Abstract Introduction Advanced Glycation End-Products (AGEs) are a diverse group of highly reactive molecules that play a vital role in the development of neurodegenerative disorders, such as Parkinson's Disease (PD), leading to a decline in functional and cognitive capacity. The objective of this study was to assess the intake and quantification of AGEs in individuals with PD and to correlate them with their functional and cognitive abilities. Methods This was a cross-sectional study involving 20 PD patients and 20 non-PD individuals as the Control group (C). The autofluorescence reader was used to evaluate skin AGEs, while food recall was used to quantify AGEs consumed for three different days. The Montreal Cognitive Assessment, Short Physical Performance Battery, and handgrip tests were used. PD patients demonstrated greater impairment in functional capacity compared to the control group. Results Dominant Handgrip (p = 0.02) and motor performance, in the sit and stand test (p = 0.01) and Short Physical Performance Battery (SPPB) (p = 0.01) were inferior in PD patients than the control group. Although PD patients tended to consume less AGEs than the control group, AGE intake was negatively correlated with handgrip strength in individuals with PD (r = -0.59; p < 0.05). Conclusion PD patients had lower strength and functional capacity, suggesting that the effects of AGEs might be exacerbated during chronic diseases like Parkinson's. EndProducts End Products (AGEs disorders Parkinsons Parkinson s PD, , (PD) abilities crosssectional cross sectional 2 nonPD non C. C . (C) days Assessment 0.02 002 0 02 performance 0.01 001 01 SPPB (SPPB r 0.59 059 59 -0.59 0.05. 005 0.05 05 0.05) Parkinsons. s. (PD (C 0.0 00 0.5 5 -0.5 0. -0. -0 -

Abstract Objective The present study aimed to investigate FOXO3a deregulation in Uterine Smooth Muscle Tumors (USMT) and its potential association with cancer development and prognosis. Methods The authors analyzed gene and protein expression profiles of FOXO3a in 56 uterine Leiomyosarcomas (LMS), 119 leiomyomas (comprising conventional and unusual leiomyomas), and 20 Myometrium (MM) samples. The authors used techniques such as Immunohistochemistry (IHC), FISH/CISH, and qRT-PCR for the present analyses. Additionally, the authors conducted an in-silico analysis to understand the interaction network involving FOXO3a and its correlated genes. Results This investigation revealed distinct expression patterns of the FOXO3a gene and protein, including both normal and phosphorylated forms. Expression levels were notably elevated in LMS, and Unusual Leiomyomas (ULM) compared to conventional Leiomyomas (LM) and Myometrium (MM) samples. This upregulation was significantly associated with metastasis and Overall Survival (OS) in LMS patients. Intriguingly, FOXO3a deregulation did not seem to be influenced by EGF/HER-2 signaling, as there were minimal levels of EGF and VEGF expression detected, and HER-2 and EGFR were negative in the analyzed samples. In the examination of miRNAs, the authors observed upregulation of miR-96-5p and miR-155-5p, which are known negative regulators of FOXO3a, in LMS samples. Conversely, the tumor suppressor miR-let7c-5p was downregulated. Conclusions In summary, the outcomes of the present study suggest that the imbalance in FOXO3a within Uterine Smooth Muscle Tumors might arise from both protein phosphorylation and miRNA activity. FOXO3a could emerge as a promising therapeutic target for individuals with Unusual Leiomyomas and Leiomyosarcomas (ULM and LMS), offering novel directions for treatment strategies. FOXOa FOXO USMT (USMT prognosis 5 , (LMS) 11 comprising leiomyomas, leiomyomas) 2 MM (MM samples IHC, IHC (IHC) FISHCISH FISH CISH FISH/CISH qRTPCR qRT PCR analyses Additionally insilico silico genes forms ULM LM (LM OS (OS patients Intriguingly EGF/HER2 EGFHER2 EGFHER EGF/HER HER EGF/HER- signaling detected HER2 HER- miRNAs miR965p miRp miR 96 5p p miR1555p, miR1555p 155 5p, miR-155-5p Conversely miRlet7c5p miRletcp let7c let c downregulated summary activity LMS) strategies (LMS 1 (IHC 9 15 miRlet letc

