Molecular transduction in receptor-ligand systems by planar electromagnetic fields / Transdução molecular em sistemas receptor-ligante por campos electromagnéticos planares

The coupling of a ligand with a molecular receptor induces a signal that travels through the receptor, reaching the internal domain and triggering a response cascade. In previous work on T-cell receptors and their coupling with foreign antigens, we observed the presence of planar molecular patterns able to generate electromagnetic fields within the proteins. These planes showed a coherent (synchronized) behavior, replicating immediately in the intracellular domain that which occurred in the extracellular domain as the ligand was coupled. In the present study, we examined this molecular transduction - the capacity of the coupling signal to penetrate deep inside the receptor molecule and induce a response. We verified the presence of synchronized behavior in diverse receptor ligand systems. To appreciate this diversity, we present four biochemically different systems - TCR-peptide, calcium pump-ADP, haemoglobin-oxygen, and gp120-CD4 viral coupling. The confirmation of synchronized molecular transduction in each of these systems suggests that the proposed mechanism would occur in all biochemical receptor-ligand systems.

A ligação de um ligante com um receptor molecular induz um sinal que viaja através do receptor, chegando ao domínio interno e disparando uma cascata de resposta. Em trabalhos anteriores em receptores de células T e sua ligação com antígenos estranhos, observamos a presença de padrões moleculares planares capazes de gerar campos eletromagnéticos dentro das proteínas. Esses planos mostraram um comportamento coerente (sincronizado), replicando, instantaneamente, no domínio intracelular o que ocorreu no domínio extracelular, enquanto o ligante era acoplado. No presente estudo, examinamos essa transdução – a capacidade de um sinal de acoplamento de penetrar profundamente a molécula receptora e induzir uma resposta. Verificamos a presença de um comportamento coerente em sistemas diversos de receptor-ligante. Para apreciar essa diversidade, apresentamos quatro sistemas bioquímicos diferentes: TCR-peptídeo, ADP-bomba de cálcio, hemoglobina-oxigênio e gp120-CD4 acoplamento viral. A confirmação de transdução molecular sincronizada em cada um desses sistemas sugere que o mecanismo proposto ocorreria em todos os sistemas bioquímicos receptor-ligante.

Association between Adverse Maternal Clinical Outcomes and Imbalance of Cytokines and Angiogenic Factors in Preterm Preeclampsia / Associação entre desfechos maternos adversos e desbalanço de citocinas e fatores angiogênicos em pré-eclâmpsia pré-termo

Abstract Objective Preeclampsia (PE) is a pregnancy-specific syndrome characterized by abnormal levels of cytokines and angiogenic factors, playing a role in the disease development. The present study evaluated whether immunological markers are associated with the gestational age and with the disease severity in preeclamptic women. Methods Ninety-five women who developed PE were stratified for gestational age as preterm PE (< 37 weeks) and term PE (≥ 37 weeks of gestation) and compared for disease severity as well as plasma concentration of angiogenic factors and cytokines. The concentrations of placental growth factor (PlGF), vascular endothelial growth factor (VEGF), Fms-like soluble tyrosine kinase (sFlt-1) and soluble endoglin (sEng), as well as the cytokines, tumor necrosis factor-α (TNF-α) and interleukin 10 (IL-10), were determined by enzyme-linked immunosorbent assay (ELISA). Results The comparison between preeclamptic groups showed a higher percentage of severe cases in preterm PE (82.1%) than in term PE (35.9%). Similarly, the concentrations of TNF-α, sFlt-1, and sEng, as well as TNF-α/IL-10 and sFlt-1/PlGF ratios were significantly higher in the preterm PE group. In contrast, concentrations of PlGF, VEGF, and IL-10 were significantly lower in women with preterm PE. Negative correlations between TNF-α and IL-10 (r = 0.5232) and between PlGF and sFlt1 (r = 0.4158) were detected in the preterm PE. Conclusion In pregnant women with preterm PE, there is an imbalance between immunological markers, with the predominance of anti-angiogenic factors and TNF-α, associated with adverse maternal clinical outcomes.

Resumo Objetivo A pré-eclâmpsia (PE) é uma síndrome específica da gravidez caracterizada por níveis anormais de citocinas e fatores angiogênicos, que desempenham um papel no desenvolvimento da doença. Este estudo avaliou se os marcadores imunológicos estão associados à idade gestacional e à gravidade da doença em mulheres com pré-eclâmpsia. Métodos Noventa e cinco mulheres que desenvolveram PE foram estratificadas pela idade gestacional em PE pré-termo (< 37 semanas) e PE a termo (≥ 37 semanas de gestação) e comparadas quanto à gravidade da doença, bem como à concentração plasmática de fatores angiogênicos e citocinas. As concentrações de fator de crescimento placentário (PlGF), fator de crescimento endotelial vascular (VEGF), tirosina quinase solúvel semelhante a Fms (sFlt-1) e endoglina solúvel (sEng), bem como as citocinas, fator de necrose tumoral alfa (TNF- α) e interleucina 10 (IL-10), foram determinados porensaio de imunoabsorção enzimática (ELISA, na sigla em inglês). Resultados A comparação entre os grupos com pré-eclâmpsia mostrou maior porcentagem de casos graves em PE pré-termo (82,1%) do que em PE a termo (35,9%). Da mesma forma, as concentrações de TNF-α, sFlt-1 e sEng, bem como as razões TNF-α/IL-10 e sFlt-1/PlGF foram significativamente maiores no grupo de PE pré-termo. Em contraste, as concentrações de PlGF, VEGF e IL-10 foram significativamente menores em mulheres com PE pré-termo. Correlações negativas entre TNF-α e IL-10 (r = 0.5232) e entre PlGF e sFlt1 (r = 0.4158) foram detectadas no grupo de PE pré-termo. Conclusão Em gestantes com PE pré-termo, ocorre um desequilíbrio entre os marcadores imunológicos, com predomínio de fatores antiangiogênicos e TNF-α, associados a desfechos clínicos maternos adversos.

