Series D: e-Books on BioMedicine – Metabolomics, Immunology, Infectious Diseases, Reproductive Genomic Endocrinology
Volume Four: Human Reproductive System,
Genomic Endocrinology and Cancer Types
Series Content Consultant:
Larry H. Bernstein, MD, FCAP,
Emeritus CSO, LPBI Group
http://www.amazon.com/dp/B08VTFWVKM
Available on Amazon.com since 2/2/2021
Product details
- ASIN : B08VTFWVKM
- Publisher : Leaders in Pharmaceutical Business Intelligence (LPBI) Group; 1st edition (February 2, 2021)
- Publication date : February 2, 2021
- Language : English
- File size : 1206 KB
- Text-to-Speech : Enabled
- Enhanced typesetting : Enabled
- X-Ray : Not Enabled
- Word Wise : Not Enabled
- Print length : 66 pages
- Lending : Enabled
Human Reproductive System,
Genomic Endocrinology and Cancer Types
Prof. Stephen J. Williams, PhD, Editor
Prof. Sudipta Saha, PhD, Editor
and
Aviva Lev-Ari, PhD, RN, Editor
2021
Image Source: Courtesy of Google Images
Aviva Lev-Ari, PhD, RN
UC, Berkeley, PhD’83
Editor-in-Chief BioMed e-Book Series
Leaders in Pharmaceutical Business Intelligence (LPBI) Group, Boston
avivalev-ari@alum.berkeley.edu
All the 18 volumes by LPBI Group’s Experts, Authors, Writers published on AMAZON.COM are on the Kindle Store bookshelf on Medicine and Life Sciences
https://lnkd.in/ekWGNqA
List of Contributors to Volume Four
&
Book Structure
| Sudipta Saha, PhD | Larry H. Bernstein, MD, FCAP | Stephen J. Williams, PhD |
Aviva Lev-Ari, PhD, RN |
|
|
TOTAL # Articles |
24 | 37 | 5 |
20 |
| PREFACE |
|
PREFACE | Context comment | |
| Volume Introduction |
Introduction |
Introduction | ||
| Part 1 | Introduction
1.5, |
1.2, 1.3, 1.6, | 1.1, 1.4, | |
| Part 2
Introduction by Dr. Irina Robu |
2.2, 2.3, 2.4, | |||
| Part 3 | 3.1, 3.2, 3.3, 3.4, | |||
| Part 4 | 4.2, 4.4, |
4.1, |
Introduction
4.5, |
4.3, 4.6, |
| Part 5
Introduction by Dr. Irina Robu |
5.8, 5.10, 5.11, |
5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.9, |
||
| Part 6 | Introduction
6.1, 6.2, 6.3, 6.4, |
6.6 | 6.5, 6.7, | |
| Part 7
Introduction by Prof. Feldman |
7.1, 7.2, 7.3, 7.4, 7.7, 7.8, 7.9, 7.10, | 7.2, 7.5, 7.6, | ||
| Part 8
Introduction by Dr. Irina Robu |
8.6, | 8.1, 8.2, 8.3, 8.4, 8.5, | ||
| Part 9
Introduction by Dr. Irina Robu |
9.1, 9.3, 9.4, 9.5 |
9.2, 9.5, | ||
| Part 10 | 10.3.2.3,
10.3.3.6, |
10.1, 10.2,
10.3.1.1, 10.3.1.3, 10.3.1.4, 10.3.2.7, 10.3.3.3, 10.3.4.1 10.3.4.2 10.3.4.3 10.3.4.5 |
Introduction 10.3.2.1, 10.3.2.2, 10.3.2.9, 10.3.2.10, 10.3.3.4 Summary |
10.3.1.2,
10.3.2.4 10.3.2.5, 10.3.3.1 10.3.3.2 10.3.3.5 10.3.4.2 10.3.4.4 10.3.4.5 |
| Volume Summary
& EPILOGUE |
Saha Volume Summary |
Larry | SJW
EPILOGUE |
Aviva |
| Dr. Irina Robu
2.1, 10.3.2.8 Part 2, 5, 8, 9: Introductions _____________ Prof. Feldman Introduction to Part 7, 7.2 _____________ Prabodh Kandala Part 10, 10.3.2.6, _____________ |
||||
|
TOTAL |
24 | 37 | 5 |
20 |
Abbreviated eTOCs
PREFACE by Dr. Stephen J. Williams, PhD
Volume Introduction
Voices of Dr. Stephen J. Williams, PhD and Voice of Dr. Aviva Lev-Ari, PhD, RN
Part 1: General Topics on Human Reproduction
Introduction – Dr. Sudipta Saha, PhD
1.1 Top 10 Medical Innovations for 2018, 2020 and 2021 by Cleveland Clinic
1.3 Justice Ginsberg Written Dissent
1.4 Micronutrients, Macronutrients and Dietary Patterns: Nutrition and Fertility
1.5 Antiviral drug for hepatitis B not beneficial for reducing mother-to-child transmission
Part 2: Innovations in Cell Biology and Embryology
Introduction – Dr. Irina Robu, PhD
2.1 Embryo Stem Cells Out of Skin
2.2 The Three Parent Technique to Avoid Mitochondrial Disease in Embryo
2.3 Mitochondria Replacement Therapy
Part 3: Cell Signaling
3.1 Signaling transduction tutorial
3.3 Signaling and Signaling Pathways
3.4 Summary of Signaling and Signaling Pathways
Part 4: Genomics in Prenatal and Childhood Wellness
Introduction – Dr. Stephen J. Williams, PhD
4.1 Genes, proteomes, and their interaction
4.3 Panel Discussion Genomics in Prenatal and Childhood Disorders
4.4 The function of the junk jumping gene (LINE1) uncovered
4.5 How NGS Will Revolutionize Reproductive Diagnostics: November Meeting, Boston MA
Part 5: Discoveries in Endocrinology
Introduction – Dr. Irina Robu, PhD
5.1 Roy O. Greep Award for Outstanding Research in Endocrinology
5.3 Adrenal Cortex
5.4 Sex Hormones
5.5 Thyroid Function and Disorders
5.6 Pituitary Neuroendocrine Axis
5.7 Endocrine Action on Midbrain
5.8 Genders redefined by Biology
5.9 Pharmacological Action of Steroid Hormones
5.11 Personal Care Chemicals and Puberty Onset
Part 6: Frontier of Female Endocrinology
Introduction – Dr. Sudipta Saha, Ph.D.