RESUMO O câncer de mama é comum em mulheres, mas sua etiologia ainda não é totalmente compreendida. Vários fatores podem contribuir para sua gênese, genética, estilo de vida e meio ambiente. A melatonina pode estar envolvida no processo de câncer de mama. Portanto, o objetivo deste estudo é avaliar a influência dos níveis de melatonina no câncer de mama por meio de uma revisão sistemática e meta-análise. Realizamos uma revisão sistemática de acordo com as recomendações do Prisma. Os principais bancos de dados, Medline, Embase e Cochrane, foram consultados. Não houve restrição quanto ao ano de publicação e idioma. Os dados de revisão sistemática obtidos de abril de 2017 a setembro a 2017 foram analisados. A meta-análise foi conduzida pelo programa RevMan 5.3 fornecido pela Cochrane Collaboration. De um total de 570 artigos, nove foram incluídos nesta revisão. As análises foram conduzidas em mulheres com câncer de mama e pacientes controle, dos quais 10% e 90% estavam no período reprodutivo e após a menopausa, respectivamente. O nível mais baixo de melatonina foi encontrado em aproximadamente 55% dos estudos com câncer de mama na pós-menopausa. As meta-análises de estudos demonstraram os baixos níveis de melatonina em doentes com câncer da mama (n=963), em comparação com os pacientes de controle (n=1.332), sendo a diferença de médias entre os estudos da −3,54 (CI −6,01, −1,06). Outra diferença é demonstrada nas comparações entre pacientes fumantes, sendo a diferença da média entre 1,80 [0,97-2,63]. Nossos dados sugerem que baixos níveis de melatonina podem ser um fator de risco para câncer de mama.

SUMMARY Breast Cancer is common in women, but its etiology is not yet fully understood. Several factors may contribute to its genesis, such as genetics, lifestyle, and the environment. Melatonin may be involved in the process of breast cancer. Therefore, the aim of this study is to evaluate the influence of the levels of melatonin on breast cancer through a systematic review and meta-analysis. We performed a systematic review according to PRISMA recommendations. The primary databases MEDLINE, Embase, and Cochrane were consulted. There was no restriction on the year of publication and language. Data of systematic reviews from April 2017 to September to 2017 were analyzed. The meta-analysis was conducted using RevMan 5.3 software provided by the Cochrane Collaboration. From a total of 570 articles, 9 manuscripts were included in this review. They analy onzed women with breast cancer and control patients, of which 10% and 90% were in the reproductive period and after menopause, respectively. The lowest level of melatonin was found in approximately 55% of studies with breast cancer in post-menopause. The metanalyses of the studies demonstrated low levels of melatonin in breast cancer patients (n=963) compared with control patients (n= 1332), with a mean difference between the studies of −3.54 (CI −6.01, −1.06). Another difference found was in the comparison between smoking patients, with an average difference between 1.80 [0.97-2.63]. Our data suggest that low levels of melatonin might be a risk factor for breast cancer.

OBJECTIVE: To evaluate the influence of estrogen therapy and estrogen-progestin therapy on homocysteine and C-reactive protein levels in postmenopausal women. METHODS: In total, 99 postmenopausal women were included in this double-blind, randomized clinical trial and divided into three groups: Group A used estrogen therapy alone (2.0 mg of 17β-estradiol), Group B received estrogen-progestin therapy (2.0 mg of 17 β-estradiol +1.0 mg of norethisterone acetate) and Group C received a placebo (control). The length of treatment was six months. Serum measurements of homocysteine and C-reactive protein were carried out prior to the onset of treatment and following six months of therapy. RESULTS: After six months of treatment, there was a 20.7% reduction in homocysteine levels and a 100.5% increase in C-reactive protein levels in the group of women who used estrogen therapy. With respect to the estrogen-progestin group, there was a 12.2% decrease in homocysteine levels and a 93.5% increase in C-reactive protein levels. CONCLUSION: Our data suggested that hormone therapy (unopposed estrogen or estrogen associated with progestin) may have a positive influence on decreasing cardiovascular risk due to a significant reduction in homocysteine levels.

