tbuckley/cabot-search huggingface dataset:
Autologous Vs. Allogeneic Stem Cell Transplantation in Double-Expressor Lymphoma
Authors: Issa F. Khouri, Stephen K. Gruschkus, Celina Ledesma, Paolo Anderlini, Qaiser Bashir, May Daher, Swami P. Iyer, David Marin, Rohtesh Mehta, Amanda L. Olson, Uday R. Popat, Felipe Samaniego, Muzaffar H. Qazilbash, Jin S. Im, Gabriela Rondon, Richard E. Champlin, Alison Gulbis, Ken H. Young
Journal: Blood (2020)
Safety and Efficacy of the Contact Activation Inhibitor AB023 in Patients with End-Stage Renal Disease on Chronic Hemodialysis: A Phase 2, Double-Blind, Randomized, Placebo-Controlled Trial
Authors: Christina U Lorentz, Norah G Verbout, Joseph J Shatzel, Michael Wallisch, Brandon D Markway, Monica T Hinds, Owen J T McCarty, David Gailani, Jeffrey I. Weitz, Erik I Tucker, András Gruber
Journal: Blood (2020)
Abstract IA17: Measuring and modeling cancer evolution with single cell approaches
Authors: Sohrab Shah
Journal: Cancer Research (2020)

Abstract In this talk, I will provide an overview or advances in single cell whole genome sequencing to study the properties of cancer evolution. Using recently published direct library preparation (DLP+) we used scaled timeseries analysis of model systems to derive predictive models of clone-specific fitness. We defined both genetic and pharmacologic perturbations and measured clonal population abundances at single cell resolution over granular time intervals. We then combined the statistical power of phylogenetics and population genetics to quantitate fitness coefficients of distinct clones. We show how our models are predictive through reproducibility experiments and provide a quantitative formalism to interpret the impact perturbations on fitness landscapes. We show that systemic chemotherapy can dramatically alter the fitness properties of cancer cells leading to clone-specific expansion of resistant populations and eradication of high fitness clones in the untreated context. Our results have implication for how to effectively model the impact of drug selection in pre-clinical model systems. Citation Format: Sohrab Shah. Measuring and modeling cancer evolution with single cell approaches [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr IA17.
Mutational Landscape of Relapsed Core-Binding Factor Acute Myeloid Leukemia (CBF-AML)
Authors: Anna Dolnik, Nikolaus Jahn, Eric Sträng, Sibylle Cocciardi, Frank G. Rücker, Ekaterina Panina, Tamara J. Blätte, Julia Katharina Herzig, Andrea Corbacioglu, Daniela Weber, Anika Schrade, Verena I Gaidzik, Sabrina Skambraks, Katharina S. Götze, Michael Luebbert, Walter Fiedler, Thomas Schroeder, Corinna Hahn, Felicitas Thol, Michael Heuser, Arnold Ganser, Peter Paschka, Hartmut Döhner, Konstanze Döhner, Lars Bullinger
Journal: Blood (2020)
Clinical, Molecular, and Prognostic Comparisons between Clonal Cytopenias of Undetermined Significance and Lower-Risk Myelodysplastic Syndromes - a Study of 184 Molecularly Annotated Patients
Authors: Marissa Li, Terra Lasho, Alejandro Ferrer, Naseema Gangat, Aref Al-Kali, Abhishek A. Mangaonkar, Michelle Elliot, Mark Litzow, William J Hogan, Animesh Pardanani, Alexandra Wolanskyj-Spinner, Kaaren K. Reichard, Matthew T Howard, Rebecca L. King, Mithun Vinod Shah, Hassan B. Alkhateeb, Kebede H. Begna, Ayalew Tefferi, Christy Finke, Moritz Binder, Horatiu Olteanu, Mrinal M. Patnaik
Journal: Blood (2020)
