Day 2 :
Keynote Forum
Paul J Davis
Albany Medical College, USA
Keynote: Anti-apoptotic and pro-angiogenic properties of thyroid hormone may oppose cancer chemotherapy
Time : 9:30-10:10
Biography:
Davis is a graduate of Harvard Medical School and had his postgraduate medical training at Albert Einstein College of Medicine and the NIH. His academic positions have included Chair, Department of Medicine, Albany Medical College. He has served as President, American Thyroid Association, as a member of the Board of Directors of thern American Board of Internal Medicine and he is Co-Head, Faculty of 1000 – Endocrinology. He serves on multiple Editorial Boards of His scientific interests include molecularrnmechanisms of actions of nonpeptide hormones, particularly, thyroid hormone. He and his colleagues described the cell surface receptor for thyroid hormone on integrinrnavb3 that underlies the pro-angiogenic activity of the hormone and the proliferative action of the hormone on cancer cells. He has co-authored more than 200 original research articles and 30 textbook chapters and he has edited three medical textbooks.
Abstract:
The principal secretory product of the thyroid gland, L-thyroxine (T4), is anti-apoptotic at physiological concentrations in a number of cancer cell lines. Among the mechanisms of anti-apoptosis activated by the hormone is interference with the Ser-15 phosphorylation (activation) of p53 and with TNFα/Fas-induced apoptosis. The hormone also decreases cellular abundance and activation of proteolytic caspases and of BAX and causes increased expression of X-linked inhibitor of apoptosis (XIAP). The antiapoptoticrn effects of thyroid hormone largely are initiated at a cell surface thyroid hormone receptor on the extracellular domain of integrin αvβ3 that is amply expressed and activated in cancer cells. Tetraiodothyroacetic acid (tetrac) is a T4 derivative that, in a modelrnof resveratrol-induced p53-dependent apoptosis in glioma cells, blocks the anti-apoptotic action of thyroid hormone, permitting specific serine phosphorylation of p53 and apoptosis to proceed. In a nanoparticulate formulation limiting its action to αvβ3, tetrac modulates integrin-dependent effects on gene expression in human cancer cell lines that include stimulation of expression of apanel of pro-apoptotic genes and downregulated transcription of defensive anti-apoptotic XIAP and MCL1 genes. By a variety ofrnmechanisms, thyroid hormone (T4) acts as an endogenous anti-apoptotic factor that may oppose chemotherapy-induced apoptosis in αvβ3-expressing cancer cells. It is possible to oppose this anti-apoptotic activity pharmacologically by reducing circulating levels of T4 or by blocking effects of T4 that are initiated at αvβ3.
- fs
Biography:
s
Abstract:
s
- Hormones & Steroids
Session Introduction
Katherine Sherif
Professor of Medicine Vice Chair, Department of Medicine Thomas Jefferson University, USA
Title: Hormone Therapy: Two Decades of Treating Menopausal Symptoms & Improving Metabolic Parameters
Biography:
She is currently the professor of Medicine, Vice Chair at Department of Medicine Thomas Jefferson University, USA
Abstract:
Despite a large body of data describing the health benefits of hormone therapy, hormone prescribing rates remain low. Clinicians continue to cling to the belief that hormones are dangerous. The metabolic benefits of hormones are unequivocal but the issue is clouded by conflicting messages from the medical community, conservative recommendations from international associations and the tendency to repeat what you’ve heard instead of reading for yourself. My clinical lecture will: 1. broadly review the effects of estradiol and progesterone on female physiology 2. describe the risks and benefits of hormone replacement 3. make recommendations to use hormone therapy for primary care physicians
Mache Seibel
University of Massachusetts Medical School
USA
Title: The Estrogen Window: The Key Understanding Hormone Therapy
Biography:
Mache Seibel, MD is a distinguished alumnus of the University of Texas Medical Branch. He was a member of the Harvard Faculty of Medicine for 20 years and is currently a professor at the University of Massachusetts Medical School. Dr. Seibel is past Editor in Chief of Sexuality, Reproduction and Menopause and currently Editor of My Menopause Magazine and Founder of MenopauseBreakthrough.com online course for women in menopause. He has published over 200 scientific articles and chapters and written 15 books. His latest book is The Estrogen Window.
Abstract:
For nearly two decades, estrogen has been perceived as a source of symptom relief for menopause and causing an increased risk of breast cancer, dementia and heart disease. As a result, use of estrogen has declined to low levels and many doctors choose not to prescribe it. That left nearly a generation of menopausal women without treatment and as a result, created a negative effect on their health, their relationships and their work. However, new analysis of the existing information and a body of new work have shown that estrogen not only improves the symptoms of menopause but has the potential to reduce the risk of heart disease, dementia and breast cancer – if it is taken in the estrogen window. It can also improve women's quality of life and performance in the workplace. Once the estrogen window has closed, symptom relief is diminished and hormone therapy may increase the risk of breast cancer, dementia and heart disease. This presentation will define the estrogen window. It will reveal the background for how we got into this confused state, the impact not taking estrogen has had on women's lives, when estrogen should be taken to optimize benefits and lower risks, the differences in risk and benefit between estrogen alone and estrogen plus progestogen and how to minimize those risks, and when to stop estrogen. At the end of the presentation, the audience will have a clear, current and evidence based understanding of hormone therapy for the care of menopausal women.
