Differential Effect of ITE on the Aryl Hydrocarbon Receptor Signaling in Breast Cancer Tissue: A Histopathological Study / Efecto Diferencial de ITE en la Señalización del Receptor de Hidrocarburo de Arilo en Tejido de Cáncer de Mama: Un Estudio Histopatológico

SUMMARY: Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is highly expressed in various types of cancers including breast cancer. However, the role of AhR with its endogenous ligand 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) on the progression of breast cancer remains poorly understood. We aimed to investigate cell proliferation and migration states in breast cancer after activating AhR with the endogenous ligand ITE. Breast cancer tissue was evaluated by cell lines, immunohistochemistry, reverse transcription-polymerase chain reaction, cell proliferation, flow cytometry, migration assays and western blot techniques. We found that AhR was widely expressed in breast cancer tissues and metastasis lymph node tissues, but not in normal tissues. The expression AhR was independent between the age, grades and TNM classifications for breast cancer tissues. ITE treatment significantly induced the activation of AhR in a time-dependent manner in both MCF-7 and T47D breast cancer cell lines. Meanwhile, ITE did not affect the cell migration but significantly suppressed the cell proliferation in estrogen receptor positive (ER+) MCF-7 andT47D cells, which probably attribute to the induction of cell cycle arrest in G1 phase and shortened S phase. Further mechanism study showed that ERK1/2 and AKT signaling were required for the activation of AhR in MCF-7 cells. These data suggest that AhR is a potential new target for treating patients with breast cancer. ITE may be more potentially used for therapeutic intervention for breast cancer with the kind of ER(+).

El receptor de hidrocarburo de arilo (AhR) es un factor de transcripción activado por ligando que se expresa en gran medida en varios tipos de cáncer, incluido el cáncer de mama. Sin embargo, el papel de AhR con su ligando endógeno 2- (1'H-indol-3'-carbonil)-tiazol-4-ácido carboxílico metil éster (ITE) en la progresión del cáncer de mama sigue siendo poco conocido. Nuestro objetivo fue investigar la proliferación celular y los estados de migración en el cáncer de mama después de activar AhR con el ligando endógeno ITE. El tejido de cáncer de mama se evaluó mediante líneas celulares, inmunohistoquímica, reacción en cadena de la polimerasa con transcriptasa inversa, proliferación celular, citometría de flujo, ensayos de migración y técnicas de transferencia Western. Descubrimos que AhR se expresó ampliamente en tejidos de cáncer de mama y en linfonodos con metástasis, pero no en tejidos normales. La expresión AhR fue independiente entre la edad, grados y clasificaciones TNM para tejidos de cáncer de mama. El tratamiento con ITE indujo significativamente la activación de AhR de manera dependiente del tiempo en las líneas celulares de cancer de mama MCF-7 y T47D. Mientras tanto, ITE no afectó la migración celular, pero suprimió significativamente la proliferación celular en células MCF-7 y T47D con receptor de estrógeno positivo (ER+), lo que probablemente se atribuye a la inducción de la detención del ciclo celular en la fase G1 y la fase S acortada. Un estudio adicional del mecanismo mostró que las señales de ERK1/2 y AKT eran necesarias para la activación de AhR en las células MCF-7. Estos datos sugieren que AhR es un nuevo objetivo potencial para el tratamiento de pacientes con cáncer de mama. ITE puede ser utilizado más potencialmente en la intervención terapéutica para el cáncer de mama con el tipo de ER (+).

Alterações osteometabólicas em pacientes em tratamento antineoplásico: revisão de escopo / Osteometabolic changes in patients under antineoplastic treatment: scoping review

Objetivo: sintetizar as principais evidências acerca das alterações osteometabólicas presentes nos pacientes em tratamento antineoplásico. Métodos: trata-se de uma revisão de escopo, seguindo a metodologia do Instituto Joanna Briggs, nas bases de dados PubMed/MedLine, Cochrane Library, LILACS, The British Library e Google Scholar. A revisão está protocolada no Open Science Framework. Resultados: muitos antineoplásicos possuem efeito na arquitetura óssea, reduzindo sua densidade, tais como moduladores seletivos de receptores de estrogênio, inibidores da aromatase, terapia de privação androgênica, e glicocorticoides. Para evitar tais desfechos, o tratamento e prevenção podem ser realizados pela suplementação de cálcio e vitamina D, exercícios físicos, uso de bifosfonatos, denosumab, e moduladores seletivos do receptor de estrogênio. Conclusão: pessoas com maior risco de desenvolver câncer também possuem maior risco de osteopenia e osteoporose, quando processo já estabelecido e em tratamento antineoplásico, devido ao compartilhamento de fatores de risco. Torna-se evidente a necessidade da densitometria óssea nos pacientes em tratamento contra o câncer para de prevenção e promoção de saúde óssea nesses pacientes, além de mais pesquisas com alto nivel de evidência para subsidiar tal uso.

