tbuckley/cabot-search huggingface dataset:
Rates of retroperitoneal lymph node dissection for stage I non-seminomatous germ cell tumors: Results from the National Cancer Database.
Authors: Mohammed Haseebuddin, Elizabeth Handorf, Alexander Kutikov, Nikhil Waingankar, Elizabeth R. Plimack, Robert G. Uzzo, Marc C. Smaldone
Journal: Journal of Clinical Oncology (2015)

395 Background: Per existing best practice guidelines, careful observation with serial imaging (active surveillance) or primary chemotherapy have supplanted primary retroperitoneal lymph node dissection (RPLND) for stage I non-seminomatous germ cell tumors (NSGCT). Hypothesizing that rates of primary RPLND have declined over the past decade, our objective was to assess temporal trends in primary treatment for stage I NSGCT using a large national cancer registry. Methods: The National Cancer Database (NCDB) was queried for all patients diagnosed with stage I NSGCT from 1998-2011. Temporal trends for receipt of primary RPLND, chemotherapy, or observation (defined as no treatment) were assessed. Adjusting for patient, demographics (age, ethnicity, race, insurance status, education, income, geographic location), and clinicopathologic characteristics (stage), multivariable logistic models were used to examine the association between available covariates and receipt of primary RPLND. Results: Of 15,822 patients identified over the study period, 9,001 (56.9%), 2,937 (18.6%), and 3,884 (24.5%) underwent observation, RPLND, and chemotherapy respectively. While rates of observation minimally changed over time (56.3 to 55.0%, p=0.85), a significant decrease in utilization of RPLND (23.0 to 12.4%, p&lt;0.001) was matched by a significant increase in receipt of primary chemotherapy (20.7 to 32.5%, p&lt;0.001). Rates of RPLND declined across all age groups—age &lt; 30 (24.3% to 12.1%, P&lt;0.0001), age 30-39 (21.6% to 13.8%, p &lt;0.0001), age 40-49 (23.1% to 11.4%, p&lt;0.0001), age&gt;50 (20.0% to 11.7%, p = 0.02). Following adjustment, stage T2 (OR 0.79 [CI 0.72-0.87]) and T3 (OR 0.33 [CI 0.24-0.96]), and age categories 40-49 years (OR 0.83 [CI 0.72-0.94]) and ≥50 years (OR 0.66 [CI 0.52-0.82]) were associated with decreased utilization of RPLND. Conclusions: In hospitals reporting to the NCDB, utilization of primary RPLND for stage I NSGCT has significantly decreased over the last decade, while receipt of primary chemotherapy has increased over the same period. While employed in more than 50% of patients, rates of observation remain unchanged.
Glutaminase Inhibition Selectively Slows the Growth of Primary Acute Myeloid Leukemia (AML) Cells with Isocitrate Dehydrogenase (IDH) Mutations.
Authors: Ashkan Emadi, Sung Ah Jun, Takashi Tsukamoto, Amir T Fathi, Mark D. Minden, Chi Van Dang
Journal: Blood (2012)
Anti-Factor B and Anti-C3b Autoantibodies in C3 Glomerulopathy and Ig-Associated Membranoproliferative GN
Authors: Maria Chiara Marinozzi, Lubka T. Roumenina, Sophie Chauvet, Alexandre Hertig, Dominique Bertrand, Jérome Olagne, Marie Frimat, Tim Ulinski, Georges Deschênes, Stephane Burtey, Michel Delahousse, Bruno Moulin, Christophe Legendre, Véronique Frémeaux-Bacchi, Moglie Le Quintrec
Journal: Journal of the American Society of Nephrology (2017)

