Inverse correlation between heparan sulfate composition and heparanase-1 gene expression in thyroid papillary carcinomas: a potential role in tumor metastasis.

PURPOSE: Heparanase-1 (HPR1) is an endoglycosidase that degrades the side chains of heparan sulfate proteoglycan (HSPG), a key component in cell surfaces, the extracellular matrix (ECM), and the basement membrane (BM). The purpose of this study was to evaluate HPR1 expression in thyroid neoplasms and its effect in degrading the HSPG substrates in the ECM and BM and to determine its role in thyroid tumor metastasis. EXPERIMENTAL DESIGN: HPR1 mRNA expression was analyzed by using in situ hybridization with a digoxigenin-labeled antisense RNA probe on paraffin-embedded tumor sections and reverse transcription-PCR (RT-PCR) in fresh tumor tissues. HPR1 protein expression was analyzed by using immunohistochemical staining with an anti-HPR1 rabbit antiserum and immunofluorescence (IF) with an anti-HPR1 monoclonal antibody. The effect of HPR1 expression in thyroid neoplasms was analyzed by examining the presence and integrity of the HSPG substrates in the ECM and BM using IF staining with a specific monoclonal antibody against heparan sulfate. The relationship of HPR1 expression in papillary thyroid carcinomas (PTCs) with various clinicopathological parameters was analyzed statistically. The role of HPR1 in thyroid tumor metastasis was further examined by comparing HPR1 levels in 10 thyroid tumor cell lines to their invasive and metastatic potential. RESULTS: In situ hybridization analysis of 81 tumor samples (62 papillary carcinomas and 19 follicular adenomas) revealed that HPR1 was expressed at a much higher frequency in PTCs than in follicular adenomas (P<0.05). RT-PCR analyses of fresh tumor tissues revealed that HPR1 mRNA could be detected in primary and metastatic thyroid papillary carcinomas. HPR1 expression was confirmed at the protein level by immunohistochemical staining and IF stainings. IF analysis of HSPG revealed that HS was deposited abundantly in the BM of normal thyroid follicles and benign follicular adenomas but was absent in most thyroid papillary carcinomas. A lack of heparan sulfate in PTCs inversely correlated with HPR1 expression. Clinicopathological data analyses revealed that PTCs with local and distant metastases scored HPR1 positive at a significantly higher frequency than nonmetastatic thyroid cancers (P=0.02). To further explore the role of HPR1 in tumor metastases, we characterized HPR1 expression in 10 thyroid tumor cell lines using RT-PCR and Western blot and measured HPR1 enzymatic activity using a novel ELISA. HPR1 was differentially expressed in different types of cell lines; overexpression of HPR1 in two tumor cell lines led to a dramatic increase of their invasive potential in vitro in an artificial BM. CONCLUSIONS: Our study suggests that HPR1 expressed in papillary carcinomas is functional and that HPR1 expression is associated with thyroid tumor malignancy and may significantly contribute to thyroid tumor metastases.

Combretastatin A4 phosphate has primary antineoplastic activity against human anaplastic thyroid carcinoma cell lines and xenograft tumors.

Anaplastic thyroid carcinoma (ATC) is a fatal malignancy the clinical outcome of which is unaltered by current therapeutic modalities. A recent phase 1 clinical trial of combretastatin A4 phosphate (CA4P) produced a long-lasting total remission in a patient with ATC. CA4P is a tubulin-binding agent derived from the African bush willow, Combretum caffrum, which possesses tumor vascular-targeting activity. In order to discriminate primary antineoplastic effects from tumor antivascular activity, we evaluated CA4P cytotoxicity in eight human ATC cell lines and compared it to paclitaxel, another tubulin-binding agent with significant clinical activity. CA4P displayed significant cytotoxicity against the ATC cell lines, comparable to that of paclitaxel, and these effects were longer lasting in two cell lines compared to the duration of paclitaxel. We further investigated the effects of CA4P on xenograft tumors from four ATC cell lines injected in athymic nude mice. Significantly lower tumor weights were observed in animals treated with CA4P compared to those treated with vehicle alone. Continuous monitoring of xenograft tumor volumes from one of the ATC cell lines also revealed a significantly lower rate of tumor growth in the CA4P-treated mice compared to those receiving vehicle alone. These results suggest that antitumoral effects of CA4P can be consequent to a combination of primary antineoplastic effects as well as the potential destruction of tumor vasculature.

Low-sodium diet self-management intervention in heart failure: pilot study results.

BACKGROUND: Self-care management of a low-sodium diet is a critical component of comprehensive heart failure (HF) treatment. AIMS: The primary purpose of this study was to examine the effectiveness of an educational intervention on reducing the dietary sodium intake of patients with HF. Secondary purposes were to examine the effects of the intervention on attitudes, subjective norm, and perceived behavioural control towards following a low-sodium diet. METHODS: This was a randomized clinical trial of an educational intervention based on The Theory of Planned Behavior. Patients were randomized to either a usual care (n=25) or intervention group (n=27) with data collection at baseline, 6 weeks, and 6 months. The intervention group received low-sodium diet instructions and the usual care group received no dietary instructions. Nutrition Data Systems-Research software was used to identify the sodium content of foods on food diaries. Attitudes, subjective norm, and perceived behavioural control were measured using the Dietary Sodium Restriction Questionnaire. RESULTS: Analysis of covariance (between-subjects effects) revealed that dietary sodium intake did not differ between usual care and intervention groups at 6 weeks; however, dietary sodium intake was lower in the intervention group (F=7.3, df=1,29, p=0.01) at 6 months. Attitudes subscale scores were higher in the intervention group at 6 weeks (F=7.6, df=1, 38, p<0.01). CONCLUSION: Carefully designed educational programmes have the potential to produce desired patient outcomes such as low-sodium diet adherence in patients with heart failure.

Theory-based low-sodium diet education for heart failure patients.

Theory-based teaching strategies for promoting adherence to a low-sodium diet among patients with heart failure are presented in this article. The strategies, which are based on the theory of planned behavior, address patient attitude, subjective norm, and perceived control as patients learn how to follow a low-sodium diet. Home health clinicians can select a variety of the instructional techniques presented to meet individual patient learning needs.