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Archive for the ‘DNA repair’ Category


Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

A mutated gene called RAS gives rise to a signalling protein Ral which is involved in tumour growth in the bladder. Many researchers tried and failed to target and stop this wayward gene. Signalling proteins such as Ral usually shift between active and inactive states.

 

So, researchers next tried to stop Ral to get into active state. In inacvtive state Ral exposes a pocket which gets closed when active. After five years, the researchers found a small molecule dubbed BQU57 that can wedge itself into the pocket to prevent Ral from closing and becoming active. Now, BQU57 has been licensed for further development.

 

Researchers have a growing genetic data on bladder cancer, some of which threaten to overturn the supposed causes of bladder cancer. Genetics has also allowed bladder cancer to be reclassified from two categories into five distinct subtypes, each with different characteristics and weak spots. All these advances bode well for drug development and for improved diagnosis and prognosis.

 

Among the groups studying the genetics of bladder cancer are two large international teams: Uromol (named for urology and molecular biology), which is based at Aarhus University Hospital in Denmark, and The Cancer Genome Atlas (TCGA), based at institutions in Texas and Boston. Each team tackled a different type of cancer, based on the traditional classification of whether or not a tumour has grown into the muscle wall of the bladder. Uromol worked on the more common, earlier form, non-muscle-invasive bladder cancer, whereas TCGA is looking at muscle-invasive bladder cancer, which has a lower survival rate.

 

The Uromol team sought to identify people whose non-invasive tumours might return after treatment, becoming invasive or even metastatic. Bladder cancer has a high risk of recurrence, so people whose non-invasive cancer has been treated need to be monitored for many years, undergoing cystoscopy every few months. They looked for predictive genetic footprints in the transcriptome of the cancer, which contains all of a cell’s RNA and can tell researchers which genes are turned on or off.

 

They found three subgroups with distinct basal and luminal features, as proposed by other groups, each with different clinical outcomes in early-stage bladder cancer. These features sort bladder cancer into genetic categories that can help predict whether the cancer will return. The researchers also identified mutations that are linked to tumour progression. Mutations in the so-called APOBEC genes, which code for enzymes that modify RNA or DNA molecules. This effect could lead to cancer and cause it to be aggressive.

 

The second major research group, TCGA, led by the National Cancer Institute and the National Human Genome Research Institute, that involves thousands of researchers across USA. The project has already mapped genomic changes in 33 cancer types, including breast, skin and lung cancers. The TCGA researchers, who study muscle-invasive bladder cancer, have looked at tumours that were already identified as fast-growing and invasive.

 

The work by Uromol, TCGA and other labs has provided a clearer view of the genetic landscape of early- and late-stage bladder cancer. There are five subtypes for the muscle-invasive form: luminal, luminal–papillary, luminal–infiltrated, basal–squamous, and neuronal, each of which is genetically distinct and might require different therapeutic approaches.

 

Bladder cancer has the third-highest mutation rate of any cancer, behind only lung cancer and melanoma. The TCGA team has confirmed Uromol research showing that most bladder-cancer mutations occur in the APOBEC genes. It is not yet clear why APOBEC mutations are so common in bladder cancer, but studies of the mutations have yielded one startling implication. The APOBEC enzyme causes mutations early during the development of bladder cancer, and independent of cigarette smoke or other known exposures.

 

The TCGA researchers found a subset of bladder-cancer patients, those with the greatest number of APOBEC mutations, had an extremely high five-year survival rate of about 75%. Other patients with fewer APOBEC mutations fared less well which is pretty surprising.

 

This detailed knowledge of bladder-cancer genetics may help to pinpoint the specific vulnerabilities of cancer cells in different people. Over the past decade, Broad Institute researchers have identified more than 760 genes that cancer needs to grow and survive. Their genetic map might take another ten years to finish, but it will list every genetic vulnerability that can be exploited. The goal of cancer precision medicine is to take the patient’s tumour and decode the genetics, so the clinician can make a decision based on that information.

 

References:

 

https://www.ncbi.nlm.nih.gov/pubmed/29117162

 

https://www.ncbi.nlm.nih.gov/pubmed/27321955

 

https://www.ncbi.nlm.nih.gov/pubmed/28583312

 

https://www.ncbi.nlm.nih.gov/pubmed/24476821

 

https://www.ncbi.nlm.nih.gov/pubmed/28988769

 

https://www.ncbi.nlm.nih.gov/pubmed/28753430

 

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Breakthroughs: Insights From the Personalized Medicine & Diagnostics Track at the 2017 BIO International Convention

Guest Author: David Davenport, Office Administrator, Personalized Medicine Coalition

 

“Health care today is reactive and costly … anything but personalized … but we are now entering a new era where health care is becoming proactive, preventive, highly personalized and most importantly predictive,” said J. Craig Venter, Ph.D., Founder, President, CEO, J. Craig Venter Institute, during his opening keynote at the Personalized Medicine and Diagnostics Track at the 2017 BIO International Convention in San Diego from June 21 – 22. The track, co-organized by PMC, brought together thought leaders to discuss breakthroughs in advancing personalized medicine. From those conversations several themes emerged:

Complex genetic data require a “knowledge network” to translate into personalized care.