In C3 glomerulopathy (C3G), the alternative pathway of complement is frequently overactivated by autoantibodies that stabilize the C3 convertase C3bBb. Anti-C3b and anti-factor B (anti-FB) IgG have been reported in three patients with C3G. We screened a cohort of 141 patients with C3G and Ig-associated membranoproliferative GN (Ig-MPGN) for anti-FB and anti-C3b autoantibodies using ELISA. We identified seven patients with anti-FB IgG, three patients with anti-C3b IgG, and five patients with anti-FB and anti-C3b IgG. Of these 15 patients, ten were diagnosed with Ig-MPGN. Among those patients with available data, 92% had a nephrotic syndrome, 64% had AKI, and 67% had a documented infection. Patients negative for anti-C3b and anti-FB IgG had much lower rates of infection (17 [25%] patients with C3G and one [10%] patient with Ig-MPGN). After 48 months, four of 15 (26%) positive patients had developed ESRD or died. All 15 patients had high plasma Bb levels, six (40%) patients had low levels of C3, and nine (60%) patients had high levels of soluble C5b9. In vitro, IgG purified from patients with anti-FB Abs selectively enhanced C3 convertase activity; IgG from patients with anti-C3b/anti-FB Abs enhanced C3 and C5 cleavage. IgG from patients with anti-C3b Abs stabilized C3bBb and perturbed C3b binding to complement receptor 1 but did not perturb binding to factor H. In conclusion, the prevalence of anti-C3b/anti-FB Abs and alternative pathway activation is similar in Ig-MPGN and C3G, suggesting similar pathogenic mechanisms. Identification of the underlying defect in Ig-MPGN could lead to improved treatment.
CBT can benefit patients with severe depression, say researchers
Authors: Jacqui Wise
Journal: BMJ (2017)

Patients with the most severe depression can expect to get as much benefit from cognitive behavioural therapy (CBT) as those with less severe symptoms, a meta-analysis published in the British Journal of Psychiatry has found.1

Psychotherapies have traditionally been believed to be better suited to treating people with mild depression. But the influence of symptom severity has not been studied …
Relationship between m-TOR-Mediated Upregulation of Glycolysis, Chemoresistance, and Prognosis in Patients with ALL.
Authors: Daniela Buglio, Marina Konopleva, Teresa McQueen, Ismael Samudio, Kristine R. Broglio, Vivian Ruvolo, Rooha Contractor, Wenjing Chen, Hagop Kantarjian, Michael Andreeff, Mary A. Weiser
Journal: Blood (2005)
Superior Outcomes Using Medium-Dose VP-16/CY/TBI to CY/TBI as a Conditioning Regimen for Allogeneic Stem Cell Transplantation for Adult Patients with Acute Lymphoblastic Leukemia.
Authors: Akio Shigematsu, Junji Tanaka, Ritsuro Suzuki, Takakazu Kawase, Hideki Akiyama, Takahiro Fukuda, Keiki Kumano, Fumiaki Yoshiba, Heiwa Kanamori, Naoki Kobayashi, Takashi Fukuhara, Masahiro Imamura
Journal: Blood (2009)
Role of Chemotherapy before Allogeneic Stem Cell Transplantation (ALLO-SCT) from an HLA-Identical Sibling Donor for Myelodysplastic Syndrome (MDS).
Authors: Kunihisa Nakai, Yoshinobu Kanda, Shirou Fukuhara, Hisashi Sakamaki, Shinichiro Okamoto, Yoshihisa Kodera, Ryuji Tanosaki, Satoshi Takahashi, Takafumi Matsushima, Yoshiko Atsuta, Nobuyuki Hamajima, Masaharu Kasai, Shunichi Kato
Journal: Blood (2004)
Fibrinogen Supports Colitis-Associated Adenoma Progression through a Mechanism Coupled to Engagement of the Leukocyte Integrin αMβ2.
Authors: Netanel Horowitz, Kris A. Steinbrecher, Maureen A. Shaw, Kelley A. Barney, Matthew Flick, Eleana Harmel-Laws, David Witte, Elizabeth A. Blevins, Joseph S. Palumbo
Journal: Blood (2009)
Organ Siderosis In a Murine Graft-Versus-Host-Model After Allogeneic Stem Cell Transplantations Unrelated to Red Cell Transfusion
Authors: Axel Nogai, Reinhard Ziebig, Martina U. Muckenthaler, Eckhard Thiel, Lutz Uharek, Michael Notter
Journal: Blood (2010)
TARGT Gene Therapy Platform for Correction of Anemia in End-Stage Renal Disease
Authors: Shany Blum, Nir Shapir, Reem Miari, Benny Lerner, Belly Koren, Keren Doenyas-Barak, Shai Efrati, Pablo E Pergola, Doron Schwartz, Gil Chernin, Yoram Yagil, Serge Guzy, Abraham Nyska, Garry A Neil
Journal: New England Journal of Medicine (2017)