Marialuigia Spinelli
University of Naples Federico II,
Italy
Title: Combining hysteroscopy and intrauterine levonorgestrel-releasing system for treatment of atypical hyperplasia and endometrial cancer
Biography:
Post-specialization fellowship in Neurosciences and Reproductive Sciences University Hospital of Bern (Switzerland)
Abstract:
Endometrial cancer is one of the most common gynecologic malignancy, with an increasing number of cases diagnosed in pre-menopausal women, including 4% diagnosed in women less than 40 years of age. While hysterectomy with bilateral salpingo-oophorectomy with assessment of the retroperitoneal lymph nodes is standard initial treatment, younger women with early stage-disease may desire fertility sparing options.
We report our experience with organ-preserving treatment applied in 48 patients of reproductive age with atypical hyperplasia or early-stage (1A) endometrial cancer. All of them would like to preserve their reproductive potential. All cases were treated with the combination of resectoscopic endometrial ablation, followed by the intrauterine-insertion of levonorgestrel intrauterine hormonal system containing 52 mg levonorgestrel (Mirena®, Bayer, Germany) for at least 12 months. Hysteroscopic three-monthly follow-up with endometrial biopsy was accomplished in 44 out of 48 patients. At 24 month-follow-up 41 patients obtained a complete remission. Furthermore, 15 of them became pregnant, 10 of them delivered at term and 1 has an ongoing pregnancy.
This type of therapy was effective for almost all cases and may be offered to be used as an alternative to radical surgery in women with atypical endometrial hyperplasia or early stage 1A well-differentiated endometrial cancer in women of reproductive age.
Mark Feitelson
Department of Biology
Temple University
USA
Title: Potential Utility of Natural Compounds in the Prevention and Treatment of Hormone Sensitive Cancers
Biography:
Mark Feitelson is currently working in Department of Biology at Temple University, USA
Abstract:
Natural compounds have been shown to be of useful for the treatment of cancers in preclinical models, but given that cancers are multi-step, efforts have focused upon formulating combination therapies that target early stage tumors in a hypoxic environment, block epithelial-mesenchymal transition (EMT) during tumor metastasis, inhibit uncontrolled cell cycle progression, and target cancer stem cells to help prevent tumor relapse. Combinations of natural compounds will also be presented that are likely to be useful against estrogen dependent breast cancer as well as androgen dependent and independent stages of prostate cancer. Results will summarize what is likely to be the most important natural compounds and molecular targets that will results in arrested proliferation during tumor pathogenesis as well as recommendations for the application of natural compound combinations in preclinical models and in human clinical trials.
Biography:
Melody L. Fortune completed her Ph.D. from Mississippi State University while working full time at the Mississippi State Department of Health as the Director for the Breast and Cervical Cancer Program. She is currently the Assistant Professor in Healthcare Administration at Delta State University (DSU). She was awarded the Connected Educator Award during her first year at DSU. Prior to coming to DSU she founded the MS Witness Project; a 501(c) (3) faith based non-profit organization. She initiated the Pink Ribbon Gala in 2005, which funds raised assists those who have been diagnosed with cancer in Mississippi.
Abstract:
BACKGROUND: Public Health Law 101-354 was enacted to reduce breast and cervical cancer morbidity and mortality rates via education, screening, and adequate timely follow-up. The program has provided breast and cervical cancer screening for hundreds of thousands of women, followed by the National Breast and Cervical Cancer Early Detection Program Treatment Act, Public Law 106-354, which provided for treatment services for women diagnosed with malignant or pre-malignant conditions of the breast and/or cervix. Data were analyzed to determine whether women in Mississippi who were screened in the Breast and Cervical Cancer Program have been positively impacted by the enactment of this legislation by detecting breast cancer at an early stage, when it is more successfully treated.
OBJECTIVES: By the end of the session the participant will be able to understand how public health policies via Public Laws 101-354 and 106-354 impacted women in Mississippi. Participants will also gain better insight as to whether those two laws reduced late stage breast cancer rates for women in Mississippi.
DATA ANALYSIS: Secondary data for this study were obtained from the BCCP database for women screened over a ten year interval. The Breast and Cervical Cancer Program data were analyzed to determine the effectiveness of a public health policy that was implemented to influence breast and cervical cancer outcomes by providing a health care coverage for medically underserved women.
RESULTS: Findings from this study demonstrated that more women were diagnosed with breast cancer as a result of increased screenings. But, women in the BCCP continued to be diagnosed at later stages of breast cancer diseases.
