Ikeda, Misako; Kobayashi, Nobuaki; Shinkai, Masaharu; Kudo, Makoto; Kaneko, Takeshi

2016-01-01

Currently, amrubicin is permitted for relapsed small-cell lung carcinoma (SCLC) only in Japan. The efficacy and adverse effects of amrubicin as reported by previous studies varied greatly. The inclusion criterion was a prospective study that was able to provide data for efficacy and safety by the AMR single agent regimen as second-line chemotherapy for a patient with SCLC. Binary data were meta-analyzed with the random-model generic inverse variance method. We included nine articles consisted of 803 patients. The pooled three-, six-, and nine-month progression-free survival were 63% (95% CI 57–69%, I2 = 53%), 28% (95% CI 21–35%, I2 = 71%), and 10% (95% CI 6–14%, I2 = 41%), respectively. The pooled six-, 12-, and 18-month overall survival were 69% (95% CI 61–78%, I2 = 83%), 36% (95% CI 28–44%, I2 = 80%), and 15% (95% CI 8–21%, I2 = 81%), respectively. Amrubicin seemed much more beneficial for Japanese patients. However, compared to the efficacy of topotecan presented in a previous meta-analysis, amrubicin may be a better treatment option than topotecan for both Japanese and Euro-American. Adverse effects by amrubicin were almost exclusively observed to be hematological. Notably, grade III/IV neutropenia incidence was 70% and febrile neutropenia incidence was 12%. PMID:26750506

Prognostic value of fluorine-18 fludeoxyglucose positron emission tomography parameters differs according to primary tumour location in small-cell lung cancer.

PubMed

Nobashi, Tomomi; Koyasu, Sho; Nakamoto, Yuji; Kubo, Takeshi; Ishimori, Takayoshi; Kim, Young H; Yoshizawa, Akihiko; Togashi, Kaori

2016-01-01

To investigate the prognostic value of fluorine-18 fludeoxyglucose (FDG) positron emission tomography (PET) parameters for small-cell lung cancer (SCLC), according to the primary tumour location, adjusted by conventional prognostic factors. From 2008 to 2013, we enrolled consecutive patients with histologically proven SCLC, who had undergone FDG-PET/CT prior to initial therapy. The primary tumour location was categorized into central or peripheral types. PET parameters and clinical variables were evaluated using univariate and multivariate analysis. A total of 69 patients were enrolled in this study; 28 of these patients were categorized as having the central type and 41 patients as having the peripheral type. In univariate analysis, stage, serum neuron-specific enolase, whole-body metabolic tumour volume (WB-MTV) and whole-body total lesion glycolysis (WB-TLG) were found to be significant in both types of patients. In multivariate analysis, the independent prognostic factor was found to be stage in the central type, but WB-MTV and WB-TLG in the peripheral type. Kaplan-Meier analysis demonstrated that patients with peripheral type with limited disease and low WB-MTV or WB-TLG showed significantly better overall survival than all of the other groups (p < 0.0083). The FDG-PET volumetric parameters were demonstrated to be significant and independent prognostic factors in patients with peripheral type of SCLC, while stage was the only independent prognostic factor in patients with central type of SCLC. FDG-PET is a non-invasive method that could potentially be used to estimate the prognosis of patients, especially those with peripheral-type SCLC.

Novel Humoral Prognostic Markers in Small-Cell Lung Carcinoma: A Prospective Study

PubMed Central

Gozzard, Paul; Chapman, Caroline; Vincent, Angela; Lang, Bethan; Maddison, Paul

2015-01-01

Purpose Favourable small cell lung carcinoma (SCLC) survival outcomes have been reported in patients with paraneoplastic neurological disorders (PNDs) associated with neuronal antibodies (Neur-Abs), but the presence of a PND might have expedited diagnosis. Our aim was to establish whether neuronal antibodies, independent of clinical neurological features, correlate with SCLC survival. Experimental Design 262 consecutive SCLC patients were examined: of these, 24 with neurological disease were excluded from this study. The remaining 238 were tested for a broad array of Neur-Abs at the time of cancer diagnosis; survival time was established from follow-up clinical data. Results Median survival of the non-PND cohort (n = 238) was 9.5 months. 103 patients (43%) had one or more antigen-defined Neur-Abs. We found significantly longer median survival in 23 patients (10%) with HuD/anti-neuronal nuclear antibody type 1 (ANNA-1, 13.0 months P = 0.037), but not with any of the other antigen-defined antibodies, including the PND-related SOX2 (n = 56, 24%). An additional 28 patients (12%) had uncharacterised anti-neuronal nuclear antibodies (ANNA-U); their median survival time was longer still (15.0 months, P = 0.0048), contrasting with the survival time in patients with non-neuronal anti-nuclear antibodies (detected using HEp-2 cells, n = 23 (10%), 9.25 months). In multivariate analyses, both ANNA-1 and ANNA-U independently reduced the mortality hazard by a ratio of 0.532 (P = 0.01) and 0.430 (P<0.001) respectively. Conclusions ANNAs, including the newly described ANNA-U, may be key components of the SCLC immunome and have a potential role in predicting SCLC survival; screening for them could add prognostic value that is similar in magnitude to that of limited staging at diagnosis. PMID:26606748

A prospective pilot study of genome-wide exome and transcriptome profiling in patients with small cell lung cancer progressing after first-line therapy

PubMed Central

Byron, Sara A.; Aldrich, Jessica; Sangal, Ashish; Barilla, Heather; Kiefer, Jeffrey A.; Carpten, John D.; Craig, David W.; Whitsett, Timothy G.

2017-01-01

Background Small cell lung cancer (SCLC) that has progressed after first-line therapy is an aggressive disease with few effective therapeutic strategies. In this prospective study, we employed next-generation sequencing (NGS) to identify therapeutically actionable alterations to guide treatment for advanced SCLC patients. Methods Twelve patients with SCLC were enrolled after failing platinum-based chemotherapy. Following informed consent, genome-wide exome and RNA-sequencing was performed in a CLIA-certified, CAP-accredited environment. Actionable targets were identified and therapeutic recommendations made from a pharmacopeia of FDA-approved drugs. Clinical response to genomically-guided treatment was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Results The study completed its accrual goal of 12 evaluable patients. The minimum tumor content for successful NGS was 20%, with a median turnaround time from sample collection to genomics-based treatment recommendation of 27 days. At least two clinically actionable targets were identified in each patient, and six patients (50%) received treatment identified by NGS. Two had partial responses by RECIST 1.1 on a clinical trial involving a PD-1 inhibitor + irinotecan (indicated by MLH1 alteration). The remaining patients had clinical deterioration before NGS recommended therapy could be initiated. Conclusions Comprehensive genomic profiling using NGS identified clinically-actionable alterations in SCLC patients who progressed on initial therapy. Recommended PD-1 therapy generated partial responses in two patients. Earlier access to NGS guided therapy, along with improved understanding of those SCLC patients likely to respond to immune-based therapies, should help to extend survival in these cases with poor outcomes. PMID:28586388

Minimal Pleural Effusion in Small Cell Lung Cancer: Proportion, Mechanisms, and Prognostic Effect.

PubMed

Ryu, Jeong-Seon; Lim, Jun Hyeok; Lee, Jeong Min; Kim, Woo Chul; Lee, Kyung-Hee; Memon, Azra; Lee, Seul-Ki; Yi, Bo-Rim; Kim, Hyun-Jung; Hwang, Seung-Sik

2016-02-01

To determine the frequency and investigate possible mechanisms and prognostic relevance of minimal (<10-mm thickness) pleural effusion in patients with small cell lung cancer (SCLC). The single-center retrospective study was approved by the institutional review board of the hospital, and informed consent was waived by the patients. A cohort of 360 consecutive patients diagnosed with SCLC by using histologic analysis was enrolled in this study. Based on the status of pleural effusion on chest computed tomographic (CT) scans at diagnosis, patients were classified into three groups: no pleural effusion, minimal pleural effusion, and malignant pleural effusion. Eighteen variables related to patient, environment, stage, and treatment were included in the final model as potential confounders. Minimal pleural effusion was present in 74 patients (20.6%) and malignant pleural effusion in 83 patients (23.0%). Median survival was significantly different in patients with no, minimal, or malignant pleural effusion (median survival, 11.2, 5.93, and 4.83 months, respectively; P < .001, log-rank test). In the fully adjusted final model, patients with minimal pleural effusion had a significantly increased risk of death compared with those with no pleural effusion (adjusted hazard ratio, 1.454 [95% confidence interval: 1.012, 2.090]; P = .001). The prognostic effect was significant in patients with stage I-III disease (adjusted hazard ratio, 2.751 [95% confidence interval: 1.586, 4.773]; P < .001), but it disappeared in stage IV disease. An indirect mechanism representing mediastinal lymphadenopathy was responsible for the accumulation in all but one patient with minimal pleural effusion. Minimal pleural effusion is a common clinical finding in staging SCLC. Its presence is associated with worse survival in patients and should be considered when CT scans are interpreted. © RSNA, 2015.

UTSW Researchers Identify Potential Therapeutic Targets for High-grade Neuroendocrine Lung Cancers | Office of Cancer Genomics

Cancer.gov

Neuroendocrine specific lung cancers comprise about 10% of non-small cell lung cancer (NSCLC) cases and all small cell lung cancer (SCLC) cases. Studies have previously shown that the transcription factor achaete-scute homolog 1 (ASCL1) is a cancer “lineage” factor required for the development and survival of SCLC, and is highly expressed in neuroendocrine-specific NSCLC (NE-NSCLC).

Temperature dependent electrical characterization of organic Schottky diode based on thick MgPc films

NASA Astrophysics Data System (ADS)

Singh, J.; Sharma, R. K.; Sule, U. S.; Goutam, U. K.; Gupta, Jagannath; Gadkari, S. C.

2017-07-01

Magnesium phthalocyanine (MgPc) based Schottky diode on indium tin oxide (ITO) substrate was fabricated by thermal evaporation method. The dark current voltage characteristics of the prepared ITO-MgPc-Al heterojunction Schottky diode were measured at different temperatures. The diode showed the non-ideal rectification behavior under forward and reverse bias conditions with a rectification ratio (RR) of 56 at  ±1 V at room temperature. Under forward bias, thermionic emission and space charge limited conduction (SCLC) were found to be the dominant conduction mechanisms at low (below 0.6 V) and high voltages (above 0.6 V) respectively. Under reverse bias conditions, Poole-Frenkel (field assisted thermal detrapping of carriers) was the dominant conduction mechanism. Three different approaches namely, I-V plots, Norde and Cheung methods were used to determine the diode parameters including ideality factor (n), barrier height (Φb), series resistance (R s) and were compared. SCLC mechanism showed that the trap concentration is 5.52  ×  1022 m-3 and it lies at 0.46 eV above the valence band edge.

Analysis of GD2/GM2 synthase mRNA as a biomarker for small cell lung cancer.

PubMed

Chen, Lin-Chi; Brown, Andrew B; Cheung, Irene Y; Cheung, Nai-Kong V; Kris, Mark G; Krug, Lee M

2010-02-01

GD2/GM2 synthase is a key enzyme in the synthesis of GD2 and GM2 gangliosides found on the surface of neuroblastoma and small cell lung carcinoma (SCLC) cells. In neuroblastoma, persistent levels of GD2/GM2 synthase RNA in bone marrow (BM) following therapy portend poorer progression-free and overall survival. We conducted this study to determine if GD2/GM2 synthase RNA could be detected in SCLC cell lines and human tissues, and whether mRNA transcript levels corresponded with disease status. Initially, a pilot study enrolled patients with SCLC to determine the rate of GD2 expression at various points in the patients' disease course. Peripheral blood (PB), bone marrow and tumor tissues were used to measure GD2/GM2 synthase levels. In addition, SCLC cell lines were analyzed for GD2/GM2 synthase expression. Based on data from that initial analysis, a prospective trial was developed enrolling patients with newly diagnosed SCLC and following them serially. GD2/GM2 synthase transcript was determined by a sensitive quantitative reverse transcription-PCR (qRT-PCR) assay and normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Six SCLC cell lines were assayed for expression of GD2/GM2 synthase, and high expression was detected in all. GD2/GM2 synthase transcript levels were obtained from tumor tissue, BM, or PB of 29 patients in the pilot study. 6/10 (60%) tumor tissues or BM samples were positive (median 332.7 units; range 13-2323 units); 8/19 (42%) untreated patients were GD2/GM2 synthase positive in their PB prior to beginning therapy (median 10.2; range 5.1-32.2); 3/4 (75%) patients who were first tested when they developed recurrent disease were positive in their PB (median 16.1; range 8.5-19.9). The fourth patient had an initial value of 2.0 (negative), which increased to 8.4 (positive) within 1 month without treatment. Seven of 12 patients with baseline positive GD2/GM2 synthase values had post-treatment levels measured, all of which were 50% decrease following successful treatment. Patients in the prospective trial demonstrated lower rates of positivity, with only 3/26 (12%) patients exhibiting detectable transcript levels in the peripheral blood prior to treatment. All 3 of these patients had their transcript levels fall below 5 after treatment. 11/26 patients had baseline levels of zero. Bone marrow was drawn at baseline on 7 patients in the prospective trial and 3 (43%) had transcript levels above 5 (range 0.65-27.43 units). There was no correlation between elevated levels in the BM and elevated levels in the PB. Although initial studies demonstrated that GD2/GM2 synthase transcripts were measurable in the peripheral blood of SCLC patients at diagnosis and declined with successful treatment, in a separate prospective study, these results could not be confirmed. Thus, GD2/GM2 is not a reliable biomarker in SCLC. Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

Hematologic variables associated with brain failure in patients with small-cell lung cancer.

PubMed

Suzuki, Ryoko; Wei, Xiong; Allen, Pamela K; Welsh, James W; Komaki, Ritsuko; Lin, Steven H

2018-06-12

We sought factors associated with the development of brain metastases after treatment of small cell lung cancer (SCLC) in patients without brain involvement at diagnosis. We analyzed 293 patients with SCLC without brain metastases who received chemotherapy, thoracic radiation therapy (TRT), or both in 2001-2015. Pretreatment hematologic markers (platelet count, neutrophil count, lymphocyte count, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and lactate dehydrogenase) and other clinical characteristics were evaluated for correlation with brain metastases-free survival (BMFS). Cutoffs were established with receiver operating characteristics curves. Factors significant in univariate analysis were used to build a multivariate Cox model for BMFS. Median follow-up time was 14.3 months. Brain metastases developed in 115 patients (39%)-32% of those with low pretreatment platelet counts (PPC) (≤270 × 10 9 /L) and 46% of those with high PPC (>270 × 10 9 /L). Median BMFS time for all patients was 27.9 months. Two-year BMFS rates were worse for patients with high PPC (14.6% vs. 22.1% low, P = 0.009). High PPC was independently associated with inferior BMFS (P = 0.038), as were receipt of TRT <45 Gy and no prophylactic cranial irradiation (both P < 0.001). High PPC was associated with increased rates of brain metastasis in patients with SCLC with no evidence of brain disease at diagnosis. Copyright © 2018. Published by Elsevier B.V.

Localization of Small‐cell Lung Cancer Xenografts with Iodine‐125‐, Indium‐111‐, and Rhenium‐188‐Somatostatin Analogs

PubMed Central

Hosono, Masako N.; Haberberger, Thomas; Zamora, Paul O.; Guhlke, Stefan; Bender, Hans; Russ Knapp, F. F.; Biersack, Hans J.

1996-01-01

We examined the potential of radiolabeled somatostatin analogs, 125I‐Tyr‐3‐octreotide (125I‐octreotide), 111In‐DTPA(diethylenetriaminepentaacetatic acid)‐d‐Phe‐1‐octreotide (111In‐octreotide), and 188Re‐octreotide for targeting small‐cell lung cancer (SCLC) in a mouse model. Tyr‐3‐octreotide was labeled with 125I by the chloramine T method, and 111In‐octreotide was obtained as a kit, while 188Re was eluted from a 188W/188Re generator, and octreotide was directly labeled with 188Re by reducing disulfide bonds. The 125I‐, 111In‐, and 188Re‐octreotides were injected i.v. into athymic mice bearing NCI‐H69 tumors, and the biodistributions were determined at 15 min, and 2, 4, 8, and 24 h. Tumor uptakes were 0.5±0.2, 0.3±0.1, 0.3±0.1 %ID/g, and tumor‐to‐blood ratios were 1.8, 11.9, 1.2 at 8 h for 125I‐, 111In‐, and 188Re‐octreotides, respectively. Accumulations of 111In‐octreotide in normal tissues were lower than those of 125I‐ and 188Re‐octreotides. 188Re‐octreotide can be used to localize SCLC lesions as efficiently as radioiodinated octreotide. However, 111In‐octreotide was the most suitable agent to obtain high tumor‐to‐normal tissue contrast for localizing SCLC. PMID:8878464

A phase IIa study of HA-irinotecan, formulation of hyaluronic acid and irinotecan targeting CD44 in extensive-stage small cell lung cancer.

PubMed

Alamgeer, Muhammad; Neil Watkins, D; Banakh, Ilia; Kumar, Beena; Gough, Daniel J; Markman, Ben; Ganju, Vinod

2018-04-01

Preclinical studies in small cell lung cancer (SCLC) have shown that hyaluronic acid (HA) can be effectively used to deliver chemotherapy and selectively decrease CD44 expressing (stem cell-like) tumour cells. The current study aimed to replicate these findings and obtain data on safety and activity of HA-irinotecan (HA-IR). Eligible patients with extensive stage SCLC were consented. A safety cohort (n = 5) was treated with HA-IR and Carboplatin (C). Subsequently, the patients were randomised 1:1 to receive experimental (HA-IR + C) or standard (IR + C) treatment, to a maximum of 6 cycles. The second line patients were added to the study and treated with open label HA-IR + C. Tumour response was measured after every 2 cycles. Baseline tumour specimens were stained for CD44s and CD44v6 expression. Circulating tumour cells (CTCs) were enumerated before each treatment cycle. Out of 39 patients screened, 34 were evaluable for the study. The median age was 66 (range 39-83). The overall response rates were 69% and 75% for experimental and standard arms respectively. Median progression free survival was 42 and 28 weeks, respectively (p = 0.892). The treatments were well tolerated. The incidence of grade III/IV diarrhea was more common in the standard arm, while anaemia was more common in the experimental arm. IHC analysis suggested that the patients with CD44s positive tumours may gain survival benefit from HA-IR. HA-IR is well tolerated and active in ES-SCLC. The effect of HA-IR on CD44s + cancer stem-like cells provide an early hint towards a potential novel target.

A rare case of palatin tonsillar metastasis from small cell lung cancer.

PubMed

D'Antonio, Chiara; Lombardini, Alberto; Onesti, Concetta Elisa; Falcone, Rosa; Romiti, Adriana; Lombardi, Marianna; Lauro, Salvatore; Marchetti, Paolo

2016-12-01

Tonsillar metastases are absolutely rare. Small cell lung cancer (SCLC) is known to be the most frequent histological type of tonsillar metastases, however the way of tumor cells spreading to tonsil remains controversial. We described a case report of 76-year-old man with SCLC and tonsillar metastases, to highlight the importance of oral cavity evaluation as a part of a clinical exam and to show the rare tumor cells spreading.

A "live" biopsy in a small-cell lung cancer patient by detection of circulating tumor cells.

PubMed

Bevilacqua, Simona; Gallo, Marianna; Franco, Renato; Rossi, Antonio; De Luca, Antonella; Rocco, Gaetano; Botti, Gerardo; Gridelli, Cesare; Normanno, Nicola

2009-07-01

A 71-year-old patient with a pulmonary lesion was diagnosed with a low-grade neuroendocrine tumor following examination of a fine needle aspiration biopsy. Analysis of a peripheral blood sample with the CellSearch system revealed the presence of putative circulating tumor cells (CTC) that were positive for EpCAM and cytokeratin (CK) expression. Since EpCAM is not usually expressed in neuroendocrine tumors, we performed a biopsy of liver metastases. Morphological and immunophenotypical characterization revealed that the patient had an EpCAM and CK positive small-cell lung cancer (SCLC). By using the CellSearch apparatus, EpCAM/CK positive CTC were detected in peripheral blood samples from 3 out of 4 additional SCLC patients. This study is the first to demonstrate that CTC can be identified in SCLC patients by using the CellSearch system.

Phase II trial of fenretinide (NSC 374551) in patients with recurrent small cell lung cancer.

PubMed

Schneider, Bryan J; Worden, Francis P; Gadgeel, Shirish M; Parchment, Ralph E; Hodges, Collette M; Zwiebel, James; Dunn, Rodney L; Wozniak, Antoinette J; Kraut, Michael J; Kalemkerian, Gregory P

2009-12-01

Alterations in retinoid signaling appear to be involved in the pathogenesis of small cell lung cancer (SCLC). Fenretinide [N-(4-hydroxyphenyl)retinamide], a synthetic retinoid, inhibits the growth of SCLC cells in vitro via the induction of apoptosis. Since these data suggested that SCLC is the adult solid tumor that is most susceptible to fenretinide, a trial to evaluate the clinical activity of fenretinide in patients with SCLC was considered the definitive test of its clinical potential in adult oncology. Patients with progressive SCLC after one or two prior chemotherapy regimens and a performance status of 0-2 were eligible for the study. Patients with stable, treated brain metastases were eligible. Fenretinide 900 mg/m(2) twice daily was administered orally on days 1-7 of each 21-day cycle. Blood and saliva were collected pre-treatment and on day 7 of cycle 1 to measure fenretinide and retinol levels by high-pressure liquid chromatography (HPLC). Nineteen patients were enrolled. Fifteen patients had one prior chemotherapy regimen and four patients had two prior regimens. The median time from diagnosis to enrollment was 10 months. A median of two cycles of fenretinide was administered. There were no objective responses, but four of 17 evaluable patients (24%) had stable disease after 2-17 cycles. The median time to treatment failure was 5.7 weeks overall, while the four patients with stable disease demonstrated treatment failure at 11, 13, 19, and 52 weeks. Median survival was 25 weeks, with one patient alive 22 months after the start of treatment. The 1-year survival rate was 29%. Toxicity included mild, reversible visual changes (haziness, altered night vision), grade 1-3 nausea/vomiting, and grade 1-2 diarrhea. The mean day 7 plasma fenretinide level was 2.90 +/- 1.66 μg/ml (7.40 +/- 4.25 muM; n = 14). The mean pre-treatment and day 7 plasma retinol levels were 0.47 +/- 0.16 μg/ml and 0.05 +/- 0.07 μg/ml (n = 8), respectively. The mean day 7 salivary fenretinide level was 0.08 +/- 0.18 μg/ml, with no correlation between salivary and plasma drug levels. Fenretinide is well tolerated in patients with SCLC and stabilization of disease was noted in 24% of patients with this aggressive disease. However, after the first stage of enrollment, the response rate did not meet criteria to proceed with full trial accrual. Plasma concentrations of fenretinide that induce cytotoxicity in vitro in SCLC cell lines are clinically achievable, but there were no objective responses. Non-invasive drug monitoring using saliva underestimates systemic exposure.

[Relation between the level of TPS, NSE, CEA and beta2-mG in the serum and the biological behavior of small cell lung cancer].

PubMed

Chen, Ming-sheng; Xu, Yan; Ma, Jing; Wu, Chang-gui; Hao, Xiao-ke; Lu, Bao-bi; Liu, Tian

2007-08-01

To study the relation between the level of tissue polypeptide specific antigen (TPS), neuron-specific enolase (NSE), carcinoembryonic antigen (CEA) and beta(2)-microglobulin (beta(2)-mG) in serum and the biological behavior of lung cancer for the more scientific diagnosis of lung cancer. To detect the level of TPS, NSE, CEA and beta(2)-mG in the serum of 94 patients with small cell lung cancer (SCLC), 86 patients with benign pulmonary diseases (BPD) and 89 patients in normal control group, the level of serum were examined by ELISA and immunoradiometric assay. The level of TPS and NSE in the serum of SCLC group [(437.8+/-516.6) U/L, (76.8+/-91.4) microg/L] were much higher than those in BPD group [(143.6+/-78.7) U/L, (13.3+/-10.8) microg/L] and normal group [(98.4+/-58.9) U/L, (10.1+/-5.7) microg/L, P<0.01)], and the level of CEA and beta(2)-mG in the serum of SCLC group were also obviously higher than those in normal group and BPD group (P<0.01). The sensitivity, specificity and accuracy of SCLC'S diagnosis by an indicator of TPS and NSE were 84.4%, 87.8%, 83.6% and 79.3%, 93.7%, 88.3%, respectively, and were much higher than CEA and beta(2)-Mg. In addition, the level of TPS and NSE in the patients' serum with metastatic SCLC were markedly higher than those in the patients with SCLC without metastasis, increased with the number of metastatic focuses. In clinical practice, the possibility of smokers suffering from lung cancer disease is 8 to 10 times higher than that of no-smokers, and 10 to 24 times higher of the people who smoked 30 to 40 cigarettes per day. From this comparison, the amount of smoking was closely related to the occurrence of lung cancer. TPS, NSE, CEA and beta(2)-mG in serum are useful for early diagnosis of lung cancer. There is complementarity in the combined detection of the level of TPS, NSE, CEA and beta(2)-MG. Their levels have close correlation with lung cancer, histological grades and lymphoid nodule metastasis.

A rare case of palatin tonsillar metastasis from small cell lung cancer

PubMed Central

D’Antonio, Chiara; Lombardini, Alberto; Falcone, Rosa; Romiti, Adriana; Lombardi, Marianna; Lauro, Salvatore; Marchetti, Paolo

2016-01-01

Tonsillar metastases are absolutely rare. Small cell lung cancer (SCLC) is known to be the most frequent histological type of tonsillar metastases, however the way of tumor cells spreading to tonsil remains controversial. We described a case report of 76-year-old man with SCLC and tonsillar metastases, to highlight the importance of oral cavity evaluation as a part of a clinical exam and to show the rare tumor cells spreading. PMID:28149765

Adjuvant chemotherapy versus chemoradiotherapy for small cell lung cancer with lymph node metastasis: a retrospective observational study with use of a national database in Japan.

PubMed

Urushiyama, Hirokazu; Jo, Taisuke; Yasunaga, Hideo; Yamauchi, Yasuhiro; Matsui, Hiroki; Hasegawa, Wakae; Takeshima, Hideyuki; Hiraishi, Yoshihisa; Mitani, Akihisa; Fushimi, Kiyohide; Nagase, Takahide

2017-09-02

The optimal postoperative treatment strategy for small cell lung cancer (SCLC) remains unclear, especially in patients with lymph node metastasis. We aimed to compare the outcomes of patients with SCLC and lymph node metastasis treated with postoperative adjuvant chemotherapy or chemoradiotherapy. We retrospectively collected data on patients with postoperative SCLC diagnosed with N1 and N2 lymph node metastasis from the Diagnosis Procedure Combination database in Japan, between July 2010 and March 2015. We extracted data on patient age, sex, comorbidities, and TNM classification at lung surgery; operative procedures, chemotherapy drugs, and radiotherapy during hospitalization; and discharge status. Recurrence-free survival was compared between the chemotherapy and chemoradiotherapy groups using multivariable Cox regression analysis. Median recurrence-free survival was 1146 days (95% confidence interval [CI], 885-1407) in the chemotherapy group (n = 489) and 873 days (95% CI, 464-1282) in the chemoradiotherapy group (n = 75). There was no significant difference between these after adjusting for patient backgrounds (hazard ratio, 1.29; 95% CI, 0.91-1.84). There was no significant difference in recurrence-free survival between patients with SCLC and N1-2 lymph node metastasis treated with postoperative adjuvant chemotherapy and chemoradiotherapy. Further randomized clinical trials are needed to address this issue.

Production of insulin-like growth factor binding proteins by small-cell lung cancer cell lines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jaques, G.; Kiefer, P.; Rotsch, M.

1989-10-01

Conditioned serum-free media (CM) from small-cell lung cancer (SCLC) cell lines were examined for the presence of insulin-like growth-factor-binding proteins (IGF-BP). 6/9 SCLC cell lines secreted binding proteins with high affinity for IGFs. When ({sup 125}I)IGF-1 or ({sup 125}I)IGF-II was incubated with the CMs, complexes of tracer with proteins could be demonstrated by gel filtration, by precipitation with polyethylenglycol, and after adsorption of unbound tracer with activated charcoal. Analysis of binding data according to the method of Scatchard resulted in linear plots for IGF-I and IGF-II. Cross-linking of ({sup 125}I)IGF-I or ({sup 125}I)IGF-II to the CMs followed by sodium dodecylmore » sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) under nonreducing conditions revealed the presence of IGF-BPs with molecular masses in the range of 24-32 kDa. Northern blot hybridization with an IGF-BP cDNA probe encoding a low-molecular-weight IGF-BP from a human placenta cDNA library and Western blot analysis with a corresponding polyclonal antibody showed no expression of this gene. These data demonstrate that SCLC cell lines release IGF-BPs in culture supernatants, which differ from IGF-BPs detected in liver and placenta. These IGF-BPs might be important mediators in the autocrine/paracrine growth regulation of IGFs in SCLC.« less

Reliability Studies of Ceramic Capacitors.

DTIC Science & Technology

1983-07-01

increases. This case has been found to be a good approximation for single crystals with high chemical and structural purity. Shallow traps may arise as a...theory, this sudden increase may be otherwise explained. Single crystals of ZnS have been found to exhibit this vertical increase in the current...Smith and Rose observed SCLC behavior in CdS single crystals . Branwood and Tredgold 2 8 and Branwood et al. 2 9 measured BaTiO 3 single crystals and

Charge transport studies in donor-acceptor block copolymer PDPP-TNT and PC71BM based inverted organic photovoltaic devices processed in room conditions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Srivastava, Shashi B.; Singh, Samarendra P., E-mail: samarendra.singh@snu.edu.in; Sonar, Prashant

2015-07-15

Diketopyrrolopyrole-naphthalene polymer (PDPP-TNT), a donor-acceptor co-polymer, has shown versatile behavior demonstrating high performances in organic field-effect transistors (OFETs) and organic photovoltaic (OPV) devices. In this paper we report investigation of charge carrier dynamics in PDPP-TNT, and [6,6]-phenyl C{sub 71} butyric acid methyl ester (PC71BM) bulk-heterojunction based inverted OPV devices using current density-voltage (J-V) characteristics, space charge limited current (SCLC) measurements, capacitance-voltage (C-V) characteristics, and impedance spectroscopy (IS). OPV devices in inverted architecture, ITO/ZnO/PDPP-TNT:PC71BM/MoO{sub 3}/Ag, are processed and characterized at room conditions. The power conversion efficiency (PCE) of these devices are measured ∼3.8%, with reasonably good fill-factor 54.6%. The analysis ofmore » impedance spectra exhibits electron’s mobility ∼2 × 10{sup −3} cm{sup 2}V{sup −1}s{sup −1}, and lifetime in the range of 0.03-0.23 ms. SCLC measurements give hole mobility of 1.12 × 10{sup −5} cm{sup 2}V{sup −1}s{sup −1}, and electron mobility of 8.7 × 10{sup −4} cm{sup 2}V{sup −1}s{sup −1}.« less

Experimental Investigation of the Effect of Manufactured Sand and Lightweight Sand on the Properties of Fresh and Hardened Self-Compacting Lightweight Concretes.

PubMed

Zhu, Yiyun; Cui, Hongzhi; Tang, Waiching

2016-08-29

Self-compacting lightweight concrete (SCLC) is a promising construction material for building applications, but most SCLCs today are made with river sand (RS). There is an increasing demand for environmental protection, as well as materials with a high strength/density ratio. The manufactured sand (MS) and lightweight sand (LS) as fine aggregates in cement-based composite materials have been receiving more attention among researchers. However, there is not much information about the effects of MS and LS on the properties of the fresh and hardened SCLCs. In this paper, the properties of fresh and hardened SCLC made with MS and LS were investigated by a series of experiments. SCLCs made with RS served as the control in this study. The test results show that increasing the sand ratio (from 0.40-0.50) decreased the filling ability and led to an increased T 50 time, which is the time spent for the concrete to reach the 500 mm spread circle, for all of the fresh SCLCs. Although the passing ability of MS-SCLCs and LS-SCLCs is not as good as RS-SCLCs, their results are still within an acceptable range. The ratio of mechanical properties to density was found to increase with an increase of the sand ratio for all of the hardened SCLCs. MS-SCLCs presented the highest compressive strength among all of the SCLCs studied. Although the mean compressive strength of LS-SCLCs is lower than those of the other two SCLCs by 8%, their strength to density ratio is higher than others by 15%, and the ratio increases remarkably with the increase of the sand ratio. Permeability test results showed that the permeability coefficient of MS-SCLC is remarkably lower than that of LS-SCLC, but slightly higher than that of RS-SCLC.

Duration of Chemotherapy for Small Cell Lung Cancer: A Meta-Analysis

PubMed Central

Zhou, Hang; Zeng, Chao; Wei, Yang; Zhou, Jin; Yao, Wenxiu

2013-01-01

Background Maintenance chemotherapy is widely provided to patients with small cell lung cancer (SCLC). However, the benefits of maintenance chemotherapy compared with observation are a subject of debate. Methodology and Principal Findings To identify relevant literature, we systematically searched the Medline, Embase, and Cochrane Central Register of Controlled Trials databases. Eligible trials included patients with SCLC who either received maintenance chemotherapy (administered according to a continuous or switch strategy) or underwent observation. The primary outcome was 1-year mortality, and secondary outcomes were 2-year mortality, overall survival (OS), and progression-free survival (PFS). Of the 665 studies found in our search, we identified 14 relevant trials, which together reported data on 1806 patients with SCLC. When compared with observation, maintenance chemotherapy had no effect on 1-year mortality (odds ratio [OR]: 0.88; 95% confidence interval [CI]: 0.66–1.19; P = 0.414), 2-year mortality (OR: 0.82; 95% CI: 0.57–1.19; P = 0.302), OS (hazard ratio [HR]: 0.87; 95% CI: 0.71–1.06; P = 0.172), or PFS (HR: 0.87; 95% CI: 0.62–1.22; P = 0.432). However, subgroup analyses indicated that maintenance chemotherapy was associated with significantly longer PFS than observation in patients with extensive SCLC (HR, 0.72; 95% CI: 0.58–0.89; P = 0.003). Additionally, patients who were managed using the continuous strategy of maintenance chemotherapy appeared to be at a disadvantage in terms of PFS compared with patients who only underwent observation (HR, 1.27; 95% CI: 1.04–1.54; P = 0.018). Conclusions/Significance Maintenance chemotherapy failed to improve survival outcomes in patients with SCLC. However, a significant advantage in terms of PFS was observed for maintenance chemotherapy in patients with extensive disease. Additionally, our results suggest that the continuous strategy is inferior to observation; its clinical value needs to be investigated in additional trials. PMID:24023692

Positive Interaction Between Prophylactic Cranial Irradiation And Maintenance Sunitinib For Untreated Extensive Stage Small Cell Lung Cancer Patients After Standard Chemotherapy: A Secondary Analysis Of CALGB 30504 (Alliance)

PubMed Central

Salama, Joseph K.; Gu, Lin; Wang, Xiaofei; Pang, Herbert H.; Bogart, Jeffrey A.; Crawford, Jeffrey; Schild, Steven E.; Vokes, Everett E.; Ready, Neal E.

2015-01-01

Background Prophylactic cranial irradiation (PCI) has become a standard option for extensive stage small cell lung cancer (ES-SCLC) patients. CALGB 30504 was a randomized phase II study of sunitinib vs placebo in ES-SCLC patients responding to platinum-based therapy requiring pre-enrollment brain imaging. PCI was at the discretion of treating physicians. We performed a secondary analysis of CALGB 30504 to determine the impact of PCI on ES-SCLC patients. Methods Fisher’s exact and Wilcoxon rank-sum tests were conducted to test the differences between PCI and non-PCI patients. Kaplan-Meier analyses described PFS and OS for PCI and non-PCI patients. Results 85 patients received maintenance (41 placebo, 44 sunitinib). 41 received PCI, 44 did not. Characteristics were balanced between PCI and no-PCI patients. PCI patients receiving sunitinib had non-significant 2.7-month PFS improvement (5.0 months vs. 2.3 months, p=0.14, HR=0.62 (95% CI: 0.33–1.18)), trending toward improved OS (8.9 months vs. 5.4 months, p=0.053, HR: 0.47 (0.22–1.03)). PCI was associated with a trend toward improved median PFS (2.9 months vs. 2.2 months, p=0.096, HR=0.69 (95% CI 0.45–1.07)), but not median OS (PCI 8.3 months vs. no PCI 8.7 months, p=0.76, HR=1.07 (95% CI 0.67–1.71)). Placebo patients had no PFS or OS difference. Conclusions Trends for improved PFS and OS were seen in patients receiving PCI and sunitinib supporting the need for further prospective research evaluating the integration of maintenance systemic therapy and PCI in ES-SCLC. Improved outcomes for ES-SCLC patients after induction chemotherapy may require PCI and systemic therapy to achieve control of both intracranial and extracranial disease. PMID:26723241

Experimental Investigation of the Effect of Manufactured Sand and Lightweight Sand on the Properties of Fresh and Hardened Self-Compacting Lightweight Concretes

PubMed Central

Zhu, Yiyun; Cui, Hongzhi; Tang, Waiching

2016-01-01

Self-compacting lightweight concrete (SCLC) is a promising construction material for building applications, but most SCLCs today are made with river sand (RS). There is an increasing demand for environmental protection, as well as materials with a high strength/density ratio. The manufactured sand (MS) and lightweight sand (LS) as fine aggregates in cement-based composite materials have been receiving more attention among researchers. However, there is not much information about the effects of MS and LS on the properties of the fresh and hardened SCLCs. In this paper, the properties of fresh and hardened SCLC made with MS and LS were investigated by a series of experiments. SCLCs made with RS served as the control in this study. The test results show that increasing the sand ratio (from 0.40–0.50) decreased the filling ability and led to an increased T50 time, which is the time spent for the concrete to reach the 500 mm spread circle, for all of the fresh SCLCs. Although the passing ability of MS-SCLCs and LS-SCLCs is not as good as RS-SCLCs, their results are still within an acceptable range. The ratio of mechanical properties to density was found to increase with an increase of the sand ratio for all of the hardened SCLCs. MS-SCLCs presented the highest compressive strength among all of the SCLCs studied. Although the mean compressive strength of LS-SCLCs is lower than those of the other two SCLCs by 8%, their strength to density ratio is higher than others by 15%, and the ratio increases remarkably with the increase of the sand ratio. Permeability test results showed that the permeability coefficient of MS-SCLC is remarkably lower than that of LS-SCLC, but slightly higher than that of RS-SCLC. PMID:28773857

5-Bromodeoxyuridine induced differentiation of a human small cell lung cancer cell line is associated with alteration of gene expression.

PubMed

Chen, Yuan; Pacyna-Gengelbach, Manuela; Deutschmann, Nicole; Ye, Fei; Petersen, Iver

2007-02-16

Small cell lung cancer (SCLC) appears to arise from neuroendocrine cells with the potential to differentiate into a variety of lung epithelial cell lineages. In order to investigate molecular events underlying the cell type transition in SCLC, we treated a SCLC cell line H526 with a differentiation inducing agent 5-bromodeoxyuridine (BrdU). The treatment led to a dramatic conversion from suspension cells to adherent cells exhibiting an epithelioid phenotype, which remarkably reduced the ability of colony formation in soft agar and suppressed the tumor growth rate in nude mice. The phenotypic transition was consistent with upregulation of surfactant protein C (SFTPC), thyroid transcription factor 1 (TTF-1), Connexin 26 (Cx26), insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1), as well as homeobox genes LAGY, PITX1, and HOXB2. Our data suggest that BrdU induced cell differentiation could be linked to the development of a less aggressively phenotype in small cell lung cancer.

Cell signaling molecules as drug targets in lung cancer: an overview.

PubMed

Mukherjee, Tapan K; Paul, Karan; Mukhopadhyay, Srirupa

2011-07-01

Lung being one of the vital and essential organs in the body, lung cancer is a major cause of mortality in the modern human society. Lung cancer can be broadly subdivided into nonsmall cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Although NSCLC is sometimes treated with surgery, the advanced and metastatic NSCLC and SCLC usually respond better to chemotherapy and radiation. The most important targets of these chemotherapeutic agents are various intracellular signaling molecules. The primary focus of this review article is to summarize the description of various cell signaling molecules involved in lung cancer development and their regulation by chemotherapeutic agents. Extensive research work in recent years has identified several cellular signaling molecules that may be intricately involved in the complexity of lung cancer. Some of these cell signaling molecules are epidermal growth factor receptors, vascular endothelial growth factor receptors, mammalian target of rapamycin, mitogen-activated protein kinase phosphatase-1, peroxisome proliferator-activated receptor-gamma, matrix metalloproteinases and receptor for advanced glycation end-products. The present review will strengthen our current knowledge regarding the efficacy of the above-mentioned cell signaling molecules as potential beneficial drug targets against lung cancer.

Short-course whole-brain radiotherapy (WBRT) for brain metastases due to small-cell lung cancer (SCLC).

PubMed

Bohlen, Guenther; Meyners, Thekla; Kieckebusch, Susanne; Lohynska, Radka; Veninga, Theo; Stalpers, Lukas J A; Schild, Steven E; Rades, Dirk

2010-04-01

Many patients with brain metastases due to SCLC have a poor survival prognosis. The most common treatment is whole-brain radiotherapy (WBRT). This retrospective study compares short-course WBRT with 5x4Gy in 1 week to standard WBRT with 10x3Gy in 2 weeks. Forty-four SCLC patients receiving WBRT with 5x4Gy were compared to 102 patients receiving 10x3Gy for survival (OS) and local (intracerebral) control (LC). Seven further potential prognostic factors were investigated: age, gender, Karnofsky Performance Score (KPS), number of brain metastases, extracerebral metastases, interval from tumor diagnosis to WBRT, RPA (Recursive Partitioning Analysis) class. After 5x4Gy, 12-month OS was 15%, versus 22% after 10x3Gy (p=0.69). On multivariate analysis, improved OS was associated with age or=70 (p<0.001), <4 brain metastases (p=0.011), and RPA class 1 (p<0.001). 12-month LC was 34% after 5x4Gy versus 25% after 10x3Gy (p=0.32). On multivariate analysis, improved LC was associated with KPS >or=70 (p<0.001), <4 brain metastases (p=0.027), and RPA class 1 (p<0.001). In patients with brain metastases due to SCLC, short-course WBRT with 5x4Gy provided similar outcomes as 10x3Gy and appears preferable, particularly for patients with poor estimated survival.

Effusion cytomorphology of small round cell tumors.

PubMed

Ikeda, Katsuhide; Tsuta, Koji

2016-01-01

Small round cell tumors (SRCTs) are a group of tumors composed of small, round, and uniform cells with high nuclear/cytoplasmic (N/C) ratios. The appearance of SRCT neoplastic cells in the effusion fluid is very rare. We reported the cytomorphological findings of SRCTs in effusion cytology, and performed statistical and mathematical analyses for a purpose to distinguish SRCTs. We analyzed the cytologic findings of effusion samples from 40 SRCT cases and measured the lengths of the nuclei, cytoplasms, and the cell cluster areas. The SRCT cases included 14 Ewing sarcoma (EWS)/primitive neuroectodermal tumor cases, 5 synovial sarcoma cases, 6 rhabdomyosarcoma cases, 9 small cell lung carcinoma (SCLC) cases, and 6 diffuse large B-cell lymphoma (DLBL) cases. Morphologically, there were no significant differences in the nuclear and cytoplasmic lengths in cases of EWS, synovial sarcoma, and rhabdomyosarcoma. The cytoplasmic lengths in cases of SCLC and DLBL were smaller than those of EWS, synovial sarcoma, and rhabdomyosarcoma. The nuclear density of the cluster in SCLC was higher than that in other SRCTs, and cases of DLBL showed a lack of anisokaryosis and anisocytosis. We believe that it might be possible to diagnose DLBL and SCLC from cytologic analysis of effusion samples but it is very difficult to use this method to distinguish EWS, synovial sarcoma, and rhabdomyosarcoma. Statistical and mathematical analyses indicated that nuclear density and dispersion of nuclear and cytoplasmic sizes are useful adjuncts to conventional cytologic diagnostic criteria, which are acquired from experience.

Prognostic role of integrin β1, E-cadherin, and rac1 expression in small cell lung cancer.

PubMed

Chang, Myung Hee; Lee, Kyungji; Lee, Kyo-Young; Kim, Yeon Sil; Kim, Young Kyoon; Kang, Jin-Hyoung

2012-01-01

Integrin β(1) mediates cellular adhesion to the extracellular matrix (ECM) and is correlated with highly invasive and metastatic behavior in small cell lung cancer (SCLC). E-cadherin (ECAD) is a calcium-dependent cell-cell adhesion receptor that restricts invasion of cells and reduces metastasis. Rac1 is involved in the regulation of the actin cytoskeleton, adhesion, migration, invasion, and tumor metastasis. The aim of this study was to examine integrin β(1) , ECAD and rac1 expression in SCLC and to analyze the prognostic value of these markers in patients with SCLC. We analyzed integrin β(1) , ECAD, and rac1 expression in 112 SCLC tissues by immunohistochemical staining. Correlative analyses between integrin β(1) , ECAD, and rac1 expression and cliniopathological factors were performed. A total of 65 patients had extensive disease (ED) (58%), and 47 had limited disease (LD) (42%). The median follow-up duration was 61 months (range: 14-117 months), and the median progression free survival (PFS) and overall survival (OS) were 6.1 months (range: 4.8-7.4 months) and 9.7 months (range: 8.1-11.3 months), respectively. The expression of integrin β(1) , ECAD, and rac1 protein was observed in 64, 73, and 99 of SCLC tissues, respectively. The correlative analyses between integrin β(1) , ECAD, or rac1 expression and various clinical parameters did not show any statistical significance. However, the ECAD expression was associated with OS in the entire cohort. In contrast, the expression of integrin β(1) and rac1 was not associated with PFS or OS. In a subgroup analysis, patients with less than two metastasis had significantly longer OS (p = 0.047) if their tumors expressed integrin β(1) compared to those without integrin β(1) expression. In addition, OS was longer for patients with ECAD positive tumors compared to those whose tumors did not express ECAD in males (p = 0.032) and patients who never smoked (p < 0.001). Multivariate analysis showed that LD (p = 0.004), overall response rate (p = 0.003), and expression of ECAD (p = 0.015) were the independent good prognostic factors for OS. LD (p = 0.024), overall response rate (p < 0.001), and less than two metastasis (p = 0.003) were prognostic factors for longer PFS. These results suggest that ECAD expression may be useful as a prognostic indicator in patients with SCLC. © 2011 The Authors. APMIS © 2011 APMIS.

[Current treatment concepts of lung cancer].

PubMed

Kaiser, F; Engelhardt, M; Rawluk, J; Mertelsmann, R; Passlick, B; Wäsch, R

2011-09-01

Lung cancer occurs with a median age of 69 years. The main cause is cigarette smoking. For both genders lung cancer is the third-most frequent tumor in Germany. While in an operable tumor stage 30-80% of the patients can reach long-term survival, the prognosis in the metastasised stage is unfavourable with a 5-year overall survival rate of 6% for small cell lung cancer (SCLC) and 18% for non-small cell lung cancer (NSCLC). Lung cancer is subject of intense research to improve the outcome. This article gives an overview of current treatment options. © Georg Thieme Verlag KG Stuttgart · New York.

Inhibition of SUR1 Decreases the Vascular Permeability of Cerebral Metastases1

PubMed Central

Thompson, Eric M; Pishko, Gregory L; Muldoon, Leslie L; Neuwelt, Edward A

2013-01-01

Inhibition of sulfonylurea receptor 1 (SUR1) by glyburide has been shown to decrease edema after subarachnoid hemorrhage. We investigated if inhibiting SUR1 reduces cerebral edema due to metastases, the most common brain tumor, and explored the putative association of SUR1 and the endothelial tight junction protein, zona occludens-1 (ZO-1). Nude rats were intracerebrally implanted with small cell lung carcinoma (SCLC) LX1 or A2058 melanoma cells (n = 36). Rats were administered vehicle, glyburide (4.8 µg twice, orally), or dexamethasone (0.35 mg, intravenous). Blood-tumor barrier (BTB) permeability (Ktrans) was evaluated before and after treatment using dynamic contrast-enhanced magnetic resonance imaging. SUR1 and ZO-1 expression was evaluated using immunofluorescence and Western blots. In both models, SUR1 expression was significantly increased (P < .05) in tumors. In animals with SCLC, control mean Ktrans (percent change ± standard error) was 101.8 ± 36.6%, and both glyburide (-21.4 ± 14.2%, P < .01) and dexamethasone (-14.2 ± 13.1%, P < .01) decreased BTB permeability. In animals with melanoma, compared to controls (117.1 ± 43.4%), glyburide lowered BTB permeability increase (3.2 ± 15.4%, P < .05), while dexamethasone modestly lowered BTB permeability increase (63.1 ± 22.1%, P > .05). Both glyburide (P < .001) and dexamethasone (P < .01) decreased ZO-1 gap formation. By decreasing ZO-1 gaps, glyburide was at least as effective as dexamethasone at halting increased BTB permeability caused by SCLC and melanoma. Glyburide is a safe, inexpensive, and efficacious alternative to dexamethasone for the treatment of cerebral metastasis-related vasogenic edema. PMID:23633925

Clinical value of Pro-GRP and T lymphocyte subpopulation for the assessment of immune functions of lung cancer patients after DC-CIK biological therapy.

PubMed

He, Lijie; Wang, Jing; Chang, Dandan; Lv, Dandan; Li, Haina; Zhang, Heping

2018-02-01

The present study investigated the aptness of assessing the levels of progastrin-releasing peptide (Pro-GRP) in addition to the T lymphocyte subpopulation in lung cancer patients prior to and after therapy for determining immune function. A total of 45 patients with lung cancer were recruited and stratified in to a non-small cell lung cancer (NSCLC) and an SCLC group. Prior to and after treatment by combined biological therapy comprising chemotherapy or chemoradiotherapy followed by three cycles of retransformation of autologous dendritic cells-cytokine-induced killer cells (DC-CIK), the peripheral blood was assessed for populations of CD3 + , CD4 + , CD8 + and regulatory T cells (Treg) by flow cytometry, and for the levels of pro-GRP, carcinoembryonic antigen, neuron-specific enolase and Cyfra 21-1. The results revealed that in NSCLC patients, CD8 + T lymphocytes and Treg populations were decreased, and that CD3 + and CD4 + T lymphocytes as well as the CD4 + /CD8 + ratio were increased after therapy; in SCLC patients, CD3 + , CD4 + and CD8 + T lymphocytes were increased, while Treg cells were decreased after treatment compared with those at baseline. In each group, Pro-GRP was decreased compared with that prior to treatment, and in the SCLC group only, an obvious negative correlation was identified between Pro-GRP and the T lymphocyte subpopulation. Furthermore, a significant correlation between Pro-GRP and Tregs was identified in each group. In conclusion, the present study revealed that the immune function of the patients was improved after biological therapy. The results suggested a significant correlation between Pro-GRP and the T lymphocyte subpopulation in SCLC patients. Detection of Pro-GRP may assist the early clinical diagnosis of SCLC and may also be used to assess the immune regulatory function of patients along with the T lymphocyte subpopulation. Biological therapy with retransformed autologous DC-CIK was indicated to enhance the specific elimination of tumor cells and improve the immune surveillance function in cancer patients, and also restrained the immune evasion of the tumor, leading to decreased Pro-GRP levels.

Predictors of pulmonary toxicity in limited stage small cell lung cancer patients treated with induction chemotherapy followed by concurrent platinum-based chemotherapy and 70 Gy daily radiotherapy: CALGB 30904.

PubMed

Salama, Joseph K; Pang, Herbert; Bogart, Jeffrey A; Blackstock, A William; Urbanic, James J; Hogson, Lydia; Crawford, Jeffrey; Vokes, Everett E

2013-12-01

Standard therapy for limited stage small cell lung cancer (L-SCLC) is concurrent chemotherapy and radiotherapy followed by prophylactic cranial radiotherapy. Predictors of post chemoradiotherapy pulmonary toxicity in limited stage (LS) small cell lung cancer (SCLC) patients are not well defined. Current guidelines are derived from non-small cell lung cancer regimens, and do not account for the unique biology of this disease. Therefore, we analyzed patients on three consecutive CALGB LS-SCLC trials treated with concurrent chemotherapy and daily high dose radiotherapy (70 Gy) to determine patient and treatment related factors predicting for post-treatment pulmonary toxicity. Patients treated on CALGB protocols 39808, 30002, 30206 investigating two cycles of chemotherapy followed by concurrent chemotherapy and 70 Gy daily thoracic radiation therapy were pooled. Patient, tumor, and treatment related factors were evaluated to determine predictors of grade 3–5 pulmonary toxicities after concurrent chemoradiotherapy. 100 patients were included. No patient experienced grade 4–5 post-treatment pulmonary toxicity. Patients who experienced post-treatment pulmonary toxicity were more likely to be older (median age 69 vs 60, p = 0.09) and have smaller total lung volumes (2565 cc vs 3530 cc, p = 0.05).). Furthermore,exposure of larger volumes of lung to lower (median V5 = 70%, p = 0.09, median V10 = 63%, p = 0.07), inter-mediate (median V20 = 50, p = 0.04) and high (median V60 = 25%, p = 0.01) doses of radiation were all associated with post-treatment grade 3 pulmonary toxicity, as was a larger mean lung radiation dose(median 31 Gy) p = 0.019. Post-treatment pulmonary toxicity following the completion of 2 cycles of chemotherapy followed by concurrent chemotherapy and high dose daily radiation therapy was uncommon. Care should be taken to minimize mean lung radiation exposure, as well as volumes of low, intermediate and high doses of radiation.

Benefit from ifosfamide treatment in small-cell lung cancer: A meta-analysis

PubMed Central

YANG, HUIZHEN; MA, YUN; LIU, ZHIDA; WANG, ZHENG; HAN, BAOHUI; MA, LIJUN

2015-01-01

This study was conducted to compare the efficacy and safety of ifosfamide plus etoposide plus platinum (IEP) to that of etoposide plus platinum (EP) in patients with previously untreated small-cell lung cancer (SCLC). The Cochrane Library, Embase, MEDLINE and Chinese Biomedical Literature databases were searched to identify all randomized controlled trials comparing IEP to EP in patients with histologically proven SCLC. Two investigators independently assessed the quality of the relevant trials and extracted data. We analyzed the data using Review Manager software, version 4.2.8. A total of 4 trials with 447 previously untreated SCLC patients were included in this meta-analysis. The results of the meta-analysis indicated that there were no significant differences in the overall response [relative risk (RR) = 1.07, 95% confidence interval (CI): 0.97-1.19], 1-year survival rate (RR=1.22, 95% CI: 0.96-1.55) and 2-year survival rate (RR=1.52, 95% CI: 0.75-3.07) between the IEP and EP regimens. However, there were significant differences between the IEP and EP regimens regarding the incidence of grade 3/4 neutropenia (RR=1.52, 95% CI: 1.07-2.17) and grade 3/4 vomiting (RR=1.78, 95% CI: 1.02-3.11). In conclusion, our results suggested that IEP is not superior to EP regimen for the treatment of previously untreated SCLC, whereas the IEP regimen is associated with more severe hematological and gastrointestinal toxicities compared to EP. Therefore, the use of ifosfamide in multimodality treatment regimens requires further investigation. PMID:25798279

Benefit from ifosfamide treatment in small-cell lung cancer: A meta-analysis.

PubMed

Yang, Huizhen; Ma, Yun; Liu, Zhida; Wang, Zheng; Han, Baohui; Ma, Lijun

2015-03-01

This study was conducted to compare the efficacy and safety of ifosfamide plus etoposide plus platinum (IEP) to that of etoposide plus platinum (EP) in patients with previously untreated small-cell lung cancer (SCLC). The Cochrane Library, Embase, MEDLINE and Chinese Biomedical Literature databases were searched to identify all randomized controlled trials comparing IEP to EP in patients with histologically proven SCLC. Two investigators independently assessed the quality of the relevant trials and extracted data. We analyzed the data using Review Manager software, version 4.2.8. A total of 4 trials with 447 previously untreated SCLC patients were included in this meta-analysis. The results of the meta-analysis indicated that there were no significant differences in the overall response [relative risk (RR) = 1.07, 95% confidence interval (CI): 0.97-1.19], 1-year survival rate (RR=1.22, 95% CI: 0.96-1.55) and 2-year survival rate (RR=1.52, 95% CI: 0.75-3.07) between the IEP and EP regimens. However, there were significant differences between the IEP and EP regimens regarding the incidence of grade 3/4 neutropenia (RR=1.52, 95% CI: 1.07-2.17) and grade 3/4 vomiting (RR=1.78, 95% CI: 1.02-3.11). In conclusion, our results suggested that IEP is not superior to EP regimen for the treatment of previously untreated SCLC, whereas the IEP regimen is associated with more severe hematological and gastrointestinal toxicities compared to EP. Therefore, the use of ifosfamide in multimodality treatment regimens requires further investigation.

Argininosuccinate synthetase (ASS) deficiency in high-grade pulmonary neuroendocrine carcinoma: an opportunity for personalized targeted therapy.

PubMed

Walts, Ann E; Bomalaski, John S; Ines, Delma; Orsulic, Sandra

2015-08-01

Cells deficient in argininosuccinate synthetase (ASS) must absorb the arginine they need for growth from circulating blood. Treatment with pegylated arginine deiminase (ADI-PEG 20) selectively eliminates arginine from the circulation and has shown some efficacy against ASS-deficient tumors including small cell lung cancer (SCLC). We sought to assess ASS expression in a cohort of high-grade pulmonary neuroendocrine carcinomas (PNEC) which include SCLC and large cell neuroendocrine carcinoma (LCNEC). Sixty-nine PNEC (49 SCLC and 20 LCNEC) were retrieved from our pathology archives. Formalin-fixed paraffin-embedded sections of the 54 primary tumors, 15 metastases and appropriate positive and negative controls were immunostained using an ASS-specific monoclonal antibody. Positive staining in <30 % of the tumor was scored as weak; staining in ≥30 % of the tumor was scored as strong. The absence of staining in the tumor was recorded as ASS negative. 58 % of the PNEC including 61.2 % of the SCLC and 50 % of the LCNEC were ASS negative. These ASS-negative tumors included 63 % of the primary and 40 % of the metastatic lesions tested. More than 50 % of the high-grade PNEC tested lack immunohistochemically detectable ASS, suggesting that they are auxotrophic for arginine and potential candidates for arginine deprivation therapy. PNEC comprise about 25 % of primary lung cancers and have a 5-year overall survival of only 5-10 %, underscoring the need for new and more effective therapies. Immunostaining for ASS has potential to improve the selection of patients with PNEC for arginine deprivation therapy with ADI-PEG 20.

Staurosporine and Extracellular Matrix Proteins Mediate the Conversion of Small Cell Lung Carcinoma Cells into a Neuron-Like Phenotype

PubMed Central

Veit, Nadine; Courts, Cornelius; Glassmann, Alexander; Janzen, Viktor; Madea, Burkhard; Reinartz, Markus; Harzen, Anne; Nowak, Michael; Perner, Sven; Winter, Jochen; Probstmeier, Rainer

2014-01-01

Small cell lung carcinomas (SCLCs) represent highly aggressive tumors with an overall five-year survival rate in the range of 5 to 10%. Here, we show that four out of five SCLC cell lines reversibly develop a neuron-like phenotype on extracellular matrix constituents such as fibronectin, laminin or thrombospondin upon staurosporine treatment in an RGD/integrin-mediated manner. Neurite-like processes extend rapidly with an average speed of 10 µm per hour. Depending on the cell line, staurosporine treatment affects either cell cycle arrest in G2/M phase or induction of polyploidy. Neuron-like conversion, although not accompanied by alterations in the expression pattern of a panel of neuroendocrine genes, leads to changes in protein expression as determined by two-dimensional gel electrophoresis. It is likely that SCLC cells already harbour the complete molecular repertoire to convert into a neuron-like phenotype. More extensive studies are needed to evaluate whether the conversion potential of SCLC cells is suitable for therapeutic interventions. PMID:24586258

Electrical transport properties of an isolated CdS microrope composed of twisted nanowires

NASA Astrophysics Data System (ADS)

Yu, Gui-Feng; Yu, Miao; Pan, Wei; Han, Wen-Peng; Yan, Xu; Zhang, Jun-Cheng; Zhang, Hong-Di; Long, Yun-Ze

2015-01-01

CdS is one of the important II-VI group semiconductors. In this paper, the electrical transport behavior of an individual CdS microrope composed of twisted nanowires is studied. It is found that the current-voltage ( I- V) characteristics show two distinct power law regions from 360 down to 60 K. Space-charge-limited current (SCLC) theory is used to explain these temperature- and electric-field-dependent I-V curves. The I-V data can be well fitted by this theory above 100 K, and the corresponding carrier mobility, trap energy, and trap concentration are also obtained. However, the I-V data exhibit some features of the Coulomb blockade effect below 80 K.

Effects of sol aging on resistive switching behaviors of HfOx resistive memories

NASA Astrophysics Data System (ADS)

Hsu, Chih-Chieh; Sun, Jhen-Kai; Tsao, Che-Chang; Chen, Yu-Ting

2017-03-01

This work investigates effects of long-term sol-aging time on sol-gel HfOx resistive random access memories (RRAMs). A nontoxic solvent of ethanol is used to replace toxic 2-methoxyethanol, which is usually used in sol-gel processes. The top electrodes are fabricated by pressing indium balls onto the HfOx surface rather than by using conventional sputtering or evaporation processes. The maximum process temperature is limited to be 100 ℃. Therefore, influences of plasma and high temperature on HfOx film can be avoided. Under this circumstance, effects of sol aging time on the HfOx films can be more clearly studied. The current conduction mechanisms in low and high electric regions of the HfOx RRAM are found to be dominated by Ohmic conduction and trap-filled space charge limited conduction (TF-SCLC), respectively. When the sol aging time increases, the resistive switching characteristic of the HfOx layer becomes unstable and the transition voltage from Ohmic conduction to TF-SCLC is also increased. This suggests that an exceedingly long aging time will give a HfOx film with more defect states. The XPS results are consistent with FTIR analysis and they can further explain the unstable HfOx resistive switching characteristic induced by sol aging.

Photosensitive space charge limited current in screen printed CdTe thin films

NASA Astrophysics Data System (ADS)

Vyas, C. U.; Pataniya, Pratik; Zankat, Chetan K.; Patel, Alkesh B.; Pathak, V. M.; Patel, K. D.; Solanki, G. K.

2018-05-01

Group II-VI Compounds have emerged out as most suitable in the class of photo sensitive material. They represent a strong position in terms of their applications in the field of detectors as well as photo voltaic devices. Cadmium telluride is the prime member of this Group, because of high acceptance of this material as active component in opto-electronic devices. In this paper we report preparation and characterization of CdTe thin films by using a most economical screen printing technique in association with sintering at 510°C temperature. Surface morphology and smoothness are prime parameters of any deposited to be used as an active region of devices. Thus, we studied of the screen printed thin film by means of atomic force microscopy (AFM) and scanning electron microscopy (SEM) for this purpose. However, growth processes induced intrinsic defects in fabricated films work as charge traps and affect the conduction process significantly. So the conduction mechanism of deposited CdTe thin film is studied under dark as well as illuminated conditions. It is found that the deposited films showed the space charge limited conduction (SCLC) mechanism and hence various parameters of space charge limited conduction (SCLC) of CdTe film were evaluated and discussed and the photo responsive resistance is also presented in this paper.

Bandlike Transport in Ferroelectric-Based Organic Field-Effect Transistors

NASA Astrophysics Data System (ADS)

Laudari, A.; Guha, S.

2016-10-01

The dielectric constant of polymer-ferroelectric dielectrics may be tuned by changing the temperature, offering a platform for monitoring changes in interfacial transport with the polarization strength in organic field-effect transistors (FETs). Temperature-dependent transport studies of FETs are carried out from a solution-processed organic semiconductor, 6,13-bis(triisopropylsilylethynyl)pentacene (TIPS-pentacene), using both ferroelectric- and nonferroelectric-gate insulators. Nonferroelectric dielectric-based TIPS-pentacene FETs show a clear activated transport, in contrast to the ferroelectric dielectric polymer, poly(vinylidene fluoride-trifluoroethylene), where a negative temperature coefficient of the mobility is observed in the ferroelectric temperature range. The current-voltage (I -V ) characteristics from TIPS-pentacene diodes signal a space-charge-limited conduction (SCLC) for a discrete set of trap levels, suggesting that charge injection and transport occurs through regions of ordering in the semiconductor. The carrier mobility extracted from temperature-dependent I -V characteristics from the trap-free SCLC region shows a negative coefficient beyond 200 K, similar to the trend observed in FETs with the ferroelectric dielectric. At moderate temperatures, the polarization-fluctuation-dominant transport inherent in a ferroelectric dielectric, in conjunction with the nature of traps, results in an effective detrapping of the shallow-trap states into more mobile states in TIPS-pentacene.

Organic-inorganic Au/PVP/ZnO/Si/Al semiconductor heterojunction characteristics

NASA Astrophysics Data System (ADS)

Mokhtari, H.; Benhaliliba, M.

2017-11-01

The paper reports the fabrication and characterization of a novel Au/PVP/ZnO/Si/Al semiconductor heterojunction (HJ) diode. Both inorganic n type ZnO and organic polyvinyl pyrrolidone (PVP) layers have grown by sol-gel spin-coating route at 2000 rpm. The front and back metallic contacts are thermally evaporated in a vacuum at pressure of 10-6 Torr having a diameter of 1.5 mm and a thickness of 250 nm. The detailed analysis of the forward and reverse bias current-voltage characteristics has been provided. Consequently, many electronic parameters, such as ideality factor, rectification coefficient, carrier concentration, series resistance, are then extracted. Based upon our results a non-ideal diode behavior is revealed and ideality factor exceeds the unity (n > 4). A high rectifying (~4.6 × 10 4) device is demonstrated. According to Cheung-Cheung and Norde calculation models, the barrier height and series resitance are respectively of 0.57 eV and 30 kΩ. Ohmic and space charge limited current (SCLC) conduction mechanisms are demonstrated. Such devices will find applications as solar cell, photodiode and photoconductor.

Two microRNA panels to discriminate three subtypes of lung carcinoma in bronchial brushing specimens.

PubMed

Huang, Wei; Hu, Jie; Yang, Da-wei; Fan, Xin-ting; Jin, Yi; Hou, Ying-yong; Wang, Ji-ping; Yuan, Yun-feng; Tan, Yun-shan; Zhu, Xiong-Zeng; Bai, Chun-xue; Wu, Ying; Zhu, Hong-guang; Lu, Shao-hua

2012-12-01

Effective treatment for lung cancer requires accuracy in subclassification of carcinoma subtypes. To identify microRNAs in bronchial brushing specimens for discriminating small cell lung cancer (SCLC) from non-small cell lung cancer (NSCLC) and for further differentiating squamous cell carcinoma (SQ) from adenocarcinoma (AC). Microarrays were used to screen 723 microRNAs in laser-captured, microdissected cancer cells from 82 snap-frozen surgical lung specimens. Quantitative reverse-transcriptase polymerase chain reaction was performed on 153 macrodissected formalin-fixed, paraffin-embedded (FFPE) surgical lung specimens to evaluate seven microRNA candidates discovered from microarrays. Two microRNA panels were constructed on the basis of a training cohort (n = 85) and validated using an independent cohort (n = 68). The microRNA panels were applied as differentiators of SCLC from NSCLC and of SQ from AC in 207 bronchial brushing specimens. Two microRNA panels yielded high diagnostic accuracy in discriminating SCLC from NSCLC (miR-29a and miR-375; area under the curve [AUC], 0.991 and 0.982 for training and validation data set, respectively) and in differentiating SQ from AC (miR-205 and miR-34a; AUC, 0.977 and 0.982 for training and validation data set, respectively) in FFPE surgical lung specimens. Moreover, the microRNA panels accurately differentiated SCLC from NSCLC (AUC, 0.947) and SQ from AC (AUC, 0.962) in bronchial brushing specimens. We found two microRNA panels that accurately discriminated between the three subtypes of lung carcinoma in bronchial brushing specimens. The identified microRNA panels may have considerable clinical value in differential diagnosis and optimizing treatment strategies based on lung cancer subtypes.

Hospitalization costs of lung cancer diagnosis in Turkey: Is there a difference between histological types and stages?

