TGFß in malignant canine mammary tumors: relation with angiogenesis, immunologic markers and prognostic role.

Transforming growth factor-ß (TGFß) and FoxP3 regulatory T cells (Treg) are involved in human breast carcinogenesis. This topic is not well documented in canine mammary tumors (CMT). In this work, the tumoral TGFß expression was assessed by immunohistochemistry in 67 malignant CMT and its correlation to previously determined FoxP3, VEGF, and CD31 markers and other clinicopathologic parameters was evaluated. The high levels of TGFß were statistically significantly associated with skin ulceration, tumor necrosis, high histological grade of malignancy (HGM), presence of neoplastic intravascular emboli and presence of lymph node metastases. The observed levels of TGFß were positively correlated with intratumoral FoxP3 (strong correlation), VEGF (weak correlation) and CD31 (moderate correlation). Tumors that presented a concurrent high expression of TGFß/FoxP3, TGFß/VEGF, and TGFß/CD31 markers were statistically significantly associated with parameters of tumor malignancy (high HGM, presence of vascular emboli and nodal metastasis). Additionally, shorter overall survival (OS) time was statistically significantly associated with tumors with an abundant TGFß expression and with concurrent high expression of TGFß/FoxP3, TGFß/VEGF, and TGFß/CD31. The presence of lymph node metastasis increased 11 times the risk of disease-related death, arising as an independent predictor of poor prognosis in the multivariable analysis. In conclusion, TGFß and Treg cells seem involved in tumor progression emerging as potential therapeutic targets for future immunotherapy studies.

Frequency and clinical relevance of anti-Mi-2 autoantibody in adult Brazilian patients with dermatomyositis.

BACKGROUND: To analyze the frequency and clinical relevance of anti-Mi-2 autoantibody in a representative sample of patients with dermatomyositis. METHODS: This longitudinal inception cohort study, from 2001 to 2017, included 87 definite adult dermatomyositis. Anti-Mi-2 analysis was performed using a commercial kit. RESULTS: Seventeen patients (19.5%) had anti-Mi-2 and 70 (80.5%) did not have this autoantibody. The following parameters were equally distributed between the patients with versus without anti-Mi-2: mean age at the disease diagnosis onset, median follow-up time, constitutional symptoms (baseline), cutaneous cumulative lesions, dysphagia, joint and pulmonary involvement. There was also no difference between the groups in relation to follow-up time, disease relapsing, treatment, disease status, deaths and occurrence of neoplasia. In contrast, patients with anti-Mi2 antibodies had higher frequency of elevated serum levels of muscle enzymes at disease onset (median: creatine phosphokinase 6240 [3800-9148] U/L and aldolase 60.0 [35.0-138.0] U/L), lower frequency of pulmonary involvement at disease onset (5.9%), less current glucocorticoid dose (median: 0 [0-10] mg/day), and higher frequency of disease remission during follow-up (58.8%) in comparison with patients without anti-Mi-2 autoantibody (484 [115-4880] and 12.1 [6.3-70.0] U/L, 40.0%, 0 [0-10] mg/day, 27.1%, respectively). CONCLUSION: The anti-Mi-2 autoantibody was found in one fifth of patients with dermatomyositis. This autoantibody was associated with a lower occurrence of pulmonary involvement, a higher frequency of disease in remission, and elevated levels of muscle enzymes. There was also no correlation regarding the frequency of disease relapsing or neoplasia development.

Assessing the Interleukin 35 Immunoexpression in Malignant Canine Mammary Tumors: Association With Clinicopathological Parameters and Prognosis.

BACKGROUND/AIM: IL-35 has a prominent immunosuppressive role and its overexpression has been reported in human breast cancer. However, the impact of IL-35 in canine mammary carcinogenesis has not been addressed yet. The present study determined the clinicopathological significance of IL-35 immunoexpression and its correlation with overall survival (OS) in 72 malignant canine mammary tumor (CMT) patients. MATERIALS AND METHODS: Formalin-fixed paraffin-embedded malignant CMT samples (n=72) were submitted to immunohistochemical staining to detect IL-35 expression. Survival curves were obtained by the Kaplan-Meier method and the log-rank test was used for the survival estimates. Cox proportional hazard model for multivariate analysis was also performed. RESULTS: IL-35 overexpression was associated with: skin ulceration, tumor necrosis, mitotic index, nuclear pleomorphism, tumor differentiation, histological grade of malignancy (HGM), neoplastic intravascular emboli and lymph node metastasis. Additionally, IL-35 was also correlated with a worse overall survival in multivariate analysis, arising as an independent predictor of poor prognosis. CONCLUSION: IL-35 is associated with carcinogenesis and worse prognosis of CMT.

