Resistance Training-Induced Gains in Muscle Strength and Power Mediate the Improvement in Walking Speed in Middle-Aged Women Who Are Breast Cancer Survivors.

ABSTRACT: Santagnello, SB, Martins, FM, de Oliveira Junior, GN, de Sousa, JdeFR, Nomelini, RS, Murta, EFC, and Orsatti, FL. Resistance training-induced gains in muscle strength and power mediate the improvement in walking speed in middle-aged women who are breast cancer survivors. J Strength Cond Res 38(4): 773-782, 2024-(a) Ascertain whether lower muscle mass, strength (1 repetition maximum [1RM]), and power (Pmax) in middle-aged women who are breast cancer survivors (BCS), when compared with women of a similar age never diagnosed with cancer (WNC), are related with lower walking speed (WS). (b) Ascertain whether changes in WS are associated with changes in muscle mass, 1RM, and (or) Pmax after resistance training (RT) in middle-aged BCS. A cross-section study was performed. Twenty WNC and 21 BCS were evaluated for lean mass of legs (LLM), 1RM (knee extension), muscle quality index (MQI = 1RM/LLM), Pmax (maximum muscle power-knee extension), and fast WS (10 and 400-meters). Randomized clinical trial was performed. The BCS were randomly divided into the control group ( n = 9) and the RT group ( n = 11). Breast cancer survivors exhibited lower 1RM (24.2%, p ˂ 0.001), Pmax (30.6%, p ˂ 0.001), MQI (22.2%, p = 0.001), and WS (10-m = 17.0%, p ˂ 0.001 and 400-m = 10.5%, p = 0.002) than WNC. Resistance training increased 1RM (31.6%, p = 0.001), MP (29.0%, p = 0.012), MQI (28.5%, p = 0.008), and WS (10-m = 9.4%, p = 0.009 and 400-m = 6.2%, p = 0.006) in BCS. The changes in WS were positively associated with 1RM (10-m = 68%, p = 0.001 and 400-m = 37%, p = 0.036) and Pmax (10-m = 56%, p = 0.005 and 400-m = 40%, p = 0.027) and MQI (10-m = 63%, p = 0.043 and 400-m = 37%, p = 0.035). Resistance training-induced gains in muscle strength and power mediate the improvement in WS in middle-aged BCS. Resistance training is an effective strategy to improve WS in middle-aged BCS.

Immunostaining of stromal CD56 cells in ovarian malignancies.

OBJECTIVES: The aim of this study was to evaluate CD56 immunostaining in the stroma of benign and malignant ovarian epithelial neoplasms and associate the CD56 immunostaining with prognostic factors and survival in ovarian cancer. METHODS: Patients with ovarian epithelial neoplasia (n=77) were studied with a prospective cohort. The CD56 immunostaining was evaluated in the peritumoral stroma. Two groups were evaluated: benign ovarian neoplasms (n=40) and malignant ovarian neoplasms (n=37). Data were recorded for histological type and grade, International Federation of Gynecology and Obstetrics staging, molecular subtype, and lymph node metastases. Fisher's exact test and Kaplan-Meier survival curves were used, with a significance level of ≤0.05. RESULTS: We found greater CD56 stromal immunostaining in malignant neoplasms when compared to the group of benign neoplasms (p=0.00001). There was no significant difference in relation to the prognostic factors and survival. CONCLUSION: Malignant ovarian neoplasms showed higher stromal CD56 immunostaining. As the prognostic value of natural killer in ovarian cancer is controversial, knowing the specific function of each cell present both in the tumor tissue and systemically may help guide successful immunotherapies in the near future.

Lower-Body Resistance Training Reduces Interleukin-1ß and Transforming Growth Factor-ß1 Levels and Fatigue and Increases Physical Performance in Breast Cancer Survivors.

ABSTRACT: Martins, FM, Santagnello, SB, de Oliveira Junior, GN, de Sousa, JdFR, Michelin, MA, Nomelini, RS, Murta, EFC, and Orsatti, FL. Lower-body resistance training reduces interleukin-1ß and transforming growth factor-ß1 levels and fatigue and increases physical performance in breast cancer survivors. J Strength Cond Res 37(2): 439-451, 2023-This article ascertains whether resistance training (RT) improves inflammatory markers, fatigue (sensations and fatigability), and physical performance in breast cancer survivors (BCS) and investigates whether the changes in the inflammatory markers, fatigue, and physical performance are associated with each other. Volunteers were randomly divided into 2 groups: control group (n = 11) and RT group (n = 11). Resistance training (3 sets of 8-12 repetitions with 80% 1 repetition maximum (1RM) on 4 exercises-leg extension, leg curl, 45° leg press, and calf raise) was performed 3 times a week for 12 weeks. Self-reported fatigue (SRF), fatigability (critical torque [CT] and W prime [W']), muscle strength, and circulating inflammatory markers were assessed using the Brief Fatigue Inventory, iDXA, 1RM test, protocol of 60 maximal voluntary isometric contractions, and enzyme-linked immunosorbent assay, respectively. Resistance training reduced interleukin (IL)-1ß, transforming growth factor (TGF)-ß1, and SRF score and increased muscle strength, 6-minute walk test (6MWT), CT, and W'. In the RT group, the changes in SRF were positively associated with the changes in IL-1ß. The changes in muscle strength were associated with the changes in CT and W', and the changes in the 6MWT were associated with the changes in CT, W', muscle strength, and SRF. Resistance training improved fatigue and physical performance and reduced IL-1ß, and TGF-ß1 in BCS. Although improvement in fatigability seems to be dependent on the increase in muscle strength, improvement in the sensation of fatigue seems to be dependent on the reduction in IL-1ß after RT. Increase in physical performance seems to be dependent on improvement in muscle strength and fatigue.