Paul J Davis
Albany College of Pharmacy and Health Sciences
USA
Title: Targeted delivery of generic chemotherapeutic agents to solid tumors via systemic nanotetrac (Nano-diamino-tetrac)
Time : 11:55-12:25
Biography:
Paul J. Davis is currently working in Albany College of Pharmacy and Health Sciences, USA
Abstract:
The principal secretory product of the thyroid gland, L-thyroxine (T4), is anti-apoptotic at physiological concentrations in a number of cancer cell lines. Among the mechanisms of anti-apoptosis activated by the hormone are interference with the Ser-15 phosphorylation (activation) of p53 and with TNFa/Fas-induced apoptosis. The hormone also decreases cellular abundance and activation of proteolytic caspases and of BAX and causes increased expression of X-linked inhibitor of apoptosis (XIAP). The anti-apoptotic effects of thyroid hormone largely are initiated at a cell surface thyroid hormone receptor on the extracellular domain of integrin avb3 that is amply expressed and activated in cancer cells. Tetraiodothyroacetic acid (tetrac) is a T4 derivative that, in a model of resveratrol-induced p53-dependent apoptosis in glioma cells, blocks the anti-apoptotic action of thyroid hormone, permitting specific serine phosphorylation of p53 and apoptosis to proceed. In a nanoparticulate formulation limiting its action to avb3, tetrac modulates integrin-dependent effects on gene expression in human cancer cell lines that include stimulation of expression of a panel of pro-apoptotic genes and downregulated transcription of defensive anti-apoptotic XIAP and MCL1 genes. By a variety of mechanisms, thyroid hormone (T4) acts as an endogenous anti-apoptotic factor that may oppose chemotherapy-induced apoptosis in avb3-expressing cancer cells. It is possible to oppose this anti-apoptotic activity pharmacologically by reducing circulating levels of T4 or by blocking effects of T4 that are initiated at avb3.
Dr Peter Tunbridge
Private Clinical Practice
Adelaide
South Australia
Title: There is more to cancer than just genes
Biography:
Dr Tunbridge is in private clinical practice in Adelaide, South Australia. He specialises in treatment of complex metabolic disorders, thyroid disease and disorders of oestrogen metabolism. His background in Science is in Immunology, Biochemistry and Immunology. Before studying Medicine, he worked on the thiamine pathway and was the first to discover a genetic basis to thiamine deficiency which was subsequently shown to be the MTHFR gene polymorphism. He has recently finished a meta-analysis of the relationship of the MTHFR with E2 metabolism and its effect on intracellular glucose metabolism. He is currently setting up a research programme to examine the role of intra-cellular levels of T3 causing conversion of glucose into Ground Substance and how this may be the actual cause of all arthritis. He holds the position of Lecturer in Clinical Medicine at Adelaide University. He is Foundation Editor, and Editor-in-Chief of the International online Medical Journal on Steroids, “Global Hormonal Health†He is an Author with 2 published books to date, “The Human Codeâ€, and “Short Pantsâ€
Abstract:
The current model for cancer is no longer valid.
There are too many unanswered questions in its aetiology, physiology and clinical outcomes.
This presentation is to outline a totally new model based on;
1. Visceral fat stem cells
2. Glucose overload metabolism
3. The role of Ground Substance
4. The role of Hormones
5. The actual cause of metastases
6. What the Oncogene represents
Hopefully this model which is based on a meta-analysis of current published, peer reviewed literature will stimulate new ideas and treatments.
Rene Wenzl
Medical University of Vienna, Austria
Title: Hormonal treatment in patients with Endometriosis
Biography:
Rene Wenzl has completed his residency in Obstetrics and Gynecology from Medical School of Vienna in 1995 and Master degree of Science from Donau-Universität-Krems in 2005. He has been a senior physician at the Department of OB/GYN in 2004 and was announced as Head of the Centre for Endometriosis at the Medical University of Vienna in 2010. His scientific dedication applies to the research of pathogenesis and effective treatment of endometriosis and its concomitant diseases. He is fellow member for various societies such as The Johns Hopkins Medical and Surgical Association, European Society for Gynecological Endoscopy and New York Academy of Science. He has published more than 70 papers in reputed journals and is serving as an Editorial Board Member of repute.
Abstract:
Endometriosis is a painful, chronic disease occurring when endometrium is located outside the uterus, affecting at least 6 million women worldwide. Symptoms like dysmenorrhea, dyspareunia, dysuria, fatigue or other gastrointestinal indications such as diarrhea, constipation, nausea are responsible for severe aggravation of women’s life. Endometriosis compromises the quality of life of countless women worldwide and is a leading cause of disability. Clinical symptoms of endometriosis can be very heterogeneous leading to a long interval between onset of symptoms (commonly 7 years) and surgical diagnosis. Treatment for endometriosis is usually with medications or surgery. Supplemental hormones are sometimes effective in reducing or eliminating the pain of endometriosis. That's because the rise and fall of hormones during the menstrual cycle causes endometrial implants to thicken, break down and bleed. Hormone medication may slow the growth and prevent new implants of endometrial tissue such as hormonal contraceptives, Gonadotropin-releasing hormone (Gn-RH) agonists and antagonists, Progesterone and progestin or Danazol. The lecture should provide an overview of current treatment options apart from surgical interventions such as laparoscopy and hysterectomy.
