112 results on '"Al-Saad S"'
Search Results
2. Low Expression of miR-424-3p is Highly Correlated with Clinical Failure in Prostate Cancer
- Author
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Richardsen, E., Andersen, S., Al-Saad, S., Rakaee, M., Nordby, Y., Pedersen, M. I., Ness, N., Ingebriktsen, L. M., Fassina, A., Taskén, K. A., Mills, I. G., Donnem, T., Bremnes, R. M., and Busund, L. T.
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- 2019
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- View/download PDF
3. Co-expression of PDGF-B and VEGFR-3 strongly correlates with lymph node metastasis and poor survival in non-small-cell lung cancer
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Donnem, T., Al-Saad, S., Al-Shibli, K., Busund, L.-T., and Bremnes, R.M.
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- 2010
- Full Text
- View/download PDF
4. Gene Expression, Function and Ischemia Tolerance in Male and Female Rat Hearts After Sub-Toxic Levels of Angiotensin II
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Aljabri, M. B., Lund, T., Höper, A. C., Andreasen, T. V., Al-Saad, S., Lindal, S., and Ytrehus, K.
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- 2011
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5. Pregnancy protects against antiangiogenic and fibrogenic effects of angiotensin II in rat hearts
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Aljabri, M. B., Songstad, N. T., Lund, T., Serrano, M. C., Andreasen, T. V., Al-Saad, S., Lindal, S., Sitras, V., Acharya, G., and Ytrehus, K.
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- 2011
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6. A genome-wide linkage and association scan reveals novel loci for autism
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Weiss, L.A. Arking, D.E. Daly, M.J. Chakravarti, A. Brune, C.W. West, K. O'Connor, A. Hilton, G. Tomlinson, R.L. West, A.B. Cook Jr., E.H. Green, T. Chang, S.-C. Gabriel, S. Gates, C. Hanson, E.M. Kirby, A. Korn, J. Kuruvilla, F. McCarroll, S. Morrow, E.M. Neale, B. Purcell, S. Sasanfar, R. Sougnez, C. Stevens, C. Altshuler, D. Gusella, J. Santangelo, S.L. Sklar, P. Tanzi, R. Anney, R. Bailey, A.J. Baird, G. Battaglia, A. Berney, T. Betancur, C. Bölte, S. Bolton, P.F. Brian, J. Bryson, S.E. Buxbaum, J.D. Cabrito, I. Cai, G. Cantor, R.M. Coon, H. Conroy, J. Correia, C. Corsello, C. Crawford, E.L. Cuccaro, M.L. Dawson, G. De Jonge, M. Devlin, B. Duketis, E. Ennis, S. Estes, A. Farrar, P. Fombonne, E. Freitag, C.M. Gallagher, L. Geschwind, D.H. Gilbert, J. Gill, M. Gillberg, C. Goldberg, J. Green, A. Green, J. Guter, S.J. Haines, J.L. Hallmayer, J.F. Hus, V. Klauck, S.M. Korvatska, O. Lamb, J.A. Laskawiec, M. Leboyer, M. Le Couteur, A. Leventha, B.L. Liu, X.-Q. Lord, C. Lotspeich, L.J. Maestrini, E. Magalhaes, T. Mahoney, W. Mantoulan, C. McConachie, H. McDougle, C.J. McMahon, W.M. Marshall, C.R. Miller, J. Minshew, N.J. Monaco, A.P. Munson, J. Nurnberger Jr., J.I. Oliveira, G. Pagnamenta, A. Papanikolaou, K. Parr, J.R. Paterson, A.D. Pericak-Vance, M.A. Pickles, A. Pinto, D. Piven, J. Posey, D.J. Poustka, A. Poustka, F. Regan, R. Reichert, J. Renshaw, K. Roberts, W. Roge, B. Rutter, M.L. Salt, J. Schellenberg, G.D. Scherer, S.W. Sheffield, V. Sutcliffe, J.S. Szatmari, P. Tansey, K. Thompson, A.P. Tsiantis, J. Van Engeland, H. Vicente, A.M. Vieland, V.J. Volkmar, F. Wallace, S. Wassink, T.H. Wijsman, E.M. Wing, K. Wittemeyer, K. Yaspan, B.L. Zwaigenbaum, L. Yoo, S.-Y. Hill, R.S. Mukaddes, N.M. Balkhy, S. Gascon, G. Al-Saad, S. Hashmi, A. Ware, J. Joseph, R.M. LeClair, E. Partlow, J.N. Barry, B. Walsh, C.A. Pauls, D. Moilanen, I. Ebeling, H. Mattila, M.-L. Kuusikko, S. Jussila, K. Ignatius, J. Tolouei, A. Ghadami, M. Rostami, M. Hosseinipour, A. Valujerdi, M. Andresen, K. Winkloski, B. Haddad, S. Kunkel, L. Kohane, Z. Tran, T. Won Kong, S. O'Neil, S.B. Hundley, R. Holm, I. Peters, H. Baroni, E. Cangialose, A. Jackson, L. Albers, L. Becker, R. Bridgemohan, C. Friedman, S. Munir, K. Nazir, R. Palfrey, J. Schonwald, A. Simmons, E. Rappaport, L.A. Gauthier, J. Mottron, L. Joober, R. Rouleau, G. Rehnstrom, K. Von Wendt, L. Peltonen, L.
- Abstract
Although autism is a highly heritable neurodevelopmental disorder, attempts to identify specific susceptibility genes have thus far met with limited success. Genome-wide association studies using half a million or more markers, particularly those with very large sample sizes achieved through meta-analysis, have shown great success in mapping genes for other complex genetic traits. Consequently, we initiated a linkage and association mapping study using half a million genome-wide single nucleotide polymorphisms (SNPs) in a common set of 1,031 multiplex autism families (1,553 affected offspring). We identified regions of suggestive and significant linkage on chromosomes 6q27 and 20p13, respectively. Initial analysis did not yield genome-wide significant associations; however, genotyping of top hits in additional families revealed an SNP on chromosome 5p15 (between SEMA5A and TAS2R1) that was significantly associated with autism (P = 2 × 10-7). We also demonstrated that expression of SEMA5A is reduced in brains from autistic patients, further implicating SEMA5A as an autism susceptibility gene. The linkage regions reported here provide targets for rare variation screening whereas the discovery of a single novel association demonstrates the action of common variants.
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- 2009
7. Effects of some Growth Promoters on Blood Hematology and Serum Composition of Broiler Chickens
- Author
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Al-Saad, S., primary, Abbod, M., additional, and Yones, A. Abo, additional
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- 2014
- Full Text
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8. 1093 The Prognostic Value of Intraepithelial and Stromal Innate Immune System Cells in Non-Small Cell Lung Carcinoma
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Al-Shibli, K., primary, Al-Saad, S., additional, Donnem, T., additional, Persson, M., additional, Bremnes, R., additional, and Busund, L.T., additional
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- 2012
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9. Gene Expression, Function and Ischemia Tolerance in Male and Female Rat Hearts After Sub-Toxic Levels of Angiotensin II
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Aljabri, M. B., primary, Lund, T., additional, Höper, A. C., additional, Andreasen, T. V., additional, Al-Saad, S., additional, Lindal, S., additional, and Ytrehus, K., additional
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- 2010
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10. Expression of angiogenic genes in tumor and stroma as biomarkers of prognosis in NSCLC.
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Jantus, E., primary, Sanmartin, E., additional, Blasco, A., additional, Sirera, R., additional, Guijarro, R., additional, Donnem, T., additional, Al-Saad, S., additional, Busund, L., additional, Bremnes, R. M., additional, and Camps, C., additional
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- 2010
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11. The prognostic impact of NF-κB p105, vimentin, E-cadherin and Par6 expression in epithelial and stromal compartment in non-small-cell lung cancer
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Al-Saad, S, primary, Al-Shibli, K, additional, Donnem, T, additional, Persson, M, additional, Bremnes, R M, additional, and Busund, L-T, additional
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- 2008
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12. The prognostic value of intraepithelial and stromal innate immune system cells in non-small cell lung carcinoma
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Al-Shibli, K., primary, Al-Saad, S., additional, Donnem, T., additional, Persson, M., additional, Bremnes, R., additional, and Lill-Tove, B., additional
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- 2008
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- View/download PDF
13. Prognostic impact of angiogenic markers in tumor and stromal cells in non-small cell lung cancer (NSCLC)
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Donnem, T., primary, Al-Saad, S., additional, Al-Shibli, K., additional, Delghandi, M. P., additional, Persson, M., additional, Nilsen, M., additional, Busund, L. T., additional, and Bremnes, R. M., additional
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- 2007
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14. A rare cause of respiratory distress
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BARR, S., primary and AL-SAAD, S., additional
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- 2001
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15. Frequency of unemployment among epileptic patients in Tikrit, Iraq
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Al Saad, S. K., primary and Al Khayat, Al Khayat, additional
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- 2001
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16. Prognostic Impact of MiR-155 in Non-Small Cell Lung Cancer Evaluated by in Situ Hybridization
- Author
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Al-Saad Samer, Lonvik Kenneth, Sorbye Sveinung W, Berg Thomas, Eklo Katrine, Donnem Tom, Al-Shibli Khalid, Andersen Sigve, Stenvold Helge, Bremnes Roy M, and Busund Lill-Tove
- Subjects
Medicine - Abstract
Abstract Background In recent years, microRNAs (miRNAs) have been found to play an essential role in tumor development. In lung tumorigenesis, targets and pathways of miRNAs are being revealed, and further translational research in this field is warranted. MiR-155 is one of the miRNAs most consistently involved in various neoplastic diseases. We aimed to investigate the prognostic impact of the multifunctional miR-155 in non-small cell lung cancer (NSCLC) patients. Methods Tumor tissue samples from 335 resected stage I to IIIA NSCLC patients were obtained and tissue microarrays (TMAs) were constructed with four cores from each tumor specimen. In situ hybridization (ISH) was used to evaluate the expression of miR-155. Results There were 191 squamous cell carcinomas (SCCs), 95 adenocarcinomas (ACs), 31 large cell carcinomas and 18 bronchioalveolar carcinomas. MiR-155 expression did not have a significant prognostic impact in the total cohort (P = 0.43). In ACs, high miR-155 expression tended to a significant negative prognostic effect on survival in univariate analysis (P = 0.086) and was an independent prognostic factor in multivariate analysis (HR 1.87, CI 95% 1.01 - 3.48, P = 0.047). In SCC patients with lymph node metastasis, however, miR-155 had a positive prognostic impact on survival in univariate (P = 0.034) as well as in multivariate (HR 0.45, CI 95% 0.21-0.96, P = 0.039) analysis. Conclusions The prognostic impact of miR-155 depends on histological subtype and nodal status in NSCLC.