greater than 99.9%.
Broad and Conserved Immune Regulation by Genetically Heterogeneous Melanoma Cells
Authors: Natalie J. Neubert, Laure Tillé, David Barras, Charlotte Soneson, Petra Baumgaertner, Donata Rimoldi, David Gfeller, Mauro Delorenzi, Silvia A. Fuertes Marraco, Daniel E. Speiser
Journal: Cancer Research (2017)

Abstract Although mutations drive cancer, it is less clear to what extent genetic defects control immune mechanisms and confer resistance to T-cell-based immunotherapy. Here, we studied the reactions of malignant and benign melanocyte lines to cytotoxic CD8+ T cells (CTL) using flow cytometry and gene expression analyses. We found rapid and broad upregulation of immune-regulatory genes, essentially triggered by CTL-derived IFNγ and augmented by TNFα. These reactions were predominantly homogenous, independent of oncogenic driver mutations, and similar in benign and malignant cells. The reactions exhibited both pro- and antitumorigenic potential and primarily corresponded to mechanisms that were conserved, rather than acquired, by mutations. Similar results were obtained from direct ex vivo analysis of the tumor microenvironment. Thus, immune regulation in the tumor landscape may often be driven by conserved mechanisms, which may explain why T-cell–based immunotherapy can provide durable benefits with relatively infrequent escape. Cancer Res; 77(7); 1623–36. ©2017 AACR.
Genome-Wide Analysis Reveals Frequent Inactivating Mutations of Acetyltransferase Genes In B-Cell Lymphoma
Authors: Laura Pasqualucci, David Dominguez-Sola, Annalisa Chiarenza, Giulia Fabbri, Adina Grunn, Vladimir Trifonov, Lawryn H. Kasper, Stephanie Lerach, Ma Jing, Davide Rossi, Charles Mullighan, Gianluca Gaidano, Raul Rabadan, Paul K. Brindle, Riccardo Dalla-Favera
Journal: Blood (2010)
NHS chief warns of more financial challenges
Authors: Anne Gulland
Journal: BMJ (2017)

Despite government claims to the contrary, spending on the NHS in England will fall, with 2018-19 set to be a tough year, NHS England’s chief executive, Simon Stevens, has told MPs.

Giving evidence to the House of Commons Committee of Public Accounts on Wednesday 11 January Stevens said that over the next three years funding was “going to be highly constrained.”

He said, “In 2018-19, as I said in October, real terms NHS spending per person in England is going to go down, 10 years after [the collapse of the investment bank] Lehman Brothers and austerity began. We all understand why that is, but let’s not pretend that’s not placing huge pressure on the service.”