PubMed

Türk, Murat; Yıldırım, Fatma; Yurdakul, Ahmet Selim; Öztürk, Can

2016-12-01

To establish the direct costs of diagnosing lung cancer in hospitalized patients. Hospital data of patients who were hospitalized and diagnosed as lung cancer between September 2013 and August 2014 were retrospectively analyzed. Patients who underwent surgery for diagnosis and who were initiated with cancer treatment during the same hospital stay were excluded from study. Histological types and stages of lung cancer were determined. Expenses were grouped as laboratory costs, pathology costs, diagnostic imaging costs, overnight room charges, medication costs, blood center costs, consumable expenditures' costs and inpatient service charges (including consultants' service, electrocardiogram, follow-up, nursing services, diagnostic interventions). Of the 68 patients, 55 (81%) had non-small cell lung cancer (NSCLC), 13 (19%) had small cell lung cancer (SCLC). 47% of patients with NSCLC had stage 4 disease and 86% of patients with SCLC had extensive stage disease. Median total cost per patient was 910 (95% CI= 832-1291) Euros (€). Of all costs, 37% were due to inpatient service charges and 22% were medication costs. Median total cost per patient was 912 (95% CI= 783-1213) € in NSCLC patients and 908 (95% CI= 456-2203) € in SCLC patients (p> 0.05). In NSCLC group, total cost per patient was 873 (95% CI= 591-1143) € in stage 1-2-3 diseases and 975 (95% CI= 847-1536) € in stage 4 disease (p> 0.05). In SCLC group total cost per patient was 937 € in limited stage and 502 (95% CI= 452-2508) € in extensive stage (p> 0.05). There is no significant difference between costs related to diagnosis of different lung cancer types and stages in patients hospitalized in a university hospital.

Analysis of circulating angiogenic biomarkers from patients in two phase III trials in lung cancer of chemotherapy alone or chemotherapy and thalidomide

PubMed Central

Young, R J; Tin, A W; Brown, N J; Jitlal, M; Lee, S M; Woll, P J

2012-01-01

Background: Thalidomide has potent anti-inflammatory and anti-angiogenic properties. It was evaluated in combination with chemotherapy in two randomised placebo-controlled trials in patients with small cell lung cancer (SCLC, n=724) and advanced non-small cell lung cancer (NSCLC, n=722). Neither study demonstrated an improvement in overall survival with the addition of thalidomide to chemotherapy. This study investigated circulating angiogenic biomarkers in a subset of these patients. Methods: Serial plasma samples were collected in a cohort of patients enrolled in these two trials (n=95). Vascular endothelial growth factor (VEGF), soluble truncated form of VEGF receptor-2 (sVEGFR-2), interleukin-8 (IL-8), tumour necrosis factor-α (TNF-α), basic fibroblast growth factor (bFGF) and soluble intercellular adhesion molecule-1 (sICAM-1) levels were measured by enzyme-linked immunosorbent assays. Results were correlated with patient clinical data including stage, response rate and progression-free survival (PFS). Results: Baseline biomarker levels were not significantly different between SCLC and NSCLC. For pooled treatment groups, limited stage SCLC was associated with lower baseline VEGF (P=0.046), sICAM-1 (P=0.008) and IL-8 (P=0.070) than extensive stage disease. Low baseline IL-8 was associated with a significantly improved PFS in both SCLC and NSCLC (P=0.028), and a greater reduction in IL-8 was associated with a significantly improved tumour response (P=0.035). Baseline angiogenic factor levels, however, did not predict response to thalidomide. Conclusion: Circulating angiogenic biomarkers did not identify patients who benefited from thalidomide treatment. PMID:22353811

Cabazitaxel Versus Topotecan in Patients with Small-Cell Lung Cancer with Progressive Disease During or After First-Line Platinum-Based Chemotherapy.

PubMed

Evans, Tracey L; Cho, Byoung Chul; Udud, Katalin; Fischer, Juergen R; Shepherd, Frances A; Martinez, Pablo; Ramlau, Rodryg; Syrigos, Konstantinos N; Shen, Liji; Chadjaa, Mustapha; Wolf, Martin

2015-08-01

Patients with small-cell lung cancer (SCLC) typically respond well to initial chemotherapy. However, relapse invariably occurs, and topotecan, the only approved second-line treatment option, has limited efficacy. Taxanes have activity in SCLC, and cabazitaxel is a second-generation taxane with potential for enhanced activity in chemorefractory malignancies. Patients with SCLC who relapsed after initial platinum-based chemotherapy were randomly assigned to receive cabazitaxel 25 mg/m every 21 days or topotecan 1.5 mg/m on days 1-5 every 21 days. Two patient subgroups, defined by chemosensitive and chemo-resistant/refractory disease, were assessed in combination and separately. The safety profile of cabazitaxel and topotecan was consistent with previous studies, and despite considerable toxicity in both arms, no new safety concerns were identified. Patients receiving cabazitaxel had inferior progression-free survival compared with topotecan (1.4 versus 3.0 months, respectively; two-sided p < 0.0001; hazard ratio = 2.17, 95% confidence interval = 1.563-3.010), and results were similar in both the chemosensitive and chemorefractory subgroups. No complete responses were observed in either arm, and no partial responses were observed in the cabazitaxel group. The partial response rate in the topotecan arm was 10%. Median overall survival was 5.2 months in the cabazitaxel arm and 6.8 months in the topotecan arm (two-sided p = 0.0125; hazard ratio = 1.57, 95% confidence interval = 1.10-2.25). Cabazitaxel, a next-generation taxane, had inferior efficacy when compared with standard-dose topotecan in the treatment of relapsed SCLC. Topotecan remains a suboptimal therapy, and continued efforts to develop improved second-line treatments are warranted.

Omitting elective nodal irradiation during thoracic irradiation in limited-stage small cell lung cancer--evidence from a phase II trial.

PubMed

Colaco, Rovel; Sheikh, Hamid; Lorigan, Paul; Blackhall, Fiona; Hulse, Paul; Califano, Raffaele; Ashcroft, Linda; Taylor, Paul; Thatcher, Nicholas; Faivre-Finn, Corinne

2012-04-01

Omitting elective nodal irradiation (ENI) in limited-stage disease small cell lung cancer (LD-SCLC) is expected to result in smaller radiation fields. We report on data from a randomised phase II trial that omitted ENI in patients receiving concurrent chemo-radiotherapy for LD-SCLC. 38 patients with LD-SCLC were randomised to receive once-daily (66 Gy in 33 fractions) or twice-daily (45 Gy in 30 fractions) radiotherapy (RT). 3D-conformal RT was given concurrently with cisplatin and etoposide starting with the second cycle of a total of four cycles. The gross tumour volume was defined as primary tumour with involved lymph nodes (nodes ≥1 cm in short axis) identifiable with CT imaging. ENI was not used. Six recurrence patterns were identified: recurrence within planning target volume (PTV) only, recurrence within PTV+regional nodal recurrence and/or distant recurrence, isolated nodal recurrence outside PTV, nodal recurrence outside PTV+distant recurrence, distant metastases only and no recurrence. At median follow-up 16.9 months, 31/38 patients were evaluable and 14/31 patients had relapsed. There were no isolated nodal recurrences. Eight patients relapsed with intra-thoracic disease: 2 within PTV only, 4 within PTV and distantly and 2 with nodal recurrence outside PTV plus distant metastases. Rates of grade 3+ acute oesophagitis and pneumonitis in the 31 evaluable patients were 23 and 3% respectively. In our study of LD-SCLC, omitting ENI based on CT imaging was not associated with a high risk of isolated nodal recurrence, although further prospective studies are needed to confirm this. Routine ENI omission will be further evaluated prospectively in the ongoing phase III CONVERT trial (NCT00433563). Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Conduction Mechanism and Improved Endurance in HfO2-Based RRAM with Nitridation Treatment

NASA Astrophysics Data System (ADS)

Yuan, Fang-Yuan; Deng, Ning; Shih, Chih-Cheng; Tseng, Yi-Ting; Chang, Ting-Chang; Chang, Kuan-Chang; Wang, Ming-Hui; Chen, Wen-Chung; Zheng, Hao-Xuan; Wu, Huaqiang; Qian, He; Sze, Simon M.

2017-10-01

A nitridation treatment technology with a urea/ammonia complex nitrogen source improved resistive switching property in HfO2-based resistive random access memory (RRAM). The nitridation treatment produced a high performance and reliable device which results in superior endurance (more than 109 cycles) and a self-compliance effect. Thus, the current conduction mechanism changed due to defect passivation by nitrogen atoms in the HfO2 thin film. At a high resistance state (HRS), it transferred to Schottky emission from Poole-Frenkel in HfO2-based RRAM. At low resistance state (LRS), the current conduction mechanism was space charge limited current (SCLC) after the nitridation treatment, which suggests that the nitrogen atoms form Hf-N-Ox vacancy clusters (Vo +) which limit electron movement through the switching layer.

Clinical initiatives linking Japanese and Swedish healthcare resources on cancer studies utilizing Biobank Repositories.

PubMed

Nishimura, Toshihide; Kawamura, Takeshi; Sugihara, Yutaka; Bando, Yasuhiko; Sakamoto, Shigeru; Nomura, Masaharu; Ikeda, Norihiko; Ohira, Tatsuo; Fujimoto, Junichiro; Tojo, Hiromasa; Hamakubo, Takao; Kodama, Tatsuhiko; Andersson, Roland; Fehniger, Thomas E; Kato, Harubumi; Marko-Varga, György

2014-12-01

The Tokyo Medical University Hospital in Japan and the Lund University hospital in Sweden have recently initiated a research program with the objective to impact on patient treatment by clinical disease stage characterization (phenotyping), utilizing proteomics sequencing platforms. By sharing clinical experiences, patient treatment principles, and biobank strategies, our respective clinical teams in Japan and Sweden will aid in the development of predictive and drug related protein biomarkers. Data from joint lung cancer studies are presented where protein expression from Neuro- Endocrine lung cancer (LCNEC) phenotype patients can be separated from Small cell- (SCLC) and Large Cell lung cancer (LCC) patients by deep sequencing and spectral counting analysis. LCNEC, a subtype of large cell carcinoma (LCC), is characterized by neuroendocrine differentiation that small cell lung carcinoma (SCLC) shares. Pre-therapeutic histological distinction between LCNEC and SCLC has so far been problematic, leading to adverse clinical outcome. An establishment of protein targets characteristic of LCNEC is quite helpful for decision of optimal therapeutic strategy by diagnosing individual patients. Proteoform annotation and clinical biobanking is part of the HUPO initiative (http://www.hupo.org) within chromosome 10 and chromosome 19 consortia.

Paraneoplastic neurologic disorders in small cell lung carcinoma

PubMed Central

Woodhall, Mark; Chapman, Caroline; Nibber, Anjan; Waters, Patrick; Vincent, Angela; Lang, Bethan; Maddison, Paul

2015-01-01

Objective: To determine the frequency and range of paraneoplastic neurologic disorders (PNDs) and neuronal antibodies in small cell lung carcinoma (SCLC). Methods: Two hundred sixty-four consecutive patients with biopsy-proven SCLC were recruited at the time of tumor diagnosis. All patients underwent full neurologic examination. Serum samples were taken prior to chemotherapy and analyzed for 15 neuronal antibodies. Thirty-eight healthy controls were analyzed in parallel. Results: PNDs were quite prevalent (n = 24, 9.4%), most frequently Lambert-Eaton myasthenic syndrome (3.8%), sensory neuronopathy (1.9%), and limbic encephalitis (1.5%). Eighty-seven percent of all patients with PNDs had antibodies to SOX2 (62.5%), HuD (41.7%), or P/Q VGCC (50%), irrespective of their syndrome. Other neuronal antibodies were found at lower frequencies (GABAb receptor [12.5%] and N-type VGCC [20.8%]) or very rarely (GAD65, amphiphysin, Ri, CRMP5, Ma2, Yo, VGKC complex, CASPR2, LGI1, and NMDA receptor [all <5%]). Conclusions: The spectrum of PNDs is broader and the frequency is higher than previously appreciated, and selected antibody tests (SOX2, HuD, VGCC) can help determine the presence of an SCLC. PMID:26109714

Prevalence of Enhancer of Zeste Homolog 2 in Patients with Resected Small Cell Lung Cancer.

PubMed

Toyokawa, Gouji; Takada, Kazuki; Tagawa, Tetsuzo; Kinoshita, Fumihiko; Kozuma, Yuka; Matsubara, Taichi; Haratake, Naoki; Takamori, Shinkichi; Akamine, Takaki; Hirai, Fumihiko; Yamada, Yuichi; Hamamoto, Ryuji; Oda, Yoshinao; Maehara, Yoshihiko

2018-06-01

Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that is deeply involved in cancer pathogenesis. Although clinicopathological significance of EZH2 in non-small cell lung cancer has been gradually elucidated, such significance in small cell lung cancer (SCLC) has yet to be fully investigated. Forty patients with resected SCLC were analyzed for EZH2. EZH2 expression was evaluated using the Allred score (0-8) and was classified into negative (0-6) and positive (7 and 8). We evaluated the association between EZH2 and the clinicopathological characteristics and postoperative survivals. Among 40 patients, 15 (37.5%) and 25 (62.5%) were classified as being negative and positive for EZH2, respectively. Fisher's exact test demonstrated no significant associations between the positivity for EZH2 and clinicopathological characteristics. No significant differences were observed in recurrence-free and overall survivals between EZH2-negative/low and EZH2-high patients. EZH2 was frequently observed in patients with resected SCLC, but no significant associations were found between its expression and the clinicopathological characteristics and postoperative survivals. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Epirubicin plus paclitaxel regimen as second-line treatment of patients with small-cell lung cancer.

PubMed

Pasello, Giulia; Carli, Paolo; Canova, Fabio; Bonanno, Laura; Polo, Valentina; Zago, Giulia; Urso, Loredana; Conte, Pierfranco; Favaretto, Adolfo

2015-04-01

Most patients with small cell lung cancer (SCLC) experience relapse within one year after first-line treatment. The aim of this study was to describe activity and safety of second-line with epirubicin at 70 mg/m(2) followed by paclitaxel at 135 mg/m(2) on day 1 every three weeks for a maximum of six cycles. This is a retrospective review of all patients with SCLC evaluated for second-line treatment between 2003 and 2013 at our Institution. Sixty-eight patients received the study regimen of epirubicin with paclitaxel. We observed partial response in 19 (30%), stable disease in 22 (34%) and total early failure rate in 23 (36%) patients. Median progression free and overall survival were 21.8 and 26.5 weeks, respectively. Haematological toxicities were as follows: grade 3-4 leukopenia and neutropenia in 18 (31%) and 30 (22%) of patients, respectively; grade 3 anaemia and grade 4 thrombocytopenia were reported in 2 (3%) and 5 (9%) of patients, respectively. Epirubicin with paclitaxel is an active and tolerable second-line regimen in patients with SCLC. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

End-of-life chemotherapy is associated with poor survival and aggressive care in patients with small cell lung cancer.

PubMed

Zhu, Yingming; Tang, Ke; Zhao, Fen; Zang, Yuanwei; Wang, Xiaodong; Li, Zhenxiang; Sun, Xindong; Yu, Jinming

2018-05-29

Concerns regarding end-of-life (EOL) chemotherapy are being increasingly raised. Tumor chemosensitivity may influence the decision for aggressive chemotherapy near the EOL. Data on EOL chemotherapy in highly chemosensitive tumors, such as small cell lung cancer (SCLC), are scarce. A total of 143 SCLC decedents were consecutively included. Data about clinical factors and treatment modalities were obtained from the electronic medical records. The relationships among EOL chemotherapy, clinical features, overall survival (OS), and aggressive care were investigated. About 64% of patients had chemosensitive disease. In total, 30.8 and 16.1% of patients received EOL chemotherapy within the last 1 and 2 months of life, respectively. Younger age was associated with a higher rate of EOL chemotherapy. We determined that EOL chemotherapy was related to inferior OS not only in the entire group, but also in the chemosensitive subgroup. Furthermore, more intensive care was observed among patients who underwent EOL chemotherapy compared with those who did not. EOL chemotherapy was correlated with shorter survival and more aggressive care in patients with SCLC. More research is needed to develop indications for terminating palliative chemotherapy, to help physicians and patients with their difficult choices.

Poly ADP-ribose polymerase-1 as a potential therapeutic target in Merkel cell carcinoma.

PubMed

Ferrarotto, Renata; Cardnell, Robert; Su, Shirley; Diao, Lixia; Eterovic, A Karina; Prieto, Victor; Morrisson, William H; Wang, Jing; Kies, Merrill S; Glisson, Bonnie S; Byers, Lauren Averett; Bell, Diana

2018-03-23

Patients with metastatic Merkel cell carcinoma are treated similarly to small cell lung cancer (SCLC). Poly ADP-ribose polymerase-1 (PARP1) is overexpressed in SCLC and response to PARP inhibitors have been reported in patients with SCLC. Our study explores PARP as a therapeutic target in Merkel cell carcinoma. We evaluated PARP1 expression and Merkel cell polyomavirus (MCPyV) in 19 patients with Merkel cell carcinoma. Target exome-sequencing was performed in 14 samples. Sensitivity to olaparib was tested in 4 Merkel cell carcinoma cell lines. Most Merkel cell carcinomas (74%) express PARP1 at high levels. Mutations in DNA-damage repair genes were identified in 9 samples (64%), occurred exclusively in head neck primaries, and correlated with TP53/RB1 mutations. The TP53/RB1 mutations were more frequent in MCPyV-negative tumors. Sensitivity to olaparib was seen in the Merkel cell carcinoma line with highest PARP1 expression. Based on PARP1 overexpression, DNA-damage repair gene mutations, platinum sensitivity, and activity of olaparib in a Merkel cell carcinoma line, clinical trials with PARP inhibitors are warranted in Merkel cell carcinoma. © 2018 Wiley Periodicals, Inc.

Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors.

PubMed

George, Julie; Walter, Vonn; Peifer, Martin; Alexandrov, Ludmil B; Seidel, Danila; Leenders, Frauke; Maas, Lukas; Müller, Christian; Dahmen, Ilona; Delhomme, Tiffany M; Ardin, Maude; Leblay, Noemie; Byrnes, Graham; Sun, Ruping; De Reynies, Aurélien; McLeer-Florin, Anne; Bosco, Graziella; Malchers, Florian; Menon, Roopika; Altmüller, Janine; Becker, Christian; Nürnberg, Peter; Achter, Viktor; Lang, Ulrich; Schneider, Peter M; Bogus, Magdalena; Soloway, Matthew G; Wilkerson, Matthew D; Cun, Yupeng; McKay, James D; Moro-Sibilot, Denis; Brambilla, Christian G; Lantuejoul, Sylvie; Lemaitre, Nicolas; Soltermann, Alex; Weder, Walter; Tischler, Verena; Brustugun, Odd Terje; Lund-Iversen, Marius; Helland, Åslaug; Solberg, Steinar; Ansén, Sascha; Wright, Gavin; Solomon, Benjamin; Roz, Luca; Pastorino, Ugo; Petersen, Iver; Clement, Joachim H; Sänger, Jörg; Wolf, Jürgen; Vingron, Martin; Zander, Thomas; Perner, Sven; Travis, William D; Haas, Stefan A; Olivier, Magali; Foll, Matthieu; Büttner, Reinhard; Hayes, David Neil; Brambilla, Elisabeth; Fernandez-Cuesta, Lynnette; Thomas, Roman K

2018-03-13

Pulmonary large-cell neuroendocrine carcinomas (LCNECs) have similarities with other lung cancers, but their precise relationship has remained unclear. Here we perform a comprehensive genomic (n = 60) and transcriptomic (n = 69) analysis of 75 LCNECs and identify two molecular subgroups: "type I LCNECs" with bi-allelic TP53 and STK11/KEAP1 alterations (37%), and "type II LCNECs" enriched for bi-allelic inactivation of TP53 and RB1 (42%). Despite sharing genomic alterations with adenocarcinomas and squamous cell carcinomas, no transcriptional relationship was found; instead LCNECs form distinct transcriptional subgroups with closest similarity to SCLC. While type I LCNECs and SCLCs exhibit a neuroendocrine profile with ASCL1 high /DLL3 high /NOTCH low , type II LCNECs bear TP53 and RB1 alterations and differ from most SCLC tumors with reduced neuroendocrine markers, a pattern of ASCL1 low /DLL3 low /NOTCH high , and an upregulation of immune-related pathways. In conclusion, LCNECs comprise two molecularly defined subgroups, and distinguishing them from SCLC may allow stratified targeted treatment of high-grade neuroendocrine lung tumors.

Electrical transport properties of an isolated CdS microrope composed of twisted nanowires.

PubMed

Yu, Gui-Feng; Yu, Miao; Pan, Wei; Han, Wen-Peng; Yan, Xu; Zhang, Jun-Cheng; Zhang, Hong-Di; Long, Yun-Ze

2015-01-01

CdS is one of the important II-VI group semiconductors. In this paper, the electrical transport behavior of an individual CdS microrope composed of twisted nanowires is studied. It is found that the current-voltage (I-V) characteristics show two distinct power law regions from 360 down to 60 K. Space-charge-limited current (SCLC) theory is used to explain these temperature- and electric-field-dependent I-V curves. The I-V data can be well fitted by this theory above 100 K, and the corresponding carrier mobility, trap energy, and trap concentration are also obtained. However, the I-V data exhibit some features of the Coulomb blockade effect below 80 K.

The influence of preferred orientation and poling temperature on the polarization switching current in PZT thin films

NASA Astrophysics Data System (ADS)

Xiao, Mi; Zhang, Weikang; Zhang, Zebin; Zhang, Ping; Lan, Kuibo

2017-07-01

In this paper, Pb(Zr0.52Ti0.48)O3 (PZT) thin films with different preferred orientation were prepared on platinized silicon substrates by a modified sol-gel method. Our results indicate that the polarization switching current in PZT thin films is dependent on preferred orientation and poling temperature. In our measurements, (111)-oriented PZT has a larger polarization switching current than randomly oriented PZT, and with the increase of the degree of (111) preferred orientation and the poling temperature, the polarization switching current gradually increase. Considering the contact of PZT thin film with electrodes, the space-charged limited conduction (SCLC) combined with domain switching mechanism may be responsible for such phenomena. By analyzing the conduction data, we found the interface-limited Schottky emission (ES) and bulk-limited Poole-Frenkel hopping (PF) are not suitable for our samples.

Theory of space charge limited currents in films and nanowires with dopants

NASA Astrophysics Data System (ADS)

Zhang, Xiaoguang; Pantelides, Sokrates

2015-03-01

We show that proper description of the space charge limited currents (SCLC) in a homogeneous bulk material must account fully for the effect of the dopants and the interplay between dopants and traps. The sharp rise in the current at the trap-filled-limit (TFL) is partially mitigated by the dopant energy levels and the Frenkel effect, namely the lowering of the ionization energy by the electric field, which is screened by the free carriers. In nanowires, lack of effective screening causes the trap occupation at small biases to reach a high level comparable to the TFL in bulk. This explains the high current density in SCLCs observed in nanowires. This work is supported by the LDRD program at ORNL. Portion of this research was conducted at the Center for Nanophase Materials Sciences, which is a DOE Office of Science User Facility.

Methylenetetrahydrofolate reductase gene C677T and A1298C polymorphisms in patients with small cell and non-small cell lung cancer.

PubMed

Siemianowicz, Krzysztof; Gminski, Jan; Garczorz, Wojciech; Slabiak, Natalia; Goss, Malgorzata; Machalski, Marek; Magiera-Molendowska, Helena

2003-01-01

Two mutations of methylenetetrahydrofolate reductase (MTHFR) gene (C677T and A1298C) may lead to a decreased activity of the enzyme. These mutations may change a risk of some cancers. We evaluated these two polymorphisms of MTHFR in patients with small cell lung cancer (SCLC) and non-small cell lung cancer (NCSCL). All lung cancer patients had statistically significantly higher percentage of MTHFR 677TT genotype in comparison with non-cancer controls. There were no statistically significant differences in the distribution of MTHFR 1298 genotypes. Neither of the polymorphisms presented any statistically significant differences between SCLC and NSCLC.

CV2/CRMP5-antibody-related Paraneoplastic Optic Neuropathy Associated with Small-cell Lung Cancer.

PubMed

Nakajima, Masanori; Uchibori, Ayumi; Ogawa, Yuki; Miyazaki, Tai; Ichikawa, Yaeko; Kaneko, Kimihiko; Takahashi, Toshiyuki; Nakashima, Ichiro; Shiraishi, Hirokazu; Motomura, Masakatsu; Chiba, Atsuro

2018-06-01

A 61-year-old woman who had smoked for 41 years developed subacute dizziness, ataxic gait, opsoclonus, and right visual impairment. She had right optic disc swelling and optic nerve gadolinium enhancement on magnetic resonance imaging. She had small-cell lung cancer (SCLC), with CV2/collapsin response mediator protein (CRMP) 5 and HuD antibodies in her serum and cerebrospinal fluid. She was diagnosed with paraneoplastic optic neuropathy (PON) accompanied by paraneoplastic opsoclonus-ataxia syndrome. Her symptoms improved after removing the SCLC. Classical PON is rare in Japan. We recommend assaying for CV2/CRMP5 antibodies and searching for cancer in elderly patients with subacute painless visual impairment.

Emerging application of genomics-guided therapeutics in personalized lung cancer treatment.

PubMed

Zaman, Aubhishek; Bivona, Trever G

2018-05-01

In lung cancer, genomics-driven comprehensive molecular profiling has identified novel chemically and immunologically addressable vulnerabilities, resulting in an increasing application of precision medicine by targeted inactivation of tumor oncogenes and immunogenic activation of host anti-tumor surveillance as modes of treatment. However, initially profound response of these targeted therapies is followed by relapse due to therapy-resistant residual disease states. Although distinct mechanisms and frameworks for therapy resistance have been proposed, accounting for and upfront prediction of resistance trajectories has been challenging. In this review, we discuss in both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), the current standing, and challenges associated with genomics-guided strategies for personalized therapy against both oncogenic alterations as well as post-therapy resistance mechanisms. In NSCLC, we catalog the targeted therapy approaches against most notable oncogenic alterations such as epidermal growth factor receptor (EGFR), serine/threonine-protein kinase b-raf (BRAF), Kirsten rat sarcoma viral proto-oncogene (KRAS), anaplastic lymphoma kinase (ALK), ROS1 proto-oncogene receptor tyrosine kinase (ROS1). For SCLC, currently highly recalcitrant to targeted therapy, we enumerate a range of exciting and maturing precision medicine approaches. Furthermore, we discuss a number of immunotherapy approaches, in combination or alone, that are being actively pursued clinically in lung cancer. This review not only highlights common mechanistic themes underpinning different classes of resistance and discusses tumor heterogeneity as a source of residual disease, but also discusses potential ways to overcome these barriers. We emphasize how an extensive understanding of these themes can predict and improve therapeutic strategies, such as through poly-therapy approaches, to forestall tumor evolution upfront.

Protocol for the CONVERT trial-Concurrent ONce-daily VErsus twice-daily RadioTherapy: an international 2-arm randomised controlled trial of concurrent chemoradiotherapy comparing twice-daily and once-daily radiotherapy schedules in patients with limited stage small cell lung cancer (LS-SCLC) and good performance status.

PubMed

Faivre-Finn, Corinne; Falk, Sally; Ashcroft, Linda; Bewley, Michelle; Lorigan, Paul; Wilson, Elena; Groom, Nicki; Snee, Michael; Fournel, Pierre; Cardenal, Felipe; Bezjak, Andrea; Blackhall, Fiona

2016-01-20

Concurrent ONce-daily VErsus twice-daily RadioTherapy (CONVERT) is the only multicentre, international, randomised, phase III trial open in Europe and Canada looking at optimisation of chemoradiotherapy (RT) in limited stage small cell lung cancer (LS-SCLC). Following on from the Turrisi trial of once-daily versus twice-daily (BD) concurrent chemoradiotherapy, there is a real need for a new phase III trial using modern conformal RT techniques and investigating higher once-daily radiation dose. This trial has the potential to define a new standard chemo-RT regimen for patients with LS-SCLC and good performance status. 447 patients with histologically or cytologically proven diagnosis of SCLC were recruited from 74 centres in eight countries between 2008 and 2013. Patients were randomised to receive either concurrent twice-daily RT(45 Gy in 30 twice-daily fractions over 3 weeks) or concurrent once-daily RT(66 Gy in 33 once-daily fractions over 6.5 weeks) both starting on day 22 of cycle 1. Patients are followed up until death. The primary end point of the study is overall survival and secondary end points include local progression-free survival, metastasis-free survival, acute and late toxicity based on the Common Terminology Criteria for Adverse Events V.3.0, chemotherapy and RTdose intensity. The trial received ethical approval from NRES Committee North West-Greater Manchester Central (07/H1008/229). There is a trial steering committee, including independent members and an independent data monitoring committee. Results will be published in a peer-reviewed journal and presented at international conferences. ISRCTN91927162; Pre-results. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Prospective study of proton-beam radiation therapy for limited-stage small cell lung cancer.

PubMed

Rwigema, Jean-Claude M; Verma, Vivek; Lin, Liyong; Berman, Abigail T; Levin, William P; Evans, Tracey L; Aggarwal, Charu; Rengan, Ramesh; Langer, Corey; Cohen, Roger B; Simone, Charles B

2017-11-01

Existing data supporting the use of proton-beam therapy (PBT) for limited-stage small cell lung cancer (LS-SCLC) are limited to a single 6-patient case series. This is the first prospective study to evaluate clinical outcomes and toxicities of PBT for LS-SCLC. This study prospectively analyzed patients with primary, nonrecurrent LS-SCLC definitively treated with PBT and concurrent chemotherapy from 2011 to 2016. Clinical backup intensity-modulated radiotherapy (IMRT) plans were generated for each patient and were compared with PBT plans. Outcome measures included local control (LC), recurrence-free survival (RFS), and overall survival (OS) rates and toxicities. Thirty consecutive patients were enrolled and evaluated. The median dose was 63.9 cobalt gray equivalents (range, 45-66.6 cobalt gray equivalents) in 33 to 37 fractions delivered daily (n = 18 [60.0%]) or twice daily (n = 12 [40.0%]). The concurrent chemotherapy was cisplatin/etoposide (n = 21 [70.0%]) or carboplatin/etoposide (n = 9 [30.0%]). In comparison with the backup IMRT plans, PBT allowed statistically significant reductions in the cord, heart, and lung mean doses and the volume receiving at least 5 Gy but not in the esophagus mean dose or the lung volume receiving at least 20 Gy. At a median follow-up of 14 months, the 1-/2-year LC and RFS rates were 85%/69% and 63%/42%, respectively. The median OS was 28.2 months, and the 1-/2-year OS rates were 72%/58%. There was 1 case each (3.3%) of grade 3 or higher esophagitis, pneumonitis, anorexia, and pericardial effusion. Grade 2 pneumonitis and esophagitis were seen in 10.0% and 43.3% of patients, respectively. In the first prospective registry study and largest analysis to date of PBT for LS-SCLC, PBT was found to be safe with a limited incidence of high-grade toxicities. Cancer 2017;123:4244-4251. © 2017 American Cancer Society. © 2017 American Cancer Society.

Efficacy and toxicity differences in lung cancer populations in the era of clinical trials globalization: the 'common arm' approach.

PubMed

Mack, Philip C; Gandara, David R; Lara, Primo N

2012-12-01

Historically, notable variability has been observed in clinical trial outcomes between different regions and populations worldwide, even when employing the same cytotoxic regimen in lung cancer. These divergent results underscore the inherent challenges in interpreting trials conducted abroad and raise questions regarding the general applicability of transnational clinical trials. Various reasons have been postulated to account for these differences in efficacy and toxicity, including trial design, eligibility criteria, patient demographics and, perhaps most intriguingly, population-related pharmacogenomics. However, without methodology to control for such variables, these hypotheses remain largely untested. The authors previously developed the 'common arm' approach in order to directly compare efficacy and toxicity results of trials simultaneously performed in different countries. By standardizing clinical trial-associated variables such as treatment regimens (dose, schedule, and so on), eligibility, staging, response and toxicity criteria, this approach has the potential to determine the underlying reasons for divergences in trial outcomes across countries, and whether population-associated polymorphisms contribute to these differences. In the past decade, Japanese and US investigators have applied the common arm analytic method to trials in both extensive-stage small-cell lung cancer (SCLC) and advanced nonSCLC. In the SCLC analysis, a comparison of the cisplatin/irinotecan arms from both trials revealed significant differences in response rates and overall survival. Significant differences were also observed in the distribution of gender and performance status. The common arm analysis in nonSCLC included two trials from Japan and one from the USA, each containing a 'common' carboplatin/paclitaxel arm. Clinical results were similar in the two Japanese trials, but were significantly different from the US trial with regard to survival, neutropenia, febrile neutropenia and anemia. The underlying basis for these divergent outcomes is discussed. The common arm methodology provides a template for identifying and interpreting patient outcome differences across populations, and is an instructive lesson in the burgeoning era of clinical trials globalization.

Network analysis of semiconducting Zn1-xCdxS based photosensitive device using impedance spectroscopy and current-voltage measurement

NASA Astrophysics Data System (ADS)

Datta, Joydeep; Das, Mrinmay; Dey, Arka; Halder, Soumi; Sil, Sayantan; Ray, Partha Pratim

2017-10-01

ZnCdS is an intermediate ternary alloy type semiconducting material which has huge tunable structural, optical and electrical properties. Here, we have synthesized Zn1-xCdxS compound and characterized its structural, optical and charge transport properties. It is seen that the particle size is greatly influenced by the amount of alloy concentration of cadmium. The performance of semiconductor device such as Schottky diode depends mainly on the charge transportation through the metal-semiconductor junction. So, we have fabricated Al/Zn1-xCdxS/ITO device and investigated the bias dependent impedance properties through equivalent circuit network analysis to study the electron lifetime and interfacial region resistance. The result of network analysis indicates that the charge transportation through Al- Zn0.6Cd0.4S is better than the other fabricated devices. For further explanation, we have studied the capacitance-voltage (C-V) characteristic under dark and current-voltage (I-V) characteristic under dark and light. We have investigated barrier height, depletion layer width and employed SCLC (space charge limited current) theory in I-V characteristics to determine mobility, transit time and diffusion length. The mobility and diffusion length for Zn0.6Cd0.4S fabricated device are derived as 23.01 m2 V-1 s-1 and 4.4 μm respectively while both the values are less for the other devices. These values are enhanced upon illumination for all the devices but superiority comes from the Al/Zn0.6Cd0.4S/ITO device and it leads us to measure the photosensitivity, responsivity, specific detectivity. As expected, the photosensing parameters are enhanced for the Zn0.6Cd0.4S fabricated device. So, this literature not only explores the metal semiconductor charge transportation using impedance spectroscopy (IS) network analysis and SCLC theory but also explain it from the structural point of view.

Small cell lung cancer: Recruitment of macrophages by circulating tumor cells

PubMed Central

Hamilton, Gerhard; Rath, Barbara; Klameth, Lukas; Hochmair, Maximilan J.

2016-01-01

ABSTRACT Tumor-associated macrophages (TAMs) play an important role in tumor progression, suppression of antitumor immunity and dissemination. Blood monocytes infiltrate the tumor region and are primed by local microenvironmental conditions to promote tumor growth and invasion. Although many of the interacting cytokines and factors are known for the tumor-macrophage interactions, the putative contribution of circulating tumor cells (CTCs) is not known so far. These specialized cells are characterized by increased mobility, ability to degrade the extracellular matrix (ECM) and to enter the blood stream and generate secondary lesions which is a leading cause of death for the majority of tumor patients. The first establishment of two permanent CTC lines, namely BHGc7 and 10, from blood samples of advanced stage small cell lung cancer (SCLC) patients allowed us to investigate the CTC-immune cell interaction. Cocultures of peripheral blood mononuclear cells (PBMNCs) with CTCs or addition of CTC-conditioned medium (CTC-CM) in vitro resulted in monocyte-macrophage differentiation and appearance of CD14+, CD163weak and CD68+ macrophages expressing markers of TAMs. Furthermore, we screened the supernatants of CTC-primed macrophages for presence of approximately 100 cytokines and compared the expression with those induced by the local metastatic SCLC26A cell line. Macrophages recruited by SCLC26A-CM showed expression of osteopontin (OPN), monocyte chemoattractant protein-1 (MCP-1), IL-8, chitinase3-like 1 (CHI3L1), platelet factor (Pf4), IL-1ra and matrix metalloproteinase-9 (MMP-9) among other minor cytokines/chemokines. In contrast, BHGc7-CM induced marked overexpression of complement factor D (CFD)/adipsin and vitamin D-BP (VDBP), as well as increased secretion of OPN, lipocalin-2 (LCN2), CHI3L1, uPAR, MIP-1 and GDF-15/MIC-1. BHGc10, derived independently from relapsed SCLC, revealed an almost identical pattern with added expression of ENA-78/CXCL5. CMs of the non-tumor HEK293 cell line revealed no induction of macrophages, whereas incubation of PBMNCs with recombinant CHI3L1 gave positive results. Thus, the specific contributions of CTCs in SCLC affect CFD/adipsin, possibly involved in immunity/cachexia, VDBP which gives rise to group-specific component protein-derived macrophage-activating factor (GcMAF), GDF-15/MIC-1 which enhances the malignant phenotype of tumor cells and ENA-78/CXCL5 which attracts angiogenic neutrophils. In conclusion, CTCs are competent to specifically manipulate TAMs to increase invasiveness, angiogenesis, immunosuppression and possibly lipid catabolism. PMID:27141354

Small cell lung cancer: Recruitment of macrophages by circulating tumor cells.

PubMed

Hamilton, Gerhard; Rath, Barbara; Klameth, Lukas; Hochmair, Maximilan J

2016-03-01

Tumor-associated macrophages (TAMs) play an important role in tumor progression, suppression of antitumor immunity and dissemination. Blood monocytes infiltrate the tumor region and are primed by local microenvironmental conditions to promote tumor growth and invasion. Although many of the interacting cytokines and factors are known for the tumor-macrophage interactions, the putative contribution of circulating tumor cells (CTCs) is not known so far. These specialized cells are characterized by increased mobility, ability to degrade the extracellular matrix (ECM) and to enter the blood stream and generate secondary lesions which is a leading cause of death for the majority of tumor patients. The first establishment of two permanent CTC lines, namely BHGc7 and 10, from blood samples of advanced stage small cell lung cancer (SCLC) patients allowed us to investigate the CTC-immune cell interaction. Cocultures of peripheral blood mononuclear cells (PBMNCs) with CTCs or addition of CTC-conditioned medium (CTC-CM) in vitro resulted in monocyte-macrophage differentiation and appearance of CD14 + , CD163 weak and CD68 + macrophages expressing markers of TAMs. Furthermore, we screened the supernatants of CTC-primed macrophages for presence of approximately 100 cytokines and compared the expression with those induced by the local metastatic SCLC26A cell line. Macrophages recruited by SCLC26A-CM showed expression of osteopontin (OPN), monocyte chemoattractant protein-1 (MCP-1), IL-8, chitinase3-like 1 (CHI3L1), platelet factor (Pf4), IL-1ra and matrix metalloproteinase-9 (MMP-9) among other minor cytokines/chemokines. In contrast, BHGc7-CM induced marked overexpression of complement factor D (CFD)/adipsin and vitamin D-BP (VDBP), as well as increased secretion of OPN, lipocalin-2 (LCN2), CHI3L1, uPAR, MIP-1 and GDF-15/MIC-1. BHGc10, derived independently from relapsed SCLC, revealed an almost identical pattern with added expression of ENA-78/CXCL5. CMs of the non-tumor HEK293 cell line revealed no induction of macrophages, whereas incubation of PBMNCs with recombinant CHI3L1 gave positive results. Thus, the specific contributions of CTCs in SCLC affect CFD/adipsin, possibly involved in immunity/cachexia, VDBP which gives rise to group-specific component protein-derived macrophage-activating factor (GcMAF), GDF-15/MIC-1 which enhances the malignant phenotype of tumor cells and ENA-78/CXCL5 which attracts angiogenic neutrophils. In conclusion, CTCs are competent to specifically manipulate TAMs to increase invasiveness, angiogenesis, immunosuppression and possibly lipid catabolism.

Outcome and prognostic factors in single brain metastases from small-cell lung cancer.

PubMed

Bernhardt, Denise; Adeberg, Sebastian; Bozorgmehr, Farastuk; Opfermann, Nils; Hörner-Rieber, Juliane; König, Laila; Kappes, Jutta; Thomas, Michael; Unterberg, Andreas; Herth, Felix; Heußel, Claus Peter; Warth, Arne; Debus, Jürgen; Steins, Martin; Rieken, Stefan

2018-02-01

Whole brain radiation therapy (WBRT) is historically the standard of care for patients with brain metastases (BM) from small-cell lung cancer (SCLC), although locally ablative treatments are the standard of care for patients with 1-4 BM from other solid tumors. The objective of this analysis was to find prognostic factors influencing overall survival (OS) and intracranial progression-free survival (iPFS) in SCLC patients with single BM (SBM) treated with WBRT. A total of 52 patients were identified in the authors' cancer center database with histologically confirmed SCLC and contrast-enhanced magnet resonance imaging (MRI) or computed tomography (CT), which confirmed SBM between 2006 and 2015 and were therefore treated with WBRT. A Kaplan-Meier survival analysis was performed for OS analyses. The log-rank (Mantel-Cox) test was used to compare survival curves. Univariate Cox proportional-hazards ratios (HRs) were used to assess the influence of cofactors on OS and iPFS. The median OS after WBRT was 5 months and the median iPFS after WBRT 16 months. Patients that received surgery prior to WBRT had a significantly longer median OS of 19 months compared to 5 months in the group receiving only WBRT (p = 0.03; HR 2.24; 95% confidence interval [CI] 1.06-4.73). Patients with synchronous disease had a significantly longer OS compared to patients with metachronous BM (6 months vs. 3 months, p = 0.005; HR 0.27; 95% CI 0.11-0.68). Univariate analysis for OS revealed a statistically significant effect for metachronous disease (HR 2.25; 95% CI 1.14-4.46; p = 0.019), initial response to first-line chemotherapy (HR 0.58; 95% CI 0.35-0.97; p = 0.04), and surgical resection (HR 0.36; 95% CI 0.15-0.88; p = 0.026). OS was significantly affected by metachronous disease in multivariate analysis (HR 2.20; 95% CI 1.09-4.45; p = 0.028). Univariate analysis revealed that surgery followed by WBRT can improve OS in patients with SBM in SCLC. Furthermore, synchronous disease and response to initial chemotherapy appeared to be major prognostic factors. Multivariate analysis revealed metachronous disease as a significantly negative prognostic factor on OS. The value of WBRT, stereotactic radiosurgery (SRS), or surgery alone or in combination for patients with a limited number of BM in SCLC should be evaluated in further prospective clinical trials.

Enhanced bipolar resistive switching behavior in polar Cr-doped barium titanate thin films without electro-forming process

NASA Astrophysics Data System (ADS)

Thakre, Atul; Kumar, Ashok

2017-12-01

An enhanced, repeatable and robust resistive switching phenomenon was observed in Cr substituted BaTiO3 polar ferroelectric thin films; fabricated and deposited by the sol-gel approach and spin coating technique, respectively. An enhanced bistable bipolar resistive switching (BRS) phenomenon without electro-forming process, low switching voltage (˜ 2 V) and moderate retention characteristics of 104 s along with a high Roff/Ron resistance ratio ˜103 was achieved. The current conduction analysis showed that the space charge limited conduction (SCLC) and Schottky emission conduction dominate in the high voltage range, while thermally active charge carriers (ohmic) in the lower voltage range. The impedance spectroscopy study indicates the formation of current conducting path and rupturing of oxygen vacancies during SET and RESET process.

Paraneoplastic syndromes related to lung cancer.

PubMed

McClelland, Mary T

2010-06-01

Paraneoplastic syndromes (PNSs) are defined as signs or symptoms that occur as a result of organ or tissue damage at locations that are remote from the primary tumor site or metastases. Many cancers are associated with PNSs; however, small cell lung cancer (SCLC) is the most prevalent. In SCLC, the systems primarily affected by PNSs include the endocrine system, the neurologic system, and the integumental system. This article provides an overview of primary disorders and classical syndromes, as well as symptom management associated with each system. PNSs are rare, and the best approach is to treat the underlying tumor. Therefore, oncology nurses and other healthcare practitioners should be familiar with PNSs so that they can take prompt and proper courses of action, potentially leading to positive outcomes for patients.

Prognostic Significance of Modified Advanced Lung Cancer Inflammation Index (ALI) in Patients with Small Cell Lung Cancer_ Comparison with Original ALI.

PubMed

Kim, Eun Young; Kim, Nambeom; Kim, Young Saing; Seo, Ja-Young; Park, Inkeun; Ahn, Hee Kyung; Jeong, Yu Mi; Kim, Jeong Ho

2016-01-01

Advanced lung cancer inflammation index (ALI, body mass index [BMI] x serum albumin/neutrophil-lymphocyte ratio [NLR]) has been shown to predict overall survival (OS) in small cell lung cancer (SCLC). CT enables skeletal muscle to be quantified, whereas BMI cannot accurately reflect body composition. The purpose was to evaluate prognostic value of modified ALI (mALI) using CT-determined L3 muscle index (L3MI, muscle area at L3/height2) beyond original ALI. L3MIs were calculated using the CT images of 186 consecutive patients with SCLC taken at diagnosis, and mALI was defined as L3MI x serum albumin/NLR. Using chi-squared test determined maximum cut-offs for low ALI and low mALI, the prognostic values of low ALI and low mALI were tested using Kaplan-Meier method and Cox proportional hazards analysis. Finally, deviance statistics was used to test whether the goodness of fit of the prognostic model is improved by adding mALI as an extra variable. Patients with low ALI (cut-off, 31.1, n = 94) had shorter OS than patients with high ALI (median, 6.8 months vs. 15.8 months; p < 0.001), and patients with low mALI (cut-off 67.7, n = 94) had shorter OS than patients with high mALI (median, 6.8 months vs. 16.5 months; p < 0.001). There was no significant difference in estimates of median survival time between low ALI and low mALI (z = 0.000, p = 1.000) and between high ALI and high mALI (z = 0.330, p = 0.740). Multivariable analysis showed that low ALI was an independent prognostic factor for shorter OS (HR, 1.67, p = 0.004), along with advanced age (HR, 1.49, p = 0.045), extensive disease (HR, 2.27, p < 0.001), supportive care only (HR, 7.86, p < 0.001), and elevated LDH (HR, 1.45, p = 0.037). Furthermore, goodness of fit of this prognostic model was not significantly increased by adding mALI as an extra variable (LR difference = 2.220, p = 0.136). The present study confirms mALI using CT-determined L3MI has no additional prognostic value beyond original ALI using BMI. ALI is a simple and useful prognostic indicator in SCLC.

Differential expression and prognostic value of the chemokine receptor CXCR4 in bronchopulmonary neuroendocrine neoplasms.

PubMed

Kaemmerer, Daniel; Reimann, Christiane; Specht, Elisa; Wirtz, Ralph M; Sayeg, Manal; Baum, Richard P; Schulz, Stefan; Lupp, Amelie

2015-02-20

For many tumors, the overexpression of the chemokine receptor CXCR4 is associated with increased malignancy and poor patient outcomes. However, comprehensive data for neuroendocrine neoplasms of the lung are still lacking. CXCR4 expression was evaluated in a panel of bronchopulmonary neuroendocrine neoplasms (BP-NEN) comprising typical carcinoids (n = 26), atypical carcinoids (n = 30), and small cell lung cancers (SCLC, n = 34). Samples were analyzed by immunohistochemistry using the novel monoclonal rabbit anti-human CXCR4 antibody UMB-2 and by qRT-PCR. The expression was correlated with clinical data and overall patient survival. CXCR4 was predominantly localized at the plasma membrane of the tumor cells. CXCR4 was expressed with a high intensity in almost all of the 30 SCLC samples. In contrast, it was detected infrequently and with low intensity in the typical carcinoid and atypical carcinoid samples. There was a significant correlation between the immunohistochemistry and qRT-PCR data. Additionally, there was a significant negative relationship between CXCR4 expression and overall survival. With increasing malignancy, BP-NEN clearly differ in the extent of CXCR4 expression. As in other tumor entities, CXCR4 overexpression significantly correlates with negative patient outcome. Due to its particular high expression rate in SCLC, CXCR4 may serve as a promising new target for diagnostic and pharmacological intervention as well as for peptide receptor-based radionuclide therapy.

Expression of apoptosis-regulatory genes in lung tumour cell lines: relationship to p53 expression and relevance to acquired drug resistance.

PubMed Central

Reeve, J. G.; Xiong, J.; Morgan, J.; Bleehen, N. M.

1996-01-01

As a first step towards elucidating the potential role(s) of bcl-2 and bcl-2-related genes in lung tumorigenesis and therapeutic responsiveness, the expression of these genes has been examined in a panel of lung cancer cell lines derived from untreated and treated patients, and in cell lines selected in vitro for multidrug resistance. Bcl-2 was hyperexpressed in 15 of 16 small-cell lung cancer (SCLC) cell lines and two of five non-small-cell lung cancer (NSCLC) lines compared with normal lung and brain, and hyperexpression was not chemotherapy related. Bcl-x was hyperexpressed in the majority of SCLC and NSCLC cell lines as compared with normal tissues, and all lung tumour lines preferentially expressed bcl-x1-mRNA, the splice variant form that inhibits apoptosis. Bax gene transcripts were hyperexpressed in most SCLC and NSCLC cell lines examined compared with normal adult tissues. Mutant p53 gene expression was detected in the majority of the cell lines and no relationship between p53 gene expression and the expression of either bcl-2, bcl-x or bax was observed. No changes in bcl-2, bcl-x and bax gene expression were observed in multidrug-resistant cell lines compared with their drug-sensitive counterparts. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:8630278

A phase 2, open-label, multi-center study of amuvatinib in combination with platinum etoposide chemotherapy in platinum-refractory small cell lung cancer patients

PubMed Central

Byers, Lauren Averett; Horn, Leora; Ghandi, Jitendra; Kloecker, Goetz; Owonikoko, Taofeek; Waqar, Saiama Naheed; Krzakowski, Maciej; Cardnell, Robert J.; Fujimoto, Junya; Taverna, Pietro; Azab, Mohammad; Camidge, David Ross

2017-01-01

Background Amuvatinib (MP-470) is a multi-targeted kinase inhibitor with potent activity against c-Kit, synergistic with DNA-damaging agents. We evaluated amuvatinib in combination with platinum-etoposide (EP) chemotherapy by objective response rate, survival, and tolerability in platinum-refractory small cell lung cancer (SCLC) patients. Methods This study used a Simon 2-stage design requiring ≥3 centrally confirmed responses in the first 21 subjects. Subjects received EP with 300 mg amuvatinib orally three times daily in cycles of 21 days. A three-day amuvatinib run-in period before EP occurred in Cycle 1. Subjects received the same EP chemotherapy regimen given prior to progression/relapse. Results Among 23 subjects treated, we observed four PRs (17.4%) per RECIST 1.1, only two of which were centrally confirmed (8.7%, response duration 119, 151 days). Three subjects (13%) had confirmed stable disease. c-Kit H-score was ≥100 in two subjects whose respective durations of disease control were 151 and 256 days. Conclusions The addition of amuvatinib to EP chemotherapy in unselected, platinum-refractory SCLC did not meet the primary endpoint of ≥3 confirmed responses in stage 1. However, high c-Kit expression in two subjects with durable disease control suggests the potential for further study of amuvatinib in SCLC patients with high c-Kit expression. PMID:29113403

A phase 2, open-label, multi-center study of amuvatinib in combination with platinum etoposide chemotherapy in platinum-refractory small cell lung cancer patients.

PubMed

Byers, Lauren Averett; Horn, Leora; Ghandi, Jitendra; Kloecker, Goetz; Owonikoko, Taofeek; Waqar, Saiama Naheed; Krzakowski, Maciej; Cardnell, Robert J; Fujimoto, Junya; Taverna, Pietro; Azab, Mohammad; Camidge, David Ross

2017-10-06

Amuvatinib (MP-470) is a multi-targeted kinase inhibitor with potent activity against c-Kit, synergistic with DNA-damaging agents. We evaluated amuvatinib in combination with platinum-etoposide (EP) chemotherapy by objective response rate, survival, and tolerability in platinum-refractory small cell lung cancer (SCLC) patients. This study used a Simon 2-stage design requiring ≥3 centrally confirmed responses in the first 21 subjects. Subjects received EP with 300 mg amuvatinib orally three times daily in cycles of 21 days. A three-day amuvatinib run-in period before EP occurred in Cycle 1. Subjects received the same EP chemotherapy regimen given prior to progression/relapse. Among 23 subjects treated, we observed four PRs (17.4%) per RECIST 1.1, only two of which were centrally confirmed (8.7%, response duration 119, 151 days). Three subjects (13%) had confirmed stable disease. c-Kit H-score was ≥100 in two subjects whose respective durations of disease control were 151 and 256 days. The addition of amuvatinib to EP chemotherapy in unselected, platinum-refractory SCLC did not meet the primary endpoint of ≥3 confirmed responses in stage 1. However, high c-Kit expression in two subjects with durable disease control suggests the potential for further study of amuvatinib in SCLC patients with high c-Kit expression.

18FDG-PET based radiation planning of mediastinal lymph nodes in limited disease small cell lung cancer changes radiotherapy fields: a planning study.

PubMed

van Loon, Judith; Offermann, Claudia; Bosmans, Geert; Wanders, Rinus; Dekker, André; Borger, Jacques; Oellers, Michel; Dingemans, Anne-Marie; van Baardwijk, Angela; Teule, Jaap; Snoep, Gabriel; Hochstenbag, Monique; Houben, Ruud; Lambin, Philippe; De Ruysscher, Dirk

2008-04-01

To investigate the influence of selective irradiation of 18FDG-PET positive mediastinal nodes on radiation fields and normal tissue exposure in limited disease small cell lung cancer (LD-SCLC). Twenty-one patients with LD-SCLC, of whom both CT and PET images were available, were studied. For each patient, two three-dimensional conformal treatment plans were made with selective irradiation of involved lymph nodes, based on CT and on PET, respectively. Changes in treatment plans as well as dosimetric factors associated with lung and esophageal toxicity were analyzed and compared. FDG-PET information changed the treatment field in 5 patients (24%). In 3 patients, this was due to a decrease and in 2 patients to an increase in the number of involved nodal areas. However, there were no significant differences in gross tumor volume (GTV), lung, and esophageal parameters between CT- and PET-based plans. Incorporating FDG-PET information in radiotherapy planning for patients with LD-SCLC changed the treatment plan in 24% of patients compared to CT. Both increases and decreases of the GTV were observed, theoretically leading to the avoidance of geographical miss or a decrease of radiation exposure of normal tissues, respectively. Based on these findings, a phase II trial, evaluating PET-scan based selective nodal irradiation, is ongoing in our department.

Sensitivity Analysis of Biome-Bgc Model for Dry Tropical Forests of Vindhyan Highlands, India

NASA Astrophysics Data System (ADS)

Kumar, M.; Raghubanshi, A. S.

2011-08-01

A process-based model BIOME-BGC was run for sensitivity analysis to see the effect of ecophysiological parameters on net primary production (NPP) of dry tropical forest of India. The sensitivity test reveals that the forest NPP was highly sensitive to the following ecophysiological parameters: Canopy light extinction coefficient (k), Canopy average specific leaf area (SLA), New stem C : New leaf C (SC:LC), Maximum stomatal conductance (gs,max), C:N of fine roots (C:Nfr), All-sided to projected leaf area ratio and Canopy water interception coefficient (Wint). Therefore, these parameters need more precision and attention during estimation and observation in the field studies.

Highly uniform and reliable resistive switching characteristics of a Ni/WOx/p+-Si memory device

NASA Astrophysics Data System (ADS)

Kim, Tae-Hyeon; Kim, Sungjun; Kim, Hyungjin; Kim, Min-Hwi; Bang, Suhyun; Cho, Seongjae; Park, Byung-Gook

2018-02-01

In this paper, we investigate the resistive switching behavior of a bipolar resistive random-access memory (RRAM) in a Ni/WOx/p+-Si RRAM with CMOS compatibility. Highly unifrom and reliable bipolar resistive switching characteristics are observed by a DC voltage sweeping and its switching mechanism can be explained by SCLC model. As a result, the possibility of metal-insulator-silicon (MIS) structural WOx-based RRAM's application to Si-based 1D (diode)-1R (RRAM) or 1T (transistor)-1R (RRAM) structure is demonstrated.

[Analysis of Prognostic Factors and Clinical Characteristics for Patients with Limited Stage Small Cell Lung Cancer with Pleural Effusion].

PubMed

Xu, Kunpeng; Wang, Youyou; Qi, Jing; Zhao, Lujun; Wang, Ping

2018-01-20

Malignant pleural effusion (PE) was generally defined as pleural effusion containing tumors with poor prognosis. Some kinds of undefined pleural effusions due to too small amount of effusion had poor prognosis too. This study aimed to analyze the clinical characteristics and prognostic factors of patients who suffered from limited-stage small cell lung cancer (LS-SCLC) complicated with pleural effusion. A retrospective analysis included 542 patients who were diagnosed with LS-SCLC and had treatment in our hospital from October 2007 to January 2016. We had observed 109 patients who were diagnosed with pleural effusion at their first visit to the doctor. We analyzed the clinical characters, survival time and the prognostic factors of the 109 patients. Our main observation targets were overall survival (OS) and progression free survival (PFS). The median OS and PFS of whole group were 29.4 and 18.2 months. Before treatment, survival time of patients with PE were significantly shorter than patients without PE (median OS: 21.0 vs 31.7 months; median PFS: 14.1 vs 9.1 months; Log-rank, P=0.001, P=0.014). Multi-factor analysis of multivariate Cox shows PE was the independent prognostic factor of LS-SCLC (P=0.04). Single factor analysis showed factors affecting PE patient's survival time included clinical stages, lymph node (LN) stages, KPS scores, pulmonary atelectasis and the state of pleural after treatment. Cox multi-factor analysis reminded that the state of pleural effusion after treatment was the independent prognostic factor of LS-SCLC complicated with pleural effusion (P=0.016). There were three groups was apportioned patients without pleural effusion before treatment (group 1; n=433), patients whose pleural effusion disappeared after treatment (group 2; n=67) and patients whose pleural effusion didn't disappear after treatment (group 3; n=32).The median OS were 31.7, 23.2, 16.8 months in the group 1, 2, 3 and the median PFS were 19.1, 17.9, 11.4 months. Obvious difference was noted by the comparison of survival time of these three groups (Log-rank P<0.001, P<0.002). The difference between group 2 and group 3 was significant (Log-rank P=0.046, P=0.013) while no obvious difference was noted during comparison of group 1 and group 2. For patients who have LS-SCLC complicated with PE, there is no remarkable difference between chemoradiotherapy and chemotherapy alone. The survival time of patients who suffered from limited-stage small cell lung cancer complicated with pleural effusion was obviously shortened. The disappearing of pleural effusion after treatment was the independent favorable prognostic factor of survival. How to treat needed further investigation.

Impact of sociodemographic factors on the radiotherapeutic management of lung cancer: Results of a Quality Research in Radiation Oncology survey.

PubMed

Rengan, Ramesh; Ho, Alex; Owen, Jean B; Komaki, R; Khalid, Najma; Wilson, J Frank; Movsas, Benjamin

2014-01-01

The objective of this study is to describe the impact of sociodemographic (SOC) factors on the management of lung cancer patients treated at radiation therapy facilities participating in the Quality Research in Radiation Oncology survey. A 2-stage stratified random sample of lung cancer patients treated in 2006 to 2007 at 45 facilities yielded 340 stage I-III non-small cell lung cancer (NSCLC) and 144 limited-stage small cell lung cancer (LS-SCLC) cases. Five SOC variables based on data from the 2000 US Census were analyzed for association with the following clinical factors: patients living in urban versus rural settings (U/R); median household income (AHI); % below poverty level (PPV); % unemployed (PUE); and % with college education (PCE). The 340 NSCLC patients were stage I, 16%; stage II, 11%; stage III, 62%; stage unknown, 11%. Histologic subtypes were adenocarcinoma, 31.8%; squamous cell carcinoma, 35.3%; large cell carcinoma, 3.2%; and NSCLC NOS, 27.7%. The median age was 66 years. Median Karnofsky performance status (KPS) was 80. The 144 LS-SCLC had a median age of 63; 73 were male (50.7%). Median KPS was 80. Stereotactic body radiation therapy (SBRT) and modern imaging utilization was associated with treatment at facilities located in higher SOC regions. SBRT was employed in 46.8% stage I NSCLC patients treated in centers where %PUE was below median versus 14.8% in centers where %PUE was above median (P = .02). Four-dimensional computed tomography was utilized in 14.2% of patients treated in centers located in regions with %PPV below median versus 3.7% in centers located in regions with %PPV above median (P < .01). SCLC patients were more likely to receive all of their planned RT when treated at centers located in regions with lower PPV (95.0% vs 79.1%; P = .04). SOC factors may impact use of modern treatment planning and delivery and multidisciplinary management of NSCLC and SCLC. These results may suggest an impact of these SOC factors on access to health care. © 2014 Published by Elsevier Inc. on behalf of American Society for Radiation Oncology.

Triple test with tumor markers CYFRA 21.1, HE4, and ProGRP might contribute to diagnosis and subtyping of lung cancer.

PubMed

Korkmaz, Elif Tugce; Koksal, Deniz; Aksu, Funda; Dikmen, Z Gunnur; Icen, Duygu; Maden, Emin; Onder, Sevgen; Akbiyik, Filiz; Emri, Salih

2018-05-02

Early diagnosis and histological subtyping are important issues in the management of patients with lung cancer (LC). The aim of this study is to investigate the diagnostic value of a panel of serum tumor markers in newly diagnosed patients with LC. Venous blood samples were collected from 99 patients with LC (42 adenocarcinoma, 35 squamous, and 22 small cell carcinoma) and 30 patients with benign lung disease. Progastrin releasing peptide (ProGRP), squamous cell carcinoma antigen (SCCAg), cytokeratin 19-fragments (CYFRA 21.1), human epididymis protein 4 (HE4), Chromogranin A (CgA) and neuron specific enolase (NSE) levels were measured. The diagnostic value of the biomarkers was assessed with ROC curve analyses; the area under the curve (AUC) was calculated. Serum CYFRA 21.1, ProGRP, SCCAg, NSE levels were significantly higher in LC patients. While ProGRP levels were higher (p = 0.009) in SCLC; CYFRA 21.1 and SCCAg levels were higher in NSCLC (p = 0.019 and p = 0.001, respectively). The sensitivity and specificity of tumor markers were 72%, 83% for CYFRA 21.1; 70%, 57% for HE4; 18%, 93% for ProGRP; 43%, 77% for SCCAg; 54%, 53% for CgA; 73%, 50% for NSE. CYFRA 21.1 (p < 0.001, r = 0.394), HE4 (p = 0.014, r = 0.279) and CgA (p = 0.023, r = 0.259) levels were positively correlated with tumor stage in NSCLC. CgA levels were significantly higher in extensive stage SCLC (p = 0.004). CYFRA 21.1 had the highest diagnostic value for LC (AUC = 0.865). When it is combined with HE4, diagnostic value increased (AUC = 0.899). ProGRP had the highest diagnostic value (AUC = 0.875, p < 0.001) for discriminating SCLC from NSCLC. A panel of three tumor markers CYFRA 21.1, HE4 and ProGRP may play a role for discriminating LC from benign lung disease and subtyping as SCLC. Copyright © 2018 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

The drift-diffusion interpretation of the electron current within the organic semiconductor characterized by the bulk single energy trap level

NASA Astrophysics Data System (ADS)

Cvikl, B.

2010-01-01

The closed solution for the internal electric field and the total charge density derived in the drift-diffusion approximation for the model of a single layer organic semiconductor structure characterized by the bulk shallow single trap-charge energy level is presented. The solutions for two examples of electric field boundary conditions are tested on room temperature current density-voltage data of the electron conducting aluminum/tris(8-hydroxyquinoline aluminum/calcium structure [W. Brütting et al., Synth. Met. 122, 99 (2001)] for which jexp∝Va3.4, within the interval of bias 0.4 V≤Va≤7. In each case investigated the apparent electron mobility determined at given bias is distributed within a given, finite interval of values. The bias dependence of the logarithm of their lower limit, i.e., their minimum values, is found to be in each case, to a good approximation, proportional to the square root of the applied electric field. On account of the bias dependence as incorporated in the minimum value of the apparent electron mobility the spatial distribution of the organic bulk electric field as well as the total charge density turn out to be bias independent. The first case investigated is based on the boundary condition of zero electric field at the electron injection interface. It is shown that for minimum valued apparent mobilities, the strong but finite accumulation of electrons close to the anode is obtained, which characterize the inverted space charge limited current (SCLC) effect. The second example refers to the internal electric field allowing for self-adjustment of its boundary values. The total electron charge density is than found typically to be of U shape, which may, depending on the parameters, peak at both or at either Alq3 boundary. It is this example in which the proper SCLC effect is consequently predicted. In each of the above two cases, the calculations predict the minimum values of the electron apparent mobility, which substantially exceed the corresponding published measurements. For this reason the effect of the drift term alone is additionally investigated. On the basis of the published empirical electron mobilities and the diffusion term revoked, it is shown that the steady state electron current density within the Al/Alq3 (97 nm)/Ca single layer organic structure may well be pictured within the drift-only interpretation of the charge carriers within the Alq3 organic characterized by the single (shallow) trap energy level. In order to arrive at this result, it is necessary that the nonzero electric field, calculated to exist at the electron injecting Alq3/Ca boundary, is to be appropriately accounted for in the computation.

Power- and Low-Resistance-State-Dependent, Bipolar Reset-Switching Transitions in SiN-Based Resistive Random-Access Memory

NASA Astrophysics Data System (ADS)

Kim, Sungjun; Park, Byung-Gook

2016-08-01

A study on the bipolar-resistive switching of an Ni/SiN/Si-based resistive random-access memory (RRAM) device shows that the influences of the reset power and the resistance value of the low-resistance state (LRS) on the reset-switching transitions are strong. For a low LRS with a large conducting path, the sharp reset switching, which requires a high reset power (>7 mW), was observed, whereas for a high LRS with small multiple-conducting paths, the step-by-step reset switching with a low reset power (<7 mW) was observed. The attainment of higher nonlinear current-voltage ( I-V) characteristics in terms of the step-by-step reset switching is due to the steep current-increased region of the trap-controlled space charge-limited current (SCLC) model. A multilevel cell (MLC) operation, for which the reset stop voltage ( V STOP) is used in the DC sweep mode and an incremental amplitude is used in the pulse mode for the step-by-step reset switching, is demonstrated here. The results of the present study suggest that well-controlled conducting paths in a SiN-based RRAM device, which are not too strong and not too weak, offer considerable potential for the realization of low-power and high-density crossbar-array applications.

Etoposide Injection

MedlinePlus

... medications to treat a certain type of lung cancer (small cell lung cancer; SCLC). Etoposide is in a class of medications ... organs where eggs are formed), another type of lung cancer (non-small cell lung cancer; NSCLC), and Kaposi's ...

Bcl-2-independent induction of apoptosis by neuropeptide receptor antagonist in human small cell lung carcinoma cells.

PubMed

Matsumoto, Y; Kawatani, M; Simizu, S; Tanaka, T; Takada, M; Imoto, M

2000-01-01

The broad-spectrum antagonist of neuropeptide receptor, [D-Arg1, D-Phe5, D-Trp7,9, Leu11]substance P, induced apoptosis selectively in human small cell lung carcinoma (SCLC) cells, which express gastrin-releasing peptide receptor, but not in other types of tumor cells as well as normal cells. The addition of gastrin-releasing peptide or bombesin and the inhibitor of caspase-3 suppressed [D-Arg1, D-Phe5, D-Trp7,9, Leu11]substance P-induced apoptosis. Moreover, [D-Arg1, D-Phe5, D-Trp7,9, Leu11]substance P-induced apoptosis was not suppressed by Bcl-2 over-expression. Thus, blockage of gastrin-releasing peptide receptor-mediated signaling may provide a novel therapeutic option in SCLC which has become resistant to conventional chemotherapeutic agents.

