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BioMEMS The Market aspects of Oligonucleotide-Chips, Products and Applications, Competition, January 21, 2016

Curator: Gérard LOISEAU, ESQ

 

BioMEMS

The Market aspects of Oligonucleotide-Chips, Products, Applications, Competition 

January 21, 2016

2015-2020

The oligonucleotide synthesis market is expected to reach USD 1.918.6Billion at a CAGR of 10.1% by 2020 from USD 1.078.1Billion in 2015.

SOURCE

MARKETSANDMARKETS marketsandmarkets.com/

 

PLAYERS

  • Agilent Technologies Inc.
  • BioAutomation Corp.
  • Biosearch Technologies
  • Gen9 Inc.
  • GenScript Inc.
  • Illumina Inc.
  • Integrated DNA Technologies
  • New England Biolabs Inc.
  • Nitto Denko Avecia Inc.
  • OriGene Technologies Inc.
  • Sigma-Aldrich Corporation
  • Thermo Fisher Scientific Inc.
  • TriLink Biotechnologies

 

Agilent Technologies
 CA NYSE :A


http://www.agilent.com/

  • Agilent was created as a spin off from Hewlett-Packard Company in 1999.
  • Agilent Technologies Inc. is engaged in the life sciences, diagnostics and applied chemical markets. The Company provides application focused solutions that include instruments, software, services and consumables for the entire laboratory workflow. The Company has three business segments:

the life sciences and applied markets business,

the diagnostics and genomics business, and

the Agilent Cross Lab business

  • The Company’s life sciences and applied markets business segment brings together the Company’s analytical laboratory instrumentation and informatics.
  • The Company’s diagnostics and genomics business segment consists of three businesses: the Dako business, the genomics business and the nucleic acid solutions business.
  • The Company’s Agilent Cross Lab business segment combines its analytical laboratory services and consumables business

SOURCE

http://reuters.com/

PRODUCTS AND SERVICES

https://www.agilent.com/en-us/default#collapse-0

  • October 09, 2015 03:21 PM Eastern Daylight Time
  • CARPINTERIA, Calif.–(BUSINESS WIRE)–Dako, an Agilent Technologies company and a worldwide provider of cancer diagnostics, today announced the U.S. Food and Drug Administration has approved a new test that can identify PD-L1 expression levels on the surface of non-small cell lung cancer tumor cells and provide information on the survival benefit with OPDIVO® (nivolumab) for patients with non-squamous NSCLC.

SOURCE

BUSINESS WIRE busibesswire.com/

 

BioAutomation Corp.

 TX


 

http://bioautomation.com/

          PRODUCTS AND SERVICES

  • DNA and RNA synthesis reagents for the MerMades

 

Note: The MerMade 192E Oligonucleotide synthesizer is designed to synthesize DNA, RNA & LNA oligonucleotides in a column format

          PARTNERSHIPS

  • HONGENE BIOTECH : BIOAUTOMATION is the exclusive distributor for the Americas
  • EMD MILLIPORE
  • BIOSEARCH TECHNOLOGIES

 

DISTRIBUTORS

  • LINK TECHNOLOGIES : UK
  • AME BIOSCIENCE : UK
  • BOSUNG SCIENCE : KOREA
  • DNA CHEM : CHINA
  • WAKO : JAPAN
  • ACE PROBE : INDIA

SOURCE

bioautomation.com/

 

Biosearch Technologies
 CA


http://biosearchtech.com/

          PRODUCTS

  • qPCR & SNP Genotyping
  • Custom Oligonucleotides
  • – highly sophisticated oligonucleotides
  • – simple PCR primers
  • Oligos in Plates
  • RNA FISH
  • Synthesis Reagents
  • Immunochemicals
  • Primers
  • Probes
  • Large-Scale Synthesis Oligos
  • Intermediate-Scale Synthesis Oligos

          SERVICES

  • GMP & Commercial Services
  • OEM & Kit Manufacturing
  • qPCR Design Collaborations

          DISTRIBUTORS

Argentina | Australia | Austria | Brazil | Canada |Chile | China | Colombia | Czech Republic | Denmark | Ecuador | Finland | Germany |Hong Kong | Israel | Italy | Japan | Korea | Malaysia | Mexico | New Zealand | Norway | Paraguay | Peru| Philippines | Poland | Romania | Singapore | South Africa | Spain | Sweden |Switzerland | Taiwan ROC | Thailand | Turkey | United Kingdom | Uruguay | Vietnam

SOURCE

biosearchtech.com/

 

Gen9 Inc.
 MA 


http://www.gen9bio.com/

          PRODUCTS

Gen9 is building on advances in synthetic biology to power a scalable fabrication capability that will significantly increase the world’s capacity to produce DNA content. The privately held company’s next-generation gene synthesis technology allows for the high-throughput, automated production of DNA constructs at lower cost and higher accuracy than previous methods on the market. Founded by world leaders in synthetic biology, Gen9 aims to ensure the constructive application of synthetic biology in industries ranging from enzyme and chemical production to pharmaceuticals and biofuels.

          SERVICES

  • Synthetic Biology
  • Gene Synthesis Services
  • Variant Libraries
  • Gene Sequence Design Services

         INVESTORS

  • Agilent Technologies : Private Equity
  • CAMBRIDGE, Mass. and SANTA CLARA, Calif. — April 24, 2013 —Gen9 Receives $21 Million Strategic Investment from Agilent Technologies

SOURCE

gen9bio.com/

 

GenScript Inc.
 NJ 


http://www.genscript.com/

  • GenScript is the largest gene synthesis provider in the USA
  • GenScript Corporation, a biology contract research organization, provides biological research and drug discovery services to pharmaceutical companies, biotech firms, and research institutions in the United States, Europe, and Japan. It offers bio-reagent, custom molecular biology, custom peptide, protein production, custom antibody production, drug candidates testing, assay development and screening, lead optimization, antibody drug development, gene synthesis, and assay-ready cell line production services.
  • The company also offers molecular biology, peptide, protein, immunoassay, chemicals, and cell biology products. It offers its products through distributors in Tokyo, Japan; and Seoul, Korea. GenScript Corporation has a strategic partnership with Immunologix, Inc. The company was founded in 2002 and is based in Piscataway, New Jersey. It has subsidiaries in France, Japan, and China.

 

Note: As of October 24, 2011, Immunologix, Inc. was acquired by Intrexon Corporation. Immunologix, Inc. develops and produces antibody-based therapeutics for various biological targets. It produces human monoclonal antibodies against viral, bacterial, and tumor antigens, as well as human auto antigens.

Intrexon Corporation, founded in 1998, is a leader in synthetic biology focused on collaborating with companies in Health, Food, Energy, Environment and Consumer sectors to create biologically based products that improve quality of life and the health of the planet.

 

 

             PRODUCTS AND SERVICES

  • Gene synthesis
  • Antibody services
  • Protein Services
  • Peptide services

 

               INVESTORS


Note: The Balloch Group (‘TBG’) was established in 2001 by Howard Balloch (Canada‘s ambassador to China from 1996 to 2001). TBG has since grown from a market-entry consultancy working with North American clients in China to a leading advisory and merchant banking firm serving both domestic Chinese companies and multinational corporations. TBG was ranked as the number one boutique investment bank in China by ChinaVenture in 2008.

Kleiner, Perkins, Caufield and Byers

 

Illumina
Inc. CA


http://illumina.com/

 

Monica Heger : SAN FRANCISCO (GenomeWeb) – Illumina today announced two new next-generation sequencing platforms, a targeted sequencing system called MiniSeq and a semiconductor sequencer that is still under development.

Illumina disclosed the initiatives during a presentation at the JP Morgan Healthcare conference held here today. During the presentation, Illumina CEO Jay Flatley also announced a new genotyping array called Infinium XT; a partnership with Bio-Rad to develop a single-cell sequencing workflow; preliminary estimates of its fourth-quarter 2015 revenues; and an update on existing products. The presentation followed the company’s announcement on Sunday that it has launched a new company called Grail to develop a next-generation sequencing test for early cancer detection from patient blood samples.

The MiniSeq system, which is based on Illumina’s current sequencing technology, will begin shipping early this quarter and has a list price of $49,500. It can perform a variety of targeted DNA and RNA applications, from single-gene to pathway sequencing, and promises “all-in” prices, including library prep and sequencing, of $200 to $300 per sample, Flatley said during the JP Morgan presentation.

SOURCES

https://www.genomeweb.com/sequencing-technology/illumina-unveils-mini-targeted-sequencer-semiconductor-sequencing-project-jp

http://investor.biospace.com/biospace/quote?Symbol=ILMN

 

              PRODUCTS AND SERVICES

  •               Mid to large scale manufacturing assets
  •               Analytical Labs
  •               Pre-clinical
  •               Clinical
  •               Launched products

 

              COMPETITORS

https://finance.yahoo.com/q/co?s=ILMN+Competitors Tue, Feb 2, 2016, 2:16pm EST – US Markets

ILMN PVT1 AFFX LMNX Industry
Market Cap: 22.75B N/A 1.13B 835.66M 134.14M
Employees: 3,700 10,000 1,200 745 45.00
Qtrly Rev Growth (yoy): 0.14 N/A -0.01 0.07 0.18
Revenue (ttm): 2.14B 3.80B1 357.74M 235.37M 8.47M
Gross Margin (ttm): 0.73 N/A 0.63 0.71 0.58
EBITDA (ttm): 770.84M N/A 46.64M 52.99M -12.31M
Operating Margin (ttm): 0.30 N/A 0.08 0.17 -1.62
Net Income (ttm): 510.36M 430.90M1 11.22M 39.29M N/A
EPS (ttm): 3.42 N/A 0.13 0.93 -0.34
P/E (ttm): 45.43 N/A 104.40 20.91 25.33
PEG (5 yr expected): 2.68 N/A 4.66 0.55 N/A
P/S (ttm): 10.87 N/A 3.13 3.45 13.65

 

Pvt1 = Life Technologies Corporation (privately held)

AFFX = Affymetrix Inc.

LMNX = Luminex Corporation

 

 

Integrated DNA Technologies (IDT)
IOWA + CA

http://www.com/

 

Integrated DNA Technologies, Inc. (IDT), the global leader in nucleic acid synthesis, serving all areas of life sciences research and development, offers products for a broad range of genomics applications. IDT’s primary business is the production of custom, synthetic nucleic acids for molecular biology applications, including qPCR, sequencing, synthetic biology, and functional genomics. The company manufactures and ships an average of 44,000 custom nucleic acids per day to more than 82,000 customers worldwide. For more information, visit idtdna.com.

 

               PRODUCTS AND SERVICES

               https://eu.idtdna.com/site

  • DNA & RNA Synthesis
  • Custom DNA Oligos 96- & 384-Well Plates Ultramer Oligos Custom RNA Oligos SameDay Oligos HotPlates ReadyMade Primers Oligo Modifications Freedom
  • Dyes GMP for Molecular Diagnostics Large Scale Oligo Synthesis

 

Note : Skokie, IL – December 1, 2015. Integrated DNA Technologies Inc. (“IDT”), the global leader in custom nucleic acid synthesis, has entered into a definitive agreement to acquire the oligonucleotide synthesis business of AITbiotech Pte. Ltd. in Singapore (“AITbiotech”). With this acquisition, IDT expands its customer base across Southeast Asia making it possible for these additional customers to now have access to its broad range of products for genomic applications. AITbiotech will continue operations in its other core business areas.

 

New England Biolabs Inc.
 MA 


http://www.neb.com/

 

                PRODUCTS AND SERVICES

  •                 Restriction Endonucleases
  •                 PCR, Polymerases & Amplification Technologies
  •                 DNA Modifying Enzymes
  •                 Library Preparation for Next Generation Sequencing
  •                 Nucleic Acid Purification
  •                 Markers & Ladders
  •                 RNA Reagents
  •                 Gene Expression
  •                 Cellular Analysis

SOURCE

neb.com/

 

Nitto Denko Avecia Inc.
 MA


http://avecia.com/

 

With over 20 years of experience in oligonucleotide development and production, and over 1000 sequences manufactured, Avecia has played an integral role in the advancing oligo therapeutic market. Our mission is to continue to build value for our customers, as they progress through drug development into commercialization. And as a member of the Nitto Denko Corporation (nitto.com), Avecia is committed to the future of the oligonucleotide market. We are driven by innovative ideas and flexible solutions, designed to provide our customers with the best in service, quality, and technology.

 

SOURCE

http://avecia.com/

 

Note : 1918 Nitto Electric Industrial Co., Ltd. forms in Ohsaki, Tokyo, to produce electrical insulating materials in Japan.

2011 Acquires Avecia Biotechnology Inc. in the U.S.A.

 

 

OriGene Technologies Inc.
 CA

http://www.com/

 

OriGene Technologies, Inc. develops, manufactures, and sells genome wide research and diagnostic products for pharmaceutical, biotechnology, and academic research applications. The company offers cDNA clones, including TrueORF cDNA, viral ORF, destination vectors, TrueClones (human), TrueClones (mouse), organelle marker plasmids, MicroRNA tools, mutant and variant clones, plasmid purification kits, transfection reagents, and gene synthesis service; and HuSH shRNA, siRNA, miRNA, qPCR reagents, plasmid purification products, transfection reagents, PolyA+ and total RNA products, first-strand cDNA synthesis, and CRISPR/Cas9 genome products. It also provides proteins and lysates, such as purified human proteins, over-expression cell lysates, mass spectrometry standard proteins, and protein purification reagents; UltraMAB IHC antibodies, TrueMAB primary antibodies, anti-tag and fluorescent proteins, ELISA antibodies, luminex antibodies, secondary antibodies, and controls and others; and anatomic pathology products, including IHC antibodies, detection systems, and IHC accessories

The company offers luminex and ELISA antibody pairs, autoantibody profiling arrays, ELISA kits, cell assay kits, assay reagents, custom development, and fluorogenic cell assays; TissueFocus search tools; tissue sections; tissue microarrays, cancer protein lysate arrays, TissueScan cDNA arrays, tissue blocks, and quality control products, as well as tissue RNA, DNA, and protein lysates; and lab essentials. Its research areas include cancer biomarker research, RNAi, pathology IHC, stem cell research, ion channels, and protein kinase products. The company provides gene synthesis and molecular biology services, genome editing, custom cloning, custom shRNA, purified protein, monoclonal antibody development, and assay development. It sells its products through distributors worldwide, as well as online. OriGene Technologies, Inc. was incorporated in 1995 and is based in Rockville, Maryland.

SOURCE

http://BLOOMBERG.com

               PRODUCTS AND SERVICES

  •                cDNA Clones
Human, mouse, rat
Expression validated
  •                RNAi
shRNA, siRNA
microRNA & 3’UTR clones
  •                Gene Synthesis
Codon optimization
Variant libraries
  •                Real-time PCR
Primer pairs, panels
SYBR green reagents
  •                Lab Essentials
DNA/RNA purification kits
Transfection reagents
  •                Anatomic Pathology
UltraMAB antibodies
Specificity validated
  •                Recombinant Proteins
10,000 human proteins
from mammalian system
  •                Antibodies
TrueMAB primary antibodies
Anti-tag antibodies
  •                Assays and Kits
ELISA & Luminex antibodies
Autoantibody Profiling Array
  •                Cancer & Normal Tissues
Pathologist verified
gDNA, RNA, sections, arrays

SOURCE

origene.com/

 

Sigma-Aldrich Corporation 
MI 


http://www.sigmaaldrich.com/

Louis, MO – November 18, 2015 Merck KGaA, Darmstadt, Germany, Completes Sigma-Aldrich Acquisition

Merck KGaA today announced the completion of its $17 billion acquisition of Sigma-Aldrich, creating one of the leaders in the $130 billion global industry to help solve the toughest problems in life science.

Press Release: 18-Nov-2015

Letter to our Life Science Customers from Dr. Udit Batra

The life science business of Merck KGaA, Darmstadt, Germany brings together the world-class products and services, innovative capabilities and exceptional talent of EMD Millipore and Sigma-Aldrich to create a global leader in the life science industry.

Everything we do starts with our shared purpose – to solve the toughest problems in life science by collaborating with the global scientific community. 

This combination is built on complementary strengths, which will enable us to serve you even better as one organization than either company could alone.

This means providing a broader portfolio with a catalog of more than 300,000 products, including many of the most respected brands in the industry, greater geographic reach, and an unmatched combination of industry-leading capabilities.

                PRODUCTS AND SERVICES

                http://www.sigmaaldrich.com/configurator/servlet/DesignCenter?btnOpen_0.x=1

                http://www.sigmaaldrich.com/content/dam/sigma-aldrich/common/quality-products.jpg

 

Thermo Fisher Scientific Inc.
 MA 
NYSE :TMO


http://thermofisher.com/

Thermo Fisher Scientific Inc. is a provider of analytical instruments, equipment, reagents and consumables, software and services for research, manufacturing, analysis, discovery and diagnostics. The company operates through four segments: Life Sciences Solutions, provides reagents, instruments and consumables used in biological and medical research, discovery and production of new drugs and vaccines as well as diagnosis of disease; Analytical Instruments, provides instruments, consumables, software and services that are used in the laboratory; Specialty Diagnostics, offers diagnostic test kits, reagents, culture media, instruments and associated products, and Laboratory Products and Services, offers self-manufactured and sourced products for the laboratory.