He added that 2018 was “poised to be the toughest …
The Role of Total Body Irradiation (TBI) in the High-Dose Regimen of Patients with Follicular Lymphoma (FL) Treated with Autologous Stem Cell Transplant (ASCT) in the Rituximab Era. A Retrospective Study of the EBMT Lymphoma Working Party
Authors: Inas El-Najjar, Ariane Boumendil, Jian Jian Luan, Catherine Thieblemont, Didier Blaise, Kirsty Thomson, Steven Le Gouill, Severine Lissandre, Alessandro Rambaldi, Jean-Pierre Jouet, Pierre Biron, Massimo Fabrizio Martelli, Herve Tilly, David Pohlreich, Michael Pfreundschuh, Catherine Cordonnier, Charles Crawley, Jean-Yves Cahn, Jean Paul Vernant, John G. Gribben, Gordon Cook, Nigel H. Russell, Augustin Ferrant, Silvia Montoto, Peter Dreger
Journal: Blood (2011)
Arginase-1 Is Increased in Hodgkin Lymphoma, Associated to Poor Outcome and Positively Correlated to Semiquantitative PET Parameters
Authors: Alessandra Romano, Alessandro Stefano, Cosentino Sebastiano, Giorgio Russo, Nunziatina Laura Parrinello, Calogero Vetro, Piera La Cava, Daniele Tibullo, Cesarina Giallongo, Annalisa Chiarenza, Amalia Figuera, Giovanna Motta, Laura Caruso, Vanessa Mocciaro, Massimo Ippolito, Ugo Consoli, Francesco Di Raimondo
Journal: Blood (2014)
Flexible sigmoidoscopy screening for colorectal cancer
Authors: Ulrike Haug
Journal: BMJ (2017)

Different outcomes in men and women are a challenge for decision makers

An increasing number of countries have implemented or are about to implement programmes for colorectal cancer screening. Unlike existing screening programmes for breast and cervical cancer, colorectal cancer screening affects both men and women. This trivial and obvious fact entails several questions that are far from trivial—eg, are the established tools for colorectal cancer screening equally effective among men and women? To adequately address this issue, subgroup analyses by sex of randomised screening trials with long term follow-up are needed. However, single trials often do not have a sufficient sample size to allow for meaningful subgroup analyses. Pooling of trials is then the only way to answer these questions. Following this rationale, Holme and colleagues1 initiated a joint analysis of three large scale randomised trials on flexible sigmoidoscopy screening conducted in Italy,2 Norway,3 and the United States,4 and they present the findings in The …
NS5A resistance-associated substitutions in patients with genotype 1 hepatitis C virus: Prevalence and effect on treatment outcome
Authors: Stefan Zeuzem, Masashi Mizokami, Stephen Pianko, Alessandra Mangia, Kwang-Hyub Han, Ross Martin, Evguenia Svarovskaia, Hadas Dvory-Sobol, Brian Doehle, Charlotte Hedskog, Chohee Yun, Diana M. Brainard, Steven Knox, John G. McHutchison, Michael D. Miller, Hongmei Mo, Wan-Long Chuang, Ira Jacobson, Gregory J. Dore, Mark Sulkowski
Journal: Journal of Hepatology (2017)
Complement C5a receptor is the key initiator of neutrophil adhesion igniting immune complex–induced arthritis
Authors: Yoshishige Miyabe, Chie Miyabe, Thomas T. Murooka, Edward Y. Kim, Gail A. Newton, Nancy D. Kim, Bodduluri Haribabu, Francis W. Luscinskas, Thorsten R. Mempel, Andrew D. Luster
Journal: Science Immunology (2017)

The deposition of immune complexes (IC) in tissues induces a "type III hypersensitivity" that results in tissue damage and underlies the pathogenesis of many autoimmune diseases. The neutrophil is the first immune cell recruited into sites of IC deposition and plays a critical role in shaping the overall tissue response. However, the mechanism by which IC initiate and propagate neutrophil infiltration into tissue is not known. Here, using intravital multiphoton joint imaging of IC-induced arthritis in live mice, we found that the complement C5a receptor (C5aR) was the key initiator of neutrophil adhesion on joint endothelium. C5a presented on joint endothelium induced β2 integrin-dependent neutrophil arrest, facilitating neutrophil spreading and transition to crawling, and subsequent leukotriene B4 receptor (BLT1)-mediated extravasation of the first neutrophils. The chemokine receptor CCR1 promoted neutrophil crawling on the joint endothelium while CXCR2 amplified late neutrophil recruitment and survival once in the joint. Thus, imaging arthritis has defined a new paradigm for type III hypersensitivity where C5a directly initiates neutrophil adhesion on the joint endothelium igniting inflammation.
Development and Therapeutic Potential of Small-Molecule Modulators of Circadian Systems
Authors: Zheng Chen, Seung-Hee Yoo, Joseph S. Takahashi
Journal: The Annual Review of Pharmacology and Toxicology (2017)

