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Carlo Palmieri - One of the best experts on this subject based on the ideXlab platform.
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iris study a phase ii study of the steroid sulfatase Inhibitor irosustat when added to an Aromatase Inhibitor in er positive breast cancer patients
Breast Cancer Research and Treatment, 2017Co-Authors: Hironobu Sasano, Carlo Palmieri, Robert Stein, Xinxue Liu, Emma Hudson, Hanna Nicholas, Fouzia Guestini, Chris HolcombeAbstract:Irosustat is a first-generation, orally active, irreversible steroid sulfatase Inhibitor. We performed a multicentre, open label phase II trial of the addition of Irosustat to a first-line Aromatase Inhibitor (AI) in patients with advanced BC to evaluate the safety of the combination and to test the hypothesis that the addition of Irosustat to AI may further suppress estradiol levels and result in clinical benefit. Postmenopausal women with ER-positive locally advanced or metastatic breast cancer who had derived clinical benefit from a first-line AI and who subsequently progressed were enrolled. The first-line AI was continued and Irosustat (40 mg orally daily) added. The primary endpoint was clinical benefit rate (CBR). Secondary endpoints included safety, tolerability, and pharmacodynamic end points. Twenty-seven women were recruited, four discontinued treatment without response assessment. Based on local reporting, the CBR was 18.5% (95% CI 6.3–38.1%) on an intent to treat basis, increasing to 21.7% (95% CI 7.4–43.7%) by per-protocol analysis. In those patients that achieved clinical benefit (n = 5), the median (interquartile range) duration was 9.4 months (8.1–11.3) months. The median progression-free survival time was 2.7 months (95% CI 2.5–4.6) in both the ITT and per-protocol analyses. The most frequently reported grade 3/4 toxicities were dry skin (28%), nausea (13%), fatigue (13%), diarrhoea (8%), headache (7%), anorexia (7%) and lethargy (7%). The addition of Irosustat to Aromatase Inhibitor therapy resulted in clinical benefit with an acceptable safety profile. The study met its pre-defined success criterion by both local and central radiological assessments.
Haryanti Haryanti - One of the best experts on this subject based on the ideXlab platform.
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pengaruh rangsangan hormon Aromatase Inhibitor dan oodev terhadap perubahan kelamin dan perkembangan gonad ikan kerapu sunu plectropomus leopardus
Jurnal Riset Akuakultur, 2018Co-Authors: Hirmawan Tirta Yudha, Agus Oman Sudrajat, Haryanti HaryantiAbstract:Permasalahan utama yang dihadapi dalam penyediaan calon induk ikan kerapu sunu Plectropomus leopardus hasil budidaya yang bersifat hermaprodit sekuensial adalah keterlambatan dalam perkembangan gonad dan perubahan gonad dari betina menjadi jantan. Manipulasi hormonal merupakan cara yang paling efektif dan efisien dalam memacu perkembangan reproduksi dan pematangan gonad. Tujuan dari penelitian ini adalah untuk mendapatkan dosis hormon Aromatase Inhibitor dan oodev yang tepat untuk memacu perubahan kelamin dan perkembangan gonad ikan kerapu sunu. Ikan uji yang digunakan sebanyak 35 ekor F-1 dengan bobot rerata 2,3 ± 0,28 kg. Penelitian dilakukan selama dua bulan. Induksi hormon dilakukan melalui penyuntikan setiap dua minggu sekali dengan empat dosis Aromatase Inhibitor dan oodev yang berbeda; A (Aromatase Inhibitor 1 mg kg-1 ikan), O (oodev 1 mL kg-1 ikan), AO1 (Aromatase Inhibitor 0,1 mg kg-1 ikan + oodev 1 mL kg-1 ikan), AO2 (Aromatase Inhibitor 1 mg kg-1 ikan + oodev 1 mL kg-1 ikan), dan K (plasebo). Hasil penelitian menunjukkan bahwa kombinasi Aromatase Inhibitor 1 mg kg-1 ikan dan oodev 1 mL kg-1 ikan efektif untuk merangsang perubahan kelamin. Perlakuan tersebut dapat meningkatkan konsentrasi testosteron dalam darah (2,819 ng/mL) setelah delapan minggu pemeliharaan. Berdasarkan hasil histologi gonad dan observasi terhadap ekspresi gen terkait reproduksi menggunakan gen target DMRT1 dan SOX3 menunjukkan bahwa perlakuan hormon AO2 (Aromatase Inhibitor 1 mg kg-1 ikan + oodev 1 mL kg-1 ikan) terbukti dapat memacu perubahan kelamin dari betina menjadi jantan dan kematangan gonad pada ikan kerapu sunu Plectropomus leopardus. The main problems faced in providing prospective broodstock of protogynous hermaphrodite coral trout grouper Plectropomus leopardus are lateness of gonadal development and gonadal sex reversal from female to male. Hormonal manipulation is the most effective way to induce reproductive development and gonadal maturation. The present study aimed to determine an effective dose of Aromatase