SOURCE

http://REUTERS.com

 

                PRODUCTS AND SERVICES

  •                 Oligos Value – Standard – Plate
  •                 Primers
  •                 Probes
  •                 Nucleotides

 

                BRANDS

  1.                THERMO SCIENTIFIC
  2.                 APPLIED BIOSYSTEMS
  3.                 INVITROGEN
  4.                 FISHER SCIENTIFIC
  5.                 UNITY LAB SERVICES

 

                 PARTNERSHIPS

AFFYMETRIX : NASDAQ : AFFX : affymetrix.com/

WALTHAM, Mass. & SANTA CLARA, Calif.–(BUSINESS WIRE)–Jan. 8, 2016– Thermo Fisher Scientific Inc. (NYSE:TMO), the world leader in serving science, and Affymetrix Inc. (NASDAQ:AFFX), a leading provider of cellular and genetic analysis products, today announced that their boards of directors have unanimously approved Thermo Fisher’s acquisition of Affymetrix for $14.00 per share in cash. The transaction represents a purchase price of approximately $1.3 billion.

SOURCE

http://BUSINESSWIRE.com

 

TriLink Biotechnologies
 CA 


http://www.com/

 

              PRODUCTS

              Oligonucleotides

  •               DNA Oligos
  •               RNA Oligos
  •               Modified Oligos
  •               Specialty Oligos

              Nucleotides

  •               NTPs (Nucleoside Triphosphates)
  •               Biphosphates
  •               Monophosphates

 

              SERVICES

  •              Custom Chemistry
  •              Reagents
  •              Aptamers

 

             PARTNERSHIPS

  • LIFE TECHNOLOGIES,
  • TERMO FISHER SCIENTIFIC since July 2015 thermofisher.com/
  • GENMARK genmarkdx.com/

SOURCE

http://trilinkbiotech.com/

 

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

Gene Editing: The Role of Oligonucleotide Chips

https://pharmaceuticalintelligence.com/2016/01/07/gene-editing-the-role-of-oligonucleotide-chips/

Gene Editing for Exon 51: Why CRISPR Snipping might be better than Exon Skipping for DMD

https://pharmaceuticalintelligence.com/2016/01/23/gene-editing-for-exon-51-why-crispr-snipping-might-be-better-than-exon-skipping-for-dmd/

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Read Full Post »


Hand Held DNA Sequencer

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Point-of-Care DNA Sequencer Inching Closer to Widespread Use as Beta-Testers Praise Oxford Technologies’ Pocketsize, Portable Nanopore Device

November 4, 2015

MinION could help achieve NIH’s goal of $1,000 human genome sequencing and in remote clinics and outbreak zones shift testing away from medical laboratories

Point-of-care DNA sequencing  technology is edging ever closer to widespread commercial use as the Oxford Nanopore MinION sequencer  draws praise and registers successes in pre-release testing.

A pocketsize gene-sequencing machine such as the MinION could transform the marketplace by shifting DNA testing to remote clinics and outbreak zones while eliminating the need to return samples to clinical laboratories for analysis. Such devices also are expected to increase the need for trained genetic pathologists andmedical technologists.

After Much Anticipation, MinION Delivers on Promises

The MinION, produced by United Kingdom-based Oxford Nanopore Technologies, is a miniaturized instrument about the size of a USB memory stick that plugs directly into a PC or laptop computer’s USB port. Unlike bench-top sequencers, the MinION uses nanopore “strand sequencing” technology to deliver ultra-long-read-length single-molecule sequence data.

“The USB-powered sequencer contains thousands of wells, each containing nanopores—narrow protein channels that are only wide enough for a single strand of DNA. When DNA enters the channels, each base gives off a unique electronic signature that can be detected by the system, providing a readout of the DNA sequence,” reported

After several years of unfulfilled promises, Oxford began delivering the MinION in the spring of 2014 to researchers participating in its early access program called MAP . For a $1,000 access fee, participants receive a starter kit and may purchase consumable supplies. The current price for additional flow cells ranges from $900 for one to $500 per piece when purchased in 48-unit quantities.

 

Nick Loman, an Independent Research Fellow in the Institute for Microbiology and Infection at the University of Birmingham, UK, had questioned if MinION’s promise would ever be realized. But the USB-size sequencer won him over after he used it to detect Salmonella within 15 minutes in samples sent from a local hospital.

 

Loman received the MinION in May 2014 as part of the MAP program and quickly tested its usefulness. After using the device to sequence a strain of Pseudomonas aeruginosa, a common hospital-acquired infection (HAI), he next helped solve the riddle of an outbreak of Salmonella infection in a Birmingham hospital that had affected 30 patients and staff.

“The hospital wanted to understand quickly what was happening,” Loman stated. “But routine genome sequencing is quite slow. It usually takes weeks or even months to get information back.”

Using MinION, Loman detected Salmonella in some of the samples sent from the hospital in less than 15 minutes. Ultimately, the main source of the outbreak was traced to a German egg supplier.

“The MinION just blew me away,” Loman stated in Wired. “The idea that you could do sequencing on a sort of USB stick that you can chuck around does stretch credulity.”

Portable Sequencing Opens Up Intriguing Possibilities for Pathologists

In May 2015, Oxford released a second version of the device, the MinION MkI. According to the company website, the updated MinION is a “full production device featuring improvements of performance and ease of use,” such as improved temperature control and updated mechanism to engage the device with the consumable flow cells.

“The bench-top sequencers opened up the market to a certain degree,” Loman says. “You started seeing [them] in intensive research groups and in the clinic. But what if anyone could have this hanging off their key ring and go do sequencing? That’s an insane idea, and we don’t really know what it’s going to mean in terms of the potential applications. We’re very much at the start of thinking about what we might be able to do, if anyone can just sequence anything, anywhere they are.”

 

Joshua Quick, a PhD candidate at the University of Birmingham, UK believes Oxford Nanopore Technologies’ portable and inexpensive device will change the gene sequencing landscape.

 

Accuracy One Trade-off for Portability

Beta-testers have shown that the miniature device can read out relatively long stretches of genetic sequence with increasing accuracy, but according to the report in the journal Nature , the MinION MkI will need to correct several shortcomings found in the original sequencer:

• It is not practical to sequence large genomes with the device, with some experts estimating it would take a year for the original version to sequence the equivalent of a human genome.

• The machine has a high error rate compared with those of existing full-sized sequencers, misidentifying DNA sequence 5%–30% of the time.

• It also has difficulties reading sections of genome that contain long stretches of a single DNA base.

Yet researchers who have used the device remain enthusiastic about the future of this fourth-generation sequencing technique, which may have the potential to achieve the $1,000-per-human-genome goal set by the National Institutes of Health  (NIH).

“This is the democratization of sequencing,” Joshua Quick, a PhD candidate at the University of Birmingham, told Nature. “You don’t have to rely on expensive infrastructure and costly equipment.”

News accounts did not provide information about Oxford Nanopore’s plans to obtain an EU mark for its MinION device. That will be the next step to demonstrating that the device is ready for widespread clinical use. At the same time, clinical laboratory managers and pathologist should take note of the capabilities of the MinION MkI as described above. Researchers are already finding it useful to identify infectious diseases in clinical setting where other diagnostic methods have not yet identified the agent causing the infection.

Read Full Post »


Why Does Cytotoxic Chemotherapy Still Remain a Mainstay in Many Chemotherapeutic Regimens? [6.1.1]

 

Reporter: Stephen J. Williams, Ph.D.

At the 2015 AACR National Meeting, Drs. Anthony Letai, Dr. Michael Hermann, Dr. Rene Bernards, and Dr. Guido Kroemer gave The 2015 Stanley J. Korsmeyer Memorial Symposium: Cell Death and Cancer Therapy: Why Has Conventional Chemotherapy Been So Successful?

Cytotoxic chemotherapy, for which the mechanism of action is centered on the ability of the drug to kill a cell by either necrosis, genotoxic, apoptosis, or autophagy mechanisms rather than just halting cell growth, is still, in this era of personalized and cytostatic therapies, is still a mainstay in many treatment regimens for a majority of cancers. Treatment regimens such as MOPP (mechlorethamine, Oncovin, procarbazine, prednisone), CMF (cyclophosphamide, methotrexate, 5-fluorouracil) , carboplatin with taxol, and even with personalized therapies, which usually are given in combination with a cytotoxic agent. However treatment regimens containing these cytotoxic chemotherapeutics show some of the best survival rates. The abstract for the Symposium is given below:

In this current era of precisely targeted therapies and –omics technologies, it is often forgotten that no medical therapy has cured, and continues to cure, more people of cancer than conventional chemotherapy. Notwithstanding its superior performance across many cancer types, the mechanism of the therapeutic index of conventional agents, largely targeting ubiquitous elements like DNA and microtubules, is poorly understood. The textbook explanation of conventional chemotherapy’s working by killing supposedly rapidly dividing cancer cells lacks clinical evidence and flies in the face of many obvious clinical counter-examples. In the session,m the speakers will describe how conventional cytotoxic chemotherapy preferentially kills cancer cells. Moreover, they will describe how clinical response to chemotherapy might be better predicted.

This post is presented as the speakers titles and a brief curation of their papers related to the subject matter.

Anthony G. Letai, Dana-Farber Cancer Institute, Boston, MA. Conventional chemotherapy cures people by exploiting apoptotic priming.

Conventional chemotherapy has an amazing track record that is often under-appreciated in today’s world of genomics and targeted pathway inhibitors. Conventional chemotherapy is responsible for curing millions of cancer patients over the past 5 decades. That is, millions of patients have presented to their doctors with an otherwise fatal malignancy, were given a finite course of chemotherapy (largely DNA and microtubule perturbing agents) and had their cancer eradicated, never to return. Perhaps as remarkable as the magnitude of the achievement of conventional chemotherapy is the magnitude of our ignorance of why it should ever work, and why it works far better in some tumors than in others. Textbook explanations rely on concepts of differential proliferation rates in cancers that are incompletely supported in the clinical literature. Successful chemotherapy treatments usually kill via the mitochondrial pathway of apoptosis. We have found that simple functional measurements of the pre-treatment state of the tumor cell can be rapidly made with BH3 profiling. These measurements demonstrate that a major, if not the major, reason for a therapeutic index for cancer chemotherapy is that chemo-sensitive cancer cells are simply more primed for apoptosis than normal cells. Moreover, apoptotic priming can be measured to make clinical predictions regarding quality of response on an individualized basis. Enhancing pretreatment priming of cancer cells with selectively acting targeted agents is a promising strategy to extend the demonstrated curative power of conventional chemotherapy.

Maturation Stage of T-cell Acute Lymphoblastic Leukemia Determines BCL-2 versus BCL-XL Dependence and Sensitivity to ABT-199

Triona Ni Chonghaile, Justine E. Roderick, Cian Glenfield, Jeremy Ryan, Stephen E. Sallan, Lewis B. Silverman, Mignon L. Loh, Stephen P. Hunger, Brent Wood, Daniel J. DeAngelo, Richard Stone, Marian Harris, Alejandro Gutierrez, Michelle A. Kelliher, Anthony Letai

Cancer Discov. Author manuscript; available in PMC 2015 March 1.

Published in final edited form as: Cancer Discov. 2014 September; 4(9): 1074–1087. Published online 2014 July 3. doi: 10.1158/2159-8290.CD-14-0353

 

High Mitochondrial Priming Sensitizes hESCs to DNA-Damage-Induced Apoptosis

Julia C. Liu, Xiao Guan, Jeremy A. Ryan, Ana G. Rivera, Caroline Mock, Vishesh Agrawal, Anthony Letai, Paul H. Lerou, Galit Lahav

Cell Stem Cell. Author manuscript; available in PMC 2014 October 3.

Published in final edited form as: Cell Stem Cell. 2013 October 3; 13(4): 483–491. Published online 2013 August 15. doi: 10.1016/j.stem.2013.07.018

Correction in: volume 13 on page 634

 

Prolonged mitotic arrest triggers partial activation of apoptosis, resulting in DNA damage and p53 induction

James D. Orth, Alexander Loewer, Galit Lahav, Timothy J. Mitchison

Mol Biol Cell. 2012 February 15; 23(4): 567–576. doi: 10.1091/mbc.E11-09-0781

 

Stem cells: Balancing resistance and sensitivity to DNA damage

Julia C. Liu, Paul H. Lerou, Galit Lahav

Trends Cell Biol. Author manuscript; available in PMC 2015 May 1.

Published in final edited form as: Trends Cell Biol. 2014 May; 24(5): 268–274. Published online 2014 April 7. doi: 10.1016/j.tcb.2014.03.002

 

Michael T. Hermann, MIT Koch Institute for Integrated Cancer Research, Cambridge MA. Using convential chemotherapy as targeted agents.

Exploiting the Synergy between Carboplatin and ABT-737 in the Treatment of Ovarian Carcinomas

Harsh Vardhan Jain, Alan Richardson, Michael Meyer-Hermann, Helen M. Byrne

PLoS One. 2014; 9(1): e81582. Published online 2014 January 6.

 

Rene Bernards, Netherlands Cancer Institute, Amsterdam, The Netherlands. Identifying responders to chemotherapies through functional genomics

MED12 Controls the Response to Multiple Cancer Drugs through Regulation of TGF-β Receptor Signaling

Sidong Huang, Michael Hölzel, Theo Knijnenburg, Andreas Schlicker, Paul Roepman, Ultan McDermott, Mathew Garnett, Wipawadee Grernrum, Chong Sun, Anirudh Prahallad, Floris H. Groenendijk, Lorenza Mittempergher, Wouter Nijkamp, Jacques Neefjes, Ramon Salazar, Peter ten Dijke, Hidetaka Uramoto, Fumihiro Tanaka, Roderick L. Beijersbergen, Lodewyk F.A. Wessels, René Bernards

Cell. Author manuscript; available in PMC 2013 June 5.

Published in final edited form as: Cell. 2012 November 21; 151(5): 937–950.

 

Sorafenib synergizes with metformin in NSCLC through AMPK pathway activation

Floris H Groenendijk, Wouter W Mellema, Eline van der Burg, Eva Schut, Michael Hauptmann, Hugo M Horlings, Stefan M Willems, Michel M van den Heuvel, Jos Jonkers, Egbert F Smit, René Bernards

Int J Cancer. 2015 March 15; 136(6): 1434–1444. Published online 2014 August 1.

 

The Corepressor CTBP2 Is a Coactivator of Retinoic Acid Receptor/Retinoid X Receptor in Retinoic Acid Signaling

Prashanth Kumar Bajpe, Guus J. J. E. Heynen, Lorenza Mittempergher, Wipawadee Grernrum, Iris A. de Rink, Wouter Nijkamp, Roderick L. Beijersbergen, Rene Bernards, Sidong Huang

Mol Cell Biol. 2013 August; 33(16): 3343–3353. doi: 10.1128/MCB.01213-12

 

Using Functional Genetics to Understand Breast Cancer Biology

Alan Ashworth, Rene Bernards

Cold Spring Harb Perspect Biol. 2010 July; 2(7): a003327. doi: 10.1101/cshperspect.a003327

 

 

SMARCE1 suppresses EGFR expression and controls responses to MET and ALK inhibitors in lung cancer

Andreas I Papadakis, Chong Sun, Theo A Knijnenburg, Yibo Xue, Wipawadee Grernrum, Michael Hölzel, Wouter Nijkamp, Lodewyk FA Wessels, Roderick L Beijersbergen, Rene Bernards, Sidong Huang

Cell Res. 2015 April; 25(4): 445–458. Published online 2015 February 6.

 

The Good, the Bad, and the Ugly: in search of gold standards for assessing functional genetic screen quality

Bastiaan Evers, Rene Bernards, Roderick L Beijersbergen

Mol Syst Biol. 2014 July; 10(7): 738. Published online 2014 July 1.

 

An Integrative Genomic and Proteomic Analysis of PIK3CA, PTEN, and AKT Mutations in Breast Cancer

Katherine Stemke-Hale, Ana Maria Gonzalez-Angulo, Ana Lluch, Richard M. Neve, Wen-Lin Kuo, Michael Davies, Mark Carey, Zhi Hu, Yinghui Guan, Aysegul Sahin, W. Fraser Symmans, Lajos Pusztai, Laura K. Nolden, Hugo Horlings, Katrien Berns, Mien-Chie Hung, Marc J. van de Vijver, Vicente Valero, Joe W. Gray, René Bernards, Gordon B. Mills, Bryan T. Hennessy

Cancer Res. Author manuscript; available in PMC 2009 August 1.

Published in final edited form as: Cancer Res. 2008 August 1; 68(15): 6084–6091.

 

CTF Meeting 2012: Translation of the Basic Understanding of the Biology and Genetics of NF1, NF2, and Schwannomatosis Toward the Development of Effective Therapies

Brigitte C. Widemann, Maria T. Acosta, Sylvia Ammoun, Allan J. Belzberg, Andre Bernards, Jaishri Blakeley, Antony Bretscher, Karen Cichowski, D. Wade Clapp, Eva Dombi, Gareth D. Evans, Rosalie Ferner, Cristina Fernandez-Valle, Michael J. Fisher, Marco Giovannini, David H. Gutmann, C. Oliver Hanemann, Robert Hennigan, Susan Huson, David Ingram, Joe Kissil, Bruce R. Korf, Eric Legius, Roger J. Packer, Andrea I McClatchey, Frank McCormick, Kathryn North, Minja Pehrsson, Scott R. Plotkin, Vijaya Ramesh, Nancy Ratner, Susann Schirmer, Larry Sherman, Elizabeth Schorry, David Stevenson, Douglas R. Stewart, Nicole Ullrich, Annette C. Bakker, Helen Morrison

Am J Med Genet A. Author manuscript; available in PMC 2014 September 1.

Published in final edited form as: Am J Med Genet A. 2014 March; 0(3): 563–578. Published

 

Analysis of the MammaPrint Breast Cancer Assay in a Predominantly Postmenopausal Cohort

Ben S. Wittner, Dennis C. Sgroi, Paula D. Ryan, Tako J. Bruinsma, Annuska M. Glas, Anitha Male, Sonika Dahiya, Karleen Habin, Rene Bernards, Daniel A. Haber, Laura J. Van’t Veer, Sridhar Ramaswamy Clin Cancer Res. Author manuscript; available in PMC 2011 May 7.