Differential expression and prognostic value of the chemokine receptor CXCR4 in bronchopulmonary neuroendocrine neoplasms

PubMed Central

Specht, Elisa; Wirtz, Ralph M.; Sayeg, Manal; Baum, Richard P.; Schulz, Stefan; Lupp, Amelie

2015-01-01

Introduction For many tumors, the overexpression of the chemokine receptor CXCR4 is associated with increased malignancy and poor patient outcomes. However, comprehensive data for neuroendocrine neoplasms of the lung are still lacking. Methods CXCR4 expression was evaluated in a panel of bronchopulmonary neuroendocrine neoplasms (BP-NEN) comprising typical carcinoids (n = 26), atypical carcinoids (n = 30), and small cell lung cancers (SCLC, n = 34). Samples were analyzed by immunohistochemistry using the novel monoclonal rabbit anti-human CXCR4 antibody UMB-2 and by qRT-PCR. The expression was correlated with clinical data and overall patient survival. Results CXCR4 was predominantly localized at the plasma membrane of the tumor cells. CXCR4 was expressed with a high intensity in almost all of the 30 SCLC samples. In contrast, it was detected infrequently and with low intensity in the typical carcinoid and atypical carcinoid samples. There was a significant correlation between the immunohistochemistry and qRT-PCR data. Additionally, there was a significant negative relationship between CXCR4 expression and overall survival. Conclusions With increasing malignancy, BP-NEN clearly differ in the extent of CXCR4 expression. As in other tumor entities, CXCR4 overexpression significantly correlates with negative patient outcome. Due to its particular high expression rate in SCLC, CXCR4 may serve as a promising new target for diagnostic and pharmacological intervention as well as for peptide receptor-based radionuclide therapy. PMID:25671300

Comparative evaluation of three proliferation markers, Ki-67, TOP2A, and RacGAP1, in bronchopulmonary neuroendocrine neoplasms: Issues and prospects.

PubMed

Neubauer, Elisa; Wirtz, Ralph M; Kaemmerer, Daniel; Athelogou, Maria; Schmidt, Lydia; Sänger, Jörg; Lupp, Amelie

2016-07-05

The classification of bronchopulmonary neuroendocrine neoplasms (BP-NEN) into four tumor entities (typical carcinoids (TC), atypical carcinoids (AC), small cell lung cancers (SCLC), large cell neuroendocrine lung carcinomas (LCNEC)) is difficult to perform accurately, but important for prognostic statements and therapeutic management decisions. In this regard, we compared the expression of three proliferation markers, Ki-67, Topoisomerase II alpha (TOP2A), and RacGAP1, in a series of tumor samples from 104 BP-NEN patients (24 TC, 21 AC, 52 SCLC, 7 LCNEC) using different evaluation methods (immunohistochemistry (IHC): Average evaluation, Hotspot evaluation, digital image analysis; RT-qPCR).The results indicated that all three markers had increased protein and mRNA expression with poorer differentiation and correlated well with each other, as well as with grading, staging, and poor survival. Compared with Ki-67 and TOP2A, RacGAP1 allowed for a clearer prognostic statement. The cut-off limits obtained for Ki-67-Average (IHC) were TC-AC 1.5, AC-SCLC 19, and AC-LCNEC 23.5. The Hotspot evaluation generated equal to higher, the digital image analysis generally lower between-entity cut-off limits.All three markers enabled a clear-cut differentiation between the BP-NEN entities, and all methods evaluated were suitable for marker assessment. However, to define optimal cut-off limits, the Ki-67 evaluation methods should be standardized. RacGAP1 appeared to be a new marker with great potential.

Space charge limited current measurements on conjugated polymer films using conductive atomic force microscopy.

PubMed

Reid, Obadiah G; Munechika, Keiko; Ginger, David S

2008-06-01

We describe local (~150 nm resolution), quantitative measurements of charge carrier mobility in conjugated polymer films that are commonly used in thin-film transistors and nanostructured solar cells. We measure space charge limited currents (SCLC) through these films using conductive atomic force microscopy (c-AFM) and in macroscopic diodes. The current densities we measure with c-AFM are substantially higher than those observed in planar devices at the same bias. This leads to an overestimation of carrier mobility by up to 3 orders of magnitude when using the standard Mott-Gurney law to fit the c-AFM data. We reconcile this apparent discrepancy between c-AFM and planar device measurements by accounting for the proper tip-sample geometry using finite element simulations of tip-sample currents. We show that a semiempirical scaling factor based on the ratio of the tip contact area diameter to the sample thickness can be used to correct c-AFM current-voltage curves and thus extract mobilities that are in good agreement with values measured in the conventional planar device geometry.

The effect of down regulation of calcineurin Aα by lentiviral vector-mediated RNAi on the biological behavior of small-cell lung cancer and its bone metastasis.

PubMed

Ma, Ning-Qiang; Liu, Li-Li; Min, Jie; Wang, Jun-Wei; Jiang, Wei-Feng; Liu, Yan; Feng, Yan-Guo; Su, Hai-Chuan; Feng, Ying-Ming; Zhang, He-Long

2011-12-01

Bone is the third most common site of cancer metastasis. Over 30 to 40% of lung cancers can develop skeletal metastasis and no effective curative therapy exists in clinic cases. Previously we screened the different expression of proteins between SBC-5 cells and SBC-3 cells by proteomic study methods (MALDI-TOF/TOF-MS) and found that calcineurin (hereafter referred as Cn) overexpresses in SBC-5 which has special priority in metastasis to bone in a multiple-organ metastasis mice model. However the roles of Cn in osteotropism of SCLC remain to be elucidated. At present study, we decrease CnAα expression in SBC-5 by lentiviral vector-mediated RNAi and found that down regulation of CnAα gene expression can decrease the proliferation and colony formation rate, impede the cell cycle progression, reduce the cell migration and invasion, and inhibit cells adhering to bone matrix, but not change the apoptosis rate of SBC-5 in vitro. In vivo down or up regulation of CnAα gene expression can only decrease or increase the bone metastasis rate, but not affect the metastasis rate to the visceral organs. Our research reveals that CnAα is closely related to the osteotropism metastasis of SCLC and a candidate tumor promotor gene for developing bone metastases.

Electrical transport properties of thermally evaporated phthalocyanine (H 2Pc) thin films

NASA Astrophysics Data System (ADS)

El-Nahass, M. M.; Farid, A. M.; Attia, A. A.; Ali, H. A. M.

2006-08-01

Thin films of H 2Pc of various thicknesses have been deposited onto glass substrates using thermal evaporation technique at room temperature. The dark electrical resistivity measurements were carried out at different temperatures in the range 298-473 K. An estimation of mean free path ( lo) of charge carriers in H 2Pc thin films was attempted. Measurements of thermoelectric power confirm that H 2Pc thin films behave as a p-type semiconductor. The current density-voltage characteristics of Au/H 2Pc/Au at room temperature showed ohmic conduction mechanism at low voltages. At higher voltages the space-charge-limited conduction (SCLC) accompanied by an exponential trap distribution was dominant. The temperature dependence of current density allows the determination of some essential parameters such as the hole mobility ( μh), the total trap concentration ( Nt), the characteristic temperature ( Tt) and the trap density P( E).

Quantitative analysis of charge trapping and classification of sub-gap states in MoS2 TFT by pulse I-V method

NASA Astrophysics Data System (ADS)

Park, Junghak; Hur, Ji-Hyun; Jeon, Sanghun

2018-04-01

The threshold voltage instabilities and huge hysteresis of MoS2 thin film transistors (TFTs) have raised concerns about their practical applicability in next-generation switching devices. These behaviors are associated with charge trapping, which stems from tunneling to the adjacent trap site, interfacial redox reaction and interface and/or bulk trap states. In this report, we present quantitative analysis on the electron charge trapping mechanism of MoS2 TFT by fast pulse I-V method and the space charge limited current (SCLC) measurement. By adopting the fast pulse I-V method, we were able to obtain effective mobility. In addition, the origin of the trap states was identified by disassembling the sub-gap states into interface trap and bulk trap states by simple extraction analysis. These measurement methods and analyses enable not only quantitative extraction of various traps but also an understanding of the charge transport mechanism in MoS2 TFTs. The fast I-V data and SCLC data obtained under various measurement temperatures and ambient show that electron transport to neighboring trap sites by tunneling is the main charge trapping mechanism in thin-MoS2 TFTs. This implies that interfacial traps account for most of the total sub-gap states while the bulk trap contribution is negligible, at approximately 0.40% and 0.26% in air and vacuum ambient, respectively. Thus, control of the interface trap states is crucial to further improve the performance of devices with thin channels.

Quantitative analysis of charge trapping and classification of sub-gap states in MoS2 TFT by pulse I-V method.

PubMed

Park, Junghak; Hur, Ji-Hyun; Jeon, Sanghun

2018-04-27

The threshold voltage instabilities and huge hysteresis of MoS 2 thin film transistors (TFTs) have raised concerns about their practical applicability in next-generation switching devices. These behaviors are associated with charge trapping, which stems from tunneling to the adjacent trap site, interfacial redox reaction and interface and/or bulk trap states. In this report, we present quantitative analysis on the electron charge trapping mechanism of MoS 2 TFT by fast pulse I-V method and the space charge limited current (SCLC) measurement. By adopting the fast pulse I-V method, we were able to obtain effective mobility. In addition, the origin of the trap states was identified by disassembling the sub-gap states into interface trap and bulk trap states by simple extraction analysis. These measurement methods and analyses enable not only quantitative extraction of various traps but also an understanding of the charge transport mechanism in MoS 2 TFTs. The fast I-V data and SCLC data obtained under various measurement temperatures and ambient show that electron transport to neighboring trap sites by tunneling is the main charge trapping mechanism in thin-MoS 2 TFTs. This implies that interfacial traps account for most of the total sub-gap states while the bulk trap contribution is negligible, at approximately 0.40% and 0.26% in air and vacuum ambient, respectively. Thus, control of the interface trap states is crucial to further improve the performance of devices with thin channels.

Comparative evaluation of three proliferation markers, Ki-67, TOP2A, and RacGAP1, in bronchopulmonary neuroendocrine neoplasms: Issues and prospects

PubMed Central

Neubauer, Elisa; Wirtz, Ralph M.; Kaemmerer, Daniel; Athelogou, Maria; Schmidt, Lydia; Sänger, Jörg; Lupp, Amelie

2016-01-01

The classification of bronchopulmonary neuroendocrine neoplasms (BP-NEN) into four tumor entities (typical carcinoids (TC), atypical carcinoids (AC), small cell lung cancers (SCLC), large cell neuroendocrine lung carcinomas (LCNEC)) is difficult to perform accurately, but important for prognostic statements and therapeutic management decisions. In this regard, we compared the expression of three proliferation markers, Ki-67, Topoisomerase II alpha (TOP2A), and RacGAP1, in a series of tumor samples from 104 BP-NEN patients (24 TC, 21 AC, 52 SCLC, 7 LCNEC) using different evaluation methods (immunohistochemistry (IHC): Average evaluation, Hotspot evaluation, digital image analysis; RT-qPCR). The results indicated that all three markers had increased protein and mRNA expression with poorer differentiation and correlated well with each other, as well as with grading, staging, and poor survival. Compared with Ki-67 and TOP2A, RacGAP1 allowed for a clearer prognostic statement. The cut-off limits obtained for Ki-67-Average (IHC) were TC-AC 1.5, AC-SCLC 19, and AC-LCNEC 23.5. The Hotspot evaluation generated equal to higher, the digital image analysis generally lower between-entity cut-off limits. All three markers enabled a clear-cut differentiation between the BP-NEN entities, and all methods evaluated were suitable for marker assessment. However, to define optimal cut-off limits, the Ki-67 evaluation methods should be standardized. RacGAP1 appeared to be a new marker with great potential. PMID:27259241

POSITIVE study: physical exercise program in non-operable lung cancer patients undergoing palliative treatment.

PubMed

Wiskemann, Joachim; Hummler, Simone; Diepold, Christina; Keil, Melanie; Abel, Ulrich; Steindorf, Karen; Beckhove, Philipp; Ulrich, Cornelia M; Steins, Martin; Thomas, Michael

2016-07-19

Patients with advanced stage non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC) often experience multidimensional impairments, affecting quality of life during their course of disease. In lung cancer patients with operable disease, several studies have shown that exercise has a positive impact on quality of life and physical functioning. There is limited evidence regarding efficacy for advanced lung cancer patients undergoing palliative treatment. Therefore, the POSITIVE study aims to evaluate the benefit of a 24-week exercise intervention during palliative treatment in a randomized controlled setting. The POSITIVE study is a randomized, controlled trial investigating the effects of a 24-week exercise intervention during palliative treatment on quality of life, physical performance and immune function in advanced, non-operable lung cancer patients. 250 patients will be recruited in the Clinic for Thoracic Diseases in Heidelberg, enrolment begun in November 2013. Main inclusion criterion is histologically confirmed NSCLC (stage IIIa, IIIb, IV) or SCLC (Limited Disease-SCLC, Extensive Disease-SCLC) not amenable to surgery. Patients are randomized into two groups. Both groups receive weekly care management phone calls (CMPCs) with the goal to assess symptoms and side effects. Additionally, one group receives a combined resistance and endurance training (3x/week). Primary endpoints are quality of life assessed by the Functional Assessment of Cancer Therapy for patients with lung cancer (FACT-L, subcategory Physical Well-Being) and General Fatigue measured by the Multidimensional Fatigue Inventory (MFI-20). Secondary endpoints are physical performance (maximal voluntary isometric contraction, 6-min walk distance), psychosocial (depression and anxiety) and immunological parameters and overall survival. The aim of the POSITIVE trial is the evaluation of effects of a 24-week structured and guided exercise intervention during palliative treatment stages. Analysis of various outcomes (such as quality of life, physical performance, self-efficacy, psychosocial and immunological parameters) will contribute to a better understanding of the potential of exercise in advanced lung cancer patients. In contrast to other studies with advanced oncological patients the POSITIVE trial provides weekly phone calls to support patients both in the intervention and control group and to segregate the impact of physical activity on quality of life. ClinicalTrials.gov NCT02055508 (Date: December 12, 2013).

Drug Combination Synergy in Worm-like Polymeric Micelles Improves Treatment Outcome for Small Cell and Non-Small Cell Lung Cancer.

PubMed

Wan, Xiaomeng; Min, Yuanzeng; Bludau, Herdis; Keith, Andrew; Sheiko, Sergei S; Jordan, Rainer; Wang, Andrew Z; Sokolsky-Papkov, Marina; Kabanov, Alexander V

2018-03-27

Nanoparticle-based systems for concurrent delivery of multiple drugs can improve outcomes of cancer treatments, but face challenges because of differential solubility and fairly low threshold for incorporation of many drugs. Here we demonstrate that this approach can be used to greatly improve the treatment outcomes of etoposide (ETO) and platinum drug combination ("EP/PE") therapy that is the backbone for treatment of prevalent and deadly small cell lung cancer (SCLC). A polymeric micelle system based on amphiphilic block copolymer poly(2-oxazoline)s (POx) poly(2-methyl-2-oxazoline- block-2-butyl-2-oxazoline- block-2-methyl-2-oxazoline) (P(MeOx- b-BuOx- b-MeOx) is used along with an alkylated cisplatin prodrug to enable co-formulation of EP/PE in a single high-capacity vehicle. A broad range of drug mixing ratios and exceptionally high two-drug loading of over 50% wt. drug in dispersed phase is demonstrated. The highly loaded POx micelles have worm-like morphology, unprecedented for drug loaded polymeric micelles reported so far, which usually form spheres upon drug loading. The drugs co-loading in the micelles result in a slowed-down release, improved pharmacokinetics, and increased tumor distribution of both drugs. A superior antitumor activity of co-loaded EP/PE drug micelles compared to single drug micelles or their combination as well as free drug combination was demonstrated using several animal models of SCLC and non-small cell lung cancer.

Etoposide and cisplatin versus irinotecan and cisplatin in patients with limited-stage small-cell lung cancer treated with etoposide and cisplatin plus concurrent accelerated hyperfractionated thoracic radiotherapy (JCOG0202): a randomised phase 3 study.

PubMed

Kubota, Kaoru; Hida, Toyoaki; Ishikura, Satoshi; Mizusawa, Junki; Nishio, Makoto; Kawahara, Masaaki; Yokoyama, Akira; Imamura, Fumio; Takeda, Koji; Negoro, Shunichi; Harada, Masao; Okamoto, Hiroaki; Yamamoto, Nobuyuki; Shinkai, Tetsu; Sakai, Hiroshi; Matsui, Kaoru; Nakagawa, Kazuhiko; Shibata, Taro; Saijo, Nagahiro; Tamura, Tomohide

2014-01-01

Four cycles of etoposide plus cisplatin and accelerated hyperfractionated thoracic radiotherapy (AHTRT) is the standard of care for limited-stage small-cell lung cancer (SCLC). Irinotecan plus cisplatin significantly improved overall survival compared with etoposide plus cisplatin for extensive-stage SCLC. We compared these regimens for overall survival of patients with limited-stage SCLC. We did this phase 3 study in 36 institutions in Japan. Eligibility criteria included age 20-70 years, Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and adequate organ functions. Eligible patients with previously untreated limited-stage SCLC received one cycle of etoposide plus cisplatin (intravenous etoposide 100 mg/m(2) on days 1-3; intravenous cisplatin 80 mg/m(2) on day 1) plus AHTRT (1.5 Gy twice daily, 5 days a week, total 45 Gy over 3 weeks). Patients without progressive disease following induction therapy were randomised (1:1 ratio, using a minimisation method with biased-coin assignment balancing on ECOG performance status [0 vs 1], response to induction chemoradiotherapy [complete response plus near complete response vs partial response and stable disease], and institution) to receive either three further cycles of consolidation etoposide plus cisplatin or irinotecan plus cisplatin (intravenous irinotecan 60 mg/m(2) on days 1, 8, 15; intravenous cisplatin 60 mg/m(2) on day 1). Patients, physicians, and investigators were aware of allocation. The primary endpoint was overall survival after randomisation; primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00144989, and the UMIN Clinical Trials Registry, number C000000095. 281 patients were enrolled between Sept 1, 2002, and Oct 2, 2006. After induction etoposide plus cisplatin and AHTRT, 258 patients were randomised to consolidation etoposide plus cisplatin (n=129) or irinotecan plus cisplatin (n=129). In the etoposide plus cisplatin group, median overall survival was 3.2 years (95% CI 2.4-4.1). In the irinotecan and cisplatin group, median overall survival was 2.8 years (95% CI 2.4-3.6); overall survival did not differ between the two groups (hazard ratio 1.09 [95% CI 0.80-1.46], one-sided stratified log-rank p=0.70). The most common adverse events of grade 3 or 4 were neutropenia (120 [95%] in the etoposide plus cisplatin group vs 101 [78%] in the irinotecan plus cisplatin group), anaemia (44 [35%] vs 50 [39%]), thrombocytopenia (26 [21%] vs six [5%]), febrile neutropenia (21 [17%] vs 18 [14%]), and diarrhoea (two [2%] vs 13 [10%]). There was one treatment-related adverse event leading to death in each group (radiation pneumonitis in the etoposide plus cisplatin group; brain infarction in the irinotecan plus cisplatin group). Four cycles of etoposide plus cisplatin and AHTRT should continue to be the standard of care for limited-stage SCLC. National Cancer Center and the Ministry of Health, Labour, and Welfare of Japan. Copyright © 2014 Elsevier Ltd. All rights reserved.

Understanding Local and Macroscopic Electron Mobilities in the Fullerene Network of Conjugated Polymer-based Solar Cells. Time-Resolved Microwave Conductivity and Theory

DOE Office of Scientific and Technical Information (OSTI.GOV)

Aguirre, Jordan C.; Arntsen, Christopher D.; Hernandez, Samuel

2013-09-23

The efficiency of bulk heterojunction (BHJ) organic photovoltaics is sensitive to the morphology of the fullerene network that transports electrons through the device. This sensitivity makes it difficult to distinguish the contrasting roles of local electron mobility (how easily electrons can transfer between neighboring fullerene molecules) and macroscopic electron mobility (how well-connected is the fullerene network on device length scales) in solar cell performance. In this work, a combination of density functional theory (DFT) calculations, flash-photolysis time-resolved microwave conductivity (TRMC) experiments, and space-charge-limit current (SCLC) mobility estimates are used to examine the roles of local and macroscopic electron mobility inmore » conjugated polymer/fullerene BHJ photovoltaics. The local mobility of different pentaaryl fullerene derivatives (so-called ‘shuttlecock’ molecules) is similar, so that differences in solar cell efficiency and SCLC mobilities result directly from the different propensities of these molecules to self-assemble on macroscopic length scales. These experiments and calculations also demonstrate that the local mobility of phenyl-C60 butyl methyl ester (PCBM) is an order of magnitude higher than that of other fullerene derivatives, explaining why PCBM has been the acceptor of choice for conjugated polymer BHJ devices even though it does not form an optimal macroscopic network. The DFT calculations indicate that PCBM's superior local mobility comes from the near-spherical nature of its molecular orbitals, which allow strong electronic coupling between adjacent molecules. In combination, DFT and TRMC techniques provide a tool for screening new fullerene derivatives for good local mobility when designing new molecules that can improve on the macroscopic electron mobility offered by PCBM.« less

Classification of pulmonary neuroendocrine tumors: new insights.

PubMed

Pelosi, Giuseppe; Sonzogni, Angelica; Harari, Sergio; Albini, Adriana; Bresaola, Enrica; Marchiò, Caterina; Massa, Federica; Righi, Luisella; Gatti, Gaia; Papanikolaou, Nikolaos; Vijayvergia, Namrata; Calabrese, Fiorella; Papotti, Mauro

2017-10-01

Neuroendocrine tumors of the lung (Lu-NETs) embrace a heterogeneous family of neoplasms classified into four histological variants, namely typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC). Defining criteria on resection specimens include mitotic count in 2 mm 2 and the presence or absence of necrosis, alongside a constellation of cytological and histological traits including cell size and shape, nuclear features and overall architecture. Clinically, TC are low-grade malignant tumors, AC intermediate-grade malignant tumors and SCLC/LCNEC high-grade malignant full-blown carcinomas with no significant differences in survival between them. Homologous tumors arise in the thymus that occasionally have some difficulties in differentiating from the lung counterparts when presented with large unresectable or metastatic lesions. Immunohistochemistry (IHC) helps refine NE diagnosis at various anatomical sites, particularly on small-sized tissue material, in which only TC and small cell carcinoma categories can be recognized easily on hematoxylin & eosin stain, while AC and LCNEC can only be suggested on such material. The Ki-67 labeling index effectively separates carcinoids from small cell carcinoma and may prove useful for the clinical management of a metastatic disease to help the therapeutic decision-making process. Although carcinoids and high-grade neuroendocrine carcinomas in the lung and elsewhere make up separate tumor categories on molecular grounds, emerging data supports the concept of secondary high-grade NETs arising in the preexisting carcinoids, whose clinical and biological relevance will have to be placed into the proper context for the optimal management of these patients. In this review, we will discuss the selected, recent literature with a focus on current issues regarding Lu-NET nosology, i.e., classification, derivation and tumor evolution.

[Limbic encephalitis with antibodies against intracellular antigens].

PubMed

Morita, Akihiko; Kamei, Satoshi

2010-04-01

Limbic encephalitis is a paraneoplastic syndrome that is often associated with small cell lung cancer (SCLC), breast cancer, testicular tumors, teratoma, Hodgkin's lymphoma and thymoma. The common clinical manifestations of limbic encephalitis are subacute onset, cognitive dysfunction, seizures and psychiatric symptoms. Paraneoplastic neurological disorders are considered to occur because of cytotoxic T cell responses and antibodies against target neuronal proteins that are usually expressed by an underlying tumor. The main intracellular antigens related to limbic encephalitis are Hu, Ma2, and less frequently CV2/CRMP5 and amphiphysin. The anti-Hu antibody, which is involved in cerebellar degeneration and extensive or multifocal encephalomyelitis such as limbic encephalitis is closely associated with a history of smoking and SCLC. The anti-Ma2 antibody is associated with encephalitis of the limbic system, hypothalamus and brain-stem. For this reason, some patients with limbic encephalitis have sleep disorders (including REM sleep abnormalities), severe hypokinesis and gaze palsy in addition to limbic dysfunction. In men aged less than 50 years, anti-Ma2 antibody encephalitis is almost always associated with testicular germ-cell tumors that are occasionally difficult to detect. In older men and women, the most common tumors are non-SCLC and breast cancer. Limbic encephalitis associated with cell-surface antigens (e.g., voltage-gated potassium channels, NMDA receptors) is mediated by antibodies and often improves after a reduction in the antibody titer and after tumor resection. Patients with antibodies against intracellular antigens, except for those with anti-Ma2 antibodies and testicular tumors, are less responsive. Early diagnosis and treatment with immunotherapy, tumor resection or both are important for improving or stabilizing the condition of limbic encephalitis.

Spermidine/spermine N1-acetyltransferase (SSAT) activity in human small-cell lung carcinoma cells following transfection with a genomic SSAT construct.

PubMed

Murray-Stewart, Tracy; Applegren, Nancy B; Devereux, Wendy; Hacker, Amy; Smith, Renee; Wang, Yanlin; Casero, Robert A

2003-07-15

Spermidine/spermine N (1)-acetyltransferase (SSAT) activity is typically highly inducible in non-small-cell lung carcinomas in response to treatment with anti-tumour polyamine analogues, and this induction is associated with subsequent cell death. In contrast, cells of the small-cell lung carcinoma (SCLC) phenotype generally do not respond to these compounds with an increase in SSAT activity, and usually are only moderately affected with respect to growth. The goal of the present study was to produce an SSAT-overexpressing SCLC cell line to further investigate the role of SSAT in response to these anti-tumour analogues. To accomplish this, NCI-H82 SCLC cells were stably transfected with plasmids containing either the SSAT genomic sequence or the corresponding cDNA sequence. Individual clones were selected based on their ability to show induced SSAT activity in response to exposure to a polyamine analogue, and an increase in the steady-state SSAT mRNA level. Cells transfected with the genomic sequence exhibited a significant increase in basal SSAT mRNA expression, as well as enhanced SSAT activity, intracellular polyamine pool depletion and growth inhibition following treatment with the analogue N (1), N (11)-bis(ethyl)norspermine. Cells containing the transfected cDNA also exhibited an increase in the basal SSAT mRNA level, but remained phenotypically similar to vector control cells with respect to their response to analogue exposure. These studies indicate that both the genomic SSAT sequence and polyamine analogue exposure play a role in the transcriptional and post-transcriptional regulation and subsequent induction of SSAT activity in these cells. Furthermore, this is the first production of a cell line capable of SSAT protein induction from a generally unresponsive parent line.

Thoracic radiation therapy improves the overall survival of patients with extensive-stage small cell lung cancer with distant metastasis.

PubMed

Zhu, Hui; Zhou, Zongmei; Wang, Yan; Bi, Nan; Feng, Qinfu; Li, Junling; Lv, Jima; Chen, Dongfu; Shi, Yuankai; Wang, Luhua

2011-12-01

The authors conducted a retrospective study to evaluate the effects of thoracic radiation therapy (TRT) for patients with extensive-stage small cell lung cancer (ED-SCLC). Between January 2003 and December 2006, the records of 119 patients who were diagnosed with ED-SCLC (all with distant metastasis [M1]) were included in the study. Sixty patients received chemotherapy (ChT) and TRT (ChT/TRT), and 59 patients received ChT alone. The ChT regimens consisted of either carboplatin and etoposide (CE) or cisplatin and etoposide (PE). The total dose of TRT ranged from 40 to 60 grays (Gy) at 1.8 to 2.0 Gy per fraction. For the entire group, the median survival was 13 months, and the 2-year and 5-year overall survival (OS) rates were 26.1% and 6.5%, respectively. The median survival and the 2-year and 5-year OS rates were 17 months, 35%, and 7.1%, respectively, in the ChT/TRT group and 9.3 months, 17%, and 5.1%, respectively, in the ChT group (P = .014). However, this improvement was achieved at the expense of low toxicity. Multivariate analysis revealed that receiving ≥4 cycles of ChT (P = .032) and TRT (P = .005) were favorable prognostic factors for OS. Of all toxicities, only high-grade leucopenia (grade >3) was more frequent in the ChT/TRT group. The addition of TRT to ChT improved the OS of patients with ED-SCLC. Furthermore, receiving ≥4 cycles of ChT and TRT were independent, favorable prognostic factors for OS. Copyright © 2011 American Cancer Society.

Efficacy of prophylactic cranial irradiation in patients with limited-disease small-cell lung cancer who were confirmed to have no brain metastasis via magnetic resonance imaging after initial chemoradiotherapy.

PubMed

Mamesaya, Nobuaki; Wakuda, Kazushige; Omae, Katsuhiro; Miyawaki, Eriko; Kotake, Mie; Fujiwara, Takumi; Kawamura, Takahisa; Kobayashi, Haruki; Nakashima, Kazuhisa; Omori, Shota; Ono, Akira; Kenmotsu, Hirotsugu; Naito, Tateaki; Murakami, Haruyasu; Mori, Keita; Harada, Hideyuki; Endo, Masahiro; Nakajima, Takashi; Takahashi, Toshiaki

2018-04-03

Prophylactic cranial irradiation (PCI) is recommended for patients with limited-disease small-cell lung cancer (LD-SCLC) who achieved good response to definitive chemoradiotherapy. However, most clinical studies lacked brain imaging scans before PCI. Our study aimed to investigate whether PCI has a survival benefit in patients who have no brain metastases (BM) confirmed via magnetic resonance imaging (MRI) before PCI. Eighty patients were included in this study. Sixty patients received PCI (PCI group) and 20 patients did not (non-PCI group). OS was not significantly different between the two groups. The median OS time was 4.3 years (95% CI: 2.6 years-8.6 years) in the PCI group and was not reached (NR) (95% CI: 1.9 years-NR) in the non-PCI group ( p = 0.542). Moreover, no differences were observed in the 3-year rates of PFS (46.2% and 44.4%, p = 0.720) and cumulative incidence of BM (24.0% vs. 27%, p = 0.404). Our result suggests that PCI may not have a survival benefit in patients with LD-SCLC confirmed to have no BM after initial therapy, even if patients achieve a good response to definitive chemoradiotherapy. We retrospectively evaluated patients with LD-SCLC who were confirmed to have no BM via MRI after initial chemoradiotherapy at the Shizuoka Cancer Center between September 2002 and August 2015. The overall survival (OS), progression-free survival (PFS), and cumulative incidence of BM were estimated using the Kaplan-Meier method between patients who received PCI and those who did not. Propensity score matching was used to balance baseline characteristics.

Chemotherapy in combination with cytokine-induced killer cell transfusion: An effective therapeutic option for patients with extensive stage small cell lung cancer.

PubMed

Huang, Jianmin; Kan, Quancheng; Lan; Zhao, Xuan; Zhang, Zhen; Yang, Shuangning; Li, Hong; Wang, Liping; Xu, Li; Cheng, Zhe; Zhang, Yi

2017-05-01

In the past decade of clinical studies, the combination of chemotherapy with cytokine induced killer (CIK) cell transfusion has confirmed a promised efficacy in several types of cancer. CIK cells are a mixture of T lymphocytes, generated from peripheral blood mononuclear cells induced by multiple cytokines. This study was aimed to evaluate the clinical efficacy of chemotherapy combined with CIK- cell therapy in patients with extensive stage small cell lung cancer (ES SCLC). Forty four patients with ES SCLC were enrolled in this study. All the patients received treatment from Oct 2010 to Sep 2013 in the First Affiliated Hospital of Zhengzhou University. Included patients were equally divided into 2 groups according to the treatment strategies. Patients in the combined treatment group received chemotherapy combined with CIK-cell transfusion and patients in the control group received chemotherapy alone. The short-term effects, overall survival (OS), progress free survival (PFS) and therapy-related adverse events were analyzed retrospectively. Short-term efficacy evaluation indicated that the total response rates in the combined treatment group and control group were 40.9% (9/22) and 9.1% (2/22), respectively. There was a significant difference between the two groups (p=0.0339). Furthermore, the PFS of the combined treatment group was significantly longer than that of the control group (8 vs. 4months, P=0.005). No severe side effect was observed after transfusion of CIK cells. These results indicated that chemotherapy combined with CIK-cell immunotherapy might provide a safe and effective treatment for patients with ES SCLC. Copyright © 2016. Published by Elsevier B.V.

Efficacy of prophylactic cranial irradiation in patients with limited-disease small-cell lung cancer who were confirmed to have no brain metastasis via magnetic resonance imaging after initial chemoradiotherapy

PubMed Central

Mamesaya, Nobuaki; Wakuda, Kazushige; Omae, Katsuhiro; Miyawaki, Eriko; Kotake, Mie; Fujiwara, Takumi; Kawamura, Takahisa; Kobayashi, Haruki; Nakashima, Kazuhisa; Omori, Shota; Ono, Akira; Kenmotsu, Hirotsugu; Naito, Tateaki; Murakami, Haruyasu; Mori, Keita; Harada, Hideyuki; Endo, Masahiro; Nakajima, Takashi; Takahashi, Toshiaki

2018-01-01

Background Prophylactic cranial irradiation (PCI) is recommended for patients with limited-disease small-cell lung cancer (LD-SCLC) who achieved good response to definitive chemoradiotherapy. However, most clinical studies lacked brain imaging scans before PCI. Our study aimed to investigate whether PCI has a survival benefit in patients who have no brain metastases (BM) confirmed via magnetic resonance imaging (MRI) before PCI. Results Eighty patients were included in this study. Sixty patients received PCI (PCI group) and 20 patients did not (non-PCI group). OS was not significantly different between the two groups. The median OS time was 4.3 years (95% CI: 2.6 years–8.6 years) in the PCI group and was not reached (NR) (95% CI: 1.9 years–NR) in the non-PCI group (p = 0.542). Moreover, no differences were observed in the 3-year rates of PFS (46.2% and 44.4%, p = 0.720) and cumulative incidence of BM (24.0% vs. 27%, p = 0.404). Conclusions Our result suggests that PCI may not have a survival benefit in patients with LD-SCLC confirmed to have no BM after initial therapy, even if patients achieve a good response to definitive chemoradiotherapy. Patients and Methods We retrospectively evaluated patients with LD-SCLC who were confirmed to have no BM via MRI after initial chemoradiotherapy at the Shizuoka Cancer Center between September 2002 and August 2015. The overall survival (OS), progression-free survival (PFS), and cumulative incidence of BM were estimated using the Kaplan–Meier method between patients who received PCI and those who did not. Propensity score matching was used to balance baseline characteristics. PMID:29707139

Lack of any association between blood groups and lung cancer, independent of histology.

PubMed

Oguz, Arzu; Unal, Dilek; Tasdemir, Arzu; Karahan, Samet; Aykas, Fatma; Mutlu, Hasan; Cihan, Yasemin Benderli; Kanbay, Mehmet

2013-01-01

Lung cancer, the leading cause of cancer deaths, is divided into 2 main classes based on its biology, therapy and prognosis: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Many cases are at an advanced stage at diagnosis, which is a major obstacle to improving outcomes. It is important to define the high risk group patients for early diagnosis and chance of cure. Blood group antigens are chemical components on erythrocyte membranes but they are also expressed on a variety of epithelial cells. Links between ABO blood groups with benign or malignant diseases, such as gastric and pancreas cancers, have been observed for a long time. In this study, we aimed to investigate any possible relationship between lung cancer histological subtypes and ABO-Rh blood groups. The files of 307 pathologically confirmed lung cancer patients were were reviewed retrospectively. Cases with a serologically determined blood group and Rh factor were included and those with a history of another primary cancer were excluded, leaving a total of 221. The distribution of blood groups of the lung cancer patients were compared with the distribution of blood groups of healthy donors admitted to the Turkish Red Crescent Blood Service in our city in the year 2012. There was no significant difference between patients with lung cancer of either type and the control group in terms of distribution of ABO blood groups and Rh factor (p: 0.073). There was also no relationship with non small cell cancer histological subtypes. In this study, we found no relationship between the ABO-Rhesus blood groups and NSCLC and SCLC groups. To our knowledge this is the first analysis of ABO blood groups in SCLC patients.

High field conduction in Pb doped amorphous Se-Te system

NASA Astrophysics Data System (ADS)

Anjali, Patial, Balbir Singh; Thakur, Nagesh

2018-05-01

In the present study, DC conductivity measurements of as-Se80-xTe20Pbx (x = 0, 1 and 2) glassy alloys are made in the temperature range 298-318 K and in the voltage range 0-180 V. Current-voltage (I-V) characteristics point toward ohmic behavior at low electric field and non-ohmic is observed at high electric field. The variation of ln(I/V) against V are nearly found straight curves but slope of these curves does not decrease linearly with temperature indicates that the space charge limited conduction (SCLC) is absent. Instead the linear relation between ln(I) and V1/2 confirms that the conduction is either Poole-Frenkel type or Schottky emission. A detailed analysis shows that the dominant mechanism is Poole-Frenkel type conduction.

Prospective study of etoposide scheduling in combination chemotherapy for limited disease small cell lung carcinoma.

PubMed

Abratt, R P; Willcox, P A; de Groot, M; Goodman, H T; Jansen, E R; Salton, D G

1991-01-01

78 patients with limited disease small cell lung carcinoma (SCLC) were entered into a prospective randomised study of two combination regimens (AVE-5 and AVE-1) that differed only in the scheduling of etoposide. Patients in the AVE-5 arm received etoposide intravenously 60 mg/m2 on day 1 and orally 120 mg/m2 on days 2-5 of each cycle. Patients in the AVE-1 arm received etoposide 300 mg/m2 intravenously on day 1. Patients in both arms received doxorubicin and vincristine on day 1 of each cycle. The complete (53% vs. 26%) and the overall (75% vs. 52%) response rates were significantly higher in the AVE-5 arm. Median survival was also increased from 11 to 14 months in this arm. Toxicity was low and similar in both groups. The daily administration of etoposide in low toxicity combination therapy for SCLC is important. This can be conveniently achieved by using etoposide orally.

Small cell lung cancer presenting as unilateral rhinorrhoea.

PubMed

Haymes, Adam; Mahalingam, Sridhayan; Choudhury, Natasha

2017-08-03

The metastatic spread of infraclavicular malignancies to the nasal cavity is rare. We describe the case of a 58-year-old man who presented with a 4-month history of right-sided rhinorrhoea, maxillary hypoesthesia, hyposmia and hypogeusia. Clinical examination revealed an irregular mass within the right nasal cavity. Immunohistochemical analyses of biopsies were consistent with small cell carcinoma of indeterminate origin. A positron emission tomography scan demonstrated extensive mediastinal lymphadenopathy with collapse-consolidation of the right lung's middle lobe and no other sites of metastasis. Following discussion at the lung multidisciplinary team meeting, a diagnosis of metastatic small cell lung cancer (SCLC) was made; the patient was staged with N3, M1b disease and palliative chemo-radiotherapy was started. To the best of our knowledge, this report represents the first documented case of a solitary nasal cavity metastasis arising from a SCLC. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Immune checkpoint inhibitors in lung cancer: current status and future directions.

PubMed

Fan, Yun; Mao, Weimin

2017-04-01

Recently, the immune checkpoint inhibitors that target programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) have made a breakthrough in treating advanced non-small cell lung cancer (NSCLC) with the efficacy of approximately 20%; among which, nivolumab has acquired treatment indications in lung squamous cell carcinoma. The inhibitors targeting cytotoxic T lymphocyte associated antigen 4 (CTLA-4) are also undergoing clinical trials. Researches on immune checkpoint inhibitors have been rapidly implemented in a variety of different types of lung cancer, such as small cell lung cancer (SCLC) and locally advanced NSCLC, and these inhibitors began to be applied in combination with some established treatments, including chemotherapy, targeting therapy and radiotherapy. Undoubtedly, the immune checkpoint inhibitors have become a hot spot in the research and treatment of lung cancer. However, many problems wait to be solved, such as searching for ideal biomarkers, constituting the best criteria for curative effect evaluation, exploring different combination treatment models, and clearly understanding the mechanisms of primary or secondary drug resistance. Along with these problems to be successfully solved, the immune checkpoint inhibitors will have more broad applications in lung cancer therapy.

Charge Carrier Transport Mechanism Based on Stable Low Voltage Organic Bistable Memory Device.

PubMed

Ramana, V V; Moodley, M K; Kumar, A B V Kiran; Kannan, V

2015-05-01

A solution processed two terminal organic bistable memory device was fabricated utilizing films of polymethyl methacrylate PMMA/ZnO/PMMA on top of ITO coated glass. Electrical characterization of the device structure showed that the two terminal device exhibited favorable switching characteristics with an ON/OFF ratio greater than 1 x 10(4) when the voltage was swept between - 2 V and +3 V. The device maintained its state after removal of the bias voltage. The device did not show degradation after a 1-h retention test at 120 degrees C. The memory functionality was consistent even after fifty cycles of operation. The charge transport switching mechanism is discussed on the basis of carrier transport mechanism and our analysis of the data shows that the charge carrier trans- port mechanism of the device during the writing process can be explained by thermionic emission (TE) and space-charge-limited-current (SCLC) mechanism models while erasing process could be explained by the FN tunneling mechanism. This demonstration provides a class of memory devices with the potential for low-cost, low-power consumption applications, such as a digital memory cell.

An overview of mortality & predictors of small-cell and non-small cell lung cancer among Saudi patients.

PubMed

Alghamdi, Hatim I; Alshehri, Ali F; Farhat, Ghada N

2018-03-01

Lung cancer ranks as the top cancer worldwide in terms of incidence and constitutes a major health problem. About 90% of lung cancer cases are diagnosed at advance stage where treatment is not available. Despite evidence that lung cancer screening improves survival, guidelines for lung cancer screening are still a subject for debate. In Saudi Arabia, only 14% of lung cancers are diagnosed at early stage and researches on survival and its predictors are lacking. This overview analysis was conducted on predictors of lung cancer mortality according to the two major cancer types, small-cell lung cancers (SCLCs) and non-small cell lung cancers (NSCLCs) in Saudi Arabia. A secondary data analysis was performed on small-cell lung cancers (SCLCs) and Non-small cell lung cancers (NSCLCs) registered in the Saudi Cancer Registry (SCR) for the period 2009-2013 to estimate predictors of mortality for both lung cancer types. A total of 404 cases (197 SCLC and 207 NSCLC) were included in the analysis, all Saudi nationals. A total of 213 (52.75%) deaths occurred among lung cancer patients, 108 (54.82%) among SCLCs and 105 (50.72%) among NCSLCs. Three quarter of patients are diagnosis with advance stage for both SCLC & NSCLC. Univariate analysis revealed higher mean age at diagnosis in dead patients compared to alive patients for SCLCs (p=0.04); but not NSCLCs, a lower mortality for NSCLCs diagnosed in 2013 (p=0.025) and a significant difference in stage of tumor (p=0.006) and (p=0.035) for both SCLC and NSCLC respectively. In multiple logistic regression, stage of tumor was a strong predictor of mortality, where distant metastasis increased morality by 6-fold (OR=5.87, 95% CI: 2.01 - 17.19) in SCLC and by 3-fold (OR=3.29, 95% CI: 1.22 - 8.85) in NSCLC, compared to localized tumors. Those with NSCLC who were diagnosed in 2013 were less likely to die by 64% compared to NSCLC diagnosed in 2009 (OR=0.36, 95% CI: 0.14 - 0.93). Age, sex, topography and laterality were not associated with mortality for both types of lung cancer. We observed that the stage of the tumor is the strongest predictor of mortality for both SCLCs and NSCLs. This confirms the impact of diagnostic stage on survival. However, establishing Saudi-specific lung cancer screening guidelines will require further research on the benefits and harms of screening modalities in the Saudi population. Copyright © 2017 Ministry of Health, Saudi Arabia. All rights reserved.

On electrical and interfacial properties of iron and platinum Schottky barrier diodes on (111) n-type Si0.65Ge0.35

NASA Astrophysics Data System (ADS)

Hamri, D.; Teffahi, A.; Djeghlouf, A.; Chalabi, D.; Saidane, A.

2018-04-01

Current-voltage (I-V), capacitance-voltage-frequency (C-V-f) and conductance-voltage-frequency (G/ω-V-f) characteristics of Molecular Beam Epitaxy (MBE)-deposited Fe/n-Si0.65Ge0.35 (FM1) and Pt/n-Si0.65Ge0.35(PM2) (111) orientated Schottky barrier diodes (SBDs) have been investigated at room-temperature. Barrier height (ΦB0), ideality factor (n) and series resistance (RS) were extracted. Dominant current conduction mechanisms were determined. They revealed that Poole-Frenkel-type conduction mechanism dominated reverse current. Differences in shunt resistance confirmed the difference found in leakage current. Under forward bias, quasi-ohmic conduction is found at low voltage regions and space charge-limited conduction (SCLC) at higher voltage regions for both SBDs. Density of interface states (NSS) indicated a difference in interface reactivity. Distribution profiles of series resistance (RS) with bias gives a peak in depletion region at low-frequencies that disappears with increasing frequencies. These results show that interface states density and series resistance of Schottky diodes are important parameters that strongly influence electrical properties of FM1 and PM2 structures.

Molecular packing and electronic processes in amorphous-like polymer bulk heterojunction solar cells with fullerene intercalation.

PubMed

Xiao, Ting; Xu, Haihua; Grancini, Giulia; Mai, Jiangquan; Petrozza, Annamaria; Jeng, U-Ser; Wang, Yan; Xin, Xin; Lu, Yong; Choon, Ng Siu; Xiao, Hu; Ong, Beng S; Lu, Xinhui; Zhao, Ni

2014-06-09

The interpenetrating morphology formed by the electron donor and acceptor materials is critical for the performance of polymer:fullerene bulk heterojunction (BHJ) photovoltaic (PV) cells. In this work we carried out a systematic investigation on a high PV efficiency (>6%) BHJ system consisting of a newly developed 5,6-difluorobenzo[c] thiadiazole-based copolymer, PFBT-T20TT, and a fullerene derivative. Grazing incidence X-ray scattering measurements reveal the lower-ordered nature of the BHJ system as well as an intermixing morphology with intercalation of fullerene molecules between the PFBT-T20TT lamella. Steady-state and transient photo-induced absorption spectroscopy reveal ultrafast charge transfer (CT) at the PFBT-T20TT/fullerene interface, indicating that the CT process is no longer limited by exciton diffusion. Furthermore, we extracted the hole mobility based on the space limited current (SCLC) model and found that more efficient hole transport is achieved in the PFBT-T20TT:fullerene BHJ as compared to pure PFBT-T20TT, showing a different trend as compared to the previously reported highly crystalline polymer:fullerene blend with a similar intercalation manner. Our study correlates the fullerene intercalated polymer lamella morphology with device performance and provides a coherent model to interpret the high photovoltaic performance of some of the recently developed weakly-ordered BHJ systems based on conjugated polymers with branched side-chain.

Ella Baker: A Leader Behind the Scenes.

ERIC Educational Resources Information Center

Dallard, Shyrlee

This book examines the life of Ella Baker, the civil rights worker who was a key figure in the formation of the Student Nonviolent Coordinating Committee (SNCC), the Southern Christian Leadership Conference (SCLC), and other civil rights organizations. The biography, which is aimed at young readers aged 10 and older, recounts the history of the…

Anti-Ma-associated encephalitis due to dysgerminoma in a woman with Swyer syndrome.

PubMed

Al-Thubaiti, Ibtisam; Al-Hayek, Kefah; Binfalah, Mohammed

2013-04-09

Paraneoplastic limbic encephalitis (PLE)/diencephalitis associated with anti-Ma2 antibodies was linked to testicular cancer and non-small-cell lung cancer (non-SCLC).(1,2) We report a case of anti-Ma-associated PLE/diencephalitis due to dysgerminoma in a woman with gonadal dysgenesis, or Swyer syndrome.

Clinical trial studies safety and efficacy of adding a kinase inhibitor to chemotherapy with topotecan in small cell lung cancer | Center for Cancer Research

Cancer.gov

Dr. Anish Thomas, Staff Clinician in the Thoracic and Gastrointestinal Oncology Branch (TGIB), is leading a trial of combination therapy in small cell lung cancer (SCLC), a fast-growing malignancy that occurs most commonly in smokers. Learn more...

Development of Antidepressants as Novel Agents To Treat Small Cell Lung Cancer

DTIC Science & Technology

2014-08-01

least in part by the capacity of these drugs to disrupt autocrine survival loops between neuro - transmitters and their receptors at the surface of SCLC...Ser10 (p-H3; Millipore), cleaved caspase-3 (CC3; Cell Signal- ing Technology), insulin (DAKO), and synaptophysin (SYN; Neuro - mics). Alexa Fluor

Primary Analysis of a Phase II Randomized Trial Radiation Therapy Oncology Group (RTOG) 0212: Impact of Different Total Doses and Schedules of Prophylactic Cranial Irradiation on Chronic Neurotoxicity and Quality of Life for Patients With Limited-Disease Small-Cell Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wolfson, Aaron H., E-mail: awolfson@med.miami.edu; Bae, Kyounghwa; Komaki, Ritsuko

2011-09-01

Purpose: To determine the effect of dose and fractionation schedule of prophylactic cranial irradiation (PCI) on the incidence of chronic neurotoxicity (CNt) and changes in quality of life for selected patients with limited-disease small-cell lung cancer (LD SCLC). Methods and Materials: Patients with LD SCLC who achieved a complete response after chemotherapy and thoracic irradiation were eligible for randomization to undergo PCI to a total dose of 25 Gy in 10 daily fractions (Arm 1) vs. the experimental cohort of 36 Gy. Those receiving 36 Gy underwent a secondary randomization between daily 18 fractions (Arm 2) and twice-daily 24 fractionsmore » (Arm 3). Enrolled patients participated in baseline and follow-up neuropsychological test batteries along with quality-of-life assessments. Results: A total of 265 patients were accrued, with 131 in Arm 1, 67 in Arm 2, and 66 in Arm 3 being eligible. There are 112 patients (42.2%) alive with 25.3 months of median follow-up. There were no significant baseline differences among groups regarding quality-of-life measures and one of the neuropsychological tests, namely the Hopkins Verbal Learning Test. However, at 12 months after PCI there was a significant increase in the occurrence of CNt in the 36-Gy cohort (p = 0.02). Logistic regression analysis revealed increasing age to be the most significant predictor of CNt (p = 0.005). Conclusions: Because of the increased risk of developing CNt in study patients with 36 Gy, a total PCI dose of 25 Gy remains the standard of care for patients with LD SCLC attaining a complete response to initial chemoradiation.« less

Primary resistance to osimertinib due to SCLC transformation: Issue of T790M determination on liquid re-biopsy.

PubMed

Minari, R; Bordi, P; Del Re, M; Facchinetti, F; Mazzoni, F; Barbieri, F; Camerini, A; Comin, C E; Gnetti, L; Azzoni, C; Nizzoli, R; Bortesi, B; Rofi, E; Petreni, P; Campanini, N; Rossi, G; Danesi, R; Tiseo, M

2018-01-01

EGFR T790M mutation is the most common mechanism of resistance to first-/second-generation EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) and could be overcome by third-generation EGFR-TKIs, such as osimertinib. Liquid biopsy, a non-invasive technique used to test the presence of the resistant mutation, may help avoiding tissue re-biopsy. However, analysing only circulating-free DNA, information about other less frequent and coexisting resistance mechanisms may remain unrevealed. All patients reported in this series participated in the ASTRIS trial, a real world treatment study testing the efficacy of osimertinib (80mg os die) in advanced T790M-positive NSCLC progressed to prior EGFR-TKI. Patients were considered eligible to osimertinib if T790M positive on tissue or plasma samples. In our patients, EGFR molecular testing on blood sample was conducted with digital droplet PCR (ddPCR). We report our experience of five patients treated with osimertinib after T790M detection on liquid biopsy that presented a disease progression at first tumor assessment mediated by SCLC transformation, as evidenced at tissue re-biopsies. All patients showed low ratio T790M/activating mutation in the blood before osimertinib (lower than 0.03). For three patients, EGFR mutational analysis was T790M-negative when re-assessed by using a less sensitive method (therascreen ® ) on the same liquid biopsy sample analysed by ddPCR before osimertinib therapy. Although liquid biopsy is a relevant tool to diagnose T790M presence in NSCLC patients resistant to EGFR-TKI, in case of a low ratio T790M/activating mutation, tissue biopsy should be considered to exclude the presence of SCLC transformation and/or other concomitant resistance mechanisms. Copyright © 2017 Elsevier B.V. All rights reserved.

Phase Ib study of the mitochondrial inhibitor ME-344 plus topotecan in patients with previously treated, locally advanced or metastatic small cell lung, ovarian and cervical cancers.

PubMed

Diamond, Jennifer R; Goff, Barbara; Forster, Martin D; Bendell, Johanna C; Britten, Carolyn D; Gordon, Michael S; Gabra, Hani; Waterhouse, David M; Poole, Mark; Ross Camidge, D; Hamilton, Erika; Moore, Kathleen M

2017-10-01

Background This multicenter, open-label, phase Ib study was designed to assess the safety, pharmacokinetics and preliminary efficacy of ME-344, a mitochondrial inhibitor, administered in combination with the topoisomerase I inhibitor, topotecan, in patients with previously treated, locally advanced or metastatic small cell lung (SCLC), ovarian and cervical cancers. Patients and methods In Part 1, patients received ME-344 10 mg/kg intravenously weekly on days 1, 8, 15 and 22 in combination with topotecan 4 mg/m 2 on days 1, 8, and 15 of a 28 day cycle. Cycles were repeated until disease progression or unacceptable toxicity. Patients were evaluated for dose-limiting toxicity (DLT) in cycle 1 and ME-344 pharmacokinetic samples were obtained. In Part 2, patients with locally advanced or metastatic SCLC and ovarian cancer were enrolled in expansion cohorts treated at the recommended phase II dose (RP2D) determined in Part 1. Results Fourteen patients were enrolled in Part 1 and no DLTs were observed. The RP2D of ME-344 in combination with topotecan was established as 10 mg/kg. In Part 2, 32 patients were enrolled. The most common treatment-emergent all-grade and grade 3/4 toxicities included fatigue (65.2%, 6.5%), neutropenia (56.5%, 43.5%) and thrombocytopenia (50%, 23.9%). One patient with recurrent ovarian cancer experienced a partial response by RECIST 1.1 and 21 patients achieved stable disease as best response. Conclusions The combination of ME-344 10 mg/kg weekly and topotecan 4 mg/m 2 was tolerable, however, the degree of anti-cancer activity does not support further investigation of the combination in unselected patients with SCLC, ovarian and cervical cancers.

Dual occurrence of ALK G1202R solvent front mutation and small cell lung cancer transformation as resistance mechanisms to second generation ALK inhibitors without prior exposure to crizotinib. Pitfall of solely relying on liquid re-biopsy?

PubMed

Ou, Sai-Hong Ignatius; Lee, Thomas K; Young, Lauren; Fernandez-Rocha, Maria Y; Pavlick, Dean; Schrock, Alexa B; Zhu, Viola W; Milliken, Jeffrey; Ali, Siraj M; Gitlitz, Barbara J

2017-04-01

Development of the acquired ALK G1202R solvent front mutation and small cell lung cancer (SCLC) transformation have both been independently reported as resistance mechanisms to ALK inhibitors in ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC) patients but have not been reported in the same patient. Here we report an ALK+ NSCLC patient who had disease progression after ceritinib and then alectinib where an ALK G1202R mutation was detected on circulating tumor (ct) DNA prior to enrollment onto a trial of another next generation ALK inhibitor, lorlatinib. The patient's central nervous system (CNS) metastases responded to lorlatinib together with clearance of ALK G1202R mutation by repeat ctDNA assay. However, the patient developed a new large pericardial effusion. Resected pericardium from the pericardial window revealed SCLC transformation with positive immunostaining for synaptophysin, chromogranin, and ALK (D5F3 antibody). Comprehensive genomic profiling (CGP) of the tumor infiltrating pericardium revealed the retainment of an ALK rearrangement with emergence of an inactivating Rb1 mutation (C706Y) and loss of exons 1-11 in p53 that was not detected in the original tumor tissue at diagnosis. The patient was subsequently treated with carboplatin/etoposide and alectinib, but had rapid clinical deterioration and died. The patient never received crizotinib. This case illustrates that multiple/compound resistance mechanisms to ALK inhibitors can occur and provide supporting information that loss of p53 and Rb1 are important in SCLC transformation. If clinically feasible, tissue-based re-biopsy allowing histological examination and CGP remains the gold standard to assess resistance mechanism(s) and to direct subsequent rational clinical care. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

Real-World EQ5D Health Utility Scores for Patients With Metastatic Lung Cancer by Molecular Alteration and Response to Therapy.

PubMed

Labbé, Catherine; Leung, Yvonne; Silva Lemes, João Gabriel; Stewart, Erin; Brown, Catherine; Cosio, Andrea Perez; Doherty, Mark; O'Kane, Grainne M; Patel, Devalben; Cheng, Nicholas; Liang, Mindy; Gill, Gursharan; Rett, Alexandra; Naik, Hiten; Eng, Lawson; Mittmann, Nicole; Leighl, Natasha B; Bradbury, Penelope A; Shepherd, Frances A; Xu, Wei; Liu, Geoffrey; Howell, Doris

2017-07-01

Economic analyses of upcoming treatments for lung cancer benefit from real-world health utility scores (HUSs) in an era of targeted therapy. A longitudinal cohort study at Princess Margaret Cancer Centre evaluated 1571 EQ5D-3L-derived HUSs in 475 outpatients with metastatic lung cancer across various disease states. Patients with epidermal growth factor receptor (EGFR) (n = 183) and anaplastic lymphoma kinase (ALK) (n = 38) driver alterations were enriched through targeted enrolment; patients with wild-type non-small-cell lung cancer (WT NSCLC) (n = 224) and small-cell lung cancer (SCLC) (n = 30) were sampled randomly. For patients stable on most appropriate treatment, the mean HUSs were 0.81 and 0.82 in patients receiving EGFR and ALK tyrosine kinase inhibitors (TKIs) respectively (with similar HUSs across agents), which were higher than patients with WT NSCLC (0.78; P = .04) and SCLC receiving chemotherapy (0.72; P = .06). In mutation-specific comparisons, disease stability on appropriate therapy resulted in significantly higher mean HUSs (P < .002-.02) than when disease was progressing (mean HUS: EGFR, 0.70; ALK, 0.69; WT NSCLC, 0.66; SCLC, 0.52). When evaluating treatment-related toxicities, significant inverse relationships were observed between HUS and the severity of fatigue and decreased appetite in the EGFR group. There was also a significant inverse relationship between the total number of clinically significant symptoms and HUS, both in patients who were EGFR-mutated and patients with WT NSCLC. In a North American setting, HUSs generated from patients with metastatic lung cancer are higher in treated, stable patients carrying driver mutations. This is partially explainable by treatment toxicity and patient symptom differences. Such differences in scores should be considered in economic analyses. Copyright © 2016 Elsevier Inc. All rights reserved.

Dosimetric rationale and early experience at UFPTI of thoracic proton therapy and chemotherapy in limited-stage small cell lung cancer.

PubMed

Colaco, Rovel J; Huh, Soon; Nichols, Romaine C; Morris, Christopher G; D'Agostino, Harry; Flampouri, Stella; Li, Zuofeng; Pham, Dat C; Bajwa, Abubakr A; Hoppe, Bradford S

2013-04-01

Concurrent chemoradiotherapy (CRT) is the standard of care in patients with limited-stage small cell lung cancer (SCLC). Treatment with conventional x-ray therapy (XRT) is associated with high toxicity rates, particularly acute grade 3+ esophagitis and pneumonitis. We present outcomes for the first known series of limited-stage SCLC patients treated with proton therapy and a dosimetric comparison of lung and esophageal doses with intensity-modulated radiation therapy (IMRT). Six patients were treated: five concurrently and one sequentially. Five patients received 60-66 CGE in 30-34 fractions once daily and one patient received 45 CGE in 30 fractions twice daily. All six patients received prophylactic cranial irradiation. Common Terminology Criteria for Adverse Events, v3.0, was used to grade toxicity. IMRT plans were also generated and compared with proton plans. The median follow-up was 12.0 months. The one-year overall and progression-free survival rates were 83% and 66%, respectively. There were no cases of acute grade 3+ esophagitis or acute grade 2+ pneumonitis, and no other acute grade 3+ non-hematological toxicities were seen. One patient with a history of pulmonary fibrosis and atrial fibrillation developed worsening symptoms four months after treatment requiring oxygen. Three patients died: two of progressive disease and one after a fall; the latter patient was disease-free at 36 months after treatment. Another patient recurred and is alive, while two patients remain disease-free at 12 months of follow-up. Proton therapy proved superior to IMRT across all esophageal and lung dose volume points. In this small series of SCLC patients treated with proton therapy with radical intent, treatment was well tolerated with no cases of acute grade 3+ esophagitis or acute grade 2+ pneumonitis. Dosimetric comparison showed better sparing of lung and esophagus with proton therapy. Proton therapy merits further investigation as a method of reducing the toxicity of CRT.

Prophylactic Cranial Irradiation in Extensive Disease Small-Cell Lung Cancer: Short-Term Health-Related Quality of Life and Patient Reported Symptoms—Results of an International Phase III Randomized Controlled Trial by the EORTC Radiation Oncology and Lung Cancer Groups

PubMed Central

Slotman, Berend J.; Mauer, Murielle E.; Bottomley, Andrew; Faivre-Finn, Corinne; Kramer, Gijs W.P.M.; Rankin, Elaine M.; Snee, Michael; Hatton, Matthew; Postmus, Pieter E.; Collette, Laurence; Senan, Suresh

2009-01-01

Purpose Prophylactic cranial irradiation (PCI) in patients with extensive-disease small-cell lung cancer (ED-SCLC) leads to significantly fewer symptomatic brain metastases and improved survival. Detailed effects of PCI on health-related quality of life (HRQOL) are reported here. Patients and Methods Patients (age, 18 to 75 years; WHO ≤ 2) with ED-SCLC, and any response to chemotherapy, were randomly assigned to either observation or PCI. Health-related quality of life (HRQOL) and patient-reported symptoms were secondary end points. The European Organisation for the Research and Treatment of Cancer core HRQOL tool (Quality of Life Questionnaire C30) and brain module (Quality of Life Questionnaire Brain Cancer Module) were used to collect self-reported patient data. Six HRQOL scales were selected as primary HRQOL end points: global health status; hair loss; fatigue; and role, cognitive and emotional functioning. Assessments were performed at random assignment, 6 weeks, 3 months, and then 3-monthly up to 1 year and 6-monthly thereafter. Results Compliance with the HRQOL assessment was 93.7% at baseline and dropped to 60% at 6 weeks. Short-term results up to 3 months showed that there was a negative impact of PCI on selected HRQOL scales. The largest mean difference between the two arms was observed for fatigue and hair loss. The impact of PCI on global health status as well as on functioning scores was more limited. For global health status, the observed mean difference was eight points on a scale 0 to 100 at 6 weeks (P = .018) and 3 months (P = .055). Conclusion PCI should be offered to all responding ED SCLC patients. Patients should be informed of the potential adverse effects from PCI. Clinicians should be alert to these; monitor their patients; and offer appropriate support, clinical, and psychosocial care. PMID:19047288

Phase II study of maintenance pembrolizumab in patients with extensive-stage small cell lung cancer (SCLC).

PubMed

Gadgeel, Shirish M; Pennell, Nathan A; Fidler, Mary Jo; Halmos, Balazs; Bonomi, Philip; Stevenson, James; Schneider, Bryan; Sukari, Ammar; Ventimiglia, Jaclyn; Chen, Wei; Galasso, Cathy; Wozniak, Antoinette; Boerner, Julie; Kalemkerian, Gregory P

2018-05-15

To assess the efficacy of maintenance pembrolizumab in extensive-stage small cell lung cancer (SCLC) patients, after treatment with platinum/etoposide. Extensive-stage SCLC patients with a response or stable disease following induction chemotherapy were eligible. Pembrolizumab at a dose of 200 mg IV every 3 weeks was initiated within 8 weeks of the last cycle of chemotherapy. The primary endpoint of the study was progression-free survival (PFS) from study registration, with overall survival (OS) as a key secondary endpoint. Available tumor tissue was assessed for PD-L1 expression both in the tumor cells and surrounding stroma. Blood for circulating tumor cells was collected before the first, second and third cycles of pembrolizumab. Of the 45 patients enrolled, 56% were male and 22% had treated brain metastases. The median PFS was 1.4 months (95%CI- 1.3-2.8), with 1-year PFS of 13%. The median OS was 9.6 months (95%CI- 7.0-12), with 1-year OS of 37%. Of the 30 tumors that could be assessed, 3 had PD-L1 expression (≥ 1%) in the tumor cells. Twenty tumors could be assessed for PD-L1 expression in the stroma. The median PFS in the 8 patients with tumors positive for stromal interface PD-L1 expression was 6.5 months (95% CI-1.1-12.8) compared to 1.3 months (95%CI- 0.6-2.5) in 12 patients with tumors negative for this marker. No unexpected toxicities were observed. Maintenance pembrolizumab did not appear to improve median PFS compared to historical data. However, 1-year PFS of 13% and OS of 37% suggest that a subset of patients did benefit from pembrolizumab. Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

A phase I study of amrubicin and fixed dose of irinotecan (CPT-11) in relapsed small cell lung cancer: Japan multinational trial organization LC0303.

PubMed

Kawahara, Masaaki; Kubo, Akihito; Komuta, Kiyoshi; Fujita, Yuka; Sasaki, Yoshiaki; Fukushima, Masanori; Daimon, Takashi; Furuse, Kiyoyuki; Mishima, Michiaki; Mio, Tadashi

2012-12-01

To determine the maximum tolerated dose of amrubicin (AMR) with a fixed dose of irinotecan (CPT-11). Patients having pathologically proven small cell lung cancer (SCLC) relapsed after one or two chemotherapies, and Eastern Cooperative Oncology Group performance status of 0 to 2 were eligible for the study. CPT-11 was delivered as 50 mg/m2 on days 1 and 8, every 21 days. AMR was delivered on day 1. Doses of AMR were level 1: 80 mg/m2, level 2: 90 mg/m2, and level 3: 100 mg/m2. Dose elevation was determined using the modified continuous reassessment method. Tolerability was assessed after the first cycle. Another two cycles were conducted when disease progression or unacceptable toxicities were not observed. Eighteen patients (mean age: 66.3 years) were enrolled. A total of 40 courses were conducted. Grade 3/4 toxicities of the first cycle were leukocytopenia: 11 (61%, grade 3/4: 8/3); neutropenia: 15 (83%, grade 3/4: 6/9); and thrombocytopenia: three (17%, grade 3/4: 2/1). Other grade 3 toxicities observed were febrile neutropenia, one; infection, three; diarrhea, one; and dyspnea, one. Dose-limiting toxicity was observed in two of six patients at level 2 (neutropenia and febrile neutropenia) and in one of six at level 3 (thrombocytopenia and infection). The maximum tolerated dose was level 3, and so, the recommended dose for phase II trials was judged to be 90 mg/m2. Objective response was obtained in four of eight patients who were able to evaluate responses. Median survival time was 13 months, with 68% at 1-year survival rate. This combination was well tolerated and showed encouraging activities in SCLC. Randomized phase II trials are being planned in chemonaive SCLC.

Identification and Characterization of Cells with Cancer Stem Cell Properties in Human Primary Lung Cancer Cell Lines

PubMed Central

Suo, Zhenhe; Munthe, Else; Solberg, Steinar; Ma, Liwei; Wang, Mengyu; Westerdaal, Nomdo Anton Christiaan; Kvalheim, Gunnar; Gaudernack, Gustav

2013-01-01

Lung cancer (LC) with its different subtypes is generally known as a therapy resistant cancer with the highest morbidity rate worldwide. Therapy resistance of a tumor is thought to be related to cancer stem cells (CSCs) within the tumors. There have been indications that the lung cancer is propagated and maintained by a small population of CSCs. To study this question we established a panel of 15 primary lung cancer cell lines (PLCCLs) from 20 fresh primary tumors using a robust serum-free culture system. We subsequently focused on identification of lung CSCs by studying these cell lines derived from 4 representative lung cancer subtypes such as small cell lung cancer (SCLC), large cell carcinoma (LCC), squamous cell carcinoma (SCC) and adenocarcinoma (AC). We identified a small population of cells strongly positive for CD44 (CD44high) and a main population which was either weakly positive or negative for CD44 (CD44low/−). Co-expression of CD90 further narrowed down the putative stem cell population in PLCCLs from SCLC and LCC as spheroid-forming cells were mainly found within the CD44highCD90+ sub-population. Moreover, these CD44highCD90+ cells revealed mesenchymal morphology, increased expression of mesenchymal markers N-Cadherin and Vimentin, increased mRNA levels of the embryonic stem cell related genes Nanog and Oct4 and increased resistance to irradiation compared to other sub-populations studied, suggesting the CD44highCD90+ population a good candidate for the lung CSCs. Both CD44highCD90+ and CD44highCD90− cells in the PLCCL derived from SCC formed spheroids, whereas the CD44low/− cells were lacking this potential. These results indicate that CD44highCD90+ sub-population may represent CSCs in SCLC and LCC, whereas in SCC lung cancer subtype, CSC potentials were found within the CD44high sub-population. PMID:23469181

Common TDP1 Polymorphisms in Relation to Survival among Small Cell Lung Cancer Patients: A Multicenter Study from the International Lung Cancer Consortium.