6.1 Artificial ovary instead of conventional hormone replacement
6.2 The viability of Anti-Müllerian Hormone (AMH) level as fertility marker
6.3 The immune system clock of pregnancy
6.4 A genetic switch to control female sexual behavior
6.6 Hormone Therapy
6.7 Endometriosis: Genomics Diagnosis @UCSF
Part 7: Male Sexual Function and Fertility
Introduction – Dr. Marc Feldman, PhD
7.3 Cannabis smoking showed increased sperm count
7.4 Spermatogenic defects in sex reversed mice
7.8 Promising research for a male birth control pill
7.10 Lifelong Contraceptive Device for Men: Mechanical Switch to Control Fertility on Wish
Part 8: Metabolomics and Microbiome Genomics
Introduction – Dr. Irina Robu, PhD
8.1 Metabolic Genomics and Pharmaceutics, Vol. 1 of BioMed Series D available on Amazon.com Kindle Store
8.2 Introduction to Metabolomics
8.3 Metabolomics Summary and Perspective
8.5 Lipid Metabolism
8.6 Controversy prevails on whether C-section babies need mother’s microbes
Part 9: Diabetes and the Insulin Treatment
Introduction – Dr. Irina Robu, PhD
9.1 Fat Cells Reprogrammed to Make Insulin
9.3 Gastrointestinal Endocrinology
9.5 Metformin, thyroid pituitary axis, diabetes mellitus, and metabolism
Part 10: Cancer of the Human Reproductive and Genitourinary Systems
10.3 Cancers Types in the Human Reproductive and Genitourinary Systems
Introduction by Dr. Stephen J. Williams, PhD
10.3.1 Breast Cancer
10.3.1.1 Targeted Therapy for Triple Negative Breast Cancer
10.3.1.3 New Risk Stratification for Breast Cancer
10.3.1.4 Breast Cancer Extratumor Microenvironment has Effect on Progression
10.3.2 Ovarian Cancer
10.3.2.2 A Curated History of the Science Behind the Ovarian Cancer β-Blocker Trial
10.3.2.3 Beta-Blockers help in better survival in ovarian cancer
10.3.2.4 Efficacy of Ovariectomy in Presence of BRCA1 vs BRCA2 and the Risk for Ovarian Cancer
10.3.2.6 Squeezing Ovarian Cancer Cells to Predict Metastatic Potential: Cell Stiffness as Possible Biomarker
10.3.2.7 Targeting PARP
10.3.2.8 Efficiency of PARP inhibitors beyond BRCA mutations
10.3.3 Cervical and Endometrial Cancer
10.3.3.3 Papilloma viruses for cervical cancer
10.3.4 Prostate Cancer
10.3.4.1 Who and when should we screen for prostate cancer?
10.3.4.2 Prostate Cancer: Diagnosis and Novel Treatment – Articles of Note @PharmaceuticalIntelligence.com
10.3.4.3 Targeting PARP in Prostate Cancer
10.3.4.4 Prostate Cancer: Androgen-driven “Pathomechanism” in Early-onset Forms of the Disease
Summary for Part 10 by Dr. Stephen J. Williams, PhD
Volume Summary by Dr. Sudipta Saha, PhD
EPILOGUE by Dr. Stephen J. Williams, PhD
Volume Four Starts HERE
PREFACE to Series D: Volume Four
by Dr. Stephen J. Williams, PhD
In honor of the Series D, Lead Author/Editor
Larry H. Bernstein, MD FCAP
-
Podcast with Dr. Larry H. Bernstein, MD, FCAP, Interview by Gail S. Thornton, PhDc, Narrator’s Voice: Stephen J. Williams, PhD
-
Podcasts with other contributors to this volumes are in the link, below
https://pharmaceuticalintelligence.com/audio-podcasts/
The first volume in Series D on Metabolomics was the brainchild of Dr. Larry H. Bernstein, our ex-Chief Scientific Officer (CSO) and was the Scientific Content Consultant of four of our five e-Series in the BioMed e-Series:
Dr. Bernstein served as Senior Editor in all our other Series
- Series A: e-Books on Cardiovascular Diseases
- Series B: Frontiers in Genomics Research
- Series C: e-Books on Cancer & Oncology
- Series D: e-Books on BioMedicine – Metabolomics, Immunology, Infectious Diseases, Reproductive Genomic Endocrinology
Volume One: Metabolic Genomics & Pharmaceutics
Series D, Volume Four: Human Reproductive System, Genomic Endocrinology and Cancer Types
Dr. Bernstein played a special role on the first volume in Series A: Cardiovascular Diseases, six volumes. Volume 1: focused on Nitric Oxide role in disease and in wellness and in Volume IV on Translation Medicine and Regenerative Medicine. Series B: two volumes on Genomics, Series C: two volumes on Cancer. Series E: He was a key contributor to Volumes 1 and 4 and he is the sole Author of Volumes 2 and 3.
Of special note in Series D: Volume 1 on Metabolomics. It was single handed by Dr. Bernstein, on a myriad of topics on Metabolism, Nutrition, Glycobiology and the new fields of “OMICS” related to the above.
As such it was the original plan to have Dr. Bernstein write the preface to this final volume of this series on this topic of Reproductive Endocrinology. The human hormonal system was dear to his heart and one of his main expertise. However due to health concerns, the writing of this Preface became my own editorial assignment.
I would consider myself a student of Dr. Bernstein, as he had been my mentor (along with Dr. Aviva Lev-Ari) in the art of scientific curation and development of medical e-books. Dr. Bernstein has always envisioned these series of ebooks to be a good source of didactic training and reference for the medical student and scientists. As such, I will write this Preface more in Dr. Bernstein thought and words as I can, as he certainly is the content expertise on this matter, and on a subject matter dear to his heart. It is, therefore, with great respect and an equal amount of trepidation, that I write this Preface to this final volume of Series D. As such, I will begin with an overarching thought:
We are Products of Our Experiences
The above statement might seem innocuous to most, however to the scientist/clinician, experiences, whether in the laboratory or clinic, establish the basis or root of a scientist’s view on subject areas as well as deepened understanding and appreciation on the discoveries and tribulations which led the disciplines of his/her work to the present state of scientific endeavors.
To explain this, I will first explain using my own experiences, and how these experiences led to my own multi-disciplinary viewpoints on biology and disease. Next, I will show how Dr. Bernstein’s vast experience over the years has formulated his overarching, multi-disciplinary viewpoint on medicine and pathology.
Being under the tutelage of such an experienced mentor with vast expertise, and getting to understand his viewpoints, has been an invaluable learning experience for me, and am truly grateful to Dr. Bernstein for his time, effort, and discourse, both scientific and nonscientific, we would have on various subjects, My scientific training started in the Toxicology program at the Philadelphia College of Pharmacy & Science (later named University of the Sciences in Philadelphia, I prefer the former name the college was the first School of Pharmacy in the United States).
This toxicology program was just initiated by Dr. Gary Lage, at the bequest of many major pharmaceutical companies to develop the first-in-nation program to train young scientists in the field of toxicology. I was in the earliest graduating classes of this newly founded program and later realized what great timing it had been. I have always seemed to gravitate to the more applied and translational fields, even at an early age. And the opportunities, especially in research, afforded to me at such a small, intimate environment helped solidify my appreciation for the multi-disciplinary nature of biomedicine. At this time, molecular biology and the fields of oncogenesis were at its infancy, and the terms translational research and precision medicine were not in existence.
The field of immunooncology had not gained traction from the initial discoveries of James Allison. Scientific discovery was still young but soon to be very rapid and exiting. Since this new program in Toxicology was taught by pharmacologists, my appreciation and viewpoint of cancer and oncogenesis centered on the mechanism of action of chemicals to result in carcinogenesis, giving me an appreciation of the dose-effect relationship or lack thereof (No-Observed Effect Limit) of many carcinogens.
Later in my professional life, I came to the realization of the uniqueness of this mindset due to my early training, as many in my chosen field had focused on mutated proto-oncogenes as drivers of the cancer process (potentially due to a focus on molecular biology) and had largely ignored metabolic changes that occurred or precluded the oncogenic state. Later in my research efforts, I would notice that many tumors, preferentially solid tumors, may require a predisposing cellular state, or ‘priming’ for oncogenesis.
My next experiences would involve the noncanonical nature of proteins, enzymes and (in general) the whole pathologic process. This term ‘noncanonical’ would appear to follow me all through out my scientific endeavors, even to today. When the Philadelphia Eagles coach Buddy Ryan said “what comes around goes around” I hadn’t realized what a fitting phrase this could be in many situations.
At the start of my PhD thesis work under Dr. Michael Sirover, we were attempting to purify what we felt was the product of our clone of the human uracil DNA glycosylase, an enzyme critical in the base excision DNA repair process. However, at that time, GenBank was not something you easily access and had to have an appointment to scan your sequence in, as this was all on a UNIX server. It appeared our clone was 100% identical to the subunit of GAPDH (glyceraldehyde 3 phosphate dehydrogenase), however, our lab’s results suggested that GAPDH might be a multifunctional protein. This idea landed the lab in hot water of course and my thesis project on this was in essence over because of being shunned from the field. We therefore embarked on investigating nitric oxide-induced post translational modifications of GAPDH and summarily found these modification may regulate some of GAPDH’s pleiotropic functions, eventually, GAPDH was accepted as a multifunctional protein.
As the field of cancer research was exploding, just as I entered my postdoctoral years, I felt behind the curve in my knowledge of molecular biology and the genetic basis of cancer, especially with respect to oncogenes and tumor suppressors. I was extremely fortunate though to have a great mentor, Dr. Thomas Hamilton, who over his years had vast experience in the molecular basis of ovarian oncogenesis as well as the pharmacology of its treatment and development of acquired resistance to such treatments.
Others, at Fox Chase Cancer Center, and collaborators and colleagues in the cancer field who I had the luck to associate with at international meetings, gave me much needed appreciations for the genetic basis of cancer as well as the new paradigms of translational research, the ‘omics and big data revolution, and precision medicine. These were all new and invaluable experiences, however maybe I had strayed from the older view of metabolism as a potential drive in cancer view.
Dr. Bernstein brought me back and am glad I had the opportunity to interact with him on this ebook project, which brought me back to appreciating the overall viewpoint of disease progression.
I want to discuss how Dr. Bernstein’s experiences, especially the numerous colleagues he has worked with has firmed his unique views on medicine and pathology. Dr. Bernstein’s CV and list of collaborators reads like a Who’s Who in Medicine: people like Harry Maisel, Averill Liebow. Nathan Kaplan, Johannes Everse, Norio Shioura, Percy Russel, Herschel Sidransky, Sherman Bloom, Dhristos Tsokos, Gustave Davis, Walter Pleban, Jowseph Babb, Inder Mayall, Yves Ingenbleek, Otto Warburg, Gil David, Ronald Coifmann, Larry Kaplan, as well as numerous others.
It is this vast network of medical expertise, as well as Dr. Bernstein’s own vast knowledge and expertise, that has formulated this crucial work of bringing metabolism into the ‘omics era and the new role metabolomics will have to play in the future of medical research and personalized treatment. The reader needs to read each of these volumes in its entirely to fully appreciate both the past discoveries which are leading to today’s therapies as well as gaining a wide and multi-disciplinary view of the pathologic process.
Voice of Aviva Lev-Ari, PhD, RN
Series D: e-Books on BioMedicine – Metabolomics, Immunology, Infectious Diseases, Reproductive Genomic Endocrinology
Series D: is the only series in our BioMed e-Series that focus on the clinical aspects of several biological systems and biological processes in human body:
- Volume One: Metabolic Genomics & Pharmaceutics
- Series D, Volume Two & Three: The Immune System, Stress Signaling, Infectious Diseases and Therapeutic Implications
- Series D, Volume Four: Human Reproductive System, Genomic Endocrinology and Cancer Types
This volume on the human reproductive system, genomic endocrinology and cancer types of the Human reproductive system would not have been possible to have been written by our Team unless we would have had completed covering the most critical biological processes to life, such as Metabolism (Volume 1), the Immune System (Volume 2), Infectious Disease (Volume 3) and the final volume to be presented below, on the Endocrine system, what is known to date in Genomics of endocrine glandes and the cardinal functions played by hormones that are affecting reproduction and infertility, as well as the occurrence and development of cancer in the organs of the reproductive system.
