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JCI online ahead of print table of contents for May 16, 2014

Targeting microbial translocation attenuates SIV-mediated inflammation

Patients with HIV often present with signs of immune activation and systemic inflammation, both of which are hypothesized to directly contribute to the development of AIDs in infected individuals. HIV and the related simian immunodeficiency virus (SIV) damage the gut mucosa, leading to translocation of microbes from the intestinal lumen to the general circulation, but it is not clear if microbial translocation is directly responsible for chronic HIV-associated inflammation. In this issue of the Journal of Clinical Investigation, Ivona Pandrea and colleagues at University of Pittsburgh report on a study that validates the microbial translocation hypothesis in SIV-infected pigtail macaques. Sevelamer, a drug that is used to reduce systemic LPS levels in chronic kidney disease patients, was given to SIV-infected animlas to reduce microbial translocation in the gut. Compared to controls, sevelamer-treated animals had decreased systemic LPS and reduced activation of peripheral CD4+ T cells. Importantly, sevelamer treatment dramatically lowered viral titers in the blood and reduced coagulation biomarkers that are associated with the development of cardiovascular co-morbidities. In the accompanying commentary, Liang Shan and Robert Siliciano of John's Hopkins School of Medicine discusse how control of microbial translocation could improve HIV outcomes.

TITLE: Early microbial translocation blockade reduces SIV-mediated inflammation and viral replication

University of Pittsburgh, Pittsburgh, PA, USA
Phone: 412-624-3242; E-mail:

MEDIA CONTACT Allison Hydzik
University of Pittsburgh
Phone: 412-647-9975;

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ACCOMPANYING COMMENTARY TITLE: Unraveling the relationship between microbial translocation and systemic immune activation in HIV infection

AUTHOR CONTACT: Robert F. Siliciano
Johns Hopkins Univ Schl Of Medicine, Baltimore, MD, USA
Phone: 410/955-2958; Fax: 410-955-0964; E-mail:

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Estrogen underlies sex-specific responses to sildenafil

Heart disease is the leading cause of death in both men and women; however, the disease has a somewhat different clinical presentation in women that has been attributed to estrogen levels. Interestingly, estrogen may underlie sex-specific differences in the efficacy of treatments for heart disease. In the issue of the Journal of Clinical Investigation, Eiki Takimoto and colleagues at Johns Hopkins University School of Medicine investigated the impact of estrogen on the cardioprotective effects of sildenafil, a cGMP-specific phosphodiesterase 5 (PDE5) inhibitor. PDE5 inhibitors block hydrolysis of cGMP, leading to activation of the cGMP-dependent kinase Iα (PKGIα), which prevent pathogenic remodeling of the heart. Using two different murine models of heart disease, Takimoto and colleagues determined that sildenafil ameliorates cardiac pathology in an estrogen-dependent manner in female mice. In female hearts, estrogen maintained constitutive activation of eNOS, leading to tonic synthesis of cGMP; in contrast, male hearts exhibited stress-induced eNOS activation and cGMP synthesis, making sildenafil's effects independent of estrogen. In the accompanying commentary, Elizabeth Murphy and Charles Steenbergen discuss how sex-dependent differences in therapeutic responses should be taken into consider for both treatment options and clinical trial design.

TITLE: PDE5 inhibitor efficacy is estrogen dependent in female heart disease

Johns Hopkins University School of Medicine, Baltimore, MD, USA
Phone: 410-955-4813; Fax: 410-502-2558; E-mail:

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ACCOMPANYING COMMENTARY TITLE: Sex, drugs, and trial design: sex influences the heart and drug responses

AUTHOR CONTACT: Elizabeth Murphy
NHLBI, NIH, Bethesda, MD, USA
Phone: 301.496.5828; E-mail:

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Vaccine-induced cell population inhibits SIV vaccine efficacy