Immunostaining of stromal CD56 cells in ovarian malignancies

SUMMARY OBJECTIVES: The aim of this study was to evaluate CD56 immunostaining in the stroma of benign and malignant ovarian epithelial neoplasms and associate the CD56 immunostaining with prognostic factors and survival in ovarian cancer. METHODS: Patients with ovarian epithelial neoplasia (n=77) were studied with a prospective cohort. The CD56 immunostaining was evaluated in the peritumoral stroma. Two groups were evaluated: benign ovarian neoplasms (n=40) and malignant ovarian neoplasms (n=37). Data were recorded for histological type and grade, International Federation of Gynecology and Obstetrics staging, molecular subtype, and lymph node metastases. Fisher's exact test and Kaplan-Meier survival curves were used, with a significance level of ≤0.05. RESULTS: We found greater CD56 stromal immunostaining in malignant neoplasms when compared to the group of benign neoplasms (p=0.00001). There was no significant difference in relation to the prognostic factors and survival. CONCLUSION: Malignant ovarian neoplasms showed higher stromal CD56 immunostaining. As the prognostic value of natural killer in ovarian cancer is controversial, knowing the specific function of each cell present both in the tumor tissue and systemically may help guide successful immunotherapies in the near future.

Mast cells and M2 macrophages in ovarian cancer.

The objectives of this study were to investigate the immunohistochemical expression of markers of mast cells and M2 macrophages in benign and malignant ovarian neoplasms and to examine the prognostic value of this expression in ovarian cancer. The study was performed with samples from 32 patients, divided into benign (n = 16) and malignant (n = 16) neoplasm groups. Samples obtained by surgical resection were submitted to immunohistochemical analysis. Higher proportions of M2 macrophages (p = .041) and mast cells (p = .0054) were present in malignant than benign ovarian neoplasms. Histological grade 2/3 was related to higher proportions of M2 macrophages compared with grade 1 (p = .0102). Stages II-IV were also related to higher proportions of M2 macrophages (p = .0102). Logistic regression revealed that M2 macrophages predicted malignancy [odds ratio (OR) = 1.017; 95% confidence interval (CI), 1.003-1.037; p = .017], but that mastocytes had greater predictive value for this outcome (OR = 1.127; 95% CI, 1.018-1.105; p = .013). M2 macrophages predicted more advanced histological grades (OR = 1.060; 95% CI, 1.010-1.218; p = .003). The proportions of M2 macrophages and mast cells were greater in malignant than in benign ovarian neoplasms. Larger proportions of cells expressing M2 macrophages were related to more advanced histological grades and disease stages, and thus to worse prognoses for ovarian cancer.Impact StatementWhat is already known on this subject? Concentrations of mast cells and M2 macrophages have been observed in several tumour types, but their significance remains uncertain.What do the results of this study add? The proportions of M2 macrophages and mast cells were greater in malignant than in benign ovarian neoplasms. Larger proportions of cells expressing M2 macrophages were related to higher histological grades and more advanced stages of the disease.What are the implications of these findings for clinical practice and/or further research? Larger proportions of cells expressing M2 macrophages were related to worse prognoses for malignant ovarian neoplasia. The discovery of new prognostic factors in ovarian cancer may be the target of studies on new treatments and immunotherapies for this disease. In addition, it can help guide the oncologist towards more aggressive treatments for patients with worse prognostic factors.

Absolute band neutrophils count is a predictor of overall survival in advanced uterine cervical cancer.