 

Guido Kroemer, INSERM U848- Institute Gustave-Roussy, Villejuif, France. A hallmark of successful cancer therapies: Reinstatement of immunosurvelliance.

Immune infiltrate in cancer Gautier Stoll, Laurence Zitvogel, Guido Kroemer

Aging (Albany NY) 2015 June; 7(6): 358–359. Published online 2015 June 25.

 

Corrigendum: “Combinatorial Strategies for the Induction of Immunogenic Cell Death”

Lucillia Bezu, Ligia C. Gomes-da-Silva, Heleen Dewitte, Karine Breckpot, Jitka Fucikova, Radek Spisek, Lorenzo Galluzzi, Oliver Kepp, Guido Kroemer

Front Immunol. 2015; 6: 275. Published online 2015 June 1. doi: 10.3389/fimmu.2015.00275

Corrects: Front Immunol. 2015; 6: 187.

 

Meta-analysis of organ-specific differences in the structure of the immune infiltrate in major malignancies

Gautier Stoll, Gabriela Bindea, Bernhard Mlecnik, Jérôme Galon, Laurence Zitvogel, Guido Kroemer

Oncotarget. 2015 May 20; 6(14): 11894–11909. Published online 2015 May 19

 

Other posts on this site on Cytotoxicity and Cancer include

Novel Approaches to Cancer Therapy [11.1]

Misfolded Proteins – from Little Villains to Little Helpers… Against Cancer

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

A Synthesis of the Beauty and Complexity of How We View Cancer

Good and Bad News Reported for Ovarian Cancer Therapy

 

 

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Cancer Biology and Genomics for Disease Diagnosis (Vol. I) Now Available for Amazon Kindle


Cancer Biology and Genomics for Disease Diagnosis (Vol. I) Now Available for Amazon Kindle

Reporter: Stephen J Williams, PhD

Leaders in Pharmaceutical Business Intelligence would like to announce the First volume of their BioMedical E-Book Series C: e-Books on Cancer & Oncology

Volume One: Cancer Biology and Genomics for Disease Diagnosis

CancerandOncologyseriesCcoverwhich is now available on Amazon Kindle at                          http://www.amazon.com/dp/B013RVYR2K.

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. 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 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.

We invite e-Readers to write an Article Reviews on Amazon for this e-Book on Amazon. All forthcoming BioMed e-Book Titles can be viewed at:

https://pharmaceuticalintelligence.com/biomed-e-books/

Leaders in Pharmaceutical Business Intelligence, launched in April 2012 an Open Access Online Scientific Journal is a scientific, medical and business multi expert authoring environment in several domains of  life sciences, pharmaceutical, healthcare & medicine industries. The venture operates as an online scientific intellectual exchange at their website http://pharmaceuticalintelligence.com and for curation and reporting on frontiers in biomedical, biological sciences, healthcare economics, pharmacology, pharmaceuticals & medicine. In addition the venture publishes a Medical E-book Series available on Amazon’s Kindle platform.

Analyzing and sharing the vast and rapidly expanding volume of scientific knowledge has never been so crucial to innovation in the medical field. WE are addressing need of overcoming this scientific information overload by:

  • delivering curation and summary interpretations of latest findings and innovations
  • on an open-access, Web 2.0 platform with future goals of providing primarily concept-driven search in the near future
  • providing a social platform for scientists and clinicians to enter into discussion using social media
  • compiling recent discoveries and issues in yearly-updated Medical E-book Series on Amazon’s mobile Kindle platform

This curation offers better organization and visibility to the critical information useful for the next innovations in academic, clinical, and industrial research by providing these hybrid networks.

Table of Contents for Cancer Biology and Genomics for Disease Diagnosis

Preface

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

Part I. Historical Perspective of Cancer Demographics, Etiology, and Progress in Research

Chapter 1:  The Occurrence of Cancer in World Populations

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

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

Chapter 4: How Epigenetic and Metabolic Factors Affect Tumor Growth

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

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

Chapter 7:  Personalized Medicine and Targeted Therapy

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

Chapter 8:  Diagnosis                                     

Chapter 9:  Detection

Chapter 10:  Biomarkers

Chapter 11:  Imaging In Cancer

Chapter 12: Nanotechnology Imparts New Advances in Cancer Treatment, Detection, &  Imaging                                 

Epilogue by Larry H. Bernstein, MD, FACP: Envisioning New Insights in Cancer Translational Biology

 

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Imaging-guided cancer treatment


Imaging-guided cancer treatment

Writer & reporter: Dror Nir, PhD

It is estimated that the medical imaging market will exceed $30 billion in 2014 (FierceMedicalImaging). To put this amount in perspective; the global pharmaceutical market size for the same year is expected to be ~$1 trillion (IMS) while the global health care spending as a percentage of Gross Domestic Product (GDP) will average 10.5% globally in 2014 (Deloitte); it will reach ~$3 trillion in the USA.

Recent technology-advances, mainly miniaturization and improvement in electronic-processing components is driving increased introduction of innovative medical-imaging devices into critical nodes of major-diseases’ management pathways. Consequently, in contrast to it’s very small contribution to global health costs, medical imaging bears outstanding potential to reduce the future growth in spending on major segments in this market mainly: Drugs development and regulation (e.g. companion diagnostics and imaging surrogate markers); Disease management (e.g. non-invasive diagnosis, guided treatment and non-invasive follow-ups); and Monitoring aging-population (e.g. Imaging-based domestic sensors).

In; The Role of Medical Imaging in Personalized Medicine I discussed in length the role medical imaging assumes in drugs development.  Integrating imaging into drug development processes, specifically at the early stages of drug discovery, as well as for monitoring drug delivery and the response of targeted processes to the therapy is a growing trend. A nice (and short) review highlighting the processes, opportunities, and challenges of medical imaging in new drug development is: Medical imaging in new drug clinical development.

The following is dedicated to the role of imaging in guiding treatment.

Precise treatment is a major pillar of modern medicine. An important aspect to enable accurate administration of treatment is complementing the accurate identification of the organ location that needs to be treated with a system and methods that ensure application of treatment only, or mainly to, that location. Imaging is off-course, a major component in such composite systems. Amongst the available solution, functional-imaging modalities are gaining traction. Specifically, molecular imaging (e.g. PET, MRS) allows the visual representation, characterization, and quantification of biological processes at the cellular and subcellular levels within intact living organisms. In oncology, it can be used to depict the abnormal molecules as well as the aberrant interactions of altered molecules on which cancers depend. Being able to detect such fundamental finger-prints of cancer is key to improved matching between drugs-based treatment and disease. Moreover, imaging-based quantified monitoring of changes in tumor metabolism and its microenvironment could provide real-time non-invasive tool to predict the evolution and progression of primary tumors, as well as the development of tumor metastases.

A recent review-paper: Image-guided interventional therapy for cancer with radiotherapeutic nanoparticles nicely illustrates the role of imaging in treatment guidance through a comprehensive discussion of; Image-guided radiotherapeutic using intravenous nanoparticles for the delivery of localized radiation to solid cancer tumors.

 Graphical abstract

 Abstract

One of the major limitations of current cancer therapy is the inability to deliver tumoricidal agents throughout the entire tumor mass using traditional intravenous administration. Nanoparticles carrying beta-emitting therapeutic radionuclides [DN: radioactive isotops that emits electrons as part of the decay process a list of β-emitting radionuclides used in radiotherapeutic nanoparticle preparation is given in table1 of this paper.) that are delivered using advanced image-guidance have significant potential to improve solid tumor therapy. The use of image-guidance in combination with nanoparticle carriers can improve the delivery of localized radiation to tumors. Nanoparticles labeled with certain beta-emitting radionuclides are intrinsically theranostic agents that can provide information regarding distribution and regional dosimetry within the tumor and the body. Image-guided thermal therapy results in increased uptake of intravenous nanoparticles within tumors, improving therapy. In addition, nanoparticles are ideal carriers for direct intratumoral infusion of beta-emitting radionuclides by convection enhanced delivery, permitting the delivery of localized therapeutic radiation without the requirement of the radionuclide exiting from the nanoparticle. With this approach, very high doses of radiation can be delivered to solid tumors while sparing normal organs. Recent technological developments in image-guidance, convection enhanced delivery and newly developed nanoparticles carrying beta-emitting radionuclides will be reviewed. Examples will be shown describing how this new approach has promise for the treatment of brain, head and neck, and other types of solid tumors.

The challenges this review discusses

  • intravenously administered drugs are inhibited in their intratumoral penetration by high interstitial pressures which prevent diffusion of drugs from the blood circulation into the tumor tissue [1–5].
  • relatively rapid clearance of intravenously administered drugs from the blood circulation by kidneys and liver.
  • drugs that do reach the solid tumor by diffusion are inhomogeneously distributed at the micro-scale – This cannot be overcome by simply administering larger systemic doses as toxicity to normal organs is generally the dose limiting factor.
  • even nanoparticulate drugs have poor penetration from the vascular compartment into the tumor and the nanoparticles that do penetrate are most often heterogeneously distributed

How imaging could mitigate the above mentioned challenges

  • The inclusion of an imaging probe during drug development can aid in determining the clearance kinetics and tissue distribution of the drug non-invasively. Such probe can also be used to determine the likelihood of the drug reaching the tumor and to what extent.

Note: Drugs that have increased accumulation within the targeted site are likely to be more effective as compared with others. In that respect, Nanoparticle-based drugs have an additional advantage over free drugs with their potential to be multifunctional carriers capable of carrying both therapeutic and diagnostic imaging probes (theranostic) in the same nanocarrier. These multifunctional nanoparticles can serve as theranostic agents and facilitate personalized treatment planning.

  • Imaging can also be used for localization of the tumor to improve the placement of a catheter or external device within tumors to cause cell death through thermal ablation or oxidative stress secondary to reactive oxygen species.

See the example of Vintfolide in The Role of Medical Imaging in Personalized Medicine

vinta

Note: Image guided thermal ablation methods include radiofrequency (RF) ablation, microwave ablation or high intensity focused ultrasound (HIFU). Photodynamic therapy methods using external light devices to activate photosensitizing agents can also be used to treat superficial tumors or deeper tumors when used with endoscopic catheters.

  • Quality control during and post treatment

For example: The use of high intensity focused ultrasound (HIFU) combined with nanoparticle therapeutics: HIFU is applied to improve drug delivery and to trigger drug release from nanoparticles. Gas-bubbles are playing the role of the drug’s nano-carrier. These are used both to increase the drug transport into the cell and as ultrasound-imaging contrast material. The ultrasound is also used for processes of drug-release and ablation.

 HIFU

Additional example; Multifunctional nanoparticles for tracking CED (convection enhanced delivery)  distribution within tumors: Nanoparticle that could serve as a carrier not only for the therapeutic radionuclides but simultaneously also for a therapeutic drug and 4 different types of imaging contrast agents including an MRI contrast agent, PET and SPECT nuclear diagnostic imaging agents and optical contrast agents as shown below. The ability to perform multiple types of imaging on the same nanoparticles will allow studies investigating the distribution and retention of nanoparticles initially in vivo using non-invasive imaging and later at the histological level using optical imaging.

 multi

Conclusions

Image-guided radiotherapeutic nanoparticles have significant potential for solid tumor cancer therapy. The current success of this therapy in animals is most likely due to the improved accumulation, retention and dispersion of nanoparticles within solid tumor following image-guided therapies as well as the micro-field of the β-particle which reduces the requirement of perfectly homogeneous tumor coverage. It is also possible that the intratumoral distribution of nanoparticles may benefit from their uptake by intratumoral macrophages although more research is required to determine the importance of this aspect of intratumoral radionuclide nanoparticle therapy. This new approach to cancer therapy is a fertile ground for many new technological developments as well as for new understandings in the basic biology of cancer therapy. The clinical success of this approach will depend on progress in many areas of interdisciplinary research including imaging technology, nanoparticle technology, computer and robot assisted image-guided application of therapies, radiation physics and oncology. Close collaboration of a wide variety of scientists and physicians including chemists, nanotechnologists, drug delivery experts, radiation physicists, robotics and software experts, toxicologists, surgeons, imaging physicians, and oncologists will best facilitate the implementation of this novel approach to the treatment of cancer in the clinical environment. Image-guided nanoparticle therapies including those with β-emission radionuclide nanoparticles have excellent promise to significantly impact clinical cancer therapy and advance the field of drug delivery.

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

Curator, Writer: Stephen J. Williams, Ph.D.

lung cancer

(photo credit: cancer.gov)

A report Lung Cancer Genome Surveys Find Many Potential Drug Targets, in the NCI Bulletin,

http://www.cancer.gov/ncicancerbulletin/091812/page2

summarizes the clinical importance of five new lung cancer genome sequencing projects. These studies have identified genetic and epigenetic alterations in hundreds of lung tumors, of which some alterations could be taken advantage of using currently approved medications.

The reports, all published this month, included genomic information on more than 400 lung tumors. In addition to confirming genetic alterations previously tied to lung cancer, the studies identified other changes that may play a role in the disease.

Collectively, the studies covered the main forms of the disease—lung adenocarcinomas, squamous cell cancers of the lung, and small cell lung cancers.

“All of these studies say that lung cancers are genomically complex and genomically diverse,” said Dr. Matthew Meyerson of Harvard Medical School and the Dana-Farber Cancer Institute, who co-led several of the studies, including a large-scale analysis of squamous cell lung cancer by The Cancer Genome Atlas (TCGA) Research Network.

Some genes, Dr. Meyerson noted, were inactivated through different mechanisms in different tumors. He cautioned that little is known about alterations in DNA sequences that do not encode genes, which is most of the human genome.

Four of the papers are summarized below, with the first described in detail, as the Nature paper used a multi-‘omics strategy to evaluate expression, mutation, and signaling pathway activation in a large cohort of lung tumors. A literature informatics analysis is given for one of the papers.  Please note that links on GENE names usually refer to the GeneCard entry.

Paper 1. Comprehensive genomic characterization of squamous cell lung cancers[1]

The Cancer Genome Atlas Research Network Project just reported, in the journal Nature, the results of their comprehensive profiling of 230 resected lung adenocarcinomas. The multi-center teams employed analyses of

  • microRNA
  • Whole Exome Sequencing including
    • Exome mutation analysis
    • Gene copy number
    • Splicing alteration
  • Methylation
  • Proteomic analysis

Summary:

Some very interesting overall findings came out of this analysis including:

  • High rates of somatic mutations including activating mutations in common oncogenes
  • Newly described loss of function MGA mutations
  • Sex differences in EGFR and RBM10 mutations
  • driver roles for NF1, MET, ERBB2 and RITI identified in certain tumors
  • differential mutational pattern based on smoking history
  • splicing alterations driven by somatic genomic changes
  • MAPK and PI3K pathway activation identified by proteomics not explained by mutational analysis = UNEXPLAINED MECHANISM of PATHWAY ACTIVATION

however, given the plethora of data, and in light of a similar study results recently released, there appears to be a great need for additional mining of this CGAP dataset. Therefore I attempted to curate some of the findings along with some other recent news relevant to the surprising findings with relation to biomarker analysis.

Makeup of tumor samples

230 lung adenocarcinomas specimens were categorized by:

Subtype

33% acinar

25% solid

14% micro-papillary

9% papillary

8% unclassified

5% lepidic

4% invasive mucinous
Gender

Smoking status

81% of patients reported past of present smoking

The authors note that TCGA samples were combined with previous data for analysis purpose.

A detailed description of Methodology and the location of deposited data are given at the following addresses:

Publication TCGA Web Page: https://tcga-data.nci.nih.gov/docs/publications/luad_2014/

Sequence files: https://cghub.ucsc.edu

Results:

Gender and Smoking Habits Show different mutational patterns

 

WES mutational analysis

  1. a) smoking status

– there was a strong correlations of cytosine to adenine nucleotide transversions with past or present smoking. In fact smoking history separated into transversion high (past and previous smokers) and transversion low (never smokers) groups, corroborating previous results.

mutations in groups              Transversion High                   Transversion Low

TP53, KRAS, STK11,                 EGFR, RB1, PI3CA

     KEAP1, SMARCA4 RBM10

 

  1. b) Gender

Although gender differences in mutational profiles have been reported, the study found minimal number of significantly mutated genes correlated with gender. Notably:

  • EGFR mutations enriched in female cohort
  • RBM10 loss of function mutations enriched in male cohort

Although the study did not analyze the gender differences with smoking patterns, it was noted that RBM10 mutations among males were more prevalent in the transversion high group.

Whole exome Sequencing and copy number analysis reveal Unique, Candidate Driver Genes

Whole exome sequencing revealed that 62% of tumors contained mutations (either point or indel) in known cancer driver genes such as:

KRAS, EGFR, BRMF, ERBB2

However, authors looked at the WES data from the oncogene-negative tumors and found unique mutations not seen in the tumors containing canonical oncogenic mutations.

Unique potential driver mutations were found in

TP53, KEAP1, NF1, and RIT1

The genomics and expression data were backed up by a proteomics analysis of three pathways:

  1. MAPK pathway
  2. mTOR
  3. PI3K pathway

…. showing significant activation of all three pathways HOWEVER the analysis suggested that activation of signaling pathways COULD NOT be deduced from DNA sequencing alone. Phospho-proteomic analysis was required to determine the full extent of pathway modification.

For example, many tumors lacked an obvious mutation which could explain mTOR or MAPK activation.