Objective: To summarize the main evidence regarding osteometabolic changes in patients undergoing antineoplastic treatment. Methods: This is a scoping review, following the methodology of the Joanna Briggs Institute, using PubMed/MedLine, Cochrane Library, LILACS, The British Library, and Google Scholar. This review is registered in the Open Science Framework. Results: Many antineoplastics affect bone architecture by reducing its density, such as selective estrogen receptor modulators, aromatase inhibitors, androgen deprivation therapy, and glucocorticoids. To avoid such outcomes, treatment and prevention can be achieved by calcium and vitamin D supplementation, physical exercise, use of bisphosphonates, denosumab, and selective estrogen receptor modulators. Conclusion: people at a higher risk of developing cancer also have a higher risk of osteopenia and osteoporosis when the process is already established and undergoing antineoplastic treatment because of the grouping of risk factors. The need for bone densitometry in patients undergoing cancer treatment to prevent and promote bone health in these patients is evident, in addition to more research with a high level of evidence to support such use.

Immunofluorescence Analysis of Estrogen and Progesterone Receptors and Ki-67 Nuclear Protein in Canine Uteri Treated with Medroxyprogesterone Acetate During Anestrus / Análisis de Inmunofluorescencia de Receptores de Estrógeno y Progesterona y Proteína Nuclear Ki-67 en Úteros Caninos Tratados con Acetato de Medroxiprogesterona Durante el Anestr

SUMMARY: Estradiol and progesterone receptors play an essential role in the changes occurring in the uterus during the estrus cycle in dogs (Canis lupus familiaris). In order to investigate the potential effect of progestational agent medroxyprogesterone acetate (MPA) when is used during anestrus on the expression of estradiol receptors [ER], progesterone receptors [PR] and nuclear protein Ki67, we evaluated uterine tissue immunohistochemically. Uteri were grouped as nulliparous (control, n=11), multiparous (n=11) and treated with MPA (n=11; nulliparous with two treatments; 5mg/kg; i.m.). The amount and location of PR, ER and Ki67 were studied on the epithelial surface, apical and basal regions of the endometrium and myometrium using immunohistochemical techniques with a spectral confocal microscope and analyzed by ANOVA. Differences in ER were observed between the multiparous and MPA-treated groups in the apical region of the endometrium (p=0.0022). Differences in cell proliferation were detected between the nulliparous and multiparous groups (p=0.0037) and nulliparous and MPA-treated groups (p=0.0003) in the basal region of the endometrium. In conclusion, two doses of MPA (5mg/kg; i.m.) do not have a significant effect on the expression of ER and PR; however, they inhibit cell proliferation in the basal region of the endometrium, which includes the stroma, subepithelial cell layer, compact layer, and spongy layer. The clinical and long-term effect of this treatment should be evaluated in subsequent studies.

Los receptores de estradiol y progesterona juegan un rol fundamental en los cambios que se producen en el útero durante el ciclo estral de las perras (Canis lupus familiaris). El objetivo de este estudio fue evaluar las expresiones de ER-a y PR en el útero y la proliferación de células endometriales detectando la expresión nuclear de la proteína Ki67 en perras expuestas a la progestina sintética MPA y compararlas con perras nulíparas y multíparas expuestas a progesterona luteal. Úteros fueron agrupados como nulíparas (control, n=11), multíparas (n=11) y tratadas con MPA (n=11; nulíparas con dos tratamientos; 5 mg/kg; i.m.). La expresión de PR, ER-a y Ki67 fue evaluada en la regiones apicales y basales del endometrio y miometrio con un microscopio confocal espectral. Se observó diferencias en ER-a entre los grupos multíparas y tratados con MPA en la región apical del endometrio (p=0,0022). Se detectaron diferencias en la proliferación celular entre los grupos de nulíparas y multíparas (p=0,0037) y los grupos de nulíparas y tratados con MPA (p=0,0003) en la región basal del endometrio. En conclusión, dos dosis de MPA (5mg/kg; i.m.) no tienen un efecto significativo sobre la expresión de ER y PR; sin embargo, inhiben la proliferación celular en la región basal del endometrio, el cual incluye a estroma, capa de células subepiteliales, estratos compacto y esponjoso. El efecto clínico a largo plazo de este tratamiento debe ser evaluado en estudios posteriores.

Effects of bisphenol A and bisphenol analogs on the nervous system / 中华医学杂志(英文版)

Estrogen impacts neural development; meanwhile, it has a protective effect on the brain. Bisphenols, primarily bisphenol A (BPA), can exert estrogen-like or estrogen-interfering effects by binding with estrogen receptors. Extensive studies have suggested that neurobehavioral problems, such as anxiety and depression, can be caused by exposure to BPA during neural development. Increasing attention has been paid to the effects on learning and memory of BPA exposure at different developmental stages and in adulthood. Further research is required to elucidate whether BPA increases the risk of neurodegenerative diseases and the underlying mechanisms, as well as to assess whether BPA analogs, such as bisphenol S and bisphenol F, influence the nervous system.