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- 2011
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17. A genome-wide linkage and association scan reveals novel loci for autism
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Zak Kohane, Jeremy Goldberg, Carine Mantoulan, Shaun Purcell, Jessica Brian, Magdalena Laskawiec, Christopher A. Walsh, Irma Moilanen, Ridha Joober, Peter Szatmari, Olena Korvatska, Kerim Munir, James F. Gusella, Rudolph E. Tanzi, David L. Pauls, Generoso G. Gascon, Christine Stevens, Linda Lotspeich, John I. Nurnberger, Ramzi Nazir, Jonathan Green, Brian L. Yaspan, Marion Leboyer, Ann P. Thompson, Shun-Chiao Chang, Carolyn Bridgemohan, Louise Gallagher, Jeff Munson, Michael Gill, Guiqing Cai, Fritz Poustka, Regina Regan, Aislyn Cangialose, Gerard D. Schellenberg, Christopher J. McDougle, Christina Corsello, Wendy Roberts, Thomas H. Wassink, Majid Ghadami, Ellen M. Hanson, Benjamin M. Neale, Stacey Gabriel, Lonnie Zwaigenbaum, John Tsiantis, Hanna Ebeling, Sabine M. Klauck, Elaine LeClair, Bernie Devlin, Steven A. McCarroll, Ashley O'Connor, Andrew Pickles, Emily L. Crawford, Katja Jussila, Helen McConachie, Christopher Gillberg, Brenda E. Barry, Lou Kunkel, Seung Yun Yoo, Jennifer N. Partlow, Stephanie Brewster O'Neil, Ingrid A. Holm, Judith Miller, Guy A. Rouleau, Val C. Sheffield, Catherine Lord, Judith S. Palfrey, Ellen M. Wijsman, Astrid M. Vicente, Azam Hosseinipour, Ronald E. Becker, James S. Sutcliffe, Fred R. Volkmar, Marja Leena Mattila, Katerina Papanikolaou, Jennifer Reichert, Edwin H. Cook, Pamela Sklar, Elena Maestrini, Hilary Coon, Sek Won Kong, Stephen A. Haddad, Todd Green, Gillian Baird, Andrew Kirby, Patrick Bolton, Robert Sean Hill, Eric M. Morrow, Tom Berney, Jonathan L. Haines, Maryam Valujerdi, Casey Gates, David J. Posey, Karola Rehnström, Alistair T. Pagnamenta, Christine M. Freitag, Eric Fombonne, Janice Ware, Christian R. Marshall, Janine A. Lamb, Lauren A. Weiss, Agatino Battaglia, Nancy J. Minshew, Roksana Sasanfar, Elizabeth Baroni, Maretha de Jonge, Lennart von Wendt, Gina Hilton, Dalila Pinto, Nahit Motavalli Mukaddes, Ala Tolouei, Catalina Betancur, Michael Rutter, Tram Tran, Eftichia Duketis, Laurent Mottron, Margaret A. Pericak-Vance, Kristen West, Joachim Hallmayer, Kirsty Wing, Kerstin Wittemeyer, Rachel J. Hundley, Herman van Engeland, Judith Conroy, Mark J. Daly, Asif Hashmi, Michael L. Cuccaro, Geraldine Dawson, Sanna Kuusikko, Richard Anney, Anthony P. Monaco, Brian Winkloski, Samira Al-Saad, Dan E. Arking, Veronica J. Vieland, Stephen W. Scherer, Soher Balkhy, Kara Andresen, Rebecca L. Tomlinson, Joseph D. Buxbaum, Aravinda Chakravarti, Xiao-Qing Liu, Lindsay Jackson, Jaakko Ignatius, Catarina Correia, Leonard Rappaport, Heather Peters, Julie Gauthier, John R. Gilbert, Jeremy R. Parr, Carrie Sougnez, Katherine E. Tansey, Bennett L. Leventha, Annemarie Poustka, Daniel H. Geschwind, Annette Estes, Leena Peltonen, Maryam Rostami, Jeff Salt, David Altshuler, Simon Wallace, Susan E. Bryson, William M. Mahoney, Katy Renshaw, Robert M. Joseph, Lisa H. Albers, Inês Cabrito, Sean Ennis, Vanessa Hus, Guiomar Oliveira, Ann Le Couteur, Joseph Piven, Sandra L. Friedman, Penny Farrar, Joshua M. Korn, Sven Bölte, Camille W. Brune, Esau Simmons, Susan L. Santangelo, Andrew D. Paterson, Rita M. Cantor, Andrew B. West, Finny G Kuruvilla, Tiago R. Magalhaes, Andrew Green, Alison Schonwald, Stephen J. Guter, Anthony J. Bailey, Bernadette Rogé, William M. McMahon, Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Johns Hopkins University (JHU), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Génétique de l'autisme = Genetics of Autism (NPS-01), Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Betancur, Catalina, University of Helsinki, Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), WEISS LA, ARKING DE, and GENE DISCOVERY PROJECT OF JOHNS HOPKINS & THE AUTISM CONSORTIUM, DALY MJ, CHAKRAVARTI A, BRUNE CW, WEST K, O'CONNOR A, HILTON G, TOMLINSON RL, WEST AB, COOK EH JR, CHAKRAVARTI A, WEISS LA, GREEN T, CHANG SC, GABRIEL S, GATES C, HANSON EM, KIRBY A, KORN J, KURUVILLA F, MCCARROLL S, MORROW EM, NEALE B, PURCELL S, SASANFAR R, SOUGNEZ C, STEVENS C, ALTSHULER D, GUSELLA J, SANTANGELO SL, SKLAR P, TANZI R, DALY MJ, ANNEY R, BAILEY AJ, BAIRD G, BATTAGLIA A, BERNEY T, BETANCUR C, BÖLTE S, BOLTON PF, BRIAN J, BRYSON SE, BUXBAUM JD, CABRITO I, CAI G, CANTOR RM, COOK EH JR, COON H, CONROY J, CORREIA C, CORSELLO C, CRAWFORD EL, CUCCARO ML, DAWSON G, DE JONGE M, DEVLIN B, DUKETIS E, ENNIS S, ESTES A, FARRAR P, FOMBONNE E, FREITAG CM, GALLAGHER L, GESCHWIND DH, GILBERT J, GILL M, GILLBERG C, GOLDBERG J, GREEN A, GREEN J, GUTER SJ, HAINES JL, HALLMAYER JF, HUS V, KLAUCK SM, KORVATSKA O, LAMB JA, LASKAWIEC M, LEBOYER M, COUTEUR AL, LEVENTHAL BL, LIU XQ, LORD C, LOTSPEICH LJ, MAESTRINI E, MAGALHAES T, MAHONEY W, MANTOULAN C, MCCONACHIE H, MCDOUGLE CJ, MCMAHON WM, MARSHALL CR, MILLER J, MINSHEW NJ, MONACO AP, MUNSON J, NURNBERGER JI JR, OLIVEIRA G, PAGNAMENTA A, PAPANIKOLAOU K, PARR JR, PATERSON AD, PERICAK-VANCE MA, PICKLES A, PINTO D, PIVEN J, POSEY DJ, POUSTKA A, POUSTKA F, REGAN R, REICHERT J, RENSHAW K, ROBERTS W, ROGE B, RUTTER ML, SALT J, SCHELLENBERG GD, SCHERER SW, SHEFFIELD V, SUTCLIFFE JS, SZATMARI P, TANSEY K, THOMPSON AP, TSIANTIS J, VAN ENGELAND H, VICENTE AM, VIELAND VJ, VOLKMAR F, WALLACE S, WASSINK TH, WIJSMAN EM, WING K, WITTEMEYER K, YASPAN BL, ZWAIGENBAUM L, MORROW EM, YOO SY, HILL RS, MUKADDES NM, BALKHY S, GASCON G, AL-SAAD S, HASHMI A, WARE J, JOSEPH RM, LECLAIR E, PARTLOW JN, BARRY B, WALSH CA, PAULS D, MOILANEN I, EBELING H, MATTILA ML, KUUSIKKO S, JUSSILA K, IGNATIUS J, SASANFAR R, TOLOUEI A, GHADAMI M, ROSTAMI M, HOSSEINIPOUR A, VALUJERDI M, SANTANGELO SL, ANDRESEN K, WINKLOSKI B, HADDAD S, KUNKEL L, KOHANE Z, TRAN T, KONG SW, O'NEIL SB, HANSON EM, HUNDLEY R, HOLM I, PETERS H, BARONI E, CANGIALOSE A, JACKSON L, ALBERS L, BECKER R, BRIDGEMOHAN C, FRIEDMAN S, MUNIR K, NAZIR R, PALFREY J, SCHONWALD A, SIMMONS E, RAPPAPORT LA, GAUTHIER J, MOTTRON L, JOOBER R, FOMBONNE E, ROULEAU G, REHNSTROM K, VON WENDT L, PELTONEN L.
- Subjects
Perturbação Autística ,Internationality ,Genetic Linkage ,Genome-wide association study ,MESH: Semaphorins ,Semaphorins ,[SDV.GEN] Life Sciences [q-bio]/Genetics ,0302 clinical medicine ,Neurodevelopmental disorder ,Heritability of autism ,MESH: Nerve Tissue Proteins ,Association mapping ,Genetics ,0303 health sciences ,Multidisciplinary ,MESH: Polymorphism, Single Nucleotide ,MESH: Genetic Predisposition to Disease ,Brain ,Chromosome Mapping ,Chromosomes, Human, Pair 5 ,MESH: Membrane Proteins ,MESH: Chromosomes, Human, Pair 5 ,MESH: Autistic Disorder ,MESH: Genetic Linkage ,Single-nucleotide polymorphism ,Nerve Tissue Proteins ,Biology ,Polymorphism, Single Nucleotide ,Article ,03 medical and health sciences ,MESH: Brain ,Genetic linkage ,medicine ,Humans ,Genetic Predisposition to Disease ,Autistic Disorder ,MESH: Sample Size ,030304 developmental biology ,Genetic association ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,MESH: Humans ,Membrane Proteins ,medicine.disease ,Sample Size ,Perturbações do Desenvolvimento Infantil e Saúde Mental ,MESH: Genome-Wide Association Study ,MESH: Internationality ,Autism ,MESH: Chromosome Mapping ,Predisposição Genética para Doença ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
Member of the Autism Genome Project Consortium: Astrid M. Vicente Although autism is a highly heritable neurodevelopmental disorder, attempts to identify specific susceptibility genes have thus far met with limited success. Genome-wide association studies using half a million or more markers, particularly those with very large sample sizes achieved through meta-analysis, have shown great success in mapping genes for other complex genetic traits. Consequently, we initiated a linkage and association mapping study using half a million genome-wide single nucleotide polymorphisms (SNPs) in a common set of 1,031 multiplex autism families (1,553 affected offspring). We identified regions of suggestive and significant linkage on chromosomes 6q27 and 20p13, respectively. Initial analysis did not yield genome-wide significant associations; however, genotyping of top hits in additional families revealed an SNP on chromosome 5p15 (between SEMA5A and TAS2R1) that was significantly associated with autism (P = 2 x 10(-7)). We also demonstrated that expression of SEMA5A is reduced in brains from autistic patients, further implicating SEMA5A as an autism susceptibility gene. The linkage regions reported here provide targets for rare variation screening whereas the discovery of a single novel association demonstrates the action of common variants.
- Published
- 2009
18. Outcomes of Second-Line Therapies in Patients With Metastatic de Novo and Treatment-Emergent Neuroendocrine Prostate Cancer: A Multi-Institutional Study.
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Eule CJ, Hu J, Al-Saad S, Collier K, Boland P, Lewis AR, McKay RR, Narayan V, Bosse D, Mortazavi A, Rose TL, Costello BA, Bryce AH, and Lam ET
- Subjects
- Male, Humans, Middle Aged, Aged, Retrospective Studies, Platinum, Prognosis, Prostate-Specific Antigen, Prostatic Neoplasms pathology
- Abstract
Background: De novo neuroendocrine prostate cancer (NEPC) and treatment-emergent neuroendocrine prostate cancer (T-NEPC) are rare diseases with a poor prognosis. After first-line platinum chemotherapy, there is no consensus on second-line treatments., Patients and Methods: Patients with a pathologic diagnosis of de novo NEPC or T-NEPC between 2000 and 2020 who received first-line platinum and any second-line systemic therapy were selected and standardized clinical data was collected via the electronic health record at each institution. The primary endpoint was overall survival (OS) based on second-line therapy. Secondary endpoints included objective response rate (ORR) to second-line therapy, PSA response, and time on treatment., Results: Fifty-eight patients (32 de novo NEPC, 26 T-NEPC) from 8 institutions were included. At de novo NEPC or T-NEPC diagnosis, the overall cohort had a median age of 65.0 years (IQR 59.2-70.3) and median PSA of 3.0 ng/dL (IQR 0.6-17.9). Following first-line platinum chemotherapy, 21 patients (36.2%) received platinum chemotherapy, 10 (17.2%) taxane monotherapy, 11 (19.0%) immunotherapy, 10 (17.2%) other chemotherapy, and 6 (16.2%) other systemic therapy. Among 41 evaluable patients, the ORR was 23.5%. The mOS after start of second-line therapy was 7.4 months (95% CI 6.1-11.9)., Conclusions: In this retrospective study, patients with de novo NEPC or T-NEPC who received second-line therapy were treated with wide variety of treatment regimens, reflecting the lack of consensus in this setting. Most patients received chemotherapy-based treatments. Overall prognosis was poor and ORR was low in the second line regardless of treatment choice., (Copyright © 2023 Elsevier Inc. All rights reserved.)