Volume Introduction
Voice of Dr. Stephen J. Williams, PhD
This is the fourth volume of the Series D: e-Books on BioMedicine – Metabolomics, Immunology, Infectious Diseases and Reproductive Genomic Endocrinology.
Whereas the first volume focused on a thorough didactic on the concepts behind metabolomics (the integration of the studies of metabolism but integrating ‘omics features such as big data, metabolome networks, proteomics and protein networks and genomics), the subsequent volumes, and this current one, explains the concepts in light of the clinical challenges we face today. Each of the chapters is geared for the level of a medical student and can be an excellent main source of information or supplemental material for medical school educational purposes. In addition, it can be also used as a reference for licensing board exams, and a reference source to supplement baccalaureate level biology courses.
The current volume, Volume 4, is divided on topics related to Reproductive Genomic Endocrinology and discusses how our current view in endocrinology and embryology has changed due to the advances in genomic, proteomic, and metabolomic technologies, especially in the diagnosis and treatment of diseases and conditions on a hormonal and/or endocrine basis.
First, a general discussion on issues related to human reproduction are discussed, including bioethical concerns not seen in the pre genomics era. Reproductive biology and endocrinology are presented with new knowledge obtained from metabolomic studies. Part 2 discusses embryology emerging from the knowledge we have been acquiring on the cell biology of stem cells, including medical uses of these pluripotent cell types. The book further explains new findings in endocrinology and female and male reproduction as well as new insights into cellular signaling. In the last two chapters, specific examples of new clinical breakthroughs brought on by the combination of our new knowledge of metabolomics, stem cell biology, endocrinology, genomics, and transcriptomics, especially in the areas of diabetes and cancer. New treatments for diabetes, based on reprogramming stem cells are discussed in chapter 9. Chapter 10 discusses cancers related to the endocrine system and how the knowledge of the metabolome and proteome have advanced new treatments in hormonal-based cancers.
Voice of Dr. Aviva Lev-Ari, PhD, RN
This volume is unique in covering in one book the following cardinal interrelated aspects of wellness and disease:
- Causality,
- Intermediation,
- Detection, and
- Dysfunctions, maladaptations and the pathologies of reproductive organs
CAUSALITY
This aspects is presented as Discoveries in Endocrinology: Adrenal Cortex Sex Hormones, Thyroid Function and Disorders. Pituitary Neuroendocrine Axis, Endocrine Action on Midbrain, Pharmacological Action of Steroid Hormones, Changes in Levels of Sex Hormones and N-Terminal Pro–B-Type Natriuretic Peptide as Biomarker for Cardiovascular Diseases and
INTERMEDIATION
Intermediation covers Hypermetabolism, Nutrition and Fertility, Diabetes and Sexual Hormones, Genders redefined by Biology and Personal Care Chemicals and Puberty Onset.
DETECTION by Genomics
NGS Will Revolutionize Reproductive Diagnostics: i.e., Endometriosis: Genomics Diagnosis @UCSF and new fertility marker. Male Sexual Function and Fertility: Male Infertility and Genomics: Fertile men carried a complete set of the sperm RNA elements; however, most of the infertile men did not.
REPRODUCTIVE ORGANS: Dysfunctions and Pathologies
The book covers Impairments in Pathological States: Endocrine Disorders, Stress Hypermetabolism and Cancer. Dedicated chapters are to
- Breast Cancer,
- Ovarian Cancer,
- Cervical and Endometrial Cancer,
- Prostate Cancer.
Not covered in the book is Testicular cancer. It is encouraging to report that in 2020, 5-year relative survival rates for testicular cancer:
| SEER stage | 5-year relative survival rate |
|---|---|
| Localized | 99% |
| Regional | 96% |
| Distant | 73% |
| All SEER stages combined | 95% |
List of Contributors
Links to Bios
Dr. Larry H. Bernstein, MD, FCAP
1.2, 1.3, 1.6, 3.1, 3.2, 3.3, 3.4, 4.1, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.9, 6.6, 8.1, 8.2, 8.3, 8.4, 8.5, 9.1, 9.3, 9.4, 9.5 10.1, 10.2, 10.3.1.1, 10.3.1.3, 10.3.1.4, 10.3.2.7, 10.3.3.3, 10.3.4.1, 10.3.4.2, 10.3.4.3, 10.3.4.5
Prof. Stephen J. Williams, PhD, Editor
PREFACE, Volume Introduction, 4.5, Part 10: Introduction, 10.3.2.1, 10.3.2.2, 10.3.2.9, 10.3.2.10, 10.3.3.4, Part 10: Summary, EPILOGUE
Prof. Sudipta Saha, PhD, Editor
Part 1: Introduction, 1.5, 2.2, 2.3, 2.4, 4.2, 4.4, 5.8, 5.10, 5.11,
Part 6: Introduction, 6.1, 6.2, 6.3, 6.4, 7.1, 7.2, 7.3, 7.4, 7.7, 7.8, 7.9, 7.10, 8.6, 10.3.2.3, 10.3.3.6,
Volume Summary
Dr. Aviva Lev-Ari, PhD, RN, Editor
Volume Introduction, 1.1, 1.4, 4.3, 4.6, 6.5, 6.7, 7.2, 7.5, 7.6, 9.2, 9.5, 10.3.1.2, 10.3.2.4, 10.3.2.5, 10.3.3.1, 10.3.3.2, 10.3.3.5, 10.3.4.2, 10.3.4.4, 10.3.4.5
Dr. Irina Robu, PhD
Part 2, 5, 8, 9: Introductions, 2.1, 10.3.2.8
Prof. Marcus W. Feldman, PhD
Part 7: Introduction, 7.2
Dr. Prabodh Kandala, PhD
Part 10: 10.3.2.6
electronic Table of Contents, Volume Four
Part 1: General Topics on Human Reproduction
Introduction
by Dr. Sudipta Saha, PhD
A gene therapy for blood disorders, a new class of medications for cystic fibrosis, an increased access to telemedicine are some of the innovations that will enhance healing and change healthcare in the coming year according to distinguished panel of clinicians and researchers. This section initially gives a brief account of ten such innovations. Legal rights in birth control, etc. also has been discussed in details in this segment. The other discussion in this section is on female infertility which is a global medical and social condition caused by various pathophysiological alterations. While in developing countries this condition is related to preventive, diagnostic and therapeutic inadequacy, multiple ovarian endocrine dysfunctions in industrialized nations are apparently associated with improper life-styles.
Micronutrients have essential roles in fertility, and inadequate levels can have an adverse impact on the ability to conceive. It has been reported that a proportion of women of childbearing age in general, as well as those who struggle to conceive, have lower than recommended levels of certain micronutrients. Thus, there is a rationale to supplement with vitamins and minerals before conception to optimize nutritional status and perhaps have positive effect on fertility. This segment also discusses the mother-to-child transmission of hepatitis B virus in spite of use of antiviral drug taken during pregnancy and after delivery. Finally the various types of neonatal pathophysiology has been discussed in details.
1.1 Top 10 Medical Innovations for 2018, 2020 and 2021 by Cleveland Clinic
Reporter: Aviva Lev-Ari, PhD, RN
1.2 Reason in Hobby Lobby
Curator: Larry H. Bernstein, MD, FCAP
https://pharmaceuticalintelligence.com/2014/07/08/reason-in-hobby-lobby-3/
1.3 Justice Ginsberg Written Dissent
Curator and Reporter: Larry H. Bernstein, MD, FCAP
https://pharmaceuticalintelligence.com/2014/07/08/justice-ginsberg-written-dissent/
1.4 Micronutrients, Macronutrients and Dietary Patterns: Nutrition and Fertility
Reporter: Aviva Lev-Ari, PhD, RN
1.5 Antiviral drug for hepatitis B not beneficial for reducing mother-to-child transmission
Reporter and Curator: Dr. Sudipta Saha, Ph.D.
1.6 Neonatal Pathophysiology
Writer and Curator: Larry H. Bernstein, MD, FCAP
https://pharmaceuticalintelligence.com/2015/02/22/neonatal-pathophysiology/
Part 2: Innovations in Cell Biology and Embryology
Introduction
by Dr. Irina Robu
2.1 Embryo Stem Cells Out of Skin
Reporter: Irina Robu, PhD
https://pharmaceuticalintelligence.com/2019/05/08/embryo-stem-cells-out-of-skin/
2.2 The Three Parent Technique to Avoid Mitochondrial Disease in Embryo
Reporter and Curator: Dr. Sudipta Saha, Ph.D.