Paul J Davis
Albany Medical College, USA
Title: Modulation of angiogenesis and anti-angiogenesis at targets on integrin ï¡vï¢3
Time : 13:40-14:50
Biography:
Davis is a graduate of Harvard Medical School and had his postgraduate medical training at Albert Einstein College of Medicine and the NIH. His academic positions have included Chair, Department of Medicine, Albany Medical College. He has served as President, American Thyroid Association, as a member of the Board of Directors of the American Board of Internal Medicine and he is Co-Head, Faculty of 1000–Endocrinology. He serves on multiple Editorial Boards of His scientific interests include molecular mechanisms of actions of nonpeptide hormones, particularly, thyroid hormone. He and his colleagues described the cell surface receptor for thyroid hormone on integrin avb3 that underlies the pro-angiogenic activity of the hormone and the proliferative action of the hormone on cancer cells. He has co-authored more than 200 original research articles and 30 textbook chapters and he has edited three medical textbooks.
Abstract:
Plasma membrane integrin avb3 is extensively involved in angiogenesis. Generously expressed on dividing endothelial cells and tumor cells, avb3 mediates cell-cell interactions and interactions with angiogenesis-relevant extracellular matrix (ECM) proteins such as osteopontin, vitronectin and von Willebrand factor. avb3 also engages in crosstalk with adjacent vascular growth factor receptors. We have described small molecule ligands of the integrin, such as thyroid hormone, that exert extensive control over blood vessel formation. Acting at the integrin, L-thyroxine (T4) (< 10-10 M free hormone) and 3,3’,5-triiodo-L-thyronine (T3) rapidly stimulate angiogenesis in the chick chorioallantoic membrane (CAM) model and Matrigel® microtubule formation system. Nanoparticulate T4 (agarose-T4) does not gain access to the cell interior and is equipotent angiogenically to unmodified T4. T4 is equipotent to VEGF and bFGF in the CAM model. The hormone receptor on avb3 mediates upregulation by T4 of a set of genes relevant to angiogenesis, including basic fibroblast growth factor (bFGF; FGF2) and several matrix metalloproteinases (MMPs). T4 also supports endothelial cell migration towards a vitronectin cue. Tetraiodothyroacetic acid (tetrac), a deaminated derivative of T4, inhibits binding of T4 and T3 to avb3 and, unmodified or reformulated as a poly(lactic-co-glycolic acid) nanoparticle (Nanotetrac; Nano-diamino-tetrac; NDAT), this agent antagonizes all of the pro-angiogenic actions of T4 and T3. Nanotetrac is anti-angiogenic by additional mechanisms unrelated to the binding of T4 and T3. These avb3-dependent actions include inhibition of the angiogenic actions of VEGF, bFGF and PDGF—reflecting, we propose, disruption of crosstalk between the integrin and nearby receptors for vascular growth factors—and stimulation of expression of the anti-angiogenic thrombospondin 1 (TSP1) gene in tumor cells. Also relevant to angiogenesis are the actions of Nanotetrac to decrease expression of VEGFA, EGFR, MMP-2, MMP-9 genes and miR-21 abundance. The microRNA increases cellular HIF-1a and VEGF content. Finally, resveratrol and testosterone are other small molecule ligands of avb3 that modulate angiogenesis. The pro-angiogenic action of resveratrol has been shown to be expressed via the avb3 receptor site for stilbenes, but the possibility that the dihydrotestosterone effect on HIF-1a is avb3-requiring has not yet been examined. In summary, integrin avb3 has small molecule ligands that regulate angiogenesis. A set of disparate thyroid hormone analogues is the best studied of such ligands and by multiple molecular mechanisms these analogues are pro- or anti-angiogenic.
- Growth Supplements
- Steroids in Women Health
- CorticoSteroids
Session Introduction
Mohammad Yasin Mohammad
Middle East University
Jordan
Title: Biotransformation of some anabolic steroids by Rhizopus stolonifer
Biography:
Mohammad Yasin Mohammad is currently a professor at Middle East University, Jordan
Abstract:
Microorganisms have been used extensively for hydroxylation of anabolic steroids since their enzymes can catalyze reactions with high regio- and stereospecifity. Their ability to oxidize steroidal compounds has immense synthetic and commercial importance. Selected anabolic steroids (oxandrolone (1), mestanolone (2) and 17-methyl-1-testosterone (3)) were subjected to biotransformation using the plant pathogen fungus Rhizopus stolonifer. Oxandrolone (1) and mestanolone (2) are anabolic synthetic derivatives of testosterone that act on androgen receptors [1]. 17-Methyl-1-testosterone (3) is an anabolic synthetic derivative of mestanolone (2). Incubation of oxandrolone (1) with R. stolonifer yielded metabolites 4-6 , [2]. While incubation of mestanolone (2) and 17-methyl-1-testosterone (3) with R. stolonifer produced metabolites 7, 8 and 9, 10 , [3], respectively. Structures of compounds 4-10 were deduced through comparative spectroscopic studies with substrates 1-3. The stereochemistry in compounds 4-8 and 10 were determined by NOESY spectrum and single-crystal X-ray diffraction studies for metabolite 4 (Figure-4). Compounds 1 and 5 showed a significant β-glucuronidase inhibitory activity.
