Artesunate promotes Th1 differentiation from CD4+ T cells to enhance cell apoptosis in ovarian cancer via miR-142

The aim of this study was to evaluate the influence of artesunate on Th1 differentiation and its anti-tumor effect on ovarian cancer. A Murine ovarian cancer model was established by ID8 cells transplantation. The expression of miR-142 and Sirt1 proteins in peripheral CD4+ T cells were quantified with qRT-PCR and western blot, respectively. Peripheral CD4+ T cells were induced for Th1 differentiation. The percentages of apoptosis of Th1/CD4+ T cells and ovarian cancer cells were analyzed by flow cytometry. The IFN-γ level was examined through enzyme-linked immunosorbent assay. Artesunate promoted miR-142 expression in peripheral CD4+ T cells and Th1 differentiation from CD4+ T cells. Artesunate promoted cell apoptosis of ovarian cancer cells by inducing Th1 differentiation. By up-regulating miR-142, artesunate suppressed Sirt1 level and promoted Th1 differentiation. Artesunate enhanced the pro-apoptotic effects of Th1 cells on ovarian cancer via the miR-142/Sirt1 pathway. Artesunate promoted Th1 differentiation from CD4+ T cells by down-regulating Sirt1 through miR-142, thereby enhancing cell apoptosis in ovarian cancer.

Encefalitis autoinmunitaria asociada a anticuerpos contra el receptor N-metil-D-aspartato: presentación de dos casos / Autoimmune encephalitis associated to antibodies against the N-methyl-D-aspartate receptor: Report of two cases

Resumen La encefalitis asociada a anticuerpos contra receptores N-metil-D-aspartato es un síndrome neurológico que se presenta más comúnmente en mujeres jóvenes y frecuentemente se asocia al teratoma de ovario. Se caracteriza por un cuadro clínico agudo con síntomas generales inespecíficos que evoluciona hacia deterioro neurológico, psicosis y convulsiones; en su etapa más avanzada, se asocia con movimientos anormales y disautonomía. Se reportan dos casos en mujeres de 23 y 12 años. Dada su baja incidencia, se explica el proceso clínico que llevó a su diagnóstico y las opciones de tratamiento empleadas.

Abstract Anti-N-methyl-D-aspartate receptor encephalitis is a neurological syndrome that is more common in young women and is often associated with ovarian teratoma. It is characterized by acute general unspecific symptoms that evolve to neurological deterioration, psychosis and seizures. In its more advanced stage it is associated with abnormal movements and dysautonomia. We report two cases in women of 23 and 12 years of age. Given its low incidence, we present the clinical exercise that led to their diagnoses and the treatment options employed.

Elevated chromogranin A serum levels in ovarian carcinoma patients.

Background: The observation of neuroendocrine activity during clinical course of ovarian cancer, suggested the use of neuroendocrine serum markers to detect this tumor. Aim: To evaluate the usefulness of serum measurements of chromogranin A (CgA) in the various stages of ovarian cancer. Materials and Methods: We measured serum concentrations of CgA and cancer antigen 125 (CA125) in 79 women at different clinical stages of ovarian cancer, enrolled between 2000 and 2007, and in a control group of 50 female volunteers. Results: CgA showed increased levels in patients with ovarian cancer as compared with healthy subjects, as it has been seen for CA125 serum levels. We also observed significant increase in CgA and CA125 serum levels when comparing patients with ovarian cancer in stage I versus stage II (P < 0.001); stage I versus stage III (P < 0.001); stage I versus stage IV (P < 0.001); stage II versus stage III (P < 0.001); stage II versus stage IV (P < 0.001). In patients with ovarian carcinoma in stage IV we observed a correlation between CgA and CA125 with a difference of 0.718 (P < 0.001). Conclusions: CgA serum levels were elevated in ovarian cancer and increased with the stage. Further studies are needed to elucidate the role of CgA as a prognostic indicator during treatment for ovarian cancer.