PURPOSE: Neutrophils play a role during the oncogenic process, and their count can be a prognostic marker. The objective was to evaluate the association of band and segmented neutrophils with prognostic factors, overall survival, and disease-free survival in advanced uterine cervical cancer (IIB to IVB staging). METHODS: This study evaluated 88 patients diagnosed with uterine cervical cancer staging IIB to IVB. The recorded data from medical records were age, parity, staging, histological type, absolute count of total neutrophils, band neutrophils and segmented neutrophils, disease-free survival, and overall survival. Receiver-operating characteristic (ROC) curve was used to obtain the area under the curve (AUC) and determine the best cut-off values for each parameter. Survival was verified by the Kaplan-Meier method, and multivariate analysis was performed by Cox regression. The level of significance was ≤ 0.05. RESULTS: Regarding the total neutrophils, band, and segmented neutrophils count, a cut-off value of 6187/mm3, 273 mm3 and 6062/mm3 were found, respectively. Overall survival was shorter in patients with total neutrophils greater than 6187/mm3 (p = 0.012), band neutrophils greater than 273/mm3 (p = 0.001), and segmented neutrophils greater than 6062/mm3 (p = 0.013). After multivariate analysis considering the two types of neutrophils, only band neutrophils greater than 273/mm3 remained as an independent factor for shorter overall survival. CONCLUSION: The absolute count of band neutrophils greater than 273/mm3 was a potential predictor of shorter overall survival in women with invasive cervical cancer. This count can be of great clinical use, in addition to being inexpensive, less invasive, and easy to perform.

Giant luteinized follicular cyst of pregnancy / Cisto folicular luteinizado gigante da gestação

Functional cysts usually do not cause symptoms or require surgical intervention. We reported a 17-year-old primi-gravida, gestational age of 10 weeks and 2 days, and ultrasound showing anechoic cyst in the right parauterine re-gion without septa, with a larger diameter of 13.5cm, 632ml, and Doppler color without peripheral vascularization. The patient was oligosymptomatic during gestation. At 37 weeks and 6 days, gestation was interrupted, when the cyst had 2600 ml by ultrasonography. Fetal extraction was performed by cesarean delivery, and a large adnexal cyst visualized on the right was removed. The histopathological analysis of the surgical specimen revealed a cystic le-sion coated by luteinized cells with discrete hyperchromatic and slightly pleomorphic nuclei, with underlying fibrous stroma with sparse luteinized cells, characterizing a giant luteinized follicular cyst of pregnancy. The prevalence of ovarian masses in pregnancy is rare, usually not exceeding 5 cm in diameter, and disappearing spontaneously in the second trimester. The patient in the case report had a cyst of 632 ml, increasing in volume to 2600 ml at the time of delivery. Definitive preoperative diagnosis of ovarian masses is still difficult, and predictive criteria for malignancy include the use of tumor markers, ultrasound, and Doppler. The association of these tests should guide the clinician to define the best time for surgical intervention. The association of these tests should guide the clinician to define the best time for surgical intervention (AU)

Os cistos funcionais geralmente não causam sintomas ou requerem intervenção cirúrgica. Relatamos o caso de uma primigesta de 17 anos, idade gestacional de 10 semanas e 2 dias, e ultrassonografia mostrando cisto anecoico em região parauterina direita sem septos, com maior diâmetro de 13,5cm, volume 632ml e Doppler sem vascularização periférica. A paciente permaneceu oligossintomática durante a gestação. Com 37 semanas e 6 dias, a gestação foi interrompida, quando o cisto apresentava 2.600 ml pela ultrassonografia. A extração fetal foi realizada por cesaria-na, e um grande cisto anexial visualizado à direita foi removido. A análise histopatológica da peça cirúrgica revelou lesão cística revestida por células luteinizadas com núcleos discretamente hipercromáticos e levemente pleomór-ficos, com estroma fibroso subjacente com células luteinizadas esparsas, caracterizando cisto folicular luteinizado gigante da gravidez. A prevalência de massas ovarianas na gravidez é rara, geralmente não ultrapassam o diâmetro de 5 cm, e desaparecem espontaneamente no segundo trimestre. A paciente do relato de caso apresentou cisto de 632 ml, aumentando de volume para 2600 ml no momento do parto. O diagnóstico pré-operatório definitivo de massas ovarianas ainda é difícil, e os critérios preditivos de malignidade incluem o uso de marcadores tumorais, ultrassonografia e Doppler. A associação desses testes deve orientar o clínico para definir o melhor momento para a intervenção cirúrgica (AU)

Blood count and fasting blood glucose level in the assessment of prognosis and survival in advanced cervical cancer.

