Leaders in Pharmaceutical Business Intelligence (LPBI) Group

Series C: e-Books on Cancer & Oncology

VOLUME ONE 

Cancer Biology and Genomics

for

Disease Diagnosis

2015

http://www.amazon.com/dp/B013RVYR2K

Stephen J. Williams, PhD, Senior Editor

sjwilliamspa@comcast.net

Tilda Barliya, PhD, Editor

tildabarliya@gmail.com

Ritu Saxena, PhD, Editor

ritu.uab@gmail.com

Leaders in Pharmaceutical Business Intelligence 

A scanning electron micrograph of a squamous cell carcinoma, a type of skin cancer. The cell has been frozen and split open to reveal its nucleus.

Credit: Anne Weston, LRI, CRUK. Wellcome Images

Aviva Lev-Ari, PhD, RN

Editor-in-Chief BioMed e-Series of e-Books

Leaders in Pharmaceutical Business Intelligence, Boston

avivalev-ari@alum.berkeley.edu

Other e-Books in the BioMedicine e-Series

Series A: e-Books on Cardiovascular Diseases

Content Consultant: Justin D Pearlman, MD, PhD, FACC

Volume One: Perspectives on Nitric Oxide

Sr. Editor: Larry Bernstein, MD, FCAP, Editor: Aviral Vatsa, PhD and Content Consultant: Stephen J Williams, PhD

available on Kindle Store @ Amazon.com

http://www.amazon.com/dp/B00DINFFYC

Volume Two: Cardiovascular Original Research: Cases in Methodology Design for Content Co-Curation

Curators: Justin D Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP, Aviva Lev-Ari, PhD, RN

• Causes
• Risks and Biomarkers
• Therapeutic Implications

Volume Three: Etiologies of CVD: Epigenetics, Genetics & Genomics

Curators: Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

• Causes
• Risks and Biomarkers
• Therapeutic Implications

Volume Four: Therapeutic Promise: CVD, Regenerative & Translational Medicine

Curators: Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

• Causes
• Risks and Biomarkers
• Therapeutic Implications

Volume Five: Pharmaco-Therapies for CVD

Curators: Justin D Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

• Causes
• Risks and Biomarkers
• Therapeutic Implications

Volume Six: Interventional Cardiology, Cardiac Surgery and Cardiovascular Imaging for Disease Diagnosis and Guidance of Treatment  

Curators: Justin D Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

• Causes
• Risks and Biomarkers
• Therapeutic Implications

Series B: e-Books on Genomics & Medicine

Content Consultant: Larry H Bernstein, MD, FCAP

Volume 1: Genomics and Individualized Medicine

Sr. Editor: Stephen J Williams, PhD

Editors: Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

Volume 2: Methodological Breakthroughs in NGS

Editor: Marcus Feldman, PhD, Prof. of Genetics, Stanford University

Volume 3: Institutional Leadership in Genomics

Editors: Marcus Feldman, PhD and Aviva Lev-Ari, PhD, RN 

Series C: e-Books on Cancer & Oncology

Content Consultant: Larry H Bernstein, MD, FCAP

Volume 1: Cancer and Genomics

Sr. Editor: Stephen J Williams, PhD

Editors: Ritu Saxena, PhD, Tilda Barliya, PhD

Volume 2: Cancer Therapies: Metabolic, Genomics, Interventional, Immunotherapy and Nanotechnology in Therapy Delivery

Author, Curator and Editor: Larry H Bernstein, MD, FCAP

Guest Authors: Stephen J Williams, PhD, Dror Nir, PhD and Tilda Barliya, PhD, Demet Sag, PhD, Raphael Nir, PhD, Michael Briggs, PhD

Volume 3: Cancer Patients’ Resources on Therapies

Sr. Editor: TBA

Series D: e-Books on BioMedicine

Volume 1: Metabolic Genomics & Pharmaceutics

Author, Curator and Editor: Larry H Bernstein, MD, FCAP

Volume 2: Infectious Diseases

Editor: TBA

Volume 3: Immunology and Therapeutics

Editor: TBA

Series E: Titles in the Strategic Plan for 2015

Volume 1: The Patient’s Voice: Personal Experience with Invasive Medical Procedures

Editor: TBA 

Volume 2: Interviews with Scientific Leaders

Editor: TBA

Volume 3: Milestones in Physiology & Discoveries in Medicine and Genomics

Author, Curator and Editor: Larry H Bernstein, MD, FCAP

Open Access Online Journal

http://www.pharmaceuticalIntelligence.com

is a scientific, medical and business, multi-expert authoring environment for information syndication in several domains of Life Sciences, Medicine, Pharmaceutical and Healthcare Industries, BioMedicine, Medical Technologies & Devices. Scientific critical interpretations and original articles are written by PhDs, MDs, MD/PhDs, PharmDs, Technical MBAs as Experts, Authors, Writers (EAWs) on an Equity Sharing basis.

This e-Book is a comprehensive review of recent Original Research on Cancer & Genomics including related opportunities for Targeted Therapy written by Experts, Authors, Writers. The results of Original Research are gaining value added for the e-Reader by the Methodology of Curation. The e-Book’s articles have been published on the Open Access Online Scientific Journal, since April 2012.  All new articles on this subject, will continue to be incorporated, as published with periodical updates. © Leaders in Pharmaceutical Business Intelligence, all rights reserved.

 

List of Contributors to Volume One

(Note: original authored and curated  articles are in bold-faced type). Other articles represent reports of interesting literature)

Preface

Cancer is the second most cause of medically related deaths in the developed world.  However, concerted efforts among most developed nations to eradicate the disease, such as increased government funding for cancer research and a mandated ‘war on cancer’ in the mid 70’s has translated into remarkable improvements in diagnosis, early detection, and cancer survival rates for many individual cancer.  For example, survival rate for breast and colon cancer have improved dramatically over the last 40 years.  In the UK, overall median survival times have improved from one year in 1972 to 5.8 years for patients diagnosed in 2007.  In the US, the overall 5 year survival improved from 50% for all adult cancers and 62% for childhood cancer  in 1972 to 68% and childhood cancer rate improved to 82% in 2007. However, for some cancers, including lung, brain, pancreatic and ovarian cancer, there has been little improvement in survival rates since the “war on cancer” has started.

Many of the improvements in survival rates are a direct result of the massive increase in the knowledge of tumor biology obtained through ardent basic research.  Breakthrough discoveries regarding oncogenes, cancer cell signaling, survival, and regulated death mechanisms, tumor immunology, genetics and molecular biology, biomarker research, and now nanotechnology and imaging, have directly led to the advances we now we in early detection, chemotherapy, personalized medicine, as well as new therapeutic modalities such as cancer vaccines and immunotherapies and combination chemotherapies.  Molecular and personalized therapies such as trastuzumab and aromatase inhibitors for breast cancer, imatnib for CML and GIST related tumors, bevacizumab for advanced colorectal cancer have been a direct result of molecular discoveries into the nature of cancer.

This ebook highlights some of the recent trends and discoveries in cancer research and cancer treatment, with particular attention how new technological and informatics advancements have ushered in paradigm shifts in how we think about, diagnose, and treat cancer.  The book is organized with the 8 hallmarks of cancer in mind, concepts which are governing principles of cancer from Drs. Hanahan and Weinberg (Hallmarks of Cancer).

1. Maintaining Proliferative Signals
2. Avoiding Immune Destruction
3. Evading Growth Suppressors
4. Resisting Cell Death
5. Becoming Immortal
6. Angiogenesis
7. Deregulating Cellular Energy
8. Activating Invasion and Metastasis

Therefore the reader is asked to understand how each of these underlying principles are being translated to current breakthrough discoveries, in association with the basic biological knowledge we have amassed through diligent research and how these principals and latest research can be used by the next generation of cancer scientist and oncologist to provide the future breakthroughs.  As the past basic research had provided a new platform for the era of genomics in oncology, it is up to this next generation of scientists and oncologists to provide the basic research for the next platform which will create the future breakthroughs to combat this still deadly disease.

Volume Introduction by Larry H. Bernstein, MD, FACP 

The evolution of cancer therapy and cancer research: How we got here?

The evolution of progress we have achieved in cancer research, diagnosis, and therapeutics has  originated from an emergence of scientific disciplines and the focus on cancer has been recent. We can imagine this from a historical perspective with respect to two observations. The first is that the oldest concepts of medicine lie with the anatomic dissection of animals and the repeated recurrence of war, pestilence, and plague throughout the middle ages, and including the renaissance.  In the awakening, architecture, arts, music, math, architecture and science that accompanied the invention of printing blossomed, a unique collaboration of individuals working in disparate disciplines occurred, and those who were privileged received an education, which led to exploration, and with it, colonialism.  This also led to the need to increasingly, if not without reprisal, questioning long-held church doctrines. It was in Vienna that Rokitansky developed the discipline of pathology, and his student Semelweis identified an association between then unkown infection and childbirth fever.

The extraordinary accomplishments of John Hunter in anatomy and surgery came during the twelve years war, and his student, Edward Jenner, observed the association between cowpox and smallpox resistance. The development of a nursing profession is associated with the work of Florence Nightengale during the Crimean War (at the same time as Leo Tolstoy). These events preceded the work of Pasteur, Metchnikoff, and Koch in developing a germ theory, although Semelweis had committed suicide by infecting himself with syphilis.  The first decade of the Nobel Prize was dominated by discoveries in infectious disease and public health (Ronald Ross, Walter Reed) and we know that the Civil War in America saw an epidemic of Yellow Fever, and the Armed Services Medical Museum was endowed with a large repository of osteomyelitis specimens. We also recall that the Russian physician and playright, Anton Checkov, wrote about the conditions in prison camps.

But the pharmacopeia was about to open with the discoveries of insulin, antibiotics, vitamins, and thyroid hormones, and Karl Landsteiner’s discovery of red cell antigenic groups (but also pioneered in discoveries in meningitis and poliomyelitis, and conceived of the term hapten) with the introduction of transfusion therapy, that would lead to transplantation medicine.  The next phase would be the discovery of cancer, which was highlighted by the identification of leukemia by Rudolph Virchow, who cautioned about the limitations of microscopy. This period is highlighted by the classic work – “Microbe Hunters”.

