Utility of melatonin in mitigating ionizing radiation-induced testis injury through synergistic interdependence of its biological properties

BACKGROUND: Ionizing radiations (IR) have widespread useful applications in our daily life; however, they have unfavorable effects on reproductive health. Maintaining testicular health following IR exposure is an important requirement for reproductive potential. The current study explored the role of melatonin (MLT) in mitigating IR-induced injury in young adult rat testis. METHODS: Rats were given daily MLT (25 mg/kg) for 3 and 14 days after receiving 4 Gy γ-radiation. RESULTS: Serum MLT levels and other antioxidants, including glutathione content, and the activity of glutathione peroxidase and glutathione reductase in the testis of the irradiated rats were remarkably maintained by MLT administration in irradiated rats. Hence, the hydrogen peroxide level declined with remarkably reduced formation of oxidative stress markers, 4-hydroxynonenal, and 8-Hydroxy-2'-deoxyguanosine in the testis of irradiated animals after MLT administration. The redox status improvement caused a remarkable regression of proapoptotic protein (p53, Cyto-c, and caspase-3) in the testis and improved inflammatory cytokines (CRP and IL-6), and anti-inflammatory cytokine (interleukin IL-10) in serum. This is associated with restoration of disturbed sex hormonal balance, androgen receptor upregulation, and testicular cell proliferation activity in irradiated rats, explaining the improvement of sperm parameters (count, motility, viability, and deformation). Consequently, spermatogenic cell depletion and decreased seminiferous tubule diameter and perimeter were attenuated by MLT treatment post irradiation. Moreover, the testis of irradiated-MLT-treated rats showed well-organized histological architecture and normal sperm morphology. CONCLUSIONS: These results show that radiation-induced testicular injury is mitigated following IR exposure through synergistic interdependence between the antioxidant, anti-inflammatory, anti-apoptotic, and anti-DNA damage actions of MLT.

Progress on TMPRSS2-ERG fusion gene product transcription regulation mechanism in prostate cancer cells / 中国临床药理学与治疗学

Prostate cancer is the most common malignant tumor in men in Europe and the United States, but the mechanism of prostate cancer occurrence and development is not completely clear. In prostate cancer, the TMPRSS2-ERG fusion gene has a high incidence, which promotes ERG overexpression and causes changes in target genes and signaling pathways, such as androgen receptors, spotted zinc finger structural proteins, Notch pathways. In-depth understanding of the transcriptional regulation mechanism of TMPRSS2-ERG fusion gene products in prostate cancer cells can provide new targets for drug action in the treatment of prostate cancer.

Carcinoma ductal in situ de la mama con características apocrinas: reporte de un caso / Ductal carcinoma in situ of the breast with apocrine characteristics: case report

Resumen Se presenta el caso de una femenina de 69 años con un carcinoma ductal in situ de la mama, el cual presentaba diferenciación apocrina y alto grado nuclear. La forma de presentación clínica se hizo patente en forma de microcalcificaciones detectadas en la mamografía, y corroboradas histológicamente como comedonecrosis. La diferenciación apocrina se comprobó por medio de tinciones de inmunohistoquímica. El diagnóstico se realizó en una biopsia excisional, pero dado a que uno de los márgenes se encontraba comprometido, la paciente se sometió posteriormente a una mastectomía.

Abstract We present the case of a 69 year old female diagnosed with a ductal in situ carcinoma of the breast. The tumor had apocrine differentiation and a high nuclear grade. The clinical presentation corresponded to microcalcifications detected on mammography, which were histologically patent in the form of comedo type necrosis. The aforementioned apocrine differentiation was reassured using the aid of immunohistochemistry. The biopsy was an excisional biopsy, but due to positive quirurgical margins, the patient was later reintervened for total mastectomy.

¿Es posible identificar factores pronósticos y predictivos en Cáncer de Mama Triple Negativo? / Is it possible to identify prognostic and predictive factors in Triple Negative breast cancer?