Isbel GarcÃa Figueredo
Institute of Oncology and Radiobiology
Cuba
Title: Testosterone, estrogen and insulin in the development of prostate cancer
Biography:
Isbel GarcÃa is a PhD student; she has a master degree in Laboratory Science, from Havana University of Cuba. She is a project leader of two projects, at the Institute of Oncology and Radiobiology: “Hormonal behavior in Prostate intraepithelial neoplasia and Cancer: Its role as tumor markers.†and, “New Urine Molecular Tumor Markers to Improve Prostate Cancer Diagnosisâ€. She has published 12 papers and has been proposed as a reviser in MEDWAVE magazine. She was a member of a scientific board of her institute for five years. She is also, an assistant professor of the Medicine Faculty “Manuel Fajardoâ€.
Abstract:
Introduction: Prostate cancer (PCa) is the second most frequently diagnosed cancer in men and the second leading cause of cancer death in the male. This phenomenon could be due to hormonal changes during aging. So in this conference we will briefly summarize the biochemistry of androgens, estrogens and insulin in relation to prostate cancer development and advanced phenotypes.
Background: In the elderly, the androgen levels drop significantly, whereas their estrogen levels remain unchanged or increased, making the estrogen to androgen ratio elevated in the aging prostate. There are also a relationship between different serum testosterone levels and intraprostatic androgen receptor fluxes, signaling efficiency and downstream physiological responses. In addition, we would like to point out that the epidemiological studies indicate a correlation between PCa and circulating estrogen levels, among different ethnic/racial groups with diverse PCa incidence. But some of them emphasize that low testosterone levels may actually be a marker of more-aggressive prostate cancer. The estrogens actions are mediated by estrogen receptors (ERs), alpha (α) and beta (β). The continuing controversy over the function of ERβs in prostate carcinogenesis could be due to variable expression levels of different ERβ isoforms in benign versus malignant tissues during different stages of the process. On the other hand, the insulin and its insulin growing factors had an essential role in prostate cancer carcinogenesis and in prostate cancer aggressive phenotype. Furthermore, the overexpression of insulin receptors (IRs) in prostate cancer and the association between IR expression or IR/IGF1R activation has been found in both stromal and epithelial prostate tissue compartments but changes with cancer progression that becoming an autocrine signal to it.
Conclusions: Until now, elucidating mechanisms of paracrine/steroid hormone-induced changes in cellular differentiation, proliferation, and gene expression, and carcinogenesis give us confusing results let us to know that he crosstalk between the hormonal milieus are essential for prostate cancer development.
Outcome/Impact: On the knowledge of the mechanisms involved in prostatic carcinogenesis.
Biography:
Gihane khalil was graduated from faculty of medicine, Alexandria University, Egypt at 1996, complete her PhD in Chemical pathology at 2007, she is an assistant professor of Chemical pathology since February 20013. She is director of Chemical Pathology Lab in Medical Research Institute ,Alexandria university. She has published more than 15 papers in International journals in the field of Diabetes, obesity and breast cancer.
Abstract:
Overweight and obesity are the leading causes for the development of multiple adverse metabolic effects. Retinol Binding Protein 4 (RBP4), a peptide secreted from adipocytes and hepatocytes, provides a new link between obesity and insulin resistance. The objective of this work is to determine RBP4 serum levels and evaluate its relationship with serum testosterone (T), serum estradiol (E2), E2/T ratio and insulin resistance in overweight and obese Egyptian men. The study included 65 men which were subdivided into (20 normal weight, 20overweight and 25 obese). Their mean age was (43.88±5.52). Serum RBP4 was measured by the enzyme linked immunosorbent assay. Serum RBP4 and E2/T ratio were significantly higher, while serum T was significantly lower in overweight and obese groups as compared with normal weight group. In all subjects, serum RBP4 correlated positively with BMI, waist circumference, waist-to-hip ratio (WHR), HOMA-IR, serum E2 and E2/T ratio. In contrast, it correlated negatively with quantitative insulin sensitivity check index (QUICKI) and serum T. In multiple linear regression analysis serum RBP4 was dependently associated with E2/T ratio. It could be concluded that serum RBP4 is elevated in overweight and obese as compared with normal weight subjects, and that the disturbance in E2/T ratio seem to affect RBP4 serum levels and insulin sensitivity in obese men.