A multidisciplinary approach has led us to a unique multidisciplinary or systems view of cancer, with different fields of study offering their unique expertise, contributions, and viewpoints on the etiology of cancer.  Diverse fields in immunology, biology, biochemistry, toxicology, molecular biology, virology, mathematics, social activism and policy, and engineering have made such important contributions to our understanding of cancer, that without cooperation among these diverse fields our knowledge of cancer would never had evolved as it has. In a series of posts “Heroes in Medical Research:” the work of researchers are highlighted as examples of how disparate scientific disciplines converged to produce seminal discoveries which propelled the cancer field, although, at the time, they seemed like serendipitous findings.  In the post Heroes in Medical Research: Barnett Rosenberg and the Discovery of Cisplatin (Translating Basic Research to the Clinic) discusses the seminal yet serendipitous discoveries by bacteriologist Dr. Barnett Rosenberg, which eventually led to the development of cisplatin, a staple of many chemotherapeutic regimens. Molecular biologist Dr. Robert Ting, working with soon-to-be Nobel Laureate virologist Dr. James Gallo on AIDS research and the associated Karposi’s sarcoma identified one of the first retroviral oncogenes, revolutionizing previous held misconceptions of the origins of cancer (described in Heroes in Medical Research: Dr. Robert Ting, Ph.D. and Retrovirus in AIDS and Cancer).  The 20^th century also saw the development of revolutionary tools for cancer research (highlighted in the post Heroes in Medical Research: Developing Models for Cancer Research), which greatly enhanced both our understanding of the neoplastic process, the genetic factors involved in cancer, and gave us the ability to rapidly develop new cancer chemotherapeutics.

Each of these paths of discovery in cancer research have led to the unique strategies of cancer therapeutics and detection for the purpose of reducing the burden of human cancer.  However, we must recall that this work has come at great cost, while it is indeed cause for celebration. The current failure rate of clinical trials at over 70 percent, has been a cause for disappointment, and has led to serious reconsideration of how we can proceed with greater success. The result of the evolution of the cancer field is evident in the many parts and chapters of this ebook.  Volume 4 contains chapters that are in a predetermined order:

1. The concepts of neoplasm, malignancy, carcinogenesis,  and metastatic potential, which encompass:

(a)   How cancer cells bathed in an oxygen rich environment rely on anaerobic glycolysis for energy, and the secondary consequences of sarcopenia associated with progression

(b)  How advances in genetic analysis, molecular and cellular biology, metabolomics have expanded our basic knowledge of the mechanisms which are involved in cellular transformation to the cancerous state.

(c)   How molecular techniques continue to advance our understanding how genetics, epigenetics, and alterations in cellular metabolism contribute to cancer and afford new pathways for therapeutic intervention.

1. The distinct features of cancers of specific tissue sites of origin
2. The diagnosis of cancer by

(a)   Clinical presentation

(b)  Age of onset and stage of life

(c)   Biomarker features

(d)  Radiological and ultrasound imaging

1. Treatments
2. Prognostic differences within and between cancer types

We have introduced the emergence of a disease of great complexity that has been clouded in more questions than answers until the emergence of molecular biology in the mid 20^th century, and then had to await further discoveries going into the 21^st century.  What gave the research impetus was the revelation of

(1)  the mechanism of transcription of the DNA into amino acid sequences

(2)  the identification of stresses imposed on cellular function

(3)  the elucidation of the substructure of the cell – cell membrane, mitochondria, ribosomes, lysosomes – and their functions, respectively

(4)  the elucidation of oligonucleotide sequences

(5)  the further elucidation of functionally relevant noncoding ncDNA

(6)  the technology to synthesis mRNA and siRNA sequences

(7)  the repeated discovery of isoforms of critical enzymes and their pleiotropic properties

(8)  the regulatory pathways involved in “signaling”

This is a brief outline of the modern progression of advances in our understanding of cancer.  Let us go back to the beginning and check out a sequence of Nobel Prizes awarded and related work that have a historical relationship to what we know.  The first discovery was the finding by Louis Pasteur that fungi that grew in an oxygen poor environment did not put down filaments.  They did not utilize oxygen and they produced used energy by fermentation.  This was the basis for Otto Warburg sixty years later to make the comparison to cancer cells that grew in the presence of oxygen, but relied on anaerobic glycolysis. He used a manometer to measure respiration in tissue one cell layer thick to measure CO₂ production in an adiabatic system.

The Nobel Prize in Physiology or Medicine 1922
Archibald V. Hill, Otto Meyerhof

Prize motivation: “for his discovery relating to the production of heat in the muscle”

Hill started his research work in 1909. It was due to J.N. Langley, Head of the Department of Physiology at that time that Hill took up the study on the nature of muscular contraction. Langley drew his attention to the important (later to become classic) work carried out by Fletcher and Hopkins on the problem of lactic acid in muscle, particularly in relation to the effect of oxygen upon its removal in recovery.

In 1919 he took up again his study of the physiology of muscle, and came into close contact with Meyerhof of Kiel who, approaching the problem from a different angle, has arrived at results closely analogous to his study. They have cooperated continuously ever since, by personal contact and through correspondence. In 1919 Hill’s friend W. Hartree, mathematician and engineer, joined in the myothermic investigations – a cooperation which had rewarding results.

Otto Meyerhof

Under the influence of Otto Warburg, then at Heidelberg, Meyerhof became more and more interested in cell physiology. . In 1923 he was offered a Professorship of Biochemistry in the United States, but Germany was unwilling to lose him and in 1924 he was asked by the Kaiser Wilhelm Gesellschaft to join the group working at Berlin-Dahlem, which included C. Neuberg, F. Haber, M. Polyani, and H. Freundlich.
In 1929 he was asked to take charge of the newly founded Kaiser Wilhelm Institute for Medical Research at Heidelberg. In 1938 conditions became too difficult for him and he decided to leave Germany. From 1938 to 1940 he was Director of Research at the Institut de Biologie physico-chimique at Paris.  In 1940, however, when the Nazis invaded France, he had to move to the United States, where the post of Research Professor of Physiological Chemistry had been created for him by the University of Pennsylvania and the Rockefeller Foundation.  Meyerhof’s own account states that he was occupied chiefly with oxidation mechanisms in cells and with extending methods of gas analysis through the calorimetric measurement of heat production, and especially the respiratory processes of nitrifying bacteria.

The physico-chemical analogy between oxygen respiration and alcoholic fermentation caused him to study both these processes in the same subject, namely, yeast extract. By this work he discovered a co-enzyme of respiration, which could be found in all the cells and tissues up till then investigated. At the same time he also found a co-enzyme of alcoholic fermentation. He also discovered the capacity of the SH-group to transfer oxygen; after Hopkins had isolated from cells the SH bodies concerned, Meyerhof showed that the unsaturated fatty acids in the cell are oxidized with the help of the sulphydryl group. After studying closer the respiration of muscle, Meyerhof investigated the energy changes in muscle.

The previous speaker has already told you about the considerable progress achieved by the English scientists Fletcher and Hopkins by their recognition of the fact that lactic acid formation in the muscle is closely connected with the contraction process. These investigations were the first to throw light upon the highly paradoxical fact, already established by the physiologist Hermann, that the muscle can perform a

considerable part of its external function in the complete absence of oxygen. As, on the other hand, it was indisputable that in the last resort the energy for muscle activity comes from the oxidation of nutriment, the connection between activity and combustion clearly had to be an indirect one. In fact, Fletcher and Hopkins observed that in the absence of oxygen in the muscle, lactic acid appears, slowly in the relaxed state and rapidly in the active state, and that this lactic acid disappears again in the presence of oxygen. Obviously, then, oxygen is involved not while the muscle is active, but only when it is in the relaxed state

The Nobel Prize in Physiology or Medicine 1937

Albert von Szent-Györgyi Nagyrápolt

“for his discoveries in connection with the biological combustion processes, with special reference to vitamin C and the catalysis of fumaric acid”

The Nobel Prize in Physiology or Medicine 1953

Hans Adolf Krebs 

“for his discovery of the citric acid cycle” 

In the course of the 1920’s and 1930’s great progress was made in the study of the intermediary reactions by which sugar is anaerobically fermented to lactic acid or to ethanol and carbon dioxide. The success was mainly due to the joint efforts of the schools of Meyerhof, Embden, Parnas, von Euler, Warburg and the Coris, who built on the pioneer work of Harden and of Neuberg. This work brought to light the main intermediary steps of anaerobic fermentations. In contrast, very little was known in the earlier 1930’s

about the intermediary stages through which sugar is oxidized in living cells. When, in 1930, I left the laboratory of Otto Warburg (under whose guidance I had worked since 1926 and from whom I have learnt more than from any other single teacher), I was confronted with the question of selecting a

major field of study and I felt greatly attracted by the problem of the intermediary pathway of oxidations. These reactions represent the main energy source in higher organisms, and in view of the importance of energy production to living organisms (whose activities all depend on a continuous supply of energy) the problem seemed well worthwhile studying. 

Fritz Albert Lipmann 

“for his discovery of co-enzyme A and its importance for intermediary metabolism”.

In my development, the recognition of facts and the rationalization of these facts into a unified picture, have interplayed continuously. After my apprenticeship with Otto Meyerhof, a first interest on my own became the phenomenon we call the Pasteur effect, this peculiar depression of the wasteful fermentation in the respiring cell. By looking for a chemical explanation of this economy measure on the cellular level, I was prompted into a study of the mechanism of pyruvic acid oxidation, since it is at the pyruvic stage

where respiration branches off from fermentation. For this study I chose as a promising system a relatively simple looking pyruvic acid oxidation enzyme in a certain strain of Lactobacillus delbrueckii1.

The most important event during this whole period, I now feel, was the accidental observation that in the L. delbrueckii system, pyruvic acid oxidation was completely dependent on the presence of inorganic phosphate. This observation was made in the course of attempts to replace oxygen by methylene

blue. To measure the methylene blue reduction manometrically, I had to switch to a bicarbonate buffer instead of the otherwise routinely used phosphate. In bicarbonate, pyruvate oxidation was very slow, but the addition of a little phosphate caused a remarkable increase in rate. The phosphate effect was removed by washing with a phosphate free acetate buffer. Then it appeared that the reaction was really fully dependent on phosphate.