Once Weekly Selinexor, Bortezomib, and Dexamethasone Versus Twice Weekly Bortezomib and Dexamethasone in Relapsed or Refractory Multiple Myeloma: Age and Frailty Subgroup Analyses from the Phase 3 Boston Study
Authors: Holger W Auner, Maria Gavriatopoulou, Sosana Delimpasi, Maryana Simonova, Ivan Spicka, Ludek Pour, Meletios A Dimopoulos, Irina Kryachok, Halyna Pylypenko, Xavier Leleu, Vadim A Doronin, Ganna Usenko, Roman Hajek, Reuben Benjamin, Tuphan Kanti Dolai, Dinesh Kumar Sinha, Christopher P. Venner, Mamta Garg, Don A. Stevens, Hang Quach, Sundar Jagannath, Philippe Moreau, Moshe Y. Levy, Ashraf Z. Badros, Larry D. Anderson, Nizar J. Bahlis, Thierry Facon, Maria Mateos, Michele Cavo, Anita A. Joshi, Yi Chai, Melina Arazy, Jatin Shah, Sharon Shacham, Michael G Kauffman, Paul G. Richardson, Sebastian Grosicki
Journal: Blood (2020)
Transcriptomes of Major Proximal Tubule Cell Culture Models
Authors: Syed J. Khundmiri, Lihe Chen, Eleanor D. Lederer, Chin-Rang Yang, Mark A. Knepper
Journal: Journal of the American Society of Nephrology (2020)

Cultured cell lines are widely used for research in the physiology, pathophysiology, toxicology, and pharmacology of the renal proximal tubule. The lines that are most appropriate for a given use depend upon the genes expressed. New tools for transcriptomic profiling using RNA sequencing (RNA-Seq) make it possible to catalog expressed genes in each cell line.
Comparison of Haploidentical Bone Marrow versus Matched Unrelated Donor Peripheral Blood Stem Cell Transplantation with Posttransplant Cyclophosphamide in Patients with Acute Leukemia
Authors: Arnon Nagler, Myriam Labopin, Bhagirathbhai Dholaria, Emanuele Angelucci, Boris Afanasyev, Jan J. Cornelissen, Simona Sica, Ellen Meijer, Fabio Ciceri, Gwendolyn Van Gorkom, Nicolaus Kröger, Hans Martin, Pietro Pioltelli, Antonio Risitano, Jonathan Canaani, Bipin N. Savani, Jaime Sanz, Mohamad Mohty
Journal: Clinical Cancer Research (2020)

Posttransplant cyclophosphamide (PTCy) is increasingly being utilized as a principle GvHD prophylaxis strategy in allogeneic hematopoietic cell transplantation (allo-HCT). A haploidentical (haplo) or matched unrelated donor (UD) is a valid option in the absence of a matched related donor.We compared the outcomes of patients with acute leukemia who underwent haplo bone marrow (haplo-BM, N = 401) versus UD mobilized peripheral blood stem cells (UD-PB, N = 192) transplantation in the setting of PTCy.The median follow-up duration was 36 months in the haplo-BM group and 16.6 months in the UD-PB group, respectively (P < 0.01). Myeloablative conditioning was used in 64.6% and 42.7% of haplo-BM and UD-PB patients, respectively (P < 0.01). Cumulative incidence of neutrophil engraftment at day 30 was 87% in haplo-BM versus 94% in UD-PB, respectively (P = 0.21). In the multivariate analysis, the risk of grade 2-4 acute GvHD (HR = 0.53, P = 0.01) and chronic GvHD (HR = 0.50, P = 0.02) was significantly lower in the haplo-BM group compared with the UD-PB group. There was no significant difference between the study groups with respect to relapse incidence, nonrelapse mortality, leukemia-fee survival, overall survival, or GvHD-free and relapse-free survival.The use of a haplo donor with a BM graft resulted in a lower incidence of GvHD compared with a UD-PB stem cell graft in the setting of PTCy for patients with acute leukemia. However, differences in GvHD did not translate into a difference in survival outcomes. Based upon these data, UD-PB or haplo-BM should be considered equally acceptable sources for allo-HCT.