OBJECTIVE: The objective of this study was to verify whether the parameters of the blood count and the fasting glucose level before treatment are related to prognosis and survival in cervical cancer (IIB-IVB staging). METHODS: Patients with cervical cancer (stages IIB-IVB) were evaluated (n=80). Age, parity, staging, histological grade, histological type, hemoglobin, red blood cells, hematocrit, neutrophil, lymphocyte and platelet counts, red blood cell distribution width, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, fasting glucose levels, overall survival, and disease-free survival were evaluated. The results of laboratory parameters were compared using the Mann-Whitney U test. Receiver operating characteristic curve was used to obtain the area under the curve and determine the best cutoff values for each parameter. Survival was verified by using the Kaplan-Meier method, followed by the log-rank test. The level of significance was ≤0.05. RESULTS: Regarding staging, lower hemoglobin values (p=0.0013), red blood cells (p=0.009), hematocrit (p=0.0016), higher leukocytes (p=0.0432), neutrophils (p=0.0176), platelets (p=0.0140), red blood cell distribution width (RDW) (p=0.0073), neutrophil-lymphocyte ratio (p=0.0039), platelet-lymphocyte ratio (p=0.0006), and fasting glucose level (p=0.0278) were found in IIIA-IVB compared with IIB staging. Shorter disease-free survival was associated with hemoglobin ≤12.3 g/dl (p=0.0491), hematocrit ≤38.5% (p=0.05), neutrophil-lymphocyte ratio >2.9 (p=0.0478), and platelet-lymphocyte ratio >184.9 (p=0.0207). Shorter overall survival was associated with hemoglobin ≤12.3 g/dl (p=0.0131), hematocrit ≤38.5% (p=0.0376), neutrophil-lymphocyte ratio >2.9 (p=0.0258), and platelet-lymphocyte ratio >184.9 (p=0.0038). CONCLUSION: The analysis of these low-cost and easily accessible parameters could be a way to monitor patients in order to predict treatment failures and act as early as possible.

Blood count and fasting blood glucose level in the assessment of prognosis and survival in advanced cervical cancer

SUMMARY OBJECTIVE: The objective of this study was to verify whether the parameters of the blood count and the fasting glucose level before treatment are related to prognosis and survival in cervical cancer (IIB-IVB staging). METHODS: Patients with cervical cancer (stages IIB-IVB) were evaluated (n=80). Age, parity, staging, histological grade, histological type, hemoglobin, red blood cells, hematocrit, neutrophil, lymphocyte and platelet counts, red blood cell distribution width, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, fasting glucose levels, overall survival, and disease-free survival were evaluated. The results of laboratory parameters were compared using the Mann-Whitney U test. Receiver operating characteristic curve was used to obtain the area under the curve and determine the best cutoff values for each parameter. Survival was verified by using the Kaplan-Meier method, followed by the log-rank test. The level of significance was ≤0.05. RESULTS: Regarding staging, lower hemoglobin values (p=0.0013), red blood cells (p=0.009), hematocrit (p=0.0016), higher leukocytes (p=0.0432), neutrophils (p=0.0176), platelets (p=0.0140), red blood cell distribution width (RDW) (p=0.0073), neutrophil-lymphocyte ratio (p=0.0039), platelet-lymphocyte ratio (p=0.0006), and fasting glucose level (p=0.0278) were found in IIIA-IVB compared with IIB staging. Shorter disease-free survival was associated with hemoglobin ≤12.3 g/dl (p=0.0491), hematocrit ≤38.5% (p=0.05), neutrophil-lymphocyte ratio >2.9 (p=0.0478), and platelet-lymphocyte ratio >184.9 (p=0.0207). Shorter overall survival was associated with hemoglobin ≤12.3 g/dl (p=0.0131), hematocrit ≤38.5% (p=0.0376), neutrophil-lymphocyte ratio >2.9 (p=0.0258), and platelet-lymphocyte ratio >184.9 (p=0.0038). CONCLUSION: The analysis of these low-cost and easily accessible parameters could be a way to monitor patients in order to predict treatment failures and act as early as possible.

CIN Extension at Colposcopy: Relation to Treatment and Blood Parameters.

OBJECTIVE: To determine the colposcopic lesion size that predicts the presence of residual lesion in patients with cervical intraepithelial neoplasia (CIN) 2/3, to aid gynaecologists in selecting conservative management. METHODS: Data from 51 patients with low- and high-grade squamous intraepithelial lesions were evaluated. Colposcopic images were captured and lesion areas were calculated. Polymerase chain reaction (PCR) for human papillomavirus was performed. Laboratory parameters were evaluated. Receiver operating characteristic (ROC) curves were used to obtain cut-off values for lesion area. The performance of PCR in the detection of high-grade CIN was assessed. A flowchart was created to compare the costs of related procedures in the Brazilian health system. RESULTS: For CIN 2/3 treated with excisional surgery, the best cut-off value for lesion area below which no residual lesion was present was 21 019 pixels2 (58.87 mm2). The cut-off value that predicted compromised surgical margins was 155 577.65 pixels2 (435.75 mm2). Among all patients with CIN, lesion area correlated inversely with neutrophil/lymphocyte ratio (NLR; r = -0.446, P = 0.001), platelet/lymphocyte ratio (PLR; r = -0.438, P = 0.001), and absolute number of leukocytes (r = -0.351, P = 0.011). Conservative clinical management with semi-annual clinical follow-up was found to reduce direct costs to the Brazilian Health System by R $909.82 (US $169.42). CONCLUSION: CIN reflects systemic alteration, leading to altered NLRs, PLRs, and absolute numbers of leukocytes. Patients with high-grade CIN and colposcopic lesion areas <21 019 pixels2 could benefit from conservative management, which would result in cost savings for the Brazilian health system.