2.3 Mitochondria Replacement Therapy
Curator and Reporter: Dr. Sudipta Saha, Ph.D.
https://pharmaceuticalintelligence.com/2019/04/14/mitochondria-replacement-therapy/
2.4 scPopCorn: A New Computational Method for Subpopulation Detection and their Comparative Analysis Across Single-Cell Experiments
Curator or Reporter: Dr. Sudipta Saha, Ph.D.
https://pharmaceuticalintelligence.com/2019/07/16/scpopcorn-a-new-computational-method-for-subpopulation-detection-and-their-comparative-analysis-across-single-cell-experiments/
Part 3: Cell Signaling
3.1 Signaling transduction tutorial
Reporter and Curator: Larry H. Bernstein, MD, FCAP
https://pharmaceuticalintelligence.com/2014/08/12/signaling-transduction-tutorial/
3.2 Introduction to Signaling
Curator: Larry H. Bernstein, MD, FCAP
https://pharmaceuticalintelligence.com/2014/10/30/introduction-to-signaling/
3.3 Signaling and Signaling Pathways
Curator: Larry H. Bernstein, MD, FCAP
https://pharmaceuticalintelligence.com/2014/08/12/signaling-and-signaling-pathways/
3.4 Summary of Signaling and Signaling Pathways
Author and Curator: Larry H Bernstein, MD, FCAP
https://pharmaceuticalintelligence.com/2014/11/01/summary-of-signaling-and-signaling-pathways/
Part 4: Genomics in Prenatal and Childhood Wellness
Introduction
by Dr. Stephen J. Williams
This chapter discusses the genetic, epigenetic, proteomic and transcriptional aspects of reproductive and neonatal disorders. The chapter starts with a tutorial on the process of transcriptional and epigenetic control of gene expression and also explains, in detail, the process of protein translation. There have been much advances in the area of diagnostic genomics most notably technical breakthroughs in our ability to rapidly and reliably sequence genomes from patients however, over time, it has become clear that one has to look at the totality of changes, including changes in the cellular portrait of proteins, the proteome, and its concordant epigenetic or post translational modifications occurring in the proteome in a given disease, treatment, or patient cohort.
Perspectives on the clinical implications toward understanding the complexities and regulation of the proteome are presented. Technological advances in mass spectrometry have allowed us to analyze changes occurring across the spectrum of cellular protein networks in multiple disease states and proteomic responses to therapies. As discussed in the following articles, the importance of these advances is clearly seen in revolutionizing reproductive diagnostics, and currently is assisting pediatricians in diagnosing and treating multiple childhood disorders in a more personalized medicine paradigm. International experts in these clinical fields weigh in on the impact these advances in analyzing and understanding the changes in these cellular networks play in treating children and patients in a series of panel discussions from clinical conferences.
4.1 Genes, proteomes, and their interaction
Author and Curator: Larry H. Bernstein, MD, FCAP
https://pharmaceuticalintelligence.com/2014/07/28/genes-proteomes-and-their-interaction/
4.2 MicroRNA in Reproduction
Reporter and Curator: Dr. Sudipta Saha, Ph.D.
https://pharmaceuticalintelligence.com/2016/11/09/microrna-in-reproduction/
4.3 Panel Discussion Genomics in Prenatal and Childhood Disorders
Curator or Reporter: Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2014/11/13/100pm-11132014-panel-discussion-genomics-in-prenatal-and-childhood-disorders-10th-annual-personalized-medicine-conference-at-the-harvard-medical-school-boston/
4.4 The function of the junk jumping gene (LINE1) uncovered
Reporter and Curator: Dr. Sudipta Saha, Ph.D.
4.5 How NGS Will Revolutionize Reproductive Diagnostics: November Meeting, Boston MA
Reporter: Stephen J. Williams, Ph.D.
4.6 1:00PM 11/13/2014 – Panel Discussion Genomics in Prenatal and Childhood Disorders @10th Annual Personalized Medicine Conference at the Harvard Medical School, Boston
Reporter: Aviva Lev-Ari, PhD, RN
Part 5: Discoveries in Endocrinology
Introduction
by Dr. Irina Robu
5.1 Roy O. Greep Award for Outstanding Research in Endocrinology
Curator: Larry H Bernstein, MD, FCAP
5.2 The Fred Conrad Koch Lifetime Achievement Award—the Society’s highest honor—recognizes the lifetime achievements and exceptional contributions of an individual to the field of endocrinology
Curator: Larry H. Bernstein, MD, FCAP
5.3 Adrenal Cortex
Writer and Curator: Larry H Bernstein, MD, FCAP
https://pharmaceuticalintelligence.com/2015/02/07/adrenal-cortex/
5.4 Sex Hormones
Author: Larry H Bernstein, MD, FCAP
https://pharmaceuticalintelligence.com/2015/02/07/sex-hormones/
5.5 Thyroid Function and Disorders
Writer and Curator: Larry H. Bernstein, MD, FCAP
https://pharmaceuticalintelligence.com/2015/02/05/thyroid-function-and-disorders/
5.6 Pituitary Neuroendocrine Axis
Writer and Curator: Larry H. Bernstein, MD, FCAP
https://pharmaceuticalintelligence.com/2015/02/04/pituitary-neuroendocrine-axis/
5.7 Endocrine Action on Midbrain
Curator or Reporter: Larry H. Bernstein, MD, FCAP
https://pharmaceuticalintelligence.com/2015/02/12/endocrine-action-on-midbrain/
5.8 Genders redefined by Biology
Reporter and Curator: Dr. Sudipta Saha, Ph.D.
https://pharmaceuticalintelligence.com/2018/03/10/genders-redefined-by-biology/
5.9 Pharmacological Action of Steroid Hormones
Curator: Larry H. Bernstein, MD, FCAP
https://pharmaceuticalintelligence.com/2014/10/27/pharmacological-action-of-steroid-hormones/
5.10 Changes in Levels of Sex Hormones and N-Terminal Pro–B-Type Natriuretic Peptide as Biomarker for Cardiovascular Diseases
Reporter and Curator: Dr. Sudipta Saha, Ph.D.
5.11 Personal Care Chemicals and Puberty Onset
Reporter and Curator: Dr. Sudipta Saha, Ph.D.
https://pharmaceuticalintelligence.com/2018/12/16/personal-care-chemicals-and-puberty-onset/
Part 6: Frontier of Female Endocrinology
Introduction
by Dr. Sudipta Saha, Ph.D.
Infertility is defined as the inability to conceive after one year of regular coitus without contraception. Approximately 10% to 20% of childbearing-age couples are infertile in the United States. The demand for infertility investigations has increased dramatically in recent decades. A lot of advancements have taken place in the last decade in the research of reproduction and fertility. Hormone replacement therapies in menopause are not a good solution as it has its side effects. In replacement bioengineered ovarian constructs may help in the same therapy with natural production of required hormones. Although low AMH and high FSH are general indicators of diminished egg quantity in a female but modern research showed that although these are good predictors of egg content but are not full proof predictors of fertility or pregnancy ability.
A mathematical algorithm based immunological timeline has been proposed by modern research that can predict on the maturity of the fetus. A PGF2α based genetic switch for sexual behavior in females has been identified in fish model. A female libido enhancer like Viagra in male has been identified to treat hypoactive sexual desire disorder in premenopausal women. Scientists have also identified patterns of genetic activity that could help in early detection of disorders like endometriosis that affects millions of women worldwide. Different inhibitors and enhancers of hormones are also identified for the modulation of fertility. In the following section some of these research advancements have been discussed in a concise manner.
6.1 Artificial ovary instead of conventional hormone replacement
Reporter and Curator: Dr. Sudipta Saha, Ph.D.
6.2 The viability of Anti-Müllerian Hormone (AMH) level as fertility marker
Reporter and Curator: Dr. Sudipta Saha, Ph.D.
6.3 The immune system clock of pregnancy
Reporter and Curator: Dr. Sudipta Saha, Ph.D.
https://pharmaceuticalintelligence.com/2017/09/13/the-immune-system-clock-of-pregnancy/
6.4 A genetic switch to control female sexual behavior
Reporter and Curator: Dr. Sudipta Saha, Ph.D.
6.5 Sexual Desire Disorder in Pre-menopausal Women: Addyi (flibanserin) is intended to increase libido – ‘Female Viagra’ approved by FDA
Reporter: Aviva Lev-Ari, PhD
6.6 Hormone Therapy
Writer and Curator: Larry H. Bernstein, MD, FCAP
https://pharmaceuticalintelligence.com/2015/05/15/hormone-therapy-9-4/
6.7 Endometriosis: Genomics Diagnosis @UCSF
Reporter: Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2014/11/24/endometriosis-genomics-diagnosis-ucsf/
Part 7: Male Sexual Function and Fertility
Introduction
By Prof. Marcus W. Feldman, PhD
Burnet C. and Mildred Finley Wohlford Professor of Biology
Director, Morrison Institute for Population and Resource Studies
Co-Director, Stanford Center for Computational, Evolutionary and Human Genomics
Sperm count declines have been correlated with environmental deterioration, lifestyle changes, and overall morbidity and mortality. In Western countries, an increasing proportion of men have sperm counts below the threshold for sub-fertility or infertility. Although tobacco-smoking is a risk factor for infertility, men who have smoked marijuana at some time in their lives show an increase in their sperm count over those who have never smoked it. Some mice without a Y chromosome develop into males. These XOsra are always sterile, while only a minority of XYsra males have anatomical defects and are sterile. Using the pattern of X-ray refraction, filaments of the lysozyme-like protein, SLLP1, which is believed to be involved in targeting the mammalian egg, have been visualized and their structure revealed.
Human male infertility has been shown to be associated with an incomplete set of sperm RNA elements. Testosterone therapy delivered to men aged 65 and above with reduced serum testosterone levels improved sexual function, walking performance, and mood but had no significant effect on alleviating fatigue.