Timing of Daratumumab Administered Pre-Mobilization in Multiple Myeloma Impacts Pre-Harvest Peripheral Blood CD34+ Cell Counts and Plerixafor Use
Authors: Danny Luan, Paul J Christos, Michael Ancharski, Danielle Guarneri, Roger Pearse, Adriana C Rossi, Tsiporah B. Shore, Sebastian Mayer, Adrienne A. Phillips, Jingmei Hsu, Ljiljana V. Vasovic, Yen-Michael S. Hsu, Koen van Besien, Ruben Niesvizky, Cara A. Rosenbaum
Journal: Blood (2020)
Genomic Analysis of <i>FLT3</i> Mutations in a Comprehensive NGS Multicenter Study of AML: HM-Screen-Japan 01
Authors: Kentaro Fukushima, SungGi Chi, Hirohiko Shibayama, Naoko Hosono, Takahiro Yamauchi, Seiichiro Katagiri, Akihiko Gotoh, Takanobu Morishita, Masamitsu Yanada, Kazuhito Yamamoto, Naohito Fujishima, Naoto Takahashi, Reiki Ogasawara, Takeshi Kondo, Yoshikazu Utsu, Nobuyuki Aotsuka, Kensuke Usuki, Takaaki ONO, Tsutomu Kobayashi, Junya Kuroda, Hiroto Horiguchi, Satoshi Iyama, Suguru Fukuhara, Koji Izutsu, Makoto Nakamura, Kensuke Kojima, Kenichi Miyamoto, Yosuke Minami
Journal: Blood (2020)
Molecular Subgroups of T Cell Acute Lymphoblastic Leukemia in Adults Treated According to GMALL Protocols
Authors: Martin Neumann, Lorenz Bastian, Sonja Hänzelmann, Alina Hartmann, Heiko Trautmann, Jutta Ortiz Tanchez, Cornelia Schlee, Michael P Schroeder, Lars R. Fransecky, Sebastian Vosberg, Walter Fiedler, Nael Alakel, Mustafa Kondakci, Michael Starck, Stefan Schwartz, Carsten Müller-Tidow, Folker Schneller, Albert Reichle, Thomas Burmeister, Philipp A. Greif, Monika Brüggemann, Nicola Goekbuget, Claudia D Baldus
Journal: Blood (2020)
IL-10–producing innate lymphoid cells increased in patients with house dust mite allergic rhinitis following immunotherapy
Authors: Tadech Boonpiyathad, Pongsakokorn Tantilipikorn, Kiat Ruxrungtham, Panitan Pradubpongsa, Wat Mitthamsiri, Aurélie Piedvache, Pattarawat Thantiworasit, Sunee Sirivichayakul, Alain Jacquet, Narissara Suratannon, Pantipa Chatchatee, Naho Morisaki, Hirohisa Saito, Atik Sangasapaviriya, Kenji Matsumoto, Hideaki Morita
Journal: Journal of Allergy and Clinical Immunology (2020)
Single Cell Profiling Reveals Unique CXCL13 Positive T Cell Subsets in the Tumor Microenvironment of Lymphocyte Rich Classic Hodgkin Lymphoma
Authors: Tomohiro Aoki, Lauren C. Chong, Katsuyoshi Takata, Katy Milne, Elizabeth Chavez, Tomoko Miyata-Takata, Susana Ben-Neriah, Doria Unrau, Adele Telenius, Merrill Boyle, Pedro Farinha, Andrew P. Weng, Kerry J. Savage, David W. Scott, Sohrab P Shah, Brad H. Nelson, Christian Steidl
Journal: Blood (2020)
Whole-Genome Analysis of Adult T-Cell Leukemia/Lymphoma
Authors: Yasunori Kogure, Takuro Kameda, Junji Koya, Ayako Kamiunten, Kotaro Shide, Tomonori Hidaka, Yoko Kubuki, Makoto Yoshimitsu, Kisato Nosaka, Yoshitaka Imaizumi, Mizuki Watanabe, Yuki Saito, Marni B McClure, Mariko Tabata, Sumito Shingaki, Kota Yoshifuji, Yuichi Shiraishi, Michihiro Hidaka, Atae Utsunomiya, Urvi A. Shah, Ana Acuna-Villaorduna, Aditi Shastri, R. Alejandro Sica, Murali Janakiram, Juan Carlos Ramos, Tatsuhiro Shibata, Akifumi Takaori-Kondo, Yasushi Miyazaki, Masao Matsuoka, Kenji Ishitsuka, Seishi Ogawa, B. Hilda Ye, Kazuya Shimoda, Keisuke Kataoka