Circadian timekeeping systems drive oscillatory gene expression to regulate essential cellular and physiological processes. When the systems are perturbed, pathological consequences ensue and disease risks rise. A growing number of small-molecule modulators have been reported to target circadian systems. Such small molecules, identified via high-throughput screening or derivatized from known scaffolds, have shown promise as drug candidates to improve biological timing and physiological outputs in disease models. In this review, we first briefly describe the circadian system, including the core oscillator and the cellular networks. Research progress on clock-modulating small molecules is presented, focusing on development strategies and biological efficacies. We highlight the therapeutic potential of small molecules in clock-related pathologies, including jet lag and shiftwork; various chronic diseases, particularly metabolic disease; and aging. Emerging opportunities to identify and exploit clock modulators as novel therapeutic agents are discussed.
Oncogenes without a neighboring tumor-suppressor gene are more prone to amplification
Authors: William K.K. Wu, Xiangchun Li, Xiansong Wang, Rudin Z.W. Dai, Alfred S.L. Cheng, Maggie H.T. Wang, Thomas Kwong, Tai C. Chow, Jun Yu, Matthew T.V. Chan, Sunny H. Wong
Journal: Molecular Biology and Evolution (2016)

Focal copy number gains or losses are important genomic hallmarks of cancer. The genomic distribution of oncogenes and tumor-suppressor genes (TSG) in relation to focal copy number aberrations is unclear. Our analysis revealed that the mean distance of TSGs from oncogenes was significantly shorter than that of noncancer genes, suggesting that oncogenes and TSGs tend to be in close physical proximity in the human genome. Such relationship was conserved in mouse and drosophila. Pan-cancer analysis using data from The Cancer Genome Atlas indicated that oncogenes without a nearby TSG are more prone to amplification. In conclusion, our study provides evidence for the nonrandom distribution of oncogenes and TSGs across different species. Our data also support that the existence of a neighboring TSG can suppress amplification of an oncogene, shedding new light on a previously unappreciated protective mechanism of TSGs.
Angiogenesis in Multiple Myeloma (MM): Angiogenic Switch or Reflexion of Plasma Cell Number? A Gene Expression Based Survey in Primary Myeloma Cells and the Bone Marrow Microenvironment.
Authors: Dirk Hose, John DeVos, Christiane Heiß, Jean-Francois Rossi, Angela Rösen-Wolff, Axel Benner, Karène Mahtouk, Michael Hundemer, Thierry X. Reme, Jens Hillengass, Katja Herde, Uta Mazitschek, Jérôme Moreaux, Sabine Wenisch, Véronique Pantesco, Anna Jauch, Eric Jourdan, Hartmut Goldschmidt, Bernard Klein, Thomas Möhler
Journal: Blood (2006)
Patterns of immune development in urban preschoolers with recurrent wheeze and/or atopy
Authors: James E. Gern, Agustin Calatroni, Katy F. Jaffee, Henry Lynn, Amy Dresen, William W. Cruikshank, Howard M. Lederman, Hugh A. Sampson, Wayne Shreffler, Leonard B. Bacharier, Peter J. Gergen, Diane R. Gold, Meyer Kattan, George T. O'Connor, Megan T. Sandel, Robert A. Wood, Gordon R. Bloomberg
Journal: Journal of Allergy and Clinical Immunology (2017)
Predictive Factors of Relative Dose Intensity Reduction in Clinical Practice for First Line Treatment in Patients with Non-Hodgkin and Hodgkin Lymphoma
Authors: Ana Marques Pereira, Maria do Céu Trindade, Jorge Espírito Santo, Ricardo Costa, Adriana Teixeira, Emília Magalhães, Rute Vieira, Herlander Marques
Journal: Blood (2008)
Adenosquamous Carcinoma of the Pancreas Demonstrated on 18F-FDG PET/CT Imaging
Authors: Lei Jiang, Hongting Nie, Lei Zhu, Yan Xiu, Hongcheng Shi
Journal: Clinical Nuclear Medicine (2017)

