Browsing by Author "Onaitis, Mark"

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    Hedgehog-GLI Signaling Inhibition Suppresses Tumor Growth in Squamous Lung Cancer
    (2014) Huang, Lingling

    Lung squamous cell carcinoma (LSCC) comprises ~30% of non-small cell lung cancers, and currently lacks effective targeted therapies. Previous immunohistochemical and microarray studies reported overexpression of Hedgehog (HH)-GLI signaling components in LSCC. However, they addressed neither the tumor heterogeneity nor the requirement for HH-GLI signaling. Here, we investigated the role of HH-GLI signaling in LSCC, and studied the therapeutic potential of HH-GLI pathway suppression.

    Gene expression datasets of two independent LSCC patient cohorts were analyzed to study the activation of HH-GLI signaling. Four human LSCC cell lines were examined for HH-GLI signaling components. Cell proliferation and apoptosis were assayed in these cells after blocking the HH-GLI pathway by lentiviral-shRNA knockdown or small molecule inhibitors. Xenografts in immunodeficient mice were used to determine the in vivo efficacy of GLI inhibitor GANT61.

    In both patient cohorts, we found that activation of HH-GLI signaling was significantly associated with the classical subtype of LSCC. GLI2 expression level was significantly higher than GLI1, and displayed strong positive correlations with the prominent markers for the classical subtype (SOX2, TP63 and PIK3CA) on chromosome 3q. In cell lines, genetic knockdown of SMO produced minor effects on cell survival, while GLI2 knockdown significantly reduced proliferation and induced extensive apoptosis. Consistently, the SMO inhibitor GDC-0449 resulted in limited cytotoxicity in LSCC cells, whereas the GLI inhibitor GANT61 was very effective. Importantly, GANT61 demonstrated specific in vivo anti-tumor activity in xenograft models of GLI-positive cell lines.

    Taken together, we report SMO-independent regulation of GLI in LSCC, and demonstrate an important role for GLI2 in LSCC. Different from standard-of-care chemotherapy or small molecule inhibition of kinase signaling cascades, we present a novel and potent strategy to treat a subset of LSCC patients by targeting the GLI transcriptional network.

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    ItemOpen Access
    Right Minithoracotomy Versus Median Sternotomy for Mitral Valve Surgery: A Propensity Matched Study.
    (The Annals of thoracic surgery, 2015-08) Tang, Paul; Onaitis, Mark; Gaca, Jeffrey G; Milano, Carmelo A; Stafford-Smith, Mark; Glower, Donald

    Background

    The efficacy of conventional median sternotomy versus a right minithoracotomy (RT) approach to mitral valve surgery was evaluated in a single high-volume institution.

    Methods

    A retrospective analysis of a single institution's experience was performed using propensity matching of 1,694 patients who underwent mitral valve surgery during a 15-year period. Patients who had procedures that were not usually performed through an RT approach were excluded. Using 1:1 propensity score matching, we obtained 215 matched patients in each group for outcomes analysis.

    Results

    There was no difference in the median year of operation between the two groups (2002 versus 2001; p = 0.142). The RT approach was not a predictor of postoperative mortality. Predictors of mortality included increasing age, diabetes, smoking, preoperative dialysis, lung disease, advanced congestive heart failure class, and peripheral vascular disease. The RT approach was associated with less new-onset atrial fibrillation (8% versus 16%; p = 0.018), pneumonia (1% versus 5%; p = 0.049), respiratory failure (3% versus 8%; p = 0.036), and acute renal failure (2% versus 7%; p = 0.006), lower chest tube output (350 versus 840 mL; p < 0.001), and fewer red blood transfusions (2 versus 3 units; p = 0.001).

    Conclusions

    Right minithoracotomy compared with median sternotomy for mitral valve surgery was associated with less postoperative atrial fibrillation, respiratory complications, acute renal failure, chest tube output, and use of packed red blood cells. Given study limitations, the RT approach for mitral valve surgery may have advantages over median sternotomy in selected patients.