Frequency and clinical relevance of anti-Mi-2 autoantibody in adult Brazilian patients with dermatomyositis

Abstract Background: To analyze the frequency and clinical relevance of anti-Mi-2 autoantibody in a representative sample of patients with dermatomyositis. Methods: This longitudinal inception cohort study, from 2001 to 2017, included 87 definite adult dermatomyositis. Anti-Mi-2 analysis was performed using a commercial kit. Results: Seventeen patients (19.5%) had anti-Mi-2 and 70 (80.5%) did not have this autoantibody. The following parameters were equally distributed between the patients with versus without anti-Mi-2: mean age at the disease diagnosis onset, median follow-up time, constitutional symptoms (baseline), cutaneous cumulative lesions, dysphagia, joint and pulmonary involvement. There was also no difference between the groups in relation to follow-up time, disease relapsing, treatment, disease status, deaths and occurrence of neoplasia. In contrast, patients with anti-Mi2 antibodies had higher frequency of elevated serum levels of muscle enzymes at disease onset (median: creatine phosphokinase 6240 [3800-9148] U/L and aldolase 60.0 [35.0-138.0] U/L), lower frequency of pulmonary involvement at disease onset (5.9%), less current glucocorticoid dose (median: 0 [0-10] mg/day), and higher frequency of disease remission during follow-up (58.8%) in comparison with patients without anti-Mi-2 autoantibody (484 [115-4880] and 12.1 [6.3-70.0] U/L, 40.0%, 0 [0-10] mg/day, 27.1%, respectively). Conclusion: The anti-Mi-2 autoantibody was found in one fifth of patients with dermatomyositis. This autoantibody was associated with a lower occurrence of pulmonary involvement, a higher frequency of disease in remission, and elevated levels of muscle enzymes. There was also no correlation regarding the frequency of disease relapsing or neoplasia development.

Promotion of adjustment to the exercise of parental role in adolescente

Introduction: Parental exercise itself constitutes a very demanding challenge - however, when pregnancy occurs in adolescence, often unplanned, it converges tasks of different stages of development, irreversibly modifying an identity, roles and functions, not only of the young woman, but also of her family. Objectives: Applying the Dynamic Model of Family Assessment and Intervention (MDAIF), by Figueiredo (2012), and assessing the impact of nursing care in the pro-motion of skills for a transition to the parental role's exercise in the teenager and her family. Methods: Qualitative study, conducted based on MDAIF, as a theoretical and ope-rational reference, in clinical and community context in Primary Health Care, based on the process of family intervention who experienced an adolescent pregnancy. Seven nursing consultations to family were carried out, as a unit, from April to May 2016. Results and discussion: Extended family, with several subsystems and strict limits. Middle-class family. Although unplanned, and the antagonistic relationship with her parents, the instrumental and emotional support provided by them became critical in adapting to motherhood and the newborn's development. Conclusions: With MDAIF's use, nurses have developed their skills for a personalized approach to the family, centered on the adaptation and holistic transition to the parental process. It also made it possible to respond to the identified family needs, not only through the restructuring of a parental and personal identity, based on values, personal and professional goals and priorities (the teenager pursued her academic training), but also promoting a family environment based on trust and harmony

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Bidirectional Regulation of COX-2 Expression Between Cancer Cells and Macrophages.

BACKGROUND/AIM: Our aim was to investigate the crosstalk between tumor and immune cells (M2 macrophages) and its effects on cyclo-oxygenase-2 (COX2) regulation in canine mammary tumors (CMT). MATERIALS AND METHODS: Sh1b CMT cells and human BT474 mammary or HT29 colon cancer cells were co-cultured with canine peripheral blood mononuclear cells (PBMCs) or with macrophage-like differentiated THP1 monocytes (dTHP1). Intracellular COX2 expression by PBMCs, dTHP1 and cancer cells was evaluated by flow cytometry. RESULTS: Co-culturing of Sh1b and canine PBMCs induced COX2 overexpression in CMT cells. In turn, COX2 expression by PBMCs, mostly CD68+ macrophages, was attenuated by co-culture with Sh1b (p=0.0001). In accordance, co-culture with dTHP1 prompted intracellular production of COX2 in both Sh1b CMT cells and HT29 human colon cancer cells and reduced production of COX2 in BT474 human mammary cancer cells. The intracellular COX2 expression from dTHP1 decreased when treated with conditioned medium from cultured Sh1b and HT29 cancer cells. CONCLUSION: Bidirectional COX2 regulation between cancer and monocytes/macrophages might shape a tolerogenic tumor microenvironment in CMT.