PubMed

Lohavanichbutr, Pawadee; Sakoda, Lori C; Amos, Christopher I; Arnold, Susanne M; Christiani, David C; Davies, Michael P A; Field, John K; Haura, Eric B; Hung, Rayjean J; Kohno, Takashi; Landi, Maria Teresa; Liu, Geoffrey; Liu, Yi; Marcus, Michael W; O'Kane, Grainne M; Schabath, Matthew B; Shiraishi, Kouya; Slone, Stacey A; Tardón, Adonina; Yang, Ping; Yoshida, Kazushi; Zhang, Ruyang; Zong, Xuchen; Goodman, Gary E; Weiss, Noel S; Chen, Chu

2017-12-15

Purpose: DNA topoisomerase inhibitors are commonly used for treating small-cell lung cancer (SCLC). Tyrosyl-DNA phosphodiesterase (TDP1) repairs DNA damage caused by this class of drugs and may therefore influence treatment outcome. In this study, we investigated whether common TDP1 single-nucleotide polymorphisms (SNP) are associated with overall survival among SCLC patients. Experimental Design: Two TDP1 SNPs (rs942190 and rs2401863) were analyzed in 890 patients from 10 studies in the International Lung Cancer Consortium (ILCCO). The Kaplan-Meier method and Cox regression analyses were used to evaluate genotype associations with overall mortality at 36 months postdiagnosis, adjusting for age, sex, race, and tumor stage. Results: Patients homozygous for the minor allele (GG) of rs942190 had poorer survival compared with those carrying AA alleles, with a HR of 1.36 [95% confidence interval (CI): 1.08-1.72, P = 0.01), but no association with survival was observed for patients carrying the AG genotype (HR = 1.04, 95% CI, 0.84-1.29, P = 0.72). For rs2401863, patients homozygous for the minor allele (CC) tended to have better survival than patients carrying AA alleles (HR = 0.79; 95% CI, 0.61-1.02, P = 0.07). Results from the Genotype Tissue Expression (GTEx) Project, the Encyclopedia of DNA Elements (ENCODE), and the ePOSSUM web application support the potential function of rs942190. Conclusions: We found the rs942190 GG genotype to be associated with relatively poor survival among SCLC patients. Further investigation is needed to confirm the result and to determine whether this genotype may be a predictive marker for treatment efficacy of DNA topoisomerase inhibitors. Clin Cancer Res; 23(24); 7550-7. ©2017 AACR . ©2017 American Association for Cancer Research.

Phase 1/2 Study of the CD56-Targeting Antibody-Drug Conjugate Lorvotuzumab Mertansine (IMGN901) in Combination With Carboplatin/Etoposide in Small-Cell Lung Cancer Patients With Extensive-Stage Disease.

PubMed

Socinski, Mark A; Kaye, Frederic J; Spigel, David R; Kudrik, Fred J; Ponce, Santiago; Ellis, Peter M; Majem, Margarita; Lorigan, Paul; Gandhi, Leena; Gutierrez, Martin E; Nepert, Dale; Corral, Jesus; Ares, Luis Paz

2017-01-01

This trial assessed the safety and efficacy of LM in combination with carboplatin/etoposide therapy compared to carboplatin/etoposide treatment alone in patients with previously untreated extensive-disease small-cell lung cancer (ED-SCLC). A run-in phase 1 stage was used to determine the recommended phase 2 dose and characterize the dose-limiting toxicities of LM in combination with carboplatin/etoposide followed by LM alone in patients with CD56-positive solid tumors. In phase 2, chemotherapy-naive ED-SCLC patients were randomized 2:1 to carboplatin AUC (area under the plasma concentration vs. time curve) of 5 day 1 + etoposide 100 mg/m 2 days 1 to 3 plus LM (arm 1) or alone (arm 2). In the phase 1 study (n = 33), a dose of LM at 112 mg/m 2 with carboplatin/etoposide was identified as the recommended phase 2 dose. However, because of an increased incidence of peripheral neuropathy events during early phase 2, this dose was reduced to 90 mg/m 2 . In phase 2, a total of 94 and 47 evaluable patients were assigned to arms 1 and 2, respectively. No difference in median progression-free survival was observed between arms 1 and 2 (6.2 vs. 6.7 months). The most common treatment-emergent adverse event leading to discontinuation was peripheral neuropathy (29%). A total of 21 patients had a treatment-emergent adverse event leading to death (18 in arm 1 and 3 in arm 2); for 10 individuals, this was an infection (pneumonia or sepsis) deemed to be related to the study drug. The combination of LM plus carboplatin/etoposide did not improve efficacy over standard carboplatin/etoposide doublet therapy in ED-SCLC patients and showed increased toxicity, including a higher incidence of serious infections with fatal outcomes. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Immunotoxins recognising a new epitope on the neural cell adhesion molecule have potent cytotoxic effects against small cell lung cancer.

PubMed

Zangemeister-Wittke, U; Collinson, A R; Frösch, B; Waibel, R; Schenker, T; Stahel, R A

1994-01-01

The present study describes a comparison of two potent immunotoxins which utilise an identical targeting component, a monoclonal antibody (SEN7) specific for small cell lung cancer (SCLC), conjugated to two different effector components, blocked ricin (bR) and Pseudomonas exotoxin A (PE). SEN7 recognises a novel epitope on the neural cell adhesion molecule (NCAM) which is highly associated with SCLC. The immunotoxins SEN7-PE and SEN7-bR were selectively and potently active against a number of SCLC cell lines, of both classic and variant morphologies, inhibiting the incorporation of [3H]leucine with IC50 values ranging between 22 pM and 85 pM and between 7 pM and 62 pM for SEN7-PE and SEN7-bR respectively. Intoxication by both immunotoxins proceeded rapidly following short 2 h lag phases; the initial rates of protein synthesis inhibition occurred with t50 values of 6.5 h for SEN7-PE and 5.5 h for SEN7-bR. Monensin drastically enhanced the cytotoxic activity of the weakly active SEN7-ricin A-chain by 2,100-fold and of SEN7-bR by 80-fold but had no effect on SEN7-PE. In limiting dilution assays, four and more than 4.5 logs of clonogenic SW2 tumour cells were selectively eliminated from the cultures during continuous exposure to the immunotoxins SEN7-PE and SEN7-bR respectively, while antigen-negative cells required up to 1,000-fold more drug for a similar cell kill. SW2 cells surviving SEN7-bR treatment in the cultures did not express NCAM and consequently were not selectively killed by SEN7 immunotoxins. SW2 cells surviving continuous exposure to SEN7-PE showed no alteration in NCAM expression but were more resistant to intoxication mediated by PE. These cells were still sensitive to SEN7-bR.

Phase 2 Study of Accelerated Hypofractionated Thoracic Radiation Therapy and Concurrent Chemotherapy in Patients With Limited-Stage Small-Cell Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xia, Bing; Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou; Hong, Ling-Zhi

Purpose: To prospectively investigate the efficacy and toxicity of accelerated hypofractionated thoracic radiation therapy (HypoTRT) combined with concurrent chemotherapy in the treatment of limited-stage small-cell lung cancer (LS-SCLC), with the hypothesis that both high radiation dose and short radiation time are important in this setting. Methods and Materials: Patients with previously untreated LS-SCLC, Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate organ function were eligible. HypoTRT of 55 Gy at 2.5 Gy per fraction over 30 days was given on the first day of the second or third cycle of chemotherapy. An etoposide/cisplatin regimen was given to 4 tomore » 6 cycles. Patients who had a good response to initial treatment were offered prophylactic cranial irradiation. The primary endpoint was the 2-year progression-free survival rate. Results: Fifty-nine patients were enrolled from July 2007 through February 2012 (median age, 58 years; 86% male). The 2-year progression-free survival rate was 49.0% (95% confidence interval [CI] 35.3%-62.7%). Median survival time was 28.5 months (95% CI 9.0-48.0 months); the 2-year overall survival rate was 58.2% (95% CI 44.5%-71.9%). The 2-year local control rate was 76.4% (95% CI 63.7%-89.1%). The severe hematologic toxicities (grade 3 or 4) were leukopenia (32%), neutropenia (25%), and thrombocytopenia (15%). Acute esophagitis and pneumonitis of grade ≥3 occurred in 25% and 10% of the patients, respectively. Thirty-eight patients (64%) received prophylactic cranial irradiation. Conclusion: Our study showed that HypoTRT of 55 Gy at 2.5 Gy per fraction daily concurrently with etoposide/cisplatin chemotherapy has favorable survival and acceptable toxicity. This radiation schedule deserves further investigation in LS-SCLC.« less

Genetic variation predicting cisplatin cytotoxicity associated with overall survival in lung cancer patients receiving platinum-based chemotherapy †, ‡

PubMed Central

Tan, Xiang-Lin; Moyer, Ann M.; Fridley, Brooke L.; Schaid, Daniel J.; Niu, Nifang; Batzler, Anthony J.; Jenkins, Gregory D.; Abo, Ryan P.; Li, Liang; Cunningham, Julie M.; Sun, Zhifu; Yang, Ping; Wang, Liewei

2011-01-01

Purpose Inherited variability in the prognosis of lung cancer patients treated with platinum-based chemotherapy has been widely investigated. However, the overall contribution of genetic variation to platinum response is not well established. To identify novel candidate SNPs/genes, we performed a genome-wide association study (GWAS) for cisplatin cytotoxicity using lymphoblastoid cell lines (LCLs), followed by an association study of selected SNPs from the GWAS with overall survival (OS) in lung cancer patients. Experimental Design GWAS for cisplatin were performed with 283 ethnically diverse LCLs. 168 top SNPs were genotyped in 222 small cell and 961 non-small cell lung cancer (SCLC, NSCLC) patients treated with platinum-based therapy. Association of the SNPs with OS was determined using the Cox regression model. Selected candidate genes were functionally validated by siRNA knockdown in human lung cancer cells. Results Among 157 successfully genotyped SNPs, 9 and 10 SNPs were top SNPs associated with OS for patients with NSCLC and SCLC, respectively, although they were not significant after adjusting for multiple testing. Fifteen genes, including 7 located within 200 kb up or downstream of the four top SNPs and 8 genes for which expression was correlated with three SNPs in LCLs were selected for siRNA screening. Knockdown of DAPK3 and METTL6, for which expression levels were correlated with the rs11169748 and rs2440915 SNPs, significantly decreased cisplatin sensitivity in lung cancer cells. Conclusions This series of clinical and complementary laboratory-based functional studies identified several candidate genes/SNPs that might help predict treatment outcomes for platinum-based therapy of lung cancer. PMID:21775533

Novel donor-acceptor polymer containing 4,7-bis(thiophen-2-yl)benzo[c][1,2,5]thiadiazole for polymer solar cells with power conversion efficiency of 6.21%.

PubMed

Han, Liangliang; Bao, Xichang; Hu, Tong; Du, Zhengkun; Chen, Weichao; Zhu, Dangqiang; Liu, Qian; Sun, Mingliang; Yang, Renqiang

2014-06-01

In order to improve the solution processability of 4,7-bis(thiophen-2-yl)benzo[c][1,2,5]thiadiazole (DTBT)-based polymers, novel donor-acceptor polymer PTOBDTDTBT containing DTBT and benzo[1,2-b:4,5-b']dithiophene (BDT) with conjugated side chain is designed and synthesized with narrow band gap 1.67 eV and low lying HOMO energy level -5.4 eV. The blend film of PTOBDTDTBT and PC71 BM exhibits uniform and smooth film with root-mean-square (RMS) surface roughness 1.15 nm because of the excellent solubility of PTOBDTDTBT when six octyloxy side chains are introduced. The hole mobility of the blend film is measured to be 4.4 × 10(-5) cm(2) V(-1) s(-1) by the space-charge-limited current (SCLC) model. The optimized polymer solar cells (PSCs) based on PTOBDTDTBT/PC71 BM exhibits an improved PCE of 6.21% with Voc = 0.80 V, Jsc = 11.94 mA cm(-2) and FF = 65.10%, one of the highest PCE in DTBT containing polymers. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The Birth of the Citizenship Schools: Entwining the Struggles for Literacy and Freedom

ERIC Educational Resources Information Center

Levine, David P.

2004-01-01

This essay focuses on the formative years of the Citizenship Training Program as a Highlander project in the Charleston area. Informally known as Citizenship Schools, this adult education program began in 1958 under the sponsorship of Tennessee's Highlander Folk School, which handed over to the Southern Christian Leadership Conference (SCLC) in…

Multistate storage nonvolatile memory device based on ferroelectricity and resistive switching effects of SrBi2Ta2O9 films

NASA Astrophysics Data System (ADS)

Song, Zhiwei; Li, Gang; Xiong, Ying; Cheng, Chuanpin; Zhang, Wanli; Tang, Minghua; Li, Zheng; He, Jiangheng

2018-05-01

A memory device with a Pt/SrBi2Ta2O9(SBT)/Pt(111) structure was shown to have excellent combined ferroelectricity and resistive switching properties, leading to higher multistate storage memory capacity in contrast to ferroelectric memory devices. In this device, SBT polycrystalline thin films with significant (115) orientation were fabricated on Pt(111)/Ti/SiO2/Si(100) substrates using CVD (chemical vapor deposition) method. Measurement results of the electric properties exhibit reproducible and reliable ferroelectricity switching behavior and bipolar resistive switching effects (BRS) without an electroforming process. The ON/OFF ratio of the resistive switching was found to be about 103. Switching mechanisms for the low resistance state (LRS) and high resistance state (HRS) currents are likely attributed to the Ohmic and space charge-limited current (SCLC) behavior, respectively. Moreover, the ferroelectricity and resistive switching effects were found to be mutually independent, and the four logic states were obtained by controlling the periodic sweeping voltage. This work holds great promise for nonvolatile multistate memory devices with high capacity and low cost.

Prophylactic cranial irradiation: recent outcomes and innovations.

PubMed

Snider, James W; Gondi, Vinai; Brown, Paul D; Tome, Wolfgang; Mehta, Minesh P

2014-05-01

Brain metastases represent a frequent problem in several malignancies. They can shorten survival while causing significant morbidity and impairment in the patient's quality of life. Prophylactic cranial irradiation (PCI) has become an integral part of the standard of care in small cell lung cancer (SCLC), yet its role in other malignancies remains the subject of significant discussion. Its role has been extensively investigated in non-small cell lung cancer and less so for breast cancer and other malignancies. Improvements in medical care as well as in whole brain radiotherapy (WBRT) techniques may improve the risk-benefit ratio of this therapy so as to expand its role in cancer care. The use of memantine in WBRT patients as well as the use of hippocampal avoidance techniques are of particular interest in this effort. Herein, we review the history of PCI, its current use, and areas of investigation in the application of PCI.

Bipolar resistive switching in graphene oxide based metal insulator metal structure for non-volatile memory applications

NASA Astrophysics Data System (ADS)

Singh, Rakesh; Kumar, Ravi; Kumar, Anil; Kashyap, Rajesh; Kumar, Mukesh; Kumar, Dinesh

2018-05-01

Graphene oxide based devices have attracted much attention recently because of their possible application in next generation electronic devices. In this study, bipolar resistive switching characteristics of graphene oxide based metal insulator metal structure were investigated for nonvolatile memories. The graphene oxide was prepared by the conventional Hummer's method and deposited on ITO coated glass by spin-coating technique. The dominant mechanism of resistive switching is the formation and rupture of the conductive filament inside the graphene oxide. The conduction mechanism for low and high resistance states are dominated by two mechanism the ohmic conduction and space charge limited current (SCLC) mechanism, respectively. Atomic Force Microscopy, X-ray diffraction, Cyclic-Voltammetry were conducted to observe the morphology, structure and behavior of the material. The fabricated device with Al/GO/ITO structure exhibited reliable bipolar resistive switching with set & reset voltage of -2.3 V and 3V respectively.

Processing/structure/property Relationships of Barium Strontium Titanate Thin Films for Dynamic Random Access Memory Application.

NASA Astrophysics Data System (ADS)

Peng, Cheng-Jien

The purpose of this study is to see the application feasibility of barium strontium titanate (BST) thin films on ultra large scale integration (ULSI) dynamic random access memory (DRAM) capacitors through the understanding of the relationships among processing, structure and electrical properties. Thin films of BST were deposited by multi-ion -beam reactive sputtering (MIBERS) technique and metallo -organic decomposition (MOD) method. The processing parameters such as Ba/Sr ratio, substrate temperature, annealing temperature and time, film thickness and doping concentration were correlated with the structure and electric properties of the films. Some effects of secondary low-energy oxygen ion bombardment were also examined. Microstructures of BST thin films could be classified into two types: (a) Type I structures, with multi-grains through the film thickness, for amorphous as-grown films after high temperature annealing, and (b) columnar structure (Type II) which remained even after high temperature annealing, for well-crystallized films deposited at high substrate temperatures. Type I films showed Curie-von Schweidler response, while Type II films showed Debted type behavior. Type I behavior may be attributed to the presence of a high density of disordered grain boundaries. Two types of current -voltage characteristics could be seen in non-bombarded films depending on the chemistry of the films (doped or undoped) and substrate temperature during deposition. Only the MIBERS films doped with high donor concentration and deposited at high substrate temperature showed space-charge -limited conduction (SCLC) with discrete shallow traps embedded in trap-distributed background at high electric field. All other non-bombarded films, including MOD films, showed trap-distributed SCLC behavior with a slope of {~}7.5-10 due to the presence of grain boundaries through film thickness or traps induced by unavoidable acceptor impurities in the films. Donor-doping could significantly improve the time -dependent dielectric breakdown (TDDB) behavior of BST thin films, mostly likely due to the lower oxygen vacancy concentration resulted from donor-doping.

Mutated cancer autoantigen implicated cause of paraneoplastic myasthenia gravis.

PubMed

Zekeridou, Anastasia; Griesmann, Guy E; Lennon, Vanda A

2018-05-09

Anti-tumor immune responses are postulated to initiate paraneoplastic neurological disorders when proteins normally restricted to neural cells are expressed as oncoproteins. Mutated oncopeptides could bypass self-tolerant T-cells to activate cytotoxic effector T-lymphocytes and requisite helper T-lymphocytes to stimulate autoantibody production by B-lymphocytes. We investigated muscle-type nicotinic acetylcholine receptor (AChR) antigen expression at transcriptional and protein levels in a small-cell lung cancer line (SCLC) established from a patient with AChR-IgG-positive myasthenia gravis. I We identified mRNA transcripts encoding the two AChR α1-subunit isoforms, and seven alternative-splicing products, three yielding premature stop codons. Despite detecting native muscle-type AChR pentamers in the tumor, we did not identify mutant α1-peptides. However, we found α1-subunit-derived peptides bound to tumor MHC1-protein. In a control SCLC from an ANNA-1(anti-Hu)-IgG-positive patient, we identified MHC1-complexed Hu protein-derived peptides, but not AChR peptides. Our findings support onconeural protein products as pertinent immunogens initiating paraneoplastic neurological autoimmunity. This article is protected by copyright. All rights reserved. © 2018 Wiley Periodicals, Inc.

Patient selection for whole brain radiotherapy (WBRT) in a large lung cancer cohort: Impact of a new Dutch guideline on brain metastases.

PubMed

Hendriks, Lizza E L; Troost, Esther G C; Steward, Allan; Bootsma, Gerben P; De Jaeger, Katrien; van den Borne, Ben E E M; Dingemans, Anne-Marie C

2014-07-01

Median survival after diagnosis of brain metastases is, depending on the Recursive Partitioning Analysis (RPA) classes, 7.1 (class I) to 2.3 months (class III). In 2011 the Dutch guideline on brain metastases was revised, advising to withhold whole brain radiotherapy (WBRT) in RPA class III. In this large retrospective study, we evaluated the guideline's use in daily practice. Data of 428 lung cancer patients undergoing WBRT for brain metastases (2004-2012) referred from three Dutch hospitals were retrospectively analyzed. Details on Karnofsky performance score (KPS), age, control of primary tumor, extracranial metastases, histology, and survival after diagnosis of brain metastases were collected. RPA class was determined using the first four items. In total 327 patients had non-small cell lung cancer (NSCLC) and 101 small cell lung cancer (SCLC). For NSCLC, 6.1%, 71.9%, and 16.2% were classified as RPA I, II, and III, respectively, and 5.8% could not be classified. For SCLC this was 8.9%, 66.3%, 14.9%, and 9.9%, respectively. Before the revised guideline was implemented, 11.3-21.3% of WBRT patients were annually classified as RPA III. In the year thereafter, this was 13.0% (p = 0.646). Median survival (95% CI) for NSCLC RPA class I, II, and III was 11.4 (9.9-12.9), 4.0 (3.4-4.7), and 1.7 (1.3-2.0) months, respectively. For SCLC this was 7.9 (4.1-11.7), 4.7 (3.3-6.1), and 1.7 (1.5-1.8) months. Although it is advised to withhold WBRT in RPA class III patients, in daily practice 11.3-21.3% of WBRT-treated patients were classified as RPA III. The new guideline did not result in a decrease. Reasons for referral of RPA III patients despite a low KPS were not found. Despite WBRT, survival of RPA III patients remains poor and this poor outcome should be stressed in practice guidelines. Therefore, better awareness amongst physicians would prevent some patients from being treated unnecessarily.

Reduction of chemotherapy-induced febrile leucopenia by prophylactic use of ciprofloxacin and roxithromycin in small-cell lung cancer patients: an EORTC double-blind placebo-controlled phase III study.

PubMed

Tjan-Heijnen, V C; Postmus, P E; Ardizzoni, A; Manegold, C H; Burghouts, J; van Meerbeeck, J; Gans, S; Mollers, M; Buchholz, E; Biesma, B; Legrand, C; Debruyne, C; Giaccone, G

2001-10-01

CDE (cyclophosphamide, doxorubicin, etoposide) is one of the standard chemotherapy regimens in the treatment of small-cell lung cancer (SCLC), with myelosuppression as dose-limiting toxicity. In this trial the impact of prophylactic antibiotics on incidence of febrile leucopenia (FL) during chemotherapy for SCLC was evaluated. Patients with chemo-naïve SCLC were randomized to standard-dose CDE (C 1,000 mg/m2 day 1, D 45 mg/m2 day 1, E 100 mg/m2 days 1-3. i.v., q 3 weeks, x5) or to intensified CDE chemotherapy (125% dose, q 2 weeks, x4, with filgrastim 5 microg/kg/day days 4-13) to assess the impact on survival (n = 240 patients). Patients were also randomized to prophylactic antibiotics (ciprofloxacin 750 mg plus roxithromycin 150 mg, bid. days 4-13) or to placebo in a 2 x 2 factorial design (first 163 patients). This manuscript focuses on the antibiotics question. The incidence of FL during the first cycle was 25% of patients in the placebo and 11% in the antibiotics arm (P = 0.010; 1-sided), with an overall incidence through all cycles of 43% vs. 24% respectively (P = 0.007; 1-sided). There were less Gram-positive (12 vs. 4), Gram-negative (20 vs. 5) and clinically documented (38 vs. 15) infections in the antibiotics arm. The use of therapeutic antibiotics was reduced (P = 0.013; 1-sided), with less hospitalizations due to FL (31 vs. 17 patients, P = 0.013: 1-sided). However, the overall number of days of hospitalization was not reduced (P = 0.05; 1-sided). The number of infectious deaths was nil in the antibiotics vs. five (6%) in the placebo arm (P = 0.022; 2-sided). Prophylactic ciprofloxacin plus roxithromycin during CDE chemotherapy reduced the incidence of FL, the number of infections, the use of therapeutic antibiotics and hospitalizations due to FL by approximately 50%, with reduced number of infectious deaths. For patients with similar risk for FL, the prophylactic use of antibiotics should be considered.

Preparation and characterization of BiFeO3/La0.7Sr0.3MnO3 heterostructure grown on SrTiO3 substrate

NASA Astrophysics Data System (ADS)

Zhao, Chenwei; Zhou, Chaochao; Chen, Changle

2017-09-01

In this paper, BiFeO3/La0.7Sr0.3MnO3 heterostructure is fabricated on the SrTiO (100) substrate using the pulsed laser deposition method (PLD). Magnetization hystersis loops of the BiFeO3/La0.7Sr0.3MnO3 heterostructure are obtained at 300 K and 80 K. The heterostructure exhibits evident ferromagnetic characteristic at both room temperature and 80 K. At 80 K, magnetization of the heterostructure is stronger than room temperature magnetic measure. The temperature dependence of resistance of the heterostructure with different currents is also studied. With different currents, there appears to be a peak resistance about 180 K. When I is 50 uA, ΔR is 68.4%. And when I is 100 uA, ΔR is 79.3%. The BiFeO3/La0.7Sr0.3MnO3 heterostructure exhibits a positive colossal magnetoresistance (MR) effect over a temperature range of 80-300 K. In our heterostructure, maximum magnetic resistance appears in 210 K, and MR = 44.34%. Mechanism analysis of the leakage current at room temperature shows that the leakage current is the interface-limited Schottky emission, but not dominated by the Poole-Frenkel emission or SCLC.

Anisotropic charge transport in large single crystals of π-conjugated organic molecules.

PubMed

Hourani, Wael; Rahimi, Khosrow; Botiz, Ioan; Koch, Felix Peter Vinzenz; Reiter, Günter; Lienerth, Peter; Heiser, Thomas; Bubendorff, Jean-Luc; Simon, Laurent

2014-05-07

The electronic properties of organic semiconductors depend strongly on the nature of the molecules, their conjugation and conformation, their mutual distance and the orientation between adjacent molecules. Variations of intramolecular distances and conformation disturb the conjugation and perturb the delocalization of charges. As a result, the mobility considerably decreases compared to that of a covalently well-organized crystal. Here, we present electrical characterization of large single crystals made of the regioregular octamer of 3-hexyl-thiophene (3HT)8 using a conductive-atomic force microscope (C-AFM) in air. We find a large anisotropy in the conduction with charge mobility values depending on the crystallographic orientation of the single crystal. The smaller conduction is in the direction of π-π stacking (along the long axis of the single crystal) with a mobility value in the order of 10(-3) cm(2) V(-1) s(-1), and the larger one is along the molecular axis (in the direction normal to the single crystal surface) with a mobility value in the order of 0.5 cm(2) V(-1) s(-1). The measured current-voltage (I-V) curves showed that along the molecular axis, the current followed an exponential dependence corresponding to an injection mode. In the π-π stacking direction, the current exhibits a space charge limited current (SCLC) behavior, which allows us to estimate the charge carrier mobility.

Optical and electrical properties of P3HT:graphene composite based devices

NASA Astrophysics Data System (ADS)

Yadav, Anjali; Verma, Ajay Singh; Gupta, Saral Kumar; Negi, Chandra Mohan Singh

2018-04-01

The polymer-carbon derivate composites are well known for their uses and performances in the photovoltaic and optoelectronic industries. In this paper, we synthesis P3HT:graphene composites and discuss their optical and electrical properties. The composites have been prepared by using spin-coating technique onto the glass substrates. It has been found that the incorporation of graphene reduces absorption intensity. However, absorption peak remain unchanged with addition of graphene. The surface morphology studies display homogeneous distribution of graphene with P3HT. Raman studies suggest that chemical structure was not affected by graphene doping. Devices having the structure of glass/ITO/P3HT/ Al and glass ITO/P3HT:graphene/Al were then fabricated. I-V behavior of the fabricated devices was found to be similar to the Schottky diode. ITO/P3HT:graphene/Al structure shows tremendous increase in current values as compared to the ITO/P3HT/Al. Furthermore, charge transport mechanism were studied by analyzing the double logarithmic J-V characteristics curve, which indicates that the current at low voltage follows Ohmic behavior, trap-charge limited conduction (TCLC) mechanism at an intermediate voltage and space charge limited conduction (SCLC) mechanism at sufficiently high voltages.

Histologic transformation from adenocarcinoma to both small cell lung cancer and squamous cell carcinoma after treatment with gefitinib: A case report.

PubMed

Yao, Yufeng; Zhu, Zhouyu; Wu, Yimin; Chai, Ying

2018-05-01

In the past decade, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) treatment had been an important therapy for treating advanced EGFR-mutated lung cancer patients. However, a large number of these patients with EGFR-TKIs treatment always acquired resistance to these drugs in one year. The histologic transformation is an important resistance mechanism. Here we reported a 41-year-old man with EGFR-mutated lung adenocarcinoma and he showed histologic transformation to both small-cell lung cancer (SCLC) and squamous cell carcinoma (SCC) after treatment of gefitinib. A case of EGFR-mutated lung cancer. Medical thoracoscopy examination was performed and the patient was diagnosed as a EGFR-mutated lung adenocarcinoma. Then gefitinib was administered orally at a dose of 250 mg daily. The patient received treatment with chemotherapy (etoposide 0.1 g day 2-5 +  cis-platinum 30 mg day 2-4) after acquiring resistance to gefitinib. The patient died in April 2017 that survived for 32 months from lung cancer was found for the first time. To the best of our knowledge, it is the first case of EGFR-mutated lung adenocarcinoma transforming to both SCLC and SCC which was treated with and responded to gefitinib.

A global view of regulatory networks in lung cancer: An approach to understand homogeneity and heterogeneity.

PubMed

Lu, Jiapei; Wang, William; Xu, Menglin; Li, Yuping; Chen, Chengshui; Wang, Xiangdong

2017-02-01

A number of new biotechnologies are used to identify potential biomarkers for the early detection of lung cancer, enabling a personalized therapy to be developed in response. The combinatorial cross-regulation of hundreds of biological function-specific transcription factors (TFs) is defined as the understanding of regulatory networks of molecules within the cell. Here we integrated global databases with 537 patients with lung adenocarcinoma (ADC), 140 with lung squamous carcinoma (SCC), 9 with lung large-cell carcinoma (LCC), 56 with small-cell lung cancer (SCLC), and 590 without cancer with the understanding of TF functions. The present review aims at the homogeneity or heterogeneity of gene expression profiles among subtypes of lung cancer. About 5, 136, 52, or 16 up-regulated or 19, 24, 122, or 97down-regulated type-special TF genes were identified in ADC, SCC, LCC or SCLC, respectively. DNA-binding and transcription regulator activity associated genes play a dominant role in the differentiation of subtypes in lung cancer. Subtype-specific TF gene regulatory networks with elements should be an alternative for diagnostic and therapeutic targets for early identification of lung cancer and can provide insightful clues to etiology and pathogenesis. Copyright © 2016 Elsevier Ltd. All rights reserved.

Semiconducting molecular crystals: Bulk in-gap states modified by structural and chemical defects

NASA Astrophysics Data System (ADS)

Haas, S.; Krellner, C.; Goldmann, C.; Pernstich, K. P.; Gundlach, D. J.; Batlogg, B.

2007-03-01

Charge transport in organic molecular crystals is strongly influenced by the density of localized in-gap states (traps). Thus, a profound knowledge of the defect states' origin is essential. Temperature-dependent space-charge limited current (TD-SCLC) spectroscopy was used as a powerful tool to quantitatively study the density of states (DOS) in high-quality rubrene and pentacene single crystals. In particular, changes of the DOS due to intentionally induced chemical and structural defects were monitored. For instance, the controlled exposure of pentacene and rubrene to x-ray radiation results in a broad over-all increase of the DOS. Namely, the ionizing radiation induces a variety of both chemical and structural defects. On the other hand, exposure of rubrene to UV-excited oxygen is reflected in a sharp peak in the DOS, whereas in a similar experiment with pentacene oxygen acts as a dopant, and possible defects are metastable on the time-scale of the measurement, thus leaving the extracted DOS virtually unchanged.

A Safety and Tolerability Study of INCAGN02385 in Select Advanced Malignancies

ClinicalTrials.gov

2018-05-15

Cervical Cancer; Microsatellite Instability (MSI)-High Endometrial Cancer; Gastric Cancer (Including Stomach and Gastroesophageal Junction [GEJ]); Esophageal Cancer; Hepatocellular Carcinoma; Melanoma (Uveal Melanoma Excluded); Merkel Cell Carcinoma; Mesothelioma; MSI-high Colorectal Cancer; Non-small Cell Lung Cancer (NSCLC); Ovarian Cancer; Squamous Cell Carcinoma of the Head and Neck (SCCHN); Small Cell Lung Cancer (SCLC); Renal Cell Carcinoma (RCC); Triple-negative Breast Cancer; Urothelial Carcinoma; Diffuse Large B-cell Lymphoma

Multi-Institutional Experience of Stereotactic Ablative Radiation Therapy for Stage I Small Cell Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Verma, Vivek; Simone, Charles B.; Allen, Pamela K.

Purpose: For inoperable stage I (T1-T2N0) small cell lung cancer (SCLC), national guidelines recommend chemotherapy with or without conventionally fractionated radiation therapy. The present multi-institutional cohort study investigated the role of stereotactic ablative radiation therapy (SABR) for this population. Methods and Materials: The clinical and treatment characteristics, toxicities, outcomes, and patterns of failure were assessed in patients with histologically confirmed stage T1-T2N0M0 SCLC. Kaplan-Meier analysis was used to evaluate the survival outcomes. Univariate and multivariate analyses identified predictors of outcomes. Results: From 24 institutions, 76 lesions were treated in 74 patients (median follow-up 18 months). The median age and tumor sizemore » was 72 years and 2.5 cm, respectively. Chemotherapy and prophylactic cranial irradiation were delivered in 56% and 23% of cases, respectively. The median SABR dose and fractionation was 50 Gy and 5 fractions. The 1- and 3-year local control rate was 97.4% and 96.1%, respectively. The median disease-free survival (DFS) duration was 49.7 months. The DFS rate was 58.3% and 53.2% at 1 and 3 years, respectively. The median, 1-year, and 3-year disease-specific survival was 52.3 months, 84.5%, and 64.4%, respectively. The median, 1-year, and 3-year overall survival (OS) was 17.8 months, 69.9%, and 34.0% respectively. Patients receiving chemotherapy experienced an increased median DFS (61.3 vs 9.0 months; P=.02) and OS (31.4 vs 14.3 months; P=.02). The receipt of chemotherapy independently predicted better outcomes for DFS/OS on multivariate analysis (P=.01). Toxicities were uncommon; 5.2% experienced grade ≥2 pneumonitis. Post-treatment failure was most commonly distant (45.8% of recurrence), followed by nodal (25.0%) and “elsewhere lung” (20.8%). The median time to each was 5 to 7 months. Conclusions: From the findings of the largest report of SABR for stage T1-T2N0 SCLC to date, SABR (≥50 Gy) with chemotherapy should be considered a standard option.« less

Weak sharing of genetic association signals in three lung cancer subtypes: evidence at the SNP, gene, regulation, and pathway levels.

PubMed

O'Brien, Timothy D; Jia, Peilin; Caporaso, Neil E; Landi, Maria Teresa; Zhao, Zhongming

2018-02-27

There are two main types of lung cancer: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC has many subtypes, but the two most common are lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). These subtypes are mainly classified by physiological and pathological characteristics, although there is increasing evidence of genetic and molecular differences as well. Although some work has been done at the somatic level to explore the genetic and biological differences among subtypes, little work has been done that interrogates these differences at the germline level to characterize the unique and shared susceptibility genes for each subtype. We used single-nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS) of European samples to interrogate the similarity of the subtypes at the SNP, gene, pathway, and regulatory levels. We expanded these genotyped SNPs to include all SNPs in linkage disequilibrium (LD) using data from the 1000 Genomes Project. We mapped these SNPs to several lung tissue expression quantitative trait loci (eQTL) and enhancer datasets to identify regulatory SNPs and their target genes. We used these genes to perform a biological pathway analysis for each subtype. We identified 8295, 8734, and 8361 SNPs with moderate association signals for LUAD, LUSC, and SCLC, respectively. Those SNPs had p < 1 × 10 - 3 in the original GWAS or were within LD (r 2 > 0.8, Europeans) to the genotyped SNPs. We identified 215, 320, and 172 disease-associated genes for LUAD, LUSC, and SCLC, respectively. Only five genes (CHRNA5, IDH3A, PSMA4, RP11-650 L12.2, and TBC1D2B) overlapped all subtypes. Furthermore, we observed only two pathways from the Kyoto Encyclopedia of Genes and Genomes shared by all subtypes. At the regulatory level, only three eQTL target genes and two enhancer target genes overlapped between all subtypes. Our results suggest that the three lung cancer subtypes do not share much genetic signal at the SNP, gene, pathway, or regulatory level, which differs from the common subtype classification based upon histology. However, three (CHRNA5, IDH3A, and PSMA4) of the five genes shared between the subtypes are well-known lung cancer genes that may act as general lung cancer genes regardless of subtype.

Analysis of incidental radiation dose to uninvolved mediastinal/supraclavicular lymph nodes in patients with limited-stage small cell lung cancer treated without elective nodal irradiation.

PubMed

Ahmed, Irfan; DeMarco, Marylou; Stevens, Craig W; Fulp, William J; Dilling, Thomas J

2011-01-01

Classic teaching states that treatment of limited-stage small cell lung cancer (L-SCLC) requires large treatment fields covering the entire mediastinum. However, a trend in modern thoracic radiotherapy is toward more conformal fields, employing positron emission tomography/computed tomography (PET/CT) scans to determine the gross tumor volume (GTV). This analysis evaluates the dosimetric results when using selective nodal irradiation (SNI) to treat a patient with L-SCLC, quantitatively comparing the results to standard Intergroup treatment fields. Sixteen consecutive patients with L-SCLC and central mediastinal disease who also underwent pretherapy PET/CT scans were studied in this analysis. For each patient, we created SNI treatment volumes, based on the PET/CT-based criteria for malignancy. We also created 2 ENI plans, the first without heterogeneity corrections, as per the Intergroup 0096 study (ENI(off)) and the second with heterogeneity corrections while maintaining constant the number of MUs delivered between these latter 2 plans (ENI(on)). Nodal stations were contoured using published guidelines, then placed into 4 "bins" (treated nodes, 1 echelon away, >1 echelon away within the mediastinum, contralateral hilar/supraclavicular). These were aggregated across the patients in the study. Dose to these nodal bins and to tumor/normal structures were compared among these plans using pairwise t-tests. The ENI(on) plans demonstrated a statistically significant degradation in dose coverage compared with the ENI(off) plans. ENI and SNI both created a dose gradient to the lymph nodes across the mediastinum. Overall, the gradient was larger for the SNI plans, although the maximum dose to the "1 echelon away" nodes was not statistically different. Coverage of the GTV and planning target volume (PTV) were improved with SNI, while simultaneously reducing esophageal and spinal cord dose though at the expense of modestly reduced dose to anatomically distant lymph nodes within the mediastinum. The ENI(on) plans demonstrate that intergroup-style treatments, as actually delivered, had statistically reduced coverage to the mediastinum and tumor volumes than was reported. Furthermore, SNI leads to improved tumor coverage and reduced esophageal/spinal cord dose, which suggests the possibility of dose escalation using SNI. Copyright © 2011 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.

Integrative physicians and an herbal cancer "cure".

PubMed

Ben-Arye, Eran; Rosenberg, Shoshana Keren; Samuels, Noah

2016-08-01

Oncologists are frequently asked about herbal remedies claiming to "cure" cancer, or at least delay its progression. While complementary and integrative medicine (CIM) should be aimed primarily at improving quality-of-life (QOL) related concerns, "wonder cures" are part of an alternative health belief model providing hope for a "miracle" where conventional treatment has failed. We describe a physician with extensive small-cell lung cancer (SCLC) undergoing chemotherapy, with significant toxicities and impaired daily function. He had come for an integrative physician (IP) consultation, provided by a medical doctor dually trained in CIM and supportive cancer care, taking place in a conventional supportive cancer care service. We describe the IP consultation in general and regarding an herbal remedy which was being promoted as a "cure" for cancer. The subsequent patient-tailored CIM treatment process, in which patients receive evidence-based guidance on treatments which address QOL-related concerns, are presented.

EFFECTS OF TiOx INTERLAYER ON RESISTANCE SWITCHING OF Pt/TiOx/ZnO/n+-Si STRUCTURES

NASA Astrophysics Data System (ADS)

Li, Hongxia; Lv, Xiaojun; Xi, Junhua; Wu, Xin; Mao, Qinan; Liu, Qingmin; Ji, Zhenguo

2014-08-01

In this paper, we fabricated Pt/TiOx/ZnO/n+-Si structures by inserting TiOx interlayer between Pt top electrode (TE) and ZnO thin film for non-volatile resistive random access memory (ReRAM) applications. Effects of TiOx interlayer with different thickness on the resistance switching of Pt/TiOx/ZnO/n+-Si structures were investigated. Conduction behaviors in high and low resistance state (HRS and LRS) fit well with the trap-controlled space-charge-limited conduction (SCLC) and Ohmic behavior, respectively. Variations of set and reset voltages and HRS and LRS resistances of Pt/TiOx/ZnO/n+-Si structures were investigated as a function of TiOx thickness. Switching cycling tests were attempted to evaluate the endurance reliability of Pt/TiOx/ZnO/n+-Si structures. Additionally, the switching mechanism was analyzed by the filament model.

Efficient Terahertz Emission from InAs Nanowires

DTIC Science & Technology

2011-09-16

are specific to high aspect ratio geometries. DOI: 10.1103/PhysRevB.84.115421 PACS number(s): 73.21.−b, 81.07.Gf I . MOTIVATION Manipulation of...43 The symmetric nature of the I -V curve in Fig. 4(b) afforded by the two ohmic41,42 contacts despite their geometrically asymmetric nature, is...consistent with SCLC (a bulk-limited regime). This is in marked contrast to rectifying I -V characteristics observed for Au catalyst/Ge nanowire contacts

Phase I dose-escalation studies of roniciclib, a pan-cyclin-dependent kinase inhibitor, in advanced malignancies.

PubMed

Bahleda, Rastislav; Grilley-Olson, Juneko E; Govindan, Ramaswamy; Barlesi, Fabrice; Greillier, Laurent; Perol, Maurice; Ray-Coquard, Isabelle; Strumberg, Dirk; Schultheis, Beate; Dy, Grace K; Zalcman, Gérard; Weiss, Glen J; Walter, Annette O; Kornacker, Martin; Rajagopalan, Prabhu; Henderson, David; Nogai, Hendrik; Ocker, Matthias; Soria, Jean-Charles

2017-06-06

To evaluate safety, pharmacokinetics, and maximum tolerated dose of roniciclib in patients with advanced malignancies, with dose expansion to evaluate clinical benefit at the recommended phase II dose (RP2D). Two phase I dose-escalation studies evaluated two roniciclib dosing schedules: 3 days on/4 days off or 4 weeks on/2 weeks off. The expansion phase included patients with small-cell lung cancer (SCLC), ovarian cancer, or tumour mutations involving the CDK signalling pathway. Ten patients were evaluable in the 4 weeks on/2 weeks off schedule (terminated following limited tolerability) and 47 in the 3 days on/4 days off schedule dose-escalation cohorts. On the 3 days on/4 days off schedule, RP2D was 5 mg twice daily in solid tumours (n=40); undetermined in lymphoid malignancies (n=7). Common roniciclib-related adverse events included nausea (76.6%), fatigue (65.8%), diarrhoea (63.1%), and vomiting (57.7%). Roniciclib demonstrated rapid absorption and dose-proportional increase in exposure. One partial response (1.0%) was observed. In RP2D expansion cohorts, the disease control rate (DCR) was 40.9% for patients with ovarian cancer (n=25), 17.4% for patients with SCLC (n=33), and 33.3% for patients with CDK-related tumour mutations (n=6). Roniciclib demonstrated an acceptable safety profile and moderate DCR in 3 days on/4 days off schedule.

Prediction of soil organic carbon partition coefficients by soil column liquid chromatography.

PubMed

Guo, Rongbo; Liang, Xinmiao; Chen, Jiping; Wu, Wenzhong; Zhang, Qing; Martens, Dieter; Kettrup, Antonius

2004-04-30

To avoid the limitation of the widely used prediction methods of soil organic carbon partition coefficients (KOC) from hydrophobic parameters, e.g., the n-octanol/water partition coefficients (KOW) and the reversed phase high performance liquid chromatographic (RP-HPLC) retention factors, the soil column liquid chromatographic (SCLC) method was developed for KOC prediction. The real soils were used as the packing materials of RP-HPLC columns, and the correlations between the retention factors of organic compounds on soil columns (ksoil) and KOC measured by batch equilibrium method were studied. Good correlations were achieved between ksoil and KOC for three types of soils with different properties. All the square of the correlation coefficients (R2) of the linear regression between log ksoil and log KOC were higher than 0.89 with standard deviations of less than 0.21. In addition, the prediction of KOC from KOW and the RP-HPLC retention factors on cyanopropyl (CN) stationary phase (kCN) was comparatively evaluated for the three types of soils. The results show that the prediction of KOC from kCN and KOW is only applicable to some specific types of soils. The results obtained in the present study proved that the SCLC method is appropriate for the KOC prediction for different types of soils, however the applicability of using hydrophobic parameters to predict KOC largely depends on the properties of soil concerned.

Patterns of Care for Lung Cancer in Radiation Oncology Departments of Turkey

DOE Office of Scientific and Technical Information (OSTI.GOV)

Demiral, Ayse Nur; Alicikus, Zuemre Arican; Isil Ugur, Vahide

2008-12-01

Purpose: To determine the patterns of care for lung cancer in Turkish radiation oncology centers. Methods and Materials: Questionnaire forms from 21 of 24 (87.5%) centers that responded were evaluated. Results: The most frequent histology was non-small cell lung cancer (NSCLC) (81%). The most common postoperative radiotherapy (RT) indications were close/(+) surgical margins (95%) and presence of pN2 disease (91%). The most common indications for postoperative chemotherapy (CHT) were '{>=} IB' disease (19%) and the presence of pN2 disease (19%). In Stage IIIA potentially resectable NSCLC, the most frequent treatment approach was neoadjuvant concomitant chemoradiotherapy (CHRT) (57%). In Stage IIIAmore » unresectable and Stage IIIB disease, the most frequent approach was definitive concomitant CHRT (91%). In limited SCLC, the most common treatment approach was concomitant CHRT with cisplatin+etoposide for cycles 1-3, completion of CHT to cycles 4-6, and finally prophylactic cranial irradiation in patients with complete response (71%). Six cycles of cisplatin + etoposide CHT and palliative thoracic RT, when required, was the most commonly used treatment (81%) in extensive SCLC. Sixty-two percent of centers did not have endobronchial brachytherapy (EBB) facilities. Conclusion: There is great variation in diagnostic testing, treatment strategies, indications for postoperative RT and CHT, RT features, and EBB availability for LC cases. To establish standards, national guidelines should be prepared using a multidisciplinary approach.« less

[Randomized clinical trial of IEP and EP regimens in the treatment of patients with small cell lung cancer].

PubMed

Zhou, Hui; Wang, Anlan; Huang, Zhihua; Zhou, Wenwei

2004-06-20

To observe and compare the efficacy and safety of IEP and EP regimens for small cell lung cancer (SCLC). Sixty-four patients with SCLC pathologically proved were randomly divided into IEP group ( n =32) and EP group ( n =32). All the 64 patients were evaluable for response and toxicity. In IEP group, the total responsive rate, responsive rates of limited-stage patients and extensive-stage patients were 84.4%(27/32), 100.0%(15/15) and 70.6%(12/17) respectively; while in EP group, those were 75.0%(24/32), 85.7%(12/14) and 66.7% (12/18) respectively. The median duration of remission was 6 months and 1-year survival rate was 62.5% in IEP group, and 5 months and 56.2% in EP group. There was no significant difference in response rate, median duration of remission and 1-year survival between the two groups ( P > 0.05). The main toxicity was myelosuppression. Incidences of leukopenia at grade III-IV, nausea, vomiting and alopecia were significantly higher in the IEP arm than those in the EP arm ( P < 0.01 ). High response rates and tolerable toxicities are attainable for small cell lung cancer treated with IEP and EP. IEP regimen shows a similar response rate compared with EP regimen. They might be considered as relevant regimens in initial patients with small cell lung cancer.

Lung cancer: biology and treatment options

PubMed Central

Hassan, Omer; Yang, Yi-Wei; Buchanan, Petra

2015-01-01

Lung cancer remains the leading cause of cancer mortality in men and women in the U.S. and worldwide. About 90% of lung cancer cases are caused by smoking and the use of tobacco products. However, other factors such as radon gas, asbestos, air pollution exposures, and chronic infections can contribute to lung carcinogenesis. In addition, multiple inherited and acquired mechanisms of susceptibility to lung cancer have been proposed. Lung cancer is divided into two broad histologic classes, which grow and spread differently: small-cell lung carcinomas (SCLC) and non-small cell lung carcinomas (NSCLC). Treatment options for lung cancer include surgery, radiation therapy, chemotherapy, and targeted therapy. Therapeutic-modalities recommendations depend on several factors, including the type and stage of cancer. Despite the improvements in diagnosis and therapy made during the past 25 years, the prognosis for patients with lung cancer is still unsatisfactory. The responses to current standard therapies are poor except for the most localized cancers. However, a better understanding of the biology pertinent to these challenging malignancies, might lead to the development of more efficacious and perhaps more specific drugs. The purpose of this review is to summarize the recent developments in lung cancer biology and its therapeutic strategies, and discuss the latest treatment advances including therapies currently under clinical investigation. PMID:26297204

Tunable dielectric properties of TiO2 thin film based MOS systems for application in microelectronics

NASA Astrophysics Data System (ADS)

Gyanan; Mondal, Sandip; Kumar, Arvind

2016-12-01

Post-deposition annealing (PDA) is an inherent part of a sol-gel fabrication process to achieve the optimum device performance, especially in CMOS applications. Annealing removes the oxygen vacancies and improves the structural order of the dielectric films. The process also reduces the interface related defects and improves the interfacial properties. Here, we applied a sol-gel spin-coating technique to prepare high-k TiO2 films on the p-Si substrate. These films were fired at 400 °C for the duration of 20, 40, 60 and 80 min to know the effects of annealing time on the device characteristics. The current-voltage (I-V) and capacitance-voltage (C-V) characteristics of annealed TiO2 films were examined in Al/TiO2/p-Si device configuration at room temperature. The 60 min annealed film gives the optimum performance and contained 69.5% anatase and 39.5% rutile phase with refractive index 2.40 at 550 nm. The C-V and I-V characteristic showed a significant dependence on annealing time such as variation in dielectric constant and leakage current. This allows us to tune the various electrical properties of MOS systems. The accumulation capacitance (Cox), dielectric constant (κ) and the equivalent oxide thickness (EOT) of the film fired for 60 min were found to be 458 pF, 33, and 4.25 nm, respectively with a low leakage current density (3.13 × 10-7 A/cm2) fired for 80 min at -1 V. The current conduction mechanisms at high bias voltage were dominated by trap-charge limited current (TCLC), while at small voltages, space charge limited current (SCLC) was more prominent.

[Possible role of autotransplantation in small cel bronchial carcinoma].

PubMed

Tiefengraber, E; Sebesta, C; Kier, P; Ruckser, R; Habertheuer, K H; Hinterberger, W

1995-01-01

Autologous bone marrow transplantation (ABMT) performed with recent achievements plays yet no established role in the treatment of small cell lung cancer (SCLC). The majority of treatment results obtained so far do not clearly suggest a superiority of high-dose therapy with autologous transplantation over conventional polychemo/radiotherapy. It is unknown, whether or not a subgroup of patients with, e.g., "limited disease" and chemosensitive tumor may benefit from ABMT. Randomized trials will be necessary to clarify this question.

Effect of thermal annealing treatment with titanium chelate on buffer layer in inverted polymer solar cells

NASA Astrophysics Data System (ADS)

Liu, Zhiyong; Wang, Ning; Fu, Yan

2016-12-01

The solution processable electron extraction layer (EEL) is crucial for polymer solar cells (PSCs). Here, we investigated titanium (diisopropoxide) bis(2,4-pentanedionate) (TIPD) as an EEL and fabricated inverted PSCs with a blend of poly(3-hexylthiophene) (P3HT) and indene-C60 bisadduct (ICBA) acting as the photoactive layer, with a structure of ITO/TIPD/P3HT:ICBA/MoO3/Ag. After thermal annealing treatment at 150 °C for 15 min, the PSC performances increased from 3.85% to 6.84% and they achieve stable power conversion efficiency (PCE), with a similar PCE compared with TiO2 as an EEL by the vacuum evaporated method. Fourier transform infrared spectroscopy (FTIR) and ultraviolet photoelectron spectroscopy (UPS) confirmed that the TIPD decomposed and formed the Tidbnd O bond, and the energy level of the lowest unoccupied molecular orbital and the highest occupied molecular orbital increased. The space charge limited current (SCLC) measurements further confirmed the improvement in electron collection and the transport ability using TIPD as the EEL and thermal annealing.

Effect of AlN layer on the bipolar resistive switching behavior in TiN thin film based ReRAM device for non-volatile memory application

NASA Astrophysics Data System (ADS)

Prakash, Ravi; Kaur, Davinder

2018-05-01

The effect of an additional AlN layer in the Cu/TiN/AlN/Pt stack configuration deposited using sputtering has been investigated. The Cu/TiN/AlN/Pt device shows a tristate resistive switching. Multilevel switching is facilitated by ionic and metallic filament formation, and the nature of the filaments formed is confirmed by performing a resistance vs. temperature measurement. Ohmic behaviour and trap controlled space charge limited current (SCLC) conduction mechanisms are confirmed as dominant conduction mechanism at low resistance state (LRS) and high resistance state (HRS). High resistance ratio (102) corresponding to HRS and LRS, good write/erase endurance (105) and non-volatile long retention (105s) are also observed. Higher thermal conductivity of the AlN layer is the main reasons for the enhancement of resistive switching performance in Cu/TiN/AlN/Pt cell. The above result suggests the feasibility of Cu/TiN/AlN/Pt devices for multilevel nonvolatile ReRAM application.

Relationship between primary lesion metabolic parameters and clinical stage in lung cancer.

PubMed

Sahiner, I; Atasever, T; Akdemir, U O; Ozturk, C; Memis, L

2013-01-01

The relation of PET-derived parameters as maximum standardized uptake value (SUVmax), total lesion glycolysis (TLG), metabolic tumor volume (MTV) with clinical stage in lung cancer and correlation of SUVmax of primary tumor and that of metastatic lesion was studied in lung cancer patients. Patients with lung cancer who were referred for FDG PET/CT were included in the study. PET/CT scans and pathology reports of 168 patients were assessed. A total of 146 (86.9%) of these patients had a diagnosis of non-small cell lung cancer (NSCLC) and 22 (13.1%) had small cell lung cancer (SCLC). Metabolic parameters such as SUVmax, TLG and MTV showed significant differences in all the stages in NSCLC patients (p<0.001). However, after tumors sizes <25 mm were excluded, no significant differences in SUVmax between stages were observed. No significant differences were found between these metabolic parameters and limited or extended disease SCLC. Tumor diameter correlated with primary tumor SUVmax and significant correlations between primary lesion SUVmax and metastatic lesion SUVmax were found. Although differences were found regarding indices between stages of NSCLC cases, SUVmax differences between stages seem to be caused by underestimation of SUVmax in small lesions. Other glucose metabolism indexes such as MTV and TLG show promising results in terms of prognostic stratification. Future studies are needed for better understanding of their contribution to clinical cases. Copyright © 2013 Elsevier España, S.L. and SEMNIM. All rights reserved.

Efficacy of different monotherapies in second-line treatment for small cell lung cancer: a meta-analysis of randomized controlled trials

PubMed Central

Luo, Qiuping; Wang, Ziwei; Li, Shengjie; Zhou, Jianying

2015-01-01

Second-line chemotherapy has been proved to be effective on patients with relapsed or refractory small cell lung cancer (SCLC). Although topotecan has been approved by many countries for the monotherapy with an acknowledged efficacy, its efficacy of low response rate and short median survival time is disappointing. Considering the optimal regimen of second-line therapy is yet uncertain, we conducted this meta-analysis to provide theoretical basis for making clinical decisions. A comprehensive electronic search was performed to identify eligible studies. The ending points included response, overall survival (OS), and adverse events. Odds ratios and 95% confidence interval were calculated to compare the effects. Six trials with 1369 patients were included. With regard to response rate, only amrubicin showed a significant improvement compared with topotecan. Irinotecan and etoposide did not show any advantages. When targeted on OS, neither of these monotherapy regimens exhibited any advantage when compared to topotecan. When aimed at toxicity, amrubicin showed a better effect on reducing hematologic toxicity, but a worse outcome on increasing the nonhematologic toxicity, whereas others showed equal efficacy. There is no strong evidence that any advantage for second-line treatment of SCLC when compared with topotecan, except amrubicin. And amrubicin seems to be superior to topotecan in terms of response rates, with a lower toxicity than topotecan, which is of high value in clinical application, and may be the direction of second-line monotherapy in the future. PMID:26770633

Nonstoichiometric Solution-Processed BaTiO₃ Film for Gate Insulator Applications.

PubMed

Lau, Joyce; Kim, Sangsub; Kim, Hyunki; Koo, Kwangjun; Lee, Jaeseob; Kim, Sangsoo; Choi, Byoungdeog

2018-09-01

Solution processed barium titanate (BTO) was used to fabricate an Al/BaTiO3/p-Si metal-insulator-semiconductor (MIS) structure, which was used as a gate insulator. Changes in the electrical characteristics of the film were investigated as a function of the film thickness and post deposition annealing conditions. Our results showed that a thickness of 5 layers and an annealing temperature of 650 °C produced the highest electrical performance. BaxTi1-xO3 was altered at x = 0.10, 0.30, 0.50, 0.70, 0.90, and 1.0 to investigate changes in the electrical properties as a function of composition. The highest dielectric constant of 87 was obtained for x = 0.10, while the leakage current density was suppressed as Ba content increased. The lowest leakage current density was 1.34×10-10 A/cm2, which was observed at x = 0.90. The leakage current was related to the resistivity of the film, the interface states, and grain densification. Space charge limited current (SCLC) was the dominant leakage mechanism in BTO films based on leakage current analysis. Although a Ba content of x = 0.90 had the highest trap density, the traps were mainly composed of Ti-vacancies, which acted as strong electron traps and affected the film resistivity. A secondary phase, Ba2TiO4, which was observed in cases of excess Ba, acted as a grain refiner and provided faster densification of the film during the thermal process. The absence of a secondary phase in BaO (x = 1.0) led to the formation of many interface states and degradation in the electrical properties. Overall, the insulator properties of BTO were improved when the composition ratio was x = 0.90.

Differential expression patterns of housekeeping genes increase diagnostic and prognostic value in lung cancer

PubMed Central

Chang, Yu-Chun; Ding, Yan; Dong, Lingsheng; Zhu, Lang-Jing; Jensen, Roderick V.

2018-01-01

Background Using DNA microarrays, we previously identified 451 genes expressed in 19 different human tissues. Although ubiquitously expressed, the variable expression patterns of these “housekeeping genes” (HKGs) could separate one normal human tissue type from another. Current focus on identifying “specific disease markers” is problematic as single gene expression in a given sample represents the specific cellular states of the sample at the time of collection. In this study, we examine the diagnostic and prognostic potential of the variable expressions of HKGs in lung cancers. Methods Microarray and RNA-seq data for normal lungs, lung adenocarcinomas (AD), squamous cell carcinomas of the lung (SQCLC), and small cell carcinomas of the lung (SCLC) were collected from online databases. Using 374 of 451 HKGs, differentially expressed genes between pairs of sample types were determined via two-sided, homoscedastic t-test. Principal component analysis and hierarchical clustering classified normal lung and lung cancers subtypes according to relative gene expression variations. We used uni- and multi-variate cox-regressions to identify significant predictors of overall survival in AD patients. Classifying genes were selected using a set of training samples and then validated using an independent test set. Gene Ontology was examined by PANTHER. Results This study showed that the differential expression patterns of 242, 245, and 99 HKGs were able to distinguish normal lung from AD, SCLC, and SQCLC, respectively. From these, 70 HKGs were common across the three lung cancer subtypes. These HKGs have low expression variation compared to current lung cancer markers (e.g., EGFR, KRAS) and were involved in the most common biological processes (e.g., metabolism, stress response). In addition, the expression pattern of 106 HKGs alone was a significant classifier of AD versus SQCLC. We further highlighted that a panel of 13 HKGs was an independent predictor of overall survival and cumulative risk in AD patients. Discussion Here we report HKG expression patterns may be an effective tool for evaluation of lung cancer states. For example, the differential expression pattern of 70 HKGs alone can separate normal lung tissue from various lung cancers while a panel of 106 HKGs was a capable class predictor of subtypes of non-small cell carcinomas. We also reported that HKGs have significantly lower variance compared to traditional cancer markers across samples, highlighting the robustness of a panel of genes over any one specific biomarker. Using RNA-seq data, we showed that the expression pattern of 13 HKGs is a significant, independent predictor of overall survival for AD patients. This reinforces the predictive power of a HKG panel across different gene expression measurement platforms. Thus, we propose the expression patterns of HKGs alone may be sufficient for the diagnosis and prognosis of individuals with lung cancer. PMID:29761043

Clinical and Pathologic Studies of Patients Undergoing Treatment With EGFR Inhibitors

ClinicalTrials.gov

2016-07-20

Anal, Colon, and Rectal Cancers; Head and Neck Cancer; Lung Cancer; Colon Cancer; Colonic Neoplasms; Colorectal Neoplasms; Colon/Rectal Cancer; Colon/Rectal Cancer Colon Cancer; Colon/Rectal Cancer Rectal Cancer; Colon/Rectal Cancer Anal Cancer; Head and Neck Cancers; Head and Neck Cancers Lip; Head and Neck Cancers Oral Cavity; Head and Neck Cancers Nasopharynx; Head and Neck Cancers Oropharynx; Head and Neck Cancers Hypopharynx; Head and Neck Cancers Larynx; Head and Neck Cancers Trachea; Lung Cancer Non-Small Cell Cancer (NSCLC); Lung Cancer Small Cell Lung Cancer (SCLC)

Investigation of the optical and electrical characteristics of solution-processed poly (3 hexylthiophene) (P3HT): multiwall carbon nanotube (MWCNT) composite-based devices

NASA Astrophysics Data System (ADS)

Rathore, Priyanka; Mohan Singh Negi, Chandra; Singh Verma, Ajay; Singh, Amarjeet; Chauhan, Gayatri; Regis Inigo, Anto; Gupta, Saral K.

2017-08-01

Devices comprised of solution-processed poly (3-hexylthiophene) (P3HT)/multiwall carbon nanotubes (MWCNTs), with various concentrations of MWCNTs, were fabricated and characterized. The morphology of the P3HT: MWCNT nanocomposite was characterized by using field emission scanning electron microscopy (FESEM). The optical characteristics of the nanocomposite were studied by UV/VIS/NIR spectroscopy and Raman spectroscopy. The electrical properties of the fabricated devices were characterized by measuring the current density-voltage (J-V) characteristics. While the J-V characteristics of a pristine P3HT device reveal thermal injection limited charge transport, the P3HT: MWCNT nanocomposite-based devices exhibit three distinct voltage-dependent conduction regimes. The fitting curve with measured data reveals Ohmic conduction for a low voltage range, a trap-charge limited conduction (TCLC) process at an intermediate voltage range followed by a trap free space-charge limited conduction (SCLC) process at much higher voltages. A fundamental understanding of this work can assist in creating new charge transport pathways which will provide new avenues for the development of highly efficient polymer-based optoelectronic devices.

Optical and electrical properties of TiOPc doped Alq3 thin films

NASA Astrophysics Data System (ADS)

Ramar, M.; Suman, C. K.; Tyagi, Priyanka; Srivastava, R.

2015-06-01

The Titanyl phthalocyanine (TiOPc) was doped in Tris (8-hydroxyquinolinato) aluminum (Alq3) with different concentration. The thin film of optimized doping concentration was studied extensively for optical and electrical properties. The optical properties, studied using ellipsometry, absorption and photoluminescence. The absorption peak of Alq3 and TiOPc was observed at 387 nm and 707 nm and the photo-luminescence intensity (PL) peak of doped thin film was observed at 517 nm. The DC and AC electrical properties of the thin film were studied by current density-voltage (J-V) characteristics and impedance over a frequency range of 100 Hz - 1 MHz. The electron mobility calculated from trap-free space-charge limited region (SCLC) is 0.17×10-5 cm2/Vs. The Cole-Cole plots shows that the TiOPc doped Alq3 thin film can be represented by a single parallel resistance RP and capacitance CP network with a series resistance RS (10 Ω). The value of RP and CP at zero bias was 1587 Ω and 2.568 nF respectively. The resistance RP decreases with applied bias whereas the capacitance CP remains almost constant.

Pentastatin-1, a collagen IV derived 20-mer peptide, suppresses tumor growth in a small cell lung cancer xenograft model.

PubMed

Koskimaki, Jacob E; Karagiannis, Emmanouil D; Tang, Benjamin C; Hammers, Hans; Watkins, D Neil; Pili, Roberto; Popel, Aleksander S

2010-02-01

Angiogenesis is the formation of neovasculature from a pre-existing vascular network. Progression of solid tumors including lung cancer is angiogenesis-dependent. We previously introduced a bioinformatics-based methodology to identify endogenous anti-angiogenic peptide sequences, and validated these predictions in vitro in human umbilical vein endothelial cell (HUVEC) proliferation and migration assays. One family of peptides with high activity is derived from the alpha-fibrils of type IV collagen. Based on the results from the in vitro screening, we have evaluated the ability of a 20 amino acid peptide derived from the alpha5 fibril of type IV collagen, pentastatin-1, to suppress vessel growth in an angioreactor-based directed in vivo angiogenesis assay (DIVAA). In addition, pentastatin-1 suppressed tumor growth with intraperitoneal peptide administration in a small cell lung cancer (SCLC) xenograft model in nude mice using the NCI-H82 human cancer cell line. Pentastatin-1 decreased the invasion of vessels into angioreactors in vivo in a dose dependent manner. The peptide also decreased the rate of tumor growth and microvascular density in vivo in a small cell lung cancer xenograft model. The peptide treatment significantly decreased the invasion of microvessels in angioreactors and the rate of tumor growth in the xenograft model, indicating potential treatment for angiogenesis-dependent disease, and for translational development as a therapeutic agent for lung cancer.

Physiologically based pharmacokinetic modeling for predicting irinotecan exposure in human body.

PubMed

Fan, Yingfang; Mansoor, Najia; Ahmad, Tasneem; Khan, Rafeeq Alam; Czejka, Martin; Sharib, Syed; Yang, Dong-Hua; Ahmed, Mansoor

2017-07-18

Colorectal cancer is the third leading cause of cancer-related deaths in the United States. Treatment of colorectal cancer remains a challenge to clinicians as well as drug developers. Irinotecan, a Camptothecin derivative, is successfully used for the treatment of this rapidly progressing malignancy and finds its place in the first line of therapeutic agents. Irinotecan is also effective in treating SCLC, malignant glioma and pancreatic adenocarcinoma. However, its adverse effects limit its clinical application. Mainly metabolized by hepatic route, and excreted through biliary tract, this dug has been found to possess high variation in patients in its pharmacokinetic (PK) profile. Physiologically based pharmacokinetic (PBPK) models using compartmental approach have attained their position to foresee the possible PK behavior of different drugs before their administration to patients and such models have been proposed for several anticancer agents. In this work, we used WB-PBPK technology to develop a model in a population of tumor patients who used IV irinotecan therapy. This model depicted the concentration of drug and its pharmacologically active metabolite in human body over a specific period of time. Knowledge about pharmacokinetic parameters is extracted from this profile and the model is evaluated by the observed results of clinical study presented in literature. The predicted behavior of the drug by this approach is in good agreement with the observed results and can aid in further exploration of PK of irinotecan in cancer patients, especially in those concomitantly suffer from other morbidity.

Physiologically based pharmacokinetic modeling for predicting irinotecan exposure in human body

PubMed Central

Ahmad, Tasneem; Khan, Rafeeq Alam; Czejka, Martin; Sharib, Syed; Yang, Dong-Hua; Ahmed, Mansoor

2017-01-01

Colorectal cancer is the third leading cause of cancer-related deaths in the United States. Treatment of colorectal cancer remains a challenge to clinicians as well as drug developers. Irinotecan, a Camptothecin derivative, is successfully used for the treatment of this rapidly progressing malignancy and finds its place in the first line of therapeutic agents. Irinotecan is also effective in treating SCLC, malignant glioma and pancreatic adenocarcinoma. However, its adverse effects limit its clinical application. Mainly metabolized by hepatic route, and excreted through biliary tract, this dug has been found to possess high variation in patients in its pharmacokinetic (PK) profile. Physiologically based pharmacokinetic (PBPK) models using compartmental approach have attained their position to foresee the possible PK behavior of different drugs before their administration to patients and such models have been proposed for several anticancer agents. In this work, we used WB-PBPK technology to develop a model in a population of tumor patients who used IV irinotecan therapy. This model depicted the concentration of drug and its pharmacologically active metabolite in human body over a specific period of time. Knowledge about pharmacokinetic parameters is extracted from this profile and the model is evaluated by the observed results of clinical study presented in literature. The predicted behavior of the drug by this approach is in good agreement with the observed results and can aid in further exploration of PK of irinotecan in cancer patients, especially in those concomitantly suffer from other morbidity. PMID:28636998

Electrical conduction in 100 keV Kr+ ion implanted poly (ethylene terephthalate)

NASA Astrophysics Data System (ADS)

Goyal, P. K.; Kumar, V.; Gupta, Renu; Mahendia, S.; Anita, Kumar, S.