A coupling of this pyruvate oxidation with adenylic acid phosphorylation was attempted. Addition of adenylic acid to the pyruvic oxidation system brought out a net disappearance of inorganic phosphate, accounted for as adenosine triphosphate.

Toward the end of the war, while still in the army, I discovered in an American army bookmobile several miscellaneous issues of Genetics, one containing the beautiful paper in which Luria and demonstrated for the first time rigorously, the spontaneous nature of certain bacterial mutants. I think I have never read a scientific article with such enthusiasm; for me, bacterial genetics was established. Several months later, I also “discovered” the paper by Avery, MacLeod, and McCarty6 – another fundamental revelation. In 1946 I attended the memorable symposium at Cold Spring Harbor where Delbrück and Bailey, and Hershey, revealed their discovery of virus recombination at the same time that Lederberg and Tatum announced their discovery of bacterial sexuality7. In 1947 I was invited to the Growth Symposium to present a report1 on enzyme adaptation. It became clear to me that this remarkable phenomenon was almost entirely shrouded in mystery. On the other hand, by its regularity, its specificity, and by the molecular-level interaction it exhibited between a genetic determinant and a chemical determinant, it seemed of such interest and of a significance so profound that there was no longer any question as to whether I should pursue its study.

In order to understand how this problem was considered in 1946, it would be well to remember that at that time the structure of DNA was not known, little was known about the structure of proteins, and nothing was known of their biosynthesis. It was necessary to resolve the following question: Does the inducer effect total synthesis of a new protein molecule from its precursors, or is it rather a matter of the activation, conversion, or “remodeling” of one or more precursors?

Physiology or Medicine 1955

Hugo Theorell 

For his work on the nature and effects of oxidation enzymes

From 1933 until 1935 Theorell held a Rockefeller Fellowship and worked with Otto Warburg at Berlin-Dahlem, and here he became interested in oxidation enzymes. At Berlin-Dahlem he produced, for the first time, the oxidation enzyme called «the yellow ferment» and he succeeded in splitting it reversibly into a coenzyme part, which was found to be flavin mononucleotide, and a colourless protein part. On return to Sweden, he was appointed Head of the newly established Biochemical Department of the Nobel Medical Institute, which was opened in 1937.

Physiology or Medicine 1953

Watson & Crick double helix model 

A landmark in this journey

The Nobel Prize in Physiology or Medicine 1965

François Jacob, André Lwoff and Jacques Monod

 “for their discoveries concerning genetic control of enzyme and virus synthesis”.

In 1958 the remarkable analogy revealed by genetic analysis of lysogeny and that of the induced biosynthesis of ß-galactosidase led François Jacob, with Jacques Monod, to study the mechanisms responsible for the transfer of genetic information as well as the regulatory pathways which, in the bacterial cell, adjust the activity and synthesis of macromolecules. Following this analysis, Jacob and Monod proposed a series of new concepts, those of messenger RNA, regulator genes, operons and allosteric proteins.

Francois Jacob

Having determined the constants of growth in the presence of different carbohydrates, it occurred to

me that it would be interesting to determine the same constants in paired mixtures of carbohydrates. From the first experiment on, I noticed that, whereas the growth was kinetically normal in the presence

of certain mixtures (that is, it exhibited a single exponential phase), two complete growth cycles could

be observed in other carbohydrate mixtures, these cycles consisting of two exponential phases separated by a-complete cessation of growth.

Lwoff, after considering this strange result for a moment, said to me, “That could have something to do with enzyme adaptation.”

“Enzyme adaptation? Never heard of it!” I said.

Lwoff’s only reply was to give me a copy of the then recent work of Marjorie Stephenson, in which a chapter summarized with great insight the still few studies concerning this phenomenon, which had been discovered by Duclaux at the end of the last century. Studied by Dienert and by Went as early as 1901 and then by Euler and Josephson, it was more or less rediscovered by Karström, who should be credited with giving it a name and attracting attention to its existence.

Lwoff’s intuition was correct. The phenomenon of “diauxy” that I had discovered was indeed closely related to enzyme adaptation, as my experiments, included in the second part of my doctoral dissertation, soon convinced me. It was actually a case of the “glucose effect” discovered by Dienert as early as 1900.

That agents that uncouple oxidative phosphorylation, such as 2,4-dinitrophenol, completely inhibit adaptation to lactose or other carbohydrates suggested that “adaptation” implied an expenditure of chemical potential and therefore probably involved the true synthesis of an enzyme. With Alice Audureau, I sought to discover the still quite obscure relations between this phenomenon and the one Massini, Lewis, and others had discovered: the appearance and selection of “spontaneous” mutants.

we showed that an apparently spontaneous mutation was allowing these originally “lactose-negative” bacteria to become “lactose-positive”. However, we proved that the original strain (Lac-) and the mutant strain (Lac+) did not differ from each other by the presence of a specific enzyme system, but rather by the ability to produce this system in the presence of lactose.  This mutation involved the selective control of an enzyme by a gene, and the conditions necessary for its expression seemed directly linked to the chemical activity of the system.

I had an opportunity to visit Morgan’s laboratory at the California Institute of Technology. This was a revelation for me – a revelation of genetics, at that time practically unknown in France; a revelation of what a group of scientists could be like when engaged in creative activity and sharing in a constant exchange of ideas, bold speculations, and strong criticisms. It was a revelation of personalities of great stature, such as George Beadle and others. Upon my return to France, I had again taken up the study of bacterial growth. But my mind remained full of the concepts of genetics and I was confident of its ability to analyze and convincedthat one day these ideas would be applied to bacteria.

The Nobel Prize in Physiology or Medicine 1974

Albert Claude, Christian de Duve and George E. Palade 

“for their discoveries concerning the structural and functional organization of the cell”.

In 1946-1947, I had the good fortune of spending 18 months at the Medical Nobel Institute in Stockholm, in the laboratory of Hugo Theorell, who was awarded the Nobel Prize in 1955. I then spent 6 months as a Rockefeller Foundation fellow at Washington University, under Carl and Gerty Cori who jointly received the Nobel Prize while I was there. In St. Louis, I collaborated with Earl Sutherland, Nobel laureate in 1971. Indeed, I have been very fortunate in the choice of my mentors, all sticklers for technical excellence and intellectual rigour, those prerequisites of good scientific work.

I returned to Louvain in March 1947 to take over the teaching of physiological chemistry at the medical faculty, becoming full professor in 1951. Insulin, together with glucagon which I had helped rediscover, was still my main focus of interest, and our first investigations were accordingly directed on certain enzymatic aspects of carbohydrate metabolism in liver, which were expected to throw light on the broader problem of insulin action. But fate had a surprise in store for me, in the form of a chance observation, the so-called “latency” of acid phosphatase. It was essentially irrelevant to the object of our research, but I from then on pursued this accidental finding, drawing most of my collaborators along with me. The studies led to the discovery of the lysosome, and later of the peroxisome.

In 1962, I was appointed a professor at the Rockefeller Institute in New York, now the Rockefeller University, the institution where Albert Claude had made his pioneering studies between 1929 and 1949, and where George Palade had been working since 1946.  In New York, I was able to develop a second flourishing group, which follows the same general lines of research as the Belgian group, but with a program of its own.

I created a new institute with a number of colleagues, the International Institute of Cellular and Molecular Pathology, or ICP, located on the new site of the Louvain Medical School in Brussels. The aim of the ICP is to accelerate the translation of basic knowledge in cellular and molecular biology into useful practical applications.

The Nobel Prize in Physiology or Medicine 1968

Robert W. Holley, Har Gobind Khorana and Marshall W. Nirenberg 

“for their interpretation of the genetic code and its function in protein synthesis”.

The Nobel Prize in Physiology or Medicine 1969

Max Delbrück, Alfred D. Hershey and Salvador E. Luria 

“for their discoveries concerning the replication mechanism and the genetic structure of viruses”.

The Nobel Prize in Physiology or Medicine 1975

David Baltimore, Renato Dulbecco and Howard Martin Temin 

“for their discoveries concerning the interaction between tumour viruses and the genetic material of the cell”.

The Nobel Prize in Physiology or Medicine 1976

Baruch S. Blumberg and D. Carleton Gajdusek 

“for their discoveries concerning new mechanisms for the origin and dissemination of infectious diseases”

The editors of the Nobelprize.org website of the Nobel Foundation have asked me to provide a supplement to the autobiography that I wrote in 1976 and to recount the events that happened after the award. Much of what I will have to say relates to the scientific developments since the last essay. These are described in greater detail in a scientific memoir first published in 2002 (Blumberg, B. S., Hepatitis B. The Hunt for a Killer Virus, Princeton University Press, 2002, 2004).

The Nobel Prize in Physiology or Medicine 1980

Baruj Benacerraf, Jean Dausset and George D. Snell 

“for their discoveries concerning genetically determined structures on the cell surface that regulate immunological reactions”.

The Nobel Prize in Physiology or Medicine 1992

Edmond H. Fischer and Edwin G. Krebs 

“for their discoveries concerning reversible protein phosphorylation as a biological regulatory mechanism”

The Nobel Prize in Physiology or Medicine 1994

Alfred G. Gilman and Martin Rodbell 

“for their discovery of G-proteins and the role of these proteins in signal transduction in cells”

The Nobel Prize in Physiology or Medicine 2011

Bruce A. Beutler and Jules A. Hoffmann 

“for their discoveries concerning the activation of innate immunity” and

the other half to Ralph M. Steinman

“for his discovery of the dendritic cell and its role in adaptive immunity”.

Contemporary Scientists

Renato L. Baserga, M.D.
Kimmel Cancer Center and Keck School of Medicine

Dr. Baserga’s research focuses on the multiple roles of the type 1 insulin-like growth factor receptor (IGF-IR) in the proliferation of mammalian cells. The IGF-IR activated by its ligands is mitogenic, is required for the establishment and the maintenance of the transformed phenotype, and protects tumor cells from apoptosis. It, therefore, serves as an excellent target for therapeutic interventions aimed at inhibiting abnormal growth.