Introducción Debido a su negatividad para los receptores hormonales y de her2, los cánceres de mama Triple Negativos (cmtn) no tienen tratamiento específico y es la quimioterapia la única modalidad de tratamiento sistémico. Objetivos El objetivo de este trabajo es, en primer lugar, evaluar en los cmtn la factibilidad de utilizar a la infiltración linfocitaria y a la expresión de la proteína p53 y de los receptores de andrógenos como marcadores pronósticos (sobrevida global y período libre de enfermedad), y, en segundo lugar, determinar su utilidad como elementos predictivos de respuesta a la quimioterapia. Material y método Analizamos un grupo de pacientes con diagnóstico de cmtn tratadas en el Hospital Alemán de Buenos de Aires y en el Sanatorio Mater Dei desde diciembre de 2000 a diciembre de 2012. Resultados Se analizaron 21 pacientes con cmtn. En nuestra población, la quimioterapia se asoció con menor riesgo de recaída y mortalidad. La prevalencia en la expresión de la proteína p53 fue del 61,9% en la población general, del 72,7% en las recaídas y del 66,6% en las pacientes fallecidas. El 23,8% de las pacientes estudiadas presentó expresión de receptores androgénicos. La infiltración linfocitaria tumoral (tils) promedio fue del 20,5% (5% - 60%), siendo menor cuando se evalúa exclusivamente la población de pacientes que recayeron (17,7%) y aún menor cuando se evalúa la población de pacientes fallecidas (11,7 %). Discusión La quimioterapia tuvo un rr de sobrevida de 0,15 (ic: 0,06 - 0,78) con una p: 0,0021. La expresión de la proteína p53 tuvo un rr de 1,2 como factor de riesgo de mortalidad o progresión (ic: 0,23 - 9,07; p: 0,6). La expresión de receptores androgénicos tiene un rr de 1,6 como factor de riesgo de mortalidad o progresión (ic: 0,21 - 6,24; p: 0,41). La presencia de tils mayor al 20% es predictora de mortalidad y recurrencia con una p: 0,023. Conclusiones La determinación de tils junto con la evaluación en la expresión de la proteína p53 son herramientas útiles a la hora de definir la conveniencia de un tratamiento quimioterápico ya que ambas se asocian con aumento de la sobrevida total y de la sobrevida libre de enfermedad, aunque en nuestra población esta asociación no haya sido estadísticamente significativa para la p53 y sí para la presencia de tils

Introduction Because of its negativity for hormonal and her2 receptors, Triple Negative tumors do not benefit from anti hormonal treatments or with anti her2. They have no specific treatment and chemotherapy being the only form of systemic treatment. Objectives The objective of this study is, first, to evaluate in Triple Negative tumors feasibility of using lymphocyte infiltration, the expression of p53 protein and androgen receptors as prognostic markers (overall survival and disease-free), and, second, evaluate their usefulness as predictors of response to chemotherapy. Materials and method We intend to analyze those patients diagnosed with tnbc treated at the German Hospital of Buenos Aires and at the Mater Dei Sanatorium from December 2000 to December 2012. Results Twenty-one patients with tnbc were analyzed. In our population, chemotherapy was associated with a lower risk of relapse and mortality. The prevalence in the p53 mutation was 61.9% in the general population, 72.7% in relapses and 66.6% in deceased patients. Tumor lymphocytic infiltration (tils) on average was 20.5% (5% - 60%), being lower when only the population of patients who relapsed were evaluated (17.7%), and even lower when evaluating the population of deceased patients (11.7%). Discussion Chemotherapy had a survival rr of 0.15 (ci: 0.06 - 0.78) with a p: 0.0021. The p53 protein mutation had a rr of 1.2 as a risk factor for mortality or progression (ci: 0.23 - 9.07; p: 0.6). The expression of androgen receptors has a rr of 1.6 as a risk factor for mortality or progression (ci: 0.21 - 6.24; p: 0.41). The presence of tils greater than 20% is a predictor of mortality and recurrence with a p: 0.023. Conclusions The determination of tils together with determination of the p53 protein mutation are useful tools in determining the suitability of a chemotherapeutic treatment since both are associated with increased total survival and disease-free survival, although in our population this association was not statistically significant for p53.

