Endostatin and anastellin inhibit distinct aspects of the angiogenic process

<p>Abstract</p> <p>Background</p> <p>Endostatin and anastellin, fragments of collagen type XVIII and fibronectin, respectively, belong to a family of endogenous inhibitors of angiogenesis which inhibit tumor growth and metastasis in a number of mouse models of human cancer. The mechanism of action of these inhibitors is not well understood, but they have great potential usefulness as non-toxic long-term therapy for cancer treatment.</p> <p>Methods</p> <p>In this study, we compare the anti-angiogenic properties of endostatin and anastellin using cell proliferation and transwell migration assays.</p> <p>Results</p> <p>Anastellin but not endostatin completely inhibited human dermal microvessel endothelial cell proliferation in response to serum stimulation. Both anastellin and endostatin additively inhibited endothelial cell migration in response to VEGF. Anastellin but not endostatin lowered basal levels of active ERK.</p> <p>Conclusion</p> <p>These data indicate that anastellin and endostatin exert their anti-angiogenic effects by modulating distinct steps in the angiogenic pathway and suggest that matrix-derived inhibitors of angiogenesis may exhibit higher efficacy when used in combination.</p

Evolutionary Action Score of TP53 Identifies High-Risk Mutations Associated with Decreased Survival and Increased Distant Metastases in Head and Neck Cancer

TP53 is the most frequently altered gene in head and neck squamous cell carcinoma, with mutations occurring in over two-thirds of cases, but the prognostic significance of these mutations remains elusive. In the current study, we evaluated a novel computational approach termed evolutionary action (EAp53) to stratify patients with tumors harboring TP53 mutations as high or low risk, and validated this system in both in vivo and in vitro models. Patients with high-risk TP53 mutations had the poorest survival outcomes and the shortest time to the development of distant metastases. Tumor cells expressing high-risk TP53 mutations were more invasive and tumorigenic and they exhibited a higher incidence of lung metastases. We also documented an association between the presence of high-risk mutations and decreased expression of TP53 target genes, highlighting key cellular pathways that are likely to be dysregulated by this subset of p53 mutations that confer particularly aggressive tumor behavior. Overall, our work validated EAp53 as a novel computational tool that may be useful in clinical prognosis of tumors harboring p53 mutations

Is the incidence of anaplastic thyroid cancer increasing: A population based epidemiology study

Objective: To provide an understanding of the incidence of anaplastic thyroid cancer within the United States. Methods: Patients in the Surveillance, Epidemiology, and End Results (SEER) database were included from 1973 to 2014 based on a diagnosis of anaplastic thyroid cancer using ICD O-3 codes. Patients were categorized into cohorts based on their year of diagnosis. Results: 1527 patients were diagnosed with anaplastic thyroid cancer within the SEER 18 registries. The age-adjusted incidence rate was 0.2 per 1,000,000 people (95% CI: 0.0–0.5) in 1973 and was 1.2 per 1,000,000 people (95% CI: 0.8–1.6) in 2014 (average annual percent change: 3.0% [95% CI: 2.2%–3.7%]). Patients tended to be of older age (mean age: 70.5 [range 15.0–102.0]), of female sex (62.8%), and Caucasian (81.1%). Finally, survival over time remained the same, as median disease specific survival months was 4.00 (95% CI: 2.26–5.74) from 1995 to 1999 and 4.00 (95% CI: 3.26–4.74) from 2010 to 2014. Conclusions: The incidence rate of anaplastic thyroid cancer has increased from 1973 to 2014. Interestingly, median survival in months did not greatly change overtime. Based on this increasing incidence, physicians must act appropriately to identify patients with anaplastic thyroid cancer as it possesses a high morbidity and mortality. Level of evidence: 4. Keywords: Anaplastic thyroid cancer, Thyroid cancer, Head and neck, Head and neck endocrine surgery, Head and neck oncolog

Abstract 279: Small interfering RNA targeting CD44 blocks EGFR signaling in head and neck squamous cell carcinoma (HNSCC)

Abstract INTRODUCTION: Head and Neck Squamous Cell Carcinoma (HNSCC) is a disease that accounts for 90% of the 600,000 new diagnoses of head and neck cancers worldwide each year. CD44 is a purported cancer stem cell (CSC) marker, and its colocalization with EGFR has been proposed to activate tyrosine kinase (TK) and mitogen-activated protein kinase (MAPK). Therapies tend to have dismal cure rates. Understanding the interaction between CD44 and EGFR may result in improved therapies for HNSCC. METHODS: To evaluate the effect of CD44 on EGFR, we inhibited CD44 expression in a CD44-overexpressing HNSCC cell line, CAL27, using the siRNA method. The cell line was stably transfected with a DNA plasmid designed to knock down the expression of CD44. We then performed western blots examining CD44 and phosphorylated EGFR (Y1068) in siRNA knockdown clones and in scrambled sequence, followed by implantation of the CD44siRNA clones and scramble controls in nude mice. The mice were sacrificed, and the tumors were embedded in paraffin for IHC analysis. CD44 and EGFR colocalization was examined in 5 HNSCC cases and in CAL 27 xenografts by immunohistochemistry (IHC) and laser scanning confocal microscopy (LSCM). RESULTS: Downregulation of CD44 by siRNA in CAL 27 cells inhibited constitutive EGFR phosphorylation in vitro and in vivo. Knocking down of CD44 by siRNA reduced the tumor growth in mice compared to CAL 27 and scrambled siRNA. CD44 and EGFR coexpression and colocalization were observed in 80% (4/5) of HNSCC cases and in CAL 27 xenografts. CONCLUSION: Based on these studies, targeting CD44 may provide an additional therapeutic option for HNSCC that does not respond favorably to other treatments. Anti- CD44 therapy in HNSCC may target the cancer stem cell population and alter EGFR signaling. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 279. doi:1538-7445.AM2012-279</jats:p