Endometrial Progesterone and Estrogen Receptors in Relation to Hormonal Levels in Women with Unexplained Recurrent Miscarriage / Receptores endometriais de progesterona e estrogênio em relação aos níveis hormonais em mulheres com aborto recorrente inexplicável

Abstract Objective Recurrent miscarriage has been linked to hormonal disturbance due to dysregulation of its receptors rather than to the availability of the hormone. We aimed to investigate endometrial expression of progesterone and estrogen receptors in relation to serum and endometrial hormonal levels in unexplained recurrent miscarriage. Methods The present case control study included 20 cases with unexplained recurrent miscarriage and 20 parous women as controls. Ovulation was confirmed using an ovulation kit and 10 to 12 days after detecting the urinary luteinizing hormone surge, all women were subjected to a blood sample and to an endometrial biopsy. Progesterone and estrogen levels were measured in serum and in endometrial tissue and receptor concentrations were in the endometrial sample. Results Women with recurrent miscarriage showed significantly lower concentration of receptors in both the cytoplasm and the nucleus of endometrial tissue compared with controls. The nuclear/cytoplasm ratio of progesterone receptor was significantly higher in cases compared with controls, implicating that recurrent miscarriage is probably linked to nongenomic activity of the hormone; this was also significant for estrogen receptor. Serum progesterone and estrogen hormonal levels were comparable between groups while both hormones were significantly reduced in the endometrium of recurrent miscarriage cases. Receptors significantly correlated with endometrial hormonal level but not to serum level. Conclusion Recurrent miscarriage might be linked to reduced endometrial progesterone and estrogen receptors and appears to be more related to nongenomic activity of progesterone. Endometrial receptors expression correlates to tissue hormonal level rather than to serum hormonal level.

Searching for the emotional roots of breast cancer: A cross-disciplinary analysis integrating psychology, Chinese medicine, and oncology biomarkers / 中西医结合学报

OBJECTIVE@#We employed a multidisciplinary approach incorporating theoretical ideas, clinical experience, psychology, physiology, traditional Chinese medicine (CM), modern practice of CM, and oncology to explore the effect of patients' repression of negative emotions and traumatic events on breast cancer (BC) pathogenesis.@*METHODS@#BC female patients, older than 18 years of age, with available pathology reports who were treated at Rabin Medical Center were recruited. All participants completed questionnaires regarding medical history, behavioral tendencies, negative emotions, trauma, symptoms, and pathology (from a CM perspective). Data on tumor characteristics were collected from the pathology reports. The associations were examined using hierarchical binary logistic regressions.@*RESULTS@#A total of 155 BC patients were enrolled. The median age was 52 years, with a range of 26-79; 95% were mothers; 28% had estrogen receptor (ER)-negative BC, 52% had progesterone receptor (PR)-negative BC, 48% had human epidermal growth factor receptor 2-negative BC, and antigen Ki-67 ≥ 20% was reported for 52% of tumors. Statistically significant associations were found between the emotional markers (sense of motherhood failure, and lack of self-fulfillment), avoidance behavior, and physical symptoms that are related to emotional repression based on CM. Significant associations were also found between variables associated with physical symptoms of emotional repression, which involves the production and accumulation of non-substantial phlegm (i.e., "high-lipid Qi-like microscopic phlegm"), avoidance behavior which unconsciously uses "high-lipid Qi-like microscopic phlegm" in order to achieve emotional repression, and tumor parameters including tumor grade, PR status, and Ki-67. Patients with higher levels of "high-lipid Qi-like microscopic phlegm" were more likely to have tumors with worse prognosis (PR-negative, higher grade, and higher Ki-67).@*CONCLUSION@#We demonstrated a relationship between emotional parameters, behavioral tendencies, CM parameters, and oncologic parameters in BC. Additional research is warranted to explore these associations and their relevance to clinical practice.

Intervention of ERRα Expression on Apoptosis Induction of Multiple Myeloma MM.1S Cells Cultured in Vitro / 中国实验血液学杂志

OBJECTIVE@#To investigate the effect of two different approaches ERRα strategy on the apoptosis in multiple myeloma cell line MM.1S.@*METHODS@#For the one strategy, shRNA was mediated by lentivirus. Stable cell clones were established by transfecting the lentivirus into MM.1S cells and screened by puromycin. For the other strategy, XCT790, a specific reverse agonist of ERRα, was used to treat MM.1S cells. The apoptosis of the cells was analyzed by flow cytometry after ERRα was down-regulated. Western blot assay was used to detect the apoptosis of related proteins.@*RESULTS@#The knocked down ERRα was achieved, lentivirus with shERRα were successfully infected into MM.1S and ERRα was reduced significantly. Knockdown of ERRα could induce MM.1S cell apoptosis dramatically. Meanwhile, the expression of cleaved PARP (a kind of apoptosis related markers) was significantly increased following depletion of ERRα in MM.1S cells. XCT790 could significantly down-regulate the expression of ERRα protein in MM.1S cells, which was consistent with the effect caused by shRNA.@*CONCLUSION@#Interference the expression of ERRα by shRNA or XCT790 can induce apparent apoptosis in MM.1S cells, which indicating that ERRα is crucial for the survival of myeloma cells.