 

Altered cell signaling pathways included:

  • Increased MAPK signaling due to activating KRAS
  • Higher mTOR due to inactivating STK11 leading to increased proliferation, translation

Pathway analysis of mutations revealed alterations in multiple cellular pathways including:

  • Reduced oxidative stress response
  • Nucleosome remodeling
  • RNA splicing
  • Cell cycle progression
  • Histone methylation

Summary:

Authors noted some interesting conclusions including:

  1. MET and ERBB2 amplification and mutations in NF1 and RIT1 may be unique driver events in lung adenocarcinoma
  2. Possible new drug development could be targeted to the RTK/RAS/RAF pathway
  3. MYC pathway as another important target
  4. Cluster analysis using multimodal omics approach identifies tumors based on single-gene driver events while other tumor have multiple driver mutational events (TUMOR HETEROGENEITY)

Paper 2. A Genomics-Based Classification of Human Lung Tumors[2]

The paper can be found at

http://stm.sciencemag.org/content/5/209/209ra153

by The Clinical Lung Cancer Genome Project (CLCGP) and Network Genomic Medicine (NGM),*,

Paper Summary

This sequencing project revealed discrepancies between histologic and genomic classification of lung tumors.

Methodology

– mutational analysis by whole exome sequencing of 1255 lung tumors of histologically

defined subtypes

– immunohistochemistry performed to verify reclassification of subtypes based on sequencing data

Results

  • 55% of all cases had at least one oncogenic alteration amenable to current personalized treatment approaches
  • Marked differences existed between cluster analysis within and between preclassified histo-subtypes
  • Reassignment based on genomic data eliminated large cell carcinomas
  • Prospective classification of 5145 lung cancers allowed for genomic classification in 75% of patients
  • Identification of EGFR and ALK mutations led to improved outcomes

Conclusions:

It is feasible to successfully classify and diagnose lung tumors based on whole exome sequencing data.

Paper 3. Genomic Landscape of Non-Small Cell Lung Cancer in Smokers and Never-Smokers[3]

A link to the paper can be found here with Graphic Summary: http://www.cell.com/cell/abstract/S0092-8674%2812%2901022-7?cc=y?cc=y

Methodology

  • Whole genome sequencing and transcriptome sequencing of cancerous and adjacent normal tissues from 17 patients with NSCLC
  • Integrated RNASeq with WES for analysis of
    • Variant analysis
    • Clonality by variant allele frequency anlaysis
    • Fusion genes
  • Bioinformatic analysis

Results

  • 3,726 point mutations and more than 90 indels in the coding sequence
  • Smokers with lung cancer show 10× the number of point mutations than never-smokers
  • Novel lung cancer genes, including DACH1, CFTR, RELN, ABCB5, and HGF were identified
  • Tumor samples from males showed high frequency of MYCBP2 MYCBP2 involved in transcriptional regulation of MYC.
  • Variant allele frequency analysis revealed 10/17 tumors were at least biclonal while 7/17 tumors were monoclonal revealing majority of tumors displayed tumor heterogeneity
  • Novel pathway alterations in lung cancer include cell-cycle and JAK-STAT pathways
  • 14 fusion proteins found, including ROS1-ALK fusion. ROS1-ALK fusions have been frequently found in lung cancer and is indicative of poor prognosis[4].
  • Novel metabolic enzyme fusions
  • Alterations were identified in 54 genes for which targeted drugs are available.           Drug-gable mutant targets include: AURKC, BRAF, HGF, EGFR, ERBB4, FGFR1, MET, JAK2, JAK3, HDAC2, HDAC6, HDAC9, BIRC6, ITGB1, ITGB3, MMP2, PRKCB, PIK3CG, TERT, KRAS, MMP14

Table. Validated Gene-Fusions Obtained from Ref-Seq Data

Note: Gene columns contain links for GeneCard while Gene function links are to the    gene’s GO (Gene Ontology) function.

GeneA (5′) GeneB (3′) GeneA function (link to Gene Ontology) GeneB function (link to Gene Ontology) known function (refs)
GRIP1 TNIP1 glutamate receptor IP transcriptional repressor
SGMS1 STK10 sphingolipid synthesis ser/thr kinase
RASSF3 TTYH2 GTP-binding protein chloride anion channel
KDELR2 ROS1, GOPC ER retention seq. binding proto-oncogenic tyr kinase
ACSL4 DCAF6 fatty acid synthesis ?
MARCH8 PRKG1 ubiquitin ligase cGMP dependent protein kinase
APAF1 UNC13B, TLN1 caspase activation cytoskeletal
EML4 ALK microtubule protein tyrosine kinase
EDR3,PHC3 LOC441601 polycomb pr/DNA binding ?
DKFZp761L1918,RHPN2 ANKRD27 Rhophilin (GTP binding pr ankyrin like
VANGL1 HAO2 tetraspanin family oxidase
CACNA2D3 FLNB VOC Ca++ channel filamin (actin binding)

Author’s Note:

There has been a recent literature on the importance of the EML4-ALK fusion protein in lung cancer. EML4-ALK positive lung tumors were found to be les chemo sensitive to cytotoxic therapy[5] and these tumor cells may exhibit an epitope rendering these tumors amenable to immunotherapy[6]. In addition, inhibition of the PI3K pathway has sensitized EMl4-ALK fusion positive tumors to ALK-targeted therapy[7]. EML4-ALK fusion positive tumors show dependence on the HSP90 chaperone, suggesting this cohort of patients might benefit from the new HSP90 inhibitors recently being developed[8].

Table. Significantly mutated genes (point mutations, insertions/deletions) with associated function.

Gene Function
TP53 tumor suppressor
KRAS oncogene
ZFHX4 zinc finger DNA binding
DACH1 transcription factor
EGFR epidermal growth factor receptor
EPHA3 receptor tyrosine kinase
ENSG00000205044
RELN cell matrix protein
ABCB5 ABC Drug Transporter

Table. Literature Analysis of pathways containing significantly altered genes in NSCLC reveal putative targets and risk factors, linkage between other tumor types, and research areas for further investigation.

Note: Significantly mutated genes, obtained from WES, were subjected to pathway analysis (KEGG Pathway Analysis) in order to see which pathways contained signicantly altered gene networks. This pathway term was then used for PubMed literature search together with terms “lung cancer”, “gene”, and “NOT review” to determine frequency of literature coverage for each pathway in lung cancer. Links are to the PubMEd search results.

KEGG pathway Name # of PUBMed entries containing Pathway Name, Gene ANDLung Cancer
Cell cycle 1237
Cell adhesion molecules (CAMs) 372
Glioma 294
Melanoma 219
Colorectal cancer 207
Calcium signaling pathway 175
Prostate cancer 166
MAPK signaling pathway 162
Pancreatic cancer 88
Bladder cancer 74
Renal cell carcinoma 68
Focal adhesion 63
Regulation of actin cytoskeleton 34
Thyroid cancer 32
Salivary secretion 19
Jak-STAT signaling pathway 16
Natural killer cell mediated cytotoxicity 11
Gap junction 11
Endometrial cancer 11
Long-term depression 9
Axon guidance 8
Cytokine-cytokine receptor interaction 8
Chronic myeloid leukemia 7
ErbB signaling pathway 7
Arginine and proline metabolism 6
Maturity onset diabetes of the young 6
Neuroactive ligand-receptor interaction 4
Aldosterone-regulated sodium reabsorption 2
Systemic lupus erythematosus 2
Olfactory transduction 1
Huntington’s disease 1
Chemokine signaling pathway 1
Cardiac muscle contraction 1
Amyotrophic lateral sclerosis (ALS) 1

A few interesting genetic risk factors and possible additional targets for NSCLC were deduced from analysis of the above table of literature including HIF1-α, mIR-31, UBQLN1, ACE, mIR-193a, SRSF1. In addition, glioma, melanoma, colorectal, and prostate and lung cancer share many validated mutations, and possibly similar tumor driver mutations.

KEGGinliteroanalysislungcancer

 please click on graph for larger view

Paper 4. Mapping the Hallmarks of Lung Adenocarcinoma with Massively Parallel Sequencing[9]

For full paper and graphical summary please follow the link: http://www.cell.com/cell/abstract/S0092-8674%2812%2901061-6

Highlights

  • Exome and genome characterization of somatic alterations in 183 lung adenocarcinomas
  • 12 somatic mutations/megabase
  • U2AF1, RBM10, and ARID1A are among newly identified recurrently mutated genes
  • Structural variants include activating in-frame fusion of EGFR
  • Epigenetic and RNA deregulation proposed as a potential lung adenocarcinoma hallmark

Summary

Lung adenocarcinoma, the most common subtype of non-small cell lung cancer, is responsible for more than 500,000 deaths per year worldwide. Here, we report exome and genome sequences of 183 lung adenocarcinoma tumor/normal DNA pairs. These analyses revealed a mean exonic somatic mutation rate of 12.0 events/megabase and identified the majority of genes previously reported as significantly mutated in lung adenocarcinoma. In addition, we identified statistically recurrent somatic mutations in the splicing factor gene U2AF1 and truncating mutations affecting RBM10 and ARID1A. Analysis of nucleotide context-specific mutation signatures grouped the sample set into distinct clusters that correlated with smoking history and alterations of reported lung adenocarcinoma genes. Whole-genome sequence analysis revealed frequent structural rearrangements, including in-frame exonic alterations within EGFR and SIK2 kinases. The candidate genes identified in this study are attractive targets for biological characterization and therapeutic targeting of lung adenocarcinoma.

Paper 5. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer[10]

Highlights

  • Whole exome and transcriptome (RNASeq) sequencing 29 small-cell lung carcinomas
  • High mutation rate 7.4 protein-changing mutations/million base pairs
  • Inactivating mutations in TP53 and RB1
  • Functional mutations in CREBBP, EP300, MLL, PTEN, SLIT2, EPHA7, FGFR1 (determined by literature and database mining)
  • The mutational spectrum seen in human data also present in a Tp53-/- Rb1-/- mouse lung tumor model

 

Curator Graphical Summary of Interesting Findings From the Above Studies

DGRAPHICSUMMARYNSLCSEQPOST

The above figure (please click on figure) represents themes and findings resulting from the aforementioned studies including

questions which will be addressed in Future Posts on this site.

References:

  1. Comprehensive genomic characterization of squamous cell lung cancers. Nature 2012, 489(7417):519-525.
  2. A genomics-based classification of human lung tumors. Science translational medicine 2013, 5(209):209ra153.
  3. Govindan R, Ding L, Griffith M, Subramanian J, Dees ND, Kanchi KL, Maher CA, Fulton R, Fulton L, Wallis J et al: Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell 2012, 150(6):1121-1134.
  4. Takeuchi K, Soda M, Togashi Y, Suzuki R, Sakata S, Hatano S, Asaka R, Hamanaka W, Ninomiya H, Uehara H et al: RET, ROS1 and ALK fusions in lung cancer. Nature medicine 2012, 18(3):378-381.
  5. Morodomi Y, Takenoyama M, Inamasu E, Toyozawa R, Kojo M, Toyokawa G, Shiraishi Y, Takenaka T, Hirai F, Yamaguchi M et al: Non-small cell lung cancer patients with EML4-ALK fusion gene are insensitive to cytotoxic chemotherapy. Anticancer research 2014, 34(7):3825-3830.
  6. Yoshimura M, Tada Y, Ofuzi K, Yamamoto M, Nakatsura T: Identification of a novel HLA-A 02:01-restricted cytotoxic T lymphocyte epitope derived from the EML4-ALK fusion gene. Oncology reports 2014, 32(1):33-39.
  7. Yang L, Li G, Zhao L, Pan F, Qiang J, Han S: Blocking the PI3K pathway enhances the efficacy of ALK-targeted therapy in EML4-ALK-positive nonsmall-cell lung cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 2014.
  8. Workman P, van Montfort R: EML4-ALK fusions: propelling cancer but creating exploitable chaperone dependence. Cancer discovery 2014, 4(6):642-645.
  9. Imielinski M, Berger AH, Hammerman PS, Hernandez B, Pugh TJ, Hodis E, Cho J, Suh J, Capelletti M, Sivachenko A et al: Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 2012, 150(6):1107-1120.
  10. Peifer M, Fernandez-Cuesta L, Sos ML, George J, Seidel D, Kasper LH, Plenker D, Leenders F, Sun R, Zander T et al: Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nature genetics 2012, 44(10):1104-1110.

Other posts on this site which refer to Lung Cancer and Cancer Genome Sequencing include:

Multi-drug, Multi-arm, Biomarker-driven Clinical Trial for patients with Squamous Cell Carcinoma called the Lung Cancer Master Protocol, or Lung-MAP launched by NCI, Foundation Medicine, and Five Pharma Firms

US Personalized Cancer Genome Sequencing Market Outlook 2018 –

Comprehensive Genomic Characterization of Squamous Cell Lung Cancers

International Cancer Genome Consortium Website has 71 Committed Cancer Genome Projects Ongoing

Non-small Cell Lung Cancer drugs – where does the Future lie?

Lung cancer breathalyzer trialed in the UK

Diagnosing Lung Cancer in Exhaled Breath using Gold Nanoparticles

Multi-drug, Multi-arm, Biomarker-driven Clinical Trial for patients with Squamous Cell Carcinoma called the Lung Cancer Master Protocol, or Lung-MAP launched by NCI, Foundation Medicine, and Five Pharma Firms

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Single-Cell Sequencing | August 20-21, 2014

CSHL, UCLA & Einstein to Lead Roundtable Discussions on Single-Cell Sequencing

Interactive discussions on three of the key questions researchers are facing when considering single-cell analysis will be held on the second day of the Single-Cell Sequencing Conference at Next Generation Dx Summit, taking place August 20-21, 2014 in Washington, DC. For full program details and to register, please visit NextGenerationDx.com/Single-Cell-Sequencing.

Making Single-Cell Analysis Cost Effective for Clinical Use
Moderator: James Hicks, Ph.D., Research Professor, Cancer Genomics, Cold Spring Harbor Laboratory

  • Methods for capture: What are the tradeoffs?
  • Combining RNA, DNA and protein analysis
  • What genomic assays are most informative?
  • Can assays be certifiable?

Finding a Needle in a Haystack: Towards Diagnosing Rare Soft Tissue Cancer Stem Cells (CSCs)
Moderator: Michael Masterman-Smith, Ph.D., Entrepreneurial Scientist, UCLA California NanoSystems Institute

  • Rethinking companion diagnostics for cancer to incorporate analysis of CSCs
  • Current direct methodologies of CSC detection/isolation
  • Current proxy methodologies of CSC detection/isolation
  • The hope and promise of single-cell assay tools and technologies

Why Single-Cell Sequencing?
Moderator: Jan Vijg, Ph.D., Professor and Chairman, Genetics, Albert Einstein College of Medicine
Sample limitations, e.g., prenatal diagnostics and CTCs

  • Sample limitations, e.g., prenatal diagnostics and CTCs
  • To study cell-to-cell variation, e.g., in tumors as well as normal tissues
  • To overcome technological constraints, e.g., detecting somatic mutations
  • Cell-to-cell fluctuations in gene expression can easily impair function, yet can be undetectable by measuring averages
  • How many different cell types are there?
View Brochure    |   Register (Advance Registration Ends July 18)  |   NextGenerationDx.com/Single-Cell-Sequencing


About the Conference

Sequencing data from bulk DNA or RNA from multiple cells provide global information on average states of cell populations. But with whole-genome amplification and NGS, researchers can detect variation in individual cancer cells and dissect tumor evolution. Such cancer genome sequencing will improve oncology by detecting rare tumor cells early, measuring intra-/intertumor heterogeneity, guiding chemotherapy and controlling drug resistance. The Single-Cell Sequencing conference explores the latest strategies, data analyses and clinical considerations that influence and aid cancer diagnosis, prognosis and prediction and will lead to individualized cancer therapy.

