Status of sex steroid hormone receptors in large bowel cancer

NARCIS (Netherlands)

Meggouh, F.; Lointier, P.; Pezet, D.; Saez, S.

1991-01-01

To determine the potential role of sex steroid hormones in the development of colorectal tumors in humans, specific androgen (AR), estrogen (ER), and progesterone (PGR) receptors were investigated in normal mucosa (NM) and in tumor (T) paired biopsy specimens from 94 patients. Androgen receptors

Expression of progesterone receptor protein in the ovine uterus during the estrous cycle: Effects of nutrition, arginine and FSH.

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Grazul-Bilska, Anna T; Thammasiri, Jiratti; Kraisoon, Aree; Reyaz, Arshi; Bass, Casie S; Kaminski, Samantha L; Navanukraw, Chainarong; Redmer, Dale A

2018-03-01

To evaluate expression of progesterone receptor (PGR) AB in follicle stimulating hormone (FSH)-treated or non-treated sheep administered with arginine (Arg) or saline (Sal) fed a control (C), excess (O) or restricted (U) diet, uterine tissues were collected at the early, mid and/or late luteal phases. In exp. 1, ewes from each diet were randomly assigned to one of two treatments, Arg or Sal administration three times daily from day 0 of the first estrous cycle until uterine tissue collection. In exp. 2, ewes were injected twice daily with FSH on days 13-15 of the first estrous cycle. Uterine tissues were immunostained to detect PGR followed by image analysis. PGR were detected in luminal epithelium (LE), endometrial glands (EG), endometrial stroma (ES), myometrium (Myo), and endometrial and myometrial blood vessels. The percentage of PR-positive cells and/or intensity of staining were affected by phase of the estrous cycle, plane of nutrition, and/or FSH but not by Arg. In exp. 1, percentage of PGR-positive cells in LE and EG but not in ES and Myo was greater at the early and mid than late luteal phase, was not affected by plane of nutrition, and was similar in LE and EG. Intensity of staining was affected by phase of the estrous cycle and plane of nutrition in LE, EG and Myo, and was the greatest in LE, less in EG, and least in ES and Myo. In exp. 2, percentage of PGR-positive cells in LE, EG, ES and Myo was affected by phase of the estrous cycle, but not by plane of nutrition; was greater at the early than mid luteal phase; and was greatest in LE and EG, less in luminal (superficial) ES and Myo and least in deep ES. Intensity of staining was affected by phase of the estrous cycle and plane of nutrition in all compartments but ES, and was the greatest in LE and luminal EG, less in deep EG, and least in ES and Myo. Comparison of data for FSH (superovulated) and Sal-treated (non-superovulated) ewes demonstrated that FSH affected PR expression in all evaluated

Expression of PGR, HBEGF, ITGAV, ITGB3 and SPP1 genes in eutopic endometrium of infertile women with endometriosis during the implantation window: a pilot study.

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Broi, Michele G Da; Rocha, Carlos V; Meola, Juliana; Martins, Wellington P; Carvalho, Filomena M; Ferriani, Rui A; Navarro, Paula A

2017-09-01

Alterations in endometrial receptivity may be involved in the etiopathogenesis of endometriosis-related infertility. The literature has suggested that patients with endometriosis present progestin resistance, which could affect embryo implantation. We question the presence of alterations in the expression of the progesterone receptor gene (PGR) and the genes related to endometrium-embryo interaction regulated by progesterone. This pilot study compared the expression of PGR, HBEGF, ITGAV, ITGB3, and SPP1 genes in eutopic endometrium during the implantation window (IW) in infertile women with endometriosis with that observed in the endometrium of fertile and infertile controls. In this prospective case-control study, endometrial biopsies were performed during the IW in patients aged between 18 and 45 years old, with regular cycles and without endocrine/systemic dysfunctions, divided into endometriosis (END), infertile control (IC) and fertile control (FC) groups. Total RNA extraction, cDNA synthesis, and gene expression analysis by Real-Time PCR were performed. We assessed the size of the difference that our series was powered to detect. From the 687 patients who underwent diagnostic videolaparoscopy or tubal ligation at the University Hospital, 130 were eligible. Of these, 32 had endometrial samples collected, with 17 confirmed in the IW. Fifteen samples (5 END, 5 IC and 5 FC) were analyzed. There was no significant difference in the expression of any studied gene. Our sample size allowed us to identify or discard large differences (two standard deviations) among the groups. Endometriosis doesn't cause large changes in the endometrial expression of PGR, HBEGF, ITGAV, ITGB3 and SPP1 during the IW.

Distinct functions and regulation of epithelial progesterone receptor in the mouse cervix, vagina, and uterus.

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Mehta, Fabiola F; Son, Jieun; Hewitt, Sylvia C; Jang, Eunjung; Lydon, John P; Korach, Kenneth S; Chung, Sang-Hyuk

2016-04-05

While the function of progesterone receptor (PR) has been studied in the mouse vagina and uterus, its regulation and function in the cervix has not been described. We selectively deleted epithelial PR in the female reproductive tracts using the Cre/LoxP recombination system. We found that epithelial PR was required for induction of apoptosis and suppression of cell proliferation by progesterone (P4) in the cervical and vaginal epithelium. We also found that epithelial PR was dispensable for P4 to suppress apoptosis and proliferation in the uterine epithelium. PR is encoded by the Pgr gene, which is regulated by estrogen receptor α (ERα) in the female reproductive tracts. Using knock-in mouse models expressing ERα mutants, we determined that the DNA-binding domain (DBD) and AF2 domain of ERα were required for upregulation of Pgr in the cervix and vagina as well as the uterine stroma. The ERα AF1 domain was required for upregulation of Pgr in the vaginal stroma and epithelium and cervical epithelium, but not in the uterine and cervical stroma. ERα DBD, AF1, and AF2 were required for suppression of Pgr in the uterine epithelium, which was mediated by stromal ERα. Epithelial ERα was responsible for upregulation of epithelial Pgr in the cervix and vagina. Our results indicate that regulation and functions of epithelial PR are different in the cervix, vagina, and uterus.

Expression of estrogen receptor beta in the breast carcinoma of BRCA1 mutation carriers

International Nuclear Information System (INIS)

Litwiniuk, Maria M; Rożnowski, Krzysztof; Filas, Violetta; Godlewski, Dariusz D; Stawicka, Małgorzata; Kaleta, Remigiusz; Bręborowicz, Jan

2008-01-01

Breast cancers (BC) in women carrying mutations in BRCA1 gene are more frequently estrogen receptor negative than the nonhereditary BC. Nevertheless, tamoxifen has been found to have a protective effect in preventing contralateral tumors in BRCA1 mutation carriers. The identification of the second human estrogen receptor, ERβ, raised a question of its role in hereditary breast cancer. The aim of this study was to assess the frequency of ERα, ERβ, PgR (progesterone receptor) and HER-2 expression in breast cancer patients with mutated BRCA1 gene and in the control group. The study group consisted of 48 women with BRCA1 gene mutations confirmed by multiplex PCR assay. The patients were tested for three most common mutations of BRCA1 affecting the Polish population (5382insC, C61G, 4153delA). Immunostaining for ERα, ERβ and PgR (progesterone receptor) was performed using monoclonal antibodies against ERα, PgR (DakoCytomation), and polyclonal antibody against ERβ (Chemicon). The EnVision detection system was applied. The study population comprised a control group of 120 BC operated successively during the years 1998–99. The results of our investigation showed that BRCA1 mutation carriers were more likely to have ERα-negative breast cancer than those in the control group. Only 14.5% of BRCA1-related cancers were ERα-positive compared with 57.5% in the control group (P < 0.0001). On the contrary, the expression of ERβ protein was observed in 42% of BRCA1-related tumors and in 55% of the control group. An interesting finding was that most hereditary cancers (75% of the whole group) were triple-negative: ERα(-)/PgR(-)/HER-2(-) but almost half of this group (44.4%) showed the expression of ERβ. In the case of BRCA1-associated tumors the expression of ERβ was significantly higher than the expression of ERα. This may explain the effectiveness of tamoxifen in preventing contralateral breast cancer development in BRCA1 mutation carriers

Estrogen receptor (ESR1) mRNA expression and benefit from tamoxifen in the treatment and prevention of estrogen receptor-positive breast cancer.

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Kim, Chungyeul; Tang, Gong; Pogue-Geile, Katherine L; Costantino, Joseph P; Baehner, Frederick L; Baker, Joffre; Cronin, Maureen T; Watson, Drew; Shak, Steven; Bohn, Olga L; Fumagalli, Debora; Taniyama, Yusuke; Lee, Ahwon; Reilly, Megan L; Vogel, Victor G; McCaskill-Stevens, Worta; Ford, Leslie G; Geyer, Charles E; Wickerham, D Lawrence; Wolmark, Norman; Paik, Soonmyung

2011-11-01

Several mechanisms have been proposed to explain tamoxifen resistance of estrogen receptor (ER) -positive tumors, but a clinically useful explanation for such resistance has not been described. Because the ER is the treatment target for tamoxifen, a linear association between ER expression levels and the degree of benefit from tamoxifen might be expected. However, such an association has never been demonstrated with conventional clinical ER assays, and the ER is currently used clinically as a dichotomous marker. We used gene expression profiling and ER protein assays to help elucidate molecular mechanism(s) responsible for tamoxifen resistance in breast tumors. We performed gene expression profiling of paraffin-embedded tumors from National Surgical Adjuvant Breast and Bowel Project (NSABP) trials that tested the worth of tamoxifen as an adjuvant systemic therapy (B-14) and as a preventive agent (P-1). This was a retrospective subset analysis based on available materials. In B-14, ESR1 was the strongest linear predictor of tamoxifen benefit among 16 genes examined, including PGR and ERBB2. On the basis of these data, we hypothesized that, in the P-1 trial, a lower level of ESR1 mRNA in the tamoxifen arm was the main difference between the two study arms. Only ESR1 was downregulated by more than two-fold in ER-positive cancer events in the tamoxifen arm (P < .001). Tamoxifen did not prevent ER-positive tumors with low levels of ESR1 expression. These data suggest that low-level expression of ESR1 is a determinant of tamoxifen resistance in ER-positive breast cancer. Strategies should be developed to identify, treat, and prevent such tumors.

Evaluation of estrogen receptor alpha and beta and progesterone receptor expression and correlation with clinicopathologic factors and proliferative marker Ki-67 in breast cancers

DEFF Research Database (Denmark)

Rosa, Fabíola E; Caldeira, José R F; Felipes, Joice

2008-01-01

To elucidate the molecular profile of hormonal steroid receptor status, we analyzed ER-alpha, ER-beta, and PGR mRNA and protein expression in 80 breast carcinomas using reverse transcriptase polymerase chain reaction (RT-PCR), quantitative RT-PCR, and immunohistochemical analysis. Qualitative ana...

Influence of Estradiol-17beta on Progesterone and Estrogen Receptor mRNA Expression in Porcine Follicular Granulosa Cells during Short-Term, In Vitro Real-Time Cell Proliferation

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Sylwia Ciesiółka

2016-01-01

Full Text Available Progesterone (P4 and estradiol (E2 play a significant role in mammalian reproduction. Our study demonstrated that separated porcine cumulus cells (CCs and/or granulosa cells (GCs might proliferate in vitro during short-term, real-time primary culture. The GCs were analyzed according to gene expression of the progesterone receptor (nuclear form (pgr, progesterone receptor membrane component 1 (pgrmc1, and estrogen-related receptor beta 3 (esrrb3 in relation to two housekeeping genes: actb and pbgd. GCs were cultivated in medium with the E2. Both pgr/actb and pgr/pbgd revealed higher expression between 24 and 168 h of IVC of prolonged E2 treatment and at 48 h of IVC after acute E2 administration. The pgrmc1/actb and pgrmc1/pbgd displayed increased expression after prolonged E2 treatment between 24 and 120 h of IVC. The highest level of esrrb3/actb at 120 and 144 h, as well as esrrb3/pbgd at 120 h, in untreated controls as compared to the hormone-stimulated group, was observed. We suggest that E2 significantly influences the upregulation of pgr, pgrmc1, and esrrb3 expression in porcine GCs during real-time cell proliferation. Since esrrb3 expression is stimulated by E2 in both an acute and prolonged manner, estradiol may be recognized as a potential estrogen receptor agonist in GCs.

American Society of Clinical Oncology/College Of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer.

NARCIS (Netherlands)

Hammond, M.E.; Hayes, D.F.; Dowsett, M.; Allred, D.C.; Hagerty, K.L.; Badve, S.; Fitzgibbons, P.L.; Francis, G.; Goldstein, N.S.; Hayes, M.; Hicks, D.G.; Lester, S.; Love, R.; Mangu, P.B.; McShane, L.; Miller, K.; Osborne, C.K.; Paik, S.; Perlmutter, J.; Rhodes, A.; Sasano, H.; Schwartz, J.N.; Sweep, F.C.; Taube, S.; Torlakovic, E.E.; Valenstein, P.; Viale, G.; Visscher, D.; Wheeler, T.; Williams, R.B.; Wittliff, J.L.; Wolff, A.C.

2010-01-01

PURPOSE: To develop a guideline to improve the accuracy of immunohistochemical (IHC) estrogen receptor (ER) and progesterone receptor (PgR) testing in breast cancer and the utility of these receptors as predictive markers. METHODS: The American Society of Clinical Oncology and the College of

American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer.

NARCIS (Netherlands)

Hammond, M.E.; Hayes, D.F.; Dowsett, M.; Allred, D.C.; Hagerty, K.L.; Badve, S.; Fitzgibbons, P.L.; Francis, G.; Goldstein, N.S.; Hayes, M.; Hicks, D.G.; Lester, S.; Love, R.; Mangu, P.B.; McShane, L.; Miller, K.; Osborne, C.K.; Paik, S.; Perlmutter, J.; Rhodes, A.; Sasano, H.; Schwartz, J.N.; Sweep, F.C.; Taube, S.; Torlakovic, E.E.; Valenstein, P.; Viale, G.; Visscher, D.; Wheeler, T.; Williams, R.B.; Wittliff, J.L.; Wolff, A.C.

2010-01-01

PURPOSE: To develop a guideline to improve the accuracy of immunohistochemical (IHC) estrogen receptor (ER) and progesterone receptor (PgR) testing in breast cancer and the utility of these receptors as predictive markers. METHODS: The American Society of Clinical Oncology and the College of

Nuclear progesterone receptors are up-regulated by estrogens in neurons and radial glial progenitors in the brain of zebrafish.

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Nicolas Diotel

Full Text Available In rodents, there is increasing evidence that nuclear progesterone receptors are transiently expressed in many regions of the developing brain, notably outside the hypothalamus. This suggests that progesterone and/or its metabolites could be involved in functions not related to reproduction, particularly in neurodevelopment. In this context, the adult fish brain is of particular interest, as it exhibits constant growth and high neurogenic activity that is supported by radial glia progenitors. However, although synthesis of neuroprogestagens has been documented recently in the brain of zebrafish, information on the presence of progesterone receptors is very limited. In zebrafish, a single nuclear progesterone receptor (pgr has been cloned and characterized. Here, we demonstrate that this pgr is widely distributed in all regions of the zebrafish brain. Interestingly, we show that Pgr is strongly expressed in radial glial cells and more weakly in neurons. Finally, we present evidence, based on quantitative PCR and immunohistochemistry, that nuclear progesterone receptor mRNA and proteins are upregulated by estrogens in the brain of adult zebrafish. These data document for the first time the finding that radial glial cells are preferential targets for peripheral progestagens and/or neuroprogestagens. Given the crucial roles of radial glial cells in adult neurogenesis, the potential effects of progestagens on their activity and the fate of daughter cells require thorough investigation.

American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer (unabridged version).

NARCIS (Netherlands)

Hammond, M.E.; Hayes, D.F.; Dowsett, M.; Allred, D.C.; Hagerty, K.L.; Badve, S.; Fitzgibbons, P.L.; Francis, G.; Goldstein, N.S.; Hayes, M.; Hicks, D.G.; Lester, S.; Love, R.; Mangu, P.B.; McShane, L.; Miller, K.; Osborne, C.K.; Paik, S.; Perlmutter, J.; Rhodes, A.; Sasano, H.; Schwartz, J.N.; Sweep, F.C.; Taube, S.; Torlakovic, E.E.; Valenstein, P.; Viale, G.; Visscher, D.; Wheeler, T.; Williams, R.B.; Wittliff, J.L.; Wolff, A.C.

2010-01-01

PURPOSE: To develop a guideline to improve the accuracy of immunohistochemical (IHC) estrogen receptor (ER) and progesterone receptor (PgR) testing in breast cancer and the utility of these receptors as predictive markers. METHODS: The American Society of Clinical Oncology and the College of

Characterization of hormonal receptors and human epidermal growth factor receptor-2 in tissues of women with breast cancer at Muhimbili National Hospital, Dar es salaam, Tanzania.

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Mwakigonja, Amos Rodger; Lushina, Nyanda Elias; Mwanga, Ally

2017-01-01

Breast cancer is a leading cause of morbidity and deaths among women worldwide. In Tanzania there is no published data on human epidermal growth receptor-2 (HER2/neu) expression in breast carcinoma. Hormonal receptors and HER2/neu status reportedly influence post-mastectomy adjuvant therapy and predict treatment outcome and prognosis. Here we evaluate hormonal receptors and HER-2 status in biopsies of women with breast cancer at Muhimbili National Hospital (MNH). A cross-sectional study of female breast post-modified radical mastectomy (MRM)/incisional biopsies confirmed to be carcinoma at the Histopathology Unit (January-December 2013). Tissue blocks having poor morphology, without tumor, secondary tumors, cases outside the study period and male patients were excluded. Routine staining was done followed by immunohistochemistry for estrogen (ER), and progesterone (PgR) receptors and HER2. Data analyzed using Statistical Package for Social Sciences (SPSS). A total of 218 cases were confirmed to be carcinoma including 70 meeting inclusion criteria. Age at diagnosis ranged 18-75 years and mean age was 48.36 years. Majority (64.3%) were in the 36-55 years age-group. Histologically, most (88.6%) women had invasive ductal carcinoma including 43.1% of intermediate grade. A great majority (78%) were stage three. Due to logistical constrains, 75.7% ( n  = 53/70) cases where immunostained for hormones including 43.4% (ER+), 26.4% (PgR+), and 28% (ER+/PgR+). Furthermore, 65.7% ( n  = 46/70) cases were immunostained for HER-2 and 15.2% ( n  = 7/46) were positive, 45.6% were triple negative (ER-,PgR-,HER2-), 23.9% (ER+,PgR+,HER2-) or luminal B, 2.2% (ER+,PgR-,HER2+),13% (ER-,PgR-,HER2+) and 15% (ER+,PgR-,HER2-) with none being triple positive. Hormonal receptors and HER2 expression at MNH appears to be comparable to previous Africans/African Americans reports but not with studies among Caucasians and the current proportion of triple negative breast carcinomas (TNBC) is

Characterization of hormonal receptors and human epidermal growth factor receptor-2 in tissues of women with breast cancer at Muhimbili National Hospital, Dar es salaam, Tanzania

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Amos Rodger Mwakigonja

2017-11-01

Full Text Available Abstract Background Breast cancer is a leading cause of morbidity and deaths among women worldwide. In Tanzania there is no published data on human epidermal growth receptor-2 (HER2/neu expression in breast carcinoma. Hormonal receptors and HER2/neu status reportedly influence post-mastectomy adjuvant therapy and predict treatment outcome and prognosis. Here we evaluate hormonal receptors and HER-2 status in biopsies of women with breast cancer at Muhimbili National Hospital (MNH. Methods A cross-sectional study of female breast post-modified radical mastectomy (MRM/incisional biopsies confirmed to be carcinoma at the Histopathology Unit (January–December 2013. Tissue blocks having poor morphology, without tumor, secondary tumors, cases outside the study period and male patients were excluded. Routine staining was done followed by immunohistochemistry for estrogen (ER, and progesterone (PgR receptors and HER2. Data analyzed using Statistical Package for Social Sciences (SPSS. Results A total of 218 cases were confirmed to be carcinoma including 70 meeting inclusion criteria. Age at diagnosis ranged 18–75 years and mean age was 48.36 years. Majority (64.3% were in the 36–55 years age-group. Histologically, most (88.6% women had invasive ductal carcinoma including 43.1% of intermediate grade. A great majority (78% were stage three. Due to logistical constrains, 75.7% (n = 53/70 cases where immunostained for hormones including 43.4% (ER+, 26.4% (PgR+, and 28% (ER+/PgR+. Furthermore, 65.7% (n = 46/70 cases were immunostained for HER-2 and 15.2% (n = 7/46 were positive, 45.6% were triple negative (ER-,PgR-,HER2-, 23.9% (ER+,PgR+,HER2- or luminal B, 2.2% (ER+,PgR-,HER2+,13% (ER-,PgR-,HER2+ and 15% (ER+,PgR-,HER2- with none being triple positive. Conclusions Hormonal receptors and HER2 expression at MNH appears to be comparable to previous Africans/African Americans reports but not with studies among Caucasians and the current proportion

Partially dissecting the steady-state electron fluxes in Photosystem I in wild-type and pgr5 and ndh mutants of Arabidopsis

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Jiancun eKou

2015-09-01

Full Text Available Cyclic electron flux (CEF around Photosystem I (PS I is difficult to quantify. We obtained the linear electron flux (LEFO2 through both photosystems and the total electron flux through PS I (ETR1 in Arabidopsis in CO2-enriched air. DeltaFlux = ETR1 – LEFO2 is an upper estimate of CEF, which consists of two components, an antimycin A-sensitive, PGR5 (proton gradient regulation 5 protein-dependent component and an insensitive component facilitated by a chloroplastic nicotinamide adenine dinucleotide dehydrogenase-like complex (NDH. Using wild type as well as pgr5 and ndh mutants, we observed that (1 40% of the absorbed light was partitioned to PS I; (2 at high irradiance a substantial antimycin A-sensitive CEF occurred in the wild type and the ndh mutant; (3 at low irradiance a sizable antimycin A-sensitive CEF occurred in the wild type but not in the ndh mutant, suggesting an enhancing effect of NDH in low light; and (4 in the pgr5 mutant, and the wild type and ndh mutant treated with antimycin A, a residual DeltaFlux existed at high irradiance, attributable to charge recombination and/or pseudo-cyclic electron flow. Therefore, in low-light-acclimated plants exposed to high light, DeltaFlux has contributions from various paths of electron flow through PS I.

The role of the AR/ER ratio in ER-positive breast cancer patients.

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Rangel, Nelson; Rondon-Lagos, Milena; Annaratone, Laura; Osella-Abate, Simona; Metovic, Jasna; Mano, Maria Piera; Bertero, Luca; Cassoni, Paola; Sapino, Anna; Castellano, Isabella

2018-03-01

The significance of androgen receptor (AR) in breast cancer (BC) management is not fully defined, and it is still ambiguous how the level of AR expression influences oestrogen receptor-positive (ER+) tumours. The aim of the present study was to analyse the prognostic impact of AR/ER ratio, evaluated by immunohistochemistry (IHC), correlating this value with clinical, pathological and molecular characteristics. We retrospectively selected a cohort of 402 ER+BC patients. On each tumour, IHC analyses for AR, ER, PgR, HER2 and Ki67 were performed and AR+ cases were used to calculate the AR/ER value. A cut-off of ≥2 was selected using receiver-operating characteristic (ROC) curve analyses. RNA from 19 cases with AR/ER≥2 was extracted and used for Prosigna-PAM50 assays. Tumours with AR/ER≥2 (6%) showed more frequent metastatic lymph nodes, larger size, higher histological grade and lower PgR levels than cases with AR/ERAR/ER≥2 had worse disease-free interval (DFI) and disease-specific survival (DSS) (hazard ratios (HR) = 4.96 for DFI and HR = 8.69 for DSS, both P  ≤ 0.004). According to the Prosigna-PAM50 assay, 63% (12/19) of these cases resulted in intermediate or high risk of recurrence categories. Additionally, although all samples were positive for ER assessed by IHC, the molecular test assigned 47.4% (9/19) of BCs to intrinsic non-luminal subtypes. In conclusion, the AR/ER ratio ≥2 identifies a subgroup of patients with aggressive biological features and may represent an additional independent marker of worse BC prognosis. Moreover, the Prosigna-PAM50 results indicate that a significant number of cases with AR/ER≥2 could be non-luminal tumours. © 2018 Society for Endocrinology.

Removal of reproductive suppression reveals latent sex differences in brain steroid hormone receptors in naked mole-rats, Heterocephalus glaber.

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Swift-Gallant, Ashlyn; Mo, Kaiguo; Peragine, Deane E; Monks, D Ashley; Holmes, Melissa M

2015-01-01

Naked mole-rats are eusocial mammals, living in large colonies with a single breeding female and 1-3 breeding males. Breeders are socially dominant, and only the breeders exhibit traditional sex differences in circulating gonadal steroid hormones and reproductive behaviors. Non-reproductive subordinates also fail to show sex differences in overall body size, external genital morphology, and non-reproductive behaviors. However, subordinates can transition to breeding status if removed from their colony and housed with an opposite-sex conspecific, suggesting the presence of latent sex differences. Here, we assessed the expression of steroid hormone receptor and aromatase messenger RNA (mRNA) in the brains of males and females as they transitioned in social and reproductive status. We compared in-colony subordinates to opposite-sex subordinate pairs that were removed from their colony for either 1 day, 1 week, 1 month, or until they became breeders (i.e., produced a litter). Diencephalic tissue was collected and mRNA of androgen receptor (Ar), estrogen receptor alpha (Esr1), progesterone receptor (Pgr), and aromatase (Cyp19a1) was measured using qPCR. Testosterone, 17β-estradiol, and progesterone from serum were also measured. As early as 1 week post-removal, males exhibited increased diencephalic Ar mRNA and circulating testosterone, whereas females had increased Cyp19a1 mRNA in the diencephalon. At 1 month post-removal, females exhibited increased 17β-estradiol and progesterone. The largest changes in steroid hormone receptors were observed in breeders. Breeding females had a threefold increase in Cyp19a1 and fivefold increases in Esr1 and Pgr, whereas breeding males had reduced Pgr and increased Ar. These data demonstrate that sex differences in circulating gonadal steroids and hypothalamic gene expression emerge weeks to months after subordinate animals are removed from reproductive suppression in their home colony.

Effects of OK-432 (picibanil) on the estrogen receptors of MCF-7 cells and potentiation of antiproliferative effects of tamoxifen in combination with OK-432.

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Aoyagi, H; Iino, Y; Takeo, T; Horii, Y; Morishita, Y; Horiuchi, R

1997-01-01

OK-432 (picibanil), a streptococcal preparation, has a strong biological response modifier (BRM) function and is expected to produce clinical improvement and prolongation of survival in treated cancer patients in Japan. We were interested in whether OK-432 augments estrogen receptor (ER) levels in breast cancer. To investigate the effect of the BRMs on cellular growth and the characteristics of ER and progesterone receptors (PgR) in the human breast cancer cell line MCF-7, we used OK-432, Krestin (PSK), a protein-bound polysaccharide extracted from Coriolus versicolor, and lentinan, a fungal branched (1...3)-beta-D-glycan. OK432 and PSK dose dependently inhibited DNA synthesis of MCF-7 cells, and the 50% inhibitory concentrations of OK-432 and PSK were 1.2 KE (klinische Einheit, clinical unit)/ml and 200 micrograms/ml, respectively. Lentinan showed no direct anticancer effect in vitro. We found that OK-432 induced a 2-fold increase in ER levels in MCF-7 cells at 0.005 KE/ml, but not in PgR. Lentinan and low-dose PSK did not change ER or PgR levels, but high-dose PSK decreased ER and PgR. We also studied the combined effect of OK-432 and antiestrogens, tamoxifen (TAM) and DP-TAT-59. The combined treatment with OK-432 and TAM showed an additive inhibitory effect on MCF-7 cells. These results suggest that OK-432 may augment the therapeutic effect of TAM in breast cancer.

ER, PgR, Ki67, p27Kip1, and histological grade as predictors of pathological complete response in patients with HER2-positive breast cancer receiving neoadjuvant chemotherapy using taxanes followed by fluorouracil, epirubicin, and cyclophosphamide concomitant with trastuzumab

International Nuclear Information System (INIS)

Kurozumi, Sasagu; Inoue, Kenichi; Takei, Hiroyuki; Matsumoto, Hiroshi; Kurosumi, Masafumi; Horiguchi, Jun; Takeyoshi, Izumi; Oyama, Tetsunari

2015-01-01

Neoadjuvant chemotherapy (NAC) with taxanes followed by fluorouracil, epirubicin, and cyclophosphamide (FEC), and concurrent trastuzumab is a potent regimen for HER2 over-expressing breast cancer. A high pathological complete response (pCR) rate has been achieved using this regimen; however, the predictive factors and prognostic effects of pCR currently remain unclear. In the present study, we determined whether pCR was related to histological grade (HG) and several biological factors including p27 Kip1 . We also assessed the prognosis of the pCR and non-pCR groups, and expected differences between those positive and negative for lymph node metastasis after chemotherapy. A total of 129 Japanese women with HER2-positive invasive breast cancer received either paclitaxel or docetaxel followed by FEC, with the concomitant administration of trastuzumab. The statuses of HG, ER, PgR, Ki67, and p27 Kip1 were evaluated to determine their relationship with pCR. Relapse-free survival (RFS) and overall survival (OS) were also analyzed for their relationship with pCR and pathological nodal involvement. pCR was obtained in 84 out of 129 patients and the pCR rate was 65.1 %. The pCR rates related to 5 factors were as follows: HG (grade 3, 70.0 % vs. grades 1–2, 36.8 %), ER (negative, 78.6 % vs. positive, 40.0 %), PgR (negative, 75.3 % vs. positive, 38.9 %), Ki67 (high, 72.0 % vs. low, 47.2 %), and p27 Kip1 (low, 71.0 % vs. high, 50.0 %). RFS was significantly better in the pCR group than in the non-pCR group (p = 0.018). Patients with remaining nodal disease in the pCR group had worse OS (p = 0.0002). High-HG, low-ER, low-PgR, high-Ki67, and low-p27 Kip1 were identified as predictive factors of pCR in NAC with trastuzumab, while pCR and negative nodes were predictive of better survivals. The online version of this article (doi:10.1186/s12885-015-1641-y) contains supplementary material, which is available to authorized users

CITED2 modulates estrogen receptor transcriptional activity in breast cancer cells

International Nuclear Information System (INIS)

Lau, Wen Min; Doucet, Michele; Huang, David; Weber, Kristy L.; Kominsky, Scott L.

2013-01-01

Highlights: •The effects of elevated CITED2 on ER function in breast cancer cells are examined. •CITED2 enhances cell growth in the absence of estrogen and presence of tamoxifen. •CITED2 functions as a transcriptional co-activator of ER in breast cancer cells. -- Abstract: Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (CITED2) is a member of the CITED family of non-DNA binding transcriptional co-activators of the p300/CBP-mediated transcription complex. Previously, we identified CITED2 as being overexpressed in human breast tumors relative to normal mammary epithelium. Upon further investigation within the estrogen receptor (ER)-positive subset of these breast tumor samples, we found that CITED2 mRNA expression was elevated in those associated with poor survival. In light of this observation, we investigated the effect of elevated CITED2 levels on ER function. While ectopic overexpression of CITED2 in three ER-positive breast cancer cell lines (MCF-7, T47D, and CAMA-1) did not alter cell proliferation in complete media, growth was markedly enhanced in the absence of exogenous estrogen. Correspondingly, cells overexpressing CITED2 demonstrated reduced sensitivity to the growth inhibitory effects of the selective estrogen receptor modulator, 4-hydroxytamoxifen. Subsequent studies revealed that basal ER transcriptional activity was elevated in CITED2-overexpressing cells and was further increased upon the addition of estrogen. Similarly, basal and estrogen-induced expression of the ER-regulated genes trefoil factor 1 (TFF1) and progesterone receptor (PGR) was higher in cells overexpressing CITED2. Concordant with this observation, ChIP analysis revealed higher basal levels of CITED2 localized to the TFF-1 and PGR promoters in cells with ectopic overexpression of CITED2, and these levels were elevated further in response to estrogen stimulation. Taken together, these data indicate that CITED2 functions as a transcriptional co

Effects of antiandrogenic progestins, chlormadinone and cyproterone acetate, and the estrogen 17α-ethinylestradiol (EE2), and their mixtures: Transactivation with human and rainbowfish hormone receptors and transcriptional effects in zebrafish (Danio rerio) eleuthero-embryos

Energy Technology Data Exchange (ETDEWEB)

Siegenthaler, Patricia Franziska [University of Applied Sciences and Arts Northwestern Switzerland (FHNW), School of Life Sciences, Gründenstrasse 40, CH-4132 Muttenz (Switzerland); Bain, Peter [Commonwealth Scientific and Industrial Research Organisation (CSIRO), Land and Water Flagship, PMB2, Glen Osmond, 5064 South Australia (Australia); Riva, Francesco [IRCCS – Istituto di Ricerche Farmacologiche “Mario Negri”, Environmental Biomarkers Unit, Department of Environmental Health Sciences, Via La Masa 19, I-20156 Milan (Italy); Fent, Karl, E-mail: karl.fent@fhnw.ch [University of Applied Sciences and Arts Northwestern Switzerland (FHNW), School of Life Sciences, Gründenstrasse 40, CH-4132 Muttenz (Switzerland); Swiss Federal Institute of Technology (ETH Zürich), Institute of Biogeochemistry and Pollution Dynamics, Department of Environmental System Sciences, CH-8092 Zürich (Switzerland)

2017-01-15

Highlights: • Agonistic and antagonistic activity of CMA and CPA were assessed in vitro. • CMA and CPA showed different interaction with human and fish receptors. • No progestogenic but antiandrogenic and antiglucocorticoid activity occurred in fish. • CMA and CPA showed transcriptional changes in zebrafish embryos. • Binary mixtures of the progestins with EE2 were assessed in vitro and in vivo. - Abstract: Synthetic progestins act as endocrine disrupters in fish but their risk to the environment is not sufficiently known. Here, we focused on an unexplored antiandrogenic progestin, chlormadinone acetate (CMA), and the antiandrogenic progestin cyproterone acetate (CPA). The aim was to evaluate whether their in vitro interaction with human and rainbowfish (Melanotaenia fluviatilis) sex hormone receptors is similar. Furthermore, we investigated their activity in zebrafish (Danio rerio) eleuthero-embryos. First, we studied agonistic and antagonistic activities of CMA, CPA, and 17α-ethinylestradiol (EE2), in recombinant yeast expressing either the human progesterone (PGR), androgen (AR), or estrogen receptor. The same compounds were also investigated in vitro in a stable transfection cell system expressing rainbowfish nuclear steroid receptors. For human receptors, both progestins exhibited progestogenic, androgenic and antiestrogenic activity with no antiandrogenic or estrogenic activity. In contrast, interactions with rainbowfish receptors showed no progestogenic, but antiandrogenic, antiglucocorticoid, and some antiestrogenic activity. Thus, interaction with and transactivation of human and rainbowfish PGR and AR were distinctly different. Second, we analyzed transcriptional alterations in zebrafish eleuthero‐embryos at 96 and 144 h post fertilization after exposure to CPA, CMA, EE2, and binary mixtures of CMA and CPA with EE2, mimicking the use in oral contraceptives. CMA led to slight down-regulation of the ar transcript, while CPA down-regulated ar

A phase plane graph based model of the ovulatory cycle lacking the "positive feedback" phenomenon

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Kurbel Sven

2012-08-01

Full Text Available Abstract When hormones during the ovulatory cycle are shown in phase plane graphs, reported FSH and estrogen values form a specific pattern that resembles the leaning “&" symbol, while LH and progesterone (Pg values form a "boomerang" shape. Graphs in this paper were made using data reported by Stricker et al. [Clin Chem Lab Med 2006;44:883–887]. These patterns were used to construct a simplistic model of the ovulatory cycle without the conventional "positive feedback" phenomenon. The model is based on few well-established relations: hypothalamic GnRH secretion is increased under estrogen exposure during two weeks that start before the ovulatory surge and lasts till lutheolysis. the pituitary GnRH receptors are so prone to downregulation through ligand binding that this must be important for their function. in several estrogen target tissue progesterone receptor (PgR expression depends on previous estrogen binding to functional estrogen receptors (ER, while Pg binding to the expressed PgRs reduces both ER and PgR expression. Some key features of the presented model are here listed: High GnRH secretion induced by the recovered estrogen exposure starts in the late follicular phase and lasts till lutheolysis. The LH and FSH surges start due to combination of accumulated pituitary GnRH receptors and increased GnRH secretion. The surges quickly end due to partial downregulation of the pituitary GnRH receptors (64% reduction of the follicular phase pituitary GnRH receptors is needed to explain the reported LH drop after the surge. A strong increase in the lutheal Pg blood level, despite modest decline in LH levels, is explained as delayed expression of pituitary PgRs. Postponed pituitary PgRs expression enforces a negative feedback loop between Pg levels and LH secretions not before the mid lutheal phase. Lutheolysis is explained as a consequence of Pg binding to hypothalamic and pituitary PgRs that reduces local ER expression. When hypothalamic

Estrogen Receptor (ESR1) mRNA Expression and Benefit From Tamoxifen in the Treatment and Prevention of Estrogen Receptor–Positive Breast Cancer

Science.gov (United States)

Kim, Chungyeul; Tang, Gong; Pogue-Geile, Katherine L.; Costantino, Joseph P.; Baehner, Frederick L.; Baker, Joffre; Cronin, Maureen T.; Watson, Drew; Shak, Steven; Bohn, Olga L.; Fumagalli, Debora; Taniyama, Yusuke; Lee, Ahwon; Reilly, Megan L.; Vogel, Victor G.; McCaskill-Stevens, Worta; Ford, Leslie G.; Geyer, Charles E.; Wickerham, D. Lawrence; Wolmark, Norman; Paik, Soonmyung

2011-01-01

Purpose Several mechanisms have been proposed to explain tamoxifen resistance of estrogen receptor (ER) –positive tumors, but a clinically useful explanation for such resistance has not been described. Because the ER is the treatment target for tamoxifen, a linear association between ER expression levels and the degree of benefit from tamoxifen might be expected. However, such an association has never been demonstrated with conventional clinical ER assays, and the ER is currently used clinically as a dichotomous marker. We used gene expression profiling and ER protein assays to help elucidate molecular mechanism(s) responsible for tamoxifen resistance in breast tumors. Patients and Methods We performed gene expression profiling of paraffin-embedded tumors from National Surgical Adjuvant Breast and Bowel Project (NSABP) trials that tested the worth of tamoxifen as an adjuvant systemic therapy (B-14) and as a preventive agent (P-1). This was a retrospective subset analysis based on available materials. Results In B-14, ESR1 was the strongest linear predictor of tamoxifen benefit among 16 genes examined, including PGR and ERBB2. On the basis of these data, we hypothesized that, in the P-1 trial, a lower level of ESR1 mRNA in the tamoxifen arm was the main difference between the two study arms. Only ESR1 was downregulated by more than two-fold in ER-positive cancer events in the tamoxifen arm (P < .001). Tamoxifen did not prevent ER-positive tumors with low levels of ESR1 expression. Conclusion These data suggest that low-level expression of ESR1 is a determinant of tamoxifen resistance in ER-positive breast cancer. Strategies should be developed to identify, treat, and prevent such tumors. PMID:21947828

Immunolocalization of progesterone receptors in binucleate trophoblast cells of the buffalo placenta (Bubalus bubalis

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Carlos Eduardo Ambrósio

2007-06-01

Full Text Available The binucleate trophoblast cells (CTBs of the water buffalo placenta (Bubalus bubalis were studied with emphasis on the presence of progesterone receptor. Placentomal tissues from 27 buffalos (2-10 months of pregnancy were processed and embedded in paraplast (Paraplast Embedding Media – Paraplast Plus to locate the progesterone receptors using the immunohistochemistry technique. The immunohistochemical reaction for progesterone receptor through monoclonal antibody PgR Ab2 showed staining of CTBs, caruncular epithelial and estromal cells and blood vessel estromal pericitos present in the placentome throughout the entire gestational period analyzed. These results indicate the production of progesterone with autocrine and paracrine action in the placentome growth, differentiation and functional regulation.

Molecular risk assessment of BIG 1-98 participants by expression profiling using RNA from archival tissue

International Nuclear Information System (INIS)

Antonov, Janine; Altermatt, Hans Jörg; Aebi, Stefan; Jaggi, Rolf; Popovici, Vlad; Delorenzi, Mauro; Wirapati, Pratyaksha; Baltzer, Anna; Oberli, Andrea; Thürlimann, Beat; Giobbie-Hurder, Anita; Viale, Giuseppe

2010-01-01

The purpose of the work reported here is to test reliable molecular profiles using routinely processed formalin-fixed paraffin-embedded (FFPE) tissues from participants of the clinical trial BIG 1-98 with a median follow-up of 60 months. RNA from fresh frozen (FF) and FFPE tumor samples of 82 patients were used for quality control, and independent FFPE tissues of 342 postmenopausal participants of BIG 1-98 with ER-positive cancer were analyzed by measuring prospectively selected genes and computing scores representing the functions of the estrogen receptor (eight genes, ER-8), the progesterone receptor (five genes, PGR-5), Her2 (two genes, HER2-2), and proliferation (ten genes, PRO-10) by quantitative reverse transcription PCR (qRT-PCR) on TaqMan Low Density Arrays. Molecular scores were computed for each category and ER-8, PGR-5, HER2-2, and PRO-10 scores were combined into a RISK-25 score. Pearson correlation coefficients between FF- and FFPE-derived scores were at least 0.94 and high concordance was observed between molecular scores and immunohistochemical data. The HER2-2, PGR-5, PRO-10 and RISK-25 scores were significant predictors of disease free-survival (DFS) in univariate Cox proportional hazard regression. PRO-10 and RISK-25 scores predicted DFS in patients with histological grade II breast cancer and in lymph node positive disease. The PRO-10 and PGR-5 scores were independent predictors of DFS in multivariate Cox regression models incorporating clinical risk indicators; PRO-10 outperformed Ki-67 labeling index in multivariate Cox proportional hazard analyses. Scores representing the endocrine responsiveness and proliferation status of breast cancers were developed from gene expression analyses based on RNA derived from FFPE tissues. The validation of the molecular scores with tumor samples of participants of the BIG 1-98 trial demonstrates that such scores can serve as independent prognostic factors to estimate disease free survival (DFS) in

Molecular essence and endocrine responsiveness of estrogen receptor-negative, progesterone receptor-positive, and HER2-negative breast cancer.

Science.gov (United States)

Yu, Ke-Da; Jiang, Yi-Zhou; Hao, Shuang; Shao, Zhi-Ming

2015-10-05

The clinical significance of progesterone receptor (PgR) expression in estrogen receptor-negative (ER-) breast cancer is controversial. Herein, we systemically investigate the clinicopathologic features, molecular essence, and endocrine responsiveness of ER-/PgR+/HER2- phenotype. Four study cohorts were included. The first and second cohorts were from the Surveillance, Epidemiology, and End Results database (n = 67,932) and Fudan University Shanghai Cancer Center (n = 2,338), respectively, for clinicopathologic and survival analysis. The third and fourth cohorts were from two independent publicly available microarray datasets including 837 operable cases and 483 cases undergoing neoadjuvant chemotherapy, respectively, for clinicopathologic and gene-expression analysis. Characterized genes defining subgroups within the ER-/PgR+/HER2- phenotype were determined and further validated. Clinicopathologic features and survival outcomes of the ER-/PgR+ phenotype fell in between the ER+/PgR+ and ER-/PgR- phenotypes, but were more similar to ER-/PgR-. Among the ER-/PgR+ phenotype, 30% (95% confidence interval [CI] 17-42%, pooled by a fixed-effects method) were luminal-like and 59% (95% CI 45-72%, pooled by a fixed-effects method) were basal-like. We further refined the characterized genes for subtypes within the ER-/PgR+ phenotype and developed an immunohistochemistry-based method that could determine the molecular essence of ER-/PgR+ using three markers, TFF1, CK5, and EGFR. Either PAM50-defined or immunohistochemistry-defined basal-like ER-/PgR+ cases have a lower endocrine therapy sensitivity score compared with luminal-like ER-/PgR+ cases (P defined basal-like ER-/PgR+ cases might not benefit from adjuvant endocrine therapy (log-rank P = 0.61 for sufficient versus insufficient endocrine therapy). The majority of ER-/PgR+/HER2- phenotype breast cancers are basal-like and associated with a lower endocrine therapy sensitivity score. Additional studies are needed

A double-labeling assay for simultaneous estimation and characterization of estrogen and progesterone receptors using radioiodinated estradiol and tritiaded Org 2058

International Nuclear Information System (INIS)

Ronchi, E.; Granata, G.; Brivio, M.

1986-01-01

Estrogen (ER) and progesterone receptors (PgR) appear to be a perequisite to elicit a biologic response by a hormone-target organ. Current methodologies for analysis of these proteins (e.g:dextran-coated charcoal, DCC) in single-label assay (SLA) require relatively large amounts of tissue material, time and laboriousness. Therefore, the authors have developed for breast cancer tissue an improved dual-label assay (DLA) for simultaneous titration (by DCC) and/or characterization (by sedimentation properties) of ER and PgR on the same sample, using *H1*H2*H5I-E*L2 and *H3H-Org 2058 as tracers. The interaction of *H1*H2*H5I-E*L2 with ER and plasma proteins in comparison to *H3H-E*L2 was studied in terms of specificity, time course, affinity binding and sedimentation pattern. *H1*H2*H5I-E*L2 bound the same molecular forms displayed by *H3H-E*L2 (9 and 3S) but with lower titers (about 1.3-fold), irrespective of the technique used, and did not bind to sex hormone-binding globulin. Simultaneous detection of *H1*H2*H5I and *H3H was achieved by use of a gamma counter plus a beta counter sequentially. ER and PgR titrations with DCC in DLA were in good agreement with those obtained with SLA, in terms of titers and Ka values. An analogous results was obtained with sucrose density gradient (SDG) analysis. Both the DLA methods were highly reproducible (CV<8.0%). Between the rotors available for SDG, the vertical one was preferable because of the larger number of samples processed and of less purturbation of sedimenting receptor molecules. Furthermore, a biochemical applications of the method is described. In conclusion, the DLA procedure, by simplifying ER and PgR estimation, makes it possible to study, even on small tumor biopsies, the molecular properties of these proteins in relation to the clinical response of the disease

Uterine progesterone signaling is a target for metformin therapy in PCOS-like rats.

Science.gov (United States)

Hu, Min; Zhang, Yuehui; Feng, Jiaxing; Xu, Xue; Zhang, Jiao; Zhao, Wei; Guo, Xiaozhu; Li, Juan; Vestin, Edvin; Cui, Peng; Li, Xin; Wu, Xiao-Ke; Brännström, Mats; Shao, Linus R; Billig, Håkan

2018-05-01

Impaired progesterone (P4) signaling is linked to endometrial dysfunction and infertility in women with polycystic ovary syndrome (PCOS). Here, we report for the first time that elevated expression of progesterone receptor (PGR) isoforms A and B parallels increased estrogen receptor (ER) expression in PCOS-like rat uteri. The aberrant PGR-targeted gene expression in PCOS-like rats before and after implantation overlaps with dysregulated expression of Fkbp52 and Ncoa2 , two genes that contribute to the development of uterine P4 resistance. In vivo and in vitro studies of the effects of metformin on the regulation of the uterine P4 signaling pathway under PCOS conditions showed that metformin directly inhibits the expression of PGR and ER along with the regulation of several genes that are targeted dependently or independently of PGR-mediated uterine implantation. Functionally, metformin treatment corrected the abnormal expression of cell-specific PGR and ER and some PGR-target genes in PCOS-like rats with implantation. Additionally, we documented how metformin contributes to the regulation of the PGR-associated MAPK/ERK/p38 signaling pathway in the PCOS-like rat uterus. Our data provide novel insights into how metformin therapy regulates uterine P4 signaling molecules under PCOS conditions. © 2018 Society for Endocrinology.

Positive regulation of raphe serotonin neurons by serotonin 2B receptors.

Science.gov (United States)

Belmer, Arnauld; Quentin, Emily; Diaz, Silvina L; Guiard, Bruno P; Fernandez, Sebastian P; Doly, Stéphane; Banas, Sophie M; Pitychoutis, Pothitos M; Moutkine, Imane; Muzerelle, Aude; Tchenio, Anna; Roumier, Anne; Mameli, Manuel; Maroteaux, Luc

2018-06-01

Serotonin is a neurotransmitter involved in many psychiatric diseases. In humans, a lack of 5-HT 2B receptors is associated with serotonin-dependent phenotypes, including impulsivity and suicidality. A lack of 5-HT 2B receptors in mice eliminates the effects of molecules that directly target serotonergic neurons including amphetamine derivative serotonin releasers, and selective serotonin reuptake inhibitor antidepressants. In this work, we tested the hypothesis that 5-HT 2B receptors directly and positively regulate raphe serotonin neuron activity. By ex vivo electrophysiological recordings, we report that stimulation by the 5-HT 2B receptor agonist, BW723C86, increased the firing frequency of serotonin Pet1-positive neurons. Viral overexpression of 5-HT 2B receptors in these neurons increased their excitability. Furthermore, in vivo 5-HT 2B -receptor stimulation by BW723C86 counteracted 5-HT 1A autoreceptor-dependent reduction in firing rate and hypothermic response in wild-type mice. By a conditional genetic ablation that eliminates 5-HT 2B receptor expression specifically and exclusively from Pet1-positive serotonin neurons (Htr2b 5-HTKO mice), we demonstrated that behavioral and sensitizing effects of MDMA (3,4-methylenedioxy-methamphetamine), as well as acute behavioral and chronic neurogenic effects of the antidepressant fluoxetine, require 5-HT 2B receptor expression in serotonergic neurons. In Htr2b 5-HTKO mice, dorsal raphe serotonin neurons displayed a lower firing frequency compared to control Htr2b lox/lox mice as assessed by in vivo extracellular recordings and a stronger hypothermic effect of 5-HT 1A -autoreceptor stimulation was observed. The increase in head-twitch response to DOI (2,5-dimethoxy-4-iodoamphetamine) further confirmed the lower serotonergic tone resulting from the absence of 5-HT 2B receptors in serotonin neurons. Together, these observations indicate that the 5-HT 2B receptor acts as a direct positive modulator of serotonin Pet1

Mouse models of estrogen receptor-positive breast cancer

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Shakur Mohibi

2011-01-01

Full Text Available Breast cancer is the most frequent malignancy and second leading cause of cancer-related deaths among women. Despite advances in genetic and biochemical analyses, the incidence of breast cancer and its associated mortality remain very high. About 60 - 70% of breast cancers are Estrogen Receptor alpha (ER-α positive and are dependent on estrogen for growth. Selective estrogen receptor modulators (SERMs have therefore provided an effective targeted therapy to treat ER-α positive breast cancer patients. Unfortunately, development of resistance to endocrine therapy is frequent and leads to cancer recurrence. Our understanding of molecular mechanisms involved in the development of ER-α positive tumors and their resistance to ER antagonists is currently limited due to lack of experimental models of ER-α positive breast cancer. In most mouse models of breast cancer, the tumors that form are typically ER-negative and independent of estrogen for their growth. However, in recent years more attention has been given to develop mouse models that develop different subtypes of breast cancers, including ER-positive tumors. In this review, we discuss the currently available mouse models that develop ER-α positive mammary tumors and their potential use to elucidate the molecular mechanisms of ER-α positive breast cancer development and endocrine resistance.

Progesterone receptor variation and risk of ovarian cancer is limited to the invasive endometrioid subtype: results from the Ovarian Cancer Association Consortium pooled analysis

DEFF Research Database (Denmark)

Pearce, C.L.; Wu, A.H.; Gayther, S.A.

2008-01-01

There is evidence that progesterone plays a role in the aetiology of invasive epithelial ovarian cancer. Therefore, genes involved in pathways that regulate progesterone may be candidates for susceptibility to this disease. Previous studies have suggested that genetic variants in the progesterone...... receptor gene (PGR) may be associated with ovarian cancer risk, although results have been inconsistent. We have established an international consortium to pool resources and data from many ovarian cancer case-control studies in an effort to identify variants that influence risk. In this study, three PGR...... single nucleotide polymorphisms (SNPs), for which previous data have suggested they affect ovarian cancer risk, were examined. These were +331 C/T (rs10895068), PROGINS (rs1042838), and a 3' variant (rs608995). A total of 4788 ovarian cancer cases and 7614 controls from 12 case-control studies were...

Hormone Receptor Expression Analyses in Neoplastic and Non-Neoplastic Canine Mammary Tissue by a Bead Based Multiplex Branched DNA Assay: A Gene Expression Study in Fresh Frozen and Formalin-Fixed, Paraffin-Embedded Samples.

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Annika Mohr

Full Text Available Immunohistochemistry (IHC is currently considered the method of choice for steroid hormone receptor status evaluation in human breast cancer and, therefore, it is commonly utilized for assessing canine mammary tumors. In case of low hormone receptor expression, IHC is limited and thus is complemented by molecular analyses. In the present study, a multiplex bDNA assay was evaluated as a method for hormone receptor gene expression detection in canine mammary tissues. Estrogen receptor (ESR1, progesterone receptor (PGR, prolactin receptor (PRLR and growth hormone receptor (GHR gene expressions were evaluated in neoplastic and non-neoplastic canine mammary tissues. A set of 119 fresh frozen and 180 formalin-fixed, paraffin-embedded (FFPE was comparatively analyzed and used for assay evaluation. Furthermore, a possible association between the hormone receptor expression in different histological subtypes of canine malignant mammary tumors and the castration status, breed and invasive growth of the tumor were analyzed. The multiplex bDNA assay proved to be more sensitive for fresh frozen specimens. Hormone receptor expression found was significantly decreased in malignant mammary tumors in comparison to non-neoplastic tissue and benign mammary tumors. Among the histological subtypes the lowest gene expression levels of ESR1, PGR and PRLR were found in solid, anaplastic and ductal carcinomas. In summary, the evaluation showed that the measurement of hormone receptors with the multiplex bDNA assay represents a practicable method for obtaining detailed quantitative information about gene expression in canine mammary tissue for future studies. Still, comparison with IHC or quantitative real-time PCR is needed for further validation of the present method.

Preoperative core needle biopsy is accurate in determining molecular subtypes in invasive breast cancer

International Nuclear Information System (INIS)

Chen, Xiaosong; Yuan, Ying; Fei, Xiaochun; Jin, Xiaolong; Shen, Kunwei; Sun, Long; Mao, Yan; Zhu, Siji; Wu, Jiayi; Huang, Ou; Li, Yafen; Chen, Weiguo; Wang, Jianhua

2013-01-01

Estrogen receptor (ER), progesterone receptor (PgR), HER2, and Ki67 have been increasingly evaluated by core needle biopsy (CNB) and are recommended for classifying breast cancer into molecular subtypes. However, the concordance rate between CNB and open excision biopsy (OEB) has not been well documented. Patients with paired CNB and OEB samples from Oct. 2009 to Feb. 2012 in Ruijin Hospital were included. ER, PgR, HER2, and Ki67 were determined by immunohistochemistry (IHC). Patients with HER2 IHC 2+ were further examined by FISH. Cutoff value for Ki67 high expression was 14%. Molecular subtypes were constructed as follows: Luminal A, Luminal B, Triple Negative, and HER2 positive. There were 298 invasive breast cancer patients analyzed. Concordance rates for ER, PgR, and HER2 were 93.6%, 85.9%, and 96.3%, respectively. Ki67 expression was slightly higher in OEB than in CNB samples (29.3% vs. 26.8%, P = 0.046). Good agreement (κ = 0.658) was demonstrated in evaluating molecular subtypes between CNB and OEB, with a concordance rate of 77.2%. We also used a different Ki67 cutoff value (20%) for determining Luminal A and B subtypes in HR (hormone receptor) +/HER2- diseases and the overall concordance rate was 79.2%. However, using a cut-point of Ki67 either 14% or 20% for both specimens, there will be about 14% of HR+/HER2- specimens that are called Luminal A on CNB and Luminal B on OEB. CNB was accurate in determining ER, PgR, and HER2 status as well as non-Luminal molecular subtypes in invasive breast cancer. Ki67 should be retested on OEB samples in HR+/HER2- patients to accurately distinguish Luminal A from B tumors

Experimental peptide receptor radionuclide therapy in radioiodine negative somatostatin receptor positive thyroid cancer

International Nuclear Information System (INIS)

Nilica, B.; Kroiss, A.; Putzer, D.; Uprimmy, C.; Warwitz, B.; Kendler, D.; Waitz, D.; Virgolini, I.

2015-01-01

Full text of publication follows. Purpose: This retrospective analysis evaluated the time to progression (TTP), progression free survival (PFS) and overall survival (OS) in patients with radioiodine negative thyroid cancer who had undergone peptide receptor radionuclide therapy (PRRT) with 177 Lu-DOTA-TATE, 177 Lu-DOTA-LAN, 90 Y-DOTA-TOC or 90 Y-DOTA-LAN after tumor progression. Methods: Data derived from twenty patients with either differentiated (n=15), anaplastic (n=1) or medullary (n=4) somatostatin receptor positive thyroid cancer who had received treatment with PRRT after tumor progression. TTP, PFS and OS were defined according to the clinical trial endpoints suggested by the FDA (Food and Drug Administration). Progressive disease was defined by sonography, FDG-PET, Ga-DOTA-TOC-PET, or CT (RECIST Criteria). Results: In 17 patients the median overall survival time after the first PRRT was 17.3 (range: 0.1 - 109.7) months. Three patients still alive are actually showing stable disease. The median of PFS in 20 Patients (6 with more than one PRRT-cycle or PRRT-substance) has been 10.9 (range: 0.1 - 44.0) months. The median TTP was 15.6 (range 4.4 to 29.2) months. Conclusion: PRRT appears to be useful in patients with somatostatin receptor positive but radioiodine negative thyroid cancer as a complementary palliative cytotoxic therapy. (authors)

Positive modulation of delta-subunit containing GABAA receptors in mouse neurons

DEFF Research Database (Denmark)

Vardya, Irina; Hoestgaard-Jensen, Kirsten; Nieto-Gonzalez, Jose Luis

2012-01-01

δ-subunit containing extrasynaptic GABA(A) receptors are potential targets for modifying neuronal activity in a range of brain disorders. With the aim of gaining more insight in synaptic and extrasynaptic inhibition, we used a new positive modulator, AA29504, of δ-subunit containing GABA(A) recep......δ-subunit containing extrasynaptic GABA(A) receptors are potential targets for modifying neuronal activity in a range of brain disorders. With the aim of gaining more insight in synaptic and extrasynaptic inhibition, we used a new positive modulator, AA29504, of δ-subunit containing GABA......(A) receptors in mouse neurons in vitro and in vivo. Whole-cell patch-clamp recordings were carried out in the dentate gyrus in mouse brain slices. In granule cells, AA29504 (1 μM) caused a 4.2-fold potentiation of a tonic current induced by THIP (1 μM), while interneurons showed a potentiation of 2.6-fold......-free environment using Ca²⁺ imaging in cultured neurons, AA29504 showed GABA(A) receptor agonism in the absence of agonist. Finally, AA29504 exerted dose-dependent stress-reducing and anxiolytic effects in mice in vivo. We propose that AA29504 potentiates δ-containing GABA(A) receptors to enhance tonic inhibition...

Do position and size matter? An analysis of cage and placement variables for optimum lordosis in PLIF reconstruction.

Science.gov (United States)

Landham, Priyan R; Don, Angus S; Robertson, Peter A

2017-11-01

To examine monosegmental lordosis after posterior lumbar interbody fusion (PLIF) surgery and relate lordosis to cage size, shape, and placement. Eighty-three consecutive patients underwent single-level PLIF with paired identical lordotic cages involving a wide decompression and bilateral facetectomies. Cage parameters relating to size (height, lordosis, and length) and placement (expressed as a ratio relative to the length of the inferior vertebral endplate) were recorded. Centre point ratio (CPR) was the distance to the centre of both cages and indicated mean position of both cages. Posterior gap ratio (PGR) was the distance to the most posterior cage and indicated position and cage length indirectly. Relationships between lordosis and cage parameters were explored. Mean lordosis increased by 5.98° (SD 6.86°). The cages used varied in length from 20 to 27 mm, in lordosis from 10° to 18°, and in anterior cage height from 10 to 17 mm. The mean cage placement as determined by CPR was 0.54 and by PGR was 0.16. The significant correlations were: both CPR and PGR with lordosis gain at surgery (r = 0.597 and 0.537, respectively, p lordosis with the final lordosis (r = 0.234, p lordosis (r = -0.297, p lordosis during PLIF surgery. Anterior placement with sufficient "clear space" behind the cages is recommended. In addition, cages should be of moderate height and length, so that they act as an effective pivot for lordosis.

NCBI nr-aa BLAST: CBRC-BTAU-01-2489 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-BTAU-01-2489 ref|NP_997055.1| G protein-coupled receptor for asthma susceptibi... (G-protein coupled receptor for asthma susceptibility) (G-protein coupled receptor PGR14) gb|AAQ76966.1| GP

NCBI nr-aa BLAST: CBRC-RNOR-08-0112 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-RNOR-08-0112 ref|NP_997055.1| G protein-coupled receptor for asthma susceptibi... (G-protein coupled receptor for asthma susceptibility) (G-protein coupled receptor PGR14) gb|AAQ76966.1| GP

NCBI nr-aa BLAST: CBRC-RMAC-03-0034 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-RMAC-03-0034 ref|NP_997055.1| G protein-coupled receptor for asthma susceptibi... (G-protein coupled receptor for asthma susceptibility) (G-protein coupled receptor PGR14) gb|AAQ76966.1| GP

NCBI nr-aa BLAST: CBRC-HSAP-07-0022 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-HSAP-07-0022 ref|NP_997055.1| G protein-coupled receptor for asthma susceptibi... (G-protein coupled receptor for asthma susceptibility) (G-protein coupled receptor PGR14) gb|AAQ76966.1| GP

NCBI nr-aa BLAST: CBRC-PABE-08-0027 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-PABE-08-0027 ref|NP_997055.1| G protein-coupled receptor for asthma susceptibi... (G-protein coupled receptor for asthma susceptibility) (G-protein coupled receptor PGR14) gb|AAQ76966.1| GP

NCBI nr-aa BLAST: CBRC-PTRO-08-0021 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-PTRO-08-0021 ref|NP_997055.1| G protein-coupled receptor for asthma susceptibi... (G-protein coupled receptor for asthma susceptibility) (G-protein coupled receptor PGR14) gb|AAQ76966.1| GP

NCBI nr-aa BLAST: CBRC-OGAR-01-0527 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-OGAR-01-0527 ref|NP_997055.1| G protein-coupled receptor for asthma susceptibi... (G-protein coupled receptor for asthma susceptibility) (G-protein coupled receptor PGR14) gb|AAQ76966.1| GP

NCBI nr-aa BLAST: CBRC-CFAM-14-0061 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-CFAM-14-0061 ref|NP_997055.1| G protein-coupled receptor for asthma susceptibi... (G-protein coupled receptor for asthma susceptibility) (G-protein coupled receptor PGR14) gb|AAQ76966.1| GP

Adult celiac disease with acetylcholine receptor antibody positive myasthenia gravis

Institute of Scientific and Technical Information of China (English)

Hugh J Freeman; Helen R Gillett; Peter M Gillett; Joel Oger

2009-01-01

Celiac disease has been associated with some autoimmune disorders. A 40-year-old competitive strongman with celiac disease responded to a glutenfree diet, but developed profound and generalized motor weakness with acetylcholine receptor antibody positive myasthenia gravis, a disorder reported to occur in about 1 in 5000. This possible relationship between myasthenia gravis and celiac disease was further explored in serological studies. Frozen stored serum samples from 23 acetylcholine receptor antibody positive myasthenia gravis patients with no intestinal symptoms were used to screen for celiac disease. Both endomysial and tissue transglutaminase antibodies were examined. One of 23 (or, about 4.3%) was positive for both IgA-endomysial and IgA tissue transglutaminase antibodies. Endoscopic studies subsequently showed duodenal mucosal scalloping and biopsies confirmed the histopathological changes of celiac disease. Celiac disease and myasthenia gravis may occur together more often than is currently appreciated. The presence of motor weakness in celiac disease may be a clue to occult myasthenia gravis, even in the absence of intestinal symptoms.

Lipid-rich histology in a basal-type immunoprofile breast carcinoma: histochemical and immunohistochemical analysis of a case

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Francesco Maria Maiello

2009-12-01

Full Text Available We describe the clinicopathological and morphological features of an unusual breast carcinoma classifiable as a lipid-rich variant of ductal invasive carcinoma, with a basal-type immunohistochemical profile. Basal-type breast cancers show no hormonal receptor expression, rarely over-express HER-2 but exhibit molecular high weight cytokeratins, EGFR and c-kit positivity. Special stains and histochemistry tests were used to elucidate the nature of vescicles in the neoplastic cells. Sudan IV was performed on formalin-fixed tissue. Commercially available antibodies tested were: ER, PgR, EGFR, HER2, c-kit, high molecular weight cytokeratins. Cytoplasmic lipids were highlighted as red-orange droplets on Sudan IV staining. As for immunohistochemistry, the tumor showed no reactivity to ER, PgR and HER2 (triple negative, and diffuse and strong positivity to high weight cytokeratins, EGFR and c-kit, such as a basal-type breast carcinoma. A basaloid phenotype in a lipid-rich carcinoma has not been previously reported.

Differential Potency of 2,6-Dimethylcyclohexanol Isomers for Positive Modulation of GABAA Receptor Currents.

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Chowdhury, Luvana; Croft, Celine J; Goel, Shikha; Zaman, Naina; Tai, Angela C-S; Walch, Erin M; Smith, Kelly; Page, Alexandra; Shea, Kevin M; Hall, C Dennis; Jishkariani, D; Pillai, Girinath G; Hall, Adam C

2016-06-01

GABAA receptors meet all of the pharmacological requirements necessary to be considered important targets for the action of general anesthetic agents in the mammalian brain. In the following patch-clamp study, the relative modulatory effects of 2,6-dimethylcyclohexanol diastereomers were investigated on human GABAA (α1β3γ2s) receptor currents stably expressed in human embryonic kidney cells. Cis,cis-, trans,trans-, and cis,trans-isomers were isolated from commercially available 2,6-dimethylcyclohexanol and were tested for positive modulation of submaximal GABA responses. For example, the addition of 30 μM cis,cis-isomer resulted in an approximately 2- to 3-fold enhancement of the EC20 GABA current. Coapplications of 30 μM 2,6-dimethylcyclohexanol isomers produced a range of positive enhancements of control GABA responses with a rank order for positive modulation: cis,cis > trans,trans ≥ mixture of isomers > > cis,trans-isomer. In molecular modeling studies, the three cyclohexanol isomers bound with the highest binding energies to a pocket within transmembrane helices M1 and M2 of the β3 subunit through hydrogen-bonding interactions with a glutamine at the 224 position and a tyrosine at the 220 position. The energies for binding to and hydrogen-bond lengths within this pocket corresponded with the relative potencies of the agents for positive modulation of GABAA receptor currents (cis,cis > trans,trans > cis,trans-2,6-dimethylcyclohexanol). In conclusion, the stereochemical configuration within the dimethylcyclohexanols is an important molecular feature in conferring positive modulation of GABAA receptor activity and for binding to the receptor, a consideration that needs to be taken into account when designing novel anesthetics with enhanced therapeutic indices. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Reliable PCR quantitation of estrogen, progesterone and ERBB2 receptor mRNA from formalin-fixed, paraffin-embedded tissue is independent of prior macro-dissection

DEFF Research Database (Denmark)

Tramm, Trine; Hennig, Guido; Kyndi, Marianne

2013-01-01

Gene expression analysis on messenger RNA (mRNA) purified from formalin-fixed, paraffin-embedded tissue is increasingly used for research purposes. Tissue heterogeneity may question specificity and interpretation of results from mRNA isolated from a whole slide section, and thresholds for minimal...... tumor content in the paraffin block or macrodissection are used to avoid contamination from non-neoplastic tissue. The aim was to test if mRNA from tissue surrounding breast cancer affected quantification of estrogen receptor α (ESR1), progesterone receptor (PGR) and human epidermal growth factor...... receptor 2 (ERBB2), by comparing gene expression from whole slide and tumor-enriched sections, and correlating gene expression from whole slide sections with corresponding immunohistochemistry. Gene expression, based on mRNA extracted from a training set (36 paraffin blocks) and two validation sets (133...

Positive selection within the Schizophrenia-associated GABA(A receptor beta(2 gene.

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Wing-Sze Lo

Full Text Available The gamma-aminobutyric acid type-A (GABA(A receptor plays a major role in inhibitory neurotransmissions. Intronic SNPs and haplotypes in GABRB2, the gene for GABA(A receptor beta(2 subunit, are associated with schizophrenia and correlated with the expression of two alternatively spliced beta(2 isoforms. In the present study, using chimpanzee as an ancestral reference, high frequencies were observed for the derived (D alleles of the four SNPs rs6556547, rs187269, rs1816071 and rs1816072 in GABRB2, suggesting the occurrence of positive selection for these derived alleles. Coalescence-based simulation showed that the population frequency spectra and the frequencies of H56, the haplotype having all four D alleles, significantly deviated from neutral-evolution expectation in various demographic models. Haplotypes containing the derived allele of rs1816072 displayed significantly less diversity compared to haplotypes containing its ancestral allele, further supporting positive selection. The variations in DD-genotype frequencies in five human populations provided a snapshot of the evolutionary history, which suggested that the positive selections of the D alleles are recent and likely ongoing. The divergence between the DD-genotype profiles of schizophrenic and control samples pointed to the schizophrenia-relevance of positive selections, with the schizophrenic samples showing weakened selections compared to the controls. These DD-genotypes were previously found to increase the expression of beta(2, especially its long isoform. Electrophysiological analysis showed that this long beta(2 isoform favored by the positive selections is more sensitive than the short isoform to the inhibition of GABA(A receptor function by energy depletion. These findings represent the first demonstration of positive selection in a schizophrenia-associated gene.

Coordinated Regulation Among Progesterone, Prostaglandins, and EGF-Like Factors in Human Ovulatory Follicles.

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Choi, Yohan; Wilson, Kalin; Hannon, Patrick R; Rosewell, Katherine L; Brännström, Mats; Akin, James W; Curry, Thomas E; Jo, Misung

2017-06-01

In animal models, the luteinizing hormone surge increases progesterone (P4) and progesterone receptor (PGR), prostaglandins (PTGs), and epidermal growth factor (EGF)-like factors that play essential roles in ovulation. However, little is known about the expression, regulation, and function of these key ovulatory mediators in humans. To determine when and how these key ovulatory mediators are induced after the luteinizing hormone surge in human ovaries. Timed periovulatory follicles were obtained from cycling women. Granulosa/lutein cells were collected from in vitro fertilization patients. The in vivo and in vitro expression of PGR, PTG synthases and transporters, and EGF-like factors were examined at the level of messenger RNA and protein. PGR binding to specific genes was assessed. P4 and PTGs in conditioned media were measured. PGR, PTGS2, and AREG expressions dramatically increased in ovulatory follicles at 12 to 18 hours after human chorionic gonadotropin (hCG). In human granulosa/lutein cell cultures, hCG increased P4 and PTG production and the expression of PGR, specific PTG synthases and transporters, and EGF-like factors, mimicking in vivo expression patterns. Inhibitors for P4/PGR and EGF-signaling pathways reduced hCG-induced increases in PTG production and the expression of EGF-like factors. PGR bound to the PTGS2, PTGES, and SLCO2A1 genes. This report demonstrated the time-dependent induction of PGR, AREG, and PTGS2 in human periovulatory follicles. In vitro studies indicated that collaborative actions of P4/PGR and EGF signaling are required for hCG-induced increases in PTG production and potentiation of EGF signaling in human periovulatory granulosa cells. Copyright © 2017 Endocrine Society

Ly49Q, an ITIM-bearing NK receptor, positively regulates osteoclast differentiation

International Nuclear Information System (INIS)

Hayashi, Mikihito; Nakashima, Tomoki; Kodama, Tatsuhiko; Makrigiannis, Andrew P.; Toyama-Sorimachi, Noriko; Takayanagi, Hiroshi

2010-01-01

Osteoclasts, multinucleated cells that resorb bone, play a key role in bone remodeling. Although immunoreceptor tyrosine-based activation motif (ITAM)-mediated signaling is critical for osteoclast differentiation, the significance of immunoreceptor tyrosine-based inhibitory motif (ITIM) has not been well understood. Here we report the function of Ly49Q, an Ly49 family member possessing an ITIM motif, in osteoclastogenesis. Ly49Q is selectively induced by receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL) stimulation in bone marrow-derived monocyte/macrophage precursor cells (BMMs) among the Ly49 family of NK receptors. The knockdown of Ly49Q resulted in a significant reduction in the RANKL-induced formation of tartrate-resistance acid phosphatase (TRAP)-positive multinucleated cells, accompanied by a decreased expression of osteoclast-specific genes such as Nfatc1, Tm7sf4, Oscar, Ctsk, and Acp5. Osteoclastogenesis was also significantly impaired in Ly49Q-deficient cells in vitro. The inhibitory effect of Ly49Q-deficiency may be explained by the finding that Ly49Q competed for the association of Src-homology domain-2 phosphatase-1 (SHP-1) with paired immunoglobulin-like receptor-B (PIR-B), an ITIM-bearing receptor which negatively regulates osteoclast differentiation. Unexpectedly, Ly49Q deficiency did not lead to impaired osteoclast formation in vivo, suggesting the existence of a compensatory mechanism. This study provides an example in which an ITIM-bearing receptor functions as a positive regulator of osteoclast differentiation.

Receptor-mediated targeting of 67Ga-Deferoxamine-Folate to folate-receptor-positive human kb tumor xenografts

International Nuclear Information System (INIS)

Mathias, Carla J.; Wang, Susan; Low, Philip S.; Waters, David J.; Green, Mark A.

1999-01-01

The radiochemical synthesis and stability of 67 Ga-deferoxamine-folate ([ 67 Ga]Ga-DF-Folate) were examined as a function of DF-Folate concentration. Optimal labeling occurred at DF-Folate concentrations ≥2.5 μg/mL. To define the possible biological significance of variations in product formulation, the biodistribution of [ 67 Ga]Ga-DF-Folate was examined as a function of administered deferoxamine-folate dose in an athymic mouse KB tumor model. The folate-receptor-positive KB tumors were found to concentrate the 67 Ga radiolabel in a dose-dependent fashion, consistent with saturable involvement of the folate receptor in mediating tumor accumulation of the radiopharmaceutical

Pharmacologic management of bone-related complications and bone metastases in postmenopausal women with hormone receptor-positive breast cancer

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Yardley DA

2016-05-01

Full Text Available Denise A Yardley1,2 1Sarah Cannon Research Institute, Nashville, TN, USA; 2Tennessee Oncology, Nashville, TN, USA Abstract: There is a high risk for bone loss and skeletal-related events, including bone metastases, in postmenopausal women with hormone receptor-positive breast cancer. Both the disease itself and its therapeutic treatments can negatively impact bone, resulting in decreases in bone mineral density and increases in bone loss. These negative effects on the bone can significantly impact morbidity and mortality. Effective management and minimization of bone-related complications in postmenopausal women with hormone receptor-positive breast cancer remain essential. This review discusses the current understanding of molecular and biological mechanisms involved in bone turnover and metastases, increased risk for bone-related complications from breast cancer and breast cancer therapy, and current and emerging treatment strategies for managing bone metastases and bone turnover in postmenopausal women with hormone receptor-positive breast cancer. Keywords: breast cancer, bone metastases, hormone receptor-positive, bone-related complications, interventions, management and management strategies, estrogen receptor-positive

Expression of steroid receptors in ameloblasts during amelogenesis in rat incisors

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Sophia Houari

2016-11-01

Full Text Available Endocrine disrupting chemicals (EDCs play a part in the modern burst of diseases and interfere with the steroid hormone axis. Bisphenol A (BPA, one of the most active and widely used EDCs, affects ameloblast functions, leading to an enamel hypomineralization pattern similar to that of Molar Incisor Hypomineralization (MIH. In order to explore the molecular pathways stimulated by BPA during amelogenesis, we thoroughly investigated the receptors known to directly or indirectly mediate the effects of BPA. The expression patterns of high affinity BPA receptors (ERRγ, GPR30, of ketosteroid receptors (ERs, AR, PGR, GR, MR, of the retinoid receptor RXRα and PPARγ were established using RT-qPCR analysis of RNAs extracted from microdissected enamel organ of adult rats. Their expression was dependent on the stage of ameloblast differentiation, except that of ERβ and PPARγ which remained undetectable. An additional large scale microarray analysis revealed three main groups of receptors according to their level of expression in maturation stage ameloblasts. The expression level of RXRα was the highest, similar to the vitamin D receptor (VDR, whereas the others were 13 to 612 fold lower, with AR and GR being intermediate. Immunofluorescent analysis of VDR, ERα and AR confirmed their presence mainly in maturation- stage ameloblasts. These data provide further evidence that ameloblasts express a specific combination of hormonal receptors depending on their developmental stage. This study represents the first step towards understanding dental endocrinology as well as some of the effects of EDCs on the pathophysiology of amelogenesis.

Expression of Steroid Receptors in Ameloblasts during Amelogenesis in Rat Incisors.