During the session titled The Next Frontier: Navigating Clinical Adoption of Personalized Medicine, moderated by PMC Vice President for Science Policy Daryl Pritchard, Ph.D., panelists discussed how to accelerate the clinical adoption of innovative personalized therapies. Jennifer Levin Carter, M.D., Founder and Chief Medical Officer of N-of-One, a clinical diagnostic testing interpretation service company, explained that as data grows in complexity, there is a growing need for partnerships to efficiently analyze the data and develop effective targeted treatment plans. India Hook-Barnard, Ph.D., Director of Research Strategy, Associate Director of Precision Medicine, University of California, San Francisco (UCSF), agreed and discussed the need to build a “knowledge network” that can harness data and expertise to inform provider-patient decision-making.

Discussing how personalized medicine can be integrated into community health centers lacking large research budgets, Lynn Dressler, Dr.P.H., Director of Personalized Medicine and Pharmacogenomics at Mission Health Systems, a rural community health care delivery system in Asheville, North Carolina, discussed the need to better educate physicians and patients as well as the role that a knowledge network could play in providing easy and cost-effective access to diagnostic testing services.

Delivering personalized medicine requires innovative partnerships involving industry, IT companies, providers, payers and the government.

During It’s a Converging World: Innovative Partnerships and Precision Medicine, a panel moderated by Kristin Pothier, Global Head of Life Sciences Strategy, Ernst & Young, discussed the need for “open data” where improved patient care is the shared goal, and how public-private partnerships that address education, evidence development and access to care can help foster personalized medicine.

During a session titled Nevada as a New Model for Population Health Study, Nevada-based health system Renown Health outlined a study in which it partnered with genetic testing company 23andMe to examine whether free access to genetic testing changes participants’ practices in managing their own health and facilitates the utilization of personalized medicine.

In the era of personalized medicine, measuring and delivering value requires a paradigm shift from population-based to individual-based evidence.

Following a discussion on regulatory and reimbursement challenges moderated by Bruce Quinn, M.D., Ph.D., Principal, Bruce Quinn Associates, during which panelists called for the simplification of payment structures to be more consistent, more efficient and more connected to the patient market, a panel moderated by Jennifer Snow, Director of Health Policy at Xcenda, discussed how value assessment frameworks must adapt to consider the value of personalized medicine. During The Whole Picture: Consideration of Personalized Medicine in Value Assessment Frameworks, panelist Mitch Higashi, Ph.D., Vice President, Health Economics and Outcomes Research, U.S., Bristol-Myers Squibb, called for patient-centered definitions of value and advocated for the inclusion of predictive biomarkers in all value frameworks. Donna Cryer, J.D., President, CEO, Global Liver Institute, added that the “patient must be the ultimate ‘arbiter of value’” and urged “transparency” in how value assessment frameworks are used.

Noting that different assessment frameworks have different goals, Roger Longman, CEO, Real Endpoints, called for more dynamic frameworks that allow different stakeholders to “use the same criteria but weigh them differently.” The panel concluded that to advance personalized medicine, value frameworks must be meaningful, practical and predictive for patients; reflect evolving evidence needs like real-world evidence; and consider breakthrough payment structures like bundled payments.

From Promise to Practice: The Way Forward for Personalized Medicine

During the concluding session, Creating a Universal Biomarker Program, moderated by Ian Wright, Owner, Strategic Innovations LLC, on behalf of Cedars-Sinai Precision Health, panelists discussed how to make patients the point of reference for their own care, as opposed to being compared to the “normal” range of population averages in treatment decisions using biomarkers. The speakers concluded that moving in that direction requires providers to establish baselines for each patient, along with tools and metrics to facilitate the approach.

In the words of Donna Cryer, “personalized medicine is the definition of value for a patient.” With the ability to detect diseases before they even express themselves, the promise of personalized medicine has never been greater.

However, changing the health care system to improve patient access to valuable personalized medicines requires innovation and collaboration. As PMC President Edward Abrahams, Ph.D., said during his opening remarks for the track, that change

“doesn’t come easily,” but “breakthrough” discussions like these continue to move us forward.

The complete track agenda can be downloaded here.

 

SOURCE

From: <pmc@personalizedmedicinecoalition.org>

Date: Monday, July 10, 2017 at 10:51 AM

To: Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu>

Subject: Breakthroughs From the 2017 BIO Convention’s PM & Dx Track

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Genomic Diagnostics: Three Techniques to Perform Single Cell Gene Expression and Genome Sequencing Single Molecule DNA Sequencing

Curator: Aviva Lev-Ari, PhD, RN

 

This article presents Three Techniques to Perform Single Cell Gene Expression and Genome Sequencing Single molecule DNA sequencing

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Translation of whole human genome sequencing to clinical practice: The Joint Initiative for Metrology in Biology (JIMB) is a collaboration between the National Institute of Standards & Technology (NIST) and Stanford University.

Reporter: Aviva Lev-Ari, PhD, RN

 

JIMB’s mission is to advance the science of measuring biology (biometrology). JIMB is pursuing fundamental research, standards development, and the translation of products that support confidence in biological measurements and reliable reuse of materials and results. JIMB is particularly focused on measurements and technologies that impact, are related to, or enabled by ongoing advances in and associated with the reading and writing of DNA.

Stanford innovators and industry entrepreneurs have joined forces with the measurement experts from NIST to create a new engine powering the bioeconomy. It’s called JIMB — “Jim Bee” — the Joint Initiative for Metrology in Biology. JIMB unites people, platforms, and projects to underpin standards-based research and innovation in biometrology.

