Produtos naturais da ascídia Botrylloides giganteum, das esponjas Verongula gigantea, Ircinia felix, Cliona delitrix e do nudibrânquio Tambja eliora, da costa do Brasil

Two new marine metabolites, 3Z, 6Z, 9Z-dodecatrien-1-ol (1) from the ascidian Botrylloides giganteum and 4H-pyran-2ol acetate from the sponge Ircinia felix (4) are herein reported. The known bromotyrosine compounds, 2-(3,5-dibromo-4-methoxyphenyl)-N,N,N-dimethylethanammonium (2) and 2,6-dibromo-4-(2-(trimethylammonium)ethyl)phenol (3), have been isolated from the sponge Verongula gigantea. Serotonin (5) is reported for the first time from the sponge Cliona delitrix, and tambjamines A (15) and D (16) isolated as their respective salts from the nudibranch Tambja eliora. Only tambjamine D presented cytotoxicity against CEM (IC50 12.2 µg/mL) and HL60 (IC50 13.2 µg/mL) human leukemya cells, MCF-7 breast cancer cells (IC50 13.2 µg/mL), colon HCT-8 cancer cells (IC50 10.1 µg/mL) and murine melanoma B16 cancer cells (IC50 6.7 µg/mL).

Abdome agudo como manifestação inicial de melanoma metastático: relato de caso

The malignant melanoma is a relatively common neoplasia, with origin generally in the melanocytics cells in the skin, but with presentation of other possible primary lesions, being presented in this, a case witnessed of liver and mesentery metastases with unknown primary sites.

Cohabitation with a B16F10 melanoma-bearer cage mate influences behavior and dendritic cell phenotype in mice

This study evaluated the effects of cohabitation with a B16F10 melanoma-bearer cage mate on behavior and immune functions in mice. Five different experiments were conducted. In each of them, the female mice were divided into two groups: control and experimental. One mouse of each control pair was kept undisturbed and called ""companion of health partner"" (CHP). One mouse of each experimental pair was inoculated with B16FI0 cells and the other, the subject of this study, was called ""companion sick partner"" (CSP). On Day 20 of cohabitation, behavior and immune parameters from CHP and CSP mice were analyzed. In comparison to the CHP, the CSP mice: (1) presented an increased general locomotion in the open field and a decreased exploration time and number of entries in the plus-maze open arms; (2) had an enhanced expression of the CD80 costimulatory molecule on Iab(+)CD11c(+) spleen cells, but no differences were found on lymph nodes cells; (3) presented an altered differentiation of bone marrow cells in the presence of GM-CSF, IL-4, and LPS in vitro, resulting in a lower percentage of Iab(+)CD80(+) cells; (4) had a deficit in the establishment of a Delayed Type of Hypersensitivity to ovalbumin, which was associated to an in vitro proliferation of an IL-10-producing lymphocyte subpopulation after ovalbumin stimulation. Corticosterone levels detected on Day 20 of cohabitation were similar in CHP and CSP mice. It is shown here that DCs phenotype in mice is affected by conditions associated with behavioral alterations indicative of an anxiety-like state induced by the cohabitation with a tumor-bearer conspecific. This phenomenon occurred probably through a nondependent corticosterone mechanism. (C) 2009 Elsevier Inc. All rights reserved.

Tumor-derived microvesicles modulate the establishment of metastatic melanoma in a phosphatidylserine-dependent manner

Exposure of phosphatidylserine (PS) on cellular membranes and membrane-derived microvesicles stimulates a number of anti-inflammatory responses involved in malignant processes. Herein we show that B16F10 cells, a highly metastatic melanoma cell line, produce large quantities of PS-containing microvesicles in vitro. Tumor microvesicles increased TGF-beta(1) production by cultured macrophages and, in vivo, enhanced the metastatic potential of B16F10 cells in C57BL/6 mice, both effects being reversed by annexin V. Most strikingly, microvesicles induced melanoma metastasis in BALB/c mice, which are normally resistant to this tumor cell line. Altogether, this is the first demonstration that tumor-derived microvesicles favor the establishment of melanoma metastasis in a PS-dependent manner, possibly by down-regulating the host`s inflammatory and/or anti-tumoral immune responses. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Long-term follow-up of topical 5-aminolaevulinic acid photodynamic therapy diode laser single session for non-melanoma skin cancer