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Houari, Sophia; Loiodice, Sophia; Jedeon, Katia; Berdal, Ariane; Babajko, Sylvie

2016-01-01

Endocrine disrupting chemicals (EDCs) play a part in the modern burst of diseases and interfere with the steroid hormone axis. Bisphenol A (BPA), one of the most active and widely used EDCs, affects ameloblast functions, leading to an enamel hypomineralization pattern similar to that of Molar Incisor Hypomineralization (MIH). In order to explore the molecular pathways stimulated by BPA during amelogenesis, we thoroughly investigated the receptors known to directly or indirectly mediate the effects of BPA. The expression patterns of high affinity BPA receptors (ERRγ, GPR30), of ketosteroid receptors (ERs, AR, PGR, GR, MR), of the retinoid receptor RXRα, and PPARγ were established using RT-qPCR analysis of RNAs extracted from microdissected enamel organ of adult rats. Their expression was dependent on the stage of ameloblast differentiation, except that of ERβ and PPARγ which remained undetectable. An additional large scale microarray analysis revealed three main groups of receptors according to their level of expression in maturation-stage ameloblasts. The expression level of RXRα was the highest, similar to the vitamin D receptor (VDR), whereas the others were 13 to 612-fold lower, with AR and GR being intermediate. Immunofluorescent analysis of VDR, ERα and AR confirmed their presence mainly in maturation- stage ameloblasts. These data provide further evidence that ameloblasts express a specific combination of hormonal receptors depending on their developmental stage. This study represents the first step toward understanding dental endocrinology as well as some of the effects of EDCs on the pathophysiology of amelogenesis.

Activated HER-receptors in predicting outcome of ER-positive breast cancer patients treated with adjuvant endocrine therapy

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Larsen, Mathilde Skaarup; Bjerre, Karsten; Lykkesfeldt, Anne Elisabeth

2012-01-01

) in endocrine treated breast cancer in terms of co-expression and association with disease-free survival (DFS) in 1062 patients with ER-positive tumors. Furthermore, HER2 amplification was evaluated. We found positive associations between the phosphorylated receptors. pHER1 and pHER3 were co-expressed with one......The four human epidermal growth factor receptors (HER1-4) are involved in growth stimulation and may play a role in endocrine resistance. The receptors form dimers, leading to activation by mutual phosphorylation. Our purpose was to explore the role of the activated receptors (pHER1, pHER2, pHER3...

Steroid induction of therapy-resistant cytokeratin-5-positive cells in estrogen receptor-positive breast cancer through a BCL6-dependent mechanism

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Goodman, C R; Sato, T; Peck, A R; Girondo, M A; Yang, N; Liu, C; Yanac, A F; Kovatich, A J; Hooke, J A; Shriver, C D; Mitchell, E P; Hyslop, T; Rui, H

2016-01-01

Therapy resistance remains a major problem in estrogen receptor-α (ERα)-positive breast cancer. A subgroup of ERα-positive breast cancer is characterized by mosaic presence of a minor population of ERα-negative cancer cells expressing the basal cytokeratin-5 (CK5). These CK5-positive cells are therapy resistant and have increased tumor-initiating potential. Although a series of reports document induction of the CK5-positive cells by progestins, it is unknown if other 3-ketosteroids share this ability. We now report that glucocorticoids and mineralocorticoids effectively expand the CK5-positive cell population. CK5-positive cells induced by 3-ketosteroids lacked ERα and progesterone receptors, expressed stem cell marker, CD44, and displayed increased clonogenicity in soft agar and broad drug-resistance in vitro and in vivo. Upregulation of CK5-positive cells by 3-ketosteroids required induction of the transcriptional repressor BCL6 based on suppression of BCL6 by two independent BCL6 small hairpin RNAs or by prolactin. Prolactin also suppressed 3-ketosteroid induction of CK5+ cells in T47D xenografts in vivo. Survival analysis with recursive partitioning in node-negative ERα-positive breast cancer using quantitative CK5 and BCL6 mRNA or protein expression data identified patients at high or low risk for tumor recurrence in two independent patient cohorts. The data provide a mechanism by which common pathophysiological or pharmacologic elevations in glucocorticoids or other 3-ketosteroids may adversely affect patients with mixed ERα+/CK5+ breast cancer. The observations further suggest a cooperative diagnostic utility of CK5 and BCL6 expression levels and justify exploring efficacy of inhibitors of BCL6 and 3-ketosteroid receptors for a subset of ERα-positive breast cancers. PMID:26096934

Positioning of AMPA Receptor-Containing Endosomes Regulates Synapse Architecture

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Marta Esteves da Silva

2015-11-01

Full Text Available Lateral diffusion in the membrane and endosomal trafficking both contribute to the addition and removal of AMPA receptors (AMPARs at postsynaptic sites. However, the spatial coordination between these mechanisms has remained unclear, because little is known about the dynamics of AMPAR-containing endosomes. In addition, how the positioning of AMPAR-containing endosomes affects synapse organization and functioning has never been directly explored. Here, we used live-cell imaging in hippocampal neuron cultures to show that intracellular AMPARs are transported in Rab11-positive recycling endosomes, which frequently enter dendritic spines and depend on the microtubule and actin cytoskeleton. By using chemically induced dimerization systems to recruit kinesin (KIF1C or myosin (MyosinV/VI motors to Rab11-positive recycling endosomes, we controlled their trafficking and found that induced removal of recycling endosomes from spines decreases surface AMPAR expression and PSD-95 clusters at synapses. Our data suggest a mechanistic link between endosome positioning and postsynaptic structure and composition.

Muscarinic receptor M₄ positive allosteric modulators attenuate central effects of cocaine

DEFF Research Database (Denmark)

Dall, Camilla; Weikop, Pia; Dencker, Ditte

2017-01-01

BACKGROUND: Cocaine addiction is a chronic brain disease affecting neurotransmission. Muscarinic cholinergic receptors modulate dopaminergic signaling in the reward system, and muscarinic receptor stimulation can block direct reinforcing effects of cocaine. Here, we tested the hypothesis...... that specific muscarinic M4receptor stimulation can attenuate the discriminative stimulus effects and conditioned rewarding effects of cocaine, measures believed to predict the ability of cocaine and cocaine-associated cues to elicit relapse to drug taking. METHODS: We tested the M4-selective positive...

Peroxidase activity as a marker for estrogenicity

International Nuclear Information System (INIS)

Levy, J.; Liel, Y.; Glick, S.M.

1981-01-01

We examined the possibility that peroxidase activity might be a marker for estrogen activity in established estrogen-dependent tissues: dimethylbenz[a]anthracene (DMBA)-induced rat mammary tumours and human breast cancer. In DMBA-induced tumours undergoing regression after ovariectomy or tamoxifen treatment, tumour size decreased by 50%, estradiol receptors (ER) and progesterone receptors (PgR) decreased by 25 and 20%, respectively, but peroxidase activity paradoxically increased six- to sevenfold. In DMBA tumours stimulated by estradiol treatment or by the cessation of tamoxifen administration in intact rats, tumour size increased threefold. ER and PgR increased two- and threefold, respectively, while peroxidase activity decreased 50%. These data indicate an inverse relation between tumour growth, ER and PgR on the one hand, and peroxidase activity on the other. In the human breast cancers there was a singificant negative relation between the presence of ER and peroxidase activity. By using a calibrated Sephadex G-100 column it was shown that uterine peroxidase differs in molecular weight from the peroxidase of rat mammary tumours and that of human breast cancer. (author)

Characterization of adult ghrelin and ghrelin receptor knockout mice under positive and negative energy balance

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Ghrelin and the ghrelin receptor (GH secretagogue receptor, GHS-R) are believed to have important roles in energy homeostasis. We describe results from the first studies to be conducted in congenic (N10) adult ghrelin(-/-) and Ghsr(-/-) mice under conditions of both positive (high-fat diet) and nega...

Beta receptor-mediated modulation of the late positive potential in humans.

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de Rover, Mischa; Brown, Stephen B R E; Boot, Nathalie; Hajcak, Greg; van Noorden, Martijn S; van der Wee, Nic J A; Nieuwenhuis, Sander

2012-02-01

Electrophysiological studies have identified a scalp potential, the late positive potential (LPP), which is modulated by the emotional intensity of observed stimuli. Previous work has shown that the LPP reflects the modulation of activity in extrastriate visual cortical structures, but little is known about the source of that modulation. The present study investigated whether beta-adrenergic receptors are involved in the generation of the LPP. We used a genetic individual differences approach (experiment 1) and a pharmacological manipulation (experiment 2) to test the hypothesis that the LPP is modulated by the activation of β-adrenergic receptors. In experiment 1, we found that LPP amplitude depends on allelic variation in the β1-receptor gene polymorphism. In experiment 2, we found that LPP amplitude was modulated by the β-blocker propranolol in a direction dependent on subjects' level of trait anxiety: In participants with lower trait anxiety, propranolol led to a (nonsignificant) decrease in the LPP modulation; in participants with higher trait anxiety, propranolol increased the emotion-related LPP modulation. These results provide initial support for the hypothesis that the LPP reflects the downstream effects, in visual cortical areas, of β-receptor-mediated activation of the amygdala.

Understanding the Inguinal Sinus in Sheep (Ovis aries—Morphology, Secretion, and Expression of Progesterone, Estrogens, and Prolactin Receptors

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Graça Alexandre-Pires

2017-07-01

Full Text Available Post-parturient behavior of mammalian females is essential for early parent–offspring contact. After delivery, lambs need to ingest colostrum for obtaining the related immunological protection, and early interactions between the mother and the lamb are crucial. Despite visual and auditory cues, olfactory cues are decisive in lamb orientation to the mammary gland. In sheep, the inguinal sinus is located bilaterally near the mammary gland as a skin pouch (IGS that presents a gland that secretes a strong-smelling wax. Sheep IGS gland functions have many aspects under evaluation. The objective of the present study was to evaluate sheep IGS gland functional aspects and mRNA transcription and the protein expression of several hormone receptors, such as progesterone receptor (PGR, estrogen receptor 1 (ESR1, and 2 (ESR2 and prolactin receptor (PRLR present. In addition, another aim was to achieve information about IGS ultrastructure and chemical compounds produced in this gland. All hormone receptors evaluated show expression in IGS during the estrous cycle (follicular/luteal phases, pregnancy, and the post-partum period. IGS secretion is rich in triterpenoids that totally differ from the surrounding skin. They might be essential substances for the development of an olfactory preference of newborns to their mothers.

Histopathological features of breast tumours in BRCA1, BRCA2 and mutation-negative breast cancer families

International Nuclear Information System (INIS)

Eerola, Hannaleena; Heikkilä, Päivi; Tamminen, Anitta; Aittomäki, Kristiina; Blomqvist, Carl; Nevanlinna, Heli

2005-01-01

Histopathological features of BRCA1 and BRCA2 tumours have previously been characterised and compared with unselected breast tumours; however, familial non-BRCA1/2 tumours are less well known. The aim of this study was to characterise familial non-BRCA1/2 tumours and to evaluate routine immunohistochemical and pathological markers that could help us to further distinguish families carrying BRCA1/2 mutations from other breast cancer families. Breast cancer tissue specimens (n = 262) from 25 BRCA1, 20 BRCA2 and 74 non-BRCA1/2 families were studied on a tumour tissue microarray. Immunohistochemical staining of oestrogen receptor (ER), progesterone receptor (PgR) and p53 as well as the histology and grade of these three groups were compared with each other and with the respective information on 862 unselected control patients from the archives of the Pathology Department of Helsinki University Central Hospital. Immunohistochemical staining of erbB2 was also performed among familial cases. BRCA1-associated cancers were diagnosed younger and were more ER-negative and PgR-negative, p53-positive and of higher grade than the other tumours. However, in multivariate analysis the independent factors compared with non-BRCA1/2 tumours were age, grade and PgR negativity. BRCA2 cases did not have such distinctive features compared with non-BRCA1/2 tumours or with unselected control tumours. Familial cases without BRCA1/2 mutations had tumours of lower grade than the other groups. BRCA1 families differed from mutation-negative families by age, grade and PgR status, whereas ER status was not an independent marker

Signatures of positive selection in Toll-like receptor (TLR genes in mammals

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Areal Helena

2011-12-01

Full Text Available Abstract Background Toll-like receptors (TLRs are a major class of pattern recognition receptors (PRRs expressed in the cell surface or membrane compartments of immune and non-immune cells. TLRs are encoded by a multigene family and represent the first line of defense against pathogens by detecting foreigner microbial molecular motifs, the pathogen-associated molecular patterns (PAMPs. TLRs are also important by triggering the adaptive immunity in vertebrates. They are characterized by the presence of leucine-rich repeats (LRRs in the ectodomain, which are associated with the PAMPs recognition. The direct recognition of different pathogens by TLRs might result in different evolutionary adaptations important to understand the dynamics of the host-pathogen interplay. Ten mammal TLR genes, viral (TLR3, 7, 8, 9 and non-viral (TLR1-6, 10, were selected to identify signatures of positive selection that might have been imposed by interacting pathogens and to clarify if viral and non-viral TLRs might display different patterns of molecular evolution. Results By using Maximum Likelihood approaches, evidence of positive selection was found in all the TLRs studied. The number of positively selected codons (PSC ranged between 2-26 codons (0.25%-2.65% with the non-viral TLR4 as the receptor with higher percentage of positively selected codons (2.65%, followed by the viral TLR8 (2.50%. The results indicated that viral and non-viral TLRs are similarly under positive selection. Almost all TLRs have at least one PSC located in the LRR ectodomain which underlies the importance of the pathogen recognition by this region. Conclusions Our results are not in line with previous studies on primates and birds that identified more codons under positive selection in non-viral TLRs. This might be explained by the fact that both primates and birds are homogeneous groups probably being affected by only a restricted number of related viruses with equivalent motifs to be

Characterization of estrogen receptor-negative/progesterone receptor-positive breast cancer.

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Shen, Tiansheng; Brandwein-Gensler, Margaret; Hameed, Omar; Siegal, Gene P; Wei, Shi

2015-11-01

Despite the controversies, estrogen receptor-negative/progesterone receptor-positive (ER-/PR+) breast cancers have a reported incidence of 1% to 4%. These tumors are less well defined, and it is unclear whether ER-/PR+ represents a distinct subtype. Thus, we analyzed 5374 consecutive breast cancers to characterize the clinicopathological features of this underrecognized subset of tumors. The ER-/PR+ tumors, constituting 2.3% of the total, were mostly high grade and significantly seen in younger patients and African American women when compared with the ER+/PR+ and ER+/PR- groups, but similar to that of ER-/PR- phenotype (P < .0001). A significantly prolonged relapse-free survival (RFS) was associated with the ER+/PR+ subtype when compared with the ER+/PR- (P = .0002) or ER-/PR+ (P = .0004) tumors, whereas all 3 groups showed a superior outcome to that of the ER-/PR- phenotype. In the subset of patients receiving endocrine therapy, those with ER+/PR+ tumors had a significantly prolonged RFS (P = .001) and disease-specific survival (P = .005) when compared with the group with an ER+/PR- phenotype, but did not significantly differ from those with ER-/PR+ tumors. No significant survival advantage was found between the ER+/PR- and ER-/PR+ tumors in any group of patients analyzed. Furthermore, a higher PR expression was associated with a favorable RFS and disease-specific survival in the patients with ER-/PR+ tumors. Therefore, the ER-/PR+ tumors demonstrate a similar, if not higher than, response rate to endocrine therapy when compared with the ER+/PR- tumors and thus are important to identify. Routine PR testing remains necessary in assisting clinical decision making in the pursuit of precision medicine. Copyright © 2015 Elsevier Inc. All rights reserved.

GABAA receptor: Positive and negative allosteric modulators.

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Olsen, Richard W

2018-01-31

gamma-Aminobutyric acid (GABA)-mediated inhibitory neurotransmission and the gene products involved were discovered during the mid-twentieth century. Historically, myriad existing nervous system drugs act as positive and negative allosteric modulators of these proteins, making GABA a major component of modern neuropharmacology, and suggesting that many potential drugs will be found that share these targets. Although some of these drugs act on proteins involved in synthesis, degradation, and membrane transport of GABA, the GABA receptors Type A (GABA A R) and Type B (GABA B R) are the targets of the great majority of GABAergic drugs. This discovery is due in no small part to Professor Norman Bowery. Whereas the topic of GABA B R is appropriately emphasized in this special issue, Norman Bowery also made many insights into GABA A R pharmacology, the topic of this article. GABA A R are members of the ligand-gated ion channel receptor superfamily, a chloride channel family of a dozen or more heteropentameric subtypes containing 19 possible different subunits. These subtypes show different brain regional and subcellular localization, age-dependent expression, and potential for plastic changes with experience including drug exposure. Not only are GABA A R the targets of agonist depressants and antagonist convulsants, but most GABA A R drugs act at other (allosteric) binding sites on the GABA A R proteins. Some anxiolytic and sedative drugs, like benzodiazepine and related drugs, act on GABA A R subtype-dependent extracellular domain sites. General anesthetics including alcohols and neurosteroids act at GABA A R subunit-interface trans-membrane sites. Ethanol at high anesthetic doses acts on GABA A R subtype-dependent trans-membrane domain sites. Ethanol at low intoxicating doses acts at GABA A R subtype-dependent extracellular domain sites. Thus GABA A R subtypes possess pharmacologically specific receptor binding sites for a large group of different chemical classes of

Direct labelling of the human P2X7 receptor and identification of positive and negative cooperativity of binding.

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Michel, A D; Chambers, L J; Clay, W C; Condreay, J P; Walter, D S; Chessell, I P

2007-05-01

The P2X(7) receptor exhibits complex pharmacological properties. In this study, binding of a [(3)H]-labelled P2X(7) receptor antagonist to human P2X(7) receptors has been examined to further understand ligand interactions with this receptor. The P2X(7) receptor antagonist, N-[2-({2-[(2-hydroxyethyl)amino]ethyl}amino)-5-quinolinyl]-2-tricyclo[3.3.1.1(3,7)]dec-1-ylacetamide (compound-17), was radiolabelled with tritium and binding studies were performed using membranes prepared from U-2 OS or HEK293 cells expressing human recombinant P2X(7) receptors. Binding of [(3)H]-compound-17 was higher in membranes prepared from cells expressing P2X(7) receptors than from control cells and was inhibited by ATP suggesting labelled sites represented human P2X(7) receptors. Binding was reversible, saturable and modulated by P2X(7) receptor ligands (Brilliant Blue G, KN62, ATP, decavanadate). Furthermore, ATP potency was reduced in the presence of divalent cations or NaCl. Radioligand binding exhibited both positive and negative cooperativity. Positive cooperativity was evident from bell shaped Scatchard plots, reduction in radioligand dissociation rate by unlabelled compound-17 and enhancement of radioligand binding by KN62 and unlabelled compound-17. ATP and decavanadate inhibited binding in a negative cooperative manner as they enhanced radioligand dissociation. These data demonstrate that human P2X(7) receptors can be directly labelled and provide novel insights into receptor function. The positive cooperativity observed suggests that binding of compound-17 to one subunit in the P2X(7) receptor complex enhances subsequent binding to other P2X(7) subunits in the same complex. The negative cooperative effects of ATP suggest that ATP and compound-17 bind at separate, interacting, sites on the P2X(7) receptor.

A Gata2-Dependent Transcription Network Regulates Uterine Progesterone Responsiveness and Endometrial Function

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Cory A. Rubel

2016-10-01

Full Text Available Altered progesterone responsiveness leads to female infertility and cancer, but underlying mechanisms remain unclear. Mice with uterine-specific ablation of GATA binding protein 2 (Gata2 are infertile, showing failures in embryo implantation, endometrial decidualization, and uninhibited estrogen signaling. Gata2 deficiency results in reduced progesterone receptor (PGR expression and attenuated progesterone signaling, as evidenced by genome-wide expression profiling and chromatin immunoprecipitation. GATA2 not only occupies at and promotes expression of the Pgr gene but also regulates downstream progesterone responsive genes in conjunction with the PGR. Additionally, Gata2 knockout uteri exhibit abnormal luminal epithelia with ectopic TRP63 expressing squamous cells and a cancer-related molecular profile in a progesterone-independent manner. Lastly, we found a conserved GATA2-PGR regulatory network in both human and mice based on gene signature and path analyses using gene expression profiles of human endometrial tissues. In conclusion, uterine Gata2 regulates a key regulatory network of gene expression for progesterone signaling at the early pregnancy stage.

Macrodissection prior to closed system RT-qPCR is not necessary for estrogen receptor and HER2 concordance with IHC/FISH in breast cancer.

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Gupta, Swati; Mani, Navin R; Carvajal-Hausdorf, Daniel E; Bossuyt, Veerle; Ho, Kenneth; Weidler, Jodi; Wong, Wendy; Rhees, Brian; Bates, Michael; Rimm, David L

2018-06-01

An on-demand, closed RT-qPCR, the GeneXpert (GX) system, has the potential to provide biomarker information in low-resourced settings and elsewhere. We used this system with a research use only version of the Breast Cancer STRAT4 cartridge that measures the mRNA expression levels of ERBB2, ESR1, PGR, and MKi67. Here we evaluated the impact of non-macrodissected (non m-d) versus macrodissected (m-d) samples using STRAT4 on formalin-fixed, paraffin-embedded (FFPE) core needle biopsies. Two cohorts were assessed: (1) 60 FFPE infiltrating ductal carcinoma (IDCA) cases and (2) 20 FFPE IDCA cases with ductal carcinoma in situ (DCIS) with a range of HER2 expression as determined by clinical immunohistochemistry and fluorescence in situ hybridization (IHC/FISH). We observed about half of the core needle biopsy area as invasive tumor in both IDCA (mean = 51.5%) and IDCA with DCIS (mean = 53.5%) cohorts, but also found the mRNA levels were independent of tumor area. We found excellent agreement of the mRNA transcript level between the paired samples, m-d versus non m-d, for ERBB2, ESR1, PGR, and MKi67 for both the IDCA and IDCA with DCIS cohorts. No significant difference (P > 0.99) was observed when we compared the mRNA transcript level between the paired samples m-d versus non m-d. In addition, we noted a significant concordance (P < 0.001) between RT-qPCR and IHC/FISH for HER2-positivity, ER-positivity, and PR-positivity, independent of specimen dissection. These data suggest that mRNA expression for ERBB2, ESR, and PGR is sufficiently low in surrounding tissue cells such that macrodissection is not required for assessment of key breast cancer mRNA markers and is independent of the amount of input tumor. This approach may be valuable in settings lacking pathology expertise or using specimen types, such as fine-needle aspirates, where it may be challenging to separate non-tumor from tumor tissue.

Managing arthralgia in a postmenopausal woman taking an aromatase inhibitor for hormonesensitive early breast cancer: a case study

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Bryce, Jane; Bauer, Martina; Hadji, Peyman

2012-01-01

In order to reduce the risk of recurrence, adjuvant treatment with an aromatase inhibitor (AI) is recommended for postmenopausal women following surgery for hormone receptor-positive breast cancer. AIs are associated with improved disease-free survival compared with tamoxifen. The adverse events associated with AIs resemble those of menopause, such as bone density loss and musculoskeletal symptoms. We examine the case of a postmenopausal woman who was prescribed anastrozole, a nonsteroidal AI, as adjuvant therapy following surgery for estrogen and progesterone receptor-positive (ER and PgR+) breast cancer. A 58-year-old postmenopausal woman diagnosed with ER and PgR+ breast cancer was prescribed anastrozole as adjuvant therapy following a right-inferior quadrantectomy. After experiencing joint pain and stiffness, she was prescribed paracetamol and a topical nonsteroidal anti-inflammatory drug. She was also counseled on nonpharmacological interventions. However, she continued to experience symptoms, and reported that she was not taking anastrozole regularly. The case study patient ultimately found relief by switching to letrozole, another aromatase inhibitor. This approach is supported by recent studies examining the benefits of switching strategies between aromatase inhibitors in order to relieve symptoms of arthralgia/myalgia. Both adherence and strategies for managing aromatase inhibitor-associated arthralgia are key to deriving maximal clinical benefit from AI therapy. Switching from one aromatase inhibitor to another may provide a viable option in managing adverse events and enhancing adherence to medication

Positive allosteric modulation of GABA-A receptors reduces capsaicin-induced primary and secondary hypersensitivity in rats

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Hansen, Rikke Rie; Erichsen, Helle K; Brown, David T

2012-01-01

GABA-A receptor positive allosteric modulators (PAMs) mediate robust analgesia in animal models of pathological pain, in part via enhancing injury-induced loss of GABA-A-α2 and -α3 receptor function within the spinal cord. As yet, a lack of clinically suitable tool compounds has prevented this co...

Preclinical Evaluation of 68Ga-DOTA-Minigastrin for the Detection of Cholecystokinin-2/Gastrin Receptor-Positive Tumors

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Maarten Brom

2011-03-01

Full Text Available In comparison to somatostatin receptor scintigraphy, gastrin receptor scintigraphy using 111In-DTPA-minigastrin (MG0 showed added value in diagnosing neuroendocrine tumors. We investigated whether the 68Ga-labeled gastrin analogue DOTA-MG0 is suited for positron emission tomography (PET, which could improve image quality. Targeting of cholecystokinin-2 (CCK2/gastrin receptor-positive tumor cells with DOTA-MG0 labeled with either 111In or 68Ga in vitro was investigated using the AR42J rat tumor cell line. Biodistribution was examined in BALB/c nude mice with a subcutaneous AR42J tumor. In vivo PET imaging was performed using a preclinical PET-computed tomographic scanner. DOTA-MG0 showed high receptor affinity in vitro. Biodistribution studies revealed high tumor uptake of 68Ga-DOTA-MG0: 4.4 ± 1.3 %ID/g at 1 hour postinjection. Coadministration of an excess unlabeled peptide blocked the tumor uptake (0.7 ± 0.1 %ID/g, indicating CCK2/gastrin receptor-mediated uptake (p = .0005. The biodistribution of 68Ga-DOTA-MG0 was similar to that of 111In-DOTA-MG0. Subcutaneous and intraperitoneal tumors were clearly visualized by small-animal PET imaging with 5 MBq 68Ga-DOTA-MG0. 111In- and 68Ga-labeled DOTA-MG0 specifically accumulate in CCK2/gastrin receptor-positive AR42J tumors with similar biodistribution apart from the kidneys. AR42J tumors were clearly visualized by microPET. Therefore, 68Ga-DOTA-MG0 is a promising tracer for PET imaging of CCK2/gastrin receptor-positive tumors in humans.

The progesterone receptor Val660→Leu polymorphism and breast cancer risk

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De Vivo, Immaculata; Hankinson, Susan E; Colditz, Graham A; Hunter, David J

2004-01-01

Recent evidence suggests a role for progesterone in breast cancer development and tumorigenesis. Progesterone exerts its effect on target cells by interacting with its receptor; thus, genetic variations, which might cause alterations in the biological function in the progesterone receptor (PGR), can potentially contribute to an individual's susceptibility to breast cancer. It has been reported that the PROGINS allele, which is in complete linkage disequilibrium with a missense substitution in exon 4 (G/T, valine→leucine, at codon 660), is associated with a decreased risk for breast cancer. Using a nested case-control study design within the Nurses' Health Study cohort, we genotyped 1252 cases and 1660 matched controls with the use of the Taqman assay. We did not observe any association of breast cancer risk with carrying the G/T (Val660→Leu) polymorphism (odds ratio 1.10, 95% confidence interval 0.93–1.30). In addition, we did not observe an interaction between this allele and menopausal status and family history of breast cancer as reported previously. Overall, our study does not support an association between the Val660→Leu PROGINS polymorphism and breast cancer risk

Evidence of positive selection at codon sites localized in extracellular domains of mammalian CC motif chemokine receptor proteins

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Metzger Kelsey J

2010-05-01

Full Text Available Abstract Background CC chemokine receptor proteins (CCR1 through CCR10 are seven-transmembrane G-protein coupled receptors whose signaling pathways are known for their important roles coordinating immune system responses through targeted trafficking of white blood cells. In addition, some of these receptors have been identified as fusion proteins for viral pathogens: for example, HIV-1 strains utilize CCR5, CCR2 and CCR3 proteins to obtain cellular entry in humans. The extracellular domains of these receptor proteins are involved in ligand-binding specificity as well as pathogen recognition interactions. In mammals, the majority of chemokine receptor genes are clustered together; in humans, seven of the ten genes are clustered in the 3p21-24 chromosome region. Gene conversion events, or exchange of DNA sequence between genes, have been reported in chemokine receptor paralogs in various mammalian lineages, especially between the cytogenetically closely located pairs CCR2/5 and CCR1/3. Datasets of mammalian orthologs for each gene were analyzed separately to minimize the potential confounding impact of analyzing highly similar sequences resulting from gene conversion events. Molecular evolution approaches and the software package Phylogenetic Analyses by Maximum Likelihood (PAML were utilized to investigate the signature of selection that has acted on the mammalian CC chemokine receptor (CCR gene family. The results of neutral vs. adaptive evolution (positive selection hypothesis testing using Site Models are reported. In general, positive selection is defined by a ratio of nonsynonymous/synonymous nucleotide changes (dN/dS, or ω >1. Results Of the ten mammalian CC motif chemokine receptor sequence datasets analyzed, only CCR2 and CCR3 contain amino acid codon sites that exhibit evidence of positive selection using site based hypothesis testing in PAML. Nineteen of the twenty codon sites putatively indentified as likely to be under positive

Successful combination immunotherapy of anti-gamma aminobutyric acid (GABA)A receptor antibody-positive encephalitis with extensive multifocal brain lesions.

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Fukami, Yuki; Okada, Hiroaki; Yoshida, Mari; Yamaguchi, Keiji

2017-08-31

A 78-year old woman who presented with akinetic mutism was admitted to our hospital. Brain MRI showed multifocal increased T 2 /FLAIR signal with extensive cortical-subcortical involvement. We suspected autoimmune encephalitis and the patient received methylprednisolone pulse. Her conscious level gradually recovered, but later relapsed again and presented with refractory status epilepticus. We treated her with intravenous immunoglobulin, plasma exchange and pulsed cyclophosphamide, with satisfactory response. A brain biopsy showed perivascular lymphocytic infiltrates and reactive gliosis. Anti-gamma aminobutyric acid (GABA) A receptor antibodies test came back to be positive after her recovery, and the diagnosis of anti-GABA A receptor antibody-positive encephalitis was made. This is a very rare case where brain biopsies were performed in a patient with anti-GABA A receptor antibody-positive encephalitis.

TRAIL Death Receptor-4 Expression Positively Correlates With the Tumor Grade in Breast Cancer Patients With Invasive Ductal Carcinoma

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Sanlioglu, Ahter D.; Korcum, Aylin F.; Pestereli, Elif; Erdogan, Gulgun; Karaveli, Seyda; Savas, Burhan; Griffith, Thomas S.; Sanlioglu, Salih V.

2007-01-01

Purpose: Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) selectively induces apoptosis in cancer cells but not in normal cells, and a number of clinical trials have recently been initiated to test the safety and antitumoral potential of TRAIL in cancer patients. Four different receptors have been identified to interact with TRAIL: two are death-inducing receptors (TRAIL-R1 [DR4] and TRAIL-R2 [DR5]), whereas the other two (TRAIL-R3 [DcR1] and TRAIL-R4 [DcR2]) do not induce death upon ligation and are believed to counteract TRAIL-induced cytotoxicity. Because high levels of DcR2 expression have recently been correlated with carcinogenesis in the prostate and lung, this study investigated the importance of TRAIL and TRAIL receptor expression in breast cancer patients with invasive ductal carcinoma, taking various prognostic markers into consideration. Methods and Materials: Immunohistochemical analyses were performed on 90 breast cancer patients with invasive ductal carcinoma using TRAIL and TRAIL receptor-specific antibodies. Age, menopausal status, tumor size, lymph node status, tumor grade, lymphovascular invasion, perineural invasion, extracapsular tumor extension, presence of an extensive intraductal component, multicentricity, estrogen and progesterone receptor status, and CerbB2 expression levels were analyzed with respect to TRAIL/TRAIL receptor expression patterns. Results: The highest TRAIL receptor expressed in patients with invasive ductal carcinoma was DR4. Although progesterone receptor-positive patients exhibited lower DR5 expression, CerbB2-positive tissues displayed higher levels of both DR5 and TRAIL expressions. Conclusions: DR4 expression positively correlates with the tumor grade in breast cancer patients with invasive ductal carcinoma

Abiraterone acetate, exemestane or the combination in postmenopausal patients with estrogen receptor-positive metastatic breast cancer ?

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O'Shaughnessy, J.; Campone, M.; Brain, E.; Neven, P.; Hayes, D.; Bondarenko, I.; Griffin, T. W.; Martin, J.; De Porre, P.; Kheoh, T.; Yu, M. K.; Peng, W.; Johnston, S.

2015-01-01

Background Androgen receptor (AR) signaling and incomplete inhibition of estrogen signaling may contribute to metastatic breast cancer (MBC) resistance to a nonsteroidal aromatase inhibitor (NSAI; letrozole or anastrozole). We assessed whether combined inhibition of androgen biosynthesis with abiraterone acetate plus prednisone and estradiol synthesis with exemestane (E) may be of clinical benefit to postmenopausal patients with NSAI-pretreated estrogen receptor-positive (ER+) MBC. Patients a...

A Phase I/Ib Study of Enzalutamide Alone and in Combination with Endocrine Therapies in Women with Advanced Breast Cancer.

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Schwartzberg, Lee S; Yardley, Denise A; Elias, Anthony D; Patel, Manish; LoRusso, Patricia; Burris, Howard A; Gucalp, Ayca; Peterson, Amy C; Blaney, Martha E; Steinberg, Joyce L; Gibbons, Jacqueline A; Traina, Tiffany A

2017-08-01

Purpose: Several lines of evidence support targeting the androgen signaling pathway in breast cancer. Enzalutamide is a potent inhibitor of androgen receptor signaling. Preclinical data in estrogen-expressing breast cancer models demonstrated activity of enzalutamide monotherapy and enhanced activity when combined with various endocrine therapies (ET). Enzalutamide is a strong cytochrome P450 3A4 (CYP3A4) inducer, and ETs are commonly metabolized by CYP3A4. The pharmacokinetic (PK) interactions, safety, and tolerability of enzalutamide monotherapy and in combination with ETs were assessed in this phase I/Ib study. Experimental Design: Enzalutamide monotherapy was assessed in dose-escalation and dose-expansion cohorts of patients with advanced breast cancer. Additional cohorts examined effects of enzalutamide on anastrozole, exemestane, and fulvestrant PK in patients with estrogen receptor-positive/progesterone receptor-positive (ER + /PgR + ) breast cancer. Results: Enzalutamide monotherapy ( n = 29) or in combination with ETs ( n = 70) was generally well tolerated. Enzalutamide PK in women was similar to prior data on PK in men with prostate cancer. Enzalutamide decreased plasma exposure to anastrozole by approximately 90% and exemestane by approximately 50%. Enzalutamide did not significantly affect fulvestrant PK. Exposure of exemestane 50 mg/day given with enzalutamide was similar to exemestane 25 mg/day alone. Conclusions: These results support a 160 mg/day enzalutamide dose in women with breast cancer. Enzalutamide can be given in combination with fulvestrant without dose modifications. Exemestane should be doubled from 25 mg/day to 50 mg/day when given in combination with enzalutamide; this combination is being investigated in a randomized phase II study in patients with ER + /PgR + breast cancer. Clin Cancer Res; 23(15); 4046-54. ©2017 AACR . ©2017 American Association for Cancer Research.

The prognostic value of Her4 receptor isoform expression in triple-negative and Her2 positive breast cancer patients

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Machleidt, Anna; Buchholz, Stefan; Diermeier-Daucher, Simone; Zeman, Florian; Ortmann, Olaf; Brockhoff, Gero

2013-01-01

Not only four but rather seven different human epidermal growth factor receptor related (Her) receptor tyrosine kinases (RTKs) have been described to be expressed in a variety of normal and neoplastic tissues: Her1, Her2, Her3, and additionally four Her4 isoforms have been identified. A differential expression of Her4 isoforms does not, however, play any role in either the molecular diagnostics or treatment decision for breast cancer patients. The prognostic and predictive impact of Her4 expression in breast cancer is basically unclear. We quantified the Her4 variants JM-a/CYT1, JM-a/CYT2, JM-b/CYT1, and JM-b/CYT2 by isoform-specific polymerase chain reaction (qPCR) in (i) triple-negative, (ii) Her2 positive breast cancer tissues and (iii) in benign breast tissues. In all three tissue collectives we never found the JM-b/CYT1 or the JM-b/CYT2 isoform expressed. In contrast, the two JM-a/CYT1 and JM-a/CYT2 isoforms were always simultaneously expressed but at different ratios. We identified a positive prognostic impact on overall survival (OS) in triple-negative and event-free survival (EFS) in Her2 positive patients. This finding is independent of the absolute JM-a/CYT1 to JM-a/CYT2 expression ratio. In Her2 positive patients, Her4 expression only has a favorable effect in estrogen-receptor (ER)-positive but not in ER-negative individuals. In summary, JM-a/CYT1 and JM-a/CYT2 but not JM-b isoforms of the Her4 receptor are simultaneously expressed in both triple-negative and Her2 positive breast cancer tissues. Although different expression ratios of the two JM-a isoforms did not reveal any additional information, Her4 expression basically indicates a prolonged EFS and OFS. An extended expression analysis that takes all Her receptor homologs, including the Her4 isoforms, into account might render more precisely the molecular diagnostics required for the development of optimized targeted therapies

The development of fluoroandrogens and fluoroprogestins as potential imaging agents for receptor-positive prostate and breast tumors

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Brandes, S.J.; Katzenellenbogen, J.A.

1986-01-01

The assay of progesterone receptor (PR) concentration in breast tumors and androgen receptor (AR) concentration in prostate tumors enables hormone responsive neoplasms to be distinguished from those that are non-responsive. In principle, a positron-emitting progestin or androgen with suitably high affinity and selectivity for PR and AR, respectively, and an adequately high specific activity might provide a means for imaging receptor-positive tumors and quantifying their receptor content in vivo. The use of fluorine-18 as a radiolabel, coupled with the use of positron emission transaxial tomography, appears to be a most favorable approach in the development of receptor binding radiopharmaceuticals for in vivo imaging. Therefore, we have begun a systematic investigation of the development of fluorine-substituted androgens and progestins that might be prepared in F-18 labeled form as probes for AR and PR. (author)

Transmembrane signalling at the epidermal growth factor receptor. Positive regulation by the C-terminal phosphotyrosine residues

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Magni, M; Pandiella, A; Helin, K

1991-01-01

a positive role in the regulation of transmembrane signalling at the EGF receptor. The stepwise decrease in signal generation observed in single, double and triple point mutants suggest that the role of phosphotyrosine residues is not in the participation in specific amino acid sequences, but rather...... in the double and the triple mutants. In the latter mutant, expression of the EGF-receptor-activated lipolytic enzyme phospholipase C gamma was unchanged, whereas its tyrosine phosphorylation induced by the growth factor was lowered to approx. 25% of that in the controls. In all of the cell clones employed......, the accumulation of inositol phosphates induced by treatment with fetal calf serum varied only slightly, whereas the same effect induced by EGF was consistently lowered in those lines expressing mutated receptors. This decrease was moderate for those receptors missing only the distal tyrosine (point and deletion...

Progesterone receptor membrane component 1 as the mediator of the inhibitory effect of progestins on cytokine-induced matrix metalloproteinase 9 activity in vitro.

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Allen, Terrence K; Feng, Liping; Grotegut, Chad A; Murtha, Amy P

2014-02-01

Progesterone (P4) and the progestin, 17α-hydroxyprogesterone caproate, are clinically used to prevent preterm births (PTBs); however, their mechanism of action remains unclear. Cytokine-induced matrix metalloproteinase 9 (MMP-9) activity plays a key role in preterm premature rupture of the membranes and PTB. We demonstrated that the primary chorion cells and the HTR8/SVneo cells (cytotrophoblast cell line) do not express the classical progesterone receptor (PGR) but instead a novel progesterone receptor, progesterone receptor membrane component 1 (PGRMC1), whose role remains unclear. Using HTR8/SVneo cells in culture, we further demonstrated that 6 hours pretreatment with medroxyprogesterone acetate (MPA) and dexamethasone (Dex) but not P4 or 17α-hydroxyprogesterone hexanoate significantly attenuated tumor necrosis factor α-induced MMP-9 activity after a 24-hour incubation period. The inhibitory effect of MPA, but not Dex, was attenuated when PGRMC1 expression was successfully reduced by PGRMC1 small interfering RNA. Our findings highlight a possible novel role of PGRMC1 in mediating the effects of MPA and in modulating cytokine-induced MMP-9 activity in cytotrophoblast cells in vitro.

Genetic Imaging of the Association of Oxytocin Receptor Gene (OXTR Polymorphisms with Positive Maternal Parenting

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Kalina J. Michalska

2014-02-01

Full Text Available Background: Well-validated models of maternal behavior in small-brain mammals posit a central role of oxytocin in parenting, by reducing stress and enhancing the reward value of social interactions with offspring. In contrast, human studies are only beginning to gain insights into how oxytocin modulates maternal behavior and affiliation. Methods: To explore associations between oxytocin receptor genes and maternal parenting behavior in humans, we conducted a genetic imaging study of women selected to exhibit a wide range of observed parenting when their children were 4-6 years old. Results: In response to child stimuli during functional magnetic resonance imaging, hemodynamic responses in brain regions that mediate affect, reward, and social behavior were significantly correlated with observed positive parenting. Furthermore, single nucleotide polymorphisms (rs53576 and rs1042778 in the gene encoding the oxytocin receptor were significantly associated with both positive parenting and hemodynamic responses to child stimuli in orbitofrontal cortex, anterior cingulate cortex and hippocampus. Conclusions: These findings contribute to the emerging literature on the role of oxytocin in human social behavior and support the feasibility of tracing biological pathways from genes to neural regions to positive maternal parenting behaviors in humans using genetic imaging methods.

The cognition-enhancing activity of E1R, a novel positive allosteric modulator of sigma-1 receptors

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Zvejniece, L; Vavers, E; Svalbe, B; Vilskersts, R; Domracheva, I; Vorona, M; Veinberg, G; Misane, I; Stonans, I; Kalvinsh, I; Dambrova, M

2014-01-01

Background and Purpose Here, we describe the in vitro and in vivo effects of (4R,5S)-2-(5-methyl-2-oxo-4-phenyl-pyrrolidin-1-yl)-acetamide (E1R), a novel positive allosteric modulator of sigma-1 receptors. Experimental Approach E1R was tested for sigma receptor binding activity in a [3H](+)-pentazocine assay, in bradykinin (BK)-induced intracellular Ca2+ concentration ([Ca2+]i) assays and in an electrically stimulated rat vas deferens model. E1R's effects on cognitive function were tested using passive avoidance (PA) and Y-maze tests in mice. A selective sigma-1 receptor antagonist (NE-100), was used to study the involvement of the sigma-1 receptor in the effects of E1R. The open-field test was used to detect the effects of E1R on locomotion. Key Results Pretreatment with E1R enhanced the selective sigma-1 receptor agonist PRE-084's stimulating effect during a model study employing electrically stimulated rat vasa deferentia and an assay measuring the BK-induced [Ca2+]i increase. Pretreatment with E1R facilitated PA retention in a dose-related manner. Furthermore, E1R alleviated the scopolamine-induced cognitive impairment during the PA and Y-maze tests in mice. The in vivo and in vitro effects of E1R were blocked by treatment with the selective sigma-1 receptor antagonist NE-100. E1R did not affect locomotor activity. Conclusion and Implications E1R is a novel 4,5-disubstituted derivative of piracetam that enhances cognition and demonstrates efficacy against scopolamine-induced cholinergic dysfunction in mice. These effects are attributed to its positive modulatory action on the sigma-1 receptor and this activity may be relevant when developing new drugs for treating cognitive symptoms related to neurodegenerative diseases. PMID:24490863

Trastuzumab Emtansine in Treating Older Patients With Human Epidermal Growth Factor Receptor 2-Positive Stage I-III Breast Cancer

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2018-02-01

Estrogen Receptor Status; HER2 Positive Breast Carcinoma; Progesterone Receptor Status; Stage I Breast Cancer; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage II Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage III Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer

Efficacy of chemotherapy after hormone therapy for hormone receptor-positive metastatic breast cancer.

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Mori, Ryutaro; Nagao, Yasuko

2014-01-01

According to the guidelines for metastatic breast cancer, hormone therapy for hormone receptor-positive metastatic breast cancer without life-threatening metastasis should be received prior to chemotherapy. Previous trials have investigated the sensitivity of chemotherapy for preoperative breast cancer based on the efficacy of neoadjuvant hormone therapy. In this retrospective study, we investigated the efficacy of chemotherapy for metastatic breast cancer in hormone therapy-effective and hormone therapy-ineffective cases. Patients who received chemotherapy after hormone therapy for metastatic breast cancer between 2006 and 2013 at our institution were investigated. A total of 32 patients received chemotherapy after hormone therapy for metastatic breast cancer. The median patient age was 59 years, and most of the primary tumors exhibited a T2 status. A total of 26 patients had an N(+) status, while 7 patients had human epidermal growth factor receptor 2-positive tumors. A total of 13 patients received clinical benefits from hormone therapy, with a rate of clinical benefit of subsequent chemotherapy of 30.8%, which was not significantly different from that observed in the hormone therapy-ineffective patients (52.6%). A total of 13 patients were able to continue the hormone therapy for more than 1 year, with a rate of clinical benefit of chemotherapy of 38.5%, which was not significantly different from that observed in the short-term hormone therapy patients (47.4%). The luminal A patients were able to continue hormone therapy for a significantly longer period than the non-luminal A patients (median survival time: 17.8 months vs 6.35 months, p = 0.0085). However, there were no significant differences in the response to or duration of chemotherapy. The efficacy of chemotherapy for metastatic breast cancer cannot be predicted based on the efficacy of prior hormone therapy or tumor subtype, and clinicians should administer chemotherapy in all cases of

Interaction between body mass index and hormone-receptor status as a prognostic factor in lymph-node-positive breast cancer.

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Il Yong Chung

Full Text Available The aim of this study was to determine the relationship between the body mass index (BMI at a breast cancer diagnosis and various factors including the hormone-receptor, menopause, and lymph-node status, and identify if there is a specific patient subgroup for which the BMI has an effect on the breast cancer prognosis. We retrospectively analyzed the data of 8,742 patients with non-metastatic invasive breast cancer from the research database of Asan Medical Center. The overall survival (OS and breast-cancer-specific survival (BCSS outcomes were compared among BMI groups using the Kaplan-Meier method and Cox proportional-hazards regression models with an interaction term. There was a significant interaction between BMI and hormone-receptor status for the OS (P = 0.029, and BCSS (P = 0.013 in lymph-node-positive breast cancers. Obesity in hormone-receptor-positive breast cancer showed a poorer OS (adjusted hazard ratio [HR] = 1.51, 95% confidence interval [CI] = 0.92 to 2.48 and significantly poorer BCSS (HR = 1.80, 95% CI = 1.08 to 2.99. In contrast, a high BMI in hormone-receptor-negative breast cancer revealed a better OS (HR = 0.44, 95% CI = 0.16 to 1.19 and BCSS (HR = 0.53, 95% CI = 0.19 to 1.44. Being underweight (BMI < 18.50 kg/m2 with hormone-receptor-negative breast cancer was associated with a significantly worse OS (HR = 1.98, 95% CI = 1.00-3.95 and BCSS (HR = 2.24, 95% CI = 1.12-4.47. There was no significant interaction found between the BMI and hormone-receptor status in the lymph-node-negative setting, and BMI did not interact with the menopause status in any subgroup. In conclusion, BMI interacts with the hormone-receptor status in a lymph-node-positive setting, thereby playing a role in the prognosis of breast cancer.

Blockage of progestin physiology disrupts ovarian differentiation in XX Nile tilapia (Oreochromis niloticus)

International Nuclear Information System (INIS)

Zhou, Linyan; Luo, Feng; Fang, Xuelian; Charkraborty, Tapas; Wu, Limin; Wei, Jing; Wang, Deshou

2016-01-01

Previous studies indicated that maturation inducing hormone, 17α, 20β-Dihydroxy-4-pregnen-3-one (DHP), probably through nuclear progestin receptor (Pgr), might be involved in spermatogenesis and oogenesis in fish. To further elucidate DHP actions in teleostean ovarian differentiation, we analyzed the expression of pgr in the ovary of Nile tilapia (Oreochromis niloticus), and performed RU486 (a synthetic Pgr antagonist) treatment in XX fish from 5 days after hatching (dah) to 120dah. Tilapia Pgr was abundantly expressed in the follicular cells surrounding oocytes at 30 and 90dah. Continuous RU486 treatment led to the blockage of oogenesis and masculinization of somatic cells in XX fish. Termination of RU486 treatment and maintenance in normal condition resulted in testicular differentiation, and estrogen compensation in RU486-treated XX fish successfully restored oogenesis. In RU486-treated XX fish, transcript levels of female dominant genes were significantly reduced, while male-biased genes were evidently augmented. Meanwhile, both germ cell mitotic and meiotic markers were substantially reduced. Consistently, estrogen production levels were significantly declined in RU486-treated XX fish. Taken together, our data further proved that DHP, possibly through Pgr, might be essential in the ovarian differentiation and estrogen production in fish. - Highlights: • DHP plays a critical role in early stage oogenesis of XX tilapia. • Blockage of DHP actions by RU486 treatment led to masculinization and/or sex reversal in XX tilapia. • Both DHP and estrogen are indispensable for ovarian differentiation.

Blockage of progestin physiology disrupts ovarian differentiation in XX Nile tilapia (Oreochromis niloticus)

Energy Technology Data Exchange (ETDEWEB)

Zhou, Linyan; Luo, Feng; Fang, Xuelian [Key Laboratory of Freshwater Fish Reproduction and Development (Ministry of Education), Key Laboratory of Aquatic Science of Chongqing, School of Life Sciences, Southwest University, Chongqing, 400715 (China); Charkraborty, Tapas [South Ehime Fisheries Research Center, Ehime University, Ainan, 798-4206 (Japan); Wu, Limin; Wei, Jing [Key Laboratory of Freshwater Fish Reproduction and Development (Ministry of Education), Key Laboratory of Aquatic Science of Chongqing, School of Life Sciences, Southwest University, Chongqing, 400715 (China); Wang, Deshou, E-mail: wdeshou@swu.edu.cn [Key Laboratory of Freshwater Fish Reproduction and Development (Ministry of Education), Key Laboratory of Aquatic Science of Chongqing, School of Life Sciences, Southwest University, Chongqing, 400715 (China)

2016-04-22

Previous studies indicated that maturation inducing hormone, 17α, 20β-Dihydroxy-4-pregnen-3-one (DHP), probably through nuclear progestin receptor (Pgr), might be involved in spermatogenesis and oogenesis in fish. To further elucidate DHP actions in teleostean ovarian differentiation, we analyzed the expression of pgr in the ovary of Nile tilapia (Oreochromis niloticus), and performed RU486 (a synthetic Pgr antagonist) treatment in XX fish from 5 days after hatching (dah) to 120dah. Tilapia Pgr was abundantly expressed in the follicular cells surrounding oocytes at 30 and 90dah. Continuous RU486 treatment led to the blockage of oogenesis and masculinization of somatic cells in XX fish. Termination of RU486 treatment and maintenance in normal condition resulted in testicular differentiation, and estrogen compensation in RU486-treated XX fish successfully restored oogenesis. In RU486-treated XX fish, transcript levels of female dominant genes were significantly reduced, while male-biased genes were evidently augmented. Meanwhile, both germ cell mitotic and meiotic markers were substantially reduced. Consistently, estrogen production levels were significantly declined in RU486-treated XX fish. Taken together, our data further proved that DHP, possibly through Pgr, might be essential in the ovarian differentiation and estrogen production in fish. - Highlights: • DHP plays a critical role in early stage oogenesis of XX tilapia. • Blockage of DHP actions by RU486 treatment led to masculinization and/or sex reversal in XX tilapia. • Both DHP and estrogen are indispensable for ovarian differentiation.

Structural changes at the myrtenol backbone reverse its positive allosteric potential into inhibitory GABAA receptor modulation

DEFF Research Database (Denmark)

Milanos, Sinem; Kuenzel, Katharina; Gilbert, Daniel F

2017-01-01

monoterpenes, e.g. myrtenol as positive allosteric modulator at α1β2 GABAA receptors. Here, along with pharmacophore-based virtual screening studies, we demonstrate that scaffold modifications of myrtenol resulted in loss of modulatory activity. Two independent approaches, fluorescence-based compound analysis...

Niclosamide inhibits epithelial-mesenchymal transition and tumor growth in lapatinib-resistant human epidermal growth factor receptor 2-positive breast cancer.

Science.gov (United States)

Liu, Junjun; Chen, Xiaosong; Ward, Toby; Mao, Yan; Bockhorn, Jessica; Liu, Xiaofei; Wang, Gen; Pegram, Mark; Shen, Kunwei

2016-02-01

Acquired resistance to lapatinib, a human epidermal growth factor receptor 2 kinase inhibitor, remains a clinical problem for women with human epidermal growth factor receptor 2-positive advanced breast cancer, as metastasis is commonly observed in these patients. Niclosamide, an anti-helminthic agent, has recently been shown to exhibit cytotoxicity to tumor cells with stem-like characteristics. This study was designed to identify the mechanisms underlying lapatinib resistance and to determine whether niclosamide inhibits lapatinib resistance by reversing epithelial-mesenchymal transition. Here, two human epidermal growth factor receptor 2-positive breast cancer cell lines, SKBR3 and BT474, were exposed to increasing concentrations of lapatinib to establish lapatinib-resistant cultures. Lapatinib-resistant SKBR3 and BT474 cells exhibited up-regulation of the phenotypic epithelial-mesenchymal transition markers Snail, vimentin and α-smooth muscle actin, accompanied by activation of nuclear factor-кB and Src and a concomitant increase in stem cell marker expression (CD44(high)/CD24(low)), compared to naive lapatinib-sensitive SKBR3 and BT474 cells, respectively. Interestingly, niclosamide reversed epithelial-mesenchymal transition, induced apoptosis and inhibited cell growth by perturbing aberrant signaling pathway activation in lapatinib-resistant human epidermal growth factor receptor 2-positive cells. The ability of niclosamide to alleviate stem-like phenotype development and invasion was confirmed. Collectively, our results demonstrate that lapatinib resistance correlates with epithelial-mesenchymal transition and that niclosamide inhibits lapatinib-resistant cell viability and epithelial-mesenchymal transition. These findings suggest a role of niclosamide or derivatives optimized for more favorable bioavailability not only in reversing lapatinib resistance but also in reducing metastatic potential during the treatment of human epidermal growth factor receptor

Thermodynamics and structural analysis of positive allosteric modulation of the ionotropic glutamate receptor GluA2

DEFF Research Database (Denmark)

Krintel, Christian; Frydenvang, Karla; Olsen, Lars

2012-01-01

Positive allosteric modulators of the ionotropic glutamate receptor-2 (GluA2) are promising compounds for the treatment of cognitive disorders, e.g. Alzheimer's disease. These modulators bind within the dimer interface of the ligand-binding domain and stabilize the agonist-bound conformation slow...

[Clinical relevance of ESR1 circulating mutations detection in hormone receptor positive metastatic breast cancer].

Science.gov (United States)

Clatot, Florian; Perdrix, Anne; Sefrioui, David; Sarafan-Vasseur, Nasrin; Di Fiore, Frédéric

2018-01-01

If hormone therapy is a key treatment for hormone receptor positive advanced breast cancers, secondary resistance occurs as a rule. Recently, acquired alterations of the ESR1 gene have been identified as a mechanism of resistance on aromatase inhibitor (AI) treatment. The selective pressure by AI exposure during the metastatic setting triggers the emergence of ESR1 activating mutations. In that context, the "liquid biopsy" concept has been used to detect this molecular resistance before progression. Thus, the ESR1 circulating mutation detection will soon be used in daily practice to help monitoring patients on AI treatment and provide an early change for specific therapies that still have to be determined in prospective clinical trials. This review will present the acquired ESR1 mutations, as well as the methods used for their detection in blood and the potential clinical impact of this approach for hormone receptor positive breast cancer management. Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

Undernutrition and laterality of the corpus luteum affects gene expression in oviduct and uterus of pregnant ewes

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V. de Brun

2013-11-01

Full Text Available The effect of undernutrition on gene expression of progesterone and oestrogen receptors (PGR and ESR1, and insulin-like growth factors 1 and 2 (IGF1 and IGF2 in the uterus and oviducts of ewes on day 5 after oestrus was investigated. The effect of the side of the uterus/oviduct regarding the ovary bearing a corpus luteum (CL (ipsi vs. contralateral was also analyzed. Fourteen oestrous synchronized ewes were fed either 1.5 (C, n=7 or 0.5 (L, n=7 times their maintenance requirements from the onset of the hormonal treatment (day -14, till slaughter on day 5 post-oestrus. Oviducts and samples of uterus were collected and their gene expression studied by real time RT-PCR. Undernourished ewes had greater PGR expression in the oviduct than control ewes, but lower expression of IGF1 in uterus and of IGF2 in oviducts. The ipsilateral oviduct presented lower expression of PGR, ESR1 and IGF2 mRNA than the contralateral one, but this did not occur in the uterus. In conclusion, there is an effect of undernutrition on gene expression that is transcript and organ dependent (uterus/oviduct. This work reports for the first time that growth factors and sex steroid receptor expression on day 5 after oestrus vary depending on the side of the CL-bearing ovary and the region of the reproductive tract.

Divergent estrogen receptor-positive and -negative breast cancer trends and etiologic heterogeneity in Denmark

DEFF Research Database (Denmark)

Anderson, William F; Rosenberg, Philip S; Petito, Lucia

2013-01-01

-period-cohort models to estimate age-specific EAPCs, cohort rate ratios and projections for future time periods (2011-2018). In Denmark, the overall rate of ER-positive cancers rose between 1993 and 2010 by 3.0% per year (95% CI: 2.8-3.3% per year), whereas the overall rate of ER-negative cancers fell by 2.1% per year...... (95% CI: -2.5 to -1.6% per year). The ER-positive rate increased fastest among postmenopausal women and the ER-negative rate decreased fastest among premenopausal women, reflecting that cohorts born after 1944 were at relatively higher risk of ER-positive tumors and lower risk of ER-negative tumors......Long-term breast cancer trends in incidence in the United States (US) show rising estrogen receptor (ER)-positive rates and falling ER-negative rates. We hypothesized that these divergent trends reflect etiologic heterogeneity and that comparable trends should be observed in other countries...

Androgens as therapy for androgen receptor-positive castration-resistant prostate cancer

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Lin Hui-Ping

2011-08-01

Full Text Available Abstract Prostate cancer is the most frequently diagnosed non-cutaneous tumor of men in Western countries. While surgery is often successful for organ-confined prostate cancer, androgen ablation therapy is the primary treatment for metastatic prostate cancer. However, this therapy is associated with several undesired side-effects, including increased risk of cardiovascular diseases. Shortening the period of androgen ablation therapy may benefit prostate cancer patients. Intermittent Androgen Deprivation therapy improves quality of life, reduces toxicity and medical costs, and delays disease progression in some patients. Cell culture and xenograft studies using androgen receptor (AR-positive castration-resistant human prostate cancers cells (LNCaP, ARCaP, and PC-3 cells over-expressing AR suggest that androgens may suppress the growth of AR-rich prostate cancer cells. Androgens cause growth inhibition and G1 cell cycle arrest in these cells by regulating c-Myc, Skp2, and p27Kip via AR. Higher dosages of testosterone cause greater growth inhibition of relapsed tumors. Manipulating androgen/AR signaling may therefore be a potential therapy for AR-positive advanced prostate cancer.

Confirmation of 5p12 as a susceptibility locus for progesterone-receptor- positive, lower grade breast cancer

NARCIS (Netherlands)

R.L. Milne (Roger); E.L. Goode (Ellen); M. García-Closas (Montserrat); F.J. Couch (Fergus); G. Severi (Gianluca); R. Hein (Rebecca); Z. Fredericksen (Zachary); N. Malats (Núria); M.P. Zamora (Pilar); J.I.A. Perez (Jose Ignacio Arias); J. Benítez (Javier); T. Dörk (Thilo); P. Schürmann (Peter); J.H. Karstens (Johann); P. Hillemanns (Peter); A. Cox (Angela); I.W. Brock (Ian); K.S. Elliot (Katherine); S.S. Cross (Simon); S. Seal (Sheila); C. Turnbull (Clare); A. Renwick (Anthony); N. Rahman (Nazneen); C-Y. Shen (Chen-Yang); J-C. Yu (Jyh-Cherng); C.-S. Huang (Chiun-Sheng); M.-F. Hou (Ming-Feng); B.G. Nordestgaard (Børge); S.E. Bojesen (Stig); C. Lanng (Charlotte); G.G. Alnæs (Grethe); V. Kristensen (Vessela); A.-L. Børrensen-Dale (Anne-Lise); J.L. Hopper (John); G.S. Dite (Gillian); C. Apicella (Carmel); M.C. Southey (Melissa); D. Lambrechts (Diether); B.T. Yesilyurt (Betül); O.A.M. Floris; K. Leunen; S. Sangrajrang (Suleeporn); V. Gaborieau (Valerie); P. Brennan (Paul); J.D. McKay (James); J. Chang-Claude (Jenny); S. Wang-Gohrke (Shan); P. Radice (Paolo); P. Peterlongo (Paolo); S. Manoukian (Siranoush); M. Barile (Monica); G.G. Giles (Graham); L. Baglietto (Laura); E.M. John (Esther); A. Miron (Alexander); S.J. Chanock (Stephen); J. Lissowska (Jolanta); M.E. Sherman (Mark); J.D. Figueroa (Jonine); N.V. Bogdanova (Natalia); N.N. Antonenkova (Natalia); I.V. Zalutsky (Iosif); Y.I. Rogov (Yuri); P.A. Fasching (Peter); T. Bayer (T.); A.B. Ekici (Arif); M.W. Beckmann (Matthias); H. Brenner (Hermann); H. Müller (Heike); V. Arndt (Volker); C. Stegmaier (Christa); I.L. Andrulis (Irene); J.A. Knight (Julia); G. Glendon (Gord); A.M. Mulligan (Anna Marie); A. Mannermaa (Arto); V. Kataja (Vesa); V-M. Kosma (Veli-Matti); J. Hartikainen (Jaana); A. Meindl (Alfons); J. Heil (Joerg); C.R. Bartram (Claus); R.K. Schmutzler (Rita); G. Thomas (Gilles); R.N. Hoover (Robert); O. Fletcher (Olivia); L.J. Gibson (Lorna); I. dos Santos Silva (Isabel); J. Peto (Julian); S. Nickels (Stefan); D. Flesch-Janys (Dieter); H. Anton-Culver (Hoda); A. Ziogas (Argyrios); E.J. Sawyer (Elinor); I.P. Tomlinson (Ian); M. Kerin (Michael); N. Miller (Nicola); M.K. Schmidt (Marjanka); A. Broeks (Annegien); L.J. van 't Veer (Laura); R.A.E.M. Tollenaar (Rob); P.D.P. Pharoah (Paul); A.M. Dunning (Alison); K.A. Pooley (Karen); F. Marme (Federick); A. Schneeweiss (Andreas); C. Sohn (Christof); B. Burwinkel (Barbara); A. Jakubowska (Anna); J. Lubinski (Jan); K. Jaworska (Katarzyna); K. Durda (Katarzyna); D. Kang (Daehee); K-Y. Yoo (Keun-Young); D-Y. Noh (Dong-Young); S.-H. Ahn (Sei-Hyun); D. Hunter (David); S.E. Hankinson (Susan); P. Kraft (Peter); S. Lindstrom (Stephen); X. Chen (Xiaoqing); J. Beesley (Jonathan); U. Hamann (Ute); V. Harth (Volker); C. Justenhoven (Christina); R. Winqvist (Robert); K. Pykäs (Katri); A. Jukkola-Vuorinen (Arja); M. Grip (Mervi); M.J. Hooning (Maartje); A. Hollestelle (Antoinette); R.A. Oldenburg (Rogier); M.M.A. Tilanus-Linthorst (Madeleine); E.K. Khusnutdinova (Elza); M. Bermisheva (Marina); D. Prokofieva (Darya); A. Farahtdinova (Albina); J.E. Olson (Janet); X. Wang (Xing); M.K. Humphreys (Manjeet); Q. Wang (Qing); G. Chenevix-Trench (Georgia); D.F. Easton (Douglas)

2011-01-01

textabstractBackground: The single-nucleotide polymorphism (SNP) 5p12-rs10941679 has been found to be associated with risk of breast cancer, particularly estrogen receptor (ER)-positive disease. We aimed to further explore this association overall, and by tumor histopathology, in the Breast Cancer

Toll-like receptor 4-positive macrophages protect mice from Pasteurella pneumotropica-induced pneumonia

Science.gov (United States)

Hart, Marcia L.; Mosier, Derek A.; Chapes, Stephen K.

2003-01-01

This study investigates Toll-like receptor 4 (TLR4)-positive macrophages in early recognition and clearance of pulmonary bacteria. TLR4 is a trans-membrane receptor that is the primary recognition molecule for lipopolysaccharide of gram-negative bacteria. The TLR4(Lps-del) mouse strains C57BL10/ScN (B10) and STOCK Abb(tm1) TLR4(Lps-del) Slc11a1(s)(B10 x C2D) are susceptible to pulmonary infections and develop pneumonia when naturally or experimentally infected by the opportunistic bacterium Pasteurella pneumotropica. Since these mice have the TLR4(Lps-del) genotype, we hypothesized that reconstitution of mice with TLR4-positive macrophages would provide resistance to this bacterium. A cultured macrophage cell line (C2D macrophages) and bone marrow cells from C2D mice were adoptively transferred to B10 and B10 x C2D mice by intraperitoneal injection. C2D macrophages increased B10 and B10 x C2D mouse resistance to P. pneumotropica. In C2D-recipient mice there was earlier transcription of tumor necrosis factor alpha and chemokines JE and macrophage inflammatory protein 2 (MIP-2) in the lungs of B10 and B10 x C2D mice, and there was earlier transcription of KC and MIP-1alpha in B10 x C2D mice. In addition, the course of inflammation following experimental Pasteurella challenge was altered in C2D recipients. C2D macrophages also protected B10 x C2D mice, which lack CD4(+) T cells. These data indicate that macrophages are critical for pulmonary immunity and can provide host resistance to P. pneumotropica. This study indicates that TLR4-positive macrophages are important for early recognition and clearance of pulmonary bacterial infections.

The C'-terminal interaction domain of the thyroid hormone receptor confers the ability of the DNA site to dictate positive or negative transcriptional activity

International Nuclear Information System (INIS)

Holloway, J.M.; Glass, C.K.; Adler, S.; Nelson, C.A.; Rosenfeld, M.G.

1990-01-01

To investigate mechanisms responsible for positive and negative transcriptional control, the authors have utilized two types of promoters that are diffferentially regulated by thyroid hormone (T 3 ) receptors. Promoters containing the palindromic T 3 response element TCAGGTCA TGACCTGA are positively regulated by the T 3 receptor after the administration of T 3 , whereas otherwise identical promoters containing the estrogen response element TCAGGTCA CTG TGACCTGA can be regulated negatively; converse effects are observed with the estrogen receptor. They describe evidence that the transcriptional inhibitory effects of the T 3 or estrogen receptors on the estrogen or T 3 response elements, respectively, are imposed by amino acid sequences in the C'-terminal region that colocalize with dimerization and hormone-binding domains and that these sequences can transfer inhibitory functions to other classes of transcription factors. Removal of the C'-terminal dimerization and hormone-binding domains of either the αT 3 or estrogen receptors permits each receptor to act constitutively to enhance transcription on both T 3 and estrogen response elements. It is, therefore, suggested that protein-protein interactions between receptor C' termini limit the subset of DNA binding sites on which transcriptional activation occurs

Treatment challenges for community oncologists treating postmenopausal women with endocrine-resistant, hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer

International Nuclear Information System (INIS)

Gradishar, William J

2016-01-01

Community-based oncologists are faced with challenges and opportunities when delivering quality patient care, including high patient volumes and diminished resources; however, there may be the potential to deliver increased patient education and subsequently improve outcomes. This review discusses the treatment of postmenopausal women with endocrine-resistant, hormone receptor-positive, human epidermal growth factor receptor 2- negative advanced breast cancer in order to illustrate considerations in the provision of pertinent quality education in the treatment of these patients and the management of therapy-related adverse events. An overview of endocrine-resistant breast cancer and subsequent treatment challenges is also provided. Approved treatment options for endocrine-resistant breast cancer include hormonal therapies and mammalian target of rapamycin inhibitors. Compounds under clinical investigation are also discussed

Lipid-rich carcinoma of the breast that is strongly positive for estrogen receptor: a case report and literature review

Directory of Open Access Journals (Sweden)

Oba T

2016-03-01

Full Text Available Takaaki Oba,1 Mayu Ono,1 Asumi Iesato,1 Toru Hanamura,1 Takayuki Watanabe,1 Tokiko Ito,1 Toshiharu Kanai,1 Kazuma Maeno,1 Ken-ichi Ito,1 Ayako Tateishi,2 Akihiko Yoshizawa,2 Fumiyoshi Takayama31Division of Breast, Endocrine and Respiratory Surgery, Department of Surgery, Shinshu University School of Medicine, Matsumoto, Nagano, 2Department of Laboratory Medicine, Shinshu University Hospital, 3Imaging Center, Ichinose Neurosurgical Hospital, Matsumoto, JapanAbstract: Lipid-rich carcinoma (LRC of the breast is a rare breast cancer variant that accounts for <1% of all breast malignancies. It has been reported that LRCs are negative for estrogen receptor. Here, we report a case of LRC of the breast that was strongly positive for estrogen receptor and treated with endocrine adjuvant therapy. A 52-year-old postmenopausal female noticed a lump in her right breast by self-examination and presented to our hospital. Physical examination revealed an elastic 30 mm ×20 mm hard mass in the upper medial part of her right breast. The findings obtained using ultrasonography, mammography, and contrast-enhanced magnetic resonance imaging suggested breast cancer. Core needle biopsy resulted in the diagnosis of invasive carcinoma. The patient underwent mastectomy and sentinel lymph node biopsy. Histopathologically, the tumor cells were abundant in foamy cytoplasm. Because the presence of marked cytoplasmic lipid droplets was confirmed by Sudan IV staining and electron microscopic examination of the tumor and the lipid droplets were negative for periodic acid–Schiff staining, the tumor was diagnosed as an LRC. Immunohistochemically, estrogen and progesterone receptors of the tumor were strongly positive, human epidermal growth factor receptor type 2 was negative, and the ratio of Ki-67-positive cells was ~30%. After surgery, the patient underwent combination chemotherapy with anthracycline, cyclophosphamide, and 5-fluorouracil, followed by docetaxel. Thereafter

Antioxidant activity characterization, phytochemical screening, and proximate analysis of Cermela Hutan (Phyllanthus gomphocarpus Hook. F) roots and leaves.

Science.gov (United States)

Bahari, Ebby-Anuar; Zaaba, Nur Eleza; Haron, Norhisham; Dasiman, Razif; Amom, Zulkhairi

2014-11-07

Roots and leaves of the Cermela Hutan (Phyllanthus gomphocarpus Hook. F) plant were studied to determine antioxidant activity, phytochemical compounds, proportion of carbohydrate, crude protein, moisture, ash, fat, total phenolic content (TPC), and total flavonoid content (TFC). Ten percent (10%) aqueous extract from both Phyllanthus gomphocarpus roots (PGR) and leaves (PGL) were used in this study. Antioxidant activity characterization by TPC, TFC, Ferric Reducing Antioxidant Power (FRAP), 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging activity, and phytochemical screening, as well as proximate analysis from both extracts were analyzed in this study. Phyllanthus gomphocarpus roots (PGR) and leaves (PGL) tested positive for flavonoid, saponin, tannins, and terpenoids, but PGR showed negative result for anthraquinones. In average weight of 100.0 g dry sample, the carbohydrates, protein, moisture, ash, fat, and energy content in PGR and PGL were 80.9%, 5.5%, 7.8%, 3.4%, 2.4%, and 367 Kcal/100g, and 66.5%, 14.8%, 10.7%, 6.5%, 1.5%, and 399 Kcal/100 g, respectively. Antioxidant assessments using FRAP and DPPH assay showed that PGL extracts possessed higher antioxidant capacity by reducing the ferric ion-TPTZ complex by 0.14 mg/ml ±0.0018 and higher scavenging activity, 83.83% ±0.54 as compared to PGR, 0.07 mg/ml ±0.0035 for FRAP and 62.87% ±1.33 for DPPH, respectively. The total phenolics content was significantly higher in PGL (208.77 mg GAE/g ±3.79) as compared to PGR (27.53 mg GAE/g ±0.42). However, there was no significant different in the total flavonoid contents for PGR (34.8 mg QE/g ±3.12) and PGL (32.43 mg QE/g ±3.92). Further investigations are suggested to isolate and characterize the other active constituents from this plant in combatting diseases.

Proliferation of Estrogen Receptor alpha Positive Mammary Epithelial Cells is Restrained by TGFbeta1 in Adult Mice

Energy Technology Data Exchange (ETDEWEB)

Ewan, Kenneth B.R.; Oketch-Rabah, Hellen A.; Ravani, Shraddha A.; Shyamala, G.; Moses, Harold L.; Barcellos-Hoff, Mary Helen

2005-03-03

Transforming growth factor {beta}1 (TGF{beta}1) is a potent inhibitor of mammary epithelial proliferation. In human breast, estrogen receptor {alpha} (ER{alpha}) cells rarely co-localize with markers of proliferation, but their increased frequency correlates with breast cancer risk. To determine whether TGF{beta}1 is necessary for the quiescence of ER{alpha}-positive population, we examined mouse mammary epithelial gland at estrus. Approximately 35% of cells showed TGF{beta}1 activation, which co-localized with nuclear receptor-phosphorylated Smad 2/3, indicating that TGF{beta} signaling is autocrine. Furthermore, nuclear Smad co-localized with nuclear ER{alpha}. To test whether TGF{beta} was functional, we examined genetically engineered mice with different levels of TGF{beta}1. ER{alpha} co-localization with markers of proliferation (i.e. Ki-67 or BrdU) at estrus was significantly increased in the mammary glands of Tgf{beta}1 C57/bl/129SV heterozygote mice. This relationship was maintained following pregnancy, but was absent at puberty. Conversely, mammary epithelial expression of constitutively active TGF{beta}1 via the MMTV promoter suppressed proliferation of ER{alpha} positive cells. Thus, TGF{beta}1 activation functionally restrains ER{alpha} positive cells from proliferating in adult mammary gland. Accordingly, we propose that TGF{beta}1 dysregulation may promote proliferation of ER{alpha} positive cells associated with breast cancer risk in humans.

Occult inflammatory breast cancer: review of clinical, mammographic, US and pathologic signs

International Nuclear Information System (INIS)

Cumo, Francesca; Gaioni, Maria Berenice; Bonetti, Franco; Manfrin, Erminia; Remo, Andrea; Pattaro, Christian; Policlinico G.B. Rossi, Verona

2005-01-01

Purpose: To examine the clinical, radiologic and pathologic findings of occult inflammatory breast cancer (OIBC) in order to identify features useful for diagnosis. Materials and methods: We retrospectively reviewed the records of 19 women with OIBC observed at our Department between 1992 and 2001. We analysed the clinical history, mammographic, ultrasonographic, and pathologic findings and investigated overall survival (OS), prognostic variables and radio-pathologic correlations. Results: The most common mammographic findings were: diffusely density (52.63%), trabecular thickening (42.1%), mass (36.84%). The most common US findings were axillary lymphadenopathy (68,75%), skin thickening (43.75%) and mass (56.25%). At least one inflammatory sign was found in 14 women (74%) at mammography (subcutaneous thickening, trabecular thickening, diffuse increase of density) or at US (subcutaneous thickening, diffuse increase in echogenicity due to oedema, lymph vessel dilatation). Estrogen receptors (ER) were present in 63.2% and Progesterone receptors (PgR) in 36.8%. Significant prognostic variables were ER and Ki 67. Conclusions: The typical radiological pattern of clinical inflammatory breast carcinoma is less frequently present in OIBC; nevertheless the radiologist must pay attention because frequently OIBC presents just one radiological sign and this should be enough for a diagnostic suspicion. Moreover, the absence of clinical and radiological inflammatory signs does not exclude inflammatory breasts cancer because OIBC can manifest at imaging as a mass or isolated calcification. ER and PgR are positive in a high percentage of patients and confirm that OIBC has a better prognosis that clinical inflammatory breast cancer [it

PAM50 Breast Cancer Subtyping by RT-qPCR and Concordance with Standard Clinical Molecular Markers

Directory of Open Access Journals (Sweden)

Bastien Roy RL

2012-10-01

Full Text Available Abstract Background Many methodologies have been used in research to identify the “intrinsic” subtypes of breast cancer commonly known as Luminal A, Luminal B, HER2-Enriched (HER2-E and Basal-like. The PAM50 gene set is often used for gene expression-based subtyping; however, surrogate subtyping using panels of immunohistochemical (IHC markers are still widely used clinically. Discrepancies between these methods may lead to different treatment decisions. Methods We used the PAM50 RT-qPCR assay to expression profile 814 tumors from the GEICAM/9906 phase III clinical trial that enrolled women with locally advanced primary invasive breast cancer. All samples were scored at a single site by IHC for estrogen receptor (ER, progesterone receptor (PR, and Her2/neu (HER2 protein expression. Equivocal HER2 cases were confirmed by chromogenic in situ hybridization (CISH. Single gene scores by IHC/CISH were compared with RT-qPCR continuous gene expression values and “intrinsic” subtype assignment by the PAM50. High, medium, and low expression for ESR1, PGR, ERBB2, and proliferation were selected using quartile cut-points from the continuous RT-qPCR data across the PAM50 subtype assignments. Results ESR1, PGR, and ERBB2 gene expression had high agreement with established binary IHC cut-points (area under the curve (AUC ≥ 0.9. Estrogen receptor positivity by IHC was strongly associated with Luminal (A and B subtypes (92%, but only 75% of ER negative tumors were classified into the HER2-E and Basal-like subtypes. Luminal A tumors more frequently expressed PR than Luminal B (94% vs 74% and Luminal A tumors were less likely to have high proliferation (11% vs 77%. Seventy-seven percent (30/39 of ER-/HER2+ tumors by IHC were classified as the HER2-E subtype. Triple negative tumors were mainly comprised of Basal-like (57% and HER2-E (30% subtypes. Single gene scoring for ESR1, PGR, and ERBB2 was more prognostic than the corresponding IHC markers as

Endogenous plasma estradiol in healthy men is positively correlated with cerebral cortical serotonin 2A receptor binding

DEFF Research Database (Denmark)

Frokjaer, Vibe G.; Erritzoe, David; Juul, Anders

2010-01-01

the effect of plasma sex hormone levels on neocortical 5-HT2A receptor binding as imaged with [18F]altanserin PET. The effect of endogenous sex-hormone levels was evaluated by multiple linear regression analysis. Results: Mean neocortical 5-HT2A receptor binding was positively correlated with estradiol (p......Background: Sex-hormones influence brain function and are likely to play a role in the gender predisposition to mood and anxiety disorders. Acute fluctuations of sex-hormone levels including hormonal replacement therapy appear to affect serotonergic neurotransmission, but it is unknown if baseline...... levels affect serotonergic neurotransmission. This study was undertaken to examine if baseline levels of endogenous sex hormones are associated with cerebral serotonin 2A (5-HT2A) receptor binding in men. Methods: In a group of 72 healthy men (mean age 37.5 years ±17.4 SD, range 19.6–81.7) we studied...