Effects of Nogo-A and its receptor on the repair of sciatic nerve injury in rats

Regeneration of injured peripheral nerves is an extremely complex process. Nogo-A (neurite outgrowth inhibitor-A) inhibits axonal regeneration by interacting with Nogo receptor in the myelin sheath of the central nervous system (CNS). The aim of this study was to investigate the effects of Nogo-A and its receptor on the repair of sciatic nerve injury in rats. Sprague-Dawley rats (n=96) were randomly divided into 4 groups: control group (control), sciatic nerve transection group (model), immediate repair group (immediate repair), and delayed repair group (delayed repair). The rats were euthanized 1 week and 6 weeks after operation. The injured end tissues of the spinal cord and sciatic nerve were obtained. The protein expressions of Nogo-A and Nogo-66 receptor (NgR) were detected by immunohistochemistry. The protein expressions of Nogo-A, NgR, and Ras homolog family member A (RhoA) were detected by western blot. At 1 week after operation, the pathological changes in the immediate repaired group were less, and the protein expressions of Nogo-A, NgR, and RhoA in the spinal cord and sciatic nerve tissues were decreased (P<0.05) compared with the model group. After 6 weeks, the pathological changes in the immediate repair group and the delayed repair group were alleviated and the protein expressions decreased (P<0.05). The situation of the immediate repair group was better than that of the delayed repair group. Our data suggest that the expression of Nogo-A and its receptor increased after sciatic nerve injury, indicating that Nogo-A and its receptor play an inhibitory role in the repair process of sciatic nerve injury in rats.

Chronic mucocutaneous candidiasis associated with paracoccidioidomycosis in a patient with mannose receptor deficiency: First case reported in the literature

Abstract We describe the first report of a patient with chronic mucocutaneous candidiasis associated with disseminated and recurrent paracoccidioidomycosis. The investigation demonstrated that the patient had a mannose receptor deficiency, which would explain the patient's susceptibility to chronic infection by Candida spp. and systemic infection by paracoccidioidomycosis. Mannose receptors are responsible for an important link between macrophages and fungal cells during phagocytosis. Deficiency of this receptor could explain the susceptibility to both fungal species, suggesting the impediment of the phagocytosis of these fungi in our patient.

Effect of crocin on PKHD1 and KLLN genes expression in kidney tissue of male rats treated with cadmium / Efecto de la crocina sobre la expresión de los genes PKHD1 y KLLN en tejido renal de ratas macho tratadas con cadmio

According to data from studies, antioxidant herbal compounds are, likely to have a useful role in reducing the harmful effects of environmental pollutants and toxic chemicals that most people are exposed to. Cadmium is one of the toxic elements that accumulate in many organs, especially in kidneys. The aim of this study was to investigate the effect of crocin on the expression of PKHD1 and KLLN genes in cadmium-treated rats.In this experimental study, 40 adults male Wistar rats (200-250 g) were randomly divided into the following groups: control group received normal saline, cadmium group (15mg/kg), crocin group (20mg/kg) and cadmium group daily fed with crocin at a dose of 20 mg/kg.After eight weeks of treatment, rats were dissected, and kidney tissues were removed for evaluation of PKHD1 and KLLN gene expression by real time method. The data were analyzed using one-way ANOVA and significant difference between groups was P<0.05.Our results showed an increase in PKHD1 gene expression and a decrease in KLLN gene expression in kidney tissue in the cadmium group compared to the control group (P <0.001).Also, a significant decrease in PKHD1 gene expression (P <0.001) and an increase in KLLN gene expression P <0.05) were observed in the tissues of all cadmium-treated rats compared to cadmium.Crocin consumption can have a protective effect against the impaired expression of PKHD1 and KLLN cadmium-induced apoptotic pathway.

Diversos estudios sugieren que compuestos antioxidantes de hierbas tienen un papel útil en la reducción de los efectos nocivos de los contaminantes ambientales y los químicos tóxicos a los que está expuesta la mayoría de las personas. El cadmio es uno de los elementos tóxicos que se acumulan en muchos órganos, especialmente en los riñones. El objetivo de este estudio fue investigar el efecto de la crocina en la expresión de los genes PKHD1 y KLLN en ratas tratadas con cadmio.En este estudio experimental, 40 ratas Wistar macho adultas (200-250 g) se dividieron aleatoriamente en los siguientes grupos: el grupo de control recibió solución salina normal, el grupo de cadmio (15 mg / kg), el grupo de crocina (20 mg / kg) y el grupo de cadmio alimentado diariamente con crocina a una dosis de 20 mg / kg.Después de ocho semanas de tratamiento, se disecaron las ratas y se extrajeron los tejidos renales para evaluar la expresión de los genes PKHD1 y KLLN mediante un método en tiempo real. Los datos se analizaron mediante ANOVA de una vía y la diferencia significativa entre los grupos fue P <0,05.Nuestros resultados mostraron un aumento en la expresión del gen PKHD1 y una disminución en la expresión del gen KLLN en el tejido renal en el grupo de cadmio en comparación con el grupo de control (P <0,001).Además, se observó una disminución significativa en la expresión del gen PKHD1 (P <0,001) y un aumento en la expresión del gen KLLN P <0,05) en los tejidos de todas las ratas tratadas con cadmio en comparación con el cadmio.El consumo de crocina puede tener un efecto protector contra la expresión alterada de la vía apoptótica inducida por cadmio PKHD1 y KLLN.

