Targeting surface nucleolin with a multivalent pseudopeptide delays development of spontaneous melanoma in RET transgenic mice

<p>Abstract</p> <p>Background</p> <p>The importance of cell-surface nucleolin in cancer biology was recently highlighted by studies showing that ligands of nucleolin play critical role in tumorigenesis and angiogenesis. By using a specific antagonist that binds the C-terminal tail of nucleolin, the HB-19 pseudopeptide, we recently reported that HB-19 treatment markedly suppressed the progression of established human breast tumor cell xenografts in the athymic nude mice without apparent toxicity.</p> <p>Methods</p> <p>The <it>in vivo </it>antitumoral action of HB-19 treatment was assessed on the spontaneous development of melanoma in the RET transgenic mouse model. Ten days old RET mice were treated with HB-19 in a prophylactic setting that extended 300 days. In parallel, the molecular basis for the action of HB-19 was investigated on a melanoma cell line (called TIII) derived from a cutaneous nodule of a RET mouse.</p> <p>Results</p> <p>HB-19 treatment of RET mice caused a significant delay in the onset of cutaneous tumors, several-months delay in the incidence of large tumors, a lower frequency of cutaneous nodules, and a reduction of visceral metastatic nodules while displaying no toxicity to normal tissue. Moreover, microvessel density was significantly reduced in tumors recovered from HB-19 treated mice compared to corresponding controls. Studies on the melanoma-derived tumor cells demonstrated that HB-19 treatment of TIII cells could restore contact inhibition, impair anchorage-independent growth, and reduce their tumorigenic potential in mice. Moreover, HB-19 treatment caused selective down regulation of transcripts coding matrix metalloproteinase 2 and 9, and tumor necrosis factor-α in the TIII cells and in melanoma tumors of RET mice.</p> <p>Conclusions</p> <p>Although HB-19 treatment failed to prevent the development of spontaneous melanoma in the RET mice, it delayed for several months the onset and frequency of cutaneous tumors, and exerted a significant inhibitory effect on visceral metastasis. Consequently, HB-19 could provide a novel therapeutic agent by itself or as an adjuvant therapy in association with current therapeutic interventions on a virulent cancer like melanoma.</p

Identification and Characterization of Nucleolin as a COUP-TFII Coactivator of Retinoic Acid Receptor β Transcription in Breast Cancer Cells

The orphan nuclear receptor COUP-TFII plays an undefined role in breast cancer. Previously we reported lower COUP-TFII expression in tamoxifen/endocrine-resistant versus sensitive breast cancer cell lines. The identification of COUP-TFII-interacting proteins will help to elucidate its mechanism of action as a transcriptional regulator in breast cancer.FLAG-affinity purification and multidimensional protein identification technology (MudPIT) identified nucleolin among the proteins interacting with COUP-TFII in MCF-7 tamoxifen-sensitive breast cancer cells. Interaction of COUP-TFII and nucleolin was confirmed by coimmunoprecipitation of endogenous proteins in MCF-7 and T47D breast cancer cells. In vitro studies revealed that COUP-TFII interacts with the C-terminal arginine-glycine repeat (RGG) domain of nucleolin. Functional interaction between COUP-TFII and nucleolin was indicated by studies showing that siRNA knockdown of nucleolin and an oligonucleotide aptamer that targets nucleolin, AS1411, inhibited endogenous COUP-TFII-stimulated RARB2 expression in MCF-7 and T47D cells. Chromatin immunoprecipitation revealed COUP-TFII occupancy of the RARB2 promoter was increased by all-trans retinoic acid (atRA). RARβ2 regulated gene RRIG1 was increased by atRA and COUP-TFII transfection and inhibited by siCOUP-TFII. Immunohistochemical staining of breast tumor microarrays showed nuclear COUP-TFII and nucleolin staining was correlated in invasive ductal carcinomas. COUP-TFII staining correlated with ERα, SRC-1, AIB1, Pea3, MMP2, and phospho-Src and was reduced with increased tumor grade.Our data indicate that nucleolin plays a coregulatory role in transcriptional regulation of the tumor suppressor RARB2 by COUP-TFII

Demographic, clinical and antibody characteristics of patients with digital ulcers in systemic sclerosis: data from the DUO Registry