OBJECTIVE: To investigate the clinicopathological significance of podoplanin expression in the intratumoral stroma and neoplastic cells of early stage uterine cervical cancer. MATERIALS AND METHODS: A total of 143 patients with clinical stage I and IIA uterine cervical carcinomas underwent surgery between 2000 and 2007. Clinicopathological data and slides associated with these cases were retrospectively reviewed. Immunodetection of podoplanin expression in histologic sections of tissue microarray blocks was performed using the monoclonal antibody D2-40. RESULTS: Expression of podoplanin was detected in neoplastic cells in 31/143 (21.6%) cases, with 29/31 (93.5%) of these cases diagnosed as squamous carcinoma. For all of the cases examined, the strongest signal for podoplanin expression was observed at the proliferating edge of the tumor nests. The rate of positive podoplanin expression for node-positive cases was lower than that of node-negative (18.9% vs. 22.6%, respectively). Furthermore, the rate of positive podoplanin expression in fatal cases was 10.5% vs. 21.6%, respectively. In 27/143 (18.8%) cases, podoplanin expression was detected in fibroblasts of the intratumoral stroma, and this expression did not correlate with patient age, clinical stage, tumor size, histologic type, depth of infiltration, or vascular involvement. Moreover, expression of podoplanin in intratumoral stroma fibroblasts was only negatively associated with nodal metastasis. A greater number of fatal cases was observed among negative intratumoral stroma fibroblasts (15.5% vs. 3.7%, respectively), although this difference was not significant. CONCLUSIONS: These preliminary results suggest that podoplanin may have a role in host-tumor interactions and, as a result, may represent a favorable prognostic factor for squamous cervical carcinomas.

OBJECTIVE: To analyze the amount of glycosaminoglycans in the uterine cervix during each phase of the rat estrous cycle. DESIGN: Based on vaginal smears, forty female, regularly cycling rats were divided into four groups (n = 10 for each group): GI - proestrous, GII - estrous, GIII - metaestrous and GIV - diestrous. Animals were sacrificed at each phase of the cycle, and the cervix was immediately removed and submitted to biochemical extraction and determination of sulfated glycosaminoglycans and hyaluronic acid. The results were analyzed by ANOVA followed by the Bonferroni post-hoc test. RESULTS: The uterine cervix had the highest amount of total sulfated glycosaminoglycans and dermatan sulfate during the estrous phase (8.90 ± 0.55 mg/g of cetonic extract, p<0.001; and 8.86 ± 0.57 mg/g of cetonic extract, p<0.001). In addition, there was more heparan sulfate at the cervix during the proestrous phase (0.185 ± 0.03 mg/g of cetonic extract) than during any other phase (p<0.001). There were no significant changes in the concentration of hyaluronic acid in the uterine cervix during the estrous cycle. CONCLUSION: Our data suggest that the amount of total sulfated glycosaminoglycans may be influenced by hormonal fluctuations related to the estrous cycle, with dermatan sulfate and heparan sulfate being the glycosaminoglycans most sensitive to hormonal change.

Sleep disorders have an increased incidence after menopause. The objective of this work was to evaluate the effects of isoflavone on some oxidative stress markers in postmenopausal women complaining of insomnia. Women aged between 50-65 years (n=38) were recruited and assigned to a double-blind placebo controlled study for 4 months. The treated group received 100 mg/day of isoflavones. Blood collections were conducted on three different occasions to assess total glutathione; superoxide dismutase and catalase in erythrocytes; lipid peroxidation; and homocysteine plasma concentrations. No differences between the groups were observed. However, all the patients seem to improve their oxidative stress status and homocysteine concentration after treatment. Superoxide dismutase activity was correlated with age and time of menopause at the beginning of the treatment, but these correlations were no longer observed by the end of the study. Soy isoflavones were not able to overcome the placebo effect for either oxidative stress parameters or homocysteine concentrations.