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- 2023
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19. Is laterality in breast Cancer still worth studying? Local experience in Bahrain.
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Al Saad S, Al Shenawi H, Almarabheh A, Al Shenawi N, Mohamed AI, and Yaghan R
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- Axilla pathology, Bahrain epidemiology, Cross-Sectional Studies, Female, Humans, Infant, Breast Neoplasms epidemiology, Breast Neoplasms genetics, Unilateral Breast Neoplasms
- Abstract
Background: Laterality in breast cancer means an increased frequency of left-sided breast cancers compared to right-sided breast cancers ranging between 1.05 and 1.26. It was first described in 1935 by Fellenberg, Sweden. The explanation of this phenomenon is not clear, but the association with other factors was found. This study aimed to explore the laterality of breast cancer in Bahrain as a model for Arabian countries. The association of laterality with the clinicopathological characteristics of the tumor was also analyzed to explore any applied clinical value., Methods: This is a cross-sectional, retrospective review of a particular ethnic population to study laterality of breast cancer versus a number of clinicopathological factors, as well as prognosis. The study analyzed 228 breast cancer patients treated in Arabian Gulf University facilities in Bahrain between 1999 and 2020. Three bilateral breast cancer and two malignant phyllodes patients were excluded. The following variables were analyzed: laterality ratio (Lt/Rt) and the association between laterality and clinicopathological characteristics (age at diagnosis, family history of malignancy, size of the tumor, tumor grade, histological type, hormonal receptors and HER2, axillary lymph node status, tumor stage, five-year survival rate, nulliparity, and multifocality)., Results: The laterality ratio (Lt/Rt) was 1.06 and was 0.97 for patients below 50 years of age, and 1.19 for patients 50 years of age and above. Analysis of our data showed a statistically significant association between laterality and tumor stage (p. value =0.025) at presentation, and laterality and family history of malignancy (p. value =0.052). Right-sided breast cancer was associated with a higher positive family history of malignancy and an increased ratio of locally advanced and metastatic disease, and a reduced 5-year survival in relation to size and stage. Left-sided breast cancer was associated with higher early tumor stage., Conclusion: This is the first study exploring the issue of breast cancer laterality in a defined Arabian population. The laterality ratio in this study was 1.06, which is consistent with the globally published range (1.05 to 1.26) and is increasing with increasing age. The association between breast cancer laterality, and the hormonal and HER2 is still not widely addressed in the available literature, although other clinicopathological characteristics were extensively analyzed., (© 2022. The Author(s).)
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- 2022
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20. Tertiary lymphoid structure score: a promising approach to refine the TNM staging in resected non-small cell lung cancer.
- Author
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Rakaee M, Kilvaer TK, Jamaly S, Berg T, Paulsen EE, Berglund M, Richardsen E, Andersen S, Al-Saad S, Poehl M, Pezzella F, Kwiatkowski DJ, Bremnes RM, Busund LR, and Donnem T
- Subjects
- Biomarkers, Tumor analysis, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, CD8 Antigens metabolism, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung metabolism, Cohort Studies, Follow-Up Studies, Gene Expression Regulation, Neoplastic, Humans, Immunohistochemistry, Keratins metabolism, Lung Neoplasms genetics, Lung Neoplasms metabolism, Lymphocytes, Tumor-Infiltrating metabolism, Lymphocytes, Tumor-Infiltrating pathology, Neoplasm Staging, Norway, Prognosis, Research Design, Tertiary Lymphoid Structures diagnosis, Tertiary Lymphoid Structures genetics, Tertiary Lymphoid Structures metabolism, Transcriptome, Tumor Microenvironment genetics, Tumor Microenvironment immunology, Carcinoma, Non-Small-Cell Lung pathology, Lung Neoplasms pathology, Tertiary Lymphoid Structures pathology
- Abstract
Background: We previously proposed an immune cell score (tumour node metastasis (TNM)-Immune cell score) classifier as an add-on to the existing TNM staging system for non-small cell lung cancer (NSCLC). Herein, we examined how to reliably assess a tertiary lymphoid structure (TLS) score to refine the TNM staging system., Methods: Using immunohistochemistry (CD8/cytokeratin), we quantified TLS in resected NSCLC whole-tumour tissue sections with three different scoring models on two independent collections (total of 553 patients). In a pilot setting, NanoString gene expression signatures were analysed for associations with TLS., Results: The number of TLSs significantly decreased in stage III patients as compared to stage II. The TLS score was an independent positive prognostic factor, regardless of the type of (semi)-quantification strategy used (four-scale semi-quantitative; absolute count of total TLS; subpopulation of mature TLS) or the endpoint (disease-specific survival; overall survival; time to recurrence). Subgroup analyses revealed a significant prognostic impact of TLS score within each pathological stage, patient cohort and main histological subtype. Targeted gene expression analysis showed that high TLS levels were associated with the expression of B cell and adaptive immunity genes/metagenes including tumour inflammation signature., Conclusions: The TLS score increases the prognostic power in each pathological stage and hence has the potential to refine TNM staging in resected NSCLC.
- Published
- 2021
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21. Isoflurane Increases Tolerance to Renal Ischemia Reperfusion Injury Compared to Propofol: An Experimental Study in Pigs.
- Author
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Roaldsen M, Ciosek T, Elin Richardsen, Al-Saad S, Hiten Rh Patel, and Aarsaether E
- Subjects
- Animals, Kidney, Swine, Anesthetics, Isoflurane adverse effects, Propofol, Reperfusion Injury etiology, Reperfusion Injury prevention & control
- Abstract
Purpose: To compare two clinically relevant anesthetic agents, i.e., isoflurane versus propofol with respect to protection of the kidney in a porcine renal ischemia reperfusion model. Materials and Methods: 14 hybrid pigs were randomized to anesthesia with either isoflurane or propofol prior to laparoscopic surgery. Following anesthesia, the left kidney hilum was clamped for 60 min and the right kidney removed. After 48 h of reperfusion, urine was sampled for analysis of neutrophil gelatinase-associated lipocalin (NGAL), albumin, and creatinine. The left kidney was harvested for histologic scoring of injury. Results: Histologic examination of renal injury revealed a statistically significant difference in favor of isoflurane on denuded basement membrane score (isoflurane group 1.58 ± 0.38 vs. propofol 2.42 ± 0.80, p = .026). Median (25-75 percentile) urinary albumin 3.4 g/L (2.25-7.48) vs. 8.9 g/L (3.73-13.8), ( p = .041) and urinary albumin/creatinine ratio 1.17 (0.76-1.82) vs. 1.76 (1.63-5.99), ( p = .026) were both significantly lower in the isoflurane group. Median (25-75 percentile) urinary NGAL was 167 (51-215) pg/ml in the isoflurane group compared with 362 (149-508) pg/ml in the propofol group ( p = .093). Conclusion: Isoflurane increases tolerance to renal ischemia reperfusion injury compared to propofol in this model.
- Published
- 2021
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22. Prognostic Value of Macrophage Phenotypes in Resectable Non-Small Cell Lung Cancer Assessed by Multiplex Immunohistochemistry.
- Author
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Rakaee M, Busund LR, Jamaly S, Paulsen EE, Richardsen E, Andersen S, Al-Saad S, Bremnes RM, Donnem T, and Kilvaer TK
- Subjects
- Biomarkers, Carcinoma, Non-Small-Cell Lung metabolism, Carcinoma, Non-Small-Cell Lung pathology, Cell Line, Tumor, Cohort Studies, Humans, Immunohistochemistry, Immunophenotyping, Lung Neoplasms metabolism, Lung Neoplasms pathology, Lymphatic Metastasis, Macrophages metabolism, Neoplasm Staging, Prognosis, Proportional Hazards Models, Survival Analysis, Tissue Array Analysis, Carcinoma, Non-Small-Cell Lung immunology, Carcinoma, Non-Small-Cell Lung mortality, Lung Neoplasms immunology, Lung Neoplasms mortality, Macrophages immunology
- Abstract
Macrophages are important inflammatory cells that regulate innate and adaptive immunity in cancer. Tumor-associated macrophages (TAMs) are thought to differentiate into two main phenotypes: proinflammatory M1 and protumorigenic M2. Currently, the prognostic impact of TAMs and their M1 and M2 phenotypes is unclear in non-small cell cancer (NSCLC). The present study was set up to evaluate an approach for identifying common M1 and M2 macrophage markers and explore their clinical significance in NSCLC. Using multiplex chromogenic immunohistochemistry, tissue microarrays of 553 primary tumors and 143 paired metastatic lymph nodes of NSCLC specimens were stained to detect various putative macrophage phenotypes: M1 (HLA-DR/CD68), M2 (CD163/CD68), M2 (CD204/CD68), and pan-macrophage (CD68/CK). Correlation analyses were performed to examine the relationship between TAMs and adaptive/innate immune infiltrates. HLA-DR
+ /CD68+ M1 TAM level significantly decreased from pathological stage I to III. In a compartment-specific correlation analysis, moderate to strong correlations were observed between both TAM subsets (M1 and M2) with CD3-, CD8-, CD4-, and CD45RO-positive immune cells. Survival analyses, in both stromal and intratumoral compartments, revealed that high levels of HLA-DR+ /CD68+ M1 (stroma, hazard ratio [HR] = 0.73, P = .03; intratumor, HR = 0.7, P = .04), CD204+ M2 (stroma, HR = 0.7, P = .02; intratumor, HR = 0.6, P = .004), and CD68 (stroma, HR = 0.69, P = .02; intratumor, HR = 0.73, P = .04) infiltration were independently associated with improved NSCLC-specific survival. In lymph nodes, the intratumoral level of HLA-DR+ /CD68+ M1 was an independent positive prognostic indicator (Cox model, HR = 0.38, P = .001). In conclusion, high levels of M1, CD204+ M2, and CD68 macrophages are independent prognosticators of prolonged survival in NSCLC., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2019
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23. MicroRNA 141 is associated to outcome and aggressive tumor characteristics in prostate cancer.
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Richardsen E, Andersen S, Melbø-Jørgensen C, Rakaee M, Ness N, Al-Saad S, Nordby Y, Pedersen MI, Dønnem T, Bremnes RM, and Busund LT
- Subjects
- Aged, Disease-Free Survival, Follow-Up Studies, Humans, Male, MicroRNAs genetics, Middle Aged, Prostatic Neoplasms genetics, RNA, Neoplasm genetics, Survival Rate, Gene Expression Regulation, Neoplastic, MicroRNAs biosynthesis, Prostatic Neoplasms metabolism, Prostatic Neoplasms mortality, RNA, Neoplasm biosynthesis, Up-Regulation
- Abstract
A large number of miRNAs influence key cellular processes involved in prostate tumorigenesis. Previous studies have demonstrated high expression of miRNAs in human prostate cancer (PC) tissues and cell lines. In previous microarray data, we found miR-141 to be upregulated and miR-145 to be downregulated in PC. In this large PC cohort (n = 535), we explored the prognostic role of miR-141 and miR-145 in PC. Tumor epithelial (TE) and tumor stromal (TS) areas were evaluated separately and combined (TE + TS). In situ hybridization was used to evaluate the expression of the miRNAs. We found that miR-141 (TE) correlated significantly to Gleason score ≥8 (p = 0.040) and large tumor size (≥20 mm, p = 0.025) and miR-141 (TE + TS) to Gleason grade (p = 0.001). MiR-145 correlated to pT-stage (p = 0.038), tumor size (p = 0.025), Gleason grade (p = 0.051) and PSA (p = 0.032). In univariate analysis miR-141 (TE + TS) was significantly associated with biochemical failure-free survival (BFFS, p = 0.007) and clinical failure-free survival (CFFS, p = 0.021). For miR-145, there were no differences between patients with high versus low expression. In multivariate analysis overexpression of miR-141 in tumor epithelium and tumor stroma was significantly associated with BFFS (HR = 1.07 CI95% 1.00-1.14, p = 0.007). To conclude, high expression of miR-141 appears associated with increased risk of biochemical PC recurrence.