In basic investigations, this group is presently studying the effects that the number of IGF-IRs and specific mutations in the receptor itself have on its ability to protect cells from apoptosis. This investigation is strictly correlated with IGF-IR signaling, and part of this work tries to elucidate the pathways originating from the IGF-IR that are important for its functional effects. Baserga’s group has recently discovered a new signaling pathway used by the IGF-IR to protect cells from apoptosis, a unique pathway that is not used by other growth factor receptors. This pathway depends on the integrity of serines 1280-1283 in the C-terminus of the receptor, which bind 14.3.3 and cause the mitochondrial translocation of Raf-1. Another recent discovery of this group has been the identification of a mechanism by which the IGF-IR can actually induce differentiation in certain types of cells. When cells have IRS-1 (a major substrate of the IGF-IR), the IGF-IR sends a proliferative signal; in the absence of IRS-1, the receptor induces cell differentiation. The extinction of IRS-1 expression is usually achieved by DNA methylation.

Janardan Reddy, MD
Northwestern University

The central effort of our research has been on a detailed analysis at the cellular and molecular levels of the pleiotropic responses in liver induced by structurally diverse classes of chemicals that include fibrate class of hypolipidemic drugs, and phthalate ester plasticizers, which we designated hepatic peroxisome proliferators. Our work has been central to the establishment of several principles, namely that hepatic peroxisome proliferation is associated with increases in fatty acid oxidation systems in liver, and that peroxisome proliferators, as a class, are novel nongenotoxic hepatocarcinogens. We introduced the concept that sustained generation of reactive oxygen species leads to oxidative stress and serves as the basis for peroxisome proliferator-induced liver cancer development. Furthermore, based on the tissue/cell specificity of pleiotropic responses and the coordinated transcriptional regulation of fatty acid oxidation system genes, we postulated that peroxisome proliferators exert their action by a receptor-mediated mechanism. This receptor concept laid the foundation for the discovery of a three member peroxisome proliferator-activated receptor (PPARalpha-, ß-, and gamma) subfamily of nuclear receptors. Of these, PPARalpha is responsible for peroxisome proliferator-induced pleiotropic responses, including hepatocarcinogenesis and energy combustion as it serves as a fatty acid sensor and regulates fatty acid oxidation. Our current work focuses on the molecular mechanisms responsible for PPAR action and generation of fatty acid oxidation deficient mouse knockout models. Transcription of specific genes by nuclear receptors is a complex process involving the participation of multiprotein complexes composed of transcription coactivators.

Jose Delgado de Salles Roselino, Ph.D.
Leloir Institute, Brazil

Warburg effect, in reality “Pasteur-effect” was the first example of metabolic regulation described. A decrease in the carbon flux originated at the sugar molecule towards the end metabolic products, ethanol and carbon dioxide that was observed when yeast cells were transferred from anaerobic environmental condition to an aerobic one. In Pasteur´s works, sugar metabolism was measured mainly by the decrease of sugar concentration in the yeast growth media observed after a measured period of time. The decrease of the sugar concentration in the media occurs at great speed in yeast grown in anaerobiosis condition and its speed was greatly reduced by the transfer of the yeast culture to an aerobic condition. This finding was very important for the wine industry of France in Pasteur time, since most of the undesirable outcomes in the industrial use of yeast were perceived when yeasts cells took very long time to create a rather selective anaerobic condition. This selective culture media was led by the carbon dioxide higher levels produced by fast growing yeast cells and by a great alcohol content in the yeast culture media.

This finding was required to understand Lavoisier’s results indicating that chemical and biological oxidation of sugars produced the same calorimetric results. This observation requires a control mechanism (metabolic regulation) to avoid burning living cells by fast heat released by the sugar biological oxidative processes (metabolism). In addition, Lavoisier´s results were the first indications that both processes happened inside similar thermodynamics limits. In much resumed form, these observations indicates the major reasons that led Warburg to test failure in control mechanisms in cancer cells in comparison with the ones observed in normal cells.

Biology inside classical thermo dynamics poses some challenges to scientists. For instance, all classical thermodynamics must be measured in reversible thermodynamic conditions. In an isolated system, increase in P (pressure) leads to decrease in V (volume) all this in a condition in which infinitesimal changes in one affects in the same way the other, a continuum response. Not even a quantic amount of energy will stand beyond those parameters. In a reversible system, a decrease in V, under same condition, will led to an increase in P. In biochemistry, reversible usually indicates a reaction that easily goes from A to B or B to A.

This observation confirms the important contribution of E Schrodinger in his What´s Life: “This little book arose from a course of public lectures, delivered by a theoretical physicist to an audience of about four hundred which did not substantially dwindle, though warned at the outset that the subject-matter was a difficult one and that the lectures could not be termed popular, even though the physicist’s most dreaded weapon, mathematical deduction, would hardly be utilized. The reason for this was not that the subject was simple enough to be explained without mathematics, but rather that it was much too involved to be fully accessible to mathematics.”

Hans Krebs describes the cyclic nature of the citrate metabolism. Two major research lines search to understand the mechanism of energy transfer that explains how ADP is converted into ATP. One followed the organic chemistry line of reasoning and therefore, searched how the breakdown of carbon-carbon link could have its energy transferred to ATP synthesis. A major leader of this research line was B. Chance who tried to account for two carbon atoms of acetyl released as carbon dioxide in the series of Krebs cycle reactions. The intermediary could store in a phosphorylated amino acid the energy of carbon-carbon bond breakdown. This activated amino acid could transfer its phosphate group to ADP producing ATP. Alternatively, under the possible influence of the excellent results of Hodgkin and Huxley a second line of research appears. The work of Hodgkin & Huxley indicated the storage of electrical potential energy in transmembrane ionic asymmetries and presented the explanation for the change from resting to action potential in excitable cells. This second line of research, under the leadership of P Mitchell postulated a mechanism for the transfer of oxide/reductive power of organic molecules oxidation through electron transfer as the key for energetic transfer mechanism required for ATP synthesis.

Paul Boyer could present how the energy was transduced by a molecular machine that changes in conformation in a series of 3 steps while rotating in one direction in order to produce ATP and in opposite direction in order to produce ADP plus Pi from ATP (reversibility). Nonetheless, a victorious Peter Mitchell obtained the correct result in the conceptual dispute, over the B. Chance point of view, after he used E. Coli mutants to show H gradients in membrane and its use as energy source.  However, this should not detract from the important work of Chance.

B. Chance got the simple and rapid polarographic assay method of oxidative phosphorylation and the idea of control of energy metabolism that bring us back to Pasteur. This second result seems to have being neglected in the years of obesity epidemics when we search for a single molecular mechanism required for the understanding of the build up of chemical reserve in our body. It does not mean that here the role of central nervous system is neglected .In short, in respiring mitochondria the rate of electron transport, and thus the rate of ATP production, is determined primarily by the relative concentrations of ADP, ATP and phosphate in the external media (cytosol) and not by the concentration of respiratory substrate as pyruvate. Therefore, when the yield of ATP is high as is in aerobiosis and the cellular use of ATP is not changed, the oxidation of pyruvate and therefore of glycolysis is quickly ( without change in gene expression), throttled down to the resting state. The dependence of respiratory rate on ADP concentration is also seen in intact cells. A muscle at rest and using no ATP has very low respiratory rate.

Part I

Historical Perspective of Cancer Demographics, Etiology, and Progress in Research

Chapter 1:  The Occurrence of Cancer in World Populations

1.1   Understanding Cancer

 Prabodh Kandala, PhD

1.2  Cancer Metastasis

Tilda Barliya, PhD

1.3      2013 Perspective on “War on Cancer” on December 23, 1971

Aviva Lev-Ari, PhD, RN

1.4   Global Burden of Cancer Treatment & Women Health: Market Access & Cost Concerns

Aviva Lev-Ari, PhD, RN

1.5    The Importance of Cancer Prevention Programs: New Perspectives for Fighting Cancer

Ziv Raviv, PhD

1.6      The “Cancer establishments” examined by James Watson, co-discoverer of DNA w/Crick, 4/1953,  

Larry H Bernstein, MD, FCAP

1.7      New Ecosystem of Cancer Research: Cross Institutional Team Science

Aviva Lev-Ari, PhD, RN

1.8       Cancer Innovations from across the Web

Larry H Bernstein, MD, FCAP 

1.9         Exploring the role of vitamin C in Cancer therapy

Ritu Saxena PhD

1.10        Relation of Diet and Cancer

Sudipta Saha, PhD

1.11      Association between Non-melanoma Skin Cancer and subsequent Primary Cancers in White Population 

Aviva Lev-Ari, PhD, RN

1.12       Men With Prostate Cancer More Likely to Die from Other Causes

Prabodh Kandala, PhD

1.13      Battle of Steve Jobs and Ralph Steinman with Pancreatic Cancer: How we Lost

Ritu Saxena, PhD

Chapter 2.  Rapid Scientific Advances Changes Our View on How Cancer Forms

2.1     All Cancer Cells Are Not Created Equal: Some Cell Types Control Continued Tumor Growth, Others Prepare the Way for Metastasis 