Valor pronóstico de la baja expresión del receptor de estrógeno en pacientes con cáncer de mama LUMINAL HER2 negativo / Prognostic value of low estrogen receptor expression in patients with luminal HER2-negative breast cancer

Introducción: El subtipo luminal de cáncer de mama es sensible a la terapia antiestrógenica y muestra un mejor pronóstico que el del cáncer de mama con receptor del factor de crecimiento epidérmico humano 2 enriquecido (HER2) o triple negativo. Sin embargo, el cáncer de mama tipo luminal es heterogéneo y puede tener características clínicas agresivas. Investigamos las implicaciones clínicas y pronósticas de la baja expresión del receptor de estrógeno en un grupo de carcinomas luminales HER2 negativos. Material y método: Recolectamos los datos de un grupo de 367 cánceres de mama luminales HER2 negativo que eran receptor de estrógeno (RE) positivos y receptor de progesterona (RP) positivos o negativos y los dividimos en RE+ alto (RE) y RE+ bajo (REB). Se definió REB de acuerdo a la úl- tima actualización ASCO /CAP de las recomendaciones del testeo de de RH en cáncer de mama como aquellos con expresión entre 1 y 10%. Analizamos los datos clínico-patológicos y la supervivencia según los grupos de RE y REB. Resultados: Edad media 63,9+12.8 años. Tamaño tumoral: 1,9 +0.9 cm. Se realizó Mastectomía radical modificada en 61% de los pacientes. Tipo histológico más frecuente: Ductal Infiltrante en 89,5% de los casos. Hallazgos que concuerdan con publicaciones de otros centros. Discusión: Los tumores REB resultaron en 1,6%. No hubo diferencias estadísticas en el estadio TNM y tipo histológico. Sin embargo, el grupo REB se asoció con menor edad (47 vs 57 años), tipo luminal B, mayor grado histológico y Ki 67 alto (>30%). Si bien las diferencias en supervivencia global (SG) no fueron significativas (p=0,279), observamos que a partir de los 60 meses de seguimiento la SG fue menor en el grupo REB que en el grupo RE. Conclusiones: La baja expresión del RE se asoció peor pronóstico. Podríamos considerar la baja expresión del RE como marcador pronóstico en el subtipo luminal HER2 negativo de cáncer de mama. Debido a la baja incidencia de casos REB consideramos necesario estudios adicionales con mayor número de pacientes que podrían revelar su papel negativo en el cáncer de mama.

Introduction: The luminal subtype of breast cancer is sensitive to antiestrogenic therapy and shows a better prognosis than human epidermal grow- th factor receptor 2 (HER2) enriched or triple negative breast cancer. However, luminal type breast cancer is heterogeneous and can have aggressive clinical features. We investigated the clinical and prognostic implications of low estrogen receptor expression in a group of HER2-negative luminal carcinomas. Material and method: We collected data from a group of 367 HER2 negative luminal breast cancers that were estrogen receptor (ER) positive and progesterone receptor (PR) positive or negative and divided them into ER + high (ER) and ER + low (ERL). ERL was defined when RE expression was < 10%. We analyzed the clinical-pathological data and survival accor- ding to the ER and ERL groups. Results: ERL tumors resulted in 1.6%. There were no statistical differences in TNM stage and histological type. However, the ERL group was as- sociated with younger age (47 vs 57 years), luminal type B, higher histological grade, and high Ki 67 (> 30% ). Although the differences in overall survival (OS) were not significant (p = 0.279), we observed that after 60 months of follow-up the OS was lower in the ERL group than in the ER group. Conclusions: Low ER expression was associated with a worse prognosis. We could consider low ER expression as a prognostic marker in the HER2-ne- gative luminal subtype of breast cancer. Due to the low incidence of ERL cases, we consider necessary additional studies with a larger number of patients that could reveal its negative role in breast cancer.