Metastasizing leiomyoma during pregnancy

Uterine leiomyoma is a benign tumor of myometrial tissue which affects women of reproductive age. Its prevalence increases with age and has a peak incidence at the age of forty. The term "metastasizing leiomyoma" refers to a tumor of dense connective tissue and smooth myometrial muscle cells located outside the uterus. This group of tumors can metastasize to different organs, the lung being its main focus. We present the case report of a 33-year-old female gravida 3, para 1, abortus 1, at 11 weeks of pregnancy, with pelvic masses. The diagnosis was metastasizing leiomyoma during pregnancy.

Pathways of IFN-alpha Activation in Patients with Cervical Intraepithelial Neoplasia (CIN).

OBJECTIVE: The aim of the present study was to compare the local and systemic expression of the factors linked to the interferon alpha (IFN-α) activation pathway in different degrees of cervical intraepithelial neoplasia (CIN) and cervical cancer. METHODS: A total of 128 patients with CIN I, CIN II, CIN III and cervical cancer was evaluated. The real-time polymerase chain reaction (RT-PCR) technique was used to evaluate the gene expression of IFNR1, IFNR2, IFN-α, oligoadenylate synthase (2'5'OAS), cytokine signal suppressor 1 (SOCS) 1, SOCS3, signal transducer and transcription activator 1 (STAT1), and IRF9 from 128 biopsies. A total of 46 out of 128 samples were evaluated by flow cytometry for IFNAR1, IFNAR2, STAT1, IRF7 and IFN-α in peripheral blood cells. RESULTS: Patients with CIN II and III (63 samples) had a low local expression of IFNR1, but not IFNR2. Patients with some degree of injury showed high expression of SOCS1 and SOCS3. Systemically, patients with CIN II and III (20 samples) had a significant increase in IFNR1, IFNR2, STAT1, IRF7, and IFN-α in helper, cytotoxic T lymphocytes, and in monocytes. CONCLUSION: Patients with high-grade lesions have increased systemic expression of IFN-α and its activation pathways in helper and cytotoxic T lymphocytes, as well as in monocytes due to an exacerbation of the immune response in these patients. This phenomenon is not accompanied by resolution of the lesion due to a defect in the IFN-α activation pathway that revealed by low local IFNAR1 expression and high local expression of SOCS1 and SOCS3.

OBJETIVO: O objetivo do presente estudo foi comparar a expressão local e sistêmica dos fatores ligados à via de ativação do interferon alfa (IFN-α) em diferentes graus de neoplasia intraepitelial cervical (NIC) e câncer cervical (CA) MéTODOS: Foram avaliados 128 pacientes com NIC I, NIC II, NIC III e CA. A técnica de reação de cadeia de polimerase em tempo real (RT-PCR, na sigla em inglês) foi realizada para avaliar a expressão gênica do receptor de interferon (IFNR) 1, IFNR2, IFN-α, 2'-5'-oligoadenilato sintetase (2'5'OAS), supressor de sinalização de citocina (SOCS)1, SOCS3, transdutor de sinal e ativador de transcrição 1 (STAT1) e fator regulador de interferon 9 (IRF9) das 128 biópsias. Das 128 amostras, 46 foram avaliadas por citometria de fluxo para IFNAR1, IFNAR2, STAT1, IRF7 e IFN-α em células de sangue periférico. RESULTADOS: Pacientes com NIC II e III (63 amostras) tiveram baixa expressão local de IFNR1 mas não de IFNR2. Pacientes com algum grau de lesão apresentaram alta expressão de SOCS1 e SOCS3. Sistemicamente, os pacientes com NIC II e III (20 amostras) tiveram um aumento significativo de IFNR1, IFNR2, STAT1, IRF7 e IFN-α em linfócitos T auxiliares, citotóxicos e monócitos. CONCLUSãO: Pacientes com lesões de alto grau apresentam expressão sistêmica aumentada de IFN-α e suas vias de ativação em linfócitos T auxiliares e citotóxicos, bem como em monócitos, devido à exacerbação da resposta imune nesses pacientes. Este fenômeno não é acompanhado pela resolução da lesão devido a um defeito na via de ativação do IFN-α que é revelado pela baixa expressão local de IFNR1 e alta expressão local de SOCS1 e SOCS3.

Association of laboratorial parameters and prognostic factors in uterine corpus cancer.

OBJECTIVE: The aims were to compare the red blood cells, platelet count, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, red cell distribution width, and fasting glucose in peripheral blood of patients with benign and malignant uterine neoplasms and to relate these laboratory parameters with prognostic factors and overall survival in cancer. METHODS: The results of the laboratory parameters were analyzed using the Mann-Whitney U test. Receiver operating characteristic curves were used to find the cutoff values. Overall survival was estimated using the Kaplan-Meyer method. RESULTS: Higher values of neutrophil-lymphocyte ratio and fasting glucose were found in cancer patients. Higher platelet-lymphocyte ratio values were associated with other subtypes when compared with endometrioid subtype; higher values of red cell distribution width were found in stage II/IV when compared with stage I; lower hemoglobin values were related to stage II/IV and nonendometrioid histological type. Platelet-lymphocyte ratio <145.56 was associated with longer overall survival. CONCLUSION: Hemoglobin and platelet-lymphocyte ratio values are prognostic factors in uterine corpus cancer.