Sessions include presentations spanning the opportunities of clinical single-cell analysis from:

  • Sunney Xie, Ph.D., Mallinckrodt Professor. Chemistry and Chemical Biology, Harvard University
  • Maximilian Diehn, M.D., Ph.D., Assistant Professor, Radiation Oncology, Stanford Cancer Institute, Institute for Stem Cell Biology & Regenerative Medicine, Stanford University
  • Denis Smirnov, Associate Scientific Director, US Biomarker Oncology, Janssen R&D US
  • James Hicks, Ph.D., Research Professor, Cancer Genomics, Cold Spring Harbor Laboratory
  • Jan Vijg, Ph.D., Professor and Chairman, Genetics, Albert Einstein College of Medicine
  • John F. Zhong, Ph.D., Associate Professor, Pathology, University of Southern California School of Medicine
  • Mark Hills, Ph.D., Research Scientist, Peter M. Lansdorp Laboratory, BC Cancer Research Centre
  • Michael Masterman-Smith, Ph.D., Entrepreneurial Scientist, UCLA California NanoSystems Institute
  • Parveen Kumar, Research Scientist, Thierry Voet Laboratory, Human Genetics, University of Leuven
  • Peter Nemes, Ph.D., Assistant Professor, Chemistry, George Washington University
  • Theresa Zhang, Ph.D., Vice President, Research Services, Personal Genome Diagnostics
  • Yong Wang, Ph.D., Senior Postdoctoral Fellow, Nicholas E. Navin Laboratory, Genetics, Bioinformatics, MD Anderson Cancer Center
  • Zivana Tezak, Ph.D., Associate Director, Science and Technology, Personalized Medicine, Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD), Center for Devices and Radiological Health (CDRH), FDA

 


Recommended Pre-Conference Courses

NGS Data Analysis – Determining Clinical Utility of Genome Variants
Monday, August 18 | 9:00am – 12:00pm
This course will explore the strategies of genomic data analysis and interpretation, an emergent discipline that seeks to deliver better answers from NGS data so that patients and their physicians can determine informed healthcare decisions. View Details

NGS as a Diagnostics Platform
Monday, August 18 | 2:00pm – 5:00pm
The focus of this short course will be on understanding the use of NGS in clinical diagnosis, practical implementation of NGS in clinical laboratories and analysis of large data sets by using bioinformatics tools to parse and interpret data in relation to the clinical phenotype. The concluding presentation will be dedicated to quality and standardization of NGS assays. View Details

Register   |   View Agenda   | NextGenerationDx.com

LinkedIn YouTube Twitter #NGDx14

Next Generation Dx Summit 2014
Cambridge Healthtech Institute, 250 First Avenue, Suite 300, Needham, MA 02494
www.healthtech.com

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Summary – Volume 4, Part 2: Translational Medicine in Cardiovascular Diseases


Summary – Volume 4, Part 2:  Translational Medicine in Cardiovascular Diseases

Author and Curator: Larry H Bernstein, MD, FCAP

 

We have covered a large amount of material that involves

  • the development,
  • application, and
  • validation of outcomes of medical and surgical procedures

that are based on translation of science from the laboratory to the bedside, improving the standards of medical practice at an accelerated pace in the last quarter century, and in the last decade.  Encouraging enabling developments have been:

1. The establishment of national and international outcomes databases for procedures by specialist medical societies

Stent Design and Thrombosis: Bifurcation Intervention, Drug Eluting Stents (DES) and Biodegrable Stents
Curator: Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2013/08/06/stent-design-and-thrombosis-bifurcation-intervention-drug-eluting-stents-des-and-biodegrable-stents/

On Devices and On Algorithms: Prediction of Arrhythmia after Cardiac Surgery and ECG Prediction of an Onset of Paroxysmal Atrial Fibrillation
Author, and Content Consultant to e-SERIES A: Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC
https://pharmaceuticalintelligence.com/2013/05/07/on-devices-and-on-algorithms-arrhythmia-after-cardiac-surgery-prediction-and-ecg-prediction-of-paroxysmal-atrial-fibrillation-onset/

Mitral Valve Repair: Who is a Patient Candidate for a Non-Ablative Fully Non-Invasive Procedure?
Author, and Content Consultant to e-SERIES A: Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC and Article Curator: Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2013/11/04/mitral-valve-repair-who-is-a-candidate-for-a-non-ablative-fully-non-invasive-procedure/

Cardiovascular Complications: Death from Reoperative Sternotomy after prior CABG, MVR, AVR, or Radiation; Complications of PCI; Sepsis from Cardiovascular Interventions
Author, Introduction and Summary: Justin D Pearlman, MD, PhD, FACC and Article Curator: Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2013/07/23/cardiovascular-complications-of-multiple-etiologies-repeat-sternotomy-post-cabg-or-avr-post-pci-pad-endoscopy-andor-resultant-of-systemic-sepsis/

Survivals Comparison of Coronary Artery Bypass Graft (CABG) and Percutaneous Coronary Intervention (PCI) /Coronary Angioplasty
Larry H. Bernstein, MD, Writer And Aviva Lev-Ari, PhD, RN, Curator
https://pharmaceuticalintelligence.com/2013/06/23/comparison-of-cardiothoracic-bypass-and-percutaneous-interventional-catheterization-survivals/

Revascularization: PCI, Prior History of PCI vs CABG
Curator: Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2013/04/25/revascularization-pci-prior-history-of-pci-vs-cabg/

Outcomes in High Cardiovascular Risk Patients: Prasugrel (Effient) vs. Clopidogrel (Plavix); Aliskiren (Tekturna) added to ACE or added to ARB
Reporter and Curator: Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2012/08/27/outcomes-in-high-cardiovascular-risk-patients-prasugrel-effient-vs-clopidogrel-plavix-aliskiren-tekturna-added-to-ace-or-added-to-arb/

Endovascular Lower-extremity Revascularization Effectiveness: Vascular Surgeons (VSs), Interventional Cardiologists (ICs) and Interventional Radiologists (IRs)
Curator: Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2012/08/13/coronary-artery-disease-medical-devices-solutions-from-first-in-man-stent-implantation-via-medical-ethical-dilemmas-to-drug-eluting-stents/

and more

2. The identification of problem areas, particularly in activation of the prothrombotic pathways, infection control to an extent, and targeting of pathways leading to progression or to arrythmogenic complications.

Cardiovascular Complications: Death from Reoperative Sternotomy after prior CABG, MVR, AVR, or Radiation; Complications of PCI; Sepsis from Cardiovascular Interventions Author, Introduction and Summary: Justin D Pearlman, MD, PhD, FACC and Article Curator: Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2013/07/23/cardiovascular-complications-of-multiple-etiologies-repeat-sternotomy-post-cabg-or-avr-post-pci-pad-endoscopy-andor-resultant-of-systemic-sepsis/

Anticoagulation genotype guided dosing
Larry H. Bernstein, MD, FCAP, Author and Curator
https://pharmaceuticalintelligence.com/2013/12/08/anticoagulation-genotype-guided-dosing/

Stent Design and Thrombosis: Bifurcation Intervention, Drug Eluting Stents (DES) and Biodegrable Stents
Curator: Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2013/08/06/stent-design-and-thrombosis-bifurcation-intervention-drug-eluting-stents-des-and-biodegrable-stents/

The Effects of Aprotinin on Endothelial Cell Coagulant Biology
Co-Author (Kamran Baig, MBBS, James Jaggers, MD, Jeffrey H. Lawson, MD, PhD) and Curator
https://pharmaceuticalintelligence.com/2013/07/20/the-effects-of-aprotinin-on-endothelial-cell-coagulant-biology/

Outcomes in High Cardiovascular Risk Patients: Prasugrel (Effient) vs. Clopidogrel (Plavix); Aliskiren (Tekturna) added to ACE or added to ARB
Reporter and Curator: Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2012/08/27/outcomes-in-high-cardiovascular-risk-patients-prasugrel-effient-vs-clopidogrel-plavix-aliskiren-tekturna-added-to-ace-or-added-to-arb/

Pharmacogenomics – A New Method for Druggability  Author and Curator: Demet Sag, PhD
https://pharmaceuticalintelligence.com/2014/04/28/pharmacogenomics-a-new-method-for-druggability/

Advanced Topics in Sepsis and the Cardiovascular System at its End Stage    Author: Larry H Bernstein, MD, FCAP
https://pharmaceuticalintelligence.com/2013/08/18/advanced-topics-in-Sepsis-and-the-Cardiovascular-System-at-its-End-Stage/

3. Development of procedures that use a safer materials in vascular management.

Stent Design and Thrombosis: Bifurcation Intervention, Drug Eluting Stents (DES) and Biodegrable Stents
Curator: Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2013/08/06/stent-design-and-thrombosis-bifurcation-intervention-drug-eluting-stents-des-and-biodegrable-stents/

Biomaterials Technology: Models of Tissue Engineering for Reperfusion and Implantable Devices for Revascularization
Author and Curator: Larry H Bernstein, MD, FACP and Curator: Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2013/05/05/bioengineering-of-vascular-and-tissue-models/

Vascular Repair: Stents and Biologically Active Implants
Author and Curator: Larry H Bernstein, MD, FACP and Curator: Aviva Lev-Ari, RN, PhD
https://pharmaceuticalintelligence.com/2013/05/04/stents-biologically-active-implants-and-vascular-repair/

Drug Eluting Stents: On MIT’s Edelman Lab’s Contributions to Vascular Biology and its Pioneering Research on DES
Author: Larry H Bernstein, MD, FACP and Curator: Aviva Lev-Ari, PhD, RN
http://PharmaceuticalIntelligence.com/2013/04/25/Contributions-to-vascular-biology/

MedTech & Medical Devices for Cardiovascular Repair – Curations by Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2014/04/17/medtech-medical-devices-for-cardiovascular-repair-curation-by-aviva-lev-ari-phd-rn/

4. Discrimination of cases presenting for treatment based on qualifications for medical versus surgical intervention.

Treatment Options for Left Ventricular Failure – Temporary Circulatory Support: Intra-aortic balloon pump (IABP) – Impella Recover LD/LP 5.0 and 2.5, Pump Catheters (Non-surgical) vs Bridge Therapy: Percutaneous Left Ventricular Assist Devices (pLVADs) and LVADs (Surgical)
Author: Larry H Bernstein, MD, FCAP And Curator: Justin D Pearlman, MD, PhD, FACC
https://pharmaceuticalintelligence.com/2013/07/17/treatment-options-for-left-ventricular-failure-temporary-circulatory-support-intra-aortic-balloon-pump-iabp-impella-recover-ldlp-5-0-and-2-5-pump-catheters-non-surgical-vs-bridge-therapy/

Coronary Reperfusion Therapies: CABG vs PCI – Mayo Clinic preprocedure Risk Score (MCRS) for Prediction of in-Hospital Mortality after CABG or PCI
Writer and Curator: Larry H. Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2013/06/30/mayo-risk-score-for-percutaneous-coronary-intervention/

ACC/AHA Guidelines for Coronary Artery Bypass Graft Surgery Reporter: Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2013/11/05/accaha-guidelines-for-coronary-artery-bypass-graft-surgery/

Mitral Valve Repair: Who is a Patient Candidate for a Non-Ablative Fully Non-Invasive Procedure?
Author, and Content Consultant to e-SERIES A: Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC and Article Curator: Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2013/11/04/mitral-valve-repair-who-is-a-candidate-for-a-non-ablative-fully-non-invasive-procedure/ 

5.  This has become possible because of the advances in our knowledge of key related pathogenetic mechanisms involving gene expression and cellular regulation of complex mechanisms.

What is the key method to harness Inflammation to close the doors for many complex diseases?
Author and Curator: Larry H Bernstein, MD, FCAP
https://pharmaceuticalintelligence.com/2014/03/21/what-is-the-key-method-to-harness-inflammation-to-close-the-doors-for-many-complex-diseases/

CVD Prevention and Evaluation of Cardiovascular Imaging Modalities: Coronary Calcium Score by CT Scan Screening to justify or not the Use of Statin
Curator: Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2014/03/03/cvd-prevention-and-evaluation-of-cardiovascular-imaging-modalities-coronary-calcium-score-by-ct-scan-screening-to-justify-or-not-the-use-of-statin/

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
Curator: Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2014/03/03/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-tha/

Pathophysiological Effects of Diabetes on Ischemic-Cardiovascular Disease and on Chronic Obstructive Pulmonary Disease (COPD)
Curator:  Larry H. Bernstein, MD, FCAP
https://pharmaceuticalintelligence.com/2014/01/15/pathophysiological-effects-of-diabetes-on-ischemic-cardiovascular-disease-and-on-chronic-obstructive-pulmonary-disease-copd/

Atherosclerosis Independence: Genetic Polymorphisms of Ion Channels Role in the Pathogenesis of Coronary Microvascular Dysfunction and Myocardial Ischemia (Coronary Artery Disease (CAD))
Reviewer and Co-Curator: Larry H Bernstein, MD, CAP and Curator: Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2013/12/21/genetic-polymorphisms-of-ion-channels-have-a-role-in-the-pathogenesis-of-coronary-microvascular-dysfunction-and-ischemic-heart-disease/

Notable Contributions to Regenerative Cardiology  Author and Curator: Larry H Bernstein, MD, FCAP and Article Commissioner: Aviva Lev-Ari, PhD, RD
https://pharmaceuticalintelligence.com/2013/10/20/notable-contributions-to-regenerative-cardiology/

As noted in the introduction, any of the material can be found and reviewed by content, and the eTOC is identified in attached:

http://wp.me/p2xfv8-1W

 

This completes what has been presented in Part 2, Vol 4 , and supporting references for the main points that are found in the Leaders in Pharmaceutical Intelligence Cardiovascular book.  Part 1 was concerned with Posttranslational Modification of Proteins, vital for understanding cellular regulation and dysregulation.  Part 2 was concerned with Translational Medical Therapeutics, the efficacy of medical and surgical decisions based on bringing the knowledge gained from the laboratory, and from clinical trials into the realm opf best practice.  The time for this to occur in practice in the past has been through roughly a generation of physicians.  That was in part related to the busy workload of physicians, and inability to easily access specialty literature as the volume and complexity increased.  This had an effect of making access of a family to a primary care provider through a lifetime less likely than the period post WWII into the 1980s.

However, the growth of knowledge has accelerated in the specialties since the 1980’s so that the use of physician referral in time became a concern about the cost of medical care.  This is not the place for or a matter for discussion here.  It is also true that the scientific advances and improvements in available technology have had a great impact on medical outcomes.  The only unrelated issue is that of healthcare delivery, which is not up to the standard set by serial advances in therapeutics, accompanied by high cost due to development costs, marketing costs, and development of drug resistance.

I shall identify continuing developments in cardiovascular diagnostics, therapeutics, and bioengineering that is and has been emerging.

1. Mechanisms of disease

REPORT: Mapping the Cellular Response to Small Molecules Using Chemogenomic Fitness Signatures 

Science 11 April 2014:
Vol. 344 no. 6180 pp. 208-211
http://dx.doi.org/10.1126/science.1250217

Abstract: Genome-wide characterization of the in vivo cellular response to perturbation is fundamental to understanding how cells survive stress. Identifying the proteins and pathways perturbed by small molecules affects biology and medicine by revealing the mechanisms of drug action. We used a yeast chemogenomics platform that quantifies the requirement for each gene for resistance to a compound in vivo to profile 3250 small molecules in a systematic and unbiased manner. We identified 317 compounds that specifically perturb the function of 121 genes and characterized the mechanism of specific compounds. Global analysis revealed that the cellular response to small molecules is limited and described by a network of 45 major chemogenomic signatures. Our results provide a resource for the discovery of functional interactions among genes, chemicals, and biological processes.

Yeasty HIPHOP

Laura Zahn
Sci. Signal. 15 April 2014; 7(321): ec103.   http://dx.doi.org/10.1126/scisignal.2005362

In order to identify how chemical compounds target genes and affect the physiology of the cell, tests of the perturbations that occur when treated with a range of pharmacological chemicals are required. By examining the haploinsufficiency profiling (HIP) and homozygous profiling (HOP) chemogenomic platforms, Lee et al.(p. 208) analyzed the response of yeast to thousands of different small molecules, with genetic, proteomic, and bioinformatic analyses. Over 300 compounds were identified that targeted 121 genes within 45 cellular response signature networks. These networks were used to extrapolate the likely effects of related chemicals, their impact upon genetic pathways, and to identify putative gene functions

Key Heart Failure Culprit Discovered

A team of cardiovascular researchers from the Cardiovascular Research Center at Icahn School of Medicine at Mount Sinai, Sanford-Burnham Medical Research Institute, and University of California, San Diego have identified a small, but powerful, new player in thIe onset and progression of heart failure. Their findings, published in the journal Nature  on March 12, also show how they successfully blocked the newly discovered culprit.
Investigators identified a tiny piece of RNA called miR-25 that blocks a gene known as SERCA2a, which regulates the flow of calcium within heart muscle cells. Decreased SERCA2a activity is one of the main causes of poor contraction of the heart and enlargement of heart muscle cells leading to heart failure.

Using a functional screening system developed by researchers at Sanford-Burnham, the research team discovered miR-25 acts pathologically in patients suffering from heart failure, delaying proper calcium uptake in heart muscle cells. According to co-lead study authors Christine Wahlquist and Dr. Agustin Rojas Muñoz, developers of the approach and researchers in Mercola’s lab at Sanford-Burnham, they used high-throughput robotics to sift through the entire genome for microRNAs involved in heart muscle dysfunction.

Subsequently, the researchers at the Cardiovascular Research Center at Icahn School of Medicine at Mount Sinai found that injecting a small piece of RNA to inhibit the effects of miR-25 dramatically halted heart failure progression in mice. In addition, it also improved their cardiac function and survival.

“In this study, we have not only identified one of the key cellular processes leading to heart failure, but have also demonstrated the therapeutic potential of blocking this process,” says co-lead study author Dr. Dongtak Jeong, a post-doctoral fellow at the Cardiovascular Research Center at Icahn School of  Medicine at Mount Sinai in the laboratory of the study’s co-senior author Dr. Roger J. Hajjar.

Publication: Inhibition of miR-25 improves cardiac contractility in the failing heart.Christine Wahlquist, Dongtak Jeong, Agustin Rojas-Muñoz, Changwon Kho, Ahyoung Lee, Shinichi Mitsuyama, Alain Van Mil, Woo Jin Park, Joost P. G. Sluijter, Pieter A. F. Doevendans, Roger J. :  Hajjar & Mark Mercola.     Nature (March 2014)    http://www.nature.com/nature/journal/vaop/ncurrent/full/nature13073.html

 

“Junk” DNA Tied to Heart Failure

Deep RNA Sequencing Reveals Dynamic Regulation of Myocardial Noncoding RNAs in Failing Human Heart and Remodeling With Mechanical Circulatory Support

Yang KC, Yamada KA, Patel AY, Topkara VK, George I, et al.
Circulation 2014;  129(9):1009-21.
http://dx.doi.org/10.1161/CIRCULATIONAHA.113.003863              http://circ.ahajournals.org/…/CIRCULATIONAHA.113.003863.full

The myocardial transcriptome is dynamically regulated in advanced heart failure and after LVAD support. The expression profiles of lncRNAs, but not mRNAs or miRNAs, can discriminate failing hearts of different pathologies and are markedly altered in response to LVAD support. These results suggest an important role for lncRNAs in the pathogenesis of heart failure and in reverse remodeling observed with mechanical support.

Junk DNA was long thought to have no important role in heredity or disease because it doesn’t code for proteins. But emerging research in recent years has revealed that many of these sections of the genome produce noncoding RNA molecules that still have important functions in the body. They come in a variety of forms, some more widely studied than others. Of these, about 90% are called long noncoding RNAs (lncRNAs), and exploration of their roles in health and disease is just beginning.

The Washington University group performed a comprehensive analysis of all RNA molecules expressed in the human heart. The researchers studied nonfailing hearts and failing hearts before and after patients received pump support from left ventricular assist devices (LVAD). The LVADs increased each heart’s pumping capacity while patients waited for heart transplants.