Evaluation of variants in IL6R, TLR3, and DC-SIGN genes associated with dengue in a sampled Colombian population / Evaluación de las variantes en los genes IL6R, TLR3 y DC-SIGN asociadas con dengue en una muestra de población colombiana

Abstract Introduction: Host genetics is recognized as an influential factor for the development of dengue disease. Objective: This study evaluated the association of dengue with the polymorphisms rs8192284 for gene IL6R, rs3775290 for TLR3, and rs7248637 for DC-SIGN. Materials and methods: Of the 292 surveyed subjects, 191 were confirmed for dengue fever and the remaining 101 were included as controls. The genotypes were resolved using polymerase chain reaction and restriction fragment length polymorphism (PCR- RFLP). In an attempt to determine the risk (Odds Ratio) of suffering dengue fever, data were analyzed using chi-square for alleles and logistic regression for both genotypes and allelic combinations. Confidence intervals were set to 95% for all tests regardless of the adjustment by either self-identification or ancestry. Results: For Afro-Colombians, the allele rs8192284 C offered protection against dengue [OR=0.425,(0.204-0.887), p=0.020]. The alleles rs7248637 A and rs3775290 A posed, respectively, an increased risk of dengue for Afro-Colombians [OR=2.389, (1.170-4.879), p=0.015] and Mestizos [OR=2.329, (1.283-4.226), p=0.005]. The reproducibility for rs8192284 C/C [OR=2.45, (1.05-5.76), p=0.013] remained after adjustment by Amerindian ancestry [OR=2.52, (1.04-6.09), p=0.013]. The reproducibility for rs3775290 A/A [OR=2.48, (1.09-5.65), p=0.033] remained after adjustment by European [OR=2.34, (1.02-5.35), p=0.048], Amerindian [OR=2.49, (1.09-5.66), p=0.035], and African ancestry [OR=2.37, (1.04-5.41), p=0.046]. Finally, the association of dengue fever with the allelic combination CAG [OR=2.07, (1.06-4.05), p=0.033] remained after adjustment by Amerindian ancestry [OR=2.16, (1.09-4.28), p=0.028]. Conclusions: Polymorphisms rs8192284 for IL6R, rs3775290 for TLR3, and rs7248637 for DC-SIGN were associated with the susceptibility to suffer dengue fever in the sampled Colombian population.

Resumen Introducción. La genética del huésped se reconoce como un factor que influye en el desarrollo del dengue. Objetivo. Este estudio evaluó la asociación del dengue con los polimorfismos rs8192284 del gen IL6R, rs3775290 del TLR3 y rs7248637 del DC-SIGN. Materiales y métodos. De los 292 sujetos encuestados, en 191 se confirmó la presencia de fiebre por dengue y los restantes 101 se incluyeron como controles. Los genotipos se resolvieron mediante reacción en cadena de la polimerasa y polimorfismos en la longitud de los fragmentos de restricción (PCR-RFLP). En un intento por determinar el riesgo de sufrir dengue, los datos se analizaron mediante la prueba de ji al cuadrado para los alelos y la regresión logística para los genotipos y las combinaciones alélicas. Los intervalos de confianza se calcularon a 95 % para todas las pruebas independientemente ajustadas por autoidentificación o componente genético ancestral. Resultados. En los afrocolombianos, el alelo C rs8192284 ofreció protección contra el dengue (OR=0,425; 0,204-0,887, p=0,020). Los alelos A rs7248637 y Ars3775290 plantearon un mayor riesgo de dengue para los afrocolombianos (OR=2,389; 1,170- 4,879; p=0,015) y los mestizos (OR=2,329; 1,283-4,226: p=0,005), respectivamente. La reproducibilidad para rs8192284 C/C (OR=2,45; 1,05-5,76; p=0,013) permaneció después del ajuste por el componente genético ancestral amerindio (OR=2,52; 1,04- 6,09; p=0,013). La reproducibilidad del rs3775290 A/A (OR=2,48; 1,09-5,65; p=0,033) permaneció después del ajuste por el componente europeo (OR=2,34; 1,02-5,35; p=0,048), el amerindio (OR=2,49; 1,09- 5,66; p=0,035), y el africano (OR=2,37; 1,04- 5,41; p=0,046). Por último, la asociación del dengue con la combinación alélica CAG (OR=2,07; 1,06-4,05; p=0,033) permaneció después del ajuste por el componente genético amerindio (OR=2,16; 1,09-4,28;p=0,028). Conclusión. Los polimorfismos rs8192284 en IL6R, rs3775290 en TLR3 y rs7248637 en DC-SIGN, se asociaron con la propensión a sufrir dengue en una muestra de población colombiana.