Photodynamic therapy (PDT) is based on the association of a light source and tight sensitive agents in order to cause the selective death of tumor cells. To evaluate topical 5-aminolaevulinic acid (5-ALA) and diode laser photodynamic single session therapy single session for non-melanoma skin cancer (NMSC), a long-term follow-up was performed. Nineteen Bowen`s disease (BD) and 15 basal cell. carcinoma (BCC) lesions were submitted to 6-h topical and occlusive 20% 5-ALA plus DMSO and EDTA, and later were exposed to 630 nm diode laser, 100 or 300 J cm(-2) dose. At 3 months tumor-free rate was 91.2% (31/34) whereas at 60 months, 57.7% (15/26), slightly higher in BCC (63.6%; 7/11). The relation between the reduction of the clinical response and the increase of tumor dimension observed at 18 months was lost at 60 months. The sBCC recurrence was earlier compared to the nBCC one. ALA-PDT offered important advantages: it is minimally invasive, an option for patients under risk of surgical complications; clinical feasibility; treatment of multiple lesions in only one session or lesions in poor heating sites and superior esthetical results. However, the recurrence rate increase after ALA-PDT diode laser single session can be observed at tong-term follow-up, and the repetitive sessions, an additional. advantage of the method, is strongly recommended. The clinical response and recurrence time seem to be related to the laser light dose and NMSC types/sub-types, thickness and dimension, which must be considered for the choice of the ALA-PDT. (C) 2009 Elsevier B.V. All rights reserved.

Abdominopelvic sarcoma of perivascular epithelioid cells. Report of four cases in young women, one with tuberous sclerosis

The perivascular epithelioid cell has been proposed to be the unifying proliferating cell type in a number of lesions such as angiomyolipoma, lymphangiomyomatosis, clear cell sugar tumor and renal capsuloma. With the exception of rare examples of angiomyolipoma, they are non-metastasizing. We report four examples of a new member of this family of perivascular epithelioid cell neoplasms that occur in abdominopelvic location and show metastatic properties. The patients, all women, were aged 19 to 41 years (mean, 32), and presented with a tumor mass involving the serosa of the ileum, uterus or pelvic cavity. Morphologically, the tumors were composed of sheets of large polygonal cells with glycogen-rich clear or eosinophilic cytoplasm and moderately pleomorphic nuclei, traversed by a delicate vasculature, mimicking clear cell carcinoma. There were areas of coagulative necrosis and occasional mitotic figures. Intracytoplasmic brown pigment was present in two cases. Spindly cells, smooth muscle and fat were absent. Lymphovascular invasion was present in all, lymph node metastasis was documented in two and metastasis to the ovary was present in one case. Two patients developed widespread metastatic disease after 10 and 28 months from diagnosis. One patient showed the clinical signs of tuberous sclerosis. In spite of the epithelial-like appearance, the tumor cells were negative for epithelial markers but were strongly positive with the melanogenesis-related marker HMB45. Another melanogenesis marker (MART-1) was positive in two cases. Other markers including S-100 protein, vimentin, muscle-specific actin, desmin and chromogranin A were negative. Thus, these tumors are not readily classifiable in the existing schema of known entities, and show over-lapping morpho-phenotypic features of clear cell sugar tumor of the lung and epithelioid angiomyolipoma. We consider them as sarcomas composed of a pure population of uncommitted perivascular epithelioid cell, that lack modulation toward smooth muscle or adipose cells.

Critérios histopatológicos para diagnóstico de melanoma maligno cutâneo: análise comparativa de sua freqüência em lesões benignas e melanomas de pequena espessura (< 2 mm)