Journal: Blood (2020)
The experience of point-of-care testing for influenza in Scotland in 2017/18 and 2018/19 – no gain without pain
Authors: Elizabeth M Dickson, Diogo FP Marques, Sandra Currie, Annette Little, Kirsty Mangin, Michael Coyne, Arlene Reynolds, Jim McMenamin, David Yirrell
Journal: Eurosurveillance (2020)

BackgroundDuring the 2017/18 and 2018/19 influenza seasons, molecular amplification-based point-of-care tests (mPOCT) were introduced in Scotland to aid triaging respiratory patients for hospital admission, yet communication of results to national surveillance was unaccounted for.AimThis retrospective study aims to describe steps taken to capture mPOCT data and assess impact on influenza surveillance.MethodsQuestionnaires determined mPOCT usage in 2017/18 and 2018/19. Searches of the Electronic Communication of Surveillance in Scotland (ECOSS) database were performed and compared with information stored in laboratory information management systems. Effect of incomplete data on surveillance was determined by comparing routine against enhanced data and assessing changes in influenza activity levels determined by the moving epidemic method.ResultsThe number of areas employing mPOCT increased over the two seasons (6/14 in 2017/18 and 8/14 in 2018/19). Analysis of a small number of areas (n = 3) showed capture of positive mPOCT results in ECOSS improved between seasons and remained high (> 94%). However, capture of negative results was incomplete. Despite small discrepancies in weekly activity assessments, routine data were able to identify trend, start, peak and end of both influenza seasons.ConclusionThis study has shown an improvement in capture of data from influenza mPOCT and has highlighted issues that need to be addressed for results to be accurately captured in national surveillance. With the clear benefit to patient management we suggest careful consideration should be given to the connectivity aspects of the technology in order to ensure minimal impact on national surveillance.
The Echelon-2 Trial: 5-Year Results of a Randomized, Double-Blind, Phase 3 Study of Brentuximab Vedotin and CHP (A+CHP) Versus CHOP in Frontline Treatment of Patients with CD30-Positive Peripheral T-Cell Lymphoma
Authors: Steven M. Horwitz, Owen A. O'Connor, Barbara Pro, Tim Illidge, Swami P. Iyer, Ranjana Advani, Nancy L. Bartlett, Jacob Haaber Christensen, Franck Morschhauser, Eva Domingo-Domenech, Giuseppe Rossi, Won Seog Kim, Tatyana A. Feldman, Tobias Menne, David Belada, Árpád Illés, Kensei Tobinai, Kunihiro Tsukasaki, Su-Peng Yeh, Andrei R Shustov, Andreas Hüttmann, Kerry J. Savage, Sam Yuen, Pier Luigi Zinzani, Harry Miao, Veronica Bunn, Keenan Fenton, Michelle A. Fanale, Markus Puhlmann, Lorenz Truemper
Journal: Blood (2020)
Myelodysplastic Syndromes with 20q Deletion: Incidence, Prognostic Value and Impact on Response to Azacitidine of <i>ASXL1</i> Chromosomal Deletion and Genetic Mutations