Inhibitor and oodev on sex reversal and gonadal development of coral trout grouper. There were 35 F-1 fish with an average weight of 2.3 ± 0.28 kg. This research was conducted for two months. The fish were injected with four different dosages of Aromatase Inhibitor and oodev every two weeks: A (Aromatase Inhibitor 1 mg kg-1 fish), O (1 mL oodev), AO1 (Aromatase Inhibitor 0.1 mg kg-1 fish + oodev 1 mL kg-1 fish), AO2 (Aromatase Inhibitor 1 mg kg-1 fish + oodev 1 mL kg-1 fish), and K (placebo). The results showed that the combination of Aromatase Inhibitor 1 mg kg-1 fish and oodev 1 mL kg-1 fish was effective to induce the sex change. It could increase the concentration of testosterone in the blood (2.819 ng/mL) after eight weeks of culture. Based on the results of gonadal histology and reproductive-related genes expression observations using DMRT1 and SOX3 target genes, the hormonal treatment of AO2 (Aromatase Inhibitor 1 mg kg-1 fish + oodev 1 mL kg-1 fish) was able to accelerate sex reversal from female to male and gonadal maturation in coral trout grouper Plectropomus leopardus.
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PENGARUH RANGSANGAN HORMON Aromatase Inhibitor DAN OODEV TERHADAP PERUBAHAN KELAMIN DAN PERKEMBANGAN GONAD IKAN KERAPU SUNU, Plectropomus leopardus
'Agency for Marine and Fisheries Research and Development', 2018Co-Authors: Yudha, Hirmawan Tirta, Sudrajat, Agus Oman, Haryanti HaryantiAbstract:Permasalahan utama yang dihadapi dalam penyediaan calon induk ikan kerapu sunu Plectropomus leopardus hasil budidaya yang bersifat hermaprodit sekuensial adalah keterlambatan dalam perkembangan gonad dan perubahan gonad dari betina menjadi jantan. Manipulasi hormonal merupakan cara yang paling efektif dan efisien dalam memacu perkembangan reproduksi dan pematangan gonad. Tujuan dari penelitian ini adalah untuk mendapatkan dosis hormon Aromatase Inhibitor dan oodev yang tepat untuk memacu perubahan kelamin dan perkembangan gonad ikan kerapu sunu. Ikan uji yang digunakan sebanyak 35 ekor F-1 dengan bobot rerata 2,3 ± 0,28 kg. Penelitian dilakukan selama dua bulan. Induksi hormon dilakukan melalui penyuntikan setiap dua minggu sekali dengan empat dosis Aromatase Inhibitor dan oodev yang berbeda; A (Aromatase Inhibitor 1 mg kg-1 ikan), O (oodev 1 mL kg-1 ikan), AO1 (Aromatase Inhibitor 0,1 mg kg-1 ikan + oodev 1 mL kg-1 ikan), AO2 (Aromatase Inhibitor 1 mg kg-1 ikan + oodev 1 mL kg-1 ikan), dan K (plasebo). Hasil penelitian menunjukkan bahwa kombinasi Aromatase Inhibitor 1 mg kg-1 ikan dan oodev 1 mL kg-1 ikan efektif untuk merangsang perubahan kelamin. Perlakuan tersebut dapat meningkatkan konsentrasi testosteron dalam darah (2,819 ng/mL) setelah delapan minggu pemeliharaan. Berdasarkan hasil histologi gonad dan observasi terhadap ekspresi gen terkait reproduksi menggunakan gen target DMRT1 dan SOX3 menunjukkan bahwa perlakuan hormon AO2 (Aromatase Inhibitor 1 mg kg-1 ikan + oodev 1 mL kg-1 ikan) terbukti dapat memacu perubahan kelamin dari betina menjadi jantan dan kematangan gonad pada ikan kerapu sunu Plectropomus leopardus.The main problems faced in providing prospective broodstock of protogynous hermaphrodite coral trout grouper Plectropomus leopardus are lateness of gonadal development and gonadal sex reversal from female to male. Hormonal manipulation is the most effective way to induce reproductive development and gonadal maturation. The present study aimed to determine an effective dose of Aromatase Inhibitor and oodev on sex reversal and gonadal development of coral trout grouper. There were 35 F-1 fish with an average weight of 2.3 ± 0.28 kg. This research was conducted for two months. The fish were injected with four different dosages of Aromatase Inhibitor and oodev every two weeks: A (Aromatase Inhibitor 1 mg kg-1 fish), O (1 mL oodev), AO1 (Aromatase Inhibitor 0.1 mg kg-1 fish + oodev 1 mL kg-1 fish), AO2 (Aromatase Inhibitor 1 mg kg-1 fish + oodev 1 mL kg-1 fish), and K (placebo). The results showed that the combination of Aromatase Inhibitor 1 mg kg-1 fish and oodev 1 mL kg-1 fish was effective to induce the sex change. It could increase the concentration of testosterone in the blood (2.819 ng/mL) after eight weeks of culture. Based on the results of gonadal histology and reproductive-related genes expression observations using DMRT1 and SOX3 target genes, the hormonal treatment of AO2 (Aromatase Inhibitor 1 mg kg-1 fish + oodev 1 mL kg-1 fish) was able to accelerate sex reversal from female to male and gonadal maturation in coral trout grouper Plectropomus leopardus
M Dowsett - One of the best experts on this subject based on the ideXlab platform.