Isbel GarcÃa Figueredo
Institute of Oncology and Radiobiology
Cuba
Title: Role of testosterone and estrogen in prostate cancer risk
Biography:
Isbel GarcÃa is a PhD student; she has a master degree in Laboratory Science, from Havana University of Cuba. She is a project leader of two projects, at the Institute of Oncology and Radiobiology: “Hormonal behavior in Prostate intraepithelial neoplasia and Cancer: Its role as tumor markers.†and, “New Urine Molecular Tumor Markers to Improve Prostate Cancer Diagnosisâ€. She has published 12 papers and has been proposed as a reviser in MEDWAVE magazine. She was a member of a scientific board of her institute for five years. She is also, an assistant professor of the Medicine Faculty “Manuel Fajardoâ€.
Abstract:
Aim: To identify if testosterone, estradiol and PSAT are related to the risk of developing prostate cancer.
Material and Methods: A case-control study was performed in 115 patients with benign prostatic hyperplasia (BPH), prostate cancer and controls, which underwent prostate surgery. The total PSA (TPSA), total testosterone (T) and estradiol (E) were quantified by IRMA kits, with biopsy as reference test. Multivariate logistic regression analysis was performed to evaluate the association with the presence of cancer.
Results: Although statistical differences between cancer patients and patients with BPH and those relative to the control (P <0.001), concerning the three markers, they did not show a high specificity. The T to TPSA ratio and E to TPSA ratio could discern between the three groups of patients with high sensitivity (100% and 94.12%, respectively) and specificity (91.53% and 81.58%, respectively). Multivariate analysis showed an increased risk of cancer in patients with levels of T<3 ng/mL, T to TPSA ratio <0.29 and E /TPSA <0.002642.
Discussion and Conclusions: The risk of prostate cancer is associated with low levels of T/PSAT ratio and E/TPSA ratio that increase the TPSA specificity. Showing ratios T/TPSA and E/TPSA had high sensitivity and specificity, so they could considered as prostate cancer risk predictors.
- Anabolic Steroids and Supplements
- Steroids and Cancer
Session Introduction
Donald Poirier
Research Center and University Laval
Canada
Title: A new family of steroidal 17 beta-HSD type 1 inhibitors to treat hormone-dependent breast cancers
Time : 10:10-10:40
Biography:
Professor Donald Poirier received his training in chemistry (B.Sc., 1977-1980) and organic chemistry (PhD, 1980-1985) at Université Laval (Québec City, Canada). He subsequently specialized in medicinal chemistry (Post-doctoral training at CHUL - Research Center, 1986-1990) and more recently in solid phase synthesis of small molecules of therapeutic interest. He is especially interested in the development of inhibitors of steroidogenic enzymes (17b-hydroxysteroid dehydrogenases (types 1, 2, 3, 7, 10 and 12) and steroid sulfatase) and antitumor agents for the treatment of different cancers (breast, prostate, ovary, leukemia). In addition to the synthesis of small molecules by classical chemistry, he succeeded by developing solid-phase synthesis of C18-steroid (estrane), C19-steroid (androstane) and C21-steroid (pregnane) derivatives that enabled the generation of model libraries of targeted therapeutic compounds. Thus, he developed a new sulfamate linker for solid-phase synthesis that produces two classes (phenol and sulfamate) of relevant steroidal or nonsteroidal compounds according to the conditions of cleavage. He also developed a diethylsilylacetylene linker to generate libraries of acetylenic tertiary alcohols, which are well known to be biologically more stable than their corresponding secondary alcohols.
He is also interested to additional aspects of organic chemistry (synthesis, new methodologies, NMR analysis, etc.) and medicinal chemistry (structure-activity relationships, molecular modelisation, biological assays, etc.). He is professor at the Department of Molecular Medicine (Faculty of Medicine, Université Laval, Québec City, Canada) since July 1991, researcher at CHU de Québec - Research Center (Québec City) since 1991 and director of the Organic Synthesis Service (CHU de Québec) since 2008. Professor Poirier is member of professional organizations such as ACS, CIC, OCQ, ACFAS and CRCQ. He published 202 papers and 8 patents. He was also author or co-authors of 414 presentations (invited speaker, oral and poster presentations).
