Leaders in Pharmaceutical Business Intelligence (LPBI) Group

My Memories Tell a Story to Share

Author: Larry Howard Bernstein, MD, FCAP 

Contact: 413-727-8523

Updated on 6/2/2020

In preparation for a PODCAST with Dr. Larry, we prepared the following content:

For many years, he was the Chief Scientific Officer and Member of the Board of Leaders in Pharmaceutical Business Intelligence (LPBI) Group, a Pharmaceutical Media Venture with several Cloud Based products: (1) an Open Access Online Scientific Journal

PharmaceuticalIntelligence.com, (2) a BioMed e-Series of 16 volumes in Medicine (3) A Real Time Press Coverage of Biotech and Medical Conferences (4) a Podcast Library of Interviews with Key Opinion Leaders (4) A Platform with Composition of Methods and (5) a Team of Experts, Authors, Writers.

Dr. Bernstein had contributed 1,400 curated articles to LPBI’s Journal, mentioned above and served as Editor and Content Consultant to each of the 16 volumes in LPBI’s BioMed e-Series.

Examples of the TOP articles in the Journal by e-Readers Views shows the cardinal positioning of Dr. Bernstein’s publications.

Top Posts for all days ending 2020-06-02 (Summarized)
All Time
Title	Views	Author Name	Type of Article
Home page / Archives	676,690	Internet Access	Tabulation
Is the Warburg Effect the Cause or the Effect of Cancer: A 21st Century View?	17,117	Larry H. Bernstein, MD, FACP	Investigator Initiated Research
Recent comprehensive review on the role of ultrasound in breast cancer management	14,242	Dr. D. Nir	Commission by Aviva Lev-Ari, PhD, RN
Do Novel Anticoagulants Affect the PT/INR? The Cases of XARELTO (rivaroxaban) and PRADAXA (dabigatran)	13,839	Dr. Pearlman, MD, PhD, FACC & Aviva Lev-Ari, PhD, RN	Commission by Aviva Lev-Ari, PhD, RN
Paclitaxel vs Abraxane (albumin-bound paclitaxel)	13,709	Tilda Barliya, PhD	Investigator Initiated Research
Apixaban (Eliquis): Mechanism of Action, Drug Comparison and Additional Indications	8,230	Aviva Lev-Ari, PhD, RN	Investigator Initiated Research
Clinical Indications for Use of Inhaled Nitric Oxide (iNO) in the Adult Patient Market: Clinical Outcomes after Use, Therapy Demand and Cost of Care	7,903	Dr. Pearlman, MD, PhD, FACC & Aviva Lev-Ari, PhD, RN	Investigator Initiated Research
Mesothelin: An early detection biomarker for cancer (By Jack Andraka)	6,540	Tilda Barliya, PhD	Investigator Initiated Research
Our TEAM	6,505	Internet Access	Tabulation
Biochemistry of the Coagulation Cascade and Platelet Aggregation: Nitric Oxide: Platelets, Circulatory Disorders, and Coagulation Effects	5,221	Larry H. Bernstein, MD, FACP	Investigator Initiated Research
Interaction of enzymes and hormones	4,901	Larry H. Bernstein, MD, FACP	Commission by Aviva Lev-Ari, PhD, RN
Akt inhibition for cancer treatment, where do we stand today?	4,852	Ziv Raviv, PhD	Investigator Initiated Research
AstraZeneca’s WEE1 protein inhibitor AZD1775 Shows Success Against Tumors with a SETD2 mutation	4,535	Stephen J. Williams, PhD	Investigator Initiated Research
The History and Creators of Total Parenteral Nutrition	4,511	Larry H. Bernstein, MD, FACP	Commission by Aviva Lev-Ari, PhD, RN
Newer Treatments for Depression: Monoamine, Neurotrophic Factor & Pharmacokinetic Hypotheses	4,365	Zohi Sternberg, PhD	Investigator Initiated Research
FDA Guidelines For Developmental and Reproductive Toxicology (DART) Studies for Small Molecules	4,188	Stephen J. Williams, PhD	Investigator Initiated Research
The Centrality of Ca(2+) Signaling and Cytoskeleton Involving Calmodulin Kinases and Ryanodine Receptors in Cardiac Failure, Arterial Smooth Muscle, Post-ischemic Arrhythmia, Similarities and Differences, and Pharmaceutical Targets	4,038	Dr. Pearlman, MD, PhD, FACC, Larry H. Bernstein, MD, FACP & Aviva Lev-Ari, PhD, RN	Commission by Aviva Lev-Ari, PhD, RN
Founder	3,895	Aviva Lev-Ari, PhD, RN	Investigator Initiated Research

That small sample from a universe of 1,400 articles reflects just a glimpse of the topics that he had covered in his writing.