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molecular profiling of Aromatase Inhibitor treated postmenopausal breast tumors identifies immune related correlates of resistance
Clinical Cancer Research, 2013Co-Authors: Anita K Dunbier, Zara Ghazoui, Helen Anderson, Janine Salter, Ashutosh Nerurkar, Peter Osin, R Ahern, W R Miller, Ian E Smith, M DowsettAbstract:Purpose: Estrogen withdrawal by treatment with Aromatase Inhibitors is the most effective form of endocrine therapy for postmenopausal estrogen receptor–positive (ER+) breast cancer. However, response to therapy varies markedly and understanding of the precise molecular effects of Aromatase Inhibitors and causes of resistance is limited. We aimed to identify in clinical breast cancer those genes and pathways most associated with resistance to Aromatase Inhibitors by examining the global transcriptional effects of AI treatment. Experimental Design: Baseline and 2-week posttreatment biopsies were obtained from 112 postmenopausal women with ER+ breast cancer receiving neoadjuvant anastrozole. Gene expression data were obtained from 81 baseline and 2-week paired samples. Pathway analysis identified (i) the most prevalent changes in expression and (ii) the pretreatment genes/pathways most related to poor antiproliferative response. Results: A total of 1,327 genes were differentially expressed after 2-week treatment (false discovery rate SLAMF8 and TNF as well as lymphocytic infiltration were associated with poorer response ( P Conclusions: The molecular response to Aromatase Inhibitor treatment varies greatly between patients consistent with the variable clinical benefit from Aromatase Inhibitor treatment. Higher baseline expression of an inflammatory signature is associated with poor antiproliferative response and should be assessed further as a novel biomarker and potential target for Aromatase Inhibitor-treated patients. Clin Cancer Res; 19(10); 2775–86. ©2013 AACR .
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in vivo inhibition of aromatization by exemestane a novel irreversible Aromatase Inhibitor in postmenopausal breast cancer patients
Clinical Cancer Research, 1998Co-Authors: Jürgen Geisler, Per Eystein Lonning, E Di Salle, G Ornati, N King, Gun Anker, M DowsettAbstract:The effect of exemestane (6-methylenandrosta-1,4-diene-3,17-dione) 25 mg p.o. once daily on in vivo aromatization was studied in 10 postmenopausal women with advanced breast cancer. Aromatization was determined before treatment and after 6-8 weeks on therapy by administering a bolus injection of [3H]androstenedione (500 microCi) and [14C]estrone (5 microCi) followed by measurement of the isotope ratio of urinary estrogens after high-performance liquid chromatography purification. In addition, plasma endogenous estrogens were measured with highly sensitive radioimmunoassays after separation with high-performance liquid chromatography. Treatment with exemestane suppressed whole body aromatization from a mean pretreatment value of 2.059% to 0.042% (mean suppression of 97.9%). Plasma levels of estrone, estradiol, and estrone sulfate were found to be suppressed by 94.5%, 92.2%, and 93.2%, respectively. This is the first study revealing near total Aromatase inhibition in vivo with the use of a steroidal Aromatase Inhibitor. The observation that exemestane is a highly potent Aromatase Inhibitor, together with the fact that the drug is administered p.o. and causes limited side effects, suggests that exemestane is a promising new drug for the treatment of hormone sensitive breast cancer.
Chris Holcombe - One of the best experts on this subject based on the ideXlab platform.