Authors: Iván Martín, Eva Villamón, Rosario Abellán, Maria Jose Calasanz, Aroa Irigoyen, Guillermo F Sanz, Esperanza Such, Elvira Mora Casterá, Míriam Gutiérrez, Rosa Collado, Míriam Vara, Laura Blanco, Itziar Oiartzabal, Sara Álvarez, Teresa Bernal del Castillo, Isabel Granada, Blanca Xicoy, Lurdes Zamora, Andres Jerez, Raquel Fernández, Marisa Calabuig, Francisca García, Alejandro Sanz, Rosana Díez, Ángela Gil, Raquel de Paz, Francisca López, Teresa González, Carlos Solano, Mar Tormo
Journal: Blood (2020)
Multiplexed CRISPR <i>In Vivo</i> Editing of CLL Loss-of-Function Lesions Models Transformation of Chronic Lymphocytic Leukemia into Richter's Syndrome
Authors: Elisa Ten Hacken, Tomasz Sewastianik, Robert A. Redd, Geoffrey Fell, Mohamed Uduman, Michaela Gruber, Shanye Yin, Kendell Clement, Erin Michelle Parry, Shuqiang Li, Maria Hernandez-Sanchez, Leah Billington, Elizabeth Witten, Kaitlyn J Baranowski, Lili Wang, Luca Pinello, Kenneth J. Livak, Donna S. Neuberg, Ruben D. Carrasco, Catherine J. Wu
Journal: Blood (2020)
Cabozantinib-based combination therapy for the treatment of hepatocellular carcinoma
Authors: Runze Shang, Xinhua Song, Pan Wang, Yi Zhou, Xinjun Lu, Jingxiao Wang, Meng Xu, Xinyan Chen, Kirsten Utpatel, Li Che, Binyong Liang, Antonio Cigliano, Matthias Evert, Diego F Calvisi, Xin Chen
Journal: Gut (2020)

Objective Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer with limited treatment options. Cabozantinib, an orally bioavailable multikinase inhibitor is now approved by Food and Drug Administration (FDA) for HCC patients. We evaluated the therapeutic efficacy of cabozantinib, either alone or in combination, in vitro and in vivo. Design Human HCC cell lines and HCC mouse models were used to assess the therapeutic efficacy and targeted molecular pathways of cabozantinib, either alone or in combination with the pan-mTOR inhibitor MLN0128 or the checkpoint inhibitor anti-PD-L1 antibody. Results Cabozantinib treatment led to stable disease in c-Met/β-catenin and Akt/c-Met mouse HCC while possessing limited efficacy on Akt/Ras and c-Myc liver tumours. Importantly, cabozantinib effectively inhibited c-MET and ERK activity, leading to decreased PKM2 and increased p21 expression in HCC cells and in c-Met/β-catenin and Akt/c-Met HCC. However, cabozantinib was ineffective in inhibiting the Akt/mTOR cascade. Intriguingly, a strong inhibition of angiogenesis by cabozantinib occurred regardless of the oncogenic drivers. However, cabozantinib had limited impact on other tumour microenvironment parameters, including tumour infiltrating T cells, and did not induce programmed death-ligand 1 (PD-L1) expression. Combining cabozantinib with MLN0128 led to tumour regression in c-Met/β-catenin mice. In contrast, combined treatment with cabozantinib and the checkpoint inhibitor anti-PD-L1 antibody did not provide any additional therapeutic benefit in the four mouse HCC models tested. Conclusion c-MET/ERK/p21/PKM2 cascade and VEGFR2-induced angiogenesis are the primary targets of cabozantinib in HCC treatment. Combination therapies with cabozantinib and mTOR inhibitors may be effective against human HCC.
