Research Spotlight

Posted June 15th 2016

Targeting HIV-1 Env gp140 to LOX-1 Elicits Immune Responses in Rhesus Macaques.

Gerard Zurawski Ph.D.

Gerard Zurawski Ph.D.

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Improved antigenicity against HIV-1 envelope (Env) protein is needed to elicit vaccine-induced protective immunity in humans. Here we describe the first tests in non-human primates (NHPs) of Env gp140 protein fused to a humanized anti-LOX-1 recombinant antibody for delivering Env directly to LOX-1-bearing antigen presenting cells, especially dendritic cells (DC). LOX-1, or 1ectin-like oxidized low-density lipoprotein (LDL) receptor-1, is expressed on various antigen presenting cells and endothelial cells, and is involved in promoting humoral immune responses. The anti-LOX-1 Env gp140 fusion protein was tested for priming immune responses and boosting responses in animals primed with replication competent NYVAC-KC Env gp140 vaccinia virus. Anti-LOX-1 Env gp140 vaccination elicited robust cellular and humoral responses when used for either priming or boosting immunity. Co-administration with Poly ICLC, a TLR3 agonist, was superior to GLA, a TLR4 agonist. Both CD4+ and CD8+ Env-specific T cell responses were elicited by anti-LOX-1 Env gp140, but in particular the CD4+ T cells were multifunctional and directed to multiple epitopes. Serum IgG and IgA antibody responses induced by anti-LOX-1 Env gp140 against various gp140 domains were cross-reactive across HIV-1 clades; however, the sera neutralized only HIV-1 bearing sequences most similar to the clade C 96ZM651 Env gp140 carried by the anti-LOX-1 vehicle. These data, as well as the safety of this protein vaccine, justify further exploration of this DC-targeting vaccine approach for protective immunity against HIV-1.


Posted June 15th 2016

FOXM1 and FOXQ1 are promising prognostic biomarkers and novel targets of tumor suppressive miR-342 in human colorectal cancer.

Ajay Goel Ph.D.

Ajay Goel Ph.D.

Weng, W., Y. Okugawa, S. Toden, Y. Toiyama, M. Kusunoki and A. Goel (2016). “Foxm1 and foxq1 are promising prognostic biomarkers and novel targets of tumor suppressive mir-342 in human colorectal cancer.” Clin Cancer Res.

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PURPOSE: Colorectal cancer (CRC) ranks as the third most frequent cancer type, and its incidence continues to rise gradually worldwide, highlighting the need to identify previously unrecognized molecular events that propel development of this malignancy. Recent evidence suggests that dysregulated expression of FOX family of transcription factors may be critical in various genetic disorders as well as cancer; however, the functional and clinical significance of this pathway in CRC remains unclear. EXPERIMENTAL DESIGN AND RESULTS: Herein, we performed a systematic and comprehensive discovery step by evaluating the expression of FOX family members, and identified that FOXM1 and FOXQ1 are frequently overexpressed in CRC. We subsequently confirmed these findings in two large testing cohorts (n=550), and an independent clinical validation cohort (n=134), in which high expression of FOXM1 and FOXQ1 emerged as an independent prognostic factor in CRC patients. We supported these findings by performing functional assays in which knockdown of FOXM1 and FOXQ1 resulted in inhibited cell proliferation, and suppressed migration and invasion in CRC cells. Furthermore, using bioinformatics approaches, we identified miR-342 as a novel regulator of both FOXM1 and FOXQ1. Overexpression or inhibition of miR-342 modulated the expression of both genes and contributed to phenotypic alterations in CRC cells, which was subsequently validated in a xenograft animal model. CONCLUSIONS: Collectively, we have firstly identified FOXM1 and FOXQ1 as promising prognostic biomarkers in CRC patients, and provide novel evidence that therapeutic targeting of these genes or miR-342 may be a potential treatment approach in CRC patients.


Posted June 15th 2016

Icos(+)pd-1(+)cxcr3(+) t follicular helper cells contribute to the generation of high-avidity antibodies following influenza vaccination.

Hideki Ueno M.D.

Hideki Ueno M.D.