Genome in a Bottle
Authoritative Characterization of
Benchmark Human Genomes


The Genome in a Bottle Consortium is a public-private-academic consortium hosted by NIST to develop the technical infrastructure (reference standards, reference methods, and reference data) to enable translation of whole human genome sequencing to clinical practice. The priority of GIAB is authoritative characterization of human genomes for use in analytical validation and technology development, optimization, and demonstration. In 2015, NIST released the pilot genome Reference Material 8398, which is genomic DNA (NA12878) derived from a large batch of the Coriell cell line GM12878, characterized for high-confidence SNPs, indel, and homozygous reference regions (Zook, et al., Nature Biotechnology 2014).

There are four new GIAB reference materials available.  With the addition of these new reference materials (RMs) to a growing collection of “measuring sticks” for gene sequencing, we can now provide laboratories with even more capability to accurately “map” DNA for genetic testing, medical diagnoses and future customized drug therapies. The new tools feature sequenced genes from individuals in two genetically diverse groups, Asians and Ashkenazic Jews; a father-mother-child trio set from Ashkenazic Jews; and four microbes commonly used in research. For more information click here.  To purchase them, visit:

Data and analyses are publicly available (GIAB GitHub). A description of data generated by GIAB is published here. To standardize best practices for using GIAB genomes for benchmarking, we are working with the Global Alliance for Genomics and Health Benchmarking Team (benchmarking tools).

High-confidence small variant and homozygous reference calls are available for NA12878, the Ashkenazim trio, and the Chinese son with respect to GRCh37.  Preliminary high-confidence calls with respect to GRCh38 are also available for NA12878.   The latest version of these calls is under the latest directory for each genome on the GIAB FTP.

The consortium was initiated in a set of meetings in 2011 and 2012, and the consortium holds open, public workshops in January at Stanford University in Palo Alto, CA and in August/September at NIST in Gaithersburg, MD. Slides from workshops and conferences are available online. The consortium is open and welcomes new participants.

SOURCE

Stanford innovators and industry entrepreneurs have joined forces with the measurement experts from NIST to create a new engine powering the bioeconomy. It’s called JIMB — “Jim Bee” — the Joint Initiative for Metrology in Biology. JIMB unites people, platforms, and projects to underpin standards-based research and innovation in biometrology.

JIMB World Metrology Day Symposium

JIMB’s mission is to motivate standards-based measurement innovation to facilitate translation of basic science and technology development breakthroughs in genomics and synthetic biology.

By advancing biometrology, JIMB will push the boundaries of discovery science, accelerate technology development and dissemination, and generate reusable resources.

 SOURCE

VIEW VIDEO

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Other related articles published in this Open Access Online Scientific Journal include the following:

“Genome in a Bottle”: NIST’s new metrics for Clinical Human Genome Sequencing

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/09/06/genome-in-a-bottle-nists-new-metrics-for-clinical-human-genome-sequencing/

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Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Mitochondrial disease

 

Mitochondria are present in almost all human cells, and vary in number from a few tens to many thousands. They generate the majority of a cell’s energy supply which powers every part of our body. Mitochondria have their own separate DNA, which carries just a few genes. All of these genes are involved in energy production but determine no other characteristics. And so, any faults in these genes lead only to problems in energy production. Around 1 in 6500 children is thought to be born with a serious mitochondrial disorder due to faults in mitochondrial DNA.

 

Unlike nuclear genes, mitochondrial DNA is inherited only from our mothers. Mothers can carry abnormal mitochondria and be at risk of passing on serious disease to their children, even if they themselves show only mild or no symptoms. It is for such women who by chance have a high proportion of faulty mitochondrial DNA in their eggs for which the methods of mitochondrial replacement or “donation” have been developed. This technique is also referred as the three parent technique and it involves a couple and a donor.

 

Mitochondrial Donation

 

The most developed techniques, maternal spindle transfer (MST) and pro-nuclear transfer (PNT), are based on an IVF cycle but have additional steps. Other techniques are being developed.

 

In both MST and PNT, nuclear DNA is moved from a patient’s egg or embryo containing unhealthy mitochondria to a donor’s egg or embryo containing healthy mitochondria, from which the donor’s nuclear DNA has been removed.

 

mst

Maternal spindle transfer Bredenoord, A and P. Braude (2010) “Ethics of mitochondrial gene replacement: from bench to bedside” BMJ 341.

 

pnt

Pronuclear transfer Bredenoord, A and P. Braude (2010) “Ethics of mitochondrial gene replacement: from bench to bedside” BMJ 341.

 

Research Carried Out and Safety Issues

 

There have been many experiments conducted using MST and PNT in animals. PNT has been carried out since the mid-1980s in mice. MST has been carried out in a wide range of animals. More recently mice, monkeys and human embryos have been created with the specific aim of developing MST and PNT for avoiding mitochondrial disease.

 

  • There is no evidence to show that mitochondrial donation is unsafe
  • Research is progressing well and the recommended further experiments are expected to confirm this view.

 

The main area of research needed is to observe cells derived from embryos created by MST and PNT, to see how mitochondria behave.

 

Concerns about Mitochondrial Donation

 

The scientific evidence raises some potential concerns about mitochondrial donation. Just as we all have different blood groups, we also have different types of mitochondria, called haplotypes. Some scientists have suggested that if the patient and the mitochondria donor have different mitochondrial haplotypes, there is a theoretical risk that the donor’s mitochondria won’t be able to ‘talk’ properly to the patient’s nuclear DNA, which could cause problems in the embryo and resulting child. So, mitochondria haplotype matching in the process of selecting donors may be done to avoid problems.