Differential modulation of expression of nuclear receptor mediated genes by tris(2-butoxyethyl) phosphate (TBOEP) on early life stages of zebrafish (Danio rerio)

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Ma, Zhiyuan, E-mail: zhiyuan_nju@163.com [State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing, Jiangsu 210023 (China); Yu, Yijun, E-mail: yjun.yu@gmail.com [State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing, Jiangsu 210023 (China); Tang, Song [School of Environment and Sustainability, University of Saskatchewan, Saskatoon, SK S7N 5B3 (Canada); Liu, Hongling, E-mail: hlliu@nju.edu.cn [State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing, Jiangsu 210023 (China); Su, Guanyong; Xie, Yuwei [State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing, Jiangsu 210023 (China); Giesy, John P. [State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing, Jiangsu 210023 (China); Toxicology Centre, University of Saskatchewan, Saskatoon, SK S7N 5B3 (Canada); Department of Veterinary Biomedical Sciences, University of Saskatchewan, Saskatoon, SK S7N 5B3 (Canada); Department of Biology and Chemistry, City University of Hong Kong, Kowloon, Hong Kong Special Administrative Region (Hong Kong); Hecker, Markus [School of Environment and Sustainability, University of Saskatchewan, Saskatoon, SK S7N 5B3 (Canada); Toxicology Centre, University of Saskatchewan, Saskatoon, SK S7N 5B3 (Canada); Yu, Hongxia [State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing, Jiangsu 210023 (China)

2015-12-15

Highlights: • Effects of TBOEP on expression of genes of several nuclear hormone receptors and their relationship with adverse effect pathways in zebrafish. • TBOEP was neither an agonist nor antagonist of AR or AhR as determined by use of in vitro mammalian cell-based receptor transactivation assays. • Modulation of ER- and MR-dependent pathways allowed for development of feasible receptor-mediated, critical mechanisms of toxic action. - Abstract: As one substitute for phased-out brominated flame retardants (BFRs), tris(2-butoxyethyl) phosphate (TBOEP) is frequently detected in aquatic organisms. However, knowledge about endocrine disrupting mechanisms associated with nuclear receptors caused by TBOEP remained restricted to results from in vitro studies with mammalian cells. In the study, results of which are presented here, embryos/larvae of zebrafish (Danio rerio) were exposed to 0.02, 0.1 or 0.5 μM TBOEP to investigate expression of genes under control of several nuclear hormone receptors (estrogen receptors (ERs), androgen receptor (AR), thyroid hormone receptor alpha (TRα), mineralocorticoid receptor (MR), glucocorticoid receptor (GR), aryl hydrocarbon (AhR), peroxisome proliferator-activated receptor alpha (PPARα), and pregnane × receptor (P × R)) pathways at 120 hpf. Exposure to 0.5 μM TBOEP significantly (p < 0.05, one-way analysis of variance) up-regulated expression of estrogen receptors (ERs, er1, er2a, and er2b) genes and ER-associated genes (vtg4, vtg5, pgr, ncor, and ncoa3), indicating TBOEP modulates the ER pathway. In contrast, expression of most genes (mr, 11βhsd, ube2i,and adrb2b) associated with the mineralocorticoid receptor (MR) pathway were significantly down-regulated. Furthermore, in vitro mammalian cell-based (MDA-kb2 and H4IIE-luc) receptor transactivation assays, were also conducted to investigate possible agonistic or antagonistic effects on AR- and AhR-mediated pathways. In mammalian cells, none of these pathways were

Molecular sites for the positive allosteric modulation of glycine receptors by endocannabinoids.

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Gonzalo E Yévenes

Full Text Available Glycine receptors (GlyRs are transmitter-gated anion channels of the Cys-loop superfamily which mediate synaptic inhibition at spinal and selected supraspinal sites. Although they serve pivotal functions in motor control and sensory processing, they have yet to be exploited as drug targets partly because of hitherto limited possibilities for allosteric control. Endocannabinoids (ECs have recently been characterized as direct allosteric GlyR modulators, but the underlying molecular sites have remained unknown. Here, we show that chemically neutral ECs (e.g. anandamide, AEA are positive modulators of α(1, α(2 and α(3 GlyRs, whereas acidic ECs (e.g. N-arachidonoyl-glycine; NA-Gly potentiate α(1 GlyRs but inhibit α(2 and α(3. This subunit-specificity allowed us to identify the underlying molecular sites through analysis of chimeric and mutant receptors. We found that alanine 52 in extracellular loop 2, glycine 254 in transmembrane (TM region 2 and intracellular lysine 385 determine the positive modulation of α(1 GlyRs by NA-Gly. Successive substitution of non-conserved extracellular and TM residues in α(2 converted NA-Gly-mediated inhibition into potentiation. Conversely, mutation of the conserved lysine within the intracellular loop between TM3 and TM4 attenuated NA-Gly-mediated potentiation of α(1 GlyRs, without affecting inhibition of α(2 and α(3. Notably, this mutation reduced modulation by AEA of all three GlyRs. These results define molecular sites for allosteric control of GlyRs by ECs and reveal an unrecognized function for the TM3-4 intracellular loop in the allosteric modulation of Cys-loop ion channels. The identification of these sites may help to understand the physiological role of this modulation and facilitate the development of novel therapeutic approaches to diseases such as spasticity, startle disease and possibly chronic pain.

Different Use of Cell Surface Glycosaminoglycans As Adherence Receptors to Corneal Cells by Gram Positive and Gram Negative Pathogens

Science.gov (United States)

García, Beatriz; Merayo-Lloves, Jesús; Rodríguez, David; Alcalde, Ignacio; García-Suárez, Olivia; Alfonso, José F.; Baamonde, Begoña; Fernández-Vega, Andrés; Vazquez, Fernando; Quirós, Luis M.

2016-01-01

The epithelium of the cornea is continuously exposed to pathogens, and adhesion to epithelial cells is regarded as an essential first step in bacterial pathogenesis. In this article, the involvement of glycosaminoglycans in the adhesion of various pathogenic bacteria to corneal epithelial cells is analyzed. All microorganisms use glycosaminoglycans as receptors, but arranged in different patterns depending on the Gram-type of the bacterium. The heparan sulfate chains of syndecans are the main receptors, though other molecular species also seem to be involved, particularly in Gram-negative bacteria. Adherence is inhibited differentially by peptides, including heparin binding sequences, indicating the participation of various groups of Gram-positive, and -negative adhesins. The length of the saccharides produces a major effect, and low molecular weight chains inhibit the binding of Gram-negative microorganisms but increase the adherence of Gram-positives. Pathogen adhesion appears to occur preferentially through sulfated domains, and is very dependent on N- and 6-O-sulfation of the glucosamine residue and, to a lesser extent, 2-O sulfation of uronic acid. These data show the differential use of corneal receptors, which could facilitate the development of new anti-infective strategies. PMID:27965938

Risk of estrogen receptor-positive and -negative breast cancer and single-nucleotide polymorphism 2q35-rs13387042

DEFF Research Database (Denmark)

Milne, Roger L; Benítez, Javier; Nevanlinna, Heli

2009-01-01

BACKGROUND: A recent genome-wide association study identified single-nucleotide polymorphism (SNP) 2q35-rs13387042 as a marker of susceptibility to estrogen receptor (ER)-positive breast cancer. We attempted to confirm this association using the Breast Cancer Association Consortium. METHODS: 2q35...

Are AMPA Receptor Positive Allosteric Modulators Potential Pharmacotherapeutics for Addiction?

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Lucas R. Watterson

2013-12-01

Full Text Available Positive allosteric modulators (PAMs of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA receptors are a diverse class of compounds that increase fast excitatory transmission in the brain. AMPA PAMs have been shown to facilitate long-term potentiation, strengthen communication between various cortical and subcortical regions, and some of these compounds increase the production and release of brain-derived neurotrophic factor (BDNF in an activity-dependent manner. Through these mechanisms, AMPA PAMs have shown promise as broad spectrum pharmacotherapeutics in preclinical and clinical studies for various neurodegenerative and psychiatric disorders. In recent years, a small collection of preclinical animal studies has also shown that AMPA PAMs may have potential as pharmacotherapeutic adjuncts to extinction-based or cue-exposure therapies for the treatment of drug addiction. The present paper will review this preclinical literature, discuss novel data collected in our laboratory, and recommend future research directions for the possible development of AMPA PAMs as anti-addiction medications.

First cytoplasmic loop of glucagon-like peptide-1 receptor can function at the third cytoplasmic loop position of rhodopsin.

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Yamashita, Takahiro; Tose, Koji; Shichida, Yoshinori

2008-01-01

G protein-coupled receptors (GPCRs) are classified into several families based on their amino acid sequences. In family 1, GPCRs such as rhodopsin and adrenergic receptor, the structure-function relationship has been extensively investigated to demonstrate that exposure of the third cytoplasmic loop is essential for selective G protein activation. In contrast, much less is known about other families. Here we prepared chimeric mutants between Gt-coupled rhodopsin and Gi/Go- and Gs-coupled glucagon-like peptide-1 (GLP-1) receptor of family 2 and tried to identify the loop region that functions at the third cytoplasmic loop position of rhodopsin. We succeeded in expressing a mutant having the first cytoplasmic loop of GLP-1 receptor and found that this mutant activated Gi and Go efficiently but did not activate Gt. Moreover, the rhodopsin mutant having the first loop of Gs-coupled secretin receptor of family 2 decreased the Gi and Go activation efficiencies. Therefore, the first loop of GLP-1 receptor would share a similar role to the third loop of rhodopsin in G protein activation. This result strongly suggested that different families of GPCRs have maintained molecular architectures of their ancestral types to generate a common mechanism, namely exposure of the cytoplasmic loop, to activate peripheral G protein.

Preparation and evaluation of 99mTc-EDDA/HYNIC-[Lys 3]-bombesin for imaging gastrin-releasing peptide receptor-positive tumours.

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Ferro-Flores, Guillermina; Arteaga de Murphy, Consuelo; Rodriguez-Cortés, Jeanette; Pedraza-López, Martha; Ramírez-Iglesias, María Teresa

2006-04-01

Bombesin is a peptide that was initially isolated from frog skin and which belongs to a large group of neuropeptides with many biological functions. The human equivalent is gastrin-releasing peptide (GRP), whose receptors are over-expressed in a variety of malignant tumours. To prepare a HYNIC-[Lys 3]-bombesin analogue that could be easily labelled with 99mTc from lyophilized kit formulations and to evaluate its potential as an imaging agent for GRP receptor-positive tumours. HYNIC was conjugated to the epsilon-amino group of Lys 3 residue at the N-terminal region of bombesin via succinimidyl-N-Boc-HYNIC at pH 9.0. 99mTc labelling was performed by addition of sodium pertechnetate solution and 0.2 M phosphate buffer pH 7.0 to a lyophilized formulation. Stability studies were carried out by reversed phase HPLC and ITLC-SG analyses in serum and cysteine solutions. In-vitro internalization was tested using human prostate cancer PC-3 cells with blocked and non-blocked receptors. Biodistribution and tumour uptake were determined in PC-3 tumour-bearing nude mice. 99mTc-EDDA/HYNIC-[Lys 3]-bombesin was obtained with radiochemical purities >93% and high specific activity ( approximately 0.1 GBq.nmol). Results of in-vitro studies demonstrated a high stability in serum and cysteine solutions, specific cell receptor binding and rapid internalization. Biodistribution data showed a rapid blood clearance, with predominantly renal excretion and specific binding towards GRP receptor-positive tissues such as pancreas and PC-3 tumours. 99mTc-EDDA/HYNIC-[Lys 3]-bombesin obtained from lyophilized kit formulations has promising characteristics for the diagnosis of malignant tumours that over-express the GRP receptor.

DCE-MRI texture analysis with tumor subregion partitioning for predicting Ki-67 status of estrogen receptor-positive breast cancers

KAUST Repository

Fan, Ming; Cheng, Hu; Zhang, Peng; Gao, Xin; Zhang, Juan; Shao, Guoliang; Li, Lihua

2017-01-01

Breast tumor heterogeneity is related to risk factors that lead to worse prognosis, yet such heterogeneity has not been well studied.To predict the Ki-67 status of estrogen receptor (ER)-positive breast cancer patients via analysis of tumor

Enzalutamide inhibits androgen receptor-positive bladder cancer cell growth.

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Kawahara, Takashi; Ide, Hiroki; Kashiwagi, Eiji; El-Shishtawy, Kareem A; Li, Yi; Reis, Leonardo O; Zheng, Yichun; Miyamoto, Hiroshi

2016-10-01

Emerging preclinical evidence suggests that androgen-mediated androgen receptor (AR) signals promote bladder cancer progression. However, little is known about the efficacy of an AR signaling inhibitor, enzalutamide, in the growth of bladder cancer cells. In this study, we compared the effects of enzalutamide and 2 other classic antiandrogens, flutamide and bicalutamide, on androgen-induced bladder cancer cell proliferation, migration, and invasion as well as tumor growth in vivo. Thiazolyl blue cell viability assay, flow cytometry, scratch wound-healing assay, transwell invasion assay, real-time polymerase chain reaction, and reporter gene assay were performed in AR-positive (e.g., UMUC3, TCCSUP, and 647V-AR) and AR-negative (e.g., UMUC3-AR-short hairpin RNA [shRNA], TCCSUP-AR-shRNA, 647V) bladder cancer lines treated with dihydrotestosterone and each AR antagonist. We also used a mouse xenograft model for bladder cancer. Dihydrotestosterone increased bladder cancer cell proliferation, migration, and invasion indicating that endogenous or exogenous AR was functional. Enzalutamide, hydroxyflutamide, and bicalutamide showed similar inhibitory effects, without significant agonist activity, on androgen-mediated cell viability/apoptosis, cell migration, and cell invasion in AR-positive lines. No significant effects of dihydrotestosterone as well as AR antagonists on the growth of AR-negative cells were seen. Correspondingly, in UMUC3 cells, these AR antagonists down-regulated androgen-induced expression of AR, matrix metalloproteinase-2, and interleukin-6. Androgen-enhanced AR-mediated transcriptional activity was also blocked by each AR antagonist exhibiting insignificant agonist activity. In UMUC3 xenograft-bearing mice, oral gavage treatment with each antiandrogen retarded tumor growth, and only enzalutamide demonstrated a statistically significant suppression compared with mock treatment. Our current data support recent observations indicating the involvement of

In the Blink of an Eye: Relating Positive-Feedback Sensitivity to Striatal Dopamine D2-Like Receptors through Blink Rate

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Groman, Stephanie M.; James, Alex S.; Seu, Emanuele; Tran, Steven; Clark, Taylor A.; Harpster, Sandra N.; Crawford, Maverick; Burtner, Joanna Lee; Feiler, Karen; Roth, Robert H.; Elsworth, John D.; London, Edythe D.

2014-01-01

For >30 years, positron emission tomography (PET) has proven to be a powerful approach for measuring aspects of dopaminergic transmission in the living human brain; this technique has revealed important relationships between dopamine D2-like receptors and dimensions of normal behavior, such as human impulsivity, and psychopathology, particularly behavioral addictions. Nevertheless, PET is an indirect estimate that lacks cellular and functional resolution and, in some cases, is not entirely pharmacologically specific. To identify the relationships between PET estimates of D2-like receptor availability and direct in vitro measures of receptor number, affinity, and function, we conducted neuroimaging and behavioral and molecular pharmacological assessments in a group of adult male vervet monkeys. Data gathered from these studies indicate that variation in D2-like receptor PET measurements is related to reversal-learning performance and sensitivity to positive feedback and is associated with in vitro estimates of the density of functional dopamine D2-like receptors. Furthermore, we report that a simple behavioral measure, eyeblink rate, reveals novel and crucial links between neuroimaging assessments and in vitro measures of dopamine D2 receptors. PMID:25339755

Purinergic A2b Receptor Activation by Extracellular Cues Affects Positioning of the Centrosome and Nucleus and Causes Reduced Cell Migration*

Science.gov (United States)

Ou, Young; Chan, Gordon; Zuo, Jeremy; Rattner, Jerome B.; van der Hoorn, Frans A.

2016-01-01

The tight, relative positioning of the nucleus and centrosome in mammalian cells is important for the regulation of cell migration. Under pathophysiological conditions, the purinergic A2b receptor can regulate cell motility, but the underlying mechanism remains unknown. Expression of A2b, normally low, is increased in tissues experiencing adverse physiological conditions, including hypoxia and inflammation. ATP is released from such cells. We investigated whether extracellular cues can regulate centrosome-nucleus positioning and cell migration. We discovered that hypoxia as well as extracellular ATP cause a reversible increase in the distance between the centrosome and nucleus and reduced cell motility. We uncovered the underlying pathway: both treatments act through the A2b receptor and specifically activate the Epac1/RapGef3 pathway. We show that cells lacking A2b do not respond in this manner to hypoxia or ATP but transfection of A2b restores this response, that Epac1 is critically involved, and that Rap1B is important for the relative positioning of the centrosome and nucleus. Our results represent, to our knowledge, the first report demonstrating that pathophysiological conditions can impact the distance between the centrosome and nucleus. Furthermore, we identify the A2b receptor as a central player in this process. PMID:27226580

Growth of a progesterone receptor-positive meningioma in a female patient with congenital adrenal hyperplasia.

Science.gov (United States)

O'Shea, T; Crowley, R K; Farrell, M; MacNally, S; Govender, P; Feeney, J; Gibney, J; Sherlock, M

2016-01-01

Meningioma growth has been previously described in patients receiving oestrogen/progestogen therapy. We describe the clinical, radiological, biochemical and pathologic findings in a 45-year-old woman with congenital adrenal hyperplasia secondary to a defect in the 21-hydroxylase enzyme who had chronic poor adherence to glucocorticoid therapy with consequent virilisation. The patient presented with a frontal headache and marked right-sided proptosis. Laboratory findings demonstrated androgen excess with a testosterone of 18.1 nmol/L (0-1.5 nmol) and 17-Hydroxyprogesterone >180 nmol/L (transsexual patients undergoing therapy with high-dose oestrogen and progestogens. Progesterone receptor positivity has been described previously in meningiomas. 17-Hydroxyprogesterone is elevated in CAH and has affinity and biological activity at the progesterone receptor. Therefore, we hypothesise that patients who have long-standing increased adrenal androgen precursor concentrations may be at risk of meningioma growth. Patients with long-standing CAH (particularly if not optimally controlled) may present with other complications, which may be related to long-standing elevated androgen or decreased glucocorticoid levels.Chronic poor control of CAH is associated with adrenal myelolipoma and adrenal rest tissue tumours.Meningiomas are sensitive to endocrine stimuli including progesterone, oestrogen and androgens as they express the relevant receptors.

Development and preclinical evaluation of new 124I-folate conjugates for PET imaging of folate receptor-positive tumors

International Nuclear Information System (INIS)

AlJammaz, I.; Al-Otaibi, B.; Al-Rumayan, F.; Al-Yanbawi, S.; Amer, S.; Okarvi, S.M.

2014-01-01

In an attempt to develop new folate radiotracers with favorable biochemical properties for detecting folate receptor-positive cancers, we have synthesized [ 124 I]-SIB- and [ 124 I]-SIP-folate conjugates using a straightforward and two-step simple reactions. Radiochemical yields for [ 124 I]-SIB- and [ 124 I]-SIP-folate conjugates were greater than 90 and 60% respectively, with total synthesis time of 30–40 min. Radiochemical purities were always greater than 98% without HPLC purification. These synthetic approaches hold considerable promise as rapid and simple method for 124 I-folate conjugate preparation with high radiochemical yield in short synthesis time. In vitro tests on KB cell line showed that the significant amounts of the radioconjugates were associated with cell fractions. In vivo characterization in normal Balb/c mice revealed rapid blood clearance of these radioconjugates and favorable biodistribution profile for [ 124 I]-SIP-folate conjugate over [ 124 I]-SIB-folate conjugate. Biodistribution studies of [ 124 I]-SIP-folate conjugate in nude mice bearing human KB cell line xenografts, demonstrated significant tumor uptake. The uptake in the tumors was blocked by excess injection of folic acid, suggesting a receptor-mediated process. These results demonstrate that [ 124 I]-SIP-folate conjugate may be useful as a molecular probe for detecting and staging of folate receptor-positive cancers, such as ovarian cancer and their metastasis as well as monitoring tumor response to treatment

Evaluation of Therapy Management and Patient Compliance in Postmenopausal Patients with Hormone Receptor-positive Breast Cancer Receiving Letrozole Treatment: The EvaluateTM Study

Science.gov (United States)

Fasching, P. A.; Fehm, T.; Kellner, S.; de Waal, J.; Rezai, M.; Baier, B.; Baake, G.; Kolberg, H.-C.; Guggenberger, M.; Warm, M.; Harbeck, N.; Würstlein, R.; Deuker, J.-U.; Dall, P.; Richter, B.; Wachsmann, G.; Brucker, C.; Siebers, J. W.; Fersis, N.; Kuhn, T.; Wolf, C.; Vollert, H.-W.; Breitbach, G.-P.; Janni, W.; Landthaler, R.; Kohls, A.; Rezek, D.; Noesslet, T.; Fischer, G.; Henschen, S.; Praetz, T.; Heyl, V.; Kühn, T.; Krauß, T.; Thomssen, C.; Kümmel, S.; Hohn, A.; Tesch, H.; Mundhenke, C.; Hein, A.; Rauh, C.; Bayer, C. M.; Jacob, A.; Schmidt, K.; Belleville, E.; Hadji, P.; Wallwiener, D.; Grischke, E.-M.; Beckmann, M. W.; Brucker, S. Y.

2014-01-01

Introduction: The EvaluateTM study (Evaluation of therapy management and patient compliance in postmenopausal hormone receptor-positive breast cancer patients receiving letrozole treatment) is a prospective, non-interventional study for the assessment of therapy management and compliance in the routine care of postmenopausal women with invasive hormone receptor-positive breast cancer receiving letrozole. The parameters for inclusion in the study are presented and discussed here. Material and Methods: Between January 2008 and December 2009 a total of 5045 patients in 310 study centers were recruited to the EvaluateTM study. Inclusion criteria were hormone receptor-positive breast cancer and adjuvant treatment or metastasis. 373 patients were excluded from the analysis for various reasons. Results: A total of 4420 patients receiving adjuvant treatment and 252 patients with metastasis receiving palliative treatment were included in the study. For 4181 patients receiving adjuvant treatment, treatment with the aromatase inhibitor letrozole commenced immediately after surgery (upfront). Two hundred patients had initially received tamoxifen and started aromatase inhibitor treatment with letrozole at 1–5 years after diagnosis (switch), und 39 patients only commenced letrozole treatment 5–10 years after diagnosis (extended endocrine therapy). Patient and tumor characteristics were within expected ranges, as were comorbidities and concurrent medication. Conclusion: The data from the EvaluateTM study will offer a good overview of therapy management in the routine care of postmenopausal women with hormone receptor-positive breast cancer. Planned analyses will look at therapy compliance and patient satisfaction with how information is conveyed and the contents of the conveyed information. PMID:25568468

Prediction of consensus binding mode geometries for related chemical series of positive allosteric modulators of adenosine and muscarinic acetylcholine receptors.

Science.gov (United States)

Sakkal, Leon A; Rajkowski, Kyle Z; Armen, Roger S

2017-06-05

Following insights from recent crystal structures of the muscarinic acetylcholine receptor, binding modes of Positive Allosteric Modulators (PAMs) were predicted under the assumption that PAMs should bind to the extracellular surface of the active state. A series of well-characterized PAMs for adenosine (A 1 R, A 2A R, A 3 R) and muscarinic acetylcholine (M 1 R, M 5 R) receptors were modeled using both rigid and flexible receptor CHARMM-based molecular docking. Studies of adenosine receptors investigated the molecular basis of the probe-dependence of PAM activity by modeling in complex with specific agonist radioligands. Consensus binding modes map common pharmacophore features of several chemical series to specific binding interactions. These models provide a rationalization of how PAM binding slows agonist radioligand dissociation kinetics. M 1 R PAMs were predicted to bind in the analogous M 2 R PAM LY2119620 binding site. The M 5 R NAM (ML-375) was predicted to bind in the PAM (ML-380) binding site with a unique induced-fit receptor conformation. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Low Estrogen Receptor (ER)-Positive Breast Cancer and Neoadjuvant Systemic Chemotherapy: Is Response Similar to Typical ER-Positive or ER-Negative Disease?

Science.gov (United States)

Landmann, Alessandra; Farrugia, Daniel J; Zhu, Li; Diego, Emilia J; Johnson, Ronald R; Soran, Atilla; Dabbs, David J; Clark, Beth Z; Puhalla, Shannon L; Jankowitz, Rachel C; Brufsky, Adam M; Ahrendt, Gretchen M; McAuliffe, Priscilla F; Bhargava, Rohit

2018-05-08

Pathologic complete response (pCR) rate after neoadjuvant chemotherapy was compared between 141 estrogen receptor (ER)-negative (43%), 41 low ER+ (13%), 47 moderate ER+ (14%), and 98 high ER+ (30%) tumors. Human epidermal growth factor receptor 2-positive cases, cases without semiquantitative ER score, and patients treated with neoadjuvant endocrine therapy alone were excluded. The pCR rate of low ER+ tumors was similar to the pCR rate of ER- tumors (37% and 26% for low ER and ER- respectively, P = .1722) but significantly different from the pCR rate of moderately ER+ (11%, P = .0049) and high ER+ tumors (4%, P < .0001). Patients with pCR had an excellent prognosis regardless of the ER status. In patients with residual disease (no pCR), the recurrence and death rate were higher in ER- and low ER+ cases compared with moderate and high ER+ cases. Low ER+ breast cancers are biologically similar to ER- tumors. Semiquantitative ER H-score is an important determinant of response to neoadjuvant chemotherapy.

Endocrine sensitivity of the receptor-positive T61 human breast carcinoma serially grown in nude mice

DEFF Research Database (Denmark)

Brünner, N; Spang-Thomsen, M; Skovgaard Poulsen, H

1985-01-01

A study was made on the effect of ovariectomy, 17 beta-oestradiol, and tamoxifen on the oestrogen and progesterone receptor-positive T61 human breast carcinoma grown in nude mice. The effect of the treatment was evaluated by the specific growth delay calculated on the basis of Gompertz growth cur...... but is not a sufficiently clear marker to allow prediction of the endocrine sensitivity of individual breast tumours....

Hispolon inhibits the growth of estrogen receptor positive human breast cancer cells through modulation of estrogen receptor alpha

International Nuclear Information System (INIS)

Jang, Eun Hyang; Jang, Soon Young; Cho, In-Hye; Hong, Darong; Jung, Bom; Park, Min-Ju; Kim, Jong-Ho

2015-01-01

Human estrogen receptor α (ERα) is a nuclear transcription factor that is a major therapeutic target in breast cancer. The transcriptional activity of ERα is regulated by certain estrogen-receptor modulators. Hispolon, isolated from Phellinus linteus, a traditional medicinal mushroom called Sanghwang in Korea, has been used to treat various pathologies, such as inflammation, gastroenteric disorders, lymphatic diseases, and cancers. In this latter context, Hispolon has been reported to exhibit therapeutic efficacy against various cancer cells, including melanoma, leukemia, hepatocarcinoma, bladder cancer, and gastric cancer cells. However, ERα regulation by Hispolon has not been reported. In this study, we investigated the effects of Hispolon on the growth of breast cancer cells. We found that Hispolon decreased expression of ERα at both mRNA and the protein levels in MCF7 and T47D human breast cancer cells. Luciferase reporter assays showed that Hispolon decreased the transcriptional activity of ERα. Hispolon treatment also inhibited expression of the ERα target gene pS2. We propose that Hispolon, an anticancer drug extracted from natural sources, inhibits cell growth through modulation of ERα in estrogen-positive breast cancer cells and is a candidate for use in human breast cancer chemotherapy. - Highlights: • Hispolon decreased ERα expression at both mRNA and protein levels. • Hispolon decreased ERα transcriptional activity. • Hispolon treatment inhibited expression of ERα target gene pS2. • Shikonin is a candidate chemotherapeutic target in the treatment of human breast cancer

Hispolon inhibits the growth of estrogen receptor positive human breast cancer cells through modulation of estrogen receptor alpha

Energy Technology Data Exchange (ETDEWEB)

Jang, Eun Hyang; Jang, Soon Young; Cho, In-Hye [Department of Pharmacy, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701 (Korea, Republic of); Hong, Darong [Department of Life and Nanopharmaceutical Science, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701 (Korea, Republic of); Jung, Bom; Park, Min-Ju [Department of Pharmacy, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701 (Korea, Republic of); Kim, Jong-Ho, E-mail: jonghokim@khu.ac.kr [Department of Pharmacy, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701 (Korea, Republic of)

2015-08-07

Human estrogen receptor α (ERα) is a nuclear transcription factor that is a major therapeutic target in breast cancer. The transcriptional activity of ERα is regulated by certain estrogen-receptor modulators. Hispolon, isolated from Phellinus linteus, a traditional medicinal mushroom called Sanghwang in Korea, has been used to treat various pathologies, such as inflammation, gastroenteric disorders, lymphatic diseases, and cancers. In this latter context, Hispolon has been reported to exhibit therapeutic efficacy against various cancer cells, including melanoma, leukemia, hepatocarcinoma, bladder cancer, and gastric cancer cells. However, ERα regulation by Hispolon has not been reported. In this study, we investigated the effects of Hispolon on the growth of breast cancer cells. We found that Hispolon decreased expression of ERα at both mRNA and the protein levels in MCF7 and T47D human breast cancer cells. Luciferase reporter assays showed that Hispolon decreased the transcriptional activity of ERα. Hispolon treatment also inhibited expression of the ERα target gene pS2. We propose that Hispolon, an anticancer drug extracted from natural sources, inhibits cell growth through modulation of ERα in estrogen-positive breast cancer cells and is a candidate for use in human breast cancer chemotherapy. - Highlights: • Hispolon decreased ERα expression at both mRNA and protein levels. • Hispolon decreased ERα transcriptional activity. • Hispolon treatment inhibited expression of ERα target gene pS2. • Shikonin is a candidate chemotherapeutic target in the treatment of human breast cancer.

A phase II study of combined ridaforolimus and dalotuzumab compared with exemestane in patients with estrogen receptor-positive breast cancer

DEFF Research Database (Denmark)

Baselga, José; Morales, Serafin M.; Awada, Ahmad

2017-01-01

Purpose: Combining the mTOR inhibitor ridaforolimus and the anti-IGFR antibody dalotuzumab demonstrated antitumor activity, including partial responses, in estrogen receptor (ER)-positive advanced breast cancer, especially in high proliferation tumors (Ki67 > 15%). Methods: This randomized...

Everolimus Plus Endocrine Therapy for Postmenopausal Women With Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: A Clinical Trial.

Science.gov (United States)

Royce, Melanie; Bachelot, Thomas; Villanueva, Cristian; Özgüroglu, Mustafa; Azevedo, Sergio J; Cruz, Felipe Melo; Debled, Marc; Hegg, Roberto; Toyama, Tatsuya; Falkson, Carla; Jeong, Joon; Srimuninnimit, Vichien; Gradishar, William J; Arce, Christina; Ridolfi, Antonia; Lin, Chinjune; Cardoso, Fatima

2018-03-22

Cotargeting the mammalian target of rapamycin pathway and estrogen receptor may prevent or delay endocrine resistance in patients receiving first-line treatment for advanced breast cancer. To investigate the combination of everolimus plus endocrine therapy in first-line and second-line treatment settings for postmenopausal women with estrogen receptor-positive, human epidermal growth receptor 2-negative advanced breast cancer. In the multicenter, open-label, single-arm, phase 2 BOLERO-4 (Breast Cancer Trials of Oral Everolimus) clinical trial, 245 patients were screened for eligibility; 202 were enrolled between March 7, 2013, and December 17, 2014. A median follow-up of 29.5 months had been achieved by the data cutoff date (December 17, 2016). Patients received first-line treatment with everolimus, 10 mg/d, plus letrozole, 2.5 mg/d. Second-line treatment with everolimus, 10 mg/d, plus exemestane, 25 mg/d, was offered at the investigator's discretion upon initial disease progression. The primary end point was investigator-assessed progression-free survival in the first-line setting per Response Evaluation Criteria in Solid Tumors, version 1.0. Safety was assessed in patients who received at least 1 dose of study medication and at least 1 postbaseline safety assessment. A total of 202 women treated in the first-line setting had a median age of 64.0 years (interquartile range, 58.0-70.0 years) with metastatic (194 [96.0%]) or locally advanced (8 [4.0%]) breast cancer. Median progression-free survival was 22.0 months (95% CI, 18.1-25.1 months) with everolimus and letrozole. Median overall survival was not reached; 24-month estimated overall survival rate was 78.7% (95% CI, 72.1%-83.9%). Fifty patients started second-line treatment; median progression-free survival was 3.7 months (95% CI, 1.9-7.4 months). No new safety signals were observed. In the first-line setting, the most common all-grade adverse event was stomatitis (139 [68.8%]); the most common grade 3 to 4

99mTc-EDDA/HYNIC-TOC in management of patients with head and neck somatostatin receptor positive tumors.

Science.gov (United States)

Trogrlic, Mate; Tezak, Stanko

2016-01-01

Aim of this study was to determine the value of technetium-99m-hydrazinonicotinyl-Tyr3-octreotide (99mTc-ED-DA/HYNIC-TOC) in patients with somatostatin receptor (SSR) positive tumors of head and neck region. A total number of 16 patients were enrolled in this study. Planar whole body (WB) and single photon emission computed tomography (SPECT) images were acquired at 2 and 4 hours after the injection of approximately 670 MBq of 99mTc-EDDA/HYNIC-TOC. Additional single photon emission computed tomography/computed tomography (SPECT/CT) images of the head and neck region were acquired at 4h post tracer injection. Clinical and imaging follow up were taken as the reference standard. There were 10 female and 6 male patients of age 57.7 ± 12.9 years (58.5; 32-78) years. 99mTc-EDDA/HYNIC-TOC somatostatin receptor scintigraphy (SRS) was TP in 13 patients, TN in two and FP in one. Follow up period for SRS was 31.1 ± 19.4 (29; 2-63) months. 99mTc-EDDA/HYNIC-TOC scintigraphy provided additional information in 50% of patients, with impact on patient management in the same percentage of patients. Distant metastases were found in nine out of 16 patients (56%). 99mTc-EDDA/HYNIC-TOC SRS had sensitivity of 100% (75.3-100%), specificity of 66.7% (9.4-99.2%), accuracy of 93.7%, positive predictive value of 92.9% (66.1-99.8%), and negative predictive value of 100% (15.8-100%). Somatostatin receptor scintigraphy using 99mTc-EDDA/HYNIC-TOC is very useful imaging method in the evalu-ation of patients with SSR positive tumors of head and neck region.

GABAA receptor positive allosteric modulators modify the abuse-related behavioral and neurochemical effects of methamphetamine in rhesus monkeys.

Science.gov (United States)

Berro, Laís F; Andersen, Monica L; Tufik, Sergio; Howell, Leonard L

2017-09-01

GABA A receptor positive allosteric modulators (GABA A receptor modulators) are commonly used for the treatment of insomnia. Nevertheless, the effects of these compounds on psychostimulant-induced sleep impairment are poorly understood. Because GABA A receptor modulators have been shown to decrease the abuse-related effects of psychostimulants, the aim of the present study was to evaluate the effects of temazepam (0.3, 1.0 or 3.0 mg/kg) and eszopiclone (0.3, 1.0 or 3.0 mg/kg), two GABA A receptor modulators, on the behavioral neuropharmacology of methamphetamine in adult rhesus macaques (n = 5). Sleep-like measures and general daytime activity were evaluated with Actiwatch monitors. Methamphetamine self-administration (0.03 mg/kg/inf) was evaluated during morning sessions. Methamphetamine-induced dopamine overflow was assessed through in vivo microdialysis targeting the nucleus accumbens. Nighttime treatment with either temazepam or eszopiclone was ineffective in improving sleep-like measures disrupted by methamphetamine self-administration. Acute pretreatment with a low dose of temazepam before self-administration sessions increased methamphetamine self-administration without affecting normal daytime home-cage activity. At a high dose, acute temazepam pretreatment decreased methamphetamine self-administration and attenuated methamphetamine-induced increases in dopamine in the nucleus accumbens, without decreasing general daytime activity. Acute eszopiclone treatment exerted no effects on methamphetamine intake or drug-induced increases in dopamine. Our study suggests that treatments based on GABA A receptor modulators are not effective for the treatment of sleep disruption in the context of psychostimulant use. In addition, distinct GABA A receptor modulators differentially modulated the abuse-related effects of methamphetamine, with acute treatment with the high efficacy GABA A receptor modulator temazepam decreasing the behavioral and neurochemical effects

Fundamental considerations in the design of fluorine-18 labeled progestins and androgens as imaging agents for receptor-positive tumors of the breast and prostate

International Nuclear Information System (INIS)

Brandes, S.J.; Katzenellenbogen, J.A.

1988-01-01

A review is given of the structural and functional features which are important in the design and development of imaging agents for the progesterone receptor (PR) and the androgen receptor (AR) directed towards imaging receptor-positive tumors in the breast and prostate respectively. In particular the effects of various substituents on the biological activities and homologous receptor binding of progesterone, testosterone, nortestosterone and dihydrotestosterone are discussed. The effect of fluorine substitution on the affinities of progestins and androgens for their respective receptors is described. Other ligand systems that have high affinity for AR and PR and which may provide good bases for the design of fluorine-substituted imaging agents are also discussed. Finally, previous studies with radiolabelled progestins and androgens are described. (U.K.)

Characterization of high specific activity [16 alpha-123I]Iodo-17 beta-estradiol as an estrogen receptor-specific radioligand capable of imaging estrogen receptor-positive tumors

International Nuclear Information System (INIS)

Pavlik, E.J.; Nelson, K.; Gallion, H.H.; van Nagell, J.R. Jr.; Donaldson, E.S.; Shih, W.J.; Spicer, J.A.; Preston, D.F.; Baranczuk, R.J.; Kenady, D.E.

1990-01-01

16 alpha-[123I]Iodo-17 beta-estradiol (16 alpha-[123I]E2) has been characterized for use as a selective radioligand for estrogen receptor (ERc) that is capable of generating in situ images of ERc-positive tumors. High specific activity 16 alpha-[123I]E2 (7,500-10,000 Ci/mmol) was used in all determinations. Radiochemical purity was determined by thin layer chromatography, and the selectivity of radioligand for ERc was evaluated using size exclusion high performance liquid chromatography on ERc prepared from rodent uteri. Efficiencies of radioidination approaching 100% were achieved, and excellent receptor selectivity was obtained even when the efficiency of radioiodination was as low as 10%. Low radiochemical purity was always associated with poor selectivity for ERc. No new radioligand species was generated during the course of radiodecay; however, reduced binding over time, even when increased activity was used to compensate for radiodecay, indicated that the formation of a radioinert competitor does occur. 16 alpha-[123I]E2 demonstrated stable, high affinity binding to ERc and was concentrated by ERc-positive tissues. After injecting 16 alpha-[123I]E2 in vivo, images of ERc-containing tissues were obtained, including rabbit reproductive tract and dimethylbenzanthracene-induced tumors. The demonstrations of ERc selectivity and image formation both indicate that 16 alpha-[123I]E2 should have promise as a useful new radiopharmaceutical for imaging ERc-positive cancers

The selective positive allosteric M1 muscarinic receptor modulator PQCA attenuates learning and memory deficits in the Tg2576 Alzheimer's disease mouse model.

Science.gov (United States)

Puri, Vanita; Wang, Xiaohai; Vardigan, Joshua D; Kuduk, Scott D; Uslaner, Jason M

2015-01-01

We have recently shown that the M1 muscarinic receptor positive allosteric modulator, PQCA, improves cognitive performance in rodents and non-human primates administered the muscarinic receptor antagonist scopolamine. The purpose of the present experiments was to characterize the effects of PQCA in a model more relevant to the disease pathology of Alzheimer's disease. Tg2576 transgenic mice that have elevated Aβ were tested in the novel object recognition task to characterize recognition memory as a function of age and treatment with the PQCA. The effects of PQCA were compared to the acetylcholinesterase inhibitor donepezil, the standard of care for Alzheimer's disease. In addition, the effect of co-administering PQCA and donepezil was evaluated. Aged Tg2576 mice demonstrated a deficit in recognition memory that was significantly attenuated by PQCA. The positive control donepezil also reversed the deficit. Furthermore, doses of PQCA and donepezil that were inactive on their own were found to improve recognition memory when given together. These studies suggest that M1 muscarinic receptor positive allosteric modulation can ameliorate memory deficits in disease relevant models of Alzheimer's disease. These data, combined with our previous findings demonstrating PQCA improves scopolamine-induced cognitive deficits in both rodents and non-human primates, suggest that M1 positive allosteric modulators have therapeutic potential for the treatment of Alzheimer's disease. Copyright © 2015 Elsevier B.V. All rights reserved.

Breast Tissue Composition and Immunophenotype and Its Relationship with Mammographic Density in Women at High Risk of Breast Cancer.

Directory of Open Access Journals (Sweden)

Jia-Min B Pang

Full Text Available To investigate the cellular and immunophenotypic basis of mammographic density in women at high risk of breast cancer.Mammograms and targeted breast biopsies were accrued from 24 women at high risk of breast cancer. Mammographic density was classified into Wolfe categories and ranked by increasing density. The histological composition and immunophenotypic profile were quantified from digitized haematoxylin and eosin-stained and immunohistochemically-stained (ERα, ERβ, PgR, HER2, Ki-67, and CD31 slides and correlated to mammographic density.Increasing mammographic density was significantly correlated with increased fibrous stroma proportion (rs (22 = 0.5226, p = 0.0088 and significantly inversely associated with adipose tissue proportion (rs (22 = -0.5409, p = 0.0064. Contrary to previous reports, stromal expression of ERα was common (19/20 cases, 95%. There was significantly higher stromal PgR expression in mammographically-dense breasts (p=0.026.The proportion of stroma and fat underlies mammographic density in women at high risk of breast cancer. Increased expression of PgR in the stroma of mammographically dense breasts and frequent and unexpected presence of stromal ERα expression raises the possibility that hormone receptor expression in breast stroma may have a role in mediating the effects of exogenous hormonal therapy on mammographic density.

Diuron treatment reveals the different roles of two cyclic electron transfer pathways in photosystem II in Arabidopsis thaliana.

Science.gov (United States)

Jin, Yujian; Chen, Si; Fan, Xiaoji; Song, Hao; Li, Xingxing; Xu, Jiahui; Qian, Haifeng

2017-04-01

Three ecotypes of Arabidopsis thaliana, ecotype Columbia (Wild type, Wt) and two mutants (pgr5 and ndf4), were used to evaluate the effects of diuron on photosynthetic activity of A. thaliana. It was found that diuron adversely affected the fresh weight and chlorophyll content of the plants. Chlorophyll fluorescence studies determined that the pgr5 mutant was more sensitive to diuron than Wt and the ndf4 mutant. Gene expression analysis revealed different roles for the two cyclic electron transfer (CET) pathways, NAD(P)H dehydrogenase (NDH) and proton gradient regulation (PGR5) pathways, in the plant after diuron treatment. For example, a gene in the NDH pathway, lhca5, was activated in the low dose (LD) group in the pgr5 mutant, but was down-regulated in the moderate dose (MD) group, along with two other NDH-related genes (ppl2 and ndhH). In the PGR5 pathway, the pgr5 gene was functional under conditions of increased stress (MD group), and was up-regulated to a greater extent in the ndf4 mutant than that in the Wt and pgr5 mutant. Our results suggest that the PGR5 pathway in plants is more important than the NDH pathway during resistance to environmental stress. Deficiencies in the PGR5 pathway could not be counteracted by the NDH pathway, but deficiencies in the NDH pathway could be overcome by stimulating PGR5. Copyright © 2016 Elsevier B.V. All rights reserved.

[The molecular mechanisms and morphological manifestations of leiomyoma reduction induced by selective progesterone receptor modulators].

Science.gov (United States)

Demura, T A; Revazova, Z V; Kogan, E A; Adamyan, L V

to investigate the molecular mechanisms and morphological substrate of reduced uterine leiomyoma in patients receiving the selective progesterone receptor modulator (SPRM) ulipristal acetate for 3 months, by estimating the immunohistochemical expression of the markers steroid receptor coactivator 1 (SRC-1), nuclear receptor corepressor 1 (NCoR-1), ER, PgR, Ki-67, p16, TGF-β, and VEGF in tumor tissue. The investigation enrolled 75 women with uterine leiomyoma, menorrhagias, and anemia. Group 1 included 40 patients who were treated with ulipristal for 3 months, followed by laparoscopic myomectomy. Group 2 consisted of 35 patients who underwent surgery without previous preparation. The intra- and postoperative parameters and molecular and morphological changes in the myomatous nodules were comparatively analyzed in both groups. After 3 months of therapy initiation, menorrhagia completely ceased, myomatous nodules decreased in size (pleiomyoma reduction was leiomyocyte apoptosis and dystrophy, tumor stroma sclerosis and hyalinosis with diminished Ki-67 expression and elevated p16 in the smooth muscle cells, trophic nodular tissue disorders exhibited by vascular wall sclerosis and lower VEGF and TGF-β expression, and leiomyocyte hormonal reception dysregulation that made itself evident through the reduced expression of SRC-1 with the unchanged expression of PR and ER and the maintained level of NCoR-1. The molecular mechanisms of tumor reduction involved the reduced Ki-67 expression and elevated p16, lower VEGF and TGF-β, diminished SRC-1 expression with the maintained level of PR, ER, and NCoR-1. Overall, this is suggestive of enhanced apoptosis and reduced leiomyoma proliferation and angiogenesis induced by SPRM and indicative of the expediency of using ulipristal acetate as a preoperative agent for organ-sparing surgery in reproductive-aged patients with uterine myoma, menorrhagias, and anemia.

Body mass index and survival after breast cancer diagnosis in Japanese women

International Nuclear Information System (INIS)

Kawai, Masaaki; Minami, Yuko; Nishino, Yoshikazu; Fukamachi, Kayoko; Ohuchi, Noriaki; Kakugawa, Yoichiro

2012-01-01

Body mass index (BMI) may be an important factor affecting breast cancer outcome. Studies conducted mainly in Western countries have reported a relationship between higher BMI and a higher risk of all-cause death or breast cancer-specific death among women with breast cancer, but only a few studies have been reported in Japan so far. In the present prospective study, we investigated the associations between BMI and the risk of all-cause and breast cancer-specific death among breast cancer patients overall and by menopausal status and hormone receptor status. The study included 653 breast cancer patients admitted to a single hospital in Japan, between 1997 and 2005. BMI was assessed using a self-administered questionnaire. The patients were completely followed up until December, 2008. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated according to quartile points of BMI categories, respectively: <21.2, ≥21.2 to <23.3 (reference), ≥23.3 to <25.8 and ≥25.8 kg/m 2 . During the follow-up period, 136 all-cause and 108 breast cancer-specific deaths were observed. After adjustment for clinical and confounding factors, higher BMI was associated with an increased risk of all-cause death (HR = 2.61; 95% CI: 1.01–6.78 for BMI ≥25.8 vs. ≥21.2 to <23.3 kg/m 2 ) among premenopausal patients. According to hormonal receptor status, BMI ≥25.8 kg/m 2 was associated with breast cancer-specific death (HR = 4.95; 95% CI: 1.05–23.35) and BMI <21.2 kg/m 2 was associated with all-cause (HR = 2.91; 95% CI: 1.09–7.77) and breast cancer-specific death (HR = 7.23; 95% CI: 1.57–33.34) among patients with ER + or PgR + tumors. Analysis by hormonal receptor status also showed a positive association between BMI and mortality risk among patients with ER + or PgR + tumors and with BMI ≥21.2 kg/m 2 (p for trend: 0.020 and 0.031 for all-cause and breast cancer-specific death, respectively). Our results suggest that both higher BMI and lower BMI are associated

Significance of PIK3CA Mutations in Patients with Early Breast Cancer Treated with Adjuvant Chemotherapy: A Hellenic Cooperative Oncology Group (HeCOG Study.

Directory of Open Access Journals (Sweden)

George Papaxoinis

Full Text Available The PI3K-AKT pathway is frequently activated in breast cancer. PIK3CA mutations are most frequently found in the helical (exon 9 and kinase (exon 20 domains of this protein. The aim of the present study was to examine the role of different types of PIK3CA mutations in combination with molecular biomarkers related to PI3K-AKT signaling in patients with early breast cancer.Tumor tissue samples from 1008 early breast cancer patients treated with adjuvant chemotherapy in two similar randomized trials of HeCOG were examined. Tumors were subtyped with immunohistochemistry (IHC and FISH for ER, PgR, Ki67, HER2 and androgen receptor (AR. PIK3CA mutations were analyzed by Sanger sequencing (exon 20 and qPCR (exon 9 (Sanger/qPCR mutations. In 610 cases, next generation sequencing (NGS PIK3CA mutation data were also available. PIK3CA mutations and PTEN protein expression (IHC were analyzed in luminal tumors (ER and/or PgR positive, molecular apocrine carcinomas (MAC; ER/PgR negative / AR positive and hormone receptor (ER/PgR/AR negative tumors.PIK3CA mutations were detected in 235/1008 tumors (23% with Sanger/qPCR and in 149/610 tumors (24% with NGS. Concordance between the two methods was good with a Kappa coefficient of 0.76 (95% CI 0.69-0.82. Lobular histology, low tumor grade and luminal A tumors were associated with helical domain mutations (PIK3CAhel, while luminal B with kinase domain mutations (PIK3CAkin. The overall incidence of PIK3CA mutations was higher in luminal as compared to MAC and hormone receptor negative tumors (p = 0.004. Disease-free and overall survival did not significantly differ with respect to PIK3CA mutation presence and type. However, a statistically significant interaction between PIK3CA mutation status and PTEN low protein expression with regard to prognosis was identified.The present study did not show any prognostic significance of specific PIK3CA mutations in a large group of predominantly lymph-node positive breast cancer

In situ detection of estrogen receptor dimers in breast carcinoma cells in archival materials using proximity ligation assay (PLA).

Science.gov (United States)

Iwabuchi, Erina; Miki, Yasuhiro; Ono, Katsuhiko; Onodera, Yoshiaki; Suzuki, Takashi; Hirakawa, Hisashi; Ishida, Takanori; Ohuchi, Noriaki; Sasano, Hironobu

2017-01-01

Estrogen receptor (ER) is required for carcinoma cell proliferation in the great majority of breast cancer and also functions as a dimer. ER dimeric proteins have been largely identified by BRET/FRET analyses but their in situ visualization have not yet been reported. Recently, in situ Proximity Ligation Assay (PLA) has been developed as the methods detecting protein interactions in situ. Therefore, in this study we firstly demonstrated the dimerization of ERα in breast carcinoma cell lines and tissues using PLA. The human breast carcinoma cell lines MCF-7, T-47D and MDA-MB-231 were used in this study. Cells were treated with ER agonist or antagonist and fixed in 4% PFA, and ER dimers were subsequently detected using PLA. The evaluation of ER dimers in breast carcinoma cell lines were quantified by measuring the area of dots localized in the nuclei using image analysis. We also firstly demonstrated the visualization of ER dimer patterns in 10% formalin-fixed paraffin-embedded tissues of breast cancer using PLA technique. Estradiol (E2) administration induced ERα homodimers in the nuclei of MCF-7 and T-47D but not in ER-negative MDA-MB-231. 4-OH tamoxifen also induced ERα homodimers but the subcellular localization of these ERα homodimers was predominant in cytoplasm instead of the nuclei induced by E2 treatment. ICI182,780 treatment did decrease the number of formation of ERα homodimers in MCF-7. In breast cancer patients, ERα PLA score was significantly correlated positively with ERα- or PgR (progesterone receptor) immunohistochemical scores and inversely with Ki-67-labeling index, respectively. We also demonstrated the ERα/β heterodimer as well as ERα homodimers in both breast carcinoma cell lines and surgical pathology specimens. In summary, we did firstly succeed in the visualization of ER dimeric proteins using PLA method. The evaluation of ER dimer patterns could provide pivotal information as to the prediction of response to endocrine therapy of

Immunohistochemical detection of somatostatin receptor subtypes sst1 and sst2A in human somatostatin receptor positive tumors

NARCIS (Netherlands)

L.J. Hofland (Leo); Q. Liu; P.M. van Koetsveld (Peter); J. Zuijderwijk; F. van der Ham (Frieda); R.R. de Krijger (Ronald); A. Schonbrunn; S.W.J. Lamberts (Steven)

1999-01-01

textabstractAlthough in situ hybridization has been used to examine the distribution of messenger RNA for somatostatin receptor subtypes (sst) in human tumors, the cellular localization of sst1 and sst2A receptors has not been reported. In this study, we describe the

Deep ancestry of programmed genome rearrangement in lampreys.

Science.gov (United States)

Timoshevskiy, Vladimir A; Lampman, Ralph T; Hess, Jon E; Porter, Laurie L; Smith, Jeramiah J

2017-09-01

In most multicellular organisms, the structure and content of the genome is rigorously maintained over the course of development. However some species have evolved genome biologies that permit, or require, developmentally regulated changes in the physical structure and content of the genome (programmed genome rearrangement: PGR). Relatively few vertebrates are known to undergo PGR, although all agnathans surveyed to date (several hagfish and one lamprey: Petromyzon marinus) show evidence of large scale PGR. To further resolve the ancestry of PGR within vertebrates, we developed probes that allow simultaneous tracking of nearly all sequences eliminated by PGR in P. marinus and a second lamprey species (Entosphenus tridentatus). These comparative analyses reveal conserved subcellular structures (lagging chromatin and micronuclei) associated with PGR and provide the first comparative embryological evidence in support of the idea that PGR represents an ancient and evolutionarily stable strategy for regulating inherent developmental/genetic conflicts between germline and soma. Copyright © 2017 Elsevier Inc. All rights reserved.

Transcytosis of F4 fimbriae by villous and dome epithelia in F4-receptor positive pigs supports importance of receptor-dependent endocytosis in oral immunization strategies.

Science.gov (United States)

Snoeck, Veerle; Van den Broeck, Wim; De Colvenaer, Veerle; Verdonck, Frank; Goddeeris, Bruno; Cox, Eric

2008-07-15

Very few antigens have been described that induce an intestinal immunity when given orally. Our laboratory demonstrated that oral administration of isolated F4 (K88) fimbriae of Escherichia coli to F4-receptor positive (F4R(+)) pigs induces protective mucosal immunity against challenge infection. However, presence of F4-receptors (F4R) on villous enterocytes is a prerequisite for inducing the immune response, as no F4-specific antibody-secreting cells (ASC) can be induced in F4R(-) pigs. In this study, the in vivo binding of isolated F4 fimbriae (F4) to the gut epithelium was examined in F4R(+) and F4R(-) pigs. It was further investigated whether binding of F4 to the F4R results in endocytosis in and translocation across the gut epithelium using microscopy. F4 did not adhere to the intestinal epithelium of F4R(-) pigs, whereas it strongly adhered to the villous epithelium and the follicle-associated epithelium (FAE) of the jejunum and ileum of F4R(+) pigs. Following binding to F4R, F4 was endocytosed by villous enterocytes, follicle-associated enterocytes and M cells. Transcytosis of F4 across the epithelium resulted in the appearance of F4 in the lamina propria and dome region of the jejunal and ileal PP. This is the first study showing transcytosis of fimbriae across the gut epithelium. This receptor-dependent transcytosis can explain the success of F4 fimbriae as oral immunogen for inducing protective immunity in F4R(+) pigs strengthening the importance of receptor-dependent endocytosis and translocation in oral vaccine strategies. Further identification of the receptor responsible for this transport is in progress.

Position-sensitive radiation detector

International Nuclear Information System (INIS)

Mathieson, E.; Smith, G.C.; Gilvin, P.J.

1981-01-01

Apparatus for sensing the position of radiation received has a plurality of receptors spaced in at least one line on which the position is to be determined, their outputs being associated to form at least two groups, the density of the receptors in each group varying along the line. The receptors may comprise cathode arrays of a multiwire proportional counter, with an anode array between, measuring along lines in directions x and y respectively. The density of the wires in the two groups, decreases in opposite directions. A circuit determines the ratio of the output of one group to the sum of the group outputs. In another embodiment a scintillator is viewed by a plurality of light guides, the ends of which adjacent to the scintillator form the receptors, the four groups of which each terminate on a photomultiplier. (author)

Influence of exogenous lactoferrin on the oxidant/antioxidant balance and molecular profile of hormone receptor-positive and -negative human breast cancer cells in vitro.

Science.gov (United States)

Zalutskii, I V; Lukianova, N Y; Storchai, D M; Burlaka, A P; Shvets, Y V; Borikun, T V; Todor, I M; Lukashevich, V S; Rudnichenko, Y A; Chekhun, V F

2017-07-01

To investigate the mechanisms of cytotoxic activity and pro-/antioxidant effect of lactoferrin on hormone receptor-positive and receptor-negative breast cancer cells in vitro. The study was performed on receptor-positive (MCF-7, T47D) and receptor-negative (MDA-MB-231, MDA-MB-468) human breast cancer cell lines. Immunocytochemical staining, flow cytometry, low-temperature electron paramagnetic resonance, and the Comet assay were used. Upon treatment with lactoferrin, the increased levels of reactive oxygen species (ROS) (p < 0.05), NO generation rate by inducible NO-synthase (p < 0.05) and the level of "free" iron (p < 0.05) were observed. Moreover, the effects of lactoferrin were more pronounced in receptor-negative MDA-MB-231 and MDA-MB-468 cells. These changes resulted in increased expression of proapoptotic Bax protein (p < 0.05), reduced expression of the antiapoptotic Bcl-2 protein (p < 0.05) and level of not-oxidized mitochondrial cardiolipin (1.4-1.7-fold, p < 0.05). This, in turn, caused an increase in the percentage of apoptotic cells (by 14-24%, p < 0.05). Cytotoxic effects of lactoferrin were accompanied by an increase in the percentage of DNA in the comet tail and blocking cell cycle at G2/M phase, especially in receptor-negative cell lines. The study showed that exogenous lactoferrin causes a violation of an antioxidant balance by increasing the level of ROS, "free" iron and NO generation rate, resalting in the blocking of cell cycle at G2/M-phase and apoptosis of malignant cells.

Role of plant growth regulators and a saprobic fungus in enhancement of metal phytoextraction potential and stress alleviation in pearl millet.

Science.gov (United States)

Firdaus-e-Bareen; Shafiq, Muhammad; Jamil, Sidra

2012-10-30

"Assisted phytoextraction" involving application of chemical additives such as plant growth regulators (PGRs) has become a trend in phytoremediation technology. This study identifies a cost-effective, naturally available crude PGR (PGR1) that produces the same effects as the commercial PGR (PGR2), increasing metal uptake by plants and the reduction of metal stress. Assisted phytoextraction by pearl millet (Pennisetum glaucum) from a multi-metal (Cd, Cr, Cu, Fe, Na and Zn) contaminated soil medium with tannery solid waste (TSW) soil amendments of 5 and 10%, was evaluated in a full-factorial pot trial with PGR1, PGR2 and Trichoderma pseudokoningii as factors. The effects of these phytoextraction assistants were measured through dry biomass production, heavy metal uptake, stress tolerance enzymes catalase (CAT) and superoxide dismutase (SOD), soluble protein content of plant, and phytoextraction efficiency. Dry biomass and multi-metal accumulation were the highest in the soil treatments with a combined application of PGR1, PGR2 and T. pseudokoningii and the lowest in the control. The soluble protein contents and the SOD and CAT values were the highest in the 10% TSW treatment provided with PGR2+T. pseudokoningii, while the lowest were in the control. Thus, application of crude PGR in combination with other phytoextraction assistants can increase biomass production as well as multi-metal accumulation in plants. However, the biochemical properties of the plant depend on the level of TSW stress in the soil treatment as well as the type of phytoextraction assistants. Copyright © 2012 Elsevier B.V. All rights reserved.

Alpha-conotoxin analogs with additional positive charge show increased selectivity towards Torpedo californica and some neuronal subtypes of nicotinic acetylcholine receptors

NARCIS (Netherlands)

Kasheverov, I.E.; Zhmak, M.N.; Vulfius, C.A.; Corbacheva, E.V.; Mordvintsev, D.Y.; Utkin, Y.N.; van Elk, R.; Smit, A.B.; Tsetlin, V.I.

2006-01-01

α-Conotoxins from Conus snails are indispensable tools for distinguishing various subtypes of nicotinic acetylcholine receptors (nAChRs), and synthesis of α-conotoxin analogs may yield novel antagonists of higher potency and selectivity. We incorporated additional positive charges into α-conotoxins

Uterine and placental expression of canine oxytocin receptor during pregnancy and normal and induced parturition.

Science.gov (United States)

Gram, A; Boos, A; Kowalewski, M P

2014-06-01

Oxytocin (OT) plays an important role as an inducer of uterine contractility, acting together with its receptor (OTR) to increase synthesis of prostaglandins. Although OT is commonly used in the treatment for dystocia and uterine inertia in the bitch, little attention has been paid to the role of OT in mechanisms regulating parturition in the dog, so that knowledge about the expression of OTR in the canine uterus and placenta is sparse. Consequently, the expression and cellular localization of OTR were investigated in canine utero/placental compartments and interplacental sites throughout pregnancy and at normal and antigestagen-induced parturition, by real-time PCR, immunohistochemistry, western blot and in situ hybridization. The utero/placental and interplacental expression of OTR was constant from pre-implantation until mid-gestation, with a significant increase observed at prepartum luteolysis. In antigestagen-treated mid-pregnant dogs, OTR was upregulated in both interplacental and utero/placental samples. Besides clear myometrial signals, cellular localization of OTR was evident in the endometrial surface epithelial, stromal and vascular endothelial cells. Weaker signals were observed in superficial and deep uterine glandular epithelial cells. Placental OTR was localized in maternal decidual cells and capillary pericytes. Finally, OTR was colocalized with the progesterone receptor (PGR) in maternal decidual cells, coinciding with previously reported increased availability of prostaglandins in the foetal part of the placenta during normal and induced parturition. These findings suggest involvement of OTR in the signalling cascade leading to the prepartum release of prostaglandins from the pregnant canine uterus. © 2014 Blackwell Verlag GmbH.

A highly restricted T-cell receptor dominates the CD8+ T-cell response to parvovirus B19 infection in HLA-A*2402-positive individuals

DEFF Research Database (Denmark)

Kasprowicz, V; Isa, Adiba; Jeffery, K

2006-01-01

Six of seven HLA-A*2402-positive individuals with acute parvovirus B19 infections made vigorous CD8-positive cytotoxic T-cell (CTL) responses to the viral epitope FYTPLADQF. All responders showed highly focused T-cell receptor (TCR) usage, using almost exclusively BV5.1. The BV5.1 TCR dominated...

Melatonin regulates delayed embryonic development in the short-nosed fruit bat, Cynopterus sphinx.

Science.gov (United States)

Banerjee, Arnab; Meenakumari, K J; Udin, S; Krishna, A

2009-12-01

The aim of the present study was to evaluate the seasonal variation in serum melatonin levels and their relationship to the changes in the serum progesterone level, ovarian steroidogenesis, and embryonic development during two successive pregnancies of Cynopterus sphinx. Circulating melatonin concentrations showed two peaks; one coincided with the period of low progesterone synthesis and delayed embryonic development, whereas the second peak coincided with regressing corpus luteum. This finding suggests that increased serum melatonin level during November-December may be responsible for delayed embryonic development by suppressing progesterone synthesis. The study showed increased melatonin receptors (MTNR1A and MTNR1B) in the corpus luteum and in the utero-embryonic unit during the period of delayed embryonic development. The in vitro study showed that a high dose of melatonin suppressed progesterone synthesis, whereas a lower dose of melatonin increased progesterone synthesis by the ovary. The effects of melatonin on ovarian steroidogenesis are mediated through changes in the expression of peripheral-type benzodiazepine receptor, P450 side chain cleavage enzyme, and LH receptor proteins. This study further showed a suppressive impact of melatonin on the progesterone receptor (PGR) in the utero-embryonic unit; this effect might contribute to delayed embryonic development in C. sphinx. The results of the present study thus suggest that a high circulating melatonin level has a dual contribution in retarding embryonic development in C. sphinx by impairing progesterone synthesis as well as by inhibiting progesterone action by reducing expression of PGR in the utero-embryonic unit.

Novel positive regulatory role for the SPL6 transcription factor in the N TIR-NB-LRR receptor-mediated plant innate immunity.

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Meenu S Padmanabhan

2013-03-01

Full Text Available Following the recognition of pathogen-encoded effectors, plant TIR-NB-LRR immune receptors induce defense signaling by a largely unknown mechanism. We identify a novel and conserved role for the SQUAMOSA PROMOTER BINDING PROTEIN (SBP-domain transcription factor SPL6 in enabling the activation of the defense transcriptome following its association with a nuclear-localized immune receptor. During an active immune response, the Nicotiana TIR-NB-LRR N immune receptor associates with NbSPL6 within distinct nuclear compartments. NbSPL6 is essential for the N-mediated resistance to Tobacco mosaic virus. Similarly, the presumed Arabidopsis ortholog AtSPL6 is required for the resistance mediated by the TIR-NB-LRR RPS4 against Pseudomonas syringae carrying the avrRps4 effector. Transcriptome analysis indicates that AtSPL6 positively regulates a subset of defense genes. A pathogen-activated nuclear-localized TIR-NB-LRR like N can therefore regulate defense genes through SPL6 in a mechanism analogous to the induction of MHC genes by mammalian immune receptors like CIITA and NLRC5.

Why do younger women have higher breast cancer recurrence rates after breast-conserving surgery?

International Nuclear Information System (INIS)

Nishimura, Reiki; Matsuda, Masakazu; Miyayama, Haruhiko; Okazaki, Shinji; Kai, Chiharu; Ozaki, N.

2003-01-01

Preventing breast cancer recurrence after breast-conserving surgery is an important issue. The main factors contributing to such recurrence are positive margins, absence of radiotherapy and young age. To investigate the clinical significance of age in breast-conserving surgery, we examined the relationship between clinicopathological findings or outcome and age, especially young age. The cases were divided into three groups by age; 35 years old or less, 36-50y.o. and 51y.o. or higher. Between April 1989 and March 2003, 743 patients were treated with breast-conserving surgery. There were 49 patients aged 35 years old or less (6.6%). Younger age significantly correlated with positive surgical margin, lymph node metastases, higher proliferative activity, negative estrogen receptor (ER) or progesterone receptor (PgR), larger tumor size, and shorter nipple-tumor distances. Although younger patients had a higher recurrence rate irrespective of radiotherapy, margin status had an impact on recurrence rate. Thus, the reason young age was a significant factor for breast recurrence after breast-conserving surgery was that young patients frequently had numerous risk factors such as positive margin, higher proliferative activity, positive nodes, negative ER/PgR and larger tumor. However, negative surgical margins could reduce recurrence rates even in young women. These results suggest that more suitable criteria and strategies may be needed for young patients with breast cancer. (author)

Prostate-Derived Ets Transcription Factor Overexpression is Associated with Nodal Metastasis, Hormone Receptor Positivity in Invasive Breast Cancer

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Simon Turcotte

2007-10-01

Full Text Available Prostate-derived Ets transcription factor (PDEF has recently been associated with invasive breast cancer, but no expression profile has been defined in clinical specimens. We undertook a comprehensive PDEF transcriptional expression study of 86 breast cancer clinical specimens, several cell lines, normal tissues. PDEF expression profile was analyzed according to standard clinicopathologic parameters, compared with hormonal receptor, HER-2/neu status, to the expression of the new tumor biomarker Dikkopf-1 (DKK1. Wide ranging PDEF overexpression was observed in 74% of tested tumors, at higher levels than the average expression found in normal breasts. High PDEF expression was associated with hormone receptor positivity (P < .001, moderate to good differentiation (less than grade III, P = .01, dissemination to axillary lymph nodes (P = .002. PDEF was an independent risk factor for nodal involvement (multivariate analysis, odds ratio 1.250, P = .002. It was expressed in a different subgroup compared to DKK1-expressing tumors (P < .001. Our data imply that PDEF mRNA expression could be useful in breast cancer molecular staging. Further insights into PDEF functions at the protein level, possible links with hormone receptors biology, bear great potential for new therapeutic avenues.

Phase III randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy of metastatic or locally advanced human epidermal growth factor receptor 2-positive breast cancer: the HERNATA study

DEFF Research Database (Denmark)

Andersson, Michael; Lidbrink, Elisabeth; Bjerre, Karsten

2011-01-01

To evaluate docetaxel or vinorelbine, both with trastuzumab, as first-line therapy of human epidermal growth factor receptor 2-positive advanced breast cancer.......To evaluate docetaxel or vinorelbine, both with trastuzumab, as first-line therapy of human epidermal growth factor receptor 2-positive advanced breast cancer....

Columnar cell lesions of the canine mammary gland: pathological features and immunophenotypic analysis

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Cassali Geovanni D

2010-02-01

Full Text Available Abstract Background It has been suggested that columnar cell lesions indicate an alteration of the human mammary gland involved in the development of breast cancer. They have not previously been described in canine mammary gland. The aim of this paper is describe the morphologic spectrum of columnar cell lesions in canine mammary gland specimens and their association with other breast lesions. Methods A total of 126 lesions were subjected to a comprehensive morphological review based upon the human breast classification system for columnar cell lesions. The presence of preinvasive (epithelial hyperplasia and in situ carcinoma and invasive lesions was determined and immunophenotypic analysis (estrogen receptor (ER, progesterone receptor (PgR, high molecular weight cytokeratin (34βE-12, E-cadherin, Ki-67, HER-2 and P53 was perfomed. Results Columnar cell lesions were identified in 67 (53.1% of the 126 canine mammary glands with intraepithelial alterations. They were observed in the terminal duct lobular units and characterized at dilated acini may be lined by several layers of columnar epithelial cells with elongated nuclei. Of the columnar cell lesions identified, 41 (61.2% were without and 26 (38.8% with atypia. Association with ductal hyperplasia was observed in 45/67 (67.1%. Sixty (89.5% of the columnar cell lesions coexisted with neoplastic lesions (20 in situ carcinomas, 19 invasive carcinomas and 21 benign tumors. The columnar cells were ER, PgR and E-cadherin positive but negative for cytokeratin 34βE-12, HER-2 and P53. The proliferation rate as measured by Ki-67 appeared higher in the lesions analyzed than in normal TDLUs. Conclusions Columnar cell lesions in canine mammary gland are pathologically and immunophenotypically similar to those in human breast. This may suggest that dogs are a suitable model for the comparative study of noninvasive breast lesions.

Columnar cell lesions of the canine mammary gland: pathological features and immunophenotypic analysis

International Nuclear Information System (INIS)

Ferreira, Enio; Gobbi, Helenice; Saraiva, Bruna S; Cassali, Geovanni D

2010-01-01

It has been suggested that columnar cell lesions indicate an alteration of the human mammary gland involved in the development of breast cancer. They have not previously been described in canine mammary gland. The aim of this paper is describe the morphologic spectrum of columnar cell lesions in canine mammary gland specimens and their association with other breast lesions. A total of 126 lesions were subjected to a comprehensive morphological review based upon the human breast classification system for columnar cell lesions. The presence of preinvasive (epithelial hyperplasia and in situ carcinoma) and invasive lesions was determined and immunophenotypic analysis (estrogen receptor (ER), progesterone receptor (PgR), high molecular weight cytokeratin (34βE-12), E-cadherin, Ki-67, HER-2 and P53) was perfomed. Columnar cell lesions were identified in 67 (53.1%) of the 126 canine mammary glands with intraepithelial alterations. They were observed in the terminal duct lobular units and characterized at dilated acini may be lined by several layers of columnar epithelial cells with elongated nuclei. Of the columnar cell lesions identified, 41 (61.2%) were without and 26 (38.8%) with atypia. Association with ductal hyperplasia was observed in 45/67 (67.1%). Sixty (89.5%) of the columnar cell lesions coexisted with neoplastic lesions (20 in situ carcinomas, 19 invasive carcinomas and 21 benign tumors). The columnar cells were ER, PgR and E-cadherin positive but negative for cytokeratin 34βE-12, HER-2 and P53. The proliferation rate as measured by Ki-67 appeared higher in the lesions analyzed than in normal TDLUs. Columnar cell lesions in canine mammary gland are pathologically and immunophenotypically similar to those in human breast. This may suggest that dogs are a suitable model for the comparative study of noninvasive breast lesions

Photoaffinity labeling of pituitary GnRH receptors: significance of the position of photolabel on the ligand

International Nuclear Information System (INIS)

Nikolics, K.; Szonyi, E.; Ramachandran, J.

1988-01-01

Photoreactive derivatives of GnRH and its analogues were prepared by incorporation of the 2-nitro-4(5)-azidophenylsulfenyl [2,4(5)-NAPS] group into amino acid residues at position 1, 3, 6, or 8 of the decapeptide sequence. The modification of Trp 3 by the 2,4-NAPS group led to a complete loss of the luteinizing hormone (LH) releasing as well as LH-release-inhibiting activity of the peptide. The [D-Lys(2,4-NAPS)] 6 analog was a very potent agonist that, after covalent attachment by photoaffinity labeling, caused prolonged LH secretion at a submaximal rate. [Orn(2,4-NAPS)] 8 -GnRH, a full agonist with a relative potency of 7% of GnRH, after photoaffinity labeling caused prolonged maximal LH release from cultured pituitary cells. In contrast, [Orn(2,5-NAPS)] 8 -GnRH, although being equipotent with the 2,4-NAPS isomer in terms of LH releasing ability, was unable to cause prolonged LH release after photoaffinity labeling. Thus, [Orn(2,4-NAPS)] 8 GnRH is very effective photolabeling ligand of the functionally significant pituitary GnRH receptor. Based on this compound, a pituitary peptidase resistant derivative, D-Phe 6 , [Orn(2,4-NAPS)] 8 -GnRH-(1-9)-ethylamide, was synthesized. This derivative showed high-affinity binding to pituitary membranes with a K/sub d/ comparable to those of other GnRH analogues. A radioiodinated form of this peptide was used for pituitary GnRH-receptor labeling. This derivative labeled 59- and 57-kDa proteins in rat and 58- and 56-kDa proteins in bovine pituitary membrane preparations, respectively. This peptide also labeled pituitary GnRH receptors in the solubilized state and therefore appears to be a suitable ligand for the isolation and further characterization of the receptor

Positive allosteric modulators of the α7 nicotinic acetylcholine receptor potentiate glutamate release in the prefrontal cortex of freely-moving rats

DEFF Research Database (Denmark)

Bortz, D M; Upton, B A; Mikkelsen, J D

2016-01-01

Positive allosteric modulators (PAMs) of α7 nicotinic acetylcholine receptors (α7nAChRs) exhibit pro-cognitive effects in animal models of schizophrenia and are targets for the discovery of cognition-enhancing drugs. However, little is known about their in vivo mechanism of action because...

Muscarinic M4 Receptors on Cholinergic and Dopamine D1 Receptor-Expressing Neurons Have Opposing Functionality for Positive Reinforcement and Influence Impulsivity

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Anna M. Klawonn

2018-04-01

Full Text Available The neurotransmitter acetylcholine has been implicated in reward learning and drug addiction. However, the roles of the various cholinergic receptor subtypes on different neuron populations remain elusive. Here we study the function of muscarinic M4 receptors (M4Rs in dopamine D1 receptor (D1R expressing neurons and cholinergic neurons (expressing choline acetyltransferase; ChAT, during various reward-enforced behaviors and in a “waiting”-impulsivity test. We applied cell-type-specific gene deletions targeting M4Rs in D1RCre or ChATCre mice. Mice lacking M4Rs in D1R-neurons displayed greater cocaine seeking and drug-primed reinstatement than their littermate controls in a Pavlovian conditioned place preference (CPP paradigm. Furthermore, the M4R-D1RCre mice initiated significantly more premature responses (PRs in the 5-choice-serial-reaction-time-task (5CSRTT than their littermate controls, indicating impaired waiting impulse control. In contrast, mice lacking M4Rs in cholinergic neurons did not acquire cocaine Pavlovian conditioning. The M4R-ChATCre mice were also unable to learn positive reinforcement to either natural reward or cocaine in an operant runway paradigm. Immediate early gene (IEG expression (cFos and FosB induced by repeated cocaine injections was significantly increased in the forebrain of M4R-D1RCre mice, whereas it remained normal in the M4R-ChATCre mice. Our study illustrates that muscarinic M4Rs on specific neural populations, either cholinergic or D1R-expressing, are pivotal for learning processes related to both natural reward and drugs of abuse, with opposing functionality. Furthermore, we found that neurons expressing both M4Rs and D1Rs are important for signaling impulse control.

Muscarinic M4 Receptors on Cholinergic and Dopamine D1 Receptor-Expressing Neurons Have Opposing Functionality for Positive Reinforcement and Influence Impulsivity.