Two Korean girls with complete androgen insensitivity syndrome diagnosed in infancy

Androgen insensitivity syndrome (AIS) is a rare genetic disease caused by various abnormalities in the androgen receptor (AR). The AR is an essential steroid hormone receptor that plays a critical role in male sexual differentiation and development and preservation of the male phenotype. Mutations in the AR gene on the X chromosome cause malfunction of the AR so that a 46,XY karyotype male has some physical characteristics of a woman or a full female phenotype. Depending on the phenotype, AIS can be classified as complete, partial or mild. Here, we report 2 cases of complete AIS in young children who showed complete sex reversal from male to female as a result of AR mutations. They had palpable inguinal masses and normal female external genitalia, a blind-end vagina and absent Müllerian duct derivatives. They were both 46,XY karyotype and AR gene analysis demonstrated pathologic mutations in both. Because AIS is inherited in an X-linked recessive manner, we performed genetic analysis of the female family members of each patient and found the same mutation in the mothers of both patients and in the female sibling of case 2. Gonadectomy was performed in both patients to avoid the risk of malignancy in the undescended testicles, and estrogen replacement therapy is planned for their adolescence. Individuals with complete AIS are usually raised as females and need appropriate care.

Good Response of a Salivary Duct Carcinoma to Androgen Deprivation Therapy / 대한내과학회지

Salivary duct carcinoma (SDC) is a rare, aggressive tumor. Androgen deprivation therapy (ADT) has been shown to have beneficial effects on SDC-expressing androgen receptors (ARs). A 69-year-old male with a right neck mass presented to our clinic. Computed tomography (CT) of the neck revealed a mass (6 cm diameter) on the right parotid gland, and enlarged lymph nodes. Examination of a needle biopsy sample identified SDC-expressing ARs. We performed total parotidectomy with bilateral neck dissection and concurrent postoperative chemoradiotherapy (total 66 Gy) with cisplatin (35 mg/m2), followed by another two cycles of chemotherapy (cisplatin 60 mg/m2, 5 FU 750 mg/m2). Post-treatment neck CT indicated that no residual tumor tissue remained; however, chest CT indicated recurrence in the right axilla. We initiated ADT with bicalutamide and leuprolide. Five months later, the axillar tumor tissue had almost disappeared. Our case demonstrates that ADT is effective for SDC of ARs. Therefore, clinicians should consider ADT in recurrent or metastatic SDC of ARs.

Effect of curcumin on the interaction between androgen receptor and Wnt/beta-catenin in LNCaP xenografts

PURPOSE: Curcumin is a nontoxic, chemopreventive agent possessing multifaceted functions. Our previous study showed that curcumin inhibits androgen receptor (AR) through modulation of Wnt/beta-catenin signaling in LNCaP cells. Therefore, we investigated the in vivo effects of curcumin by using LNCaP xenografts. MATERIALS AND METHODS: LNCaP cells were subcutaneously inoculated in Balb/c nude mice. When the tumor volume reached greater than 100 mm3, either curcumin (500 mg/kg body weight) or vehicle was administered through oral gavage three times weekly for 4 weeks. The expression of AR and intermediate products of Wnt/beta-catenin were assessed. RESULTS: Curcumin had an inhibitory effect on tumor growth during the early period, which was followed by a slow increase in growth over time. Tumor growth was delayed about 27% in the curcumin group. The mean prostate-specific antigen (PSA) doubling time in the curcumin group was approximately twice that in the untreated group. Curcumin significantly decreased AR expression at both the mRNA and protein level. The PSA levels tended to be reduced in the curcumin group. However, there were no significant changes in expression of Wnt/beta-catenin pathway intermediates. CONCLUSIONS: This study revealed that curcumin initially interferes with prostate cancer growth by inhibiting AR activity and possibly by reducing PSA expression. Further research is needed to investigate the plausible mechanism of the antiandrogenic action of curcumin.