 

Another potential concern is that a small amount of unhealthy mitochondrial DNA may be transferred into the donor’s egg along with the mother’s nuclear DNA. Studies carried out on MST and PNT show that some so-called mitochondrial ‘carry-over’ occurs. However, the carry-over is lower than 2% of the mitochondria in the resulting embryo, an amount which is very unlikely to be problematic for the children born.

 

References:

 

http://mitochondria.hfea.gov.uk/mitochondria/what-is-mitochondrial-disease/

 

http://mitochondria.hfea.gov.uk/mitochondria/what-is-mitochondrial-disease/new-techniques-to-prevent-mitochondrial-disease/

 

https://www.newscientist.com/article/2107219-exclusive-worlds-first-baby-born-with-new-3-parent-technique/

 

https://www.newscientist.com/article/2108549-exclusive-3-parent-baby-method-already-used-for-infertility/

 

http://www.frontlinegenomics.com/news/7889/ethical-concerns-raised-first-three-parent-ivf-baby/

 

http://www.hfea.gov.uk/docs/2011-04-18_Mitochondria_review_-_final_report.PDF

 

http://www.hfea.gov.uk/docs/Mito-Annex_VIII-science_review_update.pdf

 

http://www.hfea.gov.uk/docs/Third_Mitochondrial_replacement_scientific_review.pdf

 

https://pharmaceuticalintelligence.com/2014/02/26/three-parent-baby-making-practice-of-modifying-oocytes-for-use-in-in-vitro-fertilization-fda-hearing/

 

 

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Milestones in Physiology & Discoveries in Medicine and Genomics: Request for Book Review Writing on Amazon.com


physiology-cover-seriese-vol-3individualsaddlebrown-page2

Milestones in Physiology

Discoveries in Medicine, Genomics and Therapeutics

Patient-centric Perspective 

http://www.amazon.com/dp/B019VH97LU 

2015

 

 

Author, Curator and Editor

Larry H Bernstein, MD, FCAP

Chief Scientific Officer

Leaders in Pharmaceutical Business Intelligence

Larry.bernstein@gmail.com

Preface

Introduction 

Chapter 1: Evolution of the Foundation for Diagnostics and Pharmaceuticals Industries

1.1  Outline of Medical Discoveries between 1880 and 1980

1.2 The History of Infectious Diseases and Epidemiology in the late 19th and 20th Century

1.3 The Classification of Microbiota

1.4 Selected Contributions to Chemistry from 1880 to 1980

1.5 The Evolution of Clinical Chemistry in the 20th Century

1.6 Milestones in the Evolution of Diagnostics in the US HealthCare System: 1920s to Pre-Genomics

 

Chapter 2. The search for the evolution of function of proteins, enzymes and metal catalysts in life processes

2.1 The life and work of Allan Wilson
2.2  The  evolution of myoglobin and hemoglobin
2.3  More complexity in proteins evolution
2.4  Life on earth is traced to oxygen binding
2.5  The colors of life function
2.6  The colors of respiration and electron transport
2.7  Highlights of a green evolution

 

Chapter 3. Evolution of New Relationships in Neuroendocrine States
3.1 Pituitary endocrine axis
3.2 Thyroid function
3.3 Sex hormones
3.4 Adrenal Cortex
3.5 Pancreatic Islets
3.6 Parathyroids
3.7 Gastointestinal hormones
3.8 Endocrine action on midbrain
3.9 Neural activity regulating endocrine response

3.10 Genomic Promise for Neurodegenerative Diseases, Dementias, Autism Spectrum, Schizophrenia, and Serious Depression

 

Chapter 4.  Problems of the Circulation, Altitude, and Immunity

4.1 Innervation of Heart and Heart Rate
4.2 Action of hormones on the circulation
4.3 Allogeneic Transfusion Reactions
4.4 Graft-versus Host reaction
4.5 Unique problems of perinatal period
4.6. High altitude sickness
4.7 Deep water adaptation
4.8 Heart-Lung-and Kidney
4.9 Acute Lung Injury

4.10 Reconstruction of Life Processes requires both Genomics and Metabolomics to explain Phenotypes and Phylogenetics

 

Chapter 5. Problems of Diets and Lifestyle Changes

5.1 Anorexia nervosa
5.2 Voluntary and Involuntary S-insufficiency
5.3 Diarrheas – bacterial and nonbacterial
5.4 Gluten-free diets
5.5 Diet and cholesterol
5.6 Diet and Type 2 diabetes mellitus
5.7 Diet and exercise
5.8 Anxiety and quality of Life
5.9 Nutritional Supplements

 

Chapter 6. Advances in Genomics, Therapeutics and Pharmacogenomics

6.1 Natural Products Chemistry

6.2 The Challenge of Antimicrobial Resistance

6.3 Viruses, Vaccines and immunotherapy

6.4 Genomics and Metabolomics Advances in Cancer

6.5 Proteomics – Protein Interaction

6.6 Pharmacogenomics

6.7 Biomarker Guided Therapy

6.8 The Emergence of a Pharmaceutical Industry in the 20th Century: Diagnostics Industry and Drug Development in the Genomics Era: Mid 80s to Present