Prabodh Kandala, PhD

2.2      Hold on. Mutations in Cancer do Good

Prabodh Kandala, PhD

2.3       Is the Warburg Effect the Cause or the Effect of Cancer: A 21st Century View?

Larry H Bernstein, MD, FCAP

2.4          Naked Mole Rats Cancer-Free

Larry H Bernstein, MD, FCAP

2.5           Zebrafish—Susceptible to Cancer

Larry H Bernstein, MD, FCAP

2.6         Demythologizing Sharks, Cancer, and Shark Fins,

Larry H Bernstein, MD, FCAP

2.7       Tumor Cells’ Inner Workings Predict Cancer Progression

Prabodh Kandala, PhD

2.8      In Focus: Identity of Cancer Stem Cells

Ritu Saxena, PhD

2.9      In Focus: Circulating Tumor Cells

Ritu Saxena, PhD

2.10     Rewriting the Mathematics of Tumor Growth; Teams Use Math Models to Sort Drivers from Passengers 

Stephen J. Williams, PhD

2.11     Role of Primary Cilia in Ovarian Cancer

Aashir Awan, PhD

Chapter 3:  A Genetic Basis and Genetic Complexity of Cancer Emerges

3.1       The Binding of Oligonucleotides in DNA and 3-D Lattice Structures

Larry H Bernstein, MD, FCAP

3.2      How Mobile Elements in “Junk” DNA Promote Cancer. Part 1: Transposon-mediated Tumorigenesis. 

Stephen J. Williams, PhD

3.3      DNA: One Man’s Trash is another Man’s Treasure, but there is no JUNK after all

Demet Sag, PhD

3.4 Issues of Tumor Heterogeneity

3.4.1    Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing

Stephen J. Williams, PhD

3.4.2       Issues in Personalized Medicine: Discussions of Intratumor Heterogeneity from the Oncology Pharma forum on LinkedIn

Stephen J. Williams, PhD

3.5        arrayMap: Genomic Feature Mining of Cancer Entities of Copy Number Abnormalities (CNAs) Data

Aviva Lev-Ari, PhD, RN

3.6        HBV and HCV-associated Liver Cancer: Important Insights from the Genome

Ritu Saxena, PhD

3.7      Salivary Gland Cancer – Adenoid Cystic Carcinoma: Mutation Patterns: Exome- and Genome-Sequencing @ Memorial Sloan-Kettering Cancer Center

Aviva Lev-Ari, PhD, RN

3.8         Gastric Cancer: Whole-genome Reconstruction and Mutational Signatures

Aviva Lev-Ari, PhD, RN

3.9        Missing Gene may Drive more than a quarter of Breast Cancers

Aviva Lev-Ari, PhD, RN

3.10     Critical Gene in Calcium Reabsorption: Variants in the KCNJ and SLC12A1 genes – Calcium Intake and Cancer Protection

Aviva Lev-Ari,PhD, RN

Chapter 4: How Epigenetic and Metabolic Factors Affect Tumor Growth

4.1    Epigenetics

4.1.1     The Magic of the Pandora’s Box : Epigenetics and Stemness with Long non-coding RNAs (lincRNA)

Demet Sag, PhD, CRA, GCP

4.1.2     Stomach Cancer Subtypes Methylation-based identified by Singapore-Led Team

Aviva Lev-Ari, PhD, RN

4.1.3     The Underappreciated EpiGenome

Demet Sag, Ph.D., CRA, GCP

4.1.4     Differentiation Therapy – Epigenetics Tackles Solid Tumors

Stephen J. Williams, PhD

4.1.5      “The SILENCE of the Lambs” Introducing The Power of Uncoded RNA

Demet Sag, Ph.D., CRA, GCP

4.1.6      DNA Methyltransferases – Implications to Epigenetic Regulation and Cancer Therapy Targeting: James Shen, PhD

Aviva Lev-Ari, PhD, RN

4.2   Metabolism

4.2.1      Mitochondria and Cancer: An overview of mechanisms

Ritu Saxena, PhD

4.2.2     Bioenergetic Mechanism: The Inverse Association of Cancer and Alzheimer’s

Aviva Lev-Ari, PhD, RN

4.2.3      Crucial role of Nitric Oxide in Cancer

Ritu Saxena, PhD

4.2.4      Nitric Oxide Mitigates Sensitivity of Melanoma Cells to Cisplatin

Stephen J. Williams, PhD

4.2.5      Increased risks of obesity and cancer, Decreased risk of type 2 diabetes: The role of Tumor-suppressor phosphatase and tensin homologue (PTEN)

Aviva Lev-Ari, PhD, RN

4.2.6      Lipid Profile, Saturated Fats, Raman Spectrosopy, Cancer Cytology

Larry H Bernstein, MD, FCAP

4.3     Other Factors Affecting Tumor Growth

4.3.1      Squeezing Ovarian Cancer Cells to Predict Metastatic Potential: Cell Stiffness as Possible Biomarker

Prabodh Kandala, PhD

4.3.2      Prostate Cancer: Androgen-driven “Pathomechanism” in Early-onset Forms of the Disease

Aviva Lev-Ari, PhD, RN

Chapter 5: Advances in Breast and Gastrointestinal Cancer Research Supports Hope for Cure

5.1 Breast Cancer

5.1.1      Cell Movement Provides Clues to Aggressive Breast Cancer

Prabodh Kandala, PhD

5.1.2    Identifying Aggressive Breast Cancers by Interpreting the Mathematical Patterns in the Cancer Genome

Prabodh Kandala, PhD

5.1.3  Mechanism involved in Breast Cancer Cell Growth: Function in Early Detection & Treatment

Aviva Lev-Ari, PhD, RN

5.1.4       BRCA1 a tumour suppressor in breast and ovarian cancer – functions in transcription, ubiquitination and DNA repair

Sudipta Saha, PhD

5.1.5      Breast Cancer and Mitochondrial Mutations

Larry H Bernstein, MD, FCAP

5.1.6      MIT Scientists Identified Gene that Controls Aggressiveness in Breast Cancer Cells

Aviva Lev-Ari PhD RN

5.1.7       “The Molecular pathology of Breast Cancer Progression”

Tilda Barliya, PhD

5.1.8       In focus: Triple Negative Breast Cancer

Ritu Saxena, PhD

5.1.9       Automated Breast Ultrasound System (‘ABUS’) for full breast scanning: The beginning of structuring a solution for an acute need!

Dror Nir, PhD

5.1.10       State of the art in oncologic imaging of breast.

Dror Nir, PhD

 

5.2 Gastrointestinal Cancer

5.2.1         Colon Cancer

Tilda Barliya, PhD

5.2.2      PIK3CA mutation in Colorectal Cancer may serve as a Predictive Molecular Biomarker for adjuvant Aspirin therapy

Aviva Lev-Ari, PhD, RN

5.2.3     State of the art in oncologic imaging of colorectal cancers.

Dror Nir, PhD

5.2.4     Pancreatic Cancer: Genetics, Genomics and Immunotherapy

Tilda Barliya, PhD

5.2.5     Pancreatic cancer genomes: Axon guidance pathway genes – aberrations revealed

Aviva Lev-Ari, PhD, RN

Part II

Advent of Translational Medicine, “omics”, and Personalized Medicine Ushers in New Paradigms in Cancer Treatment and

Advances in Drug Development

Chapter 6:  Treatment Strategies

6.1 Marketed and Novel Drugs

Breast Cancer                                   

6.1.1     Treatment for Metastatic HER2 Breast Cancer

Larry H Bernstein MD, FCAP

6.1.2          Aspirin a Day Tied to Lower Cancer Mortality

Aviva Lev-Ari, PhD, RN

6.1.3       New Anti-Cancer Drug Developed

Prabodh Kandala, Ph.D.

6.1.4         Pfizer’s Kidney Cancer Drug Sutent Effectively caused REMISSION to Adult Acute Lymphoblastic Leukemia (ALL)

Aviva Lev-Ari ,PhD, RN

6.1.5     “To Die or Not To Die” – Time and Order of Combination drugs for Triple Negative Breast Cancer cells: A Systems Level Analysis

Anamika Sarkar, PhD. and Ritu Saxena, PhD

 Melanoma

6.1.6    “Thymosin alpha1 and melanoma”

 Tilda Barliya, PhD

Leukemia

6.1.7    Acute Lymphoblastic Leukemia and Bone Marrow Transplantation

Tilda Barliya PhD

6.2 Natural agents

Prostate Cancer                 

6.2.1      Scientists use natural agents for prostate cancer bone metastasis treatment

Ritu Saxena, PhD

Breast Cancer

6.2.2        Marijuana Compound Shows Promise In Fighting Breast Cancer

Prabodh Kandala, PhD

Ovarian Cancer                  

6.2.3        Dimming ovarian cancer growth

Prabodh Kandala, PhD

6.3 Potential Therapeutic Agents

Gastric Cancer                 

6.3.1       β Integrin emerges as an important player in mitochondrial dysfunction associated Gastric Cancer

Ritu Saxena, PhD

6.3.2      Arthritis, Cancer: New Screening Technique Yields Elusive Compounds to Block Immune-Regulating Enzyme

Prabodh Kandala, PhD

Pancreatic Cancer                                   

6.3.3    Usp9x: Promising therapeutic target for pancreatic cancer

Ritu Saxena, PhD

Breast Cancer                 

6.3.4       Breast Cancer, drug resistance, and biopharmaceutical targets

Larry H Bernstein, MD, FCAP

Prostate Cancer

6.3.5        Prostate Cancer Cells: Histone Deacetylase Inhibitors Induce Epithelial-to-Mesenchymal Transition

Stephen J. Williams, PhD

Glioblastoma

6.3.6      Gamma Linolenic Acid (GLA) as a Therapeutic tool in the Management of Glioblastoma

Raphael Nir, PhD, MSM, MSc

6.3.7   Akt inhibition for cancer treatment, where do we stand today?

Ziv Raviv, PhD

Chapter 7:  Personalized Medicine and Targeted Therapy

7.1   General

7.1.1        Harnessing Personalized Medicine for Cancer Management, Prospects of Prevention and Cure: Opinions of Cancer Scientific Leaders

Aviva Lev-Ari, PhD, RN

7.1.2      Personalized medicine-based cure for cancer might not be far away

Ritu Saxena, PhD

7.1.3      Personalized medicine gearing up to tackle cancer

Ritu Saxena, PhD

7.1.4       Cancer Screening at Sourasky Medical Center Cancer Prevention Center in Tel-Aviv

Ziv Raviv, PhD

7.1.5       Inspiration From Dr. Maureen Cronin’s Achievements in Applying Genomic Sequencing to Cancer Diagnostics

Aviva Lev-Ari, PhD, RN

7.1.6       Personalized Medicine: Cancer Cell Biology and Minimally Invasive Surgery (MIS)

Aviva Lev-Ari, PhD, RN

7.2 Personalized Medicine and Genomics

7.2.1       Cancer Genomics – Leading the Way by Cancer Genomics Program at UC Santa Cruz

Aviva Lev-Ari, PhD, RN

7.2.2       Whole exome somatic mutations analysis of malignant melanoma contributes to the development of personalized cancer therapy for this disease