- Published
- 2019
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24. Evaluation of tumor-infiltrating lymphocytes using routine H&E slides predicts patient survival in resected non-small cell lung cancer.
- Author
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Rakaee M, Kilvaer TK, Dalen SM, Richardsen E, Paulsen EE, Hald SM, Al-Saad S, Andersen S, Donnem T, Bremnes RM, and Busund LT
- Subjects
- Adenocarcinoma of Lung mortality, Adenocarcinoma of Lung pathology, Adenocarcinoma of Lung surgery, Aged, Carcinoma, Non-Small-Cell Lung mortality, Carcinoma, Non-Small-Cell Lung pathology, Carcinoma, Non-Small-Cell Lung surgery, Carcinoma, Squamous Cell mortality, Carcinoma, Squamous Cell pathology, Carcinoma, Squamous Cell surgery, Disease-Free Survival, Female, Humans, Lung Neoplasms mortality, Lung Neoplasms pathology, Lung Neoplasms surgery, Lymphocytes, Tumor-Infiltrating pathology, Male, Middle Aged, Neoplasm Staging, Observer Variation, Pneumonectomy, Predictive Value of Tests, Reproducibility of Results, Retrospective Studies, Risk Factors, Stromal Cells pathology, Time Factors, Adenocarcinoma of Lung immunology, Carcinoma, Non-Small-Cell Lung immunology, Carcinoma, Squamous Cell immunology, Coloring Agents, Eosine Yellowish-(YS), Hematoxylin, Lung Neoplasms immunology, Lymphocytes, Tumor-Infiltrating immunology, Staining and Labeling methods, Stromal Cells immunology
- Abstract
The presence of tumor-infiltrating lymphocytes (TILs) positively impacts the outcome of non-small cell lung cancer (NSCLC) patients. Most previous studies have assessed TILs using different immunohistochemical assays. The purpose of this study was to develop and validate a histopathological scoring model for the assessment of TILs in whole-tissue hematoxylin and eosin (H&E)-stained section slides of NSCLC patients and to evaluate the model in an immunoscore setting. Therefore, TIL was evaluated manually on H&E slides from 537 surgical specimens of primary resected stage I-III NSCLC patients. Using stromal TIL score as a stepwise discrete variable, increasing survival was seen with rising TIL level: disease-specific survival (DSS; P = .008), overall survival (P = .036) and disease-free survival (P = .006). Subgroup analysis revealed that high stromal TILs level was associated with superior DSS (P = .047) in patients with squamous cell carcinoma, but not in patients with adenocarcinoma. Multivariable analysis confirmed that high TIL levels independently predict improved prognosis for all endpoints in the overall cohort. In conclusion, high stromal TIL level is an independent favorable prognostic factor in stage I-III NSCLC patients. The comprehensive histological evaluation conducted in this study may be helpful in streamlining TIL quantification for routine clinical use in a future NSCLC immunoscore setting., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
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25. Progesterone Receptors in Prostate Cancer: Progesterone receptor B is the isoform associated with disease progression.
- Author
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Grindstad T, Richardsen E, Andersen S, Skjefstad K, Rakaee Khanehkenari M, Donnem T, Ness N, Nordby Y, Bremnes RM, Al-Saad S, and Busund LT
- Subjects
- Aged, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Multivariate Analysis, Protein Isoforms metabolism, Disease Progression, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, Receptors, Progesterone metabolism
- Abstract
The role of steroid hormones in carcinogenesis of the prostate is to some extent unraveled thorough the effect of androgen deprivation therapy on prostate cancer (PCa) progression. Other members of the steroid hormone family, such as progesterone, are also implicated in PCa, but progesterone's role remains undefined. This study aimed to examine the distribution of progesterone receptor isoforms (PGRA, PGRB) in PCa tissue and their association with clinical endpoints. This was conducted retrospectively by collecting radical prostatectomy specimens from 535 patients. Tissue was analyzed using tissue microarray, where representative tumor areas were carefully selected. Protein expression was evaluated through immunohistochemistry, in stromal and epithelial tissue. Associations between receptor expression and clinical data were considered using statistical survival analyses. Herein, we discovered a solely stromal PGRA- and a stromal and epithelial PGRB expression. Further, a high PGRB expression in tumor tissue was associated with an unfavorable prognosis in both univariate and multivariate analyses: Biochemical failure (HR: 2.0, 95% CI: 1.45-2.76, p < 0.001) and clinical failure (HR: 2.5, 95% CI: 1.29-4.85, p = 0.006). These findings are in agreement with our previous investigation on pan-PGR, indicating that the observed negative effect of PGR is represented by PGRB.
- Published
- 2018
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26. A gender specific improved survival related to stromal miR-143 and miR-145 expression in non-small cell lung cancer.
- Author
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Skjefstad K, Johannessen C, Grindstad T, Kilvaer T, Paulsen EE, Pedersen M, Donnem T, Andersen S, Bremnes R, Richardsen E, Al-Saad S, and Busund LT
- Subjects
- A549 Cells, Aged, Disease-Free Survival, Female, Humans, Lymph Nodes metabolism, Lymph Nodes pathology, Lymphatic Metastasis, Male, Middle Aged, Survival Rate, Carcinoma, Non-Small-Cell Lung metabolism, Carcinoma, Non-Small-Cell Lung mortality, Carcinoma, Non-Small-Cell Lung pathology, Gene Expression Regulation, Neoplastic, Lung Neoplasms metabolism, Lung Neoplasms mortality, Lung Neoplasms pathology, MicroRNAs biosynthesis, RNA, Neoplasm biosynthesis, Sex Characteristics
- Abstract
Micro RNAs (miRNA) are small non-coding RNAs that post-transcriptionally regulate gene expression. Dysregulation of miRNA cluster 143/145 has been reported in several malignancies, but their role in non-small cell lung cancer (NSCLC) remains elusive. This study investigates the prognostic impact of miR-143 and miR-145 in primary tumors and metastatic lymph nodes in NSCLC tissue. Tissue from 553 primary tumors and 143 matched metastatic lymph nodes were collected and tissue microarrays were constructed. In situ hybridization was used to evaluate miR-143 and miR-145 expression in tumor epithelial cells and stromal cells in the primary tumors and lymph nodes. In vivo data was supplemented with functional studies of cell lines in vitro to evaluate the role of miR-143 and miR-145 in NSCLC tumorigenesis. In our cohort, stromal miR-143 (S-miR-143) and miR-145 (S-miR-145) expression in primary tumor tissue were independent prognosticators of improved disease-specific survival (DSS) in female (S-miR-143, HR: 0.53, p = 0.019) and male patients (S-miR-145, HR: 0.58, p = 0.021), respectively. Interesting correlations between the miR cluster 143/145 and previously investigated steroid hormone receptors from the same cohort were identified, substantiating their gender dependent significance.
- Published
- 2018
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27. LAG-3 in Non-Small-cell Lung Cancer: Expression in Primary Tumors and Metastatic Lymph Nodes Is Associated With Improved Survival.
- Author
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Hald SM, Rakaee M, Martinez I, Richardsen E, Al-Saad S, Paulsen EE, Blix ES, Kilvaer T, Andersen S, Busund LT, Bremnes RM, and Donnem T
- Subjects
- Adult, Aged, Aged, 80 and over, Biomarkers, Tumor analysis, Carcinoma, Non-Small-Cell Lung mortality, Carcinoma, Non-Small-Cell Lung pathology, Disease-Free Survival, Female, Humans, Kaplan-Meier Estimate, Lung Neoplasms mortality, Lung Neoplasms pathology, Lymphatic Metastasis pathology, Lymphocytes, Tumor-Infiltrating pathology, Male, Middle Aged, Neoplasm Staging, Prognosis, Lymphocyte Activation Gene 3 Protein, Antigens, CD biosynthesis, Carcinoma, Non-Small-Cell Lung immunology, Lung Neoplasms immunology, Lymphatic Metastasis immunology, Lymphocytes, Tumor-Infiltrating immunology
- Abstract
Background: Lymphocyte activation gene-3 (LAG-3) is an immune checkpoint receptor and a putative therapeutic target in non-small-cell lung cancer (NSCLC). We explored the prognostic effect of LAG-3
+ tumor-infiltrating lymphocytes (TILs) in primary tumors and metastatic lymph nodes in NSCLC and its potential for inclusion in an immunoscore, supplementing the TNM classification., Materials and Methods: Primary tumor tissue from 553 stage I-IIIB NSCLC patients and 143 corresponding metastatic lymph nodes were collected. The expression of LAG-3 was evaluated by immunohistochemistry on tissue microarrays., Results: On univariate analysis, LAG-3+ TILs in the intraepithelial and stromal compartments of primary tumors and in the intraepithelial and extraepithelial compartments of metastatic lymph nodes were associated with improved disease-specific survival (DSS). On multivariate analysis, stromal LAG-3+ TILs were a significant independent predictor of improved DSS (hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.43-0.82; P = .002). Stromal LAG-3+ TILs did not have prognostic impact across all pathologic stages. In the metastatic lymph nodes, intraepithelial (HR, 0.61; 95% CI, 0.38-0.99; P = .049) and extraepithelial (HR, 0.54; 95% CI, 0.29-0.70; P < .001) LAG-3+ TILs were independently associated with favorable DSS., Conclusion: LAG-3+ TILs are an independent positive prognostic factor in stage I-IIIB NSCLC. LAG-3 in metastatic lymph nodes is a candidate marker for an immunoscore in NSCLC., (Copyright © 2017 Elsevier Inc. All rights reserved.)- Published
- 2018
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28. Transcription factor PAX6 as a novel prognostic factor and putative tumour suppressor in non-small cell lung cancer.
- Author
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Kiselev Y, Andersen S, Johannessen C, Fjukstad B, Standahl Olsen K, Stenvold H, Al-Saad S, Donnem T, Richardsen E, Bremnes RM, and Rasmussen Busund LT
- Subjects
- Adult, Aged, Aged, 80 and over, Carcinoma, Non-Small-Cell Lung pathology, Cell Line, Tumor, Disease-Free Survival, Female, Gene Expression Regulation, Neoplastic genetics, Gene Knockdown Techniques, Humans, Lymph Nodes pathology, Male, Middle Aged, Neoplasm Staging, Prognosis, Tumor Suppressor Proteins genetics, Biomarkers, Tumor genetics, Carcinoma, Non-Small-Cell Lung genetics, Cell Proliferation genetics, PAX6 Transcription Factor genetics
- Abstract
Lung cancer is the leading cause of cancer deaths. Novel predictive biomarkers are needed to improve treatment selection and more accurate prognostication. PAX6 is a transcription factor with a proposed tumour suppressor function. Immunohistochemical staining was performed on tissue microarrays from 335 non-small cell lung cancer (NSCLC) patients for PAX6. Multivariate analyses of clinico-pathological variables and disease-specific survival (DSS) was carried out, and phenotypic changes of two NSCLC cell lines with knockdown of PAX6 were characterized. While PAX6 expression was only associated with a trend of better disease-specific survival (DSS) (p = 0.10), the pN+ subgroup (N = 103) showed significant correlation between high PAX6 expression and longer DSS (p = 0.022). Median survival for pN + patients with high PAX6 expression was 127.4 months, versus 22.9 months for patients with low PAX6 expression. In NCI-H661 cells, knockdown of PAX6 strongly activated serum-stimulated migration. In NCI-H460 cells, PAX6 knockdown activated anchorage-independent growth. We did not observe any significant effect of PAX6 on proliferation in either of cell lines. Our findings strongly support the proposition of PAX6 as a valid and positive prognostic marker in NSCLC in node-positive patients. There is a need for further studies, which should provide mechanistical explanation for the role of PAX6 in NSCLC.