Pathways of IFN-alpha Activation in Patients with Cervical Intraepithelial Neoplasia (CIN) / Vias de ativação de IFN-alfa em pacientes com Neoplasia Intraepitelial Cervical (NIC)

Abstract Objective The aim of the present study was to compare the local and systemic expression of the factors linked to the interferon alpha (IFN-α) activation pathway in different degrees of cervical intraepithelial neoplasia (CIN) and cervical cancer. Methods A total of 128 patients with CIN I, CIN II, CIN III and cervical cancer was evaluated. The real-time polymerase chain reaction (RT-PCR) technique was used to evaluate the gene expression of IFNR1, IFNR2, IFN-α, oligoadenylate synthase (2'5′OAS), cytokine signal suppressor 1 (SOCS) 1, SOCS3, signal transducer and transcription activator 1 (STAT1), and IRF9 from 128 biopsies. A total of 46 out of 128 samples were evaluated by flow cytometry for IFNAR1, IFNAR2, STAT1, IRF7 and IFN-α in peripheral blood cells. Results Patients with CIN II and III (63 samples) had a low local expression of IFNR1, but not IFNR2. Patients with some degree of injury showed high expression of SOCS1 and SOCS3. Systemically, patients with CIN II and III (20 samples) had a significant increase in IFNR1, IFNR2, STAT1, IRF7, and IFN-α in helper, cytotoxic T lymphocytes, and in monocytes. Conclusion Patients with high-grade lesions have increased systemic expression of IFN-α and its activation pathways in helper and cytotoxic T lymphocytes, as well as in monocytes due to an exacerbation of the immune response in these patients. This phenomenon is not accompanied by resolution of the lesion due to a defect in the IFN-α activation pathway that revealed by low local IFNAR1 expression and high local expression of SOCS1 and SOCS3.

Resumo Objetivo O objetivo do presente estudo foi comparar a expressão local e sistêmica dos fatores ligados à via de ativação do interferon alfa (IFN-α) em diferentes graus de neoplasia intraepitelial cervical (NIC) e câncer cervical (CA) Métodos Foram avaliados 128 pacientes com NIC I, NIC II, NIC III e CA. A técnica de reação de cadeia de polimerase em tempo real (RT-PCR, na sigla em inglês) foi realizada para avaliar a expressão gênica do receptor de interferon (IFNR) 1, IFNR2, IFN-α, 2′-5′- oligoadenilato sintetase (2′5′OAS), supressor de sinalização de citocina (SOCS)1, SOCS3, transdutor de sinal e ativador de transcrição 1 (STAT1) e fator regulador de interferon 9 (IRF9) das 128 biópsias. Das 128 amostras, 46 foram avaliadas por citometria de fluxo para IFNAR1, IFNAR2, STAT1, IRF7 e IFN-α em células de sangue periférico. Resultados Pacientes com NIC II e III (63 amostras) tiveram baixa expressão local de IFNR1 mas não de IFNR2. Pacientes com algum grau de lesão apresentaram alta expressão de SOCS1 e SOCS3. Sistemicamente, os pacientes com NIC II e III (20 amostras) tiveram um aumento significativo de IFNR1, IFNR2, STAT1, IRF7 e IFN-α em linfócitos T auxiliares, citotóxicos e monócitos. Conclusão Pacientes com lesões de alto grau apresentam expressão sistêmica aumentada de IFN-α e suas vias de ativação em linfócitos T auxiliares e citotóxicos, bem como em monócitos, devido à exacerbação da resposta imune nesses pacientes. Este fenômeno não é acompanhado pela resolução da lesão devido a um defeito na via de ativação do IFN-α que é revelado pela baixa expressão local de IFNR1 e alta expressão local de SOCS1 e SOCS3.

Prophylactic Dendritic Cell Vaccination in Experimental Breast Cancer Controls Immunity and Hepatic Metastases.