Intratumoral FoxP3 expression is associated with angiogenesis and prognosis in malignant canine mammary tumors.

The activity of regulatory T cells (Tregs) is closely associated with the expression of FoxP3 transcription factor. FoxP3 regulatory T cells (FoxP3Treg) have immunosuppressive properties and can work for prevention of harmful autoimmune responses, however can also interfere with beneficial anti-tumor immunity. In human breast cancer these cells play a crucial role in tumor progression. In canine mammary tumors (CMT) this topic is not well-documented. This study included 80 malignant CMT and studied, by immunohistochemistry, the intratumoral FoxP3 expression together with microvessel density (MVD), vascular endothelial growth factor (VEGF) and several clinicopathological characteristics. Abundant FoxP3Treg cells were associated with tumor necrosis (p=0.001), high mitotic grade (p<0.001), more marked nuclear polymorphism (p=0.001), poor differentiation of tumors (p<0.001), high histological grade of malignancy (HGM) (p<0.001), presence of neoplastic intravascular emboli (p<0.001) and presence of lymph node metastasis (p<0.001). Intratumoral FoxP3 was correlated with MVD (r=0.827; p<0.001) and associated with VEGF (p=0.001). Additionally tumors with abundant FoxP3Treg cells were associated with shorter overall survival (OS) time in univariate and multivariate analysis (p<0.001 Kaplan-Meier curves and 7.97 hazard ratio, p<0.001 Cox proportional hazard model). Results suggest that Treg cells play a role in CMT progression and may contribute to increased angiogenesis and aggression in these tumors. The association of intratumoral FoxP3 expression with shorter OS in multivariate analysis suggests the usefulness of Treg cells as an independent prognostic marker.

Clinicopathological significance of caspase-3 and Ki-67 expression in canine mammary gland tumours.

UNLABELLED: Fifty canine mammary gland tumours (CMGT) (18 benign and 32 malignant) were studied by immunohistochemical detection of active caspase-3 and Ki-67 antigens in order to determine their association with several clinicopathological parameters. The percentage of caspase-3 positive cells was significantly higher in benign tumours as compared to their malignant counterparts (P ≤ 0.001). In the group of malignant tumours there was no significant association between active caspase-3 and the clinicopathological variables considered. The percentage of Ki- 67 positive cells was significantly higher in malignant tumours compared to the benign ones (P ≤ 0.001). In the group of malignant tumours, Ki-67 expression showed a statistically significant association with tumour size (P = 0.025), histological type (P = 0.010), mitotic grade (P ≤ 0.001), nuclear grade (P = 0.025), differentiation grade (P = 0.004), histological grade of malignancy (P = 0.002), and presence of metastases in regional lymph nodes (P = 0.025). Furthermore, this study revealed a negative correlation between the percentages of active caspase-3 and Ki-67 (r = -0.39; P = 0.04). Thus, our results suggest a loss of balance between cell death and cell division in CMGT. KEY WORDS: Apoptosis, caspase-3, Ki.

A Comparative Approach of Tumor-Associated Inflammation in Mammary Cancer between Humans and Dogs.

Infiltrating cells of the immune system are widely accepted to be generic constituents of tumor microenvironment. It has been well established that the development of mammary cancer, both in humans and in dogs, is associated with alterations in numbers and functions of immune cells at the sites of tumor progression. These tumor infiltrating immune cells seem to exhibit exclusive phenotypic and functional characteristics and mammary cancer cells can take advantage of signaling molecules released by them. Cancer related inflammation has an important role in mammary carcinogenesis, contributing to the acquisition of core hallmark capabilities that allow cancer cells to survive, proliferate, and disseminate. Indeed, recent studies in human breast cancer and in canine mammary tumors have identified a growing list of signaling molecules released by inflammatory cells that serve as effectors of their tumor-promoting actions. These include the COX-2, the tumor EGF, the angiogenic VEGF, other proangiogenic factors, and a large variety of chemokines and cytokines that amplify the inflammatory state. This review describes the intertwined signaling pathways shared by T-lymphocytic/macrophage infiltrates and important tissue biomarkers in both human and dog mammary carcinogenesis.