2012-06-01

Polyethylene terephthalate (PET) samples have been implanted to 100 keV Kr+ ions at the fluences 1×1015-- 1×1016 cm-2. From I-V characteristics, the conduction mechanism was found to be shifted from ohmic to space charge limited conduction (SCLC) after implantation. The surface conductivity of these implanted samples was found to increase with increasing implantation dose. The structural alterations in the Raman spectra of implanted PET samples indicate that such an increase in the conductivity may be attributed to the formation of conjugated double bonded carbonaceous structure in the implanted layer of PET.

Intensive combination chemotherapy, concurrent chest irradiation, and warfarin for the treatment of limited-disease small-cell lung cancer: a Cancer and Leukemia Group B pilot study.

PubMed

Aisner, J; Goutsou, M; Maurer, L H; Cooper, R; Chahinian, P; Carey, R; Skarin, A; Slawson, R; Perry, M C; Green, M R

1992-08-01

In prior Cancer and Leukemia Group B (CALGB) studies, combined chemotherapy and thoracic irradiation was superior to chemotherapy alone in limited-disease (LD) small-cell lung cancer (SCLC). A combined modality pilot study was performed to test the feasibility of adding warfarin to aggressive chemoradiotherapy for LD SCLC. Combination chemotherapy with doxorubicin 45 mg/m2 intravenously (IV) on day 1, cyclophosphamide 800 mg/m2 IV on day 1, and etoposide (ACE) 80 mg/m2 on days 1 to 3 was given every 21 days for the first three courses. The fourth and fifth courses substituted cisplatin 33 mg/m2 IV on days 1 to 3 for the doxorubicin, with concurrent chest irradiation to a total of 4,000 cGy given in 20 fractions during a 4-week period followed by a boost of 1,000 cGy in five fractions during a 1-week period. Prophylactic cranial irradiation, 3,000 cGy was given concurrently in 10 fractions during a 2-week period. Courses 6 to 8 again used ACE chemotherapy, but courses 4 to 8 were given on a 28-day schedule with dose adjustment for hematologic or renal toxicity. Warfarin was given throughout the treatment period titrated to achieve a prothrombin time (PT) of 1.5 to 2 times the control. Patients with histologically proven limited-stage SCLC, good performance status, and normal renal, hematologic, and hepatic functions were eligible. Sixty-one of 66 patients entered onto the study were eligible and assessable. Fifty-four (89%) (95%) confidence interval [CI], 78% to 95%) experienced an objective response, 35 (57%) achieved a complete response (CR) (95% CI, 44% to 70%), and 17 (28%) achieved a partial response (95% CI, 16% to 39%). Median durations were CR, 26.3 months; failure-free survival, 11.8 months; and survival, 18 months. Forty-one percent of the patients were alive at 2 years, 33% were alive at 3 years, and 25% were alive at 4 or more years. Median follow-up for survivors is 5 years (range, 3.5 to 5.9 years). Severe or life-threatening myelosuppression occurred in 90%, infection occurred in 34%, fever without documented infection occurred in 26%, and pulmonary toxicity occurred in 6%. Another 6% of patients experienced severe or life-threatening hemorrhages. There were four treatment-related fatalities. The pulmonary toxicities have been associated with the resumption of ACE chemotherapy after chest irradiation. These highly encouraging response and survival results compare favorably with any prior CALGB group study. Although they are somewhat more toxic, they are comparable to the best published results. A randomized study that examines the role of warfarin is underway.

Influence of oxygen vacancies in ALD HfO2-x thin films on non-volatile resistive switching phenomena with a Ti/HfO2-x/Pt structure

NASA Astrophysics Data System (ADS)

Sokolov, Andrey Sergeevich; Jeon, Yu-Rim; Kim, Sohyeon; Ku, Boncheol; Lim, Donghwan; Han, Hoonhee; Chae, Myeong Gyoon; Lee, Jaeho; Ha, Beom Gil; Choi, Changhwan

2018-03-01

We report a modulation of oxygen vacancies profile in atomic layer deposition (ALD) HfO2-x thin films by reducing oxidant pulse time (0.7 s-0.1 s) and study its effect on resistive switching behavior with a Ti/HfO2-x/Pt structure. Hf 4f spectra of x-ray photoelectron microscopy (XPS) and depth profile confirm varied oxygen vacancies profiles by shifts of binding energies of Hf 4f5/2 and Hf 4f7/2 main peaks and its according HfO2-x sub-oxides for each device. The ultraviolet photoelectron spectroscopy (UPS) confirms different electron affinity (χ) of HfO2 and HfO2-x thin films, implying that barrier height at Ti/oxide interface is reduced. Current transport mechanism is dictated by Ohmic conduction in fully oxidized HfO2 thin films - Device A (0.7 s) and by Trap Filled Space Charge Limited Conduction (TF-SCLC) in less oxidized HfO2-x thin films - Device B (0.3 s) and Device C (0.1 s). A switching mechanism related to the oxygen vacancies modulation in Ti/HfO2-x/Pt based resistive random access memory (RRAM) devices is used to explain carefully notified current transport mechanism variations from device-to-device. A proper endurance and long-time retention characteristics of the devices are also obtained.

Factors affecting 30-month survival in lung cancer patients.

PubMed

Mahesh, P A; Archana, S; Jayaraj, B S; Patil, Shekar; Chaya, S K; Shashidhar, H P; Sunitha, B S; Prabhakar, A K

2012-10-01

Age adjusted incidence rate of lung cancer in India ranges from 7.4 to 13.1 per 100,000 among males and 3.9 to 5.8 per 100,000 among females. The factors affecting survival in lung cancer patients in India are not fully understood. The current study was undertaken to evaluate the factors affecting survival in patients diagnosed with lung cancer attending a tertiary care cancer institute in Bangalore, Karnataka, India. Consecutive patients with primary lung cancer attending Bangalore Institute of Oncology, a tertiary care centre at Bangalore, between 2006 and 2009 were included. Demographic, clinical, radiological data were collected retrospectively from the medical records. A total of 170 consecutive subjects (128 males, 42 females) diagnosed to have lung cancer; 151 non-small cell lung cancer (NSCLC) and 19 small cell lung cancer (SCLC) were included. A higher proportion of never-smokers (54.1%) were observed, mostly presenting below the age of 60 yr. Most subjects were in stage IV and III at the time of diagnosis. More than 50 per cent of patients presented with late stage lung cancer even though the duration of symptoms is less than 2 months. The 30-month overall survival rates for smokers and never-smokers were 32 and 49 per cent, respectively. No significant differences were observed in 30 month survival based on age at presentation, gender and type of lung cancer. Cox proportional hazards model identified never-smokers and duration of symptoms less than 1 month as factors adversely affecting survival. Our results showed that lung cancer in Indians involved younger subjects and associated with poorer survival as compared to other ethnic population. Studies on large sample need to be done to evaluate risk factors in lung cancer patients.

Factors affecting 30-month survival in lung cancer patients

PubMed Central

Mahesh, P.A.; Archana, S.; Jayaraj, B.S.; Patil, Shekar; Chaya, S.K.; Shashidhar, H.P.; Sunitha, B.S.; Prabhakar, A.K.

2012-01-01

Background & objectives: Age adjusted incidence rate of lung cancer in India ranges from 7.4 to 13.1 per 100,000 among males and 3.9 to 5.8 per 100,000 among females. The factors affecting survival in lung cancer patients in India are not fully understood. The current study was undertaken to evaluate the factors affecting survival in patients diagnosed with lung cancer attending a tertiary care cancer institute in Bangalore, Karnataka, India. Methods: Consecutive patients with primary lung cancer attending Bangalore Institute of Oncology, a tertiary care centre at Bangalore, between 2006 and 2009 were included. Demographic, clinical, radiological data were collected retrospectively from the medical records. Results: A total of 170 consecutive subjects (128 males, 42 females) diagnosed to have lung cancer; 151 non-small cell lung cancer (NSCLC) and 19 small cell lung cancer (SCLC) were included. A higher proportion of never-smokers (54.1%) were observed, mostly presenting below the age of 60 yr. Most subjects were in stage IV and III at the time of diagnosis. More than 50 per cent of patients presented with late stage lung cancer even though the duration of symptoms is less than 2 months. The 30-month overall survival rates for smokers and never-smokers were 32 and 49 per cent, respectively. No significant differences were observed in 30 month survival based on age at presentation, gender and type of lung cancer. Cox proportional hazards model identified never-smokers and duration of symptoms less than 1 month as factors adversely affecting survival. Interpretation & conclusions: Our results showed that lung cancer in Indians involved younger subjects and associated with poorer survival as compared to other ethnic population. Studies on large sample need to be done to evaluate risk factors in lung cancer patients. PMID:23168702

Neurologic, neuropsychologic, and computed cranial tomography scan abnormalities in 2- to 10-year survivors of small-cell lung cancer.

PubMed

Johnson, B E; Becker, B; Goff, W B; Petronas, N; Krehbiel, M A; Makuch, R W; McKenna, G; Glatstein, E; Ihde, D C

1985-12-01

In order to evaluate the relationship between neurologic function and cranial irradiation, 20 patients treated on National Cancer Institute (NCI) small-cell lung cancer (SCLC) trials who were alive and free of cancer 2.4 to 10.6 years (median, 6.2) from the start of therapy were studied. All were tested with a neurologic history and examination, mental status examination, neuropsychologic testing, and review of serial computed cranial tomography (CCT) scans. Fifteen patients had been treated with prophylactic cranial irradiation (PCI), two patients with therapeutic cranial irradiation, and three received no cranial irradiation. All patients but one were ambulatory and none were institutionalized. Fifteen patients (75%) had neurologic complaints, 13 (65%) had abnormal neurologic examinations, 12 (60%) had abnormal mental status examinations, 13 (65%) had abnormal neuropsychologic testing, and 15 (75%) had abnormal CCT scans. Compared with those given low-dose maintenance chemotherapy during PCI using 200 to 300 rad per fraction, patients who were given high-dose induction chemotherapy during the time of cranial irradiation or large radiotherapy fractions (400 rad) were more likely to have abnormal mental status examinations (6/6 v 4/9) and abnormal neuropsychologic tests (6/6 v 4/9), but no major difference in CCT findings was present. CCT scans in the majority of cases (11/18) showed progressive ventricular dilatation or cerebral atrophy up to 8 years after stopping therapy. We conclude neurologic abnormalities are common in long-term survivors of SCLC, and may be more prominent in patients given high-dose chemotherapy during cranial irradiation or treated with large radiotherapy fractions. The CCT scan abnormalities are common and progressive years after prophylactic cranial irradiation and chemotherapy are stopped.

Increased pro-angiogenic factors, infiltrating neutrophils and CD163(+) macrophages in bronchoalveolar lavage fluid from lung cancer patients.

PubMed

Chen, Lu; Li, Qian; Zhou, Xiang-dong; Shi, Yu; Yang, Lang; Xu, Sen-lin; Chen, Cong; Cui, You-hong; Zhang, Xia; Bian, Xiu-wu

2014-05-01

Infiltration of inflammatory cells and production of pro-angiogenic factors are important in lung cancer immunity. The distributions of those cells and their contributions to the production of pro-angiogenic factors and the activation phenotype of macrophages in bronchoalveolar lavage fluid (BALF) from lung cancer patients remain unclear. We analyzed the presence of distinct inflammatory cells and the macrophage activation phenotype together with the levels of vascular endothelial growth factor (VEGF) and interleukin 8 (IL-8) within BALF from 54 smoking lung cancer patients including 36 squamous cell carcinoma (SCC), 9 adenocarcinoma (AC), and 9 small cell lung cancer (SCLC) in comparison with those from 13 non-smoking and 7 smoking patients with nonspecific chronic inflammation and 8 non-smoking normal controls. We found a significantly lower percentage of total macrophages and a much higher percentage of neutrophils among all inflammatory cells in BALF from lung cancer and non-specific chronic inflammation patients. BALF from AC patients had a significantly higher percentage of lymphocytes. CD163(+)) macrophages predominantly existed in BALF from SCLC patients. BALF of lung cancer patients had markedly higher levels of IL-8 and VEGF. Interestingly, IL-8 level was positively correlated to the numbers of neutrophils and lymphocytes. VEGF level was inversely correlated to the number of lymphocytes but positively to cancer cells in SCC cases, whereas no correlation existed between CD163(+)) macrophages and the levels of IL-8 and VEGF. Our results suggest that the detection of infiltrating inflammatory cells and pro-angiogenic factors in BALF will be helpful for diagnosis of cancerous inflammation in lungs. Copyright © 2014 Elsevier B.V. All rights reserved.

Cytology-based treatment decision in primary lung cancer: is it accurate enough?

PubMed

Sakr, Lama; Roll, Patrice; Payan, Marie-José; Liprandi, Agnès; Dutau, Hervé; Astoul, Philippe; Robaglia-Schlupp, Andrée; Loundou, Anderson; Barlesi, Fabrice

2012-03-01

Accurate distinction of lung cancer types has become increasingly important as recent trials have shown differential response to chemotherapy among non-small cell lung carcinoma (NSCLC) subtypes. Cytological procedures are frequently used but their diagnostic accuracy has been previously questioned. However, new endoscopic and cytological techniques might have improved cytological accuracy in comparison with prior findings. The aim of this study was to reassess cytological accuracy for diagnosis of lung cancer subtypes. A retrospective chart review of subjects who underwent fiberoptic bronchoscopy (FOB) for suspicion of lung cancer in 2007-2008, was undertaken. Reports of bronchoscopically derived cytological specimens were compared to those of histological material. Endoscopic findings and specific investigational techniques were taken into account. A total of 467 FOB with both cytological and histological diagnostic techniques were performed in 449 subjects. Patients consisted of 345 men and 104 women (median age, 65 yrs). Cytology proved malignancy in 157 patients. Cytologically diagnosed carcinomas were classified into squamous cell carcinoma (SqCC) in 56, adenocarcinoma (ADC) in 6, small cell lung carcinoma (SCLC) in 12, non-small cell lung carcinoma not otherwise specified (NSCLC-NOS) in 71, and unclassified carcinoma in 12. Cytology correlated fairly with biopsy specimens, as agreement was observed in 83% of SCLC, 100% of ADC, 74% of SqCC and 8% of NSCLC-NOS. Interestingly, 61% of cytologically identified NSCLC-NOS were classified as ADC by histology. Cytological accuracy improved in case of an endobronchial lesion, mainly for SqCC. These results indicate that cytological accuracy remains fair with regard to diagnosis of squamous and non-squamous lung cancer subtypes. Improvement of cytological accuracy is expected however with novel diagnostic strategies. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Development of an automated size-based filtration system for isolation of circulating tumor cells in lung cancer patients.

PubMed

Yagi, Satomi; Koh, Yasuhiro; Akamatsu, Hiroaki; Kanai, Kuninobu; Hayata, Atsushi; Tokudome, Nahomi; Akamatsu, Keiichiro; Endo, Katsuya; Nakamura, Seita; Higuchi, Masayuki; Kanbara, Hisashige; Nakanishi, Masanori; Ueda, Hiroki; Yamamoto, Nobuyuki

2017-01-01

Circulating tumor cells (CTCs), defined as tumor cells circulating in the peripheral blood of patients with solid tumors, are relatively rare. Diagnosis using CTCs is expected to help in the decision-making for precision cancer medicine. We have developed an automated microcavity array (MCA) system to detect CTCs based on the differences in size and deformability between tumor cells and normal blood cells. Herein, we evaluated the system using blood samples from non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) patients. To evaluate the recovery of CTCs, preclinical experiments were performed by spiking NSCLC cell lines (NCI-H820, A549, NCI-H23 and NCI-H441) into peripheral whole blood samples from healthy volunteers. The recovery rates were 70% or more in all cell lines. For clinical evaluation, 6 mL of peripheral blood was collected from 50 patients with advanced lung cancer and from 10 healthy donors. Cells recovered on the filter were stained. We defined CTCs as DAPI-positive, cytokeratin-positive, and CD45-negative cells under the fluorescence microscope. The 50 lung cancer patients had a median age of 72 years (range, 48-85 years); 76% had NSCLC and 20% had SCLC, and 14% were at stage III disease whereas 86% were at stage IV. One or more CTCs were detected in 80% of the lung cancer patients (median 2.5). A comparison of the CellSearch system with our MCA system, using the samples from NSCLC patients, confirmed the superiority of our system (median CTC count, 0 versus 11 for CellSearch versus MCA; p = 0.0001, n = 17). The study results suggest that our MCA system has good clinical potential for diagnosing CTCs in lung cancer.

Lung cancer incidence and survival in chromium exposed individuals with respect to expression of anti-apoptotic protein survivin and tumor suppressor P53 protein

PubMed Central

2010-01-01

Objective Workers chronically exposed to hexavalent chromium have elevated risk of lung cancer. Our study investigates the incidence of lung cancer types, age at onset of the disease, and survival time among chromium exposed workers with respect to the expression of anti-apoptotic p53 and pro-apoptotic survivin proteins. Materials and methods 67 chromium exposed workers and 104 male controls diagnosed with lung cancer were analyzed. The mean exposure time among workers was 16.7 ± 10.0(SD) years (range 1- 41 years). To investigate the possible regulation of survivin by p53 we examined the expression of both proteins using immohistochemical visualization. Results Chromium exposure significantly decreases the age of onset of the disease by 3.5 years (62.2 ± 9.1 in the exposed group vs. 65.7 ± 10.5 years in controls; P = 0.018). Small cell lung carcinoma (SCLC) amounted for 25.4% of all cases in chromium exposed workers and for 16.3% in non-exposed individuals. The mean survival time in the exposed group was 9.0 ± 12.7 vs. 12.1 ± 21.9 months in controls, but this difference was not significant. Survivin was predominantly expressed in both cell nucleus and cytoplasm, whereas p53 was expressed in the nucleus. There was a negative correlation between survivin and p53 expression. A decreased intensity of expression and fewer cells positive for survivin was detected in SCLC compared with other types of lung cancer. P53 was expressed in 94.1% and survivin in 79.6% of the samples analyzed. Conclusion The study calls attention to decreased expression of survivin, as opposed to p53, in small cell lung carcinoma. PMID:21147621

Diagnostic accuracy of bronchial brush cytology and the added value of immunohistochemistry and fluorescence in situ hybridization of pulmonary neuroendocrine tumors

PubMed Central

Reynolds, Jordan P.; Voss, Jesse S.; Brankley, Shannon M.; Caudill, Jill M.; Henry, Michael R.; Clayton, Amy C.; Halling, Kevin C.; Nassar, Aziza

2014-01-01

Background: Bronchial brush (BB) cytology carries low sensitivity for detecting neuroendocrine carcinomas (NECs), including typical carcinoid (TC) tumors of the lung. We aimed to investigate the detection of neuroendocrine tumors including TC through BB routine cytology cell block (CB), immunohistochemistry (IHC), and fluorescence in situ hybridization (FISH). Materials and Methods: A SNOMED search showed 187 lung biopsy or resection specimens from 2008 through 2011 containing neuroendocrine or carcinoid in the diagnosis. Residual BB specimens retained in PreservCyt were used to prepare a ThinPrep slide for FISH analysis. CBs were stained with H and E and IHC for chromogranin and synaptophysin. Results: Of the 187 cases, 16 had residual BB material available within 1 year of diagnosis and were used in CB preparation for IHC and FISH slides. Cytologic evaluation determined 1 case positive for malignancy (small cell lung carcinoma [SCLC]), 1 suspicious for adenocarcinoma, and 14 negative for malignancy. On the basis of histologic diagnosis, FISH was performed. SCLC showed polysomy (86% abnormal cells); 2 TC tumors showed a gain of 7p12 (15% abnormal cells) and a gain of 5q15 (72% abnormal cells), respectively. Two cases had CBs with positive immunoreactivity for chromogranin and synaptophysin. The sensitivity for detection of NEC was 18.8%, 15.4%, and 25% for cytologic evaluation, CB, and FISH, respectively. Conclusion: Neuroendocrine tumors, including TC are difficult to detect with BB cytologic evaluation, most likely because tumor cells lack in the specimen. Assessment of further studies is needed to explore the role of cytology and ancillary methods for detection of these tumors. PMID:25558272

An All-Organic Composite System for Resistive Change Memory via the Self-Assembly of Plastic-Crystalline Molecules.

PubMed

Cha, An-Na; Lee, Sang-A; Bae, Sukang; Lee, Sang Hyun; Lee, Dong Su; Wang, Gunuk; Kim, Tae-Wook

2017-01-25

An all-organic composite system was introduced as an active component for organic resistive memory applications. The active layer was prepared by mixing a highly polar plastic-crystalline organic molecule (succinonitrile, SN) into an insulating polymer (poly(methyl methacrylate), PMMA). As increasing concentrations of SN from 0 to 3.0 wt % were added to solutions of different concentrations of PMMA, we observed distinguishable microscopic surface structures on blended films of SN and PMMA at certain concentrations after the spin-casting process. The structures were organic dormant volcanos composed of micron-scale PMMA craters and disk type SN lava. Atomic force microscopy (AFM), cross-sectional transmission electron microscopy (TEM), scanning electron microscopy (SEM), and energy dispersive X-ray spectrometer (EDX) analysis showed that these structures were located in the middle of the film. Self-assembly of the plastic-crystalline molecules resulted in the phase separation of the SN:PMMA mixture during solvent evaporation. The organic craters remained at the surface after the spin-casting process, indicative of the formation of an all-organic composite film. Because one organic crater contains one SN disk, our system has a coplanar monolayer disk composite system, indicative of the simplest composite type of organic memory system. Current-voltage (I-V) characteristics of the composite films with organic craters revealed that our all-organic composite system showed unipolar type resistive switching behavior. From logarithmic I-V characteristics, we found that the current flow was governed by space charge limited current (SCLC). From these results, we believe that a plastic-crystalline molecule-polymer composite system is one of the most reliable ways to develop organic composite systems as potential candidates for the active components of organic resistive memory applications.

Multidetector computed tomography findings of central bronchopleural fistulas as sequelae of tuberculosis, chemo radiation and trauma: A report of three cases

PubMed Central

Yuksekkaya, Ruken; Ozturk, Banu; Celikyay, Fatih; Sade, Recep; Kupeli, Mustafa; Yeginsu, Ali

2013-01-01

A bronchopleural fistula (BPF) is defined as a direct pathway between the bronchial tree or lung parenchyma and the pleural space. Herein, we describe the clinical findings and imaging results of BPFs in three cases. The patients' medical histories revealed that the first had recurrent pulmonary tuberculosis, the second had small-cell lung cancer (SCLC) and had previously undergone chemoradiotherapy, and the third had trauma. Multidetector computed tomography (MDCT) showed clear communication between the airways and pleural spaces which was sufficient for a proper diagnosis without performing a bronchoscopy. PMID:26029624

Prognostic value of the neutrophil to lymphocyte ratio in lung cancer: A meta-analysis.

PubMed

Yin, Yongmei; Wang, Jun; Wang, Xuedong; Gu, Lan; Pei, Hao; Kuai, Shougang; Zhang, Yingying; Shang, Zhongbo

2015-07-01

Recently, a series of studies explored the correlation between the neutrophil to lymphocyte ratio and the prognosis of lung cancer. However, the current opinion regarding the prognostic role of the neutrophil to lymphocyte ratio in lung cancer is inconsistent. We performed a meta-analysis of published articles to investigate the prognostic value of the neutrophil to lymphocyte ratio in lung cancer. The hazard ratio (HR) and its 95% confidence interval (CI) were calculated. An elevated neutrophil to lymphocyte ratio predicted worse overall survival, with a pooled HR of 1.243 (95%CI: 1.106-1.397; P(heterogeneity)=0.001) from multivariate studies and 1.867 (95%CI: 1.487-2.344; P(heterogeneity)=0.047) from univariate studies. Subgroup analysis showed that a high neutrophil to lymphocyte ratio yielded worse overall survival in non-small cell lung cancer (NSCLC) (HR=1.192, 95%CI: 1.061-1.399; P(heterogeneity)=0.003) as well as small cell lung cancer (SCLC) (HR=1.550, 95% CI: 1.156-2.077; P(heterogeneity)=0.625) in multivariate studies. The synthesized evidence from this meta-analysis of published articles demonstrated that an elevated neutrophil to lymphocyte ratio was a predictor of poor overall survival in patients with lung cancer.

Growth and electrical transport properties of InGaN/GaN heterostructures grown by PAMBE

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sinha, Neeraj; Department of Materials Science, Gulbarga University, Gulbarga 585106; Roul, Basanta, E-mail: basantaroul@gmail.com

2015-01-15

Highlights: • InGaN thin films were grown on GaN template by PAMBE. • InGaN films were characterized by HRXRD, SEM and PL and Raman spectroscopy. • The indium incorporation in single phase InGaN films was found to be 23%. • The I–V characteristic of the InGaN/GaN heterojunction shows rectifying behavior. • Log–log plot of the I–V characteristics indicates the presence of SCLC mechanism. - Abstract: InGaN epitaxial films were grown on GaN template by plasma-assisted molecular beam epitaxy. The composition of indium incorporation in single phase InGaN film was found to be 23%. The band gap energy of single phasemore » InGaN was found to be ∼2.48 eV. The current–voltage (I–V) characteristic of InGaN/GaN heterojunction was found to be rectifying behavior which shows the presence of Schottky barrier at the interface. Log–log plot of the I–V characteristics under forward bias indicates the current conduction mechanism is dominated by space charge limited current mechanism at higher applied voltage, which is usually caused due to the presence of trapping centers. The room temperature barrier height and the ideality factor of the Schottky junction were found to 0.76 eV and 4.9 respectively. The non-ideality of the Schottky junction may be due to the presence of high pit density and dislocation density in InGaN film.« less

Influence of Methylenetetrahydrofolate Reductase C677T Polymorphism on the Risk of Lung Cancer and the Clinical Response to Platinum-Based Chemotherapy for Advanced Non-Small Cell Lung Cancer: An Updated Meta-Analysis

PubMed Central

Zhu, Ning; Gong, Yi; He, Jian; Xia, Jingwen

2013-01-01

Purpose Methylenetetrahydrofolate reductase (MTHFR) has been implicated in lung cancer risk and response to platinum-based chemotherapy in advanced non-small cell lung cancer (NSCLC). However, the results are controversial. We performed meta-analysis to investigate the effect of MTHFR C677T polymorphism on lung cancer risk and response to platinum-based chemotherapy in advanced NSCLC. Materials and Methods The databases of PubMed, Ovid, Wanfang and Chinese Biomedicine were searched for eligible studies. Nineteen studies on MTHFR C677T polymorphism and lung cancer risk and three articles on C677T polymorphism and response to platinum-based chemotherapy in advanced NSCLC, were identified. Results The results indicated that the allelic contrast, homozygous contrast and recessive model of the MTHFR C677T polymorphism were associated significantly with increased lung cancer risk. In the subgroup analysis, the C677T polymorphism was significantly correlated with an increased risk of NSCLC, with the exception of the recessive model. The dominant model and the variant T allele showed a significant association with lung cancer susceptibility of ever smokers. Male TT homozygote carriers had a higher susceptibility, but the allelic contrast and homozygote model had a protective effect in females. No relationship was observed for SCLC in any comparison model. In addition, MTHFR 677TT homozygote carriers had a better response to platinum-based chemotherapy in advanced NSCLC in the recessive model. Conclusion The MTHFR C677T polymorphism might be a genetic marker for lung cancer risk or response to platinum-based chemotherapy in advanced NSCLC. However, our results require further verification. PMID:24142642

PET and SPECT imaging of a radiolabeled minigastrin analogue conjugated with DOTA, NOTA, and NODAGA and labeled with (64)Cu, (68)Ga, and (111)In.

PubMed

Roosenburg, S; Laverman, P; Joosten, L; Cooper, M S; Kolenc-Peitl, P K; Foster, J M; Hudson, C; Leyton, J; Burnet, J; Oyen, W J G; Blower, P J; Mather, S J; Boerman, O C; Sosabowski, J K

2014-11-03

Cholecystokinin-2 (CCK-2) receptors, overexpressed in cancer types such as small cell lung cancers (SCLC) and medullary thyroid carcinomas (MTC), may serve as targets for peptide receptor radionuclide imaging. A variety of CCK and gastrin analogues has been developed, but a major drawback is metabolic instability or high kidney uptake. The minigastrin analogue PP-F11 has previously been shown to be a promising peptide for imaging of CCK-2 receptor positive tumors and was therefore further evaluated. The peptide was conjugated with one of the macrocyclic chelators DOTA, NOTA, or NODAGA. The peptide conjugates were then radiolabeled with either (68)Ga, (64)Cu, or (111)In. All (radio)labeled compounds were evaluated in vitro (IC50) and in vivo (biodistribution and PET/CT and SPECT/CT imaging). IC50 values were in the low nanomolar range for all compounds (0.79-1.51 nM). In the biodistribution studies, (68)Ga- and (111)In-labeled peptides showed higher tumor-to-background ratios than the (64)Cu-labeled compounds. All tested radiolabeled compounds clearly visualized the CCK2 receptor positive tumor in PET or SPECT imaging. The chelator did not seem to affect in vivo behavior of the peptide for (111)In- and (68)Ga-labeled peptides. In contrast, the biodistribution of the (64)Cu-labeled peptides showed high uptake in the liver and in other organs, most likely caused by high blood levels, probably due to dissociation of (64)Cu from the chelator and subsequent transchelation to proteins. Based on the present study, (68)Ga-DOTA-PP-F11 might be a promising radiopharmaceutical for PET/CT imaging of CCK2 receptor expressing tumors such as MTC and SCLC. Clinical studies are warranted to investigate the potential of this tracer.

Outcome in patients with small cell lung cancer re-irradiated for brain metastases after prior prophylactic cranial irradiation.

PubMed

Bernhardt, Denise; Bozorgmehr, Farastuk; Adeberg, Sebastian; Opfermann, Nils; von Eiff, Damian; Rieber, Juliane; Kappes, Jutta; Foerster, Robert; König, Laila; Thomas, Michael; Debus, Jürgen; Steins, Martin; Rieken, Stefan

2016-11-01

Patients with brain metastases from small-cell lung cancer (SCLC) who underwent prior prophylactic cranial irradiation (PCI) are often treated with a second course of whole brain radiation therapy (Re-WBRT) or stereotactic radiosurgery (SRS) for purposes of palliation in symptomatic patients, hope for increased life expectancy or even as an alternative to untolerated steroids. Up to date there is only limited data available regarding the effect of this treatment. This study examines outcomes in patients in a single institution who underwent cerebral re-irradiation after prior PCI. We examined the medical records of 76 patients with brain metastases who had initially received PCI between 2008 and 2015 and were subsequently irradiated with a second course of cerebral radiotherapy. Patients underwent re-irradiation using either Re-WBRT (88%) or SRS (17%). The outcomes, including symptom palliation, radiation toxicity, and overall survival (OS) following re-irradiation were analyzed. Survival and correlations were calculated using log-rank, univariate, and multivariate Cox proportional hazards-ratio analyses. Treatment-related toxicity was classified according to CTCAE v4.0. Median OS of all patients was 3 months (range 0-12 months). Median OS after Re-WBRT was 3 months (range 0-12 months). Median OS after SRS was 5 months (range 0-12 months). Karnofsky performance status scale (KPS ≥50%) was significantly associated with improved OS in both univariate (HR 2772; p=0,009) and multivariate analyses (HR 2613; p=0,024) for patients receiving Re-WBRT. No unexpected toxicity was observed and the observed toxicity remained consistently low. Symptom palliation was achieved in 40% of symptomatic patients. In conclusion, cerebral re-irradiation after prior PCI is beneficial for symptom palliation and is associated with minimal side effects in patients with SCLC. Our survival data suggests that it is primarily useful in patients with adequate performance status. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Synchronous Pulmonary Neoplasms: A Chance Occurrence or is There More Than Meets the Eye?

PubMed

Ibrahim, Uroosa; Saqib, Amina; Pant, Manisha; Garcia, Gwenalyn; Odaimi, Marcel

2018-02-06

Primary bronchus-associated lymphoid tissue (BALT) lymphoma comprises 5% of non-Hodgkin's lymphoma (NHL) and usually has an indolent course. Synchronous primary lung cancers with BALT lymphoma are seldom seen in patients with adenocarcinoma of the lung. Synchronous squamous cell carcinoma (SCC) and BALT lymphoma is an extremely rare occurrence. We report an unusual case of stage 4 BALT lymphoma requiring treatment that revealed an underlying ipsilateral mass causing a diagnostic dilemma. An 84-year-old female with a history of systemic lupus erythematosus, deep vein thrombosis, and thrombotic microangiopathy presented to the hospital with cough and dyspnea on exertion. A chest X-ray revealed right hemi-thorax opacification and computed tomography (CT) of the chest showed a large right effusion and a soft tissue density extending into the proximal right bronchus. She required repeated thoracentesis until the pleural fluid analysis showed the presence of small lymphocytes and bronchial washings revealed an abnormal B cell population consistent with extranodal marginal zone lymphoma. The patient received four cycles of bendamustine and rituximab resulting in near-complete resolution of the effusion. Four months from diagnosis, imaging showed an increase in the size of the soft tissue density with pathologic fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET). A CT-guided biopsy was consistent with squamous cell lung cancer (SCLC) and radiotherapy was started for clinical stage 2 disease since the patient was not a surgical candidate. BALT lymphoma is a low-grade malignancy classified as extranodal marginal zone lymphoma with a five-year survival rate of over 80%. Several cases of synchronous lung adenocarcinoma and BALT lymphoma have been described. However, our case is among the rare few cases of synchronous occurrence of SCLC with BALT lymphoma. This report highlights the challenges associated with establishing an accurate and timely diagnosis.

SU-E-T-664: Radiobiological Modeling of Prophylactic Cranial Irradiation in Mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Smith, D; Debeb, B; Woodward, W

Purpose: Prophylactic cranial irradiation (PCI) is a clinical technique used to reduce the incidence of brain metastasis and improve overall survival in select patients with ALL and SCLC, and we have shown the potential of PCI in select breast cancer patients through a mouse model (manuscript in preparation). We developed a computational model using our experimental results to demonstrate the advantage of treating brain micro-metastases early. Methods: MATLAB was used to develop the computational model of brain metastasis and PCI in mice. The number of metastases per mouse and the volume of metastases from four- and eight-week endpoints were fitmore » to normal and log-normal distributions, respectively. Model input parameters were optimized so that model output would match the experimental number of metastases per mouse. A limiting dilution assay was performed to validate the model. The effect of radiation at different time points was computationally evaluated through the endpoints of incidence, number of metastases, and tumor burden. Results: The correlation between experimental number of metastases per mouse and the Gaussian fit was 87% and 66% at the two endpoints. The experimental volumes and the log-normal fit had correlations of 99% and 97%. In the optimized model, the correlation between number of metastases per mouse and the Gaussian fit was 96% and 98%. The log-normal volume fit and the model agree 100%. The model was validated by a limiting dilution assay, where the correlation was 100%. The model demonstrates that cells are very sensitive to radiation at early time points, and delaying treatment introduces a threshold dose at which point the incidence and number of metastases decline. Conclusion: We have developed a computational model of brain metastasis and PCI in mice that is highly correlated to our experimental data. The model shows that early treatment of subclinical disease is highly advantageous.« less

Strategies to eradicate minimal residual disease in small cell lung cancer: high-dose chemotherapy with autologous bone marrow transplantation, matrix metalloproteinase inhibitors, and BEC2 plus BCG vaccination.

PubMed

Krug, L M; Grant, S C; Miller, V A; Ng, K K; Kris, M G

1999-10-01

In the last 25 years, treatment for small cell lung cancer (SCLC) has improved with advances in chemotherapy and radiotherapy. Standard chemotherapy regimens can yield 80% to 90% response rates and some cures when combined with thoracic irradiation in limited-stage patients. Nonetheless, small cell lung cancer has a high relapse rate due to drug resistance; this has resulted in poor survival for most patients. Attacking this problem requires a unique approach to eliminate resistant disease remaining after induction therapy. This review will focus on three potential strategies: high-dose chemotherapy with autologous bone marrow transplantation, matrix metalloproteinase inhibitors, and BEC2 plus BCG vaccination.

Hetero Bis-Addition of Spiro-Acetalized or Cyclohexanone Ring to 58π Fullerene Impacts Solubility and Mobility Balance in Polymer Solar Cells.

PubMed

Mikie, Tsubasa; Saeki, Akinori; Ikuma, Naohiko; Kokubo, Ken; Seki, Shu

2015-06-17

Fullerene bis-adducts are increasingly being studied to gain a high open circuit voltage (Voc) in bulk heterojunction organic photovoltaics (OPVs). We designed and synthesized homo and hetero bis-adduct [60]fullerenes by combining fused cyclohexanone or a five-membered spiro-acetalized unit (SAF5) with 1,2-dihydromethano (CH2), indene, or [6,6]-phenyl-C61-butyric acid methyl ester (PCBM). These new eight 56π fullerenes showed a rational rise of the lowest unoccupied molecular orbital (LUMO). We perform a systematic study on the electrochemical property, solubility, morphology, and space-charge-limited current (SCLC) mobility. The best power conversion efficiency (PCE) of 4.43% (average, 4.36%) with the Voc of 0.80 V was obtained for poly(3-hexylthiophene) (P3HT) blended with SAF5/indene hetero bis-adduct, which is a marked advancement in PCE compared to the 0.9% of SAF5 monoadduct. More importantly, we elucidate an important role of mobility balance between hole and electron that correlates with the device PCEs. Besides, an empirical equation to extrapolate the solubilities of hetero bis-adducts is proposed on the basis of those of counter monoadducts. Our work offers a guide to mitigate barriers for exploring a large number of hetero bis-adduct fullerenes for efficient OPVs.

Optical and electrical properties of TiOPc doped Alq{sub 3} thin films

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ramar, M.; Suman, C. K., E-mail: sumanck@nplindia.org; Tyagi, Priyanka

2015-06-24

The Titanyl phthalocyanine (TiOPc) was doped in Tris (8-hydroxyquinolinato) aluminum (Alq3) with different concentration. The thin film of optimized doping concentration was studied extensively for optical and electrical properties. The optical properties, studied using ellipsometry, absorption and photoluminescence. The absorption peak of Alq{sub 3} and TiOPc was observed at 387 nm and 707 nm and the photo-luminescence intensity (PL) peak of doped thin film was observed at 517 nm. The DC and AC electrical properties of the thin film were studied by current density-voltage (J-V) characteristics and impedance over a frequency range of 100 Hz - 1 MHz. The electron mobility calculated from trap-free space-chargemore » limited region (SCLC) is 0.17×10{sup −5} cm{sup 2}/Vs. The Cole-Cole plots shows that the TiOPc doped Alq{sub 3} thin film can be represented by a single parallel resistance R{sub P} and capacitance C{sub P} network with a series resistance R{sub S} (10 Ω). The value of R{sub P} and C{sub P} at zero bias was 1587 Ω and 2.568 nF respectively. The resistance R{sub P} decreases with applied bias whereas the capacitance C{sub P} remains almost constant.« less

Current-voltage characteristics of organic semiconductors: Interfacial control between organic layers and electrodes

NASA Astrophysics Data System (ADS)

Kondo, Takeshi

2007-12-01

Current-voltage (I-V) characteristics of organic molecular glasses and solution processable materials embedded between two electrodes were studied to find materials possessing high charge-carrier mobilities and to design organic memory devices. The comparison studies between TOF, FET and SCLC measurements confirm the validity of using analyses of I-V characteristics to determine the mobility of organic semiconductors. Hexaazatrinaphthylene derivatives tri-substituted by electron withdrawing groups were characterized as potential electron transporting molecular glasses. The presence of two isomers has important implications for film morphology and effective mobility. The statistical isomer mixture of hexaazatrinaphthylene derivatized with pentafluoro-phenylmethyl ester is able to form amorphous films, and electron mobilities with the range of 10--2 cm2/Vs are observed in their I-V characteristics. Single-layer organic memory devices consisting of a polymer layer embedded between an Al electrode and ITO modified with Ag nanodots (Ag-NDs) prepared by a solution-based surface assembly demonstrated a potential capability as nonvolatile organic memory device with high ON/OFF switching ratios of 10 4. This level of performance could be achieved by modifying the ITO electrodes with some Ag-NDs that act as trapping sites, reducing the current in the OFF state. Based upon the observed electrical characteristics, the currents of the low-resistance state can be attributed to a tunneling through low-resistance pathways of metal particles originating from the metal top electrode in the organic layer and that the high-resistance state is controlled by charge trapping by the metal particles including Ag-NDs. In an alternative approach, complex films of AgNO3: hexaazatrinaphthylene derivatives were studied as the active layers for all-solution processed and air-stable organic memory devices. Rewritable memory effects were observed in the devices comprised of a thin polymer dielectric layer deposited on the bottom electrode, the complex film, and a conducting polymer film as the top electrode. The electrical characteristics indicate that the accumulation of Ag+ ions at the interface of the complex film and the top electrode may contribute to the switching effect.

Transformation to SCLC after Treatment with the ALK Inhibitor Alectinib.

PubMed

Fujita, Shiro; Masago, Katsuhiro; Katakami, Nobuyuki; Yatabe, Yasushi

2016-06-01

We report an anaplastic lymphoma receptor tyrosine kinase gene (ALK)-positive patient who showed a paradoxical response to the ALK inhibitor alectinib; the primary lesion increased in size, whereas other metastatic lesions decreased markedly. A biopsy of the primary lesion confirmed an ALK rearrangement; however, the tumor had transformed histologically into small cell lung cancer. The lack of reports of small cell lung cancer transformation in ALK-positive patients implies that this outcome was unusual; this patient was treated with alectinib, which is more selective and has a greater inhibitory effect than crizotinib. This case may reveal resistance mechanisms that differ according to the agent used for treatment. Copyright © 2015 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Cytotoxic effects of pyrrolidine dithiocarbamate in small-cell lung cancer cells, alone and in combination with cisplatin.

PubMed

Tahata, Shinichi; Yuan, Bo; Kikuchi, Hidetomo; Takagi, Norio; Hirano, Toshihiko; Toyoda, Hiroo

2014-10-01

The cytocidal effect of pyrrolidine dithiocarbamate (PDTC) was investigated by focusing on cell viability, cell cycle arrest and apoptosis induction in small-cell lung cancer (SCLC) cell lines (NCI-H196 and NCI-H889). PDTC exhibited a much stronger dose-dependent cytotoxic activity against NCI-H196 compared to NCI-H889, while no such activity was observed in normal human embryonal lung fibroblast MRC-5 cells. Cell cycle arrest in S phase paralleled with suppression of c-myc expression without accompanying DNA fragmentation was observed in NCI-H196 cells. A transient increase in the intracellular ROS accompanied with an alteration of expression of oxidative stress-related genes was also confirmed in NCI-H196 cells. Furthermore, the addition of N-acetyl-l-cysteine (NAC), a free radical scavenger, not only abolished PDTC-trigger alterations of expression of these oxidative-related genes, but also almost completely abrogated PDTC-induced reduction in cell viability and morphological changes associated with cell damage. These results thus suggest that PDTC-induced cytotoxicity is attributed to its pro-oxidant activity. PDTC-induced cytotoxicity was further enhanced by CuCl2, however, abolished by bathocuproine disulfonate (BCPS), a non-permeable copper-specific chelator, supporting the plausibility that accumulation of intracellular Cu plays an important role in the cytotoxicity. Importantly, we demonstrated for the first time that PDTC downregulated the expression of ATP7A, known to be responsible for Cu efflux, but did not affect the expression of CTR1, known as a copper uptake transporter. Intriguingly, combination of much lower dose of cisplatin (5 µM) and non-toxic dose of PDTC (0.1 µM) synergistically induced a significant cytotoxicity in NCI-H196 cells. Given that ATP7A plays a critical role in the resistance of platinum-drug (such as cisplatin) representing a first-line treatment for SCLC, PDTC could be a promising candidate of adjunct therapeutic reagent for the patients requiring treatment with platinum-based regimens.

Radiation sensitivity of Merkel cell carcinoma cell lines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Leonard, J.H.; Ramsay, J.R.; Birrell, G.W.

1995-07-30

Merkel cell carcinoma (MCC), being a small cell carcinoma, would be expected to be sensitive to radiation. Clinical analysis of patients at our center, especially those with macroscopic disease, would suggest the response is quite variable. We have recently established a number of MCC cell lines from patients prior to radiotherapy, and for the first time are in a position to determine their sensitivity under controlled conditions. Some of the MCC lines grew as suspension cultures and could not be single cell cloned; therefore, it was not possible to use clonogenic survival for all cell lines. A tetrazolium based (MTT)more » assay was used for these lines, to estimate cell growth after {gamma} irradiation. Control experiments were conducted on lymphoblastoid cell lines (LCL) and the adherent MCC line, MCC13, to demonstrate that the two assays were comparable under the conditions used. We have examined cell lines from MCC, small cell lung cancer (SCLC), malignant melanomas, Epstein Barr virus (EBV) transformed lymphocytes (LCL), and skin fibroblasts for their sensitivity to {gamma} irradiation using both clonogenic cell survival and MTT assays. The results show that the tumor cell lines have a range of sensitivities, with melanoma being more resistant (surviving fraction at 2 Gy (SF2) 0.57 and 0.56) than the small cell carcinoma lines, MCC (SF2 range 0.21-0.45, mean SF2 0.30, n = 8) and SCLC (SF2 0.31). Fibroblasts were the most sensitive (SF2 0.13-0.20, mean 0.16, n = 5). The MTT assay, when compared to clonogenic assay for the MCC13 adherent line and the LCL, gave comparable results under the conditions used. Both assays gave a range of SF2 values for the MCC cell lines, suggesting that these cancers would give a heterogeneous response in vivo. The results with the two derivative clones of MCC14 (SF2 for MCC14/1 0.38, MCC14/2 0.45) would further suggest that some of them may develop resistance during clonogenic evolution. 25 refs., 3 figs., 1 tab.« less

Bombesin-like peptide receptors in human bronchial epithelial cells.

PubMed

Kane, M A; Toi-Scott, M; Johnson, G L; Kelley, K K; Boose, D; Escobedo-Morse, A

1996-01-01

Northern blot and RNAse protection assays previously failed to detect bombesin-like peptide (BLP) receptors in normal human lung tissue, but by RT/PCR cultured human bronchial epithelial (HBE) cells expressed all three BLP receptor subtypes, predominantly neuromedin B (NMB) receptor. By RT/PCR, we found expression of all three BLP receptor subtypes by human lung tissue and confirmed NMB receptor expression in six out of six HBE samples. However, transformed HBE BEAS B2B cells expressed only gastrin-releasing peptide (GRP) receptors; saturable, high-affinity (Kd = 3.5 nM) specific [125I]GRP binding confirmed functional GRP receptor, with M(r) = 75 kDa and immunologic cross-reactivity with GRP receptor from human small-cell lung carcinoma (SCLC) NCI-H345 cells. Altered regulation of BLP receptors may accompany transformation of normal lung cells to cancer.

High-performance flexible resistive memory devices based on Al2O3:GeOx composite

NASA Astrophysics Data System (ADS)

Behera, Bhagaban; Maity, Sarmistha; Katiyar, Ajit K.; Das, Samaresh

2018-05-01

In this study a resistive switching random access memory device using Al2O3:GeOx composite thin films on flexible substrate is presented. A bipolar switching characteristic was observed for the co-sputter deposited Al2O3:GeOx composite thin films. Al/Al2O3:GeOx/ITO/PET memory device shows excellent ON/OFF ratio (∼104) and endurance (>500 cycles). GeOx nanocrystals embedded in the Al2O3 matrix have been found to play a significant role in enhancing the switching characteristics by facilitating oxygen vacancy formation. Mechanical endurance was retained even after several bending. The conduction mechanism of the device was qualitatively discussed by considering Ohmic and SCLC conduction. This flexible device is a potential candidate for next-generation electronics device.

Practical use of advanced mouse models for lung cancer.

PubMed

Safari, Roghaiyeh; Meuwissen, Ralph

2015-01-01

To date a variety of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) mouse models have been developed that mimic human lung cancer. Chemically induced or spontaneous lung cancer in susceptible inbred strains has been widely used, but the more recent genetically engineered somatic mouse models recapitulate much better the genotype-phenotype correlations found in human lung cancer. Additionally, improved orthotopic transplantation of primary human cancer tissue fragments or cells into lungs of immune-compromised mice can be valuable tools for preclinical research such as antitumor drug tests. Here we give a short overview of most somatic mouse models for lung cancer that are currently in use. We accompany each different model with a description of its practical use and application for all major lung tumor types, as well as the intratracheal injection or direct injection of fresh or freeze-thawed tumor cells or tumor cell lines into lung parenchyma of recipient mice. All here presented somatic mouse models are based on the ability to (in) activate specific alleles at a time, and in a tissue-specific cell type, of choice. This spatial-temporal controlled induction of genetic lesions allows the selective introduction of main genetic lesions in an adult mouse lung as found in human lung cancer. The resulting conditional somatic mouse models can be used as versatile powerful tools in basic lung cancer research and preclinical translational studies alike. These distinctively advanced lung cancer models permit us to investigate initiation (cell of origin) and progression of lung cancer, along with response and resistance to drug therapy. Cre/lox or FLP/frt recombinase-mediated methods are now well-used techniques to develop tissue-restricted lung cancer in mice with tumor-suppressor gene and/or oncogene (in)activation. Intranasal or intratracheal administration of engineered adenovirus-Cre or lentivirus-Cre has been optimized for introducing Cre recombinase activity into pulmonary tissues, and we discuss here the different techniques underlying these applications. Concomitant with Cre/Flp recombinase-based models are the tetracycline (Tet)-inducible bitransgenic systems in which presence or absence of doxycycline can turn the expression of a specific oncogene on or off. The use of several Tet-inducible lung cancer models for NSCLC is presented here in which the reversal of oncogene expression led to complete tumor regression and provided us with important insight of how oncogene dependence influence lung cancer survival and growth. As alternative to Tet-inducible models, we discuss the application of reversible expressed, transgenic mutant estrogen receptor (ER) fusion proteins, which are regulated via systemic tamoxifen administration. Most of the various lung cancer models can be combined through the generation of transgenic compound mice so that the use of these somatic mouse models can be even more enhanced for the study of specific molecular pathways that facilitate growth and maintenance of lung cancer. Finally, this description of the practical application and methodology of mouse models for lung cancer should be helpful in assisting researchers to make the best choices and optimal use of (existing) somatic models that suits the specific experimental needs in their study of lung cancer.

A Pessimistic Explanatory Style is Prognostic for Poor Lung Cancer Survival

PubMed Central

Novotny, Paul; Colligan, Robert C.; Szydlo, Daniel W.; Clark, Matthew M.; Rausch, Sarah; Wampfler, Jason; Sloan, Jeff A.; Yang, Ping

2010-01-01

Background Several studies have demonstrated the importance of personality constructs on health behaviors and health status. Having a pessimistic outlook has been related to negative health behaviors and higher mortality. However, the construct has not been well explored in cancer populations. Methods Survival time of 534 adults, who were diagnosed with lung cancer and had a pessimistic explanatory style, was examined. The patients had completed the Minnesota Multiphasic Personality Inventory (MMPI) approximately 18.2 years prior to receiving their lung cancer diagnosis. MMPI Optimism-Pessimism (PSM) scores were divided into high (60 or more) and low scores (less than 60), and log-rank tests and Kaplan-Meier curves were used to determine survival differences. Multivariate Cox models were used for assessing prognostic values of pessimism along with other known predictors for lung cancer survival outcome. Booting strapping of the survival models was used as a sensitivity analysis. Results At the time of lung cancer diagnosis, patients were on average 67 years old; 48% were female; 85% had non-small cell lung cancer (NSCLC); 15% had small cell lung cancer (SCLC); 30% were stage I; 4% were stage II; 31% were stage III/limited; and 35% were stage IV/extensive. Patients who exhibited a non-pessimistic explanatory style survived approximately six months longer than patients classified as having a pessimistic explanatory style. Conclusion Among lung cancer patients, those having a pessimistic explanatory style experienced less favorable survival outcome, which may be related to cancer treatment decisions. Further research in this area is warranted. PMID:20139778

The seventh tumour-node-metastasis staging system for lung cancer: Sequel or prequel?

PubMed

van Meerbeeck, Jan P; Janssens, Annelies

2013-09-01

Anatomical cancer extent is an important predictor of prognosis and determines treatment choices. In non-small-cell lung cancer (NSCLC) the tumour-node-metastasis (TNM) classification developed by Pierre Denoix replaced in 1968 the Veterans Administration Lung cancer Group (VALG) classification, which was still in use for small-cell lung cancer (SCLC). Clifton Mountain suggested several improvements based on a database of mostly surgically treated United States (US) patients from a limited number of centres. This database was pivotal for a uniform reporting of lung cancer extent by the American Joint Committee of Cancer (AJCC) and the International Union against Cancer (IUCC), but it suffered increasingly from obsolete diagnostic and staging procedures and did not reflect new treatment modalities. Moreover, its findings were not externally validated in large Japanese and European databases, resulting in persisting controversies which could not be solved with the available database. The use of different mediastinal lymph-node maps in Japan, the (US) and Europe facilitated neither the exchange nor the comparison of treatment results. Peter Goldstraw, a United Kingdom (UK) thoracic surgeon, started the process of updating the sixth version in 1996 and brought it to a good end 10 years later. His goals were to improve the TNM system in lung cancer by addressing the ongoing controversies, to validate the modifications and additional descriptors, to validate the TNM for use in staging SCLC and carcinoid tumours, to propose a new uniform lymph-node map and to investigate the prognostic value of non-anatomical factors. A staging committee was formed within the International Association for the Study of Lung Cancer (IASLC) - which supervised the collection of the retrospective data from >100,000 patients with lung cancer - treated throughout the world between 1990 and 2000, analyse them with the help of solid statistics and validate externally with the Surveillance, Epidemiology and End Results (SEER) database. The ten modifications and the mediastinal lymph-node map - which were proposed in 2007 and adopted by the AJCC and IUCC in their respective seventh revision of the TNM system - were implemented as of 2010 and were rapidly adopted by the thoracic oncology community and cancer registries. As expected, not all controversies could be fully addressed, and the need for a prospective data set containing more granular information was felt early on. This data set of 25,000 consecutive incident cases will form the base for the eighth revision in 2017 and is currently being collected. Other threats are the role of stage migration and the increasing number of biological factors interfering with disease extent for prognostication. The latter issue will be addressed by the creation of a prognostic index, including several prognostic factors, of which stage will be one. For the time being, the seventh TNM classification is considered the gold standard for the description of disease extent, initial treatment allocation and the reporting of treatment results. The uniform use of the TNM descriptors and the lymph-node map by all involved in lung cancer care is to be considered a process indicator of quality.

All-polymer solar cells with bulk heterojunction nanolayers of chemically doped electron-donating and electron-accepting polymers.

PubMed

Nam, Sungho; Shin, Minjung; Park, Soohyeong; Lee, Sooyong; Kim, Hwajeong; Kim, Youngkyoo

2012-11-21

We report the improved performance of all-polymer solar cells with bulk heterojunction nanolayers of an electron-donating polymer (poly(3-hexylthiophene) (P3HT)) and an electron-accepting polymer (poly(9,9-dioctylfluorene-co-benzothiadiazole) (F8BT)), which were both doped with 4-ethylbenzenesulfonic acid (EBSA). To choose the doping ratio of P3HT for all-polymer solar cells, various EBSA doping ratios (0, 1, 3, 5, 10, 20 wt%) were tested by employing optical absorption spectroscopy, photoluminescence spectroscopy, photoelectron yield spectroscopy, and space-charge-limited current (SCLC) mobility measurement. The doping reaction of P3HT with EBSA was followed by observing the colour change in solutions. The final doping ratio for P3HT was chosen as 1 wt% from the best hole mobility measured in the thickness direction, while that for F8BT was fixed as 10 wt% (F8BT-EBSA). The polymer:polymer solar cells with bulk heterojunction nanolayers of P3HT-EBSA (EBSA-doped P3HT) and F8BT-EBSA (EBSA-doped F8BT) showed greatly improved short circuit current density (J(SC)) and open circuit voltage (V(OC)), compared to the undoped solar cells. As a result, the power conversion efficiency (PCE) was enhanced by ca. 300% for the 6 : 4 (P3HT-EBSA : F8BT-EBSA) composition and ca. 400% for the 8 : 2 composition. The synchrotron-radiation grazing incidence angle X-ray diffraction (GIXD) measurement revealed that the crystallinity of the doped nanolayers significantly increased by EBSA doping owing to the formation of advanced phase segregation morphology, as supported by the surface morphology change measured by atomic force microscopy. Thus the improved PCE can be attributed to the enhanced charge transport by the formation of permanent charges and better charge percolation paths by EBSA doping.

Tunable charge transfer properties in metal-phthalocyanine heterojunctions.

PubMed

Siles, P F; Hahn, T; Salvan, G; Knupfer, M; Zhu, F; Zahn, D R T; Schmidt, O G

2016-04-28

Organic materials such as phthalocyanine-based systems present a great potential for organic device applications due to the possibility of integrating films of different organic materials to create organic heterostructures which combine the electrical capabilities of each material. This opens the possibility to precisely engineer and tune new electrical properties. In particular, similar transition metal phthalocyanines demonstrate hybridization and charge transfer properties which could lead to interesting physical phenomena. Although, when considering device dimensions, a better understanding and control of the tuning of the transport properties still remain in the focus of research. Here, by employing conductive atomic force microscopy techniques, we provide an insight about the nanoscale electrical properties and transport mechanisms of MnPc and fluorinated phthalocyanines such as F16CuPc and F16CoPc. We report a transition from typical diode-like transport mechanisms for pure MnPc thin films to space-charge-limited current transport regime (SCLC) for Pc-based heterostructures. The controlled addition of fluorinated phthalocyanine also provides highly uniform and symmetric-polarized transport characteristics with conductance enhancements up to two orders of magnitude depending on the polarization. We present a method to spatially map the mobility of the MnPc/F16CuPc structures with a nanoscale resolution and provide theoretical calculations to support our experimental findings. This well-controlled nanoscale tuning of the electrical properties for metal transition phthalocyanine junctions stands as key step for future phthalocyanine-based electronic devices, where the low dimension charge transfer, mediated by transition metal atoms could be intrinsically linked to a transfer of magnetic moment or spin.

Estimation of lung cancer diagnosis and treatment costs based on a patient-level analysis in Catalonia (Spain).

PubMed

Corral, Julieta; Espinàs, Josep Alfons; Cots, Francesc; Pareja, Laura; Solà, Judit; Font, Rebeca; Borràs, Josep Maria

2015-02-21

Assessing of the costs of treating disease is necessary to demonstrate cost-effectiveness and to estimate the budget impact of new interventions and therapeutic innovations. However, there are few comprehensive studies on resource use and costs associated with lung cancer patients in clinical practice in Spain or internationally. The aim of this paper was to assess the hospital cost associated with lung cancer diagnosis and treatment by histology, type of cost and stage at diagnosis in the Spanish National Health Service. A retrospective, descriptive analysis on resource use and a direct medical cost analysis were performed. Resource utilisation data were collected by means of patient files from nine teaching hospitals. From a hospital budget impact perspective, the aggregate and mean costs per patient were calculated over the first three years following diagnosis or up to death. Both aggregate and mean costs per patient were analysed by histology, stage at diagnosis and cost type. A total of 232 cases of lung cancer were analysed, of which 74.1% corresponded to non-small cell lung cancer (NSCLC) and 11.2% to small cell lung cancer (SCLC); 14.7% had no cytohistologic confirmation. The mean cost per patient in NSCLC ranged from 13,218 Euros in Stage III to 16,120 Euros in Stage II. The main cost components were chemotherapy (29.5%) and surgery (22.8%). Advanced disease stages were associated with a decrease in the relative weight of surgical and inpatient care costs but an increase in chemotherapy costs. In SCLC patients, the mean cost per patient was 15,418 Euros for limited disease and 12,482 Euros for extensive disease. The main cost components were chemotherapy (36.1%) and other inpatient costs (28.7%). In both groups, the Kruskall-Wallis test did not show statistically significant differences in mean cost per patient between stages. This study provides the costs of lung cancer treatment based on patient file reviews, with chemotherapy and surgery accounting for the major components of costs. This cost analysis is a baseline study that will provide a useful source of information for future studies on cost-effectiveness and on the budget impact of different therapeutic innovations in Spain.

Serum levels of endothelial and neural cell adhesion molecules in prostate cancer.

PubMed

Lynch, D F; Hassen, W; Clements, M A; Schellhammer, P F; Wright, G L

1997-08-01

Tumorigenesis and progression to metastatic disease are accompanied by changes in the expression of cell adhesion molecules (CAMs). Normally expressed CAMs, such as E-cadherin, are lost, while others, i.e., ICAM-1, VCAM-1, NCAM, and E-selectin, are altered and overexpressed in progressive disease and metastases. Abnormal levels of these latter CAMs have been observed in melanoma and carcinomas of the colon and breast, and NCAM is overexpressed in small-cell lung carcinoma (SCLC). The objective of this study was to determine if serum levels of ICAM-1, VCAM-1, NCAM, and E-selectin could differentiate patients with benign prostate hypertrophy (BPH) from those with prostate carcinoma (CaP) and identify prostate cancers with high potential for progression to metastatic disease. Serum levels of these CAMs were determined by ELISA in serum from normal males and females and from patients with BPH and CaP before and after treatment. Sera from patients with breast carcinoma, colon carcinoma, melanoma, and small-cell lung carcinoma were also evaluated, as soluble CAMs have been reported to be elevated in these cancer patients. ICAM-1 levels were elevated in sera from patients with breast carcinoma (P = 0.0004) and melanoma (P = 0.0001). VCAM-1 levels were elevated in sera from patients with colon carcinoma (P = 0.0001). NCAM levels were elevated in the sera of patients with SCLC (P = 0.0001). Normal levels of ICAM-1, E-selectin, and NCAM were found in both BPH and pretreatment CaP patients. Median NCAM levels in hormone-refractive CaP patients were significantly greater than in BPH (P = 0.0005) and CaP patients with pathologically determined organ-confined (P = 0.0014) or nonorgan-confined disease (P = 0.0385). VCAM-1 levels were significantly elevated in both BPH patients (P = 0.0002) and CaP patients (P = 0.0002) when compared with levels for normal age-matched donors. None of the CAMs were found to offer an advantage over prostatic-specific antigen (PSA) for monitoring CaP patients following definitive radiotherapy, radical prostatectomy, or hormonal therapy. The results of this study indicate that serum ICAM-1, VCAM-1, NCAM, and E-selectin are not clinically useful biomarkers for differentiating CaP from BPH, for predicting progression, for identifying metastatic potential, or for monitoring treatment.

Association between smoking and p53 mutation in lung cancer: a meta-analysis.

PubMed

Liu, X; Lin, X J; Wang, C P; Yan, K K; Zhao, L Y; An, W X; Liu, X D

2014-01-01

To carry out a meta-analysis on the relationship between smoking and p53 gene mutation in lung cancer patients. PubMed, Web of Science, ProQest and Medline were searched by using the key words: 'lung cancer or lung neoplasm or lung carcinoma', 'p53 mutation' and 'smoking'. According to the selection criteria, 15 articles were identified and methodologically analysed by stata 12.0 software package. Crude odds ratios with 95% confidence intervals calculated using the fixed-effects model were used to assess the strength of association between smoking and p53 mutation in lung cancer. In total, 15 articles with 1770 lung cancer patients were identified; 69.6% of the patients were smokers, 30.4% were non-smokers. Overall, smokers with lung cancer had a 2.70-fold (95% confidence interval 2.04-3.59) higher risk for mutation than the non-smokers with lung cancer. In subgroup analyses, the increased risk of p53 mutation in smokers than in non-smokers was found in the non-small cell lung cancer (NSCLC) group (odds ratio = 2.38, 95% confidence interval = 1.71-3.32) and in the NSCLC and SCLC group (odds ratio = 3.82, 95% confidence interval = 2.19-6.69). This meta-analysis strongly suggests that p53 mutation is associated with smoking-induced lung cancer. Smokers with lung cancer had a higher risk for p53 mutation than non-smokers. Copyright © 2013 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

The Impact of a Multidimensional Exercise Intervention on Physical and Functional Capacity, Anxiety, and Depression in Patients With Advanced-Stage Lung Cancer Undergoing Chemotherapy.

PubMed

Quist, Morten; Adamsen, Lis; Rørth, Mikael; Laursen, Jørgen H; Christensen, Karl B; Langer, Seppo W

2015-07-01

Patients with advanced-stage lung cancer face poor survival and experience co-occurring chronic physical and psychosocial symptoms. Despite several years of research in exercise oncology, few exercise studies have targeted advanced lung cancer patients undergoing chemotherapy. The aim of the present study was to investigate the benefits of a 6-week supervised group exercise intervention and to outline the effect on aerobic capacity, strength, health-related quality of life (HRQoL), anxiety, and depression. VO2peak was assessed using an incremental exercise test. Muscle strength was measured with one repetition maximum test (1RM). HRQoL, anxiety, and depression were assessed using Functional Assessment of Cancer Therapy-Lung (FACT-L) scale and the Hospital Anxiety and Depression Scale (HADS). One hundred and forthteen patients with advanced stage lung cancer were recruited. Forty-three patients dropped out. No serious adverse events were reported. Exercise adherence in the group training was 68%. Improvements in VO2peak (P < .001) and 6-minute walk distance (P < .001) and muscle strength measurements (P < .05) were seen. There was a reduction in anxiety level (P = .0007) and improvement in the emotional well-being parameter (FACT-L) but no statistically significant changes in HRQoL were observed. The results of the present study show that during a 6-week hospital-based supervised, structured, and group-based exercise program, patients with advanced-stage lung cancer (NSCLC IIIb-IV, ED-SCLC) improve their physical capacity (VO2peak, 1RM), functional capacity, anxiety level, and emotional well-being, but not their overall HRQoL. A randomized controlled trial testing the intervention including 216 patients is currently being carried out. © The Author(s) 2015.

Neuroendocrine Tumors of the Lung: Current Challenges and Advances in the Diagnosis and Management of Well-Differentiated Disease.

PubMed

Hendifar, Andrew E; Marchevsky, Alberto M; Tuli, Richard

2017-03-01

Neuroendocrine tumors (NETs) comprise a heterogeneous group of malignancies that arise from neuroendocrine cells throughout the body, most commonly originating from the lungs and gastrointestinal tract. Lung NETs can be classified as well differentiated (low-grade typical carcinoids [TCs] and intermediate-grade atypical carcinoids [ACs]) and poorly differentiated (high-grade large cell neuroendocrine carcinoma or SCLC). The incidence of these tumors is increasing, but disease awareness remains low among thoracic specialists, who are often involved in the diagnosis and early treatment for these patients. An accurate and timely diagnosis can ensure the implementation of appropriate treatment and have a substantial impact on prognosis. However, lung NET classification and diagnosis, particularly for TCs/ACs, are complicated by several factors, including a variable natural history and nonspecific symptoms. Surgery remains the only curative option for TCs/ACs, but there is a lack of consensus between lung NET management guidelines regarding optimal treatment approaches in the unresectable/metastatic setting on account of the limited availability of high-level clinical evidence. As a result, a multidisciplinary approach to management of lung NETs is required to ensure a consistent and optimal level of care. RADIANT-4 is the first phase III trial involving a large subpopulation of patients with advanced well-differentiated lung NETs to report reductions in the risk for disease progression and death with everolimus over placebo. This led to the recent U.S. approval of everolimus-the first agent approved for advanced lung TCs/ACs. To further improve evidence-based care, additional randomized controlled trials in patients with lung carcinoids are needed. Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Charge carrier transport mechanisms in perovskite CdTiO{sub 3} fibers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Imran, Z.; Rafiq, M. A., E-mail: aftab@cantab.net; Hasan, M. M.