BACKGROUND/AIM: Liver metastases are among the principal mortality causes in cancer patients. Dendritic cell immunotherapies have shown promising results in some tumors by mediating immunological mechanisms that could be involved in liver metastases during primary tumor growth. The present study aimed to evaluate the impact of prophylactic dendritic cell vaccination on the liver of mice with 4T1 mouse breast carcinoma. MATERIALS AND METHODS: Adult female Balb/c mice were submitted or not to vaccination with dendritic cells before the induction of 4T1 tumor lineage. Liver tissues from mice were analyzed by flow cytometry (markers CD3, CD4, CD8, CD25, IL-10, IL-12, IL-17, TNF-α, IFN-γ, T-bet, GATA3, RORγt, and FoxP3) and hematoxylin-eosin. The dendritic cell vaccine was differentiated and matured ex vivo from the bone marrow. RESULTS: Prophylactic vaccination reduced areas of liver metastases (p=0.0049), induced an increase in the percentage of total T and cytotoxic T lymphocytes (p<0.0001), as well as FoxP3+ (p<0.0001). It also increased the levels of cytokines IL-10 and IL-17 in helper T lymphocytes (p<0.0001). CONCLUSION: The prophylactic dendritic cell vaccine changed the cell phenotype in the immune response of liver, and it was able to reduce metastases. Cytotoxic T cells and regulatory T lymphocytes were more present, likewise, the production of IL-10 and IL-7 simultaneously, demonstrating that the vaccine can induce a state of control of pro-inflammatory responses, which can provide a less favorable environment for metastatic tumor growth.

Immunological Characteristics between αß TDC and γδ TDC Cells in the Spleen of Breast Cancer-Induced Mice.

OBJECTIVE: To evaluate the antitumoral role of γδ TDC cells and αß TDC cells in an experimental model of breast cancer. METHODS: Thirty female Balb/c mice were divided into 2 groups: control group (n = 15) and induced-4T1 group (n = 15), in which the mice received 2 × 105 4T1 mammary tumor cell line. Following the 28-day experimental period, immune cells were collected from the spleen and analyzed by flow cytometry for comparison of αß TDC (TCRαß+ CD11c+MHCII+) and γδ TDC (TCRγδ+CD11c+MHCII+) cells regarding surface markers (CD4+ and C8+) and cytokines (IFN-γ, TNF-α, IL-12 and IL-17). RESULTS: A total of 26.53% of γδ TDC - control group (p < 0.0001) - the proportion of αß TDC was lower in splenic cells than γδ TDC; however, these 2 cell types were reduced in tumor conditions (p < 0.0001), and the proportion of IFN-γ, TNF-α, IL-12 and IL-17 cytokines produced by γδ TDC was higher than those produced by αß TDC, but it decreased under conditions of tumor-related immune system response (p < 0.0001). CONCLUSION: Healthy mice engrafted with malignant cells 4T1 breast tumor presented TDC with γδ TCR repertoire. These cells express cytotoxic molecules of lymphocytes T, producing anti-tumor proinflammatory cytokines.

OBJETIVO: Esclarecer o possível papel antitumoral das células TDC γδ e TDC αß em um modelo experimental de câncer de mama. MéTODOS: Trinta baços de camundongos Balb/c analisados por citometria de fluxo, separados entre grupo controle (n = 15) e o grupo tumoral induzido por 4T1 (n = 15). RESULTADOS: Presença de 26,53% de TDC γδ nos camundongos do grupo controle (p < 0,0001), proporção de TDC αß menor em células esplênicas do que TDC γδ; no entanto, estes dois tipos de células são reduzidos em condições tumorais (p < 0,0001), e a proporção de citocinas IFN-γ, TNF-α, IL-12 e IL-17 produzidas pelas célula TDC γδ foi maior do que as produzidas pelas células TDC αß, mas foram diminuídas sob condições de resposta ao sistema imunológico relacionada ao tumor (p < 0,0001). CONCLUSãO: Camundongos saudáveis induzidos ao tumor de mama 4T1 apresentaram TDC com repertório TCR γδ. Estas células expressam moléculas citotóxicas de linfócitos T, produzindo citocinas proinflamatórias anti-tumor.

Immunological Characteristics between αß TDC and γδ TDC Cells in the Spleen of Breast Cancer-Induced Mice / Características imunológicas entre células TDC αß e TDC γδ no baço de camundongos com câncer de mama induzido

Abstract Objective To evaluate the antitumoral role of γδ TDC cells and αβ TDC cells in an experimental model of breast cancer. Methods Thirty female Balb/c mice were divided into 2 groups: control group (n=15) and induced-4T1 group (n=15), in which the mice received 2 x 105 4T1 mammary tumor cell line. Following the 28-day experimental period, immune cells were collected from the spleen and analyzed by flow cytometry for comparison of αβ TDC (TCRαβ+ CD11c+MHCII+) and γδ TDC (TCRγδ+CD11c+MHCII+) cells regarding surface markers (CD4+ and C8+) and cytokines (IFN-γ, TNF-α, IL-12 and IL-17). Results A total of 26.53% of γδ TDC- control group (p<0.0001) - the proportion of αβ TDC was lower in splenic cells than γδ TDC; however, these 2 cell types were reduced in tumor conditions (p<0.0001), and the proportion of IFN-γ, TNF-α, IL-12 and IL-17 cytokines produced by γδ TDC was higher than those produced by αβ TDC, but it decreased under conditions of tumor-related immune system response (p<0.0001). Conclusion Healthy mice engrafted with malignant cells 4T1 breast tumor presented TDC with γδ TCR repertoire. These cells express cytotoxic molecules of lymphocytes T, producing anti-tumor proinflammatory cytokines.

