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1. The impact of whole genome and transcriptome analysis (WGTA) on predictive biomarker discovery and diagnostic accuracy of advanced malignancies

Author

Basile Tessier‐Cloutier, Jasleen K Grewal, Martin R Jones, Erin Pleasance, Yaoqing Shen, Ellen Cai, Chris Dunham, Lynn Hoang, Basil Horst, David G Huntsman, Diana Ionescu, Anthony N Karnezis, Anna F Lee, Cheng Han Lee, Tae Hoon Lee, David DW Twa, Andrew J Mungall, Karen Mungall, Julia R Naso, Tony Ng, David F Schaeffer, Brandon S Sheffield, Brian Skinnider, Tyler Smith, Laura Williamson, Ellia Zhong, Dean A Regier, Janessa Laskin, Marco A Marra, C Blake Gilks, Steven JM Jones, and Stephen Yip

Subjects
biomarker, diagnostic, WGTA, pathology, precision medicine, oncology, Pathology, RB1-214
Abstract

Abstract In this study, we evaluate the impact of whole genome and transcriptome analysis (WGTA) on predictive molecular profiling and histologic diagnosis in a cohort of advanced malignancies. WGTA was used to generate reports including molecular alterations and site/tissue of origin prediction. Two reviewers analyzed genomic reports, clinical history, and tumor pathology. We used National Comprehensive Cancer Network (NCCN) consensus guidelines, Food and Drug Administration (FDA) approvals, and provincially reimbursed treatments to define genomic biomarkers associated with approved targeted therapeutic options (TTOs). Tumor tissue/site of origin was reassessed for most cases using genomic analysis, including a machine learning algorithm (Supervised Cancer Origin Prediction Using Expression [SCOPE]) trained on The Cancer Genome Atlas data. WGTA was performed on 652 cases, including a range of primary tumor types/tumor sites and 15 malignant tumors of uncertain histogenesis (MTUH). At the time WGTA was performed, alterations associated with an approved TTO were identified in 39 (6%) cases; 3 of these were not identified through routine pathology workup. In seven (1%) cases, the pathology workup either failed, was not performed, or gave a different result from the WGTA. Approved TTOs identified by WGTA increased to 103 (16%) when applying 2021 guidelines. The histopathologic diagnosis was reviewed in 389 cases and agreed with the diagnostic consensus after WGTA in 94% of non‐MTUH cases (n = 374). The remainder included situations where the morphologic diagnosis was changed based on WGTA and clinical data (0.5%), or where the WGTA was non‐contributory (5%). The 15 MTUH were all diagnosed as specific tumor types by WGTA. Tumor board reviews including WGTA agreed with almost all initial predictive molecular profile and histopathologic diagnoses. WGTA was a powerful tool to assign site/tissue of origin in MTUH. Current efforts focus on improving therapeutic predictive power and decreasing cost to enhance use of WGTA data as a routine clinical test.

Published
2022
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2. An in-depth analysis of the mitochondrial phylogenetic landscape of Cambodia

Author

Anita Kloss-Brandstätter, Monika Summerer, David Horst, Basil Horst, Gertraud Streiter, Julia Raschenberger, Florian Kronenberg, Torpong Sanguansermsri, Jürgen Horst, and Hansi Weissensteiner

Subjects
Medicine, Science
Abstract

Abstract Cambodia harbours a variety of human aboriginal populations that have scarcely been studied in terms of genetic diversity of entire mitochondrial genomes. Here we present the matrilineal gene pool of 299 Cambodian refugees from three different ethnic groups (Cham, Khmer, and Khmer Loeu) deriving from 16 Cambodian districts. After establishing a DNA-saving high-throughput strategy for mitochondrial whole-genome Sanger sequencing, a HaploGrep based workflow was used for quality control, haplogroup classification and phylogenetic reconstruction. The application of diverse phylogenetic algorithms revealed an exciting picture of the genetic diversity of Cambodia, especially in relation to populations from Southeast Asia and from the whole world. A total of 224 unique haplotypes were identified, which were mostly classified under haplogroups B5a1, F1a1, or categorized as newly defined basal haplogroups or basal sub-branches of R, N and M clades. The presence of autochthonous maternal lineages could be confirmed as reported in previous studies. The exceptional homogeneity observed between and within the three investigated Cambodian ethnic groups indicates genetic isolation of the whole population. Between ethnicities, genetic barriers were not detected. The mtDNA data presented here increases the phylogenetic resolution in Cambodia significantly, thereby highlighting the need for an update of the current human mtDNA phylogeny.

Published
2021
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3. Automated digital TIL analysis (ADTA) adds prognostic value to standard assessment of depth and ulceration in primary melanoma

Author

Michael R. Moore, Isabel D. Friesner, Emanuelle M. Rizk, Benjamin T. Fullerton, Manas Mondal, Megan H. Trager, Karen Mendelson, Ijeuru Chikeka, Tahsin Kurc, Rajarsi Gupta, Bethany R. Rohr, Eric J. Robinson, Balazs Acs, Rui Chang, Harriet Kluger, Bret Taback, Larisa J. Geskin, Basil Horst, Kevin Gardner, George Niedt, Julide T. Celebi, Robyn D. Gartrell-Corrado, Jane Messina, Tammie Ferringer, David L. Rimm, Joel Saltz, Jing Wang, Rami Vanguri, and Yvonne M. Saenger

Subjects
Medicine, Science
Abstract

Abstract Accurate prognostic biomarkers in early-stage melanoma are urgently needed to stratify patients for clinical trials of adjuvant therapy. We applied a previously developed open source deep learning algorithm to detect tumor-infiltrating lymphocytes (TILs) in hematoxylin and eosin (H&E) images of early-stage melanomas. We tested whether automated digital (TIL) analysis (ADTA) improved accuracy of prediction of disease specific survival (DSS) based on current pathology standards. ADTA was applied to a training cohort (n = 80) and a cutoff value was defined based on a Receiver Operating Curve. ADTA was then applied to a validation cohort (n = 145) and the previously determined cutoff value was used to stratify high and low risk patients, as demonstrated by Kaplan–Meier analysis (p ≤ 0.001). Multivariable Cox proportional hazards analysis was performed using ADTA, depth, and ulceration as co-variables and showed that ADTA contributed to DSS prediction (HR: 4.18, CI 1.51–11.58, p = 0.006). ADTA provides an effective and attainable assessment of TILs and should be further evaluated in larger studies for inclusion in staging algorithms.

Published
2021
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4. 2367

Author

Robyn Gartrell, Douglas Marks, Thomas Hart, Yan Lu, Ed Stack, Camden Esancy, Basil Horst, Yvonne Saenger, Camille Gerard, Dan Tong Jia, Paul Armenta, Daisuke Izaki, and Kristen Beck

Subjects
Medicine
Abstract

OBJECTIVES/SPECIFIC AIMS: Precise biomarkers are urgently needed to characterize the tumor immune microenvironment in primary melanoma tumors both for prognostication and to predict the benefit of immuno-therapeutic intervention. The goal of this work is to define spatial relationships between CD8+ T cells, CD68+ macrophages and Sox10+ melanoma cells in order to define features correlating with prolonged survival METHODS/STUDY POPULATION: Five micrometer slides from either the primary biopsy or subsequent wide local excision procedure were stained using Opal multiplex IHC for DAPI, CD3 (LN10, Leica), CD8 (4B11, Leica), CD68 (KP1, Biogenex), SOX10 (BC34, Biocare), HLA-DR (LN-3, Abcam), and Ki67 (MIB1, Abcam). Cell phenotypes within representative fields preselected by a trained dermato-pathologist and were visualized using the Mantra quantitative pathology workstation (PerkinElmer), and analysis of spatial distribution of CD3+ CD8+ cells analyzed using inForm® image analysis software (PerkinElmer), and Spotfire software (TIBCO). In order to test whether mIHC can better characterize the tumor immune microenvironment, we screened databases at the Herbert Irving Cancer Center (HICC) at Columbia University for stage II/III melanoma patients diagnosed between 2000 and 2012, with available FFPE of primary melanoma tissue and documented clinical follow-up. We identified a preliminary population of 57 patients to begin our analysis. Clinical follow-up was available on 35 patients of whom 21 patients were alive with no evidence of recurrence or died with no evidence of recurrence and 14 had died of melanoma. Twenty-four patients had more than 24 months of survival information available but no detailed clinical information to determine cause of death. RESULTS/ANTICIPATED RESULTS: First, we evaluated whether density of immune cells in tumor and stroma predicted prognosis in 35 patients with disease specific survival information. We find that high number of CD3+CD8+ cells in tumor correlates with Disease Specific Survival (DSS) (p=0.0323*) and CD3+CD8+ cells in stroma may also correlate with DSS (p=0.0671). This is consistent with what is known in the literature regarding tumor infiltrating lymphocytes (TILs). We also found that CD68+ cells in stroma predict poor prognosis (0.0259*). This is consist with the proposed deleterious role for macrophages in tumor progression. Next, using nearest neighbor analysis we examined the effect of HLA-DR and Ki67 expression on spatial distribution of CD3+CD8+ T cells. We find that CD8+ T cells are closer to myeloid (CD68+) cells expressing HLA-DR. This is consistent with the potential of HLA-DR expressing cells to present antigens to T cells, and suggests that T cells may preferentially interact with HLA-DR expressing myeloid cells. Conversely, we find that Ki67 expression on tumor (SOX10+) cells correlates with increased distance from CD3+CD8+ T cells relative to SOX10+Ki67-tumor cells. This finding is consistent with the observation that more advanced tumors with higher mitotic rates have decreased T cell infiltrates, and suggests that dividing melanoma cells are less likely to interact with T cells. In addition, we performed analysis to determine whether spatial relationships defined above impact prognosis. Clinical oncology follow-up was available on 35 of the 57 patients evaluated above. We compared proximity of CD3+CD8+ cells to both myeloid (CD68+) and tumor (SOX10+) cells in patients who recurred and those with no evidence of recurrence. We found that CD3+CD8+ cells in patients who had recurrence were closer to CD68+ HLA-DR− cells than in patients who had no recurrence (t-test, p=0.0377), this correlated with DSS (p=0.003). Conversely, distance from CD3+CD8+ to CD68+ HLA-DR+ in relationship to recurrence was not significant with a trend towards CD3+CD8+ T cells being closer in nonrecurrent patients (t-test, p=0.1362). DISCUSSION/SIGNIFICANCE OF IMPACT: Consistent with the literature, we find that densities of CD8+ T cells correlates with favorable outcomes in early stage melanoma. We also find that density of CD68+ macrophages in stroma correlates with poor outcome. If proximity is a surrogate for interaction, these data indicate that dividing, Ki67+, melanoma cells interact less with CD8+ T cells than do Ki67+ melanoma cells. Further, HLA-DR expression on CD68+ infiltrating cells likely enhances their interaction with T cells. Interestingly, on further analysis, CD3+CD8+ cells were significantly closer to CD68+ HLA-DR− cells in patients who recurred, implying that interactions between these cell types may not be favorable. This analysis demonstrates that spatial analysis may be useful in predicting prognosis in early stage melanoma, and this is the first report of this type of analysis predicting outcomes in primary tumor specimens to our knowledge. Further staining and analysis of the complete patient cohort (n=120) is ongoing.