Electrical transport properties of electrospun cadmium titanate (CdTiO{sub 3}) fibers have been investigated using ac and dc measurements. Air annealing of as spun fibers at 1000 °C yielded the single phase perovskite fibers having diameter ∼600 nm - 800 nm. Both the ac and dc electrical measurements were carried out at temperatures from 200 K – 420 K. The complex impedance plane plots revealed a single semicircular arc which indicates the interfacial effect due to grain boundaries of fibers. The dielectric properties obey the Maxwell-Wagner theory of interfacial polarization. In dc transport study at low voltages, data show Ohmic like behaviormore » followed by space charge limited current (SCLC) with traps at higher voltages at all temperatures (200 K – 420 K). Trap density in our fibers system is N{sub t} = 6.27 × 10{sup 17} /cm{sup 3}. Conduction mechanism in the sample is governed by 3-D variable range hopping (VRH) from 200 K – 300 K. The localized density of states were found to be N(E{sub F}) = 5.51 × 10{sup 21} eV{sup −1} cm{sup −3} at 2 V. Other VRH parameters such as hopping distance (R{sub hop}) and hopping energy (W{sub hop}) were also calculated. In the high temperature range of 320 K – 420 K, conductivity follows the Arrhenius law. The activation energy found at 2 V is 0.10 eV. Temperature dependent and higher values of dielectric constant make the perovskite CdTiO{sub 3} fibers efficient material for capacitive energy storage devices.« less

TCNQ molecular semiconductor of the Cu(II)TAAB macrocycle: Optical and electrical properties.

PubMed

Sánchez Vergara, M E; Salcedo, R; Molina, Bertha; Carrera-Téllez, R; Álvarez-Bada, J R; Hernández-García, A; Gómez-Vidales, V

2018-07-05

The present study reports the doping of a semiconducting molecular material through the formation of hydrogen bonds between the macrocycle Cu(II)(TAAB) and the electronic acceptor TCNQ. According to density functional theory (DFT) calculations and electron paramagnetic resonance (EPR) analysis, the doped compound has the shape of a distorted square pyramid, with four nitrogen atoms in the equatorial position and the apical oxygen atom from the water ligands. These water molecules can generate strong hydrogen bonds with TCNQ and the TAAB metallic complex. Thin films of copper molecular material were obtained through high vacuum evaporation and were structurally characterized by IR spectroscopy, EPR and scanning electron microscopy (SEM). Additionally, the absorption coefficient (α) and photon energy (hν) were calculated from UV-vis spectroscopy and used to determine the optical activation energy in each film, from which its semiconducting behavior was established. An important aspect to consider is that the presence of hydrogen bonds is essential to establish the semiconducting nature of these species; this chemical behavior, as well as the resulting electronic mobility, have been studied by DFT theoretical calculations, which reinforce the experimental conclusion of a relationship between Cu(II)TAAB and TCNQ moieties generated by a weak bond. Finally, I-V characteristics have been obtained from a glass/ITO/doped molecular semiconductor/Ag device using Ag and ITO electrodes. Results for the copper-based device show that, at low voltages, the conduction process is of an ohmic nature while, at higher voltages, space-charge-limited current (SCLC) is found. It is highly probable that the doping effect in TCNQ favors electronic transport due to the formation of conduction channels caused by dopant-favored anisotropy. Copyright © 2018 Elsevier B.V. All rights reserved.

Target engagement imaging of PARP inhibitors in small-cell lung cancer.

PubMed

Carney, Brandon; Kossatz, Susanne; Lok, Benjamin H; Schneeberger, Valentina; Gangangari, Kishore K; Pillarsetty, Naga Vara Kishore; Weber, Wolfgang A; Rudin, Charles M; Poirier, John T; Reiner, Thomas

2018-01-12

Insufficient chemotherapy response and rapid disease progression remain concerns for small-cell lung cancer (SCLC). Oncologists rely on serial CT scanning to guide treatment decisions, but this cannot assess in vivo target engagement of therapeutic agents. Biomarker assessments in biopsy material do not assess contemporaneous target expression, intratumoral drug exposure, or drug-target engagement. Here, we report the use of PARP1/2-targeted imaging to measure target engagement of PARP inhibitors in vivo. Using a panel of clinical PARP inhibitors, we show that PARP imaging can quantify target engagement of chemically diverse small molecule inhibitors in vitro and in vivo. We measure PARP1/2 inhibition over time to calculate effective doses for individual drugs. Using patient-derived xenografts, we demonstrate that different therapeutics achieve similar integrated inhibition efficiencies under different dosing regimens. This imaging approach to non-invasive, quantitative assessment of dynamic intratumoral target inhibition may improve patient care through real-time monitoring of drug delivery.

Progress and prospects of early detection in lung cancer

PubMed Central

Blandin Knight, Sean; Crosbie, Phil A.; Balata, Haval; Chudziak, Jakub; Hussell, Tracy; Dive, Caroline

2017-01-01

Lung cancer is the leading cause of cancer-related death in the world. It is broadly divided into small cell (SCLC, approx. 15% cases) and non-small cell lung cancer (NSCLC, approx. 85% cases). The main histological subtypes of NSCLC are adenocarcinoma and squamous cell carcinoma, with the presence of specific DNA mutations allowing further molecular stratification. If identified at an early stage, surgical resection of NSCLC offers a favourable prognosis, with published case series reporting 5-year survival rates of up to 70% for small, localized tumours (stage I). However, most patients (approx. 75%) have advanced disease at the time of diagnosis (stage III/IV) and despite significant developments in the oncological management of late stage lung cancer over recent years, survival remains poor. In 2014, the UK Office for National Statistics reported that patients diagnosed with distant metastatic disease (stage IV) had a 1-year survival rate of just 15–19% compared with 81–85% for stage I. PMID:28878044

Subcellular storage compartments of bacteriopheophorbide sensitizers

NASA Astrophysics Data System (ADS)

Moser, Joerg G.; Dembeck, U.; Hubert, M.; Spengler, Bernhard; Bayer, Rainer; Wagner, Birgit

1994-03-01

Fluorescence colocalization with the Golgi specific stain, NBD-ceramide, and the mitochondrial localizing stain, Rhodamine 123, confirmed the earlier assumption that the Golgi apparatus is one of the prominent storage compartments for bacteriopheophorbide esters in OAT 75 SCLC cells and several amelanotic melanoma cell lines (A375, Melur SP18, SkAMel 25). Furthermore, a diffuse staining of mitochondria, of non-structured cytoplasm, and an additional storage in melanine vesicles of the amelanotic melanoma cells suggests further storage compartments with quantitatively different contributions to the phototoxicity of bacteriochlorophyll-derived photosensitizers. Independent observations of early phototoxic effects on microfilamentous networks, enzymatic activities (succinate dehydrogenase, lactate dehydrogenase), and redistribution phenomena following primary uptake of the sensitizers let us assume that only a part of the 108 molecules taken up by a cell contribute directly to phototoxicity. Thus it may be asked if a proper subcellular positioning of only a few sensitizer molecules may have similar phototoxic effects as the huge amounts stored at apparently ineffective sites.

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.

Lung cancer cell lines: Useless artifacts or invaluable tools for medical science?

PubMed Central

Gazdar, Adi F.; Gao, Boning; Minna, John D.

2011-01-01

Multiple cell lines (estimated at 300–400) have been established from human small cell (SCLC) and non-small cell lung cancers (NSCLC). These cell lines have been widely dispersed to and used by the scientific community worldwide, with over 8000 citations resulting from their study. However, there remains considerable skepticism on the part of the scientific community as to the validity of research resulting from their use. These questions center around the genomic instability of cultured cells, lack of differentiation of cultured cells and absence of stromal–vascular–inflammatory cell compartments. In this report we discuss the advantages and disadvantages of the use of cell lines, address the issues of instability and lack of differentiation. Perhaps the most important finding is that every important, recurrent genetic and epigenetic change including gene mutations, deletions, amplifications, translocations and methylation-induced gene silencing found in tumors has been identified in cell lines and vice versa. These “driver mutations” represented in cell lines offer opportunities for biological characterization and application to translational research. Another potential shortcoming of cell lines is the difficulty of studying multistage pathogenesis in vitro.To overcome this problem, we have developed cultures from central and peripheral airways that serve as models for the multistage pathogenesis of tumors arising in these two very different compartments. Finally the issue of cell line contamination must be addressed and safeguarded against. A full understanding of the advantages and shortcomings of cell lines is required for the investigator to derive the maximum benefit from their use. PMID:20079948

Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors in T790M-positive non-small cell lung cancer: review on emerged mechanisms of resistance

PubMed Central

Minari, Roberta; Bordi, Paola

2016-01-01

Osimertinib, third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), has been approved in the US and EU for the treatment of EGFR mutant T790M-positive non-small cell lung cancer (NSCLC) patients resistant to first- or second-generation EGFR-TKIs, such as gefitinib, erlotinib and afatinib. Although exciting survival data and response rates have been registered in patients treated with this and other third-generation EGFR-TKIs, unfortunately acquired resistance still occurs after approximately 10 months. Mechanisms determining progression of disease are heterogeneous and not fully understood. EGFR-dependent resistance mechanisms (such as new EGFR mutations), bypass pathway activation [as erb-b2 receptor tyrosine kinase 2 (HER2) or MET amplification] and histological transformation [in small cell lung cancer (SCLC)] have been reported, similarly to previous generation TKIs. Here, we review principle mechanisms of innate and acquired resistance described in literature both in clinical and preclinical settings during NSCLC treatment with third-generation EGFR-TKIs. PMID:28149764

[High dosage therapy with stem cell transplantation in neuroendocrine carcinoma].

PubMed

Buxhofer, V; Ruckser, R; Kier, P; Habertheuer, K H; Zelenka, P; Tatzreiter, G; Dorner, S; Vedovelli, H; Sebesta, C; Hinterberger, W

2000-01-01

Neuroendocrine carcinoma and small-cell lung cancer (SCLC) are highly responsive to chemo- and radiotherapy. Nevertheless, most patients (pts.) experience relapse. At the 2nd department of medicine in the Donauspital, 4 pts. with neuroendocrine carcinomas of different primary sites underwent high-dose chemotherapy with autologous stem-cell transplantation (ASTx). Pt. 1 suffered from neuroendocrine lung cancer, pt. 2 from a small-cell carcinoma of the pancreas. Pt. 3 had a metastatic small-cell abdominal bulky tumor and pt. 4 presented with neuroendocrine carcinoma of the prostate. After 4-6 cycles induction chemotherapy pts. were consolidated with 1 cycle of HDCht and ASTx. Prior to HDCht pt. 1 and pt. 2 were in complete remission (CR) and pt. 3 and pt. 4 in partial remission. Pt. 3 converted in CR after HDCht. He is still in CR with a disease-free survival of 23 month after ASTx and 30 month after diagnosis. Pt. 1, 2 and 4 died from relapse 10, 16 and 5 month after ASTx and 16, 22 and 9 month after diagnosis. Pts. with neuroendocrine carcinomas might be suitable candidates for HDCht and ASTx.

Resistive switching characteristics of solution-processed Al-Zn-Sn-O films annealed by microwave irradiation

NASA Astrophysics Data System (ADS)

Kim, Tae-Wan; Baek, Il-Jin; Cho, Won-Ju

2018-02-01

In this study, we employed microwave irradiation (MWI) at low temperature in the fabrication of solution-processed AlZnSnO (AZTO) resistive random access memory (ReRAM) devices with a structure of Ti/AZTO/Pt and compared the memory characteristics with the conventional thermal annealing (CTA) process. Typical bipolar resistance switching (BRS) behavior was observed in AZTO ReRAM devices treated with as-deposited (as-dep), CTA and MWI. In the low resistance state, the Ohmic conduction mechanism describes the dominant conduction of these devices. On the other hand, the trap-controlled space charge limited conduction (SCLC) mechanism predominates in the high resistance state. The AZTO ReRAM devices processed with MWI showed larger memory windows, uniform distribution of resistance state and operating voltage, stable DC durability (>103 cycles) and stable retention characteristics (>104 s). In addition, the AZTO ReRAM devices treated with MWI exhibited multistage storage characteristics by modulating the amplitude of the reset bias, and eight distinct resistance levels were obtained with stable retention capability.

Outcome and prognostic factors in patients with brain metastases from small-cell lung cancer treated with whole brain radiotherapy.

PubMed

Bernhardt, Denise; Adeberg, Sebastian; Bozorgmehr, Farastuk; Opfermann, Nils; Hoerner-Rieber, Juliane; König, Laila; Kappes, Jutta; Thomas, Michael; Herth, Felix; Heußel, Claus Peter; Warth, Arne; Debus, Jürgen; Steins, Martin; Rieken, Stefan

2017-08-01

The purpose of this study was to evaluate prognostic factors associated with overall survival (OS) and neurological progression free survival (nPFS) in small-cell lung cancer (SCLC) patients with brain metastases who received whole-brain radiotherapy (WBRT). From 2003 to 2015, 229 SCLC patients diagnosed with brain metastases who received WBRT were analyzed retrospectively. In this cohort 219 patients (95%) received a total photon dose of 30 Gy in 10 fractions. The prognostic factors evaluated for OS and nPFS were: age, Karnofsky Performance Status (KPS), number of brain metastases, synchronous versus metachronous disease, initial response to chemotherapy, the Radiation Therapy Oncology Group recursive partitioning analysis (RPA) class and thoracic radiation. Median OS after WBRT was 6 months and the median nPFS after WBRT was 11 months. Patients with synchronous cerebral metastases had a significantly better median OS with 8 months compared to patients with metachronous metastases with a median survival of 3 months (p < 0.0001; HR 0.46; 95% CI 0.31-0.67). Based on RPA classification median survival after WBRT was 17 months in RPA class I, 7 months in class II and 3 months in class III (p < 0.0001). Karnofsky performance status scale (KPS < 70%) was significantly associated with OS in both univariate (HR 2.84; p < 0.001) and multivariate analyses (HR 2.56; p = 0.011). Further, metachronous brain metastases (HR 1.8; p < 0.001), initial response to first-line chemotherapy (HR 0.51, p < 0.001) and RPA class III (HR 2.74; p < 0.001) were significantly associated with OS in univariate analysis. In multivariate analysis metachronous disease (HR 1.89; p < 0.001) and initial response to chemotherapy (HR 0.61; p < 0.001) were further identified as significant prognostic factors. NPFS was negatively significantly influenced by poor KPS (HR 2.56; p = 0.011), higher number of brain metastases (HR 1.97; p = 0.02), and higher RPA class (HR 2.26; p = 0.03) in univariate analysis. In this series, the main prognostic factors associated with OS were performance status, time of appearance of intracranial disease (synchronous vs. metachronous), initial response to chemotherapy and higher RPA class. NPFS was negatively influenced by poor KPS, multiplicity of brain metastases, and higher RPA class in univariate analysis. For patients with low performance status, metachronous disease or RPA class III, WBRT should be weighed against supportive therapy with steroids alone or palliative chemotherapy.

Quinacridone-based molecular donors for solution processed bulk-heterojunction organic solar cells.

PubMed

Chen, John Jun-An; Chen, Teresa L; Kim, BongSoo; Poulsen, Daniel A; Mynar, Justin L; Fréchet, Jean M J; Ma, Biwu

2010-09-01

New soluble quinacridone-based molecules have been developed as electron donor materials for solution-processed organic solar cells. By functionalizing the pristine pigment core of quinacridone with solubilizing alkyl chains and light absorbing/charge transporting thiophene units, i.e., bithiophene (BT) and thienylbenzo[c][1,2,5]thiadiazolethienyl (BTD), we prepared a series of multifunctional quinacridone-based molecules. These molecular donors show intense absorption in the visible spectral region, and the absorption range and intensity are well-tuned by the interaction between the quinacridone core and the incorporated thiophene units. The thin film absorption edge extends with the expansion of molecular conjugation, i.e., 552 nm for N,N'-di(2-ethylhexyl)quinacridone (QA), 592 nm for 2,9-Bis(5'-hexyl-2,2'-bithiophene)-N,N'-di(2-ethylhexyl)quinacridone (QA-BT), and 637 nm for 4-(5-hexylthiophen-2-yl)-7-(thiophen-2-yl)benzo[c][1,2,5]thiadiazole (QA-BTD). The change of molecular structure also influences the electrochemical properties. Observed from cyclic voltammetry measurements, the oxidation and reduction potentials (vs ferrocene) are 0.7 and -1.83 V for QA, 0.54 and -1.76 V for QA-BT, and 0.45 and -1.68 V for QA-BTD. Uniform thin films can be generated from both single component molecular solutions and blend solutions of these molecules with [6,6]-phenyl C70-butyric acid methyl ester (PC70BM). The blend films exhibit space-charge limited current (SCLC) hole mobilities on the order of 1×10(-4) cm(2) V(-1) S(-1). Bulk heterojunction (BHJ) solar cells using these soluble molecules as donors and PC70BM as the acceptor were fabricated. Power conversion efficiencies (PCEs) of up to 2.22% under AM 1.5 G simulated 1 sun solar illumination have been achieved and external quantum efficiencies (EQEs) reach as high as ∼45%.

TRX is up-regulated by fibroblast growth factor-2 in lung carcinoma.

PubMed

Deng, Zheng-Hao; Cao, Hui-Qiu; Hu, Yong-Bin; Wen, Ji-Fang; Zhou, Jian-Hua

2011-01-01

We have previously shown that exogenous fibroblast growth factor-2 (FGF-2) inhibits apoptosis of the small-cell lung cancer (SCLC) cell line NCI-H446, but the underlying mechanism remains unknown. In this study, the protein profiles of FGF-2-treated and untreated NCI-H446 cells were determined by 2-D gel electrophoresis combined with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and bioinformatics. Differential expression analysis of the protein profiles after FGF-2 treatment identified a total of 24 protein spots, of which nine were up-regulated and 15 were down-regulated. Four proteins were identified by MALDI-TOF-MS: thioredoxin (TRX), visfatin, ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) and Cu/Zn superoxide dismutase (CuZn-SOD). Western blotting revealed that TRX was up-regulated in NCI-H446 and A549 cells treated with FGF-2. Furthermore, immunohistochemical staining confirmed that both FGF-2 and TRX were overexpressed in lung cancer tissues and could be correlated with both lymph node metastasis and clinical stage. These data indicate that TRX may be involved in the FGF-2 signaling pathway. © 2010 The Authors. APMIS © 2010 APMIS.

Electron Acceptors Based on α-Substituted Perylene Diimide (PDI) for Organic Solar Cells

DOE PAGES

Zhao, Donglin; Wu, Qinghe; Cai, Zhengxu; ...

2016-02-20

The ortho-position functionalized perylene diimide derivatives (αPPID, αPBDT) were synthesized and used as the electron acceptors in nonfullerene organic photovoltaics. Due to the good planarity of ortho-position functionalized PDI, the αPPID and αPBDT show strong tendency to form aggregate because of their enhanced intermolecular pie-pie interaction. Moreover, they maintain the pure domains and the same packing order as in the pure film if they are blended with PBT7-TH and the SCLC measurement also shows the high electron mobility. The inverted OPVs employing αPDI-based compounds as acceptor and PBT7-TH as the donor give the highest PCE of 4.92 % for αPBDTmore » based device and 3.61 % for αPPID based device, which is 39 % and 4 % higher than that for their counterpart βPBDT and βPPID. The charge separation study shows the more efficient exciton dissociation at interfaces between PDI based compounds and PBT7-TH. In conclusion, the results suggest that compared to beta-substituted ones, alpha-substituted PDI derivatives are more promising electron acceptors for OPV.« less

PREPARATION AND ELECTRICAL PROPERTIES OF BiFeO3/La0.7Sr0.3MnO3 MULTILAYERS

NASA Astrophysics Data System (ADS)

Zhu, Huiwen; Wang, Shunli; Li, Xiaoyun

2013-07-01

(La0.7Sr0.3MnO3 12 nm/BiFeO3 12 nm)10 was grown on SrTiO3 (001) substrate using rf magnetron sputtering. The structure analysis indicated that BiFeO3/La0.7Sr0.3MnO3 multilayers were highly (001)-oriented. Compared with bottom La0.7Sr0.3MnO3 electrode, the top La0.7Sr0.3MnO3 electrode displayed a rougher surface. The electric transport characteristics of the sample were investigated mainly at low temperature, and it was found that the sample exhibited resistance-temperature curves similar to those of La0.7Sr0.3MnO3 with the exception of an upturn at lower temperature region. Furthermore, a nonlinear I-V curve, which is characteristic of a tunneling conduction mechanism, was observed at 50 K. At higher temperature, the I-V curves were found to be diode-like. When the temperature was further increased to 300 K, the sample showed a space charge limited conduction (SCLC) characteristic.

Targeted two-photon PDT photo-sensitizers for the treatment of subcutaneous tumors

NASA Astrophysics Data System (ADS)

Spangler, C. W.; Rebane, A.; Starkey, J.; Drobizhev, M.

2009-06-01

New porphyrin-based photo-sensitizers have been designed, synthesized and characterized that exhibit greatly enhanced intrinsic two-photon absorption. These new photo-sensitizers have been incorporated into triad formulations that also incorporate Near-infrared (NIR) imaging agents, and small-molecule targeting agents that direct the triads to cancerous tumors' over-expressed receptor sites. PDT can be initiated deep into the tissue transparency window at 780-800 nm utilizing a regeneratively amplified Ti:sapphire laser using 100-150 fs pulses of 600-800 mW. Human tumor xenografts of human breast cancer (MDA-MB-231) and both small SCLC (NCI-H69) and NSCLC (A-459) have been successfully treated using octreotate targeting of over-expressed SST2 receptors. In particular, the lung cancer xenografts can be successfully treated by irradiating from the side of the mouse opposite the implanted tumor, thereby passing through ca. 2 cm of mouse skin, tissue and organs with no discernible damage to healthy tissue while causing regression in the tumors. These results suggest a new PDT paradigm for the noninvasive treatment of subcutaneous tumors, including the possibility that the targeting moiety could be matched to individual patient genetic profiles (patient-specific therapeutics).

Fully transparent, non-volatile bipolar resistive memory based on flexible copolyimide films

NASA Astrophysics Data System (ADS)

Yu, Hwan-Chul; Kim, Moon Young; Hong, Minki; Nam, Kiyong; Choi, Ju-Young; Lee, Kwang-Hun; Baeck, Kyoung Koo; Kim, Kyoung-Kook; Cho, Soohaeng; Chung, Chan-Moon

2017-01-01

Partially aliphatic homopolyimides and copolyimides were prepared from rel-(1'R,3S,5'S)-spiro[furan-3(2H),6'-[3]oxabicyclo[3.2.1]octane]-2,2',4',5(4H)-tetrone (DAn), 2,6-diaminoanthracene (AnDA), and 4,4'-oxydianiline (ODA) by varying the molar ratio of AnDA and ODA. We utilized these polyimide films as the resistive switching layer in transparent memory devices. While WORM memory behavior was obtained with the PI-A100-O0-based device (molar feed ratio of DAn : AnDA : ODA = 1 : 1 : 0), the PI-A70-O30-based device (molar feed ratio of DAn : AnDA : ODA = 1 : 0.7 : 0.3) exhibited bipolar resistive switching behavior with stable retention for 104 s. This result implies that the memory properties can be controlled by changing the polyimide composition. The two devices prepared from PI-A100-O0 and PI-A70-O30 showed over 90% transmittance in the visible wavelength range from 400 to 800 nm. The behavior of the memory devices is considered to be governed by trap-controlled, space-charge limited conduction (SCLC) and local filament formation. [Figure not available: see fulltext.

ShatterProof: operational detection and quantification of chromothripsis.

PubMed

Govind, Shaylan K; Zia, Amin; Hennings-Yeomans, Pablo H; Watson, John D; Fraser, Michael; Anghel, Catalina; Wyatt, Alexander W; van der Kwast, Theodorus; Collins, Colin C; McPherson, John D; Bristow, Robert G; Boutros, Paul C

2014-03-19

Chromothripsis, a newly discovered type of complex genomic rearrangement, has been implicated in the evolution of several types of cancers. To date, it has been described in bone cancer, SHH-medulloblastoma and acute myeloid leukemia, amongst others, however there are still no formal or automated methods for detecting or annotating it in high throughput sequencing data. As such, findings of chromothripsis are difficult to compare and many cases likely escape detection altogether. We introduce ShatterProof, a software tool for detecting and quantifying chromothriptic events. ShatterProof takes structural variation calls (translocations, copy-number variations, short insertions and loss of heterozygosity) produced by any algorithm and using an operational definition of chromothripsis performs robust statistical tests to accurately predict the presence and location of chromothriptic events. Validation of our tool was conducted using clinical data sets including matched normal, prostate cancer samples in addition to the colorectal cancer and SCLC data sets used in the original description of chromothripsis. ShatterProof is computationally efficient, having low memory requirements and near linear computation time. This allows it to become a standard component of sequencing analysis pipelines, enabling researchers to routinely and accurately assess samples for chromothripsis. Source code and documentation can be found at http://search.cpan.org/~sgovind/Shatterproof.

Trap assisted space charge conduction in p-NiO/n-ZnO heterojunction diode

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tyagi, Manisha; Tomar, Monika; Gupta, Vinay, E-mail: drguptavinay@gmail.com

2015-06-15

Highlights: • p-NiO/n-ZnO heterojunction diode with enhanced junction parameters has been prepared. • Temperature dependent I–V throw insight into the involved conduction mechanism. • SCLC with exponential trap distribution was found to be the dominant mechanism. • C–V measurement at different frequencies support the presence of traps. - Abstract: The development of short-wavelength p–n junction is essentially important for the realization of transparent electronics for next-generation optoelectronic devices. In the present work, a p–n heterojunction diode based on p-NiO/n-ZnO has been prepared under the optimised growth conditions exhibiting improved electrical and junction parameters. The fabricated heterojunction gives typical current–voltage (I–V)more » characteristics with good rectifying behaviour (rectification ratio ≈ 10{sup 4} at 2 V). The temperature dependent current–voltage characteristics of heterojunction diode have been studied and origin of conduction mechanism is identified. The space-charge limited conduction with exponential trap distribution having deep level trap is found to be the dominant conduction mechanism in the fabricated p–n heterojunction diode. The conduction and valence band discontinuities for NiO/ZnO heterostructure have been determined from the capacitance–voltage (C–V) measurements.« less

Helping Smokers Quit: The Smoking Cessation Leadership Center Engages Behavioral Health by Challenging Old Myths and Traditions.

PubMed

Schroeder, Steven A; Clark, Brian; Cheng, Christine; Saucedo, Catherine B

2018-01-01

Smoking is much more common among persons with behavioral health conditions (mental illnesses and/or substance use disorders). Persons with these disorders are more likely to die from smoking-related causes than any other reason. Studies have shown that stopping smoking can improve mental health function, as well as improve outcomes for substance use disorders. Yet, for a variety of reasons, smoking cessation has not been integrated into the treatment of behavioral health conditions, and in many instances tobacco use was not only condoned but encouraged. Beginning in 2007, the Smoking Cessation Leadership Center (SCLC) began engaging relevant agencies in an attempt to stimulate more vigorous smoking cessation activities. Partners included the federal Substance Abuse and Mental Health Services Administration, advocacy organizations such as the National Alliance on Mental Illness and Community Anti-Drug Coalitions of America, and clinical groups such as the American Psychiatric Nurses Association, the American Psychiatric Association, American Psychological Association, National Council on Behavioral Health, and National Association of State Mental Health Program Directors. A signature program featured 16 individual state summits involving agencies and groups from multiple sectors, all aiming to lower smoking rates in behavioral health populations. These activities mark an evolving culture change within behavioral health.

Dual Paraneoplastic Syndromes: Small Cell Lung Carcinoma-related Oncogenic Osteomalacia, and Syndrome of Inappropriate Antidiuretic Hormone Secretion: Report of a Case and Review of the Literature

PubMed Central

Ng, Roland CK

2011-01-01

Acquired isolated renal phosphate wasting associated with a tumor, known as oncogenic osteomalacia or tumor-induced osteomalacia, is a rare paraneoplastic syndrome caused by overproduction of fibroblast growth factor 23. Oncogenic osteomalacia is usually associated with benign mesenchymal tumors. Syndrome of inappropriate antidiuretic hormone secretion (SIADH), on the other hand, is a common paraneoplastic syndrome caused by small cell carcinoma (SCC). Concomitant oncogenic osteomalacia and SIADH associated with SCC is very rare with only 4 other cases reported in the literature. The authors report a case of small cell lung cancer (SCLC)-related renal wasting hypophosphatemia and concurrent SIADH, and review the literature reporting 9 other cases of SCC associated with oncogenic osteomalacia. Almost half of reported cases of renal phosphate wasting associated with SCC concomitantly presented with SIADH. These cases had initial serum phosphorus level lower and survival periods shorter than those without SIADH. This rare combination of a dual paraneoplastic syndrome and low serum phosphorus may be a poor prognostic sign. In addition, both renal phosphate wasting and SIADH usually occur in a short period of time before identification of SCC. Therefore, renal wasting hypophosphatemia with concomitant SIADH/hyponatremia should prompt a search for SCC rather than a benign mesenchymal tumor. PMID:21886301

Dual paraneoplastic syndromes: small cell lung carcinoma-related oncogenic osteomalacia, and syndrome of inappropriate antidiuretic hormone secretion: report of a case and review of the literature.

PubMed

Tantisattamo, Ekamol; Ng, Roland C K

2011-07-01

Acquired isolated renal phosphate wasting associated with a tumor, known as oncogenic osteomalacia or tumor-induced osteomalacia, is a rare paraneoplastic syndrome caused by overproduction of fibroblast growth factor 23. Oncogenic osteomalacia is usually associated with benign mesenchymal tumors. Syndrome of inappropriate antidiuretic hormone secretion (SIADH), on the other hand, is a common paraneoplastic syndrome caused by small cell carcinoma (SCC). Concomitant oncogenic osteomalacia and SIADH associated with SCC is very rare with only 4 other cases reported in the literature. The authors report a case of small cell lung cancer (SCLC)-related renal wasting hypophosphatemia and concurrent SIADH, and review the literature reporting 9 other cases of SCC associated with oncogenic osteomalacia. Almost half of reported cases of renal phosphate wasting associated with SCC concomitantly presented with SIADH. These cases had initial serum phosphorus level lower and survival periods shorter than those without SIADH. This rare combination of a dual paraneoplastic syndrome and low serum phosphorus may be a poor prognostic sign. In addition, both renal phosphate wasting and SIADH usually occur in a short period of time before identification of SCC. Therefore, renal wasting hypophosphatemia with concomitant SIADH/hyponatremia should prompt a search for SCC rather than a benign mesenchymal tumor.

CD10/NEP in non-small cell lung carcinomas. Relationship to cellular proliferation.

PubMed Central

Ganju, R K; Sunday, M; Tsarwhas, D G; Card, A; Shipp, M A

1994-01-01

The cell surface metalloproteinase CD10/neutral endopeptidase 24.11 (NEP) hydrolyzes a variety of peptide substrates and reduces cellular responses to specific peptide hormones. Because CD10/NEP modulates peptide-mediated proliferation of small cell carcinomas of the lung (SCLC) and normal fetal bronchial epithelium, we evaluated the enzyme's expression in non-small cell lung carcinomas (NSCLC). Bronchoalveolar and large cell carcinoma cell lines had low levels of CD10/NEP expression whereas squamous, adenosquamous, and adenocarcinoma cell lines had higher and more variable levels of the cell surface enzyme. Regional variations in CD10/NEP immunostaining in primary NSCLC specimens prompted us to correlate CD10/NEP expression with cell growth. In primary carcinomas of the lung, clonal NSCLC cell lines and SV40-transformed fetal airway epithelium, subsets of cells expressed primarily CD10/NEP or the proliferating cell nuclear antigen (PCNA). Cultured airway epithelial cells had the lowest levels of CD10/NEP expression when the highest percentage of cells were actively dividing; in addition, these cells grew more rapidly when cell surface CD10/NEP was inhibited. NSCLC cell lines had receptors for a variety of mitogenic peptides known to be CD10/NEP substrates, underscoring the functional significance of growth-related variability in CD10/NEP expression. Images PMID:7962523

Serum pleiotrophin could be an early indicator for diagnosis and prognosis of non-small cell lung cancer.

PubMed

Du, Zi-Yan; Shi, Min-Hua; Ji, Cheng-Hong; Yu, Yong

2015-01-01

Pleiotrophin (PTN), an angiogenic factor, is associated with various types of cancer, including lung cancer. Our aim was to investigate the possibility of using serum PTN as an early indicator regarding disease diagnosis, classification and prognosis, for patients with non-small cell lung cancer (NSCLC). Significant differences among PTN levels in patients with small cell lung cancer (SCLC, n=40), NSCLC (n=136), and control subjects with benign pulmonary lesions (n=21), as well as patients with different pathological subtypes of NSCLC were observed. A serum level of PTN of 300.1 ng/ml, was determined as the cutoff value differentiating lung cancer patients and controls, with a sensitivity and specificity of 78.4% and 66.7%, respectively. Negative correlations between serum PTN level and pathological differentiation level, stage, and survival time were observed in our cohort of patients with NSCLC. In addition, specific elevation of PTN levels in pulmonary tissue in and around NSCLC lesions in comparison to normal pulmonary tissue obtained from the same subjects was also observed (n=2). This study suggests that the serum PTN level of patients with NSCLC could be an early indicator for diagnosis and prognosis. This conclusion should be further assessed in randomized clinical trials.

Covalent organic nanosheets for effective charge transport layers in planar-type perovskite solar cells.

PubMed

Park, Soyun; Kim, Min-Sung; Jang, Woongsik; Park, Jin Kuen; Wang, Dong Hwan

2018-03-08

Herein, solvent-treated bandgap-tunable covalent organic nanosheets (CONs) were prepared via the Stille cross-coupling reaction. These materials are considered useful as interlayers in photovoltaic devices upon the alignment of energy levels between other components. Among various types of solar cells, according to the organic-interlayer study, inverted planar perovskite solar cells (PSCs) are mostly demanded to effectively transport and collect charge carriers due to their high performance. At first, the C-V analysis proved the energy levels of the frontier orbitals for CON-10 and CON-16 nanosheets; this verified the suitability of these nanosheets as hole transport layers (HTLs) with the PEDOT:PSS upon casting both films from DMSO. It became evident, however, that the hole transport property of the PEDOT:PSS on the CON-16 layer was unfavorable with the increasing UPS-proven hole injection barrier. In addition, both CONs induced a rough surface morphology; however, CON-10 showed a relatively smooth surface as compared to CON-16 based on the Scanning electron microscopy (SEM) and Atomic force microscopy (AFM) profiles; furthermore, their surface properties influenced both the PEDOT:PSS layers and the perovskite layers. Especially, the XRD profiles presented an enhanced crystallinity of the perovskite layers with CON-10. All these aspects indicate that CON-10 is a more effective HTL material, and several versions of perovskite solar cells (PSCs) have been fabricated with/without CON-10 and CON-16 together with the PEDOT:PSS to determine the more-HTL-suitable CON. As a result, the power conversion efficiencies (PCEs) of the optimized devices with CON-10 exhibited a value of 10.2%, which represented a 1% increase over those of the reference devices without the CONs and was 4% higher than that of the CON-16 devices. Moreover, the devices with CON-10 were further optimized with TiO x using Al electrodes, leading to a PCE increase of these devices that became slightly higher than the PCEs of the device with CON-10 and without TiO x . This tendency was supported by photoluminescence (PL) spectroscopy, photocurrent density (J ph ), and space-charge-limited current (SCLC) mobility results.

Influence of argon and oxygen pressure ratio on bipolar-resistive switching characteristics of CeO2- x thin films deposited at room temperature

NASA Astrophysics Data System (ADS)

Ismail, Muhammad; Ullah, Rehmat; Hussain, Riaz; Talib, Ijaz; Rana, Anwar Manzoor; Hussain, Muhammad; Mahmood, Khalid; Hussain, Fayyaz; Ahmed, Ejaz; Bao, Dinghua

2018-02-01

Cerium oxide (CeO2-x) film was deposited on Pt/Ti/SiO2/Si substrate by rf magnetron sputtering at room temperature. Resistive switching characteristics of these ceria films have been improved by increasing oxygen content during deposition process. Endurance and statistical analyses indicate that the operating stability of CeO2-x-based memory is highly dependent on the oxygen content. Results indicate that CeO2-x film-based RRAM devices exhibit optimum performance when fabricated at an argon/oxygen ratio of 6:24. An increase in the oxygen content introduced during CeO2-x film deposition not only stabilizes the conventional bipolar RS but also improves excellent switching uniformity such as large ON/OFF ratio (102), excellent switching device-to-device uniformity and good sweep endurance over 500 repeated RS cycles. Conduction in the low-resistance state (LRS) as well as in the low bias field region in the high-resistance state (HRS) is found to be Ohmic and thus supports the conductive filament (CF) theory. In the high voltage region of HRS, space charge limited conduction (SCLC) and Schottky emission are found to be the dominant conduction mechanisms. A feasible filamentary RS mechanism based on the movement of oxygen ions/vacancies under the bias voltage has been discussed.

Optical absorption and electrical properties of MPc (M =Fe, Cu, Zn)-TCNQ interfaces for optoelectronic applications

NASA Astrophysics Data System (ADS)

Sánchez Vergara, M. E.; Medrano Gallardo, D.; Vera Estrada, I. L.; Jiménez Sandoval, O.

2018-04-01

This research is related to the growth and characterization of doped molecular semiconductor metallophthalocyanine-tetracyanoquinodimethane (MPc-TCNQ) films, with M = Fe, Zn, Cu. FT-IR and Raman spectroscopies were employed to study the chemical interactions taking place in the MPc-TCNQ films. XRD was carried out to determine the crystalline structure present in the samples, due to the facility of the MPcs to be in alpha and/or beta phases. The thin films were analized by SEM and UV-vis spectroscopy in order to study their morphological and optical properties. The absorption spectra recorded in the UV-Vis region for the deposited samples showed two bands, namely the Q and Soret bands. The absorption coefficient (α) and photon energy (hν) were calculated from the UV-vis spectra, to in turn determine the optic activation energy in each film and its semiconductor behavior. The values obtained for direct transitions due to the crystallinity of the films were: 1.2, 1.4 and 2 eV for FePc-TCNQ (MMFe), ZnPc-TCNQ (MMZn) and CuPc-TCNQ (MMCu), respectively. Additionally, I-V characteristics have been obtained from fabricated glass/ITO/MM/Ag devices using ohmic contacts both after annealing. The electrical properties of the devices, e.g. carrier mobility and concentration of thermally generated holes, were extracted from the J-V characteristics. The results show that the conduction process is ohmic for the MMZn and MMCu devices, at low voltages, while at high voltages, a space-charge-limited conduction (SCLC) is present. The effect of temperature on conductivity was also measured in these samples and the lower thermal activation energy calculated was 0.37 eV for MMZn. Moreover, it was found that the temperature-dependent electric current is always higher for the MMZn device and suggests a semiconductor-like behavior with an important conductivity of the order of 103 S cm-1. Anyhow, in terms not only of electric properties, but also of optic behavior, the results suggest that all three devices manufactured, MMFe, MMCu and MMZn, are of potential use in optoelectronics. The doping effect of TCNQ favors the electronic transport, most likely due to the formation of conduction channels caused by the anisotropy induced by the dopant.

A PCR-aided transcript titration assay (PATTY) to measure topoisomerase I gene expression in human tumor specimens.

PubMed

Meersma, G J; Bakker, M; Groen, H J; Van der Zee, A G; Jensen, P B; Giaccone, G; De Vries, E G; Smit, E F

1999-01-01

Topoisomerase I (topo I) inhibitors are promising anticancer agents with demonstrated activity against a wide range of solid tumors. Quantitative information on topol mRNA levels in tumor biopsies may predict response to topo I inhibitors. A polymerase chain reaction aided transcript titration assay (PATTY) was developed to allow quantitation of topol mRNA in small samples. Concentrations of topol mRNA in total RNA samples were estimated by RT-PCR analysis in a human small cell lung cancer (SCLC) cell line (GLC,) and its topotecan (GL2C/SK and F) and camptothecin (GL2C/Campt) resistant sublines, human non-small cell lung cancer (NSCLC) and ovarian carcinoma samples. Topol PATTY showed a decreased topo I mRNA level in GLC2/SK and F (4.5 pg/100 ng total RNA) and GLC,/Campt (2.2 pg/100 ng total RNA), respectively, compared to the parent cell line GLC2 (5.4 pg/100 ng total RNA). Topol protein levels as measured by Western blotting were compatible with topol mRNA levels. Median (range) topol mRNA levels were 3.23 (2.33-5.10) pg/100 ng total RNA in resected NSCLC specimen (n = 6), and 2.03 (0.54-0.95) pg/100 ng total RNA in resected ovarian cancer specimen (n = 6). We conclude that topol PATTY is a new assay that quantitates topol mRNA levels in cell lines and small tumor samples.

[Restriction polymorphism of the proto-oncogene c-Ha-ras-1 in patients with multiple primary malignant neoplasms and non-small-cell lung cancer].

PubMed

Gaspar'ian, A V; Sel'chuk, V Iu; Iakubovskaia, M G; Zborovskaia, I B; Tatosian, A G

1997-01-01

Restriction fragment length polymorphism in the human c-Ha-ras-1 locus, associated with a minisatellite sequence, was examined in 45 multiple primary cancer (MPC) patients, 56 patients with squamous cell lung cancer (SCLC), 21 patients with lung adenocarcinoma (LAC), and 53 individuals having no oncopathology. Southern analysis of cellular DNA revealed the presence of 4 common alleles (with collective allele frequency close to 94% in the control group) and a set of rare alleles. Allele a3, (2.1 kb in size under MspI/HpaII digestion) was shown to be more frequent in the MPC than in the control group. The same tendency was observed in the patients with highly differentiated cell lung cancer. An increased frequency of the a4 allele (2.5 kb under MspI/HpaII digestion) was observed in the patients with adenocarcinomas as well as in the patients with metastases and low levels of tumor tissue differentiation. The elevated frequencies of a3 in the MPC group and of a4 in the LAC patients did not correlate with increased risk of the cancers mentioned above but was associated with type of tumor progression. Previously, it was reported that the mini-satellite sequence within the c-Ha-ras-1 locus possesses enhancer activity. Our data indirectly confirm the hypothesis that the efficiency of minisatellite modulator activity is associated with fragment size.

CROSS-DISCIPLINARY PHYSICS AND RELATED AREAS OF SCIENCE AND TECHNOLOGY: Inverse computation for cardiac sources using single current dipole and current multipole models

NASA Astrophysics Data System (ADS)

Wang, Qian; Ma, Ping; Lu, Hong; Tang, Xue-Zheng; Hua, Ning; Tang, Fa-Kuan

2009-12-01

Two cardiac functional models are constructed in this paper. One is a single current model and the other is a current multipole model. Parameters denoting the properties of these two models are calculated by a least-square fit to the measurements using a simulated annealing algorithm. The measured signals are detected at 36 observation nodes by a superconducting quantum interference device (SQUID). By studying the trends of position, orientation and magnitude of the single current dipole model and the current multipole model in the QRS complex during one time span and comparing the reconstructed magnetocardiography (MCG) of these two cardiac models, we find that the current multipole model is a more appropriate model to represent cardiac electrophysiological activity.

Lateral and Vertical Organic Transistors

NASA Astrophysics Data System (ADS)

Al-Shadeedi, Akram

An extensive study has been performed to provide a better understanding of the operation principles of doped organic field-effect transistors (OFETs), organic p-i-n diodes, Schottky diodes, and organic permeable base transistors (OPBTs). This has been accomplished by a combination of electrical and structural characterization of these devices. The discussion of doped OFETs focuses on the shift of the threshold voltage due to increased doping concentrations and the generation and transport of minority charge carriers. Doping of pentacene OFETs is achieved by co-evaporation of pentacene with the n-dopant W2(hpp)4. It is found that pentacene thin film are efficiently doped and that a conductivity in the range of 2.6 x 10-6 S cm-1 for 1 wt% to 2.5 x 10-4 S cm-1 for 16 wt% is reached. It is shown that n-doped OFET consisting of an n-doped channel and n-doped contacts are ambipolar. This behavior is surprising, as n-doping the contacts should suppress direct injection of minority charge carriers (holes). It was proposed that minority charge carrier injection and hence the ambipolar characteristic of n-doped OFETs can be explained by Zener tunneling inside the intrinsic pentacene layer underneath the drain electrode. It is shown that the electric field in this layer is indeed in the range of the breakdown field of pentacene based p-i-n Zener homodiodes. Doping the channel has a profound influence on the onset voltage of minority (hole) conduction. The onset voltage can be shifted by lightly n-doping the channel. The shift of onset voltage can be explained by two mechanisms: first, due to a larger voltage that has to be applied to the gate in order to fully deplete the n-doped layer. Second, it can be attributed to an increase in hole trapping by inactive dopants. Moreover, it has been shown that the threshold voltage of majority (electron) conduction is shifted by an increase in the doping concentration, and that the ambipolar OFETs can be turned into unipolar OFETs at high doping concentrations. In subsequent chapters, the working mechanisms of OPBTs are discussed. OPBTs consist of two Schottky diodes (top and bottom diode), and the charge transport in these C60-based Schottky diodes is studied first. Two transport regimes can be distinguished in forward direction - injection limited currents (ILCs) and space charge limited currents (SCLCs). It is found that the current increases exponentially with applied voltage in the ILC regime and depends quadratically on the applied voltage in the SCLC regime. Furthermore, it is observed that the forward and backward currents of the Schottky diode are increased by decreasing the C60 layer thickness, increasing the active area, and increasing the temperature. Furthermore, in order to reach a high performance, various treatments have been applied. Air exposure, a variation of the thickness of the top electrode, as well as annealing of the diodes are used to optimize the diodes. OPBTs are processed by using the semiconductor C60 due its high charge carrier mobility and good film-forming properties. Again, the working mechanism of OPBTs is studied by electrical characterization (base-sweep measurements and output characteristics). To achieve a high performance of OPBTs, various treatments and techniques have been applied. The annealing of the OPBTs after fabrication changes the morphology of the base electrode. Thus, openings (pinholes) are formed in the base electrode, which enables a high current transfer from the upper to lower semiconductor layer. The formation of openings is proved by analyzing SEM and TEM image of the base electrode. Adding a doped layer at the emitter is another process to optimize the OPBTs. The doped layer ensures a high charge carrier injection at the emitter, leading to a high transmission and current gain. Furthermore, it has been observed that the ON/OFF ratio and transconductance of OPBTs increases by decreasing their active area. A very high transconductance gm of 37 S/cm2 is reached, which has the potential to boost the switching speed of organic transistors to 5 MHz. Furthermore, it is shown that the base electrode thickness is an essential parameter for OPBTs. The current gain beta decreases by increasing thickness of base electrode, whereas the ON/OFF ratio increases for thicker base electrodes.

Optimisation of immunofluorescence methods to determine MCT1 and MCT4 expression in circulating tumour cells.

PubMed

Kershaw, Stephen; Cummings, Jeffrey; Morris, Karen; Tugwood, Jonathan; Dive, Caroline

2015-05-10

The monocarboxylate transporter-1 (MCT1) represents a novel target in rational anticancer drug design while AZD3965 was developed as an inhibitor of this transporter and is undergoing Phase I clinical trials ( http://www.clinicaltrials.gov/show/NCT01791595 ). We describe the optimisation of an immunofluorescence (IF) method for determination of MCT1 and MCT4 in circulating tumour cells (CTC) as potential prognostic and predictive biomarkers of AZD3965 in cancer patients. Antibody selectivity was investigated by western blotting (WB) in K562 and MDAMB231 cell lines acting as positive controls for MCT1 and MCT4 respectively and by flow cytometry also employing the control cell lines. Ability to detect MCT1 and MCT4 in CTC as a 4(th) channel marker utilising the Veridex™ CellSearch system was conducted in both human volunteer blood spiked with control cells and in samples collected from small cell lung cancer (SCLC) patients. Experimental conditions were established which yielded a 10-fold dynamic range (DR) for detection of MCT1 over MCT4 (antibody concentration 6.25 μg/mL; integration time 0.4 seconds) and a 5-fold DR of MCT4 over MCT 1 (8 μg/100 μL and 0.8 seconds). The IF method was sufficiently sensitive to detect both MCT1 and MCT4 in CTCs harvested from cancer patients. The first IF method has been developed and optimised for detection of MCT 1 and MCT4 in cancer patient CTC.

Association of locally produced IL10 and TGFb1 with tumor size, histological type and presence of metastases in patients with lung carcinoma.

PubMed

Karlicic, Vukoica; Vukovic, Jelena; Stanojevic, Ivan; Sotirovic, Jelena; Peric, Aleksandar; Jovic, Milena; Cvijanovic, Vlado; Djukic, Mirjana; Banovic, Tatjana; Vojvodic, Danilo

2016-01-01

Advanced lung carcinoma is charasterized with fast disease progression. Interleukin (IL)10 and transforming growth factor (TGF)b1 are immunosuppressive mediators and their role in lung carcinoma pathogenesis and in the antitumor response has not yet been elucidated. The purpose of this study was to correlate IL10 and TGFb1 levels in the serum and lung tumor microcirculation with clinical stage, disease extent, histological features and TNM stage. The study included 41 lung cancer patients in clinical stage III and IV. Histological type was determined immunohistochemically, while tumor size, localization and dissemination were determined radiologically by multislice computerized tomography (MSCT). IL10 and TGFb1 levels were quantified with commercial flow cytometric test in serum and lung tumor microcirculation samples. Non small cell lung cancer (NSCLC) patients had significantly elevated TGFb1 while small cell lung cancer (SCLC) patients had significantly increased IL10 in tumor microcirculation. IL10 was significantly elevated in patients with the largest tumors, as well as in patients with III clinical stage and without metastases, both in the serum and tumor microcirculation. TGFb1 was significantly increased in serum and tumor microcirculation in patients with larger tumors. We found significant correlation between these two immunosuppressive cytokines, IL10 and TGFb1, in tumor microcirculation but not in patient serum samples. IL10 and TGFb1 in systemic and tumor microcirculation are significantly associated with particular histological type of lung cancer, tumor size and degree of disease extent.

"EXHALE": exercise as a strategy for rehabilitation in advanced stage lung cancer patients: a randomized clinical trial comparing the effects of 12 weeks supervised exercise intervention versus usual care for advanced stage lung cancer patients.

PubMed

Quist, Morten; Langer, Seppo W; Rørth, Mikael; Christensen, Karl Bang; Adamsen, Lis

2013-10-14

Lung cancer is the leading cause of cancer death in North America and Western Europe. Patients with lung cancer in general have reduced physical capacity, functional capacity, poor quality of life and increased levels of anxiety and depression. Intervention studies indicate that physical training can address these issues. However, there is a lack of decisive evidence regarding the effect of physical exercise in patients with advanced lung cancer. The aim of this study is to evaluate the effects of a twelve weeks, twice weekly program consisting of: supervised, structured training in a group of advanced lung cancer patients (cardiovascular and strength training, relaxation). A randomized controlled trial will test the effects of the exercise intervention in 216 patients with advanced lung cancer (non-small cell lung cancer (NSCLC) stage IIIb-IV and small cell lung cancer (SCLC) extensive disease (ED)). Primary outcome is maximal oxygen uptake (VO₂peak). Secondary outcomes are muscle strength (1RM), functional capacity (6MWD), lung capacity (Fev1) and patient reported outcome (including anxiety, depression (HADS) and quality of life (HRQOL)). The present randomized controlled study will provide data on the effectiveness of a supervised exercise intervention in patients receiving systemic therapy for advanced lung cancer. It is hoped that the intervention can improve physical capacity and functional level, during rehabilitation of cancer patients with complex symptom burden and help them to maintain independent function for as long as possible. http://ClinicalTrials.gov, NCT01881906.

A coronal magnetic field model with horizontal volume and sheet currents

NASA Technical Reports Server (NTRS)

Zhao, Xuepu; Hoeksema, J. Todd

1994-01-01

When globally mapping the observed photospheric magnetic field into the corona, the interaction of the solar wind and magnetic field has been treated either by imposing source surface boundary conditions that tacitly require volume currents outside the source surface or by limiting the interaction to thin current sheets between oppositely directed field regions. Yet observations and numerical Magnetohydrodynamic (MHD) calculations suggest the presence of non-force-free volume currents throughout the corona as well as thin current sheets in the neighborhoods of the interfaces between closed and open field lines or between oppositely directed open field lines surrounding coronal helmet-streamer structures. This work presents a model including both horizontal volume currents and streamer sheet currents. The present model builds on the magnetostatic equilibria developed by Bogdan and Low and the current-sheet modeling technique developed by Schatten. The calculation uses synoptic charts of the line-of-sight component of the photospheric magnetic field measured at the Wilcox Solar Observatory. Comparison of an MHD model with the calculated model results for the case of a dipole field and comparison of eclipse observations with calculations for CR 1647 (near solar minimum) show that this horizontal current-current-sheet model reproduces polar plumes and axes of corona streamers better than the source-surface model and reproduces polar plumes and axes of corona streamers better than the source-surface model and reproduces coro nal helmet structures better than the current-sheet model.

Lung neuroendocrine tumours: deep sequencing of the four World Health Organization histotypes reveals chromatin-remodelling genes as major players and a prognostic role for TERT, RB1, MEN1 and KMT2D.

PubMed

Simbolo, Michele; Mafficini, Andrea; Sikora, Katarzyna O; Fassan, Matteo; Barbi, Stefano; Corbo, Vincenzo; Mastracci, Luca; Rusev, Borislav; Grillo, Federica; Vicentini, Caterina; Ferrara, Roberto; Pilotto, Sara; Davini, Federico; Pelosi, Giuseppe; Lawlor, Rita T; Chilosi, Marco; Tortora, Giampaolo; Bria, Emilio; Fontanini, Gabriella; Volante, Marco; Scarpa, Aldo

2017-03-01

Next-generation sequencing (NGS) was applied to 148 lung neuroendocrine tumours (LNETs) comprising the four World Health Organization classification categories: 53 typical carcinoid (TCs), 35 atypical carcinoid (ACs), 27 large-cell neuroendocrine carcinomas, and 33 small-cell lung carcinomas. A discovery screen was conducted on 46 samples by the use of whole-exome sequencing and high-coverage targeted sequencing of 418 genes. Eighty-eight recurrently mutated genes from both the discovery screen and current literature were verified in the 46 cases of the discovery screen, and validated on additional 102 LNETs by targeted NGS; their prevalence was then evaluated on the whole series. Thirteen of these 88 genes were also evaluated for copy number alterations (CNAs). Carcinoids and carcinomas shared most of the altered genes but with different prevalence rates. When mutations and copy number changes were combined, MEN1 alterations were almost exclusive to carcinoids, whereas alterations of TP53 and RB1 cell cycle regulation genes and PI3K/AKT/mTOR pathway genes were significantly enriched in carcinomas. Conversely, mutations in chromatin-remodelling genes, including those encoding histone modifiers and members of SWI-SNF complexes, were found at similar rates in carcinoids (45.5%) and carcinomas (55.0%), suggesting a major role in LNET pathogenesis. One AC and one TC showed a hypermutated profile associated with a POLQ damaging mutation. There were fewer CNAs in carcinoids than in carcinomas; however ACs showed a hybrid pattern, whereby gains of TERT, SDHA, RICTOR, PIK3CA, MYCL and SRC were found at rates similar to those in carcinomas, whereas the MEN1 loss rate mirrored that of TCs. Multivariate survival analysis revealed RB1 mutation (p = 0.0005) and TERT copy gain (p = 0.016) as independent predictors of poorer prognosis. MEN1 mutation was associated with poor prognosis in AC (p = 0.0045), whereas KMT2D mutation correlated with longer survival in SCLC (p = 0.0022). In conclusion, molecular profiling may complement histology for better diagnostic definition and prognostic stratification of LNETs. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Stratification established by peeling detrainment from gravity currents: laboratory experiments and models

NASA Astrophysics Data System (ADS)

Hogg, Charlie; Dalziel, Stuart; Huppert, Herbert; Imberger, Jorg; Department of Applied Mathematics; Theoretical Physics Team; CentreWater Research Team

2014-11-01

Dense gravity currents feed fluid into confined basins in lakes, the oceans and many industrial applications. Existing models of the circulation and mixing in such basins are often based on the currents entraining ambient fluid. However, recent observations have suggested that uni-directional entrainment into a gravity current does not fully describe the mixing in such currents. Laboratory experiments were carried out which visualised peeling detrainment from the gravity current occurring when the ambient fluid was stratified. A theoretical model of the observed peeling detrainment was developed to predict the stratification in the basin. This new model gives a better approximation of the stratification observed in the experiments than the pre-existing entraining model. The model can now be developed such that it integrates into operational models of lakes.

Analysis and modeling of leakage current sensor under pulsating direct current

NASA Astrophysics Data System (ADS)

Li, Kui; Dai, Yihua; Wang, Yao; Niu, Feng; Chen, Zhao; Huang, Shaopo

2017-05-01

In this paper, the transformation characteristics of current sensor under pulsating DC leakage current is investigated. The mathematical model of current sensor is proposed to accurately describe the secondary side current and excitation current. The transformation process of current sensor is illustrated in details and the transformation error is analyzed from multi aspects. A simulation model is built and a sensor prototype is designed to conduct comparative evaluation, and both simulation and experimental results are presented to verify the correctness of theoretical analysis.

Model development and validation of geometrically complex eddy current coils using finite element methods

NASA Astrophysics Data System (ADS)

Brown, Alexander; Eviston, Connor

2017-02-01

Multiple FEM models of complex eddy current coil geometries were created and validated to calculate the change of impedance due to the presence of a notch. Capable realistic simulations of eddy current inspections are required for model assisted probability of detection (MAPOD) studies, inversion algorithms, experimental verification, and tailored probe design for NDE applications. An FEM solver was chosen to model complex real world situations including varying probe dimensions and orientations along with complex probe geometries. This will also enable creation of a probe model library database with variable parameters. Verification and validation was performed using other commercially available eddy current modeling software as well as experimentally collected benchmark data. Data analysis and comparison showed that the created models were able to correctly model the probe and conductor interactions and accurately calculate the change in impedance of several experimental scenarios with acceptable error. The promising results of the models enabled the start of an eddy current probe model library to give experimenters easy access to powerful parameter based eddy current models for alternate project applications.

Integration of RAM-SCB into the Space Weather Modeling Framework

DOE PAGES

Welling, Daniel; Toth, Gabor; Jordanova, Vania Koleva; ...

2018-02-07

We present that numerical simulations of the ring current are a challenging endeavor. They require a large set of inputs, including electric and magnetic fields and plasma sheet fluxes. Because the ring current broadly affects the magnetosphere-ionosphere system, the input set is dependent on the ring current region itself. This makes obtaining a set of inputs that are self-consistent with the ring current difficult. To overcome this challenge, researchers have begun coupling ring current models to global models of the magnetosphere-ionosphere system. This paper describes the coupling between the Ring current Atmosphere interaction Model with Self-Consistent Magnetic field (RAM-SCB) tomore » the models within the Space Weather Modeling Framework. Full details on both previously introduced and new coupling mechanisms are defined. Finally, the impact of self-consistently including the ring current on the magnetosphere-ionosphere system is illustrated via a set of example simulations.« less

Integration of RAM-SCB into the Space Weather Modeling Framework

DOE Office of Scientific and Technical Information (OSTI.GOV)

Welling, Daniel; Toth, Gabor; Jordanova, Vania Koleva

We present that numerical simulations of the ring current are a challenging endeavor. They require a large set of inputs, including electric and magnetic fields and plasma sheet fluxes. Because the ring current broadly affects the magnetosphere-ionosphere system, the input set is dependent on the ring current region itself. This makes obtaining a set of inputs that are self-consistent with the ring current difficult. To overcome this challenge, researchers have begun coupling ring current models to global models of the magnetosphere-ionosphere system. This paper describes the coupling between the Ring current Atmosphere interaction Model with Self-Consistent Magnetic field (RAM-SCB) tomore » the models within the Space Weather Modeling Framework. Full details on both previously introduced and new coupling mechanisms are defined. Finally, the impact of self-consistently including the ring current on the magnetosphere-ionosphere system is illustrated via a set of example simulations.« less

Investigation of the effects of external current systems on the MAGSAT data utilizing grid cell modeling techniques

NASA Technical Reports Server (NTRS)

Klumpar, D. M. (Principal Investigator)

1982-01-01

The feasibility of modeling magnetic fields due to certain electrical currents flowing in the Earth's ionosphere and magnetosphere was investigated. A method was devised to carry out forward modeling of the magnetic perturbations that arise from space currents. The procedure utilizes a linear current element representation of the distributed electrical currents. The finite thickness elements are combined into loops which are in turn combined into cells having their base in the ionosphere. In addition to the extensive field modeling, additional software was developed for the reduction and analysis of the MAGSAT data in terms of the external current effects. Direct comparisons between the models and the MAGSAT data are possible.

25. CURRENT METERS: GURLEY MODEL NO. 665 AT CENTER, GURLEY ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

25. CURRENT METERS: GURLEY MODEL NO. 665 AT CENTER, GURLEY MODEL NO. 625 'PYGMY' CURRENT METER AT LEFT, AND WES MINIATURE PRICE-TYPE CURRENT METER AT RIGHT. - Waterways Experiment Station, Hydraulics Laboratory, Halls Ferry Road, 2 miles south of I-20, Vicksburg, Warren County, MS

Test of bootstrap current models using high- β p EAST-demonstration plasmas on DIII-D

DOE PAGES

Ren, Qilong; Lao, Lang L.; Garofalo, Andrea M.; ...

2015-01-12

Magnetic measurements together with kinetic profile and motional Stark effect measurements are used in full kinetic equilibrium reconstructions to test the Sauter and NEO bootstrap current models in a DIII-D high-more » $${{\\beta}_{\\text{p}}}$$ EAST-demonstration experiment. This aims at developing on DIII-D a high bootstrap current scenario to be extended on EAST for a demonstration of true steady-state at high performance and uses EAST-similar operational conditions: plasma shape, plasma current, toroidal magnetic field, total heating power and current ramp-up rate. It is found that the large edge bootstrap current in these high-$${{\\beta}_{\\text{p}}}$$ plasmas allows the use of magnetic measurements to clearly distinguish the two bootstrap current models. In these high collisionality and high-$${{\\beta}_{\\text{p}}}$$ plasmas, the Sauter model overpredicts the peak of the edge current density by about 30%, while the first-principle kinetic NEO model is in close agreement with the edge current density of the reconstructed equilibrium. Furthermore, these results are consistent with recent work showing that the Sauter model largely overestimates the edge bootstrap current at high collisionality.« less

Modified Johnson-Cook model incorporated with electroplasticity for uniaxial tension under a pulsed electric current

NASA Astrophysics Data System (ADS)

Kim, Moon-Jo; Jeong, Hye-Jin; Park, Ju-Won; Hong, Sung-Tae; Han, Heung Nam

2018-01-01

An empirical expression describing the electroplastic deformation behavior is suggested based on the Johnson-Cook (JC) model by adding several functions to consider both thermal and athermal electric current effects. Tensile deformation behaviors are carried out for an AZ31 magnesium alloy and an Al-Mg-Si alloy under pulsed electric current at various current densities with a fixed duration of electric current. To describe the flow curves under electric current, a modified JC model is proposed to take the electric current effect into account. Phenomenological descriptions of the adopted parameters in the equation are made. The modified JC model suggested in the present study is capable of describing the tensile deformation behaviors under pulsed electric current reasonably well.

Equivalent Electromagnetic Constants for Microwave Application to Composite Materials for the Multi-Scale Problem

PubMed Central

Fujisaki, Keisuke; Ikeda, Tomoyuki

2013-01-01

To connect different scale models in the multi-scale problem of microwave use, equivalent material constants were researched numerically by a three-dimensional electromagnetic field, taking into account eddy current and displacement current. A volume averaged method and a standing wave method were used to introduce the equivalent material constants; water particles and aluminum particles are used as composite materials. Consumed electrical power is used for the evaluation. Water particles have the same equivalent material constants for both methods; the same electrical power is obtained for both the precise model (micro-model) and the homogeneous model (macro-model). However, aluminum particles have dissimilar equivalent material constants for both methods; different electric power is obtained for both models. The varying electromagnetic phenomena are derived from the expression of eddy current. For small electrical conductivity such as water, the macro-current which flows in the macro-model and the micro-current which flows in the micro-model express the same electromagnetic phenomena. However, for large electrical conductivity such as aluminum, the macro-current and micro-current express different electromagnetic phenomena. The eddy current which is observed in the micro-model is not expressed by the macro-model. Therefore, the equivalent material constant derived from the volume averaged method and the standing wave method is applicable to water with a small electrical conductivity, although not applicable to aluminum with a large electrical conductivity. PMID:28788395

Nearshore Current Model Workshop Summary.

DTIC Science & Technology

1983-09-01

dissipation , and wave-current interaction. b. Incorporation into models of wave-breaking. c. Parameterization of turbulence in models. d. Incorporation...into models of surf zone energy dissipation . e. Methods to specify waves and currents on the boundaries of the grid. f. Incorporation into models of...also recommended. Improvements should include nonlinear and irregular wave effects and improved models of wave-breaking and wave energy dissipation in

Investigation of the effects of external current systems on the MAGSAT data utilizing grid cell modeling techniques

NASA Technical Reports Server (NTRS)

Klumpar, D. M. (Principal Investigator)

1981-01-01

Progress is reported in reading MAGSAT tapes in modeling procedure developed to compute the magnetic fields at satellite orbit due to current distributions in the ionosphere. The modeling technique utilizes a linear current element representation of the large-scale space-current system.

The two-way relationship between ionospheric outflow and the ring current

DOE Office of Scientific and Technical Information (OSTI.GOV)

Welling, Daniel T.; Jordanova, Vania Koleva; Glocer, Alex

It is now well established that the ionosphere, because it acts as a significant source of plasma, plays a critical role in ring current dynamics. However, because the ring current deposits energy into the ionosphere, the inverse may also be true: the ring current can play a critical role in the dynamics of ionospheric outflow. This study uses a set of coupled, first-principles-based numerical models to test the dependence of ionospheric outflow on ring current-driven region 2 field-aligned currents (FACs). A moderate magnetospheric storm event is modeled with the Space Weather Modeling Framework using a global MHD code (Block Adaptivemore » Tree Solar wind Roe-type Upwind Scheme, BATS-R-US), a polar wind model (Polar Wind Outflow Model), and a bounce-averaged kinetic ring current model (ring current atmosphere interaction model with self-consistent magnetic field, RAM-SCB). Initially, each code is two-way coupled to all others except for RAM-SCB, which receives inputs from the other models but is not allowed to feed back pressure into the MHD model. The simulation is repeated with pressure coupling activated, which drives strong pressure gradients and region 2 FACs in BATS-R-US. It is found that the region 2 FACs increase heavy ion outflow by up to 6 times over the non-coupled results. The additional outflow further energizes the ring current, establishing an ionosphere-magnetosphere mass feedback loop. This study further demonstrates that ionospheric outflow is not merely a plasma source for the magnetosphere but an integral part in the nonlinear ionosphere-magnetosphere-ring current system.« less

The two-way relationship between ionospheric outflow and the ring current

DOE PAGES

Welling, Daniel T.; Jordanova, Vania Koleva; Glocer, Alex; ...

2015-06-01

It is now well established that the ionosphere, because it acts as a significant source of plasma, plays a critical role in ring current dynamics. However, because the ring current deposits energy into the ionosphere, the inverse may also be true: the ring current can play a critical role in the dynamics of ionospheric outflow. This study uses a set of coupled, first-principles-based numerical models to test the dependence of ionospheric outflow on ring current-driven region 2 field-aligned currents (FACs). A moderate magnetospheric storm event is modeled with the Space Weather Modeling Framework using a global MHD code (Block Adaptivemore » Tree Solar wind Roe-type Upwind Scheme, BATS-R-US), a polar wind model (Polar Wind Outflow Model), and a bounce-averaged kinetic ring current model (ring current atmosphere interaction model with self-consistent magnetic field, RAM-SCB). Initially, each code is two-way coupled to all others except for RAM-SCB, which receives inputs from the other models but is not allowed to feed back pressure into the MHD model. The simulation is repeated with pressure coupling activated, which drives strong pressure gradients and region 2 FACs in BATS-R-US. It is found that the region 2 FACs increase heavy ion outflow by up to 6 times over the non-coupled results. The additional outflow further energizes the ring current, establishing an ionosphere-magnetosphere mass feedback loop. This study further demonstrates that ionospheric outflow is not merely a plasma source for the magnetosphere but an integral part in the nonlinear ionosphere-magnetosphere-ring current system.« less

The inclusion of ocean-current effects in a tidal-current model as forcing in the convection term and its application to the mesoscale fate of CO2 seeping from the seafloor

NASA Astrophysics Data System (ADS)

Sakaizawa, Ryosuke; Kawai, Takaya; Sato, Toru; Oyama, Hiroyuki; Tsumune, Daisuke; Tsubono, Takaki; Goto, Koichi

2018-03-01

The target seas of tidal-current models are usually semi-closed bays, minimally affected by ocean currents. For these models, tidal currents are simulated in computational domains with a spatial scale of a couple hundred kilometers or less, by setting tidal elevations at their open boundaries. However, when ocean currents cannot be ignored in the sea areas of interest, such as in open seas near coastlines, it is necessary to include ocean-current effects in these tidal-current models. In this study, we developed a numerical method to analyze tidal currents near coasts by incorporating pre-calculated ocean-current velocities. First, a large regional-scale simulation with a spatial scale of several thousand kilometers was conducted and temporal changes in the ocean-current velocity at each grid point were stored. Next, the spatially and temporally interpolated ocean-current velocity was incorporated as forcing into the cross terms of the convection term of a tidal-current model having computational domains with spatial scales of hundreds of kilometers or less. Then, we applied this method to the diffusion of dissolved CO2 in a sea area off Tomakomai, Japan, and compared the numerical results and measurements to validate the proposed method.