[Artigo Parcialmente Retratado] Prevalência da infecção por Helicobacter pylori em pacientes dispépticos e associação com fatores de riscos clínicos para o desenvolvimento de adenocarcinoma gástrico / [article partial retraction] prevalence of helicobacter pylori infection in dyspeptic patients and its association with clinical risk factors for developing gastric adenocarcinoma

ABSTRACT BACKGROUND: In Brazil, particularly in the underdeveloped localities, the prevalence of Helicobacter pylori (H. pylori) infections can range up to 90%. These rates are higher in older individuals and vary by country region. H. pylori infections are linked to the development of gastric pathologies, namely mild to moderate gastritis, gastroenteritis, peptic ulcer, intestinal metaplasia, and gastric cancer. In 1994, this organism was classified by the International Agency for Research on Cancer (IARC) as pertaining to the Group 1 carcinogen for gastric adenocarcinoma etiology. Gastric cancer represents a significant public health problem, being the fourth most common malignant tumor and the second largest cause of cancer-related deaths. OBJECTIVE: To investigate the prevalence of H. pylori infection in dyspeptic patients and determine the link between clinical risk factors and gastric adenocarcinoma diagnosis. METHODS: Polymerase chain reaction (PCR) analysis was employed for molecular diagnosis of gastric tissue biopsies collected from 113 dyspeptic patients at the University Hospital of Federal University of Goiás. Molecular analyses allowed the identification of H. pylori infections. Furthermore, histopathological examinations were performed to determine the clinical risks of developing gastric malignancies. RESULTS: The test results identified 69 individuals older than 44 years, from 75 (66.4%) positive H. pylori infection samples. The prevalence of gastric adenocarcinoma in this study was 1.3%. Among the infected patients, six (8.2%) had high risk, and 67 (91.8%) had a low risk of developing gastric cancer (P<0.05). CONCLUSION: This study shows a high prevalence of H. pylori infection and identifies its contribution to gastric inflammations, which in the long term are manifested in high-risk clinical factors for the development of gastric adenocarcinoma.

RESUMO CONTEXTO: No Brasil, particularmente nas áreas mais pobres, a prevalência da infecção por Helicobacter pylori pode variar até 90%. Esses índices aumentam com o envelhecimento da população e são distintos entre as diferentes regiões do país. Podendo manifestar diferentes sintomatologias, essa infecção está diretamente relacionada com o desenvolvimento de patologias gástricas como gastrite leve a moderada, gastroenterites, úlcera péptica, metaplasia intestinal e principalmente, o câncer gástrico. Em 1994 a bactéria foi categorizada pela International Agency for Research on Cancer (IARC) como carcinógeno do Grupo 1 para adenocarcinoma gástrico, tipo de câncer que representa um importante problema de saúde pública, sendo o quarto tumor maligno mais comum e a segunda maior causa de mortes por câncer no mundo. OBJETIVO: Analisar a prevalência da bactéria em pacientes dispépticos e avaliar a associação de fatores de risco clínicos para desenvolvimento de adenocarcinoma gástrico. MÉTODOS: Biópsias de tecido gástrico coletadas de 113 pacientes dispépticos, atendidos no Hospital das Clínicas da Universidade Federal de Goiás, foram submetidas a diagnóstico molecular por meio de Reação em Cadeia da Polimerase, para identificação da infecção por Helicobacter pylori, e exame histopatológico, para avaliar o risco clínico de desenvolvimento de adenocarcinoma gástrico. RESULTADOS: Foram diagnosticadas 75 (66,4%) amostras positivas para infecção por Helicobacter pylori, sendo 69 indivíduos maiores de 44 anos de idade. A prevalência do adenocarcinoma gástrico nesse estudo foi de 1,3% e dentre os pacientes positivos para a infecção bacteriana seis (8,2%) possuem alto risco e 67 (91,8%) baixo risco de desenvolver esse tipo de câncer (P<0,05). CONCLUSÃO: Esse estudo mostra uma alta prevalência da infecção por H. pylori na população estudada e identifica sua intrínseca contribuição para inflamações gástricas, que a longo prazo se manifestam em fatores clínicos de alto risco para o desenvolvimento de adenocarcinoma gástrico.

Macrophages subpopulations in chronic periapical lesions according to clinical and morphological aspects

Abstract: The aim of this study was to evaluate macrophage M1 and M2 subpopulations in radicular cysts (RCs) and periapical granulomas (PGs) and relate them to clinical and morphological aspects. M1 macrophages were evaluated by the percentage of CD68 immunostaining associated with the inflammatory cytokine TNF-α, and M2 macrophages, by its specific CD163 antibody. The CD68+/CD163+ ratio was adopted to distinguish between the two macrophage subpopulations. Clinical, radiographic, symptomatology, treatment, and morphological parameters of lesions were collected and a significance level of p = 0.05 was adopted for statistical analysis. The results showed that the CD68+/CD163+ ratio was higher in the RCs (median = 1.22, p = 0.002), and the highest TNF-α immunostaining scores were found in RCs (p = 0.018); in PGs, the CD68+/CD163+ ratio was lower and associated with a greater CD163+ immunostaining (median = 1.02, p <0.001). The TNF-α in cyst epithelium had a score of 3 in 10 cases and predominance of M1 macrophages by CD68+/CD163+ (median = 2.23). In addition, CD68+ cells had higher percentage of immunostaining in smaller RCs (p = 0.034). Our findings suggest that increased CD68 immunostaining associated with TNF-α cytokine in RCs results in a greater differentiation of the M1 phenotype. The higher CD163 immunostaining in PGs results in greater differentiation of the M2 phenotype. Therefore, the inflammatory state promoted by M1 macrophages is related to growth and progression of RCs; on the other hand, the immunomodulatory state of M2 macrophages is related to maintenance of PGs.