Science.gov (United States)

Klawonn, Anna M; Wilhelms, Daniel B; Lindström, Sarah H; Singh, Anand Kumar; Jaarola, Maarit; Wess, Jürgen; Fritz, Michael; Engblom, David

2018-01-01

The neurotransmitter acetylcholine has been implicated in reward learning and drug addiction. However, the roles of the various cholinergic receptor subtypes on different neuron populations remain elusive. Here we study the function of muscarinic M4 receptors (M4Rs) in dopamine D1 receptor (D1R) expressing neurons and cholinergic neurons (expressing choline acetyltransferase; ChAT), during various reward-enforced behaviors and in a "waiting"-impulsivity test. We applied cell-type-specific gene deletions targeting M4Rs in D1RCre or ChATCre mice. Mice lacking M4Rs in D1R-neurons displayed greater cocaine seeking and drug-primed reinstatement than their littermate controls in a Pavlovian conditioned place preference (CPP) paradigm. Furthermore, the M4R-D1RCre mice initiated significantly more premature responses (PRs) in the 5-choice-serial-reaction-time-task (5CSRTT) than their littermate controls, indicating impaired waiting impulse control. In contrast, mice lacking M4Rs in cholinergic neurons did not acquire cocaine Pavlovian conditioning. The M4R-ChATCre mice were also unable to learn positive reinforcement to either natural reward or cocaine in an operant runway paradigm. Immediate early gene (IEG) expression ( cFos and FosB ) induced by repeated cocaine injections was significantly increased in the forebrain of M4R-D1RCre mice, whereas it remained normal in the M4R-ChATCre mice. Our study illustrates that muscarinic M4Rs on specific neural populations, either cholinergic or D1R-expressing, are pivotal for learning processes related to both natural reward and drugs of abuse, with opposing functionality. Furthermore, we found that neurons expressing both M4Rs and D1Rs are important for signaling impulse control.

Aspirin regulation of c-myc and cyclinD1 proteins to overcome tamoxifen resistance in estrogen receptor-positive breast cancer cells.

Science.gov (United States)

Cheng, Ran; Liu, Ya-Jing; Cui, Jun-Wei; Yang, Man; Liu, Xiao-Ling; Li, Peng; Wang, Zhan; Zhu, Li-Zhang; Lu, Si-Yi; Zou, Li; Wu, Xiao-Qin; Li, Yu-Xia; Zhou, You; Fang, Zheng-Yu; Wei, Wei

2017-05-02

Tamoxifen is still the most commonly used endocrine therapy drug for estrogen receptor (ER)-positive breast cancer patients and has an excellent outcome, but tamoxifen resistance remains a great impediment to successful treatment. Recent studies have prompted an anti-tumor effect of aspirin. Here, we demonstrated that aspirin not only inhibits the growth of ER-positive breast cancer cell line MCF-7, especially when combined with tamoxifen, but also has a potential function to overcome tamoxifen resistance in MCF-7/TAM. Aspirin combined with tamoxifen can down regulate cyclinD1 and block cell cycle in G0/G1 phase. Besides, tamoxifen alone represses c-myc, progesterone receptor (PR) and cyclinD1 in MCF-7 cell line but not in MCF-7/TAM, while aspirin combined with tamoxifen can inhibit the expression of these proteins in the resistant cell line. When knocking down c-myc in MCF-7/TAM, cells become more sensitive to tamoxifen, cell cycle is blocked as well, indicating that aspirin can regulate c-myc and cyclinD1 proteins to overcome tamoxifen resistance. Our study discovered a novel role of aspirin based on its anti-tumor effect, and put forward some kinds of possible mechanisms of tamoxifen resistance in ER-positive breast cancer cells, providing a new strategy for the treatment of ER-positive breast carcinoma.

Prognostic value of Bcl-2 in two independent populations of estrogen receptor positive breast cancer patients treated with adjuvant endocrine therapy

DEFF Research Database (Denmark)

Larsen, Mathilde S; Bjerre, Karsten; Giobbie-Hurder, Anita

2012-01-01

Estrogen receptor (ER) status is not an optimal marker for response to adjuvant endocrine therapy since approximately 30% of patients with ER-positive tumors eventually relapse. Bcl-2 is regulated by ER and may thus be considered as an indicator of ER activity and a candidate supplementary marker...

Tamoxifen or letrozole versus standard methods for women with estrogen-receptor positive breast cancer undergoing oocyte or embryo cryopreservation in assisted reproduction

NARCIS (Netherlands)

Dahhan, Taghride; Balkenende, Eva; van Wely, Madelon; Linn, Sabine; Goddijn, Mariette

2013-01-01

Cryopreservation of oocytes or embryos preceded by controlled ovarian stimulation (COS) can increase the chance of future pregnancy in women with breast cancer who risk therapy-induced ovarian failure. In women with estrogen-receptor (ER) positive breast cancer, alternative COS protocols with

Adjuvant Trastuzumab in HER2-Positive Early Breast Cancer by Age and Hormone Receptor Status: A Cost-Utility Analysis.

Science.gov (United States)

Leung, William; Kvizhinadze, Giorgi; Nair, Nisha; Blakely, Tony

2016-08-01

The anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody trastuzumab improves outcomes in patients with node-positive HER2+ early breast cancer. Given trastuzumab's high cost, we aimed to estimate its cost-effectiveness by heterogeneity in age and estrogen receptor (ER) and progesterone receptor (PR) status, which has previously been unexplored, to assist prioritisation. A cost-utility analysis was performed using a Markov macro-simulation model, with a lifetime horizon, comparing a 12-mo regimen of trastuzumab with chemotherapy alone using the latest (2014) effectiveness measures from landmark randomised trials. A New Zealand (NZ) health system perspective was adopted, employing high-quality national administrative data. Incremental quality-adjusted life-years for trastuzumab versus chemotherapy alone are two times higher (2.33 times for the age group 50-54 y; 95% CI 2.29-2.37) for the worst prognosis (ER-/PR-) subtype compared to the best prognosis (ER+/PR+) subtype, causing incremental cost-effectiveness ratios (ICERs) for the former to be less than half those of the latter for the age groups from 25-29 to 90-94 y (0.44 times for the age group 50-54 y; 95% CI 0.43-0.45). If we were to strictly apply an arbitrary cost-effectiveness threshold equal to the NZ gross domestic product per capita (2011 purchasing power parity [PPP]-adjusted: US$30,300; €23,700; £21,200), our study suggests that trastuzumab (2011 PPP-adjusted US$45,400/€35,900/£21,900 for 1 y at formulary prices) may not be cost-effective for ER+ (which are 61% of all) node-positive HER2+ early breast cancer patients but cost-effective for ER-/PR- subtypes (37% of all cases) to age 69 y. Market entry of trastuzumab biosimilars will likely reduce the ICER to below this threshold for premenopausal ER+/PR- cancer but not for ER+/PR+ cancer. Sensitivity analysis using the best-case effectiveness measure for ER+ cancer had the same result. A key limitation was a lack of treatment

Adjuvant Trastuzumab in HER2-Positive Early Breast Cancer by Age and Hormone Receptor Status: A Cost-Utility Analysis.

Directory of Open Access Journals (Sweden)

William Leung

2016-08-01

Full Text Available The anti-human epidermal growth factor receptor 2 (HER2 monoclonal antibody trastuzumab improves outcomes in patients with node-positive HER2+ early breast cancer. Given trastuzumab's high cost, we aimed to estimate its cost-effectiveness by heterogeneity in age and estrogen receptor (ER and progesterone receptor (PR status, which has previously been unexplored, to assist prioritisation.A cost-utility analysis was performed using a Markov macro-simulation model, with a lifetime horizon, comparing a 12-mo regimen of trastuzumab with chemotherapy alone using the latest (2014 effectiveness measures from landmark randomised trials. A New Zealand (NZ health system perspective was adopted, employing high-quality national administrative data. Incremental quality-adjusted life-years for trastuzumab versus chemotherapy alone are two times higher (2.33 times for the age group 50-54 y; 95% CI 2.29-2.37 for the worst prognosis (ER-/PR- subtype compared to the best prognosis (ER+/PR+ subtype, causing incremental cost-effectiveness ratios (ICERs for the former to be less than half those of the latter for the age groups from 25-29 to 90-94 y (0.44 times for the age group 50-54 y; 95% CI 0.43-0.45. If we were to strictly apply an arbitrary cost-effectiveness threshold equal to the NZ gross domestic product per capita (2011 purchasing power parity [PPP]-adjusted: US$30,300; €23,700; £21,200, our study suggests that trastuzumab (2011 PPP-adjusted US$45,400/€35,900/£21,900 for 1 y at formulary prices may not be cost-effective for ER+ (which are 61% of all node-positive HER2+ early breast cancer patients but cost-effective for ER-/PR- subtypes (37% of all cases to age 69 y. Market entry of trastuzumab biosimilars will likely reduce the ICER to below this threshold for premenopausal ER+/PR- cancer but not for ER+/PR+ cancer. Sensitivity analysis using the best-case effectiveness measure for ER+ cancer had the same result. A key limitation was a lack of

Cadmium mimics the in vivo effects of estrogen in the uterus and mammary gland.

Science.gov (United States)

Johnson, Michael D; Kenney, Nicholas; Stoica, Adriana; Hilakivi-Clarke, Leena; Singh, Baljit; Chepko, Gloria; Clarke, Robert; Sholler, Peter F; Lirio, Apolonio A; Foss, Colby; Reiter, Ronald; Trock, Bruce; Paik, Soonmyoung; Martin, Mary Beth

2003-08-01

It has been suggested that environmental contaminants that mimic the effects of estrogen contribute to disruption of the reproductive systems of animals in the wild, and to the high incidence of hormone-related cancers and diseases in Western populations. Previous studies have shown that functionally, cadmium acts like steroidal estrogens in breast cancer cells as a result of its ability to form a high-affinity complex with the hormone binding domain of the estrogen receptor. The results of the present study show that cadmium also has potent estrogen-like activity in vivo. Exposure to cadmium increased uterine wet weight, promoted growth and development of the mammary glands and induced hormone-regulated genes in ovariectomized animals. In the uterus, the increase in wet weight was accompanied by proliferation of the endometrium and induction of progesterone receptor (PgR) and complement component C3. In the mammary gland, cadmium promoted an increase in the formation of side branches and alveolar buds and the induction of casein, whey acidic protein, PgR and C3. In utero exposure to the metal also mimicked the effects of estrogens. Female offspring experienced an earlier onset of puberty and an increase in the epithelial area and the number of terminal end buds in the mammary gland.

Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer.

Science.gov (United States)

Paik, Soonmyung; Tang, Gong; Shak, Steven; Kim, Chungyeul; Baker, Joffre; Kim, Wanseop; Cronin, Maureen; Baehner, Frederick L; Watson, Drew; Bryant, John; Costantino, Joseph P; Geyer, Charles E; Wickerham, D Lawrence; Wolmark, Norman

2006-08-10

The 21-gene recurrence score (RS) assay quantifies the likelihood of distant recurrence in women with estrogen receptor-positive, lymph node-negative breast cancer treated with adjuvant tamoxifen. The relationship between the RS and chemotherapy benefit is not known. The RS was measured in tumors from the tamoxifen-treated and tamoxifen plus chemotherapy-treated patients in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B20 trial. Cox proportional hazards models were utilized to test for interaction between chemotherapy treatment and the RS. A total of 651 patients were assessable (227 randomly assigned to tamoxifen and 424 randomly assigned to tamoxifen plus chemotherapy). The test for interaction between chemotherapy treatment and RS was statistically significant (P = .038). Patients with high-RS (> or = 31) tumors (ie, high risk of recurrence) had a large benefit from chemotherapy (relative risk, 0.26; 95% CI, 0.13 to 0.53; absolute decrease in 10-year distant recurrence rate: mean, 27.6%; SE, 8.0%). Patients with low-RS (< 18) tumors derived minimal, if any, benefit from chemotherapy treatment (relative risk, 1.31; 95% CI, 0.46 to 3.78; absolute decrease in distant recurrence rate at 10 years: mean, -1.1%; SE, 2.2%). Patients with intermediate-RS tumors did not appear to have a large benefit, but the uncertainty in the estimate can not exclude a clinically important benefit. The RS assay not only quantifies the likelihood of breast cancer recurrence in women with node-negative, estrogen receptor-positive breast cancer, but also predicts the magnitude of chemotherapy benefit.

99mTc-labelled HYNIC-minigastrin with reduced kidney uptake for targeting of CCK-2 receptor-positive tumours

International Nuclear Information System (INIS)

Guggenberg, E. von; Gabriel, M.; Virgolini, I.J.; Decristoforo, C.; Dietrich, H.; Skvortsova, I.

2007-01-01

Different attempts have been made to develop a suitable radioligand for targeting CCK-2 receptors in vivo, for staging of medullary thyroid carcinoma (MTC) and other receptor-expressing tumours. After initial successful clinical studies with [DTPA 0 ,DGlu 1 ]minigastrin (DTPA-MG0) radiolabelled with 111 In and 90 Y, our group developed a 99m Tc-labelled radioligand, based on HYNIC-MG0. A major drawback observed with these derivatives is their high uptake by the kidneys. In this study we describe the preclinical evaluation of the optimised shortened peptide analogue, [HYNIC 0 ,DGlu 1 ,desGlu 2-6 ]minigastrin (HYNIC-MG11). 99m Tc labelling of HYNIC-MG11 was performed using tricine and EDDA as coligands. Stability experiments were carried out by reversed phase HPLC analysis in PBS, PBS/cysteine and plasma as well as rat liver and kidney homogenates. Receptor binding and cell uptake experiments were performed using AR4-2J rat pancreatic tumour cells. Animal biodistribution was studied in AR4-2J tumour-bearing nude mice. Radiolabelling was performed at high specific activities and radiochemical purity was >90%. 99m Tc-EDDA-HYNIC-MG11 showed high affinity for the CCK-2 receptor and cell internalisation comparable to that of 99m Tc-EDDA-HYNIC-MG0. Despite high stability in solution, a low metabolic stability in rat tissue homogenates was found. In a nude mouse tumour model, very low unspecific retention in most organs, rapid renal excretion with reduced renal retention and high tumour uptake were observed. 99m Tc-EDDA-HYNIC-MG11 shows advantages over 99m Tc-EDDA-HYNIC-MG0 in terms of lower kidney retention with unchanged uptake in tumours and CCK-2 receptor-positive tissue. However, the lower metabolic stability and impurities formed in the labelling process still leave room for further improvement. (orig.)

False-positive 111In-pentetreotide Uptake in Gastritis

International Nuclear Information System (INIS)

Usmani, Sharjeel; Alshammari, Alshaima

2013-01-01

111 In-pentetreotide [ 111 In-octreoscan] is the most widely used radiolabeled somatostatin analog for evaluating neuroendocrine tumor overexpression of somatostatin receptors. False-positives studies of somatostatin receptor scintigraphy have been reported and often the cause is unexplained but assumed to be due to high number of somatostatin receptors in other pathologies. Causes of false-positives include visualization of the gallbladder, nasal mucosa and pulmonary hilar areas in respiratory infections, thyroid abnormalities, accessory spleens, recent Cerebrovascular accidents (CVA's) and activity at the site of a recent surgical incision. In infection or inflammation the cause of false-positive uptake is probably the result of tracer binding by somatostatin receptors on the inflammatory leukocytes. In this case report, we report, a 44-year-old male patient with false-positive 111 In-pentetreotide uptake due to gastritis

Convergence of glycogen synthase kinase 3β and GR signaling in response to fluoxetine treatment in chronically stressed female and male rats.

Science.gov (United States)

Mitic, Milos; Brkic, Zeljka; Lukic, Iva; Adzic, Miroslav

2017-08-30

Accumulating evidence strongly suggest that impaired glucocorticoid receptor (GR) signaling is involved in stress-related mood disorders, and nominate GR as a potential target for antidepressants (ADs). It is known that different classes of ADs affects the GR action via modifying its phosphorylation, while the mechanism through which ADs alter GR phosphorylation targeted by GSK3β, a kinase modulated via serotonin neurotransmission, are unclear. On this basis, we investigated whether GSK3β-GR signaling could be a convergence point of fluoxetine action on brain function and behavior, by examining its effect on GSK3β targeted-GR phosphorylation on threonine 171 (pGR171), and expression of GR-regulated genes in the hippocampus of female and male rats exposed to chronic isolation stress. Stress induced sex-specific GSK3β-targeted phosphorylation of pGR171 in the nucleus of the hippocampus of stressed animals. Namely, while in females stress triggered coupled action of GSK3β-pGR171 signaling, in males changes in pGR171 levels did not correspond to GSK3β activity. On the other hand, fluoxetine managed to up-regulate this pathway in sex-unbiased manner. Furthermore, fluoxetine reverted stress-induced changes in most of the analyzed genes in males, CRH, 5-HT1a and p11, while in females its effect was limited to CRH. These data further suggest that pGR171 signaling affects cellular localization of GR in response to chronic stress and fluoxetine in both sexes. Collectively, our results describe a novel convergence point between GR signaling and GSK3β pathway in rat hippocampus in response to stress and fluoxetine in both sexes and its involvement in fluoxetine-regulated brain function in males. Copyright © 2017 Elsevier B.V. All rights reserved.

Five Polymorphisms and Breast Cancer Risk: Results from the Breast Cancer Association Consortium

Science.gov (United States)

Gaudet, Mia M.; Milne, Roger L.; Cox, Angela; Camp, Nicola J.; Goode, Ellen L.; Humphreys, Manjeet K.; Dunning, Alison M.; Morrison, Jonathan; Giles, Graham G.; Severi, Gianluca; Baglietto, Laura; English, Dallas R.; Couch, Fergus J.; Olson, Janet E.; Wang, Xianshu; Chang-Claude, Jenny; Flesch-Janys, Dieter; Abbas, Sascha; Salazar, Ramona; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Lindblom, Annika; Margolin, Sara; Heikkinen, Tuomas; Kämpjärvi, Kati; Aaltonen, Kirsimari; Nevanlinna, Heli; Bogdanova, Natalia; Coinac, Irina; Schürmann, Peter; Dörk, Thilo; Bartram, Claus R.; Schmutzler, Rita K.; Tchatchou, Sandrine; Burwinkel, Barbara; Brauch, Hiltrud; Torres, Diana; Hamann, Ute; Justenhoven, Christina; Ribas, Gloria; Arias, José I.; Benitez, Javier; Bojesen, Stig E.; Nordestgaard, Børge G.; Flyger, Henrik L.; Peto, Julian; Fletcher, Olivia; Johnson, Nichola; Silva, Isabel dos Santos; Fasching, Peter A.; Beckmann, Matthias W.; Strick, Reiner; Ekici, Arif B.; Broeks, Annegien; Schmidt, Marjanka K.; van Leeuwen, Flora E.; Van’t Veer, Laura J.; Southey, Melissa C.; Hopper, John L.; Apicella, Carmel; Haiman, Christopher A.; Henderson, Brian E.; Le Marchand, Loic; Kolonel, Laurence N.; Kristensen, Vessela; Alnæs, Grethe Grenaker; Hunter, David J.; Kraft, Peter; Cox, David G.; Hankinson, Susan E.; Seynaeve, Caroline; Vreeswijk, Maaike P.G.; Tollenaar, Rob A.E.M.; Devilee, Peter; Chanock, Stephen; Lissowska, Jolanta; Brinton, Louise; Peplonska, Beata; Czene, Kamila; Hall, Per; Li, Yuqing; Liu, Jianjun; Balasubramanian, Sabapathy; Rafii, Saeed; Reed, Malcolm W.R.; Pooley, Karen A.; Conroy, Don; Baynes, Caroline; Kang, Daehee; Yoo, Keun-Young; Noh, Dong-Young; Ahn, Sei-Hyun; Shen, Chen-Yang; Wang, Hui-Chun; Yu, Jyh-Cherng; Wu, Pei-Ei; Anton-Culver, Hoda; Ziogoas, Argyrios; Egan, Kathleen; Newcomb, Polly; Titus-Ernstoff, Linda; Dietz, Amy Trentham; Sigurdson, Alice J.; Alexander, Bruce H.; Bhatti, Parveen; Allen-Brady, Kristina; Cannon-Albright, Lisa A.; Wong, Jathine; Chenevix-Trench, Georgia; Spurdle, Amanda B.; Beesley, Jonathan; Pharoah, Paul D.P.; Easton, Doug F.; Garcia-Closas, Montserrat

2009-01-01

Previous studies have suggested that minor alleles for ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 may influence breast cancer risk, but the evidence is inconclusive due to their small sample size. These polymorphisms were genotyped in more than 30,000 breast cancer cases and 30,000 controls, primarily of European descent, from 30 studies in the Breast Cancer Association Consortium. We calculated odds ratios (OR) and 95% confidence intervals (95% CI) as a measure of association. We found that the minor alleles for these polymorphisms were not related to invasive breast cancer risk overall in women of European descent: ECCR4 per-allele OR (95% CI) = 0.99 (0.97–1.02), minor allele frequency = 27.5%; TNF 1.00 (0.95–1.06), 5.0%; CASP10 1.02 (0.98–1.07), 6.5%; PGR 1.02 (0.99–1.06), 15.3%; and BID 0.98 (0.86–1.12), 1.7%. However, we observed significant between-study heterogeneity for associations with risk for single-nucleotide polymorphisms (SNP) in CASP10, PGR, and BID. Estimates were imprecise for women of Asian and African descent due to small numbers and lower minor allele frequencies (with the exception of BID SNP). The ORs for each copy of the minor allele were not significantly different by estrogen or progesterone receptor status, nor were any significant interactions found between the polymorphisms and age or family history of breast cancer. In conclusion, our data provide persuasive evidence against an overall association between invasive breast cancer risk and ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 genotypes among women of European descent. PMID:19423537

Molecular modeling of ligand-receptor interactions in the OR5 olfactory receptor.

Science.gov (United States)

Singer, M S; Shepherd, G M

1994-06-02

Olfactory receptors belong to the superfamily of seven transmembrane domain, G protein-coupled receptors. In order to begin analysis of mechanisms of receptor activation, a computer model of the OR5 olfactory receptor has been constructed and compared with other members of this superfamily. We have tested docking of the odor molecule lyral, which is known to activate the OR5 receptor. The results point to specific ligand-binding residues on helices III through VII that form a binding pocket in the receptor. Some of these residues occupy sequence positions identical to ligand-binding residues conserved among other superfamily members. The results provide new insights into possible molecular mechanisms of odor recognition and suggest hypotheses to guide future experimental studies using site-directed mutagenesis.

Identification of Insulin-Like Growth Factor-I Receptor (IGF-IR) Gene Promoter-Binding Proteins in Estrogen Receptor (ER)-Positive and ER-Depleted Breast Cancer Cells

International Nuclear Information System (INIS)

Sarfstein, Rive; Belfiore, Antonino; Werner, Haim

2010-01-01

The insulin-like growth factor I receptor (IGF-IR) has been implicated in the etiology of breast cancer. Overexpression of the IGF-IR gene is a typical feature of most primary breast cancers, whereas low IGF-IR levels are seen at advanced stages. Hence, evaluation of IGF-IR levels might be important for assessing prognosis. In the present study, we employed a proteomic approach based on DNA affinity chromatography followed either by mass spectroscopy (MS) or Western blot analysis to identify transcription factors that may associate with the IGF-IR promoter in estrogen receptor (ER)-positive and ER-depleted breast cancer cells. A biotinylated IGF-IR promoter fragment was bound to streptavidin magnetic beads and incubated with nuclear extracts of breast cancer cells. IGF-IR promoter-binding proteins were eluted with high salt and analyzed by MS and Western blots. Among the proteins that were found to bind to the IGF-IR promoter we identified zinc finger transcription factors Sp1 and KLF6, ER-α, p53, c-jun, and poly (ADP-ribosylation) polymerase. Furthermore, chromatin immune-precipitation (ChIP) analysis confirmed the direct in vivo binding of some of these transcription factors to IGF-IR promoter DNA. The functional relevance of binding data was assessed by cotransfection experiments with specific expression vectors along with an IGF-IR promoter reporter. In summary, we identified nuclear proteins that are potentially responsible for the differential expression of the IGF-IR gene in ER-positive and ER-depleted breast cancer cells

Identification of Insulin-Like Growth Factor-I Receptor (IGF-IR) Gene Promoter-Binding Proteins in Estrogen Receptor (ER)-Positive and ER-Depleted Breast Cancer Cells

Energy Technology Data Exchange (ETDEWEB)

Sarfstein, Rive [Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978 (Israel); Belfiore, Antonino [Department of Clinical and Experimental Medicine, University Magna Graecia of Catanzaro, Catanzaro 88100 (Italy); Werner, Haim, E-mail: hwerner@post.tau.ac.il [Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978 (Israel)

2010-03-25

The insulin-like growth factor I receptor (IGF-IR) has been implicated in the etiology of breast cancer. Overexpression of the IGF-IR gene is a typical feature of most primary breast cancers, whereas low IGF-IR levels are seen at advanced stages. Hence, evaluation of IGF-IR levels might be important for assessing prognosis. In the present study, we employed a proteomic approach based on DNA affinity chromatography followed either by mass spectroscopy (MS) or Western blot analysis to identify transcription factors that may associate with the IGF-IR promoter in estrogen receptor (ER)-positive and ER-depleted breast cancer cells. A biotinylated IGF-IR promoter fragment was bound to streptavidin magnetic beads and incubated with nuclear extracts of breast cancer cells. IGF-IR promoter-binding proteins were eluted with high salt and analyzed by MS and Western blots. Among the proteins that were found to bind to the IGF-IR promoter we identified zinc finger transcription factors Sp1 and KLF6, ER-α, p53, c-jun, and poly (ADP-ribosylation) polymerase. Furthermore, chromatin immune-precipitation (ChIP) analysis confirmed the direct in vivo binding of some of these transcription factors to IGF-IR promoter DNA. The functional relevance of binding data was assessed by cotransfection experiments with specific expression vectors along with an IGF-IR promoter reporter. In summary, we identified nuclear proteins that are potentially responsible for the differential expression of the IGF-IR gene in ER-positive and ER-depleted breast cancer cells.

Targeted biomarker profiling of matched primary and metastatic estrogen receptor positive breast cancers.

Directory of Open Access Journals (Sweden)

Erica B Schleifman

Full Text Available Patients with newly diagnosed, early stage estrogen receptor positive (ER+ breast cancer often show disease free survival in excess of five years following surgery and systemic adjuvant therapy. An important question is whether diagnostic tumor tissue from the primary lesion offers an accurate molecular portrait of the cancer post recurrence and thus may be used for predictive diagnostic purposes for patients with relapsed, metastatic disease. As the class I phosphatidylinositol 3' kinase (PI3K pathway is frequently activated in ER+ breast cancer and has been linked to acquired resistance to hormonal therapy, we hypothesized pathway status could evolve over time and treatment. Biomarker analyses were conducted on matched, asynchronous primary and metastatic tumors from 77 patients with ER+ breast cancer. We examined whether PIK3CA and AKT1 alterations or PTEN and Ki67 levels showed differences between primary and metastatic samples. We also sought to look more broadly at gene expression markers reflective of proliferation, molecular subtype, and key receptors and signaling pathways using an mRNA analysis platform developed on the Fluidigm BioMark™ microfluidics system to measure the relative expression of 90 breast cancer related genes in formalin-fixed paraffin-embedded (FFPE tissue. Application of this panel of biomarker assays to matched tumor pairs showed a high concordance between primary and metastatic tissue, with generally few changes in mutation status, proliferative markers, or gene expression between matched samples. The collection of assays described here has been optimized for FFPE tissue and may have utility in exploratory analyses to identify patient subsets responsive to targeted therapies.

Preparation and evaluation of a new neurotensin analog labeled with 99mTc for targeted imaging of neurotensin receptor positive tumors

International Nuclear Information System (INIS)

Nakisa Zarrabi Ahrabi; Kazem Parivar; Davood Beiki

2014-01-01

Neurotensin receptors are overexpressed in several human tumors and can be targets for tumors diagnosis and therapy. In this study, a new neurotensin analogue was labeled with 99m Tc via HYNIC and tricine/EDDA as coligands and investigated further. [HYNIC 0 , Gly 7 , Lys 9 , d-Tyr 11 ]-Neurotensin (7-13) was synthesized using a standard Fmoc strategy. Labeling with 99m Tc was performed at 100 deg C for 10 min and radiochemical analysis involved ITLC and HPLC methods. The stability of radiopeptide was checked in the presence of humane serum at 37 deg C up to 24 h. The receptor bound internalization and externalization rates were studied in neurotensin receptor expressing HT-29 cells. Biodistribution of radiopeptide was studied in nude mice bearing HT-29 tumor. Labeling yield of 98.6 ± 0.54 % (n = 3) was obtained corresponding to a specific activity of 81 MBq/nmol. Peptide conjugate showed good stability in the presence of human serum. The radioligand showed specific internalization into HT-29 cells (12.43 ± 0.52 % at 4 h). In biodistribution studies, a receptor-specific uptake was observed in neurotensin receptor positive organs so that after 1 h the uptakes in mouse intestine and tumor were 0.87 ± 0.16 and 0.63 ± 0.12 % ID/g respectively. (author)

A single amino acid substitution in the exoplasmic domain of the human growth hormone (GH) receptor confers familial GH resistance (Laron syndrome) with positive GH-binding activity by abolishing receptor homodimerization.

Science.gov (United States)

Duquesnoy, P; Sobrier, M L; Duriez, B; Dastot, F; Buchanan, C R; Savage, M O; Preece, M A; Craescu, C T; Blouquit, Y; Goossens, M

1994-01-01

Growth hormone (GH) elicits a variety of biological activities mainly mediated by the GH receptor (GHR), a transmembrane protein that, based on in vitro studies, seemed to function as a homodimer. To test this hypothesis directly, we investigated patients displaying the classic features of Laron syndrome (familial GH resistance characterized by severe dwarfism and metabolic dysfunction), except for the presence of normal binding activity of the plasma GH-binding protein, a molecule that derives from the exoplasmic-coding domain of the GHR gene. In two unrelated families, the same GHR mutation was identified, resulting in the substitution of a highly conserved aspartate residue by histidine at position 152 (D152H) of the exoplasmic domain, within the postulated interface sequence involved in homodimerization. The recombinant mutated receptor protein was correctly expressed at the plasma membrane. It displayed subnormal GH-binding activity, a finding in agreement with the X-ray crystal structure data inferring this aspartate residue outside the GH-binding domain. However, mAb-based studies suggested the critical role of aspartate 152 in the proper folding of the interface area. We show that a recombinant soluble form of the mutant receptor is unable to dimerize, the D152H substitution also preventing the formation of heterodimers of wild-type and mutant molecules. These results provide in vivo evidence that monomeric receptors are inactive and that receptor dimerization is involved in the primary signalling of the GH-associated growth-promoting and metabolic actions. Images PMID:8137822

Palbociclib: A Novel Cyclin-Dependent Kinase Inhibitor for Hormone Receptor-Positive Advanced Breast Cancer.

Science.gov (United States)

Mangini, Neha S; Wesolowski, Robert; Ramaswamy, Bhuvaneswari; Lustberg, Maryam B; Berger, Michael J

2015-11-01

To review palbociclib, a novel small-molecule inhibitor of cyclin-dependent kinases 4 and 6, and its current place in therapy for the treatment of hormone receptor (HMR)-positive, human epidermal growth factor receptor 2 (Her2)-negative advanced breast cancer. Four phase I trials, 2 phase II trials, and 1 phase III trial were identified from May 2004 to May 2015 using PubMed, American Society of Clinical Oncology (ASCO) abstracts, and European Society of Medical Oncology (ESMO) abstracts. In the first-line setting, the phase II PALbociclib: Ongoing trials in the Management of breast cAncer (PALOMA)-1 trial randomized patients to receive letrozole alone or letrozole plus palbociclib 125 mg daily for 3 weeks, followed by 1 week off, as initial therapy for advanced breast cancer. The investigator-assessed median progression-free survival (PFS) was 20. 2 months for the combination versus 10.2 months for letrozole alone (hazard ratio [HR] = 0.488; 95% CI = 0.319-0.748; 1-sided P = 0.0004). The ensuing Food and Drug Administration approval of palbociclib was given a "breakthrough therapy" designation, where preliminary evidence suggests substantial improvement over existing therapies for a serious or life-threatening disease. A confirmatory phase III trial, PALOMA-2, is under way. In patients who were previously treated with endocrine therapy for advanced breast cancer, the phase III PALOMA-3 trial randomized patients to fulvestrant plus palbociclib versus fulvestrant plus placebo. The investigator-assessed median PFS at the time of a preplanned analysis was 9.2 months with palbociclib-fulvestrant compared with 3.8 months with placebo-fulvestrant (HR = 0.42; 95% CI = 0.32-0.56; P < 0.001). Palbociclib, the first-in-class CDK4/6 inhibitor, significantly extended PFS in combination with endocrine therapy in the first and subsequent lines of treatment for HMR-positive, Her2-negative advanced breast cancer. © The Author(s) 2015.

Fragment Based Optimization of Metabotropic Glutamate Receptor 2 (mGluR2) Positive Allosteric Modulators in the Absence of Structural Information.

Science.gov (United States)

Szabó, György; Túrós, György I; Kolok, Sándor; Vastag, Mónika; Sánta, Zsuzsanna; Dékány, Miklós; Lévay, György I; Greiner, István; Natsumi, Minami; Tatsuya, Watanabe; Keserű, György M

2018-03-14

Metabotropic glutamate receptor 2 (mGluR2) positive allosteric modulators (PAMs) have been implicated as potential pharmacotherapy for psychiatric conditions. Screening our corporate compound deck, we identified a benzotriazole fragment (4) that was rapidly optimized to a potent and metabolically stable early lead (16). The highly lipophilic character of 16, together with its limited solubility, permeability, and high protein binding, however, did not allow reaching of the proof of concept in vivo. Since further attempts on the optimization of druglike properties were unsuccessful, the original hit 4 has been revisited and was optimized following the principles of fragment based drug discovery (FBDD). Lacking structural information on the receptor-ligand complex, we implemented a group efficiency (GE) based strategy and identified a new fragment like lead (60) with more balanced profile. Significant improvement achieved on the druglike properties nominated the compound for in vivo proof of concept studies that revealed the chemotype being a promising PAM lead targeting mGluR2 receptors.

Alterations of the genes involved in the PI3K and estrogen-receptor pathways influence outcome in human epidermal growth factor receptor 2-positive and hormone receptor-positive breast cancer patients treated with trastuzumab-containing neoadjuvant chemotherapy

International Nuclear Information System (INIS)

Takada, Mamoru; Miyazaki, Masaru; Sato-Otsubo, Aiko; Ogawa, Seishi; Kaneko, Yasuhiko; Higuchi, Toru; Tozuka, Katsunori; Takei, Hiroyuki; Haruta, Masayuki; Watanabe, Junko; Kasai, Fumio; Inoue, Kenichi; Kurosumi, Masafumi

2013-01-01

Chemotherapy with trastuzumab is widely used for patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer, but a significant number of patients with the tumor fail to respond, or relapse. The mechanisms of recurrence and biomarkers that indicate the response to the chemotherapy and outcome are not fully investigated. Genomic alterations were analyzed using single-nucleotide polymorphism arrays in 46 HER2 immunohistochemistry (IHC) 3+ or 2+/fluorescent in situ hybridization (FISH)+ breast cancers that were treated with neoadjuvant chemotherapy with paclitaxel, cyclophosphamid, epirubicin, fluorouracil, and trastuzumab. Patients were classified into two groups based on presence or absence of alterations of 65 cancer-associated genes, and the two groups were further classified into four groups based on genomic HER2 copy numbers or hormone receptor status (HR+/−). Pathological complete response (pCR) and relapse-free survival (RFS) rates were compared between any two of the groups. The pCR rate was 54% in 37 patients, and the RFS rate at 3 years was 72% (95% CI, 0.55-0.89) in 42 patients. The analysis disclosed 8 tumors with nonamplified HER2 and 38 tumors with HER2 amplification, indicating the presence of discordance in tumors diagnosed using current HER2 testing. The 8 patients showed more difficulty in achieving pCR (P=0.019), more frequent relapse (P=0.018), and more frequent alterations of genes in the PI3K pathway (P=0.009) than the patients with HER2 amplification. The alterations of the PI3K and estrogen receptor (ER) pathway genes generally indicated worse RFS rates. The prognostic significance of the alterations was shown in patients with a HR+ tumor, but not in patients with a HR- tumor when divided. Alterations of the PI3K and ER pathway genes found in patients with a HR+ tumor with poor outcome suggested that crosstalk between the two pathways may be involved in resistance to the current chemotherapy with trastuzumab. We

Brain metastasis in human epidermal growth factor receptor 2-positive breast cancer: from biology to treatment

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Koo, Tae Ryool [Dept. of Radiation Oncology, Hallym University Chuncheon Sacred Heart Hospital, Chuncheon (Korea, Republic of); Kim, In Ah [Dept. of Radiation Oncology, Seoul National University Bundang Hospital, Seongnam (Korea, Republic of)

2016-03-15

Overexpression of human epidermal growth factor receptor 2 (HER2) is found in about 20% of breast cancer patients. With treatment using trastuzumab, an anti-HER2 monoclonal antibody, systemic control is improved. Nonetheless, the incidence of brain metastasis does not be improved, rather seems to be increased in HER2-positive breast cancer. The mainstay treatment for brain metastases is radiotherapy. According to the number of metastatic lesions and performance status of patients, radiosurgery or whole brain radiotherapy can be performed. The concurrent use of a radiosensitizer further improves intracranial control. Due to its large molecular weight, trastuzumab has a limited ability to cross the blood-brain barrier. However, small tyrosine kinase inhibitors such as lapatinib, has been noted to be a promising agent that can be used as a radiosensitizer to affect HER2-positive breast cancer. This review will outline general management of brain metastases and will focus on preclinical findings regarding the radiosensitizing effect of small molecule HER2 targeting agents.

The Determinations of Estrogen and Progesterone Receptor in Breast Cancer Cell by Radioimmunoassay Method

International Nuclear Information System (INIS)

Kim, Chi Yeul

1981-01-01

The estrogen and progesterone receptors which are bound to the cytoplasmic protein of cancer cells were measured in 20 patients with the early breast cancer by means of radioimmunoassay using charcoal. 1) The patients with estrogen receptor positive were 13 (65%) of 20 cases and with progestrone receptor positive were 7 cases (35%) in the early breast cancer. 2) Coexistence of estrogen and progesterone receptor positive was noted in 7 cases (35%). The cases of estrogen receptor positive and progesterone receptor negative were 6 cases (33.3%), while there were no cases of estrogen receptor negative with progesterone receptor positive. 3) Coincidence of estrogen and progesterone negative was noticed in 7 cases (35%). Conclusively it is considered that the measurement of estrogen and progesterone receptors has relevance as predictive value, in the response to hormonal manipulations and chemotherapy for breast cancer patients.

How calcium makes endocytic receptors attractive

DEFF Research Database (Denmark)

Andersen, Christian B F; Moestrup, Søren K

2014-01-01

of the receptor. Endosomal acidification and calcium efflux lead to the essential ligand-receptor affinity switch and separation. Recent data, including crystal structures of receptor-ligand complexes, now reveal how calcium, in different types of domain scaffolds, functions in a common way as a removable...... 'lynchpin' that stabilizes favorable positioning of ligand-attractive receptor residues. In addition to explaining how calcium depletion can cause ligand-receptor dissociation, the new data add further insight into how acidification contributes to dissociation through structural changes that affect...... the receptor calcium sites....

Somatostatin receptor scintigraphy in patients with cat-scratch disease

International Nuclear Information System (INIS)

Krause, R.; Schnedl, W.J.; Hoier, S.; Piswanger-Soelkner, C.; Lipp, R.W.; Daxboeck, F.; Reisinger, E.C.

2006-01-01

Aim: somatostatin receptor scintigraphy images various neoplastic, granulomatous, and auto-immun diseases. Cat-scratch disease in an infectious granulomatous disease usually affecting the lymphnodes. It is not known whether cat-scratch disease provides positive somatostatin receptor scintigrams. Patients, methods: twelve patients with lymphadenitis and suspected cat-scratch disease were investigated by immunofluorescence antibody testing and somatostatin receptor scintigraphy. Suppurated lymphnodes were extracted or drained and Bartonella henselae specific PCR was then performed. Results: eleven of 12 patients showed IgG antibodies against B. henselea. SRS showed positive scintigraphic results in 6 of 11 patients with CSD. B. henselae DNA was detected in tissue of lymphnodes from 4 of 5 patients with lymphnode extraction or lymphnode drainage. SRS demonstrated positive scintigrams in all patients with a positive PCR. In one patient with suspected CSD SRS was negative as well as antibody testing. Conclusion: somatostatin receptor scintigraphy correlated with positive Bartonella henselae specific PCR tests and positive Bartonella henselae specific antibody tests in patients with CSD. (orig.)

Somatostatin receptor scintigraphy in patients with cat-scratch disease

Energy Technology Data Exchange (ETDEWEB)

Krause, R.; Schnedl, W.J.; Hoier, S. [Div. of Infectious Diseases, Dept. of Internal Medicine, Univ. Graz (Austria); Piswanger-Soelkner, C.; Lipp, R.W. [Div. of Nuclear Medicine, Dept. of Internal Medicine, Univ. Graz (Austria); Daxboeck, F. [Clinical Inst. for Hygiene and Medical Microbiology, Div. of Hospital Hygiene, Univ. of Vienna (Austria); Reisinger, E.C. [Div. of Infectious Diseases and Tropical Medicine, Dept. of Internal Medicine, Univ. Rostock (Germany)

2006-07-01

Aim: somatostatin receptor scintigraphy images various neoplastic, granulomatous, and auto-immun diseases. Cat-scratch disease in an infectious granulomatous disease usually affecting the lymphnodes. It is not known whether cat-scratch disease provides positive somatostatin receptor scintigrams. Patients, methods: twelve patients with lymphadenitis and suspected cat-scratch disease were investigated by immunofluorescence antibody testing and somatostatin receptor scintigraphy. Suppurated lymphnodes were extracted or drained and Bartonella henselae specific PCR was then performed. Results: eleven of 12 patients showed IgG antibodies against B. henselea. SRS showed positive scintigraphic results in 6 of 11 patients with CSD. B. henselae DNA was detected in tissue of lymphnodes from 4 of 5 patients with lymphnode extraction or lymphnode drainage. SRS demonstrated positive scintigrams in all patients with a positive PCR. In one patient with suspected CSD SRS was negative as well as antibody testing. Conclusion: somatostatin receptor scintigraphy correlated with positive Bartonella henselae specific PCR tests and positive Bartonella henselae specific antibody tests in patients with CSD. (orig.)

Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial.

Science.gov (United States)

Albain, Kathy S; Barlow, William E; Shak, Steven; Hortobagyi, Gabriel N; Livingston, Robert B; Yeh, I-Tien; Ravdin, Peter; Bugarini, Roberto; Baehner, Frederick L; Davidson, Nancy E; Sledge, George W; Winer, Eric P; Hudis, Clifford; Ingle, James N; Perez, Edith A; Pritchard, Kathleen I; Shepherd, Lois; Gralow, Julie R; Yoshizawa, Carl; Allred, D Craig; Osborne, C Kent; Hayes, Daniel F

2010-01-01

The 21-gene recurrence score assay is prognostic for women with node-negative, oestrogen-receptor-positive breast cancer treated with tamoxifen. A low recurrence score predicts little benefit of chemotherapy. For node-positive breast cancer, we investigated whether the recurrence score was prognostic in women treated with tamoxifen alone and whether it identified those who might not benefit from anthracycline-based chemotherapy, despite higher risks of recurrence. The phase 3 trial SWOG-8814 for postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer showed that chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil (CAF) before tamoxifen (CAF-T) added survival benefit to treatment with tamoxifen alone. Optional tumour banking yielded specimens for determination of recurrence score by RT-PCR. In this retrospective analysis, we assessed the effect of recurrence score on disease-free survival by treatment group (tamoxifen vs CAF-T) using Cox regression, adjusting for number of positive nodes. There were 367 specimens (40% of the 927 patients in the tamoxifen and CAF-T groups) with sufficient RNA for analysis (tamoxifen, n=148; CAF-T, n=219). The recurrence score was prognostic in the tamoxifen-alone group (p=0.006; hazard ratio [HR] 2.64, 95% CI 1.33-5.27, for a 50-point difference in recurrence score). There was no benefit of CAF in patients with a low recurrence score (score or =31; log-rank p=0.033; HR 0.59, 0.35-1.01), after adjustment for number of positive nodes. The recurrence score by treatment interaction was significant in the first 5 years (p=0.029), with no additional prediction beyond 5 years (p=0.58), although the cumulative benefit remained at 10 years. Results were similar for overall survival and breast-cancer-specific survival. The recurrence score is prognostic for tamoxifen-treated patients with positive nodes and predicts significant benefit of CAF in tumours with a high recurrence score. A low recurrence

Obesity is associated with a poorer prognosis in women with hormone receptor positive breast cancer.

Science.gov (United States)

Robinson, Penelope J; Bell, Robin J; Davis, Susan R

2014-11-01

Whether moderate to severe obesity (body mass index (BMI)≥30 to women, recruited within 12 months of their diagnosis of hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) invasive breast cancer completed an enrolment questionnaire and an annual follow-up questionnaire every 12 months for another 5 years. The impact of obesity on time to either local or distant recurrence or new breast cancer, or death due to breast cancer was determined by Cox regression. Women in the most extreme categories of BMI (women, mean age, 58.4±11.6 years, 53.8% had Stage 1 disease and 88.9% received oral adjuvant endocrine therapy (OAET) within 2 years of diagnosis. The likelihood of an event was significantly associated with moderate to severe obesity (HR=1.71, 95%CI, 1.12-2.62, p=0.014), disease beyond Stage 1 (HR=2.87, 95% CI 1.73-4.75, pobesity (HR 3.23, 95%CI 1.48-7.03, p=0.003) and OAET use (HR 0.41, 95%CI 0.17-0.98, p=0.046) were significantly associated with an event. Moderate to severe obesity is associated with a poorer invasive breast cancer prognosis; this is also true for women with Stage 1 disease, and is independent of age and treatment. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Comparison of the effects of the GABAB receptor positive modulator BHF177 and the GABAB receptor agonist baclofen on anxiety-like behavior, learning, and memory in mice.

Science.gov (United States)

Li, Xia; Risbrough, Victoria B; Cates-Gatto, Chelsea; Kaczanowska, Katarzyna; Finn, M G; Roberts, Amanda J; Markou, Athina

2013-07-01

γ-Aminobutyric acid B (GABAB) receptor activation is a potential therapeutic approach for the treatment of drug addiction, pain, anxiety, and depression. However, full agonists of this receptor induce side-effects, such as sedation, muscle relaxation, tolerance, and cognitive disruption. Positive allosteric modulators (PAMs) of the GABAB receptor may have similar therapeutic effects as agonists with superior side-effect profiles. The present study behaviorally characterized N-([1R,2R,4S]-bicyclo[2.2.1]hept-2-yl)-2-methyl-5-(4-[trifluoromethyl]phenyl)-4-pyrimidinamine (BHF177), a GABAB receptor PAM, in mouse models of anxiety-like behavior, learning and memory. In addition, the effects of BHF177 were compared with the agonist baclofen. Unlike the anxiolytic chlordiazepoxide, baclofen (0.5, 1.5, and 2.5 mg/kg, intraperitoneally) and BHF177 (10, 20, and 40 mg/kg, orally) had no effect on anxiety-like behavior in the elevated plus maze, light/dark box, or Vogel conflict test. Baclofen increased punished drinking in the Vogel conflict test, but this effect may be attributable to the analgesic actions of baclofen. At the highest dose tested (2.5 mg/kg), baclofen-treated mice exhibited sedation-like effects (i.e., reduced locomotor activity) across many of the tests, whereas BHF177-treated mice exhibited no sedation-like effects. BHF177 exhibited pro-convulsion properties only in mice, but not in rats, indicating that this effect may be species-specific. At doses that were not sedative or pro-convulsant, baclofen and BHF177 had no selective effects on fear memory retrieval in contextual and cued fear conditioning or spatial learning and memory in the Barnes maze. These data suggest that BHF177 has little sedative activity, no anxiolytic-like profile, and minimal impairment of learning and memory in mice. Copyright © 2013 Elsevier Ltd. All rights reserved.

CYP19A1 polymorphisms and clinical outcomes in postmenopausal women with hormone receptor-positive breast cancer in the BIG 1-98 trial

DEFF Research Database (Denmark)

Leyland-Jones, Brian; Gray, Kathryn P; Abramovitz, Mark

2015-01-01

To determine whether CYP19A1 polymorphisms are associated with abnormal activity of aromatase and with musculoskeletal and bone side effects of aromatase inhibitors. DNA was isolated from tumor specimens of 4861 postmenopausal women with hormone receptor-positive breast cancer enrolled in the BIG 1...

Utility of the CPS+EG staging system in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer treated with neoadjuvant chemotherapy.

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Marmé, Frederik; Lederer, Bianca; Blohmer, Jens-Uwe; Costa, Serban Dan; Denkert, Carsten; Eidtmann, Holger; Gerber, Bernd; Hanusch, Claus; Hilfrich, Jörn; Huober, Jens; Jackisch, Christian; Kümmel, Sherko; Loibl, Sibylle; Paepke, Stefan; Untch, Michael; von Minckwitz, Gunter; Schneeweiss, Andreas

2016-01-01

Pathologic complete response after neoadjuvant chemotherapy (NACT) correlates with overall survival (OS) in primary breast cancer. A recently described staging system based on pre-treatment clinical stage (CS), final pathological stage (PS), estrogen receptor (ER) status and nuclear grade (NG) leads to a refined estimation of prognosis in unselected patients. Its performance in luminal type breast cancers has not been determined. This study investigates the clinical utility of this CPS+EG score when restricted to hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) patients and compares the results to a cohort of unselected patients. The CPS+EG score was calculated for 6637 unselected patients and 2454 patients with HR+/HER2- tumours who received anthracycline/taxane-based NACT within 8 prospective German trials. Five-year disease-free survival (DFS) and OS were 75.6% and 84.1% for the unselected cohort and 80.6% and 87.8% for the HR+/HER2- subgroup, respectively. The CPS+EG system distinguished different prognostic groups with 5-year DFS ranging from 0% to 91%. The CPS+EG system leads to an improved categorisation of patients by outcome compared to CS, PS, ER or NG alone. When applying the CPS+EG score to the HR+/HER2- subgroup, a shift to lower scores was observed compared to the overall population, but 5-year DFS and OS for the individual scores were identical to that observed in the overall population. In HR+/HER2- patients, the CPS+EG staging system retains its ability to facilitate a refined stratification of patients according to outcome. It can help to select candidates for post-neoadjuvant clinical trials in luminal breast cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.

High rabbit abundance proves detrimental to the population growth rate in European rabbit (Oryctolagus cuniculus L. extensive breeding enclosures

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L. Ruiz-Aizpurua

2014-09-01

Full Text Available The European rabbit (Oryctolagus cuniculus L. is a key prey species in Mediterranean ecosystems that has declined in its natural ranges as a result of diseases and loss of habitat. This situation has led to the production of wild rabbits in enclosures in which they can acclimate and breed. The efficiency of these enclosures as extensive breeding systems is defined by their population growth rate (PGR. The aim of this study is to analyse the effect of rabbit abundance on the PGR. This has been done by creating general linear models to explain autumn and spring PGR with the use of rabbit abundance estimates, enclosure size, aerial predation and previous PGR as possible explanatory variables. Rabbit abundance and enclosure size negatively affected the autumn PGR, while only rabbit abundance affected the spring PGR in the best-fit models. It is suggested that maintaining rabbit densities at fewer than 30 rabbits per hectare might help to optimise the efficiency inside enclosures.

Chemotherapy-induced amenorrhea and the resumption of menstruation in premenopausal women with hormone receptor-positive early breast cancer.

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Koga, Chinami; Akiyoshi, Sayuri; Ishida, Mayumi; Nakamura, Yoshiaki; Ohno, Shinji; Tokunaga, Eriko

2017-09-01

For premenopausal women with breast cancer, information on the effects of chemotherapy and the risk of infertility is important. In this study, the effect of chemotherapy on the ovarian function in premenopausal women with hormone receptor-positive breast cancer was investigated, with an age-stratified analysis of the appearance of amenorrhea and the resumption of menstruation after the use of chemotherapy with anthracyclines or taxanes. Premenopausal women diagnosed with operable Stage I-III hormone receptor-positive breast cancer and underwent neoadjuvant or adjuvant chemotherapy with the standard regimen of anthracyclines and/or taxanes were included. The patients were classified into age groups in 5-year increments, and the rates of chemotherapy-induced amenorrhea (CIA), resumption of menstruation, and duration of CIA after chemotherapy were analyzed. The subjects consisted of 101 patients (median age 45 years). CIA occurred in 97 (96%) patients and 40 patients resumed menstruation. In all patients aged ≤39 years menstruation restarted, whereas in all patients aged ≥50 years, menstruation did not restart. For the patients who resumed menstruation, the younger the patients, the sooner menstruation tended to restart. The resumption of menstruation occurred within 1 year for younger patients aged around 30 years, but for those aged ≥35 years, 60% of cases took around 2-3 years for resumption. The incidence of CIA, the resumption of menstruation and duration of CIA after chemotherapy depend greatly on the patient's age.

Expression of p40 (∆Np63) protein in meningiomas, an unexpected finding: immunohistochemical study and evaluation of its possible prognostic role.

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Guadagno, Elia; Del Basso De Caro, Marialaura; Pignatiello, Sara; Sciammarella, Concetta; Solari, Domenico; Cappabianca, Paolo; Maiuri, Francesco; Dones, Flavia

2016-09-01

According to the 2007 WHO (World Health Organization) Classification, meningiomas are divided into three grades of malignancy, with different recurrence rate, based exclusively on histopathological parameters. Loss/reduction of PgR (Progesterone Receptor) expression and increased Ki67 L.I. (Labeling Index) have been proven as possible prognostic factors able to predict the relapse of the disease. However, they sometimes result unreliable, especially when discordant. p40 is the short form of the p53 homologue gene p63, also named ∆Np63, and its antibody has recently been introduced as a highly specific diagnostic marker of the squamous cell carcinoma of the lung. Nevertheless its expression has been found in many other unconventional sites (e.g. placenta, urotheluim, etc). Herein we assessed the immuno-expression of p40 protein in a series of 72 meningiomas (35 grade I and 37 grade II) and analyzed its correlation with clinicopathological parameters, overall survival and recurrence free interval. We found that a high p40 score correlated with high histological grade, presence of recurrence, increased Ki67 L.I. and loss/reduction of PgR signal. Moreover, a higher expression of p40 was shown to be a significant prognostic factor for the development of recurrences and resulted a prognostic independent variable in multivariate analysis. Overall, for the first time, we investigated the expression of p40 protein in meningiomas and explored its usefulness as prognostic marker in addition to PgR and Ki67 L.I.

Fulvestrant radiosensitizes human estrogen receptor-positive breast cancer cells

International Nuclear Information System (INIS)

Wang, Jing; Yang, Qifeng; Haffty, Bruce G.; Li, Xiaoyan; Moran, Meena S.

2013-01-01

Highlights: ► Fulvestrant radiosensitizes MCF-7 cells. ► Fulvestrant increases G1 arrest and decreases S phase in MCF-7 cells. ► Fulvestrant down-regulates DNA-PKcs and RAD51 in MCF-7 cells. -- Abstract: The optimal sequencing for hormonal therapy and radiation are yet to be determined. We utilized fulvestrant, which is showing promise as an alternative to other agents in the clinical setting of hormonal therapy, to assess the cellular effects of concomitant anti-estrogen therapy (fulvestrant) with radiation (F + RT). This study was conducted to assess the effects of fulvestrant alone vs. F + RT on hormone-receptor positive breast cancer to determine if any positive or negative combined effects exist. The effects of F + RT on human breast cancer cells were assessed using MCF-7 clonogenic and tetrazolium salt colorimetric (MTT) assays. The assays were irradiated with a dose of 0, 2, 4, 6 Gy ± fulvestrant. The effects of F + RT vs. single adjuvant treatment alone on cell-cycle distribution were assessed using flow cytometry; relative expression of repair proteins (Ku70, Ku80, DNA-PKcs, Rad51) was assessed using Western Blot analysis. Cell growth for radiation alone vs. F + RT was 0.885 ± 0.013 vs. 0.622 ± 0.029 @2 Gy, 0.599 ± 0.045 vs. 0.475 ± 0.054 @4 Gy, and 0.472 ± 0.021 vs. 0.380 ± 0.018 @6 Gy RT (p = 0.003). While irradiation alone induced G2/M cell cycle arrest, the combination of F + RT induced cell redistribution in the G1 phase and produced a significant decrease in the proportion of cells in G2 phase arrest and in the S phase in breast cancer cells (p < 0.01). Furthermore, levels of repair proteins DNA-PKcs and Rad51 were significantly decreased in the cells treated with F + RT compared with irradiation alone. F + RT leads to a decrease in the surviving fraction, increased cell cycle arrest, down regulating of nonhomologous repair protein DNA-PKcs and homologous recombination repair protein RAD51. Thus, our findings suggest that F + RT

Sex-dependent anti-stress effect of an α5 subunit containing GABAA receptor positive allosteric modulator

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Sean C. Piantadosi

2016-11-01

Full Text Available Rationale: Current first-line treatments for stress-related disorders such as Major Depressive Disorder (MDD act on monoaminergic systems and take weeks to achieve a therapeutic effect with poor response and low remission rates. Recent research has implicated the GABAergic system in the pathophysiology of depression, including deficits in interneurons targeting the dendritic compartment of cortical pyramidal cells. Objectives: The present study evaluates whether SH-053-2'F-R-CH3 (denoted α5-PAM, a positive allosteric modulator selective for α5-subunit containing GABAA receptors found predominantly on cortical pyramidal cell dendrites has anti-stress effects. Methods: Female and male C57BL6/J mice were exposed to unpredictable chronic mild stress (UCMS and treated with α5-PAM acutely (30 minutes prior to assessing behavior or chronically before being assessed behaviorally. Results: Acute and chronic α5-PAM treatments produce a pattern of decreased stress-induced behaviors (denoted as behavioral emotionality across various tests in female, but not in male mice. Behavioral Z-scores calculated across a panel of tests designed to best model the range and heterogeneity of human symptomatology confirmed that acute and chronic α5-PAM treatments consistently produce significant decreases in behavioral emotionality in several independent cohorts of females. The behavioral responses to α5-PAM could not be completely accounted for by differences in drug brain disposition between female and male mice. In mice exposed to UCMS, expression of the Gabra5 gene was increased in the frontal cortex after acute treatment and in hippocampus after chronic treatment with α5-PAM in females only, and these expression changes correlated with behavioral emotionality. Conclusions: We showed that acute and chronic positive modulation of α5 subunit-containing GABAA receptors elicit anti-stress effects in a sex-dependent manner, suggesting novel therapeutic modalities.

Androgen receptor positive triple negative breast cancer: Clinicopathologic, prognostic, and predictive features.

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Kristine Astvatsaturyan

Full Text Available Overexpression of the androgen receptor (AR characterizes a distinct molecular subset of triple negative breast carcinomas (TNBC. The role of AR as a prognostic/predictive biomarker in TNBC is controversial, but increasing evidence suggests that this subset may respond to therapeutic agents targeting AR. Evaluation of AR has not been standardized, and criteria for selection of patients for antiandrogen therapy remain controversial. In this study we determine the appropriate threshold of AR immunoreactivity to define AR positive (AR+ TNBC, describe the clinicopathologic features of AR+ TNBC, and discuss the utility of AR positivity as a prognostic and predictive marker in TNBC.135 invasive TNBC processed in accordance with ASCO/CAP guidelines, were immunostained for AR. Clinicopathologic features of AR+ TNBC were analyzed and compared to AR negative (AR- TNBC. Patients' age, tumor size, tumor grade, lymph node status, proliferation rate, immunopositivity for EGFR, CK5/6, Ki-67, and disease free survival (DFS were evaluated statistically.A 1% cutpoint was confirmed as the appropriate threshold for AR positivity. Using this cutpoint 41% of 135 TNBC were AR+. AR+ TNBC occurred in older women, were larger, had lower mean proliferation rate and increased incidence of axillary metastasis than AR- TNBC. 76% of TNBC with apocrine morphology were AR+. A subset of AR+TNBC expressed basal markers (EGFR and CK5/6. A prognostic model was created.AR identifies a heterogeneous group of TNBC. Additional evaluation of EGFR expression allowed us to stratify TNBCs into 3 risk groups with significant differences in DFS and therapeutic implications: low-risk (AR+ EGFR- which represents the LAR molecular subtype with the best prognosis and may benefit the most from anti-androgen therapies; high-risk (AR- EGFR+ which represents the basal molecular subtype with the worst prognosis and may benefit the most from chemotherapy regimens; intermediate-risk (AR+EGFR+ and AR

The impact of tamoxifen on breast recurrence, cosmesis, complications, and survival in estrogen receptor-positive early-stage breast cancer

International Nuclear Information System (INIS)

Fowble, Barbara; Fein, Douglas A.; Hanlon, Alexandra L.; Eisenberg, Burton L.; Hoffman, John P.; Sigurdson, Elin R.; Daly, Mary B.; Goldstein, Lori J.

1996-01-01

Purpose: To evaluate the impact of tamoxifen on breast recurrence, cosmesis, complications, overall and cause-specific survival in women with Stage I-II breast cancer and estrogen receptor positive tumors undergoing conservative surgery and radiation. Methods and Materials: From 1982 to 1991, 491 women with estrogen receptor positive Stage I-II breast cancer underwent excisional biopsy, axillary dissection, and radiation. The median age of the patient population was 60 years with 21% < 50 years of age. The median follow-up was 5.3 years (range 0.1 to 12.8). Sixty-nine percent had T1 tumors and 83% had histologically negative axillary nodes. Reexcision was performed in 49% and the final margin of resection was negative in 64%. One hundred fifty-four patients received tamoxifen and 337 patients received no adjuvant therapy. None of the patients received adjuvant chemotherapy. Results: There were no significant differences between the two groups for age, race, clinical tumor size, histology, the use of reexcision, or median total dose to the primary. Patients who received tamoxifen were more often axillary node positive (44% tamoxifen vs. 5% no tamoxifen), and, therefore, a greater percentage received treatment to the breast and regional nodes. The tamoxifen patients less often had unknown margins of resection (9% tamoxifen vs. 22% no tamoxifen). The 5-year actuarial breast recurrence rate was 4% for the tamoxifen patients compared to 7% for patients not receiving tamoxifen (p 0.21). Tamoxifen resulted in a modest decrease in the 5-year actuarial risk of a breast recurrence in axillary node-negative patients, in those with unknown or close margins of resection, and in those who underwent a single excision. Axillary node-positive patients had a clinically significant decrease in the 5-year actuarial breast recurrence rate (21 vs. 4%; p 0.08). The 5-year actuarial rate of distant metastasis was not significantly decreased by the addition of adjuvant tamoxifen in all

The two-state dimer receptor model: a general model for receptor dimers.

Science.gov (United States)

Franco, Rafael; Casadó, Vicent; Mallol, Josefa; Ferrada, Carla; Ferré, Sergi; Fuxe, Kjell; Cortés, Antoni; Ciruela, Francisco; Lluis, Carmen; Canela, Enric I

2006-06-01

Nonlinear Scatchard plots are often found for agonist binding to G-protein-coupled receptors. Because there is clear evidence of receptor dimerization, these nonlinear Scatchard plots can reflect cooperativity on agonist binding to the two binding sites in the dimer. According to this, the "two-state dimer receptor model" has been recently derived. In this article, the performance of the model has been analyzed in fitting data of agonist binding to A(1) adenosine receptors, which are an example of receptor displaying concave downward Scatchard plots. Analysis of agonist/antagonist competition data for dopamine D(1) receptors using the two-state dimer receptor model has also been performed. Although fitting to the two-state dimer receptor model was similar to the fitting to the "two-independent-site receptor model", the former is simpler, and a discrimination test selects the two-state dimer receptor model as the best. This model was also very robust in fitting data of estrogen binding to the estrogen receptor, for which Scatchard plots are concave upward. On the one hand, the model would predict the already demonstrated existence of estrogen receptor dimers. On the other hand, the model would predict that concave upward Scatchard plots reflect positive cooperativity, which can be neither predicted nor explained by assuming the existence of two different affinity states. In summary, the two-state dimer receptor model is good for fitting data of binding to dimeric receptors displaying either linear, concave upward, or concave downward Scatchard plots.

Preclinical evaluation of a positron emitting progestin ([18F]fluoro-16 alpha-methyl-19-norprogesterone) for imaging progesterone receptor positive tumours with positron emission tomography

NARCIS (Netherlands)

Verhagen, Aalt; Luurtsema, Gert; PESSER, JW; DEGROOT, TJ; OOSTERHUIS, JW; Vaalburg, Willem; Wouda, S.

Three 21-fluoro-progestins were investigated as potential imaging agents for the in vivo assessment of human progesterone receptor positive neoplasms with positron emission tomography. In competitive binding assays these compounds demonstrated high specificity, competing only for progesterone

Prognostic and Predictive Value of the 21-Gene Recurrence Score Assay in a Randomized Trial of Chemotherapy for Postmenopausal, Node-Positive, Estrogen Receptor-Positive Breast Cancer

Science.gov (United States)

Albain, Kathy S.; Barlow, William E.; Shak, Steven; Hortobagyi, Gabriel N.; Livingston, Robert B.; Yeh, I-Tien; Ravdin, Peter; Bugarini, Roberto; Baehner, Frederick L.; Davidson, Nancy E.; Sledge, George W.; Winer, Eric P.; Hudis, Clifford; Ingle, James N.; Perez, Edith A.; Pritchard, Kathleen I.; Shepherd, Lois; Gralow, Julie R.; Yoshizawa, Carl; Allred, D. Craig; Osborne, C. Kent; Hayes, Daniel F.

2010-01-01

SUMMARY Background The 21-gene Recurrence Score assay (RS) is prognostic for women with node-negative, estrogen receptor (ER)-positive breast cancer (BC) treated with tamoxifen. A low RS predicts little benefit of chemotherapy. For node-positive BC, we investigated whether RS was prognostic in women treated with tamoxifen alone and whether it identified those who might not benefit from anthracycline-based chemotherapy, despite higher recurrence risks. Methods The phase III trial S8814 for postmenopausal women with node-positive, ER-positive BC showed that CAF chemotherapy prior to tamoxifen (CAF-T) added survival benefit to tamoxifen alone. Optional tumor banking yielded specimens for RS determination by RT-PCR. We evaluated the effect of RS on disease-free survival (DFS) by treatment group (tamoxifen versus CAF-T) using Cox regression adjusting for number of positive nodes. Findings There were 367 specimens (40% of parent trial) with sufficient RNA (tamoxifen, 148; CAF-T, 219). The RS was prognostic in the tamoxifen arm (p=0.006). There was no CAF benefit in the low RS group (logrank p=0.97; HR=1.02, 95% CI (0.54,1.93)), but major DFS improvement for the high RS subset (logrank p=.03; HR=0.59, 95% CI (0.35, 1.01)), adjusting for number of positive nodes. The RS-by-treatment interaction was significant in the first 5 years (p=0.029), with no additional prediction beyond 5 years (p=0.58), though the cumulative benefit remained at 10 years. Results were similar for overall survival and BC-specific survival. Interpretation In this retrospective analysis, the RS is prognostic for tamoxifen-treated patients with positive nodes and predicts significant CAF benefit in tumors with a high RS. A low RS identifies women who may not benefit from anthracycline-based chemotherapy despite positive nodes. PMID:20005174

Influence of Plant Growth Retardants on Quality of Codonopsis Radix

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Yinyin Liao

2017-10-01

Full Text Available Plant growth retardant (PGR refers to organics that can inhibit the cell division of plant stem tip sub-apical meristem cells or primordial meristem cell. They are widely used in the cultivation of rhizomatous functional plants; such as Codonopsis Radix, that is a famous Chinese traditional herb. However, it is still unclear whether PGR affects the medicinal quality of C. Radix. In the present study, amino acid analyses, targeted and non-targeted analyses by ultra-performance liquid chromatography combined with time-of-flight mass spectrometry (UPLC-TOF-MS and gas chromatography-MS were used to analyze and compare the composition of untreated C. Radix and C. Radix treated with PGR. The contents of two key bioactive compounds, lobetyolin and atractylenolide III, were not affected by PGR treatment. The amounts of polysaccharides and some internal volatiles were significantly decreased by PGR treatment; while the free amino acids content was generally increased. Fifteen metabolites whose abundance were affected by PGR treatment were identified by UPLC-TOF-MS. Five of the up-regulated compounds have been reported to show immune activity, which might contribute to the healing efficacy (“buqi” of C. Radix. The results of this study showed that treatment of C. Radix with PGR during cultivation has economic benefits and affected some main bioactive compounds in C. Radix.

Mechanism of pyrogallol red oxidation induced by free radicals and reactive oxidant species. A kinetic and spectroelectrochemistry study.

Science.gov (United States)

Atala, E; Velásquez, G; Vergara, C; Mardones, C; Reyes, J; Tapia, R A; Quina, F; Mendes, M A; Speisky, H; Lissi, E; Ureta-Zañartu, M S; Aspée, A; López-Alarcón, C

2013-05-02

Pyrogallol red (PGR) presents high reactivity toward reactive (radical and nonradical) species (RS). This property of PGR, together with its characteristic spectroscopic absorption in the visible region, has allowed developing methodologies aimed at evaluating the antioxidant capacity of foods, beverages, and human fluids. These methods are based on the evaluation of the consumption of PGR induced by RS and its inhibition by antioxidants. However, at present, there are no reports regarding the degradation mechanism of PGR, limiting the extrapolation to how antioxidants behave in different systems comprising different RS. In the present study, we evaluate the kinetics of PGR consumption promoted by different RS (peroxyl radicals, peroxynitrite, nitrogen dioxide, and hypochlorite) using spectroscopic techniques and detection of product by HPLC mass spectrometry. The same pattern of oxidation and spectroscopic properties of the products is observed, independently of the RS employed. Mass analysis indicates the formation of only one product identified as a quinone derivative, excluding the formation of peroxides or hydroperoxides and/or chlorinated compounds, in agreement with FOX's assays and oxygen consumption experiments. Cyclic voltammetry, carried out at different pH's, shows an irreversible oxidation of PGR, indicating the initial formation of a phenoxy radical and a second charge transfer reaction generating an ortho-quinone derivative. Spectroelectrochemical oxidation of PGR shows oxidation products with identical UV-visible absorption properties to those observed in RS-induced oxidation.

Prognostic significance of urokinase plasminogen activator and plasminogen activator inhibitor-1 mRNA expression in lymph node- and hormone receptor-positive breast cancer

International Nuclear Information System (INIS)

Leissner, Philippe; Verjat, Thibault; Bachelot, Thomas; Paye, Malick; Krause, Alexander; Puisieux, Alain; Mougin, Bruno

2006-01-01

One of the most thoroughly studied systems in relation to its prognostic relevance in patients with breast cancer, is the plasminogen activation system that comprises of, among others, the urokinase Plasminogen Activator (uPA) and its main inhibitor, the Plasminogen Activator Inhibitor-1 (PAI-1). In this study, we investigated the prognostic value of uPA and PAI-1 at the mRNA level in lymph node- and hormone receptor-positive breast cancer. The study included a retrospective series of 87 patients with hormone-receptor positive and axillary lymph node-positive breast cancer. All patients received radiotherapy, adjuvant anthracycline-based chemotherapy and five years of tamoxifen treatment. The median patient age was 54 and the median follow-up time was 79 months. Distant relapse occurred in 30 patients and 22 patients died from breast cancer during follow-up. We investigated the prognostic value of uPA and PAI-1 at the mRNA level as measured by real-time quantitative RT-PCR. uPA and PAI-1 gene expression was not found to be correlated with any of the established clinical and pathological factors. Metastasis-free Survival (MFS) and Breast Cancer specific Survival (BCS) were significantly shorter in patients expressing high levels of PAI-1 mRNA (p < 0.0001; p < 0.0001; respectively). In Cox multivariate analysis, the level of PAI-1 mRNA appeared to be the strongest prognostic factor for MFS (Hazard Ratio (HR) = 10.12; p = 0.0002) and for BCS (HR = 13.17; p = 0.0003). Furthermore, uPA gene expression was not significantly associated neither with MFS (p = 0.41) nor with BCS (p = 0.19). In a Cox-multivariate regression analysis, uPA expression did not demonstrate significant independent prognostic value. These findings indicate that high PAI-1 mRNA expression represents a strong and independent unfavorable prognostic factor for the development of metastases and for breast cancer specific survival in a population of hormone receptor- and lymph node-positive breast cancer

Prognostic significance of urokinase plasminogen activator and plasminogen activator inhibitor-1 mRNA expression in lymph node- and hormone receptor-positive breast cancer

Directory of Open Access Journals (Sweden)

Krause Alexander

2006-08-01

Full Text Available Abstract Background One of the most thoroughly studied systems in relation to its prognostic relevance in patients with breast cancer, is the plasminogen activation system that comprises of, among others, the urokinase Plasminogen Activator (uPA and its main inhibitor, the Plasminogen Activator Inhibitor-1 (PAI-1. In this study, we investigated the prognostic value of uPA and PAI-1 at the mRNA level in lymph node- and hormone receptor-positive breast cancer. Methods The study included a retrospective series of 87 patients with hormone-receptor positive and axillary lymph node-positive breast cancer. All patients received radiotherapy, adjuvant anthracycline-based chemotherapy and five years of tamoxifen treatment. The median patient age was 54 and the median follow-up time was 79 months. Distant relapse occurred in 30 patients and 22 patients died from breast cancer during follow-up. We investigated the prognostic value of uPA and PAI-1 at the mRNA level as measured by real-time quantitative RT-PCR. Results uPA and PAI-1 gene expression was not found to be correlated with any of the established clinical and pathological factors. Metastasis-free Survival (MFS and Breast Cancer specific Survival (BCS were significantly shorter in patients expressing high levels of PAI-1 mRNA (p PAI-1 mRNA appeared to be the strongest prognostic factor for MFS (Hazard Ratio (HR = 10.12; p = 0.0002 and for BCS (HR = 13.17; p = 0.0003. Furthermore, uPA gene expression was not significantly associated neither with MFS (p = 0.41 nor with BCS (p = 0.19. In a Cox-multivariate regression analysis, uPA expression did not demonstrate significant independent prognostic value. Conclusion These findings indicate that high PAI-1 mRNA expression represents a strong and independent unfavorable prognostic factor for the development of metastases and for breast cancer specific survival in a population of hormone receptor- and lymph node-positive breast cancer patients.

Selective and interactive effects of D2 receptor antagonism and positive allosteric mGluR4 modulation on waiting impulsivity.

Science.gov (United States)

Isherwood, Sarah N; Robbins, Trevor W; Nicholson, Janet R; Dalley, Jeffrey W; Pekcec, Anton

2017-09-01

Metabotropic glutamate receptor 4 (mGluR4) and dopamine D 2 receptors are specifically expressed within the indirect pathway neurons of the striato-pallidal-subthalamic pathway. This unique expression profile suggests that mGluR4 and D 2 receptors may play a cooperative role in the regulation and inhibitory control of behaviour. We investigated this possibility by testing the effects of a functionally-characterised positive allosteric mGluR4 modulator, 4-((E)-styryl)-pyrimidin-2-ylamine (Cpd11), both alone and in combination with the D 2 receptor antagonist eticlopride, on two distinct forms of impulsivity. Rats were trained on the five-choice serial reaction time task (5-CSRTT) of sustained visual attention and segregated according to low, mid, and high levels of motor impulsivity (LI, MI and HI, respectively), with unscreened rats used as an additional control group. A separate group of rats was trained on a delay discounting task (DDT) to assess choice impulsivity. Systemic administration of Cpd11 dose-dependently increased motor impulsivity and impaired attentional accuracy on the 5-CSRTT in all groups tested. Eticlopride selectively attenuated the increase in impulsivity induced by Cpd11, but not the accompanying attentional impairment, at doses that had no significant effect on behavioural performance when administered alone. Cpd11 also decreased choice impulsivity on the DDT (i.e. increased preference for the large, delayed reward) and decreased locomotor activity. These findings demonstrate that mGluR4s, in conjunction with D 2 receptors, affect motor- and choice-based measures of impulsivity, and therefore may be novel targets to modulate impulsive behaviour associated with a number of neuropsychiatric syndromes. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Determination of HER2 phosphorylation at tyrosine 1221/1222 improves prediction of poor survival for breast cancer patients with hormone receptor-positive tumors

DEFF Research Database (Denmark)

Frogne, Thomas; Laenkholm, Anne-Vibeke; Lyng, Maria B

2009-01-01

INTRODUCTION: High expression of total HER2 protein confers poor prognosis for breast cancer patients. HER2 is a member of the HER family consisting of four receptors, HER1 to HER4. HER receptor activity is regulated by a variety of mechanisms, and phosphorylation of the C-terminal part of the HER...... metastases, by evaluating the expression of phosphorylated HER1, HER2, HER3, Erk, Akt and the total level of HER4 and HER2. METHODS: Immunohistochemical analysis was performed on 268 primary breast tumors and 30 paired metastatic lesions from postmenopausal women with hormone receptor-positive breast tumors...... of Akt and Erk were quite uniformly expressed in the categories; negative, moderate or strong. In univariate analysis, expression of total HER2, pHER1, pHER2 and pHER3 was significantly associated with poor disease-free survival. Strong HER4 expression was associated with prolonged disease-free as well...