Ziv Raviv, PhD

7.2.3       Genotype-based Analysis for Cancer Therapy using Large-scale Data Modeling: Nayoung Kim, PhD(c)

Aviva Lev-Ari, PhD, RN

7.2.4         Cancer Genomic Precision Therapy: Digitized Tumor’s Genome (WGSA) Compared with Genome-native Germ Line: Flash-frozen specimen and Formalin-fixed paraffin-embedded Specimen Needed

Aviva Lev-Ari, PhD, RN

7.2.5         LEADERS in Genome Sequencing of Genetic Mutations for Therapeutic Drug Selection in Cancer Personalized Treatment: Part 2

Aviva Lev-Ari, PhD, RN

7.2.6       Ethical Concerns in Personalized Medicine: BRCA1/2 Testing in Minors and Communication of Breast Cancer Risk

Stephen J. Williams, PhD

7.3  Personalized Medicine and Targeted Therapy

7.3.1     The Development of siRNA-Based Therapies for Cancer

Ziv Raviv, PhD

7.3.2       mRNA interference with cancer expression

Larry H Bernstein, MD, FCAP

7.3.3       CD47: Target Therapy for Cancer

Tilda Barliya, PhD

7.3.4      Targeting Mitochondrial-bound Hexokinase for Cancer Therapy

Ziv Raviv, PhD

7.3.5       GSK for Personalized Medicine using Cancer Drugs needs Alacris systems biology model to determine the in silico effect of the inhibitor in its “virtual clinical trial”

Aviva Lev-Ari, PhD, RN

7.3.6         Personalized Pancreatic Cancer Treatment Option

Aviva Lev-Ari, PhD, RN

7.3.7        New scheme to routinely test patients for inherited cancer genes

Stephen J. Williams, PhD

7.3.8        Targeting Untargetable Proto-Oncogenes

Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

7.3.9        The Future of Translational Medicine with Smart Diagnostics and Therapies: PharmacoGenomics 

Demet Sag, PhD

7.4 Personalized Medicine in Specific Cancers

7.4.1      Personalized medicine and Colon cancer

Tilda Barliya, PhD

7.4.2      Comprehensive Genomic Characterization of Squamous Cell Lung Cancers

Aviva Lev-Ari, PhD, RN

7.4.3        Targeted Tumor-Penetrating siRNA Nanocomplexes for Credentialing the Ovarian Cancer Oncogene ID4

Sudipta Saha, PhD

7.4.4        Cancer and Bone: low magnitude vibrations help mitigate bone loss

Ritu Saxena, PhD

7.4.5         New Prostate Cancer Screening Guidelines Face a Tough Sell, Study Suggests

Prabodh Kandala, PhD

Part III

Translational Medicine, Genomics, and New Technologies Converge to Improve Early Detection

Diagnosis, Detection And Biomarkers

Chapter 8:  Diagnosis

Diagnosis: Prostate Cancer

8.1        Prostate Cancer Molecular Diagnostic Market – the Players are: SRI Int’l, Genomic Health w/Cleveland Clinic, Myriad Genetics w/UCSF, GenomeDx and BioTheranostics

Aviva Lev-Ari PhD RN

8.2         Today’s fundamental challenge in Prostate cancer screening

Dror Nir, PhD

Diagnosis & Guidance: Prostate Cancer

8.3      Prostate Cancers Plunged After USPSTF Guidance, Will It Happen Again?

Aviva Lev-Ari, PhD, RN

Diagnosis, Guidance and Market Aspects: Prostate Cancer

8.4       New Prostate Cancer Screening Guidelines Face a Tough Sell, Study Suggests

Prabodh Kandala, PhD

Diagnosis: Lung Cancer

8.5      Diagnosing lung cancer in exhaled breath using gold nanoparticles

Tilda Barliya PhD

Chapter 9:  Detection

Detection: Prostate Cancer

9.1     Early Detection of Prostate Cancer: American Urological Association (AUA) Guideline

Dror Nir, PhD

Detection: Breast & Ovarian Cancer

9.2       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

Aviva Lev-Ari, PhD, RN

Detection: Aggressive Prostate Cancer

9.3     A Blood Test to Identify Aggressive Prostate Cancer: a Discovery @ SRI International, Menlo Park, CA

Aviva Lev-Ari, PhD, RN

Diagnostic Markers & Screening as Diagnosis Method

9.4      Combining Nanotube Technology and Genetically Engineered Antibodies to Detect Prostate Cancer Biomarkers

Stephen J. Williams, PhD

Detection: Ovarian Cancer

9.5      Warning signs may lead to better early detection of ovarian cancer

Prabodh Kandala, PhD

9.6       Knowing the tumor’s size and location, could we target treatment to THE ROI by applying imaging-guided intervention?

Dror Nir, PhD

Chapter 10:  Biomarkers

Biomarkers: Pancreatic Cancer

10.1        Mesothelin: An early detection biomarker for cancer (By Jack Andraka)

Tilda Barliya, PhD

Biomarkers: All Types of Cancer, Genomics and Histology

10.2                  Stanniocalcin: A Cancer Biomarker

Aashir Awan, PhD

10.3         Breast Cancer: Genomic Profiling to Predict Survival: Combination of Histopathology and Gene Expression Analysis

Aviva Lev-Ari, PhD, RN

Biomarkers: Pancreatic Cancer

10.4         Biomarker tool development for Early Diagnosis of Pancreatic Cancer: Van Andel Institute and Emory University

Aviva Lev-Ari, PhD, RN

10.5     Early Biomarker for Pancreatic Cancer Identified

Prabodh Kandala, PhD

Biomarkers: Head and Neck Cancer

10.6        Head and Neck Cancer Studies Suggest Alternative Markers More Prognostically Useful than HPV DNA Testing

Aviva Lev-Ari, PhD, RN

10.7      Opens Exome Service for Rare Diseases & Advanced Cancer @Mayo Clinic’s OncoSpire

Aviva Lev-Ari, PhD, RN

Diagnostic Markers and Screening as Diagnosis Methods

10.8         In Search of Clarity on Prostate Cancer Screening, Post-Surgical Followup, and Prediction of Long Term Remission

Larry H Bernstein, MD, FCAP

Chapter 11  Imaging In Cancer

11.1  Introduction by Dror Nir, PhD

The concept of personalized medicine has been around for many years. Recent advances in cancer treatment choice, availability of treatment modalities, including “adaptable” drugs and the fact that patients’ awareness increases, put medical practitioners under pressure to better clinical assessment of this disease prior to treatment decision and quantitative reporting of treatment outcome. In practice, this translates into growing demand for accurate, noninvasive, nonuser-dependent probes for cancer detection and localization. The advent of medical-imaging technologies such as image-fusion, functional-imaging and noninvasive tissue characterisation is playing an imperative role in answering this demand thus transforming the concept of personalized medicine in cancer into practice. The leading modality in that respect is medical imaging. To date, the main imaging systems that can provide reasonable level of cancer detection and localization are: CT, mammography, Multi-Sequence MRI, PET/CT and ultrasound. All of these require skilled operators and experienced imaging interpreters in order to deliver what is required at a reasonable level. It is generally agreed by radiologists and oncologists that in order to provide a comprehensive work-flow that complies with the principles of personalized medicine, future cancer patients’ management will heavily rely on computerized image interpretation applications that will extract from images in a standardized manner measurable imaging biomarkers leading to better clinical assessment of cancer patients.

Read more: The Incentive for Imaging based cancer patient’ management and Imaging-biomarkers is Imaging-based tissue characterization

Dror Nir, PhD

 

11.2  Ultrasound

11.2.1        2013 – YEAR OF THE ULTRASOUND

Dror Nir, PhD

11.2.2      Imaging: seeing or imagining? (Part 1)

Dror Nir, PhD

11.2.3        Early Detection of Prostate Cancer: American Urological Association (AUA) Guideline

Dror Nir, PhD

11.2.4        Today’s fundamental challenge in Prostate cancer screening

Dror Nir, PhD

11.2.5       State of the art in oncologic imaging of Prostate

Dror Nir, PhD

11.2.6        From AUA 2013: “HistoScanning”- aided template biopsies for patients with previous negative TRUS biopsies

Dror Nir, PhD

11.2.7     On the road to improve prostate biopsy

Dror Nir, PhD

11.2.8       Ultrasound imaging as an instrument for measuring tissue elasticity: “Shear-wave Elastography” VS. “Strain-Imaging”

Dror Nir, PhD

11.2.9       What could transform an underdog into a winner?

Dror Nir, PhD

11.2.10        Ultrasound-based Screening for Ovarian Cancer

Dror Nir, PhD

11.2.11        Imaging Guided Cancer-Therapy – a Discipline in Need of Guidance

Dror Nir, PhD

11.3   MRI & PET/MRI

11.3.1     Introducing smart-imaging into radiologists’ daily practice

Dror Nir, PhD

11.3.2     Imaging: seeing or imagining? (Part 2)

[Part 1 is included in the ultrasound section above]

Dror Nir, PhD

11.3.3    Imaging-guided biopsies: Is there a preferred strategy to choose?

Dror Nir, PhD

11.3.4     New clinical results support Imaging-guidance for targeted prostate biopsy

Dror Nir, PhD

11.3.5      Whole-body imaging as cancer screening tool; answering an unmet clinical need?

Dror Nir, PhD

11.3.6        State of the art in oncologic imaging of Lymphoma

Dror Nir, PhD

11.3.7      A corner in the medical imaging’s ECO system

Dror Nir, PhD

 

11.4  CT, Mammography & PET/CT 

11.4.1      Causes and imaging features of false positives and false negatives on 18F-PET/CT in oncologic imaging

Dror Nir, PhD

11.4.2     Minimally invasive image-guided therapy for inoperable hepatocellular carcinoma

Dror Nir, PhD

11.4.3        Improving Mammography-based imaging for better treatment planning

Dror Nir, PhD

11.4.4       Closing the Mammography gap

Dror Nir, PhD

11.4.5       State of the art in oncologic imaging of lungs

Dror Nir, PhD

11.4.6       Ovarian Cancer and fluorescence-guided surgery: A report

Tilda Barliya, PhD

11.5  Optical Coherent Tomography (OCT)

11.5.1       Optical Coherent Tomography – emerging technology in cancer patient management

Dror Nir, PhD

11.5.2     New Imaging device bears a promise for better quality control of breast-cancer lumpectomies – considering the cost impact

Dror Nir, PhD

11.5.3        Virtual Biopsy – is it possible?

Dror Nir, PhD

11.5.4      New development in measuring mechanical properties of tissue

Dror Nir, PhD

Summary by Dror Nir, PhD

Establishing personalized medicine is expected to reduce over-diagnosis and treatment of cancer. This is a major unmet need in health-care systems worldwide. We have reasons to believe that investing in the development of innovative imaging technologies that will generate imaging-biomarkers characteristics of cancer will significantly improve cancer management and will generate good return on investment for all stakeholders.