Research towards a male contraceptive pill has been on a backburner for many years. Scientists at Baylor College of Medicine have found that deletion of 30 out of 2,300 genes that are active in testes of mice produces infertility. This suggests an avenue for laboratory testing of chemicals that might disable functions of these genes and suggests targets for a male contraceptive pill. Another male contraceptive target is an enzyme in sperm cells’ outer membrane that is involved in sperm motility. Blocking this enzyme, ABHD2, could produce an effective male contraceptive. A third avenue towards male contraception involves a switching device, inserted in the vas deferens that stops sperm flow through this organ. The device, made of a medical-grade polymer often used in implants, is undergoing clinical trials.
7.1 Trends in Sperm Count
Reporter and Curator: Dr. Sudipta Saha, Ph.D.
https://pharmaceuticalintelligence.com/2017/07/27/trends-in-sperm-count/
7.2 Decline in Sperm Count – Epigenetics, Well-being and the Significance for Population Evolution and Demography
Dr. Marc Feldman, Expert Opinion on the significance of Sperm Count Decline on the Future of Population Evolution and Demography
Dr. Sudipta Saha, Effects of Sperm Quality and Quantity on Human Reproduction
Dr. Aviva Lev-Ari, Psycho-Social Effects of Poverty, Unemployment and Epigenetics on Male Well-being, Physiological Conditions affecting Sperm Quality and Quantity
7.3 Cannabis smoking showed increased sperm count
Curator or Reporter: Dr. Sudipta Saha, Ph.D.
https://pharmaceuticalintelligence.com/2019/02/21/cannabis-smoking-showed-increased-sperm-count/
7.4 Spermatogenic defects in sex reversed mice
Curator or Reporter: Dr. Sudipta Saha, Ph.D.
https://pharmaceuticalintelligence.com/2016/02/29/spermatogenic-defects-in-sex-reversed-mice-2/
7.5 Fertilization: Protein Architecture of the Sperm’s Acrosomal Matrix, Filaments in Sperm Head Organelle Target the Egg
Reporter: Aviva Lev-Ari, PhD, RN
7.6 Male Infertility and Genomics: Fertile men carried a complete set of the sperm RNA elements; however, most of the infertile men did not
Reporter: Aviva Lev-Ari, PhD, RN
7.7 Testosterone treatment improved primarily sexual function than walking or vitality in older men with low testosterone levels
Reporter and Curator: Dr. Sudipta Saha, Ph.D.
7.8 Promising research for a male birth control pill
Reporter and Curator: Dr. Sudipta Saha, Ph.D.
https://pharmaceuticalintelligence.com/2017/03/23/promising-research-for-a-male-birth-control-pill/
7.9 Cellular switch molecule for sperm motility control: a novel target for male contraception and infertility treatments
Reporter and Curator: Sudipta Saha, Ph.D.
7.10 Lifelong Contraceptive Device for Men: Mechanical Switch to Control Fertility on Wish
Reporter and Curator: Dr. Sudipta Saha, Ph.D.
Part 8: Metabolomics and Microbiome Genomics
Introduction
by Dr. Irina Robu, PhD
8.1 Metabolic Genomics and Pharmaceutics, Vol. 1 of BioMed Series D available on Amazon.com Kindle Store
http://www.amazon.com/dp/B012BB0ZF0
Author: Larry H. Bernstein, MD, FCAP
8.2 Introduction to Metabolomics
Author: Larry H. Bernstein, MD, FCAP
https://pharmaceuticalintelligence.com/2014/10/21/introduction-to-metabolomics/
8.3 Metabolomics Summary and Perspective
Author and Curator: Larry H Bernstein, MD, FCAP
https://pharmaceuticalintelligence.com/2014/10/16/metabolomics-summary-and-perspective/
8.4 Summary to Metabolomics
Author and Curator: Larry H. Bernstein, MD, FCAP
https://pharmaceuticalintelligence.com/2014/11/08/introduction-to-metabolomics-2/
8.5 Lipid Metabolism
Reporter and Curator: Larry H. Bernstein, MD, FCAP
https://pharmaceuticalintelligence.com/2014/08/15/lipid-metabolism/
8.6 Controversy prevails on whether C-section babies need mother’s microbes
Curator or Reporter: Dr. Sudipta Saha, Ph.D.
Part 9: Diabetes and the Insulin Treatment
Introduction
by Dr. Irina Robu, PhD
Over the years, occurrence of diabetes has increased not only nationally and globally. It is currently, the leading cause of mortality. And the underlying cause of diabetes varies by type, but all can lead to excess sugar in the blood. Diabetes is a condition in which the body can’t regulate or properly use sugar in the blood. The pancreas plays an essential role in controlling the levels and within the pancreas hundreds of cells, known as islets of Langerhands regulate blood glucose. The beta cells inside the islets produce insulin which is then released into the blood stream. And when sugar level reaches a specific threshold, it then signals the other cells to take up sugar. And as a result, the human body is always balancing the blood sugar. But in diabetes the blood sugar is elevated because either the pancreas doesn’t produce enough insulin, type I diabetes or because the cells in the body fail to respond to the insulin ( type II diabetes)
Type 1 diabetes can develop at any age, but it is more common in childhood and adolescence, whereas type 2 diabetes is more common in people over the age of 40.
With no full cure available, the range of management options are needed such as finger pricks, blood tests, meal planning and painful injections. The current treatment for diabetes focuses more on monitoring blood glucose levels in addition to noninsulin therapies such as insulin sensitizers, alpha-glucosidase inhibitors, incretins, pramlintide, bromocriptine and insulin therapies (insulin and insulin analogues). Type I diabetes patients struggle to balance their blood sugar and are given insulin to help them control the glucose levels multiple times a day. Type II diabetes patients can control it via diet and exercise, but some of them have to take up insulin injections to control sugar levels or additional medications to deal with the complications of the disease. Despite the ability to monitor blood glucose in real time, recombinant insulins and noninsulin therapies, treatment for diabetes remains less than ideal.
Even though, cell therapy is one of the biggest hopes near emerging a cure for diabetes. One problem with transplantation of islets is that patients need to be given islets from more than one organ donor, which means the patients who receive the transplant need powerful immunosuppressants drugs to stop the immune system from attacking the new islets. Replacing the absent insulin producing cells could possibly recover normal insulin production and cure patients.
One of the best alternatives comes from the Diabetes Research Institute in US , is currently developing a bioengineered mini-organ where insulin-producing cells are encapsulated within a protective barrier. And in 2016, the institute announced that the first patient in Europe treated with this in an ongoing phase trial I/II no longer needs insulin therapy. A similar device is being developed by Viacyte, where after the phase I trial, the company is working on revamping the engraftment of insulin-producing cells. Another by Orgenesis where cells from the patient’s liver are transformed into insulin-producing cells to avoid the issues of sourcing cells from donors.
There have been countless improvements to reduce the toll from diabetes-related complications through enhancements in insulin administration and glucose monitoring, but the perfect treatment will be the replacement of the missing insulin-producing pancreatic beta cells.
9.1 Fat Cells Reprogrammed to Make Insulin
Curator: Larry H. Bernstein, MD, FCAP
https://pharmaceuticalintelligence.com/2016/04/14/fat-cells-reprogrammed-to-make-insulin/
9.2 Diabetes is caused by Leaky Calcium Channels in Pancreatic Beta Cells – research @Columbia University Medical Center: The Role of RyR2 in Regulation of Insulin Release and Glucose Homeostasis
Reporter: Aviva Lev-Ari, PhD, RN
9.3 Gastrointestinal Endocrinology
Writer and Curator: Larry H Bernstein, MD, FCAP
https://pharmaceuticalintelligence.com/2015/02/10/gastrointestinal-endocrinology/
9.4 Pancreatic Islets
Writer and Curator: Larry H. Bernstein, MD, FCAP
https://pharmaceuticalintelligence.com/2015/02/08/pancreatic-islets/
9.5 Metformin, thyroid pituitary axis, diabetes mellitus, and metabolism
Author and Curator: Larry H, Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN
Part 10: Cancer of the Human Reproductive and
Genitourinary Systems
10.1 Introduction to Impairments in Pathological States: Endocrine Disorders, Stress Hypermetabolism and Cancer
Author and Curator: Larry H. Bernstein, MD, FCAP
10.2 Summary and Perspectives: Impairments in Pathological States: Endocrine Disorders, Stress Hypermetabolism and Cancer
Author and Curator: Larry H. Bernstein, MD, FCAP
10.3 Cancers Types in the Human Reproductive and Genitourinary Systems
Introduction
by Stephen J. Williams, PhD
The following chapter deals with hormone-related cancers, these being cancers predominantly arising in the genitourinary system and including breast cancer, as well as the thyroid and osteosarcoma. Before the mid 80’s, oncogenesis was seen the result of uncontrolled cellular proliferation, and the focus in the cancer field was on abhorrent cell cycle regulation. However, it became apparent the etiology of many cancers involved and required the presence of hormonal factors (reviewed in (Henderson & Feigelson, 2000).
These group of cancers were referred to as the hormone-related cancers, some of which are highlighted in this chapter. This new developing polygenic model of cancer predisposition ultimately led to a paradigm shift in the detection, chemoprevention, and treatment of such cancers, namely using molecular biomarkers of hormone receptors to classify tumors (detection) with the hormone antagonists like tamoxifen and raloxifene (prevention) and other Synthetic Estrogen-Modulators (or SERMS) and antiandrogens (treatment). Some details of the history and underlying discoveries which led to this paradigm shift will be discussed in the Epilogue of this Chapter.