An Improved Path-Generating Regulator for Two-Wheeled Robots to Track the Circle/Arc Passage

Directory of Open Access Journals (Sweden)

Jun Dai

2014-01-01

Full Text Available The improved path-generating regulator (PGR is proposed to path track the circle/arc passage for two-wheeled robots. The PGR, which is a control method for robots so as to orient its heading toward the tangential direction of one of the curves belonging to the family of path functions, is applied to navigation problem originally. Driving environments for robots are usually roads, streets, paths, passages, and ridges. These tracks can be seen as they consist of straight lines and arcs. In the case of small interval, arc can be regarded as straight line approximately; therefore we extended the PGR to drive the robot move along circle/arc passage based on the theory that PGR to track the straight passage. In addition, the adjustable look-ahead method is proposed to improve the robot trajectory convergence property to the target circle/arc. The effectiveness is proved through MATLAB simulations on both the comparisons with the PGR and the improved PGR with adjustable look-ahead method. The results of numerical simulations show that the adjustable look-ahead method has better convergence property and stronger capacity of resisting disturbance.

Comparative Functional Alanine Positional Scanning of the α-Melanocyte Stimulating Hormone and NDP-Melanocyte Stimulating Hormone Demonstrates Differential Structure-Activity Relationships at the Mouse Melanocortin Receptors.

Science.gov (United States)

Todorovic, Aleksandar; Ericson, Mark D; Palusak, Ryan D; Sorensen, Nicholas B; Wood, Michael S; Xiang, Zhimin; Haskell-Luevano, Carrie

2016-07-20

The melanocortin system has been implicated in the regulation of various physiological functions including melanogenesis, steroidogenesis, energy homeostasis, and feeding behavior. Five melanocortin receptors have been identified to date and belong to the family of G protein-coupled receptors (GPCR). Post-translational modification of the proopiomelanocortin (POMC) prohormone leads to the biosynthesis of the endogenous melanocortin agonists, including α-melanocyte stimulating hormone (α-MSH), β-MSH, γ-MSH, and adrenocorticotropic hormone (ACTH). All the melanocortin agonists derived from the POMC prohormone contain a His-Phe-Arg-Trp tetrapeptide sequence that has been implicated in eliciting the pharmacological responses at the melanocortin receptors. Herein, an alanine (Ala) positional scan is reported for the endogenous α-MSH ligand and the synthetic, more potent, NDP-MSH peptide (Ac-Ser(1)-Tyr(2)-Ser(3)-Nle(4)-Glu(5)-His(6)-DPhe(7)-Arg(8)-Trp(9)-Gly(10)-Lys(11)-Pro(12)-Val(13)-NH2) at the cloned mouse melanocortin receptors to test the assumption that the structure-activity relationships of one ligand would apply to the other. Several residues outside of the postulated pharmacophore altered potency at the melanocortin receptors, most notably the 1560-, 37-, and 15-fold potency loss when the Glu(5) position of α-MSH was substituted with Ala at the mMC1R, mMC3R, and mMC4R, respectively. Importantly, the altered potencies due to Ala substitutions in α-MSH did not necessarily correlate with equivalent Ala substitutions in NDP-MSH, indicating that structural modifications and corresponding biological activities in one of these melanocortin ligands may not be predictive for the other agonist.

Estrogen-related receptor beta interacts with Oct4 to positively regulate Nanog gene expression

NARCIS (Netherlands)

D.L.C. van den Berg (Debbie); W. Zhang (Wensheng); A. Yates (Adam); M.P. Engelen (Erik); K. Takacs (Katalin); K. Bezstarosti (Karel); J.A.A. Demmers (Jeroen); I. Chambers (Ian); R.A. Poor (Raymond)

2008-01-01

textabstractEmbryonic stem (ES) cell self-renewal is regulated by transcription factors, including Oct4, Sox2, and Nanog. A number of additional transcriptional regulators of ES cell self-renewal have recently been identified, including the orphan nuclear receptor estrogen-related receptor beta

Molecular analysis of the androgen-receptor gene in a family with receptor-positive partial androgen insensitivity: an unusual type of intronic mutation

NARCIS (Netherlands)

H.T. Brüggenwirth (Hennie); A.L.M. Boehmer (Annemie); S. Ramnarain; M.C. Verleun-Mooijman; D.P.E. Satijn (David); J. Trapman (Jan); J.A. Grootegoed (Anton); A.O. Brinkmann (Albert)

1997-01-01

textabstractIn the coding part and the intron-exon boundaries of the androgen-receptor gene of a patient with partial androgen insensitivity, no mutation was found. The androgen receptor of this patient displayed normal ligand-binding parameters and migrated as a

Preparation and biological evaluation of [(99m)Tc/EDDA/Tricine/HYNIC(0), BzThi(3)]-octreotide for somatostatin receptor-positive tumor imaging.

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Erfani, Mostafa; Shafiei, Mohammad; Mazidi, Mohammad; Goudarzi, Mostafa

2013-04-01

Somatostatin-derived analogues play an important role in the diagnosis and treatment of neuroendocrine tumors. The aim of this study was to evaluate a new somatostatin analogue designed for labeling with (99m)Tc: [6-hydrazinopyridine-3-carboxylic acid (HYNIC(0)), β-(3-benzothienyl)-Ala (BzThi(3))]-octreotide ([HYNIC]-BOC), using ethylenediamine-N,N'-diacetic acid (EDDA) and tricine as coligands. Synthesis was performed on a solid phase using a standard Fmoc strategy. The HYNIC-peptide conjugate was radiolabeled with (99m)Tc and characterized by ITLC and high-performance liquid chromatography (HPLC). In vitro studies were carried out in sstr2 expressing AR4-2J cell lines. In vivo distribution studies were performed in rats bearing the AR4-2J tumor. The radiolabeled complex could be prepared at high-specific activities and >95% radiochemical yield as determined by HPLC. The peptide conjugate showed high-affinity binding for sstr2. The radioligand showed high and specific internalization into AR4-2J cells (18.19%±0.21% at 4 hours). In vivo distribution studies in rats bearing tumor have shown a receptor-specific uptake of radioactivity in somatostatin receptor-positive organs. After 4 hours, uptake in the AR4-2J tumor was 1.71%±0.36% injected dose per gram tissue (%ID/g). These data show that [(99m)Tc/EDDA/Tricine/HYNIC(0), BzThi(3)]-octreotide is a specific radioligand for the somatostatin receptor-positive tumors and is a suitable candidate for clinical studies.

Impact of palbociclib combinations on treatment of advanced estrogen receptor-positive/human epidermal growth factor 2-negative breast cancer

Directory of Open Access Journals (Sweden)

Boér K

2016-10-01

Full Text Available Katalin Boér Department of Medical Oncology, Szent Margit Hospital, Budapest, Hungary Abstract: Breast cancer is a heterogeneous disease with multiple subgroups based on clinical and molecular characteristics. For the largest subgroup of breast cancers, hormone receptor-positive/human epidermal growth factor 2 (HER2-negative tumors, hormone treatment is the mainstay of therapy and is likely to result in significant improvement in disease outcomes. However, some of these cancers demonstrate de novo or acquired resistance to endocrine therapy. Despite intensive research to develop new strategies to enhance the efficacy of currently available treatment options for hormone receptor-positive breast cancer, progress has been slow, and there were few advances for a period of 10 years. In 2012, a new molecularly targeted therapeutic strategy, inhibition of mammalian target of rapamycin with everolimus, was introduced into clinical practice. Everolimus, in combination with a steroidal aromatase inhibitor, exemestane, resulted in an increase in progression-free survival, but not overall survival in patients with estrogen receptor (ER+ve advanced disease who had progressed on hormone therapy. In 2015, the first cyclin-dependent kinases 4/6 (CDK4/6 inhibitor, palbociclib, received accelerated US Food and Drug Administration approval for use in combination with letrozole for the treatment of postmenopausal ER+ve/HER2-ve advanced breast cancer as initial, endocrine-based therapy. The addition of palbociclib to endocrine therapy resulted in longer progression-free survival than letrozole alone. One year later, palbociclib received a new indication, use in combination with fulvestrant, in both premenopausal and postmenopausal females with advanced breast cancer of the same subtype with disease progression following endocrine therapy. Adding palbociclib to fulvestrant resulted in a significantly increased median progression-free survival compared to fulvestrant

Technical validation of an RT-qPCR in vitro diagnostic test system for the determination of breast cancer molecular subtypes by quantification of ERBB2, ESR1, PGR and MKI67 mRNA levels from formalin-fixed paraffin-embedded breast tumor specimens.

Science.gov (United States)

Laible, Mark; Schlombs, Kornelia; Kaiser, Katharina; Veltrup, Elke; Herlein, Stefanie; Lakis, Sotiris; Stöhr, Robert; Eidt, Sebastian; Hartmann, Arndt; Wirtz, Ralph M; Sahin, Ugur

2016-07-07

MammaTyper is a novel CE-marked in vitro diagnostic RT-qPCR assay which assigns routinely processed breast cancer specimens into the molecular subtypes Luminal A-like, Luminal B-like (HER2 positive or negative), HER2 positive (non-luminal) and Triple negative (ductal) according to the mRNA expression of ERBB2, ESR1, PGR and MKI67 and the St Gallen consensus surrogate clinical definition. Until now and regarding formalin-fixed, paraffin-embedded material (FFPE), this has been a task mostly accomplished by immunohistochemistry (IHC). However the discrepancy rates of IHC for the four breast cancer biomarkers are frequently under debate, especially for Ki-67 which carries the highest degree of inter- and even intra-observer variability. Herein we describe a series of studies in FFPE specimens which aim to fully validate the analytical performance of the MammaTyper assay, including the site to site reproducibility of the individual marker measurements. Tumor RNA was extracted with the novel RNXtract RNA extraction kit. Synthetic RNA was used to assess the sensitivity of the RNXtract kit. DNA and RNA specific qPCR assays were used so as to determine analyte specificity of RNXtract. For the assessment of limit of blank, limit of detection, analytical measurement range and PCR efficiency of the MammaTyper kit serial dilutions of samples were used. Analytical precision studies of MammaTyper were built around two different real time PCR platforms and involved breast tumor samples belonging to different subtypes analyzed across multiple sites and under various stipulated conditions. The MammaTyper assay robustness was tested against RNA input variations, alternative extraction methods and tumor cell content. Individual assays were linear up to at least 32.33 and 33.56 Cqs (quantification cycles) for the two qPCR platforms tested. PCR efficiency ranged from 99 to 109 %. In qPCR platform 1, estimates for assay specific inter-site standard deviations (SD) were between 0.14 and

Technical validation of an RT-qPCR in vitro diagnostic test system for the determination of breast cancer molecular subtypes by quantification of ERBB2, ESR1, PGR and MKI67 mRNA levels from formalin-fixed paraffin-embedded breast tumor specimens

International Nuclear Information System (INIS)

Laible, Mark; Schlombs, Kornelia; Kaiser, Katharina; Veltrup, Elke; Herlein, Stefanie; Lakis, Sotiris; Stöhr, Robert; Eidt, Sebastian; Hartmann, Arndt; Wirtz, Ralph M.; Sahin, Ugur

2016-01-01

MammaTyper is a novel CE-marked in vitro diagnostic RT-qPCR assay which assigns routinely processed breast cancer specimens into the molecular subtypes Luminal A-like, Luminal B-like (HER2 positive or negative), HER2 positive (non-luminal) and Triple negative (ductal) according to the mRNA expression of ERBB2, ESR1, PGR and MKI67 and the St Gallen consensus surrogate clinical definition. Until now and regarding formalin-fixed, paraffin-embedded material (FFPE), this has been a task mostly accomplished by immunohistochemistry (IHC). However the discrepancy rates of IHC for the four breast cancer biomarkers are frequently under debate, especially for Ki-67 which carries the highest degree of inter- and even intra-observer variability. Herein we describe a series of studies in FFPE specimens which aim to fully validate the analytical performance of the MammaTyper assay, including the site to site reproducibility of the individual marker measurements. Tumor RNA was extracted with the novel RNXtract RNA extraction kit. Synthetic RNA was used to assess the sensitivity of the RNXtract kit. DNA and RNA specific qPCR assays were used so as to determine analyte specificity of RNXtract. For the assessment of limit of blank, limit of detection, analytical measurement range and PCR efficiency of the MammaTyper kit serial dilutions of samples were used. Analytical precision studies of MammaTyper were built around two different real time PCR platforms and involved breast tumor samples belonging to different subtypes analyzed across multiple sites and under various stipulated conditions. The MammaTyper assay robustness was tested against RNA input variations, alternative extraction methods and tumor cell content. Individual assays were linear up to at least 32.33 and 33.56 Cqs (quantification cycles) for the two qPCR platforms tested. PCR efficiency ranged from 99 to 109 %. In qPCR platform 1, estimates for assay specific inter-site standard deviations (SD) were between 0.14 and 0

Sex steroid receptor expression in idiopathic pulmonary fibrosis.

Science.gov (United States)

Mehrad, Mitra; Trejo Bittar, Humberto E; Yousem, Samuel A

2017-08-01

Usual interstitial pneumonia (UIP) is characterized by progressive scarring of the lungs and is associated with high morbidity and mortality despite therapeutic interventions. Sex steroid receptors have been demonstrated to play an important role in chronic lung conditions; however, their significance is unknown in patients with UIP. We retrospectively reviewed 40 idiopathic UIP cases for the expression of hormonal receptors. Forty cases including 10 normal lung, 10 cryptogenic organizing pneumonia, 10 idiopathic organizing diffuse alveolar damage, 7 hypersensitivity pneumonitis, and 3 nonspecific interstitial pneumonitis served as controls. Immunohistochemistry for estrogen receptor α, progesterone receptor (PR), and androgen receptor was performed in all groups. Expression of these receptors was assessed in 4 anatomic/pathologic compartments: alveolar and bronchiolar epithelium, arteries/veins, fibroblastic foci/airspace organization, and old scar. All UIPs (100%) stained positive for PR in myofibroblasts in the scarred areas, whereas among the control cases, only 1 nonspecific interstitial pneumonitis case stained focally positive and the rest were negative. PR was positive in myocytes of the large-sized arteries within the fibrotic areas in 31 cases (77.5%). PR was negative within the alveolar and bronchial epithelium, airspace organization, and center of fibroblastic foci; however, weak PR positivity was noted in the peripheral fibroblasts of the fibroblastic foci where they merged with dense fibrous connective tissue scar. All UIP and control cases were negative for androgen receptor and estrogen receptor α. This is the first study to show the expression of PR within the established fibrotic areas of UIP, indicating that progesterone may have profibrotic effects in UIP patients. Hormonal therapy by targeting PR could be of potential benefit in patients with UIP/IPF. Copyright © 2017 Elsevier Inc. All rights reserved.

Nuclear Receptors, RXR, and the Big Bang.

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Evans, Ronald M; Mangelsdorf, David J

2014-03-27

Isolation of genes encoding the receptors for steroids, retinoids, vitamin D, and thyroid hormone and their structural and functional analysis revealed an evolutionarily conserved template for nuclear hormone receptors. This discovery sparked identification of numerous genes encoding related proteins, termed orphan receptors. Characterization of these orphan receptors and, in particular, of the retinoid X receptor (RXR) positioned nuclear receptors at the epicenter of the "Big Bang" of molecular endocrinology. This Review provides a personal perspective on nuclear receptors and explores their integrated and coordinated signaling networks that are essential for multicellular life, highlighting the RXR heterodimer and its associated ligands and transcriptional mechanism. Copyright © 2014 Elsevier Inc. All rights reserved.

Positively charged residues at the five-fold symmetry axis of cell culture-adapted foot-and-mouth disease virus permit novel receptor interactions.

Science.gov (United States)

Berryman, Stephen; Clark, Stuart; Kakker, Naresh K; Silk, Rhiannon; Seago, Julian; Wadsworth, Jemma; Chamberlain, Kyle; Knowles, Nick J; Jackson, Terry

2013-08-01

Field isolates of foot-and-mouth disease virus (FMDV) have a restricted cell tropism which is limited by the need for certain RGD-dependent integrin receptors. In contrast, cell culture-adapted viruses use heparan sulfate (HS) or other unidentified molecules as receptors to initiate infection. Here, we report several novel findings resulting from cell culture adaptation of FMDV. In cell culture, a virus with the capsid of the A/Turkey/2/2006 field isolate gained the ability to infect CHO and HS-deficient CHO cells as a result of a single glutamine (Q)-to-lysine (K) substitution at VP1-110 (VP1-(Q)110(K)). Using site-directed mutagenesis, the introduction of lysine at this same site also resulted in an acquired ability to infect CHO cells by type O and Asia-1 FMDV. However, this ability appeared to require a second positively charged residue at VP1-109. CHO cells express two RGD-binding integrins (α5β1 and αvβ5) that, although not used by FMDV, have the potential to be used as receptors; however, viruses with the VP1-(Q)110(K) substitution did not use these integrins. In contrast, the VP1-(Q)110(K) substitution appeared to result in enhanced interactions with αvβ6, which allowed a virus with KGE in place of the normal RGD integrin-binding motif to use αvβ6 as a receptor. Thus, our results confirmed the existence of nonintegrin, non-HS receptors for FMDV on CHO cells and revealed a novel, non-RGD-dependent use of αvβ6 as a receptor. The introduction of lysine at VP1-110 may allow for cell culture adaptation of FMDV by design, which may prove useful for vaccine manufacture when cell culture adaptation proves intractable.

Positively Charged Residues at the Five-Fold Symmetry Axis of Cell Culture-Adapted Foot-and-Mouth Disease Virus Permit Novel Receptor Interactions

Science.gov (United States)

Berryman, Stephen; Clark, Stuart; Kakker, Naresh K.; Silk, Rhiannon; Seago, Julian; Wadsworth, Jemma; Chamberlain, Kyle; Knowles, Nick J.

2013-01-01

Field isolates of foot-and-mouth disease virus (FMDV) have a restricted cell tropism which is limited by the need for certain RGD-dependent integrin receptors. In contrast, cell culture-adapted viruses use heparan sulfate (HS) or other unidentified molecules as receptors to initiate infection. Here, we report several novel findings resulting from cell culture adaptation of FMDV. In cell culture, a virus with the capsid of the A/Turkey/2/2006 field isolate gained the ability to infect CHO and HS-deficient CHO cells as a result of a single glutamine (Q)-to-lysine (K) substitution at VP1-110 (VP1-Q110K). Using site-directed mutagenesis, the introduction of lysine at this same site also resulted in an acquired ability to infect CHO cells by type O and Asia-1 FMDV. However, this ability appeared to require a second positively charged residue at VP1-109. CHO cells express two RGD-binding integrins (α5β1 and αvβ5) that, although not used by FMDV, have the potential to be used as receptors; however, viruses with the VP1-Q110K substitution did not use these integrins. In contrast, the VP1-Q110K substitution appeared to result in enhanced interactions with αvβ6, which allowed a virus with KGE in place of the normal RGD integrin-binding motif to use αvβ6 as a receptor. Thus, our results confirmed the existence of nonintegrin, non-HS receptors for FMDV on CHO cells and revealed a novel, non-RGD-dependent use of αvβ6 as a receptor. The introduction of lysine at VP1-110 may allow for cell culture adaptation of FMDV by design, which may prove useful for vaccine manufacture when cell culture adaptation proves intractable. PMID:23740982

Disease management patterns for postmenopausal women in Europe with hormone-receptor-positive, human epidermal growth factor receptor-2 negative advanced breast cancer.

Science.gov (United States)

André, Fabrice; Neven, Patrick; Marinsek, Nina; Zhang, Jie; Baladi, Jean-Francois; Degun, Ravi; Benelli, Giancarlo; Saletan, Stephen; Jerusalem, Guy

2014-06-01

International guidelines for hormone-receptor-positive (HR(+)), human epidermal growth factor receptor-2 negative (HER2(-)) advanced breast cancer (BC) recommend sequential lines of hormonal therapy (HT), and only recommend chemotherapy for patients with extensive visceral involvement or rapidly progressive disease. This study evaluated actual physician-reported treatments for advanced BC in Europe. We conducted a retrospective chart review of 355 postmenopausal women with HR(+), HER2(-) advanced BC who progressed on ≥1 line of HT (adjuvant or advanced) and completed ≥1 line of chemotherapy (advanced). Treatment choice was evaluated for each line of therapy. Of 355 patients, 111 (31%) received first-line chemotherapy, whereas 218 (61%) and 26 (7%) switched from HT to chemotherapy in second and third line, respectively. More patients receiving first-line HT had bone metastases (73% vs 27% chemotherapy). Patients treated with first-line chemotherapy had more brain (12% vs 3% HT) or extensive liver (13% vs 6% HT) metastases. Subgroup analysis of 188 patients who received first-line HT and had de novo advanced BC or relapsed/recurrent disease more than 1 year after adjuvant therapy found that the majority (89%; n = 167) of these patients switched to chemotherapy in second line. However, among these 167 patients, 27% had no significant changes in metastases between first and second line. Among the 73% of patients who had significant changes in metastases, 20% had no brain metastases or extensive visceral disease. Our study suggests that the guideline-recommended use of multiple HT lines is open to interpretation and that optimal treatment for European postmenopausal women with HR(+), HER2(-) advanced BC who responded to HT may not be achieved.

Differences in expression of the cancer stem cell marker aldehyde dehydrogenase 1 among estrogen receptor-positive/human epidermal growth factor receptor type 2-negative breast cancer cases with early, late, and no recurrence.

Science.gov (United States)

Miyoshi, Yuichiro; Shien, Tadahiko; Ogiya, Akiko; Ishida, Naoko; Yamazaki, Kieko; Horii, Rie; Horimoto, Yoshiya; Masuda, Norikazu; Yasojima, Hiroyuki; Inao, Touko; Osako, Tomofumi; Takahashi, Masato; Tomioka, Nobumoto; Endo, Yumi; Hosoda, Mitsuchika; Doihara, Hiroyoshi; Miyoshi, Shinichiro; Yamashita, Hiroko

2016-07-02

The significance of the expression of aldehyde dehydrogenase 1 (ALDH1), a cancer stem cell marker, for predicting the recurrence of estrogen receptor (ER)-positive/human epidermal growth factor receptor type 2 (HER2)-negative breast cancer is still poorly understood. The value of ALDH1 in predicting the time of recurrence remains unknown. In total, 184 patients with early distant recurrence, 134 patients with late distant recurrence, and 321 control patients without recurrence for more than 10 years after starting initial treatment for ER-positive/HER2-negative breast cancer, registered in 9 institutions, were analyzed. We assessed relationships between ALDH1 and other clinicopathological features, and ALDH1 expression was compared among the three groups. The relationship between ALDH1 expression and overall survival after recurrence was also evaluated in each group. The rates of ALDH1 expression positivity (more than 1 %) in the early, late, and no recurrence groups were 18.4 %, 13.4 %, and 8.4 %, respectively. ALDH1 expression correlated significantly with lymph node metastases (p = 0.048) and the Ki-67 labeling index (p factor independently predicting overall survival after the detection of recurrence (adjusted OR 1.451, 95 % CI 0.985-2.085, p = 0.059). Among patients with ER-positive/HER2-negative breast cancer, ALDH1 expression was more common in those with early recurrence, and this expression was found to be associated with a more aggressive breast cancer phenotype than that in the patients without recurrence. Further study is needed to clarify the prognostic significance of the heterogeneity of cancer stem cells and to confirm their role in resistance to chemotherapy.

Height, age at menarche and risk of hormone receptor-positive and -negative breast cancer: a cohort study.

Science.gov (United States)

Ritte, Rebecca; Lukanova, Annekatrin; Tjønneland, Anne; Olsen, Anja; Overvad, Kim; Mesrine, Sylvie; Fagherazzi, Guy; Dossus, Laure; Teucher, Birgit; Steindorf, Karen; Boeing, Heiner; Aleksandrova, Krasimira; Trichopoulou, Antonia; Lagiou, Pagona; Trichopoulos, Dimitrios; Palli, Domenico; Grioni, Sara; Mattiello, Amalia; Tumino, Rosario; Sacerdote, Carlotta; Quirós, José Ramón; Buckland, Genevieve; Molina-Montes, Esther; Chirlaque, María-Dolores; Ardanaz, Eva; Amiano, Pilar; Bueno-de-Mesquita, Bas; van Duijnhoven, Franzel; van Gils, Carla H; Peeters, Petra Hm; Wareham, Nick; Khaw, Kay-Tee; Key, Timothy J; Travis, Ruth C; Krum-Hansen, Sanda; Gram, Inger Torhild; Lund, Eiliv; Sund, Malin; Andersson, Anne; Romieu, Isabelle; Rinaldi, Sabina; McCormack, Valerie; Riboli, Elio; Kaaks, Rudolf

2013-06-01

Associations of breast cancer overall with indicators of exposures during puberty are reasonably well characterized; however, uncertainty remains regarding the associations of height, leg length, sitting height and menarcheal age with hormone receptor-defined malignancies. Within the European Prospective Investigation into Cancer and Nutrition cohort, Cox proportional hazards models were used to describe the relationships of adult height, leg length and sitting height and age at menarche with risk of estrogen and progesterone receptor negative (ER-PR-) (n = 990) and ER+PR+ (n = 3,524) breast tumors. Height as a single risk factor was compared to a model combining leg length and sitting height. The possible interactions of height, leg length and sitting height with menarche were also analyzed. Risk of both ER-PR- and ER+PR+ malignancies was positively associated with standing height, leg length and sitting height and inversely associated with increasing age at menarche. For ER+PR+ disease, sitting height (hazard ratios: 1.14[95% confidence interval: 1.08-1.20]) had a stronger risk association than leg length (1.05[1.00-1.11]). In comparison, for ER-PR- disease, no distinct differences were observed between leg length and sitting height. Women who were tall and had an early menarche (≤13 years) showed an almost twofold increase in risk of ER+PR+ tumors but no such increase in risk was observed for ER-PR- disease. Indicators of exposures during rapid growth periods were associated with risks of both HR-defined breast cancers. Exposures during childhood promoting faster development may establish risk associations for both HR-positive and -negative malignancies. The stronger associations of the components of height with ER+PR+ tumors among older women suggest possible hormonal links that could be specific for postmenopausal women. Copyright © 2012 UICC.

Positive Charges on the Surface of Thaumatin Are Crucial for the Multi-Point Interaction with the Sweet Receptor.

Science.gov (United States)

Masuda, Tetsuya; Kigo, Satomi; Mitsumoto, Mayuko; Ohta, Keisuke; Suzuki, Mamoru; Mikami, Bunzo; Kitabatake, Naofumi; Tani, Fumito

2018-01-01

Thaumatin, an intensely sweet-tasting protein, elicits sweet taste with a threshold of only 50 nM. Previous studies from our laboratory suggested that the complex model between the T1R2-T1R3 sweet receptor and thaumatin depends critically on the complementarity of electrostatic potentials. In order to further validate this model, we focused on three lysine residues (Lys78, Lys106, and Lys137), which were expected to be part of the interaction sites. Three thaumatin mutants (K78A, K106A, and K137A) were prepared and their threshold values of sweetness were examined. The results showed that the sweetness of K106A was reduced by about three times and those of K78A and K137A were reduced by about five times when compared to wild-type thaumatin. The three-dimensional structures of these mutants were also determined by X-ray crystallographic analyses at atomic resolutions. The overall structures of mutant proteins were similar to that of wild-type but the electrostatic potentials around the mutated sites became more negative. Since the three lysine residues are located in 20-40 Å apart each other on the surface of thaumatin molecule, these results suggest the positive charges on the surface of thaumatin play a crucial role in the interaction with the sweet receptor, and are consistent with a large surface is required for interaction with the sweet receptor, as proposed by the multipoint interaction model named wedge model.

Positive Charges on the Surface of Thaumatin Are Crucial for the Multi-Point Interaction with the Sweet Receptor

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Tetsuya Masuda

2018-02-01

Full Text Available Thaumatin, an intensely sweet-tasting protein, elicits sweet taste with a threshold of only 50 nM. Previous studies from our laboratory suggested that the complex model between the T1R2-T1R3 sweet receptor and thaumatin depends critically on the complementarity of electrostatic potentials. In order to further validate this model, we focused on three lysine residues (Lys78, Lys106, and Lys137, which were expected to be part of the interaction sites. Three thaumatin mutants (K78A, K106A, and K137A were prepared and their threshold values of sweetness were examined. The results showed that the sweetness of K106A was reduced by about three times and those of K78A and K137A were reduced by about five times when compared to wild-type thaumatin. The three-dimensional structures of these mutants were also determined by X-ray crystallographic analyses at atomic resolutions. The overall structures of mutant proteins were similar to that of wild-type but the electrostatic potentials around the mutated sites became more negative. Since the three lysine residues are located in 20–40 Å apart each other on the surface of thaumatin molecule, these results suggest the positive charges on the surface of thaumatin play a crucial role in the interaction with the sweet receptor, and are consistent with a large surface is required for interaction with the sweet receptor, as proposed by the multipoint interaction model named wedge model.

Human epidermal growth factor receptor 2-positive breast cancer: which cytotoxic agent best complements trastuzumab's efficacy in vitro?

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Hurrell T

2013-06-01

Full Text Available Tracey Hurrell, Kim OuthoffDepartment of Pharmacology, University of Pretoria, Pretoria, South AfricaIntroduction: Despite trastuzumab having enhanced selectivity for human epidermal growth factor receptor 2 (HER-2 overexpressing breast cancer cells, treatment is hampered by interindividual variation and tumors with high mitogenic potential. The lack of significant clinical benefit in certain patient cohorts suggests that HER-2 expression is ineffective as a sole prognostic indicator of response to therapy. Therefore, optimizing the clinical role of trastuzumab in drug combinations remains critical for clinical success.Aim: To investigate the effects of trastuzumab in combination with either doxorubicin or geldanamycin on in vitro cell viability, cell cycling, apoptosis and relative HER-2 expression in HER-2-positive (SK-BR-3 and estrogen receptor-positive (MCF-7 breast adenocarcinoma models.Results: HER-2-rich SK-BR-3 cells demonstrated a greater sensitivity to the effects of doxorubicin than MCF-7 cells. Concurrent trastuzumab exposure resulted in a further reduction in cell viability. This decreased cell viability induced by doxorubicin was associated with activation of executioner caspases as well as with alterations in cell-cycle kinetics, primarily promoting S-phase accumulation. Doxorubicin had no effect on surface HER-2 density expression. Geldanamycin reduced cell viability significantly greater in SK-BR-3 than MCF-7 cells, and was associated with G2 cell-cycle accumulation. The addition of trastuzumab did not augment these effects. Geldanamycin promoted substantial reductions in relative surface HER-2 density in SK-BR-3 cells.Conclusion: The in vitro data supported the rationale for using doxorubicin in trastuzumab-based therapies. Therefore, despite the incidence of cardiotoxicity, doxorubicin could retain a fundamental role in treating HER-2-positive breast cancer. While geldanamycin is a potent cytotoxic agent, its concurrent use

Endocrine therapy use among elderly hormone receptor-pos...

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U.S. Department of Health & Human Services — Clinical guidelines recommend that women with hormone-receptor positive breast cancer receive endocrine therapy (selective estrogen receptor modulators or aromatase...

The 21-gene Recurrence Score® assay predicts distant recurrence in lymph node-positive, hormone receptor-positive, breast cancer patients treated with adjuvant sequential epirubicin- and docetaxel-based or epirubicin-based chemotherapy (PACS-01 trial).

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Penault-Llorca, Frédérique; Filleron, Thomas; Asselain, Bernard; Baehner, Frederick L; Fumoleau, Pierre; Lacroix-Triki, Magali; Anderson, Joseph M; Yoshizawa, Carl; Cherbavaz, Diana B; Shak, Steven; Roca, Lise; Sagan, Christine; Lemonnier, Jérôme; Martin, Anne-Laure; Roché, Henri

2018-05-04

The 21-gene Recurrence Score (RS) result predicts outcome and chemotherapy benefit in node-negative and node-positive (N+), estrogen receptor-positive (ER+) patients treated with endocrine therapy. The purpose of this study was to evaluate the prognostic impact of RS results in N+, hormone receptor-positive (HR+) patients treated with adjuvant chemotherapy (6 cycles of FEC100 vs. 3 cycles of FEC100 followed by 3 cycles of docetaxel 100 mg/m 2 ) plus endocrine therapy (ET) in the PACS-01 trial (J Clin Oncol 2006;24:5664-5671). The current study included 530 HR+/N+ patients from the PACS-01 parent trial for whom specimens were available. The primary objective was to evaluate the relationship between the RS result and distant recurrence (DR). There were 209 (39.4%) patients with low RS (< 18), 159 (30%) with intermediate RS (18-30) and 162 (30.6%) with high RS (≥ 31). The continuous RS result was associated with DR (hazard ratio = 4.14; 95% confidence interval: 2.67-6.43; p <  0.001), adjusting for treatment. In multivariable analysis, the RS result remained a significant predictor of DR (p <  0.001) after adjustment for number of positive nodes, tumor size, tumor grade, Ki-67 (immunohistochemical status), and chemotherapy regimen. There was no statistically significant interaction between RS result and treatment in predicting DR (p = 0.79). After adjustment for clinical covariates, the 21-gene RS result is a significant prognostic factor in N+/HR+ patients receiving adjuvant chemoendocrine therapy. Not applicable.

Abiraterone acetate, exemestane or the combination in postmenopausal patients with estrogen receptor-positive metastatic breast cancer.

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O'Shaughnessy, J; Campone, M; Brain, E; Neven, P; Hayes, D; Bondarenko, I; Griffin, T W; Martin, J; De Porre, P; Kheoh, T; Yu, M K; Peng, W; Johnston, S

2016-01-01

Androgen receptor (AR) signaling and incomplete inhibition of estrogen signaling may contribute to metastatic breast cancer (MBC) resistance to a nonsteroidal aromatase inhibitor (NSAI; letrozole or anastrozole). We assessed whether combined inhibition of androgen biosynthesis with abiraterone acetate plus prednisone and estradiol synthesis with exemestane (E) may be of clinical benefit to postmenopausal patients with NSAI-pretreated estrogen receptor-positive (ER+) MBC. Patients (N = 297) were stratified by the number of prior therapies for metastatic disease (0-1 versus 2) and by prior NSAI use (adjuvant versus metastatic), and randomized (1 : 1 : 1) to receive oral once daily 1000 mg abiraterone acetate plus 5 mg prednisone (AA) versus AA with 25 mg E (AAE) versus 25 mg E alone (E). Each treatment arm was well balanced with regard to the proportion of patients with AR-positive breast cancer. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, clinical benefit rate, duration of response, and overall response rate. There was no significant difference in PFS with AA versus E (3.7 versus 3.7 months; hazard ratio [HR] = 1.1; 95% confidence interval [CI] 0.82-1.60; P = 0.437) or AAE versus E (4.5 versus 3.7 months; HR = 0.96; 95% CI 0.70-1.32; P = 0.794). Increased serum progesterone concentrations were observed in both arms receiving AA, but not with E. Grade 3 or 4 treatment-emergent adverse events associated with AA, including hypokalemia and hypertension, were less common in patients in the E (2.0% and 2.9%, respectively) and AA arms (3.4% and 1.1%, respectively) than in the AAE arm (5.8% for both). Adding AA to E in NSAI-pretreated ER+ MBC patients did not improve PFS compared with treatment with E. An AA-induced progesterone increase may have contributed to this lack of clinical activity. NCT01381874. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical

Abiraterone acetate, exemestane or the combination in postmenopausal patients with estrogen receptor-positive metastatic breast cancer†

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O'Shaughnessy, J.; Campone, M.; Brain, E.; Neven, P.; Hayes, D.; Bondarenko, I.; Griffin, T. W.; Martin, J.; De Porre, P.; Kheoh, T.; Yu, M. K.; Peng, W.; Johnston, S.

2016-01-01

Background Androgen receptor (AR) signaling and incomplete inhibition of estrogen signaling may contribute to metastatic breast cancer (MBC) resistance to a nonsteroidal aromatase inhibitor (NSAI; letrozole or anastrozole). We assessed whether combined inhibition of androgen biosynthesis with abiraterone acetate plus prednisone and estradiol synthesis with exemestane (E) may be of clinical benefit to postmenopausal patients with NSAI-pretreated estrogen receptor-positive (ER+) MBC. Patients and methods Patients (N = 297) were stratified by the number of prior therapies for metastatic disease (0–1 versus 2) and by prior NSAI use (adjuvant versus metastatic), and randomized (1 : 1 : 1) to receive oral once daily 1000 mg abiraterone acetate plus 5 mg prednisone (AA) versus AA with 25 mg E (AAE) versus 25 mg E alone (E). Each treatment arm was well balanced with regard to the proportion of patients with AR-positive breast cancer. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, clinical benefit rate, duration of response, and overall response rate. Results There was no significant difference in PFS with AA versus E (3.7 versus 3.7 months; hazard ratio [HR] = 1.1; 95% confidence interval [CI] 0.82–1.60; P = 0.437) or AAE versus E (4.5 versus 3.7 months; HR = 0.96; 95% CI 0.70–1.32; P = 0.794). Increased serum progesterone concentrations were observed in both arms receiving AA, but not with E. Grade 3 or 4 treatment-emergent adverse events associated with AA, including hypokalemia and hypertension, were less common in patients in the E (2.0% and 2.9%, respectively) and AA arms (3.4% and 1.1%, respectively) than in the AAE arm (5.8% for both). Conclusions Adding AA to E in NSAI-pretreated ER+ MBC patients did not improve PFS compared with treatment with E. An AA-induced progesterone increase may have contributed to this lack of clinical activity. ClinicalTrials.gov NCT01381874. PMID:26504153

Gating function of isoleucine-116 in TM-3 (position III:16/3.40) for the activity state of the CC-chemokine receptor 5 (CCR5)

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Steen, A; Sparre-Ulrich, A H; Thiele, Stefanie

2014-01-01

TM receptors - it is a leucine indicating an altered function. Here, we describe the significance of this position and its possible interaction with TM-3 for CCR5 activity. EXPERIMENTAL APPROACH: The effects of [L203F]-CCR5 in TM-5 (position V:13/5.47), [I116A]-CCR5 in TM-3 (III:16/3.40) and [L203F...... ) with a threefold increase in agonist potency. In silico, [I116A]-CCR5 switched χ1-angle in [L203F]-CCR5. Furthermore, [I116A]-CCR5 was constitutively active to a similar degree as [L203F]-CCR5. Tyr(244) in TM-6 (VI:09/6.44) moved towards TM-5 in silico, consistent with its previously shown function for CCR5...... in the active state, a mechanism proposed previously for the β2 -adrenoceptor. The results provide an understanding of chemokine receptor function and thereby information for the development of biased and non-biased antagonists and inverse agonists....

Preclinical evaluation of [99mTc/EDDA/tricine/HYNIC0, 1-Nal3, Thr8]-octreotide as a new analogue in the detection of somatostatin-receptor-positive tumors.

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Gandomkar, Mostafa; Najafi, Reza; Shafiei, Mohammad; Mazidi, Mohammad; Ebrahimi, Sayed Esmaeil Sadat

2007-08-01

Radiolabeled somatostatin analogues are important tools for the in vivo localization and targeted radionuclide therapy of somatostatin-receptor-positive tumors. The aim of this study was to evaluate a new somatostatin analogue designed for the labeling with (99m)Tc: [6-hydrazinopyridine-3-carboxylic acid (HYNIC(0)), 1-Nal(3), Thr(8)]-octreotide ([HYNIC]-NATE), using ethylenediamine-N,N'-diacetic acid (EDDA) and tricine as coligands. Synthesis was preformed on a solid phase using a standard Fmoc strategy. Labeling with (99m)Tc was performed at 100 degrees C for 10 min using SnCl(2) as a reductant. Radiochemical analysis involved ITLC and high-performance liquid chromatography methods. Peptide conjugate affinity was determined in AR4-2J cell membranes. The internalization and externalization rates were studied in sstr(2)-expressing AR4-2J cells. Biodistribution of radiopeptide was studied in rats bearing the AR4-2J tumor. Radiolabeling was performed at high specific activities, and radiochemical purity was >95%. Peptide conjugate showed high affinity binding for sstr(2). The radioligand showed a moderate and specific internalization into AR4-2J cells (14.13+/-0.61% at 4 h). In animal biodistribution studies, a receptor-specific uptake of radioactivity was observed in somatostatin-receptor-positive organs. After 4 h, uptake in the AR4-2J tumor was 1.33+/-0.23%ID/g (percentage of injected dose per gram of tissue). These data show that [(99m)Tc/EDDA/tricine/HYNIC]-NATE is a specific radioligand for the somatostatin-receptor-positive tumors and is a suitable candidate for clinical studies.

Preclinical evaluation of [99mTc/EDDA/tricine/HYNIC0, 1-Nal3, Thr8]-octreotide as a new analogue in the detection of somatostatin-receptor-positive tumors

International Nuclear Information System (INIS)

Gandomkar, Mostafa; Najafi, Reza; Shafiei, Mohammad; Mazidi, Mohammad; Ebrahimi, Sayed Esmaeil Sadat

2007-01-01

Purpose: Radiolabeled somatostatin analogues are important tools for the in vivo localization and targeted radionuclide therapy of somatostatin-receptor-positive tumors. The aim of this study was to evaluate a new somatostatin analogue designed for the labeling with 99m Tc: [6-hydrazinopyridine-3-carboxylic acid (HYNIC 0 ), 1-Nal 3 , Thr 8 ]-octreotide ([HYNIC]-NATE), using ethylenediamine-N,N'-diacetic acid (EDDA) and tricine as coligands. Methods: Synthesis was preformed on a solid phase using a standard Fmoc strategy. Labeling with 99m Tc was performed at 100 o C for 10 min using SnCl 2 as a reductant. Radiochemical analysis involved ITLC and high-performance liquid chromatography methods. Peptide conjugate affinity was determined in AR4-2J cell membranes. The internalization and externalization rates were studied in sstr 2 -expressing AR4-2J cells. Biodistribution of radiopeptide was studied in rats bearing the AR4-2J tumor. Results: Radiolabeling was performed at high specific activities, and radiochemical purity was >95%. Peptide conjugate showed high affinity binding for sstr 2 . The radioligand showed a moderate and specific internalization into AR4-2J cells (14.13±0.61% at 4 h). In animal biodistribution studies, a receptor-specific uptake of radioactivity was observed in somatostatin-receptor-positive organs. After 4 h, uptake in the AR4-2J tumor was 1.33±0.23%ID/g (percentage of injected dose per gram of tissue). Conclusion: These data show that [ 99m Tc/EDDA/tricine/HYNIC]-NATE is a specific radioligand for the somatostatin-receptor-positive tumors and is a suitable candidate for clinical studies

Napsin A and Thyroid Transcription Factor-1-Positive Cerebellar Tumor with Epidermal Growth Factor Receptor Mutation

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Taiji Kuwata

2011-12-01

Full Text Available We present a very rare case of cerebellar metastasis of unknown origin, in which a primary lung adenocarcinoma was diagnosed by pathological examination of a cerebellar metastatic tumor, using immunohistochemical markers and epidermal growth factor receptor (EGFR mutation of primary lung cancer. A 69-year-old woman was admitted to our hospital because of a hemorrhagic cerebellar tumor and multiple small brain tumors. She underwent cerebellar tumor resection. On pathological examination, the tumor was diagnosed as adenocarcinoma. However, the primary tumor site was unidentifiable even with several imaging inspections. On immunohistochemical analysis, the resected tumor was positive for napsin A and thyroid transcription factor-1. In addition, an EGFR mutation was detected in the tumor. Therefore, primary lung cancer was diagnosed and the patient was started on gefitinib (250 mg/day therapy.

Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN)

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Howard, James F; Utsugisawa, Kimiaki; Benatar, Michael

2017-01-01

BACKGROUND: Complement is likely to have a role in refractory generalised myasthenia gravis, but no approved therapies specifically target this system. Results from a phase 2 study suggested that eculizumab, a terminal complement inhibitor, produced clinically meaningful improvements in patients...... with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis. We further assessed the efficacy and safety of eculizumab in this patient population in a phase 3 trial. METHODS: We did a phase 3, randomised, double-blind, placebo-controlled, multicentre study (REGAIN) in 76...... hospitals and specialised clinics in 17 countries across North America, Latin America, Europe, and Asia. Eligible patients were aged at least 18 years, with a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or more, Myasthenia Gravis Foundation of America (MGFA) class II-IV disease...

Androgen Receptor Expression in Thai Breast Cancer Patients

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Suthat Chottanapund

2016-09-01

Full Text Available The aim of this study was to investigate prevalence and related factors of androgen receptor (AR expression in Thai breast cancer patients. A descriptive study was done in 95 patients, who were admitted to Charoenkrung Pracharak Hospital, Bangkok (2011–2013. Statistical relationships were examined between AR protein expression, tumor status, and patient characteristics. Compared with those from Western countries, ethnic Thai patients were younger at age of diagnosis and had a higher proliferative index (high Ki-67 expression, which indicates unfavorable prognosis. In addition, 91% of the Thai breast tumors that were positive for any of the following receptors, estrogen receptor (ER, progesterone receptor (PR, and human epidermal growth factor receptor 2 (HER2 also expressed the AR protein, while in triple negative breast tumors only 33% were AR positive. ER and PR expression was positively related with AR expression, while AR expression was inversely correlated to Ki-67 expression. AR status was strongly correlated with ER and PR status in Thai patients. There is an inverse relationship between Ki-67 and AR, which suggests that AR may be a prognostic factor for breast cancer.

The ability of PAM50 risk of recurrence score to predict 10-year distant recurrence in hormone receptor-positive postmenopausal women with special histological subtypes

DEFF Research Database (Denmark)

Laenkholm, Anne-Vibeke; Jensen, Maj-Britt; Eriksen, Jens Ole

2018-01-01

INTRODUCTION: The Prosigna-PAM50 risk of recurrence (ROR) score has been validated in randomized clinical trials to predict 10-year distant recurrence (DR) in hormone receptor-positive breast cancer. Here, we examine the ability of Prosigna for predicting DR at 10 years in a subgroup of postmenop...

Myasthenic Crisis Complicated with Myxedema, Positive for Both Anti-acetylcholine Receptor and Anti-muscle-specific Tyrosine Kinase Antibodies.

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Horiuchi, Kazuhiro; Nagai, Azusa; Wakita, Masahiro; Ito, Shotaro; Takamura, Kei; Houzen, Hideki

2018-01-15

We herein report the case of myasthenic crisis occurring in a 51-year-old man. He had experienced ptosis, increased body weight with edema, and fatigue with dyspnea. He presented at our emergency department with disturbed consciousness. He was originally diagnosed with myxedema coma, and he required artificial respiration. Because his weakness persisted and he was positive for anti-acetylcholine receptor antibodies and anti-muscle-specific tyrosine kinase antibodies, we diagnosed myasthenic crisis after various examinations. His clinical response to treatment was good and he was discharged in an ambulatory status 3 months after admission. This case demonstrates that myasthenic crisis may occur in association with myxedema.

Rictor positively regulates B cell receptor signaling by modulating actin reorganization via ezrin.

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Lu Huang

2017-08-01

Full Text Available As the central hub of the metabolism machinery, the mammalian target of rapamycin complex 2 (mTORC2 has been well studied in lymphocytes. As an obligatory component of mTORC2, the role of Rictor in T cells is well established. However, the role of Rictor in B cells still remains elusive. Rictor is involved in B cell development, especially the peripheral development. However, the role of Rictor on B cell receptor (BCR signaling as well as the underlying cellular and molecular mechanism is still unknown. This study used B cell-specfic Rictor knockout (KO mice to investigate how Rictor regulates BCR signaling. We found that the key positive and negative BCR signaling molecules, phosphorylated Brutons tyrosine kinase (pBtk and phosphorylated SH2-containing inositol phosphatase (pSHIP, are reduced and enhanced, respectively, in Rictor KO B cells. This suggests that Rictor positively regulates the early events of BCR signaling. We found that the cellular filamentous actin (F-actin is drastically increased in Rictor KO B cells after BCR stimulation through dysregulating the dephosphorylation of ezrin. The high actin-ezrin intensity area restricts the lateral movement of BCRs upon stimulation, consequently reducing BCR clustering and BCR signaling. The reduction in the initiation of BCR signaling caused by actin alteration is associated with a decreased humoral immune response in Rictor KO mice. The inhibition of actin polymerization with latrunculin in Rictor KO B cells rescues the defects of BCR signaling and B cell differentiation. Overall, our study provides a new pathway linking cell metablism to BCR activation, in which Rictor regulates BCR signaling via actin reorganization.

Dietary acrylamide intake and estrogen and progesterone receptor-defined postmenopausal breast cancer risk

DEFF Research Database (Denmark)

Pedersen, Grete S; Hogervorst, Janneke G F; Schouten, Leo J

2010-01-01

and risk of postmenopausal breast cancer stratified by estrogen and progesterone receptor status. This study was embedded within the Netherlands Cohort Study on diet and cancer, which was initiated in 1986 enrolling 62,573 women aged 55-69 years at baseline. After 13.3 years of follow-up, 2225 incident...... breast cancer cases were ascertained, with hormone receptor status information for 43%. Cox proportional hazards analysis was applied to determine hazard ratios in quintiles of dietary acrylamide intake stratifying on estrogen receptor (ER) and progesterone receptor (PR) and smoking status....... No association was observed for overall breast cancer or receptor-negative breast cancer risk, irrespective of smoking status. A statistically non-significantly increased risk of ER positive, PR positive and joint receptor-positive breast cancer was found in never-smoking women. The multivariable-adjusted hazard...

A search for presynaptic inhibitory histamine receptors in guinea-pig tissues: Further H3 receptors but no evidence for H4 receptors.

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Petri, Doris; Schlicker, Eberhard

2016-07-01

The histamine H4 receptor is coupled to Gi/o proteins and expressed on inflammatory cells and lymphoid tissues; it was suggested that this receptor also occurs in the brain or on peripheral neurones. Since many Gi/o protein-coupled receptors, including the H3 receptor, serve as presynaptic inhibitory receptors, we studied whether the sympathetic neurones supplying four peripheral tissues and the cholinergic neurones in the hippocampus from the guinea-pig are equipped with release-modulating H4 and H3 receptors. For this purpose, we preincubated tissue pieces from the aorta, atrium, renal cortex and vas deferens with (3)H-noradrenaline and hippocampal slices with (3)H-choline and determined the electrically evoked tritium overflow. The stimulation-evoked overflow in the five superfused tissues was inhibited by the muscarinic receptor agonist oxotremorine, which served as a positive control, but not affected by the H4 receptor agonist 4-methylhistamine. The H3 receptor agonist R-α-methylhistamine inhibited noradrenaline release in the peripheral tissues without affecting acetylcholine release in the hippocampal slices. Thioperamide shifted the concentration-response curve of histamine in the aorta and the renal cortex to the right, yielding apparent pA2 values of 8.0 and 8.1, respectively, which are close to its affinity at other H3 receptors but higher by one log unit than its pKi at the H4 receptor of the guinea-pig. In conclusion, histamine H4 receptors could not be identified in five experimental models of the guinea-pig that are suited for the detection of presynaptic inhibitory receptors whereas H3 receptors could be shown in the peripheral tissues but not in the hippocampus. This article is part of the Special Issue entitled 'Histamine Receptors'. Copyright © 2015 Elsevier Ltd. All rights reserved.

Pattern of hormone receptors and human epidermal growth factor ...

African Journals Online (AJOL)

Introduction: Breast cancer is the most common cancer among women globally. With immunohistochemistry (IHC), breast cancer is classified into four groups based on IHC profile of estrogen receptor (ER)/progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2/neu) expression, positive (+) and/or ...

Phase II Study of Neoadjuvant Anthracycline-Based Regimens Combined With Nanoparticle Albumin-Bound Paclitaxel and Trastuzumab for Human Epidermal Growth Factor Receptor 2-Positive Operable Breast Cancer.

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Tanaka, Satoru; Iwamoto, Mitsuhiko; Kimura, Kosei; Matsunami, Nobuki; Morishima, Hirotaka; Yoshidome, Katsuhide; Nomura, Takashi; Morimoto, Takashi; Yamamoto, Daigo; Tsubota, Yu; Kobayashi, Toshihiro; Uchiyama, Kazuhisa

2015-06-01

We treated patients with operable human epidermal growth factor receptor 2-positive breast cancer with neoadjuvant anthracycline regimens followed by nanoparticle albumin-bound paclitaxel plus trastuzumab. Of the 44 patients, 49% achieved a pathologic complete response (pCR). The pCR rate was 36% and 71% in the patients with estrogen receptor-positive and -negative cancer, respectively. Neoadjuvant therapy using this combination appears to be effective and safe. Introduction: Neoadjuvant chemotherapy plus trastuzumab. Neoadjuvant chemotherapy plus trastuzumab results in a 30% to 50% pathologic complete response (pCR) rate in human epidermal growth factor receptor 2 (HER2)-positive breast cancer and has been associated with improved therapeutic outcomes. Thus, the pCR rate can be useful in evaluating novel agents in this patient population. Nanoparticle albumin-bound (nab)-paclitaxel (PTX) can reduce the toxicity of PTX while maintaining its efficacy. The present study evaluated the activity and safety of nab-PTX as a neoadjuvant treatment of HER2(+) breast cancer. We treated patients with stage I to IIIA breast cancer using neoadjuvant epirubicin/cyclophosphamide (EC) or 5-fluorouracil/epirubicin/cyclophosphamide every 3 weeks (q3w) for 4 cycles, followed by nab-PTX (260 mg/m(2)) plus trastuzumab q3w for 4 cycles. The primary endpoint was the pCR rate. The secondary endpoints included the clinical response rate, disease-free survival, pathologic response rate (defined as pCR or minimal residual invasive disease only in the breast), breast-conserving surgery rate, and safety. Forty-six patients were enrolled. One patient met the exclusion criteria because of the coexistence of another malignant disease; therefore, we evaluated 45 patients in the entire study. One patient experienced rapid disease progression during EC therapy, leaving 44 patients evaluable for nab-PTX treatment. Of the 45 patients, 49% achieved a pCR. The pCR rate was 36% and 71% in those with

Partial least squares based gene expression analysis in estrogen receptor positive and negative breast tumors.

Science.gov (United States)

Ma, W; Zhang, T-F; Lu, P; Lu, S H

2014-01-01

Breast cancer is categorized into two broad groups: estrogen receptor positive (ER+) and ER negative (ER-) groups. Previous study proposed that under trastuzumab-based neoadjuvant chemotherapy, tumor initiating cell (TIC) featured ER- tumors response better than ER+ tumors. Exploration of the molecular difference of these two groups may help developing new therapeutic strategies, especially for ER- patients. With gene expression profile from the Gene Expression Omnibus (GEO) database, we performed partial least squares (PLS) based analysis, which is more sensitive than common variance/regression analysis. We acquired 512 differentially expressed genes. Four pathways were found to be enriched with differentially expressed genes, involving immune system, metabolism and genetic information processing process. Network analysis identified five hub genes with degrees higher than 10, including APP, ESR1, SMAD3, HDAC2, and PRKAA1. Our findings provide new understanding for the molecular difference between TIC featured ER- and ER+ breast tumors with the hope offer supports for therapeutic studies.

β-Catenin Is a Positive Regulator of Estrogen Receptor-α Function in Breast Cancer Cells

Energy Technology Data Exchange (ETDEWEB)

Gupta, Nibedita; Schmitt, Fee; Grebhardt, Sina; Mayer, Doris, E-mail: d.mayer@dkfz.de [Hormones and Signal Transduction Group, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 581, 69120 Heidelberg (Germany)

2011-07-22

Estrogen receptor-alpha (ERα) is a key factor in the development of breast cancer in humans. The expression and activity of ERα is regulated by a multitude of intracellular and extracellular signals. Here we show a cross-talk between β-catenin and ERα in human breast cancer cells. Knockdown of β-catenin by RNAi resulted in significant reduction of ERα mRNA and/or protein levels in MCF-7, T-47D, and BT-474 breast cancer cells and in significant reduction of estradiol-induced expression of the ERα target genes pS2 and GREB1. In addition β-catenin silencing resulted in significant decrease of growth of MCF-7 cells both in the absence and presence of estradiol. β-catenin and ERα could not be co-immunoprecipitated by ERα antibodies from lysates of E2-treated or untreated cells suggesting lack of direct physical interaction. It is concluded that β-catenin is a positive regulator of ERα mRNA and protein expression.

Synthesis and preliminary evaluation of [11C]NE-100 labeled in two different positions as a PET σ receptor ligand

International Nuclear Information System (INIS)

Ishiwata, Kiichi; Noguchi, Junko; Ishii, Shin-Ichi; Hatano, Kentaro; Ito, Kengo; Nabeshima, Toshitaka; Senda, Michio

1998-01-01

N,N-Dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine (NE-100) was labeled with 11 C in two different positions by the alkylation of an N-despropyl precursor with [ 11 C]propyl iodide and of an O-desmethyl precursor with [ 11 C]methyl iodide and was evaluated for the potential as a tracer for mapping σ 1 receptors in the CNS and peripheral organs by PET. Following i.v. injection of [N-propyl- 11 C]NE-100 or [O-methyl- 11 C]NE-100 into mice, the two tracers showed similar tissue distribution patterns except for the liver and brain. With the coinjected carrier NE-100 or haloperidol, the uptake of [N-propyl- 11 C]NE-100 by the liver, pancreas and spleen was significantly decreased at 15 min after injection, whereas the effect was not significant for [O-methyl- 11 C]NE-100. The coinjection of NE-100 enhanced the brain uptake of the two tracers. Haloperidol also enhanced the brain uptake of [N-propyl- 11 C]NE-100, but not that of [O-methyl- 11 C]NE-100. The regional brain distribution assessed with [O-methyl- 3 H]NE-100 was consistent with the distribution pattern of the σ receptors. Four σ drugs reduced the regional brain uptake of [O-methyl- 3 H]NE-100 to 70%-90% of the control. In an ex vivo autoradiographic study of the rat brain, the uptake of [O-methyl- 11 C]NE-100 was blocked by carrier NE-100 or haloperidol (53%-59% of the control in the cortex), which suggests a receptor-specific distribution. These results show that [O-methyl- 11 C]NE-100 has limited potential as a PET ligand for mapping σ 1 receptors in the peripheral organs and the CNS because of high nonspecific binding

Breast cancer-specific survival in patients with lymph node-positive hormone receptor-positive invasive breast cancer and Oncotype DX Recurrence Score results in the SEER database.

Science.gov (United States)

Roberts, Megan C; Miller, Dave P; Shak, Steven; Petkov, Valentina I

2017-06-01

The Oncotype DX ® Breast Recurrence Score™ (RS) assay is validated to predict breast cancer (BC) recurrence and adjuvant chemotherapy benefit in select patients with lymph node-positive (LN+), hormone receptor-positive (HR+), HER2-negative BC. We assessed 5-year BC-specific survival (BCSS) in LN+ patients with RS results in SEER databases. In this population-based study, BC cases in SEER registries (diagnosed 2004-2013) were linked to RS results from assays performed by Genomic Health (2004-2014). The primary analysis included only patients (diagnosed 2004-2012) with LN+ (including micrometastases), HR+ (per SEER), and HER2-negative (per RT-PCR) primary invasive BC (N = 6768). BCSS, assessed by RS category and number of positive lymph nodes, was calculated using the actuarial method. The proportion of patients with RS results and LN+ disease (N = 8782) increased over time between 2004 and 2013, and decreased with increasing lymph node involvement from micrometastases to ≥4 lymph nodes. Five-year BCSS outcomes for those with RS < 18 ranged from 98.9% (95% CI 97.4-99.6) for those with micrometastases to 92.8% (95% CI 73.4-98.2) for those with ≥4 lymph nodes. Similar patterns were found for patients with RS 18-30 and RS ≥ 31. RS group was strongly predictive of BCSS among patients with micrometastases or up to three positive lymph nodes (p < 0.001). Overall, 5-year BCSS is excellent for patients with RS < 18 and micrometastases, one or two positive lymph nodes, and worsens with additionally involved lymph nodes. Further analyses should account for treatment variables, and longitudinal updates will be important to better characterize utilization of Oncotype DX testing and long-term survival outcomes.

PAF receptor structure: a hypothesis.

Science.gov (United States)

Godfroid, J J; Dive, G; Lamotte-Brasseur, J; Batt, J P; Heymans, F

1991-12-01

Different hypotheses of the structure of platelet-activating factor (PAF) receptor based on structure-activity relationships of agonists and antagonists are reviewed. For an agonistic effect, strong hydrophobic interactions and an ether function are required in position-1 of the glycerol backbone; chain length limitations and steric hindrance demand a small group in position-2. The unusual structural properties of non-PAF-like antagonists required 3-D electrostatic potential calculations. This method applied to seven potent antagonists suggests a strong "Cache-orielles" (ear-muff) effect, i.e., two strong electronegative wells (isocontour at -10 Kcal/mole) are located at 180 degrees to each other and at a relatively constant distance. Initial consideration of the "Cache-oreilles" effect implied the structure of a bipolarized cylinder of 10-12 A diameter for the receptor. However, very recent results on studies with agonists and antagonists structurally similar to PAF suggest that the receptor may in fact be a multi-polarized cylinder.

Genomic organization of a receptor from sea anemones, structurally and evolutionary related to glycoprotein hormone receptors from mamals

DEFF Research Database (Denmark)

Vibede, N; Hauser, Frank; Williamson, M

1998-01-01

organization of this sea anemone receptor. The receptor gene contains eight introns that are all localized within a region coding for the large extracellular N terminus. These introns occur at the same positions and have the same intron phasing as eight introns in the genes coding for the mammalian...

The scaffold protein MEK Partner 1 is required for the survival of estrogen receptor positive breast cancer cells

Directory of Open Access Journals (Sweden)

Marina Mihaela

2012-07-01

Full Text Available Abstract MEK Partner 1 (MP1 or MAPKSP1 is a scaffold protein that has been reported to function in multiple signaling pathways, including the ERK, PAK and mTORC pathways. Several of these pathways influence the biology of breast cancer, but MP1’s functional significance in breast cancer cells has not been investigated. In this report, we demonstrate a requirement for MP1 expression in estrogen receptor (ER positive breast cancer cells. MP1 is widely expressed in both ER-positive and negative breast cancer cell lines, and in non-tumorigenic mammary epithelial cell lines. However, inhibition of its expression using siRNA duplexes resulted in detachment and apoptosis of several ER-positive breast cancer cell lines, but not ER-negative breast cancer cells or non-tumorigenic mammary epithelial cells. Inhibition of MP1 expression in ER-positive MCF-7 cells did not affect ERK activity, but resulted in reduced Akt1 activity and reduced ER expression and activity. Inhibition of ER expression did not result in cell death, suggesting that decreased ER expression is not the cause of cell death. In contrast, pharmacological inhibition of PI3K signaling did induce cell death in MCF-7 cells, and expression of a constitutively active form of Akt1 partially rescued the cell death observed when the MP1 gene was silenced in these cells. Together, these results suggest that MP1 is required for pro-survival signaling from the PI3K/Akt pathway in ER-positive breast cancer cells.

Effects of intraperitoneal administration of the GABAB receptor positive allosteric modulator 2,6-di tert-butyl-4-(2-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) on food intake in non-deprived rats.

Science.gov (United States)

Ebenezer, Ivor S

2012-09-05

γ-Aminobutyric acid-(B) (GABA(B)) receptor positive allosteric modulators (PAMs) act on an allosteric site on the GABA(B) receptor to potentiate the effects of GABA and GABA(B) receptor agonists. It has previously been demonstrated that the GABA(B) receptor agonist baclofen increases food intake in non-deprived rats. The aim of this study was to investigate whether the GABA(B) receptor PAM 2,6-di tert-butyl-4-(2-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) would (i) increase food intake, and (ii) potentiate the hyperphagic effects of baclofen in rats. In Experiment 1, the effects of intraperitoneal (i.p.) administration of CGP7930 (1, 6 and 12 mg/kg) was investigated on food intake in non-deprived male Wistar rats. The 12 mg/kg dose of CGP7930 significantly increased cumulative food intake 30, 60 and 120 min (PGABA and GABA(B) receptor agonists by allosteric modulation of the GABA(B) receptor. Copyright © 2012 Elsevier B.V. All rights reserved.

Radiosequence analysis of the human progestin receptor charged with [3H]promegestone. A comparison with the glucocorticoid receptor

International Nuclear Information System (INIS)

Stroemstedt, P.E.B.; Berkenstam, A.; Joernvall, H.G.; Gustafsson, J.A.; Carlstedt-Duke, J.

1990-01-01

Partially purified preparations of the human progestin receptor and the human and rat glucocorticoid receptor proteins were covalently charged with the synthetic progestin, [ 3 H]promegestone, by photoaffinity labeling. After labeling, the denaturated protein was cleaved and the mixture of peptides subjected to radiosequence analysis as previously described for the rat glucocorticoid receptor protein. The radioactivity labels identified, corresponded to Met-759 and Met-909 after photoaffinity labeling of the human progestin receptor, and Met-622 and Cys-754 after labeling of the rat glucocorticoid receptor. The residues labeled in the glucocorticoid receptor are the same as those previously reported to bind triamcinolone actonide. The corresponding residues were also labeled in the human glucocorticoid receptor. Met-759 of the progestin receptor and Met-622 of the rat glucocorticoid receptor are positioned within a segment with an overall high degree of sequence similarity and are equivalent. However, Met-909 (progestin receptor) and Cys-754 (glucocorticoid receptor) do not occur within equivalent segments of the two proteins. Thus, although the two classes of steroid hormone share a common structure within the A-ring, there are subtle differences in their interaction with the two separate receptor proteins

Reconstruction of the Chemotaxis Receptor-Kinase Assembly

International Nuclear Information System (INIS)

Park, S.; Borbat, P.; Gonzalez-Bonet, G.; Bhatnagar, J.; Pollard, A.; Freed, J.; Bilwes, A.; Crane, B.

2006-01-01

In bacterial chemotaxis, an assembly of transmembrane receptors, the CheA histidine kinase and the adaptor protein CheW processes environmental stimuli to regulate motility. The structure of a Thermotoga maritima receptor cytoplasmic domain defines CheA interaction regions and metal ion-coordinating charge centers that undergo chemical modification to tune receptor response. Dimeric CheA-CheW, defined by crystallography and pulsed ESR, positions two CheWs to form a cleft that is lined with residues important for receptor interactions and sized to clamp one receptor dimer. CheW residues involved in kinase activation map to interfaces that orient the CheW clamps. CheA regulatory domains associate in crystals through conserved hydrophobic surfaces. Such CheA self-contacts align the CheW receptor clamps for binding receptor tips. Linking layers of ternary complexes with close-packed receptors generates a lattice with reasonable component ratios, cooperative interactions among receptors and accessible sites for modification enzymes

Joint relative risks for estrogen receptor-positive breast cancer from a clinical model, polygenic risk score, and sex hormones.

Science.gov (United States)

Shieh, Yiwey; Hu, Donglei; Ma, Lin; Huntsman, Scott; Gard, Charlotte C; Leung, Jessica W T; Tice, Jeffrey A; Ziv, Elad; Kerlikowske, Karla; Cummings, Steven R

2017-11-01

Models that predict the risk of estrogen receptor (ER)-positive breast cancers may improve our ability to target chemoprevention. We investigated the contributions of sex hormones to the discrimination of the Breast Cancer Surveillance Consortium (BCSC) risk model and a polygenic risk score comprised of 83 single nucleotide polymorphisms. We conducted a nested case-control study of 110 women with ER-positive breast cancers and 214 matched controls within a mammography screening cohort. Participants were postmenopausal and not on hormonal therapy. The associations of estradiol, estrone, testosterone, and sex hormone binding globulin with ER-positive breast cancer were evaluated using conditional logistic regression. We assessed the individual and combined discrimination of estradiol, the BCSC risk score, and polygenic risk score using the area under the receiver operating characteristic curve (AUROC). Of the sex hormones assessed, estradiol (OR 3.64, 95% CI 1.64-8.06 for top vs bottom quartile), and to a lesser degree estrone, was most strongly associated with ER-positive breast cancer in unadjusted analysis. The BCSC risk score (OR 1.32, 95% CI 1.00-1.75 per 1% increase) and polygenic risk score (OR 1.58, 95% CI 1.06-2.36 per standard deviation) were also associated with ER-positive cancers. A model containing the BCSC risk score, polygenic risk score, and estradiol levels showed good discrimination for ER-positive cancers (AUROC 0.72, 95% CI 0.65-0.79), representing a significant improvement over the BCSC risk score (AUROC 0.58, 95% CI 0.50-0.65). Adding estradiol and a polygenic risk score to a clinical risk model improves discrimination for postmenopausal ER-positive breast cancers.

Nootropic α7 nicotinic receptor allosteric modulator derived from GABAA receptor modulators

Science.gov (United States)

Ng, Herman J.; Whittemore, Edward R.; Tran, Minhtam B.; Hogenkamp, Derk J.; Broide, Ron S.; Johnstone, Timothy B.; Zheng, Lijun; Stevens, Karen E.; Gee, Kelvin W.

2007-01-01

Activation of brain α7 nicotinic acetylcholine receptors (α7 nAChRs) has broad therapeutic potential in CNS diseases related to cognitive dysfunction, including Alzheimer's disease and schizophrenia. In contrast to direct agonist activation, positive allosteric modulation of α7 nAChRs would deliver the clinically validated benefits of allosterism to these indications. We have generated a selective α7 nAChR-positive allosteric modulator (PAM) from a library of GABAA receptor PAMs. Compound 6 (N-(4-chlorophenyl)-α-[[(4-chloro-phenyl)amino]methylene]-3-methyl-5-isoxazoleacet-amide) evokes robust positive modulation of agonist-induced currents at α7 nAChRs, while preserving the rapid native characteristics of desensitization, and has little to no efficacy at other ligand-gated ion channels. In rodent models, it corrects sensory-gating deficits and improves working memory, effects consistent with cognitive enhancement. Compound 6 represents a chemotype for allosteric activation of α7 nAChRs, with therapeutic potential in CNS diseases with cognitive dysfunction. PMID:17470817

Expression of GABAergic receptors in mouse taste receptor cells.

Directory of Open Access Journals (Sweden)

Margaret R Starostik

Full Text Available BACKGROUND: Multiple excitatory neurotransmitters have been identified in the mammalian taste transduction, with few studies focused on inhibitory neurotransmitters. Since the synthetic enzyme glutamate decarboxylase (GAD for gamma-aminobutyric acid (GABA is expressed in a subset of mouse taste cells, we hypothesized that other components of the GABA signaling pathway are likely expressed in this system. GABA signaling is initiated by the activation of either ionotropic receptors (GABA(A and GABA(C or metabotropic receptors (GABA(B while it is terminated by the re-uptake of GABA through transporters (GATs. METHODOLOGY/PRINCIPAL FINDINGS: Using reverse transcriptase-PCR (RT-PCR analysis, we investigated the expression of different GABA signaling molecules in the mouse taste system. Taste receptor cells (TRCs in the circumvallate papillae express multiple subunits of the GABA(A and GABA(B receptors as well as multiple GATs. Immunocytochemical analyses examined the distribution of the GABA machinery in the circumvallate papillae. Both GABA(A-and GABA(B- immunoreactivity were detected in the peripheral taste receptor cells. We also used transgenic mice that express green fluorescent protein (GFP in either the Type II taste cells, which can respond to bitter, sweet or umami taste stimuli, or in the Type III GAD67 expressing taste cells. Thus, we were able to identify that GABAergic receptors are expressed in some Type II and Type III taste cells. Mouse GAT4 labeling was concentrated in the cells surrounding the taste buds with a few positively labeled TRCs at the margins of the taste buds. CONCLUSIONS/SIGNIFICANCE: The presence of GABAergic receptors localized on Type II and Type III taste cells suggests that GABA is likely modulating evoked taste responses in the mouse taste bud.

Potentiation of peptide receptor radionuclide therapy by the PARP inhibitor olaparib

NARCIS (Netherlands)

J. Nonnekens (Julie); M. van Kranenburg (Melissa); C.E.M.T. Beerens (Cecile); M. Suker (Mustafa); M. Doukas (Michael); C.H.J. van Eijck (Casper); M. de Jong (Marcel); D.C. van Gent (Dik)

2016-01-01

textabstractMetastases expressing tumor-specific receptors can be targeted and treated by binding of radiolabeled peptides (peptide receptor radionuclide therapy or PRRT). For example, patients with metastasized somatostatin receptor-positive neuroendocrine tumors (NETs) can be treated with

Steroid receptor status in breast cancer: the roles of radioreceptor assay and immunohistochemistry

International Nuclear Information System (INIS)

Myint Aye Mu; Ch'ong

1997-01-01

A total of 24 cases of female breast cancer were reviewed, typed and graded based on the WHO classification. The steroid receptors (oestrogen and progesterone receptors) status was assessed using radio-receptor assay (RRA) and immunohistochemical (IH) method. The data showed that there were 21 cases of infiltrating ductal carcinoma of the breast and 3 cases of medullary carcinoma. The age of the patients ranged from 36 to 71 years and 4 patients were post-menopausal. The oestrogen receptor (ER) and progesteronc receptor (PR) status were analyzed by radio-receptor assay using 'H-oestradiol and 3 H-ORG respectively, and also by IH using immunoperoxidase detection assay (DAKO LSAB 2 Kit. Peroxidase K 677). Primary antibodies used were also procured from Dako Corp. and these were mouse anti-human ER and rabbit anti-human PR antibodies. On RRA analysis, 22 (95.7%) cases showed ER positivity (i.e. >20 fmol/mg of cytosol protien), and the ER content ranged from 16.64 to 297.8 fmovmg of cytosol protein. All cases showed PR positivity, and PR content ranged from 20.56 to 364 fmoumg of cytosol protein. A significant positive correlation was found between the ER content and PR content of tumour tissues (r = 0.7132, p<0.003). No significant association was found between ER content and menopausal status or histological grade IH showed that 10 of 24 cases (41.67%) showed ER positivity of which 8 were also PR positive. PR status was negative in all ER negative tissues. A decreasing trend in ER positivity was observed with worsening in histological grade (67% positivity in Grade 1, 50% positivity in Grade 11, and 33% positivity in Grade 111). ER and PR positivity occurred more frequently in pre-menopausal women. The results of this study showed that the result derived from IH method were found to have association with grade of tumour and confirmed findings by other workers. These findings revealed that although the quantitative data from radio-receptor assay for estimation of

Syntheses of 7-Substituted α-Cyperone Derivatives for Selective Sigma-1 Receptor over Cannabinoid-1 Receptor Binding Affinities

Energy Technology Data Exchange (ETDEWEB)

Park, Juyoung; Shin, Younggyun; Yoon, Sunghwa [Ajou Univ., Suwon (Korea, Republic of); Kim, Keewon; Kwon, Youngbae [ChonBuk National Univ., Jeonju (Korea, Republic of)

2013-11-15

We have successfully synthesized seven α-cyperone derivatives and found that the presence of a hydrogen bond donor/acceptor groups at the C7 position of α-cyperone significantly affects specificity and potency of CB{sub 1} receptor binding affinity over sigma-1 receptor binding affinity. In particular, the presence of the amino moiety at the C7 position of α-cyperone is beneficial for binding to sigmia-1 receptor. The molecular mechanism of compound 8 involved in the high binding affinity to sigma-1 receptor is under investigation. We first synthesized α-cyperone 1 by following the previously reported synthetic routes.15-19 In brief, azeotropic imination of (+)-dihydrocarvone and (R)-(+)-1-phenylethylamine followed by alkylation with a slight excess of ethyl vinyl ketone (EVK) in THF at 40 .deg. C produced the Micheal adduct. The resulting adduct was hydrolyzed and then treated with sodium methoxide at room temperature to give an easily separable mixture of α-cyperone 1 and its side product. Flash chromatography resulted in pure α-cyperone 1 in a 30% yield from (+)-dihydrocarvone.

Selective mode of action of guanidine-containing non-peptides at human NPFF receptors.

Science.gov (United States)

Findeisen, Maria; Würker, Cäcilia; Rathmann, Daniel; Meier, René; Meiler, Jens; Olsson, Roger; Beck-Sickinger, Annette G

2012-07-12

The binding pocket of both NPFF receptors was investigated, focusing on subtype-selective behavior. By use of four nonpeptidic compounds and the peptide mimetics RF9 and BIBP3226, agonistic and antagonistic properties were characterized. A set of Ala receptor mutants was generated. The binding pocket was narrowed down to the upper part of transmembrane helices V, VI, VII and the extracellular loop 2. Positions 5.27 and 6.59 have been shown to have a strong impact on receptor activation and were suggested to form an acidic, negatively charged binding pocket in both NPFF receptor subtypes. Additionally, position 7.35 was identified to play an important role in functional selectivity. According to docking experiments, the aryl group of AC-216 interacts with position 7.35 in the NPFF(1) but not in the NPFF(2) receptor. These results provide distinct insights into the receptor specific binding pockets, which is necessary for the development of drugs to address the NPFF system.

Asparagine, valine, and threonine in the third extracellular loop of muscarinic receptor have essential roles in the positive cooperativity of strychnine-like allosteric modulators

Czech Academy of Sciences Publication Activity Database

Jakubík, Jan; Krejčí, Alena; Doležal, Vladimír

2005-01-01

Roč. 313, č. 2 (2005), s. 688-696 ISSN 0022-3565 R&D Projects: GA ČR(CZ) GA309/02/1331; GA ČR(CZ) GP305/02/D090; GA AV ČR(CZ) IAA5011306; GA MŠk(CZ) LC554 Institutional research plan: CEZ:AV0Z50110509 Keywords : muscarinic receptors * positive cooperativity * mutation Subject RIV: ED - Physiology Impact factor: 4.098, year: 2005

Genetic Variations in the Human Cannabinoid Receptor Gene Are Associated with Happiness

Science.gov (United States)

Matsunaga, Masahiro; Isowa, Tokiko; Yamakawa, Kaori; Fukuyama, Seisuke; Shinoda, Jun; Yamada, Jitsuhiro; Ohira, Hideki

2014-01-01

Happiness has been viewed as a temporary emotional state (e.g., pleasure) and a relatively stable state of being happy (subjective happiness level). As previous studies demonstrated that individuals with high subjective happiness level rated their current affective states more positively when they experience positive events, these two aspects of happiness are interrelated. According to a recent neuroimaging study, the cytosine to thymine single-nucleotide polymorphism of the human cannabinoid receptor 1 gene is associated with sensitivity to positive emotional stimuli. Thus, we hypothesized that our genetic traits, such as the human cannabinoid receptor 1 genotypes, are closely related to the two aspects of happiness. In Experiment 1, 198 healthy volunteers were used to compare the subjective happiness level between cytosine allele carriers and thymine-thymine carriers of the human cannabinoid receptor 1 gene. In Experiment 2, we used positron emission tomography with 20 healthy participants to compare the brain responses to positive emotional stimuli of cytosine allele carriers to that of thymine-thymine carriers. Compared to thymine-thymine carriers, cytosine allele carriers have a higher subjective happiness level. Regression analysis indicated that the cytosine allele is significantly associated with subjective happiness level. The positive mood after watching a positive film was significantly higher for the cytosine allele carriers compared to the thymine-thymine carriers. Positive emotion-related brain region such as the medial prefrontal cortex was significantly activated when the cytosine allele carriers watched the positive film compared to the thymine-thymine carriers. Thus, the human cannabinoid receptor 1 genotypes are closely related to two aspects of happiness. Compared to thymine-thymine carriers, the cytosine allele carriers of the human cannabinoid receptor 1 gene, who are sensitive to positive emotional stimuli, exhibited greater magnitude

Genetic variations in the human cannabinoid receptor gene are associated with happiness.