- Published
- 2018
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29. Corrigendum to "Prognostic relevance of estrogen receptor α, β and aromatase expression in non-small cell lung cancer" [Steroids 113 (2016) 5-13].
- Author
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Skjefstad K, Grindstad T, Rakaee Khanehkenari M, Richardsen E, Donnem T, Kilvaer T, Andersen S, Bremnes RM, Busund LT, and Al-Saad S
- Published
- 2018
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30. Evaluation of the proliferation marker Ki-67 in a large prostatectomy cohort.
- Author
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Richardsen E, Andersen S, Al-Saad S, Rakaee M, Nordby Y, Pedersen MI, Ness N, Grindstad T, Movik I, Dønnem T, Bremnes R, and Busund LT
- Subjects
- Cohort Studies, Humans, Male, Multivariate Analysis, Prognosis, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, Retrospective Studies, Cell Proliferation, Ki-67 Antigen metabolism, Prostatectomy, Prostatic Neoplasms surgery
- Abstract
The tumor proliferation index marker Ki-67 is strongly associated with tumor cell proliferation, growth and progression, and is widely used in routine clinicopathological investigation. Prostate cancer is a complex multifaceted and biologically heterogeneous disease, and overtreatment of localized, low volume indolent tumors, is evident. Here, we aimed to assess Ki-67 expression and related outcomes of 535 patients treated with radical prostatectomy. The percentage of tumor epithelial cells expressing Ki-67 was determined by immunohistochemical assay, both digital image analysis and visual scoring by light microscope were used for quantification. The association of Ki-67 and prostate cancer was evaluated, as well as its prognostic value. There was a positive correlation between high expression of Ki-67 and Gleason score > 7 (p < 0.001) as well as tumor size (≥ 20 mm, p = 0.03). In univariate analyses, a high expression of Ki-67 in tumor epithelium was significantly associated with biochemical failure (BF) (digital scoring, p = 0.014) and (visual scoring, p = 0.004). In the multivariate analyses, a high level of Ki-67 was an independent poor prognostic factor for biochemical failure-free survival (BFFS) (Visual scoring, Ki67, p = 0.012, HR:1.50, CI95% 1.10-2.06). In conclusion, high Ki-67 expression is an independent negative prognostic marker for biochemical failure. Our findings support the role of Ki-67 as a significant, poor prognostic factor for in prostate cancer outcome.
- Published
- 2017
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31. The impact of MET, IGF-1, IGF1R expression and EGFR mutations on survival of patients with non-small-cell lung cancer.
- Author
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Al-Saad S, Richardsen E, Kilvaer TK, Donnem T, Andersen S, Khanehkenari M, Bremnes RM, and Busund LT
- Subjects
- Aged, Carcinoma, Non-Small-Cell Lung diagnosis, Carcinoma, Non-Small-Cell Lung epidemiology, Carcinoma, Non-Small-Cell Lung pathology, Chromosomes, Human, Pair 7 genetics, Female, Gene Dosage, Gene Expression Regulation, Neoplastic, Humans, Immunohistochemistry, Lung metabolism, Lung Neoplasms diagnosis, Lung Neoplasms epidemiology, Lung Neoplasms pathology, Male, Middle Aged, Mutation, Prognosis, Receptor, IGF Type 1, Retrospective Studies, Survival Analysis, Carcinoma, Non-Small-Cell Lung genetics, ErbB Receptors genetics, Insulin-Like Growth Factor I genetics, Lung pathology, Lung Neoplasms genetics, Proto-Oncogene Proteins c-met genetics, Receptors, Somatomedin genetics
- Abstract
Introduction: To compare the efficacy of silver in situ hybridization (SISH) and immunohistochemistry (IHC) in detecting MET and IGF1R alterations and to investigate their prevalence and prognostic significance. A possible correlation between MET receptor expression, MET gene alterations and the two most frequent occurring EGFR gene mutations was also investigated., Materials and Methods: Stage I to IIIA tumors from 326 patients with NSCLC were immunohistochemically tested for protein expression of MET and IGF-1. Their cytoplasmic expression was compared with the gene copy number of the MET and IGF1Rgenes by SISH in paraffin-embedded, formalin-fixed material. Correlations were made with the immunohistochemical expression of two frequent EGFR mutations and clinicopathological variables. Univariate and multivariate survival analyses was used to evaluate the prognostic efficacy of the tested markers., Results: In univariate analyses, high cytoplasmic MET expression showed a significant negative prognostic effect in adenocarcinoma patients (p = 0.026). MET gene to chromosome 7 ratio was a significant positive prognostic marker (p = 0.005), probably only due to the highly negative prognostic significance of chromosome 7 polysomy (p = 0.002). High IGF1R gene copy number was a negative prognostic marker for all NSCLC patients (p = 0.037). In the multivariate analysis, polysomy of chromosome 7 in tumor cells correlated significantly and independently with a poor prognosis (p = 0.011). In patients with adenocarcinoma, a high cytoplasmic MET expression was an independent negative prognostic marker (p = 0.013). In males a high IGF1R gene copy number to chromosome 15 count ratio was significantly and independently correlated to a poor prognosis (p = 0.018)., Conclusion: MET protein expression provides superior prognostic information compared with SISH. Polysomy of chromosome 7 is an independent negative prognostic factor in NSCLC patients. This finding has an important implication while examining genes located on chromosome 7 by means of SISH. High IGF1R gene copy number to chromosome 15 count ratio is an independent predictor of inferior survival in male patients with primary NSCLC.
- Published
- 2017
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32. Glomangiopericytoma (Hemangiopericytoma) of the maxillary sinus and sinonasal tract.
- Author
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Al Saad S, Al Hadlaq R, and Al-Zaher N
- Subjects
- Adult, Female, Hemangiopericytoma pathology, Humans, Young Adult, Hemangiopericytoma diagnosis, Maxillary Sinus pathology
- Published
- 2017
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33. Assessing PDL-1 and PD-1 in Non-Small Cell Lung Cancer: A Novel Immunoscore Approach.
- Author
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Paulsen EE, Kilvaer TK, Khanehkenari MR, Al-Saad S, Hald SM, Andersen S, Richardsen E, Ness N, Busund LT, Bremnes RM, and Donnem T
- Subjects
- Adenocarcinoma immunology, Adenocarcinoma metabolism, Adenocarcinoma secondary, Adult, Aged, Aged, 80 and over, B7-H1 Antigen immunology, Biomarkers, Tumor metabolism, Carcinoma, Large Cell immunology, Carcinoma, Large Cell metabolism, Carcinoma, Large Cell secondary, Carcinoma, Non-Small-Cell Lung metabolism, Carcinoma, Non-Small-Cell Lung secondary, Carcinoma, Squamous Cell immunology, Carcinoma, Squamous Cell metabolism, Carcinoma, Squamous Cell secondary, Female, Follow-Up Studies, Humans, Immunoenzyme Techniques, Lung Neoplasms metabolism, Lung Neoplasms pathology, Lymphatic Metastasis, Male, Middle Aged, Neoplasm Staging, Prognosis, Programmed Cell Death 1 Receptor immunology, Retrospective Studies, Survival Rate, Tissue Array Analysis, Antigen-Antibody Complex immunology, B7-H1 Antigen metabolism, Carcinoma, Non-Small-Cell Lung immunology, Lung Neoplasms immunology, Lymphocytes, Tumor-Infiltrating immunology, Programmed Cell Death 1 Receptor metabolism
- Abstract
Introduction: Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) or its ligand, PD-L1, have gained momentum in the treatment of non-small cell lung cancer (NSCLC). However, their prognostic significance remains controversial. The present study evaluated the expression of PD-L1 and PD-1 and their potential role in an Immunoscore, supplementing the TNM classification of NSCLC., Materials and Methods: Tissue microarrays constructed from tumor tissue samples from 2 cohorts of a total of 536 patients (University Hospital of North Norway, n = 285; Nordland Hospital, n = 251) with primary resected stage I to IIIA NSCLC. PD-L1 and PD-1 were evaluated by immunohistochemistry in the primary tumor and metastatic lymph node tissue., Results: In univariate analysis, a high density of PD-L1
+ immune cells in the stromal compartment (S-PD-L1) and PD-1+ intraepithelial tumor infiltrating lymphocytes (T-PD-1) was associated with favorable disease-specific survival (DSS; S-PD-L1, P = .004; T-PD-1, P = .012), both limited to the squamous cell carcinoma histologic subgroup (S-PD-L1, P = .002; T-PD-1, P = .034). A combined low S-PD-L1 and T-PD-1 was associated with poor survival in all patients (DSS: hazard ratio [HR], 1.81; 95% confidence interval [CI], 1.37-2.40; P < .001) at both centers and for all pathologic stages. In multivariate analysis, S-PD-L1 and T-PD-1 were independent positive prognostic factors, and combined low scores remained an independent prognosticator for poor survival (DSS: HR, 1.72; 95% CI, 1.29-2.28; P < .001; disease-free survival, P = .001; overall survival, P = .005)., Conclusion: Our study identified S-PD-L1 and T-PD-1 as independent positive prognostic factors for NSCLC patients. Their combination added significant prognostic impact within each pathologic stage and hence are feasible to include in a TNM Immunoscore., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2017
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34. Erratum to: Prognostic impact of CXCL16 and CXCR6 in non-small cell lung cancer: combined high CXCL16 expression in tumor stroma and cancer cells yields improved survival.
- Author
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Hald SM, Kiselev Y, Al-Saad S, Richardsen E, Johannessen C, Eilertsen M, Kilvaer TK, Al-Shibli K, Andersen S, Busund LT, Bremnes RM, and Donnem T
- Published
- 2016
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35. Prognostic effect of intratumoral neutrophils across histological subtypes of non-small cell lung cancer.
- Author
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Rakaee M, Busund LT, Paulsen EE, Richardsen E, Al-Saad S, Andersen S, Donnem T, Bremnes RM, and Kilvaer TK
- Subjects
- Adenocarcinoma mortality, Adult, Aged, Aged, 80 and over, Antigens, CD metabolism, Antigens, CD34 metabolism, Biomarkers, Tumor metabolism, Carcinoma, Non-Small-Cell Lung immunology, Carcinoma, Non-Small-Cell Lung mortality, Carcinoma, Squamous Cell mortality, Cell Adhesion Molecules metabolism, Disease Progression, Epithelium metabolism, Female, GPI-Linked Proteins metabolism, Humans, Immunohistochemistry, Kaplan-Meier Estimate, Lung Neoplasms mortality, Lymphatic Metastasis, Male, Middle Aged, Neoplasm Staging, Neutrophils immunology, Prognosis, Retrospective Studies, Tissue Array Analysis, Adenocarcinoma pathology, Carcinoma, Non-Small-Cell Lung pathology, Carcinoma, Squamous Cell pathology, Lung Neoplasms pathology, Neutrophils metabolism
- Abstract
Recent data indicate that tumor-associated neutrophils (TANs) serve a dual role in tumor progression and regression. CD66b is a neutrophil marker and has been associated with patient outcome in various cancers. However, its clinical impact in non-small cell lung cancer (NSCLC) remains controversial. 536 NSCLC patients, of which 172 harbored lymph node metastases, were included in this study. Tissue microarrays were constructed and multiplexed immunohistochemistry of CD66b, CD34 and pan-keratin was performed to evaluate the localization and quantity of CD66b+ TANs. High intratumoral CD66b+ TANs density in squamous cell carcinoma (SCC) subgroup was an independent positive prognosticator for disease-specific survival (P = 0.038). In contrast, high intratumoral TANs density was an independent negative prognostic factor in the adenocarcinoma (ADC) subgroup (P= 0.032). Likewise, in ADC patients with lymph node metastases, high level of intratumoral TANs was associated with poor prognosis (P = 0.003). Stromal CD66b+ TANs were not associated with outcome of NSCLC patients. In conclusion, CD66b+ TANs show diverging prognostic effect in NSCLC patients according to histological subgroups. The presence of CD66b+ TANs could prove pivotal for development of an immunoscore in ADC NSCLC patients.
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- 2016
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36. Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior.