Influence of Androgen Receptor Expression on the Survival Outcomes in Breast Cancer: A Meta-Analysis / 한국유방암학회지

PURPOSE: Despite the fact that the androgen receptor (AR) is known to be involved in the pathogenesis of breast cancer, its prognostic effect remains controversial. In this meta-analysis, we explored AR expression and its impact on survival outcomes in breast cancer. METHODS: We searched PubMed, EMBASE, Cochrane Library, ScienceDirect, SpringerLink, and Ovid databases and references of articles to identify studies reporting data until December 2013. Disease-free survival (DFS) and overall survival (OS) were analyzed by extracting the number of patients with recurrence and survival according to AR expression. RESULTS: There were 16 articles that met the criteria for inclusion in our meta-analysis. DFS and OS were significantly longer in patients with AR expression compared with patients without AR expression (odds ratio [OR], 0.60; 95% confidence interval [CI], 0.40-0.90; OR, 0.53; 95% CI, 0.38-0.73, respectively). In addition, hormone receptor (HR) positive patients had a longer DFS when AR was also expressed (OR, 0.63; 95% CI, 0.41-0.98). For patients with triple negative breast cancer (TNBC), AR expression was also associated with longer DFS and OS (OR, 0.44, 95% CI, 0.26-0.75; OR, 0.26, 95% CI, 0.12-0.55, respectively). Furthermore, AR expression was associated with a longer DFS and OS in women (OR, 0.42, 95% CI, 0.27-0.64; OR, 0.47, 95% CI, 0.38-0.59, respectively). However, in men, AR expression was associated with a worse DFS (OR, 6.00; 95% CI, 1.46-24.73). CONCLUSION: Expression of AR in breast cancer might be associated with better survival outcomes, especially in patients with HR-positive tumors and TNBC, and women. Based on this meta-analysis, we propose that AR expression might be related to prognostic features and contribute to clinical outcomes.

Expression of prostate cancer related long non-coding RNAs in prostate cancer and its biological function / 第二军医大学学报

Objective To investigate the expression of prostate cancer related long non-coding RNAs (PCRL) in prostate cancer and its biological function. Methods The expression levels of PCRL in prostatic cancer tissues, adjacent tissues and tissues of other organs were examined by qRT-PCR. The expression levels of PCRL in androgen-dependent (LNCaP-AD), androgen-independent (LNCaP-AI) prostatic cancer cell lines and normal prostate epithelial cells (RWPE-1) were also compared by using qRT-PCR. Finally, the expression levels of androgen receptor were compared between LNCaP-AD and LNCaP-AI prostatic cancer cells by qRT-PCR after siRNA interference of PCRL expression. Results PCRL were highly expressed in the prostate and prostatic cancer tissues. Expression of PCRL was notably higher in LNCaP-AI cells than in LNCaP-AD and RWPE-1 cells. Interference of PCRL expression in LNCaP-AI and LNCaP-AD cells significantly increased androgen receptor level (P<0. 000 1 for LNCaP-AI cells). Conclusion Overexpression of PCRL in prostatic cancer is related to the progression of prostatic cancer; and regulatory relation may exist between PCRL and androgen receptor.

Is the Expression of Androgen Receptor Protein Associated With the Length of AC Repeats in the Type III 5-alpha Reductase Gene in Prostate Cancer Patients?

PURPOSE: Type III 5-alpha reductase (SRD5A3; steroid 5-alpha reductase 3) may be associated with the progression of prostate cancer (PCa). The aim of our study was to determine whether the length of AC repeats in the SRD5A3 gene is associated with the risk of PCa and the expression of androgen receptor (AR) protein in Korean men. MATERIALS AND METHODS: We compared the length of AC repeats in the short tandem repeat (STR) region of the SRD5A3 gene in 68 PCa patients and 81 control subjects by genotyping. A total of 55 patients in the PCa group underwent radical prostatectomy. We evaluated the expression of AR protein by using Western blotting and tested the association between the type of AC repeats in the SRD5A3 gene and AR protein expression and clinical and pathologic parameters. RESULTS: The short type of STR had less than 21 copies of AC repeats in the SRD5A3 gene. The SS type (short and short type) of STR of the SRD5A3 gene was 2.2 times as likely to occur in PCa patients as in controls (odds ratio, 2.21; 95% confidence interval, 1.14 to 4.31; p=0.019). However, AC repeats of the SRD5A3 gene were not associated with AR protein expression or clinical or pathologic parameters in PCa samples. CONCLUSIONS: These results suggest that the short AC repeats of SRD5A3 polymorphism are associated with an increased risk of PCa. SRD5A3 polymorphism may contribute to a genetic predisposition for PCa.