INTRODUÇÃO: A histopatologia convencional continua sendo o padrão-ouro no diagnóstico dos melanomas cutâneos, apesar do progresso da imuno-histoquímica e da biologia molecular. Os critérios microscópicos existentes para esse diagnóstico são numerosos, porém nenhum deles é específico para se afirmar que uma determinada lesão é maligna quando ele está presente, ou é benigna na sua ausência. Alguns critérios têm uma relevância maior para o diagnóstico em relação a outros. OBJETIVO: Este estudo propõe uma análise daqueles critérios considerados mais importantes, comparando sua presença em lesões melanocíticas benignas e melanomas. MATERIAL E MÉTODOS: Foram estudadas 33 lesões melanocíticas benignas (nevo de Spitz: 13; nevo de Reed: 6; nevo displásico: 6; nevo congênito: 3; nevo adquirido: 3; nevo combinado: 1; nevo recorrente: 1), bem como 101 casos de melanomas extensivo/superficiais: 25 intra-epidérmicos e 76 invasivos de pequena espessura (< 2 mm). RESULTADOS: Alguns critérios mostraram alta freqüência em lesões benignas, apresentando pouca especificidade, enquanto outros tiveram menor positividade nas benignas, e alta freqüência nas malignas, mostrando sua maior especificidade e importância no diagnóstico dos melanomas. CONCLUSÃO: Os cinco critérios que mostraram diferenças estatisticamente significativas na comparação com as lesões benignas foram (em ordem decrescente de freqüência): 1. proliferação linear de células isoladas na camada basal; 2. início e fim da lesão com células isoladas; 3. melanócitos na camada granular; 4. disseminação pagetóide extensa; 5. nucléolos grandes, irregulares ou múltiplos. Os melanomas de pequena espessura não apresentam parte dos critérios considerados mais importantes, como falta de maturação, necrose e mitoses profundas.

Ocular melanoma and mammary mucinous carcinoma in an African lion

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Critérios anatomopatológicos para melanoma maligno cutâneo: análise qualitativa de sua eficácia e revisão da literatura

São bastante conhecidos pelos patologistas o desafio e a dificuldade que algumas lesões melanocíticas apresentam no momento de seu diagnóstico. A falta de uniformidade na maneira de aplicar os critérios diagnósticos é, sem dúvida, uma das causas principais dos altos índices de discordância descritos na literatura. O objetivo deste trabalho é tentar diminuir esta discordância e, para isso, foram selecionados os 12 critérios considerados mais importantes para o diagnóstico de melanoma: 1) tamanho; 2) simetria; 3) delimitação lateral; 4) maturação; 5) disseminação pagetóide; 6) necrose/ulceração; 7) infiltrado inflamatório; 8) regressão; 9) atipias celulares; 10) mitoses; 11) melanização; 12) proliferação de células isoladas. Foram expostas as características de cada um deles e sua aplicação no diagnóstico dos melanomas, lembrando sempre as possíveis exceções, onde estes critérios podem estar presentes em lesões melanocíticas benignas. Posteriormente, em três tabelas, estabeleceu-se o diagnóstico diferencial entre melanoma e três condições melanocíticas benignas que costumam apresentar maiores dificuldades no diagnóstico diferencial. Como nenhum critério deve ser considerado isoladamente, a aplicação rigorosa do conjunto de dados aqui fornecido pode ajudar substancialmente o patologista cirúrgico generalista (não-especialista em lesões melanocíticas) a resolver alguns problemas na sua rotina diária.

The Effect of Propolis on Th1/Th2 Cytokine Expression and Production by Melanoma-bearing Mice Submitted to Stress

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Haplotype effects on matrix metalloproteinase-1 gene promoter activity in cancer cells

Increased expression of matrix metalloproteinase-1 (MMP1) is associated with poor prognosis in cancers. Several single nucleotide polymorphisms (-1607GG > G, -839G > A, -755G > T, -519A > G, -422T > A, -340C > T, and 320C > T) in the MMP1 gene promoter have recently been identified. In this study, we assessed the functional effects of these polymorphisms on MMP1 gene promoter activity in cell lines of melanoma (A2058 and A375), breast cancer (MCF7 and MDA-MB-231), lung cancer (A549 and H69), and colorectal cancer (HT-29, SW-620) by comparing the promoter strengths of 10 most common haplotypes deriving from these polymorphisms. In A2058 cells, the GG-G-G-A-T-T-T and GG-G-G-A-C-T haplotypes had 2-fold higher promoter activity than the GG-G-T-A-T-T-C, GG-G-G-A-A-T-T, GG-G-G-A-T-T-C, and GG-G-G-A-A-C-T haplotypes, which in turn, had 3-fold higher promoter activity than the G-G-T-A-A-C-T, G-A-T-G-T-T-T, G-A-T-G-A-C-T, and G-A-T-G-A-T-G haplotypes. In A375 and MDA-MB-231 cells, high expression haplotypes include not only the -1607GG-bearing haplotypes but also the G-A-T-G-A-T-T haplotype containing the -1607G allele. A similar trend was detected in A549 cells. In addition, in A549 cells, the GG-G-G-A-T-T-T haplotype had > 2-fold higher promoter activity than several other 1607GG-bearing haplotypes. In MCF7 cells, the GG-G-G-A-T-T-T and G-G-T-A-A-C-T haplotypes had 1.5- to 4-fold higher promoter activity than the other haplotypes. These results suggest that the polymorphisms exert haplotype effects on the transcriptional regulation of the MMP1 gene in cancer cells, and indicate a need to examine haplotypes rather than any single polymorphism in genetic epidemiologic studies of the MMP1 gene in cancers.