In addition, in 2020 the Journal ontology has 700 Categories of Research, more than 50% were create by Dr. Bernstein for allowing a precise classification of the wide range of topics his life body of research had covered, chiefly: Cancer, Genomics, Pathology, Coagulation, Cardiovascular, Nutrition, Cell Biology and Biochemistry Processes, at large.

Dr. Bernstein served on the Board of Director of NAACLS and the American Library Association Commission on Accreditation and he is listed in the America’s Top Physicians.

He has three patents:

1. Measuring Lactate Dehydrogenase Isoenzymes by differential inhibition of heart and muscle enzymes using the inhibition by a triplex formed by pyruvate – NAD+ and LDH.

2. Measuring the mitochondrial Malate Dehydrogenase using the inhibition of mMDH by a triplex formed by OAA – NAD+ – and mMDH in the laboratory of Nathan Oren Kaplan (NAS).

3. Measuring a cancer modified MDH by loss of mMDH inhibition with Prof. Johannes Everse. In addition, only a provisional patent was filed for Converting Hematology Based Data into an Inferential Interpretation under the direction of Prof. Ronald Raphael Coifman (NAS). No patent was filed for the statistical determination of myocardial infarct using two assays for creatine kinase MB. No patent was filed for the diagnosis of myaocardial infarct using a neural network under the supervision of Izaak Mayzlin, eminent mathematician from former Soviet Union;
No patent was filed for the determination of myocardial infarct using Kullback Entropy.

My lab was the only one to get down to reliable measurements of transthyretin of 20 mg/L. I co-chaired the First International Transthyretin Congress in Strasbourg, at the invitation of Yves Ingenbleek, MD, PhD, Professor of Pharmacology, University Louis Pasteur, Strasbourg.

I chaired the 14th and was an invited participant in the 17th Ross Roundtable on Nutrition, Organized and Chaired the Beckman Roundtable on Pre-albumin in Los Angeles, was responsible for the AACC first document of Standards of Clinical Laboratory Practice with Lawrence Kaplan, and was recipient of the Labbe/Garry award of the Nutrition Division of AACC).

Other projects in normalizing the NT-proBNP for age and estimated glomerular filtration rate (eGFR), were successful, but widespread implementation is even more gradual than was TTR.

• Could you tell us about the research project that had the most significance in your career?

You worked with two noted researchers – Gil David and Yale University’s Chairman of the Mathematics Department Ronald Coifman – to develop a software system which is today’s equivalent of electronic health records that gathers medical information, generates metrics and analyzes data in real-time, providing a health diagnosis for an individual’s medical condition.

4/19/2020

The Schwartz and Auslander Families

I was born a triplet to David and Lillian Bernstein on December 28, 1941, the first set of triplets born in Highland Park Hospital in some 20 years, but on graduation from Mumford High School, Detroit, Michigan in 1960, we were one of three sets of triplets. We were Larry, Leslie and Linda, who were preceded by Sharon, a sister two years older, also a December baby. Our parents were middle class and our father was a dental technician, so a family with four children was not easy to bring up. We always lived in a household of two families, with my uncle Irving and aunt Elsie Bernstein, living in the lower level, having two children, Barbara, who was our age, and Richard, who was the older brother. When we were born, under the circumstance of my grandmother, Bobby Mulvin (Mulvina in Hungarian), three calls were made in successive days to inform the family in Cleveland, Ohio, of our birth. My mother’s father and mother were Julius and Mulvina Schwartz, from the Hungarian edge of Austria on the Raba River, who moved the family to Cleveland as the intentions of Hitler became clear. My mother had two older brothers and a younger sister, David, Herman and Bernice. David had already been a United States citizen when the Schwartz family moved to the United States in 1931, and Herman was a third year medical student in Budapest after completing a year in Vienna, having been valedictorian of his high school class after special arrangement of his local catholic priest. But Herman had to move from Hungary months prior to graduation because immigration would close. Lillian was 18 years age when she brought her 11 year old sister to America. Julius and David worked in the dry cleaning business in Cleveland. There was also a Mulvina cousin, Biederman, who was a jeweler in Vienna who moved to Cleveland, but his father did not escape the Nazis. Their children were Alan and Marvin, Lois, Robert and Barbara (Liss), Lucille and Janice. Another two generations have passed. Robert was a merit scholar in upstate New York, became a reporter on the Miami Herald, and had three children. He died too young of leukemia. Barbara married and had 3 Wolfe children, two boys and a girl.