The development of an efficacious HIV vaccine has been challenging. Adjuvants are a critical addition to vaccines to help target and potentiate vaccine-induced immune responses, and several have been used in an attempt to boost HIV-specific immune response with limited success. In this issue of the Journal of Clinical Investigation, Yongjun Sui, Jay Berzofsky, and colleagues at the National Cancer institute examined the effect of different combinations of molecular adjuvants in an SIV vaccine that has previously been shown to provide some protection against rectal SIV challenge in macaques. Adjuvants included components that promote viral protection, improve T cell anti-viral responses, and also inhibit negative immune regulators. The vaccine with the full complement of adjuvants reduced viral load; however, adjuvant alone performed as well as or better than the vaccine. Further investigations revealed that vaccine alone induced higher numbers of myeloid-derived suppressor cells (MDSCs), which suppress the CD8+ T cell-mediated anti-viral response. Additionally, MDSC levels positively correlated with set-point viral loads, indicating that these cells critically affect vaccine efficacy. In the accompanying commentary, Sallie Permar and Herman Staats of Duke University discuss how these findings new finding may benefit future HIV vaccine design.

TITLE: Vaccine-induced myeloid cell population dampens protective immunity to SIV

NCI, Bethesda, MD, USA
Phone: 301-435-8350; E-mail:


Jay A. Berzofsky
NCI, Bethesda, MD, USA
Phone: 301.496.6874; Fax: 301.480.0681; E-mail:

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ACCOMPANYING COMMENTARY TITLE: Which comes first: the antigen or the adjuvant?

Duke University, Durham, NC, USA
Phone: 919-684-6335; E-mail:

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Enhancing efficacy of the cancer drug cetuximab

Cetuximab is a monoclonal antibody that targets EGFR, which is frequently mutated in various forms of cancer. Currently, cetuximab is FDA approved to treat colorectal cancer (CRC) and head and neck squamous cell carcinoma (HNSCC); however, only 10-20% of patients respond to cetuximab alone. The anti-tumor effects of cetuximab are mediated in part by antibody-dependent cell-mediated cytotoxicity (ADCC) in which the IgG1 constant fragment of cetuximab binds FcγR on NK cells to trigger degranulation. In this issue of the Journal of Clinical Investigation, Holbrook Kohrt and colleagues at Stanford University sought to identify inducible costimulatory molecules on NK cells that enhanced ADCC in an attempt to identify strategies to enhance the efficacy of cetuximab. The athours found that CD137 was upregulated after exposure to cetuximab-bound cancer cells. Using murine models of CRC and HNSCC, Kohrt and colleagues demonstrated that administration of cetuximab followed by an agonistic anti-CD137 antibody had a synergistic effect on NK cell degranulation and tumor-specific cytotoxicity, leading to prolonged survival. In an accompanying commentary, Julie Baumann and Jennifer Grandis of the University of Pittsburg discuss how strategies to enhance secondary immune responses to tumor-targeted antibodies might translate to the clinic.

TITLE: Targeting CD137 enhances the efficacy of cetuximab

AUTHOR CONTACT: Holbrook Kohrt
Stanford University, Stanford, CA, USA
Phone: 650 725-2988; Fax: 650 724-6182; E-mail:

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ACCOMPANYING COMMENTARY TITLE: Targeting secondary immune responses to cetuximab: CD137 and the outside story

Cancer Institute. University of Pittsburgh, Pittsburgh, PA, USA
Phone: 412-623-7833; Fax: 412-648-6579; E-mail:

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HEMATOLOGY TITLE: Elevated sphingosine-1-phosphate promotes sickling and sickle cell disease progression

University of Texas-Medical School, Houston, TX, USA
Phone: 713-500-5039; Fax: 713-500-652; E-mail:

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TITLE: β-cateninregulated myeloid cell adhesion and migration determine wound healing

AUTHOR CONTACT: Benjamin Alman
Duke University, Durham, NC, USA
Phone: 919.613.6935; Fax: 919.613.6991;

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TITLE: Synthetic triterpenoid induces 15-PGDH expression and suppresses inflammation-driven colon carcinogenesis

Case Western Reserve University and University Hospitals, Cleveland, OH, USA
Phone: 216-844-3345; Fax: 216-844-5321; E-mail:

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VASCULAR BIOLOGY TITLE: RASA1 Functions in EPHB4 signaling pathway to suppress endothelial mTORC1 activity

Hampton University, Hampton, VA, USA
Phone: 757.728.6030; Fax: 757.728.6051;

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Contact: Corinne Williams
Journal of Clinical Investigation

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