Abstract:
PBRM is steroid derivative recently developed in our research group as anticancer agents. PBRM, or 3-{[(16β,17β)-3- (2-bromoethyl)-17-hydroxyestra-1(10,2,4-trien-16-yl]methyl} benzamide, was synthesized from estrone (E1) using a sequence of eight steps in an overall yield of 11%. PBRM inactivated the transformation of E1 into estradiol (E2), the most potent estrogen, by the action of steroidogenic enzyme 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD 1), which is thought to play a pivotal role in the progression of estrogen-dependent breast cancer. In fact, PBRM inhibited the 17β-HSD1 in T-47D cells (IC50 = 83 nM), in the pure enzyme (Ki = 381 nM, kinact = 0.084 min-1) and did not inhibit other key enzymes such as 17β-HSD2, 17β-HSD7, 17β-HSD12, CYP3A4 and CYP-2D6, suggesting a good selectivity of action. In the presence of microsomes, PBRM was gradually transformed into an oxidized form of PBRM (100% after 12h). This PBRM metabolite has proven almost as active as PBRM for the transformation of E1 to E2 by 17β-HSD1 (49 and 87% vs. 87 and 95% of inhibition at 0.1 and 1 μM, respectively). When injected subcutaneously (sc) in mouse, PBRM is the major product (660 ng/mL at 5h) found in blood and oxidized PBRM is present in small quantities (8.5 ng/mL at 5h). Most tissues reach their maximum level of PBRM 6h after sc injection. PBRM was observed mostly in digestive tract over the first 6h, but did not accumulate in any other organ. It was recuperated in feces (93%) and in urine (7%), with 68% of the elimination occurring in the first 24h. Interestingly, in the estrogen-sensitive breast cancer cell line T-47D and in ovariectomized mice (uterine and vagina weight), PBRM showed no estrogenic activity. When tested on the T-47D xenograft tumor model in female ovariectomized nude mice, PBRM (250 μg/mouse/day) fully blocked (100%) the tumor growth induced with exogenous E1 (0.1 μg/mouse/day). In summary, PBRM represent a new generation of 17β-HSD1 inhibitors that generated promising in vitro and in vivo results against breast cancer cells and tumor model.
Alan Prem Kumar
National University of Singapore
Singapore
Title: DEAD-box RNA Helicase DP103 as a Biomarker for Therapeutic Response to Docetaxel
Biography:
Dr. Alan Prem Kumar earned his Ph.D. from University of North Texas, USA. From his Ph.D. work, he discovered a novel regulatory protein, PyrR for the pyrimidine biosynthetic pathway in Pseudomonas. Dr. Kumar then pursued Postdoctoral training in Cancer Research at Sidney Kimmel Cancer Center, California, USA. He was awarded a Postdoctoral Fellowship for his work on the role of nuclear receptors in the transcriptional regulation of human myeloperoxidase, a leukocyte enzyme implicated as causative agent in atherosclerosis and Alzheimer’s disease. Dr. Kumar relocated back to Singapore to join the Faculty of Medicine, National University of Singapore as an independent Principal Investigator to continue on his expertise on nuclear receptor signaling in cancer biology. His current research focus in the areas of signaling by nuclear receptors and oncogenes in breast tumor cells as well as the development of molecular therapeutics and biomarkers of drug action in breast cancer.
Abstract:
Resistance to chemotherapy offers limitations to the treatment of breast cancer. This has generated an increased interest in identifying new biomarkers to better predict drug responses among patients. Gene expression analysis and immuno-histochemistry profiling of patient samples, randomized to a combination of docetaxel and doxorubicin, revealed a chemotherapy induced decrease in DP103 expression among responders, and an increase among non-responders. These clinical findings were also validated in-vitro, using representative cell lines to mimic responders, and their corresponding drug resistant subtypes as non-responders. Upon stratification by the receptor status, the predictive value of DP103 was only observed in patient samples and cell lines with ERα-positive status and not with ERα-negative status. The observed changes in DP103 expression was well correlated to a similar drug induced change in the expression of ERα; raising a possibility of a cross-talk between DP103 and ERα. ChIP-Seq analysis and estradiol-stimulation studies validated DP103 to be an estrogen-inducible gene. Interestingly, DP103 was also indentified as a potential modulator of ERα transcriptional activity. Silencing DP103 inhibited estradiol-induced ERα DNA-binding activity, expression of ERα target genes, cell growth and colony forming ability. These findings summarise a novel role of DP103 in acquired drug resistance; presenting a potential surrogate biomarker for predicting drug response in breast cancer. In addition, we have also uncovered a positive feed-forward loop between DP103 and ERα that could regulate the activity of the latter in ERα positive breast cancer.
Pandurangan Ramaraj
A.T. Still University, USA
Title: Differential Effects of Dehydroepiandrosterone (DHEA) between Mouse and Human Melanoma Cell Lines
Time : 10:40-11:10
Biography:
He is currently working in Department of Biochemistry, Kirksville College of Osteopathic Medicine at A.T. Still University, USA
Abstract:
Androgens such as dehydroepiandrosterone (DHEA), androstenedione (AD) and testosterone (T) are essential for healthy skin. They play important roles in growth and differentiation of sebocytes, hair growth and wound healing in the skin. Decrease in DHEA level with age was attributed to cancer and other problems of aging. So, the effect of DHEA on melanoma, a fatal form of skin cancer was checked. DHEA’s purported beneficial effects (such as anti-cancer action) were observed in mouse and other rodents, but not in humans. Our previous study on DHEA biological functions using a variety of cell lines showed that the differences existed not only at the systemic level, but also at the cellular level. Hence, we decided to compare the in-vitro effects of DHEA between mouse (B16F10) and human (BLM) melanoma cell lines. Results indicated that DHEA actions were mediated through androgen receptor (AR) in both cell lines. DHEA showed significant growth inhibition and induced autophagy in mouse cell line, whereas it showed a muffled inhibition and induced apoptosis in human cell line. Moreover, co-incubation of DHEA with progesterone showed an additive effect in decreasing the cell growth in mouse cell line, but not in human cell line. These differential in-vitro effects between mouse and human melanoma cell lines were in line with previously published in-vivo and in-vitro effects of DHEA.