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Doan RN, Bae BI, Cubelos B, Chang C, Hossain AA, Al-Saad S, Mukaddes NM, Oner O, Al-Saffar M, Balkhy S, Gascon GG, Nieto M, and Walsh CA
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- Alleles, Animals, Cerebral Cortex metabolism, Gene Dosage, Genetic Variation, Genome, Human, Homeodomain Proteins genetics, Humans, Introns, Mice, Mice, Transgenic, Nuclear Proteins genetics, Quantitative Trait Loci, Regulatory Elements, Transcriptional, Repressor Proteins genetics, Transcription Factors, Autism Spectrum Disorder genetics, Cognition, Genetic Predisposition to Disease, Neurogenesis genetics, Point Mutation, Social Behavior
- Abstract
Comparative analyses have identified genomic regions potentially involved in human evolution but do not directly assess function. Human accelerated regions (HARs) represent conserved genomic loci with elevated divergence in humans. If some HARs regulate human-specific social and behavioral traits, then mutations would likely impact cognitive and social disorders. Strikingly, rare biallelic point mutations-identified by whole-genome and targeted "HAR-ome" sequencing-showed a significant excess in individuals with ASD whose parents share common ancestry compared to familial controls, suggesting a contribution in 5% of consanguineous ASD cases. Using chromatin interaction sequencing, massively parallel reporter assays (MPRA), and transgenic mice, we identified disease-linked, biallelic HAR mutations in active enhancers for CUX1, PTBP2, GPC4, CDKL5, and other genes implicated in neural function, ASD, or both. Our data provide genetic evidence that specific HARs are essential for normal development, consistent with suggestions that their evolutionary changes may have altered social and/or cognitive behavior. PAPERCLIP., (Copyright © 2016 Elsevier Inc. All rights reserved.)
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- 2016
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37. Estrogen receptors α and β and aromatase as independent predictors for prostate cancer outcome.
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Grindstad T, Skjefstad K, Andersen S, Ness N, Nordby Y, Al-Saad S, Fismen S, Donnem T, Khanehkenari MR, Busund LT, Bremnes RM, and Richardsen E
- Subjects
- Aged, Disease-Free Survival, Humans, Male, Middle Aged, Prostatectomy, Survival Rate, Aromatase metabolism, Biomarkers, Tumor metabolism, Estrogen Receptor alpha metabolism, Estrogen Receptor beta metabolism, Neoplasm Proteins metabolism, Prostatic Neoplasms metabolism, Prostatic Neoplasms mortality, Prostatic Neoplasms surgery
- Abstract
Androgens are considered important in normal prostate physiology and prostate cancer (PCa) pathogenesis. However, androgen-targeted treatment preventing PCa recurrence is still lacking. This indicates additional mediators contributing to cancer development. We sought to determine the prognostic significance of estrogen receptors, ERα and -β, and the aromatase enzyme in PCa. Tissue microarrays were created from 535 PCa patients treated with radical prostatectomy. Expression of ERα, ERβ and aromatase were evaluated using immunohistochemistry. Representative tumor epithelial (TE) and tumor stromal (TS) areas were investigated separately. Survival analyses were used to evaluate the markers correlation to PCa outcome. In univariate analyses, ERα in TS was associated with delayed time to clinical failure (CF) (p = 0.042) and PCa death (p = 0.019), while ERβ was associated with reduced time to biochemical failure (BF) (p = 0.002). Aromatase in TS and TE was associated with increased time to BF and CF respectively (p = 0.016, p = 0.046). Multivariate analyses supported these observations, indicating an independent prognostic impact of all markers. When stratifying the analysis according to different surgical centers the results were unchanged. In conclusion, significant prognostic roles of ERα, ERβ and aromatase were discovered in the in PCa specimens of our large multicenter cohort.
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- 2016
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38. Prognostic relevance of estrogen receptor α, β and aromatase expression in non-small cell lung cancer.
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Skjefstad K, Grindstad T, Khanehkenari MR, Richardsen E, Donnem T, Kilvaer T, Andersen S, Bremnes RM, Busund LT, and Al-Saad S
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- Adult, Aged, Aged, 80 and over, Aromatase metabolism, Breast Neoplasms metabolism, Breast Neoplasms pathology, Carcinoma, Non-Small-Cell Lung enzymology, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung physiopathology, Cell Line, Tumor, Estrogen Receptor alpha metabolism, Estrogen Receptor beta metabolism, Female, Humans, In Vitro Techniques, Lung Neoplasms enzymology, Lung Neoplasms genetics, Lung Neoplasms physiopathology, Male, Middle Aged, Prognosis, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, Aromatase genetics, Biomarkers, Tumor metabolism, Carcinoma, Non-Small-Cell Lung diagnosis, Estrogen Receptor alpha genetics, Estrogen Receptor beta genetics, Gene Expression Regulation, Neoplastic, Lung Neoplasms diagnosis
- Abstract
Sex steroids and their receptors are important in the fetal development of normal lung tissue. In addition emerging evidence reveals their significance in lung cancer pathogenesis. This encourages the exploitation of hormone receptors as treatment targets in lung cancer, as it has been successfully used in breast cancer. This study investigates the prognostic impact of estrogen receptor (ER) α and β and the aromatase (AR) enzyme in non-small cell lung cancer (NSCLC) patients. Tumor tissue from 335 NSCLC patients was collected and tissue microarrays (TMAs) were constructed. Immunohistochemical analyses were performed to evaluate the expression of ERα, ERβ and AR in the cytoplasme and nuclei of cells in the tumor epithelial and stromal compartment. By use of survival statistics we investigated the markers impact on disease-specific survival (DSS). Nuclear ERβ expression in tumor epithelial cells in female patients (HR 3.03; 95% CI 1.39-6.61) and tumor cell AR expression in all patients (HR 1.55; 95% CI 1.08-2.23) were significant negative prognostic markers of disease-specific survival in our cohort. High ERβ expression correlates with worse outcome in female patients. Further, patients with high AR expression had an unfavorable prognostic outcome compared with patients expressing low AR levels. These results emphasize the importance of sex steroids role in NSCLC, and, as anti-hormonal drugs are widely available, could lead to the development of novel palliative or even adjuvant treatment strategies in this patient population., (Copyright © 2016 Elsevier Inc. All rights reserved.)
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- 2016
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39. The presence of intraepithelial CD45RO+ cells in resected lymph nodes with metastases from NSCLC patients is an independent predictor of disease-specific survival.
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Kilvaer TK, Paulsen EE, Khanehkenari MR, Al-Saad S, Johansen RM, Al-Shibli K, Bremnes RM, Busund LT, and Donnem T
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- Adenocarcinoma immunology, Adult, Aged, Aged, 80 and over, Carcinoma, Squamous Cell immunology, Female, Humans, Lymph Node Excision, Lymphatic Metastasis, Male, Middle Aged, Neoplasm Staging, Prognosis, Survival Analysis, Carcinoma, Non-Small-Cell Lung immunology, Leukocyte Common Antigens metabolism, Lung Neoplasms immunology, Lymphocytes, Tumor-Infiltrating immunology, Tissue Array Analysis methods
- Abstract
Background: Operable non-small cell lung cancer (NSCLC) patients whose tumours have spread to regional or central lymph nodes at the time of diagnosis have dismal prognoses compared with those who have limited disease. The current TNM staging system for NSCLC poorly distinguishes patients with lymph-node metastases who will succumb to, and those who will eventually be cured from, their disease. This novel study: (1) evaluates the presence of different subsets of intraepithelial tumour-infiltrating lymphocytes (TILs) in lymph nodes with metastases from NSCLC patients; (2) explores the impact of intraepithelial TILs in lymph nodes on survival; (3) correlates their presence with both intraepithelial and stromal TILs in their corresponding primary tumours., Methods: Metastatic lymph-node tissue from 143N+ NSCLC patients was collected and tissue microarrays were constructed. Immunohistochemistry was used to evaluate the presence of intraepithelial CD3+, CD4+, CD8+, CD20+ and CD45RO+ TILs and their impact on survival., Results: A high level of intraepithelial CD45RO+ TILs in lymph-node metastases from N+ NSCLC patients was an independent positive prognostic factor for disease-specific survival in all patients (HR=0.58, P=0.029) and in squamous cell carcinoma (HR=0.31, P=0.006), but not in adenocarcinoma patients., Conclusions: The presence of intraepithelial CD45RO+ cells in lymph-node metastases from N+ NSCLC patients predicts favourable disease-specific survival and outperforms the established TNM staging system in the SCC subgroup.
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- 2016
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40. Keratin 34betaE12/keratin7 expression is a prognostic factor of cancer-specific and overall survival in patients with early stage non-small cell lung cancer.
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Pøhl M, Olsen KE, Holst R, Donnem T, Busund LT, Bremnes RM, Al-Saad S, Andersen S, Richardsen E, Ditzel HJ, and Hansen O
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- Adult, Aged, Aged, 80 and over, Carcinoma, Non-Small-Cell Lung mortality, Carcinoma, Non-Small-Cell Lung pathology, Carcinoma, Non-Small-Cell Lung surgery, Cohort Studies, Female, Humans, Immunohistochemistry, Kaplan-Meier Estimate, Keratins genetics, Lung Neoplasms mortality, Lung Neoplasms pathology, Lung Neoplasms surgery, Male, Middle Aged, Reproducibility of Results, Retrospective Studies, Survival Rate, Biomarkers, Tumor metabolism, Carcinoma, Non-Small-Cell Lung metabolism, Keratin-7 metabolism, Keratins metabolism, Lung Neoplasms metabolism
- Abstract
Background: Carcinomas and their metastases often retain the keratin patterns of their epithelial origin, and are therefore useful as lineage-specific markers in diagnostic pathology. Recently, it has become clear that intermediate filaments composed by keratins play a role in modulation of cell proliferation, migration, and possibly cancer invasion, factors impacting prognosis in early stage non-small cell lung cancer (NSCLC)., Material and Methods: Tumor tissue from a retrospective Danish cohort of 177 patients with completely resected NSCLC, stage I-IIIA tumors, were analyzed for keratin 7 (K7) and keratin 34βE12 expression by immunohistochemistry and validated in a comparable independent Norwegian cohort of 276 stage I-IIIA NSCLC patients., Results: Based on keratin 34βE12/K7 expression, three subgroups with significantly different median cancer-specific survival rates were identified (34βE12+/K7+, 168 months vs. 34βE12+/K7+, 73 months vs. 34βE12-/K7+, 30 months; p = 0.0004). In multivariate analysis, stage II-IIIA (HR 2.9), 34βE12+/K7+ (HR 1.90) and 34βE12-/K7+ (HR 3.7), were prognostic factors of poor cancer-specific survival (CSS) (p < 0.001). Validation in the Norwegian cohort confirmed that stage II-IIIA (HR 2.3), 34βE12+/K7+ (HR 1.6), and 34βE12-/K7+ (HR 2.0) were prognostic factors of poor CSS (p < 0.05). Multivariate Cox proportional-hazard analysis demonstrated that 34βE12+/K7 + and 34βE12+/K7 + status was significantly associated with poor overall survival (p < 0.05)., Conclusion: Keratin 34βE12/K7 expression is a prognostic parameter in resected early stage NSCLC that allows identification of high-risk NSCLC patients with poor cancer-specific and overall survival.
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- 2016
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41. CD45RO(+) Memory T Lymphocytes--a Candidate Marker for TNM-Immunoscore in Squamous Non-Small Cell Lung Cancer.