Intratumoral CD3+ T-lymphocytes immunoexpression and its association with c-Kit, angiogenesis, and overall survival in malignant canine mammary tumors.

In this study 80 malignant CMT were submitted to immunohistochemical detection of CD3, c-kit, VEGF, and CD31, together with clinicopathological parameters of tumor aggressiveness. CD3+ T-cells and c-kit overexpression revealed a positive correlation with VEGF (r = 0.503, P < 0.0001; r = 0.284, P = 0.023 for CD3 and c-kit, resp.) and CD31 (r = 0.654, P < 0.0001; r = 0.365, P = 0.003 for CD3 and c-kit, resp.). A significant association (P = 0.039) and a positive correlation (r = 0.263, P = 0.039) between CD3 and c-kit were also observed. High CD3/VEGF, c-kit/VEGF, and CD3/c-kit tumors were associated with elevated grade of malignancy (P < 0.0001 for all groups), presence of intravascular emboli (P < 0.0001 for CD3/VEGF and CD3/c-kit; P = 0.002 for c-kit/VEGF), and presence of lymph node metastasis (P < 0.0001 for all groups). Tumors with high CD3/VEGF (P = 0.006), c-kit/VEGF (P < 0.0001), and CD3/c-kit (P = 0.002) were associated with poor prognosis. Interestingly high c-kit/VEGF tumors retained their significance by multivariate analysis arising as independent prognostic factor.

Positive Interplay Between CD3+ T-lymphocytes and Concurrent COX-2/EGFR Expression in Canine Malignant Mammary Tumors.

BACKGROUND/AIM: The ability of tumors to evade the immune system is one of cancer hallmarks. In breast cancer, it has been demonstrated that the cyclooxygenase-2(+)/ epidermal growth factor receptor(+) (COX-2(+)/EGFR(+)) status might influence tumor microenvironment allowing escape of cancer cells to the immune system. This topic is unknown in canine mammary tumors (CMT). Therefore, the potential relationship between CD3(+) T-lymphocytes and concurrent COX-2/EGFR expression was investigated. MATERIALS AND METHODS: Formalin-fixed paraffin-embedded malignant CMT samples (n=63) were submitted to immunohistochemical staining to detect CD3, COX-2 and EGFR. RESULTS: Tumoral CD3(+) T-lymphocytes were significantly associated with tubular differentiation grade (p=0.006), tumor necrosis (p=0.025), histological grade of malignancy (p=0.027) and presence of lymph node metastasis (p=0.009). A correlation between COX-2 and EGFR was observed (r=0.741, p<0.0001). The COX-2(+)/EGFR(+) group was associated with tumor size (p=0.002), mitotic index (p=0.019), histological grade of malignancy (p=0.035) and presence of lymph node metastasis (p=0.041). CD3(+) T-lymphocytes and COX-2/EGFR groups were significantly associated (p=0.025) and positively correlated (r=0.399; p=0.003). CONCLUSION: The present results suggest that the COX-2(+)/EGFR(+) status may be part of a strategy adopted by tumor cells to evade the cytotoxic tumor-specific immune responses.

A role for T-lymphocytes in human breast cancer and in canine mammary tumors.

Chronic inflammation in the tumor microenvironment has a prominent role in carcinogenesis and benefits the proliferation and survival of malignant cells, promoting angiogenesis and metastasis. Mammary tumors are frequently infiltrated by a heterogeneous population of immune cells where T-lymphocytes have a great importance. Interestingly, similar inflammatory cell infiltrates, cytokine and chemokine expression in humans and canine mammary tumors were recently described. However, in both species, despite all the scientific evidences that appoint for a significant role of T-lymphocytes, a definitive conclusion concerning the effectiveness of T-cell dependent immune mechanisms has not been achieved yet. In the present review, we describe similarities between human breast cancer and canine mammary tumors regarding tumor T-lymphocyte infiltration, such as relationship of TILs and mammary tumors malignancy, association of ratio CD4+/ CD8+ T-cells with low survival rates, promotion of tumor progression by Th2 cells actions, and association of great amounts of Treg cells with poor prognostic factors. This apparent parallelism together with the fact that dogs develop spontaneous tumors in the context of a natural immune system highlight the dog as a possible useful biological model for studies in human breast cancer immunology.

EGFR and microvessel density in canine malignant mammary tumours.

The epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase receptor which has been shown to have an important role in human breast cancer. Its role appears to be associated with increased angiogenesis and metastasis. In order to clarify its role in canine mammary tumours (CMT), 61 malignant neoplasms were studied by using immunohistochemistry, comparing expression of EGFR, microvessel density (MVD) by CD31 immunolabelling and characteristics of tumour aggressiveness. High EGFR immunoexpression was statistically significantly associated with tumour size, tumour necrosis, mitotic grade, histological grade of malignancy and clinical stage. High CD31 immunoreactivity was statistically significantly associated with tubule formation, histological grade of malignancy and clinical stage. A positive correlation between EGFR and CD31 immunoexpression (r = 0.843; P < 0.001) was also observed. Results suggest that an over-expression of EGFR may contribute to increased angiogenesis and aggression in malignant CMT, presenting the possibility of using EGFR inhibitors in the context of metastatic disease treatment.

T-lymphocytic infiltrate in canine mammary tumours: clinic and prognostic implications.

In recent years, considerable progress has been made in understanding the role of the immune system in tumour progression. However, in canine mammary tumours (CMT), the prognostic value of T-lymphocytes is not established. The aims of the present study were to characterize T-lymphocytic infiltrate in 57 canine mammary tumours (21 benign and 36 malign), by immunohistochemical detection of CD3 antigen, and to determine its association with several clinicopathological parameters and overall survival. CD3+ positive cells were counted in 10 high-power fields within the tumour (i.e. The tumour-infiltrating T-lymphocytes, TIL), in the peripheral area of the tumour and in the adnexal non-tumoural mammary gland. CD3(+) TILs were significantly more frequent in benign than in malignant tumours (p<0.001). Conversely, peripheral CD3(+) TILs were significantly more frequent in malignant than in benign neoplasias (p<0.001). For CD3(+) T-lymphocytes in the adnexal non-tumoural mammary gland, there was no statistical difference in their frequency between benign and malignant tumours. On survival analysis, there was a tendency towards an association of a higher number of CD3(+) TILs and a shorter overall survival (p=0.08). Interestingly for CD3(+) T-lymphocytes in the adnexal non-tumoural mammary gland, a statistically significant relationship was observed, with a higher number of lymphocytes conferring a reduced overall survival (p=0.045). Further studies will be required to better understand the biological implications of the current findings.

Canine mammary tumours as a model to study human breast cancer: most recent findings.

Clinical and molecular similarities between canine mammary tumours and human breast cancer have been described in recent decades. Clinically, the similarities are very strong: spontaneous tumours, hormonal aetiology, age of onset and an identical course of the disease. The clinical characteristics that have an impact on the clinical outcome are also identical: tumour size, lymph node invasiveness and clinical stage. Nowadays, as far as human medicine is concerned, the goal is to identify prognostic factors, mainly at the molecular level, such as those involved in metastasis, which could be used as therapeutic targets to support a better outcome. Moreover, in this area, canine mammary tumours seem to mimic human breast cancer, as a range of similarities are found at the molecular level concerning the overexpression of steroid receptors, proliferation markers, epidermal growth factor, p53 supressor gene mutations, metalloproteinases, cyclooxygenases, among many others. Clinical and molecular data that support canine mammary tumours as a model to study human breast cancer are analysed in this review. Additionally, it is shown that some recent molecular targets in canine mammary tumours may be seen as indicators for similar research to be performed in the corresponding human disease.

Concentration and emission sources of airborne metals in particulate matter in the industrial district of Médio Paraíba, state of Rio de Janeiro, Brazil.

Total suspended particles and 12 airborne metals were determined in 4 sampling sites in the industrial region of Médio Paraíba, Brazil. The geometrical means for the four sampling locals were (in units of microg/m3): 65.9 in Barra Mansa, 57.3 in Jardim Paraíba (Volta Redonda), 41.7 in Resende, and 48.9 in Volta Grande (Volta Redonda). These values are lower than levels previously determined in urban and industrial locals of the Metropolitan Area of Rio de Janeiro. For metals, the higher concentrations were obtained for Ca, Zn, Al, Fe, and Mg. Ca, Zn, and Al levels are higher than those determined in other industrial areas. These three metals are used in steel manufacturing, the main economical activity of the region. Enrichment factors for Zn, Cu, Cd, and Pb are higher than 10, suggesting an industrial input. Statistical analysis show a high correlation among Ca, Mg, Zn, Cr, Al, Mn, and Fe, all of them used as raw materials in steel manufacturing and/or accumulated as industrial blast furnace slag and steelworks slag.