6.09 The Union of Biomarkers and Drug Development

6.10 Proteomics and Biomarker Discovery

6.11 Epigenomics and Companion Diagnostics

 

Chapter  7

Integration of Physiology, Genomics and Pharmacotherapy

7.1 Richard Lifton, MD, PhD of Yale University and Howard Hughes Medical Institute: Recipient of 2014 Breakthrough Prizes Awarded in Life Sciences for the Discovery of Genes and Biochemical Mechanisms that cause Hypertension

7.2 Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

7.3 Diagnostics and Biomarkers: Novel Genomics Industry Trends vs Present Market Conditions and Historical Scientific Leaders Memoirs

7.4 Synthetic Biology: On Advanced Genome Interpretation for Gene Variants and Pathways: What is the Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging

7.5 Diagnosing Diseases & Gene Therapy: Precision Genome Editing and Cost-effective microRNA Profiling

7.6 Imaging Biomarker for Arterial Stiffness: Pathways in Pharmacotherapy for Hypertension and Hypercholesterolemia Management

7.7 Neuroprotective Therapies: Pharmacogenomics vs Psychotropic drugs and Cholinesterase Inhibitors

7.8 Metabolite Identification Combining Genetic and Metabolic Information: Genetic association links unknown metabolites to functionally related genes

7.9 Preserved vs Reduced Ejection Fraction: Available and Needed Therapies

7.10 Biosimilars: Intellectual Property Creation and Protection by Pioneer and by

7.11 Demonstrate Biosimilarity: New FDA Biosimilar Guidelines

 

Chapter 7.  Biopharma Today

8.1 A Great University engaged in Drug Discovery: University of Pittsburgh

8.2 Introduction – The Evolution of Cancer Therapy and Cancer Research: How We Got Here?

8.3 Predicting Tumor Response, Progression, and Time to Recurrence

8.4 Targeting Untargetable Proto-Oncogenes

8.5 Innovation: Drug Discovery, Medical Devices and Digital Health

8.6 Cardiotoxicity and Cardiomyopathy Related to Drugs Adverse Effects

8.7 Nanotechnology and Ocular Drug Delivery: Part I

8.8 Transdermal drug delivery (TDD) system and nanotechnology: Part II

8.9 The Delicate Connection: IDO (Indolamine 2, 3 dehydrogenase) and Cancer Immunology

8.10 Natural Drug Target Discovery and Translational Medicine in Human Microbiome

8.11 From Genomics of Microorganisms to Translational Medicine

8.12 Confined Indolamine 2, 3 dioxygenase (IDO) Controls the Homeostasis of Immune Responses for Good and Bad

 

Chapter 9. BioPharma – Future Trends

9.1 Artificial Intelligence Versus the Scientist: Who Will Win?

9.2 The Vibrant Philly Biotech Scene: Focus on KannaLife Sciences and the Discipline and Potential of Pharmacognosy

9.3 The Vibrant Philly Biotech Scene: Focus on Computer-Aided Drug Design and Gfree Bio, LLC

9.4 Heroes in Medical Research: The Postdoctoral Fellow

9.5 NIH Considers Guidelines for CAR-T therapy: Report from Recombinant DNA Advisory Committee

9.6 1st Pitch Life Science- Philadelphia- What VCs Really Think of your Pitch

9.7 Multiple Lung Cancer Genomic Projects Suggest New Targets, Research Directions for Non-Small Cell Lung Cancer

9.8 Heroes in Medical Research: Green Fluorescent Protein and the Rough Road in Science

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

9.10 The SCID Pig II: Researchers Develop Another SCID Pig, And Another Great Model For Cancer Research

Epilogue

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genomicsinpersonalizedmedicinecovervolumeone

Content Consultant: Larry H Bernstein, MD, FCAP

Genomics Orientations for Personalized Medicine

Volume One

http://www.amazon.com/dp/B018DHBUO6

electronic Table of Contents

Chapter 1

1.1 Advances in the Understanding of the Human Genome The Initiation and Growth of Molecular Biology and Genomics – Part I

1.2 CRACKING THE CODE OF HUMAN LIFE: Milestones along the Way – Part IIA

1.3 DNA – The Next-Generation Storage Media for Digital Information

1.4 CRACKING THE CODE OF HUMAN LIFE: Recent Advances in Genomic Analysis and Disease – Part IIC

1.5 Advances in Separations Technology for the “OMICs” and Clarification of Therapeutic Targets

1.6 Genomic Analysis: FLUIDIGM Technology in the Life Science and Agricultural Biotechnology

Chapter 2

2.1 2013 Genomics: The Era Beyond the Sequencing of the Human Genome: Francis Collins, Craig Venter, Eric Lander, et al.