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iris study a phase ii study of the steroid sulfatase Inhibitor irosustat when added to an Aromatase Inhibitor in er positive breast cancer patients
Breast Cancer Research and Treatment, 2017Co-Authors: Hironobu Sasano, Carlo Palmieri, Robert Stein, Xinxue Liu, Emma Hudson, Hanna Nicholas, Fouzia Guestini, Chris HolcombeAbstract:Irosustat is a first-generation, orally active, irreversible steroid sulfatase Inhibitor. We performed a multicentre, open label phase II trial of the addition of Irosustat to a first-line Aromatase Inhibitor (AI) in patients with advanced BC to evaluate the safety of the combination and to test the hypothesis that the addition of Irosustat to AI may further suppress estradiol levels and result in clinical benefit. Postmenopausal women with ER-positive locally advanced or metastatic breast cancer who had derived clinical benefit from a first-line AI and who subsequently progressed were enrolled. The first-line AI was continued and Irosustat (40 mg orally daily) added. The primary endpoint was clinical benefit rate (CBR). Secondary endpoints included safety, tolerability, and pharmacodynamic end points. Twenty-seven women were recruited, four discontinued treatment without response assessment. Based on local reporting, the CBR was 18.5% (95% CI 6.3–38.1%) on an intent to treat basis, increasing to 21.7% (95% CI 7.4–43.7%) by per-protocol analysis. In those patients that achieved clinical benefit (n = 5), the median (interquartile range) duration was 9.4 months (8.1–11.3) months. The median progression-free survival time was 2.7 months (95% CI 2.5–4.6) in both the ITT and per-protocol analyses. The most frequently reported grade 3/4 toxicities were dry skin (28%), nausea (13%), fatigue (13%), diarrhoea (8%), headache (7%), anorexia (7%) and lethargy (7%). The addition of Irosustat to Aromatase Inhibitor therapy resulted in clinical benefit with an acceptable safety profile. The study met its pre-defined success criterion by both local and central radiological assessments.
Kenny A Rodriguezwallberg - One of the best experts on this subject based on the ideXlab platform.
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gnrh agonist trigger for women with breast cancer undergoing fertility preservation by Aromatase Inhibitor fsh stimulation
Reproductive Biomedicine Online, 2010Co-Authors: Kutluk Oktay, Ilgin Turkcuoglu, Kenny A RodriguezwallbergAbstract:Abstract Aromatase Inhibitors can be utilized to minimize oestrogen exposure in breast cancer patients undergoing gonadotrophin stimulation. This retrospective-prospective study determined whether using a gonadotrophin-releasing hormone agonist (GnRHa) trigger instead of human chorionic gonadotrophin (HCG) would reduce oestrogen exposure and improve cycle outcomes in Aromatase Inhibitor cycles. Seventy-four breast cancer patients who desired fertility preservation, with normal ovarian reserve and n =47) or leuprolide acetate 1mg (GnRHa, n =27) as trigger. Oestradiol measurements were repeated 4days after the trigger and subjects were evaluated for ovarian hyperstimulation syndrome (OHSS). In the GnRHa group, oestradiol concentrations dropped significantly after the trigger than the HCG group ( P =0.013) and there was a lower incidence of OHSS. GnRHa trigger resulted in a higher number and percentage of mature oocytes and a higher number of cryopreserved embryos or oocytes compared with HCG. GnRHa trigger improves outcomes by increasing the yield of mature oocytes and embryos in Aromatase Inhibitor cycles and also decreases the post-trigger oestradiol exposure as well as OHSS risks in women with breast cancer.
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gnrh agonist trigger for women with breast cancer undergoing fertility preservation by Aromatase Inhibitor fsh stimulation
Reproductive Biomedicine Online, 2010Co-Authors: Kutluk Oktay, Ilgin Turkcuoglu, Kenny A RodriguezwallbergAbstract:Aromatase Inhibitors can be utilized to minimize oestrogen exposure in breast cancer patients undergoing gonadotrophin stimulation. This retrospective-prospective study determined whether using a gonadotrophin-releasing hormone agonist (GnRHa) trigger instead of human chorionic gonadotrophin (HCG) would reduce oestrogen exposure and improve cycle outcomes in Aromatase Inhibitor cycles. Seventy-four breast cancer patients who desired fertility preservation, with normal ovarian reserve and < 45 years of age received letrozole 5mg/day plus recombinant FSH 150-300 IU/day for ovarian stimulation. Subjects either received HCG 5000-10,000 IU (n=47) or leuprolide acetate 1mg (GnRHa, n=27) as trigger. Oestradiol measurements were repeated 4 days after the trigger and subjects were evaluated for ovarian hyperstimulation syndrome (OHSS). In the GnRHa group, oestradiol concentrations dropped significantly after the trigger than the HCG group (P=0.013) and there was a lower incidence of OHSS. GnRHa trigger resulted in a higher number and percentage of mature oocytes and a higher number of cryopreserved embryos or oocytes compared with HCG. GnRHa trigger improves outcomes by increasing the yield of mature oocytes and embryos in Aromatase Inhibitor cycles and also decreases the post-trigger oestradiol exposure as well as OHSS risks in women with breast cancer.