Estrogen receptor mRNA determined by Quantitative Real-Time PCR in the nasal mucosa of women taking oral contraceptives / Receptor ARNm de estrógeno determinado por PCR Cuantitativa en Tiempo Real en la mucosa nasal de mujeres tratadas con anticonceptivos orales

SUMMARY: Estrogen receptors (ER) have been identified in human nasal mucosa, but its physiologic and pathologic impacts are not totally established. ER have been demonstrated in nasal mucosa by several authors, mainly by immunohistochemical method in nasal mucosa samples surgically removed. The present study aimed to quantify ERα and ERβ mRNA concentration by using an absolute quantitative real-time PCR in cells from nasal mucosa smear of women under oral contraceptive therapy. Nasal epithelium smear samples were collected from 110 patients divided in two groups: 55 women who present regular menstrual cycle without using contraceptives and 55 women who present regular menstrual cycle and have been using oral contraceptives for more than 3 months. All the patients answered a rhinitis symptoms questionnaire. The current study showed the potential usefulness of nasal turbinate mucosa cell sourcing, collected through swab, for extracting useful RNA for gene expression. We have identified the predominant expression of ERα isoform in a ratio 10-15 times higher compared to ERβ isoform. There is a tendency for positive correlation between the ERb isoform and the rhinitis severity score.

RESUMEN: Se han identificado receptores de estrógeno (RE) en la mucosa nasal humana, sin embargo sus impactos fisiológicos y patológicos aún no están totalmente establecidos. Varios autores han demostrado RE en la mucosa nasal, principalmente por método inmunohistoquímico en muestras obtenidas quirúrgicamente. El presente estudio tuvo como objetivo cuantificar la concentración de ARNm de REa y REb mediante el uso de una PCR cuantitativa absoluta en tiempo real en células de frotis de mucosa nasal de mujeres bajo terapia anticonceptiva oral. Se recolectaron muestras de frotis de epitelio nasal de 110 pacientes divididas en dos grupos: 55 mujeres que presentan ciclo menstrual regular sin uso de anticonceptivos y 55 mujeres que presentan ciclo menstrual regular con uso de anticonceptivos orales durante más de 3 meses. Todas las pacientes respondieron un cuestionario de síntomas de rinitis. El estudio actual mostró la utilidad de la obtención de células de la mucosa de la concha nasal, recolectadas a través de un hisopo, para extraer ARN para la expresión génica. Hemos identificado la expresión predominante de la isoforma REμ en una proporción de 10 a 15 veces mayor en comparación con la isoforma REß. Hemos identificado la expresión predominante de la isoforma REα en una proporción de 10 a 15 veces mayor en comparación con la isoforma REß. Existe una tendencia a una correlación positiva entre la isoforma REß y la puntuación de gravedad de la rinitis.

Cáncer de mama localmente avanzado. Neoadyuvancia: indicaciones y seguimiento / Locally advanced breast carcinoma. Neoadjuvant treatment: indications and follow up

El cáncer de mama localmente avanzado (CMLA) se manifiesta con grandes tumores (T3-4) y/o gran carga adenopática (N 1-2-3), sin metástasis a distancia e incluye estadios clínicos: II b, III a, III b y III c. La quimioterapia neoadyuvante (QTNA) es el tratamiento inicial para gran parte de las pacientes con CMLA y está indicada en pacientes con cáncer de mama operable e inoperable. Este tratamiento presenta algunas ventajas como la reducción del tamaño del tumor primario (downstaging) y de ganglios positivos, permitiendo así más cirugías conservadoras, y la medición directa de la sensibilidad de las células tumorales. Un rol similar cumple la terapia endocrina neoadyuvante en tumores con receptores de estrógeno (RE) y receptores de progesterona (RP) positivos, al demostrar beneficios en reducción del volumen tumoral. Los anticuerpos monoclonales anti Her2 asociados a la QTNA aumentan la efectividad de esta última. La respuesta del CMLA a la neoadyuvancia se evalúa con la clínica y el estudio histológico de la pieza quirúrgica, con esta última, se monitorea enfermedad residual a través de la respuesta patológica completa (RCp) que es un importante factor pronóstico de la sobrevida libre de enfermedad (SLE) como de la sobrevida global (SG). El carcinoma mamario inflamatorio (CMI) posee distintas características clínicas, epidemiológicas y biológicas donde el tratamiento de inicio es la QTNA.

Immunohistochemical and clinicopathologic features of estrogen receptor-negative, progesterone receptor-positive, HER-2 negative breast carcinomas