Published
2017
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5. Methicillin-Resistant Staphylococcus aureus Adaptation to Human Keratinocytes

Author

Grace Soong, Franklin Paulino, Sarah Wachtel, Dane Parker, Matthew Wickersham, Dongni Zhang, Armand Brown, Christine Lauren, Margaret Dowd, Emily West, Basil Horst, Paul Planet, and Alice Prince

Subjects
Microbiology, QR1-502
Abstract

ABSTRACT Skin is the most common site of Staphylococcus aureus infection. While most of these infections are self-limited, recurrent infections are common. Keratinocytes and recruited immune cells participate in skin defense against infection. We postulated that S. aureus is able to adapt to the milieu within human keratinocytes to avoid keratinocyte-mediated clearance. From a collection of S. aureus isolated from chronically infected patients with atopic dermatitis, we noted 22% had an agr mutant-like phenotype. Using several models of human skin infection, we demonstrate that toxin-deficient, agr mutants of methicillin-resistant S. aureus (MRSA) USA300 are able to persist within keratinocytes by stimulating autophagy and evading caspase-1 and inflammasome activation. MRSA infection induced keratinocyte autophagy, as evidenced by galectin-8 and LC3 accumulation. Autophagy promoted the degradation of inflammasome components and facilitated staphylococcal survival. The recovery of more than 58% agr or RNAIII mutants (P < 0.0001) of an inoculum of wild-type (WT) MRSA from within wortmannin-treated keratinocytes compared to control keratinocytes reflected the survival advantage for mutants no longer expressing agr-dependent toxins. Our results illustrate the dynamic interplay between S. aureus and keratinocytes that can result in the selection of mutants that have adapted specifically to evade keratinocyte-mediated clearance mechanisms. IMPORTANCE Human skin is a major site of staphylococcal infection, and keratinocytes actively participate in eradication of these pathogens. We demonstrate that methicillin-resistant Staphylococcus aureus (MRSA) is ingested by keratinocytes and activates caspase-1-mediated clearance through pyroptosis. Toxin-deficient MRSA mutants are selected within keratinocytes that fail to induce caspase-1 activity and keratinocyte-mediated clearance. These intracellular staphylococci induce autophagy that enhances their intracellular survival by diminishing inflammasome components. These findings suggest that S. aureus mutants, by exploiting autophagy, can persist within human keratinocytes.

Published
2015
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6. Supplementary Figures and Tables from Inhibition of Mitochondrial Matrix Chaperones and Antiapoptotic Bcl-2 Family Proteins Empower Antitumor Therapeutic Responses

Author

Markus D. Siegelin, Dario C. Altieri, Peter Canoll, Jeffrey N. Bruce, Kevin A. Roth, Matei Banu, Basil Horst, Rolando Perez-Lorenzo, Chang Shu, Elena Bianchetti, Chiaki Tsuge Ishida, and Georg Karpel-Massler

Abstract

Suppl. fig. 1: Patient derived-xenograft cells are susceptible to the combination treatment of Gamitrinib and clinically validated BH3-mimetics; Suppl. fig. 2: Transgenically-derived murine glioblastoma cells are susceptible to the combination treatment of Gamitrinib and clinically validated BH3-mimetics; Suppl. fig. 3: Carcinoma cells of different origin are sensitive to the combination treatment of Gamitrinib and clinically validated BH3-mimetics Suppl. fig. 4: The combination treatment of either broad or selective BH3-mimetics with mitochondrial matrix chaperone inhibitors elicits enhanced apoptosis Suppl. fig. 5: The combination treatment of selective BH3-mimetics, ABT199, WEHI-539, A-1210477 with Gamitrinib-TPP elicits enhanced apoptosis Suppl. fig. 6: Selective BH3-mimetics elicit enhanced loss of mitochondrial membrane potential in the presence of Gamitrinib-TPP in a cell-type dependent manner Suppl. fig. 7: The pan-BH3-mimetic GX15-070 and Gamitrinib induce enhanced apoptotic cell death in glioblastoma cells Suppl. fig. 8: Gamitrinib elicits an endoplasmic reticulum stress signature at the level of transcription. Suppl. fig. 9: Knockdown of Usp9X and Mcl-1 is sufficient to sensitize melanoma and glioblastoma cells to the cytotoxic effects of ABT263 Suppl. fig. 10: Suppression of Noxa counteracts Gamitrinib-mediated suppression of Usp9X and Mcl-1 Suppl. fig. 11: Organ toxicity analysis of mice treated with ABT263 and G-TPP Suppl. fig. 12: The combination treatment of Gamitrinib-TPP and ABT263 leads to a reduction in tumor growth in an orthotopic model of triple-receptor negative breast cancer Table S1: Consolidated representation of qualitative combined anti-proliferative effects of G-TPP (G) and ABT263 (A) or GX15-070 (GX) on different cancer cells. Table S2: ABT263 or GX15-070 treatment yields a synergistic antiproliferative effect on U251, GBM6 and GBM39 glioma cells in the presence of G-TPP. Table S3: Consolidated representation of qualitative combined anti-proliferative effects of G-TPP and ABT263 on WC62, MeWo and COLO 829 malignant melanoma cells. Table S4: Consolidated representation of qualitative combined anti-proliferative effects of G-TPP and the selective Bcl-xL inhibitor WEHI-539, the selective Bcl-2 inhibitor ABT199 and the selective Mcl-1 inhibitor A1210477 on U87MG, LN229 and T98G established glioblastoma cells as well as GBM6 primary cultured glioblastoma cells

Published
2023
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9. Data from Inhibition of Mitochondrial Matrix Chaperones and Antiapoptotic Bcl-2 Family Proteins Empower Antitumor Therapeutic Responses

Author

Markus D. Siegelin, Dario C. Altieri, Peter Canoll, Jeffrey N. Bruce, Kevin A. Roth, Matei Banu, Basil Horst, Rolando Perez-Lorenzo, Chang Shu, Elena Bianchetti, Chiaki Tsuge Ishida, and Georg Karpel-Massler

Abstract

Rational therapeutic approaches based on synthetic lethality may improve cancer management. On the basis of a high-throughput drug screen, we provide preclinical proof of concept that targeting the mitochondrial Hsp90 chaperone network (mtHsp90) and inhibition of Bcl-2, Bcl-xL, and Mcl-1 is sufficient to elicit synthetic lethality in tumors recalcitrant to therapy. Our analyses focused on BH3 mimetics that are broad acting (ABT263 and obatoclax) or selective (ABT199, WEHI-539, and A1210477), along with the established mitochondrial matrix chaperone inhibitor gamitrinib-TPP. Drug combinations were tested in various therapy-resistant tumors in vitro and in vivo in murine model systems of melanoma, triple-negative breast cancer, and patient-derived orthotopic xenografts (PDX) of human glioblastoma. We found that combining BH3 mimetics and gamitrinib-TPP blunted cellular proliferation in a synergistic manner by massive activation of intrinsic apoptosis. In like manner, suppressing either Bcl-2, Bcl-xL, or Mcl-1 recapitulated the effects of BH3 mimetics and enhanced the effects of gamitrinib-TPP. Mechanistic investigations revealed that gamitrinib-TPP activated a PERK-dependent integrated stress response, which activated the proapoptotic BH3 protein Noxa and its downstream targets Usp9X and Mcl-1. Notably, in the PDX glioblastoma and BRAFi-resistant melanoma models, this drug combination safely and significantly extended host survival. Our results show how combining mitochondrial chaperone and Bcl-2 family inhibitors can synergize to safely degrade the growth of tumors recalcitrant to other treatments. Cancer Res; 77(13); 3513–26. ©2017 AACR.

Published
2023
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10. Combination immunotherapy including OncoVEXmGMCSF creates a favorable tumor immune micro-environment in transgenic BRAF murine melanoma

Author

Robyn D. Gartrell, Zoë Blake, Emanuelle M. Rizk, Rolando Perez-Lorenzo, Stuart P. Weisberg, Ines Simoes, Camden Esancy, Yichun Fu, Danielle R. Davari, Luke Barker, Grace Finkel, Manas Mondal, Hanna E. Minns, Samuel W. Wang, Benjamin T. Fullerton, Francisco Lozano, Codruta Chiuzan, Basil Horst, and Yvonne M. Saenger

Subjects
Cancer Research, Oncology, Immunology, Immunology and Allergy
Published
2022
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11. Combination immunotherapy including OncoVEX

Author

Robyn D, Gartrell, Zoë, Blake, Emanuelle M, Rizk, Rolando, Perez-Lorenzo, Stuart P, Weisberg, Ines, Simoes, Camden, Esancy, Yichun, Fu, Danielle R, Davari, Luke, Barker, Grace, Finkel, Manas, Mondal, Hanna E, Minns, Samuel W, Wang, Benjamin T, Fullerton, Francisco, Lozano, Codruta, Chiuzan, Basil, Horst, and Yvonne M, Saenger

Subjects
Oncolytic Virotherapy, Proto-Oncogene Proteins B-raf, Mice, Oncolytic Viruses, Tumor Microenvironment, Animals, Immunologic Factors, Antineoplastic Agents, Immunotherapy, Melanoma
Abstract

Talimogene Laherparepvec (OncoVEX

Published
2021

12. Immune biomarkers are more accurate in prediction of survival in ulcerated than in non-ulcerated primary melanomas

Author

Ellen H de Moll, Rui Chang, Robert G. Phelps, Shira Y. Wieder, Sara H. Perkins, Sacha Gnjatic, Tammie Ferringer, Basil Horst, Jonathan Yao, Sebastian Bernardo, Romain Remark, Jerry E. Chipuk, Miriam B. Birge, Yichun Fu, Yingzhi Qian, Marina Moskalenko, and Yvonne M. Saenger

Subjects
Adult, Cancer Research, Pathology, medicine.medical_specialty, Skin Neoplasms, Immunology, Article, Lymphocytes, Tumor-Infiltrating, Immune system, Immune infiltration, Biomarkers, Tumor, medicine, Humans, Immunology and Allergy, Melanoma, neoplasms, Survival analysis, Aged, Retrospective Studies, Aged, 80 and over, Tumor-infiltrating lymphocytes, business.industry, Middle Aged, medicine.disease, Immunohistochemistry, Survival Analysis, digestive system diseases, Oncology, Biomarker (medicine), business, Tumor immunology
Abstract

Ulcerated melanomas may have a unique biology and microenvironment. We test whether markers of immune infiltration correlate with clinical outcome in ulcerated compared to non-ulcerated primary melanoma tumors.Sixty-two stage II-III cutaneous melanomas, 32 ulcerated and 30 non-ulcerated, were analyzed for tumor-infiltrating lymphocytes (TILs). Immunohistochemistry (IHC) was performed for CD2, a marker previously shown to correlate with overall survival (OS) and recurrence-free survival (RFS) in this patient population. IHC using antibody, VE1, to BRAF V600E was also performed on a subset of 41 tumors to assess the relationship of BRAF mutation to immune markers.We found, using Cox regression models, that the presence of TILs was associated with improved OS (p = 0.034) and RFS (p = 0.002) in ulcerated melanoma tumors, but not in non-ulcerated melanoma (p = 0.632, 0.416). CD2 expression also was correlated with improved OS (p = 0.021) and RFS (p = 0.001) in ulcerated melanoma, but no relationship was seen in non-ulcerated melanoma (p = 0.427, 0.682). In this small population, BRAF status did not correlate with TILs or CD2+ count.Our data show that immune markers including TILs and CD2 count correlate more closely with survival in ulcerated melanomas than that in non-ulcerated melanomas. We propose that immune biomarkers may be particularly relevant to ulcerated, as compared to non-ulcerated, melanomas and that this merits study in larger populations.