OBJECTIVES: The Digital Ulcers Outcome (DUO) Registry was designed to describe the clinical and antibody characteristics, disease course and outcomes of patients with digital ulcers associated with systemic sclerosis (SSc). METHODS: The DUO Registry is a European, prospective, multicentre, observational, registry of SSc patients with ongoing digital ulcer disease, irrespective of treatment regimen. Data collected included demographics, SSc duration, SSc subset, internal organ manifestations, autoantibodies, previous and ongoing interventions and complications related to digital ulcers. RESULTS: Up to 19 November 2010 a total of 2439 patients had enrolled into the registry. Most were classified as either limited cutaneous SSc (lcSSc; 52.2%) or diffuse cutaneous SSc (dcSSc; 36.9%). Digital ulcers developed earlier in patients with dcSSc compared with lcSSc. Almost all patients (95.7%) tested positive for antinuclear antibodies, 45.2% for anti-scleroderma-70 and 43.6% for anticentromere antibodies (ACA). The first digital ulcer in the anti-scleroderma-70-positive patient cohort occurred approximately 5 years earlier than the ACA-positive patient group. CONCLUSIONS: This study provides data from a large cohort of SSc patients with a history of digital ulcers. The early occurrence and high frequency of digital ulcer complications are especially seen in patients with dcSSc and/or anti-scleroderma-70 antibodies

Competition-based, quantitative chemical proteomics in breast cancer cells identifies new target profiles for sulforaphane

Sulforaphane is a small molecule isothiocyanate which exhibits anticancer potential, yet its biological targets remain poorly understood. Here we employ a competition-based chemical proteomics strategy to profile sulforaphane's targets and identify over 500 targets along with their relative affinities. These targets provide a new set of mediators for sulforaphane's bioactivity, and aid understanding of its complex mode of action

Vivências de mulheres com diagnóstico de doença sexualmente transmissível - DST Experiencias de Mujeres con Diagnóstico de Enfermedad Sexualmente Transmisible - ETS Women's Experiences with Sexually Transmitted Disease Diagnosis - STD

As doenças sexualmente transmissíveis (DSTs) constituem problema de saúde pública em virtude da sua alta ocorrência. Nas mulheres, o controle é um desafio devido às implicações sociais e de gênero. Esse estudo objetiva conhecer como as mulheres vivenciam o diagnóstico de uma DST e as repercussões da revelação desse diagnóstico ao parceiro sexual. Estudo exploratório-descritivo desenvolvido em uma unidade de saúde de referência para DST de Fortaleza-Ceará. A coleta de dados foi realizada nos meses de fevereiro e março de 2006 e analisada em duas categorias: vivências das mulheres com o diagnóstico da DST e repercussões da revelação do diagnóstico da DST ao parceiro sexual. Constatou-se que a ocorrência de uma DST resulta em impacto negativo para as mulheres em relação ao convívio social e ao relacionamento com o parceiro sexual. O aconselhamento desempenha papel fundamental para redução do estresse. Os serviços de saúde devem valorizar os aspectos emocionais relacionados ao diagnóstico da DST, visando contribuir com a melhoria da qualidade de vida das mulheres e na abordagem do parceiro.<br>Las enfermedades sexualmente transmisibles (ETS) son un grave problema de salud pública, debido a alto prevalecimiento. En las mujeres, el control es un desafío, debido a las implicaciones sociales y de géneros. El objetivo de este estudio es saber como las mujeres viven la diagnosis de una ETS y las repercusiones de la revelación de esta diagnosis a su pareja sexual. Es un estudio exploratorio y descriptivo desarrollado en una unidad de salud de referencia para ETS de Fortaleza - Ceará (Brasil). La cosecha de datos fue realizada en los meses de febrero y marzo de 2006 y analizada en dos categorías: experiencias de mujeres con diagnóstico de ETS y las repercusiones de la revelación a la pareja sexual. Se constató que la ocurrencia de una ETS resulta en impacto negativo para las mujeres en relación al convivió social y al relaciones con la pareja sexual. El acto de aconsejar desempeña papel fundamental para la reducción de estrese. Los servicios de salud deben valorar los aspectos emocionales relacionados al diagnóstico de ETS, visando contribuir para el mejoramiento de la calidad de vida de las mujeres y en el abordaje de la pareja.<br>The sexually transmissible diseases (STD) constitutes problem of public health, because of the high prevalence. For the women, the control is a challenge, because of the social implications and mainly of gender. This objective of this study was to know as the women feel the diagnosis of a STD and the repercussions of the revelation of this diagnosis to the sexual partner. Exploratory-descriptive study developed in a unit of reference health for STD in Fortaleza Ceará (Brazil). The collection of the data was accomplished the months of February and March in 2006 and the analyzed in two categories: women's experiences with STD diagnosis and the repercussion of the revelation of the STD diagnosis to the sexual partner. It was verified that the occurrence of other STD results a negative impact for the woman in a social relationship with a sexual partner. A word of advice is a fundamental work to reduce the stress. The services of health should valorize the emotional aspects related of the diagnosis other STD, with the vision to contribute with the improvement of the quality of the woman life and approach with the partner