It has become established that many risk factors for the development of cancer involves hormonal balances. For instance, estrogens unopposed to progestins are a known risk factor for endometrial cancer (Henderson, Ross, Pike, & Casagrande, 1982; Key & Pike, 1988a, 1988b). Estrogens also have been implicated as a risk in the etiology of breast cancer with evidence from both animal models and from epidemiologic data. Very compelling data from studies on menarchie (ovulatory cycle) and oral contraceptive use as well as data from the hormone replacement studies have linked estrogens and reproductive cycling to incidence of breast cancer.
With respect to risk factors in the etiology of ovarian cancer, it had been known that nulliparity, or lack of giving offspring, is a very high-risk factor for development of ovarian cancer. Conversely, use of oral contraceptives, including estrogen and high-dose progestin, is negatively correlated with ovarian cancer risk and deemed as a preventative measure. Interestingly, although treatment of breast, prostate and endometrial cancers, especially those with corresponding hormone receptor positive status have been successfully treated with anti-hormonal agents, this cannot be said for treatment regiments for ovarian cancer, where for thirty years the mainstay therapeutic regimen has been a platinum analog with a taxane. Below is a table of corresponding risk factors and protective factors related to hormones.
Table. Risk and Protective factors of hormonal basis for various cancers
| Breast Cancer | Endometrial Cancer | Ovarian Cancer | |||
| Risk factors | Protective factors | Risk factors | Protective factors | Risk factors | Protective factors |
| Increased hormone | Oral contraceptive | Unopposed estrogen | Decrease estrogen | Nulliparity | Multiparity |
| Early menarche | Young age at first baby | Sequential Oral contraceptives | Combined oral contraceptives | Fertility treatment | Oral contraceptives |
| Late menopause | Prolonged lactation | Estrogen replacement | pregnancy | ||
| Hormone replacement | raloxifene | ||||
However, due to our new ability to genetically classify tumors, it has been identified that many high-risk breast and ovarian cancers have a genetically heritable component, although usually this is only about 10% of cancers. Although this may seem disadvantageous, our new found ability to define genetic sub-cohorts of patients, in the instance of breast, endometrial, and ovarian cancer into BRCA wild type or mutants has ushered in a new paradigm for treatment, such as the use of PARP inhibitors in these patients to produce what is termed “synthetic lethality”. Synthetic lethality happens when the cytotoxicity of a certain drug is greatly enhanced or “appears” due to a certain genetic background such as a genetic defect or gain of function. In the case of cancers exhibiting a BRCA1/2 mutation and subsequent loss of the higher fidelity homologous recombination repair of DNA lesions, the inhibition of PARP1 forces the cell into the more error prone nonhomologous repair mechanisms and subsequent increases the frequency of DNA strand breaks. For reference the reader is directed to a great review and following figures by Thomas Helleday (Helleday, 2011).
Figure from (Helleday, 2011). Pathways underlying PARP-BRCA synthetic lethality. (A) SSB replication run-off model. PARP-1 is involved in repair of SSBs, which may in the presence of
a PARP inhibitor persist and collapse a replication fork into a one-ended DSB. Since BRCA defective cancer cells lack HR, the resulting DSBs would be selectively toxic to the cancer cells. (B) PARP-1 trapping model. PARP inhibitors trap PARP-1 onto SSBs formed spontaneously or as an intermediate during BER. Trapped PARP-1 may pose an obstacle to replication that would require HR to bypass. (C) Replication restart model. In the case of normal replication, forks will stall owing to lack of replication factors or by obstacles on the DNA template. PARP and HR are activated at stalled forks and mediate distinct pathways for restart. The advent of the addition of PARP inhibitors for ovarian cancer has been the first major therapeutic advance for this disease in over thirty years.
References
Helleday, T. (2011). The underlying mechanism for the PARP and BRCA synthetic lethality: clearing up the misunderstandings. [Review]. Mol Oncol, 5(4), 387-393. doi: 10.1016/j.molonc.2011.07.001
Henderson, B. E., & Feigelson, H. S. (2000). Hormonal carcinogenesis. [Review]. Carcinogenesis, 21(3), 427-433. doi: 10.1093/carcin/21.3.427
Henderson, B. E., Ross, R. K., Pike, M. C., & Casagrande, J. T. (1982). Endogenous hormones as a major factor in human cancer. [Review]. Cancer Res, 42(8), 3232-3239.
Key, T. J., & Pike, M. C. (1988a). The dose-effect relationship between ‘unopposed’ oestrogens and endometrial mitotic rate: its central role in explaining and predicting endometrial cancer risk. Br J Cancer, 57(2), 205-212. doi: 10.1038/bjc.1988.44
Key, T. J., & Pike, M. C. (1988b). The role of oestrogens and progestagens in the epidemiology and prevention of breast cancer. [Review]. Eur J Cancer Clin Oncol, 24(1), 29-43. doi: 10.1016/0277-5379(88)90173-3
10.3.1 Breast Cancer
10.3.1.1 Targeted Therapy for Triple Negative Breast Cancer
Curator: Larry H. Bernstein, MD, FCAP
10.3.1.2 No Significant Long-term Risk of Breast Cancer caused by Ovarian Stimulation for in Vitro Fertilization
Reporter: Aviva Lev-Ari, PhD, RN
10.3.1.3 New Risk Stratification for Breast Cancer
Curator: Larry H. Bernstein, MD, FCAP
https://pharmaceuticalintelligence.com/2016/03/18/new-risk-stratification-for-breast-cancer/
10.3.1.4 Breast Cancer Extratumor Microenvironment has Effect on Progression
Curator: Larry H. Bernstein, MD, FCAP
10.3.2 Ovarian Cancer
10.3.2.1 Study Finds that Both Women and their Primary Care Physicians Confusion over Ovarian Cancer Symptoms May Lead to Misdiagnosis
Reporter: Stephen J. Williams, PhD
10.3.2.2 A Curated History of the Science Behind the Ovarian Cancer β-Blocker Trial
Curator: Stephen J. Williams, PhD
10.3.2.3 Beta-Blockers help in better survival in ovarian cancer
Curator: Dr. Sudipta Saha, Ph.D
10.3.2.4 Efficacy of Ovariectomy in Presence of BRCA1 vs BRCA2 and the Risk for Ovarian Cancer
Reporter: Aviva Lev Ari, PhD, RN
10.3.2.5 Testing for Multiple Genetic Mutations via NGS for Patients: Very Strong Family History of Breast & Ovarian Cancer, Diagnosed at Young Ages, & Negative on BRCA Test
Reporter: Aviva Lev Ari, PhD, RN
10.3.2.6 Squeezing Ovarian Cancer Cells to Predict Metastatic Potential: Cell Stiffness as Possible Biomarker
Reporter/curator: Prabodh Kandala, PhD
10.3.2.7 Targeting PARP
Curator: Larry H. Bernstein, MD, FCAP
https://pharmaceuticalintelligence.com/2016/05/19/targeting-parp/
10.3.2.8 Efficiency of PARP inhibitors beyond BRCA mutations
Reporter: Irina Robu, PhD
10.3.2.9 Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on Novel Targets and Therapies 2:35PM
Reporter: Stephen J. Williams, PhD
10.3.2.10 Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 27, 2020 Mini symposium on Drugging Undrugged Cancer Targets 1:30 pm – 5:00PM
Reporter: Stephen J. Williams, PhD
10.3.3 Cervical and Endometrial Cancer
10.3.3.1 New Findings in Endometrial Cancer: Mutations, Molecular Types and Immune Responses Evoked by Mutation-prone Endometrial, Ovarian Cancer Subtypes
Curator: Aviva Lev-Ari, PhD, RN
10.3.3.2 Inactivation of the human papillomavirus E6 or E7 gene in cervical carcinoma cells using a bacterial CRISPR/Cas
Author: Aviva Lev-Ari, PhD, RN
10.3.3.3 Papilloma viruses for cervical cancer
Curator: Larry H. Bernstein, MD, FCAP
https://pharmaceuticalintelligence.com/2015/10/10/papilloma-viruses-for-cervical-cancer/
10.3.3.4 National Cancer Institute Director Neil Sharpless says mortality from delays in cancer screenings due to COVID19 pandemic could result in tens of thousands of extra deaths in next decade
Reporter: Stephen J Williams, Ph.D.
10.3.3.5 Head and Neck Cancer Studies Suggest Alternative Markers More Prognostically Useful than HPV DNA Testing
Reporter: Aviva Lev-Ari, PhD, RN
10.3.3.6 Exome sequencing of serous endometrial tumors shows recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes
Curator: Dr. Sudipta Saha, Ph.D
10.3.4 Prostate Cancer
10.3.4.1 Who and when should we screen for prostate cancer?
Curator: Larry H. Bernstein, MD, FCAP
https://pharmaceuticalintelligence.com/2016/01/07/who-and-when-should-we-screen-for-prostate-cancer/
10.3.4.2 Prostate Cancer: Diagnosis and Novel Treatment – Articles of Note @PharmaceuticalIntelligence.com
Curators: Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN
10.3.4.3 Targeting PARP in Prostate Cancer
Curator: Larry H. Bernstein, MD, FCAP
https://pharmaceuticalintelligence.com/2016/06/10/targeting-parp-in-prostate-cancer/
10.3.4.4 Prostate Cancer: Androgen-driven “Pathomechanism” in Early-onset Forms of the Disease
Curator: Aviva Lev-Ari, PhD, RN
10.3.4.5 Cancer Signaling Pathways and Tumor Progression: Images of Biological Processes in the Voice of a Pathologist Cancer Expert
Cancer Expert Author and Illustration Curator: Larry H Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN
Summary of Part 10
by Stephen J. Williams, PhD
A Century of discovery to the development of estrogen-modulatory therapy – a brief history
The discovery that cancer growth could be driven by hormones
Late 19th Century
The discoveries in the later 19th century discovery laid the groundwork for the development, a century later, of tamoxifen and other selective estrogen modulators (SERMs), important today in the treatment and prevention of breast cancer. In 1878 Thomas Beatson discovered that the breasts of rabbits stopped producing milk after he removed the ovaries. His results were presented to the Edinburgh Medico-Chirurgical Society in 1896:
“This fact seemed to me of great interest, for it pointed to one organ holding control over the secretion of another and separate organ.”