Published
2015
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13. 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): late breaking abstracts

Author

Sonja Althammer, Keith Steele, Marlon Rebelatto, Tze Heng Tan, Tobias Wiestler, Guenter Schmidt, Brandon Higgs, Xia Li, Li Shi, Xiaoping Jin, Joyce Antal, Ashok Gupta, Koustubh Ranade, Gerd Binning, Joaquim Bellmunt, Ronald de Wit, David J. Vaughn, Yves Fradet, Jae Lyun Lee, Lawrence Fong, Nicholas J. Vogelzang, Miguel A. Climent, Daniel P. Petrylak, Toni K. Choueiri, Andrea Necchi, Winald Gerritsen, Howard Gurney, David I. Quinn, Stéphane Culine, Cora N. Sternberg, Yabing Mai, Markus Puhlmann, Rodolfo F. Perini, Dean F. Bajorin, Padmanee Sharma, Margaret K. Callahan, Emiliano Calvo, Joseph W. Kim, Filipo de Braud, Patrick A. Ott, Petri Bono, Rathi N. Pillai, Michael Morse, Dung T. Le, Matthew Taylor, Pavlina Spilliopoulou, Johanna Bendell, Dirk Jaeger, Emily Chan, Scott J. Antonia, Paolo A. Ascierto, Delphine Hennicken, Marina Tschaika, Alex Azrilevich, Jonathan Rosenberg, Ofer Levy, Christopher Chan, Gady Cojocaru, Spencer Liang, Eran Ophir, Sudipto Ganguly, Amir Toporik, Maya Kotturi, Tal Fridman Kfir, Benjamin M. Murter, Kathryn Logronio, Liat Dassa, Ling Leung, Shirley Greenwald, Meir Azulay, Sandeep Kumar, Zoya Alteber, Xiaoyu Pan, Arthur Machlenkin, Yair Benita, Andrew W. Drake, Ayelet Chajut, Ran Salomon, Ilan Vankin, Einav Safyon, John Hunter, Zurit Levine, Mark White, Rom Leidner, Hyunseok Kang, Robert Haddad, Neil H. Segal, Lori J. Wirth, Robert L. Ferris, F. Stephen Hodi, Rachel E. Sanborn, Thomas F. Gajewski, William Sharfman, Dan McDonald, Shivani Srivastava, Xuemin Gu, Penny Phillips, Chaitali Passey, Tanguy Seiwert, Tsadik Habtetsion, Gang Zhou, Donastas Sakellariou-Thompson, Cara Haymaker, Caitlin Creasy, Mark Hurd, Naohiro Uraoka, Jaime Rodriguez Canales, Scott Koptez, Patrick Hwu, Anirban Maitra, Chantale Bernatchez, Scott M. Coyle, Kole T. Roybel, Levi J. Rupp, Stephen P. Santoro, Stephanie Secrest, Michael Spelman, Hanson Ho, Tina Gomes, Tiffany Tse, Chia Yung-Wu, Jack Taunton, Wendell Lim, Peter Emtage, Tarsem Moudgil, Carmen Ballesteros-Merino, Traci Hilton, Christopher Paustian, David Page, Walter Urba, Bernard Fox, Bryan Bell, Ashish Patel, Tove Olafsen, Daulet Satpayev, Michael Torgov, Filippo Marchioni, Jason Romero, Ziyue Karen Jiang, Charles Zamilpa, Jennifer S. Keppler, Alessandro Mascioni, Fang Jia, Chen-Yu Lee, Jean Gudas, Ryan J. Sullivan, Yujin Hoshida, Theodore Logan, Nikhil Khushalani, Anita Giobbie-Hurder, Kim Margolin, Joanna Roder, Rupal Bhatt, Henry Koon, Thomas Olencki, Thomas Hutson, Brendan Curti, Shauna Blackmon, James W. Mier, Igor Puzanov, Heinrich Roder, John Stewart, Asim Amin, Marc S. Ernstoff, Joseph I. Clark, Michael B. Atkins, Howard L. Kaufman, Jeffrey Sosman, Sabina Signoretti, David F. McDermott, Abraham A. Anderson, Mohammed M. Milhem, Robert H. I. Andtbacka, David Minor, Kevin S. Gorski, Daniel M. Baker, Omid Hamid, Emmanuel Akporiaye, Yoshinobu Koguchi, Kim Sutcliffe, Kristie Conder, Thomas Marron, Nina Bhardwaj, Linda Hammerich, Fiby George, Seunghee Kim-Schulze, Tibor Keler, Tom Davis, Elizabeth Crowley, Andres Salazar, Joshua Brody, Arta Monjazeb, Megan E. Daly, Jonathan Riess, Tianhong Li, William J. Murphy, Karen Kelly, Zhiwei Hu, Rulong Shen, Amanda Campbell, Elizabeth McMichael, Lianbo Yu, Bhuvaneswari Ramaswam, Cheryl A. London, Tian Xu, William Carson, Kathleen M. Kokolus, Elizabeth A. Repasky, Todd D. Schell, Joseph D. Drabick, David J. Messenheimer, Shawn Jensen, Mark Rubinstein, Kristina Andrijauskaite, Marzena Swiderska-syn, Kristin Lind, Agnes Choppin, Marina K. Roell, John Wrangle, Peter Rhode, Hing Wong, Shamim Ahmad, Mason Webb, Rasha Abu-Eid, Rajeev Shrimali, Vivek Verma, Atbin Doroodchi, Zuzana Berrong, David Yashar, Raed Samara, Mikayel Mkrtichyan, Samir Khleif, Steven Powell, Mark Gitau, Christopher Sumey, Andrew Terrell, Michele Lohr, Ryan K. Nowak, Steven McGraw, Ash Jensen, Miran Blanchard, Kathryn A. Gold, Ezra E. W. Cohen, Christie Ellison, Lora Black, John Lee, William Chad Spanos, Erik Wennerberg, Emily Schwitzer, Claire Lhuillier, Graeme Koelwyn, Rebecca Hiner, Lee Jones, Sandra Demaria, Vandeveer Amanda, John W. Greiner, Jeffrey Schlom, Michelle Bookstaver, Christopher M. Jewell, Andrew Gunderson, Brian Boulmay, Rui Li, Bradley Spieler, Kyle Happel, Zipei Feng, Christopher Dubay, Brenda Fisher, Sandra Aung, Eileen Mederos, Carlo B. Bifulco, Michael McNamara, Keith Bahjat, William Redmond, Augusto Ochoa, Hong-Ming Hu, Adi Mehta, Fridtjof Lund-Johansen, Frank Bedu-Addo, Greg Conn, Michael King, Panna Dutta, Robert Shepard, Mark Einstein, Sylvia Adams, Ena Wang, Ping Jin, Yelena Novik, Debra Morrison, Ruth Oratz, Franco M. Marincola, David Stroncek, Judith Goldberg, Silvia C. Formenti, Jérôme Galon, Bernhard Mlecnik, Florence Marliot, Fang-Shu Ou, Alessandro Lugli, Inti Zlobec, Tilman T. Rau, Iris D. Nagtegaal, Elisa Vink-Borger, Arndt Hartmann, Carol Geppert, Michael H. Roehrl, Prashant Bavi, Pamela S. Ohashi, Julia Y. Wang, Linh T. Nguyen, SeongJun Han, Heather L. MacGregor, Sara Hafezi-Bakhtiari, Bradley G. Wouters, Yutaka Kawakami, Boryana Papivanova, Mingli Xu, Tomonobu Fujita, Shoichi Hazama, Nobuaki Suzuki, Hiroaki Nagano, Kiyotaka Okuno, Kyogo Itoh, Eva Zavadova, Michal Vocka, Jan Spacek, Lubos Petruzelka, Bohuslav Konopasek, Pavel Dundr, Helena Skalova, Toshihiko Torigoe, Noriyuki Sato, Tomohisa Furuhata, Ichiro Takemasa, Marc Van den Eynde, Anne Jouret-Mourin, Jean-Pascal Machiels, Tessa Fredriksen, Lucie Lafontaine, Bénédicte Buttard, Sarah Church, Pauline Maby, Helen Angell, Mihaela Angelova, Angela Vasaturo, Gabriela Bindea, Anne Berger, Christine Lagorce, Prabhu S. Patel, Hemangini H. Vora, Birva Shah, Jayendrakumar B. Patel, Kruti N. Rajvik, Shashank J. Pandya, Shilin N. Shukla, Yili Wang, Guanjun Zhang, Giuseppe V. Masucci, Emilia K. Andersson, Fabio Grizzi, Luigi Laghi, Gerardo Botti, Fabiana Tatangelo, Paolo Delrio, Gennaro Cilberto, Franco Marincola, Daniel J. Sargent, Bernard A. Fox, Alain Algazi, Katy Tsai, Michael Rosenblum, Prachi Nandoskar, Amy Li, John Nonomura, Kathryn Takamura, Mary Dwyer, Erica Browning, Reneta Talia, Chris Twitty, Sharron Gargosky, Jean Campbell, Mai Le, Robert H. Pierce, Adil Daud, Robyn Gartrell, Douglas Marks, Edward Stack, Yan Lu, Daisuke Izaki, Kristen Beck, Dan Tong Jia, Paul Armenta, Ashley White-Stern, Yichun Fu, Zoe Blake, Bret Taback, Basil Horst, Yvonne M. Saenger, Steven Leonardo, Keith Gorden, Ross B. Fulton, Kathryn Fraser, Takashi O. Kangas, Richard Walsh, Kathleen Ertelt, Jeremy Graff, Mark Uhlik, Jennifer S. Sims, Liang Lei, Takashi Tsujiuchi, Jeffrey N. Bruce, Peter Canoll, Anthony W Tolcher, Evan W Alley, Gurunadh Chichili, Jan E Canoll, Paul Moore, Ezio Bonvini, Syd Johnson, Sadhna Shankar, James Vasselli, Jon Wigginton, and John Powderly