AB0131 Ankylosing spondylitis in women
Authors: NG Papadopoulos, TI Temekonidis, P Katsimbri, N Tsifetaki, AA Drosos
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> To investigate whether ankylosing spondylitis (AS) in women comprises a different clinical group compared to men. <h3>Methods</h3> Seventy-eight patients with AS were diagnosed and followed up since 1981. We reevaluated all these patients by entering the demographic, clinical, laboratory, radiological and therapeutic disease characteristics in the database. <h3>Results</h3> Seventy patients were identified as AS. Eight were excluded. Six developed psoriasis during follow up, one had Forestier?s disease and one developed Paget?s disease of bone. Sixty-one were men and 9 women. There were no differences between men and women concerning the age at disease onset. However, an infection had proceeded the diagnosis of AS in women (p &lt; 0.01). Axial and peripheral arthritis were similar between the two groups, although the elbows were more frequently involved in women (p &lt; 0.05). Concerning systemic manifestations, no differences were found between the two groups. Finally, female patients had higher values of erythrocyte sedimentation rate (ESR) (47.5 [21.6]) compared to men (31.1 [23.0]) (p &lt; 0.05) and presented more frequently with anaemia of chronic disease (ACD) (p &lt; 0.01). <h3>Conclusion</h3> AS in women is a rare condition (1:8). It seems that it is not a mild disease. The clinical picture is almost similar to men, but expresses high values of ESR and ACD.
Survival Varies By Age and Histology in Classical Hodgkin Lymphoma: A Report from the Children's Oncology Group
Authors: Justine M. Kahn, Kara M. Kelly, Qinglin Pei, Yue Wu, Debra L. Friedman, Tara O. Henderson, David C. Hodgson, Joel A. Kaplan, Frank G. Keller, Smita Bhatia, Cindy L. Schwartz, Sharon M. Castellino
Journal: Blood (2020)
Dual Targeting of Mitochondrial Vulnerability Using Complex I Inhibitor Iacs-010759 with Bcl-2 Inhibitor Venetoclax and Azacitidine in Pre-Clinical Acute Myeloid Leukemia (AML) Models
Authors: Qi Zhang, Lina Han, Alessia Lodi, Connie Weng, Vinitha Mary Kuruvilla, Antonio Cavazos, Helen Ma, Abhishek Maiti, Yoko Tabe, Joseph R Marszalek, Stefano Tiziani, Marina Konopleva
Journal: Blood (2020)
Profile of Checkpoint Molecules Expression on Bone Marrow Cell Populations in Patients with High-Risk Myelodysplastic Syndrome
Authors: Nikolai Yu. Tcvetkov, Elena V. Morozova, Olga S. Epifanovskaya, Elena V. Babenko, Maria V. Barabanshikova, Kirill V. Lepik, Eugene A. Bakin, Julia J. Vlasova, Anna G. Smirnova, Axel R. Zander, Ivan S. Moiseev
Journal: Blood (2020)
In pancreatic cancer, chemotherapy increases antitumor responses to tumor-associated antigens and potentiates DNA vaccination
Authors: Giorgia Mandili, Claudia Curcio, Sara Bulfamante, Laura Follia, Giulio Ferrero, Emanuela Mazza, Moitza Principe, Francesca Cordero, Maria Antonietta Satolli, Rosella Spadi, Andrea Evangelista, Daniele Giordano, Duy Viet, Paola Cappello, Francesco Novelli
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Pancreatic ductal adenocarcinoma (PDA) is an almost incurable tumor that is mostly resistant to chemotherapy (CT). Adaptive immune responses to tumor-associated antigens (TAA) have been reported, but immunotherapy (IT) clinical trials have not yet achieved any significant increase in survival, confirming the suppressive environment of PDA. As CT has immune-modulating properties, we investigated the effect of gemcitabine (GEM) in antitumor effector responses to TAA in patients with PDA. Methods The IgG antibody repertoire in patients with PDA before and after CT was profiled by serological proteome analysis and ELISA and their ability to activate complement-dependent cytotoxicity (CDC) was measured. Peripheral T cells were stimulated in vitro with recombinant TAA, and specific proliferation, IFN-γ/IL-10 and CD8 + /Treg ratios were measured. Mice that spontaneously developed PDA were treated with GEM and inoculated with an ENO1 (α−Enolase) DNA vaccine. In some experimental groups, the effect of depleting CD4, CD8 and B cells by specific antibodies was also evaluated. Results CT increased the number of TAA recognized by IgG and their ability to activate CDC. Evaluation of the IFN-γ/IL-10 ratio and CD8+/Treg ratios revealed that CT treatment shifted T cell responses to ENO1, G3P (glyceraldheyde-3-phosphate dehydrogenase), K2C8 (keratin, type II cytoskeletal 8) and FUBP1 (far upstream binding protein 1), four of the most recognized TAA, from regulatory to effector. In PDA mice models, treatment with GEM prior to ENO1 DNA vaccination unleashed CD4 antitumor activity and strongly impaired tumor progression compared with mice that were vaccinated or GEM-treated alone. Conclusions Overall, these data indicate that, in PDA, CT enhances immune responses to TAA and renders them suitable targets for IT.