Bentebibel, S. E., S. Khurana, N. Schmitt, P. Kurup, C. Mueller, G. Obermoser, A. K. Palucka, R. A. Albrecht, A. Garcia-Sastre, H. Golding and H. Ueno (2016). “Icos(+)pd-1(+)cxcr3(+) t follicular helper cells contribute to the generation of high-avidity antibodies following influenza vaccination.” Sci Rep 6: 26494.

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The immune mechanism leading to the generation of protective antibody responses following influenza trivalent inactivated vaccine (TIV) vaccinations remains largely uncharacterized. We recently reported that TIV vaccination induced a transient increase of circulating ICOS(+)PD-1(+)CXCR3(+) T follicular helper (cTfh) cells in blood, which positively correlated with the induction of protective antibody responses measured at day 28. However, whether and how these T cells directly contribute to antibody response remains unclear. In this study, we analyzed the changes after TIV vaccination in the amount and the avidity of the polyclonal antibodies specific for the HA1 subunit of the pandemic H1N1 virus, and analyzed the correlation with the increase of ICOS(+)PD-1(+)CXCR3(+) cTfh cells. We found that both the amount and the avidity of specific antibodies rapidly increased during the first 7 days after TIV. Importantly, the increase of ICOS(+)PD-1(+)CXCR3(+) cTfh cells strongly correlated with the increase in the avidity of antibodies, particularly in subjects who did not have high affinity antibodies at baseline. We propose that ICOS(+)PD-1(+)CXCR3(+) Tfh cells directly contribute to the generation of high-avidity antibodies after TIV vaccinations by selectively interacting with high affinity B cells at extrafollicular sites.


Posted June 15th 2016

Development of a squamous cell carcinoma of the hand and wrist after cardiac transplantation.

Brian Lima M.D.

Brian Lima M.D.

Carey, S., W. T. Jackson, M. A. Hitchcock, B. Lima and S. Hall (2016). “Development of a squamous cell carcinoma of the hand and wrist after cardiac transplantation.” Am J Cardiol 117(11): 1853-1854.

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Described are the findings in a 57-year-old man who developed a large carcinoma 2 years after heart transplantation. Mental anxiety or depression may have contributed to a delay in seeking medical care. The result was amputation of the right arm below the elbow.


Posted June 15th 2016

Urine colorimetry to detect Low rifampin exposure during tuberculosis therapy: a proof-of-concept study.

Tawanda Gumbo M.D.

Tawanda Gumbo M.D.

Zentner, I., H. P. Schlecht, L. Khensouvann, N. Tamuhla, M. Kutzler, V. Ivaturi, J. G. Pasipanodya, T. Gumbo, C. A. Peloquin, G. P. Bisson and C. Vinnard (2016). “Urine colorimetry to detect low rifampin exposure during tuberculosis therapy: A proof-of-concept study.” BMC Infect Dis 16(1): 242.

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BACKGROUND: The cost and complexity of current approaches to therapeutic drug monitoring during tuberculosis (TB) therapy limits widespread use in areas of greatest need. We sought to determine whether urine colorimetry could have a novel application as a form of therapeutic drug monitoring during anti-TB therapy. METHODS: Among healthy volunteers, we evaluated 3 dose sizes of rifampin (150 mg, 300 mg, and 600 mg), performed intensive pharmacokinetic sampling, and collected a timed urine void at 4 h post-dosing. The absorbance peak at 475 nm was measured after rifamycin extraction. The optimal cutoff was evaluated in a study of 39 HIV/TB patients undergoing TB treatment in Botswana. RESULTS: In the derivation study, a urine colorimetric assay value of 4.0 x 10(-2) Abs, using a timed void 4 h after dosing, demonstrated a sensitivity of 92 % and specificity of 60 % to detect a peak rifampin concentration (Cmax) under 8 mg/L, with an area under the ROC curve of 0.92. In the validation study, this cutoff was specific (100 %) but insensitive (28 %). We observed similar test characteristics for a target Cmax target of 6.6 mg/L, and a target area under the drug concentration-versus-time curve (AUC0-8) target of 24.1 mg*hour/L. CONCLUSIONS: The urine colorimetric assay was specific but insensitive to detect low rifampin serum concentrations among HIV/TB patients. In future work we will attempt to optimize sampling times and assay performance, with the goal of delivering a method that can translate into a point-of-care assessment of rifampin exposure during anti-TB therapy.