Directory of Open Access Journals (Sweden)

Masahiro Matsunaga

Full Text Available Happiness has been viewed as a temporary emotional state (e.g., pleasure and a relatively stable state of being happy (subjective happiness level. As previous studies demonstrated that individuals with high subjective happiness level rated their current affective states more positively when they experience positive events, these two aspects of happiness are interrelated. According to a recent neuroimaging study, the cytosine to thymine single-nucleotide polymorphism of the human cannabinoid receptor 1 gene is associated with sensitivity to positive emotional stimuli. Thus, we hypothesized that our genetic traits, such as the human cannabinoid receptor 1 genotypes, are closely related to the two aspects of happiness. In Experiment 1, 198 healthy volunteers were used to compare the subjective happiness level between cytosine allele carriers and thymine-thymine carriers of the human cannabinoid receptor 1 gene. In Experiment 2, we used positron emission tomography with 20 healthy participants to compare the brain responses to positive emotional stimuli of cytosine allele carriers to that of thymine-thymine carriers. Compared to thymine-thymine carriers, cytosine allele carriers have a higher subjective happiness level. Regression analysis indicated that the cytosine allele is significantly associated with subjective happiness level. The positive mood after watching a positive film was significantly higher for the cytosine allele carriers compared to the thymine-thymine carriers. Positive emotion-related brain region such as the medial prefrontal cortex was significantly activated when the cytosine allele carriers watched the positive film compared to the thymine-thymine carriers. Thus, the human cannabinoid receptor 1 genotypes are closely related to two aspects of happiness. Compared to thymine-thymine carriers, the cytosine allele carriers of the human cannabinoid receptor 1 gene, who are sensitive to positive emotional stimuli, exhibited greater

Genetic variations in the human cannabinoid receptor gene are associated with happiness.

Science.gov (United States)

Matsunaga, Masahiro; Isowa, Tokiko; Yamakawa, Kaori; Fukuyama, Seisuke; Shinoda, Jun; Yamada, Jitsuhiro; Ohira, Hideki

2014-01-01

Happiness has been viewed as a temporary emotional state (e.g., pleasure) and a relatively stable state of being happy (subjective happiness level). As previous studies demonstrated that individuals with high subjective happiness level rated their current affective states more positively when they experience positive events, these two aspects of happiness are interrelated. According to a recent neuroimaging study, the cytosine to thymine single-nucleotide polymorphism of the human cannabinoid receptor 1 gene is associated with sensitivity to positive emotional stimuli. Thus, we hypothesized that our genetic traits, such as the human cannabinoid receptor 1 genotypes, are closely related to the two aspects of happiness. In Experiment 1, 198 healthy volunteers were used to compare the subjective happiness level between cytosine allele carriers and thymine-thymine carriers of the human cannabinoid receptor 1 gene. In Experiment 2, we used positron emission tomography with 20 healthy participants to compare the brain responses to positive emotional stimuli of cytosine allele carriers to that of thymine-thymine carriers. Compared to thymine-thymine carriers, cytosine allele carriers have a higher subjective happiness level. Regression analysis indicated that the cytosine allele is significantly associated with subjective happiness level. The positive mood after watching a positive film was significantly higher for the cytosine allele carriers compared to the thymine-thymine carriers. Positive emotion-related brain region such as the medial prefrontal cortex was significantly activated when the cytosine allele carriers watched the positive film compared to the thymine-thymine carriers. Thus, the human cannabinoid receptor 1 genotypes are closely related to two aspects of happiness. Compared to thymine-thymine carriers, the cytosine allele carriers of the human cannabinoid receptor 1 gene, who are sensitive to positive emotional stimuli, exhibited greater magnitude

Potential ligand-binding residues in rat olfactory receptors identified by correlated mutation analysis

Science.gov (United States)

Singer, M. S.; Oliveira, L.; Vriend, G.; Shepherd, G. M.

1995-01-01

A family of G-protein-coupled receptors is believed to mediate the recognition of odor molecules. In order to identify potential ligand-binding residues, we have applied correlated mutation analysis to receptor sequences from the rat. This method identifies pairs of sequence positions where residues remain conserved or mutate in tandem, thereby suggesting structural or functional importance. The analysis supported molecular modeling studies in suggesting several residues in positions that were consistent with ligand-binding function. Two of these positions, dominated by histidine residues, may play important roles in ligand binding and could confer broad specificity to mammalian odor receptors. The presence of positive (overdominant) selection at some of the identified positions provides additional evidence for roles in ligand binding. Higher-order groups of correlated residues were also observed. Each group may interact with an individual ligand determinant, and combinations of these groups may provide a multi-dimensional mechanism for receptor diversity.

Overview of receptor-based source apportionment studies for speciated atmospheric mercury

OpenAIRE

Cheng, I.; Xu, X.; Zhang, L.

2015-01-01

Receptor-based source apportionment studies of speciated atmospheric mercury are not only concerned with source contributions but also with the influence of transport, transformation, and deposition processes on speciated atmospheric mercury concentrations at receptor locations. Previous studies applied multivariate receptor models including principal components analysis and positive matrix factorization, and back trajectory receptor models including potential source contri...

Differential Modulation of GABAA and NMDA Receptors by an α7-nicotinic Acetylcholine Receptor Agonist in Chronic Glaucoma

Directory of Open Access Journals (Sweden)

Xujiao Zhou

2017-12-01

Full Text Available Presynaptic modulation of γ-aminobutyric acid (GABA release by an alpha7 nicotinic acetylcholine receptor (α7-nAChR agonist promotes retinal ganglion cell (RGC survival and function, as suggested by a previous study on a chronic glaucomatous model from our laboratory. However, the role of excitatory and inhibitory amino acid receptors and their interaction with α7-nAChR in physiological and glaucomatous events remains unknown. In this study, we investigated GABAA and N-methyl-D-aspartate (NMDA receptor activity in control and glaucomatous retinal slices and the regulation of amino acid receptor expression and function by α7-nAChR. Whole-cell patch-clamp recordings from RGCs revealed that the α7-nAChR specific agonist PNU-282987 enhanced the amplitude of currents elicited by GABA and reduced the amplitude of currents elicited by NMDA. The positive modulation of GABAA receptor and the negative modulation of NMDA receptor (NMDAR by PNU-282987-evoked were prevented by pre-administration of the α7-nAChR antagonist methyllycaconitine (MLA. The frequency and the amplitude of glutamate receptor-mediated miniature glutamatergic excitatory postsynaptic currents (mEPSCs were not significantly different between the control and glaucomatous RGCs. Additionally, PNU-282987-treated slices showed no alteration in the frequency or amplitude of mEPSCs relative to control RGCs. Moreover, we showed that expression of the α1 subunit of the GABAA receptor was downregulated and the expression of the NMDAR NR2B subunit was upregulated by intraocular pressure (IOP elevation, and the changes of high IOP were blocked by PNU-282987. In conclusion, retina GABAA and NMDARs are modulated positively and negatively, respectively, by activation of α7-nAChR in in vivo chronic glaucomatous models.

The impact of tamoxifen on breast recurrence, cosmesis, complications, and survival in estrogen receptor positive early stage breast cancer

International Nuclear Information System (INIS)

Fowble, B.; Fein, D.A.; Hanlon, A.L.; Eisenberg, B.L.; Hoffman, J.P.; Sigurdson, E.R.; Daly, M.B.; Goldstein, L.J.

1995-01-01

Purpose: In the NSABP B14 trial evaluating tamoxifen (tam) in axillary node negative, estrogen receptor positive tumors fewer breast recurrences were observed in patients treated with conservative surgery and radiation who received tam compared to the observation arm. An additional series, however, has suggested that tam adversely impacts on the cosmetic result. To further address these issues we compared the outcome of estrogen receptor positive tumors treated with conservative surgery and radiation with or without tam. Materials and Methods: From 1982 to 1991, 491 women with estrogen receptor positive stage I-II breast cancer underwent excisional biopsy, axillary dissection and radiation. The median age of the patient population was 60 years (range 39-85). The median followup was 5.3 years (range .1-12.8). 69% had T1 tumors and 83% had histologically negative axillary nodes. Reexcision was performed in 49%. The final margin of resection was negative in 64%, unknown in 18%, and close or positive in 19%. None of the patients received adjuvant chemotherapy. 154 patients received tam and 337 received no adjuvant therapy. Patients who received tam were more often axillary node positive (44% tam vs 5% no tam) and less often had unknown margins (9% tam vs 22% no tam). There were no significant differences for the 2 groups for median age, primary tumor size, histology, race, or use of reexcision. Results: The 5 yr act rate of breast recurrence was 4% for the tam patients compared to 7% for patients not receiving tam (p=.21). At 8 yrs, the breast recurrence rates were 4% for the tam patients compared to 11% for the no tam patients (p=.05). However, at 9 years the rates were 17% tam vs 14% no tam (p=.21). The benefit from tam in terms of a decreased 5 year actuarial breast recurrence rate was most evident for patients who did not have a reexcision (3% tam vs 10% no tam, p=.15), had unknown margins (7% tam vs 13% no tam, p=.37) or close margins (0% tam vs 11% no tam, p=.34

The impact of tamoxifen on breast recurrence, cosmesis, complications, and survival in estrogen receptor positive early stage breast cancer

Energy Technology Data Exchange (ETDEWEB)

Fowble, B; Fein, D A; Hanlon, A L; Eisenberg, B L; Hoffman, J P; Sigurdson, E R; Daly, M B; Goldstein, L J

1995-07-01

Purpose: In the NSABP B14 trial evaluating tamoxifen (tam) in axillary node negative, estrogen receptor positive tumors fewer breast recurrences were observed in patients treated with conservative surgery and radiation who received tam compared to the observation arm. An additional series, however, has suggested that tam adversely impacts on the cosmetic result. To further address these issues we compared the outcome of estrogen receptor positive tumors treated with conservative surgery and radiation with or without tam. Materials and Methods: From 1982 to 1991, 491 women with estrogen receptor positive stage I-II breast cancer underwent excisional biopsy, axillary dissection and radiation. The median age of the patient population was 60 years (range 39-85). The median followup was 5.3 years (range .1-12.8). 69% had T1 tumors and 83% had histologically negative axillary nodes. Reexcision was performed in 49%. The final margin of resection was negative in 64%, unknown in 18%, and close or positive in 19%. None of the patients received adjuvant chemotherapy. 154 patients received tam and 337 received no adjuvant therapy. Patients who received tam were more often axillary node positive (44% tam vs 5% no tam) and less often had unknown margins (9% tam vs 22% no tam). There were no significant differences for the 2 groups for median age, primary tumor size, histology, race, or use of reexcision. Results: The 5 yr act rate of breast recurrence was 4% for the tam patients compared to 7% for patients not receiving tam (p=.21). At 8 yrs, the breast recurrence rates were 4% for the tam patients compared to 11% for the no tam patients (p=.05). However, at 9 years the rates were 17% tam vs 14% no tam (p=.21). The benefit from tam in terms of a decreased 5 year actuarial breast recurrence rate was most evident for patients who did not have a reexcision (3% tam vs 10% no tam, p=.15), had unknown margins (7% tam vs 13% no tam, p=.37) or close margins (0% tam vs 11% no tam, p=.34

Repeated administration of alpha7 nicotinic acetylcholine receptor (nAChR) agonists, but not positive allosteric modulators, increases alpha7 nAChR levels in the brain

DEFF Research Database (Denmark)

Christensen, Ditte Z; Mikkelsen, Jens D; Hansen, Henrik H

2010-01-01

AChR binding sites in several brain regions, particularly in the prefrontal cortex. The alpha7 nAChR agonists SSR180711 and PNU-282987 also increase [(125)I]-BTX binding, suggesting that this is a general consequence of alpha7 nAChR agonism. Interestingly, the alpha7 nAChR positive allosteric modulators PNU......The alpha7 nicotinic acetylcholine receptor (nAChR) is an important target for treatment of cognitive deficits in schizophrenia and Alzheimer's disease. However, the receptor desensitizes rapidly in vitro, which has led to concern regarding its applicability as a clinically relevant drug target....... Here we investigate the effects of repeated agonism on alpha7 nAChR receptor levels and responsiveness in vivo in rats. Using [(125)I]-alpha-bungarotoxin (BTX) autoradiography we show that acute or repeated administration with the selective alpha7 nAChR agonist A-582941 increases the number of alpha7 n...

Characterization of Aromatase Expression in the Adult Male and Female Mouse Brain. I. Coexistence with Oestrogen Receptors α and β, and Androgen Receptors

Science.gov (United States)

Stanić, Davor; Dubois, Sydney; Chua, Hui Kheng; Tonge, Bruce; Rinehart, Nicole; Horne, Malcolm K.; Boon, Wah Chin

2014-01-01

Aromatase catalyses the last step of oestrogen synthesis. There is growing evidence that local oestrogens influence many brain regions to modulate brain development and behaviour. We examined, by immunohistochemistry, the expression of aromatase in the adult male and female mouse brain, using mice in which enhanced green fluorescent protein (EGFP) is transcribed following the physiological activation of the Cyp19A1 gene. EGFP-immunoreactive processes were distributed in many brain regions, including the bed nucleus of the stria terminalis, olfactory tubercle, medial amygdaloid nucleus and medial preoptic area, with the densest distributions of EGFP-positive cell bodies in the bed nucleus and medial amygdala. Differences between male and female mice were apparent, with the density of EGFP-positive cell bodies and fibres being lower in some brain regions of female mice, including the bed nucleus and medial amygdala. EGFP-positive cell bodies in the bed nucleus, lateral septum, medial amygdala and hypothalamus co-expressed oestrogen receptor (ER) α and β, or the androgen receptor (AR), although single-labelled EGFP-positive cells were also identified. Additionally, single-labelled ERα−, ERβ- or AR-positive cell bodies often appeared to be surrounded by EGFP-immunoreactive nerve fibres/terminals. The widespread distribution of EGFP-positive cell bodies and fibres suggests that aromatase signalling is common in the mouse brain, and that locally synthesised brain oestrogens could mediate biological effects by activating pre- and post-synaptic oestrogen α and β receptors, and androgen receptors. The higher number of EGFP-positive cells in male mice may indicate that the autocrine and paracrine effects of oestrogens are more prominent in males than females. PMID:24646567

Expression of Hormonal Carcinogenesis Genes and Related Regulatory microRNAs in Uterus and Ovaries of DDT-Treated Female Rats.

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Kalinina, T S; Kononchuk, V V; Gulyaeva, L F

2017-10-01

The insecticide dichlorodiphenyltrichloroethane (DDT) is a nonmutagenic xenobiotic compound able to exert estrogen-like effects resulting in activation of estrogen receptor-α (ERα) followed by changed expression of its downstream target genes. In addition, studies performed over recent years suggest that DDT may also influence expression of microRNAs. However, an impact of DDT on expression of ER, microRNAs, and related target genes has not been fully elucidated. Here, using real-time PCR, we assessed changes in expression of key genes involved in hormonal carcinogenesis as well as potentially related regulatory oncogenic/tumor suppressor microRNAs and their target genes in the uterus and ovaries of female Wistar rats during single and chronic multiple-dose DDT exposure. We found that applying DDT results in altered expression of microRNAs-221, -222, -205, -126a, and -429, their target genes (Pten, Dicer1), as well as genes involved in hormonal carcinogenesis (Esr1, Pgr, Ccnd1, Cyp19a1). Notably, Cyp19a1 expression seems to be also regulated by microRNAs-221, -222, and -205. The data suggest that epigenetic effects induced by DDT as a potential carcinogen may be based on at least two mechanisms: (i) activation of ERα followed by altered expression of the target genes encoding receptor Pgr and Ccnd1 as well as impaired expression of Cyp19a1, affecting, thereby, cell hormone balance; and (ii) changed expression of microRNAs resulting in impaired expression of related target genes including reduced level of Cyp19a1 mRNA.

A stable neurotensin-based radiopharmaceutical for targeted imaging and therapy of neurotensin receptor-positive tumours

International Nuclear Information System (INIS)

Garcia-Garayoa, Elisa; Blaeuenstein, Peter; Blanc, Alain; Maes, Veronique; Tourwe, Dirk; Schubiger, P.A.

2009-01-01

Neurotensin (NT) and its high affinity receptor (NTR1) are involved in several neoplastic processes. Thus, NT-based radiopharmaceuticals are potential tracers for targeted diagnosis and therapy of NTR-positive tumours. A new analogue based on NT(8-13), NT-XIX, with the three enzymatic cleavage sites stabilised, was synthesised and tested. The synthesis was performed by Boc strategy. Labelling with 99m Tc/ 188 Re was performed using the tricarbonyl technique. Metabolic stability was tested in vitro and in vivo. NT-XIX was further characterised in vitro in HT-29 cells and in vivo in nude mice with HT-29 xenografts. NT-XIX showed much longer half-lives than non-stabilised analogues. Binding to NTR1 was highly specific, although the affinity was lower than that of natural NT. Bound activity rapidly internalised into HT-29 cells and 50% remained trapped after 24 h. In the time-course biodistribution, the highest uptake was found in the tumour at all p.i. times. In vivo uptake was specific, and accumulation of activity in the kidneys was low. Radioactivity clearance from healthy organs was faster than that from the tumour, resulting in improved tumour-to-tissue ratios and good SPECT/CT imaging. Treatment with 188 Re-NT-XIX (30 MBq, in three or four fractions) decreased tumour growth by 50% after 3 weeks. The high in vivo stability and the favourable in vivo behaviour makes NT-XIX an excellent candidate for the imaging and therapy of NTR1-positive tumours. (orig.)

Prevalence of Circulating Tumor Cells After Adjuvant Chemotherapy With or Without Anthracyclines in Patients With HER2-negative, Hormone Receptor-positive Early Breast Cancer.

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Schramm, Amelie; Schochter, Fabienne; Friedl, Thomas W P; de Gregorio, Nikolaus; Andergassen, Ulrich; Alunni-Fabbroni, Marianna; Trapp, Elisabeth; Jaeger, Bernadette; Heinrich, Georg; Camara, Oumar; Decker, Thomas; Ober, Angelika; Mahner, Sven; Fehm, Tanja N; Pantel, Klaus; Fasching, Peter A; Schneeweiss, Andreas; Janni, Wolfgang; Rack, Brigitte K

2017-07-01

Use of anthracycline-based chemotherapy in patients with early breast cancer (EBC) has been well-established but is often associated with cardiotoxicity. Based on data suggesting a limited benefit of anthracyclines in human epidermal growth factor receptor 2 (HER2)-negative patients, the Simultaneous Study of Docetaxel Based Anthracycline Free Adjuvant Treatment Evaluation, as well as Life Style Intervention Strategies (SUCCESS) C study randomized patients to either anthracycline-containing or anthracycline-free chemotherapy. Given the proven prognostic value of circulating tumor cells (CTCs) in EBC, we compared the prevalence of CTCs after chemotherapy between both treatment arms for a preliminary efficacy assessment. The SUCCESS C trial (NCT00847444) is an open-label, phase III study randomizing 3547 patients with HER2-negative EBC to either 3 cycles of epirubicin, 5-fluorouracil, and cyclophosphamide followed by 3 cycles of docetaxel (FEC-DOC) or 6 cycles of docetaxel and cyclophosphamide (DOC-C). CTC status was prospectively evaluated in hormone receptor-positive patients at the time of last chemotherapy cycle using the US Food and Drug Administration-approved CellSearch System (Janssen Diagnostics). Data on CTC status were available for 1766 patients. Overall, CTCs were found in 221 (12.5%) patients. Univariate analyses revealed that presence of CTCs at time of last chemotherapy cycle was not significantly associated with tumor or patient characteristics (all P > .1). There was no significant difference with respect to presence of CTCs between patients randomized to FEC-DOC or DOC-C (11.5% vs. 13.6%; P = .18). The comparable prevalence of CTCs at the time of last chemotherapy cycle may indicate that anthracycline-free chemotherapy is equally effective to anthracycline-containing chemotherapy in HER2-negative, hormone receptor-positive EBC. However, efficacy data from the final survival analysis of SUCCESS C have to be awaited to confirm these preliminary

Molecular Insights into the Transmembrane Domain of the Thyrotropin Receptor.

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Vanessa Chantreau

Full Text Available The thyrotropin receptor (TSHR is a G protein-coupled receptor (GPCR that is member of the leucine-rich repeat subfamily (LGR. In the absence of crystal structure, the success of rational design of ligands targeting the receptor internal cavity depends on the quality of the TSHR models built. In this subfamily, transmembrane helices (TM 2 and 5 are characterized by the absence of proline compared to most receptors, raising the question of the structural conformation of these helices. To gain insight into the structural properties of these helices, we carried out bioinformatics and experimental studies. Evolutionary analysis of the LGR family revealed a deletion in TM5 but provided no information on TM2. Wild type residues at positions 2.58, 2.59 or 2.60 in TM2 and/or at position 5.50 in TM5 were substituted to proline. Depending on the position of the proline substitution, different effects were observed on membrane expression, glycosylation, constitutive cAMP activity and responses to thyrotropin. Only proline substitution at position 2.59 maintained complex glycosylation and high membrane expression, supporting occurrence of a bulged TM2. The TSHR transmembrane domain was modeled by homology with the orexin 2 receptor, using a protocol that forced the deletion of one residue in the TM5 bulge of the template. The stability of the model was assessed by molecular dynamics simulations. TM5 straightened during the equilibration phase and was stable for the remainder of the simulations. Our data support a structural model of the TSHR transmembrane domain with a bulged TM2 and a straight TM5 that is specific of glycoprotein hormone receptors.

The RNA binding protein HuR differentially regulates unique subsets of mRNAs in estrogen receptor negative and estrogen receptor positive breast cancer

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Chen Jing

2010-04-01

Full Text Available Abstract Background The discordance between steady-state levels of mRNAs and protein has been attributed to posttranscriptional control mechanisms affecting mRNA stability and translation. Traditional methods of genome wide microarray analysis, profiling steady-state levels of mRNA, may miss important mRNA targets owing to significant posttranscriptional gene regulation by RNA binding proteins (RBPs. Methods The ribonomic approach, utilizing RNA immunoprecipitation hybridized to microarray (RIP-Chip, provides global identification of putative endogenous mRNA targets of different RBPs. HuR is an RBP that binds to the AU-rich elements (ARE of labile mRNAs, such as proto-oncogenes, facilitating their translation into protein. HuR has been shown to play a role in cancer progression and elevated levels of cytoplasmic HuR directly correlate with increased invasiveness and poor prognosis for many cancers, including those of the breast. HuR has been described to control genes in several of the acquired capabilities of cancer and has been hypothesized to be a tumor-maintenance gene, allowing for cancers to proliferate once they are established. Results We used HuR RIP-Chip as a comprehensive and systematic method to survey breast cancer target genes in both MCF-7 (estrogen receptor positive, ER+ and MDA-MB-231 (estrogen receptor negative, ER- breast cancer cell lines. We identified unique subsets of HuR-associated mRNAs found individually or in both cell types. Two novel HuR targets, CD9 and CALM2 mRNAs, were identified and validated by quantitative RT-PCR and biotin pull-down analysis. Conclusion This is the first report of a side-by-side genome-wide comparison of HuR-associated targets in wild type ER+ and ER- breast cancer. We found distinct, differentially expressed subsets of cancer related genes in ER+ and ER- breast cancer cell lines, and noted that the differential regulation of two cancer-related genes by HuR was contingent upon the cellular

The GRIN-Global Information Management System – Public Interface Demonstration and Input Opportunity

Science.gov (United States)

The GRIN-Global (GG) Information Management System, under development for the past three years, provides the world's crop genebanks and plant genetic resource (PGR) users with a powerful, flexible, easy-to-use PGR information management system. Developed jointly by the USDA Agricultural Research Ser...

The GRIN-Global Information Management System – A Preview and Opportunity for Public User Input

Science.gov (United States)

The GRIN-Global Information Management System, under development for the past two years, will provide the world's crop genebanks and plant genetic resource (PGR) users with a powerful, flexible, easy-to-use PGR information management system. Developed jointly by the USDA Agricultural Research Servi...

Structure-activity relationships of the melanocortin tetrapeptide Ac-His-DPhe-Arg-Trp-NH2 at the mouse melanocortin receptors. Part 3: modifications at the Arg position.

Science.gov (United States)

Holder, Jerry Ryan; Xiang, Zhimin; Bauzo, Rayna M; Haskell-Luevano, Carrie

2003-01-01

The melanocortin pathway is involved in the regulation of several physiological functions including skin pigmentation, steroidogenesis, obesity, energy homeostasis, and exocrine gland function. This melanocortin pathway consists of five known G-protein coupled receptors, endogenous agonists derived from the proopiomelanocortin (POMC) gene transcript, the endogenous antagonists Agouti and the Agouti-related protein (AGRP) and signals through the intracellular cAMP signal transduction pathway. The melanocortin-3 receptor (MC3R) and melanocortin-4 receptor (MC4R) located in the brain are implicated as participating in the metabolic and food intake aspects of energy homeostasis and are stimulated by melanocortin agonists such as alpha-melanocyte stimulation hormone (alpha-MSH). All the endogenous (POMC-derived) melanocortin agonists contain the putative message sequence "His-Phe-Arg-Trp." Herein, we report 12 tetrapeptides, based upon the template Ac-His(6)-DPhe(7)-Arg(8)-Trp(9)-NH(2) (alpha-MSH numbering) that have been modified at the Arg(8) position by neutral, basic, or acidic amino acid side chains. These peptides have been pharmacologically characterized for agonist activity at the mouse melanocortin receptors MC1R, MC3R, MC4R, and MC5R. The most notable results of this study include the observation that removal of the guanidinyl side chain moiety results in decreased melanocortin receptor potency, but that this Arg(8) side chain is not critical for melanocortin receptor agonist activity. Additionally, incorporation of the homoArg(8) residue results in 56-fold MC4R versus MC3R selectivity, and the Orn(8) residue results in 123-fold MC4R versus MC5R and 63-fold MC5R versus MC3R selectivity. Copyright 2002 Elsevier Science Inc.

Characterization of Angiotensin II Molecular Determinants Involved in AT1 Receptor Functional Selectivity.

Science.gov (United States)

Domazet, Ivana; Holleran, Brian J; Richard, Alexandra; Vandenberghe, Camille; Lavigne, Pierre; Escher, Emanuel; Leduc, Richard; Guillemette, Gaétan

2015-06-01

The octapeptide angiotensin II (AngII) exerts a variety of cardiovascular effects through the activation of the AngII type 1 receptor (AT1), a G protein-coupled receptor. The AT1 receptor engages and activates several signaling pathways, including heterotrimeric G proteins Gq and G12, as well as the extracellular signal-regulated kinases (ERK) 1/2 pathway. Additionally, following stimulation, βarrestin is recruited to the AT1 receptor, leading to receptor desensitization. It is increasingly recognized that specific ligands selectively bind and favor the activation of some signaling pathways over others, a concept termed ligand bias or functional selectivity. A better understanding of the molecular basis of functional selectivity may lead to the development of better therapeutics with fewer adverse effects. In the present study, we developed assays allowing the measurement of six different signaling modalities of the AT1 receptor. Using a series of AngII peptide analogs that were modified in positions 1, 4, and 8, we sought to better characterize the molecular determinants of AngII that underlie functional selectivity of the AT1 receptor in human embryonic kidney 293 cells. The results reveal that position 1 of AngII does not confer functional selectivity, whereas position 4 confers a bias toward ERK signaling over Gq signaling, and position 8 confers a bias toward βarrestin recruitment over ERK activation and Gq signaling. Interestingly, the analogs modified in position 8 were also partial agonists of the protein kinase C (PKC)-dependent ERK pathway via atypical PKC isoforms PKCζ and PKCι. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Standard Pathologic Features Can Be Used to Identify a Subset of Estrogen Receptor-Positive, HER2 Negative Patients Likely to Benefit from Neoadjuvant Chemotherapy.

Science.gov (United States)

Petruolo, Oriana A; Pilewskie, Melissa; Patil, Sujata; Barrio, Andrea V; Stempel, Michelle; Wen, Hannah Y; Morrow, Monica

2017-09-01

The benefit of neoadjuvant chemotherapy (NAC) in patients with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancers and in invasive lobular carcinoma (ILC) is uncertain due to the low rates of pathologic complete response (pCR). The aim of this study was to determine if pathologic features can identify subsets likely to benefit from NAC. Patients with stage I-III ER+, HER2- breast cancer receiving NAC were retrospectively reviewed. Endpoints were downstaging to breast-conserving surgery (BCS) and nodal pCR after NAC. Patients were grouped by progesterone receptor (PR) status and grade/differentiation (high grade or poor [HP] vs. non-HP). From 2007 to 2016, 402 ER+/HER2- cancers in patients receiving NAC were identified. Median age was 50 years, 98% were clinical stage II-III, and 75% were cN+. Overall pCR rate was 5%; breast pCR in 7% and nodal pCR in 15% of cN+ patients (p benefit from NAC are those with PR- and HP tumors. Patients with ILC are unlikely to downstage in the breast or axilla compared with IDC. The use of these criteria can assist in defining the initial treatment approach.

Kidney protection during peptide receptor radionuclide therapy with somatostatin analogues.

NARCIS (Netherlands)

Rolleman, E.J.; Melis, M.; Valkema, R.; Boerman, O.C.; Krenning, E.P.; Jong, M. de

2010-01-01

This review focuses on the present status of kidney protection during peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues. This treatment modality for somatostatin receptor-positive tumours is limited by renal reabsorption and retention of radiolabelled peptides

Prognostic utility of the 21-gene assay in hormone receptor-positive operable breast cancer compared with classical clinicopathologic features.

Science.gov (United States)

Goldstein, Lori J; Gray, Robert; Badve, Sunil; Childs, Barrett H; Yoshizawa, Carl; Rowley, Steve; Shak, Steven; Baehner, Frederick L; Ravdin, Peter M; Davidson, Nancy E; Sledge, George W; Perez, Edith A; Shulman, Lawrence N; Martino, Silvana; Sparano, Joseph A

2008-09-01

Adjuvant! is a standardized validated decision aid that projects outcomes in operable breast cancer based on classical clinicopathologic features and therapy. Genomic classifiers offer the potential to more accurately identify individuals who benefit from chemotherapy than clinicopathologic features. A sample of 465 patients with hormone receptor (HR) -positive breast cancer with zero to three positive axillary nodes who did (n = 99) or did not have recurrence after chemohormonal therapy had tumor tissue evaluated using a 21-gene assay. Histologic grade and HR expression were evaluated locally and in a central laboratory. Recurrence Score (RS) was a highly significant predictor of recurrence, including node-negative and node-positive disease (P < .001 for both) and when adjusted for other clinical variables. RS also predicted recurrence more accurately than clinical variables when integrated by an algorithm modeled after Adjuvant! that was adjusted to 5-year outcomes. The 5-year recurrence rate was only 5% or less for the estimated 46% of patients who have a low RS (< 18). The 21-gene assay was a more accurate predictor of relapse than standard clinical features for individual patients with HR-positive operable breast cancer treated with chemohormonal therapy and provides information that is complementary to features typically used in anatomic staging, such as tumor size and lymph node involvement. The 21-gene assay may be used to select low-risk patients for abbreviated chemotherapy regimens similar to those used in our study or high-risk patients for more aggressive regimens or clinical trials evaluating novel treatments.

New radiopharmaecuticals for receptor scintigraphy and radionuclide therapy

International Nuclear Information System (INIS)

Virgolini, I.; Traub, T.; Leimer, M.; Novotny, C.; Pangerl, T.; Ofluoglu, S.; Halvadjieva, E.; Smith-Jones, P.; Flores, J.; Li, S.R.; Angelberger, P.; Havlik, E.; Andreae, F.; Raderer, M.; Kurtaran, A.; Niederle, B.; Dudczak, R.

2000-01-01

In vitro data have demonstrated a high amount of receptors for various hormones and peptides on malignant cells of neuroendocrine origin. Among these, binding sites for member of the SST-family (hSSTR1-5) are frequently found, and their expression has led to therapeutic and diagnostic attempts to specifically target these receptors. Receptor scintigraphy using radiolabeled peptide ligands has proved its effectiveness in clinical practice. In addition, initial results have indicated a clinical potential for receptor-targeted radiotherapy. Based on somatostatin (SST) receptor (R) recognition, the novel radiopharmaceuticals 111 In/ 9 0Y-DOTA-lanreotide developed at the University of Vienna as well as 111 In/ 9 0Y-DOTA-DPhe 1 -Tyr 3 -octreotide (NOVARTIS) both have provided promising data for diagnosis and treatment of hSSTR-positive tumors. SSTR scintigraphy using 111 In-DTPA-DPhe 1 -octreotide has a high positive predictive value for the vast majority of neuroendocrine tumors and has gained its place in the diagnostic work-up as well as follow-up of patients. Here it was used 111 In-DOTA-lanreotide scintigraphy in 166 patients since 1997 and have seen positive results in 93% of patients. In 42 patients with neuroendocrine tumors comparative data were obtained. As opposed to 111 In-DTPA-DPhe 1 -octreotide and 111 In-DOTA-DPhe 1 -Tyr 3 -octreotide, discrepancies in the scintigraphic results were seen in about one third of patients concerning both the tumor uptake as well as tumor lesion detection. Initial results both with 9 0Y-DOTA-lanreotide as well as 9 0Y-DOTA-DPhe 1 -Tyr 3 -octreotide has pointed out the clinical potential of radionuclide receptor-targeted radiotherapy. This new therapy could offer palliation and disease control at a reduced cost. The final peptide therapy strategy is most probably cheaper than conventional radio therapies or prolonged chemo therapies. Overall, receptor-mediated radiotherapy with 9 0Y-DOTA-lanreotide/ 9 0Y-DOTA-DPhe 1 -Tyr 3

MIG-6 negatively regulates STAT3 phosphorylation in uterine epithelial cells

Science.gov (United States)

Yoo, Jung-Yoon; Yang, Woo Sub; Lee, Jae Hee; Kim, Byung Gak; Broaddus, Russell R.; Lim, Jeong M.; Kim, Tae Hoon; Jeong, Jae-Wook

2017-01-01

Endometrial cancer is the most common malignancy of the female genital tract. Progesterone (P4) has been used for several decades in endometrial cancer treatment, especially in women who wish to retain fertility. However, it is unpredictable which patients will respond to P4 treatment and which may have a P4 resistant cancer. Therefore, identifying the mechanism of P4 resistance is essential to improve the therapies for endometrial cancer. Mitogen-inducible gene 6 (Mig-6) is a critical mediator of progesterone receptor (PGR) action in the uterus. In order to study the function of Mig-6 in P4 resistance, we generated a mouse model in which we specifically ablated Mig-6 in uterine epithelial cells using Sprr2f-cre mice (Sprr2fcre+Mig-6f/f). Female mutant mice develop endometrial hyperplasia due to aberrant phosphorylation of STAT3 and proliferation of the endometrial epithelial cells. The results from our immunoprecipitation and cell culture experiments showed that MIG-6 inhibited phosphorylation of STAT3 via protein interactions. Our previous study showed P4 resistance in mice with Mig-6 ablation in Pgr positive cells (Pgrcre/+Mig-6f/f). However, Sprr2fcre+Mig-6f/f mice were P4 responsive. P4 treatment significantly decreased STAT3 phosphorylation and epithelial proliferation in the uterus of mutant mice. We showed that Mig-6 has an important function of tumor suppressor via inhibition of STAT3 phosphorylation in uterine epithelial cells and the anti-tumor effects of P4 are mediated by the endometrial stroma. This data helps to develop a new signaling pathway in the regulation of steroid hormones in the uterus, and to overcome P4 resistance in human reproductive diseases, such as endometrial cancer. PMID:28925396

Worse prognosis in breast cancer patients can be predicted by immunohistochemical analysis of positive MMP-2 and negative estrogen and progesterone receptors

Directory of Open Access Journals (Sweden)

Edneia A. S. Ramos

Full Text Available Summary Introduction: Breast cancer is the most cause of death, and approximately 90% of these deaths are due to metastases. Matrix metalloproteinase-2 (MMP-2 gelatinase activity is able to degrade a major constituent of the tumor microenvironment, type IV collagen. Two well-established proteins used as markers in clinical practice for breast cancer are the receptors for estrogen (ER and progesterone (PR. Although the presence of these receptors has been associated with a better prognosis, loss of these proteins can occur during tumor progression, with subsequent resistance to hormone therapy. Objective: To study the correlation among MMP-2, ER, and PR, as well as the establishment of the metastatic process in primary breast tumors. Method: Breast cancer samples (n=44 were analyzed by immunohistochemistry for MMP-2, ER, and PR. Results: We observed that 90% of patients who had metastases and died showed positive staining for MMP-2 (p=0.0082 for both. Using Kaplan-Meier analysis, we found that negative ER patients who were also positive for MMP-2 had even worse disease-free survival (DFS and overall survival (OS (p= 0.012 and p=0.005, respectively. Similar results were found in PR-negative patients for DFS (a trend p=0.077 and OS (p=0.038. Conclusion: Regardless of our small sample size (n=44, the data obtained strongly suggest that MMP-2 in combination with already well-established markers could help to predict the emergence of metastases and death in patients with breast cancer.

IL-6 Overexpression in ERG-Positive Prostate Cancer Is Mediated by Prostaglandin Receptor EP2.

Science.gov (United States)

Merz, Constanze; von Mässenhausen, Anne; Queisser, Angela; Vogel, Wenzel; Andrén, Ove; Kirfel, Jutta; Duensing, Stefan; Perner, Sven; Nowak, Michael

2016-04-01

Prostate cancer is the most diagnosed cancer in men and multiple risk factors and genetic alterations have been described. The TMPRSS2-ERG fusion event and the overexpression of the transcription factor ERG are present in approximately 50% of all prostate cancer patients, however, the clinical outcome is still controversial. Prostate tumors produce various soluble factors, including the pleiotropic cytokine IL-6, regulating cellular processes such as proliferation and metastatic segregation. Here, we used prostatectomy samples in a tissue microarray format and analyzed the co-expression and the clinicopathologic data of ERG and IL-6 using immunohistochemical double staining and correlated the read-out with clinicopathologic data. Expression of ERG and IL-6 correlated strongly in prostate tissue samples. Forced expression of ERG in prostate tumor cell lines resulted in significantly increased secretion of IL-6, whereas the down-regulation of ERG decreased IL-6 secretion. By dissecting the underlying mechanism in prostate tumor cell lines we show the ERG-mediated up-regulation of the prostanoid receptors EP2 and EP3. The prostanoid receptor EP2 was overexpressed in human prostate cancer tissue. Furthermore, the proliferation rate and IL-6 secretion in DU145 cells was reduced after treatment with EP2-receptor antagonist. Collectively, our study shows that the expression of ERG in prostate cancer is linked to the expression of IL-6 mediated by the prostanoid receptor EP2. Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Palbociclib in hormone receptor positive advanced breast cancer: A cost-utility analysis.

Science.gov (United States)

Raphael, J; Helou, J; Pritchard, K I; Naimark, D M

2017-11-01

The addition of palbociclib to letrozole improves progression-free survival in the first-line treatment of hormone receptor positive advanced breast cancer (ABC). This study assesses the cost-utility of palbociclib from the Canadian healthcare payer perspective. A probabilistic discrete event simulation (DES) model was developed and parameterised with data from the PALOMA 1 and 2 trials and other sources. The incremental cost per quality-adjusted life-month (QALM) gained for palbociclib was calculated. A time horizon of 15 years was used in the base case with costs and effectiveness discounted at 5% annually. Time-to- progression and time-to-death were derived from a Weibull and exponential distribution. Expected costs were based on Ontario fees and other sources. Probabilistic sensitivity analyses were conducted to account for parameter uncertainty. Compared to letrozole, the addition of palbociclib provided an additional 14.7 QALM at an incremental cost of $161,508. The resulting incremental cost-effectiveness ratio was $10,999/QALM gained. Assuming a willingness-to-pay (WTP) of $4167/QALM, the probability of palbociclib to be cost-effective was 0%. Cost-effectiveness acceptability curves derived from a probabilistic sensitivity analysis showed that at a WTP of $11,000/QALM gained, the probability of palbociclib to be cost-effective was 50%. The addition of palbociclib to letrozole is unlikely to be cost-effective for the treatment of ABC from a Canadian healthcare perspective with its current price. While ABC patients derive a meaningful clinical benefit from palbociclib, considerations should be given to increase the WTP threshold and reduce the drug pricing, to render this strategy more affordable. Copyright © 2017 Elsevier Ltd. All rights reserved.

Tannic Acid Preferentially Targets Estrogen Receptor-Positive Breast Cancer

Directory of Open Access Journals (Sweden)

Brian W. Booth

2013-01-01

Full Text Available Research efforts investigating the potential of natural compounds in the fight against cancer are growing. Tannic acid (TA belongs to the class of hydrolysable tannins and is found in numerous plants and foods. TA is a potent collagen cross-linking agent; the purpose of this study was to generate TA-cross-linked beads and assess the effects on breast cancer cell growth. Collagen beads were stable at body temperature following crosslinking. Exposure to collagen beads with higher levels of TA inhibited proliferation and induced apoptosis in normal and cancer cells. TA-induced apoptosis involved activation of caspase 3/7 and caspase 9 but not caspase 8. Breast cancer cells expressing the estrogen receptor were more susceptible to the effects of TA. Taken together the results suggest that TA has the potential to become an anti-ER+ breast cancer treatment or preventative agent.

Progranulin as a prognostic biomarker for breast cancer recurrence in patients who had hormone receptor-positive tumors: a cohort study.

Directory of Open Access Journals (Sweden)

Dong Hoe Koo

Full Text Available Progranulin (PGRN is considered to play an important role in breast cancer tumorigenesis and in inhibiting tamoxifen-induced apoptosis. We aimed to determine whether PGRN levels are associated with breast cancer recurrence after curative surgery.We evaluated the associations between preoperative serum PGRN levels and breast cancer recurrence in a cohort of 697 newly diagnosed breast cancer patients who underwent curative surgery between April 2001 and December 2004. The mean age ± standard deviation (SD was 46 ± 9.8 years, and all patients with hormone receptor (HR-positive tumors received adjuvant tamoxifen therapy. At a median follow-up of 62.2 months (range, 2.9-98.2, 89 patients (12.8% had experienced a recurrence and 51 patients (7.3% had died. In the HR-positive group, serum PGRN levels were associated with recurrence according to the log-rank test for trend (p for trend = 0.049. There was no association between PGRN levels and recurrence in the HR-negative group (p for trend = 0.658. Adjusted hazard ratios, including possible confounders, revealed a linear relationship between serum PGRN levels and recurrence in the HR-positive group (p for trend = 0.049, and this association was further strengthened after excluding patients who had no lymph node metastasis (p for trend = 0.038.Serum PGRN levels were clinically significant for predicting recurrence in patients with HR-positive breast cancer during adjuvant tamoxifen therapy.

125I-labeled 8-phenylxanthine derivatives: antagonist radioligands for adenosine A1 receptors

International Nuclear Information System (INIS)

Linden, J.; Patel, A.; Earl, C.Q.; Craig, R.H.; Daluge, S.M.

1988-01-01

A series of 8-phenylxanthine derivatives has been synthesized with oxyacetic acid on the para phenyl position to increase aqueous solubility and minimize nonspecific binding and iodinatable groups on the 1- or 3-position of the xanthine ring. The structure-activity relationship for binding of these compounds to A1 adenosine receptors of bovine and rat brain and A2 receptors of human platelets was examined. The addition of arylamine or photosensitive aryl azide groups to the 3-position of xanthine had little effect on A1 binding affinity with or without iodination, whereas substitutions at the 1-position caused greatly reduced A1 binding affinity. The addition of an aminobenzyl group to the 3-position of the xanthine had little effect on A2 binding affinity, but 3-aminophenethyl substitution decreased A2 binding affinity. Two acidic 3-(arylamino)-8-phenylxanthine derivatives were labeled with 125 I and evaluated as A1 receptor radioligands. The new radioligands bound to A1 receptors with KD values of 1-1.25 nM. Specific binding represented over 80% of total binding. High concentrations of NaCl or other salts increased the binding affinity of acidic but not neutral antagonists, suggesting that interactions between ionized xanthines and receptors may be affected significantly by changes in ionic strength. On the basis of binding studies with these antagonists and isotope dilution with the agonist [ 125 I]N6-(4-amino-3-iodobenzyl)adenosine, multiple agonist affinity states of A1 receptors have been identified

Construction of covalently coupled, concatameric dimers of 7TM receptors

DEFF Research Database (Denmark)

Terpager, Marie; Scholl, D Jason; Kubale, Valentina

2009-01-01

-Ala repeats flanked by flexible spacers and positively charged residues to ensure correct inside-out orientation plus an extracellular HA-tag to construct covalently coupled dimers of 7TM receptors. Such 15 TM concatameric homo- and heterodimers of the beta(2)-adrenergic and the NK(1) receptors, which...... for either of the protomers, which was not observed upon simple coexpression of the two receptors. It is concluded that covalently joined 7TM receptor dimers with surprisingly normal receptor properties can be constructed with use of an artificial transmembrane connector, which perhaps can be used to fuse...

Progesterone receptor isoform A may regulate the effects of neoadjuvant aglepristone in canine mammary carcinoma

DEFF Research Database (Denmark)

Guil-Luna, Silvia; Stenvang, Jan; Brünner, Nils

2014-01-01

RNA expression of progesterone receptor isoforms A and B in mammary carcinomas in dogs treated with 20 mg/Kg of aglepristone (n¿=¿22) or vehicle (n¿=¿5) twice before surgery.ResultsFormalin-fixed, paraffin-embedded tissue samples taken before and after treatment were used to analyse total progesterone receptor......-receptor positive and isoform-A positive tumours in aglepristone-treated dogs.ConclusionsThese findings suggest that the antiproliferative effects of aglepristone in canine mammary carcinomas are mediated by progesterone receptor isoform A....

GRIN-Global: An International Project to Develop a Global Plant Genebank Information Management System

Science.gov (United States)

The mission of the GRIN-Global Project is to create a new, scalable version of the Germplasm Resource Information System (GRIN) to provide the world’s crop genebanks with a powerful, flexible, easy-to-use plant genetic resource (PGR) information management system. The system will help safeguard PGR ...

Hexa-histidin tag position influences disulfide structure but not binding behavior of in vitro folded N-terminal domain of rat corticotropin-releasing factor receptor type 2a

OpenAIRE

Klose, Jana; Wendt, Norbert; Kubald, Sybille; Krause, Eberhard; Fechner, Klaus; Beyermann, Michael; Bienert, Michael; Rudolph, Rainer; Rothemund, Sven

2004-01-01

The oxidative folding, particularly the arrangement of disulfide bonds of recombinant extracellular N-terminal domains of the corticotropin-releasing factor receptor type 2a bearing five cysteines (C2 to C6), was investigated. Depending on the position of a His-tag, two types of disulfide patterns were found. In the case of an N-terminal His-tag, the disulfide bonds C2–C3 and C4–C6 were found, leaving C5 free, whereas the C-terminal position of the His-tag led to the disulfide pattern C2–C5 a...

Proton receptor GPR68 expression in dendritic-cell-like S100β-positive cells of rat anterior pituitary gland: GPR68 induces interleukin-6 gene expression in extracellular acidification.

Science.gov (United States)

Horiguchi, Kotaro; Higuchi, Masashi; Yoshida, Saishu; Nakakura, Takashi; Tateno, Kozue; Hasegawa, Rumi; Takigami, Shu; Ohsako, Shunji; Kato, Takako; Kato, Yukio

2014-11-01

S100β-positive cells, which do not express the classical pituitary hormones, appear to possess multifunctional properties and are assumed to be heterogeneous in the anterior pituitary gland. The presence of several protein markers has shown that S100β-positive cells are composed of populations such as stem/progenitor cells, epithelial cells, astrocytes and dendritic cells. Recently, we succeeded in separating S100β-positive cells into round-cell (dendritic-cell-like) and process-cell types. We also found the characteristic expression of anti-inflammatory factors (interleukin-6, Il-6) and membrane receptors (integrin β-6) in the round type. Here, we further investigate the function of the subpopulation of S100β-positive cells. Since IL-6 is also a paracrine factor that regulates hormone producing-cells, we examine whether a correlation exists among extracellular acid stress, IL-6 and hormone production by using primary cultures of anterior pituitary cells. Dendritic-cell-like S100β-positive cells notably expressed Gpr68 (proton receptor) and Il-6. Furthermore, the expression of Il-6 and proopiomelanocortin (Pomc) was up-regulated by extracellular acidification. The functional role of IL-6 and GPR68 in the gene expression of Pomc during extracellular acidification was also examined. Small interfering RNA for Il-6 up-regulated Pomc expression and that for Gpr68 reversed the down-regulation of Il-6 and up-regulated Pomc expression by extracellular acidification. Thus, S100β-positive dendritic-like cells can sense an increase in extracellular protons via GPR68 and respond by the production of IL-6 in order to suppress the up-regulation of Pomc expression.

Immunohistochemical Expression of Vitamin-D Receptor in Oral and ...

African Journals Online (AJOL)

user

Receptor in Oral and Skin Squamous Cell Carcinoma of a Black African Subpopulation. *Corresponding Author ... Objective:The nuclear vitamin D receptor (VDR) is involved in multiple pathways that have a role to .... Figure1: Sections A (++) and B (+++) of OSCC showing nuclear positivity (red arrows) for malignant nests of ...

Effects of GABA-B receptor positive modulator on ketamine-induced psychosis-relevant behaviors and hippocampal electrical activity in freely moving rats.

Science.gov (United States)

Ma, Jingyi; Stan Leung, L

2017-10-01

Decreased GABA B receptor function is proposed to mediate some symptoms of schizophrenia. In this study, we tested the effect of CGP7930, a GABA B receptor positive allosteric modulator, on ketamine-induced psychosis-relevant behaviors and hippocampal electrical activity in behaving rats. Electrodes were bilaterally implanted into the hippocampus, and cannulae were placed into the lateral ventricles of Long-Evans rats. CGP7930 or vehicle was injected intraperitoneally (i.p.) or intracerebroventricularly (i.c.v.), alone or 15 min prior to ketamine (3 mg/kg, subcutaneous) injection. Paired click auditory evoked potentials in the hippocampus (AEP), prepulse inhibition (PPI), and locomotor activity were recorded before and after drug injection. CGP7930 at doses of 1 mg/kg (i.p.) prevented ketamine-induced deficit of PPI. CGP7930 (1 mg/kg i.p.) also prevented the decrease in gating of hippocampal AEP and the increase in hippocampal gamma (65-100 Hz) waves induced by ketamine. Unilateral i.c.v. infusion of CGP7930 (0.3 mM/1 μL) also prevented the decrease in gating of hippocampal AEP induced by ketamine. Ketamine-induced behavioral hyperlocomotion was suppressed by 5 mg/kg i.p. CGP7930. CGP7930 alone, without ketamine, did not significantly affect integrated PPI, locomotion, gating of hippocampal AEP, or gamma waves. CGP7930 (1 mg/kg i.p.) increased heterosynaptically mediated paired pulse depression in the hippocampus, a measure of GABA B receptor function in vivo. CGP7930 reduces the behavioral and electrophysiological disruptions induced by ketamine in animals, and the hippocampus may be one of the neural targets where CGP7930 exerts its actions.

GABA regulates the rat hypothalamic-pituitary-adrenocortical axis via different GABA-A receptor alpha-subtypes

DEFF Research Database (Denmark)

Mikkelsen, Jens D; Bundzikova, Jana; Larsen, Marianne Hald

2008-01-01

dependent on the composition of the GABA-A receptor subunits through which they act. We show here that positive modulators of alpha(1)-subtype containing GABA-A receptors with zolpidem (10 mg/kg) increase HPA activity in terms of increase in plasma corticosterone and induction of Fos in the PVN, whereas...... after positive modulation of GABA-A receptors composed of alpha(1)-subunit(s) affects a selective afferent system than the PVN, which is distinct from another afferent system(s) activated by non alpha(1)-containing GABA-A receptors....

Structure-activity relationships of the melanocortin tetrapeptide Ac-His-DPhe-Arg-Trp-NH(2) at the mouse melanocortin receptors. 1. Modifications at the His position.

Science.gov (United States)

Holder, Jerry Ryan; Bauzo, Rayna M; Xiang, Zhimin; Haskell-Luevano, Carrie

2002-06-20

The melanocortin pathway is an important participant in obesity and energy homeostasis. The centrally located melanocortin-3 and melanocortin-4 receptors (MC3R, MC4R) are involved in the metabolic and food intake aspects of energy homeostasis and are stimulated by melanocortin agonists such as alpha-melanocyte stimulation hormone (alpha-MSH). The melanocortin agonists contain the putative message sequence "His-Phe-Arg-Trp", and it has been well documented that inversion of chirality of the Phe to DPhe results in a dramatic increase in melanocortin receptor potency. Herein, we report a tetrapeptide library based on the template Ac-His-DPhe-Arg-Trp-NH(2), consisting of 17 members that have been modified at the His(6) position (alpha-MSH numbering) and pharmacologically characterized for agonist activity at the mouse melanocortin receptors MC1R, MC3R, MC4R, and MC5R. These studies provide further experimental evidence that the His(6) position can determine MC4R versus MC3R agonist selectivity and that chemically nonreactive side chains may be substituted for the imidazole ring (generally needs to be side chain protected in synthetic schemes) in the design of MC4R-selective, small-molecule, non-peptide agonists. Specifically, the tetrapeptide containing the amino-2-naphthylcarboxylic acid (Anc) amino acid at the His position resulted in a potent agonist at the mMC4R (EC(50) = 21 nM), was a weak mMC3R micromolar antagonist (pA(2) = 5.6, K(i) = 2.5 microM), and possessed >4700-fold agonist selectivity for the MC4R versus the MC3R. Substitution of the His(6) amino acid in the tetrapeptide template by the Phe, Anc, 3-(2-thienyl)alanine (2Thi), and 3-(4-pyridinyl)alanine (4-Pal) resulted in equipotency or only up to a 7-fold decrease in potency, compared to the His(6)-containing tetrapeptide at the mMC4R, demonstrating that these amino acid side chains may be substituted for the imidazole in the design of MC4R-selective non-peptide molecules.

High throughput, cell type-specific analysis of key proteins in human endometrial biopsies of women from fertile and infertile couples

Science.gov (United States)

Leach, Richard E.; Jessmon, Philip; Coutifaris, Christos; Kruger, Michael; Myers, Evan R.; Ali-Fehmi, Rouba; Carson, Sandra A.; Legro, Richard S.; Schlaff, William D.; Carr, Bruce R.; Steinkampf, Michael P.; Silva, Susan; Leppert, Phyllis C.; Giudice, Linda; Diamond, Michael P.; Armant, D. Randall

2012-01-01

BACKGROUND Although histological dating of endometrial biopsies provides little help for prediction or diagnosis of infertility, analysis of individual endometrial proteins, proteomic profiling and transcriptome analysis have suggested several biomarkers with altered expression arising from intrinsic abnormalities, inadequate stimulation by or in response to gonadal steroids or altered function due to systemic disorders. The objective of this study was to delineate the developmental dynamics of potentially important proteins in the secretory phase of the menstrual cycle, utilizing a collection of endometrial biopsies from women of fertile (n = 89) and infertile (n = 89) couples. METHODS AND RESULTS Progesterone receptor-B (PGR-B), leukemia inhibitory factor, glycodelin/progestagen-associated endometrial protein (PAEP), homeobox A10, heparin-binding EGF-like growth factor, calcitonin and chemokine ligand 14 (CXCL14) were measured using a high-throughput, quantitative immunohistochemical method. Significant cyclic and tissue-specific regulation was documented for each protein, as well as their dysregulation in women of infertile couples. Infertile patients demonstrated a delay early in the secretory phase in the decline of PGR-B (P localization provided important insights into the potential roles of these proteins in normal and pathological development of the endometrium that is not attainable from transcriptome analysis, establishing a basis for biomarker, diagnostic and targeted drug development for women with infertility. PMID:22215622

Glycaemic Response to some Commonly Eaten Fruits in Type 2 ...

African Journals Online (AJOL)

Background: It is not known which of the commonly consumed fruits in Nigeria are suitable for persons with diabetes mellitus especially with regards to the attendant plasma glucose response (PGR) to consumption of such fruits. Objectives: To determine and compare the PGR to commonly eaten fruits in patients with ...

Efficacy of palbociclib plus fulvestrant after everolimus in hormone receptor-positive metastatic breast cancer.

Science.gov (United States)

du Rusquec, Pauline; Palpacuer, Clément; Campion, Loic; Patsouris, Anne; Augereau, Paule; Gourmelon, Carole; Robert, Marie; Dumas, Laurence; Caroline, Folliard; Campone, Mario; Frenel, Jean-Sébastien

2018-04-01

Palbociclib, a CDK4-6 inhibitor, combined with endocrine therapy (ET) is a new standard of treatment for Hormone Receptor-positive Metastatic Breast Cancer. We present the first real-life efficacy and tolerance data of palbociclib plus fulvestrant in this population. From November 2015 to November 2016, patients receiving in our institution palbociclib + fulvestrant according to the Temporary Authorization for Use were prospectively analyzed. 60 patients were treated accordingly; median age was 61 years; 50 patients (83.3%) had visceral metastasis, and 10 (16.7%) had bone-only disease. Patients had previously received a median of 5 (1-14) lines of treatment, including ET (median 3) and chemotherapy (median 2); 28 (46.7%) received previously fulvestrant and all everolimus. With a median follow-up of 10.3 months, median progression-free survival (mPFS) was 5.8 months (95% CI 3.9-7.3). Patients pretreated with fulvestrant had a similar PFS of 6.4 months (HR 1.00; 95% CI 0.55-1.83; P = 1.00). The most common AEs (adverse events) were neutropenia (93%), anemia (65%), and thrombocytopenia (55%). In this heavily pretreated population including everolimus, fulvestrant plus palbociclib provides an mPFS of 5.8 months with the same magnitude of benefit for fulvestrant-pretreated patients.

Neoadjuvant letrozole for postmenopausal estrogen receptor-positive, HER2-negative breast cancer patients, a study from the Danish Breast Cancer Cooperative Group (DBCG)

DEFF Research Database (Denmark)

Skriver, Signe Korsgaard; Laenkholm, Anne-Vibeke; Rasmussen, Birgitte Bruun

2018-01-01

response and 55% of patients had partial pathological response. ER at 100%, ductal subtype, tumor size below 2 cm and lymph node-negative status was significantly associated with a better response to NET and malignancy grade 3 with a poorer response to NET. One patient progressed during treatment......INTRODUCTION: Neoadjuvant endocrine treatment (NET) is a low-toxicity approach to achieve operability in locally advanced breast cancer, and to facilitate breast conservation in early breast cancer, particular in patients with highly estrogen receptor (ER) positive and HER2-negative disease. Here......, we report the results obtained by neoadjuvant letrozole in patients with early breast cancer in a phase-II design. MATERIAL AND METHODS: A total of 119 postmenopausal women with ER-positive, HER2-negative operable breast cancer were assigned to four months of neoadjuvant letrozole before definitive...

Plant Genetic Resources: Selected Issues from Genetic Erosion to Genetic Engineering

Directory of Open Access Journals (Sweden)

Karl Hammer

2008-04-01

Full Text Available Plant Genetic Resources (PGR continue to play an important role in the development of agriculture. The following aspects receive a special consideration:1. Definition. The term was coined in 1970. The genepool concept served as an important tool in the further development. Different approaches are discussed.2. Values of Genetic Resources. A short introduction is highlighting this problem and stressing the economic usfulness of PGR.3. Genetic Erosion. Already observed by E. Baur in 1914, this is now a key issue within PGR. The case studies cited include Ethiopia, Italy, China, S Korea, Greece and S. Africa. Modern approaches concentrate on allelic changes in varieties over time but neglect the landraces. The causes and consequences of genetic erosion are discussed.4. Genetic Resources Conservation. Because of genetic erosion there is a need for conservation. PGR should be consigned to the appropriate method of conservation (ex situ, in situ, on-farm according to the scientific basis of biodiversity (genetic diversity, species diversity, ecosystem diversity and the evolutionary status of plants (cultivated plants, weeds, related wild plants (crop wild relatives.5. GMO. The impact of genetically engineered plants on genetic diversity is discussed.6. The Conclusions and Recommendations stress the importance of PGR. Their conservation and use are urgent necessities for the present development and future survival of mankind.

Translational PK-PD modelling of molecular target modulation for the AMPA receptor positive allosteric modulator Org 26576.

Science.gov (United States)

Bursi, Roberta; Erdemli, Gul; Campbell, Robert; Hutmacher, Matthew M; Kerbusch, Thomas; Spanswick, David; Jeggo, Ross; Nations, Kari R; Dogterom, Peter; Schipper, Jacques; Shahid, Mohammed

2011-12-01

The α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor potentiator Org 26576 represents an interesting pharmacological tool to evaluate the utility of glutamatergic enhancement towards the treatment of psychiatric disorders. In this study, a rat-human translational pharmacokinetic-pharmacodynamic (PK-PD) model of AMPA receptor modulation was used to predict human target engagement and inform dose selection in efficacy clinical trials. Modelling and simulation was applied to rat plasma and cerebrospinal fluid (CSF) pharmacokinetic and pharmacodynamic measurements to identify a target concentration (EC(80)) for AMPA receptor modulation. Human plasma pharmacokinetics was determined from 33 healthy volunteers and eight major depressive disorder patients. From four out of these eight patients, CSF PK was also determined. Simulations of human CSF levels were performed for several doses of Org 26576. Org 26576 (0.1-10 mg/kg, i.v.) potentiated rat hippocampal AMPA receptor responses in an exposure-dependant manner. The rat plasma and CSF PK data were fitted by one-compartment model each. The rat CSF PK-PD model yielded an EC(80) value of 593 ng/ml (90% confidence interval 406.8, 1,264.1). The human plasma and CSF PK data were simultaneously well described by a two-compartment model. Simulations showed that in humans at 100 mg QD, CSF levels of Org 26576 would exceed the EC(80) target concentration for about 2 h and that 400 mg BID would engage AMPA receptors for 24 h. The modelling approach provided useful insight on the likely human dose-molecular target engagement relationship for Org 26576. Based on the current analysis, 100 and 400 mg BID would be suitable to provide 'phasic' and 'continuous' AMPA receptor engagement, respectively.

p75 neurotrophin receptor positive dental pulp stem cells: new hope for patients with neurodegenerative disease and neural injury.

Science.gov (United States)

Dai, Jie-wen; Yuan, Hao; Shen, Shun-yao; Lu, Jing-ting; Zhu, Xiao-fang; Yang, Tong; Zhang, Jiang-fei; Shen, Guo-fang

2013-08-01

Neurodegenerative diseases and neural injury are 2 of the most feared disorders that afflict humankind by leading to permanent paralysis and loss of sensation. Cell based treatment for these diseases had gained special interest in recent years. Previous studies showed that dental pulp stem cells (DPSCs) could differentiate toward functionally active neurons both in vitro and in vivo, and could promote neuranagenesis through both cell-autonomous and paracrine neuroregenerative activities. Some of these neuroregenerative activities were unique to tooth-derived stem cells and superior to bone marrow stromal cells. However, DPSCs used in most of these studies were mixed and unfractionated dental pulp cells that contain several types of cells, and most were fibroblast cells while just contain a small portion of DPSCs. Thus, there might be weaker ability of neuranagenesis and more side effects from the fibroblast cells that cannot differentiate into neural cells. p75 neurotrophin receptor (p75NTR) positive DPSCs subpopulation was derived from migrating cranial neural crest cells and had been isolated from DPSCs, which had capacity of differentiation into neurons and repairing neural system. In this article, we hypothesize that p75NTR positive DPSCs simultaneously have greater propensity for neuronal differentiation and fewer side effects from fibroblast, and in vivo transptantation of autologous p75NTR positive DPSCs is a novel method for neuranagenesis. This will bring great hope to patients with neurodegenerative disease and neural injury.

Regional tectonic framework of the Pranhita Godavari basin, India

Science.gov (United States)

Biswas, S. K.

2003-03-01

The Pranhita-Godavari Gondwana rift (PGR) has a co-genetic relationship with Permo-Triassic reactivation of the Narmada-Son Geofracture (NSG). The Satpura Gondwana basin represents the terminal depocentre against the NSG, which restricted the northwestward propagation of the PGR. The NE-SW tensional stress responsible for the NW-SE trending PGR could not propagate beyond the ramp formed by uplift along the NSG and transformed kinetically into an ENE directed horizontal shear along the NSG, inducing large scale strike-slip movements. The latter dynamics were responsible for ENE extension of the Satpura rift as a pull-apart basin. The PGR extends up to the present east coast of India, where it is apparently terminated by the NE-SW trending Bapatla ridge along the Eastern Ghat Rift (EGR). The subsurface data, however, shows that the PGR extends across the Bapatla ridge and continues beneath the Cretaceous-Tertiary sediments of the Krishna-Godavari basin (KG) in the EGR. Thus, the Permo-Triassic PGR appears to have continued in the Indo-Antarctic plate before the Cretaceous break up. The EGR, during break up of the continents, cuts across the PGR and the KG basin was superimposed on it. The PGR site is located on a paleo-suture between the Dharwar and Bastar proto-cratons. The master faults developed bordering the rift, and the intra-rift higher order faults followed the pre-existing fabric. The transverse transfer zones manifested as basement ridges, divide the rift into segments of tectono-sedimentary domains. The major domains are the Chintalapudi, Godavari, and Chandrapur sub-basins, each of which subsided differentially. The central Godavari sub-basin subsided most and shows maximum structural complexity and sediment accommodation. The rifting started with initial half-graben faulting along the northeastern master fault and expanded by successive half graben faulting. This gave rise to intra-basinal horsts and grabens, which exercised control on the syn

Benefit of adjuvant chemotherapy with or without trastuzumab in pT1ab node-negative human epidermal growth factor receptor 2-positive breast carcinomas: results of a national multi-institutional study.

Science.gov (United States)

de Nonneville, Alexandre; Gonçalves, Anthony; Zemmour, Christophe; Classe, Jean M; Cohen, Monique; Lambaudie, Eric; Reyal, Fabien; Scherer, Christophe; Muracciole, Xavier; Colombo, Pierre E; Giard, Sylvia; Rouzier, Roman; Villet, Richard; Chopin, Nicolas; Darai, Emile; Garbay, Jean R; Gimbergues, Pierre; Sabiani, Laura; Coutant, Charles; Sabatier, Renaud; Bertucci, François; Boher, Jean M; Houvenaeghel, Gilles

2017-04-01

Benefit of adjuvant trastuzumab-based chemotherapy for node-positive and/or >1 cm human epidermal growth factor receptor 2-positive (HER2+) breast carcinomas has been clearly demonstrated in randomized clinical trials. Yet, evidence that adjuvant chemotherapy with or without trastuzumab is effective in pT1abN0 HER2+ tumors is still limited. The primary objective of this study was to investigate the impact of adjuvant chemotherapy ± trastuzumab on outcome in this subpopulation. A total of 356 cases of pT1abN0M0 HER2 + breast cancers were retrospectively identified from a large cohort of 22,334 patients, including 1248 HER2+ patients who underwent primary surgery at 17 French centers, between December 1994 and January 2014. The primary end point was disease-free survival (DFS). A multivariate Cox model was built, including adjuvant chemotherapy, tumor size, hormone receptor status, and Scarff Bloom Richardson (SBR) grade. A total of 138 cases (39%) were treated with trastuzumab-based chemotherapy, 29 (8%) with chemotherapy alone, and 189 (53%) received neither trastuzumab nor chemotherapy. Adjuvant chemotherapy ± trastuzumab was associated with a significant DFS benefit (3-year 99 vs. 90%, and 5-year 96 vs. 84%, Hazard ratio, HR 0.26 [0.10-0.67]; p = 0.003, logrank test) which was maintained in multivariate analysis (HR 0.19 [0.07-0.52]; p = 0.001). Metastasis-free survival was also increased (HR 0.25 [0.07-0.86]; p = 0.018, logrank test) at 3-year (99 vs. 95%) and 5-year (98 vs. 89%) censoring. Exploratory subgroup analysis found DFS benefit to be significant in hormone receptor-negative, hormone receptor-positive, and pT1b tumors, but not in pT1a tumors. Adjuvant chemotherapy ± trastuzumab is associated with a significantly reduced risk of recurrence in subcentimeter node-negative HER2+ breast cancers. Most of the benefit may be driven by pT1b tumors.

Detection of melatonin receptor mRNA in human muscle

International Nuclear Information System (INIS)

Li Lei

2004-01-01

To verify the expression of melatonin receptor mRNA in human, muscle, muscle beside vertebrae was collected to obtain total RNA and the mRNA of melatonin receptor was detected by RT-PCR method. The electrophoretic results of RT-PCR products by mt 1 and MT 2 primer were all positive and the sequence is corresponding with human melatonin receptor cDNA. It suggests that melatonin may act on the muscle beside vertebrae directly and regulate its growth and development. (authors)

Prostanoid Receptors Involved in Regulation of the Beating Rate of Neonatal Rat Cardiomyocytes

Science.gov (United States)

Mechiche, Hakima; Grassin-Delyle, Stanislas; Robinet, Arnaud; Nazeyrollas, Pierre; Devillier, Philippe

2012-01-01

Although prostanoids are known to be involved in regulation of the spontaneous beating rate of cultured neonatal rat cardiomyocytes, the various subtypes of prostanoid receptors have not been investigated in detail. In our experiments, prostaglandin (PG)F2α and prostanoid FP receptor agonists (fluprostenol, latanoprost and cloprostenol) produced a decrease in the beating rate. Two prostanoid IP receptor agonists (iloprost and beraprost) induced first a marked drop in the beating rate and then definitive abrogation of beating. In contrast, the prostanoid DP receptor agonists (PGD2 and BW245C) and TP receptor agonists (U-46619) produced increases in the beating rate. Sulprostone (a prostanoid EP1 and EP3 receptor agonist) induced marked increases in the beating rate, which were suppressed by SC-19220 (a selective prostanoid EP1 antagonist). Butaprost (a selective prostanoid EP2 receptor agonist), misoprostol (a prostanoid EP2 and EP3 receptor agonist), 11-deoxy-PGE1 (a prostanoid EP2, EP3 and EP4 receptor agonist) did not alter the beating rate. Our results strongly suggest that prostanoid EP1 receptors are involved in positive regulation of the beating rate. Prostanoid EP1 receptor expression was confirmed by western blotting with a selective antibody. Hence, neonatal rat cardiomyocytes express both prostanoid IP and FP receptors (which negatively regulate the spontaneous beating rate) and prostanoid TP, DP1 and EP1 receptors (which positively regulate the spontaneous beating rate). PMID:22984630

Establishment of a novel high-affinity IgE receptor-positive canine mast cell line with wild-type c-kit receptors

International Nuclear Information System (INIS)

Amagai, Yosuke; Tanaka, Akane; Ohmori, Keitaro; Matsuda, Hiroshi

2008-01-01

Much is known regarding participations of mast cells with innate and acquired immunity by secreting various cytokines and chemical mediators. However, details of mast cell biology still remain unclear. In this study, we successfully established a novel growth factor-independent mast cell line (MPT-1) derived from canine mast cell tumor. MPT-1 cells manifested factor-independent proliferation as floating cells containing a large amount of histamine, as well as chymase-like dog mast cell protease 3, in cytosolic granules. Particularly, MPT-1 cells expressed high-affinity IgE receptors (FcεRI) and wild-type c-kit receptors. Degranulation of MPT-1 cells was induced not only by stimulation with calcium ionophore but also by cross-linkage of the surface IgE. Given that MPT-1 is the first mast cell line with FcεRI which has no c-kit mutations, MPT-1 cells may provide great contribution for investigation of IgE-mediated activation mechanisms of mast cells, leading to development of effective treatment for allergic disorders

Frontal D2/3 Receptor Availability in Schizophrenia Patients Before and After Their First Antipsychotic Treatment

DEFF Research Database (Denmark)

Nørbak-Emig, Henrik; Ebdrup, Bjørn H; Fagerlund, Birgitte

2016-01-01

the relation between frontal D2/3 receptor availability and treatment effect on positive symptoms. METHODS: Twenty-five antipsychotic-naïve first-episode schizophrenia patients were examined with the Positive and Negative Syndrome Scale, tested with the cognitive test battery Cambridge Neuropsychological Test......BACKGROUND: We have previously reported associations between frontal D2/3 receptor binding potential positive symptoms and cognitive deficits in antipsychotic-naïve schizophrenia patients. Here, we examined the effect of dopamine D2/3 receptor blockade on cognition. Additionally, we explored.......56, P=.003; D2/3 receptor binding potential right frontal cortex rho = 0.48, P=.016). CONCLUSIONS: Our data support the hypothesis of a negative influence of D2/3 receptor blockade on specific cognitive functions in schizophrenia. This is highly clinically relevant given the well-established association...

Constitutional variants are not associated with HER2-positive breast cancer: results from the SIGNAL/PHARE clinical cohort

OpenAIRE

Pivot, Xavier; Romieu, Gilles; Fumoleau, Pierre; Rios, Maria; Bonnefoi, Herv?; Bachelot, Thomas; Souli?, Patrick; Jouannaud, Christelle; Bourgeois, Hugues; Petit, Thierry; Tennevet, Isabelle; Assouline, David; Mathieu, Marie-Christine; Jacquin, Jean-Philippe; Lavau-Denes, Sandrine

2017-01-01

Human epidermal growth factor receptor 2-positive breast cancer is a subtype of interest regarding its outcome and the impressive impact of human epidermal growth factor receptor 2 targeted therapy. Constitutional variants may be involved in the aetiology of human epidermal growth factor receptor 2-positive breast cancer, and we propose a case?case study to test the hypothesis that single nucleotide polymorphisms may be associated with human epidermal growth factor receptor 2 status. A Genome...

Noradrenergic α1 Receptor Antagonist Treatment Attenuates Positive Subjective Effects of Cocaine in Humans: A Randomized Trial

Science.gov (United States)

Newton, Thomas F.; De La Garza, Richard; Brown, Gregory; Kosten, Thomas R.; Mahoney, James J.; Haile, Colin N.

2012-01-01

Background Preclinical research implicates dopaminergic and noradrenergic mechanisms in mediating the reinforcing effects of drugs of abuse, including cocaine. The objective of this study was to evaluate the impact of treatment with the noradrenergic α1 receptor antagonist doxazosin on the positive subjective effects of cocaine. Methods Thirteen non-treatment seeking, cocaine-dependent volunteers completed this single-site, randomized, placebo-controlled, within-subjects study. In one study phase volunteers received placebo and in the other they received doxazosin, with the order counterbalanced across participants. Study medication was masked by over-encapsulating doxazosin tablets and matched placebo lactose served as the control. Study medication treatment was initiated at 1 mg doxazosin or equivalent number of placebo capsules PO/day and increased every three days by 1 mg. After receiving 4 mg doxazosin or equivalent number of placebo capsules participants received masked doses of 20 and 40 mg cocaine IV in that order with placebo saline randomly interspersed to maintain the blind. Results Doxazosin treatment was well tolerated and doxazosin alone produced minimal changes in heart rate and blood pressure. During treatment with placebo, cocaine produced dose-dependent increases in subjective effect ratings of “high”, “stimulated”, “like cocaine”, “desire cocaine”, “any drug effect”, and “likely to use cocaine if had access” (p<.001). Doxazosin treatment significantly attenuated the effects of 20 mg cocaine on ratings of “stimulated”, “like cocaine”, and “likely to use cocaine if had access” (p<.05). There were trends for doxazosin to reduce ratings of “stimulated”, “desire cocaine”, and “likely to use cocaine if had access” (p<.10). Conclusions Medications that block noradrenergic α1 receptors, such as doxazosin, may be useful as treatments for cocaine dependence, and should be evaluated further. Trial

Sex Hormone Receptor Repertoire in Breast Cancer

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Gerald M. Higa

2013-01-01

Full Text Available Classification of breast cancer as endocrine sensitive, hormone dependent, or estrogen receptor (ER positive refers singularly to ERα. One of the oldest recognized tumor targets, disruption of ERα-mediated signaling, is believed to be the mechanistic mode of action for all hormonal interventions used in treating this disease. Whereas ERα is widely accepted as the single most important predictive factor (for response to endocrine therapy, the presence of the receptor in tumor cells is also of prognostic value. Even though the clinical relevance of the two other sex hormone receptors, namely, ERβ and the androgen receptor remains unclear, two discordant phenomena observed in hormone-dependent breast cancers could be causally related to ERβ-mediated effects and androgenic actions. Nonetheless, our understanding of regulatory molecules and resistance mechanisms remains incomplete, further compromising our ability to develop novel therapeutic strategies that could improve disease outcomes. This review focuses on the receptor-mediated actions of the sex hormones in breast cancer.