OBJETIVO: Avaliar as taxas de fluxo no estudo urodinâmico (EUD) em pacientes com disfunção do trato urinário inferior e registrar os efeitos do diagnóstico final do EUD e da idade das pacientes sobre estas variáveis. MÉTODOS: Estudo retrospectivo que incluiu 205 mulheres. As pacientes foram divididas em três grupos: menos de 45 anos; entre 45 e 60 anos e mais que 60 anos. Estudamos os comportamentos dos fluxos máximo, médio e da pressão de abertura do detrusor (Padet) com o evoluir da idade. De forma semelhante, realizamos comparações das variáveis fluxos máximo e médio, Padet e vesical no fluxo máximo, consoante o diagnóstico final do EUD. RESULTADOS: Há forte declínio dos fluxos máximo, médio e da Padet com o evoluir da idade, sendo que a queda dos fluxos máximo e médio é significante quando comparamos as mulheres com mais de 65 anos (21,8 ml/s e 9,2 ml/s, respectivamente) com aquelas entre 45 e 60 anos (29 ml/s e 12,6 ml/s, respectivamente) e as demais (27,9 ml/s e 11,7 ml/s, respectivamente). Observamos redução significativa da Padet no grupo com mais de 60 anos (13,4 cmH2O) quando comparadas àquele com menos de 45 anos (21,2 cmH2O). A Padet teve redução significativa nas pacientes com incontinência urinária de esforço (IUE) associada a defeito esfincteriano (13,8 cmH2O) diagnosticados no EUD quando comparadas aquelas assintomáticas (20,7 cmH2O). CONCLUSÃO: Há diminuição das taxas de fluxo com o aumento da idade. Mulheres com IUE têm micção com menor Padet.

OBJECTIVE: The purpose was to evaluate urine flow rates in an urodynamic study (US) of patients with symptoms of lower urinary tract dysfunction and to record effects of final urodynamic diagnosis and age on these variables. METHODS: Retrospective analysis of 205 women who had undergone urogynecological investigation. Patients were divided into three age groups: A (< 45 years); B (45 - 60 years) and C (> 60 years). Comportment of urine flow rates and opening detrusor pressure with increasing age were studied and resulting charts recorded. Comparison of maximum and average urine flow rates, opening detrusor pressure and detrusor pressure at the maximal flow according to final urodynamic diagnostic were also made. RESULTS: There was a decline of urine flow rates with increase of age, which was more significant between groups A X C and B X C. There was also a decline in opening detrusor pressure with aging, which was significant between groups A X C. When analyzing opening detrusor pressure according to final urodynamic diagnosis, a significant decline of this variable was observed in patients with urinary stress incontinence and intrinsic sphincter deficiency in relation to those who were asymptomatic. CONCLUSION: Urine flow rates decreased with age. Women with urinary stress incontinence and intrinsic sphincter deficiency void at a lower detrusor pressure.

OBJECTIVE: To evaluate the effects of estrogen treatment in combination with gestrinone on an experimental rat model of endometriosis. METHODS: Uterine transplants were attached to the peritoneum of female Wistar rats via a surgical autotransplantation technique. The implanted area was measured during the proestrus phase and after hormonal treatment. We performed morphometric analysis and examined the macroscopic and morphometric alterations of endometrial implants after hormonal treatment in ovariectomized rats. RESULTS: The high dose of estrogen caused macroscopic increases in the endometrial implant group compared with other groups, which were similar to increases in the proestrus phase. The low dose showed morphometric development of implants, such as an increase in number of endometrial glands, leukocyte infiltration and mitosis. Gestrinone antagonized both doses of estrogen. CONCLUSION: Our findings suggest that gestrinone antagonizes estrogen's effects on rat peritoneal endometrial implants.

OBJECTIVE: To evaluate the effect of different concentrations of estrogen on the ovarian superficial epithelium in senile female rats. Design: Fifty female rats at 15 months of age and with irregular estrous cycles were selected and randomly divided into five experimental groups containing equal numbers of animals in each: GPROP, control group receiving vehicle only; GE0.05mg, group receiving conjugated equine estrogens (CEE) at a dose of 50 µg/kg; GE0.5mg, group receiving CEE at 500 µg/kg; GE1mg, group receiving CEE at 1 mg/kg; and GE2mg, receiving CEE at 2 mg/kg. The length of treatment was 21 days. After this period, the animals were anesthetized and the ovaries were fixed in 10% formaldehyde and processed for routine histology. Histomorphology was analyzed by light microscopy, and histomorphometrics were evaluated using the Imagelab program. RESULTS: In the GPROP and GE0.05mg groups, the superficial epithelium of the ovary had a simple cuboidal shape, and as the estrogen dose increased, the epithelium thickened, with pseudo-stratified or stratified epithelium appearing in the GE2mg group. The animals in the group given the highest estrogen dose (GE2mg) showed the thickest ovarian epithelium and the largest perimeter and surface area of the surface ovarian epithelium (P < 0.01). However, the difference in epithelium thickness between the GE0.5mg and GE1mg groups was only slight. CONCLUSION: Our data suggest that CEE at a dose of 2 mg/kg may induce marked proliferation of rat ovarian epithelium.