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Durvalumab, medicine.medical_treatment, Immunology, Improved survival, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Immunology and Allergy, Pharmacology, business.industry, Cancer, Immunotherapy, medicine.disease, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Molecular Medicine, Non small cell, business
Abstract

O1 Combinatorial CD8+ and PD-L1+ cell densities correlate with response and improved survival in non-small cell lung cancer (NSCLC) patients treated with durvalumab #### Sonja Althammer1, Keith Steele2, Marlon Rebelatto2, Tze Heng Tan1, Tobias Wiestler1, Guenter Schmidt1, Brandon Higgs2, Xia

Published
2016
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14. 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part two

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Casey Ager, Matthew Reilley, Courtney Nicholas, Todd Bartkowiak, Ashvin Jaiswal, Michael Curran, Tina C. Albershardt, Anshika Bajaj, Jacob F. Archer, Rebecca S. Reeves, Lisa Y. Ngo, Peter Berglund, Jan ter Meulen, Caroline Denis, Hormas Ghadially, Thomas Arnoux, Fabien Chanuc, Nicolas Fuseri, Robert W. Wilkinson, Nicolai Wagtmann, Yannis Morel, Pascale Andre, Michael B. Atkins, Matteo S. Carlino, Antoni Ribas, John A. Thompson, Toni K. Choueiri, F. Stephen Hodi, Wen-Jen Hwu, David F. McDermott, Victoria Atkinson, Jonathan S. Cebon, Bernie Fitzharris, Michael B. Jameson, Catriona McNeil, Andrew G. Hill, Eric Mangin, Malidi Ahamadi, Marianne van Vugt, Mariëlle van Zutphen, Nageatte Ibrahim, Georgina V. Long, Robyn Gartrell, Zoe Blake, Ines Simoes, Yichun Fu, Takuro Saito, Yingzhi Qian, Yan Lu, Yvonne M. Saenger, Sadna Budhu, Olivier De Henau, Roberta Zappasodi, Kyle Schlunegger, Bruce Freimark, Jeff Hutchins, Christopher A. Barker, Jedd D. Wolchok, Taha Merghoub, Elena Burova, Omaira Allbritton, Peter Hong, Jie Dai, Jerry Pei, Matt Liu, Joel Kantrowitz, Venus Lai, William Poueymirou, Douglas MacDonald, Ella Ioffe, Markus Mohrs, William Olson, Gavin Thurston, Cristian Capasso, Federica Frascaro, Sara Carpi, Siri Tähtinen, Sara Feola, Manlio Fusciello, Karita Peltonen, Beatriz Martins, Madeleine Sjöberg, Sari Pesonen, Tuuli Ranki, Lukasz Kyruk, Erkko Ylösmäki, Vincenzo Cerullo, Fabio Cerignoli, Biao Xi, Garret Guenther, Naichen Yu, Lincoln Muir, Leyna Zhao, Yama Abassi, Víctor Cervera-Carrascón, Mikko Siurala, João Santos, Riikka Havunen, Suvi Parviainen, Akseli Hemminki, Angus Dalgleish, Satvinder Mudan, Mark DeBenedette, Ana Plachco, Alicia Gamble, Elizabeth W. Grogan, John Krisko, Irina Tcherepanova, Charles Nicolette, Pooja Dhupkar, Ling Yu, Eugenie S. Kleinerman, Nancy Gordon, Italia Grenga, Lauren Lepone, Sofia Gameiro, Karin M. Knudson, Massimo Fantini, Kwong Tsang, James Hodge, Renee Donahue, Jeffrey Schlom, Elizabeth Evans, Holm Bussler, Crystal Mallow, Christine Reilly, Sebold Torno, Maria Scrivens, Cathie Foster, Alan Howell, Leslie Balch, Alyssa Knapp, John E. Leonard, Mark Paris, Terry Fisher, Siwen Hu-Lieskovan, Ernest Smith, Maurice Zauderer, William Fogler, Marilyn Franklin, Matt Thayer, Dan Saims, John L. Magnani, Jian Gong, Michael Gray, George Fromm, Suresh de Silva, Louise Giffin, Xin Xu, Jason Rose, Taylor H. Schreiber, Sofia R. Gameiro, Paul E. Clavijo, Clint T. Allen, James W. Hodge, Kwong Y. Tsang, Jane Grogan, Nicholas Manieri, Eugene Chiang, Patrick Caplazi, Mahesh Yadav, Patrick Hagner, Hsiling Chiu, Michelle Waldman, Anke Klippel, Anjan Thakurta, Michael Pourdehnad, Anita Gandhi, Ian Henrich, Laura Quick, Rob Young, Margaret Chou, Andrew Hotson, Stephen Willingham, Po Ho, Carmen Choy, Ginna Laport, Ian McCaffery, Richard Miller, Kimberly A. Tipton, Kenneth R. Wong, Victoria Singson, Chihunt Wong, Chanty Chan, Yuanhiu Huang, Shouchun Liu, Jennifer H. Richardson, W. Michael Kavanaugh, James West, Bryan A. Irving, Ritika Jaini, Matthew Loya, Charis Eng, Melissa L. Johnson, Alex A. Adjei, Mateusz Opyrchal, Suresh Ramalingam, Pasi A. Janne, George Dominguez, Dmitry Gabrilovich, Laura de Leon, Jeannette Hasapidis, Scott J. Diede, Peter Ordentlich, Scott Cruickshank, Michael L. Meyers, Matthew D. Hellmann, Pawel Kalinski, Amer Zureikat, Robert Edwards, Ravi Muthuswamy, Nataša Obermajer, Julie Urban, Lisa H. Butterfield, William Gooding, Herbert Zeh, David Bartlett, Olga Zubkova, Larissa Agapova, Marina Kapralova, Liudmila Krasovskaia, Armen Ovsepyan, Maxim Lykov, Artem Eremeev, Vladimir Bokovanov, Olga Grigoryeva, Andrey Karpov, Sergey Ruchko, Alexandr Shuster, Danny N. Khalil, Luis Felipe Campesato, Yanyun Li, Adam S. Lazorchak, Troy D. Patterson, Yueyun Ding, Pottayil Sasikumar, Naremaddepalli Sudarshan, Nagaraj Gowda, Raghuveer Ramachandra, Dodheri Samiulla, Sanjeev Giri, Rajesh Eswarappa, Murali Ramachandra, David Tuck, Timothy Wyant, Jasmin Leshem, Xiu-fen Liu, Tapan Bera, Masaki Terabe, Birgit Bossenmaier, Gerhard Niederfellner, Yoram Reiter, Ira Pastan, Leiming Xia, Yang Xia, Yangyang Hu, Yi Wang, Yangyi Bao, Fu Dai, Shiang Huang, Elaine Hurt, Robert E. Hollingsworth, Lawrence G. Lum, Alfred E. Chang, Max S. Wicha, Qiao Li, Thomas Mace, Neil Makhijani, Erin Talbert, Gregory Young, Denis Guttridge, Darwin Conwell, Gregory B. Lesinski, Rodney JM Macedo Gonzales, Austin P. Huffman, Ximi K. Wang, Ran Reshef, Andy MacKinnon, Jason Chen, Matt Gross, Gisele Marguier, Peter Shwonek, Natalija Sotirovska, Susanne Steggerda, Francesco Parlati, Amani Makkouk, Mark K. Bennett, Ethan Emberley, Tony Huang, Weiqun Li, Silinda Neou, Alison Pan, Jing Zhang, Winter Zhang, Netonia Marshall, Thomas U. Marron, Judith Agudo, Brian Brown, Joshua Brody, Christopher McQuinn, Matthew Farren, Hannah Komar, Reena Shakya, Thomas Ludwug, Y. Maurice Morillon, Scott A. Hammond, John W. Greiner, Pulak R. Nath, Anthony L. Schwartz, Dragan Maric, David D. Roberts, Aung Naing, Kyriakos P. Papadopoulos, Karen A. Autio, Deborah J. Wong, Manish Patel, Gerald Falchook, Shubham Pant, Patrick A. Ott, Melinda Whiteside, Amita Patnaik, John Mumm, Filip Janku, Ivan Chan, Todd Bauer, Rivka Colen, Peter VanVlasselaer, Gail L. Brown, Nizar M. Tannir, Martin Oft, Jeffrey Infante, Evan Lipson, Ajay Gopal, Sattva S. Neelapu, Philippe Armand, Stephen Spurgeon, John P. Leonard, Rachel E. Sanborn, Ignacio Melero, Thomas F. Gajewski, Matthew Maurer, Serena Perna, Andres A. Gutierrez, Raphael Clynes, Priyam Mitra, Satyendra Suryawanshi, Douglas Gladstone, Margaret K. Callahan, James Crooks, Sheila Brown, Audrey Gauthier, Marc Hillairet de Boisferon, Andrew MacDonald, Laura Rosa Brunet, William T. Rothwell, Peter Bell, James M. Wilson, Fumi Sato-Kaneko, Shiyin Yao, Shannon S. Zhang, Dennis A. Carson, Cristina Guiducci, Robert L. Coffman, Kazutaka Kitaura, Takaji Matsutani, Ryuji Suzuki, Tomoko Hayashi, Ezra E. W. Cohen, David Schaer, Yanxia Li, Julie Dobkin, Michael Amatulli, Gerald Hall, Thompson Doman, Jason Manro, Frank Charles Dorsey, Lillian Sams, Rikke Holmgaard, Krishnadatt Persaud, Dale Ludwig, David Surguladze, John S. Kauh, Ruslan Novosiadly, Michael Kalos, Kyla Driscoll, Hardev Pandha, Christy Ralph, Kevin Harrington, Brendan Curti, Wallace Akerley, Sumati Gupta, Alan Melcher, David Mansfield, David R. Kaufman, Emmett Schmidt, Mark Grose, Bronwyn Davies, Roberta Karpathy, Darren Shafren, Katerina Shamalov, Cyrille Cohen, Naveen Sharma, James Allison, Tala Shekarian, Sandrine Valsesia-Wittmann, Christophe Caux, Aurelien Marabelle, Brian M. Slomovitz, Kathleen M. Moore, Hagop Youssoufian, Marshall Posner, Poonam Tewary, Alan D. Brooks, Ya-Ming Xu, Kithsiri Wijeratne, Leslie A. A. Gunatilaka, Thomas J. Sayers, John P. Vasilakos, Tesha Alston, Simon Dovedi, James Elvecrog, Iwen Grigsby, Ronald Herbst, Karen Johnson, Craig Moeckly, Stefanie Mullins, Kristen Siebenaler, Julius SternJohn, Ashenafi Tilahun, Mark A. Tomai, Katharina Vogel, Eveline E. Vietsch, Anton Wellstein, Martin Wythes, Stefano Crosignani, Joseph Tumang, Shilpa Alekar, Patrick Bingham, Sandra Cauwenberghs, Jenny Chaplin, Deepak Dalvie, Sofie Denies, Coraline De Maeseneire, JunLi Feng, Kim Frederix, Samantha Greasley, Jie Guo, James Hardwick, Stephen Kaiser, Katti Jessen, Erick Kindt, Marie-Claire Letellier, Wenlin Li, Karen Maegley, Reece Marillier, Nichol Miller, Brion Murray, Romain Pirson, Julie Preillon, Virginie Rabolli, Chad Ray, Kevin Ryan, Stephanie Scales, Jay Srirangam, Jim Solowiej, Al Stewart, Nicole Streiner, Vince Torti, Konstantinos Tsaparikos, Xianxian Zheng, Gregory Driessens, Bruno Gomes, Manfred Kraus, Chunxiao