Dosagem do antígeno ca125 para acompanhamento de tratamento e seguimento pós-tratamento de neoplasia maligna epitelial de ovário / Dosage of ca125 antigen for treatment follow-up and post-treatment follow-up of malignant ovarian epithelial neoplasia

O carcinoma de ovário é a neoplasia maligna ginecológica mais letal, com incidência mundial de 200.000 novos casos a o ano. Dados internacionais estimam que cerca de 75% dos novos diagnósticos são realizados em estágios avançados, o que é responsável, em parte, pela alta mortalida de associada. Cerca de 90% dos carcinomas de ovário são de origem epitelial, da superfície epitelial ovariana ou derivados mullerianos, como as tubas uterinas (trompas de Falópio). Os adenocarcinomas primários peritoneais são classificados e tratados como carcinomas ovarianos epiteliais. Os demais tumores ovarianos derivam de outras células, como as germinativas, estromais ou mistas, e não serão abordados, por apresentarem comportamento e tratamentos distintos. O Antígeno CA 125: Evoluindo das enzimas ou hormônios, tem-se verificado, nas duas últimas décadas, um aumento do número dos chamados marcadores tumorais (substâncias circulantes, substâncias celulares, receptores de membrana celular, índices celular e nuclear, células, genes e expressões genéticas), cuja validade ou se consolidou como definitiva ou se inutilizou por ineficaz. Essa evolução se deu não só em termos de métodos laboratoriais (por exemplo, a gonadotrofina coriônica humana (hCG) medida na urina de 24 horas substituída pela dosagem sérica da fração beta dessa gonadotrofina (beta-hCG), como marcador de neoplasia de origem trofoblástica ou germinativa), mas também de elementos (a proteinúria de Bence-Jones substituída pela eletroforese de imunoglobulinas, como marcador de neoplasia de células plasmáticas) e mesmo de estruturas nucleares (o cromossoma Philadelphia e o gene bcr-abl, em casos de leucemia mielóide crônica). O CA 125 é um dos marcadores tumoral que ainda têm um papel questionável em neoplasia maligna epitelial de ovário. Alterações nos seus níveis séricos podem ser utilizadas como uma indicação de resposta terapêutica ou de progressão tumoral, mas ele não tem uma clara função na detecção, no diagnóstico ou no prognóstico desta neoplasia. Aproximadamente 50% das doentes de câncer de ovário que têm dosagens séricas normais de CA 125 persistem com tumor residual ao final da terapia. O CA 125 tem sua validade restrita à avaliação da resposta terapêutica e da progressão tumoral, em casos de diagnóstico confirmado de neoplasia maligna epitelial de ovário ou de tuba uterina sob tratamento antineoplásico. O Diagnóstico e estadiamento do câncer de ovário frequentemente se manifesta em estágios avançados, com a ocorrência de sintomas vagos, como distensão abdominal, dor abdominal ou pélvica, sintomas urinários, surgimento de massa abdominal, flatulência ou saciedade precoce relacionada a metástases peritoneais. Em alguns casos, pode ocorrer dispneia devido à ascite ou a derrame pleural associado. Os sintomas inicialmente não levam de imediato à suspeita de câncer. Sua evolução e persistência em mulheres entre 40 e 65 anos, faixa etária na qual a incidência torna-se mais frequente, pode levar o médico a suspeitar e diagnosticar esta neoplasia. O Diagnóstico laboratorial dos carcinomas epiteliais de ovário podem ser responsáveis pela produção do marcador tumoral CA 125. Esta glicoproteína pode estar presente em concentrações elevadas em pacientes com câncer de ovário, porém isoladamente não é útil como exame de triagem ou diagnóstico, podendo ser válido para o acompanhamento das pacientes em tratamento antineoplásico e durante seu seguimento. Monitorização do Tratamento: Avaliação da resposta terapêutica: Após o término do tratamento primário para o câncer epitelial de ovário, é de interesse avaliar se houve resposta completa (RC) por tomografia abdominal total e, no caso de doença metastática extra- abdominal pré-existente, tomografia também de tórax. O uso do marcador CA 125 é amplamente difundido como avaliação de resposta e doença persistente. Entretanto, cerca de 50% das pacientes com valores normais de CA 125 após a quimioterapia apresentam doença residual se avaliadas por cirurgia de second look. Estimativa do Impacto Orçamentário: A incorporação de um procedimento específico para a dosagem do CA 125, para acompanhamento de doentes de neoplasia maligna epitelial de ovário ou de trompa uterina ou de carcinomatose peritoneal, sob tratamento antineoplásico, não traria impacto financeiro para o SUS e orientaria uma melhor utilização deste marcador. Recomendação da CONITEC: Os membros da CONITEC presentes na 7ª reunião ordinária do dia 02/08/2012 recomendaram a incorporação da dosagem do antígeno CA125 para acompanhamento de tratamento e seguimento pós-tratamento de neoplasia maligna epitelial de ovário, conforme Diretrizes Diagnósticas e Terapêuticas (DDT) a ser elaborada pelo Ministério da Saúde. A Portaria CTIE/MS Nº37, de 27 de dezembro de 2012 - Torna pública a decisão de incorporar a dosagem do antígeno CA125 para acompanhamento de tratamento e seguimento pós-tratamento de neoplasia maligna epitelial de ovário no Sistema Único de Saúde.