I have described the Cleveland side of the family. My mother worked making ties in Cleveland for a friend of my father’s family. She helped bring him to Detroit and married my mother. My father came from Czeckoslovakia, his father having a tree farm on the Carpathian mountains, near the border with Poland. He became a Schochet (kosher chicken). He had a sister, Rivka. Rivka married a cantor after her husband died. My grandmother was in the Auslander family. Auslander means out of the land. A rabbi brought his family out of Spain and changed the family name to Auslander. My grandfather was Meyer and grandmother was Rachel (Bobby Rochel). They lived two streets from the elementary school, so we had lunch at the grandparents house. My grandmother had sisters Esther, Edna, Katie, Jeanette. We go to a next generation rich in talent. This family lived in the city of Detroit, which has an interesting history.

The Jewish Community

Grandfather Meyer was very orthodox, but he shaved, and attended the Gelitzioner Shul, but our mother objected to her children going to an orthodox yeshiva school that was too rigid. Our mother read a lot to become knowledgable and also fluent in the English language. Our father read the Detroit Free Press and the business section daily. Some of our family went to the reform synagogue, Temple Israel, that did not use rigorous Hebrew in prayer. We attended the Bnai Moshe synagogue, which had Rabbi Moses Lehrman, whose daughter became an English teacher at our school. There was a cantor, and there was a superb reader of the Torah (Baal Koreh). The president of the Bnai Moshe was the founder of a salami that was the equal to that in New York.

Detroit

Detroit was a city on the Detroit River that was once known as Fort Ponchartrain at the time of the Revolutionary War with the British. There were Indians at the edge of the Upper Peninsula. The Upper Peninsula was obtained by Governor Lewis Cass from Wisconsin an a trade that made Toledo a part of Ohio. Detroit and the Detroit River became a crossing point for Negroes at the time of flight from the Southern states during the Civil War. Windsor, Ontario was a point of transfer of liquor from Winsor, Ontario. Detroit became important when Henry Ford brought automation into auto manufacturing, and it was followed by Dodge/Crysler and General Motors. Neighboring Dearborn, Michigan became a city where there was later a Ford Museum, and it was known to be only for whites and non-jews. There was also before my arrival an anti-Semitic priest, Father Coughlin. In addition, Henry Ford was known to disseminate “The Elders of Zion. So the city was somewhat divided, as perhaps other cities – like New York. Philadelphia, Chicago, and Los Angeles – that had distinctly jewish and black neighborhoods that one might consider ghettos. The city of Highland Park, within Detroit, was Polish. The jewish neighborhood migrated from Chicago Boulevard toward Livernois, and beyond to beyond Seven Mile Road, and eventually beyond Eight Mile Road, the Detroit border.

My early childhood was on Sturtevant, between Linwood and Dexter. Linwood extended to middle Detroit, where there was an automobile convention center. There was a theater at the corner of Linwood and Livernois. There was an upper middle class neighborhood adjacent to Oak Park, and a zoo on Woodward Avenue. The synagogue my family attended was on Dexter, and there was a butcher shop, a bakery, and the Dexter Davison Market. My aunt Edna had an ice cream parlor a short distance from the synagogue on Dexter. She had two sons and one became a doctor and the other a professor.
The McCullough elementary school and across the street a United Hebrew School were walking distance from where my family lived, with many children on our street. Milk was delivered to a milkbox, and an alternative way of entering the home was through the milkbox. The next door neighbor had a dog named Blackie. He was child friendly. There were many children in the neighborhood. My best friend in elementary school was an Armenian boy, Michael Michalian.