In their study, the researchers found that unlike other RNA molecules, expression patterns of long noncoding RNAs could distinguish between two major types of heart failure and between failing hearts before and after they received LVAD support.

“The myocardial transcriptome is dynamically regulated in advanced heart failure and after LVAD support. The expression profiles of lncRNAs, but not mRNAs or miRNAs, can discriminate failing hearts of different pathologies and are markedly altered in response to LVAD support,” wrote the researchers. “These results suggest an important role for lncRNAs in the pathogenesis of heart failure and in reverse remodeling observed with mechanical support.”

‘Junk’ Genome Regions Linked to Heart Failure

In a recent issue of the journal Circulation, Washington University investigators report results from the first comprehensive analysis of all RNA molecules expressed in the human heart. The researchers studied nonfailing hearts and failing hearts before and after patients received pump support from left ventricular assist devices (LVAD). The LVADs increased each heart’s pumping capacity while patients waited for heart transplants.

“We took an unbiased approach to investigating which types of RNA might be linked to heart failure,” said senior author Jeanne Nerbonne, the Alumni Endowed Professor of Molecular Biology and Pharmacology. “We were surprised to find that long noncoding RNAs stood out.

In the new study, the investigators found that unlike other RNA molecules, expression patterns of long noncoding RNAs could distinguish between two major types of heart failure and between failing hearts before and after they received LVAD support.

“We don’t know whether these changes in long noncoding RNAs are a cause or an effect of heart failure,” Nerbonne said. “But it seems likely they play some role in coordinating the regulation of multiple genes involved in heart function.”

Nerbonne pointed out that all types of RNA molecules they examined could make the obvious distinction: telling the difference between failing and nonfailing hearts. But only expression of the long noncoding RNAs was measurably different between heart failure associated with a heart attack (ischemic) and heart failure without the obvious trigger of blocked arteries (nonischemic). Similarly, only long noncoding RNAs significantly changed expression patterns after implantation of left ventricular assist devices.

Comment

Decoding the noncoding transcripts in human heart failure

Xiao XG, Touma M, Wang Y
Circulation. 2014; 129(9): 958960,  http://dx.doi.org/10.1161/CIRCULATIONAHA.114.007548 

Heart failure is a complex disease with a broad spectrum of pathological features. Despite significant advancement in clinical diagnosis through improved imaging modalities and hemodynamic approaches, reliable molecular signatures for better differential diagnosis and better monitoring of heart failure progression remain elusive. The few known clinical biomarkers for heart failure, such as plasma brain natriuretic peptide and troponin, have been shown to have limited use in defining the cause or prognosis of the disease.1,2 Consequently, current clinical identification and classification of heart failure remain descriptive, mostly based on functional and morphological parameters. Therefore, defining the pathogenic mechanisms for hypertrophic versus dilated or ischemic versus nonischemic cardiomyopathies in the failing heart remain a major challenge to both basic science and clinic researchers. In recent years, mechanical circulatory support using left ventricular assist devices (LVADs) has assumed a growing role in the care of patients with end-stage heart failure.3 During the earlier years of LVAD application as a bridge to transplant, it became evident that some patients exhibit substantial recovery of ventricular function, structure, and electric properties.4 This led to the recognition that reverse remodeling is potentially an achievable therapeutic goal using LVADs. However, the underlying mechanism for the reverse remodeling in the LVAD-treated hearts is unclear, and its discovery would likely hold great promise to halt or even reverse the progression of heart failure.

 

Efficacy and Safety of Dabigatran Compared With Warfarin in Relation to Baseline Renal Function in Patients With Atrial Fibrillation: A RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) Trial Analysis

Circulation. 2014; 129: 951-952     http://dx.doi.org/10.1161/​CIR.0000000000000022

In patients with atrial fibrillation, impaired renal function is associated with a higher risk of thromboembolic events and major bleeding. Oral anticoagulation with vitamin K antagonists reduces thromboembolic events but raises the risk of bleeding. The new oral anticoagulant dabigatran has 80% renal elimination, and its efficacy and safety might, therefore, be related to renal function. In this prespecified analysis from the Randomized Evaluation of Long-Term Anticoagulant Therapy (RELY) trial, outcomes with dabigatran versus warfarin were evaluated in relation to 4 estimates of renal function, that is, equations based on creatinine levels (Cockcroft-Gault, Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) and cystatin C. The rates of stroke or systemic embolism were lower with dabigatran 150 mg and similar with 110 mg twice daily irrespective of renal function. Rates of major bleeding were lower with dabigatran 110 mg and similar with 150 mg twice daily across the entire range of renal function. However, when the CKD-EPI or MDRD equations were used, there was a significantly greater relative reduction in major bleeding with both doses of dabigatran than with warfarin in patients with estimated glomerular filtration rate ≥80 mL/min. These findings show that dabigatran can be used with the same efficacy and adequate safety in patients with a wide range of renal function and that a more accurate estimate of renal function might be useful for improved tailoring of anticoagulant treatment in patients with atrial fibrillation and an increased risk of stroke.

Aldosterone Regulates MicroRNAs in the Cortical Collecting Duct to Alter Sodium Transport.

Robert S Edinger, Claudia Coronnello, Andrew J Bodnar, William A Laframboise, Panayiotis V Benos, Jacqueline Ho, John P Johnson, Michael B Butterworth

Journal of the American Society of Nephrology (Impact Factor: 8.99). 04/2014;     http://dx. DO.org/I:10.1681/ASN.2013090931

Source: PubMed

ABSTRACT A role for microRNAs (miRs) in the physiologic regulation of sodium transport in the kidney has not been established. In this study, we investigated the potential of aldosterone to alter miR expression in mouse cortical collecting duct (mCCD) epithelial cells. Microarray studies demonstrated the regulation of miR expression by aldosterone in both cultured mCCD and isolated primary distal nephron principal cells.

Aldosterone regulation of the most significantly downregulated miRs, mmu-miR-335-3p, mmu-miR-290-5p, and mmu-miR-1983 was confirmed by quantitative RT-PCR. Reducing the expression of these miRs separately or in combination increased epithelial sodium channel (ENaC)-mediated sodium transport in mCCD cells, without mineralocorticoid supplementation. Artificially increasing the expression of these miRs by transfection with plasmid precursors or miR mimic constructs blunted aldosterone stimulation of ENaC transport.

Using a newly developed computational approach, termed ComiR, we predicted potential gene targets for the aldosterone-regulated miRs and confirmed ankyrin 3 (Ank3) as a novel aldosterone and miR-regulated protein.

A dual-luciferase assay demonstrated direct binding of the miRs with the Ank3-3′ untranslated region. Overexpression of Ank3 increased and depletion of Ank3 decreased ENaC-mediated sodium transport in mCCD cells. These findings implicate miRs as intermediaries in aldosterone signaling in principal cells of the distal kidney nephron.

 

2. Diagnostic Biomarker Status

A prospective study of the impact of serial troponin measurements on the diagnosis of myocardial infarction and hospital and 6-month mortality in patients admitted to ICU with non-cardiac diagnoses.

Marlies Ostermann, Jessica Lo, Michael Toolan, Emma Tuddenham, Barnaby Sanderson, Katie Lei, John Smith, Anna Griffiths, Ian Webb, James Coutts, John hambers, Paul Collinson, Janet Peacock, David Bennett, David Treacher

Critical care (London, England) (Impact Factor: 4.72). 04/2014; 18(2):R62.   http://dx.doi.org/:10.1186/cc13818

Source: PubMed

ABSTRACT Troponin T (cTnT) elevation is common in patients in the Intensive Care Unit (ICU) and associated with morbidity and mortality. Our aim was to determine the epidemiology of raised cTnT levels and contemporaneous electrocardiogram (ECG) changes suggesting myocardial infarction (MI) in ICU patients admitted for non-cardiac reasons.
cTnT and ECGs were recorded daily during week 1 and on alternate days during week 2 until discharge from ICU or death. ECGs were interpreted independently for the presence of ischaemic changes. Patients were classified into 4 groups: (i) definite MI (cTnT >=15 ng/L and contemporaneous changes of MI on ECG), (ii) possible MI (cTnT >=15 ng/L and contemporaneous ischaemic changes on ECG), (iii) troponin rise alone (cTnT >=15 ng/L), or (iv) normal. Medical notes were screened independently by two ICU clinicians for evidence that the clinical teams had considered a cardiac event.
Data from 144 patients were analysed [42% female; mean age 61.9 (SD 16.9)]. 121 patients (84%) had at least one cTnT level >=15 ng/L. A total of 20 patients (14%) had a definite MI, 27% had a possible MI, 43% had a cTNT rise without contemporaneous ECG changes, and 16% had no cTNT rise. ICU, hospital and 180 day mortality were significantly higher in patients with a definite or possible MI.Only 20% of definite MIs were recognised by the clinical team. There was no significant difference in mortality between recognised and non-recognised events.At time of cTNT rise, 100 patients (70%) were septic and 58% were on vasopressors. Patients who were septic when cTNT was elevated had an ICU mortality of 28% compared to 9% in patients without sepsis. ICU mortality of patients who were on vasopressors at time of cTNT elevation was 37% compared to 1.7% in patients not on vasopressors.
The majority of critically ill patients (84%) had a cTnT rise and 41% met criteria for a possible or definite MI of whom only 20% were recognised clinically. Mortality up to 180 days was higher in patients with a cTnT rise.

 

Prognostic performance of high-sensitivity cardiac troponin T kinetic changes adjusted for elevated admission values and the GRACE score in an unselected emergency department population.

Moritz BienerMatthias MuellerMehrshad VafaieAllan S JaffeHugo A Katus,Evangelos Giannitsis

Clinica chimica acta; international journal of clinical chemistry (Impact Factor: 2.54). 04/2014;   http://dx.doi.org/10.1016/j.cca.2014.04.007

Source: PubMed

ABSTRACT To test the prognostic performance of rising and falling kinetic changes of high-sensitivity cardiac troponin T (hs-cTnT) and the GRACE score.
Rising and falling hs-cTnT changes in an unselected emergency department population were compared.
635 patients with a hs-cTnT >99th percentile admission value were enrolled. Of these, 572 patients qualified for evaluation with rising patterns (n=254, 44.4%), falling patterns (n=224, 39.2%), or falling patterns following an initial rise (n=94, 16.4%). During 407days of follow-up, we observed 74 deaths, 17 recurrent AMI, and 79 subjects with a composite of death/AMI. Admission values >14ng/L were associated with a higher rate of adverse outcomes (OR, 95%CI:death:12.6, 1.8-92.1, p=0.01, death/AMI:6.7, 1.6-27.9, p=0.01). Neither rising nor falling changes increased the AUC of baseline values (AUC: rising 0.562 vs 0.561, p=ns, falling: 0.533 vs 0.575, p=ns). A GRACE score ≥140 points indicated a higher risk of death (OR, 95%CI: 3.14, 1.84-5.36), AMI (OR,95%CI: 1.56, 0.59-4.17), or death/AMI (OR, 95%CI: 2.49, 1.51-4.11). Hs-cTnT changes did not improve prognostic performance of a GRACE score ≥140 points (AUC, 95%CI: death: 0.635, 0.570-0.701 vs. 0.560, 0.470-0.649 p=ns, AMI: 0.555, 0.418-0.693 vs. 0.603, 0.424-0.782, p=ns, death/AMI: 0.610, 0.545-0.676 vs. 0.538, 0.454-0.622, p=ns). Coronary angiography was performed earlier in patients with rising than with falling kinetics (median, IQR [hours]:13.7, 5.5-28.0 vs. 20.8, 6.3-59.0, p=0.01).
Neither rising nor falling hs-cTnT changes improve prognostic performance of elevated hs-cTnT admission values or the GRACE score. However, rising values are more likely associated with the decision for earlier invasive strategy.

 

Troponin assays for the diagnosis of myocardial infarction and acute coronary syndrome: where do we stand?

Arie Eisenman

ABSTRACT: Under normal circumstances, most intracellular troponin is part of the muscle contractile apparatus, and only a small percentage (< 2-8%) is free in the cytoplasm. The presence of a cardiac-specific troponin in the circulation at levels above normal is good evidence of damage to cardiac muscle cells, such as myocardial infarction, myocarditis, trauma, unstable angina, cardiac surgery or other cardiac procedures. Troponins are released as complexes leading to various cut-off values depending on the assay used. This makes them very sensitive and specific indicators of cardiac injury. As with other cardiac markers, observation of a rise and fall in troponin levels in the appropriate time-frame increases the diagnostic specificity for acute myocardial infarction. They start to rise approximately 4-6 h after the onset of acute myocardial infarction and peak at approximately 24 h, as is the case with creatine kinase-MB. They remain elevated for 7-10 days giving a longer diagnostic window than creatine kinase. Although the diagnosis of various types of acute coronary syndrome remains a clinical-based diagnosis, the use of troponin levels contributes to their classification. This Editorial elaborates on the nature of troponin, its classification, clinical use and importance, as well as comparing it with other currently available cardiac markers.

Expert Review of Cardiovascular Therapy 07/2006; 4(4):509-14.   http://dx.doi.org/:10.1586/14779072.4.4.509 

 

Impact of redefining acute myocardial infarction on incidence, management and reimbursement rate of acute coronary syndromes.

Carísi A Polanczyk, Samir Schneid, Betina V Imhof, Mariana Furtado, Carolina Pithan, Luis E Rohde, Jorge P Ribeiro

ABSTRACT: Although redefinition for acute myocardial infarction (AMI) has been proposed few years ago, to date it has not been universally adopted by many institutions. The purpose of this study is to evaluate the diagnostic, prognostic and economical impact of the new diagnostic criteria for AMI. Patients consecutively admitted to the emergency department with suspected acute coronary syndromes were enrolled in this study. Troponin T (cTnT) was measured in samples collected for routine CK-MB analyses and results were not available to physicians. Patients without AMI by traditional criteria and cTnT > or = 0.035 ng/mL were coded as redefined AMI. Clinical outcomes were hospital death, major cardiac events and revascularization procedures. In-hospital management and reimbursement rates were also analyzed. Among 363 patients, 59 (16%) patients had AMI by conventional criteria, whereas additional 75 (21%) had redefined AMI, an increase of 127% in the incidence. Patients with redefined AMI were significantly older, more frequently male, with atypical chest pain and more risk factors. In multivariate analysis, redefined AMI was associated with 3.1 fold higher hospital death (95% CI: 0.6-14) and a 5.6 fold more cardiac events (95% CI: 2.1-15) compared to those without AMI. From hospital perspective, based on DRGs payment system, adoption of AMI redefinition would increase 12% the reimbursement rate [3552 Int dollars per 100 patients evaluated]. The redefined criteria result in a substantial increase in AMI cases, and allow identification of high-risk patients. Efforts should be made to reinforce the adoption of AMI redefinition, which may result in more qualified and efficient management of ACS.

International Journal of Cardiology 03/2006; 107(2):180-7. · 5.51 Impact Factor   http://www.sciencedirect.com/science/article/pii/S0167527305005279

 

3. Biomedical Engineerin3g

Safety and Efficacy of an Injectable Extracellular Matrix Hydrogel for Treating Myocardial Infarction 

Sonya B. Seif-Naraghi, Jennifer M. Singelyn, Michael A. Salvatore,  et al.
Sci Transl Med 20 February 2013 5:173ra25  http://dx.doi.org/10.1126/scitranslmed.3005503

Acellular biomaterials can stimulate the local environment to repair tissues without the regulatory and scientific challenges of cell-based therapies. A greater understanding of the mechanisms of such endogenous tissue repair is furthering the design and application of these biomaterials. We discuss recent progress in acellular materials for tissue repair, using cartilage and cardiac tissues as examples of application with substantial intrinsic hurdles, but where human translation is now occurring.

 Acellular Biomaterials: An Evolving Alternative to Cell-Based Therapies

J. A. Burdick, R. L. Mauck, J. H. Gorman, R. C. Gorman,
Sci. Transl. Med. 2013; 5, (176): 176 ps4    http://stm.sciencemag.org/content/5/176/176ps4

Acellular biomaterials can stimulate the local environment to repair tissues without the regulatory and scientific challenges of cell-based therapies. A greater understanding of the mechanisms of such endogenous tissue repair is furthering the design and application of these biomaterials. We discuss recent progress in acellular materials for tissue repair, using cartilage and cardiac tissues as examples of applications with substantial intrinsic hurdles, but where human translation is now occurring.


Instructive Nanofiber Scaffolds with VEGF Create a Microenvironment for Arteriogenesis and Cardiac Repair

Yi-Dong Lin, Chwan-Yau Luo, Yu-Ning Hu, Ming-Long Yeh, Ying-Chang Hsueh, Min-Yao Chang, et al.
Sci Transl Med 8 August 2012; 4(146):ra109.   http://dx.doi.org/ 10.1126/scitranslmed.3003841

Angiogenic therapy is a promising approach for tissue repair and regeneration. However, recent clinical trials with protein delivery or gene therapy to promote angiogenesis have failed to provide therapeutic effects. A key factor for achieving effective revascularization is the durability of the microvasculature and the formation of new arterial vessels. Accordingly, we carried out experiments to test whether intramyocardial injection of self-assembling peptide nanofibers (NFs) combined with vascular endothelial growth factor (VEGF) could create an intramyocardial microenvironment with prolonged VEGF release to improve post-infarct neovascularization in rats. Our data showed that when injected with NF, VEGF delivery was sustained within the myocardium for up to 14 days, and the side effects of systemic edema and proteinuria were significantly reduced to the same level as that of control. NF/VEGF injection significantly improved angiogenesis, arteriogenesis, and cardiac performance 28 days after myocardial infarction. NF/VEGF injection not only allowed controlled local delivery but also transformed the injected site into a favorable microenvironment that recruited endogenous myofibroblasts and helped achieve effective revascularization. The engineered vascular niche further attracted a new population of cardiomyocyte-like cells to home to the injected sites, suggesting cardiomyocyte regeneration. Follow-up studies in pigs also revealed healing benefits consistent with observations in rats. In summary, this study demonstrates a new strategy for cardiovascular repair with potential for future clinical translation.