Correlation of AR, EGFR, and HER2 Expression Levels in Prostate Cancer: Immunohistochemical Analysis and Chromogenic In Situ Hybridization / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The androgen receptor (AR) plays a central role in prostate cancer. Evidence from several groups indicates that epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) may enhance AR activity in prostate cancer cell lines. This study was designed to investigate the protein expression of AR, EGFR, and HER2 and to determine whether the EGFR and HER2 genes are amplified in prostate cancer tissues. MATERIALS AND METHODS: The protein expression levels of AR, EGFR, and HER2 in a tissue microarray block of 66 prostate cancer samples were investigated by immunohistochemical analysis and chromogenic in situ hybridization was used to determine whether the EGFR and HER2 genes were amplified in these tissues. RESULTS: The AR and EGFR proteins were expressed in 59.1% and 40.9% of prostate cancers, respectively, but their expression levels were not significantly associated with clinicopathologic factors. Of the cases in which tissues were negative for EGFR protein expression, 69.2% were positive for AR protein expression; however, AR protein expression was significantly reduced (44.4%) in tissues in which EGFR protein was expressed. HER2 expression was detected in only 1 case (1.5%). No amplification of the EGFR or HER2 genes was found in prostate cancer specimens. CONCLUSION: This study was limited by small number of subjects, but it can still be inferred that the expression levels of the AR and EGFR proteins are inversely correlated in prostate cancer patients. The potential utility of EGFR and HER2 as prognostic factors or therapeutic targets warrants further study.

Roles of androgen receptor and Wnt signaling pathway in prostate cancer / 第二军医大学学报

Abnormal activation of Wnt signaling pathway plays an important role in the development and progression of prostate cancer; androgen receptor (AR) is the key for the transformation of androgen-independent prostate cancer (AIPC), and AR signaling pathway is now the focus of prostate cancer research. Many signal pathways can affect AR signaling pathway; in this paper we review the Wnt signaling pathway, androgen receptor and their crosstalk in prostate cancer.

Amenorréia primária e cariótipo XY: identificando pacientes em risco / Primary amenorrhea and XY karyotype: identifying patients in risk

OBJETIVO: verificar a prevalência e as características clínicas de pacientes com amenorréia primária e cariótipo XY avaliadas em nosso Serviço com o intuito de identificar achados que possam auxiliar em seu reconhecimento. MÉTODOS: no período de Janeiro de 1975 a Novembro de 2007, foram avaliadas 104 pacientes com amenorréia primária. Para todos os casos foi realizada a análise pelo cariótipo por bandas GTG. Destas, 21 (20,2%) apresentavam uma constituição 46,XY. Contudo, duas foram excluídas do estudo por terem prontuários incompletos. Das 19 pacientes que compuseram a amostra, a maior parte veio encaminhada pela ginecologia (63,2%). Suas idades variaram entre 16 e 41 anos (média de 22,1 anos). Realizou-se uma coleta de dados sobre sua história familiar e pregressa, exame físico e resultados de exames complementares. Para determinação dos seus diagnósticos levaram-se em consideração essas informações. RESULTADOS: a síndrome de resistência aos androgênios foi o diagnóstico predominante (n=12; 63,2%). Cinco pacientes (26,3%) apresentavam disgenesia gonadal pura XY (DGP XY), uma (5,3%) deficiência de 17-alfa hidroxilase e uma (5,3%) deficiência de 5-alfa redutase. Achados clínicos freqüentemente observados nessas pacientes incluíram desenvolvimento anormal dos caracteres sexuais secundários (n=19), agenesia uterina com vagina em fundo de saco (n=14), história familiar de amenorréia (n=8) e gônadas palpáveis no canal inguinal (n=5). Duas delas apresentavam história de hérnia inguinal. Hipertensão arterial sistêmica foi diagnosticada somente na paciente com deficiência de 17-alfa hidroxilase, e malignização gonadal, naquela com DGP XY. CONCLUSÕES: a freqüência de pacientes com cariótipo XY (20%) foi superior à usualmente descrita na literatura (3 a 11%). Acreditamos que isso tenha relação com a forma de encaminhamento das pacientes ao Serviço...