Role of retinoic receptors in lung carcinogenesis

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Renyi-Vamos Ferenc

2008-07-01

Full Text Available Abstract Several in vitro and in vivo studies have examined the positive and negative effects of retinoids (vitamin A analogs in premalignant and malignant lesions. Retinoids have been used as chemopreventive and anticancer agents because of their pleiotropic regulator function in cell differentiation, growth, proliferation and apoptosis through interaction with two types of nuclear receptors: retinoic acid receptors and retinoid X receptors. Recent investigations have gradually elucidated the function of retinoids and their signaling pathways and may explain the failure of earlier chemopreventive studies. In this review we have compiled basic and recent knowledge regarding the role of retinoid receptors in lung carcinogenesis. Sensitive and appropriate biological tools are necessary for screening the risk population and monitoring the efficacy of chemoprevention. Investigation of retinoid receptors is important and may contribute to the establishment of new strategies in chemoprevention for high-risk patients and in the treatment of lung cancer.

Responses to microbial challenges by SLAMF receptors

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Boaz Job Van Driel

2016-01-01

Full Text Available The SLAMF Family (SLAMF of cell surface glycoproteins is comprised of nine glycoproteins and whilst SLAMF1, 3, 5, 6, 7, 8, 9 are self-ligand receptors, SLAMF2 and SLAMF4 interact with each other. Their interactions induce signal transduction networks in trans, thereby shaping immune cell-cell communications. Collectively, these receptors modulate a wide range of functions, such as myeloid cell and lymphocyte development and, T and B cell responses to microbes and parasites. In addition, several SLAMF receptors serve as microbial sensors, which either positively or negatively modulate the function of macrophages, dendritic cells, neutrophils and NK cells in response to microbial challenges. The SLAMF receptor-microbe interactions contribute both to intracellular microbicidal activity as well as to migration of phagocytes to the site of inflammation. In this review, we describe the current knowledge on how the SLAMF receptors and their specific adapters SAP and EAT-2 regulate innate and adaptive immune responses to microbes.

Urolinin: The First Linear Peptidic Urotensin-II Receptor Agonist.

Science.gov (United States)

Bandholtz, Sebastian; Erdmann, Sarah; von Hacht, Jan Lennart; Exner, Samantha; Krause, Gerd; Kleinau, Gunnar; Grötzinger, Carsten

2016-11-23

This study investigated the role of individual U-II amino acid positions and side chain characteristics important for U-IIR activation. A complete permutation library of 209 U-II variants was studied in an activity screen that contained single substitution variants of each position with one of the other 19 proteinogenic amino acids. Receptor activation was measured using a cell-based high-throughput fluorescence calcium mobilization assay. We generated the first complete U-II substitution map for U-II receptor activation, resulting in a detailed view into the structural features required for receptor activation, accompanied by complementary information from receptor modeling and ligand docking studies. On the basis of the systematic SAR study of U-II, we created 33 further short and linear U-II variants from eight to three amino acids in length, including d- and other non-natural amino acids. We identified the first high-potency linear U-II analogues. Urolinin, a linear U-II agonist (nWWK-Tyr(3-NO 2 )-Abu), shows low nanomolar potency as well as improved metabolic stability.

Night work and breast cancer risk defined by human epidermal growth factor receptor-2 (HER2) and hormone receptor status: A population-based case-control study in France.

Science.gov (United States)

Cordina-Duverger, Emilie; Koudou, Yves; Truong, Thérèse; Arveux, Patrick; Kerbrat, Pierre; Menegaux, Florence; Guénel, Pascal

Night work has been associated with risk of breast cancer but this association needs to be confirmed. Because breast cancer is an etiologically heterogeneous disease, we explored the association of night work with breast cancer subtypes defined by tumor status (positive of negative) for estrogen-receptor (ER), progesterone-receptor (PR) and human epidermal growth factor-receptor 2 (HER2). Using the data from a case-control study in France including 975 cases and 1317 controls, we found that the odds ratios for ER+, PR+ or HER2+ breast cancers subtypes were significantly elevated, while no association with night shift work was observed for ER, PR or HER2-negative tumors. After stratification by menopausal status, the associations of night work with receptor-positive breast tumor subtypes were clearly seen in premenopausal women (odds ratios 2.04, 1.98 and 2.80, respectively) but did not appear in postmenopausal women. This study provides evidence that working at night may increase risk of ER, PR and HER2-positive subtypes of breast cancer particularly among premenopausal women.

Beta-adrenergic receptors of lymphocytes in children with allergic respiratory diseases

International Nuclear Information System (INIS)

Bittera, I.; Gyurkovits, K.; Falkay, G.; Eck, E.; Koltai, M.

1988-01-01

The beta-adrenergic receptor binding sites on peripheral lymphocytes in children with bronchial asthma (n = 16) and seasonal allergic rhinitis (n = 8) were examined in comparison with normal controls (n = 18) by means of 124 I-cyanopindolol. The number of beta-adrenergic receptors was significantly lower in the asthmatic group (858 +/- 460/lymphocyte) than in the controls (1564 +/- 983/lymphocyte). The value (1891 +/- 1502/lymphocyte in children with allergic rhinitis was slightly higher than that in healthy controls. Of the 24 patients suffering from allergic diseases of the lower or upper airways, the bronchial histamine provocation test was performed in 21; 16 gave positive results, while 5 were negative. No difference in beta-adrenergic receptor count was found between the histamine-positive and negative patients. Neither was there any correlation between the number of beta-adrenergic receptors and the high (16/24) and low (8/24) serum IgE concentrations found in allergic patients. The significant decrease in beta-adrenergic receptor count in asthmatic children lends support to Szentivanyi's concept. Further qualitative and quantitative analysis of lymphocyte beta-adrenergic receptors may provide an individual approach to the treatment of bronchial asthma with beta-sympathomimetic drugs

Evidence for Alpha Receptors in the Human Ureter

Science.gov (United States)

Madeb, Ralph; Knopf, Joy; Golijanin, Dragan; Bourne, Patricia; Erturk, Erdal

2007-04-01

An immunohistochemical and western blot expression analysis of human ureters was performed in order to characterize the alpha-1-adrenergic receptor distribution along the length of the human ureteral wall. Mapping the distribution will assist in understanding the potential role alpha -1-adrenergic receptors and their subtype density might have in the pathophysiology of ureteral colic and stone passage. Patients diagnosed with renal cancer or bladder cancer undergoing nephrectomy, nephroureterectomy, or cystectomy had ureteral specimens taken from the proximal, mid, distal and tunneled ureter. Tissues were processed for fresh frozen examination and fixed in formalin. None of the ureteral specimens were involved with cancer. Serial histologic sections and immunohistochemical studies were performed using antibodies specific for alpha-1-adrenergic receptor subtypes (alpha 1a, alpha 1b, alpha 1d). The sections were examined under a light microscope and scored as positive or negative. In order to validate and quantify the alpha receptor subtypes along the human ureter. Western blotting techniques were applied. Human ureter stained positively for alpha -1-adrenergic receptors. Immunostaining appeared red, with intense reaction in the smooth muscle of the ureter and endothelium of the neighboring blood vessels. There was differential expression between all the receptors with the highest staining for alpha-1D subtype. The highest protein expression for all three subtypes was in the renal pelvis and decreased with advancement along the ureter to the distal ureter. At the distal ureter, there was marked increase in expression as one progressed towards the ureteral orifice. The same pattern of protein expression was exhibited for all three alpha -1-adrenergic receptor subtypes. We provide preliminary evidence for the ability to detect and quantify the alpha-1-receptor subtypes along the human ureter which to the best of our knowledge has never been done with

Mu receptor binding of some commonly used opioids and their metabolites

International Nuclear Information System (INIS)

Chen, Zhaorong; Irvine, R.J.; Somogyi, A.A.; Bochner, F.

1991-01-01

The binding affinity to the μ receptor of some opioids chemically related to morphine and some of their metabolites was examined in rat brain homogenates with 3 H-DAMGO. The chemical group at position 6 of the molecule had little effect on binding. Decreasing the length of the alkyl group at position 3 decreased the K i values (morphine < codeine < ethylmorphine < pholcodine). Analgesics with high clinical potency containing a methoxyl group at position 3 had relatively weak receptor binding, while their O-demethylated metabolites had much stronger binding. Many opioids may exert their pharmacological actions predominantly through metabolites

Mu receptor binding of some commonly used opioids and their metabolites

Energy Technology Data Exchange (ETDEWEB)

Chen, Zhaorong; Irvine, R.J. (Univ. of Adelaide (Australia)); Somogyi, A.A.; Bochner, F. (Univ. of Adelaide (Australia) Royal Adelaide Hospital (Australia))

1991-01-01

The binding affinity to the {mu} receptor of some opioids chemically related to morphine and some of their metabolites was examined in rat brain homogenates with {sup 3}H-DAMGO. The chemical group at position 6 of the molecule had little effect on binding. Decreasing the length of the alkyl group at position 3 decreased the K{sub i} values (morphine < codeine < ethylmorphine < pholcodine). Analgesics with high clinical potency containing a methoxyl group at position 3 had relatively weak receptor binding, while their O-demethylated metabolites had much stronger binding. Many opioids may exert their pharmacological actions predominantly through metabolites.

Biological characterization and selection criteria of adjuvant chemotherapy for early breast cancer: experience from the Italian observational NEMESI study

International Nuclear Information System (INIS)

Clavarezza, Matteo; Marchetti, Paolo; Gori, Stefania; Carrozza, Francesco; Maiello, Evaristo; Giotta, Francesco; Dondi, Davide; Venturini, Marco; Mustacchi, Giorgio; Casadei Gardini, Andrea; Del Mastro, Lucia; De Matteis, Andrea; Riccardi, Ferdinando; Adamo, Vincenzo; Aitini, Enrico; Amoroso, Domenico

2012-01-01

International treatment guidelines recommend administration of adjuvant chemotherapy in early breast cancer based on clinical, prognostic and predictive parameters. An observational study (NEMESI) was conducted in 63 Italian oncology centres in patients with early breast cancer. Age, performance status, concomitant disease, menopausal status, histology, tumor dimension (pT), axillary lymph node status (pN), grading (G), estrogen and progesterone receptor (ER and PgR), proliferative index (ki67 or MIB-1), human epidermal growth factor receptor 2 (HER2) and type of adjuvant treatment were recorded. The primary objective of the study was to define parameters influencing the decision to prescribe adjuvant chemotherapy and the type of chemotherapy. Data for 1894 patients were available. 69.0% postmenopausal, 67.0% pT1, 22.3% pTmic/pT1a/pT1b, 61.0% pN0, 48.7% luminal A, 18.1% luminal B, 16.1% HER2 positive, 8.7% triple negative, 8.4% unknown. 57.8% received adjuvant chemotherapy: 38.1% of luminal A, 67.3% luminal B, 88.2% HER2-positive, 97.6% triple negative. Regimens administered: 9.1% CMF-like, 48.8% anthracyclines, 38.4% anthracyclines plus taxanes, 3.7% taxanes alone. Increasing pT/pN and, marginally, HER2-positive were associated with the prescription of anthracyclines plus taxanes. Suboptimal schedules (CMF-like or AC/EC or FEC-75) were prescribed in 37.3% receiving chemotherapy, even in HER2-positive and triple negative disease (36.5% and 34.0%, respectively). This study showed an overprescription of adjuvant chemotherapy for early breast cancer, particularly referred to luminal A. pT, pN and, marginally, HER2 were the principal determinants for the choice of chemotherapy type. Suboptimal chemotherapy regimens were adopted in at least one third of HER2-positve and triple negative

Peroxisome proliferator-activated receptor gamma recruits the positive transcription elongation factor b complex to activate transcription and promote adipogenesis

DEFF Research Database (Denmark)

Iankova, Irena; Petersen, Rasmus K; Annicotte, Jean-Sébastien

2006-01-01

Positive transcription elongation factor b (P-TEFb) phosphorylates the C-terminal domain of RNA polymerase II, facilitating transcriptional elongation. In addition to its participation in general transcription, P-TEFb is recruited to specific promoters by some transcription factors such as c......-Myc or MyoD. The P-TEFb complex is composed of a cyclin-dependent kinase (cdk9) subunit and a regulatory partner (cyclin T1, cyclin T2, or cyclin K). Because cdk9 has been shown to participate in differentiation processes, such as muscle cell differentiation, we studied a possible role of cdk9...... with and phosphorylation of peroxisome proliferator-activated receptor gamma (PPARgamma), which is the master regulator of this process, on the promoter of PPARgamma target genes. PPARgamma-cdk9 interaction results in increased transcriptional activity of PPARgamma and therefore increased adipogenesis....

New radiopharmaceuticals for receptor scintigraphy and radionuclide therapy

Energy Technology Data Exchange (ETDEWEB)

Virgolini, I.; Traub, T.; Leimer, M.; Novotny, C.; Pangerl, T.; Ofluoglu, S.; Halvadjieva, E.; Smith-Jones, P.; Flores, J.; Li, S.R.; Angelberger, P.; Havlik, E.; Andreae, F.; Raderer, M.; Kurtaran, A.; Niederle, B.; Dudczak, R. [Vienna Univ., Vienna (Austria). Dept. of Nuclear Medicine

2000-03-01

In vitro data have demonstrated a high amount of receptors for various hormones and peptides on malignant cells of neuroendocrine origin. Among these, binding sites for member of the SST-family (hSSTR1-5) are frequently found, and their expression has led to therapeutic and diagnostic attempts to specifically target these receptors. Receptor scintigraphy using radiolabeled peptide ligands has proved its effectiveness in clinical practice. In addition, initial results have indicated a clinical potential for receptor-targeted radiotherapy. Based on somatostatin (SST) receptor (R) recognition, the novel radiopharmaceuticals {sup 111}In/{sup 9}0Y-DOTA-lanreotide developed at the University of Vienna as well as {sup 111}In/{sup 9}0Y-DOTA-DPhe{sup 1}-Tyr{sup 3}-octreotide (NOVARTIS) both have provided promising data for diagnosis and treatment of hSSTR-positive tumors. SSTR scintigraphy using {sup 111}In-DTPA-DPhe{sup 1}-octreotide has a high positive predictive value for the vast majority of neuroendocrine tumors and has gained its place in the diagnostic work-up as well as follow-up of patients. Here it was used {sup 111}In-DOTA-lanreotide scintigraphy in 166 patients since 1997 and have seen positive results in 93% of patients. In 42 patients with neuroendocrine tumors comparative data were obtained. As opposed to {sup 111}In-DTPA-DPhe{sup 1}-octreotide and {sup 111}In-DOTA-DPhe{sup 1}-Tyr{sup 3}-octreotide, discrepancies in the scintigraphic results were seen in about one third of patients concerning both the tumor uptake as well as tumor lesion detection. Initial results both with {sup 9}0Y-DOTA-lanreotide as well as {sup 9}0Y-DOTA-DPhe{sup 1}-Tyr{sup 3}-octreotide has pointed out the clinical potential of radionuclide receptor-targeted radiotherapy. This new therapy could offer palliation and disease control at a reduced cost. The final peptide therapy strategy is most probably cheaper than conventional radio therapies or prolonged chemo therapies. Overall

Effect of two different plant growth regulators on production traits of sunflower

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Dávid ERNST

2016-12-01

Full Text Available The plant growth regulators (PGR are an organic compounds that modify plant physiological processes. PGR applied to the field crops promotes photosynthesis, stimulates plant growth, improves flowering and protects plants against unfavourable year weather conditions. Listed is an assumption to the yield of high quality. The effects of year weather conditions, biological material (hybrids and foliar application of two different PGR (Terra-Sorb® Foliar – containing free amino acids and Unicum® – containing Abiestins® on the yield-forming parameters, seed yield and the oil content in seeds of three selected hybrids of sunflower (NK Brio, NK Neoma, NK Ferti were studied in this paper. The field poly-factorial experiments were realized during two growing seasons of 2012 and 2013. The experimental area is situated in the maize-growing region (climatic region: warm; climatic sub-region: mild dry or dry; climatic zone: warm and dry, with mild winter and long sunshine and soil is silt loam Haplic Luvisol. The climatic conditions in chosen experimental years were different in quantities and distribution of precipitation at main growth period of sunflower plants (June to August and allows evaluating the yield stability between used hybrids and foliar treatments. The results showed that the application of selected PGR has contributed to an increase of sunflower seed yield, mainly through increase the weight of thousand seeds (rp = 0.761; P < 0.001. Similarly, oil content in seeds was significantly higher in treatments with PGR, especially with preparation Terra-Sorb® Foliar containing free amino acids. The study describes the relationship between quality (oil content in seeds and quantity (seed yield of sunflower production (rp = ‒0.41; P < 0.01. Results showed that PGR can be an important rationalization tool of the sunflower cultivation technology.

Combined effects of goserelin and tamoxifen on estradiol level, breast density, and endometrial thickness in premenopausal and perimenopausal women with early-stage hormone receptor-positive breast cancer: a randomised controlled clinical trial.

Science.gov (United States)

Yang, H; Zong, X; Yu, Y; Shao, G; Zhang, L; Qian, C; Bian, Y; Xu, X; Sun, W; Meng, X; Ding, X; Chen, D; Zou, D; Xie, S; Zheng, Y; Zhang, J; He, X; Sun, C; Yu, X; Ni, J

2013-08-06

This study is to investigate the effects of geserelin+tamoxifen (TAM) on estradiol level, breast density (BD), endometrial thickness (ET), and blood lipids in premenopausal and perimenopausal women with hormone receptor-positive early-stage breast cancer. This study recruited 110 premenopausal and perimenopausal patients with hormone receptor-positive early-stage breast cancer between 22 June 2008 and 31 December 2009 and randomly assigned them to receive either goserelin plus TAM or TAM alone for 1.5 years. Blood levels of sex hormones and lipids and ET were determined at 0, 3, 6, 12, and 18 months. Contralateral BD was also measured at 0, 12, and 18 months. Five participants dropped out of the goserelin plus TAM group, and two participants dropped out of the TAM-alone group before initiation of endocrine therapy. The rest of patients received scheduled treatment and 3 years of median follow-up. No serious adverse effects were observed, and only two local recurrences have been observed in these patients. Estradiol level and BD were lower in the goserelin plus TAM group than in the TAM-alone group (Pwomen in the TAM-alone group exhibited endometrial thickening over the course of the study. Furthermore, no significant differences in blood lipid levels were reported between the two groups. The data from the current study demonstrated that the addition of goserelin to TAM results in downregulation of estradiol level, followed by significant reduction in BD and ET in premenopausal and perimenopausal women with hormone receptor-positive breast cancer, which may eventually lead to better outcome in these patients.

Somatostatin receptor scintigraphy on thyroid carcinoma

International Nuclear Information System (INIS)

Pan Weimin; Tan Tianzhi

2004-01-01

Purpose: To study the diagnostic value and clinical method of somatostatin receptor scintigraphy on thyroid carcinoma using 99 Tc m -RC-160 labeled with direct method as scintigraphy reagent; Methods: Somatostatin receptor scintigraphy (SRS) were performed on 25 patients with thyroid carcinoma, using 99 Tc m -RC-160 labeled with direct method as scintigraphy reagent, controlling with 131 I- whole- body- imaging(1312 -WBI). Results: Of 4 patients with MTC (medullary thyroid carcinoma), positive metastasis and primary tumour were detected on 3 patients by SRS, negative results were obtained by 131 I-WBI, the positive detective rate by SRS is 3/4; of 12 patients with PTC (papillary thyroid carcinoma), positive metastasis and primary tumour were detected on 2 patients by SRS or 131 I-WBI,1 of which only by SRS, while negative results were obtained by 131 I- WBI, the positive detective rate by SRS is 3/12; of 8 patients with FTC(follicular thyroid carcinoma), positive metastasis and primary tumour were detected on 1 patients by SRS or 131 I-WBI, and 2 positive results were obtained only by SRS, while negative by 131 I-WBI, the positive detective rate by SRS is 3/8; of 1 patients with HCC (hurthle cell carcinoma ), positive metastasis and primary tumour were detected by SRS, while negative by 131 I-WBI; Conclusions: SRS using 99 Tc m -RC-160 labeled with direct method as scintigraphy reagent has high diagnostic value on thyroid carcinoma, especially on MTC and HCC. (authors)

Disturbances of ligand potency and enhanced degradation of the human glycine receptor at affected positions G160 and T162 originally identified in patients suffering from hyperekplexia

Directory of Open Access Journals (Sweden)

Sinem eAtak

2015-12-01

Full Text Available Ligand-binding of Cys-loop receptors is determined by N-terminal extracellular loop structures from the plus as well as from the minus side of two adjacent subunits in the pentameric receptor complex. An aromatic residue in loop B of the glycine receptor (GlyR undergoes direct interaction with the incoming ligand via cation-π interactions. Recently we showed that mutated residues in loop B identified from human patients suffering from hyperekplexia disturb ligand-binding. Here, we exchanged the affected human residues by amino acids found in related members of the Cys-loop receptor family to determine the effects of side chain volume for ion channel properties. GlyR variants were characterized in vitro following transfection into cell lines in order to analyze protein expression, trafficking, degradation and ion channel function. GlyR α1 G160 mutations significantly decrease glycine potency arguing for a positional effect on neighboring aromatic residues and consequently glycine-binding within the ligand-binding pocket. Disturbed glycinergic inhibition due to T162 α1 mutations is an additive effect of affected biogenesis and structural changes within the ligand-binding site. Protein trafficking from the ER towards ER-Golgi intermediate compartment, the secretory Golgi pathways and finally the cell surface is largely diminished, but still sufficient to deliver ion channels that are functional at least at high glycine concentrations. The majority of T162 mutant protein accumulates in the ER and is conducted to ER-associated proteasomal degradation. Hence, G160 is an important determinant during glycine binding. In contrast, T162 assigns primarily receptor biogenesis whereas exchanges in functionality are secondary effects thereof.

Joint position sense and vibration sense: anatomical organisation and assessment.

Science.gov (United States)

Gilman, S

2002-11-01

Clinical examination of joint position sense and vibration sense can provide important information concerning specific cutaneous sensory receptors, peripheral nerves, dorsal roots, and central nervous system pathways and should be included as a regular component of the neurological examination. Although these sensory modalities share a spinal cord and brainstem pathway, they arise in different receptors and terminate in separate distributions within the thalamus and cerebral cortex. Consequently, both modalities should be tested as part of the neurological examination. Clinical testing of these modalities requires simultaneous stimulation of tactile receptors; hence this review will include information about the receptors and pathways responsible for tactile sensation.

An Epidemiologic Study of Genetic Variation in Hormonal Pathways in Relation to the Effect of Hormone Replacement Therapy on Breast Cancer Risk

Science.gov (United States)

2008-10-01

PGR gene to be associated with breast cancer. Using long-range PCR techniques to sequence exons 1 and 2 of PGR, and a Solexa chip from Illumina...specific histologic types associated with single SNPs in PGR, AKR1C1, AKR1C2, AKR1C3, SRD5A1, SRD5A2 and CYP3A4 Breast caner overall Ductal Lobular...1.3 0.96 T/T 92 (9.1) 120 (9.6) 1.1 0.8 1.4 72 (9.5) 1.1 0.8 1.5 27 (9.7) 1.0 0.6 1.7 0.93 CYP3A4 rs12333983 T/T 791 (77.8) 985

Sonography and CT findings in perigraft reactions after surgical implantation of vascular prostheses

International Nuclear Information System (INIS)

Scherer, G.; Roeren, T.; Paetz, B.; Hupp, T.; Kauffmann, G.W.

1995-01-01

Between January 1988 and January 1994, 24 patients with heterologeous vascular bypasses were examined with suspected diagnosis of a perigraft reaction (PGR). All patients were subjected to ultrasound and CT. PGR ist defined as a sterile inflammation along the course of a vascular prosthesis. The typical clinical presentation is a fluctuating tumour with a localised painless swelling. In all cases liquid formations could be confirmed by diagnostic imaging procedures; signs of infection could be excluded. The synopsis of the clinical presentation, the time interval after implantation of the prosthetic material and the signs of sonography and CT can reliably exclude infection of the prosthesis and confirm the diagnosis of a PGR. (orig.) [de

A phase II trial of abiraterone acetate plus prednisone in patients with triple-negative androgen receptor positive locally advanced or metastatic breast cancer (UCBG 12-1).

Science.gov (United States)

Bonnefoi, H; Grellety, T; Tredan, O; Saghatchian, M; Dalenc, F; Mailliez, A; L'Haridon, T; Cottu, P; Abadie-Lacourtoisie, S; You, B; Mousseau, M; Dauba, J; Del Piano, F; Desmoulins, I; Coussy, F; Madranges, N; Grenier, J; Bidard, F C; Proudhon, C; MacGrogan, G; Orsini, C; Pulido, M; Gonçalves, A

2016-05-01

Several expression array studies identified molecular apocrine breast cancer (BC) as a subtype that expresses androgen receptor (AR) but not estrogen receptor α. We carried out a multicentre single-arm phase II trial in women with AR-positive, estrogen, progesterone receptor and HER2-negative (triple-negative) metastatic or inoperable locally advanced BC to assess the efficacy and safety of abiraterone acetate (AA) plus prednisone. Patients with a metastatic or locally advanced, centrally reviewed, triple-negative and AR-positive (≥10% by immunohistochemistry, IHC) BC were eligible. Any number of previous lines of chemotherapy was allowed. AA (1000 mg) was administered once a day with prednisone (5 mg) twice a day until disease progression or intolerance. The primary end point was clinical benefit rate (CBR) at 6 months defined as the proportion of patients presenting a complete response (CR), partial response (PR) or stable disease (SD) ≥6 months. Secondary end points were objective response rate (ORR), progression-free survival (PFS) and safety. One hundred and forty-six patients from 27 centres consented for IHC central review. Of the 138 patients with sufficient tissue available, 53 (37.6%) were AR-positive and triple-negative, and 34 of them were included from July 2013 to December 2014. Thirty patients were eligible and evaluable for the primary end point. The 6-month CBR was 20.0% [95% confidence interval (CI) 7.7%-38.6%], including 1 CR and 5 SD ≥6 months, 5 of them still being under treatment at the time of analysis (6.4+, 9.2+, 14.5+, 17.6+, 23.4+ months). The ORR was 6.7% (95% CI 0.8%-22.1%). The median PFS was 2.8 months (95% CI 1.7%-5.4%). Fatigue, hypertension, hypokalaemia and nausea were the most common drug-related adverse events; the majority of them being grade 1 or 2. AA plus prednisone treatment is beneficial for some patients with molecular apocrine tumours and five patients are still on treatment. NCT01842321. © The Author 2016

Anticonvulsant action of GABA(B) receptor positive modulator CGP7930 in immature rats

Czech Academy of Sciences Publication Activity Database

Mareš, Pavel

2012-01-01

Roč. 100, 1-2 (2012), s. 49-54 ISSN 0920-1211 R&D Projects: GA MŠk(CZ) LC554; GA ČR(CZ) GAP304/10/1274 Institutional research plan: CEZ:AV0Z50110509 Keywords : GABA(B) receptors * cerebral cortex * epileptic afterdischarges * immature rats Subject RIV: FH - Neurology Impact factor: 2.241, year: 2012

A thyrotropin‑secreting macroadenoma with positive growth ...

African Journals Online (AJOL)

A thyrotropin‑secreting macroadenoma with positive growth hormone and prolactin immunostaining: A case report and literature review. ... thyroid hormone receptor resistance syndrome. Key words: Inappropriate thyroid stimulating hormone, thyrotropin‑secreting pituitary adenoma, thyroid stimulating hormone adenoma ...

Clinical implications of recent studies using mTOR inhibitors to treat advanced hormone receptor-positive breast cancer

International Nuclear Information System (INIS)

Arena, Francis

2014-01-01

Breast cancer is a leading cause of cancer-related death worldwide. Approximately 75% of breast cancer is hormone receptor-positive (HR + ) and is managed with endocrine therapies. However, relapse or disease progression caused by primary or acquired endocrine resistance is frequent. Phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR)-mediated signaling is one of the molecular mechanisms leading to endocrine resistance. mTOR inhibitors that target the PI3K/Akt/mTOR pathway are the first of the targeted therapies to be evaluated in clinical trials to overcome endocrine resistance. Although the clinical trial with temsirolimus, an mTOR inhibitor, did not show any benefit when compared with endocrine therapy alone, a Phase II clinical trial with sirolimus has been promising. Recently, everolimus was approved in combination with exemestane by the US Food and Drug Administration for treating postmenopausal women with advanced HR + breast cancer, based on the results of a Phase III trial. Therefore, everolimus represents the first and only targeted agent approved for combating endocrine resistance

Confirmation of 5p12 As a Susceptibility Locus for Progesterone-Receptor-Positive, Lower Grade Breast Cancer

DEFF Research Database (Denmark)

Milne, Roger L; Goode, Ellen L; García-Closas, Montserrat

2011-01-01

-negative disease; P(heterogeneity) = 2 × 10(-7)); heterogeneity by ER status was not observed (P = 0.2) once PR status was accounted for. The association was also stronger for lower grade tumors [per-allele OR (95% CI) = 1.20 (1.14-1.25), 1.13 (1.09-1.16), and 1.04 (0.99-1.08) for grade 1, 2, and 3/4, respectively......BACKGROUND: The single-nucleotide polymorphism (SNP) 5p12-rs10941679 has been found to be associated with risk of breast cancer, particularly estrogen receptor (ER)-positive disease. We aimed to further explore this association overall, and by tumor histopathology, in the Breast Cancer Association...... and histopathology were assessed using logistic regression. RESULTS: For white Europeans, the per-allele OR associated with 5p12-rs10941679 was 1.11 (95% CI = 1.08-1.14, P = 7 × 10(-18)) for invasive breast cancer and 1.10 (95% CI = 1.01-1.21, P = 0.03) for DCIS. For Asian women, the estimated OR for invasive...

Steroid metabolism and steroid receptors in dimethylbenz(a)anthracene-induced rat mammary tumors

International Nuclear Information System (INIS)

Eechaute, W.; de Thibault de Boesinghe, L.; Lacroix, E.

1983-01-01

Mammary tumors were induced in rats by treatment with dimethylbenz(a)anthracene. Cytosol receptors for 17 beta-estradiol and progesterone were estimated by means of sucrose density gradient centrifugation, and the metabolism of [ 14 C]progesterone, [ 14 C]testosterone, and 17 beta-[ 14 C]estradiol by minced tumor tissue was studied. The estradiol receptor (ER) and progesterone receptor (PR) levels of the tumors varied considerably from less than 5 to 48 fmol/mg protein for ER and to 243 fmol/mg protein for PR. Considering a receptor level lower than 5 fmol/mg protein to be negative, four groups of tumors were found: ER-negative and PR-negative; ER-positive and PR-negative; ER-negative and PR-positive; ER-positive and PR-positive. In dimethylbenz(a)anthracene-induced tumor tissue, high 5 alpha-reductase and 20 alpha-hydroxysteroid dehydrogenase activities and somewhat lower 3 alpha-hydroxysteroid dehydrogenase and 6 alpha-hydroxylase activities were found. No aromatization was detectable. Steroids, especially estradiol, were also metabolized in a high degree to unextractable metabolites. It was concluded that steroid metabolism of dimethylbenz(a)anthracene-induced rat mammary tumors was not related to the ER and/or PR concentration of tumor tissue

Carbon-11 labelling of eticlopride in two different positions - a selective high-affinity ligand for the study of dopamine D-2 receptors using PET

International Nuclear Information System (INIS)

Halldin, Christer; Hall, Haakan

1990-01-01

A new highly selective high-affinity dopamine D-2 receptor antagonist, eticlopride ((-)-(S)-5-chloro-3-ethyl-N-(1-ethyl-2-pyrrolidinyl)methyl)-6-methoxysalicylamide), was labelled with 11 C in two different positions ([N-ethyl- 11 C]eticlopride (I) and ([methyl- 11 C]eticlopride (II)). Product I was prepared by N-alkylation of the N-desethyl compound with [ 11 C]ethyl iodide. II was prepared by O-alkylation of the diphenolic precursor with [ 11 C]methyl iodide followed by separation of the two methylated products. The radiochemical yields were 15-20% (EOB) with an overall synthesis time of 45-60 min. Both compounds were isolated by semi-preparative HPLC and the radiochemical purity was in both cases > 99%. I was injected i.v. in a Cynomolgus monkey and brain radioactivity was measured by positron emission tomography (PET). The specific activity was 70 Ci/mmol at time of injection. There was a marked accumulation of radioactivity in the basal ganglia, regions known to have a high density of dopamine D-2 receptors. (author)

Genotype-Dependent Difference in 5-HT2C Receptor-Induced Hypolocomotion: Comparison with 5-HT2A Receptor Functional Activity

Directory of Open Access Journals (Sweden)

Darya V. Bazovkina

2015-01-01

Full Text Available In the present study behavioral effects of the 5-HT2C serotonin receptor were investigated in different mouse strains. The 5-HT2C receptor agonist MK-212 applied intraperitoneally induced significant dose-dependent reduction of distance traveled in the open field test in CBA/Lac mice. This effect was receptor-specific because it was inhibited by the 5-HT2C receptor antagonist RS102221. To study the role of genotype in 5-HT2C receptor-induced hypolocomotion, locomotor activity of seven inbred mouse strains was measured after MK-212 acute treatment. We found that the 5-HT2C receptor stimulation by MK-212 decreased distance traveled in the open field test in CBA/Lac, C57Bl/6, C3H/He, and ICR mice, whereas it failed to affect locomotor activity in DBA/2J, Asn, and Balb/c mice. We also compared the interstrain differences in functional response to 5-HT2C and 5-HT2A receptors activation measured by the quantification of receptor-mediated head-twitches. These experiments revealed significant positive correlation between 5-HT2C and 5-HT2A receptors functional responses for all investigated mouse strains. Moreover, we found that 5-HT2A receptor activation with DOI did not change locomotor activity in CBA/Lac mice. Taken together, our data indicate the implication of 5-HT2C receptors in regulation of locomotor activity and suggest the shared mechanism for functional responses mediated by 5-HT2C and 5-HT2A receptors.

Steroid hormone and epidermal growth factor receptors in meningiomas.

Science.gov (United States)

Horsfall, D J; Goldsmith, K G; Ricciardelli, C; Skinner, J M; Tilley, W D; Marshall, V R

1989-11-01

A prospective study of steroid hormone and epidermal growth factor receptor expression in 57 meningiomas is presented. Scatchard analysis of radioligand binding identified 20% of meningiomas as expressing classical oestrogen receptors (ER) at levels below that normally accepted for positivity, the remainder being negative. ER could not be visualized in any meningioma using immunocytochemistry. Alternatively, 74% of meningiomas demonstrated the presence of progesterone receptors (PR) by Scatchard analysis, the specificity of which could not be attributed to glucocorticoid or androgen receptors. Confirmation of classical PR presence was determined by immunocytochemical staining. The presence of epidermal growth factor receptor (EGFR) was demonstrated in 100% of meningiomas using immunocytochemical staining. These data are reviewed in the context of previously reported results and are discussed in relation to the potential for medical therapy as an adjunct to surgery.

The metabotropic glutamate receptors: structure, activation mechanism and pharmacology.

Science.gov (United States)

Pin, Jean-Philippe; Acher, Francine

2002-06-01

The metabotropic glutamate receptors are G-protein coupled receptors (GPCR) involved in the regulation of many synapses, including most glutamatergic fast excitatory synapses. Eight subtypes have been identified that can be classified into three groups. The molecular characterization of these receptors revealed proteins much more complex than any other GPCRs. They are composed of a Venus Flytrap (VFT) module where glutamate binds, connected to a heptahelical domain responsible for G-protein coupling. Recent data including the structure of the VFT module determined with and without glutamate, indicate that these receptors function as dimers. Moreover a number of intracellular proteins can regulate their targeting and transduction mechanism. Such structural features of mGlu receptors offer multiple possibilities for synthetic compounds to modulate their activity. In addition to agonists and competitive antagonists acting at the glutamate binding site, a number of non-competitive antagonists with inverse agonist activity, and positive allosteric modulators have been discovered. These later compounds share specific properties that make them good candidates for therapeutic applications. First, their non-amino acid structure makes them pass more easily the blood brain barrier. Second, they are much more selective than any other compound identified so far, being the first subtype selective molecules. Third, for the negative modulators, their non competitive mechanism of action makes them relatively unaffected by high concentrations of glutamate that may be present in disease states (e.g. stroke, epilepsy, neuropathic pain, etc.). Fourth, like the benzodiazepines acting at the GABA(A) receptors, the positive modulators offer a new way to increase the activity of these receptors in vivo, with a low risk of inducing their desensitization. The present review article focuses on the specific structural features of these receptors and highlights the various possibilities these

Head and neck position sense.

Science.gov (United States)

Armstrong, Bridget; McNair, Peter; Taylor, Denise

2008-01-01

Traumatic minor cervical strains are common place in high-impact sports (e.g. tackling) and premature degenerative changes have been documented in sports people exposed to recurrent impact trauma (e.g. scrummaging in rugby) or repetitive forces (e.g. Formula 1 racing drivers, jockeys). While proprioceptive exercises have been an integral part of rehabilitation of injuries in the lower limb, they have not featured as prominently in the treatment of cervical injuries. However, head and neck position sense (HNPS) testing and re-training may have relevance in the management of minor sports-related neck injuries, and play a role in reducing the incidence of ongoing pain and problems with function. For efficacious programmes to be developed and tested, fundamental principles associated with proprioception in the cervical spine should be considered. Hence, this article highlights the importance of anatomical structures in the cervical spine responsible for position sense, and how their interaction with the CNS affects our ability to plan and execute effective purposeful movements. This article includes a review of studies examining position sense in subjects with and without pathology and describes the effects of rehabilitation programmes that have sought to improve position sense. In respect to the receptors providing proprioceptive information for the CNS, the high densities and complex arrays of spindles found in cervical muscles suggest that these receptors play a key role. There is some evidence suggesting that ensemble encoding of discharge patterns from muscle spindles is relayed to the CNS and that a pattern recognition system is used to establish joint position and movement. Sensory information from neck proprioceptive receptors is processed in tandem with information from the vestibular system. There are extensive anatomical connections between neck proprioceptive inputs and vestibular inputs. If positional information from the vestibular system is inaccurate or

Xenobiotics and the Glucocorticoid Receptor

International Nuclear Information System (INIS)

Gulliver, Linda S M

2017-01-01

Glucocorticoid Receptor (GR) is present in virtually every human cell type. Representing a nuclear receptor superfamily, GR has several different isoforms essentially acting as ligand-dependent transcription factors, regulating glucocorticoid-responsive gene expression in both a positive and a negative manner. Although the natural ligand of the Glucocorticoid Receptor, glucocorticoids (GC) represent only some of the multiple ligands for GR. Xenobiotics, ubiquitous in the environment, bind to GR and are also capable of activating or repressing GR gene expression, thereby modulating GR cell and tissue-specific downstream effects in a multitude of ways that include responses to inflammatory, allergic, metabolic, neoplastic and autoimmune processes. Many xenobiotics, if inadequately metabolized by xenobiotic metabolizing enzymes and not wholly eliminated, could have deleterious toxic effects with potentially lethal consequences. This review examines GR, the genomic and non-genomic actions of natural and synthetic GC and the body's handling of xenobiotic compounds, before reviewing what is presently known about GR's interactions with many of the more commonly encountered and some of the less well known GR-associated xenobiotics. GR promiscuity and crosstalk with other signaling pathways is discussed, alongside novel roles for GR that include mood disorder and addiction. A knowledge of GR interactions with xenobiotics is increasingly relevant when considering aging populations and the related prevalence of neoplastic disease, together with growing concerns around human exposure to mixtures of chemicals in the environment. Furthermore, escalating rates of obesity, Type 2 diabetes; autoimmune, allergy, addiction and mood disorder-related pathologies, require novel targeted interventions and GR appears a promising pharmacological candidate. - Highlights: • Biological impact of xenobiotics acting through Glucocorticoid Receptor. • Promiscuity of Glucocorticoid

Xenobiotics and the Glucocorticoid Receptor

Energy Technology Data Exchange (ETDEWEB)

Gulliver, Linda S M, E-mail: linda.gulliver@otago.ac.nz

2017-03-15

Glucocorticoid Receptor (GR) is present in virtually every human cell type. Representing a nuclear receptor superfamily, GR has several different isoforms essentially acting as ligand-dependent transcription factors, regulating glucocorticoid-responsive gene expression in both a positive and a negative manner. Although the natural ligand of the Glucocorticoid Receptor, glucocorticoids (GC) represent only some of the multiple ligands for GR. Xenobiotics, ubiquitous in the environment, bind to GR and are also capable of activating or repressing GR gene expression, thereby modulating GR cell and tissue-specific downstream effects in a multitude of ways that include responses to inflammatory, allergic, metabolic, neoplastic and autoimmune processes. Many xenobiotics, if inadequately metabolized by xenobiotic metabolizing enzymes and not wholly eliminated, could have deleterious toxic effects with potentially lethal consequences. This review examines GR, the genomic and non-genomic actions of natural and synthetic GC and the body's handling of xenobiotic compounds, before reviewing what is presently known about GR's interactions with many of the more commonly encountered and some of the less well known GR-associated xenobiotics. GR promiscuity and crosstalk with other signaling pathways is discussed, alongside novel roles for GR that include mood disorder and addiction. A knowledge of GR interactions with xenobiotics is increasingly relevant when considering aging populations and the related prevalence of neoplastic disease, together with growing concerns around human exposure to mixtures of chemicals in the environment. Furthermore, escalating rates of obesity, Type 2 diabetes; autoimmune, allergy, addiction and mood disorder-related pathologies, require novel targeted interventions and GR appears a promising pharmacological candidate. - Highlights: • Biological impact of xenobiotics acting through Glucocorticoid Receptor. • Promiscuity of Glucocorticoid

Receptor-receptor interactions within receptor mosaics. Impact on neuropsychopharmacology.

Science.gov (United States)

Fuxe, K; Marcellino, D; Rivera, A; Diaz-Cabiale, Z; Filip, M; Gago, B; Roberts, D C S; Langel, U; Genedani, S; Ferraro, L; de la Calle, A; Narvaez, J; Tanganelli, S; Woods, A; Agnati, L F

2008-08-01

Future therapies for diseases associated with altered dopaminergic signaling, including Parkinson's disease, schizophrenia and drug addiction or drug dependence may substantially build on the existence of intramembrane receptor-receptor interactions within dopamine receptor containing receptor mosaics (RM; dimeric or high-order receptor oligomers) where it is believed that the dopamine D(2) receptor may operate as the 'hub receptor' within these complexes. The constitutive adenosine A(2A)/dopamine D(2) RM, located in the dorsal striato-pallidal GABA neurons, are of particular interest in view of the demonstrated antagonistic A(2A)/D(2) interaction within these heteromers; an interaction that led to the suggestion and later demonstration that A(2A) antagonists could be used as novel anti-Parkinsonian drugs. Based on the likely existence of A(2A)/D(2)/mGluR5 RM located both extrasynaptically on striato-pallidal GABA neurons and on cortico-striatal glutamate terminals, multiple receptor-receptor interactions within this RM involving synergism between A(2A)/mGluR5 to counteract D(2) signaling, has led to the proposal of using combined mGluR5 and A(2A) antagonists as a future anti-Parkinsonian treatment. Based on the same RM in the ventral striato-pallidal GABA pathways, novel strategies for the treatment of schizophrenia, building on the idea that A(2A) agonists and/or mGluR5 agonists will help reduce the increased dopaminergic signaling associated with this disease, have been suggested. Such treatment may ensure the proper glutamatergic drive from the mediodorsal thalamic nucleus to the prefrontal cortex, one which is believed to be reduced in schizophrenia due to a dominance of D(2)-like signaling in the ventral striatum. Recently, A(2A) receptors also have been shown to counteract the locomotor and sensitizing actions of cocaine and increases in A(2A) receptors have also been observed in the nucleus accumbens after extended cocaine self-administration, probably

Virions at the gates: receptors and the host-virus arms race.

Science.gov (United States)

Coffin, John M

2013-01-01

All viruses need to bind to specific receptor molecules on the surface of target cells to initiate infection. Virus-receptor binding is highly specific, and this specificity determines both the species and the cell type that can be infected by a given virus. In some well-studied cases, the virus-binding region on the receptor has been found to be unrelated to the receptor's normal cellular function. Resistance to virus infection can thus evolve by selection of mutations that alter amino acids in the binding region with minimal effect on normal function. This sort of positive selection can be used to infer the history of the host-virus "arms race" during their coevolution. In a new study, Demogines et al. use a combination of phylogenetic, structural, and virological analysis to infer the history and significance of positive selection on the transferrin receptor TfR1, a housekeeping protein required for iron uptake and the cell surface receptor for at least three different types of virus. The authors show that only two parts of the rodent TfR1 molecule have been subject to positive selection and that these correspond to the binding sites for two of these viruses-the mouse mammary tumor virus (a retrovirus) and Machupo virus (an arenavirus). They confirmed this result by introducing the inferred binding site mutations into the wild-type protein and testing for receptor function. Related arenaviruses are beginning to spread in human populations in South America as the cause of often fatal hemorrhagic fevers, and, although Demogines et al. could find no evidence of TfR1 mutations in this region that might have been selected as a consequence of human infection, the authors identified one such mutation in Asian populations that affects infection with these viruses.

Virions at the gates: receptors and the host-virus arms race.

Directory of Open Access Journals (Sweden)

John M Coffin

Full Text Available All viruses need to bind to specific receptor molecules on the surface of target cells to initiate infection. Virus-receptor binding is highly specific, and this specificity determines both the species and the cell type that can be infected by a given virus. In some well-studied cases, the virus-binding region on the receptor has been found to be unrelated to the receptor's normal cellular function. Resistance to virus infection can thus evolve by selection of mutations that alter amino acids in the binding region with minimal effect on normal function. This sort of positive selection can be used to infer the history of the host-virus "arms race" during their coevolution. In a new study, Demogines et al. use a combination of phylogenetic, structural, and virological analysis to infer the history and significance of positive selection on the transferrin receptor TfR1, a housekeeping protein required for iron uptake and the cell surface receptor for at least three different types of virus. The authors show that only two parts of the rodent TfR1 molecule have been subject to positive selection and that these correspond to the binding sites for two of these viruses-the mouse mammary tumor virus (a retrovirus and Machupo virus (an arenavirus. They confirmed this result by introducing the inferred binding site mutations into the wild-type protein and testing for receptor function. Related arenaviruses are beginning to spread in human populations in South America as the cause of often fatal hemorrhagic fevers, and, although Demogines et al. could find no evidence of TfR1 mutations in this region that might have been selected as a consequence of human infection, the authors identified one such mutation in Asian populations that affects infection with these viruses.

Identification of hormone-interacting amino acid residues within the steroid-binding domain of the glucocorticoid receptor in relation to other steroid hormone receptors

International Nuclear Information System (INIS)

Carlstedt-Duke, J.; Stroemstedt, P.E.; Persson, B.; Cederlund, E.; Gustafsson, J.A.; Joernvall, H.

1988-01-01

Purified rat liver glucocorticoid receptor was covalently charged with [ 3 H]glucocorticoid by photoaffinity labeling (UV irradiation of [ 3 H]triamcinolone acetonide-glucocorticoid receptor) or affinity labeling (incubation with [ 3 H]dexamethasone mesylate). After labeling, separate samples of the denatured receptor were cleaved with trypsin (directly or after prior succinylation), chymotrypsin, and cyanogen bromide. Labeled residues in the peptides obtained were identified by radiosequence analysis. The peaks of radioactivity corresponded to Met-622 and Cys-754 after photoaffinity labeling with [ 3 H]triamcinolone acetonide and Cys-656 after affinity labeling with [ 3 H]dexamethasone mesylate. The labeled residues are all positioned within hydrophobic segments of the steroid-binding domain. The patterns of hydropathy and secondary structure for the glucocorticoid receptor are highly similar to those for the progestin receptor and similar but less so to those for the estrogen receptor and to those for c-erb A

Serum soluble ST2 is associated with ER-positive breast cancer

International Nuclear Information System (INIS)

Lu, Da-peng; Zhou, Xiang-yu; Yao, Lu-tian; Liu, Cai-gang; Ma, Wei; Jin, Feng; Wu, Yun-fei

2014-01-01

ST2, a member of the interleukin (IL)-1receptor family, regulates Th1/Th2 immune responses in autoimmune and inflammatory conditions. However, the role of ST2 signaling in tumor growth and metastasis of breast cancers has not been investigated. This study investigated the possible role of soluble ST2 (sST2) in breast cancer. The serum levels of IL-33, sST2, and vascular endothelial growth factor (VEGF) in 150 breast cancer patients and 90 healthy women were measured by enzyme-linked immunosorbent assay. Estrogen receptor(ER), progesterone receptor, human epithelial receptor (HER)-2, and cell cycle regulated protein Ki-67 were measured. Clinical stage, tumor size, lymph node metastasis, and histological type were also recorded. The serum levels of sST2, IL-33, and VEGF were significantly higher in breast cancer patients than in the control group (P < 0.05, each). Serum sST2 levels in ER-positive breast cancer patients were significantly associated with age, histological type, clinical stage, tumor size, and Ki-67 status (P < 0.05, each). Moreover, the serum levels of IL-33 and sST2 in breast cancers significantly correlated with VEGF levels (IL-33: r = 0.375, P < 0.0001; sST2: r = 0.164, P = 0.045). Serum levels of sST2, IL-33, and VEGF decreased after modified radical mastectomy in ER-positive breast cancers. Serum levels of IL-33, sST2, and VEGF and clinicopathological factors were not significantly correlated with disease-free survival and overall survival of ER-positive breast cancer women during follow-up. Serum sST2 levels in ER-positive breast cancer patients are significantly associated with factors that indicate poor prognosis

Familial risks and estrogen receptor-positive breast cancer in Hong Kong Chinese women.

Science.gov (United States)

Tse, Lap Ah; Li, Mengjie; Chan, Wing-cheong; Kwok, Chi-hei; Leung, Siu-lan; Wu, Cherry; Yu, Ignatius Tak-sun; Yu, Wai-cho; Lao, Xiangqian; Wang, Xiaorong; Wong, Carmen Ka-man; Lee, Priscilla Ming-yi; Wang, Feng; Yang, Xiaohong Rose

2015-01-01

The role of family history to the risk of breast cancer was analyzed by incorporating menopausal status in Hong Kong Chinese women, with a particular respect to the estrogen receptor-positive (ER+) type. Seven hundred and forty seven breast cancer incident cases and 781 hospital controls who had completed information on family cancer history in first-degree relatives (nature father, mother, and siblings) were recruited. Odds ratio for breast cancer were calculated by unconditional multiple logistic regression, stratified by menopausal status (a surrogate of endogenous female sex hormone level and age) and type of relative affected with the disease. Further subgroup analysis by tumor type according to ER status was investigated. Altogether 52 (6.96%) breast cancer cases and 23 (2.95%) controls was found that the patients' one or more first-degree relatives had a history of breast cancer, showing an adjusted odds ratio (OR) of 2.41 (95%CI: 1.45-4.02). An excess risk of breast cancer was restricted to the ER+ tumor (OR = 2.43, 95% CI: 1.38-4.28), with a relatively higher risk associated with an affected mother (OR = 3.97, 95%CI: 1.46-10.79) than an affected sister (OR = 2.06, 95%CI: 1.07-3.97), while the relative risk was more prominent in the subgroup of pre-menopausal women. Compared with the breast cancer overall, the familial risks to the ER+ tumor increased progressively with the number of affected first-degree relatives. This study provides new insights on a relationship between family breast cancer history, menopausal status, and the ER+ breast cancer. A separate risk prediction model for ER+ tumor in Asian population is desired.

Effect of presurgical radiotherapy on the steroid receptor concentrations in primary breast carcinoma

International Nuclear Information System (INIS)

Janssens, J. Ph.; Bonte, J.; Drochmans, A.; Mulier, J.; Rutten, J.; Wittevrongel, C.; Loecker, W. de

1981-01-01

With age, oestradiol receptor concentrations increased in primary breast carcinoma while age did not seem to affect the progesterone receptor levels. Above the age of 70, all tumours examined proved to be hormone-dependent. Analysis by light microscope did not allow correlation of the receptor-positive tumours to any specific or predominant cellular structure. Presurgical radiotherapy of 20 gray significantly reduced the oestradiol and to an even greater extent the progesterone receptor concentrations in the tumours. Prebioptic irradiation with 8 gray accentuated the inhibition of steroid receptor proteins. This reduction in receptor concentration after radiotherapy should be taken into account when interpreting steroid receptor values. (author)

Ghrelin receptor inverse agonists: identification of an active peptide core and its interaction epitopes on the receptor

DEFF Research Database (Denmark)

Holst, Birgitte; Lang, Manja; Brandt, Erik

2006-01-01

[D-Arg1,D-Phe5,D-Trp7,9,Leu11]Substance P functions as a low-potency antagonist but a high-potency full inverse agonist on the ghrelin receptor. Through a systematic deletion and substitution analysis of this peptide, the C-terminal carboxyamidated pentapeptide wFwLX was identified as the core...... structure, which itself displayed relatively low inverse agonist potency. Mutational analysis at 17 selected positions in the main ligand-binding crevice of the ghrelin receptor demonstrated that ghrelin apparently interacts only with residues in the middle part of the pocket [i.e., between transmembrane...... upon both AspII:20 and GluIII:09. The identified pharmacophore can possibly serve as the basis for targeted discovery of also nonpeptide inverse agonists for the ghrelin receptor....

Metabolic products of linalool and modulation of GABAA receptors

Science.gov (United States)

Milanos, Sinem; Elsharif, Shaimaa A.; Janzen, Dieter; Buettner, Andrea; Villmann, Carmen

2017-06-01

Terpenoids are major subcomponents in aroma substances which harbor sedative physiological potential. We have demonstrated that various monoterpenoids such as the acyclic linalool enhance GABAergic currents in an allosteric manner in vitro upon overexpression of inhibitory a1b2 GABAA receptors in various expression systems. However, in plants or humans, i.e. following intake via inhalation or ingestion, linalool undergoes metabolic modifications including oxygenation and acetylation, which may affect the modulatory efficacy of the generated linalool derivatives. Here, we analyzed the modulatory potential of linalool derivatives at a1b2g2 GABAA receptors upon transient overexpression. Following receptor expression control, electrophysiological recordings in a whole cell configuration were used to determine the chloride influx upon co-application of GABA EC5-10 together with the modulatory substance. Our results show that only oxygenated linalool metabolites at carbon 8 positively affect GABAergic currents whereas derivatives hydroxylated or carboxylated at carbon 8 were rather ineffective. Acetylated linalool derivatives resulted in non-significant changes of GABAergic currents. We can conclude that metabolism of linalool reduces its positive allosteric potential at GABAA receptors compared to the significant potentiation effects of the parent molecule linalool itself.

Metabolic Products of Linalool and Modulation of GABAA Receptors

Directory of Open Access Journals (Sweden)

Sinem Milanos

2017-06-01

Full Text Available Terpenoids are major subcomponents in aroma substances which harbor sedative physiological potential. We have demonstrated that various monoterpenoids such as the acyclic linalool enhance GABAergic currents in an allosteric manner in vitro upon overexpression of inhibitory α1β2 GABAA receptors in various expression systems. However, in plants or humans, i.e., following intake via inhalation or ingestion, linalool undergoes metabolic modifications including oxygenation and acetylation, which may affect the modulatory efficacy of the generated linalool derivatives. Here, we analyzed the modulatory potential of linalool derivatives at α1β2γ2 GABAA receptors upon transient overexpression. Following receptor expression control, electrophysiological recordings in a whole cell configuration were used to determine the chloride influx upon co-application of GABA EC10−30 together with the modulatory substance. Our results show that only oxygenated linalool metabolites at carbon 8 positively affect GABAergic currents whereas derivatives hydroxylated or carboxylated at carbon 8 were rather ineffective. Acetylated linalool derivatives resulted in non-significant changes of GABAergic currents. We can conclude that metabolism of linalool reduces its positive allosteric potential at GABAA receptors compared to the significant potentiation effects of the parent molecule linalool itself.

Comparative studies on Fc receptors for IgG on resting and activated T lymphocytes

International Nuclear Information System (INIS)

Hueckel, C.; Jensen, H.L.; Rychly, J.; Sandor, M.; Erdei, A.; Gergely, J.

1986-01-01

Fc-receptors for IgG (FcγR) on resting (i.e. freshly prepared) and mitogen (Con A) or alloantigen-activated mouse spleen T cells were compared using binding of different markers such as 125 I-labelled immune complexes, 125 I-labelled anti FcγR monoclonal antibody, FITC-labelled aggr. IgG and sheep erythrocytes covered with specific antibody (EA rosetting). C3b receptors were detected by rosetting with sheep erythrocytes covered with antibody and complement (EAC rosetting). The electrophoretic mobility of the cells without or after binding of aggr. IgG was also tested. Differences between resting and activated T cells were found: (1) After activation of T cells by mitogen or alloantigen, a proportion of FcγR-positive cells increased two to four times. (2) FcγR number per FcγR-positive cell seemed to be higher on activated then on resting cells. (3) FcγR-positive resting cells did not shed their FcγR upon incubation at 4 0 C followed by incubation at 37 0 C, but FcγR-positive activated cells shed a remarkable proportion of their FcγR on the same conditions. (4) Binding of aggr. IgG caused a decrease of electrophoretic mobility of activated but not resting cells. (5) FcγR-positive resting cells were also C3b receptor-positive, whereas FcγR-positive activated cells had no detectable C3b receptors. (author)

Characteristics and treatment of human epidermal growth factor receptor 2 positive breast cancer: 43,485 cases from the National Cancer Database treated in 2010 and 2011.

Science.gov (United States)

Killelea, Brigid K; Chagpar, Anees B; Horowitz, Nina R; Lannin, Donald R

2017-02-01

Although identification of human epidermal growth factor receptor 2 (Her2) positive breast cancer represents one of the greatest advances over the past 3 decades, it has not been studied extensively on a national level. The National Cancer Database is a joint project of the American Cancer Society and the American College of Surgeons and contains data on about 70% of the cancer cases in the United States. Data on Her2 have been collected since 2010 and was used for this study. Of 298,937 cases of invasive breast cancer with known Her2 status diagnosed in 2010 and 2011, 43,485 (14.5%) were Her2 positive. Her2 positivity was greatest in Asian/Pacific Islanders and least in non-Hispanic Whites and was markedly more common in younger women. The incidence of Her2 positive tumors ranged from a low of 13.9% in the Mountain West region to a high of 16.0% in the West South Central region (P breast preservation (odds ratio = .78, confidence interval = .76 to .80). Her2 positive tumors have distinct epidemiologic, clinical, and treatment characteristics. Copyright © 2016 Elsevier Inc. All rights reserved.

Reptile Toll-like receptor 5 unveils adaptive evolution of bacterial flagellin recognition

NARCIS (Netherlands)

Voogdt, Carlos G P|info:eu-repo/dai/nl/413535169; Bouwman, Lieneke I|info:eu-repo/dai/nl/341590797; Kik, Marja J L|info:eu-repo/dai/nl/080432565; Wagenaar, Jaap A|info:eu-repo/dai/nl/126613354; van Putten, Jos P M|info:eu-repo/dai/nl/069916527

2016-01-01

Toll-like receptors (TLR) are ancient innate immune receptors crucial for immune homeostasis and protection against infection. TLRs are present in mammals, birds, amphibians and fish but have not been functionally characterized in reptiles despite the central position of this animal class in

Positive Modulatory Interactions of NMDA Receptor GluN1/2B Ligand Binding Domains Attenuate Antagonists Activity

Directory of Open Access Journals (Sweden)

Douglas Bledsoe

2017-05-01

Full Text Available N-methyl D-aspartate receptors (NMDAR play crucial role in normal brain function and pathogenesis of neurodegenerative and psychiatric disorders. Functional tetra-heteromeric NMDAR contains two obligatory GluN1 subunits and two identical or different non-GluN1 subunits that include six different gene products; four GluN2 (A–D and two GluN3 (A–B subunits. The heterogeneity of subunit combination facilities the distinct function of NMDARs. All GluN subunits contain an extracellular N-terminal Domain (NTD and ligand binding domain (LBD, transmembrane domain (TMD and an intracellular C-terminal domain (CTD. Interaction between the GluN1 and co-assembling GluN2/3 subunits through the LBD has been proven crucial for defining receptor deactivation mechanisms that are unique for each combination of NMDAR. Modulating the LBD interactions has great therapeutic potential. In the present work, by amino acid point mutations and electrophysiology techniques, we have studied the role of LBD interactions in determining the effect of well-characterized pharmacological agents including agonists, competitive antagonists, and allosteric modulators. The results reveal that agonists (glycine and glutamate potency was altered based on mutant amino acid sidechain chemistry and/or mutation site. Most antagonists inhibited mutant receptors with higher potency; interestingly, clinically used NMDAR channel blocker memantine was about three-fold more potent on mutated receptors (N521A, N521D, and K531A than wild type receptors. These results provide novel insights on the clinical pharmacology of memantine, which is used for the treatment of mild to moderate Alzheimer's disease. In addition, these findings demonstrate the central role of LBD interactions that can be exploited to develop novel NMDAR based therapeutics.

Palbociclib in Combination With Fulvestrant in Women With Hormone Receptor-Positive/HER2-Negative Advanced Metastatic Breast Cancer: Detailed Safety Analysis From a Multicenter, Randomized, Placebo-Controlled, Phase III Study (PALOMA-3).

Science.gov (United States)

Verma, Sunil; Bartlett, Cynthia Huang; Schnell, Patrick; DeMichele, Angela M; Loi, Sherene; Ro, Jungsil; Colleoni, Marco; Iwata, Hiroji; Harbeck, Nadia; Cristofanilli, Massimo; Zhang, Ke; Thiele, Alexandra; Turner, Nicholas C; Rugo, Hope S

2016-10-01

Palbociclib enhances endocrine therapy and improves clinical outcomes in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Because this is a new target, it is clinically important to understand palbociclib's safety profile to effectively manage toxicity and optimize clinical benefit. Patients with endocrine-resistant, HR-positive/HER2-negative MBC (n = 521) were randomly assigned 2:1 to receive fulvestrant (500 mg intramuscular injection) with or without goserelin with oral palbociclib (125 mg daily; 3 weeks on/1 week off) or placebo. Safety assessments at baseline and day 1 of each cycle included blood counts on day 15 for the first 2 cycles. Hematologic toxicity was assessed by using laboratory data. A total of 517 patients were treated (palbociclib, n = 345; placebo, n = 172); median follow-up was 8.9 months. With palbociclib, neutropenia was the most common grade 3 (55%) and 4 (10%) adverse event; median times to onset and duration of grade ≥3 episodes were 16 and 7 days, respectively. Asian ethnicity and below-median neutrophil counts at baseline were significantly associated with an increased chance of developing grade 3-4 neutropenia with palbociclib. Dose modifications for grade 3-4 neutropenia had no adverse effect on progression-free survival. In the palbociclib arm, febrile neutropenia occurred in 3 (<1%) patients. The percentage of grade 1-2 infections was higher than in the placebo arm. Grade 1 stomatitis occurred in 8% of patients. Palbociclib plus fulvestrant treatment was well-tolerated, and the primary toxicity of asymptomatic neutropenia was effectively managed by dose modification without apparent loss of efficacy. This study appears at ClinicalTrials.gov, NCT01942135. Treatment with palbociclib in combination with fulvestrant was generally safe and well-tolerated in patients with hormone receptor (HR)-positive metastatic breast cancer. Consistent with the drug's proposed

Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8·1 years median follow-up

DEFF Research Database (Denmark)

Regan, Meredith M; Neven, Patrick; Giobbie-Hurder, Anita

2011-01-01

Postmenopausal women with hormone receptor-positive early breast cancer have persistent, long-term risk of breast-cancer recurrence and death. Therefore, trials assessing endocrine therapies for this patient population need extended follow-up. We present an update of efficacy outcomes in the Breast...

Receptor mapping in psychiatric patients with SPECT

International Nuclear Information System (INIS)

Schlegel, S.

1997-01-01

This paper summarizes some data of our studies with the single-photon-emission-computerized tomography (SPECT), focussing on the dopamine-D2- and the benzodiazepine receptor mapping. Benzodiazepine receptors: Central benzodiazepine receptors (BZr) can be visualized with iomazenil which is an analogue of the benzodiazepine antagonist flumazenil, labeled with 123-iodine. Since the involvement of the BZr system is discussed in the pathogenesis of anxiety and depression, patients with these disorders were investigated. A third study investigated the BZr-occupancy during benzodiazepine treatment (lorazepam). Results: (a) Patients with panic disorders had lower iomazenil uptake values compared to epileptic patients. (b) Depressed patients showed a positive correlation between severity of illness and frontal uptake. (c) BZr occupancy during lorazepam treatment was measurable, but not associated with lorazepam plasma levels. Dopamine-D2-receptors: With 123-I-iodobenzamide (IBZM), and iodine-labeled dopamine receptor ligand, the D2 receptor density can be measured by a semiquantitative approach (striatum/frontal cortex=ST/FC). Therefore, we investigated the D2-receptor occupancy during treatment with typical and atypical neuroleptics in relationship to dosages (normalized with different formulas of chlorpromazine equivalents), side effects, and prolactin plasma levels. Results: Dependent on the selected formula for chlorpromazine equivalents, the ST/FC ratio was correlated with dosages. Side effects and prolactin plasma levels showed a negative association with lower ST/FC ratios. (orig.) [de

Can a Positive Allosteric Modulation of GABAergic Receptors Improve Motor Symptoms in Patients with Parkinson's Disease? The Potential Role of Zolpidem in the Treatment of Parkinson's Disease

Science.gov (United States)

Daniele, Antonio; Panza, Francesco; Greco, Antonio; Logroscino, Giancarlo; Seripa, Davide

2016-01-01

At present, patients with advanced Parkinson's disease (PD) are unsatisfactorily controlled by currently used anti-Parkinsonian dopaminergic drugs. Various studies suggest that therapeutic strategies based on nondopaminergic drugs might be helpful in PD. Zolpidem, an imidazopyridine widely used as sleep inducer, shows high affinity only for GABAA receptors containing the α-1 subunit and facilitates GABAergic neurotransmission through a positive allosteric modulation of GABAA receptors. Various observations, although preliminary, consistently suggest that in PD patients zolpidem may induce beneficial (and sometimes remarkable) effects on motor symptoms even after single doses and may also improve dyskinesias. Since a high density of zolpidem binding sites is in the two main output structures of the basal ganglia which are abnormally overactive in PD (internal globus pallidus, GPi, and substantia nigra pars reticulata, SNr), it was hypothesized that in PD patients zolpidem may induce through GABAA receptors an inhibition of GPi and SNr (and, possibly, of the subthalamic nucleus also), resulting in an increased activity of motor cortical areas (such as supplementary motor area), which may give rise to improvement of motor symptoms of PD. Randomized clinical trials are needed in order to assess the efficacy, safety, and tolerability of zolpidem in treating motor symptoms of PD. PMID:27293955

Validation of somatostatin receptor scintigraphy in the localization of neuroendocrine tumors

International Nuclear Information System (INIS)

Lamberts, S.W.J.; Reubi, J.C.; Krenning, E.P.

1993-01-01

Somatostatin analogs are used in the control of hormonal hypersecretion and tumor growth of patients with acromegaly, islet cell carcinomas and carcinoids. Recently we showed that somatostatin receptor positive tumors can be visualized in vivo after the administration of radionuclide-labeled somatostatin analogs. Receptor imaging was positive in 18/21 islet cell tumors, 32/37 carcinoids, 26/28 paragangliomas, 9/14 medullary thyroid carcinomas, and 5/7 small cell lung cancers. Somatostatin receptor imaging is an easy, harmless and painless diagnostic method. It localizes multiple and/or metastatic tumors, predicts the successful control of hormonal hypersecretion by octreotide and seems to be of prognostic value in certain types of cancer. This scintigraphic method might help in patient selection for clinical trials with somatostatin analogs in the treatment of neuroendocrine cancers. (orig.)

Validation of somatostatin receptor scintigraphy in the localization of neuroendocrine tumors

Energy Technology Data Exchange (ETDEWEB)

Lamberts, S.W.J. (Depts. of Medicine and Nuclear Medicine, Erasmus Univ., Rotterdam (Netherlands) Div. of Cell Biology and Experimental Cancer Research, Institution of Pathology, Bern Univ. (Switzerland)); Reubi, J.C. (Depts. of Medicine and Nuclear Medicine, Erasmus Univ., Rotterdam (Netherlands) Div. of Cell Biology and Experimental Cancer Research, Institution of Pathology, Bern Univ. (Switzerland)); Krenning, E.P. (Depts. of Medicine and Nuclear Medicine, Erasmus Univ., Rotterdam (Netherlands) Div. of Cell Biology and Experimental Cancer Research, Institution of Pathology, Bern Univ. (Switzerland))

1993-01-01

Somatostatin analogs are used in the control of hormonal hypersecretion and tumor growth of patients with acromegaly, islet cell carcinomas and carcinoids. Recently we showed that somatostatin receptor positive tumors can be visualized in vivo after the administration of radionuclide-labeled somatostatin analogs. Receptor imaging was positive in 18/21 islet cell tumors, 32/37 carcinoids, 26/28 paragangliomas, 9/14 medullary thyroid carcinomas, and 5/7 small cell lung cancers. Somatostatin receptor imaging is an easy, harmless and painless diagnostic method. It localizes multiple and/or metastatic tumors, predicts the successful control of hormonal hypersecretion by octreotide and seems to be of prognostic value in certain types of cancer. This scintigraphic method might help in patient selection for clinical trials with somatostatin analogs in the treatment of neuroendocrine cancers. (orig.).

EPO-independent functional EPO receptor in breast cancer enhances estrogen receptor activity and promotes cell proliferation

International Nuclear Information System (INIS)

Reinbothe, Susann; Larsson, Anna-Maria; Vaapil, Marica; Wigerup, Caroline; Sun, Jianmin; Jögi, Annika; Neumann, Drorit; Rönnstrand, Lars; Påhlman, Sven

2014-01-01

Highlights: • New anti-human EPOR antibody confirms full-length EPOR expression in breast cancer cells. • Proliferation of breast cancer cells is not affected by rhEPO treatment in vitro. • EPOR knockdown impairs proliferation of ERa positive breast cancer cells. • EPOR knockdown reduces AKT phosphorylation and ERa activity. - Abstract: The main function of Erythropoietin (EPO) and its receptor (EPOR) is the stimulation of erythropoiesis. Recombinant human EPO (rhEPO) is therefore used to treat anemia in cancer patients. However, clinical trials have indicated that rhEPO treatment might promote tumor progression and has a negative effect on patient survival. In addition, EPOR expression has been detected in several cancer forms. Using a newly produced anti-EPOR antibody that reliably detects the full-length isoform of the EPOR we show that breast cancer tissue and cells express the EPOR protein. rhEPO stimulation of cultured EPOR expressing breast cancer cells did not result in increased proliferation, overt activation of EPOR (receptor phosphorylation) or a consistent activation of canonical EPOR signaling pathway mediators such as JAK2, STAT3, STAT5, or AKT. However, EPOR knockdown experiments suggested functional EPO receptors in estrogen receptor positive (ERα + ) breast cancer cells, as reduced EPOR expression resulted in decreased proliferation. This effect on proliferation was not seen in ERα negative cells. EPOR knockdown decreased ERα activity further supports a mechanism by which EPOR affects proliferation via ERα-mediated mechanisms. We show that EPOR protein is expressed in breast cancer cells, where it appears to promote proliferation by an EPO-independent mechanism in ERα expressing breast cancer cells

EPO-independent functional EPO receptor in breast cancer enhances estrogen receptor activity and promotes cell proliferation

Energy Technology Data Exchange (ETDEWEB)

Reinbothe, Susann; Larsson, Anna-Maria; Vaapil, Marica; Wigerup, Caroline [Department of Laboratory Medicine, Translational Cancer Research, Medicon Village, Lund University, SE-223 81 Lund (Sweden); CREATE Health, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv (Israel); Sun, Jianmin [Department of Laboratory Medicine, Translational Cancer Research, Medicon Village, Lund University, SE-223 81 Lund (Sweden); Jögi, Annika [Department of Laboratory Medicine, Translational Cancer Research, Medicon Village, Lund University, SE-223 81 Lund (Sweden); CREATE Health, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv (Israel); Neumann, Drorit [Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv (Israel); Rönnstrand, Lars [Department of Laboratory Medicine, Translational Cancer Research, Medicon Village, Lund University, SE-223 81 Lund (Sweden); Påhlman, Sven, E-mail: sven.pahlman@med.lu.se [Department of Laboratory Medicine, Translational Cancer Research, Medicon Village, Lund University, SE-223 81 Lund (Sweden); CREATE Health, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv (Israel)

2014-02-28

Highlights: • New anti-human EPOR antibody confirms full-length EPOR expression in breast cancer cells. • Proliferation of breast cancer cells is not affected by rhEPO treatment in vitro. • EPOR knockdown impairs proliferation of ERa positive breast cancer cells. • EPOR knockdown reduces AKT phosphorylation and ERa activity. - Abstract: The main function of Erythropoietin (EPO) and its receptor (EPOR) is the stimulation of erythropoiesis. Recombinant human EPO (rhEPO) is therefore used to treat anemia in cancer patients. However, clinical trials have indicated that rhEPO treatment might promote tumor progression and has a negative effect on patient survival. In addition, EPOR expression has been detected in several cancer forms. Using a newly produced anti-EPOR antibody that reliably detects the full-length isoform of the EPOR we show that breast cancer tissue and cells express the EPOR protein. rhEPO stimulation of cultured EPOR expressing breast cancer cells did not result in increased proliferation, overt activation of EPOR (receptor phosphorylation) or a consistent activation of canonical EPOR signaling pathway mediators such as JAK2, STAT3, STAT5, or AKT. However, EPOR knockdown experiments suggested functional EPO receptors in estrogen receptor positive (ERα{sup +}) breast cancer cells, as reduced EPOR expression resulted in decreased proliferation. This effect on proliferation was not seen in ERα negative cells. EPOR knockdown decreased ERα activity further supports a mechanism by which EPOR affects proliferation via ERα-mediated mechanisms. We show that EPOR protein is expressed in breast cancer cells, where it appears to promote proliferation by an EPO-independent mechanism in ERα expressing breast cancer cells.

Reptile Toll-like receptor 5 unveils adaptive evolution of bacterial flagellin recognition

NARCIS (Netherlands)

Voogdt, Carlos G.P.; Bouwman, Lieneke I.; Kik, Marja J.L.; Wagenaar, Jaap A.; Putten, Van Jos P.M.

2016-01-01

Toll-like receptors (TLR) are ancient innate immune receptors crucial for immune homeostasis and protection against infection. TLRs are present in mammals, birds, amphibians and fish but have not been functionally characterized in reptiles despite the central position of this animal class in

Medium-chain fatty acid-sensing receptor, GPR84, is a proinflammatory receptor.

Science.gov (United States)

Suzuki, Masakatsu; Takaishi, Sachiko; Nagasaki, Miyuki; Onozawa, Yoshiko; Iino, Ikue; Maeda, Hiroaki; Komai, Tomoaki; Oda, Tomiichiro

2013-04-12

G protein-coupled receptor 84 (GPR84) is a putative receptor for medium-chain fatty acids (MCFAs), whose pathophysiological roles have not yet been clarified. Here, we show that GPR84 was activated by MCFAs with the hydroxyl group at the 2- or 3-position more effectively than nonhydroxylated MCFAs. We also identified a surrogate agonist, 6-n-octylaminouracil (6-OAU), for GPR84. These potential ligands and the surrogate agonist, 6-OAU, stimulated [(35)S]GTP binding and accumulated phosphoinositides in a GPR84-dependent manner. The surrogate agonist, 6-OAU, internalized GPR84-EGFP from the cell surface. Both the potential ligands and 6-OAU elicited chemotaxis of human polymorphonuclear leukocytes (PMNs) and macrophages and amplified LPS-stimulated production of the proinflammatory cytokine IL-8 from PMNs and TNFα from macrophages. Furthermore, the intravenous injection of 6-OAU raised the blood CXCL1 level in rats, and the inoculation of 6-OAU into the rat air pouch accumulated PMNs and macrophages in the site. Our results indicate a proinflammatory role of GPR84, suggesting that the receptor may be a novel target to treat chronic low grade inflammation associated-disease.

Optimal systemic therapy for premenopausal women with hormone receptor-positive breast cancer.