OBJETIVO: O alvo deste estudo foi analisar o efeito do sulfato de glicosamina no disco epifisário da tíbia em ratas ooforectomizadas. MÉTODOS: Após a ooforectomia (OVx), 28 ratas foram aleatoriamente divididas em 4 grupos experimentais de 7 animais cada, tratados da seguinte maneira: OVx 21 - veículo (0,5ml de NaCl 0.9% ip uma vez ao dia) por 21 dias; OVx GS21 230 - mg/kg peso corporal por dia de sulfato de glicosamina, 21 dias; OVx 45 - tratados com NaCl 0.9% igual ao grupo OVx 21, por 45 dias; e OVx GS45 - 230 mg/kg peso corporal por dia com sulfato de glicosamina, 45 dias. Sete animais intactos, na fase de proestro, foram usados como controle (CG). Ao completar o tratamento, os animais foram sacrificados e a articulação do joelho esquerdo foi dissecada e preparada para análise histológica. RESULTADOS: A porcentagem de cartilagem remanescente no novo osso do CG foi a menor. Os achados no grupo OVx GS45 foi significantemente menor do que no grupo OVx 21, OVx GS21 e OVx 45. A porcentagem de osso trabecular nos animais em pró-estro foi a maior. O grupo OVx GS45 mostrou valores maiores em relação aos outros grupos ooforectomizados. Esses resultados foram correspondentes aos achados em relação às células da zona proliferativa, desde que o CG teve os maiores valores e os valores do grupo OVx GS45 foram superiores aos dos grupos OVx 21, OVx GS21 e OVx 45. CONCLUSÃO: Nossos estudos sugerem que a glicosamina pode estimular o crescimento da cartilagem e do osso tibial após a ooforectomia em ratas.

OBJECTIVE: The aim of this study was to analyze the effect of glucosamine sulfate on the tibial epiphyseal disk of the ovariectomized rats. METHODS: After ovariectomy (OVx), 28 female rats were randomly divided into 4 experimental groups with 7 animals each, treated as follows: OVx 21 - vehicle (NaCl 0.9%) 0.5 mL/day) for 21 days; OVx GS21 - 230 mg/kg/day glucosamine sulphate for 21 days; OVx 45 - treated with NaCl 0.9% as above for 45 days; and OVx - GS45230 mg/kg/day glucosamine sulphate for 45 days. Seven intact animals in the proestrous phase were used as controls (CG). Upon treatment completion, the animals were sacrificed and the left knee joint was dissected and prepared for histological analysis. RESULTS: The percentage of remaining cartilage in new bone of the CG; that found in THE OVx GS45 group was significantly less than that of the OVx 21, OVx GS21, and OVx 45 groups. The percentage of trabecular bone in proestrous animals was the highest. The OVx GS45 group showed higher values compared with the other ovariectomized groups. These results were paralleled by the findings regarding the cells of the proliferative zone, since the CG had the highest values, and the values of the OVx GS45 group were greater than those of the OVx 21, OVx GS21, and OVx 45 groups. CONCLUSION: Our studies suggested that glucosamine may stimulate tibial cartilage and bone growth after ovariectomy in rats.

Due to the conflicting results regarding the association between breast cancerand the GSTM1 null mutation, our aim was to research this associationin a Brazilian population and correlations withsmoking, reproductive history and several clinical pathologies. A case-control study was performed on 105 women with breast cancer and 278 controls. Extraction of DNA was accomplished according to the protocol of the GFX® kit and polymorphism analysis by the PCR technique. The control and experimental groups were compared and statistical analysis assessed by X² or Fisher's exact test. The deletion in the GSTM1 gene in the breast cancer group had a prevalence of 32 (30.4%) individuals with the presence of null mutation. In the control group, the null mutation was present in 104 (37.4%) women. Upon comparison of the two groups, no statistically significant difference of the GSTM1 gene was observed, with an odds ratio (OR) of 0.74, 95%, confidence interval (CI) 0.45 - 1.20, p = 0.277. The results conclusively show that singlegene GSTM1 polymorphisms do not confer a substantial risk of breastcancer to its carriers. Furthermore, in this study no correlation was found between GSTs andsmoking, reproductive history and several clinical pathologies with respect to cancer risk.