Because the breast was “held in control” by the ovaries, Beatson decided to test removal of the ovaries (called oophorectomy) in advanced breast cancer and found that oophorectomy often resulted in improvement for breast cancer patients. He also suspected that “the ovaries may be the exciting cause of carcinoma” of the breast. He had discovered the stimulating effect of the female ovarian hormone (estrogen) on breast cancer, even before the hormone itself was discovered. However, it was not until 1929, by Adolf Butenandt and Edward Doisy, that the ovarian hormone in question was purified and identified as estrogen.
Mid 1900’s and the Discovery of the Estrogen Receptor: Elwood Jensen
Up to the 1950’s, most believed the mechanism of action of estrogen on tissue growth relied on the enzymatic hydroxylation at the 17-β position of estradiol utilizing NADH. However, this hypothesis did not explain the uterotropic effects of the synthetic estrogen analog diethylsilbestrol, which did not need to be hydroxylated for it growth enhancing effects. With lessons learned from a steroid chemistry fellowship in Zurich under Nobel laureate Leopold Ruzicka, Elwood Jensen went to University of Chicago as faculty under the head of Charles Huggins, who won the Nobel for his work on prostate cancer. There, Elwood, along with postdoctoral fellow Herbert Jacobson, started to investigate how small amounts of estrogen affected uterine tissue growth.
Although their initial plan to investigate potential targets of estrogen binding was hindered by the fact that, at that time Chicago did not allow experimentation with radionuclides (specifically tritiated estrogen), a local lab at Argonne National Laboratories, home of the Fermi lab notorious as a laboratory involved in the first nuclear bomb, allowed such experimentation.
They noted that an unmodified estrogen could promote uterine tissue growth. When the finding of the now debunked enzymatic theories was announced it did not receive much fanfare, and Jensen and colleagues termed the factor which bound to estrogen as “estrophilin”, later to be identified as the estrogen receptor. Subsequently, sedimentation gradient experiments by John Baxter, Pierre Chambon (who also discovered the retinoid receptors and figured out retinol signaling), Ron Evans, Bert O’Malley (a pioneer in nuclear receptor signaling and the progesterone receptor) and Keith Yamamoto led to discoveries of multiple nuclear steroid hormone receptors, ushering in a new biological cascade which could be taken advantage of for therapeutic uses. After Jack Gorski and Elwood Jensen discovered additional forms of estrogen receptors, including the cytoplasmic and nuclear forms, these additional discoveries helped Bert O’Malley’s group to show how activation of these receptors by the binding of estrogen led to activation of the transcription of multiple genes related to the cell cycle and cellular growth.
1990s: Structure/function studies of the estrogen receptor, inhibitors, and cancer therapy.
A few technologic advances such as enhanced X-ray crystallography, enzymatic radioimmunoassays, and molecular techniques developed in the 90’s allowed for the structure determination and development of specific estrogen receptor antagonists. These tools now allowed cancer researchers the ability to tease out the clinical utility and role of the estrogen receptor in hormonally sensitive cancers like breast cancer. The advances led to the discovery of one of the most impactful therapies to that date which revolutionized breast cancer treatment and led to the early push for the next era in cancer therapy, the so-called ‘precision-medicine era’. To understand this, one needs to look no further than the research of Dr. Craig Jordan, the ‘father of tamoxifen’, of which the following articles are dedicated to.
V. Craig Jordan OBE, PhD and the discovery of SERMs and Tamoxifen
Craig Jordan, OBE, PhD, has been recognized by the Endocrine Society as the 2018 Laureate of the Gerald D. Aurbach Award for Outstanding Translational Research. Dr. Jordan is the Dallas/Fort Worth Living Legend Chair of Cancer Research in the Department of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center.
Once in a while, one gets lucky enough in science to be at an institution surrounded by the greats in science. For me that was years I spent at The Fox Chase Cancer Center among great cancer researchers such as Nobel Laureates Baruch Blumberg (Hepatitis B vaccine and causality in liver cancer), Joseph Testa, Philip Tsichlis and Alfonso Bellacosa (discovery of AKT2), Nobel Laureates Erwin Rose (ubiquitin and protein degradation). There I was able to meet and interact with Dr. Jordan, who is referred to as the “father of tamoxifen,” for his work in reinventing a failed contraceptive known as ICI 46,474 as a breast cancer treatment. It always was impressive to me that such greats of science were also the most congenial, collaborative, and helpful individuals I had the pleasure to either work with or meet.
Dr. Jordan also developed the strategy of long-term adjuvant tamoxifen therapy, as well as describing and deciphering the properties of a new group of medicines called selective estrogen receptor modulators, and the first to discover the preventive abilities of both tamoxifen and the drug raloxifene.
His Laureate citation reads:
“For the discovery and development of a novel group of medicines called selective estrogen receptor modulators (SERMs) applied to address the treatment and prevention of major diseases in women. Ideally, the SERMs switch off estrogen target tissues in the breast and uterus to prevent cancer and switch on tissues to maintain bone density or lower circulating LDL to prevent coronary heart disease. The discovery that tamoxifen is metabolically activated to 4-hydroxytamoxifen (4-OHT) with a 100-fold increased affinity for the ER became the lead compound for the new SERMs raloxifene, bazedoxifene, and lasofoxifene.
Tamoxifen and raloxifene are the pioneering SERMs whose diverse applications in breast cancer treatment and prevention, as well as osteoporosis, have extended countless women’s lives. Each has scientific origins through pharmacologic discoveries in Jordan’s laboratory. Few other mechanisms-specific medicines have such broad applications. This success has stimulated all future applications for selective nuclear receptor modulators in medicine.”
Dr. Jordan has been recognized by ASCO with the American Cancer Society Award and Lecture (2006) and the David A. Karnofsky Award and Lecture (2008). In 2014, Dr. Jordan was named as one of the 50 Oncology Luminaries for his identification of the strategic applications of tamoxifen as treatment for patients with breast cancer. He has also been recognized by Queen Elizabeth and Princess Diana for his pioneering work which has saved countless lives of breast cancer patients.
An important reference on the use of SERMs such as tamoxifen and raloxifene is V. Craig Jordan. Tamoxifen or Raloxifene for Breast Cancer Chemoprevention: A Tale of Two Choices—Point. Cancer Epidemiol Biomarkers Prev November 1 2007 (16) (11) 2207-2209; DOI: 10.1158/1055-9965.EPI-07-0629
The use of SERMs now necessitated the molecular classification of Estrogen Receptor status of breast cancers and ushered in a new paradigm of precision medicine, determining clinical strategy based on molecular biomarkers specific for a given drug’s efficacy. In addition, at the same time the ongoing problem of acquired resistance to estrogen modulators, antagonists need to be dealt with. The above mentioned discoveries of the utility of PARP inhibitors, which use is also based on the identification of a mutant biomarker for its efficacy, namely loss or mutant BRCA1/2, is now a new weapon needed to combat the advent of acquired resistance to previous developed therapies. Just as discoveries a century ago had led to new paradigms of therapy, so too must today’s discoveries be translated, in the future, to therapies to circumvent the resistance developed by therapies coming to light now.
The War Will Unfortunately Go On!
Volume Summary by
Prof. Sudipta Saha, PhD, Editor
Although lot of researches are going on in reproductive biology, still it is one of the less explored field in biology compared to other study areas. Infertility is one of the major modern day problems arising from occupational hazards and lifestyle and it is also a social stigma in many societies. Added to this are the related hormonal problems and cancers. We may know the basics of reproduction as in vitro fertilization is regularly in practice nowadays worldwide but much is yet to be known about sperm motility, sperm-egg interaction and fertilization in details.
This book volume deals many such researches which are trying to put some light on the area of reproductive endocrinology and related areas. The volume starts with legal matters of reproductive rights and then goes through stem cell, cell signalling, genomics and endocrinology of reproduction. It speaks about the advancements in male and reproductive endocrinology. In recent years, the development of new technologies capable of monitoring genome function has resulted in fewer hopeful estimates and increasingly solid depictions of genome output from individual samples. It is now known that rarely a single gene can causes a disease. Multiple factors including our genome and environmental factors all play a role. The Human Genome Project and subsequent genomic revolution has not only led to advances in medicine but affects many other areas of our lives, e.g. veterinary sciences and agriculture. Advances in endocrinology genomics nowadays are helping with new diagnostic and therapeutic strategies in many conditions. In the future, all clinicians will need to become increasingly comfortable with embedding genomics into the day-to-day clinical practice, to tailor patients’ management plans to deliver more personalised medical care.