SUMMARY OBJECTIVE: Currently, there is an ongoing debate whether progesterone receptor positive and estrogen receptor negative breast carcinomas represent a true distinct subtype of tumor or a mere immunohistochemical artifact. In this study, we conducted an immunohistochemistry panel with the antibodies TFF1, EGFR, and CK5 to reclassify this phenotype in a luminal or basal-like subtype. METHODS: Tumors estrogen receptor -/progesterone receptor +, Her-2 - from a large population of breast cancer patients were selected to be studied. Immunohistochemistry with the antibodies TFF1, EGFR, and CK5 was performed. Tumors showing positivity for TFF1, regardless of EGFR and CK5 results, were classified as luminal-like carcinomas. Those lesions that were negative for TFF1, but were positive for EGFR and/or CK5, were classified as basal-like triple-negative carcinomas. When the three markers were negative, tumors were classified as undetermined. Clinical pathologic characteristics of patients and tumor recurrence were evaluated. RESULTS: Out of 1188 breast carcinomas investigated, 30 cases (2.5%) presented the estrogen receptor -/progesterone receptor +/HER2- phenotype. Of them, 27 tumors (90%) were classified as basal-like triple-negative carcinomas, one as luminal-like (3.3%), and two as undetermined tumors (6.7%). The mean follow-up for the study group was 27.7 (2.7 to 50) months. Out of the 26 patients, 6 had cancer recurrence: 2 local and 4 systemic recurrences. The average time for recurrence was 17 (8 to 38) months. CONCLUSION: Estrogen receptor -/progesterone receptor +/tumors exhibit aggressive behavior, similar to triple-negative tumors. An appropriate categorization of these tumors should be made to improve their therapeutic management.

Comparação entre expressão de receptores hormonais e de HER-2 entre células tumorais circulantes e metástases de câncer de mama / Comparison of hormonal receptor expression and HER2 status in circulating tumor cells and breast cancer metastases

Introdução: O câncer de mama é a neoplasia mais comum em mulheres. A maioria deles é diagnosticada em estágios iniciais, quando o tratamento visa a cura. Mas apesar dos avanços no tratamento, metástases à distância podem ocorrer. A biópsia das lesões metastáticas é recomendada para confirmar o status do receptor de estrogênio (RE), receptor de progesterona (RP) e receptor do fator de crescimento epidérmico humano 2 (HER2), por ocorrerem discrepâncias nesses padrões entre tumores primários e metástases em até 40% dos casos. As células tumorais circulantes (CTCs) estão relacionadas às evoluções clínicas do câncer de mama e podem potencialmente desempenhar um papel substituto aos procedimentos invasivos de rebiópsia de metástase. A tecnologia ISET® (Isolation by SizE of Tumor Cells, Rarecells-Diagnostics, Paris, França) não é usualmente empregada para detectar CTCs em pacientes com câncer de mama, embora seja reconhecida como uma ferramenta útil em alguns outros tumores. Existem dados emergentes de que a caracterização da expressão proteica das CTC pode refinar seu valor prognóstico. Sabe-se que o fator de transformação de crescimento (TGF-ß) desempenha um papel na progressão e invasividade do câncer de mama. Objetivos: Comparar a expressão de RE, RP e HER2 em tumores primários, CTCs, metástases e avaliar a expressão do receptor TGF-ß tipo 1 (TGF-ß RI) em CTCs como fator prognóstico para sobrevida global. Metodologia: Estudo realizado no A.C.Camargo Cancer Center, Brasil. As amostras de sangue foram coletadas antes da biópsia guiada por tomografia computadorizada de lesões metastáticas suspeitas e processadas pela metodologia ISET®. Os níveis de expressão proteica das CTCs foram comparados aos de tumores primários e metástases e correlacionados aos resultados clínicos. Todos os dados clínicopatológicos foram obtidos dos prontuários médicos. Resultados: Dos 39 pacientes inicialmente incluídos, 27 tiveram tanto a biópsia de metástases quanto a coleta de sangue e foram considerados para análise. As taxas de concordância para a expressão de RE, RP e HER2 entre tumores primários e metástases foram altas. Não foi observada nenhuma perda de expressão de HER2 nas metástases e os tumores triplo negativos mantiveram o mesmo padrão em todas as metástases (p <0,0001). Quando as metástases e CTCs foram classificadas como triplo negativo (TN) ou não ­ TN, as CTCs determinaram alta especificidade (93%), acurácia (84,2%) e valor preditivo negativo (88%). A sobrevida global mediana de pacientes sem expressão de TGF-ß RI em CTCs foi de 42,6 x 20,8 meses para os positivos, clinicamente relevante, porém sem significância estatística (p> 0,05). Conclusões: No câncer de mama, o papel das CTCs detectadas pelo ISET® ainda não está estabelecido. Com este estudo, sugerimos que esta metodologia possa ser útil para avaliar metástases em casos de tumores não TN, assim como a expressão de TGF-ß RI em CTCs, o que pode impactar a sobrevida. Devido à limitação da amostra, estudos futuros devem se concentrar em subtipos específicos de câncer de mama, ampliando a coorte.