Manufacturing Challenges in Regenerative Medicine

I. Martin, P. J. Simmons, D. F. Williams.
Sci. Transl. Med. 2014; 6(232): fs16.   http://dx.doi.org/10.1126/scitranslmed.3008558

Along with scientific and regulatory issues, the translation of cell and tissue therapies in the routine clinical practice needs to address standardization and cost-effectiveness through the definition of suitable manufacturing paradigms.

 

 

 

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Summary of Translational Medicine – e-Series A: Cardiovascular Diseases, Volume Four – Part 1


Summary of Translational Medicine – e-Series A: Cardiovascular Diseases, Volume Four – Part 1

Author and Curator: Larry H Bernstein, MD, FCAP

and

Curator: Aviva Lev-Ari, PhD, RN

 

Part 1 of Volume 4 in the e-series A: Cardiovascular Diseases and Translational Medicine, provides a foundation for grasping a rapidly developing surging scientific endeavor that is transcending laboratory hypothesis testing and providing guidelines to:

  • Target genomes and multiple nucleotide sequences involved in either coding or in regulation that might have an impact on complex diseases, not necessarily genetic in nature.
  • Target signaling pathways that are demonstrably maladjusted, activated or suppressed in many common and complex diseases, or in their progression.
  • Enable a reduction in failure due to toxicities in the later stages of clinical drug trials as a result of this science-based understanding.
  • Enable a reduction in complications from the improvement of machanical devices that have already had an impact on the practice of interventional procedures in cardiology, cardiac surgery, and radiological imaging, as well as improving laboratory diagnostics at the molecular level.
  • Enable the discovery of new drugs in the continuing emergence of drug resistance.
  • Enable the construction of critical pathways and better guidelines for patient management based on population outcomes data, that will be critically dependent on computational methods and large data-bases.

What has been presented can be essentially viewed in the following Table:

 

Summary Table for TM - Part 1

Summary Table for TM – Part 1

 

 

 

There are some developments that deserve additional development:

1. The importance of mitochondrial function in the activity state of the mitochondria in cellular work (combustion) is understood, and impairments of function are identified in diseases of muscle, cardiac contraction, nerve conduction, ion transport, water balance, and the cytoskeleton – beyond the disordered metabolism in cancer.  A more detailed explanation of the energetics that was elucidated based on the electron transport chain might also be in order.

2. The processes that are enabling a more full application of technology to a host of problems in the environment we live in and in disease modification is growing rapidly, and will change the face of medicine and its allied health sciences.

 

Electron Transport and Bioenergetics

Deferred for metabolomics topic

Synthetic Biology

Introduction to Synthetic Biology and Metabolic Engineering

Kristala L. J. Prather: Part-1    <iBiology > iBioSeminars > Biophysics & Chemical Biology >

http://www.ibiology.org Lecturers generously donate their time to prepare these lectures. The project is funded by NSF and NIGMS, and is supported by the ASCB and HHMI.
Dr. Prather explains that synthetic biology involves applying engineering principles to biological systems to build “biological machines”.

Dr. Prather has received numerous awards both for her innovative research and for excellence in teaching.  Learn more about how Kris became a scientist at
Prather 1: Synthetic Biology and Metabolic Engineering  2/6/14IntroductionLecture Overview In the first part of her lecture, Dr. Prather explains that synthetic biology involves applying engineering principles to biological systems to build “biological machines”. The key material in building these machines is synthetic DNA. Synthetic DNA can be added in different combinations to biological hosts, such as bacteria, turning them into chemical factories that can produce small molecules of choice. In Part 2, Prather describes how her lab used design principles to engineer E. coli that produce glucaric acid from glucose. Glucaric acid is not naturally produced in bacteria, so Prather and her colleagues “bioprospected” enzymes from other organisms and expressed them in E. coli to build the needed enzymatic pathway. Prather walks us through the many steps of optimizing the timing, localization and levels of enzyme expression to produce the greatest yield. Speaker Bio: Kristala Jones Prather received her S.B. degree from the Massachusetts Institute of Technology and her PhD at the University of California, Berkeley both in chemical engineering. Upon graduation, Prather joined the Merck Research Labs for 4 years before returning to academia. Prather is now an Associate Professor of Chemical Engineering at MIT and an investigator with the multi-university Synthetic Biology Engineering Reseach Center (SynBERC). Her lab designs and constructs novel synthetic pathways in microorganisms converting them into tiny factories for the production of small molecules. Dr. Prather has received numerous awards both for her innovative research and for excellence in teaching.

VIEW VIDEOS

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk#t=0

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk#t=12

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk#t=74

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk#t=129

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk#t=168

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk

 

II. Regulatory Effects of Mammalian microRNAs

Calcium Cycling in Synthetic and Contractile Phasic or Tonic Vascular Smooth Muscle Cells

in INTECH
Current Basic and Pathological Approaches to
the Function of Muscle Cells and Tissues – From Molecules to HumansLarissa Lipskaia, Isabelle Limon, Regis Bobe and Roger Hajjar
Additional information is available at the end of the chapter
http://dx.doi.org/10.5772/48240
1. Introduction
Calcium ions (Ca ) are present in low concentrations in the cytosol (~100 nM) and in high concentrations (in mM range) in both the extracellular medium and intracellular stores (mainly sarco/endo/plasmic reticulum, SR). This differential allows the calcium ion messenger that carries information
as diverse as contraction, metabolism, apoptosis, proliferation and/or hypertrophic growth. The mechanisms responsible for generating a Ca signal greatly differ from one cell type to another.
In the different types of vascular smooth muscle cells (VSMC), enormous variations do exist with regard to the mechanisms responsible for generating Ca signal. In each VSMC phenotype (synthetic/proliferating and contractile [1], tonic or phasic), the Ca signaling system is adapted to its particular function and is due to the specific patterns of expression and regulation of Ca.
For instance, in contractile VSMCs, the initiation of contractile events is driven by mem- brane depolarization; and the principal entry-point for extracellular Ca is the voltage-operated L-type calcium channel (LTCC). In contrast, in synthetic/proliferating VSMCs, the principal way-in for extracellular Ca is the store-operated calcium (SOC) channel.
Whatever the cell type, the calcium signal consists of  limited elevations of cytosolic free calcium ions in time and space. The calcium pump, sarco/endoplasmic reticulum Ca ATPase (SERCA), has a critical role in determining the frequency of SR Ca release by upload into the sarcoplasmic
sensitivity of  SR calcium channels, Ryanodin Receptor, RyR and Inositol tri-Phosphate Receptor, IP3R.
Synthetic VSMCs have a fibroblast appearance, proliferate readily, and synthesize increased levels of various extracellular matrix components, particularly fibronectin, collagen types I and III, and tropoelastin [1].
Contractile VSMCs have a muscle-like or spindle-shaped appearance and well-developed contractile apparatus resulting from the expression and intracellular accumulation of thick and thin muscle filaments [1].
Schematic representation of Calcium Cycling in Contractile and Proliferating VSMCs

Schematic representation of Calcium Cycling in Contractile and Proliferating VSMCs

 

Figure 1. Schematic representation of Calcium Cycling in Contractile and Proliferating VSMCs.

Left panel: schematic representation of calcium cycling in quiescent /contractile VSMCs. Contractile re-sponse is initiated by extracellular Ca influx due to activation of Receptor Operated Ca (through phosphoinositol-coupled receptor) or to activation of L-Type Calcium channels (through an increase in luminal pressure). Small increase of cytosolic due IP3 binding to IP3R (puff) or RyR activation by LTCC or ROC-dependent Ca influx leads to large SR Ca IP3R or RyR clusters (“Ca -induced Ca SR calcium pumps (both SERCA2a and SERCA2b are expressed in quiescent VSMCs), maintaining high concentration of cytosolic Ca and setting the sensitivity of RyR or IP3R for the next spike.
Contraction of VSMCs occurs during oscillatory Ca transient.
Middle panel: schematic representa tion of atherosclerotic vessel wall. Contractile VSMC are located in the media layer, synthetic VSMC are located in sub-endothelial intima.
Right panel: schematic representation of calcium cycling in quiescent /contractile VSMCs. Agonist binding to phosphoinositol-coupled receptor leads to the activation of IP3R resulting in large increase in cytosolic Ca calcium pumps (only SERCA2b, having low turnover and low affinity to Ca depletion leads to translocation of SR Ca sensor STIM1 towards PM, resulting in extracellular Ca influx though opening of Store Operated Channel (CRAC). Resulted steady state Ca transient is critical for activation of proliferation-related transcription factors ‘NFAT).
Abbreviations: PLC – phospholipase C; PM – plasma membrane; PP2B – Ca /calmodulin-activated protein phosphatase 2B (calcineurin); ROC- receptor activated channel; IP3 – inositol-1,4,5-trisphosphate, IP3R – inositol-1,4,5- trisphosphate receptor; RyR – ryanodine receptor; NFAT – nuclear factor of activated T-lymphocytes; VSMC – vascular smooth muscle cells; SERCA – sarco(endo)plasmic reticulum Ca sarcoplasmic reticulum.

 

Time for New DNA Synthesis and Sequencing Cost Curves

By Rob Carlson

I’ll start with the productivity plot, as this one isn’t new. For a discussion of the substantial performance increase in sequencing compared to Moore’s Law, as well as the difficulty of finding this data, please see this post. If nothing else, keep two features of the plot in mind: 1) the consistency of the pace of Moore’s Law and 2) the inconsistency and pace of sequencing productivity. Illumina appears to be the primary driver, and beneficiary, of improvements in productivity at the moment, especially if you are looking at share prices. It looks like the recently announced NextSeq and Hiseq instruments will provide substantially higher productivities (hand waving, I would say the next datum will come in another order of magnitude higher), but I think I need a bit more data before officially putting another point on the plot.

 

cost-of-oligo-and-gene-synthesis

cost-of-oligo-and-gene-synthesis

Illumina’s instruments are now responsible for such a high percentage of sequencing output that the company is effectively setting prices for the entire industry. Illumina is being pushed by competition to increase performance, but this does not necessarily translate into lower prices. It doesn’t behoove Illumina to drop prices at this point, and we won’t see any substantial decrease until a serious competitor shows up and starts threatening Illumina’s market share. The absence of real competition is the primary reason sequencing prices have flattened out over the last couple of data points.

Note that the oligo prices above are for column-based synthesis, and that oligos synthesized on arrays are much less expensive. However, array synthesis comes with the usual caveat that the quality is generally lower, unless you are getting your DNA from Agilent, which probably means you are getting your dsDNA from Gen9.

Note also that the distinction between the price of oligos and the price of double-stranded sDNA is becoming less useful. Whether you are ordering from Life/Thermo or from your local academic facility, the cost of producing oligos is now, in most cases, independent of their length. That’s because the cost of capital (including rent, insurance, labor, etc) is now more significant than the cost of goods. Consequently, the price reflects the cost of capital rather than the cost of goods. Moreover, the cost of the columns, reagents, and shipping tubes is certainly more than the cost of the atoms in the sDNA you are ostensibly paying for. Once you get into longer oligos (substantially larger than 50-mers) this relationship breaks down and the sDNA is more expensive. But, at this point in time, most people aren’t going to use longer oligos to assemble genes unless they have a tricky job that doesn’t work using short oligos.

Looking forward, I suspect oligos aren’t going to get much cheaper unless someone sorts out how to either 1) replace the requisite human labor and thereby reduce the cost of capital, or 2) finally replace the phosphoramidite chemistry that the industry relies upon.

IDT’s gBlocks come at prices that are constant across quite substantial ranges in length. Moreover, part of the decrease in price for these products is embedded in the fact that you are buying smaller chunks of DNA that you then must assemble and integrate into your organism of choice.

Someone who has purchased and assembled an absolutely enormous amount of sDNA over the last decade, suggested that if prices fell by another order of magnitude, he could switch completely to outsourced assembly. This is a potentially interesting “tipping point”. However, what this person really needs is sDNA integrated in a particular way into a particular genome operating in a particular host. The integration and testing of the new genome in the host organism is where most of the cost is. Given the wide variety of emerging applications, and the growing array of hosts/chassis, it isn’t clear that any given technology or firm will be able to provide arbitrary synthetic sequences incorporated into arbitrary hosts.

 TrackBack URL: http://www.synthesis.cc/cgi-bin/mt/mt-t.cgi/397

 

Startup to Strengthen Synthetic Biology and Regenerative Medicine Industries with Cutting Edge Cell Products

28 Nov 2013 | PR Web

Dr. Jon Rowley and Dr. Uplaksh Kumar, Co-Founders of RoosterBio, Inc., a newly formed biotech startup located in Frederick, are paving the way for even more innovation in the rapidly growing fields of Synthetic Biology and Regenerative Medicine. Synthetic Biology combines engineering principles with basic science to build biological products, including regenerative medicines and cellular therapies. Regenerative medicine is a broad definition for innovative medical therapies that will enable the body to repair, replace, restore and regenerate damaged or diseased cells, tissues and organs. Regenerative therapies that are in clinical trials today may enable repair of damaged heart muscle following heart attack, replacement of skin for burn victims, restoration of movement after spinal cord injury, regeneration of pancreatic tissue for insulin production in diabetics and provide new treatments for Parkinson’s and Alzheimer’s diseases, to name just a few applications.

While the potential of the field is promising, the pace of development has been slow. One main reason for this is that the living cells required for these therapies are cost-prohibitive and not supplied at volumes that support many research and product development efforts. RoosterBio will manufacture large quantities of standardized primary cells at high quality and low cost, which will quicken the pace of scientific discovery and translation to the clinic. “Our goal is to accelerate the development of products that incorporate living cells by providing abundant, affordable and high quality materials to researchers that are developing and commercializing these regenerative technologies” says Dr. Rowley

 

Life at the Speed of Light

http://kcpw.org/?powerpress_pinw=92027-podcast

NHMU Lecture featuring – J. Craig Venter, Ph.D.
Founder, Chairman, and CEO – J. Craig Venter Institute; Co-Founder and CEO, Synthetic Genomics Inc.

J. Craig Venter, Ph.D., is Founder, Chairman, and CEO of the J. Craig Venter Institute (JVCI), a not-for-profit, research organization dedicated to human, microbial, plant, synthetic and environmental research. He is also Co-Founder and CEO of Synthetic Genomics Inc. (SGI), a privately-held company dedicated to commercializing genomic-driven solutions to address global needs.

In 1998, Dr. Venter founded Celera Genomics to sequence the human genome using new tools and techniques he and his team developed.  This research culminated with the February 2001 publication of the human genome in the journal, Science. Dr. Venter and his team at JVCI continue to blaze new trails in genomics.  They have sequenced and a created a bacterial cell constructed with synthetic DNA,  putting humankind at the threshold of a new phase of biological research.  Whereas, we could  previously read the genetic code (sequencing genomes), we can now write the genetic code for designing new species.

The science of synthetic genomics will have a profound impact on society, including new methods for chemical and energy production, human health and medical advances, clean water, and new food and nutritional products. One of the most prolific scientists of the 21st century for his numerous pioneering advances in genomics,  he  guides us through this emerging field, detailing its origins, current challenges, and the potential positive advances.

His work on synthetic biology truly embodies the theme of “pushing the boundaries of life.”  Essentially, Venter is seeking to “write the software of life” to create microbes designed by humans rather than only through evolution. The potential benefits and risks of this new technology are enormous. It also requires us to examine, both scientifically and philosophically, the question of “What is life?”

J Craig Venter wants to digitize DNA and transmit the signal to teleport organisms

https://pharmaceuticalintelligence.com/2013/11/01/j-craig-venter-wants-to-digitize-dna-and-transmit-the-signal-to-teleport-organisms/

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

https://pharmaceuticalintelligence.com/2013/02/11/2013-genomics-the-era-beyond-the-sequencing-human-genome-francis-collins-craig-venter-eric-lander-et-al/

Human Longevity Inc (HLI) – $70M in Financing of Venter’s New Integrative Omics and Clinical Bioinformatics

https://pharmaceuticalintelligence.com/2014/03/05/human-longevity-inc-hli-70m-in-financing-of-venters-new-integrative-omics-and-clinical-bioinformatics/

 

 

Where Will the Century of Biology Lead Us?

By Randall Mayes

A technology trend analyst offers an overview of synthetic biology, its potential applications, obstacles to its development, and prospects for public approval.

  • In addition to boosting the economy, synthetic biology projects currently in development could have profound implications for the future of manufacturing, sustainability, and medicine.
  • Before society can fully reap the benefits of synthetic biology, however, the field requires development and faces a series of hurdles in the process. Do researchers have the scientific know-how and technical capabilities to develop the field?

Biology + Engineering = Synthetic Biology

Bioengineers aim to build synthetic biological systems using compatible standardized parts that behave predictably. Bioengineers synthesize DNA parts—oligonucleotides composed of 50–100 base pairs—which make specialized components that ultimately make a biological system. As biology becomes a true engineering discipline, bioengineers will create genomes using mass-produced modular units similar to the microelectronics and computer industries.

Currently, bioengineering projects cost millions of dollars and take years to develop products. For synthetic biology to become a Schumpeterian revolution, smaller companies will need to be able to afford to use bioengineering concepts for industrial applications. This will require standardized and automated processes.