PURPOSE: to verify the prevalence and clinical characteristics of patients with primary amenorrhea and XY caryotype, evaluated in our Service, aiming at identifying findings which could help their recognition. METHODS: from January 1975 to November 2007, 104 patients with amenorrhea were evaluated. All the cases were analyzed by the caryotype by GTG bands. Among them, 21 (20.2%) presented a XY 46 constitution. Nevertheless, two of them were excluded from the study, because of incomplete data in their patient's chart. Most of the 19 patients who formed the sample had been referred to us by the gynecology clinics (63.2%). Their ages varied from 16 to 41 years old (an average of 22.1). Data were collected about their family and previous history, physical examination and results of complementary exams and the information was taken into consideration to determine the diagnosis. RESULTS: the predominant diagnosis was resistance to androgens syndrome (n=12; 63.2%); five patients (25.3%) presented XY pure gonadal dysgenesis (XY PGD), one (5.3%) 17 alpha-hydroxylase deficiency, and one (5.3%), 5 alpha-reductase deficiency. Clinical findings frequently found in these patients included abnormal development of secondary sexual characters (n=19), uterine agenesia with a blind vagina (n=14), family history of amenorrhea (n=8), and palpable gonads in the inguinal canal (n=5). Two of them presented a history of inguinal hernia. Systemic arterial hypertension was only diagnosed in the patient with 17 alpha-hydroxylase deficiency, and gonadal malignization, in the one with XY PGD. CONCLUSIONS: the rate of patients with XY caryotype (20%) was higher than the one described in the literature (3 to 11%). It is believed that this fact is related to the way patients are usually referred to our service. Some findings from the clinical history and from the physical examination should be evaluated as a routine in individuals with primary amenorrhea...

Expression of androgen receptors in astrocytoma

Thirty-two cases of surgically removed astrocytoma were evaluated for the expression of androgen receptors(ARs) immunohistochemically and the relationships between androgen receptors, DNA ploidy pattern, and survival of patients were studied. The cases included 18 grade I/II astrocytomas, 4 anaplastic astrocytomas, and 10 glioblastoma multiforme(GBM). Positive AR was present in 12 out of 32 cases(38%), which consisted of 5 cases in grade I/II(28%), 3 cases in anaplastic astrocytoma(75%), and 4 cases in GBM(40%). For both low and high grade astrocytomas, sex and ploidy pattern were not correlated with expression of the androgen receptors. Androgen receptor expression did not significantly affect the survival time. This study confirms previous reports of a low incidence of androgen receptors in astrocytomas. In addition, it shows that expression of androgen receptors is not correlated with DNA ploidy pattern and survival of patients in astrocytoma.

Expression of androgen receptors in astrocytoma

Thirty-two cases of surgically removed astrocytoma were evaluated for the expression of androgen receptors(ARs) immunohistochemically and the relationships between androgen receptors, DNA ploidy pattern, and survival of patients were studied. The cases included 18 grade I/II astrocytomas, 4 anaplastic astrocytomas, and 10 glioblastoma multiforme(GBM). Positive AR was present in 12 out of 32 cases(38%), which consisted of 5 cases in grade I/II(28%), 3 cases in anaplastic astrocytoma(75%), and 4 cases in GBM(40%). For both low and high grade astrocytomas, sex and ploidy pattern were not correlated with expression of the androgen receptors. Androgen receptor expression did not significantly affect the survival time. This study confirms previous reports of a low incidence of androgen receptors in astrocytomas. In addition, it shows that expression of androgen receptors is not correlated with DNA ploidy pattern and survival of patients in astrocytoma.

A study on the concentration of cytosol receptors for estrogen,progestin,and androgen in human uterus / 第三军医大学学报

The concentration of cytosol receptors for estrogen(ERc).progestin(PRc).and androgen(ARc)were deterimined in the tissue specimens of uterine myoma,uterine myoadenopa-thy,and postmenopausal uterus and of normal endometrium and myometrium as well.It was found that the concentration of ERc.PRc and ARc was significantly higher in myomatous tissue than in normal myometrium.Remarkable difference existed of the concentration of sex steroid receptors between normal endometrium and adenomyosis tissue.Postmenopausal uterine tissue still retained high concentration of ERc.PRc and ARc.In addition,the regulation of sex steroids in these pathological conditions was discussed.