Science.gov (United States)

Jankowitz, Rachel C; McGuire, Kandace P; Davidson, Nancy E

2013-08-01

Although systemic therapy is one of the cornerstones of therapy for premenopausal women with early stage breast cancer, there remain many unknowns regarding its optimal use. By accident of clinical trial design, much clinical investigation in premenopausal women has focused on chemotherapy. More recently the value of endocrine therapy (tamoxifen and ovarian suppression/ablation via surgery, LHRH agonists, or chemotherapy-induced menopause) has become apparent, and some form of endocrine therapy is viewed as standard for virtually all premenopausal women with early stage invasive breast cancer that expresses estrogen and/or progesterone receptor. Critical open questions include type and duration of endocrine therapy and the development of prognostic/predictive markers to help identify patients who are likely to benefit from chemotherapy in addition to endocrine therapy. For some years, five years of tamoxifen has been viewed as the standard endocrine therapy for premenopausal hormone-responsive breast cancer, although the ATLAS trial suggests that an additional five years of tamoxifen can be considered. The MA17 trial also suggests that an additional five years of an aromatase inhibitor can be considered for women who become postmenopausal during tamoxifen therapy. Information about the value of ovarian suppression continues to emerge, most recently with the demonstration of excellent outcome with goserelin plus tamoxifen in the ABCSG12 trial. The SOFT and TEXT trials, whose accrual is now complete, should help to define optimal endocrine therapy. In addition, use of the 21-gene recurrence score assay may help to delineate the additional value of chemotherapy for patients with node-negative breast cancer, and its utility in the setting of women with 1-3 positive lymph nodes is under study in the RxPONDER trial. Nonetheless, the need for other predictive biomarkers to select appropriate therapy remains real. Finally, attention to long term benefits and side effects

Phase II randomized trial of neoadjuvant metformin plus letrozole versus placebo plus letrozole for estrogen receptor positive postmenopausal breast cancer (METEOR)

International Nuclear Information System (INIS)

Kim, Jisun; Kim, Lee Su; Han, Sehwan; Nam, Seok Jin; Kang, Han-Sung; Kim, Seung Il; Yoo, Young Bum; Jeong, Joon; Kim, Tae Hyun; Kang, Taewoo; Kim, Sung-Won; Lim, Woosung; Jung, Yongsik; Lee, Jeong Eon; Kim, Ku Sang; Yu, Jong-Han; Chae, Byung Joo; Jung, So-Youn; Kang, Eunyoung; Choi, Su Yun; Moon, Hyeong-Gon; Noh, Dong-Young; Kim, Eun-Kyu; Han, Wonshik; Kim, Min-Kyoon; Paik, Nam-Sun; Jeong, Sang-Seol; Yoon, Jung-han; Park, Chan Heun; Ahn, Sei Hyun

2014-01-01

Neoadjuvant endocrine therapy with an aromatase inhibitor has shown efficacy comparable to that of neoadjuvant chemotherapy in patients with postmenopausal breast cancer. Preclinical and clinical studies have shown that the antidiabetic drug metformin has anti-tumor activity. This prospective, multicenter, phase II randomized, placebo controlled trial was designed to evaluate the direct anti-tumor effect of metformin in non-diabetic postmenopausal women with estrogen-receptor (ER) positive breast cancer. Patients meeting the inclusion criteria and providing written informed consent will be randomized to 24 weeks of neoadjuvant treatment with letrozole (2.5 mg/day) and either metformin (2000 mg/day) or placebo. Target accrual number is 104 patients per arm. The primary endpoint will be clinical response rate, as measured by calipers. Secondary endpoints include pathologic complete response rate, breast conserving rate, change in Ki67 expression, breast density change, and toxicity profile. Molecular assays will be performed using samples obtained before treatment, at week 4, and postoperatively. This study will provide direct evidence of the anti-tumor effect of metformin in non-diabetic, postmenopausal patients with ER-positive breast cancer. ClinicalTrials.gov Identifier http://clinicaltrial.gov/ct2/show/NCT01589367?term

Maintenance of prolactin receptors in human breast cancer

International Nuclear Information System (INIS)

Ben-David, M.; Dror, Y.; Biran, S.

1981-01-01

Breast tissue specimens of 110 women with various stages of breast cancer were tested in vitro to determine their specific binding sites for human prolactin. In contrast to the case of steroid receptors, binding sites for prolactin were found in the vast majority of breast cancer tissue. Distribution profiles giving amount of prolactin receptor and their affinity coefficients were found to be similar in the tissues of women whose ages, hormonal status, or stage of breast cancer varied. These findings show that in contrast to steroid receptors, human breast cancer tissue maintains binding sites for prolactin. The findings also indicate that there may be a higher dependency of breast cancer on prolactin than on steroids. Clinical trials must be carried out to determine the role of ''positive'' prolactin receptors in prognosis and prediction of response to future hormone therapy. (author)

Refinement of glucagon-like peptide 1 docking to its intact receptor using mid-region photolabile probes and molecular modeling.

Science.gov (United States)

Miller, Laurence J; Chen, Quan; Lam, Polo C-H; Pinon, Delia I; Sexton, Patrick M; Abagyan, Ruben; Dong, Maoqing

2011-05-06

The glucagon-like peptide 1 (GLP1) receptor is an important drug target within the B family of G protein-coupled receptors. Its natural agonist ligand, GLP1, has incretin-like actions and the receptor is a recognized target for management of type 2 diabetes mellitus. Despite recent solution of the structure of the amino terminus of the GLP1 receptor and several close family members, the molecular basis for GLP1 binding to and activation of the intact receptor remains unclear. We previously demonstrated molecular approximations between amino- and carboxyl-terminal residues of GLP1 and its receptor. In this work, we study spatial approximations with the mid-region of this peptide to gain insights into the orientation of the intact receptor and the ligand-receptor complex. We have prepared two new photolabile probes incorporating a p-benzoyl-l-phenylalanine into positions 16 and 20 of GLP1(7-36). Both probes bound to the GLP1 receptor specifically and with high affinity. These were each fully efficacious agonists, stimulating cAMP accumulation in receptor-bearing CHO cells in a concentration-dependent manner. Each probe specifically labeled a single receptor site. Protease cleavage and radiochemical sequencing identified receptor residue Leu(141) above transmembrane segment one as its site of labeling for the position 16 probe, whereas the position 20 probe labeled receptor residue Trp(297) within the second extracellular loop. Establishing ligand residue approximation with this loop region is unique among family members and may help to orient the receptor amino-terminal domain relative to its helical bundle region.

Alterations in Circulating miRNA Levels following Early-Stage Estrogen Receptor-Positive Breast Cancer Resection in Post-Menopausal Women

DEFF Research Database (Denmark)

Kodahl, Annette R; Zeuthen, Pernille; Binder, Harald

2014-01-01

INTRODUCTION: Circulating microRNAs (miRNAs) exhibit remarkable stability and may serve as biomarkers in several clinical cancer settings. The aim of this study was to investigate changes in the levels of specific circulating miRNA following breast cancer surgery and evaluate whether these altera...... and could potentially be used to monitor whether all cancer cells have been removed at surgery and/or, subsequently, whether the patients develop recurrence.......INTRODUCTION: Circulating microRNAs (miRNAs) exhibit remarkable stability and may serve as biomarkers in several clinical cancer settings. The aim of this study was to investigate changes in the levels of specific circulating miRNA following breast cancer surgery and evaluate whether...... these alterations were also observed in an independent data set. METHODS: Global miRNA analysis was performed on prospectively collected serum samples from 24 post-menopausal women with estrogen receptor-positive early-stage breast cancer before surgery and 3 weeks after tumor resection using global LNA...

[Everolimus plus exemestane in postmenopausal patients with estrogen-receptor-positive advanced breast cancer - Japanese subgroup analysis of BOLERO -2].

Science.gov (United States)

Ito, Yoshinori; Masuda, Norikazu; Iwata, Hiroji; Mukai, Hirofumi; Horiguchi, Jun; Tokuda, Yutaka; Kuroi, Katsumasa; Mori, Asuka; Ohno, Nobutsugu; Noguchi, Shinzaburo

2015-01-01

In a phase 3, double-blind, randomized, international study (the BOLERO-2), the addition of mTOR inhibitor everolimus to exemestane was evaluated in postmenopausal women with estrogen-receptor-positive (ER⁺) advanced/recurrent breast cancer that was refractory to any nonsteroidal aromatase inhibitor (NSAI). This report presents the safety and updated (18- month) efficacy results from the Japanese subset (n=106) of BOLERO-2. After a median follow-up of 18 months, the median progression-free survival time was 8.5 months with everolimus plus exemestane compared to 4.2 months with placebo plus exemestane. The most common adverse events (AEs) with everolimus plus exemestane were stomatitis, rash, dysgeusia, and non-infectious lung disease. The AEs reported with the combination therapy were mostly of grade 1 or 2 and manageable with appropriate intervention. In conclusion, this combination could be a useful addition to the armamentarium of treatments for Japanese postmenopausal women with ER⁺ advanced/recurrent breast cancer progressing on NSAIs.

Pengaruh Demihipo dan ZPT (Decamon® terhadap Mortalitas Telur dan Serangan Lalat Pengorok Daun, Liriomyza huidobrensis (Blanchard pada Tanaman Kentang

Directory of Open Access Journals (Sweden)

I Wayan Supartha

2002-12-01

Full Text Available Field experiment to determine the effectiveness of demihipo and Decamon® to induce the egg extrusion and reduce L. huidobrensis population larvae on potato was conducted in Pancasari, Buleleng (Bali from February to August 1999. The results indicated that application of Decamon to the plant was significantly able to increase egg-extrusion of L. huidobrensis from the leaf compared with the other treatments. While, weekly application of insecticide (demihipo was also significantly able to reduce the Larvae population on the plant. The application of the combination of both control measure (plant growth regulator or PGR and insecticide (demihipo was the most effective control to reduce the feeding or ovipositional-punctures of adult on the leaves. Therefore, the application of PGR and insecticide was the best to prevent and reduce the population development of L. huidobrensis in the field. In general, all control measures were able to increase the yield and advantage-added of the farmer. However, the highest increased of the yield and advantage-added in wet season were given by the plant treated with PGR (Decamon®, while in dry season given by the plant treated with the combination of PGR and demihipo.

Molecular pharmacology of promiscuous seven transmembrane receptors sensing organic nutrients

DEFF Research Database (Denmark)

Wellendorph, Petrine; Johansen, Lars Dan; Bräuner-Osborne, Hans

2009-01-01

drug targets, to treat, for example, type II diabetes by mimicking food intake by potent agonists or positive allosteric modulators. The ligand-receptor interactions of the promiscuous receptors of organic nutrients thus remain an interesting subject of emerging functional importance....... in taste tissue, the gastrointestinal tract, endocrine glands, adipose tissue, and/or kidney. These receptors thus hold the potential to act as sensors of food intake, regulating, for example, release of incretin hormones from the gut, insulin/glucagon from the pancreas, and leptin from adipose tissue....... The promiscuous tendency in ligand recognition of these receptors is in contrast to the typical specific interaction with one physiological agonist seen for most receptors, which challenges the classic "lock-and-key" concept. We here review the molecular mechanisms of nutrient sensing of the calcium...

Synthesis of Tc-99m labeled 1,2,3-triazole-4-yl c-met binding peptide as a potential c-met receptor kinase positive tumor imaging agent.

Science.gov (United States)

Kim, Eun-Mi; Joung, Min-Hee; Lee, Chang-Moon; Jeong, Hwan-Jeong; Lim, Seok Tae; Sohn, Myung-Hee; Kim, Dong Wook

2010-07-15

The mesenchymal-epithelial transition factor (c-Met), which is related to tumor cell growth, angiogenesis and metastases, is known to be overexpressed in several tumor types. In this study, we synthesized technetium-99m labeled 1,2,3-triazole-4-yl c-Met binding peptide (cMBP) derivatives, prepared by solid phase peptide synthesis and the 'click-to-chelate' protocol for the introduction of tricarbonyl technetium-99m, as a potential c-Met receptor kinase positive tumor imaging agent, and evaluated their in vitro c-Met binding affinity, cellular uptake, and stability. The (99m)Tc labeled cMBP derivatives ([(99m)Tc(CO)(3)]12, [(99m)Tc(CO)(3)]13, and [(99m)Tc(CO)(3)]14) were prepared in 85-90% radiochemical yields. The cold surrogate cMBP derivatives, [Re(CO)(3)]12, [Re(CO)(3)]13, and [Re(CO)(3)]14, were shown to have high binding affinities (0.13 microM, 0.06 microM, and 0.16 microM, respectively) to a purified cMet/Fc chimeric recombinant protein. In addition, the in vitro cellular uptake and inhibition studies demonstrated the high specific binding of these (99m)Tc labeled cMBP derivatives ([(99m)Tc(CO)(3)]12-14) to c-Met receptor positive U87MG cells. 2010 Elsevier Ltd. All rights reserved.

Familial risks and estrogen receptor-positive breast cancer in Hong Kong Chinese women.

Directory of Open Access Journals (Sweden)

Lap Ah Tse

Full Text Available The role of family history to the risk of breast cancer was analyzed by incorporating menopausal status in Hong Kong Chinese women, with a particular respect to the estrogen receptor-positive (ER+ type.Seven hundred and forty seven breast cancer incident cases and 781 hospital controls who had completed information on family cancer history in first-degree relatives (nature father, mother, and siblings were recruited. Odds ratio for breast cancer were calculated by unconditional multiple logistic regression, stratified by menopausal status (a surrogate of endogenous female sex hormone level and age and type of relative affected with the disease. Further subgroup analysis by tumor type according to ER status was investigated.Altogether 52 (6.96% breast cancer cases and 23 (2.95% controls was found that the patients' one or more first-degree relatives had a history of breast cancer, showing an adjusted odds ratio (OR of 2.41 (95%CI: 1.45-4.02. An excess risk of breast cancer was restricted to the ER+ tumor (OR = 2.43, 95% CI: 1.38-4.28, with a relatively higher risk associated with an affected mother (OR = 3.97, 95%CI: 1.46-10.79 than an affected sister (OR = 2.06, 95%CI: 1.07-3.97, while the relative risk was more prominent in the subgroup of pre-menopausal women. Compared with the breast cancer overall, the familial risks to the ER+ tumor increased progressively with the number of affected first-degree relatives.This study provides new insights on a relationship between family breast cancer history, menopausal status, and the ER+ breast cancer. A separate risk prediction model for ER+ tumor in Asian population is desired.

Canine distemper virus utilizes different receptors to infect chicken embryo fibroblasts and vero cells.

Science.gov (United States)

Chen, Jun; Liang, Xiu; Chen, Pei-fu

2011-04-01

Inducing animal viruses to adapt to chicken embryos or chicken embryo fibroblasts (CEF) is a common method to develop attenuated live vaccines with full security. Canine distemper virus (CDV) also does this, but the mechanisms and particular receptors remain unclear. Virus overlay protein blot assays were carried out on CEF membrane proteins, which were extracted respectively with a Mem-PER™ kit, a radioimmunoprecipitation assay buffer or a modified co-immunoprecipitation method, and revealed a common 57 kDa positive band that differed from the 42-kDa positive band in Vero cells and also from those receptors reported in lymphocytes and 293 cells, indicating a receptor diversity of CDV and the possibility of the 57-kDa protein acting as a receptor that is involved in adaptive infection of CDV Kunming strain to CEF.

Prognostic and predictive values of EGFR overexpression and EGFR copy number alteration in HER2-positive breast cancer.

Science.gov (United States)

Lee, H J; Seo, A N; Kim, E J; Jang, M H; Kim, Y J; Kim, J H; Kim, S-W; Ryu, H S; Park, I A; Im, S-A; Gong, G; Jung, K H; Kim, H J; Park, S Y

2015-01-06

Epidermal growth factor receptor (EGFR) is overexpressed in a subset of human epidermal growth factor receptor 2 (HER2)-positive breast cancers, and coexpression of HER2 and EGFR has been reported to be associated with poor clinical outcome. Moreover, interaction between HER2 and EGFR has been suggested to be a possible basis for trastuzumab resistance. We analysed the clinical significance of EGFR overexpression and EGFR gene copy number alterations in 242 HER2-positive primary breast cancers. In addition, we examined the correlations between EGFR overexpression, trastuzumab response and clinical outcome in 447 primary, and 112 metastatic HER2-positive breast cancer patients treated by trastuzumab. Of the 242 primary cases, the level of EGFR overexpression was 2+ in 12.7% and 3+ in 11.8%. High EGFR gene copy number was detected in 10.3%. Epidermal growth factor receptor overexpression was associated with hormone receptor negativity and high Ki-67 proliferation index. In survival analyses, EGFR overexpression, but not high EGFR copy number, was associated with poor disease-free survival in all patients, and in the subgroup not receiving adjuvant trastuzumab. In 447 HER2-positive primary breast cancer patients treated with adjuvant trastuzumab, EGFR overexpression was also an independent poor prognostic factor. However, EGFR overexpression was not associated with trastuzumab response, progression-free survival or overall survival in the metastatic setting. Epidermal growth factor receptor overexpression, but not high EGFR copy number, is a poor prognostic factor in HER2-positive primary breast cancer. Epidermal growth factor receptor overexpression is a predictive factor for trastuzumab response in HER2-positive primary breast cancer, but not in metastatic breast cancer.

Ibrutinib (ImbruvicaTM) potently inhibits ErbB receptor phosphorylation and cell viability of ErbB2-positive breast cancer cells.

Science.gov (United States)

Grabinski, Nicole; Ewald, Florian

2014-12-01

Ibrutinib (formerly PCI-32765) is a specific, irreversible, and potent inhibitor of Burton's tyrosine kinase (BTK) developed for the treatment of several forms of blood cancer. It is now an FDA-approved drug marketed under the name Imbruvica(TM) (Pharmacyclics, Inc.) and successfully used as an orally administered second-line drug in the treatment of mantle cell lymphoma. Since BTK is predominantly expressed in hematopoietic cells, the sensitivity of solid tumor cells to Ibrutinib has not been analyzed. In this study, we determined the effect of Ibrutinib on breast cancer cells. We demonstrate that Ibrutinib efficiently reduces the phosphorylation of the receptor tyrosine kinases ErbB1, ErbB2 and ErbB3, thereby suppressing AKT and MAPK signaling in ErbB2-positive (ErbB2+) breast cancer cell lines. Treatment with Ibrutinib significantly reduced the viability of ErbB2+ cell lines with IC50 values at nanomolar concentrations, suggesting therapeutic potential of Ibrutinib in breast cancer. Combined treatment with Ibrutinib and the dual PI3K/mTOR inhibitor BEZ235 synergistically reduces cell viability of ErbB2+ breast cancer cells. Combination indices below 0.25 at 50% inhibition of cell viability were determined by the Chou-Talalay method. Therefore, the combination of Ibrutinib and canonical PI3K pathway inhibitors could be a new and effective approach in the treatment of breast cancer with activated ErbB receptors. Ibrutinib could thus become a valuable component of targeted therapy in aggressive ErbB2+ breast cancer.

Analgesic effect of ADX71441, a positive allosteric modulator (PAM) of GABAB receptor in a rat model of bladder pain.

Science.gov (United States)

Kannampalli, Pradeep; Poli, Sonia-Maria; Boléa, Christelle; Sengupta, Jyoti N

2017-11-01

Therapeutic use of GABA B receptor agonists for conditions like chronic abdominal pain, overactive bladder (OAB) and gastroesophageal reflux disease (GERD) is severely affected by poor blood-brain barrier permeability and potential side effects. ADX71441 is a novel positive allosteric modulator (PAM) of the GABA B receptor that has shown encouraging results in pre-clinical models of anxiety, pain, OAB and alcohol addiction. The present study investigates the analgesic effect of ADX71441 to noxious stimulation of the urinary bladder and colon in rats. In female Sprague-Dawley rats, systemic (i.p), but not intrathecal (i.t), administration of ADX71441 produced a dose-dependent decrease in viscero-motor response (VMR) to graded urinary bladder distension (UBD) and colorectal distension (CRD). Additionally, intra-cerebroventricular (i.c.v.) administration of ADX71441 significantly decreased the VMRs to noxious UBD. In electrophysiology experiments, the drug did not attenuate the responses of UBD-sensitive pelvic nerve afferent (PNA) fibers to UBD. In contrast, ADX71441 significantly decreased the responses of UBD-responsive lumbosacral (LS) spinal neurons in spinal intact rats. However, ADX71441 did not attenuate these LS neurons in cervical (C1-C2) spinal transected rats. During cystometrogram (CMG) recordings, ADX71441 (i.p.) significantly decreased the VMR to slow infusion without affecting the number of voiding contraction. These results indicate that ADX71441 modulate bladder nociception via its effect at the supra-spinal sites without affecting the normal bladder motility and micturition reflex in naïve adult rats. Copyright © 2017 Elsevier Ltd. All rights reserved.

Activation of neurokinin-1 receptors during ozone inhalation contributes to epithelial injury and repair.

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Oslund, Karen L; Hyde, Dallas M; Putney, Leialoha F; Alfaro, Mario F; Walby, William F; Tyler, Nancy K; Schelegle, Edward S

2008-09-01

We investigated the importance of neurokinin (NK)-1 receptors in epithelial injury and repair and neutrophil function. Conscious Wistar rats were exposed to 1 ppm ozone or filtered air for 8 hours, followed by an 8-hour postexposure period. Before exposure, we administered either the NK-1 receptor antagonist, SR140333, or saline as a control. Ethidium homodimer was instilled into lungs as a marker of necrotic airway epithelial cells. After fixation, whole mounts of airway dissected lung lobes were immunostained for 5-bromo-2'-deoxyuridine, a marker of epithelial proliferation. Both ethidium homodimer and 5-bromo-2'-deoxyuridine-positive epithelial cells were quantified in specific airway generations. Rats treated with the NK-1 receptor antagonist had significantly reduced epithelial injury and epithelial proliferation compared with control rats. Sections of terminal bronchioles showed no significant difference in the number of neutrophils in airways between groups. In addition, staining ozone-exposed lung sections for active caspase 3 showed no apoptotic cells, but ethidium-positive cells colocalized with the orphan nuclear receptor, Nur77, a marker of nonapoptotic, programmed cell death mediated by the NK-1 receptor. An immortalized human airway epithelial cell line, human bronchial epithelial-1, showed no significant difference in the number of oxidant stress-positive cells during exposure to hydrogen peroxide and a range of SR140333 doses, demonstrating no antioxidant effect of the receptor antagonist. We conclude that activation of the NK-1 receptor during acute ozone inhalation contributes to epithelial injury and subsequent epithelial proliferation, a critical component of repair, but does not influence neutrophil emigration into airways.

Epidermal growth factor receptor: an independent predictor of survival in astrocytic tumors given definitive irradiation

International Nuclear Information System (INIS)

An Zhu; Shaeffer, James; Leslie, Susan; Kolm, Paul; El-Mahdi, Anas M.

1996-01-01

Purpose: To determine whether the expression of epidermal growth factor receptor (EGFR) protein was predictive of patient survival independently of other prognostic factors in astrocytic tumors. Methods and Materials: Epidermal growth factor receptor protein expression was investigated immunohistochemically in formalin-fixed, paraffin-embedded surgical specimens of 55 glioblastoma multiforme, 14 anaplastic astrocytoma, and 2 astrocytomas given definitive irradiation. We evaluated the relationship of EGFR protein expression and tumor grade, histologic features, age at diagnosis, sex, patient survival, and recurrence-free survival. Results: The percentage of tumor cells which were EGFR positive related to reduced survival by Cox regression analysis in both univariate (p = 0.0424) and multivariate analysis (p = 0.0016). Epidermal growth factor receptor positivity was the only 1 of 11 clinical and histological variables associated with decreased recurrence-free survival by either univariate (p = 0.0353) or multivariate (p = 0.0182) analysis. Epidermal growth factor receptor protein expression was not related to patient age, sex, or histologic features. Conclusion: Epidermal growth factor receptor positivity was a significant and independent prognostic indicator for overall survival and recurrence-free survival for irradiated patients with astrocytic gliomas

Frontal D2/3 Receptor Availability in Schizophrenia Patients Before and After Their First Antipsychotic Treatment: Relation to Cognitive Functions and Psychopathology.

Science.gov (United States)

Nørbak-Emig, Henrik; Ebdrup, Bjørn H; Fagerlund, Birgitte; Svarer, Claus; Rasmussen, Hans; Friberg, Lars; Allerup, Peter N; Rostrup, Egill; Pinborg, Lars H; Glenthøj, Birte Y

2016-05-01

We have previously reported associations between frontal D2/3 receptor binding potential positive symptoms and cognitive deficits in antipsychotic-naïve schizophrenia patients. Here, we examined the effect of dopamine D2/3 receptor blockade on cognition. Additionally, we explored the relation between frontal D2/3 receptor availability and treatment effect on positive symptoms. Twenty-five antipsychotic-naïve first-episode schizophrenia patients were examined with the Positive and Negative Syndrome Scale, tested with the cognitive test battery Cambridge Neuropsychological Test Automated Battery, scanned with single-photon emission computerized tomography using the dopamine D2/3 receptor ligand [(123)I]epidepride, and scanned with MRI. After 3 months of treatment with either risperidone (n=13) or zuclopenthixol (n=9), 22 patients were reexamined. Blockade of extrastriatal dopamine D2/3 receptors was correlated with decreased attentional focus (r = -0.615, P=.003) and planning time (r = -0.436, P=.048). Moreover, baseline frontal dopamine D2/3 binding potential and positive symptom reduction correlated positively (D2/3 receptor binding potential left frontal cortex rho = 0.56, P=.003; D2/3 receptor binding potential right frontal cortex rho = 0.48, P=.016). Our data support the hypothesis of a negative influence of D2/3 receptor blockade on specific cognitive functions in schizophrenia. This is highly clinically relevant given the well-established association between severity of cognitive disturbances and a poor functional outcome in schizophrenia. Additionally, the findings support associations between frontal D2/3 receptor binding potential at baseline and the effect of antipsychotic treatment on positive symptoms. © The Author 2016. Published by Oxford University Press on behalf of CINP.

Structure-activity relationships of the melanocortin tetrapeptide Ac-His-DPhe-Arg-Trp-NH(2) at the mouse melanocortin receptors: part 2 modifications at the Phe position.

Science.gov (United States)

Holder, Jerry Ryan; Bauzo, Rayna M; Xiang, Zhimin; Haskell-Luevano, Carrie

2002-07-04

The melanocortin pathway is an important participant in skin pigmentation, steroidogenesis, obesity, energy homeostasis and exocrine gland function. The centrally located melanocortin-3 and melanocortin-4 receptors (MC3R, MC4R) are involved in the metabolic and food intake aspects of energy homeostasis and are stimulated by melanocortin agonists such as alpha-melanocyte stimulation hormone (alpha-MSH). The melanocortin agonists contain the putative message sequence "His-Phe-Arg-Trp," and it has been well-documented that inversion of chirality of the Phe to DPhe results in a dramatic increase in melanocortin receptor potency. Herein, we report a tetrapeptide library, based upon the template Ac-His-DPhe-Arg-Trp-NH(2), consisting of 26 members that have been modified at the DPhe(7) position (alpha-MSH numbering) and pharmacologically characterized for agonist and antagonist activity at the mouse melanocortin receptors MC1R, MC3R, MC4R, and MC5R. The most notable results of this study include the identification of the tetrapeptide Ac-His-(pI)DPhe-Arg-Trp-NH(2) that is a full nanomolar agonist at the mMC1 and mMC5 receptors, a mMC3R partial agonist with potent antagonist activity (pA(2) = 7.25, K(i) = 56 nM) and, but unexpectedly, is a potent agonist at the mMC4R (EC(50) = 25 nM). This ligand possesses novel melanocortin receptor pharmacology, as compared to previously reported peptides, and is potentially useful for in vivo studies to differentiate MC3R vs MC4R physiological roles in animal models, such as primates, where "knockout" animals are not viable options. The DNal(2') substitution for DPhe resulted in a mMC3R partial agonist with antagonist activity (pA(2) = 6.5, K(i) = 295 nM) and a mMC4R (pA(2) = 7.8, K(i) = 17 nM) antagonist possessing 60- and 425-fold decreased potency, respectively, as compared with SHU9119 at these receptors. Examination of this DNal(2')-containing tetrapeptide at the F254S and F259S mutant mMC4Rs resulted in agonist activity of this m

Flavonoids with M1 Muscarinic Acetylcholine Receptor Binding Activity

Directory of Open Access Journals (Sweden)

Meyyammai Swaminathan

2014-06-01

Full Text Available Muscarinic acetylcholine receptor-active compounds have potential for the treatment of Alzheimer’s disease. In this study, a series of natural and synthetic flavones and flavonols was assayed in vitro for their ability to inhibit radioligand binding at human cloned M1 muscarinic receptors. Several compounds were found to possess competitive binding affinity (Ki = 40–110 µM, comparable to that of acetylcholine (Ki = 59 µM. Despite the fact that these compounds lack a positively-charged ammonium group under physiological conditions, molecular modelling studies suggested that they bind to the orthosteric site of the receptor, mainly through non-polar interactions.

Possible Relevance of Receptor-Receptor Interactions between Viral- and Host-Coded Receptors for Viral-Induced Disease

Directory of Open Access Journals (Sweden)

Luigi F. Agnati

2007-01-01

Full Text Available It has been demonstrated that some viruses, such as the cytomegalovirus, code for G-protein coupled receptors not only to elude the immune system, but also to redirect cellular signaling in the receptor networks of the host cells. In view of the existence of receptor-receptor interactions, the hypothesis is introduced that these viral-coded receptors not only operate as constitutively active monomers, but also can affect other receptor function by interacting with receptors of the host cell. Furthermore, it is suggested that viruses could also insert not single receptors (monomers, but clusters of receptors (receptor mosaics, altering the cell metabolism in a profound way. The prevention of viral receptor-induced changes in host receptor networks may give rise to novel antiviral drugs that counteract viral-induced disease.

Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a german breast group 26/breast international group 03-05 study

DEFF Research Database (Denmark)

von Minckwitz, Gunter; du Bois, Andreas; Schmidt, Marcus

2009-01-01

PURPOSE: Trastuzumab shows clinical activity in human epidermal growth factor receptor 2 (HER-2)-positive early and advanced breast cancer. In the German Breast Group 26/Breast International Group 03-05 trial, we investigated if trastuzumab treatment should be continued beyond progression. METHODS......: Patients with HER-2-positive breast cancer that progresses during treatment with trastuzumab were randomly assigned to receive capecitabine (2,500 mg/m(2) body-surface area on days 1 through 14 [1,250 mg/m(2) semi-daily]) alone or with continuation of trastuzumab (6 mg/kg body weight) in 3-week cycles....... The primary end point was time to progression. RESULTS: We randomly assigned 78 patients to capecitabine and 78 patients to capecitabine plus trastuzumab. Sixty-five events and 38 deaths in the capecitabine group and 62 events and 33 deaths in the capecitabine-plus-trastuzumab group occurred during 15...

Ligand-induced internalization of neurotensin in transfected COS-7 cells: differential intracellular trafficking of ligand and receptor.

Science.gov (United States)

Vandenbulcke, F; Nouel, D; Vincent, J P; Mazella, J; Beaudet, A

2000-09-01

The neuropeptide neurotensin (NT) is known to be internalized in a receptor-mediated fashion into its target cells. To gain insight into the mechanisms underlying this process, we monitored in parallel the migration of the NT1 neurotensin receptor subtype and a fluorescent analog of NT (fluo-NT) in COS-7 cells transfected with a tagged NT1 construct. Fluo-NT internalization was prevented by hypertonic sucrose, potassium depletion and cytosol acidification, demonstrating that it proceeded via clathrin-coated pits. Within 0-30 minutes, fluo-NT accumulated together with its receptor in Acridine Orange-positive, acidic organelles. These organelles concentrated transferrin and immunostained positively for rab 5A, therefore they were early endosomes. After 30-45 minutes, the ligand and its receptor no longer colocalized. Fluo-NT was first found in rab 7-positive late endosomes and later in a nonacidic juxtanuclear compartment identified as the Trans-Golgi Network (TGN) by virtue of its staining for syntaxin 6. This juxtanuclear compartment also stained positively for rab 7 and for the TGN/pericentriolar recycling endosome marker rab 11, suggesting that the ligand could have been recruited to the TGN from either late or recycling endosomes. By that time, internalized receptors were detected in Lamp-1-immunoreactive lysosomes. These results demonstrate that neurotensin/NT1 receptor complexes follow a recycling cycle that is unique among the G protein-coupled receptors studied to date, and provide the first evidence for the targeting of a nonendogenous protein from endosomes to the TGN.

DOTA-PESIN, a DOTA-conjugated bombesin derivative designed for the imaging and targeted radionuclide treatment of bombesin receptor-positive tumours

International Nuclear Information System (INIS)

Zhang, Hanwen; Maecke, Helmut R.; Schuhmacher, Jochen; Eisenhut, Michael; Waser, Beatrice; Reubi, Jean Claude; Wild, Damian

2007-01-01

We aimed at designing and developing a novel bombesin analogue, DOTA-PEG 4 -BN(7-14) (DOTA-PESIN), with the goal of labelling it with 67/68 Ga and 177 Lu for diagnosis and radionuclide therapy of prostate and other human cancers overexpressing bombesin receptors. The 8-amino acid peptide bombesin (7-14) was coupled to the macrocyclic chelator DOTA via the spacer 15-amino-4,7,10,13-tetraoxapentadecanoic acid (PEG 4 ). The conjugate was complexed with Ga(III) and Lu(III) salts. The GRP receptor affinity and the bombesin receptor subtype profile were determined in human tumour specimens expressing the three bombesin receptor subtypes. Internalisation and efflux studies were performed with the human GRP receptor cell line PC-3. Xenografted nude mice were used for biodistribution. [Ga III /Lu III ]-DOTA-PESIN showed good affinity to GRP and neuromedin B receptors but no affinity to BB3. [ 67 Ga/ 177 Lu]-DOTA-PESIN internalised rapidly into PC-3 cells whereas the efflux from PC-3 cells was relatively slow. In vivo experiments showed a high and specific tumour uptake and good retention of [ 67 Ga/ 177 Lu]-DOTA-PESIN. [ 67 Ga/ 177 Lu]-DOTA-PESIN highly accumulated in GRP receptor-expressing mouse pancreas. The uptake specificity was demonstrated by blocking tumour uptake and pancreas uptake. Fast clearance was found from blood and all non-target organs except the kidneys. High tumour-to-normal tissue ratios were achieved, which increased with time. PET imaging with [ 68 Ga]-DOTA-PESIN was successful in visualising the tumour at 1 h post injection. Planar scintigraphic imaging showed that the 177 Lu-labelled peptide remained in the tumour even 3 days post injection. The newly designed ligands have high potential with regard to PET and SPECT imaging with 68/67 Ga and targeted radionuclide therapy with 177 Lu. (orig.)

Diagnostic sensitivity of two radio receptor assays (TRAK Assay and TRAK Dyno human) for the detection of TSH receptor antibodies

International Nuclear Information System (INIS)

Paunkovic, N.; Paunkovic, J.

2003-01-01

Radio receptor assays for the detection of TSH receptor antibodies in serum are typically based on binding the competition of TSH-R antibodies and 125I -labelled-TSH for membrane preparation of thyrocytes (TBII tests). The sensitivity of the available tests utilizing porcine cell membranes was found to be around 80%. A new test (TRAK Dyno human, BRAHMS) utilizes human recombinant TSH receptor and human standard material that is supposed to improve the performance of the test. We have compared the results of these two assays. The sensitivity of the TRAK Assay tested in 356 patients with untreated Grave's disease was found to be 85%, and 97.5% for TRAK Dyno human in 111 newly diagnosed patients. Both tests were performed from the same serum specimen for 60 of the investigated patients. The TRAK Assay was positive in 50 patients (83.2%) and TRAK Dyno human in 59 patients (98.3%). The specificity of the new radio receptor assay was also improved. (author)

Identification of neurons that express ghrelin receptors in autonomic pathways originating from the spinal cord.

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Furness, John B; Cho, Hyun-Jung; Hunne, Billie; Hirayama, Haruko; Callaghan, Brid P; Lomax, Alan E; Brock, James A

2012-06-01

Functional studies have shown that subsets of autonomic preganglionic neurons respond to ghrelin and ghrelin mimetics and in situ hybridisation has revealed receptor gene expression in the cell bodies of some preganglionic neurons. Our present goal has been to determine which preganglionic neurons express ghrelin receptors by using mice expressing enhanced green fluorescent protein (EGFP) under the control of the promoter for the ghrelin receptor (also called growth hormone secretagogue receptor). The retrograde tracer Fast Blue was injected into target organs of reporter mice under anaesthesia to identify specific functional subsets of postganglionic sympathetic neurons. Cryo-sections were immunohistochemically stained by using anti-EGFP and antibodies to neuronal markers. EGFP was detected in nerve terminal varicosities in all sympathetic chain, prevertebral and pelvic ganglia and in the adrenal medulla. Non-varicose fibres associated with the ganglia were also immunoreactive. No postganglionic cell bodies contained EGFP. In sympathetic chain ganglia, most neurons were surrounded by EGFP-positive terminals. In the stellate ganglion, neurons with choline acetyltransferase immunoreactivity, some being sudomotor neurons, lacked surrounding ghrelin-receptor-expressing terminals, although these terminals were found around other neurons. In the superior cervical ganglion, the ghrelin receptor terminals innervated subgroups of neurons including neuropeptide Y (NPY)-immunoreactive neurons that projected to the anterior chamber of the eye. However, large NPY-negative neurons projecting to the acini of the submaxillary gland were not innervated by EGFP-positive varicosities. In the celiaco-superior mesenteric ganglion, almost all neurons were surrounded by positive terminals but the VIP-immunoreactive terminals of intestinofugal neurons were EGFP-negative. The pelvic ganglia contained groups of neurons without ghrelin receptor terminal innervation and other groups with

Breast cancer with Her-22 hormone receptor-positive neu: primary systemic treatment, sentinel node biopsy and hormone

International Nuclear Information System (INIS)

Lopez C, Nayara; Sanchez M, Jose Ignacio; De Santiago G, Javier

2013-01-01

Neoadjuvant chemotherapy is an interesting option in the therapy of some breast cancer cases. Cases in which the timing for sentinel lymph node biopsy is controversial. Co-expression of estrogen receptors and Her2/neu (cc-erbB-2) in breast cancer may imply hormone resistance, especially to tamoxifen. We present a clinic case with co-expression of estrogen receptors and Her2/neu that was treated with neoadjuvant chemotherapy and previous sentinel lymph node biopsy followed by breast tumorectomy with axillar lympha- denectomy, radiotherapy and hormonotherapy with letrozol, geserelina and trastuzumab. A good treatment response as found

(−) Arctigenin and (+) Pinoresinol Are Antagonists of the Human Thyroid Hormone Receptor β

Science.gov (United States)

2015-01-01

Lignans are important biologically active dietary polyphenolic compounds. Consumption of foods that are rich in lignans is associated with positive health effects. Using modeling tools to probe the ligand-binding pockets of molecular receptors, we found that lignans have high docking affinity for the human thyroid hormone receptor β. Follow-up experimental results show that lignans (−) arctigenin and (+) pinoresinol are antagonists of the human thyroid hormone receptor β. The modeled complexes show key plausible interactions between the two ligands and important amino acid residues of the receptor. PMID:25383984

Molecular alteration of a muscarinic acetylcholine receptor system during synaptogenesis

International Nuclear Information System (INIS)

Large, T.H.; Cho, N.J.; De Mello, F.G.; Klein, W.L.

1985-01-01

Biochemical properties of the muscarinic acetylcholine receptor system of the avian retina were found to change during the period when synapses form in ovo. Comparison of ligand binding to membranes obtained before and after synaptogenesis showed a significant increase in the affinity, but not proportion, of the high affinity agonist-binding state. There was no change in receptor sensitivity to antagonists during this period. Pirenzepine binding, which can discriminate muscarinic receptor subtypes, showed the presence of a single population of low affinity sites (M2) before and after synaptogenesis. The change in agonist binding was not due to the late development of receptor function. However, detergent-solubilization of membranes eliminated differences in agonist binding between receptors from embryos and hatched chicks, suggesting a developmental change in interactions of the receptor with functionally related membrane components. A possible basis for altered interactions was obtained from isoelectric point data showing that the muscarinic receptor population underwent a transition from a predominantly low pI form (4.25) in 13 day embryos to a predominantly high pI form (4.50) in newly hatched chicks. The possibility that biochemical changes in the muscarinic receptor play a role in differentiation of the system by controlling receptor position on the surface of nerve cells is discussed

FDA Approval: Palbociclib for the Treatment of Postmenopausal Patients with Estrogen Receptor-Positive, HER2-Negative Metastatic Breast Cancer.

Science.gov (United States)

Beaver, Julia A; Amiri-Kordestani, Laleh; Charlab, Rosane; Chen, Wei; Palmby, Todd; Tilley, Amy; Zirkelbach, Jeanne Fourie; Yu, Jingyu; Liu, Qi; Zhao, Liang; Crich, Joyce; Chen, Xiao Hong; Hughes, Minerva; Bloomquist, Erik; Tang, Shenghui; Sridhara, Rajeshwari; Kluetz, Paul G; Kim, Geoffrey; Ibrahim, Amna; Pazdur, Richard; Cortazar, Patricia

2015-11-01

On February 3, 2015, the FDA granted accelerated approval to palbociclib (IBRANCE, Pfizer Inc.), an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), for use in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. The approval is based on a randomized, multicenter, open-label phase I/II trial (PALOMA-1) in 165 patients randomized to palbociclib (125 mg orally daily for 21 consecutive days, followed by 7 days off treatment) plus letrozole (2.5 mg orally daily) or letrozole alone. The phase II portion of the trial was divided into two cohorts: cohort 1 enrolled 66 biomarker-unselected patients and cohort 2 enrolled 99 biomarker-positive patients. The major efficacy outcome measure was investigator-assessed progression-free survival (PFS). A large magnitude of improvement in PFS was observed in patients receiving palbociclib plus letrozole compared with patients receiving letrozole alone (HR, 0.488; 95% confidence interval, 0.319-0.748). Multiple sensitivity analyses were supportive of clinical benefit. The most common adverse reaction in patients receiving palbociclib plus letrozole was neutropenia. This article summarizes the FDA thought process and data supporting accelerated approval based on PALOMA-1 that may be contingent upon verification and description of clinical benefit in the ongoing and fully accrued confirmatory trial PALOMA-2. ©2015 American Association for Cancer Research.

Re-Appraisal of Estrogen Receptor Negative/Progesterone Receptor Positive (ER-/PR+) Breast Cancer Phenotype: True Subtype or Technical Artefact?

Science.gov (United States)

Foley, Niamh M; Coll, J M; Lowery, A J; Hynes, S O; Kerin, M J; Sheehan, M; Brodie, C; Sweeney, K J

2017-09-11

Expression of the ER and PR receptors is routinely quantified in breast cancer as a predictive marker of response to hormonal therapy. Accurate determination of ER and PR status is critical to the optimal selection of patients for targeted therapy. The existence of an ER-/PR+ subtype is controversial, with debate centred on whether this represents a true phenotype or a technical artefact on immunohistochemistry (IHC). The aim of this study was to investigate the true incidence and clinico-pathological features of ER-/PR+ breast cancers in a tertiary referral symptomatic breast unit. Clinico-pathological data were collected on invasive breast cancers diagnosed between 1995 and 2005. IHC for ER and PR receptors was repeated on all cases which were ER-/PR+, with the same paraffin block used for the initial diagnostic testing. Concordance between the diagnostic and repeat IHC was determined using validated testing. Complete data, including ER and PR status were available for 697 patients diagnosed during the study period. On diagnostic IHC, the immunophenotype of the breast tumours was: ER+/PR+ in 396 (57%), ER-/PR- in 157 (23%), ER+/PR- in 88 (12%) and ER-/PR+ in 56 (8.6%) patients. On repeat IHC of 48/56 ER-/PR+ tumours 45.8% were ER+/PR+, 6% were ER+/PR- and 43.7% were ER-/PR- None of the cases were confirmed to be ER-/PR+. The ER-/PR+ phenotypic breast cancer is likely to be the result of technical artefact. Prompt reassessment of patients originally assigned to this subtype who re-present with symptoms should be considered to ensure appropriate clinical management.

Small Molecule Drug Discovery at the Glucagon-Like Peptide-1 Receptor

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Francis S. Willard

2012-01-01

Full Text Available The therapeutic success of peptide glucagon-like peptide-1 (GLP-1 receptor agonists for the treatment of type 2 diabetes mellitus has inspired discovery efforts aimed at developing orally available small molecule GLP-1 receptor agonists. Although the GLP-1 receptor is a member of the structurally complex class B1 family of GPCRs, in recent years, a diverse array of orthosteric and allosteric nonpeptide ligands has been reported. These compounds include antagonists, agonists, and positive allosteric modulators with intrinsic efficacy. In this paper, a comprehensive review of currently disclosed small molecule GLP-1 receptor ligands is presented. In addition, examples of “ligand bias” and “probe dependency” for the GLP-1 receptor are discussed; these emerging concepts may influence further optimization of known molecules or persuade designs of expanded screening strategies to identify novel chemical starting points for GLP-1 receptor drug discovery.

Mammographic density changes following discontinuation of tamoxifen in premenopausal women with oestrogen receptor-positive breast cancer.

Science.gov (United States)

Kim, Won Hwa; Cho, Nariya; Kim, Young-Seon; Yi, Ann

2018-04-06

To evaluate the changes in mammographic density after tamoxifen discontinuation in premenopausal women with oestrogen receptor-positive breast cancers and the underlying factors METHODS: A total of 213 consecutive premenopausal women with breast cancer who received tamoxifen treatment after curative surgery and underwent three mammograms (baseline, after tamoxifen treatment, after tamoxifen discontinuation) were included. Changes in mammographic density after tamoxifen discontinuation were assessed qualitatively (decrease, no change, or increase) by two readers and measured quantitatively by semi-automated software. The association between % density change and clinicopathological factors was evaluated using univariate and multivariate regression analyses. After tamoxifen discontinuation, a mammographic density increase was observed in 31.9% (68/213, reader 1) to 22.1% (47/213, reader 2) by qualitative assessment, with a mean density increase of 1.8% by quantitative assessment compared to density before tamoxifen discontinuation. In multivariate analysis, younger age (≤ 39 years) and greater % density decline after tamoxifen treatment (≥ 17.0%) were independent factors associated with density change after tamoxifen discontinuation (p density change with a mean density increase of 1.8%, which was associated with younger age and greater density change after tamoxifen treatment. • Increased mammographic density after tamoxifen discontinuation can occur in premenopausal women. • Mean density increase after tamoxifen discontinuation was 1.8%. • Density increase is associated with age and density decrease after tamoxifen.

α5-GABAA receptors negatively regulate MYC-amplified medulloblastoma growth

Science.gov (United States)

Sengupta, Soma; Weeraratne, Shyamal Dilhan; Sun, Hongyu; Phallen, Jillian; Rallapalli, Sundari K.; Teider, Natalia; Kosaras, Bela; Amani, Vladimir; Pierre-Francois, Jessica; Tang, Yujie; Nguyen, Brian; Yu, Furong; Schubert, Simone; Balansay, Brianna; Mathios, Dimitris; Lechpammer, Mirna; Archer, Tenley C.; Tran, Phuoc; Reimer, Richard J.; Cook, James M.; Lim, Michael; Jensen, Frances E.; Pomeroy, Scott L.; Cho, Yoon-Jae

2013-01-01

Neural tumors often express neurotransmitter receptors as markers of their developmental lineage. Although these receptors have been well characterized in electrophysiological, developmental and pharmacological settings, their importance in the maintenance and progression of brain tumors, and importantly, the effect of their targeting in brain cancers remains obscure. Here, we demonstrate high levels of GABR5, which encodes the α-subunit of the GABAA receptor complex, in aggressive MYC-driven, “Group 3” medulloblastomas. We hypothesized that modulation of α-GABAA receptors alters medulloblastoma cell survival and monitored biological and electrophysiological responses of GABR5-expressing medulloblastoma cells upon pharmacological targeting of the GABAA receptor. While antagonists, inverse agonists and non-specific positive allosteric modulators had limited effects on medulloblastoma cells, a highly specific and potent α5-GABAA receptor agonist, QHii066, resulted in marked membrane depolarization and a significant decrease in cell survival. This effect was GABR5 dependent and mediated through the induction of apoptosis as well as accumulation of cells in S and G2 phases of the cell cycle. Chemical genomic profiling of QHii066-treated medulloblastoma cells confirmed inhibition of MYC-related transcriptional activity and revealed an enrichment of HOX5 target gene expression. siRNA-mediated knockdown of HOX5 markedly blunted the response of medulloblastoma cells to QHii066. Furthermore, QHii066 sensitized GABR5 positive medulloblastoma cells to radiation and chemotherapy consistent with the role of HOX5 in directly regulating p53 expression and inducing apoptosis. Thus, our results provide novel insights into the synthetic lethal nature of α5-GABAA receptor activation in MYC-driven/Group 3 medulloblastomas and propose its targeting as a novel strategy for the management of this highly aggressive tumor. PMID:24196163

α5-GABAA receptors negatively regulate MYC-amplified medulloblastoma growth.

Science.gov (United States)

Sengupta, Soma; Weeraratne, Shyamal Dilhan; Sun, Hongyu; Phallen, Jillian; Rallapalli, Sundari K; Teider, Natalia; Kosaras, Bela; Amani, Vladimir; Pierre-Francois, Jessica; Tang, Yujie; Nguyen, Brian; Yu, Furong; Schubert, Simone; Balansay, Brianna; Mathios, Dimitris; Lechpammer, Mirna; Archer, Tenley C; Tran, Phuoc; Reimer, Richard J; Cook, James M; Lim, Michael; Jensen, Frances E; Pomeroy, Scott L; Cho, Yoon-Jae

2014-04-01

Neural tumors often express neurotransmitter receptors as markers of their developmental lineage. Although these receptors have been well characterized in electrophysiological, developmental and pharmacological settings, their importance in the maintenance and progression of brain tumors and, importantly, the effect of their targeting in brain cancers remains obscure. Here, we demonstrate high levels of GABRA5, which encodes the α5-subunit of the GABAA receptor complex, in aggressive MYC-driven, "Group 3" medulloblastomas. We hypothesized that modulation of α5-GABAA receptors alters medulloblastoma cell survival and monitored biological and electrophysiological responses of GABRA5-expressing medulloblastoma cells upon pharmacological targeting of the GABAA receptor. While antagonists, inverse agonists and non-specific positive allosteric modulators had limited effects on medulloblastoma cells, a highly specific and potent α5-GABAA receptor agonist, QHii066, resulted in marked membrane depolarization and a significant decrease in cell survival. This effect was GABRA5 dependent and mediated through the induction of apoptosis as well as accumulation of cells in S and G2 phases of the cell cycle. Chemical genomic profiling of QHii066-treated medulloblastoma cells confirmed inhibition of MYC-related transcriptional activity and revealed an enrichment of HOXA5 target gene expression. siRNA-mediated knockdown of HOXA5 markedly blunted the response of medulloblastoma cells to QHii066. Furthermore, QHii066 sensitized GABRA5 positive medulloblastoma cells to radiation and chemotherapy consistent with the role of HOXA5 in directly regulating p53 expression and inducing apoptosis. Thus, our results provide novel insights into the synthetic lethal nature of α5-GABAA receptor activation in MYC-driven/Group 3 medulloblastomas and propose its targeting as a novel strategy for the management of this highly aggressive tumor.

Presynaptic G Protein-Coupled Receptors: Gatekeepers of Addiction?

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Kari A Johnson

2016-11-01

Full Text Available Drug abuse and addiction cause widespread social and public health problems, and the neurobiology underlying drug actions and drug use and abuse is an area of intensive research. Drugs of abuse alter synaptic transmission, and these actions contribute to acute intoxication as well as the chronic effects of abused substances. Transmission at most mammalian synapses involves neurotransmitter activation of two receptor subtypes, ligand-gated ion channels that mediate fast synaptic responses, and G protein-coupled receptors (GPCRs that have slower neuromodulatory actions. The GPCRs represent a large proportion of neurotransmitter receptors involved in almost all facets of nervous system function. In addition, these receptors are targets for many pharmacotherapeutic agents. Drugs of abuse directly or indirectly affect neuromodulation mediated by GPCRs, with important consequences for intoxication, drug taking and responses to prolonged drug exposure, withdrawal and addiction. Among the GPCRs are several subtypes involved in presynaptic inhibition, most of which are coupled to the Gi/o class of G protein. There is increasing evidence that these presynaptic Gi/o-coupled GPCRs have important roles in the actions of drugs of abuse, as well as behaviors related to these drugs. This topic will be reviewed, with particular emphasis on receptors for three neurotransmitters, dopamine (D1- and D2-like receptors, endocannabinoids (CB1 receptors and glutamate (group II metabotropic glutamate (mGlu receptors. The focus is on recent evidence from laboratory animal models (and some evidence in humans implicating these receptors in the acute and chronic effects of numerous abused drugs, as well as in the control of drug seeking and taking. The ability of drugs targeting these receptors to modify drug seeking behavior has raised the possibility of using compounds targeting these receptors for addiction pharmacotherapy. This topic is also discussed, with emphasis on

AIM2-Like Receptors Positively and Negatively Regulate the Interferon Response Induced by Cytosolic DNA

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Yuki Nakaya

2017-07-01

Full Text Available Cytosolic DNAs derived from retrotransposons serve as pathogen-associated molecular patterns for pattern recognition receptors (PRRs that stimulate the induction of interferons (IFNs and other cytokines, leading to autoimmune disease. Cyclic GMP-AMP synthase is one PRR that senses retrotransposon DNA, activating type I IFN responses through the stimulator of IFN genes (STING. Absent in melanoma 2 (AIM2-like receptors (ALRs have also been implicated in these pathways. Here we show that the mouse ALR IFI205 senses cytosolic retrotransposon DNA independently of cyclic GMP-AMP production. AIM2 antagonizes IFI205-mediated IFN induction activity by sequestering it from STING. We also found that the complement of genes located in the ALR locus in C57BL/6 and AIM2 knockout mice are different and unique, which has implications for interpretation of the sensing of pathogens in different mouse strains. Our data suggest that members of the ALR family are critical to the host IFN response to endogenous DNA.

Serotonin receptors influencing cell proliferation in the jejunal crypt epithelium and in colonic adenocarcinomas.

Science.gov (United States)

Tutton, P J; Barkla, D H

1986-01-01

Serotonin has previously been shown to stimulate cell proliferation in the jejunal crypt epithelium and in colonic tumours. The original classification of serotonin receptors into D and M groups was not conductive to the understanding of these observations. The more recent classification of serotonin receptors into 5HT1 and 5HT2 groups is considered in this report. On the balance of evidence it appears that similar receptors mediate the response to serotonin in the two tissues under consideration and that these receptors resemble those of the 5HT1 group. Such receptors are usually positively linked to adenylate cyclase.

Interaction of PHM, PHI and 24-glutamine PHI with human VIP receptors from colonic epithelium: comparison with rat intestinal receptors

International Nuclear Information System (INIS)

Laburthe, M.; Couvineau, A.; Rouyer-Fessard, C.; Moroder, L.

1985-01-01

PHM, the human counterpart of porcine Peptide Histidine Isoleucine amide (PHI), is shown to be a VIP agonist with low potency on human VIP receptors located in colonic epithelial cell membranes. Its potency is identical to that of PHI but by 3 orders of magnitude lower than that of VIP itself in inhibiting 125 I-VIP binding and in stimulating adenylate cyclase activity. This contrasts markedly with the behavior of PHI on rat VIP receptors located in intestinal epithelial cell membranes where PHI is a potent agonist with a potency that is 1/5 that of VIP. In another connection, the authors show that 24-glutamine PHI has the same affinity as 24-glutamic acid PHI (the natural peptide) for rat or human VIP receptors. These results indicate that while PHI may exert some physiological function through its interaction with VIP receptors in rodents, its human counterpart PHM is a very poor agonist of VIP in human. Furthermore, they show that the drastic change in position 24 of PHI (neutral versus acid residue) does not affect the activity of PHI, at least on VIP receptors. 21 references, 1 figure

Analysis of PI3K/mTOR Pathway Biomarkers and Their Prognostic Value in Women with Hormone Receptor–Positive, HER2-Negative Early Breast Cancer

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Hamdy A. Azim

2016-04-01

.6%, respectively. PIK3CA mutations were found in 7 patients (29.2%. PI3K mutations were correlated with nuclear localization of pAKT (i.e., decreased cytoplasmic pAKT, P = .04; and increased nuclear pAKT, P = .10. There was a tendency toward an inverse correlation between PI3K mutations and the expression of pS6RP (P = .10 and p4EBP1 (P = .19. Nuclear LKB1 expression was a marker of good prognosis. It was associated with smaller tumors (P = .05, more ER (P = .08 and progesteron receptor (PgR positivity (P = .002. In the Kaplan Meier (KM model, patients with high nuclear LKB1 had longer DFS (hazard ratio = 0.36; 95% confidence interval, 0.15-1.10; P = .08. Nuclear pAKT high expression also carried a tendency toward longer DFS (hazard ratio = 0.51; 95% confidence interval, 0.11-1.16; P = .13. The expression of p4EBP1, pS6RP, and the PI3K mutational status did not show any prognostic significance in our cohort. CONCLUSION: Among the studied biomarkers, only nuclear expression of LKB1 and pAKT tended to predict better survival in breast cancer patients. PI3K mutation was correlated with the expression of nuclear pAKT but not pS6RP or p4EBP1.

Very Strong Binding for a Neutral Calix[4]pyrrole Receptor Displaying Positive Allosteric Binding

DEFF Research Database (Denmark)

Duedal, Troels; Nielsen, Kent; Olsen, Gunnar

2017-01-01

. The tetrathiafulvalene (TTF) subunits in the tetraTTF-calix[4]pyrrole receptor 1 present a nearly perfect shape and electronic complementarity to the NTCDA guest, which was confirmed by X-ray crystal structure analysis, DFT calculations, and electron density surface mapping. The complexation results in formation...... of a charge transfer complex (22⊆1), that is visualized as a color change from yellow to brown....

Divergent effects of insulin-like growth factor-1 receptor expression on prognosis of estrogen receptor positive versus triple negative invasive ductal breast carcinoma

NARCIS (Netherlands)

Hartog, Hermien; Horlings, Hugo M; van der Vegt, Bert; Kreike, Bas; Ajouaou, Abderrahim; van de Vijver, Marc J; Boezen, Hendrika; de Bock, Geertruida H; van der Graaf, Wilhelmina; Wesseling, Jelle

2011-01-01

The insulin-like growth factor type 1 receptor (IGF1R) is involved in progression of breast cancer and resistance to systemic treatment. Targeting IGF1R signaling may, therefore, be beneficial in systemic treatment. We report the effect of IGF1R expression on prognosis in invasive ductal breast

Long-term Safety of Pregnancy Following Breast Cancer According to Estrogen Receptor Status

DEFF Research Database (Denmark)

Lambertini, Matteo; Kroman, Niels; Ameye, Lieveke

2018-01-01

Safety of pregnancy in women with history of estrogen receptor (ER)-positive breast cancer remains controversial. In this multicenter case-control study, 333 patients with pregnancy after breast cancer were matched (1:3) to 874 nonpregnant patients of similar characteristics, adjusting for guaran......Safety of pregnancy in women with history of estrogen receptor (ER)-positive breast cancer remains controversial. In this multicenter case-control study, 333 patients with pregnancy after breast cancer were matched (1:3) to 874 nonpregnant patients of similar characteristics, adjusting...

Recent Duplication and Functional Divergence in Parasitic Nematode Levamisole-Sensitive Acetylcholine Receptors.

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Thomas B Duguet

2016-07-01

Full Text Available Helminth parasites rely on fast-synaptic transmission in their neuromusculature to experience the outside world and respond to it. Acetylcholine plays a pivotal role in this and its receptors are targeted by a wide variety of both natural and synthetic compounds used in human health and for the control of parasitic disease. The model, Caenorhabditis elegans is characterized by a large number of acetylcholine receptor subunit genes, a feature shared across the nematodes. This dynamic family is characterized by both gene duplication and loss between species. The pentameric levamisole-sensitive acetylcholine receptor has been characterized from C. elegans, comprised of five different subunits. More recently, cognate receptors have been reconstituted from multiple parasitic nematodes that are found to vary in subunit composition. In order to understand the implications of receptor composition change and the origins of potentially novel drug targets, we investigated a specific example of subunit duplication based on analysis of genome data for 25 species from the 50 helminth genome initiative. We found multiple independent duplications of the unc-29, acetylcholine receptor subunit, where codon substitution rate analysis identified positive, directional selection acting on amino acid positions associated with subunit assembly. Characterization of four gene copies from a model parasitic nematode, Haemonchus contortus, demonstrated that each copy has acquired unique functional characteristics based on phenotype rescue of transgenic C. elegans and electrophysiology of receptors reconstituted in Xenopus oocytes. We found evidence that a specific incompatibility has evolved for two subunits co-expressed in muscle. We demonstrated that functional divergence of acetylcholine receptors, driven by directional selection, can occur more rapidly than previously thought and may be mediated by alteration of receptor assembly. This phenomenon is common among the

The minor binding pocket: a major player in 7TM receptor activation

DEFF Research Database (Denmark)

Rosenkilde, Mette Marie; Benned-Jensen, Tau; Frimurer, Thomas M.

2010-01-01

residue located in one of two adjacent positions. Here we argue that this minor binding pocket is important for receptor activation. Functional coupling of the receptors seems to be mediated through the hydrogen bond network located between the intracellular segments of these TMs, with the allosteric...... targeted in the development of functionally biased drugs....

Angiotensin II Type 2 Receptor and Receptor Mas Are Colocalized and Functionally Interdependent in Obese Zucker Rat Kidney

DEFF Research Database (Denmark)

Patel, Sanket N; Ali, Quaisar; Samuel, Preethi

2017-01-01

The actions of angiotensin II type 2 receptor (AT2R) and the receptor Mas (MasR) are complex but show similar pronatriuretic function; particularly, AT2R expression and natriuretic function are enhanced in obese/diabetic rat kidney. In light of some reports suggesting a potential positive...... interaction between these receptors, we tested hypothesis that renal AT2R and MasR physically interact and are interdependent to stimulate cell signaling and promote natriuresis in obese rats. We found that infusion of AT2R agonist C21 in obese Zucker rats (OZR) increased urine flow and urinary Na excretion...... coimmunoprecipitated with MasR in cortical homogenate of OZR. Immunoblotting of cortical homogenate cross-linked with zero-length oxidative (sulfhydryl groups) cross-linker cupric-phenanthroline revealed a shift of AT2R and MasR bands upward with overlapping migration for their complexes which were sensitive...

The substance P/NK-1 receptor system

Indian Academy of Sciences (India)

2015-04-27

Apr 27, 2015 ... NK-1 receptor may be a promising target in the treatment of cancer; NK-1 ... the contribution of chemotherapy for adult malignancies .... nisms that regulate cellular excitability and function. ..... positive expression of Ki-67 in dysplastic epithelium ..... emotional behaviour (behaviour traits, such as depression),.

Gene expression profiling of histologically normal breast tissue in females with human epidermal growth factor receptor 2‑positive breast cancer.

Science.gov (United States)

Zubor, Pavol; Hatok, Jozef; Moricova, Petra; Kapustova, Ivana; Kajo, Karol; Mendelova, Andrea; Sivonova, Monika Kmetova; Danko, Jan

2015-02-01

Gene expression profile‑based taxonomy of breast cancer (BC) has been described as a significant breakthrough in comprehending the differences in the origin and behavior of cancer to allow individually tailored therapeutic approaches. In line with this, we hypothesized that the gene expression profile of histologically normal epithelium (HNEpi) could harbor certain genetic abnormalities predisposing breast tissue cells to develop human epidermal growth factor receptor 2 (HER2)‑positive BC. Thus, the aim of the present study was to assess gene expression in normal and BC tissue (BCTis) from patients with BC in order to establish its value as a potential diagnostic marker for cancer development. An array study evaluating a panel of 84 pathway‑ and disease‑specific genes in HER2‑positive BC and tumor‑adjacent HNEpi was performed using quantitative polymerase chain reaction in 12 patients using microdissected samples from frozen tissue. Common prognostic and predictive parameters of BC were assessed by immunohistochemistry and in situ hybridization. In the BCTis and HNEpi samples of 12 HER2‑positive subjects with BC, the expression of 2,016 genes was assessed. A total of 39.3% of genes were deregulated at a minimal two‑fold deregulation rate and 10.7% at a five‑fold deregulation rate in samples of HNEpi or BCTis. Significant differences in gene expression between BCTis and HNEpi samples were revealed for BCL2L2, CD44, CTSD, EGFR, ERBB2, ITGA6, NGFB, RPL27, SCBG2A1 and SCGB1D2 genes (Pbreast tissue revealed gene expression abnormalities that may represent potential markers of increased risk for HER2‑positive malignant transformation of breast tissue, and may be able to be employed as predictors of prognosis.

The polygenic risk for bipolar disorder influences brain regional function relating to visual and default state processing of emotional information.

Science.gov (United States)

Dima, Danai; de Jong, Simone; Breen, Gerome; Frangou, Sophia

2016-01-01

Genome-wise association studies have identified a number of common single-nucleotide polymorphisms (SNPs), each of small effect, associated with risk to bipolar disorder (BD). Several risk-conferring SNPs have been individually shown to influence regional brain activation thus linking genetic risk for BD to altered brain function. The current study examined whether the polygenic risk score method, which models the cumulative load of all known risk-conferring SNPs, may be useful in the identification of brain regions whose function may be related to the polygenic architecture of BD. We calculated the individual polygenic risk score for BD (PGR-BD) in forty-one patients with the disorder, twenty-five unaffected first-degree relatives and forty-six unrelated healthy controls using the most recent Psychiatric Genomics Consortium data. Functional magnetic resonance imaging was used to define task-related brain activation patterns in response to facial affect and working memory processing. We found significant effects of the PGR-BD score on task-related activation irrespective of diagnostic group. There was a negative association between the PGR-BD score and activation in the visual association cortex during facial affect processing. In contrast, the PGR-BD score was associated with failure to deactivate the ventromedial prefrontal region of the default mode network during working memory processing. These results are consistent with the threshold-liability model of BD, and demonstrate the usefulness of the PGR-BD score in identifying brain functional alternations associated with vulnerability to BD. Additionally, our findings suggest that the polygenic architecture of BD is not regionally confined but impacts on the task-dependent recruitment of multiple brain regions.

Surgery Should Complement Endocrine Therapy for Elderly Postmenopausal Women with Hormone Receptor-Positive Early-Stage Breast Cancer

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Olivier Nguyen

2012-01-01

Full Text Available Introduction. Endocrine therapy (ET is an integral part of breast cancer (BC treatment with surgical resection remaining the cornerstone of curative treatment. The objective of this study is to compare the survival of elderly postmenopausal women with hormone receptor-positive early-stage BC treated with ET alone, without radiation or chemotherapy, versus ET plus surgery. Materials and Methods. This is a retrospective study based on a prospective database. The medical records of postmenopausal BC patients referred to the surgical oncology service of two hospitals during an 8-year period were reviewed. All patients were to receive ET for a minimum of four months before undergoing any surgery. Results. Fifty-one patients were included and divided in two groups, ET alone and ET plus surgery. At last follow-up in exclusive ET patients (n=28, 39% had stable disease or complete response, 22% had progressive disease, of which 18% died of breast cancer, and 39% died of other causes. In surgical patients (n=23, 78% were disease-free, 9% died of recurrent breast cancer, and 13% died of other causes. Conclusions. These results suggest that surgical resection is beneficial in this group and should be considered, even for patients previously deemed ineligible for surgery.

Somatostatin receptors

DEFF Research Database (Denmark)

Møller, Lars Neisig; Stidsen, Carsten Enggaard; Hartmann, Bolette

2003-01-01

functional units, receptors co-operate. The total receptor apparatus of individual cell types is composed of different-ligand receptors (e.g. SRIF and non-SRIF receptors) and co-expressed receptor subtypes (e.g. sst(2) and sst(5) receptors) in characteristic proportions. In other words, levels of individual......-peptides, receptor agonists and antagonists. Relatively long half lives, as compared to those of the endogenous ligands, have been paramount from the outset. Motivated by theoretical puzzles or the shortcomings of present-day diagnostics and therapy, investigators have also aimed to produce subtype...

Limitations in predicting PAM50 intrinsic subtype and risk of relapse score with Ki67 in estrogen receptor-positive HER2-negative breast cancer

Science.gov (United States)

Fernand ez-Martinez, Aranzazu; Pascual, Tomás; Perrone, Giuseppe; Morales, Serafin; de la Haba, Juan; González-Rivera, Milagros; Galván, Patricia; Zalfa, Francesca; Amato, Michela; Gonzalez, Lucia; Prats, Miquel; Rojo, Federico; Manso, Luis; Paré, Laia; Alonso, Immaculada; Albanell, Joan; Vivancos, Ana; González, Antonio; Matito, Judit; González, Sonia; Fernandez, Pedro; Adamo, Barbara; Muñoz, Montserrat; Viladot, Margarita; Font, Carme; Aya, Francisco; Vidal, Maria; Caballero, Rosalía; Carrasco, Eva; Altomare, Vittorio; Tonini, Giuseppe; Prat, Aleix; Martin, Miguel

2017-01-01

PAM50/Prosigna gene expression-based assay identifies three categorical risk of relapse groups (ROR-low, ROR-intermediate and ROR-high) in post-menopausal patients with estrogen receptor estrogen receptor-positive (ER+)/ HER2-negative (HER2-) early breast cancer. Low risk patients might not need adjuvant chemotherapy since their risk of distant relapse at 10-years is below 10% with endocrine therapy only. In this study, 517 consecutive patients with ER+/HER2- and node-negative disease were evaluated for Ki67 and Prosigna. Most of Luminal A tumors (65.6%) and ROR-low tumors (70.9%) had low Ki67 values (0-10%); however, the percentage of patients with ROR-medium or ROR-high disease within the Ki67 0-10% group was 42.7% (with tumor sizes ≤2 cm) and 33.9% (with tumor sizes > 2 cm). Finally, we found that the optimal Ki67 cutoff for identifying Luminal A or ROR-low tumors was 14%. Ki67 as a surrogate biomarker in identifying Prosigna low-risk outcome patients or Luminal A disease in the clinical setting is unreliable. In the absence of a well-validated prognostic gene expression-based assay, the optimal Ki67 cutoff for identifying low-risk outcome patients or Luminal A disease remains at 14%. PMID:28423537

DOTA-PESIN, a DOTA-conjugated bombesin derivative designed for the imaging and targeted radionuclide treatment of bombesin receptor-positive tumours

Energy Technology Data Exchange (ETDEWEB)

Zhang, Hanwen; Maecke, Helmut R. [University Hospital Basel, Division of Radiological Chemistry, Department of Radiology, Basel (Switzerland); Schuhmacher, Jochen; Eisenhut, Michael [German Cancer Research Centre, Department of Radiopharmaceutical Chemistry, Heidelberg (Germany); Waser, Beatrice; Reubi, Jean Claude [University of Berne, Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, P.O. Box 62, Berne (Switzerland); Wild, Damian [University Hospital, Clinic and Institute of Nuclear Medicine, Department of Radiology, Basel (Switzerland)

2007-08-15

We aimed at designing and developing a novel bombesin analogue, DOTA-PEG{sub 4}-BN(7-14) (DOTA-PESIN), with the goal of labelling it with {sup 67/68}Ga and {sup 177}Lu for diagnosis and radionuclide therapy of prostate and other human cancers overexpressing bombesin receptors. The 8-amino acid peptide bombesin (7-14) was coupled to the macrocyclic chelator DOTA via the spacer 15-amino-4,7,10,13-tetraoxapentadecanoic acid (PEG{sub 4}). The conjugate was complexed with Ga(III) and Lu(III) salts. The GRP receptor affinity and the bombesin receptor subtype profile were determined in human tumour specimens expressing the three bombesin receptor subtypes. Internalisation and efflux studies were performed with the human GRP receptor cell line PC-3. Xenografted nude mice were used for biodistribution. [Ga{sup III}/Lu{sup III}]-DOTA-PESIN showed good affinity to GRP and neuromedin B receptors but no affinity to BB3. [{sup 67}Ga/{sup 177}Lu]-DOTA-PESIN internalised rapidly into PC-3 cells whereas the efflux from PC-3 cells was relatively slow. In vivo experiments showed a high and specific tumour uptake and good retention of [{sup 67}Ga/{sup 177}Lu]-DOTA-PESIN. [{sup 67}Ga/{sup 177}Lu]-DOTA-PESIN highly accumulated in GRP receptor-expressing mouse pancreas. The uptake specificity was demonstrated by blocking tumour uptake and pancreas uptake. Fast clearance was found from blood and all non-target organs except the kidneys. High tumour-to-normal tissue ratios were achieved, which increased with time. PET imaging with [{sup 68}Ga]-DOTA-PESIN was successful in visualising the tumour at 1 h post injection. Planar scintigraphic imaging showed that the {sup 177}Lu-labelled peptide remained in the tumour even 3 days post injection. The newly designed ligands have high potential with regard to PET and SPECT imaging with {sup 68/67}Ga and targeted radionuclide therapy with {sup 177}Lu. (orig.)

Characterization of serotonergic receptors in rabbit, porcine and human conjunctivae.

Science.gov (United States)

Turner, Helen C; Alvarez, Lawrence J; Candia, Oscar A; Bernstein, Audrey M

2003-10-01

To characterize the serotonin (5-HT) receptors linked to the modulation of adenylyl cyclase activity in rabbit, porcine and human conjunctivae. Serotonin receptor-subtype expression was examined using reverse transcription-polymerase chain reaction (RT-PCR) and receptor subtype-specific polyclonal antibodies for the immunofluorescent labeling of conjunctival cryosections. In addition, measurements of the effects of serotonergics on the short-circuit current (I(sc)) across rabbit and porcine conjunctivae were contrasted. RT-PCR assays indicated the expression of 5-HT(1B ) and 5-HT(1D) receptors, subtypes negatively coupled to adenylyl cyclase, in the rabbit conjunctiva. This approach also suggested the co-expression of 5-HT(1B), 5-HT(1D), 5-HT(1F), 5-HT(4) and 5-HT(7) mRNA's in the porcine conjunctiva, and 5-HT( 1D), 5-HT(1F) and 5-HT(7) in the human conjunctiva. Since the 5-HT(4) and 5-HT(7) receptors are positively linked to adenylyl cyclase, these results implied that the porcine and human tissues exhibited subtypes both positively and negatively linked to the enzyme. However, immunohistochemical observations, using currently available antibodies solely localized the 5-HT(7) moiety in the porcine and human epithelia, suggested that the 1B/1D forms may be minor elements. Consistent with this prospect, 5-HT was a stimulant of the transepithelial I(sc) across the porcine conjunctiva, an opposite response from earlier findings that demonstrated inhibitory effects by 5-HT on the rabbit I(sc), which are now explained by the localization of the 1B/1D receptors in the rabbit stratified epithelium. The 5-HT receptors expressed by mammalian conjunctivae are not identical. In terms of 5-HT receptor expression, the porcine tissue may be a more appropriate model for human, than is the rabbit, in that 5-HT may serve as a secretagogue in the human epithelium.

Cytologic assessment of estrogen receptor, progesterone receptor, and HER2 status in metastatic breast carcinoma.

Science.gov (United States)

Pareja, Fresia; Murray, Melissa P; Jean, Ryan Des; Konno, Fumiko; Friedlander, Maria; Lin, Oscar; Edelweiss, Marcia

2017-01-01

Discordance in the receptor status between primary breast carcinomas (PBC) and corresponding metastasis is well documented. Interrogation of the receptor status of metastatic breast carcinoma (MBC) in cytology material is common practice; however, its utility has not been thoroughly validated. We studied patients with MBC, and evaluated the concordance rates of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) between PBC surgical specimens and corresponding MBC cell blocks (CBs). We correlated the findings with clinicopathologic variables and with the fixation methods used. We searched for patients with MBC diagnosed on cytology from 2007 to 2009 and selected those with ER, PR and HER2 tested in both the PBC surgical specimens and the MBC CBs. We included CBs fixed in formalin and methanol based solution (CytoLyt®). All slides were reevaluated by cytopathologists. Clinical information was retrieved from the medical records. We studied 65 patients with PBC and MBC paired specimens. The concordance rates between PBC and MBC were 78.5%, 58.5% and 96.9%, for ER, PR and HER2, respectively. When discordant, PR status switched from positive (PBC) to negative (MBC) in most cases (23/27). The PR concordance rate was 45.2% for CBs fixed in formalin and 70.6% for those fixed with CytoLyt® (p=0.047). The ER, PR and HER2 concordance rates between the PBC and MBC CBs are similar to those reported in paired surgical specimens. PR status was the most prevalent discordance and was not accompanied by a switch in ER.

Estrogen receptor determination in endometrial carcinoma: ligand binding assay versus enzyme immunoassay

DEFF Research Database (Denmark)

Nyholm, H C; Nielsen, Anette Lynge; Lyndrup, J

1995-01-01

We compared concentrations of cytosolic estrogen receptors (ERc) measured in 35 postmenopausal endometrial carcinomas by ligand binding method (LBA) (dextran-coated charcoal assay) and enzyme immunoassay (EIA). Correlations between ERc, nuclear estrogen receptors (ERn) determined by EIA......, and cytosolic progesterone receptors (PR) measured by LBA were also studied. While ERc concentrations determined by LBA and EIA were highly correlated (r: 0.94), ERc values detected by LBA were approximately twice those found by EIA (median values of ERc: 155 vs. 64 fmol/mg cytosol protein, DCC vs. EIA......). The percentages of ERc positive tumors were 89% by LBA and 77% by EIA. The median fraction of total ER present as ERn was 63%. PR levels correlated positively with ERn concentrations (r: 0.73). We explore possible reasons why greater concentrations of ERc are determined by estradiol binding than by the ER-EIA kit...

Erythropoietin Receptor Positive Circulating Progenitor Cells and Endothelial Progenitor Cells in Patients with Different Stages of Diabetic Retinopathy

Institute of Scientific and Technical Information of China (English)

Liu-mei Hu; Guo-xu Xu; Guo-tong XU; Wei-ye Li; Xia Lei; Bo Ma; Yu Zhang; Yan Yan; Ya-lan Wu; Ge-zhi Xu; Wen Ye; Ling Wang

2011-01-01

Objective To investigate the possible involvement of erythropoietin (EPO)/erythropoietin receptor(EPOR) system in neovascularization and vascular regeneration in diabetic retinopathy (DR).Methods EPOR positive circulating progenitor cells (CPCs: CD34+) and endothelial progenitor cells (EPCs: CD34+KDR+) were assessed by flow cytometry in type 2 diabetic patients with different stages of DR. The cohort consisted of age- and sex-matched control patients without diabetes (n=7), non-prolif-erative DR (NPDR, n=7), proliferative DR (PDR, n=8), and PDR complicated with diabetic nephropathy (PDR-DN, n=7). Results The numbers of EPOR+ CPCs and EPOR+ EPCs were reduced remarkably in NPDR compared with the control group (both P<0.01), whereas rebounded in PDR and PDR-DN groups in varying degrees. Similar changes were observed in respect of the proportion of EPOR+ CPCs in CPCs (NPDR vs.control, P< 0.01) and that of EPOR+ EPCs in EPCs (NPDR vs. control, P< 0.05). Conclusion Exogenous EPO, mediated via the EPO/EPOR system of EPCs, may alleviate the im-paired vascular regeneration in NPDR, whereas it might aggravate retinal neovascularization in PDR due to a rebound of EPOR+ EPCs associated with ischemia.