Xu, Yanping Zhang, Giorgio Kradjian, Guozhong Qin, Jin Qi, Xiaomei Xu, Bo Marelli, Huakui Yu, Wilson Guzman, Rober Tighe, Rachel Salazar, Kin-Ming Lo, Jessie English, Laszlo Radvanyi, Yan Lan, Michael Postow, Yasin Senbabaoglu, Billel Gasmi, Hong Zhong, Cailian Liu, Daniel Hirschhorhn-Cymerman, Yuanyuan Zha, Gregory Malnassy, Noreen Fulton, Jae-Hyun Park, Wendy Stock, Yusuke Nakamura, Hongtao Liu, Xiaoming Ju, Rachelle Kosoff, Kimberly Ramos, Brandon Coder, Robert Petit, Michael Princiotta, Kyle Perry, Jun Zou, Ainhoa Arina, Christian Fernandez, Wenxin Zheng, Michael A. Beckett, Helena J. Mauceri, Yang-Xin Fu, Ralph R. Weichselbaum, Whitney Lewis, Yanyan Han, Yeting Wu, Chou Yang, Jing Huang, Dongyun Wu, Jin Li, Xiaoling Liang, Xiangjun Zhou, Jinlin Hou, Raffit Hassan, Thierry Jahan, Scott J. Antonia, Hedy L. Kindler, Evan W. Alley, Somayeh Honarmand, Weiqun Liu, Meredith L. Leong, Chan C. Whiting, Nitya Nair, Amanda Enstrom, Edward E. Lemmens, Takahiro Tsujikawa, Sushil Kumar, Lisa M. Coussens, Aimee L. Murphy, Dirk G. Brockstedt, Sven D. Koch, Martin Sebastian, Christian Weiss, Martin Früh, Miklos Pless, Richard Cathomas, Wolfgang Hilbe, Georg Pall, Thomas Wehler, Jürgen Alt, Helge Bischoff, Michael Geissler, Frank Griesinger, Jens Kollmeier, Alexandros Papachristofilou, Fatma Doener, Mariola Fotin-Mleczek, Madeleine Hipp, Henoch S. Hong, Karl-Josef Kallen, Ute Klinkhardt, Claudia Stosnach, Birgit Scheel, Andreas Schroeder, Tobias Seibel, Ulrike Gnad-Vogt, Alfred Zippelius, Ha-Ram Park, Yong-Oon Ahn, Tae Min Kim, Soyeon Kim, Seulki Kim, Yu Soo Lee, Bhumsuk Keam, Dong-Wan Kim, Dae Seog Heo, Shari Pilon-Thomas, Amy Weber, Jennifer Morse, Krithika Kodumudi, Hao Liu, John Mullinax, Amod A. Sarnaik, Luke Pike, Andrew Bang, Tracy Balboni, Allison Taylor, Alexander Spektor, Tyler Wilhite, Monica Krishnan, Daniel Cagney, Brian Alexander, Ayal Aizer, Elizabeth Buchbinder, Mark Awad, Leena Ghandi, Jonathan Schoenfeld, Elizabeth Lessey-Morillon, Lisa Ridnour, Neil H. Segal, Manish Sharma, Dung T. Le, Robert L. Ferris, Andrew D. Zelenetz, Ronald Levy, Izidore S. Lossos, Caron Jacobson, Radhakrishnan Ramchandren, John Godwin, A. Dimitrios Colevas, Roland Meier, Suba Krishnan, Xuemin Gu, Jaclyn Neely, John Timmerman, Claire I. Vanpouille-Box, Silvia C. Formenti, Sandra Demaria, Erik Wennerberg, Aranzazu Mediero, Bruce N. Cronstein, Michael P. Gustafson, AriCeli DiCostanzo, Courtney Wheatley, Chul-Ho Kim, Svetlana Bornschlegl, Dennis A. Gastineau, Bruce D. Johnson, Allan B. Dietz, Cameron MacDonald, Mark Bucsek, Guanxi Qiao, Bonnie Hylander, Elizabeth Repasky, William J. Turbitt, Yitong Xu, Andrea Mastro, Connie J. Rogers, Sita Withers, Ziming Wang, Lam T. Khuat, Cordelia Dunai, Bruce R. Blazar, Dan Longo, Robert Rebhun, Steven K. Grossenbacher, Arta Monjazeb, William J. Murphy, Scott Rowlinson, Giulia Agnello, Susan Alters, David Lowe, Nicole Scharping, Ashley V. Menk, Ryan Whetstone, Xue Zeng, Greg M. Delgoffe, Patricia M. Santos, Jian Shi, Greg Delgoffe, Misako Nagasaka, Ammar Sukari, Miranda Byrne-Steele, Wenjing Pan, Xiaohong Hou, Brittany Brown, Mary Eisenhower, Jian Han, Natalie Collins, Robert Manguso, Hans Pope, Yashaswi Shrestha, Jesse Boehm, W. Nicholas Haining, Kyle R. Cron, Ayelet Sivan, Keston Aquino-Michaels, Marco Orecchioni, Davide Bedognetti, Wouter Hendrickx, Claudia Fuoco, Filomena Spada, Francesco Sgarrella, Gianni Cesareni, Francesco Marincola, Kostas Kostarelos, Alberto Bianco, Lucia Delogu, Jessica Roelands, Sabri Boughorbel, Julie Decock, Scott Presnell, Ena Wang, Franco M. Marincola, Peter Kuppen, Michele Ceccarelli, Darawan Rinchai, Damien Chaussabel, Lance Miller, Andrew Nguyen, J. Zachary Sanborn, Charles Vaske, Shahrooz Rabizadeh, Kayvan Niazi, Steven Benz, Shashank Patel, Nicholas Restifo, James White, Sam Angiuoli, Mark Sausen, Sian Jones, Maria Sevdali, John Simmons, Victor Velculescu, Luis Diaz, Theresa Zhang, Jennifer S. Sims, Sunjay M. Barton, Angela Kadenhe-Chiweshe, Filemon Dela Cruz, Andrew T. Turk, Christopher F. Mazzeo, Andrew L. Kung, Jeffrey N. Bruce, Darrell J. Yamashiro, Eileen P. Connolly, Jason Baird, Marka Crittenden, David Friedman, Hong Xiao, Rom Leidner, Bryan Bell, Kristina Young, Michael Gough, Zhen Bian, Koby Kidder, Yuan Liu, Emily Curran, Xiufen Chen, Leticia P. Corrales, Justin Kline, Ethan G. Aguilar, Jennifer Guerriero, Alaba Sotayo, Holly Ponichtera, Alexandra Pourzia, Sara Schad, Ruben Carrasco, Suzan Lazo, Roderick Bronson, Anthony Letai, Richard S. Kornbluth, Sachin Gupta, James Termini, Elizabeth Guirado, Geoffrey W. Stone, Christina Meyer, Laura Helming, Nicholas Wilson, Robert Hofmeister, Natalie J. Neubert, Laure Tillé, David Barras, Charlotte Soneson, Petra Baumgaertner, Donata Rimoldi, David Gfeller, Mauro Delorenzi, Silvia A. Fuertes Marraco, Daniel E. Speiser, Tara S. Abraham, Bo Xiang, Michael S. Magee, Scott A. Waldman, Adam E. Snook, Wojciech Blogowski, Ewa Zuba-Surma, Marta Budkowska, Daria Salata, Barbara Dolegowska, Teresa Starzynska, Leo Chan, Srinivas Somanchi, Kelsey McCulley, Dean Lee, Nico Buettner, Feng Shi, Paisley T. Myers, Stuart Curbishley, Sarah A. Penny, Lora Steadman, David Millar, Ellen Speers, Nicola Ruth, Gabriel Wong, Robert Thimme, David Adams, Mark Cobbold, Remy Thomas, Mariam Al-Muftah, Michael KK Wong, Michael Morse, Joseph I. Clark, Howard L. Kaufman, Gregory A. Daniels, Hong Hua, Tharak Rao, Janice P. Dutcher, Kai Kang, Yogen Saunthararajah, Vamsidhar Velcheti, Vikas Kumar, Firoz Anwar, Amita Verma, Zinal Chheda, Gary Kohanbash, John Sidney, Kaori Okada, Shruti Shrivastav, Diego A. Carrera, Shuming Liu, Naznin Jahan, Sabine Mueller, Ian F. Pollack, Angel M. Carcaboso, Alessandro Sette, Yafei Hou, Hideho Okada, Jessica J. Field, Weiping Zeng, Vincent FS Shih, Che-Leung Law, Peter D. Senter, Shyra J. Gardai, Nicole M. Okeley, Jennifer G. Abelin, Abu Z. Saeed, Stacy A. Malaker, Jeffrey Shabanowitz, Stephen T. Ward, Donald F. Hunt, Pam Profusek, Laura Wood, Dale Shepard, Petros Grivas, Kerstin Kapp, Barbara Volz, Detlef Oswald, Burghardt Wittig, Manuel Schmidt, Julian P. Sefrin, Lars Hillringhaus, Valeria Lifke, Alexander Lifke, Anna Skaletskaya, Jose Ponte, Thomas Chittenden, Yulius Setiady, Eva Sivado, Vincent Thomas, Meddy El Alaoui, Sébastien Papot, Charles Dumontet, Mike Dyson, John McCafferty, Said El Alaoui, Praveen K. Bommareddy, Andrew Zloza, Frederick Kohlhapp, Ann W. Silk, Sachin Jhawar, Tomas Paneque, Jenna Newman, Pedro Beltran, Felicia Cao, Bang-Xing Hong, Tania Rodriguez-Cruz, Xiao-Tong Song, Stephen Gottschalk, Hugo Calderon, Sam Illingworth, Alice Brown, Kerry Fisher, Len Seymour, Brian Champion, Emma Eriksson, Jessica Wenthe, Ann-Charlotte Hellström, Gabriella Paul-Wetterberg, Angelica Loskog, Ioanna Milenova, Magnus Ståhle, Justyna Jarblad-Leja, Gustav Ullenhag, Anna Dimberg, Rafael Moreno, Ramon Alemany, Sharad Goyal, Ann Silk, Janice Mehnert, Nashat Gabrail, Jennifer Bryan, Daniel Medina, Leah Mitchell, Kader Yagiz, Fernando Lopez, Daniel Mendoza, Anthony Munday, Harry Gruber, Douglas Jolly, Steven Fuhrmann, Sasa Radoja, Wei Tan, Aldo Pourchet, Alan Frey, Ian Mohr, Matthew Mulvey, Robert H. I. Andtbacka, Merrick Ross, Sanjiv Agarwala, Kenneth Grossmann, Matthew Taylor, John Vetto, Rogerio Neves, Adil Daud, Hung Khong, Stephanie M. Meek, Richard Ungerleider, Scott Welden, Maki Tanaka, Matthew Williams, Sigrun Hallmeyer, Bernard Fox, Zipei Feng, Christopher Paustian, Carlo Bifulco, Sadia Zafar, Otto Hemminki, Simona Bramante, Lotta Vassilev, Hongjie Wang, Andre Lieber, Silvio Hemmi, Tanja de Gruijl, Anna Kanerva, Tameem Ansari, Srividya Sundararaman, Diana Roen, Paul Lehmann, Anja C. Bloom, Lewis H. Bender, Ian B. Walters, Jay A. Berzofsky, Fanny Chapelin, Eric T. Ahrens, Jeff DeFalco, Michael Harbell, Amy Manning-Bog, Alexander Scholz, Danhui Zhang, Gilson Baia, Yann Chong Tan, Jeremy Sokolove, Dongkyoon Kim, Kevin Williamson, Xiaomu Chen, Jillian Colrain, Gregg Espiritu Santo, Ngan Nguyen, Wayne Volkmuth, Norman Greenberg, William Robinson, Daniel Emerling, Charles G. Drake, Daniel P. Petrylak, Emmanuel S. Antonarakis, Adam S. Kibel, Nancy N. Chang, Tuyen Vu, Dwayne Campogan, Heather Haynes, James B. Trager, Nadeem A. Sheikh, David I. Quinn, Peter Kirk, Murali Addepalli, Thomas Chang, Ping Zhang, Marina Konakova, Katsunobu Hagihara, Steven Pai, Laurie VanderVeen, Palakshi Obalapur, Peiwen Kuo, Phi Quach, Lawrence Fong, Deborah H. Charych, Jonathan Zalevsky, John L. Langowski, Yolanda Kirksey, Ravi Nutakki, Shalini Kolarkar, Rhoneil