High School and College

We moved from the old neighborhood at the time were to attend High School. My brother and I joined the chess club and learned from Peter Wolf, who excelled at it. Mumford High School chess club won the city championship over Redford High School, taking the cup four years in succession. I also found a friend in high school a grade ahead, Fred Baskin, who was extremely bright and very social. The triplets graduated from high school and entered WSU in 1960. When we finished high school we all went to Wayne State University (WSU), where I majored in chemistry, and was a premedical student. Fred had a Merit Scholarship. I prepared myself sufficiently so that if I were not to qualify for medical school, I could follow a suitable career. My older sister, Sharon, was a very fine pianist and she entered WSU with a General Motors Scholarship three years earlier. She excelled in mathematics. She has taught piano for years and still does so at 80 years age. Fred went on to graduate school in biochemistry at University of California, Berkeley and I went on to medical school at Wayne State University upon graduation. My sister Linda did graduate work and obtained a Master degree in biology at Wayne State, married a psychiatry graduate, and they moved to California and raised two boys. I shared the same room as Leslie, but I did not see changes in him that lead to attempted suicide and admittance to the hospital. The three of us spent a summer at the NIH in a study of Schizophrenia. Leslie went to San Diego to be near Linda.

I worked very hard in my first two years of medical school. I engaged in a graduate study in embryology under Harry Maisel in the Anatomy Department, studying the evolution of the proteins of the lens of the eye (crystallins) under Prof. Harry Maisel, but I also studied the changes in the isoenzymes of lactate dehydrogenase (LD). He was an inspiring scientist, but I also had the opportunity to learn electron microscopy under Maurice Bernstein in the same department. When I finished the Master degree I returned to finish the last two years of medical school. This was a valuable experience under two inspiring mentors. In the study of the evolution of the LD isoenzymes I became extremely interested in the work of Nathan Kaplan at the Graduate University of Biochemistry in Boston, and the work of one of his graduate students who looked at the changes in the wings of avians, depending on flight characterics. I chose to go to the University of Kansas Medical School for residency and PhD in pathology. When I arrived in 1968, the pathologist whose work interested me had left to carry on the chairmanship elsewhere, but I was fortunate to meet Masahiro Chiga, who had left an Acting Chairman of Biochemistry to return to pathology. He was an inspiration. I finished less than a year when he recommended that I go to the University of California, San Diego to work with Nathan Kaplan. He modestly said that he had worked with the muscle enzyme of adenylate kinase (myokinase) that is different than the liver enzyme, but he hadn’t had the insight that Kaplan had. I stayed in touch with him until his death. My mother developed gastric cancer, quite rare then, and I visited her several times before she died. I also dated an old Mumford schoolmate, Audrey Mellon, who I married before going to San Diego.

University of Calfornia, San Diego

I found myself in a completely different environment in San Diego. One part of it was the enormous scientific environment, not only with Kaplan’s laboratory his two competent two assistants, and his several postdoctoral students, but also my engagement with several staff biochemists. There were presentations in the hallway next to Prof. Kaplan’s office, and some were from outside research institutions. It was amazing how when the medical school was opened, it had drawn talents from all of the best institutions. An unintended benefit was the beautiful ocean, the nearby La Jolla, and nearby other research centers. Dr. Kaplan was the Editor, and he cofounded Methods in Enzymology with Sidney Colowick, who had worked with Carl and Gerty Cori (Nobel Laureates) in St. Louis. They had both worked with Fritz Lippman in the discovery of Coenzyme A , the cofactor that acts as an acyl carrier, and either activates the acyl group for group transfer or electrophilic attack, or increases the acidity of the protons adjacent to the carbonyl group. He shared the Nobel Prize in Physiology in 1945 with Hans Krebs, who elucidated the Krebs cycle. Kaplan’s role in the discovery was significant. Interestingly, Hans Krebs work was related to work carried out in the laboratory of Otto Warburg (Nobel Laureate, 1937)), whose work pioneered the study of mitochondrial impairment if cancer.