Introduction: Breast cancer (BC) is the most common neoplasm in women. Most of BC are diagnosed in early stages, when treatment aims cure. Despite advances in BC treatment, distant metastases may develop. Biopsy of metastatic lesions is recommended to confirm estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status, due to discrepancies in these patterns between primary tumors/metastasis in up to 40% of cases. Circulating Tumor Cells (CTCs) are related to breast cancer outcomes and could potentially play a role surrogating invasive procedures of metastasis rebiopsy. ISET® (Isolation by SizE of Tumor Cells, Rarecells-Diagnostics, Paris, France) technology is not currently employed to detect CTCs in breast cancer patients, although recognized as a useful tool in some other tumors. There are emerging data that characterization of CTC protein expression can refine its prognostic value. Transforming growth factor (TGF)-ß play a role in progression/invasiveness of BC. Objectives: To compare ER, PR and HER2 expression in primary tumors, CTCs, metastases and to evaluate TGF-ß type 1 receptor (TGF- ß RI) expression in CTCs as prognostic factor for overall survival. Methods: Study conducted at the A.C.Camargo Cancer Center, Brazil. Blood samples were processed in ISET® before computed tomography­guided biopsy of suspected metastatic lesions. Protein expression levels in CTCs were compared to those in primary tumors/metastases and correlated to clinical outcomes. All clinicopathological data were obtained from medical records. Results: From the 39 patients initially included, 27 had both biopsy of metastases and blood collection and were considered for analysis. Concordance rates for ER, PR and HER2 expression between primary tumors/metastases were high. No loss of HER2 expression at any metastasis site and retention of the same pattern in all triplenegative (TN) tumors (p <0.0001) were observed. When metastases/CTCs were classified as TN/non­TN, CTCs showed high specificity (93%), accuracy (84.2%) and negative predictive value (88%). The median overall survival of patients with no TGF-ß RI expression in CTCs was 42.6 x 20.8 months for positive ones, clinically relevant but not statistically significant (p>0.05). Conclusions: In BC, the role of CTCs detected by ISET® is not yet established. Here, we could suggest that this methodology may be useful to evaluate metastasis in non-TN cases as also TGF-ß RI expression in CTCs, which may impact survival. Due to sample limitation, future studies must focus on specific subtypes of BC, expanding the cohort.

Regorafenib Suppresses Migration of and Induces Cell Cycle Arrest and Apoptosis in MCF-7 Cells

This study investigated the mechanism underlying the suppression of estrogen receptor-positive MCF-7 cell growth by regorafenib. MCF-7 cells were treated with regorafenib, and the effect of regorafenib on multiple cancer-associated pathways was evaluated. Although regorafenib effectively inhibited the proliferation of MCF-7 cells, it had no effect on the proliferation of the normal breast epithelial cell line MCF10A. Regorafenib suppressed MCF-7 cell migration, probably by regulating the homeostatic expression of matrix metalloproteinases and the tissue inhibitor of MMPs. Furthermore, it upregulated p21 expression, downregulated cyclin B1 and cyclin D1 expresssions, and caused cell cycle arrest. In addition, regorafenib induced apoptosis in MCF-7 cells by reducing Mcl-1 expression and activating caspase signaling. These results demonstrate that regorafenib has the potential to be an effective drug for treating breast cancer

Prognostic value of the 21-gene recurrence score in ER-positive, HER2-negative, node-positive breast cancer was similar in node-negative diseases: a single-center study of 800 patients / 医学前沿

Multi-gene assays have emerged as crucial tools for risk stratification in early-stage breast cancer. This study aimed to evaluate the prognostic significance of the 21-gene recurrence score (RS) in Chinese patients with pN0-1, estrogen receptor-positive (ER

Total flavonoids of Drynariae Rhizoma regulates ER-p38 MAPK signaling pathway to improve scopolamine-induced learning and memory impairments in model mice / 中国中药杂志

This study intended to explore the effect and mechanism of total flavonoids of Drynariae Rhizoma in improving scopola-mine-induced learning and memory impairments in model mice. Ninety four-month-old Kunming(KM) mice were randomly divided into six groups. The ones in the model group and blank group were treated with intragastric administration of normal saline, while those in the medication groups separately received the total flavonoids of Drynariae Rhizoma, Kangnaoshuai Capsules, donepezil, as well as total flavonoids of Rhizoma Drynariae plus estrogen receptor(ER) blocker by gavage. The mouse model of learning and memory impairments was established via intraperitoneal injection of scopolamine. Following the measurement of mouse learning and memory abilities in Morris water maze test, the hippocampal ERβ expression was detected by immunohistochemistry, and the expression levels of ERβ and phosphorylated p38(p-p38) in the hippocampus and B-cell lymphoma 2(Bcl-2), Bcl-2-associated death promoter(Bad), and cysteinyl aspartate-specific protease-3(caspase-3) in the apoptotic system were assayed by Western blot. The contents of malondia-ldehyde(MDA), superoxide dismutase(SOD), and nitric oxide(NO) in the hippocampus were then determined using corresponding kits. Compared with the control group, the model group exhibited significantly prolonged incubation period, reduced frequency of cros-sing the platform, shortened residence time in the target quadrant, lowered ERβ, Bcl-2 and SOD activity in the hippocampus, and increased p-p38/p38, Bad, caspase-3, MDA, and NO. Compared with the model group, the total flavonoids of Rhizoma Drynariae increased the expression of ERβ and SOD in the hippocampus, down-regulated the expression of neuronal pro-apoptotic proteins, up-re-gulated the expression of anti-apoptotic proteins, and reduced p-p38/p38, MDA, and NO. The effects of total flavonoids of Drynariae Rhizoma on the above indexes were reversed by ER blocker. It has been proved that the total flavonoids of Drynariae Rhizoma obviously alleviate scopolamine-induced learning and memory impairments in mice, which may be achieved by regulating the neuronal apoptotic system and oxidative stress via the ER-p38 mitogen-activated protein kinase(ER-p38 MAPK) signaling pathway.