Anti-genotoxic effect of aqueous extracts of sun mushroom (Agaricus blazei Murill lineage 99/26) in mammalian cells in vitro

The sun mushroom is the popular name for the Agaricus blazei Murill fungus, a mushroom native to south-eastern Brazil, which has been frequently used in popular medicine mainly in the form of tea to treat various ailments (stress, diabetes, etc.). In the present study, the genotoxic and/or anti-genotoxic effects ofA. blazei on mammalian cells in culture was assessed by checking the increase or reduction of micronucleus (MN) frequency and comets. The sun mushroom (lineage 99/26) was used as aqueous extracts prepared (2.5%) at three different temperatures (60, 25 and 4°C). The in vitro micronucleus (MN) test in binucleated cells and comet assay were used in V79 cells cultivated in HAM-F10+DMEM medium (1:1), supplemented with 10% of fetal bovine serum. The experiments were divided into four treatment types: 1. Negative control; 2. Positive control with MMS; 3. Treatments with the three forms of extracts (60, 25 and 4°C); and 4. Treatments with the extracts in different associations (simultaneous, pre-treatment, post-treatment and simultaneous after pre-incubation for 1 h) with MMS. None of the A. blazei extracts show genotoxic activity. In the comet assay no protecting effect was found. The results obtained in the MN test showed that the three forms of extracts used had protective activity, suggesting that the compound or active ingredients of A. blazei are always present in these extracts. The greater protective efficiency of the simultaneous treatment and simultaneous treatment with pre-incubation mixture with MMS suggests that the extracts have an antimutagenic action of the desmutagenic type. © 2002 Elsevier Science Ltd. All rights reserved.

Role of natural killer cells in antitumor resistance

Natural killer cells constitute a population of lymphocytes able to non-specifically destroy virus-infected and some kinds of tumor cells. Since this lytic activity was shown by non-immunized animals the phenomenon is denominated natural killer (NK) activity and contrasts with specific cytotoxicity performed by cytolytic T lymphocytes (CTLs) because it does not depends on MHC-restricted peptides recognition. In fact, the main feature of most functional receptors of NK cells (NKRs) is their ability to be inhibited by different kinds of class I MHC antigens. In the middle of the 1950's, Burnet & Thomas forged the concept of tumor immunosurveillance and NK cells can be considered one of the main figures in this phenomenon both for effector and regulatory functions. In the present review the early studies on the biology of NK cells were revisited and both their antitumor activity and dependence on the activation by cytokines are discussed.

Inhibition of eukaryotic translation initiation factor 5A (eIF5A) hypusination impairs melanoma growth

The eukaryotic translation initiation factor 5A (eIF5A) undergoes a specific post-translational modification called hypusination. This modification is required for the functionality of this protein. The compound N1-guanyl-1,7-diaminoheptane (GC7) is a potent and selective inhibitor of deoxyhypusine synthase, which catalyses the first step of eIF5A hypusination process. In the present study, the effects of GC7 on cell death were investigated using two cell lines: melan-a murine melanocytes and Tm5 marine melanoma. In vitro treatment with GC7 increased by 3-fold the number of cells presenting DNA fragmentation in Tm5 cells. Exposure to GC7 also decreased viability to both cell lines. This study also describes, for the first time, the in vivo antitumour effect of GC7, as indicated by impaired melanoma growth in C57BL/6 mice. Copyright © 2006 John Wiley & Sons, Ltd.