Respuesta al Tratamiento Neoadyuvante en pacientes con Cáncer de Mama en SOLCA-Guayaquil / Response to Neoadjuvant Treatment in patients with Breast Cancer in SOLCA Guayaquil

Introducción: La quimioterapia neoadyuvante es ampliamente aceptada como tratamiento de elección en cáncer de mama localmente avanzado. El objetivo de la presente comunicación corta es conocer la tasa de respuesta completa patológica (pRC) luego de neoadyuvancia, la frecuencia de cirugía conservadora, así como también el porcentaje de la sobrevida. Métodos: Ingresaron al estudio pacientes con cáncer de mama que recibieron tratamiento de quimioterapia neoadyuvante y luego sometidas a cirugía, fueron analizadas retrospectivamente usando historias clínicas desde enero 2009 hasta diciembre 2011 en el Instituto Oncológico Nacional Dr. ¨Juan Tanca Marengo¨ Solca-Guayaquil, se excluyeron pacientes sin suficiente información clínica y aquellas tratadas en otros centros. El procesamiento de datos se realizó mediante un sistema estadístico SPSS v20. Resultados: 1367 pacientes con cáncer de mama fueron diagnosticadas desde el año 2009-2011, se excluyeron aquellas que no reunieron los criterios de inclusión. 200 pacientes evaluables recibieron quimioterapia neoadyuvante y fueron operadas. La edad promedio al diagnóstico fue de 51 años (rango 26-79 años), el tipo histológico ductal Infiltrante fue el más frecuente 185 (92.5 %), Lobular 10 (5 %), Medular 4 (2 %) y metaplásico 1 (0.5 %). El Grado histológico II 143 (71.5 %), Grado histológico III 30 (15 %). En Estadio I: 1 (0.5 %), IIA: 25 (12.5 %), IIB: 42 (21 %), IIIA: 58 (28 %), IIIB: 69 (34.5 %), IIIC: 5 (2.5 %). Conclusión: El cáncer de mama es un grupo heterogéneo, la mayoría de pacientes acuden con enfermedad avanzada (65 %), respuesta patológica completa (16.5 %) luego de neoadyuvancia es muy similar a la obtenida en otros estudios, como es conocido el grupo triple negativo obtuvo los mejores resultados (25 %) y una mejoría en el porcentaje de la sobrevida global en este subgrupo, es importante completar el protocolo de neoadyyuvancia previo a la cirugía para aumentar la tasa de pRC y así como también la cirugía conservadora (10 %) que es el objetivo primario en neoadyuvancia.

Introduction: Neoadjuvant chemotherapy is widely accepted as the treatment of choice in locally advanced breast cancer. The objective of this short communication is to know the pathological complete response rate (pRC) after neoadjuvant, the frequency of conservative surgery, as well as the percentage of survival. Methods: Patients with breast cancer who received neoadjuvant chemotherapy treatment and then underwent surgery, were retrospectively analyzed using clinical histories from January 2009 to December 2011 at the National Cancer Institute "Dr. Juan Tanca Marengo" Solca-Guayaquil, were excluded from the study patients without sufficient clinical information and those treated in other centers. Data processing was performed using a statistical system SPSS v20. Results: 1367 patients with breast cancer were diagnosed from the year 2009-2011, those who did not meet the inclusion criteria were excluded. 200 evaluable patients received neoadjuvant chemotherapy and were operated on. The average age at diagnosis was 51 years (range 26-79 years), the intracranial ductal histological type was the most frequent 185 (92.5 %), Lobular 10 (5 %), Medular 4 (2 %) and metaplastic 1 (0.5 %). The histological grade II 143 (71.5 %), histological grade III 30 (15 %). In Stage I: 1 (0.5 %), IIA: 25 (12.5 %), IIB: 42 (21 %), IIIA: 58 (28 %), IIIB: 69 (34.5 %), IIIC: 5 (2.5 %). Conclusion: Breast cancer is a heterogeneous group, most patients come with advanced disease (65 %), complete pathological response (16.5 %) after neoadjuvant is very similar to that obtained in other studies, as is known the triple negative group obtained the best results (25 %) and an improvement in the percentage of overall survival in this subgroup, it is important to complete the neoadjuvant protocol prior to surgery to increase the pRC rate as well as conservative surgery (10 %) it is the primary objective in neoadjuvant.