Clinicopathological Features and Expression of P504s,E-cadherin,Erythroblast Transformation-specific Related Gene and Estrogen Receptor in Prostate Adenocarcinoma in Tibet / 中国医学科学院学报

Objective To investigate the clinicopathological features and immunohistochemical expression of P504s,E-cadherin,erythroblast transformation-specific related gene(ERG)and estrogen receptor(ER)in prostate adenocarcinoma in Tibet.Methods The clinical data of 15 patients with prostate adenocarcinoma diagnosed by the Department of Pathology of Tibet Autonomous Region People's Hospital from September 2013 to September 2020 were analyzed retrospectively.All patients were assigned to prognostic grade groups based on Gleason score according to the WHO 2016 criteria.Immunostaining of P504s,E-cadherin,ERG,and ER was performed.Results The age of all 15 patients ranged from 61 to 86 years.The serum prostate specific antigen(PSA)concentration was ≥20 ng/ml in 12 patients and<20 ng/ml in 3 patients.Among the 15 patients,11 underwent needle biopsy,1 transurethral resection of the prostate,and 3 radical prostatectomy.Prognostic grouping results revealed 5 cases in grade groups 1-3,4 cases in grade group 4,and 6 cases in grade group 5.Immunohistochemistrically,15 cases(100%)were positive for P504s,E-cadherin and PSA;one case(7%)was positive for ERG;all cases were negative for P63,ER and CK34βE12.Thirteen cases were followed up for 2-48 months,with 2 cases treated with total prostatectomy and 11 cases with non-surgical treatment.Two cases were lost to follow-up. Conclusions Prostate adenocarcinoma is rare relatively in Tibet.The accuracy of diagnosis can be improved by using multiple immunohistochemical markers.The cases of grades 4 and 5 by pathological confirmed are relatively common in Tibet.P504s and E-cadherin are highly expressed in prostate adenocarcinoma patients in Tibet,while ERG presents low expression,ER is unexpressed.

Clinical and X-ray characteristics for expressions of different receptors in patients with breast cancer / 中南大学学报(医学版)

OBJECTIVES@#Clarifying the expression of breast cancer receptor is the key to clinical treatment for breast cancer. This study aims to explore the correlation between X-ray and clinical characteristics of 4 molecular subtypes and their receptor types of breast cancer.@*METHODS@#A total of 439 breast cancer patients who confirmed by pathology and performed X-ray examination were enrolled. The X-ray and clinical characteristics of 4 molecular subtypes and the expression of their receptors were analyzed.@*RESULTS@#Luminal A type showed the highest proportion of spiculate masses, and the lowest calcification score, showing significant difference with other 3 subtypes (all @*CONCLUSIONS@#Four molecular subtypes of breast cancer and their receptor expressions are correlated with X-ray and clinical characteristics, which can provide a basis for clinical diagnosis and treatment.

Analysis of DFNA5 gene variant in a Chinese pedigree affected with late-onset non-syndromic hearing loss / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a Chinese pedigree affected with autosomal dominant late-onset non-syndromic hearing loss (NSHL).@*METHODS@#Clinical data of the pedigree were collected. Genomic DNA was extracted from peripheral blood samples of the proband and other family members. Trio whole exome sequencing was carried out for 19 396 genes to identify potential pathogenic variants. Sanger sequencing was carried out to verify the candidate variant in the pedigree.@*RESULTS@#The proband and his father were found to carry a c.1183+1delG p.? variant of the DFNA5 gene. The variant was confirmed to be co-segregating with the disease phenotype in the pedigree.@*CONCLUSION@#The c.1183+1delG p.? variant of the DFNA5 gene probably underlay the late onset NSHL in this pedigree. Above finding has enabled accurate genetic counseling for this pedigree.

Overcoming resistance to endocrine therapy in hormone receptor-positive human epidermal growth factor receptor 2-negative (HR / 医学前沿

New targeted therapies have been developed to overcome resistance to endocrine therapy (ET) and improve the outcome of HR