A 69-year-old woman had gradually worsening abdominal discomfort over a year. A pancreatic mass was revealed by abdominal CT. The patient underwent FDG PET/CT for staging, which demonstrated the hypermetabolic pancreatic mass with multiple liver metastases. The lesion was pathologically confirmed as pancreatic adenosquamous carcinoma after biopsy.
Combined Analysis of Treatments for Pediatric T-ALL in KYCCSG Protocols, ALL-96 and ALL-02.
Authors: Yasuhiro Okamoto, Yoshihisa Nagatoshi, Akinobu Matsuzaki, Aiko Suminoe, Hideki Nakayama, Noriko Hotta, Shuuichi Ohzono, Kyoko Fujita, Kiyoshi Kawakami, Fumio Yanai, Hiroshi Moritake, Jiro Inagaki, Yoshifumi Kawano, Jun Okamura
Journal: Blood (2009)
Essential Thrombocythemia in Young Individuals: Frequency and Risk Factors for Vascular Events and Evolution to Myelofibrosis in 126 Patients.
Authors: Alberto Alvarez-Larran, Francisco Cervantes, Beatriz Bellosillo, Manuel Giralt, Antoni Julia, Juan Carlos Hernandez-Boluda, Luis Hernandez-Nieto, Victoria Clapes, Carmen Burgaleta, Alba Bosch, Carlos Salvador, Eduardo Arellano-Rodrigo, Dolors Colomer, Carlos Besses
Journal: Blood (2006)
Prefmab: Final Analysis of Patient Preference for Subcutaneous Versus Intravenous Rituximab in Previously Untreated CD20+ Diffuse Large B-Cell Lymphoma and Follicular Lymphoma
Authors: Mathias Rummel, Tae Min Kim, Caterina Plenteda, Enrico Capochiani, Maria Mendoza, Rodney Smith, Stuart Osborne, Andrew Grigg
Journal: Blood (2015)
Mixed Lineage Leukemia Rearrangements (MLL-R) Are Determinants of High Risk Disease in Homeobox A (HOXA)-deregulated T-Lineage Acute Lymphoblastic Leukemia: A Children's Oncology Group Study
Authors: Ksenia Matlawska-Wasowska, Huining Kang, Meenakshi Devidas, Ji Wen, Richard C Harvey, Christian C Nickl, Scott Ness, Michael Rusch, Yongjin Li, Masahiro Onozawa, Carmen Martinez, Brent L Wood, Barbara Asselin, I-Ming L Chen, Kathryn G. Roberts, Andre Baruchel, Jean Soulier, Herve Dombret, Jinghui Zhang, Richard S. Larson, Elizabeth Raetz, William L. Carroll, Naomi J. Winick, Peter D. Aplan, Mignon L. Loh, Charles G. Mullighan, Stephen P Hunger, Nyla A. Heerema, Andrew J. Carroll, Kimberly P. Dunsmore, Stuart S. Winter
Journal: Blood (2015)
Vascular Events and Risk Factors for Thrombosis in Refractory Anemia with Ring Sideroblasts and Thrombocytosis (RARS-T)
Authors: Mrinal M Patnaik, Terra L. Lasho, Pooja Vijayvargiya, Christy Finke, Curtis A. Hanson, Rhett P. Ketterling, Naseema Gangat, Ayalew Tefferi
Journal: Blood (2015)
Blood Cell Replenishment and Bone Marrow Stem Cell Pool Renewal Are Regulated By Different Circadian Peaks Via Norepinephrine and TNFα/S1P Signaling
Authors: Karin Golan, Aya Ludin, Tomer Itkin, Shiri Cohen-Gur, Orit Kollet, Xin-Jiang Lu, Alexander Kalinkovich, Tsvee Lapidot
Journal: Blood (2013)
Cyclin D1 Overexpression Increases Chemosensitivity Via the Induction of Bim in Myeloma Cells.
Authors: Yoshiaki Kuroda, Akira Sakai, Naohiro Tsuyama, Shoso Munemasa, Nanae Nakaju, Mami Mizuno, Yoshiko Okikawa, Yuta Katayama, Akiro Kimura
Journal: Blood (2006)
Receptor Tyrosine Kinase-Like Orphan Receptor 1 (ROR-1) Is Expressed in Low Grade NHL and B-CLL and Activates the Non Canonical Wnt Pathway
Authors: Federica Gibellini, Colby M Chapman, Yair Herishanu, Berengere Vire, Keyvan Keyvanfar, Ndegwa Njuguna, Adrian Wiestner
Journal: Blood (2008)
Long-Term Efficacy of the Combined Immunosuppressive Therapy (IST): Cyclosporine with/without Splenectomy - in Patients with Different Forms of Myelodysplastic Syndromes
Authors: Valeri G Savchenko, Alina Kokhno, Elena N. Parovichnikova, Elena Mikhailova, Vera V. Troitskaya, Larisa A. Kuzmina, Mikhail Drokov, Valentina N. Dvirnyk, Alla M. Kovrigina, Tatiana N. Obukhova
Journal: Blood (2015)
Therapy-Related Myelodysplastic Syndrome (sMDS) /Acute Myelogenous Leukemia (sAML) in Acute Promyelocytic Leukemia (APL) Patients with Long-Lasting Molecular Remission: The GIMEMA Experience.
Authors: R. Latagliata, M. Breccia, P. Fazi, S. Gubbiotti, E. Di Bona, G. Specchia, A. Chiarenza, R. Murru, A.M. Carella, F. Ferrara, G. Rossi, L. Melillo, S. Sica, R. Invernizzi, G. Cimino, M.C. Petti, G. Avvisati, F. Lo-Coco, F. Mandelli
Journal: Blood (2005)
Benefit of Mineralocorticoid Receptor Antagonism in AKI: Role of Vascular Smooth Muscle Rac1
Authors: Jonatan Barrera-Chimal, Gwennan André-Grégoire, Aurelie Nguyen dinh Cat, Sebastian M. Lechner, Jérôme Cau, Sonia Prince, Peter Kolkhof, Gervaise Loirand, Vincent Sauzeau, Thierry Hauet, Frédéric Jaisser
Journal: Journal of the American Society of Nephrology (2017)