Vimentin and Non-Muscle Myosin IIA are Members of the Neural Precursor Cell Expressed Developmentally Down-Regulated 9 (NEDD9) Interactome in Head and Neck Squamous Cell Carcinoma Cells

Here we demonstrate an interaction between neural precursor cell expressed, developmentally-downregulated 9 (NEDD9) and the cytoskeletal proteins vimentin and non-muscle myosin IIA (NMIIA), based on co-immunoprecipitation and mass spectrometric sequence identification. Vimentin was constitutively phosphorylated at Ser56 but vimentin associated with NEDD9-was not phosphorylated at Ser56. In contrast, NMIIA bound to NEDD9 was phosphorylated on S1943 consistent with its function in invasion and secretion. Treatment of cells with the vimentin-targeting steroidal lactone withaferin A had no effect on vimentin turnover as previously reported, instead causing NEDD9 cleavage and cell death. The NMIIA-selective inhibitor blebbistatin induced cells to form long extensions and attenuated secretion of matrix metalloproteinases (MMPs) 2 and 9. While the site of vimentin interaction on NEDD9 was not defined, NMIIA was found to interact with NEDD9 at its substrate domain. NEDD9 interactions with vimentin and NMIIA are consistent with these proteins having roles in MMP secretion and cell invasion. These findings suggest that a better understanding of NEDD9 signaling is likely to reveal novel therapeutic targets for the prevention of invasion and metastasis

High-resolution computed tomography analysis of the frontal sinus ostium: A pilot study

Identification and exposure of the frontal sinus recess (FSR) during endoscopic sinus surgery (ESS) are challenging due to the variable anatomy, the narrow opening of the frontal sinus ostium (FSO), and the proximity of vital anatomic structures. Hence, a strong understanding of frontal sinus anatomy is required to prevent intracranial entry. Consistent and easily identifiable landmarks and measurements could assist safe entry into the FSO. In this study, we determine the distances from the columella and anterior nasal spine (ANS) to the nasofrontal beak (NFB) and anterior skull base (ASB) using high-resolution computed tomography (HRCT) scans. A radiographic analysis was performed at a tertiary care medical center. Measurements from the ANS to the NFB and ASB, and from the columella to the NFB and ASB were made using sagittal HRCT. Thirty-two HRCT scans were analyzed by three observers, and the mean distances and standard deviations were calculated. The mean distance from the ANS to the NFB was 52.3±3.4mm in men and 47.7±3.5mm in women (p<0.0001). Mean distance from the ANS to the ASB was 61.8±4.1mm in men and 56.5±4.1mm in women (p<0.0001). Mean distance from the columella to the NFB was 58.9±2.3mm in men and 53.0±3.3mm in women (p<0.0001), and from the columella to the ASB was 67.9±3.7mm in men and 61.3±4.1mm in women (p<0.0001). While performing FSR exposure in ESS, it is recommended to stay a distance of less than 66.9mm in men and 60.6mm in women from the columella to minimize intracranial complications

The outcomes of hypoglossal nerve stimulation in the management of OSA: A systematic review and meta-analysis

Objectives: Obstructive sleep apnea (OSA) is a prevalent disease with significant health impacts. While first line therapy is CPAP, long-term compliance is low and device misuse is common, highlighting the need for alternative therapies. Upper airway surgery is one alternative, but substantial side effects hamper efficacy. A new alternative is an implantable hypoglossal nerve stimulator (HNS). These devices utilize neuromodulation to dilate/reinforce the airway and reduce side effects associated with traditional surgery. Several recent trials investigated the efficacy of these devices. The purpose of this study was to perform meta-analysis of available HNS studies investigating treatment of OSA to analyze objective and subjective outcomes and side effects. Methods: A comprehensive literature search of PubMed and Scopus was performed. Two independent reviewers examined clinical trials investigating HNS in treatment of sleep apnea in adults. Studies with objective and subjective endpoints in sleep were included for analysis. Adverse events from trials were also recorded. Results: Across 16 studies, 381 patients were analyzed. At 6 months (p = 0.008), mean SAQLI improved by 3.1 (95%CI, 2.6–3.7). At 12 months (p < 0.0001), mean AHI was reduced by 21.1 (95%CI, 16.9–25.3), mean ODI was reduced by 15.0 (95%CI, 12.7–17.4), mean ESS was reduced by 5.0 (95%CI, 4.2–5.8), mean FOSQ improved by 3.1 (95%CI, 2.6–3.4). Pain (6.2%:0.7–16.6), tongue abrasion (11.0%:1.2–28.7), and internal (3.0%:0.3–8.4)/external device (5.8%:0.3–17.4) malfunction were common adverse events. Conclusions: HNS is a safe and effective treatment for CPAP refractory OSA. Further study comparing HNS to other therapies is required. Keywords: Surgical treatment of obstructive sleep apnea, Sleep medicine, Obstructive sleep apne