Pena, Ute Hoch, Stephen K. Doberstein, John Cha, Zach Mallon, Myra Perez, Amanda McDaniel, Snjezana Anand, Darrin Uecker, Richard Nuccitelli, Eva Wieckowski, Ravikumar Muthuswamy, Roshni Ravindranathan, Ariana N. Renrick, Menaka Thounaojam, Portia Thomas, Samuel Pellom, Anil Shanker, Duafalia Dudimah, Alan Brooks, Yu-Lin Su, Tomasz Adamus, Qifang Zhang, Sergey Nechaev, Marcin Kortylewski, Spencer Wei, Clark Anderson, Chad Tang, Jonathan Schoenhals, Efrosini Tsouko, John Heymach, Patricia de Groot, Joe Chang, Kenneth R. Hess, Adi Diab, Padmanee Sharma, David Hong, James Welsh, Andrea J. Parsons, Jardin Leleux, Stephane Ascarateil, Marie Eve Koziol, Dina Bai, Peihong Dai, Weiyi Wang, Ning Yang, Stewart Shuman, Liang Deng, Patrick Dillon, Gina Petroni, David Brenin, Kim Bullock, Walter Olson, Mark E. Smolkin, Kelly Smith, Carmel Nail, Craig L. Slingluff, Meenu Sharma, Faisal Fa’ak, Louise Janssen, Hiep Khong, Zhilan Xiao, Yared Hailemichael, Manisha Singh, Christina Vianden, Willem W. Overwijk, Andrea Facciabene, Pierini Stefano, Fang Chongyung, Stavros Rafail, Michael Nielsen, Peter Vanderslice, Darren G. Woodside, Robert V. Market, Ronald J. Biediger, Upendra K. Marathi, Kevin Hollevoet, Nick Geukens, Paul Declerck, Nathalie Joly, Laura McIntosh, Eustache Paramithiotis, Magnus Rizell, Malin Sternby, Bengt Andersson, Alex Karlsson-Parra, Rui Kuai, Lukasz Ochyl, Anna Schwendeman, James Moon, Weiwen Deng, Thomas E. Hudson, Bill Hanson, Chris S. Rae, Joel Burrill, Justin Skoble, George Katibah, Michele deVries, Peter Lauer, Thomas W. Dubensky, Xin Chen, Li Zhou, Xiubao Ren, Charu Aggarwal, Drishty Mangrolia, Roger Cohen, Gregory Weinstein, Matthew Morrow, Joshua Bauml, Kim Kraynyak, Jean Boyer, Jian Yan, Jessica Lee, Laurent Humeau, Sandra Oyola, Susan Duff, David Weiner, Zane Yang, Mark Bagarazzi, Douglas G. McNeel, Jens Eickhoff, Robert Jeraj, Mary Jane Staab, Jane Straus, Brian Rekoske, Glenn Liu, Marit Melssen, William Grosh, Nikole Varhegyi, Nadejda Galeassi, Donna H. Deacon, Elizabeth Gaughan, Maurizio Ghisoli, Minal Barve, Robert Mennel, Gladice Wallraven, Luisa Manning, Neil Senzer, John Nemunaitis, Masahiro Ogasawara, Shuichi Ota, Kaitlin M. Peace, Diane F. Hale, Timothy J. Vreeland, Doreen O. Jackson, John S. Berry, Alfred F. Trappey, Garth S. Herbert, Guy T. Clifton, Mark O. Hardin, Anne Toms, Na Qiao, Jennifer Litton, George E. Peoples, Elizabeth A. Mittendorf, Lila Ghamsari, Emilio Flano, Judy Jacques, Biao Liu, Jonathan Havel, Vladimir Makarov, Timothy A. Chan, Jessica B. Flechtner, John Facciponte, Stefano Ugel, Francesco De Sanctis, George Coukos, Sébastien Paris, Agnes Pottier, Laurent Levy, Bo Lu, Federica Cappuccini, Emily Pollock, Richard Bryant, Freddie Hamdy, Adrian Hill, Irina Redchenko, Hussein Sultan, Takumi Kumai, Valentyna Fesenkova, Esteban Celis, Ingrid Fernando, Claudia Palena, Justin M. David, Elizabeth Gabitzsch, Frank Jones, James L. Gulley, Mireia Uribe Herranz, Hiroshi Wada, Atsushi Shimizu, Toshihiro Osada, Satoshi Fukaya, Eiji Sasaki, Milad Abolhalaj, David Askmyr, Kristina Lundberg, Ann-Sofie Albrekt, Lennart Greiff, Malin Lindstedt, Dallas B. Flies, Tomoe Higuchi, Wojciech Ornatowski, Jaryse Harris, Sarah F. Adams, Todd Aguilera, Marjan Rafat, Laura Castellini, Hussein Shehade, Mihalis Kariolis, Dadi Jang, Rie vonEbyen, Edward Graves, Lesley Ellies, Erinn Rankin, Albert Koong, Amato Giaccia, Reham Ajina, Shangzi Wang, Jill Smith, Mariaelena Pierobon, Sandra Jablonski, Emanuel Petricoin, Louis M. Weiner, Lorcan Sherry, John Waller, Mark Anderson, Alison Bigley, Chantale Bernatchez, Cara Haymaker, Harriet Kluger, Michael Tetzlaff, Natalie Jackson, Ivan Gergel, Mary Tagliaferri, Patrick Hwu, Mario Snzol, Michael Hurwitz, Theresa Barberi, Allison Martin, Rahul Suresh, David Barakat, Sarah Harris-Bookman, Charles Drake, Alan Friedman, Sara Berkey, Stephanie Downs-Canner, Robert P. Edwards, Tyler Curiel, Kunle Odunsi, Tullia C. Bruno, Brandon Moore, Olivia Squalls, Peggy Ebner, Katherine Waugh, John Mitchell, Wilbur Franklin, Daniel Merrick, Martin McCarter, Brent Palmer, Jeffrey Kern, Dario Vignali, Jill Slansky, Anissa S. H. Chan, Xiaohong Qiu, Kathryn Fraser, Adria Jonas, Nadine Ottoson, Keith Gordon, Takashi O. Kangas, Steven Leonardo, Kathleen Ertelt, Richard Walsh, Mark Uhlik, Jeremy Graff, Nandita Bose, Ravi Gupta, Nitin Mandloi, Kiran Paul, Ashwini Patil, Rekha Sathian, Aparna Mohan, Malini Manoharan, Amitabha Chaudhuri, Yu Chen, Jing Lin, Yun-bin Ye, Chun-wei Xu, Gang Chen, Zeng-qing Guo, Andrey Komarov, Alex Chenchik, Michael Makhanov, Costa Frangou, Yi Zheng, Carla Coltharp, Darryn Unfricht, Ryan Dilworth, Leticia Fridman, Linying Liu, Milind Rajopadhye, Peter Miller, Fernando Concha-Benavente, Julie Bauman, Sumita Trivedi, Raghvendra Srivastava, James Ohr, Dwight Heron, Uma Duvvuri, Seungwon Kim, Heather Torrey, Toshi Mera, Yoshiaki Okubo, Eva Vanamee, Rosemary Foster, Denise Faustman, Edward Stack, Daisuke Izaki, Kristen Beck, Dan Tong Jia, Paul Armenta, Ashley White-Stern, Douglas Marks, Bret Taback, Basil Horst, Laura Hix Glickman, David B. Kanne, Kelsey S. Gauthier, Anthony L. Desbien, Brian Francica, Justin L. Leong, Leonard Sung, Ken Metchette, Shailaja Kasibhatla, Anne Marie Pferdekamper, Lianxing Zheng, Charles Cho, Yan Feng, Jeffery M. McKenna, John Tallarico, Steven Bender, Chudi Ndubaku, Sarah M. McWhirter, Elena Gonzalez Gugel, Charles J. M. Bell, Adiel Munk, Luciana Muniz, Nina Bhardwaj, Fei Zhao, Kathy Evans, Christine Xiao, Alisha Holtzhausen, Brent A. Hanks, Nathalie Scholler, Catherine Yin, Pien Van der Meijs, Andrew M. Prantner, Cecile M. Krejsa, Leia Smith, Brian Johnson, Daniel Branstetter, Paul L. Stein, Juan C. Jaen, Joanne BL Tan, Ada Chen, Timothy Park, Jay P. Powers, Holly Sexton, Guifen Xu, Steve W. Young, Ulrike Schindler, Wentao Deng, David John Klinke, Hannah M. Komar, Gregory Serpa, Omar Elnaggar, Philip Hart, Carl Schmidt, Mary Dillhoff, Ming Jin, Michael C. Ostrowski, Madhuri Koti, Katrina Au, Nichole Peterson, Peter Truesdell, Gillian Reid-Schachter, Charles Graham, Andrew Craig, Julie-Ann Francis, Beatrix Kotlan, Timea Balatoni, Emil Farkas, Laszlo Toth, Mihaly Ujhelyi, Akos Savolt, Zoltan Doleschall, Szabolcs Horvath, Klara Eles, Judit Olasz, Orsolya Csuka, Miklos Kasler, Gabriella Liszkay, Eytan Barnea, Collin Blakely, Patrick Flynn, Reid Goodman, Raphael Bueno, David Sugarbaker, David Jablons, V. Courtney Broaddus, Brian West, Paul R. Kunk, Joseph M. Obeid, Kevin Winters, Patcharin Pramoonjago, Edward B. Stelow, Todd W. Bauer, Osama E. Rahma, Adam Lamble, Yoko Kosaka, Fei Huang, Kate A. Saser, Homer Adams, Christina E. Tognon, Ted Laderas, Shannon McWeeney, Marc Loriaux, Jeffery W. Tyner, Brian J. Druker, Evan F. Lind, Zhuqing Liu, Shanhong Lu, Lawrence P. Kane, Gulidanna Shayan, Julia Femel, Ryan Lane, Jamie Booth, Amanda W. Lund, Anthony Rodriguez, Victor H. Engelhard, Alessandra Metelli, Bill X. Wu, Caroline W. Fugle, Rachidi Saleh, Shaoli Sun, Jennifer Wu, Bei Liu, Zihai Li, Zachary S. Morris, Emily I. Guy, Clinton Heinze, Jasdeep Kler, Monica M. Gressett, Lauryn R. Werner, Stephen D. Gillies, Alan J. Korman, Hans Loibner, Jacquelyn A. Hank, Alexander L. Rakhmilevich, Paul M. Harari, Paul M. Sondel, Erica Huelsmann, Joseph Broucek, Dorothee Brech, Tobias Straub, Martin Irmler, Johannes Beckers, Florian Buettner, Elke Schaeffeler, Matthias Schwab, Elfriede Noessner, Alison Wolfreys, Andre Da Costa, John Silva, Andrea Crosby, Ludovicus Staelens, Graham Craggs, Annick Cauvin, Sean Mason, Alison M. Paterson, Andrew C. Lake, Caroline M. Armet, Rachel W. O’Connor, Jonathan A. Hill, Emmanuel Normant, Ammar Adam, Detlev M. Biniszkiewicz, Scott C. Chappel, Vito J. Palombella, Pamela M. Holland, Annette Becker, Manmohan R. Leleti, Eric Newcomb, Joanne B. L. Tan, Suthee Rapisuwon, Arash Radfar, Kellie Gardner, Geoffrey Gibney, Michael Atkins, Keith R. Rennier, Robert Crowder, Ping Wang, Russell K. Pachynski, Rosa M. Santana Carrero, Sarai Rivas, Figen Beceren-Braun, Scott Anthony, Kimberly S. Schluns, Deepali Sawant, Maria Chikina, Hiroshi Yano, Creg Workman, Elise Salerno, Ileana Mauldin, Donna Deacon, Sofia Shea, Joel Pinczewski, Thomas Gajewski, Stefani Spranger, Brendan Horton, Akiko Suzuki, Pamela Leland, Bharat H. Joshi, Raj K. Puri, Randy F. Sweis, Riyue Bao, Jason Luke, Marie-Nicole Theodoraki, Frances-Mary Mogundo, Haejung Won, Dayson Moreira, Chan Gao, Xingli Zhao, Priyanka Duttagupta, Jeremy Jones, Massimo D’Apuzzo, and Sumanta Pal