2.2 DNA structure and Oligonucleotides

2.3 Genome-Wide Detection of Single-Nucleotide and Copy-Number Variation of a Single Human Cell 

2.4 Genomics and Evolution

2.5 Protein-folding Simulation: Stanford’s Framework for Testing and Predicting Evolutionary Outcomes in Living Organisms – Work by Marcus Feldman

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

2.7 Finding the Genetic Links in Common Disease: Caveats of Whole Genome Sequencing Studies

Chapter 3

3.1 Big Data in Genomic Medicine

3.2 CRACKING THE CODE OF HUMAN LIFE: The Birth of Bioinformatics & Computational Genomics – Part IIB 

3.3 Expanding the Genetic Alphabet and linking the Genome to the Metabolome

3.4 Metabolite Identification Combining Genetic and Metabolic Information: Genetic Association Links Unknown Metabolites to Functionally Related Genes

3.5 MIT Scientists on Proteomics: All the Proteins in the Mitochondrial Matrix identified

3.6 Identification of Biomarkers that are Related to the Actin Cytoskeleton

3.7 Genetic basis of Complex Human Diseases: Dan Koboldt’s Advice to Next-Generation Sequencing Neophytes

3.8 MIT Team Researches Regulatory Motifs and Gene Expression of Erythroleukemia (K562) and Liver Carcinoma (HepG2) Cell Lines

Chapter 4

4.1 ENCODE Findings as Consortium

4.2 ENCODE: The Key to Unlocking the Secrets of Complex Genetic Diseases

4.3 Reveals from ENCODE Project will Invite High Synergistic Collaborations to Discover Specific Targets  

4.4 Human Variome Project: encyclopedic catalog of sequence variants indexed to the human genome sequence

4.5 Human Genome Project – 10th Anniversary: Interview with Kevin Davies, PhD – The $1000 Genome

4.6 Quantum Biology And Computational Medicine

4.7 The Underappreciated EpiGenome

4.8 Unraveling Retrograde Signaling Pathways

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

4.10  DNA: One man’s trash is another man’s treasure, but there is no JUNK after all

Chapter 5

5.1 Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine – Part 1 

5.2 Computational Genomics Center: New Unification of Computational Technologies at Stanford

5.3 Personalized Medicine: An Institute Profile – Coriell Institute for Medical Research: Part 3

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

5.5 Genome and Genetics: Resources @Stanford, @MIT, @NIH’s NCBCS

5.6 NGS Market: Trends and Development for Genotype-Phenotype Associations Research

5.7 Speeding Up Genome Analysis: MIT Algorithms for Direct Computation on Compressed Genomic Datasets

5.8  Modeling Targeted Therapy

5.9 Transphosphorylation of E-coli Proteins and Kinase Specificity

5.10 Genomics of Bacterial and Archaeal Viruses

Chapter 6

6.1  Directions for Genomics in Personalized Medicine

6.2 Ubiquinin-Proteosome pathway, Autophagy, the Mitochondrion, Proteolysis and Cell Apoptosis: Part III

6.3 Mitochondrial Damage and Repair under Oxidative Stress

6.4 Mitochondria: More than just the “Powerhouse of the Cell”

6.5 Mechanism of Variegation in Immutans

6.6 Impact of Evolutionary Selection on Functional Regions: The imprint of Evolutionary Selection on ENCODE Regulatory Elements is Manifested between Species and within Human Populations

6.7 Cardiac Ca2+ Signaling: Transcriptional Control

6.8 Unraveling Retrograde Signaling Pathways

6.9 Reprogramming Cell Fate

6.10 How Genes Function

6.11 TALENs and ZFNs

6.12 Zebrafish—Susceptible to Cancer

6.13 RNA Virus Genome as Bacterial Chromosome

6.14 Cloning the Vaccinia Virus Genome as a Bacterial Artificial Chromosome 

6.15 Telling NO to Cardiac Risk- DDAH Says NO to ADMA(1); The DDAH/ADMA/NOS Pathway(2)

6.16  Transphosphorylation of E-coli proteins and kinase specificity

6.17 Genomics of Bacterial and Archaeal Viruses

6.18  Diagnosing Diseases & Gene Therapy: Precision Genome Editing and Cost-effective microRNA Profiling

Chapter 7

7.1 Harnessing Personalized Medicine for Cancer Management, Prospects of Prevention and Cure: Opinions of Cancer Scientific Leaders @ http://pharmaceuticalintelligence.com

7.2 Consumer Market for Personal DNA Sequencing: Part 4

7.3 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”

7.4 Drugging the Epigenome

7.5 Nation’s Biobanks: Academic institutions, Research institutes and Hospitals – vary by Collections Size, Types of Specimens and Applications: Regulations are Needed

7.6 Personalized Medicine: Clinical Aspiration of Microarrays

Chapter 8

8.1 Personalized Medicine as Key Area for Future Pharmaceutical Growth

8.2 Inaugural Genomics in Medicine – The Conference Program, 2/11-12/2013, San Francisco, CA

8.3 The Way With Personalized Medicine: Reporters’ Voice at the 8th Annual Personalized Medicine Conference, 11/28-29, 2012, Harvard Medical School, Boston, MA

8.4 Nanotechnology, Personalized Medicine and DNA Sequencing

8.5 Targeted Nucleases

8.6 Transcript Dynamics of Proinflammatory Genes

8.7 Helping Physicians identify Gene-Drug Interactions for Treatment Decisions: New ‘CLIPMERGE’ program – Personalized Medicine @ The Mount Sinai Medical Center

8.8 Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing[1]

8.9 Diagnosing Diseases & Gene Therapy: Precision Genome Editing and Cost-effective microRNA Profiling

Chapter 9

9.1 Personal Tale of JL’s Whole Genome Sequencing

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

9.3 Inform Genomics Developing SNP Test to Predict Side Effects, Help MDs Choose among Chemo Regimens

9.4 SNAP: Predict Effect of Non-synonymous Polymorphisms: How Well Genome Interpretation Tools could Translate to the Clinic