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Paulsen EE, Kilvaer T, Khanehkenari MR, Maurseth RJ, Al-Saad S, Hald SM, Al-Shibli K, Andersen S, Richardsen E, Busund LT, Bremnes R, and Donnem T
- Subjects
- Adult, Aged, Aged, 80 and over, Carcinoma, Non-Small-Cell Lung diagnosis, Carcinoma, Squamous Cell diagnosis, Cohort Studies, Female, Follow-Up Studies, Humans, Lung Neoplasms diagnosis, Lymphocytes, Tumor-Infiltrating pathology, Male, Middle Aged, Neoplasm Staging methods, Retrospective Studies, Biomarkers, Tumor metabolism, Carcinoma, Non-Small-Cell Lung metabolism, Carcinoma, Squamous Cell metabolism, Leukocyte Common Antigens metabolism, Lung Neoplasms metabolism, Lymphocytes, Tumor-Infiltrating metabolism
- Abstract
Tumor-infiltrating lymphocytes (TILs) are vital in limiting cancer progression and may supplement the TNM classification. CD45RO(+) memory TILs show major prognostic impact in various malignancies but have not been extensively explored in non-small cell lung cancer (NSCLC). In this study, we aimed to evaluate their potential in a NSCLC TNM-Immunoscore. Tissue microarrays were constructed from tumor tissue samples from two cohorts including in total 536 patients (University Hospital of North Norway, n = 285; Nordland Hospital, n = 251) with primary resected stage I to IIIA NSCLC. The density of CD45RO(+) and CD8(+) TILs in tumor epithelial and stromal compartments of the tumors was evaluated by immunohistochemistry. In univariate analyses, intraepithelial CD45RO(+) TIL density (T-CD45RO) was a significant prognostic factor for disease-specific survival (P = .007), limited to the squamous cell carcinoma (SCC) histology subgroup (P < .001), where it was significant in both cohorts (University Hospital of North Norway, P = .003; Nordland Hospital, P = .022). Combining T-CD45RO and stromal CD8(+) TIL density (S-CD8) increased the prognostic impact in SCC (P < .001) and showed a significant impact within all pathological stages (I, P = .025; II, P < .001; III, P = .001). In the multivariate analysis, T-CD45RO was an independent positive prognostic factor for SCC (hazard ratio 2.65, 95% confidence interval 1.64-4.28, P < .001), and in combination with S-CD8, the prognostic impact increased vastly (high + high versus low + low: hazard ratio 6.50, 95% confidence interval 3.54-11.91, P < .001). In conclusion, T-CD45RO was an independent prognostic factor for SCC NSCLC. When combined with S-CD8, the prognostic impact increased and was significant within each pathological stage. We propose CD45RO as a candidate marker for TNM-Immunoscore in SCC NSCLC., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2015
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42. Stromal expression of VEGF-A and VEGFR-2 in prostate tissue is associated with biochemical and clinical recurrence after radical prostatectomy.
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Nordby Y, Andersen S, Richardsen E, Ness N, Al-Saad S, Melbø-Jørgensen C, Patel HR, Dønnem T, Busund LT, and Bremnes RM
- Subjects
- Aged, Biomarkers, Tumor metabolism, Disease-Free Survival, Humans, Male, Middle Aged, Neoplasm Recurrence, Local pathology, Neovascularization, Pathologic metabolism, Prognosis, Prostate pathology, Prostate surgery, Prostatic Neoplasms pathology, Prostatic Neoplasms surgery, Stromal Cells metabolism, Stromal Cells pathology, Vascular Endothelial Growth Factor C metabolism, Vascular Endothelial Growth Factor Receptor-3 metabolism, Neoplasm Recurrence, Local metabolism, Prostate metabolism, Prostatectomy, Prostatic Neoplasms metabolism, Vascular Endothelial Growth Factor A metabolism, Vascular Endothelial Growth Factor Receptor-2 metabolism
- Abstract
Background: There is probably significant overtreatment of patients with prostate cancer due to a lack of sufficient diagnostic tools to predict aggressive disease. Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are potent mediators of angiogenesis and tumor proliferation, but have been examined to a limited extent in large prostate cancer studies. Meanwhile, recent promising results on VEGFR-2 inhibition have highlighted their importance, leading to the need for further investigations regarding their expression and prognostic impact., Design: Using tissue microarray and immunohistochemistry, the expression of VEGFs (VEGF-A and VEGF-C) and their receptors (VEGFR-2 and VEGFR-3) were measured in neoplastic tissue and corresponding stroma from radical prostatectomy specimens in 535 Norwegian patients. Their expression was evaluated semiquantatively and associations with event-free survival were calculated., Results: High expression of VEGFR-2 in either stroma or epithelium was independently associated with a higher incidence of prostate cancer relapse (HR = 4.56, P = 0.038). A high combined expression of either VEGF-A, VEGFR-2 or both in stroma was independently associated with a higher incidence of biochemical failure (HR = 1.77, P = 0.011)., Conclusions: This large study highlights the prognostic importance of VEGF-A and VEGFR-2 stromal expression. Analyses of these biomarkers may help distinguish which patients will benefit from radical treatment. Together with previous studies showing efficiency of targeting VEGFR-2 in prostate cancer, this study highlights its potential as a target for therapy, and may aid in future selection of prostate cancer patients for novel anti-angiogenic treatment., (© 2015 Wiley Periodicals, Inc.)
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- 2015
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43. The prognostic significance of CXCL16 and its receptor C-X-C chemokine receptor 6 in prostate cancer.
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Richardsen E, Ness N, Melbø-Jørgensen C, Johannesen C, Grindstad T, Nordbakken C, Al-Saad S, Andersen S, Dønnem T, Nordby Y, Bremnes RM, and Busund LT
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- Adult, Aged, Aged, 80 and over, Cell Line, Tumor, Chemokine CXCL16, Humans, Immunohistochemistry methods, Male, Middle Aged, Prognosis, Receptors, CXCR6, Cell Proliferation physiology, Chemokines, CXC metabolism, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, Receptors, Chemokine metabolism, Receptors, Scavenger metabolism, Receptors, Virus metabolism
- Abstract
The chemokine CXCL16 and its receptor, C-X-C chemokine receptor (CXCR6), affect tumor progression through different pathways, including leukocyte recruitment and function, cellular senescence, tumor cell proliferation, survival, invasion, and metastasis. We examined how the expression of CXCL16/CXCR6 in prostate cancer (PC) was related to clinicopathological features and activation of inflammatory cells. Tissue microarrays from 535 patients were constructed from tumor epithelial and tumor stromal areas of primary PC. Immunohistochemistry was used to evaluate the expression of CXCL16/CXCR6, CD3(+) T cells (CD4(+), CD8(+)), and CD20(+) B cells. Survival analyses were used to evaluate their prognostic impact. Expression of CXCL16 in PC cell lines (DU145 and PC3) and the effect on proliferation and migration were examined. High expression levels of CXCL16 [hazard ratio (HR), 2.52; 95% CI, 1.12-5.68; P = 0.026] and CXCR6 (HR, 2.29; 95% CI, 1.10-4.82; P = 0.028) were each independent predictors for clinical failure. High co-expression of CXCL16 and CXCR6 (HR, 5.1; 95% CI, 1-15.9; P = 0.05) was associated with negative prognostic factors, such as Gleason grade 4 + 3, Gleason score ≥7, vascular infiltration, and positive surgical margins. As a conclusion, high protein expression of CXCL16 and high protein co-expression of CXCL16/CXCR6 in PC were independent predictors for a worse clinical outcome., (Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
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- 2015
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44. Cancer Associated Fibroblasts in Stage I-IIIA NSCLC: Prognostic Impact and Their Correlations with Tumor Molecular Markers.
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Kilvaer TK, Khanehkenari MR, Hellevik T, Al-Saad S, Paulsen EE, Bremnes RM, Busund LT, Donnem T, and Martinez IZ
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- Actins metabolism, Aged, Carcinoma, Non-Small-Cell Lung metabolism, Cohort Studies, Disease-Free Survival, Female, Fibroblasts metabolism, Humans, Immunohistochemistry, Lung Neoplasms metabolism, Male, Middle Aged, Neoplasm Staging, Observer Variation, Prognosis, Protein Tyrosine Phosphatase, Non-Receptor Type 13 metabolism, Statistics, Nonparametric, Stromal Cells metabolism, Stromal Cells pathology, Tissue Array Analysis, Biomarkers, Tumor metabolism, Carcinoma, Non-Small-Cell Lung pathology, Fibroblasts pathology, Lung Neoplasms pathology
- Abstract
Background: Cancer Associated Fibroblasts (CAFs) are thought to regulate tumor growth and metastasis. Fibroblast Activating Protein 1 (FAP-1) is a marker for fibroblast activation and by many recognized as the main marker of CAFs. Alpha Smooth Muscle Actin (α-SMA) is a general myofibroblast marker, and can be used to identify CAFs. This study investigates the prognostic impact of FAP-1 and α-SMA in non-small cell lung cancer (NSCLC) patients and correlates their expression to 105 proteins investigated in the same cohort., Methods: Tumor specimens from 536 NSCLC patients were obtained and tissue micro-arrays were constructed. Immunohistochemistry was used to evaluate the expression of FAP-1 and α-SMA and explore their impact on survival and association with other tumor molecular markers in NSCLC patients., Results: High expression of FAP-1, but not α-SMA, in squamous cell carcinoma (SCC, P = 0.043, HR = 0.63 95% CI 0.40-0.99) was significantly associated with increased disease-specific survival. FAP-1 and α-SMA were not significantly correlated to each other. Analyses of FAP-1 and α-SMA associated with other tumor-related proteins revealed histotype-specific correlation patterns., Conclusion: The presence of FAP-1 expressing CAFs is an indicator of positive outcome for NSCLC-SCC patients. In addition, correlation analyses suggest FAP-1 and α-SMA to label different subsets of fibroblasts and their associations with other tumor-related proteins diverge according to histological subtype.
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- 2015
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45. Stromal CD8+ T-cell Density—A Promising Supplement to TNM Staging in Non-Small Cell Lung Cancer.
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Donnem T, Hald SM, Paulsen EE, Richardsen E, Al-Saad S, Kilvaer TK, Brustugun OT, Helland A, Lund-Iversen M, Poehl M, Olsen KE, Ditzel HJ, Hansen O, Al-Shibli K, Kiselev Y, Sandanger TM, Andersen S, Pezzella F, Bremnes RM, and Busund LT
- Subjects
- Aged, Biomarkers, Tumor immunology, CD8-Positive T-Lymphocytes pathology, Carcinoma, Non-Small-Cell Lung pathology, Carcinoma, Non-Small-Cell Lung surgery, Disease-Free Survival, Female, Humans, Lymphocytes, Tumor-Infiltrating pathology, Male, Middle Aged, Neoplasm Metastasis, Neoplasm Staging, Prognosis, Stromal Cells pathology, CD8-Positive T-Lymphocytes immunology, Carcinoma, Non-Small-Cell Lung immunology, Cell Count, Lymphocytes, Tumor-Infiltrating immunology, Stromal Cells immunology
- Abstract
Purpose: Immunoscore is a prognostic tool defined to quantify in situ immune cell infiltrates, which appears to be superior to the tumor-node-metastasis (TNM) classification in colorectal cancer. In non-small cell lung cancer (NSCLC), no immunoscore has been established, but in situ tumor immunology is recognized as highly important. We have previously evaluated the prognostic impact of several immunological markers in NSCLC, yielding the density of stromal CD8(+) tumor-infiltrating lymphocytes (TIL) as the most promising candidate. Hence, we validate the impact of stromal CD8(+) TIL density as an immunoscore in NSCLC., Experimental Design: The prognostic impact of stromal CD8(+) TILs was evaluated in four different cohorts from Norway and Denmark consisting of 797 stage I-IIIA NSCLC patients. The Tromso cohort (n = 155) was used as training set, and the results were further validated in the cohorts from Bodo (n = 169), Oslo (n = 295), and Denmark (n = 178). Tissue microarrays and clinical routine CD8 staining were used for all cohorts., Results: Stromal CD8(+) TIL density was an independent prognostic factor in the total material (n = 797) regardless of the endpoint: disease-free survival (P < 0.001), disease-specific survival (P < 0.001), or overall survival (P < 0.001). Subgroup analyses revealed significant prognostic impact of stromal CD8(+) TIL density within each pathologic stage (pStage). In multivariate analysis, stromal CD8(+) TIL density and pStage were independent prognostic variables., Conclusions: Stromal CD8(+) TIL density has independent prognostic impact in resected NSCLC, adds prognostic impact within each pStage, and is a good candidate marker for establishing a TNM-Immunoscore., (©2015 American Association for Cancer Research.)