Subjects
0301 basic medicine, Pharmacology, Cancer Research, medicine.medical_specialty, business.industry, medicine.medical_treatment, Immunology, Cancer, Immunotherapy, medicine.disease, 3. Good health, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, Family medicine, Molecular Medicine, Immunology and Allergy, Medicine, business
Abstract

O1 IL-15 primes an mTOR-regulated gene-expression program to prolong anti-tumor capacity of human natural killer cells #### Andreas Lundqvist1, Vincent van Hoef1, Xiaonan Zhang1, Erik Wennerberg2, Julie Lorent1, Kristina Witt1, Laia Masvidal Sanz1, Shuo Liang1, Shannon Murray3, Ola Larsson1

Published
2016
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15. Methicillin-Resistant Staphylococcus aureus Adaptation to Human Keratinocytes

Author

Christine T. Lauren, Armand O. Brown, Dane Parker, Franklin Paulino, Matthew Wickersham, Paul J. Planet, Emily S. West, Sarah Wachtel, Alice Prince, Dongni Zhang, Basil Horst, Margaret L. Dowd, and Grace Soong

Subjects
Keratinocytes, Methicillin-Resistant Staphylococcus aureus, RNAIII, Bacterial Toxins, Adaptation, Biological, Biology, medicine.disease_cause, Microbiology, Mice, Immune system, Bacterial Proteins, Virology, Autophagy, medicine, Animals, Humans, Immune Evasion, Pyroptosis, Inflammasome, biochemical phenomena, metabolism, and nutrition, bacterial infections and mycoses, Methicillin-resistant Staphylococcus aureus, QR1-502, medicine.anatomical_structure, Staphylococcus aureus, Immunology, Trans-Activators, Keratinocyte, Research Article, medicine.drug
Abstract

Skin is the most common site of Staphylococcus aureus infection. While most of these infections are self-limited, recurrent infections are common. Keratinocytes and recruited immune cells participate in skin defense against infection. We postulated that S. aureus is able to adapt to the milieu within human keratinocytes to avoid keratinocyte-mediated clearance. From a collection of S. aureus isolated from chronically infected patients with atopic dermatitis, we noted 22% had an agr mutant-like phenotype. Using several models of human skin infection, we demonstrate that toxin-deficient, agr mutants of methicillin-resistant S. aureus (MRSA) USA300 are able to persist within keratinocytes by stimulating autophagy and evading caspase-1 and inflammasome activation. MRSA infection induced keratinocyte autophagy, as evidenced by galectin-8 and LC3 accumulation. Autophagy promoted the degradation of inflammasome components and facilitated staphylococcal survival. The recovery of more than 58% agr or RNAIII mutants (P < 0.0001) of an inoculum of wild-type (WT) MRSA from within wortmannin-treated keratinocytes compared to control keratinocytes reflected the survival advantage for mutants no longer expressing agr-dependent toxins. Our results illustrate the dynamic interplay between S. aureus and keratinocytes that can result in the selection of mutants that have adapted specifically to evade keratinocyte-mediated clearance mechanisms., IMPORTANCE Human skin is a major site of staphylococcal infection, and keratinocytes actively participate in eradication of these pathogens. We demonstrate that methicillin-resistant Staphylococcus aureus (MRSA) is ingested by keratinocytes and activates caspase-1-mediated clearance through pyroptosis. Toxin-deficient MRSA mutants are selected within keratinocytes that fail to induce caspase-1 activity and keratinocyte-mediated clearance. These intracellular staphylococci induce autophagy that enhances their intracellular survival by diminishing inflammasome components. These findings suggest that S. aureus mutants, by exploiting autophagy, can persist within human keratinocytes.

Published
2015
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16. Microsatellite profiles reveal an unexpected genetic relationship between Asian populations

Author

Torpong Sanguansermsri, Jürgen Horst, Antonin Eigel, Basil Horst, Bernd Brinkmann, and B. Rolf

Subjects
Genetics, education.field_of_study, Asia, Phylogenetic tree, Genetic heterogeneity, Population, Population genetics, Genetic relationship, Biology, White People, Asian People, Gene Frequency, Genetic distance, Germany, Humans, Microsatellite, education, Allele frequency, Alleles, Genetics (clinical), Microsatellite Repeats
Abstract

Allelic frequencies for up to five short tandem repeat systems (HumTH01. HumVWA, HumF13B, HumCD4, HumD2111) were analyzed in seven population samples from Asia using the polymerase chain reaction and gel electrophoresis. No deviations from Hardy-Weinberg equilibrium were observed. Two new alleles of the CD4 and TH01 loci were detected, and sequenced and their molecular structure is presented. A phylogenetic tree based on Thai, Han Chinese (from the northeast of China), Japanese, German and Ovambo allelic frequencies was constructed and demonstrates the close relationship of the Asian populations. Additionally, allelic frequency data for the VWA and TH01 systems were determined for the south Chinese minorities Bai, Dai and Qiang and for Koreans and compared with the above data. The Bai and Dai populations were clear outliers of the cluster of all other Asians, indicating an unexpected pattern of genetic heterogeneity of the Chinese nation. Two clusters of Asian populations could be established: the Koreans and Japanese together with the Han and Qiang Chinese, and, forming a separate cluster, the Bai and Dai populations.