My own work was not with lactate dehydrogenase, but with Malate dehydrogenase, a critical enzyme linked to mitochondrial function. While LDH catalyze the conversion of pyruvate to lactate with NADH as cofactor and the transfer of a proton, the reverse reaction was inhibited by a ternary complex formed by LDH-NAD- and lactate, but this reaction was weak with the muscle type LDH compared to the heart type LDH. In a similar manner the malate dehydrogenase had a mitochondrial and cytoplasmic isoenzyme, the mitochondrial MDH forming a ternary complex, but not the cytoplasmic enzyme. I spent many months purifying the mitochondrial enzyme from 50 lb of chicken hearts with first an ammonium sulfate precipitation, then a column separation, and dialysis. A study of the mitochondrial malate dehydrogenase was followed by stopped flow analysis and that showed the inhibition by transfer of the hydrogen to form a ternary complex.

I returned to residency in pathology at UCSD under an NIH fellowship with Averill Liebow in the next year. Liebow was an internationally known expert in pulmonary pathology. He was also very amazing. A resident from Yale referred to Liebow noticing him sleeping in the back row and the professor called his name, the son of so and so, you can’t sleep in my class. His car was the first in the lot, until I came. Then when I went to the VA Hospital and parked on the other side, he noted that I parked around the corner. The chief of chemistry at the VA was an outstanding teacher and biochemist who subsequently took a position at Beckman-Coulter. I set up an assay in a study of swimming rats with Liebow. My first daughter was born during my residency and it was fascinating watching her learn to stand up. I took her to the San Diego zoo on weekends and she would stand up in her crib and say zoo, zoo. It was at this time that I collected urine specimens for a study of adenylate kinase with Percy Russell, and also took serum specimens from a study of creatine kinase MB in myocardial infarction that was done by the cardiologist Burton Sobel for my own study that was published.

At the end of my residency I had to give two years for my time deferred from the Vietnam War. Liebow called the Armed Forces Institute of Pathology in Washington to give me the best placement. I then spent the next two years working in orthopedic pathology with Lent C. Johnson, who was quite a genius. He determined the normal ratio of bone forming to bone removing cells, and did pioneering work in bone cancer. Liebow wanted me to return after the two years, but he had a stroke. At the end of two years I took a pathology position at the University of South Florida, Tampa, under Herschel Sidransky.

Herschel was an outstanding researcher from University of Pittsburg Medical School. He had several outstanding researchers in his department. I returned to my studies of malate dehydrogenase and in particular, the mitochondrial malate dehydrogenase in hepatic cancer from Herschel Sidransky’s animals. I had a grant from the Cancer Society. I also had the support in statistics from a mathematician.

Herschel became the Chairman of Pathology at George Washington University, Washington, DC. Several faculty went with him, but I received a substantial salary increase and a supportive offer from the University of South Alabama, Mobile, with a very enthusiastic pathology chairman. Just prior to leaving Florida, Naomi was born. I took on a role with the Medical Technology Program, and I also participated in program reviews, and some time later was on the National Committee for Clinical Laboratory Standards. The Chairman was a capable and enthusiastic neuropathologist who intended to build a good department, but it was not long after that the Chair of Medicine, also the Dean, set up a clinical laboratory for his own interest, without merit. I submitted a cancer grant proposal that was approvingly reviewed by the Chairman of Physiology. It was approved by the NIH without funding, with suggestions to consider. That was a point that I chose to move, and after two years, I moved the family to Des Moines, Iowa to work at the Iowa Methodist Medical Center, the second largest after University Hospital. The President of the hospital sent me a high school student and we completed a project on fetal lung maturity that we published. However, the move was not a good match, as the Chairman’s main concern was outside laboratory work and there was also a laboratory manager who was manipulative.

After two years we moved to Binghamton, New York to a position with Gustavo Reynoso, who came from Rochester, New York and was a very respected pathologist. There was a consolidation of hospitals that led to Dr. Reynoso taking the chairmanship of pathology at Norwalk Hospital, in Norwalk, Connecticut, and he procured a position for me at Bridgeport Hospital, in Bridgeport, CT. The move was very good with an excellent staff in pathology, and I was the director of chemistry and blood bank. This time I stayed for 20 years, and developed a very good relationship with the medical staff, the Chairman of Pathology, Dr. Marguerite Pinto, and particularly with my supervisors in Blood Bank and Chemistry. My Blood Bank supervisor married and moved to Greece and eventually was in charge of the Athens Blood Program.