AKI is a frequent complication in hospitalized patients. Unfortunately, there is no effective pharmacologic approach for treating or preventing AKI. In rodents, mineralocorticoid receptor (MR) antagonism prevents AKI induced by ischemia-reperfusion (IR). We investigated the specific role of vascular MR in mediating AKI induced by IR. We also assessed the protective effect of MR antagonism in IR-induced AKI in the Large White pig, a model of human AKI. In mice, MR deficiency in smooth muscle cells (SMCs) protected against kidney IR injury. MR blockade by the novel nonsteroidal MR antagonist, finerenone, or genetic deletion of MR in SMCs associated with weaker oxidative stress production. Moreover, ischemic kidneys had higher levels of Rac1-GTP, required for NADPH oxidase activation, than sham control kidneys, and genetic deletion of Rac1 in SMCs protected against AKI. Furthermore, genetic deletion of MR in SMCs blunted the production of Rac1-GTP after IR. Pharmacologic inhibition of MR also prevented AKI induced by IR in the Large White pig. Altogether, we show that MR antagonism, or deletion of the MR gene in SMCs, limited the renal injury induced by IR through effects on Rac1-mediated MR signaling. The benefits of MR antagonism in the pig provide a rational basis for future clinical trials assessing the benefits of this approach in patients with IR-mediated AKI.