A major challenge to developing synthetic biology is the complexity of biological systems. When bioengineers assemble synthetic parts, they must prevent cross talk between signals in other biological pathways. Until researchers better understand these undesired interactions that nature has already worked out, applications such as gene therapy will have unwanted side effects. Scientists do not fully understand the effects of environmental and developmental interaction on gene expression. Currently, bioengineers must repeatedly use trial and error to create predictable systems.

Similar to physics, synthetic biology requires the ability to model systems and quantify relationships between variables in biological systems at the molecular level.

The second major challenge to ensuring the success of synthetic biology is the development of enabling technologies. With genomes having billions of nucleotides, this requires fast, powerful, and cost-efficient computers. Moore’s law, named for Intel co-founder Gordon Moore, posits that computing power progresses at a predictable rate and that the number of components in integrated circuits doubles each year until its limits are reached. Since Moore’s prediction, computer power has increased at an exponential rate while pricing has declined.

DNA sequencers and synthesizers are necessary to identify genes and make synthetic DNA sequences. Bioengineer Robert Carlson calculated that the capabilities of DNA sequencers and synthesizers have followed a pattern similar to computing. This pattern, referred to as the Carlson Curve, projects that scientists are approaching the ability to sequence a human genome for $1,000, perhaps in 2020. Carlson calculated that the costs of reading and writing new genes and genomes are falling by a factor of two every 18–24 months. (see recent Carlson comment on requirement to read and write for a variety of limiting  conditions).

Startup to Strengthen Synthetic Biology and Regenerative Medicine Industries with Cutting Edge Cell Products

https://pharmaceuticalintelligence.com/2013/11/28/startup-to-strengthen-synthetic-biology-and-regenerative-medicine-industries-with-cutting-edge-cell-products/

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

https://pharmaceuticalintelligence.com/2013/05/17/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/

Synthesizing Synthetic Biology: PLOS Collections

https://pharmaceuticalintelligence.com/2012/08/17/synthesizing-synthetic-biology-plos-collections/

Capturing ten-color ultrasharp images of synthetic DNA structures resembling numerals 0 to 9

https://pharmaceuticalintelligence.com/2014/02/05/capturing-ten-color-ultrasharp-images-of-synthetic-dna-structures-resembling-numerals-0-to-9/

Silencing Cancers with Synthetic siRNAs

https://pharmaceuticalintelligence.com/2013/12/09/silencing-cancers-with-synthetic-sirnas/

Genomics Now—and Beyond the Bubble

Futurists have touted the twenty-first century as the century of biology based primarily on the promise of genomics. Medical researchers aim to use variations within genes as biomarkers for diseases, personalized treatments, and drug responses. Currently, we are experiencing a genomics bubble, but with advances in understanding biological complexity and the development of enabling technologies, synthetic biology is reviving optimism in many fields, particularly medicine.

BY MICHAEL BROOKS    17 APR, 2014     http://www.newstatesman.com/

Michael Brooks holds a PhD in quantum physics. He writes a weekly science column for the New Statesman, and his most recent book is The Secret Anarchy of Science.

The basic idea is that we take an organism – a bacterium, say – and re-engineer its genome so that it does something different. You might, for instance, make it ingest carbon dioxide from the atmosphere, process it and excrete crude oil.

That project is still under construction, but others, such as using synthesised DNA for data storage, have already been achieved. As evolution has proved, DNA is an extraordinarily stable medium that can preserve information for millions of years. In 2012, the Harvard geneticist George Church proved its potential by taking a book he had written, encoding it in a synthesised strand of DNA, and then making DNA sequencing machines read it back to him.

When we first started achieving such things it was costly and time-consuming and demanded extraordinary resources, such as those available to the millionaire biologist Craig Venter. Venter’s team spent most of the past two decades and tens of millions of dollars creating the first artificial organism, nicknamed “Synthia”. Using computer programs and robots that process the necessary chemicals, the team rebuilt the genome of the bacterium Mycoplasma mycoides from scratch. They also inserted a few watermarks and puzzles into the DNA sequence, partly as an identifying measure for safety’s sake, but mostly as a publicity stunt.

What they didn’t do was redesign the genome to do anything interesting. When the synthetic genome was inserted into an eviscerated bacterial cell, the new organism behaved exactly the same as its natural counterpart. Nevertheless, that Synthia, as Venter put it at the press conference to announce the research in 2010, was “the first self-replicating species we’ve had on the planet whose parent is a computer” made it a standout achievement.

Today, however, we have entered another era in synthetic biology and Venter faces stiff competition. The Steve Jobs to Venter’s Bill Gates is Jef Boeke, who researches yeast genetics at New York University.

Boeke wanted to redesign the yeast genome so that he could strip out various parts to see what they did. Because it took a private company a year to complete just a small part of the task, at a cost of $50,000, he realised he should go open-source. By teaching an undergraduate course on how to build a genome and teaming up with institutions all over the world, he has assembled a skilled workforce that, tinkering together, has made a synthetic chromosome for baker’s yeast.

 

Stepping into DIYbio and Synthetic Biology at ScienceHack

Posted April 22, 2014 by Heather McGaw and Kyrie Vala-Webb

We got a crash course on genetics and protein pathways, and then set out to design and build our own pathways using both the “Genomikon: Violacein Factory” kit and Synbiota platform. With Synbiota’s software, we dragged and dropped the enzymes to create the sequence that we were then going to build out. After a process of sketching ideas, mocking up pathways, and writing hypotheses, we were ready to start building!

The night stretched long, and at midnight we were forced to vacate the school. Not quite finished, we loaded our delicate bacteria, incubator, and boxes of gloves onto the bus and headed back to complete our bacterial transformation in one of our hotel rooms. Jammed in between the beds and the mini-fridge, we heat-shocked our bacteria in the hotel ice bucket. It was a surreal moment.

While waiting for our bacteria, we held an “unconference” where we explored bioethics, security and risk related to synthetic biology, 3D printing on Mars, patterns in juggling (with live demonstration!), and even did a Google Hangout with Rob Carlson. Every few hours, we would excitedly check in on our bacteria, looking for bacterial colonies and the purple hue characteristic of violacein.

Most impressive was the wildly successful and seamless integration of a diverse set of people: in a matter of hours, we were transformed from individual experts and practitioners in assorted fields into cohesive and passionate teams of DIY biologists and science hackers. The ability of everyone to connect and learn was a powerful experience, and over the course of just one weekend we were able to challenge each other and grow.

Returning to work on Monday, we were hungry for more. We wanted to find a way to bring the excitement and energy from the weekend into the studio and into the projects we’re working on. It struck us that there are strong parallels between design and DIYbio, and we knew there was an opportunity to bring some of the scientific approaches and curiosity into our studio.

 

 

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Loss of Gene Islands May Promote a Cancer Cell’s Survival, Proliferation and Evolution: A new Hypothesis (and second paper validating model) on Oncogenesis from the Elledge Laboratory

Writer, Curator: Stephen J. Williams, Ph.D.

It is well established that a critical event in the transformation of a cell to the malignant state involves the mutation of hosts of oncogenes and tumor suppressor genes, which in turn, confer on a cell the inability to properly control its proliferation.    On a genomic scale, these mutations can result in gene amplifications, loss of heterozygosity (LOH), and epigenetic changes resulting in tumorigenesis.  The “two hit hypothesis”, proposed by Dr. Al Knudson of Fox Chase Cancer Center[1], proposes that two mutations in the same gene are required for tumorigenesis, initially proposed to explain the progression of retinoblastoma in children, indicating a recessive disease.

(Excerpts from a great article explaining the two-hit-hypothesis is given at the end of this post).

And, although many tumor genomes display haploinsufficeint tumor suppressor genes, and fit the two hit model quite nicely, recent data show that most tumors display hemizygous recurrent deletions within their genomes.  Tumors display numerous recurrent hemizygous focal deletions that seem to contain no known tumor suppressor genes. For instance a recent analysis of over three thousand tumors including breast, bladder, pancreatic, ovarian and gastric cancers averaged greater than 10 deletions/tumor and 82 regions of recurrent focal deletions,

It has been proposed these great number of hemizygous deletions may be a result of:

  • a recessive tumor suppressor gene requiring mutation or silencing of second allele
  • the mutation may recur as they are located in fragile sites (unstable genomic regions)
  • single-copy loss may provide selective advantage regardless of the other allele

Note: some definitions of hemizygosity are given below.  In general at any locus, each parental chromosome can have 3 deletion states:

  1. wild type
  2. large deletion
  3. small deletion

Hemizygous deletions only involve one allele, not both alleles which is unlike the classic tumor suppressor like TP53

To see if it is possible that only one mutated allele of a tumor suppressor gene may be a casual event for tumorigenesis, Dr. Nicole Solimini and colleagues, from Dr. Stephen Elledge’s lab at Harvard, proposed a hypothesis they termed the cancer gene island model, after analyzing the regions of these hemizygous deletions for cancer related genes[2].  Dr. Soliin and colleagues analyzed whole-genome sequence data for 526 tumors in the COSMIC database comparing to a list generated from the Cancer Gene Census for homozygous loss-of-function mutations (mutations which result in a termination codon or frame-shift mutation: {this produces a premature stop in the protein or an altered sequence leading to a nonfunctional protein}.

Results of this analysis revealed:

  1. although tumors have a wide range of deletions per tumor (most epithelial high grade like ovarian, bladder, pancreatic, and esophageal adenocarcinomas had 10-14 deletions per tumor
  2. and although tumors exhibited a wide range (2- 16 ) loss of function mutations
  3. ONLY 14 of 82 recurrent deletions contained a known tumor suppressor gene and was a low frequency event
  4. Most recurrent cancer deletions do not contain putative tumor suppressor genes.

Therefore, as the authors suggest, an alternate method to the two-hit hypothesis may account for a selective growth advantage for these types of deletions, defining these low frequency hemizygous mutations in two general classes

  1. STOP genes: suppressors of tumor growth and proliferation
  2. GO genes: growth enhancers and oncogenes

Identifying potential STOP genes

To identify the STOP and GO genes the authors performed a primary screen of an shRNA library in telomerase (hTERT) immortalized human mammary epithelial cells using increased PROLIFERATION as a screening endpoint to determine STOP genes and decreased proliferation and lethality (essential genes) to determine possible GO genes. An initial screen identified 3582 possible STOP genes.  Using further screens and higher stringency criteria which focused on:

  • Only genes which increased proliferation in independent triplicate screens
  • Validated by competition assays
  • Were enriched more than four fold in three independent shRNA screens

the authors were able to focus on and validate 878 genes to determine the molecular pathways involved in proliferation.

These genes were involved in cell cycle regulation, apoptosis, and autophagy (which will be discussed in further posts).

To further validate that these putative STOP genes are relevant in human cancer, the list of validated STOP genes found in the screen was compared to the list of loss-of-function mutations in the 526 tumors in the COSMIC databaseSurprisingly, the validated STOP gene list were significantly enriched for known and possibly NOVEL tumor suppressor genes and especially loss of function and deletion mutations but also clustered in gene deletions in cancer.  This not only validated the authors’ model system and method but suggests that hemizygous deletions in multiple STOP genes may contribute to tumorigenesis

as the function of the majority of STOP genes is to restrain tumorigenesis

A few key conclusions from this study offer strength to an alternative view of oncogenesis NAMELY:

  • Loss of multiple STOP genes per deletion optimize a cancer cell’s proliferative capacity
  • Cancer cells display an insignificant loss of GO genes, minimizing negative impacts on cellular fitness
  • Haploinsufficiency in multiple STOP genes can result in similar alteration of function similar to complete loss of both alleles of
  • Cancer evolution may result from selection of hemizygous loss of high number of STOP and low number of GO genes
  • Leads to a CANCER GENE ISLAND model where there is a clonal evolution of transformed cells due to selective pressures

A link to the supplemental data containing STOP and GO genes found in validation screens and KEGG analysis can be found at the following link:

http://www.sciencemag.org/content/337/6090/104/suppl/DC1#

A link to an interview with the authors, originally posted on Harvard’s site can be found here.

Cumulative Haploinsufficiency and Triplosensitivity Drive Aneuploidy Patterns and Shape the Cancer Genome; a new paper from the Elledge group in the journal Cell

http://www.cell.com/retrieve/pii/S0092867413012877

A concern of the authors was the extent to which gene silencing could have on their model in tumors.  The validation of the model was performed in cancer cell lines and compared to tumor genome sequence in publicly available databases however a followup paper by the same group shows that haploinsufficiency contributes a greater impact on the cancer genome than these studies have suggested.

In a follow-up paper by the Elledge group in the journal Cell[3], Theresa Davoli and colleagues, after analyzing 8,200 tumor-normal pairs, show there are many more cancer driver genes than once had been predicted.  In addition, the distribution and potency of STOP genes, oncogenes, and essential genes (GO) contribute to the complex picture of aneuploidy seen in many sporadic tumors.  The authors proposed that, together with these and their previous findings, that haploinsufficiency plays a crucial role in shaping the cancer genome.

Hemizygosity and Haploinsufficiency

Below are a few definitions from Wikipedia:

Zygosity is the degree of similarity of the alleles for a trait in an organism.

Most eukaryotes have two matching sets of chromosomes; that is, they are diploid. Diploid organisms have the same loci on each of their two sets of homologous chromosomes, except that the sequences at these loci may differ between the two chromosomes in a matching pair and that a few chromosomes may be mismatched as part of a chromosomal sex-determination system. If both alleles of a diploid organism are the same, the organism is homozygous at that locus. If they are different, the organism is heterozygous at that locus. If one allele is missing, it is hemizygous, and, if both alleles are missing, it is nullizygous.

Haploinsufficiency occurs when a diploid organism has only a single functional copy of a gene (with the other copy inactivated by mutation) and the single functional copy does not produce enough of a gene product (typically a protein) to bring about a wild-type condition, leading to an abnormal or diseased state. It is responsible for some but not all autosomal dominant disorders.

Al Knudsen and The “Two-Hit Hypothesis” of Cancer

Excerpt from a Scientist article by Eugene Russo about Dr. Knudson’s Two hit Hypothesis;

for full article please follow the link http://www.the-scientist.com/?articles.view/articleNo/19649/title/-Two-Hit–Hypothesis/

The “two-hit” hypothesis was, according to many, among the more significant milestones in that rapid evolution of biomedical science. The theory explains the relationship between the hereditary and nonhereditary, or sporadic, forms of retinoblastoma, a rare cancer affecting one in 20,000 children. Years prior to the age of gene cloning, Knudson’s 1971 paper proposed that individuals will develop cancer of the retina if they either inherit one mutated retinoblastoma (Rb) gene and incur a second mutation (possibly environmentally induced) after conception, or if they incur two mutations or hits after conception.3 If only one Rb gene functions normally, the cancer is suppressed. Knudson dubbed these preventive genes anti-oncogenes; other scientists renamed them tumor suppressors.

When first introduced, the “two-hit” hypothesis garnered more interest from geneticists than from cancer researchers. Cancer researchers thought “even if it’s right, it may not have much significance for the world of cancer,” Knudson recalls. “But I had been taught from the early days that very often we learn fundamental things from unusual cases.” Knudson’s initial motivation for the model: a desire to understand the relationship between nonhereditary forms of cancer and the much rarer hereditary forms. He also hoped to elucidate the mechanism by which common cancers, such as those of the breast, stomach, and colon, become more prevalent with age.

According to the then-accepted somatic mutation theory, the more mutations, the greater the risk of cancer. But this didn’t jibe with Knudson’s own studies on childhood cancers, which suggested that, in the case of cancers such as retinoblastoma, disease onset peaks in early childhood. Knudson set out to determine the smallest number of cancer-inducing events necessary to cause cancer and the role of these events in hereditary vs. nonhereditary cancers. Based on existing data on cancer cases and some mathematical deduction, Knudson came up with the “two-hit” hypothesis.

Not until 1986, when researchers at the Whitehead Institute for Biomedical Research in Cambridge, Mass., cloned the Rb gene, would there be solid evidence to back up Knudson’s pathogenesis paradigm.4 “Even with the cloning of the gene, it wasn’t clear how general it would be,” says Knudson. There are, it turns out, several two-hit lesions, including polyposis, neurofibromitosis, and basal cell carcinoma syndrome. Other cancers show only some correspondence with the two-hit model. In the case of Wilm’s tumor, for example, the model accounts for about 15 percent of the cancer incidence; the remaining cases seem to be more complicated.

knudsonTwoHit1600

His seminal paper on the two-hit hypothesis[1]

A.G. Knudson, “Mutation and cancer: statistical study of retinoblastoma,” Proceedings of the National Academy of Sciences, 68:820-3, 1971.

The two hit hypothesis proposed by A.G. Knudson.  A description with video of Dr. Knudson talk at AACR can be found at the following link (photo creditied to A.G. Knudson and Fox Chase Cancer Center at the following link:http://www.fccc.edu/research/research-awards/knudson/index.html

Sources

1.            Knudson AG, Jr.: Mutation and cancer: statistical study of retinoblastoma. Proceedings of the National Academy of Sciences of the United States of America 1971, 68(4):820-823.

2.            Solimini NL, Xu Q, Mermel CH, Liang AC, Schlabach MR, Luo J, Burrows AE, Anselmo AN, Bredemeyer AL, Li MZ et al: Recurrent hemizygous deletions in cancers may optimize proliferative potential. Science 2012, 337(6090):104-109.

3.            Davoli T, Xu Andrew W, Mengwasser Kristen E, Sack Laura M, Yoon John C, Park Peter J, Elledge Stephen J: Cumulative Haploinsufficiency and Triplosensitivity Drive Aneuploidy Patterns and Shape the Cancer Genome. Cell 2013, 155(4):948-962.

Other papers on this site on CANCER and MUTATION include:

Cancer Mutations Across the Landscape

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

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

Breast Cancer and Mitochondrial Mutations

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

Hold on. Mutations in Cancer do good.

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

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

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