My relationship with the residents in medicine and cardiology was very collaborative. When I was in the hospital recovering from a femoral fracture, I received a call from I.J. Good, Chairman and Editor of a mathematics journal to whom I had sent cardiac enzyme data some years before. He had finished and validated a program “Diagnosis of acute myocardial infarction from two measurements of creatine kinase isoenzyme MB with use of nonparametric probability estimation”, and they successfully ran the data. We published the paper in Clinical Chemistry. The President of the College of American Pathologist complimented the work at a national meeting. I also met another pathologist, Rosser Rudolph, at a pathology meeting and he had developed a powerful mathematical program that determined the entropy of diagnostic data. We collaborated for many years. In addition, I was really privileged to work with the father of my daughter’s classmate, Isaac Mayzlin, who was an important mathematician at Moscow University. We developed an neural network algorithm for myocardial infarction.

I had a very long, satisfying role in collaboration with Dr. Walter Pleban, who was the surgeon in charge of the only burn unit in Connecticut. I had been engaged in the nutritional support program with Dr. Pleban for some years because of my work on transthyretin. Unfortunately, the criteria using decrease in serum albumin that was in use was very inadequate for early recognition. Transthyretin is a plasma protein that binds to vitamin A and declines very early in protein malnutrition. A decline in transthyretin results in impairment of methionine metabolism. I also had a longstanding relationship with Prof. Yves Ingenbleek at University Louis Pasteur, Strasbourg, in this work. When Stanley Dudrick became the Chairman of Surgery, it was a fortunate circumstance. Stanley was the pioneer in developing intravenous nutrition and was nominated for the Nobel Prize for his work.

A year after Yale University took charge of the Bridgeport Pathology Department, I took a position as Chief of Clinical Chemistry and Blood Bank at the Methodist Hospital of Brooklyn. I had a very good relationship with surgery and medicine, and had superb projects with the residents, but also had excellent high school and college students work on projects. I was 65 years old five years later, and returned to work at Norwalk Hospital in charge of the Blood Bank while the position was recruited. After finishing my work there, I went to Yale University and developed a project with Ronald R. Coifman, the retired Chairman of Mathematics and his graduate student. It lead to the development of a powerful algorithm for interpreting the hemogram that we published. There is a substantial body of research being published of a similar nature, but it is not at all clear whether or how this will be incorporated into the electronic medical record. It reminds me of the support I had at Bridgeport Hospital using a laboratory system designed by Dr. Perry Seamonds that eliminated nonessential examination of peripheral smears by rules criteria. This laboratory system also alleviated the volume of laboratory testing to relieve the burden on the physicians. A different problem I later noticed was that the Hospital Systems that were later introduced had the laboratory, but did not include the Blood Bank! However, as the electronic medical record has evolved it has taken an enormous physician, nursing, and provider time that does not justify a reduction in staff.

After I had been done with my Yale project, I developed a visual problem and stopped driving. I had problems I would later realize. I had had two incidents in a few years that I drove my car off the road because of sleep apnea. I was walking in my neighborhood and had to stop and hold on to a tree for balance. In the case of sleep apnea, it was diagnosed earlier in a sleep apnea study in Brooklyn. I had a study at Yale that brought to my realization that I had thyroid cancer, for which I had thyroidectomy. However, I had diplopia after surgery which disappeared some time later. We moved to Northampton, Massachusetts when our daughter, Naomi and her husband Daniel with grandson Joseph moved, Naomi taking a teaching position at Holyoke Community College, and Daniel working as a neurologist at the VA hospital.

Prior to moving I was contacted by Aviva Lev-Ari, PhD, RN who was building an online medical forum known as Leaders in Pharmaceutical Business Intelligence (LPBI) Group, and I became the Chief Scientific Officer (CSO).  Over the decade I wrote many articles (1,390) in the Open Access Online Scientific Journal http://pharmaceuticalintelligence.com that were included in 16 organized e-Books in Medicine. Dr. Lev-Ari’s accomplishment is quite impressive. The e-Books are all available on Amazon.com

https://lnkd.in/ekWGNqA

I stopped contributing two years ago, but a graduate student had read my work and wanted my academic guidance (in Canada). She finished her thesis and graduated a year ago. It was a privilege to work with her. Since moving to Northampton, we has been in a very good community at Lathrup.