Resumo Objetivo Esclarecer o possível papel antitumoral das células TDC γδ e TDC αβ em um modelo experimental de câncer de mama. Métodos Trinta baços de camundongos Balb/c analisados por citometria de fluxo, separados entre grupo controle (n=15) e o grupo tumoral induzido por 4T1 (n=15). Resultados Presença de 26,53% de TDC γδ nos camundongos do grupo controle (p<0,0001), proporção de TDC αβ menor em células esplênicas do que TDC γδ; no entanto, estes dois tipos de células são reduzidos emcondições tumorais (p<0,0001), e a proporção de citocinas IFN-γ, TNF-α, IL-12 e IL-17 produzidas pelas célula TDC γδ foi maior do que as produzidas pelas células TDC αβ, mas foram diminuídas sob condições de resposta ao sistema imunológico relacionada ao tumor (p<0,0001). Conclusão Camundongos saudáveis induzidos ao tumor de mama 4T1 apresentaram TDC com repertório TCR γδ. Estas células expressam moléculas citotóxicas de linfócitos T, produzindo citocinas proinflamatórias anti-tumor.

Interferon-α action in cytokine profile in eosinophilic nasal polyp cultures / Ação do interferon-α sobre o perfil de citocinas em culturas de pólipos nasais eosinofílicos

Abstract Introduction Chronic rhinosinusitis is currently classified into two types: chronic rhinosinusitis without nasal polyps and chronic rhinosinusitis with nasal polyps. In the West, approximately 80% of chronic rhinosinusitis with nasal polyps cases are characterized by a predominantly eosinophilic cell infiltrate and a Th2 cytokine pattern. Objective To evaluate the effect of Interferon-α on cytokine levels of the eosinophilic nasal polyp cell culture supernatant. Methods Cell cultures were performed based on nasal polypoid tissue samples collected from 13 patients with eosinophilic chronic rhinosinusitis with nasal polyps. Polyps were considered eosinophilic according to the histopathological examination. Cell cultures were stimulated with 3000 IU of interferon-α. Before and after the stimulus, concentrations of Interferon-γ, tumor necrosis factor αand IL 2, 4, 6 and 10, using cytometric bead array, were assessed. Results Cell samples from eosinophilic nasal polyps from 13 patients were included in the study. Twenty-four hours after interferon-α stimulation, eosinophilic nasal polyp culture supernatants showed significantly decreased IL-4 concentrations and increase in interferon-γ, IL-10 and IL-6 concentrations compared to controls. There were no significant differences in tumor necrosis factor -α and IL-2 concentrations. Conclusion We demonstrated that interferon-α in vitro alters the pattern of cytokines in cell cultures of eosinophilic nasal polyps. Analysis of these alterations suggests that interferon-α promotes a rebalancing of inflammatory profiles in cell cultures, favoring the expression of Th1 and regulatory cytokines over Th2 cytokines.

Resumo Introdução A rinossinusite crônica, atualmente, é classificada em dois tipos: Rinossinusite Crônica sem Pólipos Nasais (RSCsPN) e Rinossinusite Crônica com Pólipos Nasais (RSCcPN). No Ocidente, cerca de 80% dos casos de RSCcPN caracterizam-se por um infiltrado celular predominantemente eosinofílico e um padrão de citocinas Th2. Objetivo Avaliar o efeito do Interferon-alpha nos níveis de citocinas do sobrenadante de culturas celulares de pólipos nasais eosinofílicos. Método Foram feitas culturas celulares a partir de amostras de tecido polipoide nasal coletadas de 13 pacientes com RSCcPN eosinofílica. Os pólipos eram considerados eosinofílicos segundo exame histopatológico. As culturas celulares foram estimuladas com 3000 UI de IFN-α. Antes e após tal estímulo, foram avaliadas, no sobrenadante das culturas celulares, as concentrações do Interferon-γ (IFN-γ), do Fator de Necrose Tumoral alfa (TNF-α) e das Interleucinas (IL) 2, 4, 6 e 10, usou-se o Cytometric Bead Array. Resultados Foram incluídas no estudo amostras celulares dos pólipos nasais eosinofílicos de 13 pacientes. Vinte e quatro horas após o estímulo com IFN-α, os sobrenadantes das culturas dos pólipos nasais eosinofílicos apresentaram, de forma significante, diminuição da concentração de IL-4 e aumento das concentrações de IFN-γ, IL-10 e IL-6, em relação ao controle. Não houve diferença significante nas concentrações de TNF-α e IL-2. Conclusão Demonstramos que o IFN-α, in vitro, altera o padrão de citocinas nas culturas celulares de pólipos nasais eosinofílicos. A análise do conjunto dessas alterações sugere que o IFN-α promove, nas culturas celulares, um rebalanceamento dos perfis inflamatórios, favorece a expressão de citocinas Th1 e regulatórias, em detrimento de citocinas do padrão Th2.