Conclusion: These differential in-vitro effects of DHEA suggested a possible difference in intracellular processing of DHEA between mouse and human melanoma cell lines and this mechanism was able to explain the systemic differences observed between mouse and human in-vivo experiments.
Amandine Grimm
University of Basel
Switzerland
Title: Sex hormones, Alzheimer’s disease and mitochondria
Time : 12:35-13:05
Biography:
Dr Amandine GRIMM has performed a joint PhD between the University of Strasbourg, France, specialty Neuroscience, and the University of Basel, Switzerland, specialty Pharmaceutical Sciences. She has obtained her PhD degree in January 2015 and is now a postdoctoral fellow in the Neurobiology Lab for Brain Aging and Mental Health (Psychiatric University Clinic of Basel (Switzerland)). In the course of her Joint-PhD and postdoctoral researches, Dr. Grimm has published nine papers, including six original articles, reviews and book chapters signed as first author.
Abstract:
Metabolic impairments are common hallmarks of Alzheimer’s disease (AD), and amyloid-β (Aβ) peptide and hyperphosphorylated tau protein – the two foremost histopathological signs of AD - have been implicated in mitochondrial dysfunction.
Epidemiological studies showed that women represent two thirds of AD patients and exhibit a greater vulnerability to the disease compared to men but little is known about the influence of sex steroid hormones on AD-related mitochondrial dysfunction.
Thus, we aimed to investigate whether sex hormones could attenuate the toxic effects of Aβ and abnormal tau on bioenergetic parameters, such as ATP production, mitochondrial membrane potential (MMP), mitochondrial respiration and glycolysis, in cellular models of AD (SH-SY5Y neuroblastoma cells overexpressing either the human amyloid precursor protein (APP) or mutant tau (P301L)).
After a treatment of 24 h, the majority of these steroids were effective in enhancing bioenergetic outcomes in cells overexpressing APP and mutant tau, attenuating the mitochondrial dysfunction that is present in these cell lines when compared to the respective control cells. Interestingly, testosterone (the main male sex hormone) was more efficient in alleviating Aβ-induced mitochondrial deficits, while progesterone and estrogen (the female sex hormones) were the most effective steroids in our model of AD-related tauopathy.
Thus, our results provide new insights in re-defining the biological model of how steroids control neuronal and bioenergetic functions, and may open new avenues for the development of gender-based therapeutic approaches in AD.
This work was supported by grant from the Swiss National foundation (SNF 31003A_149728) and Synapsis Foundation.
Rene Wenzl
Medical University of Vienna
Austria
Title: Hormonal treatment in patients with Endometriosis
Biography:
René Wenzl has completed his residency in obstetrics and gynecology from Medical School of Vienna in 1995 and master degree of Science from Donau-Universität-Krems in 2005. He has been senior physician at the Department of OB/GYN in 2004 and was announced as Head of the Centre for Endometriosis at the Medical University of Vienna in 2010. His scientific dedication applies to the research of pathogenesis and effective treatment of endometriosis and its concomitant diseases. He is fellow member for various societies such as The Johns Hopkins Medical and Surgical Association, European Society for Gynecological Endoscopy and New York Academy of Science. He has published more than 70 papers in reputed journals and serving as an editorial board member of repute.
Abstract:
Endometriosis is a painful, chronic disease occurring when endometrium is located outside the uterus, affecting at least 6 million women worldwide. Symptoms like dysmenorrhea, dyspareunia, dysuria, fatigue or other gastrointestinal indications such as diarrhea, constipation, nausea are responsible for severe aggravation of women’s life. Endometriosis compromises the quality of life of countless women worldwide and is a leading cause of disability. Clinical symptoms of endometriosis can be very heterogeneous leading to a long interval between onset of symptoms (commonly 7 years) and surgical diagnosis. Treatment for endometriosis is usually with medications or surgery. Supplemental hormones are sometimes effective in reducing or eliminating the pain of endometriosis. That's because the rise and fall of hormones during the menstrual cycle causes endometrial implants to thicken, break down and bleed. Hormone medication may slow the growth and prevent new implants of endometrial tissue such as Hormonal contraceptives, Gonadotropin-releasing hormone (Gn-RH) agonists and antagonists, Progesterone and progestin or Danazol. The lecture should provide an overview of current treatment options apart from surgical interventions such laparoscopy and hysterectomy.
- Steroids in Sports
- Anabolic Steroids and Supplements