Soluble ST2 Testing: A Promising Biomarker in the Management of Heart Failure / Teste com ST2 Solúvel: Um Biomarcador Promissor no Tratamento da Insuficiência Cardíaca

Abstract ST2 is a member of the interleukin-1 receptor family biomarker and circulating soluble ST2 concentrations are believed to reflect cardiovascular stress and fibrosis. Recent studies have demonstrated soluble ST2 to be a strong predictor of cardiovascular outcomes in both chronic and acute heart failure. It is a new biomarker that meets all required criteria for a useful biomarker. Of note, it adds information to natriuretic peptides (NPs) and some studies have shown it is even superior in terms of risk stratification. Since the introduction of NPs, this has been the most promising biomarker in the field of heart failure and might be particularly useful as therapy guide.

Resumo ST2 é um biomarcador pertencente à família dos receptores de interleucina-1 e concentrações do ST2 solúvel refletem fibrose e estresse cardiovascular. Estudos recentes demonstram que o ST2 solúvel é um forte preditor de desfechos cardiovasculares em pacientes com insuficiência cardíaca crônica e aguda. Trata-se de um novo biomarcador que preenche critérios necessários para uso na prática clínica. Ele acrescenta informação aos peptídeos natriuréticos (PNs) e em alguns estudos tem sido até superior a estes em relação à estratificação de risco. Desde a introdução dos PNs, este é o biomarcador mais promissor na área de insuficiência cardíaca e pode vir a ser particularmente útil para guiar a terapia.

Avaliação da alfa-glicosidase Cqm1 de Culex quinquefasciatus e o impacto de suas mutações na fisiologia de larvas / Evaluation of a-glucosidase Cqm1 from Culex quinquefasciatus and the impact of its mutations on larvae physiology

Lysinibacillus sphaericus (Lsp) e uma bacteria entomopatogena que produz a toxina Binaria (Bin) com atividade larvicida para culicideos. A sua acao em Culex quinquefasciatus depende da ligacao da toxina Bin a alfa-glicosidase (Aglu) Cqm1, que atua como receptor no epitelio intestinal de larvas. Na colonia R2362, foram caracterizados dois alelos de resistencia ao Lsp: cqm1REC e cqm1REC-2, cujas mutacoes impedem a expressao da Aglu Cqm1. O objetivo deste trabalho foi avaliar a atividade catalitica da Cqm1 e comparar a atividade alfa-glicosidase e o desenvolvimento pre-imaginal de larvas de individuos susceptiveis (S) e resistentes (R) para cada alelo. Para isto, foram avaliados os seguintes parametros: atividade catalitica da Cqm1 recombinante; padrao de transcricao de outras Aglus paralogas a Cqm1; atividade de Aglus nativas em larvas; sobrevivencia de individuos frente a diferentes dietas. A Aglu Cqm1 mostrou atividade enzimatica otima a 37o C, pH 7,5-8,0 e utilizando o substrato sintetico pNalfaG. A atividade alfa-glicosidase total em larvas S e R foi similar, apesar da ausencia de expressao da Cqm1 nas larvas R. A investigacao in silico revelou 18 proteinas paralogas a Cqm1 e, dentre 11 investigadas, nove sao expressas em larvas S e R. A analise quantitativa de tres paralogas demonstrou que duas tem um padrao de transcricao mais elevado em larvas resistentes, sugerindo a existencia de um mecanismo de compensacao de expressao de alfa-glicosidases. O desenvolvimento pre-imaginal de larvas S foi decrescente nas seguintes dietas: racao de gatos, racao de peixes, leite desnatado, extrato de levedura e sacarose. De uma forma global, a taxa de sobrevivencia de larvas R foi inferior a S em todas as dietas testadas. Os dados obtidos mostram que as mutacoes ligadas aos alelos cqm1REC e cqm1REC-2 nao parecem impactar a atividade Aglu nas larvas e que o custo biologico observado poderia estar relacionado a outros genes e vias metabolicas.

Tumor-associated macrophages (TAMs): clinical-pathological parameters in squamous cell carcinomas of the lower lip

Abstract The objective of this study was to analyze the presence of tumor-associated macrophage (TAM) subpopulations M1 and M2 in squamous cell carcinoma of the lower lip (SCCLL) by immunohistochemitry, and to evaluate the possible role of these subtypes in the development of regional lymph node metastasis and their association with clinical and pathological parameters. Forty-two cases of SCCLL were divided into two groups (21 with and 21 without regional lymph node metastasis). The histopathological grade of malignancy was determined and the material was submitted to double staining with anti-CD68/anti-CD163 and anti-CD68/anti-HLA-DR monoclonal antibodies. The results were analyzed statistically using the Wilcoxon signed-rank and Spearman correlation tests. The M1 and M2 subpopulations were observed in all cases studied. No significant difference was observed between the quantities of M1 and M2 TAMs regarding tumor size (p > 0.05). A significantly larger number of M2 compared to M1 TAMs was observed in tumors without regional lymph node metastasis, tumors in early stages, and low-grade tumors (p < 0.05). No significant difference between the numbers of M1 and M2 TAMs was observed in tumors with regional lymph node metastasis, tumors in advanced stages, and high-grade tumors (p > 0.05). There was a positive weak correlation between M1 and M2 TAMs (r = 0.361; p = 0.019). The results suggest a more important role of M2 TAMs in early stages than advanced stages of lip carcinogenesis. The progression of SCCLL does not seem to be related to an imbalance of macrophage polarization in the microenvironment of these tumors.