Investigation of the effects of external current systems on the MAGSAT data utilizing grid cell modeling techniques

NASA Technical Reports Server (NTRS)

Klumpar, D. M. (Principal Investigator)

1982-01-01

The status of the initial testing of the modeling procedure developed to compute the magnetic fields at satellite orbit due to current distributions in the ionosphere and magnetosphere is reported. The modeling technique utilizes a linear current element representation of the large scale space-current system.

Effect of Human Model Height and Sex on Induced Current Dosimetry in Household Induction Heater Users

NASA Astrophysics Data System (ADS)

Tarao, Hiroo; Hayashi, Noriyuki; Isaka, Katsuo

Induced currents in the high-resolution, anatomical human models are numerically calculated by the impedance method. The human models are supposed to be exposed to highly inhomogeneous 20.9 kHz magnetic fields from a household induction heater (IH). In the case of the adult models, the currents ranging from 5 to 19 mA/m2 are induced for between the shoulder and lower abdomen. Meanwhile, in the case of the child models, the currents ranging from 5 to 21 mA/m2 are induced for between the head and abdomen. In particular, the induced currents near the brain tissue are almost the same as those near the abdomen. When the induced currents in the central nervous system tissues are considered, the induced currents in the child model are 2.1 to 6.9 times as large as those in the adult model under the same B-field exposure environment. These results suggest the importance of further investigation intended for a pregnant female who uses the IH as well as for a child (or the IH users of small standing height).

Comparison of predictive estimates of high-latitude electrodynamics with observations of global-scale Birkeland currents

NASA Astrophysics Data System (ADS)

Anderson, Brian J.; Korth, Haje; Welling, Daniel T.; Merkin, Viacheslav G.; Wiltberger, Michael J.; Raeder, Joachim; Barnes, Robin J.; Waters, Colin L.; Pulkkinen, Antti A.; Rastaetter, Lutz

2017-02-01

Two of the geomagnetic storms for the Space Weather Prediction Center Geospace Environment Modeling challenge occurred after data were first acquired by the Active Magnetosphere and Planetary Electrodynamics Response Experiment (AMPERE). We compare Birkeland currents from AMPERE with predictions from four models for the 4-5 April 2010 and 5-6 August 2011 storms. The four models are the Weimer (2005b) field-aligned current statistical model, the Lyon-Fedder-Mobarry magnetohydrodynamic (MHD) simulation, the Open Global Geospace Circulation Model MHD simulation, and the Space Weather Modeling Framework MHD simulation. The MHD simulations were run as described in Pulkkinen et al. (2013) and the results obtained from the Community Coordinated Modeling Center. The total radial Birkeland current, ITotal, and the distribution of radial current density, Jr, for all models are compared with AMPERE results. While the total currents are well correlated, the quantitative agreement varies considerably. The Jr distributions reveal discrepancies between the models and observations related to the latitude distribution, morphologies, and lack of nightside current systems in the models. The results motivate enhancing the simulations first by increasing the simulation resolution and then by examining the relative merits of implementing more sophisticated ionospheric conductance models, including ionospheric outflows or other omitted physical processes. Some aspects of the system, including substorm timing and location, may remain challenging to simulate, implying a continuing need for real-time specification.

Phenomenological description of depoling current in Pb0.99Nb0.02(Zr0.95Ti0.05)0.98O3 ferroelectric ceramics under shock wave compression: Relaxation model

NASA Astrophysics Data System (ADS)

Jiang, Dongdong; Du, Jinmei; Gu, Yan; Feng, Yujun

2012-05-01

By assuming a relaxation process for depolarization associated with the ferroelectric (FE) to antiferroelectric (AFE) phase transition in Pb0.99Nb0.02(Zr0.95Ti0.05)0.98O3 ferroelectric ceramics under shock wave compression, we build a new model for the depoling current, which is different from both the traditional constant current source (CCS) model and the phase transition kinetics (PTK) model. The characteristic relaxation time and new-equilibrated polarization are dependent on both the shock pressure and electric field. After incorporating a Maxwell s equation, the relaxation model developed applies to all the depoling currents under short-circuit condition and high-impedance condition. Influences of shock pressure, load resistance, dielectric property, and electrical conductivity on the depoling current are also discussed. The relaxation model gives a good description about the suppressing effect of the self-generated electric field on the FE-to-AFE phase transition at low shock pressures, which cannot be described by the traditional models. After incorporating a time- and electric-field-dependent repolarization, this model predicts that the high-impedance current eventually becomes higher than the short-circuit current, which is consistent with the experimental results in the literature. Finally, we make the comparison between our relaxation model and the traditional CCS model and PTK model.

Spacecraft Charging Current Balance Model Applied to High Voltage Solar Array Operations

NASA Technical Reports Server (NTRS)

Willis, Emily M.; Pour, Maria Z. A.

2016-01-01

Spacecraft charging induced by high voltage solar arrays can result in power losses and degradation of spacecraft surfaces. In some cases, it can even present safety issues for astronauts performing extravehicular activities. An understanding of the dominant processes contributing to spacecraft charging induced by solar arrays is important to current space missions, such as the International Space Station, and to any future space missions that may employ high voltage solar arrays. A common method of analyzing the factors contributing to spacecraft charging is the current balance model. Current balance models are based on the simple idea that the spacecraft will float to a potential such that the current collecting to the surfaces equals the current lost from the surfaces. However, when solar arrays are involved, these currents are dependent on so many factors that the equation becomes quite complicated. In order for a current balance model to be applied to solar array operations, it must incorporate the time dependent nature of the charging of dielectric surfaces in the vicinity of conductors1-3. This poster will present the factors which must be considered when developing a current balance model for high voltage solar array operations and will compare results of a current balance model with data from the Floating Potential Measurement Unit4 on board the International Space Station.

Dynamics of the exponential integrate-and-fire model with slow currents and adaptation.

PubMed

Barranca, Victor J; Johnson, Daniel C; Moyher, Jennifer L; Sauppe, Joshua P; Shkarayev, Maxim S; Kovačič, Gregor; Cai, David

2014-08-01

In order to properly capture spike-frequency adaptation with a simplified point-neuron model, we study approximations of Hodgkin-Huxley (HH) models including slow currents by exponential integrate-and-fire (EIF) models that incorporate the same types of currents. We optimize the parameters of the EIF models under the external drive consisting of AMPA-type conductance pulses using the current-voltage curves and the van Rossum metric to best capture the subthreshold membrane potential, firing rate, and jump size of the slow current at the neuron's spike times. Our numerical simulations demonstrate that, in addition to these quantities, the approximate EIF-type models faithfully reproduce bifurcation properties of the HH neurons with slow currents, which include spike-frequency adaptation, phase-response curves, critical exponents at the transition between a finite and infinite number of spikes with increasing constant external drive, and bifurcation diagrams of interspike intervals in time-periodically forced models. Dynamics of networks of HH neurons with slow currents can also be approximated by corresponding EIF-type networks, with the approximation being at least statistically accurate over a broad range of Poisson rates of the external drive. For the form of external drive resembling realistic, AMPA-like synaptic conductance response to incoming action potentials, the EIF model affords great savings of computation time as compared with the corresponding HH-type model. Our work shows that the EIF model with additional slow currents is well suited for use in large-scale, point-neuron models in which spike-frequency adaptation is important.

Modeling of Optical Waveguide Poling and Thermally Stimulated Discharge (TSD) Charge and Current Densities for Guest/Host Electro Optic Polymers

NASA Technical Reports Server (NTRS)

Watson, Michael D.; Ashley, Paul R.; Abushagur, Mustafa

2004-01-01

A charge density and current density model of a waveguide system has been developed to explore the effects of electric field electrode poling. An optical waveguide may be modeled during poling by considering the dielectric charge distribution, polarization charge distribution, and conduction charge generated by the poling field. These charge distributions are the source of poling current densities. The model shows that boundary charge current density and polarization current density are the major source of currents measured during poling and thermally stimulated discharge These charge distributions provide insight into the poling mechanisms and are directly related to E(sub A), and, alpha(sub r). Initial comparisons with experimental data show excellent correlation to the model results.

Circulation-based Modeling of Gravity Currents

NASA Astrophysics Data System (ADS)

Meiburg, E. H.; Borden, Z.

2013-05-01

Atmospheric and oceanic flows driven by predominantly horizontal density differences, such as sea breezes, thunderstorm outflows, powder snow avalanches, and turbidity currents, are frequently modeled as gravity currents. Efforts to develop simplified models of such currents date back to von Karman (1940), who considered a two-dimensional gravity current in an inviscid, irrotational and infinitely deep ambient. Benjamin (1968) presented an alternative model, focusing on the inviscid, irrotational flow past a gravity current in a finite-depth channel. More recently, Shin et al. (2004) proposed a model for gravity currents generated by partial-depth lock releases, considering a control volume that encompasses both fronts. All of the above models, in addition to the conservation of mass and horizontal momentum, invoke Bernoulli's law along some specific streamline in the flow field, in order to obtain a closed system of equations that can be solved for the front velocity as function of the current height. More recent computational investigations based on the Navier-Stokes equations, on the other hand, reproduce the dynamics of gravity currents based on the conservation of mass and momentum alone. We propose that it should therefore be possible to formulate a fundamental gravity current model without invoking Bernoulli's law. The talk will show that the front velocity of gravity currents can indeed be predicted as a function of their height from mass and momentum considerations alone, by considering the evolution of interfacial vorticity. This approach does not require information on the pressure field and therefore avoids the need for an energy closure argument such as those invoked by the earlier models. Predictions by the new theory are shown to be in close agreement with direct numerical simulation results. References Von Karman, T. 1940 The engineer grapples with nonlinear problems, Bull. Am. Math Soc. 46, 615-683. Benjamin, T.B. 1968 Gravity currents and related phenomena, J. Fluid Mech. 31, 209-248. Shin, J.O., Dalziel, S.B. and Linden, P.F. 2004 Gravity currents produced by lock exchange, J. Fluid Mech. 521, 1-34.

Prognostic role of platelet to lymphocyte ratio in non-small cell lung cancers: A meta-analysis including 3,720 patients.

PubMed

Zhao, Qing-Tao; Yuan, Zheng; Zhang, Hua; Zhang, Xiao-Peng; Wang, Hui-En; Wang, Zhi-Kang; Duan, Guo-Chen

2016-07-01

Platelet to lymphocyte ratio (PLR) was recently reported as a useful index in predicting the prognosis of lung cancer. However, the prognostic role of PLR in lung cancer remains controversial. The aim of this study was to evaluate the association between PLR and clinical outcome of lung cancer patients through a meta-analysis. Relevant literatures were retrieved from PubMed, Ovid, the Cochrane Library and Web of Science databases. Meta-analysis was performed using hazard ratio (HR) and 95% confidence intervals (CIs) as effect measures. A total of 5,314 patients from 13 studies were finally enrolled in the meta-analysis. The summary results showed that elevated PLR predicted poorer overall survival (OS) (HR: 1.526, 95%CI: 1.268-1.836, p < 0.001) in patients with lung cancer and OS (HR: 1.631, 95%CI: 1.447-1.837, p < 0.001) in patients with nonsmall cell lung cancer (NSCLC). Subgroup analysis revealed that increased PLR was also associated with poor OS in NSCLC treated by surgical resection (HR: 1.884, 95%CI: 1.308-2.714, P < 0.001) and non-surgery (HR: 1.570, 95%CI: 1.323-1.863, P < 0.001). In addition, PLR Cut-off value ≤ 160 (HR: 1.506, 95%CI: 1.292-1.756, P < 0.001) and PLR Cut-off value>160 (HR: 1.842, 95%CI: 1.523-2.228, P < 0.001). In contrast, elevated PLR was not associated with OS (HR: 1.117, 95%CI: 0.796-1.569, P > 0.05) in patients with small cell lung cancer (SCLC).This meta-analysis result suggested that elevated PLR might be a predicative factor of poor prognosis for NSCLC patients. © 2016 UICC.

[Diagnosis, prognosis, and prediction of non-small cell lung cancer. Importance of morphology, immunohistochemistry and molecular pathology].

PubMed

Warth, A

2015-11-01

Tumor diagnostics are based on histomorphology, immunohistochemistry and molecular pathological analysis of mutations, translocations and amplifications which are of diagnostic, prognostic and/or predictive value. In recent decades only histomorphology was used to classify lung cancer as either small (SCLC) or non-small cell lung cancer (NSCLC), although NSCLC was further subdivided in different entities; however, as no specific therapy options were available classification of specific subtypes was not clinically meaningful. This fundamentally changed with the discovery of specific molecular alterations in adenocarcinoma (ADC), e.g. mutations in KRAS, EGFR and BRAF or translocations of the ALK and ROS1 gene loci, which now form the basis of targeted therapies and have led to a significantly improved patient outcome. The diagnostic, prognostic and predictive value of imaging, morphological, immunohistochemical and molecular characteristics as well as their interaction were systematically assessed in a large cohort with available clinical data including patient survival. Specific and sensitive diagnostic markers and marker panels were defined and diagnostic test algorithms for predictive biomarker assessment were optimized. It was demonstrated that the semi-quantitative assessment of ADC growth patterns is a stage-independent predictor of survival and is reproducibly applicable in the routine setting. Specific histomorphological characteristics correlated with computed tomography (CT) imaging features and thus allowed an improved interdisciplinary classification, especially in the preoperative or palliative setting. Moreover, specific molecular characteristics, for example BRAF mutations and the proliferation index (Ki-67) were identified as clinically relevant prognosticators. Comprehensive clinical, morphological, immunohistochemical and molecular assessment of NSCLCs allow an optimized patient stratification. Respective algorithms now form the backbone of the 2015 lung cancer World Health Organization (WHO) classification.

Pathways Impacted by Genomic Alterations in Pulmonary Carcinoid Tumors.

PubMed

Asiedu, Michael K; Thomas, Charles F; Dong, Jie; Schulte, Sandra C; Khadka, Prasidda; Sun, Zhifu; Kosari, Farhad; Jen, Jin; Molina, Julian; Vasmatzis, George; Kuang, Ray; Aubry, Marie Christine; Yang, Ping; Wigle, Dennis A

2018-04-01

Purpose: Pulmonary carcinoid tumors account for up to 5% of all lung malignancies in adults, comprise 30% of all carcinoid malignancies, and are defined histologically as typical carcinoid (TC) and atypical carcinoid (AC) tumors. The role of specific genomic alterations in the pathogenesis of pulmonary carcinoid tumors remains poorly understood. We sought to identify genomic alterations and pathways that are deregulated in these tumors to find novel therapeutic targets for pulmonary carcinoid tumors. Experimental Design: We performed integrated genomic analysis of carcinoid tumors comprising whole genome and exome sequencing, mRNA expression profiling and SNP genotyping of specimens from normal lung, TC and AC, and small cell lung carcinoma (SCLC) to fully represent the lung neuroendocrine tumor spectrum. Results: Analysis of sequencing data found recurrent mutations in cancer genes including ATP1A2, CNNM1, MACF1, RAB38, NF1, RAD51C, TAF1L, EPHB2, POLR3B , and AGFG1 The mutated genes are involved in biological processes including cellular metabolism, cell division cycle, cell death, apoptosis, and immune regulation. The top most significantly mutated genes were TMEM41B, DEFB127, WDYHV1, and TBPL1 Pathway analysis of significantly mutated and cancer driver genes implicated MAPK/ERK and amyloid beta precursor protein (APP) pathways whereas analysis of CNV and gene expression data suggested deregulation of the NF-κB and MAPK/ERK pathways. The mutation signature was predominantly C>T and T>C transitions with a minor contribution of T>G transversions. Conclusions: This study identified mutated genes affecting cancer relevant pathways and biological processes that could provide opportunities for developing targeted therapies for pulmonary carcinoid tumors. Clin Cancer Res; 24(7); 1691-704. ©2018 AACR . ©2018 American Association for Cancer Research.

Cone-beam CT-guided radiotherapy in the management of lung cancer: Diagnostic and therapeutic value.

PubMed

Elsayad, Khaled; Kriz, Jan; Reinartz, Gabriele; Scobioala, Sergiu; Ernst, Iris; Haverkamp, Uwe; Eich, Hans Theodor

2016-02-01

Recent studies have demonstrated an increase in the necessity of adaptive planning over the course of lung cancer radiation therapy (RT) treatment. In this study, we evaluated intrathoracic changes detected by cone-beam CT (CBCT) in lung cancer patients during RT. A total of 71 lung cancer patients treated with fractionated CBCT-guided RT were evaluated. Intrathoracic changes and plan adaptation priority (AP) scores were compared between small cell lung cancer (SCLC, n = 13) and non-small cell lung cancer (NSCLC, n = 58) patients. The median cumulative radiation dose administered was 54 Gy (range 30-72 Gy) and the median fraction dose was 1.8 Gy (range 1.8-3.0 Gy). All patients were subjected to a CBCT scan at least weekly (range 1-5/week). We observed intrathoracic changes in 83 % of the patients over the course of RT [58 % (41/71) regression, 17 % (12/71) progression, 20 % (14/71) atelectasis, 25 % (18/71) pleural effusion, 13 % (9/71) infiltrative changes, and 10 % (7/71) anatomical shift]. Nearly half, 45 % (32/71), of the patients had one intrathoracic soft tissue change, 22.5 % (16/71) had two, and three or more changes were observed in 15.5 % (11/71) of the patients. Plan modifications were performed in 60 % (43/71) of the patients. Visual volume reduction did correlate with the number of CBCT scans acquired (r = 0.313, p = 0.046) and with the timing of chemotherapy administration (r = 0.385, p = 0.013). Weekly CBCT monitoring provides an adaptation advantage in patients with lung cancer. In this study, the monitoring allowed for plan adaptations due to tumor volume changes and to other anatomical changes.

Brain microvascular endothelium induced-annexin A1 secretion contributes to small cell lung cancer brain metastasis.

PubMed

Liu, Yi; Liu, Yong-Shuo; Wu, Peng-Fei; Li, Qiang; Dai, Wu-Min; Yuan, Shuai; Xu, Zhi-Hua; Liu, Ting-Ting; Miao, Zi-Wei; Fang, Wen-Gang; Chen, Yu-Hua; Li, Bo

2015-09-01

Small cell lung cancer is the most aggressive histologic subtype of lung cancer, with a strong predilection for metastasizing to brain early. However, the cellular and molecular basis is poorly known. Here, we provided evidence to reveal the role of annexin A1 in small cell lung cancer metastasis to brain. Firstly, the elevated annexin A1 serum levels in small cell lung cancer patients were associated with brain metastasis. The levels of annexin A1 were also upregulated in NCI-H446 cells, a small cell lung cancer cell line, upon migration into the mice brain. More interestingly, annexin A1 was secreted by NCI-H446 cells in a time-dependent manner when co-culturing with human brain microvascular endothelial cells, which was identified with the detections of annexin A1 in the co-cultured cellular supernatants by ELISA and western blot. Further results showed that blockage of annexin A1 in the co-cultured cellular supernatants using a neutralized antibody significantly inhibited NCI-H446 cells adhesion to brain endothelium and its transendothelial migration. Conversely, the addition of Ac2-26, an annexin A1 mimic peptide, enhanced these effects. Furthermore, knockdown of annexin A1 in NCI-H446 cells prevented its transendothelial migration in vitro and metastasis to mice brain in vivo. Our data showed that small cell lung cancer cell in brain microvasculature microenvironment could express much more annexin A1 and release it outside, which facilitated small cell lung cancer cell to gain malignant properties of entry into brain. These findings provided a potential target for the management of SCLC brain metastasis. Copyright © 2015 Elsevier Ltd. All rights reserved.

Analysis of a new homozygous deletion in the tumor suppressor region at 3p12.3 reveals two novel intronic noncoding RNA genes.

PubMed

Angeloni, Debora; ter Elst, Arja; Wei, Ming Hui; van der Veen, Anneke Y; Braga, Eleonora A; Klimov, Eugene A; Timmer, Tineke; Korobeinikova, Luba; Lerman, Michael I; Buys, Charles H C M

2006-07-01

Homozygous deletions or loss of heterozygosity (LOH) at human chromosome band 3p12 are consistent features of lung and other malignancies, suggesting the presence of a tumor suppressor gene(s) (TSG) at this location. Only one gene has been cloned thus far from the overlapping region deleted in lung and breast cancer cell lines U2020, NCI H2198, and HCC38. It is DUTT1 (Deleted in U Twenty Twenty), also known as ROBO1, FLJ21882, and SAX3, according to HUGO. DUTT1, the human ortholog of the fly gene ROBO, has homology with NCAM proteins. Extensive analyses of DUTT1 in lung cancer have not revealed any mutations, suggesting that another gene(s) at this location could be of importance in lung cancer initiation and progression. Here, we report the discovery of a new, small, homozygous deletion in the small cell lung cancer (SCLC) cell line GLC20, nested in the overlapping, critical region. The deletion was delineated using several polymorphic markers and three overlapping P1 phage clones. Fiber-FISH experiments revealed the deletion was approximately 130 kb. Comparative genomic sequence analysis uncovered short sequence elements highly conserved among mammalian genomes and the chicken genome. The discovery of two EST clusters within the deleted region led to the isolation of two noncoding RNA (ncRNA) genes. These were subsequently found differentially expressed in various tumors when compared to their normal tissues. The ncRNA and other highly conserved sequence elements in the deleted region may represent miRNA targets of importance in cancer initiation or progression. Published 2006 Wiley-Liss, Inc.

Palliative care units in lung cancer in the real-world setting: a single institution's experience and its implications.

PubMed

Masel, Eva Katharina; Schur, Sophie; Nemecek, Romina; Mayrhofer, Michael; Huber, Patrick; Adamidis, Feroniki; Maehr, Bruno; Unseld, Matthias; Watzke, Herbert Hans; Pirker, Robert

2017-01-01

Palliative care plays a crucial role in the overall management of patients with advanced lung cancer and was shown to lead to clinically meaningful improvement in quality of life, less aggressive endof-life care, and potentially prolonged survival. Here we summarize our single institution experience on palliative care in patients with lung cancer. The data of patients with lung cancer treated at the palliative care unit of the Medical University of Vienna between June 2010 and March 2013 were retrospectively reviewed. Patient characteristics, reasons for admissions, treatment as well as interventions during hospitalization, and clinical outcomes were determined. The study enrolled 91 lung cancer patients, who represented 19.8% of the 460 patients admitted to the palliative care unit. They had the following clinical characteristics: 39% females, 61% males; median age 62 years; median Karnofsky performance status 50%, 92% metastatic disease, 74% non-small cell lung cancer (NSCLC), 19% small-cell lung cancer (SCLC), 7% neuroendocrine carcinomas of the lung. Primary reasons for admission were deterioration of performance status in 40%, uncontrolled cancer-related pain in 38%, dyspnea in 13%, and psychosocial factors in 8% of the patients. Median duration of hospitalization was 16 days (range, 1-101 days). Improvement or stabilisation of tumor-related symptoms was achieved in 25% of the patients. Seventy-five percent of all patients died during their first admission. Their median survival from primary diagnosis until death was 16 months (95% confidence interval, 13.7-18.3 months). Patients with lung cancer admitted to the palliative care unit had late-stage disease. In order to provide early palliative care, the management of lung cancer patients should guarantee access to ambulatory care, inpatient care and home care as well as cooperation and communication between oncologists and palliative care physicians.

Efficacy of 99mTc-EDDA/HYNIC-TOC scintigraphy in differential diagnosis of solitary pulmonary nodules.

PubMed

Płachcińska, Anna; Mikołajczak, Renata; Maecke, Helmut; Kozak, Józef; Michalski, Andrzej; Rzeszutek, Katarzyna; Kuśmierek, Jacek

2004-10-01

Fifty consecutive patients with solitary pulmonary nodules (SPN) on chest radiographs were studied scintigraphically after the administration of a somatostatin analog 99mTc-EDDA/HYNIC-TOC. The activity amounted to 740-925 MBq and a single photon emission computed tomography (SPECT) technique was applied. Verification of the nodule etiology was based on histology or cytology and bacteriology. As additional criterion for nodule benignity, its stable size in a chest radiograph for at least 3 years was accepted. In 31 patients, malignant etiologies of nodules were found. The diagnoses included: 11 adenocarcinomas, 6 squamous-cell carcinomas, 2 large-cell carcinomas, 6 nonsmall-cell lung cancers (NSCLC) of unspecified, more detailed morphology, 2 small-cell lung cancers (SCLC), 2 typical carcinoids, and 2 metastatic tumors: leiomyosarcoma and malignant melanoma. In 19 patients, the following benign tumors were diagnosed: 6 tuberculomas, 2 other granulomas, 4 hamartomas, 2 nonspecific inflammatory infiltrates, 1 abscess, 1 peripheral carcinoid of morphological characteristics of a benign tumor, 1 ectopic lesion of thyroid tissue, and 2 benign tumors of unspecified etiology, with stable size over 3 and 5 years. Positive scintigraphic results were obtained in 28 of 31 patients (90%) with malignant SPNs; among these there were 26 of 27 (96%) cases of primary pulmonary carcinoma. The remaining 2 false-negative cases included metastatic tumors: liposarcoma and melanoma. Among 19 benign lesions, 15 (79%) did not accumulate the radiopharmaceutical. The remaining 4 tumors visible on scintigrams included: 1 tuberculoma, 1 hamartoma, 1 abscess, and 1 case of nonestablished diagnosis (with stable size over 3 years). In conclusion, scintigraphy with 99mTc-EDDA/HYNIC-TOC appears to be an effective procedure for differentiation between malignant and benign SPNs.

Clinical usefulness of 99mTc-EDDA/HYNIC-TOC scintigraphy in oncological diagnostics: a pilot study.

PubMed

Plachcinska, Anna; Mikolajczak, Renata; Maecke, Helmut; Mlodkowska, Ewa; Kunert-Radek, Jolanta; Michalski, Andrzej; Rzeszutek, Katarzyna; Kozak, Jozek; Kusmierek, Jacek

2004-04-01

The clinical usefulness of a new 99mTc-labeled somatostatin analogue has been studied from the standpoint of oncological diagnostics. The group of patients studied included 40 individuals with diagnosed malignant neoplasms (32 primary and 8 metastatic). Among the primary tumors were 7 pituitary adenomas (5 hormonally active and 2 inactive), 1 liposarcoma, 2 carcinoids, 1 breast carcinoma, and 21 cases of lung cancer (2 small cell and 19 non-small cell) were represented. The metastatic tumors consisted of: 3 malignant melanomas, 1 pheochromocytoma, 1 prostatic cancer, 1 leiomyosarcoma, 1 pancreatic carcinoma ectopically secreting ACTH, and 1 carcinoid of the thymus. The radiopharmaceutical, 99mTc-EDDA/HYNIC-octreotide, was i.v. administered at the activity of 740-925 MBq. The imaging was comprized of a whole-body scan and single photon emission computed tomography. Positive scintigrams were obtained in 4 of 5 hormonally active pituitary adenomas, in 1 of 2 cases of carcinoid, in liposarcoma, breast cancer, and all cases of small cell (SCLC) and non-small cell lung cancer (NSCLC). The neoplastic metastases were visualized in 2 of 3 cases of melanoma and in patients with pheochromocytoma, pancreatic carcinoma secreting ACTH, and thymic carcinoid. Scintigrams were negative in both hormonally inactive pituitary adenomas, in one case of metastatic malignant melanoma, leiomyosarcoma, and in cases of metastasis from the prostatic carcinomas. The results of this pilot study indicated that 99mTc-EDDA/HYNIC-TOC is a potentially useful radiopharmaceutical for the imaging of a wide range of primary and metastatic tumors. More detailed indications for the clinical usefulness of the new tracer for the imaging of selected tumor types require studies on much larger groups of patients. Special attention should be paid to the successful imaging of all cases of NSCLC.

Thymidine kinase 1 combined with CEA, CYFRA21-1 and NSE improved its diagnostic value for lung cancer.

PubMed

Jiang, Z F; Wang, M; Xu, J L

2018-02-01

Thymidine kinase 1 (TK1) is a tumor biomarker in human malignancies. The purpose of this study was to evaluate the diagnostic efficiency of this marker for lung cancer using the combined analysis of carcinoembryonic antigen (CEA), cytokeratin-19 fragment (CYFRA21-1), neuron specific enolase (NSE) and TK1. From 2013 to 2014, 147 patients with lung cancer and 228 patients with lung benign diseases who were admitted to our hospital were reviewed. Peripheral blood samples were collected for the detection of TK1, CEA, CYFRA21-1 and NSE. The diagnostic value of each marker was analyzed using receiver operating characteristic (ROC) curves and logistic regression equations. The serum levels of TK1, CEA, CYFRA21-1 and NSE were significantly higher than those in patients with lung benign diseases (all P<0.05). The TK1 concentration was dependent on TNM stage (P=0.005). The ROC curve analyses showed that the diagnostic value of TK1 combined with CEA, CYFRA21-1 and NSE in lung cancer was significantly higher than that of each biomarker alone (all P<0.0001). In addition, TK1 combined with CEA, CYFRA21-1, or NSE could also improve the diagnosis of the squamous cell carcinoma, adenocarcinoma and small cell lung cancer subtypes, respectively. The combined detection of TK1 and the other three markers significantly improved the diagnosis of lung cancer. Furthermore, the detection of TK1 combined with that of CYFRA21-1, CEA or NSE increased the diagnostic value of TK1 for lung squamous cell carcinoma, adenocarcinoma and SCLC, respectively. Copyright © 2017 Elsevier Inc. All rights reserved.

A numerical study of wave-current interaction through surface and bottom stresses: Coastal ocean response to Hurricane Fran of 1996

NASA Astrophysics Data System (ADS)

Xie, L.; Pietrafesa, L. J.; Wu, K.

2003-02-01

A three-dimensional wave-current coupled modeling system is used to examine the influence of waves on coastal currents and sea level. This coupled modeling system consists of the wave model-WAM (Cycle 4) and the Princeton Ocean Model (POM). The results from this study show that it is important to incorporate surface wave effects into coastal storm surge and circulation models. Specifically, we find that (1) storm surge models without coupled surface waves generally under estimate not only the peak surge but also the coastal water level drop which can also cause substantial impact on the coastal environment, (2) introducing wave-induced surface stress effect into storm surge models can significantly improve storm surge prediction, (3) incorporating wave-induced bottom stress into the coupled wave-current model further improves storm surge prediction, and (4) calibration of the wave module according to minimum error in significant wave height does not necessarily result in an optimum wave module in a wave-current coupled system for current and storm surge prediction.

Nonlinear interaction of the Tsugaru Warm Current and tide in the Tsugaru Strait

NASA Astrophysics Data System (ADS)

Wada, Ryota; Waseda, Takuji; Nanjo, Hirotada

2012-06-01

The Tsugaru Strait, which connects the Sea of Japan with the Pacific Ocean, is characterized by the eastward Tsugaru Warm Current (TWC) and oscillating tidal currents of similar magnitude. A 15-day current observation was conducted in one of the two narrow channels in the strait, at the northwest tip of the Shimokita Peninsula. The observation revealed that the spectral energy of the semidiurnal current exceeds that of the diurnal current, contrary to the conventional view. The Tsugaru Strait regional model was developed to study the mechanism of this spectral energy reversal (140-141.5° E, 40.4-42.6° N, 500 m grid resolution). At the eastern and western open boundaries, the model was driven by the constant Tsugaru warm current and tidal elevation, which was adjusted by comparing the model with tidal gauge observations within the channel. The relative magnitude of the spectral energies differed from that of the observation when the model was driven by tide only. However, the spectral energy levels were reversed when the model was driven by both tide and current. The nonlinear interaction of periodic tidal currents and the steady TWC was explained by the vorticity equation, which describes the production and advection of residual currents from tidal currents. According to the model results, flow separation and advection of vorticity by the TWC was the most prominent factor in this phenomenon. Because of the strong nonlinearities, flow separation around the headland occurred during the tidal period with dominant current magnitude and furnished the main difference between the diurnal and semidiurnal interactions. These phenomena were enhanced by the complex topography, and demonstrate the importance of scale interaction, especially when developing high-resolution regional models.

Reconstruction of the action potential of ventricular myocardial fibres

PubMed Central

Beeler, G. W.; Reuter, H.

1977-01-01

1. A mathematical model of membrane action potentials of mammalian ventricular myocardial fibres is described. The reconstruction model is based as closely as possible on ionic currents which have been measured by the voltage-clamp method. 2. Four individual components of ionic current were formulated mathematically in terms of Hodgkin—Huxley type equations. The model incorporates two voltage- and time-dependent inward currents, the excitatory inward sodium current, iNa, and a secondary or slow inward current, is, primarily carried by calcium ions. A time-independent outward potassium current, iK1, exhibiting inward-going rectification, and a voltage- and time-dependent outward current, ix1, primarily carried by potassium ions, are further elements of the model. 3. The iNa is primarily responsible for the rapid upstroke of the action potential, while the other current components determine the configuration of the plateau of the action potential and the re-polarization phase. The relative importance of inactivation of is and of activation of ix1 for termination of the plateau is evaluated by the model. 4. Experimental phenomena like slow recovery of the sodium system from inactivation, frequency dependence of the action potential duration, all-or-nothing re-polarization, membrane oscillations are adequately described by the model. 5. Possible inadequacies and shortcomings of the model are discussed. PMID:874889

How well do basic models describe the turbidity currents coming down Monterey and Congo Canyon?

NASA Astrophysics Data System (ADS)

Cartigny, M.; Simmons, S.; Heerema, C.; Xu, J. P.; Azpiroz, M.; Clare, M. A.; Cooper, C.; Gales, J. A.; Maier, K. L.; Parsons, D. R.; Paull, C. K.; Sumner, E. J.; Talling, P.

2017-12-01

Turbidity currents rival rivers in their global capacity to transport sediment and organic carbon. Furthermore, turbidity currents break submarine cables that now transport >95% of our global data traffic. Accurate turbidity current models are thus needed to quantify their transport capacity and to predict the forces exerted on seafloor structures. Despite this need, existing numerical models are typically only calibrated with scaled-down laboratory measurements due to the paucity of direct measurements of field-scale turbidity currents. This lack of calibration thus leaves much uncertainty in the validity of existing models. Here we use the most detailed observations of turbidity currents yet acquired to validate one of the most fundamental models proposed for turbidity currents, the modified Chézy model. Direct measurements on which the validation is based come from two sites that feature distinctly different flow modes and grain sizes. The first are from the multi-institution Coordinated Canyon Experiment (CCE) in Monterey Canyon, California. An array of six moorings along the canyon axis captured at least 15 flow events that lasted up to hours. The second is the deep-sea Congo Canyon, where 10 finer grained flows were measured by a single mooring, each lasting several days. Moorings captured depth-resolved velocity and suspended sediment concentration at high resolution (<30 second) for each of the 25 events. We use both datasets to test the most basic model available for turbidity currents; the modified Chézy model. This basic model has been very useful for river studies over the past 200 years, as it provides a rapid estimate of how flow velocity varies with changes in river level and energy slope. Chézy-type models assume that the gravitational force of the flow equals the friction of the river-bed. Modified Chézy models have been proposed for turbidity currents. However, the absence of detailed measurements of friction and sediment concentration within full-scale turbidity currents has forced modellers to make rough assumptions for these parameters. Here we use mooring data to deduce observation-based relations that can replace the previous assumptions. This improvement will significantly enhance the model predictions and allow us to better constrain the behaviour of turbidity currents.

Field-dependent critical state of high-Tc superconducting strip simultaneously exposed to transport current and perpendicular magnetic field

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xue, Cun; He, An; Yong, Huadong

We present an exact analytical approach for arbitrary field-dependent critical state of high-T{sub c} superconducting strip with transport current. The sheet current and flux-density profiles are derived by solving the integral equations, which agree with experiments quite well. For small transport current, the approximate explicit expressions of sheet current, flux-density and penetration depth for the Kim model are derived based on the mean value theorem for integration. We also extend the results to the field-dependent critical state of superconducting strip in the simultaneous presence of applied field and transport current. The sheet current distributions calculated by the Kim model agreemore » with experiments better than that by the Bean model. Moreover, the lines in the I{sub a}-B{sub a} plane for the Kim model are not monotonic, which is quite different from that the Bean model. The results reveal that the maximum transport current in thin superconducting strip will decrease with increasing applied field which vanishes for the Bean model. The results of this paper are useful to calculate ac susceptibility and ac loss.« less

The Storm Time Ring Current Dynamics and Response to CMEs and CIRs Using Van Allen Probes Observations and CIMI Simulations

NASA Astrophysics Data System (ADS)

Bingham, S.; Mouikis, C.; Kistler, L. M.; Fok, M. C. H.; Glocer, A.; Farrugia, C. J.; Gkioulidou, M.; Spence, H. E.

2016-12-01

The ring current responds differently to the different solar and interplanetary storm drivers such as coronal mass injections, (CMEs), and co-rotating interaction regions (CIRs). Delineating the differences in the ring current development between these two drivers will aid our understanding of the ring current dynamics. Using Van Allen Probes observations, we develop an empirical ring current model of the ring current pressure, the pressure anisotropy and the current density development during the storm phases for both types of storm drivers and for all MLTs inside L 6. In addition, we identify the populations (energy and species) responsible. We find that during the storm main phase and the early recovery phase the plasma sheet particles (10-80 keV) convecting from the nightside contribute the most on the ring current pressure and current density. However, during these phases, the main difference between CMEs and CIRs is in the O+ contribution. This empirical model is compared to the results of CIMI simulations of CMEs and CIRs where the model input is comprised of the superposed epoch solar wind conditions of the storms that comprise the empirical model, while different inner magnetosphere boundary conditions will be tested in order to match the empirical model results. Comparing the model and simulation results will fill our understanding of the ring current dynamics as part of the highly coupled inner magnetosphere system.

Individual differences in transcranial electrical stimulation current density

PubMed Central

Russell, Michael J; Goodman, Theodore; Pierson, Ronald; Shepherd, Shane; Wang, Qiang; Groshong, Bennett; Wiley, David F

2013-01-01

Transcranial electrical stimulation (TCES) is effective in treating many conditions, but it has not been possible to accurately forecast current density within the complex anatomy of a given subject's head. We sought to predict and verify TCES current densities and determine the variability of these current distributions in patient-specific models based on magnetic resonance imaging (MRI) data. Two experiments were performed. The first experiment estimated conductivity from MRIs and compared the current density results against actual measurements from the scalp surface of 3 subjects. In the second experiment, virtual electrodes were placed on the scalps of 18 subjects to model simulated current densities with 2 mA of virtually applied stimulation. This procedure was repeated for 4 electrode locations. Current densities were then calculated for 75 brain regions. Comparison of modeled and measured external current in experiment 1 yielded a correlation of r = .93. In experiment 2, modeled individual differences were greatest near the electrodes (ten-fold differences were common), but simulated current was found in all regions of the brain. Sites that were distant from the electrodes (e.g. hypothalamus) typically showed two-fold individual differences. MRI-based modeling can effectively predict current densities in individual brains. Significant variation occurs between subjects with the same applied electrode configuration. Individualized MRI-based modeling should be considered in place of the 10-20 system when accurate TCES is needed. PMID:24285948

An improved large signal model of InP HEMTs

NASA Astrophysics Data System (ADS)

Li, Tianhao; Li, Wenjun; Liu, Jun

2018-05-01

An improved large signal model for InP HEMTs is proposed in this paper. The channel current and charge model equations are constructed based on the Angelov model equations. Both the equations for channel current and gate charge models were all continuous and high order drivable, and the proposed gate charge model satisfied the charge conservation. For the strong leakage induced barrier reduction effect of InP HEMTs, the Angelov current model equations are improved. The channel current model could fit DC performance of devices. A 2 × 25 μm × 70 nm InP HEMT device is used to demonstrate the extraction and validation of the model, in which the model has predicted the DC I–V, C–V and bias related S parameters accurately. Project supported by the National Natural Science Foundation of China (No. 61331006).

Explicit wave action conservation for water waves on vertically sheared flows

NASA Astrophysics Data System (ADS)

Quinn, Brenda; Toledo, Yaron; Shrira, Victor

2016-04-01

Water waves almost always propagate on currents with a vertical structure such as currents directed towards the beach accompanied by an under-current directed back toward the deep sea or wind-induced currents which change magnitude with depth due to viscosity effects. On larger scales they also change their direction due to the Coriolis force as described by the Ekman spiral. This implies that the existing wave models, which assume vertically-averaged currents, is an approximation which is far from realistic. In recent years, ocean circulation models have significantly improved with the capability to model vertically-sheared current profiles in contrast with the earlier vertically-averaged current profiles. Further advancements have coupled wave action models to circulation models to relate the mutual effects between the two types of motion. Restricting wave models to vertically-averaged non-turbulent current profiles is obviously problematic in these cases and the primary goal of this work is to derive and examine a general wave action equation which accounts for these shortcoming. The formulation of the wave action conservation equation is made explicit by following the work of Voronovich (1976) and using known asymptotic solutions of the boundary value problem which exploit the smallness of the current magnitude compared to the wave phase velocity and/or its vertical shear and curvature. The adopted approximations are shown to be sufficient for most of the conceivable applications. This provides correction terms to the group velocity and wave action definition accounting for the shear effects, which are fitting for application to operational wave models. In the limit of vanishing current shear, the new formulation reduces to the commonly used Bretherton & Garrett (1968) no-shear wave action equation where the invariant is calculated with the current magnitude taken at the free surface. It is shown that in realistic oceanic conditions, the neglect of the vertical structure of the currents in wave modelling which is currently universal, might lead to significant errors in wave amplitude and the predicted wave ray paths. An extension of the work toward the more complex case of turbulent currents will also be discussed.

PREFACE: International Conference on Functional Materials and Nanotechnologies (FM&NT2012)

NASA Astrophysics Data System (ADS)

Sternberg, Andris; Muzikante, Inta; Sarakovskis, Anatolijs; Grinberga, Liga

2012-08-01

The International Conference Functional Materials and Nanotechnologies (FM&NT - 2012) was held in Riga, 17-20 April 2012 at the Institute of Solid State Physics, University of Latvia (ISSP UL). The conference was organised by ISSP UL in co-operation with National Research programme in Materials Science and Information Technologies of Latvia. The purpose of this series of conferences is to bring together scientists, researchers, engineers and students from universities, research institutes and related industrial companies working in the field of advanced material science, energy and materials technologies. The contributions of the participants were grouped according to three main topics of the conference: 1. Multifunctional Materials including advanced inorganic, organic and hybrid materials; ferroics; multiscale and multiphenomenal material modeling and simulation 2. Nanotechnologies including progressive methods, technologies and design for investigation of nanoparticles, nanostructures, nanocomposites, thin films and coatings; 3. Energy including perspective materials and technologies for renewable and hydrogen energy, fuel cells, photovoltaics and developing diverse energy systems. A special section devoted to Organic Materials was organized to commemorate a long-time organizer of the FM&NT conference series, Dr. habil. phys, academician Inta Muzikante who passed away on 15 February 2012. The number of registered participants from 21 countries was nearly 300. During the three days of the conference 2 plenary, 16 invited, 54 oral reports and 184 posters were presented. 64 papers, based on these reports, are included in this volume of IOP Conference Series: Materials Science and Engineering. Additional information about FM&NT-2012 is available at its homepage http://www.fmnt.lu.lv. The Organizing Committee would like to thank all the speakers, contributors, session chairs, referees and other involved staff for their efforts in making the FM&NT-2012 successful. The Organizing Committee sincerely hopes that the Conference gave all the participants new insights into the widespread development of functional materials and nanotechnologies and would enhance the circulation of the information released at the meeting. Inta Muzikante Andris Sternberg Liga Grinberga Anatolijs Sarakovskis Conference photograph The manuscripts are published thanks to the financial support from ERAF project 'Atbalsts starptautiskas sadarbibas projektiem zinatne un tehnologijas LU Cietvielu fizikas instituta' Nr.2010/0204/2DP/2.1.1.2.0./10/APIA/VIAA/010 Sponsors Sponsors flag Sponsors logo International Organizing Committee 1. Andris Sternberg (chairperson), Institute of Solid State Physics, University of Latvia, Latvia 2. Juras Banys, Vilnius University, Lithuania 3. Gunnar Borstel, University of Osnabrück, Germany 4. Niels E Christensen, University of Aarhus, Denmark 5. Robert A Evarestov, St. Petersburg State University, Russia 6. Claes-Goran Granqvist, Uppsala University, Sweden 7. Dag Høvik, The Research Council of Norway, Norway 8. Marco Kirm, Institute of Physics, University of Tartu, Estonia 9. Jiri Kulda, Institut Laue-Langevin, France 10. Witold Lojkowski, Institute of High Pressure Physics, Poland 11. Ergo Nommiste, University of Tartu, Estonia 12. Ingólfur Torbjörnsson, Icelandic Centre for Research, Iceland 13. Marcel H. Van de Voorde, University of Technology Delft, The Netherlands International Program Committee 1. Liga Grinberga (chairperson), Institute of Solid State Physics, University of Latvia, Latvia 2. Eugene Kotomin, Max Planck Institute for Solid State Research, Germany 3. Martins Rutkis, Institute of Solid State Physics, University of Latvia, Latvia 4. Inta Muzikante, Institute of Solid State Physics, University of Latvia, Latvia 5. Liga Berzina-Cimdina, Institute of Biomaterials and Biomechanics, Riga Technical University, Latvia 6. Janis Grabis, Institute of Inorganic Chemistry, Riga Technical University, Latvia 7. Linards Skuja, Institute of Solid State Physics, University of Latvia, Latvia 8. Maris Springis, Institute of Solid State Physics, University of Latvia, Latvia 9. Ilmars Zalite, Institute of Inorganic Chemistry, Riga Technical University, Latvia 10. Janis Zicans, Institute of Polymers, Riga Technical University, Latvia Local Committee Liga Grinberga, Anatolijs Sarakovskis, Jurgis Grube, Maris Kundzins, Anastasija Jozepa, Anna Muratova, Raitis Siatkovskis, Andris Fedotovs, Dmitrijs Bocarovs, Sniedze Abele, Mikus Voss, Andris Sivars, Peteris Lesnicenoks, Virginija Liepina. In Memoriam Dr. habil. phys. Inta Muzikante (08.01.1951-15.02.2012) Inta Muzikante Inta was born in Valmiera, a town in the northern part of Latvia. She attended school in Sigulda and high school in Riga. While at the high-school, Inta decided to study natural sciences. After graduating from high-school in 1969 she entered the physics section of the Physics and Mathematics department of University of Latvia and obtained her university degree in 1974. In parallel with University studies, Inta started to work at the Semiconductor Physics Research Lab at the University of Latvia. After graduating she was offered a position at the Physical Energetics institute of the Latvian Academy of Sciences, in the laboratory of Professor Edgars Silinsh, one of the most internationally well known Latvian physicists. Inta started researching electronic and photoelectric processes in organic crystals and thin films. This was a novel field, pioneered both internationally and in Latvia by Profesors E Silinsh, O Neilands and J Freimanis. It could be said that Inta stood at the cradle of this research field and stayed faithful to it all of her life. Her work was very successful and within a few years she advanced from research assistant to researcher and then leading research scientist. Her first scientific topic was studies of the mechanism of charge carrier photogeneration and separation in organic molecular crystals. In 1983 for a work entitled 'Charge carrier photogeneration and trapping processes in organic molecular crystals' Inta obtained her PhD degree (USSR Candidate of Sciences degree). The major part of Inta Muzikante's research activities was devoted to the investigation of electronic states in organic thin films and multilayers. Studies of electrophysical properties and energy structure of the wide class of organic compounds, such as isolators, semiconductors and conductors have been done. During these studies the complex application of conventional space charge limited current method (SCLC), differential method of SCLC, thermally modulated SCLC and thermally stimulated current was provided for local trapping state investigation. These investigations are of great importance for application in studies of organic light-emitting diodes and organic solar cells. In I Muzikante's work for the first time the existence and asymmetry of trapping states of quadrupolar origin in pentacene thin films was experimentally confirmed. In the last decade Inta Muzikante has broadened her scientific scope. The organic materials with photochromic effect became important part of her research because of their possibility of being employed in optical storage of data and molecular switching devices. Reversible trans/cis photoisomerization of azobenzene and indandione derivatives in self-assembled monolayers, LB multilayers and polymer films were studied. A turning point in Inta's life was the re-establishment of independent Republic of Latvia in 1991: the previously tightly closed international borders opened, and she was free to visit and work in the most important international scientific centers. During this period she stayed and worked at Potsdam University and the Center of Macromolecular Chemistry in Germany, South Bank University, London and Manchester University in UK, Ecole Supérieure de Physique et de Chemie Industrielles, P&M Curie University, and Angers University in France and at the Vilnius University in Lithuania. After the passing away of Professor E Silinsh in 1998, Inta took over the duties of the Head of Laboratory. In spite of the Latvian science going through hard times due to inadequate funding, she managed to preserve the lab's core staff and to further develop its scientific potential, while also continuing active research work herself. In 1998 she obtained the Dr.Habil degree for the work 'Electronic processes and states in organic molecular crystals and Langmuir-Blodgett multistructures'. Inta's research was recognized by awarding her in 1999 the recently established and prestigeous Edgar's Silinsh prize in physics by the Latvian Academy of Sciences. During this and the subsequent period, another of her many talents started to shine through: her particular skill of finding capable young people from the best high-schools in Latvia and motivating them to work in research. Several of these students have now become researchers in her lab. With Inta's demise, four PhD students lost their supervisor. Inta's research and organizational work gained even more momentum after her lab transferred to the Institute of Solid State Physics in 2003. At her new home Inta rapidly acquired the respect and sympathies of her new colleagues. Her duties as the Head of Laboratory and of Leading research scientist were soon supplemented by the tasks of the Institute deputy director for research. In 2006 Inta was elected as the Corresponding Member of the Latvian Academy of Sciences, and subsequently elected to full Academy membership in 2008. She has authored more than 240 research papers. Inta started to give lecture courses to the physics students of the University of Latvia and took up even more duties. She served as a guest editor on international journals, as an expert in European Commission, and as a representative for Latvia on a number of European scientific programs and projects. With the passing away of Inta Muzikante, the Latvian and international science community has lost an excellent scientist and a talented science organizer. However, more important and above all of her excellent professional achievements: all of us who knew her will remember her as a helpful and cordial friend.

Integrated modeling of plasma ramp-up in DIII-D ITER-like and high bootstrap current scenario discharges

NASA Astrophysics Data System (ADS)

Wu, M. Q.; Pan, C. K.; Chan, V. S.; Li, G. Q.; Garofalo, A. M.; Jian, X.; Liu, L.; Ren, Q. L.; Chen, J. L.; Gao, X.; Gong, X. Z.; Ding, S. Y.; Qian, J. P.; Cfetr Physics Team

2018-04-01

Time-dependent integrated modeling of DIII-D ITER-like and high bootstrap current plasma ramp-up discharges has been performed with the equilibrium code EFIT, and the transport codes TGYRO and ONETWO. Electron and ion temperature profiles are simulated by TGYRO with the TGLF (SAT0 or VX model) turbulent and NEO neoclassical transport models. The VX model is a new empirical extension of the TGLF turbulent model [Jian et al., Nucl. Fusion 58, 016011 (2018)], which captures the physics of multi-scale interaction between low-k and high-k turbulence from nonlinear gyro-kinetic simulation. This model is demonstrated to accurately model low Ip discharges from the EAST tokamak. Time evolution of the plasma current density profile is simulated by ONETWO with the experimental current ramp-up rate. The general trend of the predicted evolution of the current density profile is consistent with that obtained from the equilibrium reconstruction with Motional Stark effect constraints. The predicted evolution of βN , li , and βP also agrees well with the experiments. For the ITER-like cases, the predicted electron and ion temperature profiles using TGLF_Sat0 agree closely with the experimental measured profiles, and are demonstrably better than other proposed transport models. For the high bootstrap current case, the predicted electron and ion temperature profiles perform better in the VX model. It is found that the SAT0 model works well at high IP (>0.76 MA) while the VX model covers a wider range of plasma current ( IP > 0.6 MA). The results reported in this paper suggest that the developed integrated modeling could be a candidate for ITER and CFETR ramp-up engineering design modeling.

A modeling study of the radar signatures of rip currents with comparisons to data

NASA Astrophysics Data System (ADS)

O'Dea, A.; Haller, M. C.

2016-12-01

Rip currents are important components of nearshore circulation systems and can pose serious dangers to swimmers. In recent years, X-band imaging radar has been shown to be an effective remote sensor of rip currents over large spatial scales, for long durations, and with high temporal resolution. In contrast to remote sensing methods that infer rip location through the identification of morphological features (i.e. rip channels), rip detection in radar arises directly from the backscatter characteristics of the rip current flow field, thus offering the potential of direct extraction of quantitative information on rip current hydrodynamics. In this study, we present a model for the radar imaging of rip currents based on the wave action balance equation and the changes to the wind-wave spectrum at Bragg (capillary) wavelengths induced by the underlying rip current field. Model results are compared to field data (both in situ and remote sensing) from a 10-day experiment at Duck, NC conducted in September 2010. The model/data comparisons are then used to assess the physical mechanisms contributing to the radar imaging of rip currents including the role of rip current strength, wind speed, wind direction, and very short-scale wave breaking in rip current imaging. Following the methodology of Rascle et al. (J. Phys. Oceanography, 2014), the radar imaging model uses a relaxation approach that models perturbations to the equilibrium wave action spectrum induced by gradients in the underlying current field (specifically, the divergence and strain components of the deformation tensor). From the perturbed wind-wave spectrum, changes in the mean square slope (MSS) are then calculated and taken as a proxy for the change in radar backscatter intensity due to rip currents. Model simulations of rip current velocity fields for the field experiments were developed previously by Wilson et al. (J. Geophys. Res., 2014) using ROMS. The modeled velocities are used as input into the backscatter model and the predicted changes in MSS are compared with the radar observations. Modeled changes in MSS are shown to compare well with the observed occurrence and spatial scales of the rips, including their oblique orientation and their offshore extent. Remaining questions include the effect of wind direction and fetch on the imaging of rips.

Investigation of the effects of external current systems on the MAGSAT data utilizing grid cell modeling techniques

NASA Technical Reports Server (NTRS)

Klumpar, D. M. (Principal Investigator)

1982-01-01

Efforts in support of the development of a model of the magnetic fields due to ionospheric and magnetospheric electrical currents are discussed. Specifically, progress made in reading MAGSAT tapes and plotting the deviation of the measured magnetic field components with respect to a spherical harmonic model of the main geomagnetic field is reported. Initial tests of the modeling procedure developed to compute the ionosphere/magnetosphere-induced fields at satellite orbit are also described. The modeling technique utilizes a liner current element representation of the large scale current system.

Plasmasphere Modeling with Ring Current Heating

NASA Technical Reports Server (NTRS)

Guiter, S. M.; Fok, M.-C.; Moore, T. E.

1995-01-01

Coulomb collisions between ring current ions and the thermal plasma in the plasmasphere will heat the plasmaspheric electrons and ions. During a storm such heating would lead to significant changes in the temperature and density of the thermal plasma. This was modeled using a time- dependent, one-stream hydrodynamic model for plasmaspheric flows, in which the model flux tube is connected to the ionosphere. The model simultaneously solves the coupled continuity, momentum, and energy equations of a two-ion (H(+) and O(+) quasineutral, currentless plasma. Heating rates due to collisions with ring current ions were calculated along the field line using a kinetic ring current model. First, diurnally reproducible results were found assuming only photoelectron heating of the thermal electrons. Then results were found with heating of the H(+) ions by the ring current during the recovery phase of a magnetic storm.

A Description of Local Time Asymmetries in the Kronian Current Sheet

NASA Astrophysics Data System (ADS)

Nickerson, J. S.; Hansen, K. C.; Gombosi, T. I.

2012-12-01

Cassini observations imply that Saturn's magnetospheric current sheet is displaced northward above the rotational equator [C.S. Arridge et al., Warping of Saturn's magnetospheric and magnetotail current sheets, Journal of Geophysical Research, Vol. 113, August 2008]. Arridge et al. show that this hinging of the current sheet above the equator occurs over the noon, midnight, and dawn local time sectors. They present an azimuthally independent model to describe this paraboloid-like geometry. We have used our global MHD model, BATS-R-US/SWMF, to study Saturn's magnetospheric current sheet under various solar wind dynamic pressure and solar zenith angle conditions. We show that under reasonable conditions the current sheet does take on the basic shape of the Arridge model in the noon, midnight, and dawn sectors. However, the hinging distance parameter used in the Arridge model is not a constant and does in fact vary in Saturn local time. We recommend that the Arridge model should be adjusted to account for this azimuthal dependence. Arridge et al. does not discuss the shape of the current sheet in the dusk sector due to an absence of data but does presume that the current sheet will assume the same geometry in this region. On the contrary, our model shows that this is not the case. On the dusk side the current sheet hinges (aggressively) southward and cannot be accounted for by the Arridge model. We will present results from our simulations showing the deviation from axisymmetry and the general behavior of the current sheet under different conditions.

Observational support for the current sheet catastrophe model of substorm current disruption

NASA Technical Reports Server (NTRS)

Burkhart, G. R.; Lopez, R. E.; Dusenbery, P. B.; Speiser, T. W.

1992-01-01

The principles of the current sheet catastrophe models are briefly reviewed, and observations of some of the signatures predicted by the theory are presented. The data considered here include AMPTE/CCE observations of fifteen current sheet disruption events. According to the model proposed here, the root cause of the current disruption is some process, as yet unknown, that leads to an increase in the k sub A parameter. Possible causes for the increase in k sub A are discussed.

Electron kinematics in a plasma focus

NASA Technical Reports Server (NTRS)

Hohl, F.; Gary, S. P.

1977-01-01

The results of numerical integrations of the three-dimensional relativistic equations of motion of electrons subject to given electric and magnetic fields are presented. Fields due to two different models are studied: (1) a circular distribution of current filaments, and (2) a uniform current distribution; both the collapse and the current reduction phases are studied in each model. Decreasing current in the uniform current model yields 100 keV electrons accelerated toward the anode and, as for earlier ion computations, provides general agreement with experimental results.

Current and Future Flight Operating Systems

NASA Technical Reports Server (NTRS)

Cudmore, Alan

2007-01-01

This viewgraph presentation reviews the current real time operating system (RTOS) type in use with current flight systems. A new RTOS model is described, i.e. the process model. Included is a review of the challenges of migrating from the classic RTOS to the Process Model type.

The effect of Birkeland currents on magnetic field topology

NASA Technical Reports Server (NTRS)

Peroomian, Vahe; Lyons, Larry R.; Schulz, Michael

1996-01-01

A technique was developed for the inclusion of large scale magnetospheric current systems in magnetic field models. The region 1 and 2 Birkeland current systems are included in the source surface model of the terrestrial magnetosphere. The region 1 and 2 Birkeland currents are placed in the model using a series of field aligned, infinitely thin wire segments. The normal component of the magnetic field from these currents is calculated on the surface of the magnetopause and shielded using image current carrying wires placed outside of the magnetosphere. It is found that the inclusion of the Birkeland currents in the model results in a northward magnetic field in the near-midnight tail, leading to the closure of previously open flux in the tail, and a southward magnetic field in the flanks. A sunward shift in the separatrix is observed.

A model for characterizing residential ground current and magnetic field fluctuations.

PubMed

Mader, D L; Peralta, S B; Sherar, M D

1994-01-01

The current through the residential grounding circuit is an important source for magnetic fields; field variations near the grounding circuit accurately track fluctuations in this ground current. In this paper, a model is presented which permits calculation of the range of these fluctuations. A discrete network model is used to simulate a local distribution system for a single street, and a statistical model to simulate unbalanced currents in the system. Simulations of three-house and ten-house networks show that random appliance operation leads to ground current fluctuations which can be quite large, on the order of 600%. This is consistent with measured fluctuations in an actual house.

Current-induced dissipation in spectral wave models

NASA Astrophysics Data System (ADS)

Rapizo, H.; Babanin, A. V.; Provis, D.; Rogers, W. E.

2017-03-01

Despite many recent developments of the parameterization for wave dissipation in spectral models, it is evident that when waves propagate onto strong adverse currents the rate of energy dissipation is not properly estimated. The issue of current-induced dissipation is studied through a comprehensive data set in the tidal inlet of Port Phillip Heads, Australia. The wave parameters analyzed are significantly modulated by the tidal currents. Wave height in conditions of opposing currents (ebb tide) can reach twice the offshore value, whereas during coflowing currents (flood), it can be reduced to half. The wind-wave model SWAN is able to reproduce the tide-induced modulation of waves and the results show that the variation of currents is the dominant factor in modifying the wave field. In stationary simulations, the model provides an accurate representation of wave height for slack and flood tides. During ebb tides, wave energy is highly overestimated over the opposing current jet. None of the four parameterizations for wave dissipation tested performs satisfactorily. A modification to enhance dissipation as a function of the local currents is proposed. It consists of the addition of a factor that represents current-induced wave steepening and it is scaled by the ratio of spectral energy to the threshold breaking level. The new term asymptotes to the original form as the current in the wave direction tends to zero. The proposed modification considerably improves wave height and mean period in conditions of adverse currents, whereas the good model performance in coflowing currents is unaltered.

Systems, methods and computer-readable media for modeling cell performance fade of rechargeable electrochemical devices

DOEpatents

Gering, Kevin L

2013-08-27

A system includes an electrochemical cell, monitoring hardware, and a computing system. The monitoring hardware periodically samples performance characteristics of the electrochemical cell. The computing system determines cell information from the performance characteristics of the electrochemical cell. The computing system also develops a mechanistic level model of the electrochemical cell to determine performance fade characteristics of the electrochemical cell and analyzing the mechanistic level model to estimate performance fade characteristics over aging of a similar electrochemical cell. The mechanistic level model uses first constant-current pulses applied to the electrochemical cell at a first aging period and at three or more current values bracketing a first exchange current density. The mechanistic level model also is based on second constant-current pulses applied to the electrochemical cell at a second aging period and at three or more current values bracketing the second exchange current density.

Investigation of the effects of external current systems on the MAGSAT data utilizing grid cell modeling techniques

NASA Technical Reports Server (NTRS)

Klumpar, D. M. (Principal Investigator)

1982-01-01

Progress made in reducing MAGSAT data and displaying magnetic field perturbations caused primarily by external currents is reported. A periodic and repeatable perturbation pattern is described that arises from external current effects but appears as unique signatures associated with upper middle latitudes on the Earth's surface. Initial testing of the modeling procedure that was developed to compute the magnetic fields at satellite orbit due to current distributions in the ionosphere and magnetosphere is also discussed. The modeling technique utilizes a linear current element representation of the large scale space current system.

Predicting responses from Rasch measures.

PubMed

Linacre, John M

2010-01-01

There is a growing family of Rasch models for polytomous observations. Selecting a suitable model for an existing dataset, estimating its parameters and evaluating its fit is now routine. Problems arise when the model parameters are to be estimated from the current data, but used to predict future data. In particular, ambiguities in the nature of the current data, or overfit of the model to the current dataset, may mean that better fit to the current data may lead to worse fit to future data. The predictive power of several Rasch and Rasch-related models are discussed in the context of the Netflix Prize. Rasch-related models are proposed based on Singular Value Decomposition (SVD) and Boltzmann Machines.

A Semianalytical Ion Current Model for Radio Frequency Driven Collisionless Sheaths

NASA Technical Reports Server (NTRS)

Bose, Deepak; Govindan, T. R.; Meyyappan, M.; Arnold, Jim (Technical Monitor)

2001-01-01

We propose a semianalytical ion dynamics model for a collisionless radio frequency biased sheath. The model uses bulk plasma conditions and electrode boundary condition to predict ion impact energy distribution and electrical properties of the sheath. The proposed model accounts for ion inertia and ion current modulation at bias frequencies that are of the same order of magnitude as the ion plasma frequency. A relaxation equation for ion current oscillations is derived which is coupled with a damped potential equation in order to model ion inertia effects. We find that inclusion of ion current modulation in the sheath model shows marked improvements in the predictions of sheath electrical properties and ion energy distribution function.

Operational prediction of rip currents using numerical model and nearshore bathymetry from video images

NASA Astrophysics Data System (ADS)

Sembiring, L.; Van Ormondt, M.; Van Dongeren, A. R.; Roelvink, J. A.

2017-07-01

Rip currents are one of the most dangerous coastal hazards for swimmers. In order to minimize the risk, a coastal operational-process based-model system can be utilized in order to provide forecast of nearshore waves and currents that may endanger beach goers. In this paper, an operational model for rip current prediction by utilizing nearshore bathymetry obtained from video image technique is demonstrated. For the nearshore scale model, XBeach1 is used with which tidal currents, wave induced currents (including the effect of the wave groups) can be simulated simultaneously. Up-to-date bathymetry will be obtained using video images technique, cBathy 2. The system will be tested for the Egmond aan Zee beach, located in the northern part of the Dutch coastline. This paper will test the applicability of bathymetry obtained from video technique to be used as input for the numerical modelling system by comparing simulation results using surveyed bathymetry and model results using video bathymetry. Results show that the video technique is able to produce bathymetry converging towards the ground truth observations. This bathymetry validation will be followed by an example of operational forecasting type of simulation on predicting rip currents. Rip currents flow fields simulated over measured and modeled bathymetries are compared in order to assess the performance of the proposed forecast system.

Evaluation of wind induced currents modeling along the Southern Caspian Sea

NASA Astrophysics Data System (ADS)

Bohluly, Asghar; Esfahani, Fariba Sadat; Montazeri Namin, Masoud; Chegini, Fatemeh

2018-02-01

To improve our understanding of the Caspian Sea hydrodynamics, its circulation is simulated with special focus on wind-driven currents of its southern basin. The hydrodynamic models are forced with a newly developed fine resolution wind field to increase the accuracy of current modeling. A 2D shallow water equation model and a 3D baroclinic model are applied separately to examine the performance of each model for specific applications in the Caspian Sea. The model results are validated against recent field measurements including AWAC and temperature observations in the southern continental shelf region. Results show that the 2D model is able to well predict the depth-averaged current speed in storm conditions in narrow area of southern coasts. This finding suggests physical oceanographers apply 2D modeling as a more affordable method for extreme current speed analysis at the continental shelf region. On the other hand the 3D model demonstrates a better performance in reproducing monthly mean circulation and hence is preferable for surface circulation of Caspian Sea. Monthly sea surface circulation fields of the southern basin reveal a dipole cyclonic-anticyclonic pattern, a dominant eastward current along the southern coasts which intensifies from May to November and a dominant southward current along the eastern coasts in all months except February when the flow is northward. Monthly mean wind fields exhibit two main patterns including a north-south pattern occurring at warm months and collision of two wind fronts especially in the cold months. This collision occurs on a narrow region at the southern continental shelf regions. Due to wind field complexities, it leads to a major source of uncertainty in predicting the wind-driven currents. However, this source of uncertainty is significantly alleviated by applying a fine resolution wind field.

78 FR 31863 - Airworthiness Directives; Sikorsky Aircraft Corporation-Manufactured (Sikorsky) Model Helicopters...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-28

... Corporation- Manufactured (Sikorsky) Model Helicopters (type certificate currently held by Erickson Air-Crane... Corporation-manufactured Model S-64E helicopters (type certificate currently held by Erickson Air-Crane Incorporated (Erickson)). That AD currently requires inspecting and reworking the main gearbox (MGB) assembly...

Dispersive FDTD analysis of induced electric field in human models due to electrostatic discharge.