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

9.6 The Initiation and Growth of Molecular Biology and Genomics – Part I

9.7 Personalized Medicine-based Cure for Cancer Might Not Be Far Away

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

 Chapter 10

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

10.2 Imatinib (Gleevec) May Help Treat Aggressive Lymphoma: Chronic Lymphocytic Leukemia (CLL)

10.3 Winning Over Cancer Progression: New Oncology Drugs to Suppress Passengers Mutations vs. Driver Mutations

10.4 Treatment for Metastatic HER2 Breast Cancer

10.5 Personalized Medicine in NSCLC

10.6 Gene Sequencing – to the Bedside

10.7 DNA Sequencing Technology

10.8 Nobel Laureate Jack Szostak Previews his Plenary Keynote for Drug Discovery Chemistry

Chapter 11

11.1 mRNA Interference with Cancer Expression

11.2 Angiogenic Disease Research Utilizing microRNA Technology: UCSD and Regulus Therapeutics

11.3 Sunitinib brings Adult acute lymphoblastic leukemia (ALL) to Remission – RNA Sequencing – FLT3 Receptor Blockade

11.4 A microRNA Prognostic Marker Identified in Acute Leukemia 

11.5 MIT Team: Microfluidic-based approach – A Vectorless delivery of Functional siRNAs into Cells.

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

11.7 When Clinical Application of miRNAs?

11.8 How mobile elements in “Junk” DNA promote cancer. Part 1: Transposon-mediated tumorigenesis,

11.9 Potential Drug Target: Glycolysis Regulation – Oxidative Stress-responsive microRNA-320

11.10  MicroRNA Molecule May Serve as Biomarker

11.11 What about Circular RNAs?

Chapter 12

12.1 The “Cancer Establishments” Examined by James Watson, Co-discoverer of DNA w/Crick, 4/1953

12.2 Otto Warburg, A Giant of Modern Cellular Biology

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

12.4 Hypothesis – Following on James Watson

12.5 AMPK Is a Negative Regulator of the Warburg Effect and Suppresses Tumor Growth In Vivo

12.6 AKT signaling variable effects

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

12.8 Phosphatidyl-5-Inositol signaling by Pin1

Chapter 13

13.1 Nanotech Therapy for Breast Cancer

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

13.3 Exome sequencing of serous endometrial tumors shows recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes

13.4 Recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes in serous endometrial tumors

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

13.6 In focus: Melanoma Genetics

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

13.8 Breast Cancer and Mitochondrial Mutations

13.9  Long noncoding RNA network regulates PTEN transcription

Chapter 14

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

14.2 Nanotechnology and HIV/AIDS treatment

14.3 IRF-1 Deficiency Skews the Differentiation of Dendritic Cells

14.4 Sepsis, Multi-organ Dysfunction Syndrome, and Septic Shock: A Conundrum of Signaling Pathways Cascading Out of Control

14.5  Five Malaria Genomes Sequenced

14.6 Rheumatoid Arthritis Risk

14.7 Approach to Controlling Pathogenic Inflammation in Arthritis

14.8 RNA Virus Genome as Bacterial Chromosome

14.9 Cloning the Vaccinia Virus Genome as a Bacterial Artificial Chromosome

Chapter 15

15.1 Personalized Cardiovascular Genetic Medicine at Partners HealthCare and Harvard Medical School

15.2 Congestive Heart Failure & Personalized Medicine: Two-gene Test predicts response to Beta Blocker Bucindolol

15.3 DDAH Says NO to ADMA(1); The DDAH/ADMA/NOS Pathway(2)

15.4 Peroxisome Proliferator-Activated Receptor (PPAR-gamma) Receptors Activation: PPARγ Transrepression for Angiogenesis in Cardiovascular Disease and PPARγ Transactivation for Treatment of Diabetes

15.5 BARI 2D Trial Outcomes

15.6 Gene Therapy Into Healthy Heart Muscle: Reprogramming Scar Tissue In Damaged Hearts

15.7 Obstructive coronary artery disease diagnosed by RNA levels of 23 genes – CardioDx, a Pioneer in the Field of Cardiovascular Genomic  Diagnostics

15.8 Ca2+ signaling: transcriptional control

15.9 Lp(a) Gene Variant Association

15.9.1 Two Mutations, in the PCSK9 Gene: Eliminates a Protein involved in Controlling LDL Cholesterol

15.9.2. Genomics & Genetics of Cardiovascular Disease Diagnoses: A Literature Survey of AHA’s Circulation Cardiovascular Genetics, 3/2010 – 3/2013

15.9.3 Synthetic Biology: On Advanced Genome Interpretation for Gene Variants and Pathways: What is the Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging

15.9.4 The Implications of a Newly Discovered CYP2J2 Gene Polymorphism Associated with Coronary Vascular Disease in the Uygur Chinese Population

15.9.5  Gene, Meis1, Regulates the Heart’s Ability to Regenerate after Injuries.

15.10 Genetics of Conduction Disease: Atrioventricular (AV) Conduction Disease (block): Gene Mutations – Transcription, Excitability, and Energy Homeostasis