Reproductive genomics is a broad topic that includes developmental aspects, male/female/transgender populations, gametes/embryo/implantation, and the impact of reproductive disorders. Presently genetic screening of an individual is also possible before the stage of implantation. This book also relates metabolomics, microbiome genomics and some other endocrine problems with reproductive biology. Then the book talks about different types of male and female cancers related to reproduction. Therefore, this book volume gives a total idea of problems related to reproductive endocrinology and modern research advancements related to the field.
EPILOGUE by
Prof. Stephen J. Williams, PhD, Editor
This Volume explores ideas and discussions that have a deep human impact both in creating life and preventing human death. The material covered focuses on innovations in human reproduction from cellular biology to embryo stem cells, cell signaling, and genomics inclusive of NGS. Further topics include discoveries in general reproductive endocrinology and specifically at the frontier of female endocrinology artificial ovaries, the immune system clock during pregnancy and the genomics of endometriosis. Additional topics include advances in male sexual function and fertility, and metabolomics and microbiome genomics. The exciting parts of this Volume are the implications on clinical conditions such as, diabetes and insulin treatment, cancers types of the reproductive and genitourinary systems, breast cancer, ovarian cancer, cervical and endometrial cancer and prostate cancer. None of the topics in this Volume are theoretical; they are quite proven eloquently and in significant depth. The science in this Volume aims at genuine deep knowledge about truly complex systems that can change the real world for the sake of humankind.
However, to have a discussion on the impact that genomics is currently having or will have in clinical practice of reproductive endocrinology and precision medicine, we must look back at some of the predictions for the potential of genomics at the advent of this field. For this we go to Dr. Francis Collins, the spearhead for the Human Genome Project and his eloquent opinion piece in Nature from 2003 entitled A Vision for the Future of Genomics Research (Collins et al., 2003). As Dr. Collins notes, just as the great discoveries by Mendel, the determination of the genetic code and structure, and the establishment of high throughput sequencing techniques were critical for the success of the Human Genome Project, so will the efforts to map the whole human genome, together with the resultant technologies of genomics, be critical for the next era of precision medicine to come. The Human Genome Project’s new research strategies and experimental technologies resulted in an ever-expansive treasure trove of genetic data and insights into normal human physiology as well as pathologic diseases. Together with advanced and more powerful computing and bioinformatic algorithms, the results from this herculean effort would have, as he theorized, transform our ability to curate, analyze, and manipulate all sorts of genomic data for the purposes of treating patients in a more personalized manner.
While the HGP was starting, the initiators of this project also had the foresight to make an investment into studying the ethical, legal, and social implications of genomics research and its applications. This had resulted in policy boards comprising of scholars in bioethics, law, social science, clinical research, theology, and public policy to evaluate any ill effects of the new technologies on society. Dr. Collins, after having numerous discussions with the experts in the field, envisioned the future of genomics to be structured as a building, with the Human Genome Project as the Foundation and multiple floors or themes resting above such as:
- Genomics to biology
- Genomics to health
- Genomics to society
with each of these themes he presented with bold grand challenges centered on pillars of education, ethics, training, technological development, computational biology, and open access resources to scientists and clinicians. Collins and others understood the need for sound policy development bases on these pillars, themes, and foundation of the HGP. It was also predicted that such an effort of broad sweeping changes would only occur with public support and an “environment where traditional boundaries become ever more porous”.
This takes us to the current time and in an article Where is Genomics Going Next, Barbara Cheifet discusses the potential for even greater advances in the coming years with the journal Genome Biology Editorial Board (Cheifet, 2019). A few quotes from this paper include:
Genomics is a key underpinning for metagenomics. This is the case because reference-based approaches are dramatically faster and more accurate than reference-free approaches whenever the reference database is complete and correct. However, with a few exceptions (such as bacteria in the human gut of healthy Western adults), we are far from having adequate reference data.
—— Rob Knight, University of California San Diego
I believe that, increasingly, genomics will be integrated with other biological studies, such as studies of evolution, comparative genomics, transcriptomics and other Omics as well as large-scale functional studies.
I can suggest a few specifics:
1.
Structural genomics will increasingly involve the comparison of multiple genomes rather than single-species genomics. These comparisons can be quite comprehensive, offering insights above those that can be achieved by studies of a number of genes alone, or by synthetic analysis, or through deduction of ancestral genomes.
2.
Genome-wide analysis of evolutionary questions, such as studies of genes that are important for development or physiology or studies of the evolutionary genomics of human diseases that have a complex genetic basis, such as heart disease and diabetes.
3.
Genome biology of cis regulatory elements and of non-coding RNAs, with reference to functional studies and comparative analyses.
——— Hong Ma, Fudan University
The genomics field has matured, and the emphasis could now be shifting from methods-focused approaches to more theory-focused approaches, with stronger roles for machine learning in uncovering underlying principles. High-throughput sequencing and methods that rely on it have been the main driving force of genomics in the past decade. In the future, hypotheses that are based on genomic data could be investigated more thoroughly, for example with the use of CRISPR-Cas-based approaches.
———– Jernej Ule, Francis Crick Institute
And other studies such as whole exome sequencing and genome wide association in massive populations using the technologies and analytical methods emanating from the Human Genome Project were now feasible to utilize for precision medicine strategies in cardiovascular disease for example (Hou et al., 2020).
These technologies were also finding utility in determining genetic risk factors associated with fetal malformations and spontaneous abortion. Using whole exome sequencing Guo and others were able to identify multiple genetic risk factors involved in reproductive disorders
{(Guo et al., 2018) and references within}.
In the field of genomic endocrinology, a number of novel disease related genes, for endocrine disorders such as hypogonadotropic hypogonadism, congenital hyperinsulemia, have been elucidated from genomics studies. In The Future of Genomic Endocrinology, Dattani and Martinez-Barbara, note that many of these discoveries were direct result of sequencing of the human genome and genome wide association studies of disease populations (Dattani and Martinez-Barbera, 2011). These studies have made use of the rapid advances in next generation sequencing and whole genome analysis. However they note that the major challenges will be the interpretation of vast amounts of data generated using these techniques. Additionally, a unique challenge in the area of endocrinologic disorders is the fact that many of these disorders are inherited in a dominant fashion and display variability in clinical manifestation due to differences in penetrance. Also, many diseases are polygenic, which complicates the analysis of GWAS data.
However, this brings us to the present and the challenges which exist today, particularly those challenges which have surfaced now yet issues brought up by Dr. Collins years ago, namely the social inequities which may result from genomics research and precision medicine.
Dr. Amy McGuire focuses on this unique problem in The Road Ahead in Genetics and Genomics (McGuire et al., 2020). As Dr McGuire notes,
“As we embark on the third decade of this century, we are now faced with the prospect of being able not only to more accurately predict disease risk and tailor existing treatments on the basis of genetic and non-genetic factors but also to potentially cure or even eliminate some diseases entirely with gene-editing technologies. These advances raise many ethical and policy issues …”.
In order to make genomics truly equitable requires a multifaceted approach. We have already seen the inequities in the COVID-19 pandemic with African Americans and with breast cancer treatment in the poorer parts of the Appalachia as well as in African nations. Three areas are proposed to alleviate these genomic inequities:
- Ensure equitable representation in genomics research
- There must be equitable access to that research
- Striving to achieve more equitable outcomes from genomic medicine
If we can address these three problem areas, we might come to the full realization of Dr. Collins vision for the post genomic age.
As the post genomic age evolves, investigators in this field of reproductive and endocrine genomics have found it necessary to conduct new lines in research in a more collaborative way, which fosters innovation and more rapid discovery. This is evident in places such as Cornell University’s The Center for Reproductive Genomics founded in 2006.
This team effort has produced new findings in reproductive sciences such as:
- Role of non-coding RNAs and DNA repair in reproduction and germ cell development
- Elucidation of new signaling pathways of the hypothalamic-pituitary-gonadal axis
- Use of CRSPR-Cas9 to generate single nucleotide polymorphisms that mimic human infertility
- Understanding sperm function to aid assisted reproduction in endangered species
- Determining how cancer stem cells function in ovarian, breast cancer and germ cell tumors
References
Cheifet, B. (2019). Where is genomics going next? Genome biology 20, 17.
Collins, F.S., Green, E.D., Guttmacher, A.E., and Guyer, M.S. (2003). A vision for the future of genomics research. Nature 422, 835-847.
Dattani, M.T., and Martinez-Barbera, J.P. (2011). The future of genomic endocrinology. Frontiers in endocrinology 2, 11.
Guo, W., Zhu, X., Yan, L., and Qiao, J. (2018). The present and future of whole-exome sequencing in studying and treating human reproductive disorders. Journal of genetics and genomics = Yi chuan xue bao 45, 517-525.
Hou, Y.C., Yu, H.C., Martin, R., Cirulli, E.T., Schenker-Ahmed, N.M., Hicks, M., Cohen, I.V., Jonsson, T.J., Heister, R., Napier, L., et al. (2020). Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging. Proceedings of the National Academy of Sciences of the United States of America 117, 3053-3062.
McGuire, A.L., Gabriel, S., Tishkoff, S.A., Wonkam, A., Chakravarti, A., Furlong, E.E.M., Treutlein, B., Meissner, A., Chang, H.Y., Lopez-Bigas, N., et al. (2020). The road ahead in genetics and genomics. Nature reviews Genetics 21, 581-596.
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