Chapter 12. Nanotechnology Imparts New Advances in Cancer Treatment,  Detection, and Imaging                                 

 Introduction 

Nanotechnology is a multidisciplinary field of science that involves engineering, chemistry, physics and biology in the design, synthesis, characterization, and application of materials and devices whose smallest functional organization in at least one dimension is on the nanometer scale or one billionth of a meter. Applications to medicine and physiology imply materials and devices designed to interact with the body at sub-cellular molecular scales with a high degree of specificity which can potentially be translated into diagnosis, targeted drug designed to achieve maximal therapeutic affects with minimal side effects, imaging and medical devices. In this chapter, we will introduce and discuss some of the nanotechnology’s clinical applications.

12.1     DNA Nanotechnology

Tilda Barliya, PhD

12.2     Nanotechnology, personalized medicine and DNA sequencing

Tilda Barliya, PhD       

12.3     Nanotech Therapy for Breast Cancer

Tilda Barliya, PhD

12.4     Prostate Cancer and Nanotecnology

Tilda Barliya, PhD

12.5     Nanotechnology: Detecting and Treating metastatic cancer in the lymph node

Tilda Barliya, PhD

12.6     Nanotechnology Tackles Brain Cancer

Tilda Barliya, PhD

12.7     Lung Cancer (NSCLC), drug administration and nanotechnology

Tilda Barliya, PhD

Volume Epilogue by Larry H. Bernstein, MD, FACP

Epilogue: Envisioning New Insights in Cancer Translational Biology

Envisioning New Insights in Cancer Translational Biology

The foregoing  summary leads to a beginning as it is a conclusion.  It concludes a body of work in the e-book series,

Cancer Biology and Genomics for Disease Diagnosis

Perspectives in Cancer Research and Therapeutic Breakthroughs -2013

Volume One

that has been presented by the cancer team of professional expertsin various aspects of cancer research in the emerging fields of targeted  pharmacology,  nanotechnology, cancer imaging, molecular pathology, transcriptional and regulatory ‘OMICS’, metabolism, medical and allied health related sciences, synthetic biology, pharmaceutical discovery, and translational medicine.

This volume and its content have been conceived and organized to capture the organized events that emerge in embryological development, leading to the major organ systems that we recognize anatomically and physiologically as an integrated being.  We capture the dynamic interactions between the systems under stress  that are elicited by cytokine-driven hormonal responses, long thought to be circulatory and multisystem, that affect the major compartments of  fat and lean body mass, and are as much the drivers of metabolic pathway changes that emerge as epigenetics, without disregarding primary genetic diseases.

The greatest difficulty in organizing such a work is in whether it is to be merely a compilation of cancer expression organized by organ systems, or whether it is to capture developing concepts of underlying stem cell expressed changes that were once referred to as “dedifferentiation”.  In proceeding through the stages of neoplastic transformation, there occur adaptive local changes in cellular utilization of anabolic and catabolic pathways, and a retention or partial retention of functional specificities.

This effectively results in the same cancer types not all fitting into the same “shoe”. There is a sequential loss of identity associated with cell migration, cell-cell interactions with underlying stroma, and metastasis, but cells may still retain identifying “signatures” in microRNA combinatorial patterns.  The story is still incomplete, with gaps in our knowledge that challenge the imagination.

What we have laid out is a map with substructural ordered concepts forming subsets within the structural maps.  There are the traditional energy pathways with terms aerobic and anaerobic glycolysis, gluconeogenesis, triose phosphate branch chains, pentose shunt, and TCA cycle vs the Lynen cycle, the Cori cycle, glycogenolysis, lipid peroxidation, oxidative stress, autosomy and mitosomy, and genetic transcription, cell degradation and repair, muscle contraction, nerve transmission, and their involved anatomic structures (cytoskeleton, cytoplasm, mitochondria, liposomes and phagosomes, contractile apparatus, synapse.

Then there is beneath this macro-domain the order of signaling pathways that regulate these domains and through mechanisms of cellular regulatory control have pleiotropic inhibitory or activation effects, that are driven by extracellular and intracellular energy modulating conditions through three recognized structures: the mitochondrial inner membrane, the intercellular matrix, and the ion-channels.

What remains to be done?

1. There is still to be elucidated the differences in patterns within cancer types the distinct phenotypic and genotypic features that mitigate anaplastic behavior. One leg of this problem lies in the density of mitochondria, that varies between organ types, but might vary also within cell type of a common function.  Another leg of this problem has also appeared to lie in the cell death mechanism that relates to the proeosomal activity acting on both the ribosome and mitochondrion in a coordinated manner.  This is an unsolved mystery of molecular biology.
2. Then there is a need to elucidate the major differences between tumors of endocrine, sexual, and structural organs, which are distinguished by primarily a synthetic or primarily a catabolic function, and organs that are neither primarily one or the other.  For example, tumors of the thyroid and paratnhyroids, islet cells of pancreas, adrenal cortex, and pituitary glands have the longest 5 year survivals.  They and the sexual organs are in the visceral compartment.  The rest of the visceral compartment would be the liver, pancreas, salivary glands, gastrointestinal tract, and lungs (which are embryologically an outpouching of the gastrointestinal tract), kidneys and lower urinary tract.  Cancers of these organs have a much less favorable survival (brain, breast and prostate, lymphatic, blood forming organ, skin).  The case  is intermediate for breast and prostate between the endocrine organs and GI tract, based on natural history, irrespective of the available treatments.  Just consider the dilemma over what we do about screening for prostate cancer in men over the age of 60 years age who have a 70 percent incident silent carcinoma of the prostate that could be associated with unrelated cause of death.  The very rapid turnover of the gastric and colonic GI epithelium, and of the subepithelial  B cell mucosal lymphocytic structures  is associated  with a greater aggressiveness of the tumor.
3. However, we have to reconsider the observation by NO Kaplan than the synthetic and catabolic functions are highlighted by differences in the expressions of the balance of  the two major pyridine nucleotides – DPN (NAD) and TPN (NADP) – which also might be related to the density of mitochondria  which is associated with both NADP and synthetic activity, and  with efficient aerobic function.  These are in equilibrium through the “transhydrogenase reaction” co-discovered by Kaplan, in Fritz Lipmann’s laboratory. There does arise a conundrum involving the regulation of mitochondria in these high turnover epithelial tissues  that rely on aerobic energy, and generate ATP through TPN linked activity, when they undergo carcinogenesis. The cells replicate and they become utilizers of glycolysis, while at the same time, the cell death pathway is quiescent. The result becomes the introduction of peripheral muscle and liver synthesized protein cannabolization (cancer cachexia) to provide glucose  from proteolytic amino acid sources.
4. There is also the structural compartment of the lean body mass. This is the heart, skeletal structures (includes smooth muscle of GI tract, uterus, urinary bladder, brain, bone, bone marrow).  The contractile component is associated with sarcomas.  What is most striking is that the heart, skeletal muscle, and inflammatory cells are highly catabolic, not anabolic.  NO Kaplan referred tp them as DPN (NAD) tissues. This compartment requires high oxygen supply, and has a high mechanical function. But again, we return to the original observations of enrgy requirements at rest being different than at high demand.  At work, skeletal muscle generates lactic acid, but the heart can use lactic acid as fuel,.
5. The liver is supplied by both the portal vein and the hepatic artery, so it is not prone to local ischemic injury (Zahn infarct). It is exceptional in that it carries out synthesis of all the circulating transport proteins, has a major function in lipid synthesis and in glycogenesis and glycogenolysis, with the added role of drug detoxification through the P450 system.  It is not only the largest organ (except for brain), but is highly active both anabolically and catabolically (by ubiquitilation).
6. The expected cellular turnover rates for these tissues and their balance of catabolic and anabolic function would have to be taken into account to account for the occurrence and the activities of oncogenesis. This is by no means a static picture, but a dynamic organism constantly in flux imposed by internal and external challenges.  It is also important to note the the organs have a concentration of mitochondria, associated with energy synthetic and catabolic requirements provided by oxygen supply and the electron transport mechanism for oxidative phosphorylation.  For example, tissues that are primarily synthetic do not have intermitent states of resting and high demand, as seen in skeletal muscle, or perhaps myocardium (which is syncytial and uses lactic acid generated from skeletal muscle when there is high demand).
7. The existence of  lncDNA has been discovered only as a result of the human genome project (HGP). This was previously known only as “dark DNA”.  It has become clear that lncDNA has an important role in cellular regulatory activities centered in the chromatin modeling.  Moreover, just as proteins exhibit functionality in their folding, related to tertiary structure and highly influenced by location of –S-S- bridges and amino acid residue distances (allosteric effects), there is a less studied effect as the chromatin becomes more compressed within the nucleus,that should have a bearing on cellular expression.

According to Jose Eduardo de Salles Roselino , when the Na/Glucose transport system (for a review Silvermann, M. in Annu. Rev. Biochem.60: 757-794(1991)) was found in kidneys as well as in key absorptive cells of digestive tract, it should be stressed its functional relationship with “internal milieu” and real meaning, homeostasis. It is easy to understand how the major topic was presented as how to prevent diarrheal deaths in infants, while detected in early stages. However, from a biochemical point of view, as presented in Schrödinger´s What is life? (biochemistry offering a molecular view for two legs of biology, physiology and genetics). Why should it be driven to the sole target of understanding genetics? Why the understanding of physiology in molecular terms should be so neglected?