15.11 How Might Sleep Apnea Lead to Serious Health Concerns like Cardiac and Cancers?

Chapter 16

16.1 Can Resolvins Suppress Acute Lung Injury?

16.2 Lipoxin A4 Regulates Natural Killer Cell in Asthma

16.3 Biological Therapeutics for Asthma

16.4 Genomics of Bronchial Epithelial Dysplasia

16.5 Progression in Bronchial Dysplasia

Chapter 17

17.1 Breakthrough Digestive Disorders Research: Conditions Affecting the Gastrointestinal Tract.

17.2 Liver Endoplasmic Reticulum Stress and Hepatosteatosis

17.3 Biomarkers-identified-for-recurrence-in-hbv-related-hcc-patients-post-surgery

17.4  Usp9x: Promising Therapeutic Target for Pancreatic Cancer

17.5 Battle of Steve Jobs and Ralph Steinman with Pancreatic cancer: How We Lost

Chapter 18

18.1 Ubiquitin Pathway Involved in Neurodegenerative Disease

18.2 Genomic Promise for Neurodegenerative Diseases, Dementias, Autism Spectrum, Schizophrenia, and Serious Depression

18.3 Neuroprotective Therapies: Pharmacogenomics vs Psychotropic Drugs and Cholinesterase Inhibitors

18.4 Ustekinumab New Drug Therapy for Cognitive Decline Resulting from Neuroinflammatory Cytokine Signaling and Alzheimer’s Disease

18.5 Cell Transplantation in Brain Repair

18.6 Alzheimer’s Disease Conundrum – Are We Near the End of the Puzzle?

Chapter 19

19.1 Genetics and Male Endocrinology

19.2 Genomic Endocrinology and its Future

19.3 Commentary on Dr. Baker’s post “Junk DNA Codes for Valuable miRNAs: Non-coding DNA Controls Diabetes”

19.4 Therapeutic Targets for Diabetes and Related Metabolic Disorders

19.5 Secondary Hypertension caused by Aldosterone-producing Adenomas caused by Somatic Mutations in ATP1A1 and ATP2B3 (adrenal cortical; medullary or Organ of Zuckerkandl is pheochromocytoma)

19.6 Personal Recombination Map from Individual’s Sperm Cell and its Importance

19.7 Gene Trap Mutagenesis in Reproductive Research

19.8 Pregnancy with a Leptin-Receptor Mutation

19.9 Whole-genome Sequencing in Probing the Meiotic Recombination and Aneuploidy of Single Sperm Cells

19.10 Reproductive Genetic Testing

Chapter 20

20.1 Genomics & Ethics: DNA Fragments are Products of Nature or Patentable Genes?

20.2 Understanding the Role of Personalized Medicine

20.3 Attitudes of Patients about Personalized Medicine

20.4  Genome Sequencing of the Healthy

20.5   Genomics in Medicine – Tomorrow’s Promise

20.6  The Promise of Personalized Medicine

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

 20.8 Genomic Liberty of Ownership, Genome Medicine and Patenting the Human Genome

Chapter 21

Recent Advances in Gene Editing Technology Adds New Therapeutic Potential for the Genomic Era:  Medical Interpretation of the Genomics Frontier – CRISPR – Cas9

Introduction

21.1 Introducing CRISPR/Cas9 Gene Editing Technology – Works by Jennifer A. Doudna

21.1.1 Ribozymes and RNA Machines – Work of Jennifer A. Doudna

21.1.2 Evaluate your Cas9 gene editing vectors: CRISPR/Cas Mediated Genome Engineering – Is your CRISPR gRNA optimized for your cell lines?

21.1.3 2:15 – 2:45, 6/13/2014, Jennifer Doudna “The biology of CRISPRs: from genome defense to genetic engineering”

21.1.4  Prediction of the Winner RNA Technology, the FRONTIER of SCIENCE on RNA Biology, Cancer and Therapeutics  & The Start Up Landscape in BostonGene Editing – New Technology The Missing link for Gene Therapy?

21.2 CRISPR in Other Labs

21.2.1 CRISPR @MIT – Genome Surgery

21.2.2 The CRISPR-Cas9 System: A Powerful Tool for Genome Engineering and Regulation

Yongmin Yan and Department of Gastroenterology, Hepatology & Nutrition, University of Texas M.D. Anderson Cancer, Houston, USADaoyan Wei*

21.2.3 New Frontiers in Gene Editing: Transitioning From the Lab to the Clinic, February 19-20, 2015 | The InterContinental San Francisco | San Francisco, CA

21.2.4 Gene Therapy and the Genetic Study of Disease: @Berkeley and @UCSF – New DNA-editing technology spawns bold UC initiative as Crispr Goes Global

21.2.5 CRISPR & MAGE @ George Church’s Lab @ Harvard

21.3 Patents Awarded and Pending for CRISPR

21.3.1 Litigation on the Way: Broad Institute Gets Patent on Revolutionary Gene-Editing Method

21.3.2 The Patents for CRISPR, the DNA editing technology as the Biggest Biotech Discovery of the Century

2.4 CRISPR/Cas9 Applications

21.4.1  Inactivation of the human papillomavirus E6 or E7 gene in cervical carcinoma cells using a bacterial CRISPR/Cas 

21.4.2 CRISPR: Applications for Autoimmune Diseases @UCSF

21.4.3 In vivo validated mRNAs

21.4.6 Level of Comfort with Making Changes to the DNA of an Organism

21.4.7 Who will be the the First to IPO: Novartis bought in to Intellia (UC, Berkeley) as well as Caribou (UC, Berkeley) vs Editas (MIT)??

21.4.8 CRISPR/Cas9 Finds Its Way As an Important Tool For Drug Discovery & Development

Summary

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