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- 2015
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46. The prognostic role of progesterone receptor expression in non-small cell lung cancer patients: Gender-related impacts and correlation with disease-specific survival.
- Author
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Skjefstad K, Richardsen E, Donnem T, Andersen S, Kiselev Y, Grindstad T, Hald SM, Al-Shibli K, Bremnes RM, Busund LT, and Al-Saad S
- Subjects
- Adult, Aged, Disease-Free Survival, Female, Humans, Male, Middle Aged, Neoplasm Staging, Retrospective Studies, Stromal Cells metabolism, Stromal Cells pathology, Survival Rate, Carcinoma, Non-Small-Cell Lung metabolism, Carcinoma, Non-Small-Cell Lung mortality, Carcinoma, Non-Small-Cell Lung pathology, Gene Expression Regulation, Neoplastic, Lung Neoplasms metabolism, Lung Neoplasms mortality, Lung Neoplasms pathology, Neoplasm Proteins biosynthesis, Receptors, Progesterone biosynthesis, Sex Characteristics
- Abstract
Purpose: Progesterone has been shown to impact the development of hormone-sensitive cancers, such as breast and ovarian cancers. Emerging evidence has revealed a possible role of progesterone in the tumorigenesis of other cancers, including lung cancer. Herein, we aimed to elucidate the prevalence and prognostic significance of progesterone receptor (PR) expression in non-small cell lung cancer (NSCLC) tissue., Experimental: Tumor tissue samples were collected from our patient cohort consisting of 335 NSCLC patients with stage I-IIIA disease. Tissue microarrays (TMAs) were constructed, and immunohistochemical (IHC) analyses were performed to evaluate the PR expression in the tumor epithelial and stromal compartments., Results: In a univariate analysis, positive PR expression in the stromal tumor compartment (P=0.005) was significantly and independently associated with a favorable outcome for both genders. Furthermore, positive PR expression in tumor epithelial cells (P=0.003) correlated with a poor prognosis for female patients. In a multivariate analysis, positive PR expression in the tumor stroma (P=0.007) was an independent prognostic factor for improved disease-specific survival (DSS). Positive PR expression in tumor epithelial cells emerged as an independent prognostic factor in female patients (P=0.001) for poor DSS., Conclusions: We show that PR expression in tumor-surrounding stromal cells is associated with improved DSS for both male and female patients. Additionally, we reveal that positive PR expression in tumor epithelial cells is an independent, unfavorable prognosticator for DSS in female patients, making PR expression a potential marker for prognostic stratification in NSCLC., (Copyright © 2015 Elsevier Inc. All rights reserved.)
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- 2015
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47. Prognostic impact of CXCL16 and CXCR6 in non-small cell lung cancer: combined high CXCL16 expression in tumor stroma and cancer cells yields improved survival.
- Author
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Hald SM, Kiselev Y, Al-Saad S, Richardsen E, Johannessen C, Eilertsen M, Kilvaer TK, Al-Shibli K, Andersen S, Busund LT, Bremnes RM, and Donnem T
- Subjects
- Adult, Aged, Aged, 80 and over, Biomarkers, Tumor genetics, Carcinoma, Non-Small-Cell Lung pathology, Cell Line, Tumor, Cell Proliferation genetics, Chemokine CXCL16, Chemokines, CXC genetics, Female, Gene Expression Regulation, Neoplastic, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Neoplasm Staging, Neovascularization, Pathologic genetics, Neovascularization, Pathologic pathology, Prognosis, Receptors, CXCR6, Receptors, Chemokine genetics, Receptors, Scavenger genetics, Receptors, Virus genetics, Biomarkers, Tumor biosynthesis, Carcinoma, Non-Small-Cell Lung genetics, Chemokines, CXC biosynthesis, Receptors, Chemokine biosynthesis, Receptors, Scavenger biosynthesis, Receptors, Virus biosynthesis
- Abstract
Background: The chemokine CXCL16 and its receptor CXCR6 are expressed by a variety of immune cells and have been shown to influence angiogenesis. The expression of CXCR6 and CXCL16 has been examined in numerous human cancers; however no studies have yet investigated their influence on prognosis in non-small cell lung cancer (NSCLC). We aimed to explore their prognostic significance in NSCLC, in addition to examining associations with previously investigated markers., Methods: Resected tumor tissue from 335 consecutive unselected stage I-IIIA NSCLC patients (1990-2005) were collected. Immunohistochemistry was used to evaluate the expression of CXCR6 and CXCL16 on tissue microarrays. In vitro, NSCLC cells (NCI-H460, A549 cells) were transfected with CXCL16 siRNA to examine effects on proliferation., Results: In univariate analysis, ↑ stromal cell CXCL16 expression was a significant positive prognostic factor (P = 0.016). CXCR6 was expressed in cancer cells, but did not show any prognostic impact. In the multivariate analysis, combined ↑cancer, and ↑stromal cell CXCL16 expression was an independent positive prognostic factor when compared to ↓stromal and ↓cancer cell expression (HR: 0.42; 95 % CI: 0.20-0.88; P = 0.022). Knockdown of CXCL16 by siRNA resulted in accelerated proliferation of NSCLC cell lines., Conclusion: We have shown that combined ↑cancer and ↑stromal cell CXCL16 expression is an independent positive prognostic factor in NSCLC. Further studies are warranted to elucidate the biological mechanism underlying this finding.
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- 2015
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48. Cancer-associated fibroblasts from lung tumors maintain their immunosuppressive abilities after high-dose irradiation.
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Gorchs L, Hellevik T, Bruun JA, Camilio KA, Al-Saad S, Stuge TB, and Martinez-Zubiaurre I
- Abstract
Accumulating evidence supports the notion that high-dose (>5 Gy) radiotherapy (RT) regimens are triggering stronger pro-immunogenic effects than standard low-dose (2 Gy) regimens. However, the effects of RT on certain immunoregulatory elements in tumors remain unexplored. In this study, we have investigated the effects of high-dose radiotherapy (HD-RT) on the immunomodulating functions of cancer-associated fibroblasts (CAFs). Primary CAF cultures were established from lung cancer specimens derived from patients diagnosed for non-small cell lung cancer. Irradiated and non-irradiated CAFs were examined for immunomodulation in experiments with peripheral blood mononuclear cells from random, healthy donors. Regulation of lymphocytes behavior was checked by lymphocyte proliferation assays, lymphocyte migration assays, and T-cell cytokine production. Additionally, CAF-secreted immunoregulatory factors were studied by multiplex protein arrays, ELISAs, and by LC-MS/MS proteomics. In all functional assays, we observed a powerful immunosuppressive effect exerted by CAF-conditioned medium on activated T-cells (p > 0.001), and this effect was sustained after a single radiation dose of 18 Gy. Relevant immunosuppressive molecules such as prostaglandin E2, interleukin-6, and -10, or transforming growth factor-β were found in CAF-conditioned medium, but their secretion was unchanged after irradiation. Finally, immunogenic cell death responses in CAFs were studied by exploring the release of high motility group box-1 and ATP. Both alarmins remained undetectable before and after irradiation. In conclusion, CAFs play a powerful immunosuppressive effect over activated T-cells, and this effect remains unchanged after HD-RT. Importantly, CAFs do not switch on immunogenic cell death responses after exposure to HD-RT.
- Published
- 2015
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- View/download PDF
49. High progesterone receptor expression in prostate cancer is associated with clinical failure.
- Author
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Grindstad T, Andersen S, Al-Saad S, Donnem T, Kiselev Y, Nordahl Melbø-Jørgensen C, Skjefstad K, Busund LT, Bremnes RM, and Richardsen E
- Subjects
- Aged, Aged, 80 and over, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Gene Expression, Humans, Immunohistochemistry, Male, Middle Aged, Neoplasm Grading, Neoplasm Staging, Patient Outcome Assessment, Prognosis, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology, Prostatic Neoplasms therapy, Receptors, Progesterone genetics, Survival Analysis, Treatment Failure, Prostatic Neoplasms metabolism, Prostatic Neoplasms mortality, Receptors, Progesterone metabolism
- Abstract
Background: Prostate cancer is a highly heterogeneous disease and one of the leading causes of mortality in developed countries. Specific prognostic and predictive markers for prostate cancer patients are still lacking. A causal relationship between androgens and the development of prostate cancer is generally considered biologically plausible, but androgens are not the sole effector in the complexity of prostate carcinogenesis. The aim of this study was to evaluate the prognostic significance of progesterone receptor in tumor tissue of T1-3N0 prostate cancer patients undergoing prostatectomy., Methods: Tissue microarrays from 535 patients with prostate cancer were constructed. Duplicate cores of tumor cells and tumor stromal tissue from each resected specimen were extracted. Immunohistochemistry was used to evaluate the in-situ expression of progesterone receptor., Results: In univariate analyses, high tumor cell density (p = 0.006) and high tumor stromal cell density level (p = 0.045) of progesterone receptor were both significantly associated with tumor progression and clinical failure. In multivariate analysis, progesterone receptor expression in tumor cells was an independent negative prognostic factor for clinical failure (HR: 2.5, 95% CI: 1.2-5.2, p = 0.012)., Conclusion: High progesterone receptor density in tumor cells of the prostate cancer tumor is an independent negative prognostic factor for clinical failure.
- Published
- 2015
- Full Text
- View/download PDF
50. Stromal expression of MiR-21 predicts biochemical failure in prostate cancer patients with Gleason score 6.
- Author
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Melbø-Jørgensen C, Ness N, Andersen S, Valkov A, Dønnem T, Al-Saad S, Kiselev Y, Berg T, Nordby Y, Bremnes RM, Busund LT, and Richardsen E
- Subjects
- Aged, Cohort Studies, Disease Progression, Gene Expression Regulation, Neoplastic, Humans, Male, Middle Aged, Neoplasm Grading, Neoplasm Recurrence, Local genetics, Neoplasm Recurrence, Local mortality, Neoplasm Staging, Prognosis, Prostatectomy, Prostatic Neoplasms genetics, Prostatic Neoplasms mortality, Prostatic Neoplasms surgery, Real-Time Polymerase Chain Reaction, Stromal Cells metabolism, Survival Rate, Biomarkers, Tumor genetics, MicroRNAs genetics, Neoplasm Recurrence, Local diagnosis, Prostatic Neoplasms pathology, Stromal Cells pathology
- Abstract
Aim: microRNAs (miRNAs) are involved in various neoplastic diseases, including prostate cancer (PCs). The aim of this study was to investigate the miRNA profile in PC tissue, to assess their association with clinicopathologic data, and to evaluate the potential of miRNAs as diagnostic and prognostic markers., Materials and Methods: From a cohort of 535 patients submitted to radical prostatectomy (RP), a sample of 30 patients (14 patients with rapid biochemical failure (BF) and 16 patients without BF) with Gleason score 7 were analyzed. A total of 1435 miRNAs were quantified by microarray hybridization, and selected miRNAs with the highest Standard deviation (n = 50) were validated by real-time quantitative PCR (qRT-PCR). In situ hybridization (ISH) was used to evaluate the expression of miR-21., Results: miR-21 was the only miR that was significantly up-regulated in the BF group (p = 0.045) miR-21 was up-regulated in patients with BF compared with non-BF group (p = 0.05). In univariate analyses, high stromal expression of miR-21 had predictive impact on biochemical failure-free survival (BFFS) and clinical failure-free survival (CFFS) (p = 0.006 and p = 0.04, respectively). In the multivariate analysis, high stromal expression of miR-21 expression was found to be an independent prognostic factor for BFFS in patients with Gleason score 6 (HR 2.41, CI 95% 1.06-5.49, p = 0.037)., Conclusion: High stromal expression of miR-21 was associated with poor biochemical recurrence-free survival after RP. For patients with Gleason score 6, miR-21 may help predict the risk of future disease progression and thereby help select patients for potential adjuvant treatment or a more stringent follow-up.
- Published
- 2014
- Full Text
- View/download PDF
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