Published
1998
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17. Large-scale mitochondrial DNA analysis in Southeast Asia reveals evolutionary effects of cultural isolation in the multi-ethnic population of Myanmar

Author

Lukas Forer, Monika Summerer, Anita Kloss-Brandstätter, Jürgen Horst, Basil Horst, Angelika Manhart, Torpong Sanguansermsri, Sebastian Schönherr, David Horst, Dominic Pacher, Gertraud Erhart, and Hansi Weissensteiner

Subjects
Karen, Demographic history, Population genetics, Population, Culture, Myanmar, Biology, Bamar, Southeast asian, DNA, Mitochondrial, Burma, Haplogroup, White People, Burmese, Evolution, Molecular, Control region, Asian People, Genetics, Humans, education, Ecology, Evolution, Behavior and Systematics, Asia, Southeastern, Phylogeny, Migration, mtDNA control region, education.field_of_study, Base Sequence, Southeast Asia, Mitochondrial DNA, language.human_language, humanities, Gene flow, Genetics, Population, Haplotypes, Complete mtDNA genome, Evolutionary biology, FOS: Biological sciences, Genome, Mitochondrial, language, Human mitochondrial DNA haplogroup, Research Article
Abstract

Background: Myanmar is the largest country in mainland Southeast Asia with a population of 55 million people subdivided into more than 100 ethnic groups. Ruled by changing kingdoms and dynasties and lying on the trade route between India and China, Myanmar was influenced by numerous cultures. Since its independence from British occupation, tensions between the ruling Bamar and ethnic minorities increased. Results: Our aim was to search for genetic footprints of Myanmar’s geographic, historic and sociocultural characteristics and to contribute to the picture of human colonization by describing and dating of new mitochondrial DNA (mtDNA) haplogroups. Therefore, we sequenced the mtDNA control region of 327 unrelated donors and the complete mitochondrial genome of 44 selected individuals according to highest quality standards. Conclusion: Phylogenetic analyses of the entire mtDNA genomes uncovered eight new haplogroups and three unclassified basal M-lineages. The multi-ethnic population and the complex history of Myanmar were reflected in its mtDNA heterogeneity. Population genetic analyses of Burmese control region sequences combined with population data from neighboring countries revealed that the Myanmar haplogroup distribution showed a typical Southeast Asian pattern, but also Northeast Asian and Indian influences. The population structure of the extraordinarily diverse Bamar differed from that of the Karen people who displayed signs of genetic isolation. Migration analyses indicated a considerable genetic exchange with an overall positive migration balance from Myanmar to neighboring countries. Age estimates of the newly described haplogroups point to the existence of evolutionary windows where climatic and cultural changes gave rise to mitochondrial haplogroup diversification in Asia.

Published
2013

18. Can Plant-Made Copper Chaperones Heal Early Alzheimer’s Disease?

Author

Bernd Kastenholz, Basil Horst, and Jürgen Horst

Subjects
fungi, General Materials Science
Abstract

Commercially available medicinal plant extracts such as Ginkgo biloba leaf extract show no consistent pattern of clinical benefit for people with dementia or cognitive impairment, and have been suggested to be toxic to cells at higher doses. However, medicinal plants may contain other more efficient bioactive molecules apart from the well-known flavonoids and terpenoids. Therapeutic recombinant proteins, plant-made copper chaperone for superoxide dismutase (CCS) derived from Ginkgo biloba leaves, may establish and maintain physiologic Cu levels through restoration and modulation of biometal metabolism in organ systems of younger Alzheimer patients (> 50 years). Medications developed from plant-made copper chaperone proteins may delay progression during early disease stages or even be a basis for a possible causal treatment of preclinical stages of Alzheimer’s disease by preventing formation of A β plaques in the brain, a major putative factor involved in Alzheimer’s disease pathogenesis.

Published
2011
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19. Southeast Asian diversity: first insights into the complex mtDNA structure of Laos

Author

Jürgen Horst, Alexander W. Röck, Peter M. Schneider, David Horst, Bettina Zimmermann, Tanja Krämer, Anita Kloss-Brandstätter, Martin Bodner, Sourideth Sengchanh, Walther Parson, Torpong Sanguansermsri, and Basil Horst

Subjects
Male, Entomology, Mitochondrial DNA, Evolution, Population, Biology, Southeast asian, DNA, Mitochondrial, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Asian People, Genetic variation, Genetics, QH359-425, Humans, 030216 legal & forensic medicine, education, Ecology, Evolution, Behavior and Systematics, Phylogeny, 030304 developmental biology, mtDNA control region, 0303 health sciences, education.field_of_study, Haplotype, DNA, Sequence Analysis, DNA, Genetics, Population, Haplotypes, Evolutionary biology, Laos, FOS: Biological sciences, Genetic structure, Female, Research Article
Abstract

Background Vast migrations and subsequent assimilation processes have shaped the genetic composition of Southeast Asia, an area of close contact between several major ethnic groups. To better characterize the genetic variation of this region, we analyzed the entire mtDNA control region of 214 unrelated donors from Laos according to highest forensic quality standards. To detail the phylogeny, we inspected selected SNPs from the mtDNA coding region. For a posteriori data quality control, quasi-median network constructions and autosomal STR typing were performed. In order to describe the mtDNA setup of Laos more thoroughly, the data were subjected to population genetic comparisons with 16 East Asian groups. Results The Laos sample exhibited ample mtDNA diversity, reflecting the huge number of ethnic groups listed. We found several new, so far undescribed mtDNA lineages in this dataset and surrounding populations. The Laos population was characteristic in terms of haplotype composition and genetic structure, however, genetic comparisons with other Southeast Asian populations revealed limited, but significant genetic differentiation. Notable differences in the maternal relationship to the major indigenous Southeast Asian ethnolinguistic groups were detected. Conclusions In this study, we portray the great mtDNA variety of Laos for the first time. Our findings will contribute to clarify the migration history of the region. They encourage setting up regional and subpopulation databases, especially for forensic applications. The Laotian sequences will be incorporated into the collaborative EMPOP mtDNA database http://www.empop.org upon publication and will be available as the first mtDNA reference data for this country.

Published
2010

20. Gab2-mediated signaling promotes melanoma metastasis

Author

Ramon Parsons, Ijeoma Uzoma, Volker Schwipper, Ying Yang, Karen A. Chernoff, David F. Owens, Georg Brunner, David L. Rimm, Julide Tok Celebi, Benjamin D. Hopkins, J. Liebau, Sofia K. Gruvberger-Saal, Norma J. Nowak, Lindsey Bordone, and Basil Horst

Subjects
Chromosomes, Artificial, Bacterial, medicine.medical_treatment, Blotting, Western, Gene Dosage, Fluorescent Antibody Technique, Biology, Polymorphism, Single Nucleotide, Pathology and Forensic Medicine, Metastasis, Cell Movement, medicine, Biomarkers, Tumor, Gene silencing, Humans, Neoplasm Invasiveness, Neoplasm Metastasis, Protein kinase B, neoplasms, Melanoma, In Situ Hybridization, Fluorescence, Adaptor Proteins, Signal Transducing, Oligonucleotide Array Sequence Analysis, Comparative Genomic Hybridization, Reverse Transcriptase Polymerase Chain Reaction, Growth factor, Cancer, medicine.disease, Tumor progression, Tissue Array Analysis, Cancer research, Signal transduction, Signal Transduction, Regular Articles
Abstract

Metastatic melanoma is a disease with a poor prognosis that currently lacks effective treatments. Critical biological features of metastasis include acquisition of migratory competence, growth factor independence, and invasive potential. In an attempt to identify genes that contribute to melanoma pathogenesis, a genome-wide search using bacterial artificial chromosome array comparative genomic hybridization and single nucleotide polymorphism arrays in a series of 64 metastatic melanoma samples and 20 melanoma cell lines identified increased copy numbers of Gab2 located on 11q14.1. Gab2 is an adaptor protein that potentiates the activation of the Ras-Erk and PI3K-Akt pathways and has recently been implicated in human cancer; however, its role in melanoma has not been explored. In this study, we found that Gab2 was either amplified (approximately 11%) and/or overexpressed (approximately 50%) in melanoma. Gab2 protein expression correlated with clinical melanoma progression, and higher levels of expression were seen in metastatic melanomas compared with primary melanoma and melanocytic nevi. We found that overexpression of Gab2 potentiates, whereas silencing of Gab2 reduces, migration and invasion of melanoma cells. Gab2 mediated the hyperactivation of Akt signaling in the absence of growth factors, whereas inhibition of the PI3K-Akt pathway decreased Gab2-mediated tumor cell migration and invasive potential. Gab2 overexpression resulted in enhanced tumor growth and metastatic potential in vivo. These studies demonstrate a previously undefined role for Gab2 in melanoma tumor progression and metastasis.

Published
2009

21. Loss of S100A9 (MRP14) results in reduced interleukin-8-induced CD11b surface expression, a polarized microfilament system, and diminished responsiveness to chemoattractants in vitro

Author

Frank Schönlau, Clemens Sorg, Stephan Seeliger, Basil Horst, Johannes Roth, Boris V. Skryabin, Wolfgang Nacken, Anke Strey, Werner Frings, Marie-Pierre Manitz, and Matthias Gunzer

Subjects
Neutrophils, Medizin, Chemokinesis, Biology, Models, Biological, S100A9, Mice, In vivo, Cell Adhesion, Mammalian Genetic Models with Minimal or Complex Phenotypes, medicine, Animals, Calgranulin B, Calgranulin A, Interleukin 8, Molecular Biology, Mice, Knockout, CD11b Antigen, Interleukin-8, Chemotaxis, Cell Biology, Actin cytoskeleton, Cell biology, Mice, Inbred C57BL, Actin Cytoskeleton, Chemotaxis, Leukocyte, medicine.anatomical_structure, Integrin alpha M, Gene Targeting, biology.protein, Collagen, Bone marrow
Abstract

The S100A9 (MRP14) protein is abundantly expressed in myeloid cells and has been associated with various inflammatory diseases. The S100A9-deficient mice described here were viable, fertile, and generally of healthy appearance. The myelopoietic potential of the S100A9-null bone marrow was normal. S100A8, the heterodimerization partner of S100A9 was not detectable in peripheral blood cells, suggesting that even a deficiency in both S100A8 and S100A9 proteins was compatible with viable and mature neutrophils. Surprisingly, the invasion of S100A9-deficient leukocytes into the peritoneum and into the skin in vivo was indistinguishable from that in wild-type mice. However, stimulation of S100A9-deficient neutrophils with interleukin-8 in vitro failed to provoke an up-regulation of CD11b. Migration upon a chemotactic stimulus through an endothelial monolayer was markedly diminished in S100A9-deficient neutrophils. Attenuated chemokinesis of the S100A9-deficient neutrophils was observed by using a three-dimensional collagen matrix migration assay. The altered migratory behavior was associated with a microfilament system that was highly polarized in unstimulated S100A9-deficient neutrophils. Our data suggest that loss of the calcium-binding S100A9 protein reduces the responsiveness of the neutrophils upon chemoattractant stimuli at least in vitro. Alternative pathways for neutrophil emigration may be responsible for the lack of any effect in the two in vivo models we have investigated so far.

Published
2003

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