PubMed

Hirata, Akimasa; Nagai, Toshihiro; Koyama, Teruyoshi; Hattori, Junya; Chan, Kwok Hung; Kavet, Robert

2012-07-07

Contact currents flow from/into a charged human body when touching a grounded conductive object. An electrostatic discharge (ESD) or spark may occur just before contact or upon release. The current may stimulate muscles and peripheral nerves. In order to clarify the difference in the induced electric field between different sized human models, the in-situ electric fields were computed in anatomically based models of adults and a child for a contact current in a human body following ESD. A dispersive finite-difference time-domain method was used, in which biological tissue is assumed to obey a four-pole Debye model. From our computational results, the first peak of the discharge current was almost identical across adult and child models. The decay of the induced current in the child was also faster due mainly to its smaller body capacitance compared to the adult models. The induced electric fields in the forefingers were comparable across different models. However, the electric field induced in the arm of the child model was found to be greater than that in the adult models primarily because of its smaller cross-sectional area. The tendency for greater doses in the child has also been reported for power frequency sinusoidal contact current exposures as reported by other investigators.

A new theoretical model for transmembrane potential and ion currents induced in a spherical cell under low frequency electromagnetic field.

PubMed

Zheng, Yu; Gao, Yang; Chen, Ruijuan; Wang, Huiquan; Dong, Lei; Dou, Junrong

2016-10-01

Time-varying electromagnetic fields (EMF) can induce some physiological effects in neuronal tissues, which have been explored in many applications such as transcranial magnetic stimulation. Although transmembrane potentials and induced currents have already been the subjects of many theoretical studies, most previous works about this topic are mainly completed by utilizing Maxwell's equations, often by solving a Laplace equation. In previous studies, cells were often considered to be three-compartment models with different electroconductivities in different regions (three compartments are often intracellular regions, membrane, and extracellular regions). However, models like that did not take dynamic ion channels into consideration. Therefore, one cannot obtain concrete ionic current changes such as potassium current change or sodium current change by these models. The aim of the present work is to present a new and more detailed model for calculating transmembrane potentials and ionic currents induced by time-varying EMF. Equations used in the present paper originate from Nernst-Plank equations, which are ionic current-related equations. The main work is to calculate ionic current changes induced by EMF exposure, and then transmembrane potential changes are calculated with Hodgkin-Huxley model. Bioelectromagnetics. 37:481-492, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Two ways to model voltage current curves of adiabatic MgB2 wires

NASA Astrophysics Data System (ADS)

Stenvall, A.; Korpela, A.; Lehtonen, J.; Mikkonen, R.

2007-08-01

Usually overheating of the sample destroys attempts to measure voltage-current curves of conduction cooled high critical current MgB2 wires at low temperatures. Typically, when a quench occurs a wire burns out due to massive heat generation and negligible cooling. It has also been suggested that high n values measured with MgB2 wires and coils are not an intrinsic property of the material but arise due to heating during the voltage-current measurement. In addition, quite recently low n values for MgB2 wires have been reported. In order to find out the real properties of MgB2 an efficient computational model is required to simulate the voltage-current measurement. In this paper we go back to basics and consider two models to couple electromagnetic and thermal phenomena. In the first model the magnetization losses are computed according to the critical state model and the flux creep losses are considered separately. In the second model the superconductor resistivity is described by the widely used power law. Then the coupled current diffusion and heat conduction equations are solved with the finite element method. In order to compare the models, example runs are carried out with an adiabatic slab. Both models produce a similar significant temperature rise near the critical current which leads to fictitiously high n values.

Influence of channel base current and varying return stroke speed on the calculated fields of three important return stroke models

NASA Technical Reports Server (NTRS)

Thottappillil, Rajeev; Uman, Martin A.; Diendorfer, Gerhard

1991-01-01

Compared here are the calculated fields of the Traveling Current Source (TCS), Modified Transmission Line (MTL), and the Diendorfer-Uman (DU) models with a channel base current assumed in Nucci et al. on the one hand and with the channel base current assumed in Diendorfer and Uman on the other hand. The characteristics of the field wave shapes are shown to be very sensitive to the channel base current, especially the field zero crossing at 100 km for the TCS and DU models, and the magnetic hump after the initial peak at close range for the TCS models. Also, the DU model is theoretically extended to include any arbitrarily varying return stroke speed with height. A brief discussion is presented on the effects of an exponentially decreasing speed with height on the calculated fields for the TCS, MTL, and DU models.

Simulated wind-generated inertial oscillations compared to current measurements in the northern North Sea

NASA Astrophysics Data System (ADS)

Bruserud, Kjersti; Haver, Sverre; Myrhaug, Dag

2018-06-01

Measured current speed data show that episodes of wind-generated inertial oscillations dominate the current conditions in parts of the northern North Sea. In order to acquire current data of sufficient duration for robust estimation of joint metocean design conditions, such as wind, waves, and currents, a simple model for episodes of wind-generated inertial oscillations is adapted for the northern North Sea. The model is validated with and compared against measured current data at one location in the northern North Sea and found to reproduce the measured maximum current speed in each episode with considerable accuracy. The comparison is further improved when a small general background current is added to the simulated maximum current speeds. Extreme values of measured and simulated current speed are estimated and found to compare well. To assess the robustness of the model and the sensitivity of current conditions from location to location, the validated model is applied at three other locations in the northern North Sea. In general, the simulated maximum current speeds are smaller than the measured, suggesting that wind-generated inertial oscillations are not as prominent at these locations and that other current conditions may be governing. Further analysis of the simulated current speed and joint distribution of wind, waves, and currents for design of offshore structures will be presented in a separate paper.

Simulated wind-generated inertial oscillations compared to current measurements in the northern North Sea

NASA Astrophysics Data System (ADS)

Bruserud, Kjersti; Haver, Sverre; Myrhaug, Dag

2018-04-01

Measured current speed data show that episodes of wind-generated inertial oscillations dominate the current conditions in parts of the northern North Sea. In order to acquire current data of sufficient duration for robust estimation of joint metocean design conditions, such as wind, waves, and currents, a simple model for episodes of wind-generated inertial oscillations is adapted for the northern North Sea. The model is validated with and compared against measured current data at one location in the northern North Sea and found to reproduce the measured maximum current speed in each episode with considerable accuracy. The comparison is further improved when a small general background current is added to the simulated maximum current speeds. Extreme values of measured and simulated current speed are estimated and found to compare well. To assess the robustness of the model and the sensitivity of current conditions from location to location, the validated model is applied at three other locations in the northern North Sea. In general, the simulated maximum current speeds are smaller than the measured, suggesting that wind-generated inertial oscillations are not as prominent at these locations and that other current conditions may be governing. Further analysis of the simulated current speed and joint distribution of wind, waves, and currents for design of offshore structures will be presented in a separate paper.

Modeling Jupiter's current disc - Pioneer 10 outbound

NASA Astrophysics Data System (ADS)

Jones, D. E.; Melville, J. G.; Blake, M. L.

1980-07-01

A model of the magnetic field of the Jovian current disk is presented. The model uses Euler functions and the Biot-Savart law applied to a series of concentric, but not necessarily coplanar current rings. It was found that the best fit to the Pioneer 10 outbound perturbation magnetic field data is obtained if the current disk is twisted, and also bent to tend toward parallelism with the Jovigraphic equator. The inner and outer radii of the disk appear to be about 7 and 150 Jovian radii, respectively; because of the observed current disk penetrations, the bent disk also requires a deformation in the form of a bump or wrinkle whose axis tends to exhibit spiraling. Modeling of the azimuthal field shows that it is due to a thin radial current sheet, but it may actually be due in large part to penetration of a tail current sheet as suggested by Voyager observations.

Paraboloid magnetospheric magnetic field model and the status of the model as an ISO standard

NASA Astrophysics Data System (ADS)

Alexeev, I.

A reliable representation of the magnetic field is crucial in the framework of radiation belt modelling especially for disturbed conditions The empirical model developed by Tsyganenko T96 is constructed by minimizing the rms deviation from the large magnetospheric data base The applicability of the T96 model is limited mainly by quiet conditions in the solar wind along the Earth orbit But contrary to the internal planet s field the external magnetospheric magnetic field sources are much more time-dependent A reliable representation of the magnetic field is crucial in the framework of radiation belt modelling especially for disturbed conditions It is a reason why the method of the paraboloid magnetospheric model construction based on the more accurate and physically consistent approach in which each source of the magnetic field would have its own relaxation timescale and a driving function based on an individual best fit combination of the solar wind and IMF parameters Such approach is based on a priori information about the global magnetospheric current systems structure Each current system is included as a separate block module in the magnetospheric model As it was shown by the spacecraft magnetometer data there are three current systems which are the main contributors to the external magnetospheric magnetic field magnetopause currents ring current and tail current sheet Paraboloid model is based on an analytical solution of the Laplace equation for each of these large-scale current systems in the magnetosphere with a

Fundamental Algorithms of the Goddard Battery Model

NASA Technical Reports Server (NTRS)

Jagielski, J. M.

1985-01-01

The Goddard Space Flight Center (GSFC) is currently producing a computer model to predict Nickel Cadmium (NiCd) performance in a Low Earth Orbit (LEO) cycling regime. The model proper is currently still in development, but the inherent, fundamental algorithms (or methodologies) of the model are defined. At present, the model is closely dependent on empirical data and the data base currently used is of questionable accuracy. Even so, very good correlations have been determined between model predictions and actual cycling data. A more accurate and encompassing data base has been generated to serve dual functions: show the limitations of the current data base, and be inbred in the model properly for more accurate predictions. The fundamental algorithms of the model, and the present data base and its limitations, are described and a brief preliminary analysis of the new data base and its verification of the model's methodology are presented.

Modelling the Auroral Magnetosphere-Ionosphere Coupling System at Jupiter

NASA Astrophysics Data System (ADS)

Bunce, E. J.; Cowley, S.; Provan, G.

2016-12-01

The magnetosphere-ionosphere coupling system at Jupiter is a topic of central significance in understanding the fundamental properties of its large-scale plasma environment. Theoretical discussion of this topic typically considers the properties of the field-aligned current systems that form part of a large-scale magnetosphere-ionosphere coupling current system associated with momentum exchange between the ionosphere and the magnetosphere, communicated via the magnetic field. The current system associated with the main oval is believed to be related to centrifugally-driven outward radial transport of iogenic plasma that leads to sub-corotation in the middle magnetosphere. In addition to the magnetosphere-ionosphere coupling current system, upward-directed field-aligned currents may flow at the open-closed field line boundary due to the shear between outer closed field lines and open field lines, which may relate to emission poleward of the main oval. An axi-symmetric model of the plasma flow in the jovian system, the related coupling currents, and the consequent auroral precipitation based on these combined ideas was initially devised to represent typical steady-state conditions for the system and later extended to consider auroral effects resulting from sudden compressions of the magnetosphere. More recently, the model has been extended along model magnetic field lines into the magnetosphere in order to relate them to in situ observations from the NASA Juno spacecraft at Jupiter. The field-aligned coupling currents associated with the modelled current systems produce a readily-observable azimuthal field signature that bends the field lines out of magnetic meridians. Here we show the computed azimuthal fields produced by our model auroral current system throughout the region between the ionosphere and the magnetic equator, and illustrate the results by evaluation of various model parameters (e.g. field-aligned current density, accelerating voltages, accelerated energy flux) along the Juno orbits.

Accurate Modelling of Surface Currents and Internal Tides in a Semi-enclosed Coastal Sea

NASA Astrophysics Data System (ADS)

Allen, S. E.; Soontiens, N. K.; Dunn, M. B. H.; Liu, J.; Olson, E.; Halverson, M. J.; Pawlowicz, R.

2016-02-01

The Strait of Georgia is a deep (400 m), strongly stratified, semi-enclosed coastal sea on the west coast of North America. We have configured a baroclinic model of the Strait of Georgia and surrounding coastal waters using the NEMO ocean community model. We run daily nowcasts and forecasts and publish our sea-surface results (including storm surge warnings) to the web (salishsea.eos.ubc.ca/storm-surge). Tides in the Strait of Georgia are mixed and large. The baroclinic model and previous barotropic models accurately represent tidal sea-level variations and depth mean currents. The baroclinic model reproduces accurately the diurnal but not the semi-diurnal baroclinic tidal currents. In the Southern Strait of Georgia, strong internal tidal currents at the semi-diurnal frequency are observed. Strong semi-diurnal tides are also produced in the model, but are almost 180 degrees out of phase with the observations. In the model, in the surface, the barotropic and baroclinic tides reinforce, whereas the observations show that at the surface the baroclinic tides oppose the barotropic. As such the surface currents are very poorly modelled. Here we will present evidence of the internal tidal field from observations. We will discuss the generation regions of the tides, the necessary modifications to the model required to correct the phase, the resulting baroclinic tides and the improvements in the surface currents.

Finite element analysis of gradient z-coil induced eddy currents in a permanent MRI magnet.

PubMed

Li, Xia; Xia, Ling; Chen, Wufan; Liu, Feng; Crozier, Stuart; Xie, Dexin

2011-01-01

In permanent magnetic resonance imaging (MRI) systems, pulsed gradient fields induce strong eddy currents in the conducting structures of the magnet body. The gradient field for image encoding is perturbed by these eddy currents leading to MR image distortions. This paper presents a comprehensive finite element (FE) analysis of the eddy current generation in the magnet conductors. In the proposed FE model, the hysteretic characteristics of ferromagnetic materials are considered and a scalar Preisach hysteresis model is employed. The developed FE model was applied to study gradient z-coil induced eddy currents in a 0.5 T permanent MRI device. The simulation results demonstrate that the approach could be effectively used to investigate eddy current problems involving ferromagnetic materials. With the knowledge gained from this eddy current model, our next step is to design a passive magnet structure and active gradient coils to reduce the eddy current effects. Copyright © 2010 Elsevier Inc. All rights reserved.

An iterative model for the steady state current distribution in oxide-confined vertical-cavity surface-emitting lasers (VCSELs)

NASA Astrophysics Data System (ADS)

Chuang, Hsueh-Hua

The purpose of this dissertation is to develop an iterative model for the analysis of the current distribution in vertical-cavity surface-emitting lasers (VCSELs) using a circuit network modeling approach. This iterative model divides the VCSEL structure into numerous annular elements and uses a circuit network consisting of resistors and diodes. The measured sheet resistance of the p-distributed Bragg reflector (DBR), the measured sheet resistance of the layers under the oxide layer, and two empirical adjustable parameters are used as inputs to the iterative model to determine the resistance of each resistor. The two empirical values are related to the anisotropy of the resistivity of the p-DBR structure. The spontaneous current, stimulated current, and surface recombination current are accounted for by the diodes. The lateral carrier transport in the quantum well region is analyzed using drift and diffusion currents. The optical gain is calculated as a function of wavelength and carrier density from fundamental principles. The predicted threshold current densities for these VCSELs match the experimentally measured current densities over the wavelength range of 0.83 mum to 0.86 mum with an error of less than 5%. This model includes the effects of the resistance of the p-DBR mirrors, the oxide current-confining layer and spatial hole burning. Our model shows that higher sheet resistance under the oxide layer reduces the threshold current, but also reduces the current range over which single transverse mode operation occurs. The spatial hole burning profile depends on the lateral drift and diffusion of carriers in the quantum wells but is dominated by the voltage drop across the p-DBR region. To my knowledge, for the first time, the drift current and the diffusion current are treated separately. Previous work uses an ambipolar approach, which underestimates the total charge transferred in the quantum well region, especially under the oxide region. However, the total result of the drift current and the diffusion current is less significant than the Ohmic current, especially in the cavity region. This simple iterative model is applied to commercially available oxide-confined VCSELs. The simulation results show excellent agreement with experimentally measured voltage-current curves (within 3.7% for a 10 mum and within 4% for a 5 mum diameter VCSEL) and light-current curves (within 2% for a 10 mum and within 9% for a 5 mum diameter VCSEL) curves and provides insight into the detailed distributions of current and voltage within a VCSEL. This difference between the theoretically calculated results and the measured results is less than the variation shown in the data sheets for production VCSELs.

A note on evaluating model tidal currents against observations

NASA Astrophysics Data System (ADS)

Cummins, Patrick F.; Thupaki, Pramod

2018-01-01

The root-mean-square magnitude of the vector difference between modeled and observed tidal ellipses is a comprehensive metric to evaluate the representation of tidal currents in ocean models. A practical expression for this difference is given in terms of the harmonic constants that are routinely used to specify current ellipses for a given tidal constituent. The resulting metric is sensitive to differences in all four current ellipse parameters, including phase.

Comparison of current distributions in electroconvulsive therapy and transcranial magnetic stimulation

NASA Astrophysics Data System (ADS)

Sekino, Masaki; Ueno, Shoogo

2002-05-01

We compared current density distributions in electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS) by numerical calculations. The model consisted of an air region and three types of tissues with different conductivities representing the brain, the skull, and the scalp. In the ECT model, electric currents were applied through electrodes with a voltage of 100 V. In the TMS model, a figure-eight coil (6 cm diameter per coil) was placed on the vertex of the head model. An alternating current with a peak intensity of 3.0 kA and a frequency of 4.2 kHz was applied to the coil. The maximum current densities inside the brain in ECT (bilateral electrode position) and TMS were 234 and 322 A/m2, respectively. The results indicate that magnetic stimulators can generate comparable current densities to ECT. While the skull significantly affected current distributions in ECT, TMS efficiently induced eddy currents in the brain. In addition, TMS is more beneficial than ECT because the localized current distribution reduces the risk of adverse side effects.

A numerical study of the South China Sea Warm Current during winter monsoon relaxation

NASA Astrophysics Data System (ADS)

Zhang, Cong; Ding, Yang; Bao, Xianwen; Bi, Congcong; Li, Ruixiang; Zhang, Cunjie; Shen, Biao; Wan, Kai

2018-03-01

Using a Finite-Volume Community Ocean Model, we investigated the dynamic mechanism of the South China Sea Warm Current (SCSWC) in the northern South China Sea (NSCS) during winter monsoon relaxation. The model reproduces the mean surface circulation of the NSCS during winter, while model-simulated subtidal currents generally capture its current pattern. The model shows that the current over the continental shelf is generally southwestward, under a strong winter monsoon condition, but a northeastward counter-wind current usually develops between 50-and 100-m isobaths, when the monsoon relaxes. Model experiments, focusing on the wind relaxation process, show that sea level is elevated in the northwestern South China Sea (SCS), related to the persistent northeasterly monsoon. Following wind relaxation, a high sea level band builds up along the mid-shelf, and a northeastward current develops, having an obvious vertical barotropic structure. Momentum balance analysis indicates that an along-shelf pressure gradient provides the initial driving force for the SCSWC during the first few days following wind relaxation. The SCSWC subsequently reaches a steady quasi-geostrophic balance in the cross-shelf direction, mainly linked to sea level adjustment over the shelf. Lagrangian particle tracking experiments show that both the southwestward coastal current and slope current contribute to the northeastward movement of the SCSWC during winter monsoon relaxation.

Electromagnetic field radiation model for lightning strokes to tall structures

DOE Office of Scientific and Technical Information (OSTI.GOV)

Motoyama, H.; Janischewskyj, W.; Hussein, A.M.

1996-07-01

This paper describes observation and analysis of electromagnetic field radiation from lightning strokes to tall structures. Electromagnetic field waveforms and current waveforms of lightning strokes to the CN Tower have been simultaneously measured since 1991. A new calculation model of electromagnetic field radiation is proposed. The proposed model consists of the lightning current propagation and distribution model and the electromagnetic field radiation model. Electromagnetic fields calculated by the proposed model, based on the observed lightning current at the CN Tower, agree well with the observed fields at 2km north of the tower.

Fate of microplastics and mesoplastics carried by surface currents and wind waves: A numerical model approach in the Sea of Japan.

PubMed

Iwasaki, Shinsuke; Isobe, Atsuhiko; Kako, Shin'ichiro; Uchida, Keiichi; Tokai, Tadashi

2017-08-15

A numerical model was established to reproduce the oceanic transport processes of microplastics and mesoplastics in the Sea of Japan. A particle tracking model, where surface ocean currents were given by a combination of a reanalysis ocean current product and Stokes drift computed separately by a wave model, simulated particle movement. The model results corresponded with the field survey. Modeled results indicated the micro- and mesoplastics are moved northeastward by the Tsushima Current. Subsequently, Stokes drift selectively moves mesoplastics during winter toward the Japanese coast, resulting in increased contributions of mesoplastics south of 39°N. Additionally, Stokes drift also transports micro- and mesoplastics out to the sea area south of the subpolar front where the northeastward Tsushima Current carries them into the open ocean via the Tsugaru and Soya straits. Average transit time of modeled particles in the Sea of Japan is drastically reduced when including Stokes drift in the model. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Modeling tidal hydrodynamics of San Diego Bay, California

USGS Publications Warehouse

Wang, P.-F.; Cheng, R.T.; Richter, K.; Gross, E.S.; Sutton, D.; Gartner, J.W.

1998-01-01

In 1983, current data were collected by the National Oceanic and Atmospheric Administration using mechanical current meters. During 1992 through 1996, acoustic Doppler current profilers as well as mechanical current meters and tide gauges were used. These measurements not only document tides and tidal currents in San Diego Bay, but also provide independent data sets for model calibration and verification. A high resolution (100-m grid), depth-averaged, numerical hydrodynamic model has been implemented for San Diego Bay to describe essential tidal hydrodynamic processes in the bay. The model is calibrated using the 1983 data set and verified using the more recent 1992-1996 data. Discrepancies between model predictions and field data in beth model calibration and verification are on the order of the magnitude of uncertainties in the field data. The calibrated and verified numerical model has been used to quantify residence time and dilution and flushing of contaminant effluent into San Diego Bay. Furthermore, the numerical model has become an important research tool in ongoing hydrodynamic and water quality studies and in guiding future field data collection programs.

Asymmetry of the Martian Current Sheet in a Multi-fluid MHD Model

NASA Astrophysics Data System (ADS)

Panoncillo, S. G.; Egan, H. L.; Dong, C.; Connerney, J. E. P.; Brain, D. A.; Jakosky, B. M.

2017-12-01

The solar wind carries interplanetary magnetic field (IMF) lines toward Mars, where they drape around the planet's conducting ionosphere, creating a current sheet behind the planet where the magnetic field has opposite polarity on either side. In its simplest form, the current sheet is often thought of as symmetric, extending behind the planet along the Mars-Sun line. Observations and model simulations, however, demonstrate that this idealized representation is only an approximation, and the actual scenario is much more complex. The current sheet can have 3D structure, move back and forth, and be situated dawnward or duskward of the Mars-Sun line. In this project, we utilized a library of global plasma model results for Mars consisting of a collection of multi-fluid MHD simulations where solar max/min, sub-solar longitude, and the orbital position of Mars are varied individually. The model includes Martian crustal fields, and was run for identical steady solar wind conditions. This library was created for the purpose of comparing model results to MAVEN data; we looked at the results of this model library to investigate current sheet asymmetries. By altering one variable at a time we were able to measure how these variables influence the location of the current sheet. We found that the current sheet is typically shifted toward the dusk side of the planet, and that modeled asymmetries are especially prevalent during solar min. Previous model studies that lack crustal fields have found that, for a Parker spiral IMF, the current sheet will shift dawnward, while our results typically show the opposite. This could expose certain limitations in the models used, or it could reveal an interaction between the solar wind and the plasma environment of Mars that has not yet been explored. MAVEN data may be compared to the model results to confirm the sense of the modeled asymmetry. These results help us to probe the physics controlling the Martian magnetotail and atmospheric escape from Mars.

A nowcast model for tides and tidal currents in San Francisco Bay, California

USGS Publications Warehouse

Cheng, Ralph T.; Smith, Richard E.

1998-01-01

National Oceanographic and Atmospheric Administration (NOAA) installed Physical Oceanographic Real-Time System (PORTS) in San Francisco Bay, California to provide observations of tides, tidal currents, and meteorological conditions. PORTS data are used for optimizing vessel operations, increasing margin of safety for navigation, and guiding hazardous material spill prevention and response. Because tides and tidal currents in San Francisco Bay are extremely complex, limited real-time observations are insufficient to provide spatial resolution for variations of tides and tidal currents. To fill the information gaps, a highresolution, robust, semi-implicit, finite-difference nowcast numerical model has been implemented for San Francisco Bay. The model grid and water depths are defined on coordinates based on Mercator projection so the model outputs can be directly superimposed on navigation charts. A data assimilation algorithm has been established to derive the boundary conditions for model simulations. The nowcast model is executed every hour continuously for tides and tidal currents starting from 24 hours before the present time (now) covering a total of 48 hours simulation. Forty-eight hours of nowcast model results are available to the public at all times through the World Wide Web (WWW). Users can view and download the nowcast model results for tides and tidal current distributions in San Francisco Bay for their specific applications and for further analysis.

Structure of the Magnetotail Current Sheet

NASA Technical Reports Server (NTRS)

Larson, Douglas J.; Kaufmann, Richard L.

1996-01-01

An orbit tracing technique was used to generate current sheets for three magnetotail models. Groups of ions were followed to calculate the resulting cross-tail current. Several groups then were combined to produce a current sheet. The goal is a model in which the ions and associated electrons carry the electric current distribution needed to generate the magnetic field B in which ion orbits were traced. The region -20 R(sub E) less than x less than - 14 R(sub E) in geocentric solar magnetospheric coordinates was studied. Emphasis was placed on identifying the categories of ion orbits which contribute most to the cross-tail current and on gaining physical insight into the manner by which the ions carry the observed current distribution. Ions that were trapped near z = 0, ions that magnetically mirrored throughout the current sheet, and ions that mirrored near the Earth all were needed. The current sheet structure was determined primarily by ion magnetization currents. Electrons of the observed energies carried relatively little cross-tail current in these quiet time current sheets. Distribution functions were generated and integrated to evaluate fluid parameters. An earlier model in which B depended only on z produced a consistent current sheet, but it did not provide a realistic representation of the Earth's middle magnetotail. In the present study, B changed substantially in the x and z directions but only weakly in the y direction within our region of interest. Plasmas with three characteristic particle energies were used with each of the magnetic field models. A plasma was found for each model in which the density, average energy, cross-tail current, and bulk flow velocity agreed well with satellite observations.

Structure of the Magnetotail Current Sheet

NASA Technical Reports Server (NTRS)

Larson, Douglas J.; Kaufmann, Richard L.

1996-01-01

An orbit tracing technique was used to generate current sheets for three magnetotail models. Groups of ions were followed to calculate the resulting cross-tail current. Several groups then were combined to produce a current sheet. The goal is a model in which the ions and associated electrons carry the electric current distribution needed to generate the magnetic field B in which ion orbits were traced. The region -20 R(E) less than x less than -14 R(E) in geocentric solar magnetospheric coordinates was studied. Emphasis was placed on identifying the categories of ion orbits which contribute most to the cross-tail current and on gaining physical insight into the manner by which the ions carry the observed current distribution. Ions that were trapped near z = 0, ions that magnetically mirrored throughout the current sheet, and ions that mirrored near the Earth all were needed. The current sheet structure was determined primarily by ion magnetization currents. Electrons of the observed energies carried relatively little cross-tail current in these quiet time current sheets. Distribution functions were generated and integrated to evaluate fluid parameters. An earlier model in which B depended only on z produced a consistent current sheet, but it did not provide a realistic representation of the Earth's middle magnetotail. In the present study, B changed substantially in the x and z directions but only weakly in the y direction within our region of interest. Plasmas with three characteristic particle energies were used with each of the magnetic field models. A plasma was found for each model in which the density, average energy, cross-tail current, and bulk flow velocity agreed well with satellite observations.

Dynamics of Ring Current and Electric Fields in the Inner Magnetosphere During Disturbed Periods: CRCM-BATS-R-US Coupled Model

NASA Technical Reports Server (NTRS)

Buzulukova, N.; Fok, M.-C.; Pulkkinen, A.; Kuznetsova, M.; Moore, T. E.; Glocer, A.; Brandt, P. C.; Toth, G.; Rastaetter, L.

2010-01-01

We present simulation results from a one-way coupled global MHD model (Block-Adaptive-Tree Solar-Wind Roe-Type Upwind Scheme, BATS-R-US) and kinetic ring current models (Comprehensive Ring Current Model, CRCM, and Fok Ring Current, FokRC). The BATS-R-US provides the CRCM/FokRC with magnetic field information and plasma density/temperature at the polar CRCM/FokRC boundary. The CRCM uses an electric potential from the BATS-R-US ionospheric solver at the polar CRCM boundary in order to calculate the electric field pattern consistent with the CRCM pressure distribution. The FokRC electric field potential is taken from BATS-R-US ionospheric solver everywhere in the modeled region, and the effect of Region II currents is neglected. We show that for an idealized case with southward-northward-southward Bz IMF turning, CRCM-BATS-R-US reproduces well known features of inner magnetosphere electrodynamics: strong/weak convection under the southward/northward Bz; electric field shielding/overshielding/penetration effects; an injection during the substorm development; Subauroral Ion Drift or Polarization Jet (SAID/PJ) signature in the dusk sector. Furthermore, we find for the idealized case that SAID/PJ forms during the substorm growth phase, and that substorm injection has its own structure of field-aligned currents which resembles a substorm current wedge. For an actual event (12 August 2000 storm), we calculate ENA emissions and compare with Imager for Magnetopause-to-Aurora Global Exploration/High Energy Neutral Atom data. The CRCM-BATS-R-US reproduces both the global morphology of ring current and the fine structure of ring current injection. The FokRC-BATS-R-US shows the effect of a realistic description of Region II currents in ring current-MHD coupled models.

Systematic characterization of the ionic basis of rabbit cellular electrophysiology using two ventricular models.

PubMed

Romero, Lucía; Carbonell, Beatriz; Trenor, Beatriz; Rodríguez, Blanca; Saiz, Javier; Ferrero, José M

2011-10-01

Several mathematical models of rabbit ventricular action potential (AP) have been proposed to investigate mechanisms of arrhythmias and excitation-contraction coupling. Our study aims at systematically characterizing how ionic current properties modulate the main cellular biomarkers of arrhythmic risk using two widely-used rabbit ventricular models, and comparing simulation results using the two models with experimental data available for rabbit. A sensitivity analysis of AP properties, Ca²⁺ and Na⁺ dynamics, and their rate dependence to variations (±15% and ±30%) in the main transmembrane current conductances and kinetics was performed using the Shannon et al. (2004) and the Mahajan et al. (2008a,b) AP rabbit models. The effects of severe transmembrane current blocks (up to 100%) on steady-state AP and calcium transients, and AP duration (APD) restitution curves were also simulated using both models. Our simulations show that, in both virtual rabbit cardiomyocytes, APD is significantly modified by most repolarization currents, AP triangulation is regulated mostly by the inward rectifier K⁺ current (I(K1)) whereas APD rate adaptation as well as [Na⁺](i) rate dependence is influenced by the Na⁺/K⁺ pump current (I(NaK)). In addition, steady-state [Ca²⁺](i) levels, APD restitution properties and [Ca²⁺](i) rate dependence are strongly dependent on I(NaK), the L-Type Ca²⁺ current (I(CaL)) and the Na⁺/Ca²⁺ exchanger current (I(NaCa)), although the relative role of these currents is markedly model dependent. Furthermore, our results show that simulations using both models agree with many experimentally-reported electrophysiological characteristics. However, our study shows that the Shannon et al. model mimics rabbit electrophysiology more accurately at normal pacing rates, whereas Mahajan et al. model behaves more appropriately at faster rates. Our results reinforce the usefulness of sensitivity analysis for further understanding of cellular electrophysiology and validation of cardiac AP models. Copyright © 2011 Elsevier Ltd. All rights reserved.

The influence of coarse-scale environmental features on current and predicted future distributions of narrow-range endemic crayfish populations

USGS Publications Warehouse

Dyer, Joseph J.; Brewer, Shannon K.; Worthington, Thomas A.; Bergey, Elizabeth A.

2013-01-01

1.A major limitation to effective management of narrow-range crayfish populations is the paucity of information on the spatial distribution of crayfish species and a general understanding of the interacting environmental variables that drive current and future potential distributional patterns. 2.Maximum Entropy Species Distribution Modeling Software (MaxEnt) was used to predict the current and future potential distributions of four endemic crayfish species in the Ouachita Mountains. Current distributions were modelled using climate, geology, soils, land use, landform and flow variables thought to be important to lotic crayfish. Potential changes in the distribution were forecast by using models trained on current conditions and projecting onto the landscape predicted under climate-change scenarios. 3.The modelled distribution of the four species closely resembled the perceived distribution of each species but also predicted populations in streams and catchments where they had not previously been collected. Soils, elevation and winter precipitation and temperature most strongly related to current distributions and represented 6587% of the predictive power of the models. Model accuracy was high for all models, and model predictions of new populations were verified through additional field sampling. 4.Current models created using two spatial resolutions (1 and 4.5km2) showed that fine-resolution data more accurately represented current distributions. For three of the four species, the 1-km2 resolution models resulted in more conservative predictions. However, the modelled distributional extent of Orconectes leptogonopodus was similar regardless of data resolution. Field validations indicated 1-km2 resolution models were more accurate than 4.5-km2 resolution models. 5.Future projected (4.5-km2 resolution models) model distributions indicated three of the four endemic species would have truncated ranges with low occurrence probabilities under the low-emission scenario, whereas two of four species would be severely restricted in range under moderatehigh emissions. Discrepancies in the two emission scenarios probably relate to the exclusion of behavioural adaptations from species-distribution models. 6.These model predictions illustrate possible impacts of climate change on narrow-range endemic crayfish populations. The predictions do not account for biotic interactions, migration, local habitat conditions or species adaptation. However, we identified the constraining landscape features acting on these populations that provide a framework for addressing habitat needs at a fine scale and developing targeted and systematic monitoring programmes.

Forcing and variability of nonstationary rip currents

USGS Publications Warehouse

Long, Joseph W.; H.T. Özkan-Haller,

2016-01-01

Surface wave transformation and the resulting nearshore circulation along a section of coast with strong alongshore bathymetric gradients outside the surf zone are modeled for a consecutive 4 week time period. The modeled hydrodynamics are compared to in situ measurements of waves and currents collected during the Nearshore Canyon Experiment and indicate that for the entire range of observed conditions, the model performance is similar to other studies along this stretch of coast. Strong alongshore wave height gradients generate rip currents that are observed by remote sensing data and predicted qualitatively well by the numerical model. Previous studies at this site have used idealized scenarios to link the rip current locations to undulations in the offshore bathymetry but do not explain the dichotomy between permanent offshore bathymetric features and intermittent rip current development. Model results from the month‐long simulation are used to track the formation and location of rip currents using hourly statistics, and results show that the direction of the incoming wave energy strongly controls whether rip currents form. In particular, most of the offshore wave spectra were bimodal and we find that the ratio of energy contained in each mode dictates rip current development, and the alongshore rip current position is controlled by the incident wave period. Additionally, model simulations performed with and without updating the nearshore morphology yield no significant change in the accuracy of the predicted surf zone hydrodyanmics indicating that the large‐scale offshore features (e.g., submarine canyon) predominately control the nearshore wave‐circulation system.

A comparison between block and smooth modeling in finite element simulations of tDCS*

PubMed Central

Indahlastari, Aprinda; Sadleir, Rosalind J.

2018-01-01

Current density distributions in five selected structures, namely, anterior superior temporal gyrus (ASTG), hippocampus (HIP), inferior frontal gyrus (IFG), occipital lobe (OCC) and pre-central gyrus (PRC) were investigated as part of a comparison between electrostatic finite element models constructed directly from MRI-resolution data (block models), and smoothed tetrahedral finite element models (smooth models). Three electrode configurations were applied, mimicking different tDCS therapies. Smooth model simulations were found to require three times longer to complete. The percentage differences between mean and median current densities of each model type in arbitrarily chosen brain structures ranged from −33.33–48.08%. No clear relationship was found between structure volumes and current density differences between the two model types. Tissue regions nearby the electrodes demonstrated the least percentage differences between block and smooth models. Therefore, block models may be adequate to predict current density values in cortical regions presumed targeted by tDCS. PMID:26737023

Limitations Of The Current State Space Modelling Approach In Multistage Machining Processes Due To Operation Variations

NASA Astrophysics Data System (ADS)

Abellán-Nebot, J. V.; Liu, J.; Romero, F.

2009-11-01

The State Space modelling approach has been recently proposed as an engineering-driven technique for part quality prediction in Multistage Machining Processes (MMP). Current State Space models incorporate fixture and datum variations in the multi-stage variation propagation, without explicitly considering common operation variations such as machine-tool thermal distortions, cutting-tool wear, cutting-tool deflections, etc. This paper shows the limitations of the current State Space model through an experimental case study where the effect of the spindle thermal expansion, cutting-tool flank wear and locator errors are introduced. The paper also discusses the extension of the current State Space model to include operation variations and its potential benefits.

Inner Magnetosphere Modeling at the CCMC: Ring Current, Radiation Belt and Magnetic Field Mapping

NASA Astrophysics Data System (ADS)

Rastaetter, L.; Mendoza, A. M.; Chulaki, A.; Kuznetsova, M. M.; Zheng, Y.

2013-12-01

Modeling of the inner magnetosphere has entered center stage with the launch of the Van Allen Probes (RBSP) in 2012. The Community Coordinated Modeling Center (CCMC) has drastically improved its offerings of inner magnetosphere models that cover energetic particles in the Earth's ring current and radiation belts. Models added to the CCMC include the stand-alone Comprehensive Inner Magnetosphere-Ionosphere (CIMI) model by M.C. Fok, the Rice Convection Model (RCM) by R. Wolf and S. Sazykin and numerous versions of the Tsyganenko magnetic field model (T89, T96, T01quiet, TS05). These models join the LANL* model by Y. Yu hat was offered for instant run earlier in the year. In addition to these stand-alone models, the Comprehensive Ring Current Model (CRCM) by M.C. Fok and N. Buzulukova joined as a component of the Space Weather Modeling Framework (SWMF) in the magnetosphere model run-on-request category. We present modeling results of the ring current and radiation belt models and demonstrate tracking of satellites such as RBSP. Calculations using the magnetic field models include mappings to the magnetic equator or to minimum-B positions and the determination of foot points in the ionosphere.

A Dynamic Model of Mercury's Magnetospheric Magnetic Field

PubMed Central

Johnson, Catherine L.; Philpott, Lydia; Tsyganenko, Nikolai A.; Anderson, Brian J.

2017-01-01

Abstract Mercury's solar wind and interplanetary magnetic field environment is highly dynamic, and variations in these external conditions directly control the current systems and magnetic fields inside the planetary magnetosphere. We update our previous static model of Mercury's magnetic field by incorporating variations in the magnetospheric current systems, parameterized as functions of Mercury's heliocentric distance and magnetic activity. The new, dynamic model reproduces the location of the magnetopause current system as a function of systematic pressure variations encountered during Mercury's eccentric orbit, as well as the increase in the cross‐tail current intensity with increasing magnetic activity. Despite the enhancements in the external field parameterization, the residuals between the observed and modeled magnetic field inside the magnetosphere indicate that the dynamic model achieves only a modest overall improvement over the previous static model. The spatial distribution of the residuals in the magnetic field components shows substantial improvement of the model accuracy near the dayside magnetopause. Elsewhere, the large‐scale distribution of the residuals is similar to those of the static model. This result implies either that magnetic activity varies much faster than can be determined from the spacecraft's passage through the magnetosphere or that the residual fields are due to additional external current systems not represented in the model or both. Birkeland currents flowing along magnetic field lines between the magnetosphere and planetary high‐latitude regions have been identified as one such contribution. PMID:29263560

Sinusoidal voltage protocols for rapid characterisation of ion channel kinetics.

PubMed

Beattie, Kylie A; Hill, Adam P; Bardenet, Rémi; Cui, Yi; Vandenberg, Jamie I; Gavaghan, David J; de Boer, Teun P; Mirams, Gary R

2018-03-24

Ion current kinetics are commonly represented by current-voltage relationships, time constant-voltage relationships and subsequently mathematical models fitted to these. These experiments take substantial time, which means they are rarely performed in the same cell. Rather than traditional square-wave voltage clamps, we fitted a model to the current evoked by a novel sum-of-sinusoids voltage clamp that was only 8 s long. Short protocols that can be performed multiple times within a single cell will offer many new opportunities to measure how ion current kinetics are affected by changing conditions. The new model predicts the current under traditional square-wave protocols well, with better predictions of underlying currents than literature models. The current under a novel physiologically relevant series of action potential clamps is predicted extremely well. The short sinusoidal protocols allow a model to be fully fitted to individual cells, allowing us to examine cell-cell variability in current kinetics for the first time. Understanding the roles of ion currents is crucial to predict the action of pharmaceuticals and mutations in different scenarios, and thereby to guide clinical interventions in the heart, brain and other electrophysiological systems. Our ability to predict how ion currents contribute to cellular electrophysiology is in turn critically dependent on our characterisation of ion channel kinetics - the voltage-dependent rates of transition between open, closed and inactivated channel states. We present a new method for rapidly exploring and characterising ion channel kinetics, applying it to the hERG potassium channel as an example, with the aim of generating a quantitatively predictive representation of the ion current. We fitted a mathematical model to currents evoked by a novel 8 second sinusoidal voltage clamp in CHO cells overexpressing hERG1a. The model was then used to predict over 5 minutes of recordings in the same cell in response to further protocols: a series of traditional square step voltage clamps, and also a novel voltage clamp comprising a collection of physiologically relevant action potentials. We demonstrate that we can make predictive cell-specific models that outperform the use of averaged data from a number of different cells, and thereby examine which changes in gating are responsible for cell-cell variability in current kinetics. Our technique allows rapid collection of consistent and high quality data, from single cells, and produces more predictive mathematical ion channel models than traditional approaches. © 2018 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.

Automated MRI segmentation for individualized modeling of current flow in the human head.

PubMed

Huang, Yu; Dmochowski, Jacek P; Su, Yuzhuo; Datta, Abhishek; Rorden, Christopher; Parra, Lucas C

2013-12-01

High-definition transcranial direct current stimulation (HD-tDCS) and high-density electroencephalography require accurate models of current flow for precise targeting and current source reconstruction. At a minimum, such modeling must capture the idiosyncratic anatomy of the brain, cerebrospinal fluid (CSF) and skull for each individual subject. Currently, the process to build such high-resolution individualized models from structural magnetic resonance images requires labor-intensive manual segmentation, even when utilizing available automated segmentation tools. Also, accurate placement of many high-density electrodes on an individual scalp is a tedious procedure. The goal was to develop fully automated techniques to reduce the manual effort in such a modeling process. A fully automated segmentation technique based on Statical Parametric Mapping 8, including an improved tissue probability map and an automated correction routine for segmentation errors, was developed, along with an automated electrode placement tool for high-density arrays. The performance of these automated routines was evaluated against results from manual segmentation on four healthy subjects and seven stroke patients. The criteria include segmentation accuracy, the difference of current flow distributions in resulting HD-tDCS models and the optimized current flow intensities on cortical targets. The segmentation tool can segment out not just the brain but also provide accurate results for CSF, skull and other soft tissues with a field of view extending to the neck. Compared to manual results, automated segmentation deviates by only 7% and 18% for normal and stroke subjects, respectively. The predicted electric fields in the brain deviate by 12% and 29% respectively, which is well within the variability observed for various modeling choices. Finally, optimized current flow intensities on cortical targets do not differ significantly. Fully automated individualized modeling may now be feasible for large-sample EEG research studies and tDCS clinical trials.

The impact of sea surface currents in wave power potential modeling

NASA Astrophysics Data System (ADS)

Zodiatis, George; Galanis, George; Kallos, George; Nikolaidis, Andreas; Kalogeri, Christina; Liakatas, Aristotelis; Stylianou, Stavros

2015-11-01

The impact of sea surface currents to the estimation and modeling of wave energy potential over an area of increased economic interest, the Eastern Mediterranean Sea, is investigated in this work. High-resolution atmospheric, wave, and circulation models, the latter downscaled from the regional Mediterranean Forecasting System (MFS) of the Copernicus marine service (former MyOcean regional MFS system), are utilized towards this goal. The modeled data are analyzed by means of a variety of statistical tools measuring the potential changes not only in the main wave characteristics, but also in the general distribution of the wave energy and the wave parameters that mainly affect it, when using sea surface currents as a forcing to the wave models. The obtained results prove that the impact of the sea surface currents is quite significant in wave energy-related modeling, as well as temporally and spatially dependent. These facts are revealing the necessity of the utilization of the sea surface currents characteristics in renewable energy studies in conjunction with their meteo-ocean forecasting counterparts.

Modeling Requirements for Cohort and Register IT.

PubMed

Stäubert, Sebastian; Weber, Ulrike; Michalik, Claudia; Dress, Jochen; Ngouongo, Sylvie; Stausberg, Jürgen; Winter, Alfred

2016-01-01

The project KoRegIT (funded by TMF e.V.) aimed to develop a generic catalog of requirements for research networks like cohort studies and registers (KoReg). The catalog supports such kind of research networks to build up and to manage their organizational and IT infrastructure. To make transparent the complex relationships between requirements, which are described in use cases from a given text catalog. By analyzing and modeling the requirements a better understanding and optimizations of the catalog are intended. There are two subgoals: a) to investigate one cohort study and two registers and to model the current state of their IT infrastructure; b) to analyze the current state models and to find simplifications within the generic catalog. Processing the generic catalog was performed by means of text extraction, conceptualization and concept mapping. Then methods of enterprise architecture planning (EAP) are used to model the extracted information. To work on objective a) questionnaires are developed by utilizing the model. They are used for semi-structured interviews, whose results are evaluated via qualitative content analysis. Afterwards the current state was modeled. Objective b) was done by model analysis. A given generic text catalog of requirements was transferred into a model. As result of objective a) current state models of one existing cohort study and two registers are created and analyzed. An optimized model called KoReg-reference-model is the result of objective b). It is possible to use methods of EAP to model requirements. This enables a better overview of the partly connected requirements by means of visualization. The model based approach also enables the analysis and comparison of the empirical data from the current state models. Information managers could reduce the effort of planning the IT infrastructure utilizing the KoReg-reference-model. Modeling the current state and the generation of reports from the model, which could be used as requirements specification for bids, is supported, too.

River Inflows into Lakes: Basin Temperature Profiles Driven By Peeling Detrainment from Dense Underflows

NASA Astrophysics Data System (ADS)

Hogg, C. A. R.; Huppert, H. E.; Imberger, J.; Dalziel, S. B.

2014-12-01

Dense gravity currents from river inflows feed fluid into confined basins in lakes. Large inflows can influence temperature profiles in the basins. Existing parameterisations of the circulation and mixing of such inflows are often based on the entrainment of ambient fluid into the underflowing gravity currents. However, recent observations have suggested that uni-directional entrainment into a gravity current does not fully describe the transfer between such gravity currents and the ambient water. Laboratory experiments visualised peeling detrainment from the gravity current occurring when the ambient fluid was stratified. A theoretical model of the observed peeling detrainment was developed to predict the temperature profile in the basin. This new model gives a better approximation of the temperature profile observed in the experiments than the pre-existing entraining model. The model can now be developed such that it integrates into operational models of lake basins.

26. CURRENT METERS WITH FOLDING SCALE (MEASURED IN INCHES) IN ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

26. CURRENT METERS WITH FOLDING SCALE (MEASURED IN INCHES) IN FOREGROUND: GURLEY MODEL NO. 665 AT CENTER, GURLEY MODEL NO. 625 'PYGMY' CURRENT METER AT LEFT, AND WES MINIATURE PRICE-TYPE CURRENT METER AT RIGHT. - Waterways Experiment Station, Hydraulics Laboratory, Halls Ferry Road, 2 miles south of I-20, Vicksburg, Warren County, MS

Inter-model analysis of tsunami-induced coastal currents

NASA Astrophysics Data System (ADS)

Lynett, Patrick J.; Gately, Kara; Wilson, Rick; Montoya, Luis; Arcas, Diego; Aytore, Betul; Bai, Yefei; Bricker, Jeremy D.; Castro, Manuel J.; Cheung, Kwok Fai; David, C. Gabriel; Dogan, Gozde Guney; Escalante, Cipriano; González-Vida, José Manuel; Grilli, Stephan T.; Heitmann, Troy W.; Horrillo, Juan; Kânoğlu, Utku; Kian, Rozita; Kirby, James T.; Li, Wenwen; Macías, Jorge; Nicolsky, Dmitry J.; Ortega, Sergio; Pampell-Manis, Alyssa; Park, Yong Sung; Roeber, Volker; Sharghivand, Naeimeh; Shelby, Michael; Shi, Fengyan; Tehranirad, Babak; Tolkova, Elena; Thio, Hong Kie; Velioğlu, Deniz; Yalçıner, Ahmet Cevdet; Yamazaki, Yoshiki; Zaytsev, Andrey; Zhang, Y. J.

2017-06-01

To help produce accurate and consistent maritime hazard products, the National Tsunami Hazard Mitigation Program organized a benchmarking workshop to evaluate the numerical modeling of tsunami currents. Thirteen teams of international researchers, using a set of tsunami models currently utilized for hazard mitigation studies, presented results for a series of benchmarking problems; these results are summarized in this paper. Comparisons focus on physical situations where the currents are shear and separation driven, and are thus de-coupled from the incident tsunami waveform. In general, we find that models of increasing physical complexity provide better accuracy, and that low-order three-dimensional models are superior to high-order two-dimensional models. Inside separation zones and in areas strongly affected by eddies, the magnitude of both model-data errors and inter-model differences can be the same as the magnitude of the mean flow. Thus, we make arguments for the need of an ensemble modeling approach for areas affected by large-scale turbulent eddies, where deterministic simulation may be misleading. As a result of the analyses presented herein, we expect that tsunami modelers now have a better awareness of their ability to accurately capture the physics of tsunami currents, and therefore a better understanding of how to use these simulation tools for hazard assessment and mitigation efforts.

Evolving PBPK applications in regulatory risk assessment: current situation and future goals

EPA Science Inventory

The presentation includes current applications of PBPK modeling in regulatory risk assessment and discussions on conflicts between assuring consistency with experimental data in current situation and the desire for animal-free model development.

Dual Transformer Model based on Standard Circuit Elements for the Study of Low- and Mid-frequency Transients

NASA Astrophysics Data System (ADS)

Jazebi, Saeed

This thesis is a step forward toward achieving the final objective of creating a fully dual model for transformers including eddy currents and nonlinearities of the iron core using the fundamental electrical components already available in the EMTP-type programs. The model is effective for the study of the performance of transformers during power system transients. This is very important for transformer designers, because the insulation of transformers is determined with the overvoltages caused by lightning or switching operations. There are also internally induced transients that occur when a switch is actuated. For example switching actions for reconfiguration of distribution systems that offers economic advantages, or protective actions to clear faults and large short-circuit currents. Many of the smart grid concepts currently under development by many utilities rely heavily on switching to optimize resources that produce transients in the system. On the other hand, inrush currents produce mechanical forces which deform transformer windings and cause malfunction of the differential protection. Also, transformer performance under ferroresonance and geomagnetic induced currents are necessary to study. In this thesis, a physically consistent dual model applicable to single-phase two-winding transformers is proposed. First, the topology of a dual electrical equivalent circuit is obtained from the direct application of the principle of duality. Then, the model parameters are computed considering the variations of the transformer electromagnetic behavior under various operating conditions. Current modeling techniques use different topological models to represent diverse transient situations. The reversible model proposed in this thesis unifies the terminal and topological equivalent circuits. The model remains invariable for all low-frequency transients including deep saturation conditions driven from any of the two windings. The very high saturation region of the iron core magnetizing characteristic is modified with the accurate measurement of the air-core inductance. The air-core inductance is measured using a non-ideal low-power rectifier. Its dc output serves to drive the transformer into deep saturation, and its ripple provides low-amplitude variable excitation. The principal advantage of this method is its simplicity. To model the eddy current effects in the windings, a novel equivalent circuit is proposed. The circuit is derived from the principle of duality and therefore, matches the electromagnetic physical behavior of the transformer windings. It properly models the flux paths and current distribution from dc to MHz. The model is synthesized from a non-uniform concentric discretization of the windings. Concise guidelines are given to optimally calculate the width of the sub-divisions for various transient simulations. To compute the circuit parameters only information about the geometry of the windings and about their material properties is needed. The calculation of the circuit parameters does not require an iterative process. Therefore, the parameters are always real, positive, and free from convergence problems. The proposed model is tested with single-phase transformers for the calculation of magnetizing inrush currents, series ferroresonance, and Geomagnetic Induced Currents (GIC). The electromagnetic transient response of the model is compared to laboratory measurements for validation. Also, 3D finite element simulations are used to validate the electromagnetic behavior of the transformer model. Large manufacturer of transformers, power system designers, and electrical utility companies can benefit from the new model. It simplifies the design and optimization of the transformers' insulation, thereby reducing cost, and enhancing reliability of the system. The model could also be used for inrush current and differential protection studies, geomagnetic induced current studies, harmonic penetration studies, and switching transient studies.

The point spread function of the human head and its implications for transcranial current stimulation

NASA Astrophysics Data System (ADS)

Dmochowski, Jacek P.; Bikson, Marom; Parra, Lucas C.

2012-10-01

Rational development of transcranial current stimulation (tCS) requires solving the ‘forward problem’: the computation of the electric field distribution in the head resulting from the application of scalp currents. Derivation of forward models has represented a major effort in brain stimulation research, with model complexity ranging from spherical shells to individualized head models based on magnetic resonance imagery. Despite such effort, an easily accessible benchmark head model is greatly needed when individualized modeling is either undesired (to observe general population trends as opposed to individual differences) or unfeasible. Here, we derive a closed-form linear system which relates the applied current to the induced electric potential. It is shown that in the spherical harmonic (Fourier) domain, a simple scalar multiplication relates the current density on the scalp to the electric potential in the brain. Equivalently, the current density in the head follows as the spherical convolution between the scalp current distribution and the point spread function of the head, which we derive. Thus, if one knows the spherical harmonic representation of the scalp current (i.e. the electrode locations and current intensity to be employed), one can easily compute the resulting electric field at any point inside the head. Conversely, one may also readily determine the scalp current distribution required to generate an arbitrary electric field in the brain (the ‘backward problem’ in tCS). We demonstrate the simplicity and utility of the model with a series of characteristic curves which sweep across a variety of stimulation parameters: electrode size, depth of stimulation, head size and anode-cathode separation. Finally, theoretically optimal montages for targeting an infinitesimal point in the brain are shown.

Individualized model predicts brain current flow during transcranial direct-current stimulation treatment in responsive stroke patient.

PubMed

Datta, Abhishek; Baker, Julie M; Bikson, Marom; Fridriksson, Julius

2011-07-01

Although numerous published reports have demonstrated the beneficial effects of transcranial direct-current stimulation (tDCS) on task performance, fundamental questions remain regarding the optimal electrode configuration on the scalp. Moreover, it is expected that lesioned brain tissue will influence current flow and should therefore be considered (and perhaps leveraged) in the design of individualized tDCS therapies for stroke. The current report demonstrates how different electrode configurations influence the flow of electrical current through brain tissue in a patient who responded positively to a tDCS treatment targeting aphasia. The patient, a 60-year-old man, sustained a left hemisphere ischemic stroke (lesion size = 87.42 mL) 64 months before his participation. In this study, we present results from the first high-resolution (1 mm(3)) model of tDCS in a brain with considerable stroke-related damage; the model was individualized for the patient who received anodal tDCS to his left frontal cortex with the reference cathode electrode placed on his right shoulder. We modeled the resulting brain current flow and also considered three additional reference electrode positions: right mastoid, right orbitofrontal cortex, and a "mirror" configuration with the anode over the undamaged right cortex. Our results demonstrate the profound effect of lesioned tissue on resulting current flow and the ability to modulate current pattern through the brain, including perilesional regions, through electrode montage design. The complexity of brain current flow modulation by detailed normal and pathologic anatomy suggest: (1) That computational models are critical for the rational interpretation and design of individualized tDCS stroke-therapy; and (2) These models must accurately reproduce head anatomy as shown here. Copyright © 2011 Elsevier Inc. All rights reserved.

A Computational Model of the Ionic Currents, Ca2+ Dynamics and Action Potentials Underlying Contraction of Isolated Uterine Smooth Muscle

PubMed Central

Tong, Wing-Chiu; Choi, Cecilia Y.; Karche, Sanjay; Holden, Arun V.; Zhang, Henggui; Taggart, Michael J.

2011-01-01

Uterine contractions during labor are discretely regulated by rhythmic action potentials (AP) of varying duration and form that serve to determine calcium-dependent force production. We have employed a computational biology approach to develop a fuller understanding of the complexity of excitation-contraction (E-C) coupling of uterine smooth muscle cells (USMC). Our overall aim is to establish a mathematical platform of sufficient biophysical detail to quantitatively describe known uterine E-C coupling parameters and thereby inform future empirical investigations of physiological and pathophysiological mechanisms governing normal and dysfunctional labors. From published and unpublished data we construct mathematical models for fourteen ionic currents of USMCs: currents (L- and T-type), current, an hyperpolarization-activated current, three voltage-gated currents, two -activated current, -activated current, non-specific cation current, - exchanger, - pump and background current. The magnitudes and kinetics of each current system in a spindle shaped single cell with a specified surface area∶volume ratio is described by differential equations, in terms of maximal conductances, electrochemical gradient, voltage-dependent activation/inactivation gating variables and temporal changes in intracellular computed from known fluxes. These quantifications are validated by the reconstruction of the individual experimental ionic currents obtained under voltage-clamp. Phasic contraction is modeled in relation to the time constant of changing . This integrated model is validated by its reconstruction of the different USMC AP configurations (spikes, plateau and bursts of spikes), the change from bursting to plateau type AP produced by estradiol and of simultaneous experimental recordings of spontaneous AP, and phasic force. In summary, our advanced mathematical model provides a powerful tool to investigate the physiological ionic mechanisms underlying the genesis of uterine electrical E-C coupling of labor and parturition. This will furnish the evolution of descriptive and predictive quantitative models of myometrial electrogenesis at the whole cell and tissue levels. PMID:21559514

A plug flow reactor model of a vanadium redox flow battery considering the conductive current collectors

NASA Astrophysics Data System (ADS)

König, S.; Suriyah, M. R.; Leibfried, T.

2017-08-01

A lumped-parameter model for vanadium redox flow batteries, which use metallic current collectors, is extended into a one-dimensional model using the plug flow reactor principle. Thus, the commonly used simplification of a perfectly mixed cell is no longer required. The resistances of the cell components are derived in the in-plane and through-plane directions. The copper current collector is the only component with a significant in-plane conductance, which allows for a simplified electrical network. The division of a full-scale flow cell into 10 layers in the direction of fluid flow represents a reasonable compromise between computational effort and accuracy. Due to the variations in the state of charge and thus the open circuit voltage of the electrolyte, the currents in the individual layers vary considerably. Hence, there are situations, in which the first layer, directly at the electrolyte input, carries a multiple of the last layer's current. The conventional model overestimates the cell performance. In the worst-case scenario, the more accurate 20-layer model yields a discharge capacity 9.4% smaller than that computed with the conventional model. The conductive current collector effectively eliminates the high over-potentials in the last layers of the plug flow reactor models that have been reported previously.

The storm time ring current dynamics and response to CMEs and CIRs using Van Allen Probes observations and CIMI simulations

NASA Astrophysics Data System (ADS)

Mouikis, Christopher; Bingham, Samuel; Kistler, Lynn; Spence, Harlan; Gkioulidou, Matina

2017-04-01

The ring current responds differently to the different solar and interplanetary storm drivers such as coronal mass injections, (CME's), and co-rotating interaction regions (CIR's). Using Van Allen Probes observations, we develop an empirical ring current model of the ring current pressure, the pressure anisotropy and the current density development during the storm phases for both types of storm drivers and for all MLTs inside L 6. Delineating the differences in the ring current development between these two drivers will aid our understanding of the ring current dynamics. We find that during the storm main phase most of the ring current pressure in the pre-midnight inner magnetosphere is contributed by particles on open drift paths that cause the development of a strong partial ring current that causes most of the main phase Dst drop. These particles can reach as deep as L 2 and their pressure compares to the local magnetic field pressure as deep as L 3. During the recovery phase, if these particles are not lost at the magnetopause, will become trapped and will contribute to the symmetric ring current. However, the largest difference between the CME and CIR ring current responses during the storm main and early recovery phases is caused by how the 15 - 60 keV O+ responds to these drivers. This empirical model is compared to the results of CIMI simulations of a CMEs and a CIRs where the model input is comprised of the superposed epoch solar wind conditions of the storms that comprise the empirical model. Different inner magnetosphere boundary conditions are tested in order to match the empirical model results. Comparing the model and simulation results improves our understanding of the ring current dynamics as part of the highly coupled inner magnetosphere system. In addition, within the framework of this empirical model, the prediction of the EMIC wave generation linear theory is tested using the observed plasma parameters and comparing with the observations of EMIC waves.

The Effects of the Activities of Current Textbook and 5 E Model on the Attitude of the Students: Sample of "The Global Effects of Natural Resources Unit"

ERIC Educational Resources Information Center

Uzunoz, Abdulkadir

2011-01-01

This study aimed to determine the effects of the activities of current textbook and 5 E Model on the attitude of the students. This study is a research as an experimental model. For testing the effects of geography education supported by 5 E model and geography education based on activities of current textbook attitude of students, controlled…

The Earth's magnetosphere modeling and ISO standard

NASA Astrophysics Data System (ADS)

Alexeev, I.

The empirical model developed by Tsyganenko T96 is constructed by minimizing the rms deviation from the large magnetospheric data base Fairfield et al 1994 which contains Earth s magnetospheric magnetic field measurements accumulated during many years The applicability of the T96 model is limited mainly by quiet conditions in the solar wind along the Earth orbit But contrary to the internal planet s field the external magnetospheric magnetic field sources are much more time-dependent A reliable representation of the magnetic field is crucial in the framework of radiation belt modelling especially for disturbed conditions The last version of the Tsyganenko model has been constructed for a geomagnetic storm time interval This version based on the more accurate and physically consistent approach in which each source of the magnetic field would have its own relaxation timescale and a driving function based on an individual best fit combination of the solar wind and IMF parameters The same method has been used previously for paraboloid model construction This method is based on a priori information about the global magnetospheric current systems structure Each current system is included as a separate block module in the magnetospheric model As it was shown by the spacecraft magnetometer data there are three current systems which are the main contributors to the external magnetospheric magnetic field magnetopause currents ring current and tail current sheet Paraboloid model is based on an analytical solution of the Laplace

Upgrades, Current Capabilities and Near-Term Plans of the NASA ARC Mars Climate

NASA Technical Reports Server (NTRS)

Hollingsworth, J. L.; Kahre, Melinda April; Haberle, Robert M.; Schaeffer, James R.

2012-01-01

We describe and review recent upgrades to the ARC Mars climate modeling framework, in particular, with regards to physical parameterizations (i.e., testing, implementation, modularization and documentation); the current climate modeling capabilities; selected research topics regarding current/past climates; and then, our near-term plans related to the NASA ARC Mars general circulation modeling (GCM) project.

Modeling of switching regulator power stages with and without zero-inductor-current dwell time

NASA Technical Reports Server (NTRS)

Lee, F. C. Y.; Yu, Y.

1979-01-01

State-space techniques are employed to derive accurate models for the three basic switching converter power stages: buck, boost, and buck/boost operating with and without zero-inductor-current dwell time. A generalized procedure is developed which treats the continuous-inductor-current mode without dwell time as a special case of the discontinuous-current mode when the dwell time vanishes. Abrupt changes of system behavior, including a reduction of the system order when the dwell time appears, are shown both analytically and experimentally. Merits resulting from the present modeling technique in comparison with existing modeling techniques are illustrated.

Modeling dilute pyroclastic density currents on Earth and Mars

NASA Astrophysics Data System (ADS)

Clarke, A. B.; Brand, B. D.; De'Michieli Vitturi, M.

2013-12-01

The surface of Mars has been shaped extensively by volcanic activity, including explosive eruptions that may have been heavily influenced by water- or ice-magma interaction. However, the dynamics of associated pyroclastic density currents (PDCs) under Martian atmospheric conditions and controls on deposition and runout from such currents are poorly understood. This work combines numerical modeling with terrestrial field measurements to explore the dynamics of dilute PDC dynamics on Earth and Mars, especially as they relate to deposit characteristics. We employ two numerical approaches. Model (1) consists of simulation of axi-symmetric flow and sedimentation from a steady-state, depth-averaged density current. Equations for conservation of mass, momentum, and energy are solved simultaneously, and the effects of atmospheric entrainment, particle sedimentation, basal friction, temperature changes, and variations in current thickness and density are explored. The Rouse number and Brunt-Väisälä frequency are used to estimate the wavelength of internal gravity waves in a density-stratified current, which allows us to predict deposit dune wavelengths. The model predicts realistic runout distances and bedform wavelengths for several well-documented field cases on Earth. The model results also suggest that dilute PDCs on Mars would have runout distances up to three times that of equivalent currents on Earth and would produce longer-wavelength bedforms. In both cases results are heavily dependent on source conditions, grain-size characteristics, and entrainment and friction parameters. Model (2) relaxes several key simplifications, resulting in a fully 3D, multiphase, unsteady model that captures more details of propagation, including density stratification, and depositional processes. Using this more complex approach, we focus on the role of unsteady or pulsatory vent conditions typically associated with phreatomagmatic eruptions. Runout distances from Model (2) agree reasonably well with Model (1) results, but details of deposit distribution vary between the two models. Model (2) shows that the Earth case initially outpaces the Mars case due to faster propagation velocities associated with higher gravitational acceleration. However, the Mars currents ultimately out-distance the Earth currents due to slower particle settling rates, which also largely explain the longer wavelength bedforms. Model (2) also predicts a peak in the streamwise distribution of deposits farther from the source compared to equivalent results from Model (1), and produces more complex patterns of vertical distribution of particles in the moving current, which varies significantly in time and space. This combination of modeling and deposit data results in a powerful tool for testing hypotheses related to PDCs on Mars, potentially improving our capacity to interpret Martian features on both the outcrop (e.g., Home Plate) and regional scale (e.g., Apollinaris Mons).

Integrated urban systems model with multiple transportation supply agents.

DOT National Transportation Integrated Search

2012-10-01

This project demonstrates the feasibility of developing quantitative models that can forecast future networks under : current and alternative transportation planning processes. The current transportation planning process is modeled : based on empiric...

High Latitude Precipitating Energy Flux and Joule Heating During Geomagnetic Storms Determined from AMPERE Field-aligned Currents

NASA Astrophysics Data System (ADS)

Robinson, R. M.; Zanetti, L. J.; Anderson, B. J.; Korth, H.; Samara, M.; Michell, R.; Grubbs, G. A., II; Hampton, D. L.; Dropulic, A.

2016-12-01

A high latitude conductivity model based on field-aligned currents measured by the Active Magnetosphere and Planetary Electrodynamics Response Experiment (AMPERE) provides the means for complete specification of electric fields and currents at high latitudes. Based on coordinated measurements made by AMPERE and the Poker Flat Incoherent Scatter Radar, the model determines the most likely value of the ionospheric conductance from the direction, magnitude, and magnetic local time of the field-aligned current. A conductance model driven by field-aligned currents ensures spatial and temporal consistency between the calculated electrodynamic parameters. To validate the results, the Pedersen and Hall conductances were used to calculate the energy flux associated with the energetic particle precipitation. When integrated over the entire hemisphere, the total energy flux compares well with the Hemispheric Power Index derived from the OVATION-PRIME model. The conductances were also combined with the field-aligned currents to calculate the self-consistent electric field, which was then used to compute horizontal currents and Joule heating. The magnetic perturbations derived from the currents replicate most of the variations observed in ground-based magnetograms. The model was used to study high latitude particle precipitation, currents, and Joule heating for 24 magnetic storms. In most cases, the total energy input from precipitating particles and Joule heating exhibits a sharply-peaked maximum at the times of local minima in Dst, suggesting a close coupling between the ring current and the high latitude currents driven by the Region 2 field-aligned currents. The rapid increase and decrease of the high latitude energy deposition suggests an explosive transfer of energy from the magnetosphere to the ionosphere just prior to storm recovery.

Modeling of Metal-Ferroelectric-Semiconductor Field Effect Transistors

NASA Technical Reports Server (NTRS)

Duen Ho, Fat; Macleod, Todd C.

1998-01-01

The characteristics for a MFSFET (metal-ferroelectric-semiconductor field effect transistor) is very different than a conventional MOSFET and must be modeled differently. The drain current has a hysteresis shape with respect to the gate voltage. The position along the hysteresis curve is dependent on the last positive or negative polling of the ferroelectric material. The drain current also has a logarithmic decay after the last polling. A model has been developed to describe the MFSFET drain current for both gate voltage on and gate voltage off conditions. This model takes into account the hysteresis nature of the MFSFET and the time dependent decay. The model is based on the shape of the Fermi-Dirac function which has been modified to describe the MFSFET's drain current. This is different from the model proposed by Chen et. al. and that by Wu.