The Study of Otoacoustic Emissions and the Suppression of Otoacoustic Emissions in Subjects with Tinnitus and Normal Hearing: An Insight to Tinnitus Etiology

Introduction Analysis of the suppression effect is a simple method to evaluate cochlear status and central auditory mechanisms and, more specifically, the medial olivocochlear system. This structure may be involved in the generation of mechanisms that cause tinnitus and in the pathophysiology of tinnitus in patients with tinnitus and normal hearing. Objective To review the literature of the etiology of tinnitus on the lights of otoacoustic emissions in patients with normal hearing. Data Synthesis Individuals with tinnitus and normal hearing have a higher prevalence of alterations in transient-evoked otoacoustic emissions and distortion-product otoacoustic emissions than normal subjects. This fact suggests that dysfunctions of the outer hair cells (OHCs) might be important in the generation of the tinnitus; however, this feature is not always present in those who have the symptoms of tinnitus. Final Comments These findings suggest that OHC dysfunction is not necessary for tinnitus development—that is, there might be mechanisms other than OHC damage in the tinnitus development. On the other hand, OHC dysfunction alone is not sufficient to cause the symptom, because a great many individuals with OHC dysfunction did not complain about tinnitus. .

Síndrome de carcinoma basocelular nevoide con agenesia de cuerpo calloso, mutación en PTCH1 y ausencia de carcinoma basocelular

El síndrome del carcinoma basocelular nevoide (SCBCN) o de Gorlin-Goltz es un raro desorden autosómico dominante con un amplio espectro de manifestaciones clínicas. El signo cardinal es la presencia de múltiples carcinomas basocelulares (CBCs) y su ausencia demora el diagnóstico. Presentamos un adolescente de 14 años con diagnóstico de SCBCN por la presencia de queratoquistes odontogénicos, hiper­telorismo, macrocefalia y agenesia del cuerpo calloso pero sin lesiones cutáneas. La madre, de 43 años, tiene diagnóstico de SCBCN y no presenta CBCs. Para completar el estudio se realizó secuenciación bidireccional y Multiplex Ligation dependent Probe Amplification (MLPA) en sangre periférica para buscar mutaciones en PTCH1, principal gen responsable del síndrome. Se encontró una mutación germinal novel en el paciente y la madre: una duplicación de 25 pb en el exón 10 (c.1375dupl25bp). El análisis bioinformático predijo un corrimiento del marco de lectura y un codón stop prematuro, que produciría una proteína trunca más corta que lo normal. Nuestros resultados sugieren que el estudio clínico y genealógico completo con análisis genético es fundamental para la detección temprana de casos como el presente.

Nevoid Basal Cell Carcinoma Syndrome (NBCCS) or Gorlin-Goltz syndrome is a rare autosomal dominant disorder, mainly due to PTCH1 gene mutations, that comprises a broad spectrum of clinical manifestations. The presence of multiple basal cell carcinomas (BCCs) is a cardinal sign in NBCCS, therefore cases in which BCCs are absent entails a delay in the diagnosis.We present a 14 years old boy with a clinical diagnosis of NBCCS by the presence of odontogenic cysts, hypertelorism, macrocephaly, and corpus callosum agenesia, but with absence of skin lesions. His 43 years old mother has NBCCS diagnosis and no history of BCCs. For a deeper study, PTCH1 mutation screening from peripheral blood samples were performed by both bidirectional sequencing and multiplex ligation dependent probe amplification (MLPA) techniques. The proband and his mother carry 25 pb duplication in exon 10 (c.1375dupl25bp) that causes a reading frameshift with a premature stop codon. Bioinformatics analysis predicted that this mutation results in a truncated protein shorter than normal. Our results suggest that complete clinical and genealogical studies accompanied by genetic analysis are essential in the early detection of the NBCCS cases such the one presented here.

Regeneración axonal posterior a lesiones traumáticas de médula espinal: Papel crítico de galectina-1

Al producirse una lesión de médula espinal (LME), un sinnúmero de proteínas inhibidoras de la regeneración axonal ocupan el sitio de lesión en forma secuencial. La primer proteína en llegar al mismo se conoce como semaforina 3A (Sema3A), siendo además una de las más potentes por su acción de inhibir la regeneración axonal. A nivel mecanístico la unión de esta proteína al complejo-receptor neuronal neuropilin-1 (NRP-1)/PlexinA4 evita que se produzca regeneración axonal. En este trabajo de revisión se discutirá la acción de galectin-1 (Gal-1), una proteína endógena de unión a glicanos, que selectivamente se une al complejo-receptor NRP-1/PlexinA4 de las neuronas lesionadas a través de un mecanismo dependiente de interacciones lectina-glicano, interrumpiendo la señalización generada por Sema3A y permitiendo de esta manera la regeneración axonal y recuperación locomotora luego de producirse la LME. Mientras ambas formas de Gal-1 (monomérica y dimérica) contribuyen a la inactivación de la microglia, solo la forma dimérica de Gal-1 es capaz de unirse al complejo-receptor NRP-1/PlexinA4 y promover regeneración axonal. Por lo tanto, Gal-1 dimérica produce recuperación de las lesiones espinales interfiriendo en la señalización de Sema3A a través de la unión al complejo-receptor NRP-1/PlexinA4, sugiriendo el uso de esta lectina en su forma dimérica para el tratamiento de pacientes con LME.