Efficacy and Safety of Lenalidomide Based Regimens in Diffuse Large B Cell Lymphoma: A Systematic Review and Meta-Analysis of Clinical Trials
Authors: Wajeeha Aiman, Muhammad Ashar Ali, Rimsha Ali, Farwah N. Fatima, Nayab Mirza, Anum Javaid, Muhammad Yasir Anwar, Shammas Farooq Bajwa, Rohail Gul, Asrar Ahmad, Faiz Anwer
Journal: Blood (2020)
Abstract 351: Focal Adhesion Kinase Promotes Tissue Destruction in Aortic Dissection in Mice
Authors: Ryohei Majima, Hiroki Aoki, Eichi Nakao, Yohei Hashimoto, Sohei Ito, Makiko Hayashi, Satoko Ohno-urabe, Aya Frusho, Norifumi Nishida, Saki Hirakata, Yoshihiro Fukumoto
Journal: Circulation Research (2020)

Aortic dissection (AD) is a fatal disease due to the sudden destruction of the aortic medial layer. Currently, Molecular pathogenesis of AD is unknown. We investigated the role of focal adhesion kinase (FAK), a mechanosensitive signal transducer, in AD pathogenesis. We created a mouse model of AD with a continuous infusion of beta-aminopropionitrile (150 mg/kg/day), a collagen crosslink inhibitor, and angiotensin II (1,000 ng/kg/min) (BAPN + Ang II) by osmotic pumps. This AD model showed about 60% mortality within 2 weeks due to AD rupture. Immunohistochemical staining for activated FAK revealed that FAK was inactive in normal mouse aorta, but was strongly activated in the aortic walls after BAPN + Ang II infusion. Immunofluorescence staining showed that FAK was activated mainly in smooth muscle cells after the BAPN + Ang II challenge. Western blot analysis revealed that FAK was activated in 3 days after BAPN + Ang II infusion before AD development, followed by transient reduction at day 7, and re-activation after AD development at day 14. We examined the effect of PND-1186, an orally available FAK inhibitor, on the severity as determined by the AD lesion length and the mortality of AD. Mice were administered with either vehicle or PND-1186 (150 mg/kg twice daily by oral gavage) during the BAPN + Ang II challenge (n=20 for each group). Administration of PND-1186 resulted in significant reduction in the lesion length of AD (vehicle; 12.5 ± 1.65 mm, PND; 7.46 ± 1.88 mm, P&lt;0.05). The suppressive effect of PND-1186 was most significant in the aortic arch (vehicle; 2.13 ± 0.29 mm, PND; 0.85 ± 0.22 mm, P&lt;0.01). Furthermore, PND-1186 significantly improved the survival rate of mice from 40.0% to 80.0% (P&lt;0.01). Transcriptome analysis indicated that destruction and inflammation of tissue were suppressed by PND-1186 administration. These findings indicated that FAK plays an important role in AD pathogenesis, possibly by transducing the pathological stress to the tissue destructive response in the aortic walls. We propose that FAK is a potential therapeutic target to limit the fatal destruction of aortic walls in AD.