Local and Systemic STAT3 and p65 NF-KappaB Expression as Progression Markers and Functional Targets for Patients With Cervical Cancer.

Cervical cancer, which main etiologic factor is Human Papillomavirus (HPV) infection, continues to be a burden for public health systems in developing countries. Our laboratory has been working with the hypothesis that signals generated in the tumor microenvironment can modulate local and systemic immune responses. In this context, it would be reasonable to think that tumors create pro-tumoral bias in immune cells, even before they are recruited to the tumor microenvironment. To understand if and how signaling started in the tumor microenvironment can influence cells within the tumor and systemically, we investigated the expression of key proteins in signaling pathways important for cell proliferation, viability, immune responses and tolerance. Besides, we used detection of specific phosphorylated residues, which are indicative of activation for Akt, CREB, p65 NFκB, and STAT3. Our findings included the observation of a significant STAT3 expression increase and p65 NFκB decrease in circulating leukocytes in correlation with lesion grade. In light of those observations, we started investigating the result of the inhibition of STAT3 in a tumor experimental model. STAT3 inhibition impaired tumor growth, increased anti-tumor T cell responses and decreased the accumulation of myeloid cells in the spleen. The concomitant inhibition of NFκB partially reversed these effects. This study indicates that STAT3 and NFκB are involved in immunomodulatory tumor effects and STAT3 inhibition could be considered as therapy for patients with cervical cancer.

B lymphocytes can be activated to act as antigen presenting cells to promote anti-tumor responses.

Immune evasion by tumors includes several different mechanisms, including the inefficiency of antigen presenting cells (APCs) to trigger anti-tumor T cell responses. B lymphocytes may display a pro-tumoral role but can also be modulated to function as antigen presenting cells to T lymphocytes, capable of triggering anti-cancer immune responses. While dendritic cells, DCs, are the best APC population to activate naive T cells, DCs or their precursors, monocytes, are frequently modulated by tumors, displaying a tolerogenic phenotype in cancer patients. In patients with cervical cancer, we observed that monocyte derived DCs are tolerogenic, inhibiting allogeneic T cell activation compared to the same population obtained from patients with precursor lesions or cervicitis. In this work, we show that B lymphocytes from cervical cancer patients respond to treatment with sCD40L and IL-4 by increasing the CD80+CD86+ population, therefore potentially increasing their ability to activate T cells. To test if B lymphocytes could actually trigger anti-tumor T cell responses, we designed an experimental model where we harvested T and B lymphocytes, or dendritic cells, from tumor bearing donors, and after APC stimulation, transplanted them, together with T cells into RAG1-/- recipients, previously injected with tumor cells. We were able to show that anti-CD40 activated B lymphocytes could trigger secondary T cell responses, dependent on MHC-II expression. Moreover, we showed that dendritic cells were resistant to the anti-CD40 treatment and unable to stimulate anti-tumor responses. In summary, our results suggest that B lymphocytes may be used as a tool for immunotherapy against cancer.

Polypropylene and polypropylene/polyglecaprone (Ultrapro®) meshes in the repair of incisional hernia in rats.

PURPOSE: To compare the inflammatory response of three different meshes on abdominal hernia repair in an experimental model of incisional hernia. METHODS: Median fascial incision and skin synthesis was performed on 30 Wistar rats. After 21 days, abdominal hernia developed was corrected as follows: 1) No mesh; 2) Polypropylene mesh; and, 3) Ultrapro(r) mesh. After 21 days, the mesh and surrounding tissue were submitted to macroscopic (presence of adhesions, mesh retraction), microscopic analysis to identify and quantify the inflammatory and fibrotic response using a score based on a predefined scale of 0-3 degrees, evaluating infiltration of macrophages, giant cells, neutrophils and lymphocytes. RESULTS: No significant difference was seen among groups in adherences, fibrosis, giant cells, macrophages, neutrophils or lymphocytes (p>0.05). Mesh shrinkage was observed in all groups, but also no difference was observed between polypropylene and Ultrapro mesh (7.0±9.9 vs. 7.4±10.1, respectively, p=0.967). Post-operatory complications included fistula, abscess, dehiscence, serohematic collection and reherniation, but with no difference among groups (p=0.363). CONCLUSION: There is no difference between polypropylene (high-density) and Ultrapro(r) (low-density) meshes at 21 days after surgery in extraperitoneal use in rats, comparing inflammatory response, mesh shortening, adhesions or complications.

Polypropylene and polypropylene/polyglecaprone (Ultrapro(r)) meshes in the repair of incisional hernia in rats

PURPOSE: To compare the inflammatory response of three different meshes on abdominal hernia repair in an experimental model of incisional hernia. METHODS: Median fascial incision and skin synthesis was performed on 30 Wistar rats. After 21 days, abdominal hernia developed was corrected as follows: 1) No mesh; 2) Polypropylene mesh; and, 3) Ultrapro(r) mesh. After 21 days, the mesh and surrounding tissue were submitted to macroscopic (presence of adhesions, mesh retraction), microscopic analysis to identify and quantify the inflammatory and fibrotic response using a score based on a predefined scale of 0-3 degrees, evaluating infiltration of macrophages, giant cells, neutrophils and lymphocytes. RESULTS: No significant difference was seen among groups in adherences, fibrosis, giant cells, macrophages, neutrophils or lymphocytes (p>0.05). Mesh shrinkage was observed in all groups, but also no difference was observed between polypropylene and Ultrapro mesh (7.0±9.9 vs. 7.4±10.1, respectively, p=0.967). Post-operatory complications included fistula, abscess, dehiscence, serohematic collection and reherniation, but with no difference among groups (p=0.363). CONCLUSION: There is no difference between polypropylene (high-density) and Ultrapro(r) (low-density) meshes at 21 days after surgery in extraperitoneal use in rats, comparing inflammatory response, mesh shortening, adhesions or complications. .

Estudo das displasias do colo-uterino: 33 casos / Uterine cevix dysplasia: 33 cases

Säo apresentados 33 (trinta e três) casos de displasia de colo, uterino, detectados no periodo de janeiro de 1980 até setembro de 1986, que consultaram o Ambulatório de Ginecologia do Hospital Materno-Infantil Presidente Vargas do INAMPS/RS. Os casos foram retirados de um total de 500 pacientes anotadas no Livro de Registro do Setor de Patologia Cervical Uterina e Colposcopia do HMIPV nos quais em 21 (vinte e um) destes casos, a citologia oncótica mostrou 14,2% (3 casos) de displasia leve, 19% (4 casos) de displasia moderada, 76,1% (16 casos) de displasia acentuada e 1 caso näo havia anotaçäo de histologia (displasia leve). Nestes casos é apresentado o levantamento estatístico dos dados anmnésticos e epidemiológicos tais como: faixas etárias, idade média e grau das displasias, início das relaçöes sexuais, número de partos, idade do primeiro parto, etc. Relatam ainda os achados colposcópicos e os três graus de displasias, bem como a análise comparativa da citologia, colposcopia e histologia. Concluem que o uso conjunto rotineiro da citologia e da colposcopia é indispensável para o diagnóstico precoce e eficiente das displasias do colo uterino