When spinal cord injury (SCI) occurs, a great number of inhibitors of axonal regeneration consecutively invade the injured site. The first protein to reach the lesion is known as semaphorin 3A (Sema3A), which serves as a powerful inhibitor of axonal regeneration. Mechanistically binding of Sem3A to the neuronal receptor complex neuropilin-1 (NRP-1) / PlexinA4 prevents axonal regeneration. In this special article we review the effects of galectin-1 (Gal-1), an endogenous glycan-binding protein, abundantly present at inflammation and injury sites. Notably, Gal1 adheres selectively to the NRP-1/PlexinA4 receptor complex in injured neurons through glycan-dependent mechanisms, interrupts the Sema3A pathway and contributes to axonal regeneration and locomotor recovery after SCI. While both the monomeric and dimeric forms of Gal-1 contribute to ’switch-off’ classically-activated microglia, only dimeric Gal-1 binds to the NRP-1/PlexinA4 receptor complex and promotes axonal regeneration. Thus, dimeric Gal-1 promotes functional recovery of spinal lesions by interfering with inhibitory signals triggered by Sema3A adhering to the NRP-1/PlexinA4 complex, supporting the use of dimeric Gal-1 for the treatment of SCI patients.

The Duffy binding protein as a key target for a Plasmodium vivax vaccine: lessons from the Brazilian Amazon

Plasmodium vivax infects human erythrocytes through a major pathway that requires interaction between an apical parasite protein, the Duffy binding protein (PvDBP) and its receptor on reticulocytes, the Duffy antigen/receptor for chemokines (DARC). The importance of the interaction between PvDBP (region II, DBPII) and DARC to P. vivax infection has motivated our malaria research group at Oswaldo Cruz Foundation (state of Minas Gerais, Brazil) to conduct a number of immunoepidemiological studies to characterise the naturally acquired immunity to PvDBP in populations living in the Amazon rainforest. In this review, we provide an update on the immunology and molecular epidemiology of PvDBP in the Brazilian Amazon - an area of markedly unstable malaria transmission - and compare it with data from other parts of Latin America, as well as Asia and Oceania.

FASN expression, angiogenesis and lymphangiogenesis in central and peripheral giant cell lesions

Central giant cell lesion (CGCL) and peripheral giant cell lesion (PGCL) are non-neoplastic proliferative processes of the jaws. PGCL is a reactive process induced by irritant local factors and CGCL is an intra-osseous lesion of unknown etiology. Both lesions exhibit similar histologic features showing abundant mononuclear cells, admixed with a large number of multinucleated giant cells and a rich vascularized stroma with extravasated erythrocytes, hemosiderin deposition, and blood-filled pools. Recent studies have linked fatty acid synthase (FASN) with angiogenesis. Objective: To evaluate angiogenesis and lymphangiogenesis and their relationship with FASN expression in CGCL and PGCL. Material and Methods: Thirteen CGCL and 14 PGCL of the jaws were selected for immunoexpression of FASN; CD34 and CD105 (to assess blood microvessel density [MVD] and microvessel area [MVA]); and D2-40 (to assess lymphatic MVD and MVA). Results: Within PGCL and CGCL, MVD-CD34 was signifcantly higher than MVD-CD10S, followed by MVD-D2-40. Moreover, a signifcantly higher number of FASN-positive multinucleated giant cells than mononuclear cells were observed. Between PGCL and CGCL, only MVD-CD34 and all MVA were signifcantly higher in PGCL. Positive correlation between MVA-CD10S with FASNpositive mononuclear cells in both lesions was observed. Conclusions: Our results show both lesions exhibiting similar levels of FASN expression and neoangiogenesis, suggesting constitutive processes that regulate tissue maintenance. .

Modo de ação do biolarvicida Lysinibacillus sphaericus: identificação do epitopo da toxina Binária no receptor Cqm1 e base molecular da seletividade / Mode of action of biolarvicide Lysinibacillus sphaericus: identification of the epitope of the CQM1 Binary toxin receptor and molecular basis of selectivity

A toxina Binária (Bin) é o principal fator tóxico da bactéria entomopatógena Lysinibacillus sphaericus e sua ação em Culex quinquefasciatus depende da ligação com receptores no intestino das larvas. Os receptores são as a-glicosidases Cqm1, localizadas no epitélio, ligadas por uma âncora de glicosil-fosfatidilinositol. Larvas de Aedes aegypti são refratárias à toxina, pois, não apresentam receptores funcionais, apesar de apresentarem um gene que codifica a proteína Aam1, com alta similaridade à Cqm1. Devido às lacunas a respeito do espectro de ação da toxina Bin, o objetivo deste estudo foi identificar epitopos de ligação da toxina no receptor Cqm1 e determinar a base molecular da sua ação para estas espécies de vetores. Os resultados obtidos a partir da análise comparativa das proteínas Cqm1 e Aam1 levaram à identificação de um epitopo da toxina Bin no receptor Cqm1, situado uma alça na região N-terminal S129-A312. Este epitopo é composto pelos aminoácidos 155PATGGG160, não conservados em Aam1 (158AETGKL163), e os resíduos 159GG160 são críticos para a ligação com a Bin...

The Bin toxin is the main toxic factor of the bacterium Lysinibacillus sphaericuswhose action in Culex quinquefasciatuslarvae depends on its binding to the midgut epithelial receptors...