[Cytotoxic T lymphocyte associated molecule -4 [CTLA-4] gene polymorphisms in ovarian cancer patients]

Ovarian cancer is a relatively common cancer among postmenopausal women. Nowadays, there is controversy about immunotherapy of ovarian cancer patients with interleukins such as interferon to reach better out come in prognosis of patients under chemotherapy. CTLA-4 is a gene, which has an important role in homeostasis and regulation of immune response. Inhibitory nature of CTLA-4 is proved to be of significance in autoimmune diseases as well as in cancer. In this study we intend to find out the relationship between polymorphisms of this gene at the sites of +49 A/G and -318 C/T and ovarian cancer. The polymorphisms of the CTLA-4 gene at the sites of +49 A/G exon and -318 C/T promoter were investigated. Blood samples of 73 patients with ovarian cancer and 115 healthy subjects used for DNA extraction. Two groups genotypes and alleles were determined using PCR method and compared by statistical t-student test. There was no statistically significant difference in genotypes and alleles prevalence of +49 A/G and -317 C/T between two groups [p>0.05]. Further researches with larger sample size while paying attention to the relation between the gene polymorphism and stage and type of tumor is recommended

Ectopic expression of sortilin 1 [NTR-3] in patients with ovarian carcinoma

Gene expression profiling of ovarian carcinoma tissues has shown an increase of four-fold expression of SORTl gene. Sortilin 1 [NTR-3] is a 95-100 kDa protein normally expressed in heart, brain, placenta, skeletal muscle, spinal cord, thyroid, and testis. However, its expression has never been reported in normal ovary. Here, we report expression of sortilin 1 in ovarian carcinoma tissues both at gene and protein levels. Sortilin 1 was expressed in all ovarian carcinoma patients [n=15] as well as ovarian carcinoma cell lines [n=5] regardless of their phenotypic characteristics. Non-malignant ovaries [n=6] did not express sortilin 1. The molecular basis for this ectopic expression is not yet clear. Our results showed a major cell surface expression of sortilin 1 rather than ER-Golgi compartment where it is mainly expressed. This finding may introduce sortilin 1 as a novel tumor marker for diagnosis of ovarian carcinoma and may signify its therapeutic value in targeted therapy

The Comparison of Cytotoxic T-Lymphocyte Effects of Dendritic Cells Stimulated by the Folate Binding Protein Peptide Cultured with IL-15 and IL-2 in Solid Tumor

The current modalities for treating cancer employ not only single but multiple approaches involving surgery, radiotherapy and chemotherapy. Unfortunately, the survival outcome is not promising even with these approaches. Alternative approaches for cancer therapy are now emerging. Immunotherapy is aiming at both increasing the power, and in redirecting the specificity of the patients' immune system to attack the tumor cells. Recently, many studies using tumor associated lymphocytes (TAL) isolated from malignant ascites cultured in a media containing interleukin-2 exhibit antitumor responses. IL-2 is a lymphokine produced by T-cells. It facilitates activation, sustained growth and rescue from apoptosis. Lately, newly developed IL-15 has also exhibited antitumor activity similar to IL-2. IL-15 is a newly described cytokine produced from monocytes-marcrophages and T-cells. It has a different molecular structure but it functions like IL-2 by binding to the IL-2R beta and gamma c chain. These antitumor responses are mediated by the cytotoxic T lymphocytes (CTL) that recognize the antigen in the context of the MHC molecules using the T cell receptors. CD8+-CTL recognize the peptide epitopes that are processed from the cellular proteins in the context of the MHC class I molecules. These peptides have a restricted length of 8-11 amino acids. The folate binding protein (FBP) is overexpressed in over 90% of ovarian and 20-50% in breast cancers. The FBP is the source of the antigenic peptides that are recognized by a number of these CTL-TAL, and is antigenic to both ovarian and breast cancer in vivo. To define the antitumor response of IL-15 and its' FBP immunogenicity, a peptide defining epitope E39 and E75 were presented by the PMBC derived dendritic cells (DC) from healthy donors isolated by the CD14 method to ovarian and breast CTL-TAL. Stimulating both ovarian and breast CTL- TAL by E39 or E75 pulsed DC (DC-E39, DC-E75), in the presence of IL-15 and IL-2 can rapidly enhance or induce the E39 or E75 specific CTL activity. The antitumor activities were measured by a chromium release assay for the tumor specific lysis activity using the ovarian and breast cancer cell lines. The tumor specific lysis activity for the ovarian TALs for IL-15 vs IL-2 were 28.6+/-3.9% and 30.3+/-3.2%, respectively and in the breast TALs, they were 14.8+/-3.1% vs 13.5+/-2.9%, respectively. Using autologous tumor cells, a slightly higher tumor specific lysis activity was obtained for the ovarian TALs cultured in IL-15 compared to IL-2 (72.0+/-8.2% vs 68.5+/-3.6%). However, for the breast TALs, they were 39.5+/-4.2% vs 41.5+/-3.3%, respectively. IL-15 is a newly developed cytokine that shows promising antitumor activity similar to IL-2. However, it requires lower dosage and is less toxic. Therefore, IL-15 might be a potential anticancer immunotherapeutic agent.

