Research Spotlight

Posted June 15th 2016

Capsulotomy size affects hip joint kinematic stability.

Hal David Martin D.O.

Hal David Martin D.O.

Wuerz, T. H., S. H. Song, J. S. Grzybowski, H. D. Martin, R. C. Mather, 3rd, M. J. Salata, A. A. Espinoza Orias and S. J. Nho (2016). “Capsulotomy size affects hip joint kinematic stability.” Arthroscopy: May 2016 [Epub ahead of print].

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PURPOSE: To evaluate the effect of capsulotomy size and subsequent repair on the biomechanical stability of hip joint kinematics through external rotation of a cadaveric hip in neutral flexion. METHODS: Eight fresh-frozen cadaveric hip specimens were used in this study. Each hip was tested under torsional loads of 6 N.m applied by a servohydraulic frame and transmitted by a pulley system. The test conditions were (1) neutral flexion with the capsule intact, (2) neutral flexion with a 4-cm interportal capsulotomy, (3) neutral flexion with a 6-cm capsulotomy, and (4) neutral flexion with capsulotomy repair. Soft tissue was retained during all interventions. Measures indicating joint kinematics (range of motion [ROM], hysteresis area [HA], and neutral zone [NZ]) were obtained for each condition. RESULTS: For all hip specimens, the average ROM, HA, and NZ were calculated relative to the intact capsular state (100%) and expressed in terms of percentage (+/- SD). The findings for ROM were as follows: intact, 100%; 4 cm, 107.42% +/- 5.69%; 6 cm, 113.40% +/- 7.92%; and repair, 99.78% +/- 3.77%. The findings for HA were as follows: intact, 100%; 4 cm, 108.30% +/- 9.30%; 6 cm, 115.30% +/- 13.92%; and repair, 99.47% +/- 4.12%. The findings for NZ were as follows: intact, 100%; 4 cm, 139.61% +/- 62.35%; 6 cm, 169.25% +/- 78.19%; and repair, 132.03% +/- 64.38%. Statistically significant differences in ROM existed between the intact and 4-cm conditions (P = .039), the intact and 6-cm conditions (P < .0001), the 4-cm and repair conditions (P = .033), and the 6-cm and repair conditions (P < .0001). There was no statistically significant difference between the intact and repair conditions (P > .99) or between the 4- and 6-cm conditions (P = .126). CONCLUSIONS: Under laboratory-based conditions, larger-sized capsulotomies were accompanied by increases in all three measures of joint mobility: ROM, HA, and NZ at time zero. Complete capsular closure effectively restored these measures when compared with the intact condition. CLINICAL RELEVANCE: Cadaveric models consisting of the hip joint with surrounding soft tissue were used under laboratory testing conditions to investigate potential iatrogenic joint instability resulting from expansive capsulotomies, showing that complete capsular closure leads to reconstitution of original joint stability properties at time zero.


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.