From a biochemical point of view, there is a single protein, which is found to transport the cation most directly related to water maintenance, the internal solvent that bath our cells and the hydrocarbon whose concentration is kept under homeostatic control on that solvent. Completely at variance with what is presented in microorganisms as previously mentioned in Moyed and Umbarger revision (Ann. Rev42: 444(1962)) that does not regulates the environment where they live and appears to influence it only as an incidental result of their metabolism.

In case any attempt is made in order to explain why the best leg that supports scientific reasoning from biology for medical purposes was led to atrophy, several possibilities can be raised. However, none of them could be placed strictly in scientific terms. Factors that bare little relationship with scientific progress in general terms must also be taken into account.

One simple possibility of explanation can be found in one review (G. Scatchard – Solutions of Electrolytes Ann. Rev. Physical Chemistry 14: 161-176 (1963)).  A simple reading of it and the sophisticated differences among researchers will discourage one hundred per cent of biologists to keep in touch with this line of research. Biochemists may keep on reading.  However, consider that first: Complexity is not amenable to reductionist vision in all cases. Second, as coupling between scalar flows such as chemical reactions and vector flows such as diffusion flows, heat flows, and electrical current can occur only in anisotropic system…let them with their problems of solvents, ions and etc. and let our biochemical reactions on another basket. At the interface, for instance, at membrane level, we will agree that ATP is converted to ADP because it is far from equilibrium and the continuous replenishment of ATP that maintain relatively constant ATP levels inside the cell and this requires some non-stationary flow.

Our major point must be to understand that our biological limits are far clearer present in our limited ability to regulate the information stored in the DNA than in the amount of information we have in the DNA as the master regulator of the cells.

The amazing revelation that Masahiro Chiga  (discovery of liver adenylate kinase  distinct from that of muscle) taught  me (LHB) is – draw 2 circles  that intersect, one of which represents what we know, the other – what we don’t know.  We don’t teach how much we don’t know!  Even today, as much as 40 years ago, there is a lot we need to get on top of this.

The observation is rather similar to the presentations I  (Jose Eduardo de Salles Rosalino) was previously allowed to make of the conformational energy as made by R Marcus in his Nobel lecture revised (J. of  Electroanalytical Chemistry 438:(1997) p251-259. His description of the energetic coordinates of a landscape of a chemical reaction is only a two-dimensional cut of what in fact is a volcano crater (in three dimensions) ( each one varie but the sum of the two is constant. Solvational+vibrational=100% in ordinate) nuclear coordinates in abcissa. In case we could represent it by research methods that allow us to discriminate in one by one degree of different pairs of energy, we would most likely have 360 other similar representations of the same phenomenon. The real representation would take into account all those 360 representation together. In case our methodology was not that fine, for instance it discriminate only differences of minimal 10 degrees in 360 possible, will have 36 partial representations of something that to be perfectly represented will require all 36 being taken together. Can you reconcile it with ATGC? Yet, when complete genome sequences were presented they were described as we will know everything about this living being. The most important problems in biology will be viewed by limited vision always and the awareness of this limited is something we should acknowledge and teach it. Therefore, our knowledge is made up of partial representations.

Even though we may have complete genome data for the most intricate biological problems, they are not so amenable to this level of reductionism. However, from general views of signals and symptoms we could get to the most detailed molecular view and in this case the genome provides an anchor. This is somehow, what Houssay was saying to me and to Leloir when he pointed out that only in very rare occasions biological phenomena could be described in three terms: Pacco, the dog and the anesthetic (previous e-mail). The non-coding region, to me will be important guiding places for protein interactions.

Cancer Team Members @ Leaders of Pharmaceutical Business Intelligence Express Their Views on the Frontier of Cancer Research in Their OWN Domain of Expertise

Current Advanced Research Topics in MRI-based Management of Cancer Patients

Author: Dror Nir, PhD

Step forward towards quantitative and reproducible MRI of cancer patients is the combination of structure and morphology based imaging with expressions of typical bio-chemical processes using imaging contrast materials. The following list brings the latest publications on this subject in Radiology magazine.

The Effects of Applying Breast Compression in Dynamic Contrast Material–enhanced MR Imaging

Abstract
Purpose: To evaluate the effects of breast compression on breast cancer masses, contrast material enhancement of glandular tissue, and quality of magnetic resonance (MR) images in the identification and characterization of breast lesions.

Materials and Methods: This was a HIPAA-compliant, institutional review board–approved retrospective study, with waiver of informed consent. Images from 300 MR imaging examinations in 149 women (mean age ± standard deviation, 51.5 years ± 10.9; age range, 22–76 years) were evaluated. The women underwent diagnostic MR imaging (no compression) and MR-guided biopsy (with compression) between June 2008 and February 2013. Breast compression was expressed as a percentage relative to the noncompressed breast. Percentage enhancement difference was calculated between noncompressed- and compressed-breast images obtained in early and delayed contrast-enhanced phases. Breast density, lesion type (mass vs non-masslike enhancement [NMLE]), lesion size, percentage compression, and kinetic curve type were evaluated. Linear regression, receiver operating characteristic (ROC) curve analysis, and κ test were performed.

Conclusion: Breast compression during biopsy affected breast lesion detection, lesion size, and dynamic contrast-enhanced MR imaging interpretation and performance. Limiting the application of breast compression is recommended, except when clinically necessary.

Localized Prostate Cancer Detection with 18F FACBC PET/CT: Comparison with MR Imaging and Histopathologic Analysis

Abstract
Purpose: To characterize uptake of 1-amino-3-fluorine 18-fluorocyclobutane-1-carboxylic acid (18F FACBC) in patients with localized prostate cancer, benign prostatic hyperplasia (BPH), and normal prostate tissue and to evaluate its potential utility in delineation of intraprostatic cancers in histopathologically confirmed localized prostate cancer in comparison with magnetic resonance (MR) imaging.

Materials and Methods: Institutional review board approval and written informed consent were obtained for this HIPAA-compliant prospective study. Twenty-one men underwent dynamic and static abdominopelvic 18F FACBC combined positron emission tomography (PET) and computed tomography (CT) and multiparametric (MP) 3-T endorectal MR imaging before robotic-assisted prostatectomy. PET/CT and MR images were coregistered by using pelvic bones as fiducial markers; this was followed by manual adjustments. Whole-mount histopathologic specimens were sliced with an MR-based patient-specific mold. 18F FACBC PET standardized uptake values (SUVs) were compared with those at MR imaging and histopathologic analysis for lesion- and sector-based (20 sectors per patient) analysis. Positive and negative predictive values for each modality were estimated by using generalized estimating equations with logit link function and working independence correlation structure.

Conclusion: 18F FACBC PET/CT shows higher uptake in intraprostatic tumor foci than in normal prostate tissue; however, 18F FACBC uptake in tumors is similar to that in BPH nodules. Thus, it is not specific for prostate cancer. Nevertheless, combined 18F FACBC PET/CT and T2-weighted MR imaging enable more accurate localization of prostate cancer lesions than either modality alone.

Illuminating Radiogenomic Characteristics of Glioblastoma Multiforme through Integration of MR Imaging, Messenger RNA Expression, and DNA Copy Number Variation

Abstract

Purpose: To perform a multilevel radiogenomics study to elucidate the glioblastoma multiforme (GBM) magnetic resonance (MR) imaging radiogenomic signatures resulting from changes in messenger RNA (mRNA) expression and DNA copy number variation (CNV).

Materials and Methods: Radiogenomic analysis was performed at MR imaging in 23 patients with GBM in this retrospective institutional review board–approved HIPAA-compliant study. Six MR imaging features—contrast enhancement, necrosis, contrast-to-necrosis ratio, infiltrative versus edematous T2 abnormality, mass effect, and subventricular zone (SVZ) involvement—were independently evaluated and correlated with matched genomic profiles (global mRNA expression and DNA copy number profiles) in a significant manner that also accounted for multiple hypothesis testing by using gene set enrichment analysis (GSEA), resampling statistics, and analysis of variance to gain further insight into the radiogenomic signatures in patients with GBM

Conclusion: Construction of an MR imaging, mRNA, and CNV radiogenomic association map has led to identification of MR traits that are associated with some known high-grade glioma biomarkers and association with genomic biomarkers that have been identified for other malignancies but not GBM. Thus, the traits and genes identified on this map highlight new candidate radiogenomic biomarkers for further evaluation in future studies.

PET/MR Imaging: Technical Aspects and Potential Clinical Applications

Abstract

Instruments that combine positron emission tomography (PET) and magnetic resonance (MR) imaging have recently been assembled for use in humans, and may have diagnostic performance superior to that of PET/computed tomography (CT) for particular clinical and research applications. MR imaging has major strengths compared with CT, including superior soft-tissue contrast resolution, multiplanar image acquisition, and functional imaging capability through specialized techniques such as diffusion-tensor imaging, diffusion-weighted (DW) imaging, functional MR imaging, MR elastography, MR spectroscopy, perfusion-weighted imaging, MR imaging with very short echo times, and the availability of some targeted MR imaging contrast agents. Furthermore, the lack of ionizing radiation from MR imaging is highly appealing, particularly when pediatric, young adult, or pregnant patients are to be imaged, and the safety profile of MR imaging contrast agents compares very favorably with iodinated CT contrast agents. MR imaging also can be used to guide PET image reconstruction, partial volume correction, and motion compensation for more accurate disease quantification and can improve anatomic localization of sites of radiotracer uptake, improve diagnostic performance, and provide for comprehensive regional and global structural, functional, and molecular assessment of various clinical disorders. In this review, we discuss the historical development, software-based registration, instrumentation and design, quantification issues, potential clinical applications, potential clinical roles of image segmentation and global disease assessment, and challenges related to PET/MR imaging.

SOURCE

http://pharmaceuticalintelligence.com/2014/03/31/current-advanced-research-topics-in-mri-based-management-of-cancer/