The relationship of host immune cells, cytokine and nitric oxide production to tumor cells in ovarian carcinoma

This brief review focuses on the current understanding of the complex relationship of tumor-associated mononuclear cells (TAMs) with neoplastic cells, summarizing their immunological efficiency, cytokine profile and production of nutric oxide (NO) in the tumor microenvironment, with current insights on how this might affect tumor growth. Data source: Data eas obtained through Medline from articles indexed during the last 10 years. The main key words used in the research were: cancer, ovarian cancer, cytokine, nitric oxide (NO), mononuclear cell, lymphocyte, macrophage. Selection of studies and data collection: 30 studies were reviewed, which contained data regarding the production of cytokines and NO by TAMs or malignant cells, and tried to establish a correlation between these mediators and tumor growth, especially in ovarian carcinoma. Data summary: TAMs consist mainly of macrophages and T lymphocytes which present lower proliferative indices and cytotoxicity compared to autologous blood monocytes, although they are able to release various cytokines. The profile of cytokine expression could help to explain both the immunological impairment observed in patients with advanced carcinoma diseases and the potential of TAMs to exert antitumor activity, which makes these cells an attractive target for therapeutic intervention. NO is also produced in the tumor microenvironment. Several reports in animals suggest a tumoricidad role for NO, but in human tumors its role has not been well-established and may change during tumor progression.

Immunohistochemical localisation of carcinoembryonic antigen (CEA) in malignant epithelial ovarian tumours using monoclonal antibodies.

The localization of carcinoembryonic antigen (CEA) in malignant epithelial ovarian tumours was studied using immunohistochemistry. The tissue included in the study consisted of 38 ovarian cancers : 14 mucinous adenocarcinomas, 23 serous adenocarcinomas and 1 endometroid carcinoma. Peroxidase-antiperoxidase staining technique using monoclonal antibodies to CEA was used on routinely fixed paraffin embedded tissues. CEA positivity was observed in all (100%) mucinous adenocarcinomas whereas only one case of serous cyst a denocarcinoma (4.3%) was weakly positive. The only case endometroid carcinoma encountered showed patchy CEA positivity.

Dosagem de CA125 em carcinoma de ovário e outras neoplasias sólidas / Measurement of CA125 in carcinoma of the ovary and other solid neoplasms

Em 1981, Bast e col. desenvolveram um anticorpo monoclonal OC125, contra um antígeno associado ao adenocarcinoma de ovário. No presente trabalho, apresenta-se a experiência dos autores com as medidas seriadas desse antígeno no soro de pacientes com neoplasias de ovário. Os dados obtidos sugerem que o CA125 parece ter marcador útil para monitorizaçäo de pacientes com adenocarcinoma de ovário

Esterilidad producida por endometiosis / Esterility due to endometiosis

Se ha tratado de interpretar las posibles causas de esterilidad por endometriosis. Se recuerda la definición de endometriosis externa y de estrogenismo sostenido. Se trata cono único tema la probable etiología de la esterilidad producida por endometriosis, dejando de lado aquellas que pueden llegar a ocasionar la endometiosis externa. Motivos de esterilidad por endometriosis externa: a) Factores ambientales, familiares y genéticos, de gran importancia etiológica, pero desafortunadamente hasta el presente estudiados en forma incompleta. b) Alteraciones hipófiso-tiroides-ovario, en particular las producidas por hipotiroidismo a nivel ovárico y endometrial. c) problemas inmunológicos demostrados en: Mucosa endometrial, placas y quistes endometriósicos, así como en la endometriosis primaria del ovario. d) Factores mecánicos y adherenciales que favorecen bloqueos: ováricos y pelvis congelada